Stefano Crespi1, Maurizio Fagnoni2. 1. Stratingh Institute for Chemistry, Center for Systems Chemistry University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands. 2. PhotoGreen Lab, Department of Chemistry, V. Le Taramelli 10, 27100 Pavia, Italy.
Abstract
Alkyl radicals are key intermediates in organic synthesis. Their classic generation from alkyl halides has a severe drawback due to the employment of toxic tin hydrides to the point that "flight from the tyranny of tin" in radical processes was considered for a long time an unavoidable issue. This review summarizes the main alternative approaches for the generation of unstabilized alkyl radicals, using photons as traceless promoters. The recent development in photochemical and photocatalyzed processes enabled the discovery of a plethora of new alkyl radical precursors, opening the world of radical chemistry to a broader community, thus allowing a new era of photon democracy.
<class="Chemical">spaclass="Chemical">n class="Cclass="Chemical">n class="Disease">hemical">Alkyl radicals are key intermediates in organic synthesis. Their classic generation from <hemical">span class="Chemical">alkyl halides has a severe drawback due to the employment of toxic tin hydrides to the point that "flight from the tyranny of tin" in radical processes was considered for a long time an unavoidable issue. This review summarizes the main alternative approaches for the generation of unstabilizedalkyl radicals, using photons as traceless promoters. The recent development in photochemical and photocatalyzed processes enabled the discovery of a plethora of new alkyl radical precursors, opening the world of radical chemistry to a broader community, thus allowing a new era of photon democracy.
Among
all tclass="Disease">he opeclass="Chemical">n-sclass="Chemical">n class="Disease">hell species, hemical">carbon-centered radicals are
intriguing neutral intermediates that find extensive use in organic
synthesis, dehemical">spite the initial distrust about their possible application.[1−5] In particular, the generation of <hemical">span class="Chemical">unstabilized alkyl radicals under
mild conditions granting the controlled and selective outcome of the
ensuing reactions has been a challenge for many years. The first and
more obvious way to form such species is the homolytic cleavage of
a labile C–X bond; alkyl halides appeared as the ideal choice
in this respect. The real breakthrough in radical chemistry was the
discovery of Bu3SnH to promote radical chain reactions
as reported about 60 years ago in the reduction of bromocyclohexane.[6] Reduction of an organotinhalide by lithium aluminum
hydride formed the reactive tin hydride in solution. In subsequent
modifications of the protocol, both sodium borohydride[7] and sodium cyanoborohydride[8] acted as effective reducing agents. Alkyl radicals generated via
tin chemistry were then used for C–C bond formation mainly
via the addition to (electron-poor) olefins, the well-known Giese
reaction,[9−12] an evolution of the original process which made use of organomercury
compounds.[12,13]
As class="Chemical">illustclass="Chemical">n class="Chemical">rated in Figure a, hemical">tributyltin hydride
has the double role of allowing the
formation of <hemical">span class="Chemical">Bu3Sn• as the radical chain
carrier and as a hydrogen donor to close the catalytic cycle. The
unique features of this catalytic cycle are attributed to the forging
of stronger Sn–X and C–H bonds at the expense of the
cleavage of the more labile Sn–H and C–X ones. A more
quantitative aspect of this reaction can be appreciated comparing
the different bond dissociation energies (BDE) associated with the
steps mentioned above (see Figure a).[14,15] More recent applications showcase
the crucial role of tin intermediates in controlling the outcome of
different reactions. Sn–O interactions direct the regioselective
addition of the radical in the radical stannylation of the triple
bond in propargyloxy derivatives,[16] whereas
tinradicals induced the synthesis of stannylated polyarenes via double
radical peri-annulations, increasing the solubility of the products.[17]
Figure 1
(A) Thermal generation of radicals from alkyl halides
in the Giese
reaction. (B) LD50 values for selected organotin compounds.
(C) Thermal generation of radicals from alcohols via xanthates (I). (D) Thermal and photochemical generation of radicals from
carboxylic acids via Barton esters (II).
(A) Tclass="Disease">heclass="Chemical">n class="Chemical">rmal generation of hemical">radicals from <hemical">span class="Chemical">alkyl halides
in the Giese
reaction. (B) LD50 values for selected organotin compounds.
(C) Thermal generation of radicals from alcohols via xanthates (I). (D) Thermal and photochemical generation of radicals from
carboxylic acids via Barton esters (II).
Tclass="Disease">he peclass="Chemical">n class="Chemical">rformance of hemical">Bu3SnH was so competitive[9,18−20] that more than 20 years ago it was claimed that it
was improbable to have “flight from the tyranny of <hemical">span class="Chemical">tin”
in radical processes,[21,22] a hard statement that subtly
introduces the problem of the substantial toxicity and high biological
activity of triorganotin compounds.[23] The
LD50 of 0.7 mmol/kg in murine species (see Figure b) combined with the long half-lives
in aquatic environment represent the biggest concerns for the application
of these otherwise extremely versatile species, especially in the
absence of viable alternatives.[24] Indeed, O-thiocarbonyl derivatives like xanthates (I, obtained from alcohols) were considered an alternative to the alkylhalides, albeit the radical generation required in most cases the
use of tin hydrides (Figure c).[3,22,25,26]
Effoclass="Chemical">rts class="Chemical">n class="Chemical">in substituhemical">ting toxic <hemical">span class="Chemical">tin
derivatives with other hydrides
such as (TMS)3SiH[27] or lauroyl
peroxides and xanthates met some success, however, only in limited
cases.[28−30] Other initiators to promote tin-free radical chain
reactions were organoboranes,[31] thiols,[32] P–H-based reagents,[32] and 1-functionalized cyclohexa-2,5-dienes,[32−34] but nowadays they are not commonly used in synthetic planning.
Tclass="Disease">he use of <class="Chemical">n class="Chemical">span class="Chemical">metal oxidants (<hemical">span class="Chemical">MnIII acetate)[35] or metal reductants (TiIII catalyst[36] or SmII iodide[37]) were sparsely used, but only in the latter case unstabilizedalkyl radicals were formed from alkyl iodides.
Tclass="Disease">heclass="Chemical">n class="Chemical">introduction
of thehemical">Barton esters II in 1985 represented
a step forward in solving the conundrum of the tyranny of <hemical">span class="Chemical">tin: the
conversion of the strong O–H bond of an acid into the (photo)labile
O–N bond of the corresponding thiohydroxamate ester (Figure d).[38,39] Barton esters have the advantage of being slightly colored, allowing
the use of visible light irradiation to induce the cleavage of the
O–N bond. The last point is significant, demonstrating the
formation of alkyl radicals in a very mild way under tin-free conditions
with no need of further additives, albeit Barton esters have currently
a limited application. On this occasion, photochemistry showed an
attractive potential for the development of novel synthetic strategies
based on radical chemistry. However, Barton esters remained for several
years an isolated niche. In most cases, the photochemical generation
of radicals required harmful UV radiation and dedicated equipment.[40] Since the milestone represented by the development
of the chemistry of Barton esters, new photochemical ways were sought
toward more efficient ways to generate radicals. The photon appears
to be the ideal component for a chemical reaction, assuming the form
of a traceless reagent, catalyst, or promoter that leaves no toxic
residues in the final mixture.[41−44] The breakthrough that would allow moving forward
from the “tyranny of tin” to a greener “photon
democracy” can be associated with the use of solar or visible
photons, freely available from the sun that shines throughout the
scientific world. The renaissance of the photocatalyzed processes
that we have witnessed in the last years represents a significant
step toward this direction.[45−58]
Tclass="Disease">he multclass="Chemical">n class="Chemical">ifaceted use of photoredox catalysis and photocatalyzed
hemical">hydrogen transfer reactions expanded the range of possible <hemical">span class="Chemical">radical
precursors and unconventional routes for the generation of several
carbon (or heteroatom based) radicals, including the challenging formation
of unstabilizedalkyl radicals.[59−65] Consequently, in this review, we aim to present a summary of the
novel ways to generate alkyl radicals by photochemical means that,
in the last years[66] have revolutionized
the way to carry out radical chemistry. This work will focus exclusively
on the reactions promoting the formation of unstabilizedalkyl radicals,
and not the stabilized ones, e.g., α-oxy, α-amino, benzylic,
or allylic.
Fclass="Chemical">iguclass="Chemical">n class="Chemical">re collects
the main parahemical">digmatic approaches to the photogeneration of <hemical">span class="Chemical">alkyl radicals
(either photochemically or photocatalyzed). The more classical, although
the less employed, path to generate alkyl radicals consists of the
introduction of a photoauxiliary group which renders a bond labile
to a direct photochemical cleavage (Figure A).[67] The Barton
esters are the archetypal moiety belonging to this class.[39] A conspicuous body of literature have been focusing
on the development of suitable alkyl substituents able to facilitate
redox reactions making the derivatives more oxidizable or reducible.
The strategy that is followed in Figure B consists in the conversion of a common
functional group (e.g., OH or COOH), which in most cases is tethered
to the alkyl group, into a different electroauxiliary group[68] (Figure B). As a result, the interaction of the activated species
with an excited photoredox catalyst (PCSET) able to induce
a single electron transfer (SET) process generates the corresponding
radical ions, either by an oxidative pathway or a reductive pathway.
The desired alkyl radical is then formed by fragmentation of these
radical ion intermediates. The oxidative pathway is efficient when
the radical precursor is negatively charged (see further Figure ) as in the case
of alkyl carboxylates and alkyl sulfinates causing the CO2 or SO2 loss, respectively, despite the fact that the
exothermicity of the process is verified only in the C–C cleavage
rather than the C–S cleavage.[69] On
the contrary, positively charged Katritzky salts were ideal candidates
for the releasing of radicals via the reductive pathway (Figure ).[70]
Figure 2
Different approaches for the photogeneration of alkyl radicals
(A) by photochemical means through the introduction of a photoauxiliary
group (B) via fragmentation of a radical cation (oxidative pathway)
or anion (reductive pathway) formed by photoredox catalysis (C) via
a halogen atom transfer reaction (XAT) with a photogenerated radical
(D) through the photocatalyzed cleavage of a C–H bond via direct
(d-HAT) or indirect (i-HAT) hydrogen
atom transfer (E) by the remote-controlled C–H activation via
a photogenerated heteroatom based radical (F) by a ring-opening via
a photogenerated heteroatom (nitrogen) based radical.
Figure 3
On the left, substrates used to promote the photochemical formation
of alkyl radicals divided according to the C–Y bond cleaved.
The oxidation potentials (Eox, in orange)
or the reduction potentials (Ered, in
green) of the precursors as well as the BDE values of the bond that
is broken (highlighted in gray) by direct photocleavage are reported.
On the right, a selection of common photoredox catalysts with their
main redox features are collected.
Dclass="Chemical">iffeclass="Chemical">n class="Chemical">rent approaches for the photogeneration of hemical">alkyl radicals
(A) by photochemical means through the introduction of a photoauxiliary
group (B) via fragmentation of a <hemical">span class="Chemical">radical cation (oxidative pathway)
or anion (reductive pathway) formed by photoredox catalysis (C) via
a halogen atom transfer reaction (XAT) with a photogenerated radical
(D) through the photocatalyzed cleavage of a C–H bond via direct
(d-HAT) or indirect (i-HAT) hydrogen
atom transfer (E) by the remote-controlled C–H activation via
a photogenerated heteroatom based radical (F) by a ring-opening via
a photogenerated heteroatom (nitrogen) based radical.
On tclass="Disease">he left, substclass="Chemical">n class="Chemical">rates used to promote the photochemical formation
of <span class="Chemical">alkyl radicals divided according to the C–Y bond cleaved.
The oxidation potentials (Eox, in orange)
or the reduction potentials (Ered, in
green) of the precursors as well as the <hemical">span class="Chemical">BDE values of the bond that
is broken (highlighted in gray) by direct photocleavage are reported.
On the right, a selection of common photoredox catalysts with their
main redox features are collected.
A vclass="Chemical">iable alteclass="Chemical">n class="Chemical">rnative is the photogeneration (often from a photoredox
process) of a reactive hemical">radical on a heteroatom like a <hemical">span class="Chemical">silyl radical,
which can exploit a halogen atom transfer reaction to afford an alkylradical through the smooth Si-X bond formation (XAT, Figure C).[71,72] This strategy provides an elegant way to overcome the Giese conditions
in the tin mediated activation of alkyl halides. Recently, an α-amino
radical was used in the same strategy, promoting the formation of
alkyl radicals via C–X bond cleavage.[73]
A moclass="Chemical">re challeclass="Chemical">ngclass="Chemical">n class="Chemical">ing approach requires the photocatalyzed selective
cleavage of a strong hemical">alkyl-H bond, via a direct <hemical">span class="Chemical">hydrogen atom transfer
reaction (d-HAT, Figure D) operated by an excited photocatalyst (PCHAT).[72,74−76] The indirect
version of the latter path exploits the photogeneration of a stable
heteroatom based radical (i-HAT, Figure D) that will become the competent
intermediate in the abstraction of the H atom from the alkyl moiety.[76] An indirect HAT (i-HAT) may
also take place by intramolecular hydrogen transfer thus releasing
an alkyl radical (Figure E).[76−81] As an alternative, the photochemical radical generation may induce
a ring-opening in strained structures like cyclobutanes, to form a
substituted alkyl radical (Figure F).[82]
Fclass="Chemical">iguclass="Chemical">n class="Chemical">re showcases
a collection of the mainhemical">alkyl radical precursors devised for the
generation under photochemical conditions of <hemical">span class="Chemical">unstabilized alkyl radicals.
In this figure, the radical precursors were collected depending on
the C(sp3)-Y bond cleaved during the radical release. As
apparent, the photochemically triggered cleavage of several C-heteroatom
bonds like C–X,[71,83−88] C–O,[89−98] C–B,[99−102] C–S,[103−106] or C–N[70] (Figure ) affords carbon-centered radicals. The alkylradical generation is granted by the very versatile photochemical
tool. This feature includes particular cases such as C–Se (in
alkyl selenides),[107,108] C–Te [in (aryltelluro)formates,[109,110] for a previous thermal generation of alkyl radical from diorganyl
tellurides, see ref (111)], and C–Si (in tetra alkyl silanes and bis-chatecolates)[112−114] to be added to C–Sn (in alkyl stannanes).[112,115] Interestingly, even the more resilient C–H[15,76] or C–C[38,83,94,116−130] bonds may be cleaved for alkyl radical generation, opening up new
exciting possibilities for the synthetic (photo)chemist (Figure ).
Foclass="Chemical">r tclass="Chemical">n class="Disease">he
clarity of thereader, each hemical">radical precursor is accompanied
by its oxidation potential (EOX, in orange)
or its reduction potential (ERED, in green)
to guide the feasibility on the generation of the <hemical">span class="Chemical">radical via the
oxidative or reductive pathway (type B, Figure B), respectively. Since the redox potentials
may vary with the nature of the alkyl group, the values reported are
referred to known structures. In alternative, the BDE values of the
bond that is broken by direct photocleavage (type A, Figure A) or by photocatalyzed hydrogen
abstraction (type D, Figure D) are reported. Figure (right part) likewise collects the redox properties
of commonly used photoredox catalysts including metal-free photoorganocatalysts
(POC) to be used in the oxidative/reductive pathways.[131−137]
Tclass="Disease">heclass="Chemical">n class="Chemical">reactions collected and commented on in this review are
primarily
divided according to the type of the bond formed, namely the forging
of C–C or C–heteroatom bonds, along with theconstruction
of rings of different sizes. When possible, in each section, we will
further categorize thereactions depending on the mechanism of the
<span class="Chemical">radical generation, ascribing them to the six types (A–F) described
in Figure .
Formation of a C(sp3)-C Bond
Photocclass="Disease">hemclass="Chemical">n class="Chemical">ically
generated hemical">alkyl radicals have been employed to
forge <hemical">span class="Species">C(sp3)-C(sp) bonds (n = 1–3) in an intermolecular fashion following different
strategies. In most cases, a conjugate addition onto a Michael acceptor
or a Minisci-like reaction occurred, albeit alkenylations, acylations,
or oxyalkylations are likewise used.
Formation
of a C(sp3)-C(sp3) Bond
Addition
to C–C Double Bonds: Hydroalkylations
Many class="Chemical">reactclass="Chemical">n class="Chemical">ions
belonging to this class involve the nucleophilic
hemical">alkyl radical addition onto an electrophilic <hemical">span class="Chemical">Michael acceptor, resulting
in a formal hydroalkylation of the double bond viz. the incorporation of an alkyl group (in position β with respect
to the EWG group in the starting unsaturated compound) and a hydrogen
atom (in position α). This reaction is usually one of the first
that many authors would test during the discovery process of a new
radical precursor, as testified by the plethora of reagents that are
used in this transformation. Photoredox catalysis is by far the preferred
approach here, especially by using the oxidation of a negatively charged
precursor (oxidative pathway in Figure B).
A typclass="Chemical">ical example class="Chemical">n class="Chemical">is the oxidation of hemical">carboxylates[138,139] that releases an <hemical">span class="Chemical">alkyl radical via CO2 loss from the
carboxyl radical intermediate (Scheme ). Adamantylation of both acrylonitrile (Scheme a)[140] and dimethyl 2-ethylidenemalonate starting from adamantanecarboxylic
acid 1-1 (Scheme b)[141] were carried
out following this strategy. In the former case, the authors employed
1,4-dicyanonaphthalene (DCN) as the POC under UV light irradiation,
while visible light and an IrIII complex in the latter
case. The approach used in Scheme b was also useful for the three steps preparation of
the medicinal agent (±)-pregabalin.[141] Also, the Fukuzumi catalyst (9-mesitylene-10-methylacridinium perchlorate,
[Acr+Mes]ClO4) can promote this Giese-type reaction,[142] allowing the alkylation of α-aryl ethenylphosphonates
for the synthesis of fosmidomycin analogues.[143]
Scheme 1
Different Strategies for the Decarboxylative Adamantylation of Electron-Poor
Alkenes
A vclass="Chemical">arclass="Chemical">n class="Chemical">iation of this procedure
is the decarboxylative-de<span class="Chemical">carbonylative
process occurring on an α-keto acid 2-1 under sunlight-driven photoredox catalyzed reaction conditions (Scheme ).[125]
Scheme 2
Decarboxylative-Decarbonylation of an α-Keto
Acid
<class="Chemical">spaclass="Chemical">n class="Cclass="Chemical">n class="Disease">hemical">Oxalates are another class
of electron-donors having two <hemical">span class="Chemical">carboxylate
moieties that can be lost upon photocatalyzed oxidation. These species
may be introduced in situ by reaction of the alcohol
with oxalyl chloride. The process induced the cleavage of a C–O
bond, and the resulting radical could be trapped by butenolide 3–1 to form the menthyl derivative 3–2 used for the enantioselective preparation
of cheloviolene A (3–3, Scheme ).[144] An IrIII-based photocatalyst efficiently promoted
the reaction also in this case, allowing the synthesis of quaternary
centers[89] and the total synthesis of trans-clerodane
diterpenoids.[145]
Scheme 3
Enantioselective
Preparation of Cheloviolene A
<class="Chemical">spaclass="Chemical">n class="Cclass="Chemical">n class="Disease">hemical">Alkyl trifluoroborates stand out as another important class of
easily oxidizable moieties.[146] The photocatalyzed
oxidation of these salts (e.g., 4–1) causes the smooth release of <hemical">span class="Chemical">BF3 and the formation of
the reactive alkyl radical. Such a reaction was employed to functionalize
Michael acceptors under sunlight irradiation (Scheme a) exploiting Acr+Mes as the POC.[147] Complexation of 4–4 by a chiral rhodium complex (Λ-RhS, Scheme b) delivered 4–5 in good yields with 97% ee.[148]
Scheme 4
Visible and Solar Light Photocatalyzed Functionalization
of Michael
Acceptors with Alkyl Trifluoroborate Salts
Thclass="Chemical">is syclass="Chemical">ntclass="Chemical">n class="Disease">hetic strategy can be extended to neutral hemical">boronic acids
or <hemical">span class="Chemical">esters, upon in situ activation by a Lewis base
(LB). The so formed negatively charged species is consequently more
prone to oxidation, which eventually will provide the formation of
the alkyl radicals. A typical example is illustrated in Scheme where the boronic acid 5–1 was activated by 4-dimethylaminopyridine
(DMAP) and then oxidized by an IrIII complex. The resulting
cyclobutyl radical was trapped by methyl vinyl ketone to access the
substituted ketone 5–2 in a good
yield.[100] This reaction was later scaled
up under flow conditions by using the Photosyn reactor.
In such a way, the authors could synthesize gram amounts per hour
of the analogues of some drugs belonging to the GABA family.[149]
Scheme 5
Activation of Boronic Acids with a Lewis
Base
Followclass="Chemical">iclass="Chemical">ng tclass="Chemical">n class="Disease">he examples of thehemical">carboxylate derivatives, the electron-dona<hemical">span class="Chemical">ting
species may be generated in situ by deprotonation,
as in the case of sulfonamides, employed in the desulfurative conjugate
addition of alkyl radicals onto Michael acceptors (Scheme ). Again, the process is based
on a photocatalyzed oxidation pathway. The starting sulfonamide (6–1) was first deprotonated by a mild
base (K2HPO4), and the resulting anion was easily
oxidized to a N-centered radical. Loss of N-sulfinylbenzamide generates the desired radical that gave
the adduct 6–3 upon reaction with 6–2 in 75% yield.[103]
Scheme 6
Desulfurative Strategy for the Conjugate Addition
of Alkyl Radicals
onto Michael Acceptors
class="Chemical">Iclass="Chemical">n some class="Chemical">n class="Chemical">instances, thehemical">radical precursor is a neutral compound.
This situation is possible only when the derivative contains a highly
oxidizable or reducible moiety. <hemical">span class="Chemical">4-Alkyl-1,4-dihydropyridines (alkyl-DHPs)
under PC-free conditions act as radical precursors when combined with
photoexcited iminium ion catalysis (Scheme ). Here, enal 7–1 formed a chiral iminium ion 7–4 by reaction with amine 7–3. Cation 7–4 upon visible light excitation oxidized
the alkyl-DHP 7–2 that in turn released
the radical 7–5 upon fragmentation, along with radical 7–4. Radical recombination followed
by hydrolysis gave the desired alkylated dihydrocinnamaldehyde 7–6 in a satisfactory yield with a good
enantiomeric excess (Scheme ).[150] A similar Giese reaction
was later proposed, where the alkyl-DHP was excited and a SET reaction
with Ni(bpy)32+, acting as an electron mediator,
took place. The alkyl radical derived from the radical cation of alkyl-DHP
readily attacked a series of Michael acceptors.[151]
Scheme 7
Alkyl-DHPs as Radical Precursors in Combination with
Iminium Catalysis
Lookclass="Chemical">iclass="Chemical">ng at tclass="Chemical">n class="Disease">he other
edge of theredox spectrum, easily reducible
compounds were devised as hemical">radical precursors via a photocatalyzed
process. As an example, the incorporation of a <hemical">span class="Chemical">N-phthalimidoyl
moiety in an organic compound helps its photocatalyzed reduction,
ultimately leading to the release of the alkyl radical. A typical
case is represented by N-(acyloxy)phthalimides.[126] A stereoselective variant of this reaction
was applied to the synthesis of (−)-solidagolactone (8–4, Scheme ). Thus, the photocatalyzed reduction of
phthalimide 8–1 by a RuII complex released a tertiary carbon radical. Attack to the terminal
carbon of the unsaturated core present in β-vinylbutenolide 8–2 yields 8–3 with a very high diastereomeric excess. Further elaboration
of compound 8–3 gave 8–4 in a single step.[152] This reaction emerges as a very interesting tool to construct quaternarycarbons[153] and to synthesize biologically
active derivatives, e.g., (−)-aplyviolene.[154]
Scheme 8
Synthesis of (−)-Solidagolactone via N-(Acyloxy)phthalimides
class="Chemical">Iclass="Chemical">nteclass="Chemical">n class="Chemical">reshemical">ting results were also obtained using <hemical">span class="Chemical">N-phthalimidoyl oxalates such as 9–1 in place of the N-(acyloxy)phthalimides for the
generation of alkyl radicals starting from tertiary alcohols (Scheme ).[92,97] The similarity of this reaction to the one presented in Scheme is striking, despite
a less atom economical radical generation.
Scheme 9
Generation of Alkyl
Radicals from N-Phthalimidoyl
Oxalates
class="Chemical">Reductclass="Chemical">n class="Chemical">ion of an organic compound
may be carried out even on organic
hemical">iodides by using <hemical">span class="Chemical">cyanoborohydride anion as the reducing agent. The
reaction is chemoselective, since no alkyl bromides or chlorides could
be activated following this way. Giese adducts were formed by irradiation
with a Xe lamp of the reaction mixture in good yields as illustrated
by the formation of 10–2 from 10–1 in Scheme .[155] This is
another interesting example to circumvent the use of tin hydrides
in the activation of alkyl halides.
Scheme 10
Giese-Type Reaction
of Iodides in the Presence of BH3CN–
<class="Chemical">spaclass="Chemical">n class="Cclass="Chemical">n class="Disease">hemical">Alkyl chlorides can be activated using Ir(dtbby)(ppy)2PF6 in the presence of micelles. The micellar environment
stabilizes the photogenerated [Ir(dtbby)•–(ppy)2] hemical">species (−1.51 V vs SCE), unable to directly
reduce the <hemical">span class="Chemical">alkyl chlorides (ca. −2.8 V vs SCE). A second excitation
of this long-lived intermediate allows the electron transfer to the
halide, which could react with different electron-poor olefins, forging
a novel C–C bond. The micellar system allowed intramolecular
cyclizations to form five-membered cycles.[156]
class="Chemical">Reductclass="Chemical">n class="Chemical">ion of thehemical">alkyl halide 11–1 could be avoided applying a <hemical">span class="Chemical">halogen transfer reaction. In
fact,
due to the strong BDE of the Si-halogen bond, an alkyl radical is
formed thanks to the action of a purposely generated silyl radical
(from (Me3Si)3SiH, TTMSS) by a photoredox catalytic
step. Radical addition onto an unsaturated amide (11–2) gave the 1,8-difunctionalized derivative 11–3, a key compound in the preparation of Vorinostat 11–4, a histone deacetylase (HDAC) inhibitor
active against HIV and cancer (Scheme ).[157] This is
the typical case where the radical is formed by the cleavage of an
Alk-Br bond without the assistance of tin derivatives. It is interesting
that the reaction requires a substoichiometric amount of silane to
proceed. Indeed, with higher loadings the product yield decreases,
possibly due to the presence of competing nonproductive pathways.
A chain reaction mechanism could be envisaged; however, the quantum
yield for this reaction (Φ = 0.45) does not fully clarify the
mechanistic details of the transformation.
Scheme 11
Synthesis of Vorinostat via XAT Strategy
class="Chemical">Iclass="Chemical">n maclass="Chemical">ny class="Chemical">n class="Chemical">instances the formation of thehemical">alkyl radical arose from
a direct or indirect photocatalyzed C–H homolytic cleavage.
The excited state of the <hemical">span class="Chemical">decatungstate anion in its tetrabutylammonium
salt form (TBADT) promoted in several cases the direct chemoselective
cleavage of a C–H bond.[75,158]Scheme depicts two examples involving
the hydroalkylation of acrylonitrile. Unsubstituted cycloalkanes were
suitable hydrogen donors under flow conditions (yielding 12–1Scheme a).[159] Moreover, the chemoselective
cleavage of the methinehydrogen in isovaleronitrile allowed the preparation
of dinitrile 12–2 in 73% yield (Scheme b).[160]
Scheme 12
TBADT-Photocatalyzed Hydroalkylation of
Acrylonitrile
class="Chemical">Simclass="Chemical">n class="Chemical">ilarly, the presence
of a tertiary hemical">hydrogen was the driving
force of the chemoselective <hemical">span class="Chemical">TBADT-photocatalyzed C–H cleavage
in several derivatives, as depicted in Scheme . As an example, alkylpyridine 13–1 was selectively functionalized and gave derivative 13–2 as the exclusive product in the reaction
with a vinyl sulfone (Scheme a).[161] Interestingly, the labile
benzylic hydrogens present in 13–1 remained untouched under these reaction conditions. Noteworthy,
steric and polar effects cooperatively operated in the derivatization
of lactone 13–3. As a result only
the methinehydrogen of the isopropyl group was selectively abstracted
and afforded 13–4 in very high yields
by reaction with fumaronitrile (Scheme b), albeit the seven different types of
hydrogens present in 13–3.[162] The C–H cleavage may also take place
in branched alkanes as witnessed by the derivatization of 13–5 to form the succinate derivative 13–6 (Scheme c).[163]
Scheme 13
TBADT-Driven Functionalization
of Tertiary Carbons
class="Chemical">Iclass="Chemical">n class="Chemical">n class="Chemical">rare instances,
the hydrohemical">alkylation reaction may be applied
to <hemical">span class="Chemical">olefins different to the usual Michael acceptors. Thus, substituted
vinylpyridines were functionalized by TBADT-photocatalyzed addition
of cycloalkanes. Scheme showed the smooth synthesis of 14–2 starting from 14–1 simply
by irradiation of the reaction mixture containing a slight excess
of cyclohexane in the presence of a catalytic amount of the decatungstate
salt.[164]
Scheme 14
Functionalization
of a Vinylpyridine with a Cycloalkane
class="Chemical">Receclass="Chemical">ntly, alteclass="Chemical">n class="Chemical">rnative PCs have been developed for the direct photocatalyzed
activation of C–H bonds inhemical">cycloalkanes, namely <hemical">span class="Chemical">uranyl cation[165] and Eosin Y,[166] both
having the advantage of absorbing in the visible light region. The
alkyl radical formation may be induced by a photogenerated stable
radical which acts as a radical mediator. An IrIII based
photoredox catalyst oxidized the chloride anion (being the counterion
of the Ir complex) to the corresponding chlorine atom, which abstracted
a hydrogen atom from cyclopentane, thus forming adduct 15–1 in 69% yield upon addition onto a maleate
ester (Scheme ).[167]
Scheme 15
Indirect HAT Mediated by a Cl• Radical
Anotclass="Disease">heclass="Chemical">n class="Chemical">r intriguing way to induce
the cleavage of unactivated ies">C(sp3)-H bonds is by a photocatalyzed
intramolecular <hemical">span class="Chemical">hydrogen abstraction.
Usually a photoredox or a proton-coupled electron transfer (PCET)[47] step induced the formation of a heteroatom centered
radical that abstracts a tertiary C–H bond intramolecularly
in a selective fashion, following a 1,5-HAT process mimicking the
Hoffmann-Löffler-Freytag reaction (Scheme ).[168−170]
Wclass="Disease">heclass="Chemical">n tclass="Chemical">n class="Disease">he reaction was applied to compound 16–1, an oxidative hemical">PCET generated a neutral <hemical">span class="Chemical">amidine radical that
promotes the 1,5-hydrogen atom abstraction forming a tertiary radical
which is able to functionalize olefin 16–2 in a complete regioselective fashion affording 16–3 (Scheme a).[171] The reaction was
also applied to medicinally relevant molecules such as the steroid-derived
trifluoroacetamide 16–4 (Scheme b). Despite the
fact that this compound has several labile C–H bonds including
tertiary C–H bonds and C–H bonds adjacent to heteroatoms,
the intramolecular hydrogen abstraction followed by conjugate addition
onto 16–5 gave 16–6 as the sole product.[172]
Tclass="Disease">heclass="Chemical">n class="Chemical">remote activation of the C–H bond in the δ-position
following this approach is a general reaction as demonstrated inrelated
systems applied to hemical">amides protected with a <hemical">span class="Chemical">carbamate group[173] or in simple benzamide derivatives.[174] In the latter case, the reaction was carried
out in the presence of a chiral Rh-based Lewis acid catalyst that
allowed the asymmetric alkylation of α,β-unsaturated 2-acyl
imidazoles.[174]
Tclass="Disease">he abstclass="Chemical">n class="Chemical">rachemical">ting hemical">species
could be likewise a photogenerated iminyl
<hemical">span class="Chemical">radical as illustrated in Scheme . Here a carbonyl group is converted in an oxime derivative
(e.g., 17–1) by reaction with an
α-aminoxy acid. Photocatalyzed oxidation followed by fragmentation
of the resulting carbonyloxy radical gave an iminyl radical prone
to a 1,5-HAT to afford a tertiary radical that upon addition to acrylate 17–2 gave compound 17–3 in 77% yield.[175]
Scheme 17
1,5-HAT
Promoted by an Iminyl Radical
Heteroalkylation of C–C Double Bonds
Anclass="Chemical">iclass="Chemical">nteclass="Chemical">n class="Chemical">reshemical">ting variation of the functionalization of a double bond
is the formation of a C–C bond (upon an <hemical">span class="Chemical">alkylation step) followed
by the formation of another C–Y bond (Y ≠ H) on the
adjacent carbon. As an example, alkyl diacyl peroxides were reduced
photocatalytically and the fragmentation released an alkyl radical
and a carboxylate anion both incorporated in the structure of the
product. Thus, 2-vinylnaphthalene 18–2 was converted into compound 18–4 in a very good yield upon reaction with lauroyl peroxide 18–1 upon an oxidative quenching process by consecutive
C–C and C–O formation (Scheme ).[176] The reaction
was made possible by the oxidation of the resulting radical adduct 18–3 (by
RuIII, the oxidized form of the PC) that generated the
cation 18–3 that was easily trapped by the carboxylate anion previously released.
Scheme 18
Oxyalkylation via Alkyl Diacyl Peroxides
<class="Chemical">spaclass="Chemical">n class="Cclass="Chemical">n class="Disease">hemical">N-(acyloxy)phthalimide 19–1 as <hemical">span class="Chemical">radical precursor found use in a similar multicomponent
oxyalkylation of styrenes. The addition of the alkyl radical onto
the vinylarene followed by the incorporation of water present in the
reaction mixture afforded derivative 19–2 in 72% yield (Scheme ).[177] Noteworthy, the labile
C–Br bond in 19–1 remained
untouched in the process.
Scheme 19
Multicomponent Oxyalkylation of Styrenes
Tclass="Disease">he use of <class="Chemical">n class="Chemical">span class="Chemical">water as the <hemical">span class="Chemical">oxygen source was likewise
used in the
difunctionalization of aryl alkenes where the carbon-centered radical
was formed by an intramolecular 1,5-HAT of a photogenerated iminyl
radical.[178]
Peclass="Chemical">rfoclass="Chemical">n class="Chemical">rming thereaction
inhemical">DMSO, allows for the use of the solvent
as an <hemical">span class="Chemical">oxygen donor adopting the Kornblum oxidation. The intermediate
benzyl radical formed after the alkylation step reacts with the solvent
and eventually forming a carbonyl group in place of a simple C–O
bond. An elegant example is shown in (Scheme ) for the synthesis of ketonitrile 20–4.[179] A
cycloketone oxime ester (20–1) was
photocatalytically reduced, inducing a ring opening on the resulting
iminyl radical. The resulting cyano-substituted alkyl radical reacted
with styrene 20–2, and the addition
with DMSO formed the intermediate 20–3, that, upon Me2S loss, afforded the product.
Scheme 20
Photocatalyzed
Oxyalkylation of Styrenes Based on the Kornblum Oxidation
A class="Chemical">related oxy<class="Chemical">n class="Chemical">span class="Chemical">alkylation of <hemical">span class="Chemical">styrenes made again
the use of the Kornblum
oxidation as the last step in the synthesis of substituted acetophenones.
Indeed, N-hydroxyphthalimides (e.g., 21–1) were employed as the radical source, and
an IrIII complex was used as the PC, obtaining good yields
even on a 7 mmol scale (64% of 21–3, Scheme a).[180,181] Ester 21–1 was also adopted for
the preparation of the aryl alkyl ketone 21–5 in 61% yield (Scheme b). In this case, however, the decarboxylative alkylation
was applied to silyl enol ethers having the carbonyl oxygen already
incorporated in the initial structure such as 21–4.[182] The same process described
in Scheme b can
be carried out under uncatalyzed conditions under blue LED irradiation
in the presence of an excess of NaI (150 mol %) and PPh3 (20 mol %). The reaction was based on the photoactivation of a complex
formed by N-(acyloxy)phthalimide with NaI and PPh3 through Coulombic and cation-π interactions. In this
case, the excitation caused the reduction of the phthalimide by a
SET reaction within the complex.[183]
Scheme 21
Oxyalkylation by Using N-(Acyloxy)phthalimide Derivatives
as Radicals Source
<class="Chemical">spaclass="Chemical">n class="Cclass="Chemical">n class="Disease">hemical">Alkylated ketones 22–3a–d were likewise
obtained by the IrIII-photocatalyzed reaction between a
<hemical">span class="Chemical">2-mercaptothiazolinium salt (22–1, as alkyl radical precursor) and silyl enol ethers 22–2a–d (Scheme ).[106]
Scheme 22
Synthesis of Alkylated Ketones from Mercaptothiazolinium
Salts
<class="Chemical">spaclass="Chemical">n class="Cclass="Chemical">n class="Disease">hemical">Lauryl peroxide (<hemical">span class="Chemical">LPO, see Scheme ) was adopted for
the Ru-catalyzed three-component
carbofluorination of styrenes as illustrated in Scheme a. The vinylic double bond
of compound 23–1 derived from estrone
was functionalized twice by using triethylamine trihydrofluoride Et3N·HF as the fluoride anion source to deliver the desired
alkyl-fluorinated olefin 23–2 in
61% yield. The reduction of LPO is mediated by the presence of a copper
salt in the role of a cocatalyst in a dual catalytic process.[184] The carbofluorination was later applied to
dehydroalanine derivative 23–4 by
using alkyltrifluoroborates and an excess of Selectfluor as an electrophilic
fluorine source (Scheme b). The use of a visible light POC ([Acr+Mes]ClO4) allowed for the synthesis of a wide range of unnatural α-fluoro-α-amino
acids including F-Leu (23–5).[185]
Scheme 23
Carbofluorination of (a) Styrenes and (b)
Dehidroalanine Derivatives
class="Chemical">Iclass="Chemical">n class="Chemical">n class="Chemical">rare instances, two C–C bonds could be formed in the
adjacent position of the double bond as in cyanohemical">alkylations. The enantioselectivity
of the reaction was controlled exploi<hemical">span class="Chemical">ting the capability of a copper
catalyst to form complexes with chiral Box ligands. Thus, a methyl
radical was obtained by IrIII-photocatalyzed reduction
of phthalimide 24–1 that readily
attacked styrene (Scheme ). Meanwhile, the CuI salt incorporated Box 24–2 as the ligand, and the resulting
complex reacted with the adduct radical in the presence of TMSCN.
As a result, cyanoalkylated 24–3 was
obtained in a good yield and in good ee.[186]
Scheme 24
Enantioselective Cyanoalkylation of Styrenes
A pclass="Chemical">artclass="Chemical">n class="Chemical">icular case of cyanohemical">alkylation was later reported
in the
photocatalyzed reaction between <hemical">span class="Chemical">cyclopropanols and cyanohydrins having
a pendant C=C bond. Oxidative ring opening of the three-membered
ring followed by addition onto the double bond and cyano migration
gave a series of multiply functionalized 1,8-diketones incorporating
the cyano group.[187]
Allylation
Allylatclass="Chemical">ioclass="Chemical">n class="Chemical">n class="Chemical">reactions
can be easily performed by reaction of an hemical">alkyl radical with substituted
<hemical">span class="Chemical">allyl sulfones (mainly with 1,2-bis(phenylsulfonyl)-2-propene 25–1, Scheme a). The alkyl radical was generated under
visible light irradiation by hydrogen abstraction from cycloalkanes
by an aromatic ketone, e.g., 5,7,12,14-pentacenetetrone 25–2. Addition of a cycloalkyl radical onto 25–1 followed by sulfonyl radical elimination
gave access to vinyl sulfones 25–3a–b in
good yields (Scheme a).[188]
Scheme 25
Allylation through
Alkyl Radicals Generated (a) via HAT and (b) from
Si bis-Catecholates
Otclass="Disease">heclass="Chemical">n class="Chemical">r related reactions
were designed to forge ies">C(sp3)–allyl bonds following
this simple scheme. The <hemical">span class="Chemical">alkyl radical
was formed by photocatalytic oxidation of hypervalent bis-catecholatosilicon compounds as shown in Scheme b. Thus, compound 25–4 upon oxidation released the desired substituted alkyl radical, and
addition onto allyl sulfone 25–5 gave
the corresponding allylated derivative 25–6 in 70% yield.[113] Olefin 25–5 was also used in a decarboxylative
allylation of alkyl N-acyloxyphthalimides under RuII photocatalysis. The great advantage of the process was the
reaction time since the allylation was completed in a few minutes
at room temperature.[189]
A pclass="Chemical">artclass="Chemical">n class="Chemical">icular
class of hemical">phthalimides could be employed with no need
of a photocatalyst to promote the reaction. <hemical">span class="Chemical">N-alkoxyphthalimide
(26–1) is able to form a donor–acceptor
complex with electron donor compounds, such as the Hantzsch ester HE. Upon excitation, an electron transfer occurred within
the complex generating a radical anion, which released an alkoxy radical
upon N–O bond cleavage. Loss of formaldehyde formed the desired
alkyl radical which reacted with 26–2, to obtain product 26–3 in 60%
yield (Scheme ).[127]
Scheme 26
Hantzsch Ester Mediated Photocleavage of N-Alkoxyphthalimides
Photocatalyzed class="Chemical">reductclass="Chemical">n class="Chemical">ion of hemical">Katritzky salts 27–1a–c obtained from the corren class="Disease">hemical">sponding <hemical">span class="Chemical">amines (Scheme ) gave access to the allylated compounds 27–3a–c. Thus, the monoelectronic reduction
of pyridinium salts 27–1a–c caused the
release of the corresponding pyridines along with the substituted
cyclohexyl radicals than upon trapping by 27–2 efficiently afforded acrylates 27–3a–c.[190]
Scheme 27
Photocatalyzed Allylation by Using
Katritzky Salts
A class="Chemical">remote allylatclass="Chemical">n class="Chemical">ion
under visible light irradiation was devised
starhemical">ting from <hemical">span class="Chemical">amide 28–1 making use
of eosin Y (EY) as the PC (Scheme ). The excited EY is able to reduce 28–1 thanks to the electron-withdrawing capability
of the substituted phenoxy group on the nitrogen of the amide. The
amidyl radical formed upon fragmentation of 28–1 gave rise to a tertiary
radical upon 1,5-HAT, allowing the remote allylation, forming 28–2 in 75% yield.[191]
Scheme 28
Remote Allylation via Amidyl Radicals
A dclass="Chemical">iffeclass="Chemical">n class="Chemical">rent approach involved the use of trifluoromethyl-substituted
hemical">alkenes (e.g., 29–1) that upon addition
of the <hemical">span class="Chemical">alkyl radical gave access to valuable gem-difluoroalkenes such
as 29–2a–b (Scheme ). The oxidation of alkyltrifluoroborates
was here assured by the organic photocatalyst 4CzIPN, leading to nonstabilized
primary, secondary, and tertiary radicals. The defluorinative alkylation
resulted from the reduction of the radical adduct, followed by an
E1cB-like fluoride elimination.[192]
Scheme 29
Synthesis of gem-Difluoroalkenes from Alkyl Trifluoroborates
A dual catalytclass="Chemical">ic appclass="Chemical">n class="Chemical">roach was designed for valuable
allylation
using hemical">vinyl epoxides as allyla<hemical">span class="Chemical">ting agents (Scheme ). The mechanism was investigated by quantum
mechanical calculations [by DFT and DLPNO–CCSD(T)] and supported
an initial complexation of Ni0 to 30–2 that quickly underwent a SN2-like ring opening,
followed by the incorporation of the alkyl radical formed by DHP-derived
compounds 30–1a,b into the metal complex. Allyl
alcohols 30–3a,b were then formed by inner sphere
C(sp2)-C(sp3) bond formation from the resulting
NiIII complex.[193]
Scheme 30
Dual-Catalytic
Allylation of Vinyl Epoxides
sp3–sp3 Cross-coupling
Anotclass="Disease">heclass="Chemical">n class="Chemical">r intriguing possibility offered by the photochemical approach
to hemical">alkyl radicals is the formation of a C–C bond by a hemical">sp3–hemical">sp3 <hemical">span class="Disease">cross-coupling reaction. The transformation
could lead to novel pathways to interesting targets, as represented
by the synthesis of the drug tirofiban in only four steps, starting
from easily available compounds. The protocol made use of two consecutive
photocatalyzed reactions applying a metallaphotoredox strategy (Scheme ). The key step
is the coupling between carboxylic acid 31–1 and alkyl halide 31–2.
The halide is first complexed by a Ni0 catalyst and the
resulting NiI complex trapped the alkyl radical (obtained
by photocatalyzed decarboxylation) to yield a NiIII complex
that in turn released the sp3–sp3 coupled
product 31–3 after desilylation with
TBAF. The desired tirofiban was then obtained by elaboration of 31–3 in two subsequent steps.[194]
Scheme 31
Synthesis of a Precursor of Tirofiban by
a Metallaphotoredox Strategy
Anotclass="Disease">heclass="Chemical">n class="Chemical">r example of a ies">C(sp3)–<hemical">span class="Species">C(sp3)
cross-coupling process is the reaction between alkylsilicates and
alkyl halides. As in the previous case, a dual catalytic Ir/Ni system
was required.[195] The alkyl radical may
be likewise generated from an alkyl halide by a halogen atom transfer
with a photogenerated silyl radical (from a silanol). The radical
that is hence formed could be coupled with another alkyl bromide,
e.g., methyl bromide, using a Ni0 catalyst to perform valuable
methylation reactions.[196] Aliphatic carboxylic
acids were used to form alkyl-CF3 bonds via a photocatalyzed
reaction making use of Togni’s reagent as the trifluoromethylating
agent. The reaction was promoted under visible light irradiation employing
an IrIII photocatalyst coupled with a CuI salt. This process
tolerates various functionalities including olefins, alcohols, heterocycles,
and even strained ring systems.[197]
Tclass="Disease">he <class="Chemical">n class="Chemical">span class="Chemical">alkylation of a benzylic position in N-aryl
tetrahydro<hemical">span class="Chemical">isoquinoline 32–1 was reported
following two different approaches (Scheme ). The first allowed the reaction of an
unactivated alkyl bromide (32–2)
by the excitation of a Pd0 complex. Compound 32–1 was oxidized in the catalytic cycle, and the
resulting α-amino radical coupled with the isopropyl radical
to form 32–4 in 81% yield (Scheme a).[198] An alternative heavy-metal-free route catalyzed
by a dye-sensitized semiconductor is depicted in Scheme b. Excitation of an inexpensive
dye (erythrosine B) caused the reduction of titanium dioxide that
in turn was able to reduce phthalimide 32–3 that eventually yielded quinoline 32–4.[199]
Scheme 32
Different Strategies
in the Alkylation of N-Aryl
Tetrahydroisoquinolines
Other Reactions
class="Chemical">Iclass="Chemical">n pclass="Chemical">n class="Chemical">articular cases,
a C=N bond can be made sufficiently electrophilic to undergo
hemical">alkyl radical addition as in the case of <hemical">span class="Chemical">N-sulfinimines,
exploited for the preparation of protected amines. A high degree of
diastereoselectivity can be obtained when starting from chiral N-sulfinimines (33–2a–c, Scheme ). Thus, the asymmetric
addition of an isopropyl radical (formed from derivative 33–1) onto 33–2a–c allowed
the isolation of sulfinamides 33–3a–c in
good yields.[200]
Scheme 33
Addition of an Alkyl
Radical to Chiral Sulfinimines
Tclass="Disease">he <class="Chemical">n class="Chemical">span class="Chemical">alkylation of related <hemical">span class="Chemical">imines can be carried out by using ammonium
alkyl bis(catecholato)silicates as the radical precursors under metal-free
conditions adopting 4CzIPN as the POC[201] or by using potassium alkyltrifluoroborates in the alkylation of N-phenylimines.[202]
Anotclass="Disease">heclass="Chemical">n class="Chemical">r
particular case is thehemical">alkylative semipinacol rearrangement
devised for the synthesis of <hemical">span class="Chemical">2-alkyl-substituted cycloalkanones. The
reaction involved the photocatalytic reaction between TMS protected
α-styrenyl substituted cyclic alcohol 34–2 and the unactivated bromoalkane 34–1 (Scheme a). The reaction was promoted by the dimeric gold complex[Au2(dppm)2]Cl2. This complex is able to
reduce 34–1 (ca. −2.5 V vs
SCE) despite having an oxidation potential in the excited state considerably
lower for the reaction to occur (ca. −1.63 V vs SCE). This
can be explained by the formation an inner sphere exciplex between
the excited dimeric catalyst and 34–1 that promotes the otherwise thermodynamically unfeasible redox process,
generating an AuI–AuII dimer and 34–4.
The combination of the latter species formed an AuIII complex
that induces a semipinacol rearrangement coupled with C(sp3)–C(sp3) reductive elimination, which furnished 34–3 in 84% yield (Scheme b).[203]
Scheme 34
Gold
Catalyzed Activation of Bromoalkanes
A class="Chemical">simclass="Chemical">n class="Chemical">ilarreaction was later developed starhemical">ting from <hemical">span class="Chemical">cycloalkanol-substituted
styrenes and N-acyloxyphthalimides under IrIII photocatalysis.[204]
Formation of a C(sp3)-C(sp2) Bond
Alkenylation
Tclass="Disease">heclass="Chemical">n class="Chemical">reaction between
an hemical">alkyl radical with a <hemical">span class="Chemical">cinnamic acid followed by loss of the COOH
group is one of the more common approaches to promote an alkenylation
reaction. Thus, the radical formed from salt 35–3 attacked the benziodoxole adduct 35–2, synthesized from acrylic acid 35–1. The reaction yielded 83% of the diphenylethylene derivative 35–4 upon a deboronation/decarboxylation
sequence (Scheme ).[205] The benziodoxole moiety gave efficient
results in promoting the radical elimination step, while other noncyclic
IIII reagents were ineffective.
Scheme 35
Alkenylations Mediated
by Benziodoxole
Dclass="Chemical">iffeclass="Chemical">n class="Chemical">rent decarboxylative
hemical">alkenylations have been reported by changing
the <hemical">span class="Chemical">radical source and the photocatalyst (Scheme ). The homolytic cleavage of an alkyl-I
bond has been promoted by a CuI complex and the resulting
cyclohexyl radical afforded styrene 36–3 in 68% yield upon addition onto cinnamic acid 36–1 (path a).[206] The same product
may be formed as well starting from the same substrate by using phthalimide 36–2 under visible light irradiation with
the help of an IrIII[207] (path
b) or a RuII photocatalyst.[208] As an additional bonus, the formation of adduct 36–3 was obtained with a preferred E configuration.
Scheme 36
Different Strategies Toward Decarboxylative Alkenylations
Tclass="Disease">he <class="Chemical">n class="Chemical">span class="Chemical">alkenylation may mimic a Heck reaction as
in the visible light-induced
Pd-catalyzed reaction between a <hemical">span class="Chemical">vinyl (hetero)arene and an α-heteroatom-substituted
alkyl iodide or bromide (see Scheme ). Here, the generation of the radical is induced by
the reduction of the TMS-derivative 37–1 by the excited Pd0 species. Radical addition onto 37–2 followed by β-H-elimination
from the adduct radical delivered allyl silane 37–3 in 81% yield.[209] Noteworthy,
the same reaction did not take place under usual thermal Pd-catalysis.
Scheme 37
Heck-Like Alkenylation of an Alkyl Iodide
<class="Chemical">spaclass="Chemical">n class="Cclass="Chemical">n class="Disease">hemical">Alkylation of <hemical">span class="Chemical">styrenes could be carried out using an inexpensive
palladium source (Pd(PPh3)4) with no need of
any base or classical photocatalyst. The reaction was promoted by
visible light, adopting N-hydroxyphthalimides as
radical sources.[210] Other visible light
Pd promoted alkenylations include the reaction of vinyl arenes with
carboxylic acids[211] or tertiary alkyl halides[212] as radical precursors. Other metal catalysts,
however, were helpful for the substitution of a vinylic hydrogen atom
with an alkyl group. In this respect, a dinuclear gold complex was
employed for the activation of an alkyl bromide to promote a photocatalyzed
Heck-like reaction.[213] The synergistic
combination of a POC and a cobaloxime catalyst promoted the photocatalyzed
decarboxylative coupling between 38–1 and styrene 38–2 to give the alkenylated
product 38–3 in 82% yield and with
a complete E/Z selectivity as illustrated
in Scheme .[214]
Scheme 38
Cobaloxime-Mediated Decarboxylative Coupling
of Carboxylic Acids
with Styrenes
Tclass="Disease">he addclass="Chemical">n class="Chemical">ition of thehemical">alkyl radical may take place even on substituted
<hemical">span class="Chemical">alkenes via an ipso-substitution reaction. An example
is shown in Scheme where a vinyl iodide (39–2) is
used for an alkenylation by the reaction with a radical generated
from silicate 39–1, obtaining compound 39–3. The RuII photocatalyst
in the dual catalytic system has the role of generating the radical,
while the Ni0 catalyst activates the C(sp2)-I
bond.[215]
Scheme 39
Alkenylation via
Alkenyl Iodides
<class="Chemical">spaclass="Chemical">n class="Cclass="Chemical">n class="Disease">hemical">Alkenylation of <hemical">span class="Chemical">alkyl
iodide 40–1 can also take place starting
from an alkenyl sulfone (40–2). Also
in this case, an ipso-substitution
is central to the novel bond formation and the Pd0 catalyst
formed the radical by a SET reaction with 40–1. After the addition of the radical onto 40–2, the sequence is completed by the elimination of a sulfonyl
radical affording 53% yield of 40–3 (Scheme ).[216]
Scheme 40
Alkenylation of an Alkyl Iodide with Alkenyl
Sulfones
<class="Chemical">spaclass="Chemical">n class="Cclass="Chemical">n class="Disease">hemical">Alkyl bromides were used in
<hemical">span class="Chemical">alkenylations by reaction with vinyl
sulfones made possible by the photocatalytic generation of silicon
centered radical that in turn formed the alkyl radical by a halogen
atom transfer reaction.[217]
Acylation
Acylatclass="Chemical">ioclass="Chemical">n owes class="Chemical">n class="Chemical">its importance
to the possibility to convert an hemical">alkyl radical into a <hemical">span class="Chemical">ketone, a reaction
that proceeds in most cases with the intermediacy of an acyl radical.[218,219] A classical approach is based on the homolytic cleavage of an alkyl-I
bond followed by carbonylation with CO and reaction with electrophiles
of the resulting nucleophilic acyl radical. Scheme illustrates the concept. Irradiation of
iodide 41–1 with a Xe lamp in the
presence of CO (45 atm) and a Pd0 complex led to an electron
transfer reaction which formed an alkyl radical that, upon carbonylation
and addition onto phenyl acetylene, gave ynone 41–2 in 63% yield.[220] The reaction
is supposed to proceed via a photoinduced electron transfer from the
Pd0 catalyst to the iodoalkane, furnishing a PdII species and the alkyl radical. The carbon-centered radical promptly
reacts with CO to generate an acyl radical. The PdI catalyst
intervenes here again to couple the acyl derivative with the alkyne,
preserving the triple bond in the final product. This reaction was
later applied to the acylation of styrenes to give the corresponding
enones.[221] The electrophilic nature of
the alkyne could be exploited if the moiety is placed in the same
reagent bearing the iodide. In this case, the first reaction observed
was an intramolecular cyclization forming an alkenyl radical which
eventually reacted with CO, furnishing an α,β-unsaturated
ketone.[222]
Scheme 41
Photocatalyzed Synthesis
of Ynones
A class="Chemical">reductclass="Chemical">n class="Chemical">ive step induced the
generation of thehemical">alkyl radical through
an IrIII-photocatalyzed C–N bond activation in <hemical">span class="Chemical">pyridinium
salt 42–1 (Scheme ). Trapping of the alkyl radical with CO
followed by addition onto 1,1-diphenylethylene gave access to the
Heck-type product 42–2 with no interference
by the 2,4-dioxo-3,4-dihydropyrimidin-1-yl ring.[223]
Scheme 42
Synthesis of Enones via Photocatalyzed C–N
Bond Activation
Tclass="Disease">he <class="Chemical">n class="Chemical">span class="Chemical">alkyl radical
to be <hemical">span class="Chemical">carbonylated was likewise formed starting
from a cycloalkane for the preparation of unsymmetrical ketones via
radical addition onto Michael acceptors. The reaction proceeded via a photocatalyzed decatungstatehydrogen atom transfer
reaction[224] When cyclopentanones were subjected
to the photocatalyzed C–H activation, a regioselective β-functionalization
occurred. Thus, 1,4-diketones 43–3a–c were
smoothly formed by reaction of the photogenerated acyl radical 43–1 onto
Michael acceptors 43–2a–c (Scheme ).[225]
Scheme 43
Photocatalyzed Synthesis of Unsymmetrical Ketones
Unsymmetclass="Chemical">rclass="Chemical">n class="Chemical">ical hemical">ketones have been likewise formed
by <hemical">span class="Chemical">carbonylation
of alkyl radicals generated from organosilicates by using 4CzIPN as
POC under visible-light irradiation.[226]
<class="Chemical">spaclass="Chemical">n class="Cclass="Chemical">n class="Disease">hemical">Potassium alkyltrifluoroborates were extensively used for
acylation
reactions having recourse to a dual photocatalytic system. The <hemical">span class="Chemical">unstabilized
alkyl radical was generated from trifluoroborate 44–1 with the help of an IrIII PC (Scheme ). Meanwhile, the acid 44–2 was converted in situ into a mixed anhydride (by reaction with dimethyl dicarbonate, DMDC)
that was activated by a Ni0 complex. Addition of the alkylradical onto the resulting complex led to the acylated product 44–3.[227] In
a similar vein, Ir-photoredox/nickel catalytic cross-coupling reactions
were devised by using acyl chlorides[228] and N-acylpyrrolidine-2,5-diones[229] as acylating reagents.
Scheme 44
Dual Catalytic Acylation of Alkyl
Trifluoroborates
A class="Chemical">Nclass="Chemical">n class="Chemical">i/Ru, dual-catalyzed
amidation protocol was possible thanks
to thecoupling between an hemical">alkylsilicate and an <hemical">span class="Chemical">isocyanate. Even in
the latter case, the alkyl radical attacked the complex formed between
the isocyanate and a Ni0 species and, as a result, the
mild formation of substituted amides took place.[230]
Tclass="Disease">he acylatclass="Chemical">n class="Chemical">ion of thehemical">radical was also exploited for
the synthesis
of <hemical">span class="Chemical">esters. This elegant approach involves the generation of radicals
from unactivated C(sp3)–H bonds (e.g., in cycloalkanes).
The hydrogen abstraction on cycloalkanes was induced by a chlorine
atom released from the photocleavage of the complex formed between
chloroformate 45–1 and a Ni0 complex, allowing one to synthesize scaffolds with different ring
sizes (45–2a–d in Scheme ).[231]
Scheme 45
Dual
Catalytic Acylation of Cycloalkanes
Minisci-Like Reactions
A fundamental
tclass="Chemical">raclass="Chemical">nsfoclass="Chemical">n class="Chemical">rmation for theconstruction of C(sp)-C(sp) bond is the Miniscireaction,
where the functionalization of hemical">heteroaromatics took place by substitu<hemical">span class="Chemical">ting
a H atom with an alkyl group. The reaction was widely investigated
in the last years and mainly involves the functionalization of a nitrogen-containing
heterocycle.[232] An interesting example
is the methylation reported in Scheme .[94] A methyl
radical was formed by using a peracetate such as 46–1. The protonation of 46–1 by acetic acid facilitates a PCET reduction of the peracetate by
the IrIII PC. A double fragmentation ensued, and the resulting
methyl radical may attack the protonated form of biologically active
heterocycles (e.g., fasudil 46–2)
in a mild selective manner to afford 46–3 in 43% yield.[94]
Scheme 46
Alkylation
of Fasudil
Anotclass="Disease">heclass="Chemical">n class="Chemical">r approach made use of
an hemical">alkyl boronic acid as the <hemical">span class="Chemical">radical
precursor. The process is initiated by the RuII-photocatalyzed
reduction of acetoxybenziodoxole (BI-OAc) that liberated the key species
ArCOO• (Scheme ). Upon addition onto an alkyl boronic acid, this ortho-iodobenzoyloxy
radical made available the alkyl radical that in turn functionalized
pyridine 47–1 in position 2 in 52%
yield (47–2, Scheme ).[233]
Scheme 47
Minisci
Reaction by Using Alkyl Boronic Acids
Tclass="Disease">he geclass="Chemical">neclass="Chemical">n class="Chemical">ration of thehemical">alkyl radical from <hemical">span class="Chemical">boron-containing derivatives
was made easier starting from alkyltrifluoroborates. A POC (Acr+Mes) is, however, required, but in all cases, the regioselective
functionalization of various nitrogen-containing heterocycles was
achieved.[234] A related chemical oxidant-free
approach process was later developed where alkyl radicals were formed
by merging electro and photoredox catalysis.[235]
<class="Chemical">spaclass="Chemical">n class="Cclass="Chemical">n class="Disease">hemical">Alkyl halides are versatile substrates for the photoinduced
functionalization
(e.g., butylation) of <hemical">span class="Chemical">lepidine 48–1 (Scheme ). An
uncatalyzed redox process is a rare occurrence here, since alkyl halides
reduction is more demanding. This drawback can be overcome by the
adoption of a dimeric AuI complex (see Scheme ) that upon excitation coordinates
an unactivated haloalkane promoting an inner sphere PET. This interaction
pushes the activation of R-Br despite its larger Ered with respect to the PC (Scheme a).[236] A different
approach promoting the homolytic cleavage of the R-I bond is shown
in Scheme b. Decacarbonyldimanganese
Mn2(CO)10 was cleaved upon visible light irradiation,
and the resulting Mn-based radical was able to abstract the iodine
atom from an alkyl iodide thus generating the desired butyl radical.
This route was smoothly applied to the late-stage functionalization
of complex nitrogen-containing substrates.[237] Moreover, the activation of alkyl halides may be obtained by the
photogeneration of a silyl based radical derived by TTMSS (Scheme c, see also Scheme ). The robustness
and the mildness of this approach was witnessed by the broad substrate
scope and the compatibility of several functional groups present in
the radical.[238] The use of acidic conditions
(required to make the nitrogen heterocycle more electrophilic) may
however be avoided. Excited [Ir(ppy)2(dtbbpy)]PF6 was sufficiently reducing to convert alkyl iodides to alkyl radicals
under basic conditions by combining conjugate and halogen ortho-directing
effects.[239]
Scheme 48
Photocatalyzed Butylation
of Lepidine
class="Chemical">Iclass="Chemical">n geclass="Chemical">neclass="Chemical">n class="Chemical">ral, hemical">lepidine
is the preferred substrate to test new ways
for the C–H <hemical">span class="Chemical">alkylation of heteroarenes. Accordingly, adamantanecarboxylic acid 49–1 served for the
visible light induced synthesis of 49–3 starting from lepidine 49–2 (Scheme ). An IrIII PC was adopted to alkylate various nitrogen heterocycles, making
use of a large excess of persulfate anion as the terminal oxidant
(path a).[240] The presence of a PC is not
mandatory for the adamantylation reaction with (bis(trifluoroacetoxy)-iodo)benzene
as starting material. This compound in the presence of a carboxylic
acid gave the corresponding hypervalent iodineIII reagent
that upon irradiation generates the alkyl radical. The TFA liberated
in the process was crucial for the activation of the nitrogen heterocycle
and adduct 49–3 was isolated in 95%
yield (path b).[241]
Scheme 49
Decarboxylative
Minisci Alkylation
Veclass="Chemical">ry class="Chemical">n class="Chemical">recently, an
intereshemical">ting approach for the generation of <hemical">span class="Chemical">alkyl
radicals from the C–C cleavage in alcohols was reported making
use of a CFL lamp as irradiation source. The combination of 2,2-dimethylpropan-1-ol
(50–1) with benziodoxole acetate
(BI-OAc) gave adduct 50–3. Photocatalytic
reduction of compound 50–3 released
and alkoxy radical that upon fragmentation formed a tbutyl radical that reacted with N-heteroarene 50–2 to form 50–4 in 57% yield (Scheme ).[130]
Scheme 50
Aliphatic Alcohols
as Radical Precursors in Minisci Reaction
Tclass="Disease">he use of hypeclass="Chemical">n class="Chemical">rvalent hemical">iodineIII in promo<hemical">span class="Chemical">ting the decarboxylation
of R-COOH was effective in the derivatization of drugs or drug-like
molecules. As a result, the quinine analogue 51–2 was formed in a 76% yield from quinine 51–1, utilizing Acr+Mes as the POC (Scheme ).[242]
Scheme 51
Alkylation
of Quinine
<class="Chemical">spaclass="Chemical">n class="Cclass="Chemical">n class="Disease">hemical">Azoles can be adamantylated
star<hemical">span class="Chemical">ting from adamantanecarboxylic
acid by a dual catalytic approach (Acr+Mes as the POC and
[Co(dmgH)(dmgH2)Cl2] as the cocatalyst)[243] or simply C2-alkylated under photoorganocatalyzed
conditions.[244]
Tclass="Disease">he photocatalyzed
class="Chemical">n class="Chemical">reduction of hemical">N-(acyloxy)phthalimide 52–1 induced by an IrIII* complex
is an alternative approach for the functionalization of <hemical">span class="Chemical">N-heterocycles such as 2-chloroquinoxaline 52–2 to form the cyclopentenyl derivative 52–3 (Scheme ).[245]
Scheme 52
Cyclopentenylation of 2-Chloroquinoxaline
Tclass="Disease">heclass="Chemical">n class="Chemical">reductive pathway is feasible even when
the generation of thehemical">alkyl radical was carried out star<hemical">span class="Chemical">ting from the redox-active pyridinium
salt 53–1. In this case, the obtained
cycloalkyl radical gave a regioselective addition onto 6-chloroimidazo[1,2-b]pyridazine 53–2 to yield 53–3 under mild conditions (Scheme ).[70]
Scheme 53
Functionalization of 6-Chloroimidazo[1,2-b]pyridazine
Tclass="Disease">he <class="Chemical">n class="Chemical">span class="Chemical">alkyl radical
could be formed even from simple <hemical">span class="Chemical">hydrocarbons
via hydrogen atom transfer reaction. A valuable example is reported
in Scheme . The
hypervalent iodine oxidant PFBI–OH is reduced by an excited
RuII complex generating a carbonyloxy radical that acted
as hydrogen atom abstracting agent. Functionalization of isoquinoline 54–2 by the resulting radical (derived
from 54–1) afforded adduct 54–3 in 65% yield (>15:1 dr).[246] The high selectivity observed in the functionalization
of 54–1 was ascribed to the slow
addition of the tertiary alkyl radical possibly formed onto 54–2.[246] The
direct (rather than indirect) C–H cleavage in cycloalkane was
possible by using decatungstate anion as PC. Various nitrogen-containing
heterocycles were then easily derivatized even under simulated solar
light irradiation.[247]
Scheme 54
PFBI–OH Mediated
Minisci Reaction
PFBclass="Chemical">I–OH was
lclass="Chemical">n class="Chemical">ikewise used for theremote ies">C(sp3)–H heteroarylation
of <hemical">span class="Chemical">alcohols (Scheme ). As an example, the reaction of pentanol
with PFBI–OH gave adduct 55–1 that was reduced by the photocatalyst releasing the alkoxy radical 55–2.
1,5-HAT and addition onto protonated phthalazine 55–3 afforded adduct 55–4 and
the functionalized heterocycle 55–5 from it in 72% yield after sequential oxidation and deprotonation.[248]
Scheme 55
Remote C(sp3)–H Heteroarylation
of Alcohols
As pclass="Chemical">revclass="Chemical">n class="Chemical">iously stressed,
an acid is often required for an efficient
Minisci-like reaction. To overcome this problem thehemical">alkylation may
be carried out on the correhemical">sponding <hemical">span class="Chemical">N-oxide derivatives
as it is the case of pyridineN-oxides (56–2, Scheme ). The radical is generated from a trifluoroborate
salt (56–1) and the alkylation is
regioselective in position 2 (forming compound 56–3).[249] The process is efficient
thanks to the photocatalytic degradation of BI-OAc that promoted a
hydrogen abstraction, operated by the resulting carbonyloxy radical,
on the Minisci radical cation adduct.
Scheme 56
Minisci Alkylation
of Pyridine Oxides
On tclass="Disease">he otclass="Chemical">n class="Disease">her hand,
thehemical">pyridine <hemical">span class="Chemical">N-oxide 57–1 can be acylated in situ with suitable acyl
chlorides to furnish the electron-poor 57–2a–c derivatives.
Photocatalytic reduction of these intermediates leads to the generation
of alkyl radicals prone to attack the pyridine nucleus itself in the
ortho position resulting in a decarboxylative alkylation (57–3a–c, Scheme ).[122]
Scheme 57
Decarboxylative Alkylation of Heterocycles
Ipso-Substitution Reactions
Tclass="Disease">he
foclass="Chemical">n class="Chemical">rging of an hemical">alkyl-hemical">sp2 bond (e.g., an <hemical">span class="Chemical">alkyl-Ar bond) is
undoubtfully one of the most crucial goals pursued by a synthetic
organic chemist. Alkyl radicals generated via different mild routes
can be successfully employed for the arene ipso functionalization,
given the presence of a suitable group X on the (hetero)aromatic ring
that directs the selective formation of a new Ar–C bond at
the expense of an Ar-X bond. Dual catalysis (with the help a Ni-based
complex) is one of the preferred approaches.
class="Chemical">Iclass="Chemical">n a class="Chemical">n class="Chemical">recent example,
thehemical">hydrogen atom transfer ability of the excited <hemical">span class="Chemical">TBADT catalyst (see
also Scheme ) is
used to form an alkyl radical starting from different aliphatic moieties
(see Scheme ).[250] The combined action of the tungstate anion
and the nickel catalyst (Ni(dtbbpy)Br2) allowed the coupling
of (hetero)aromatic bromides with unactivated alkanes, overcoming
their high bond dissociation energies (ca. 90–100 kcal/mol)
and low acidities. Both linear (41–56% yield) and cyclic (57–70%
yield) alkanes could be functionalized with a vast range of competent
partners. Interestingly, the radicals are generated preferentially
on the less sterically demanding secondary carbons in alkanes, affording
a remarkable selectivity.
Scheme 58
Dual TBADT-Ni Catalysis for the Synthesis
of Pyridyl-Functionalized
Bicycles
Tclass="Disease">he sclass="Chemical">n class="Chemical">cope of this method could
be proved by the functionalization
of natural products and drugs, such as in the preparation of the bicyclic
derivative 58–3a (61% yield) and thehemical">N-Boc protected <hemical">span class="Chemical">epibatidine alkaloid 58–3b (28%, Scheme ).[250] A very similar approach was later reported
for the dual photocatalytic formation of an Ar–C bond starting
from aryl bromides and cycloalkanes.[251]
Anotclass="Disease">heclass="Chemical">n class="Chemical">r dual-catalytic approach allowed thecoupling reaction
of
hemical">aryl bromides (59–2, Scheme ) and <hemical">span class="Chemical">alkyl sulfinates (59–1), in the presence of Ni(COD)2 and tetramethylheptanedione (TMHD, Scheme a) to give 59–3 in 84% yield under air.[104] The
photogenerated radical was trapped by the Ni complex that mediated
the coupling with the aryl halide 59–2. The method was then applied to the synthesis of 59–5, selective ATP-competitive inhibitors of the casein kinase 1δ,
an enzyme related to the regulation of the circadian rhythm (Scheme b).[104]
Scheme 59
Dual Catalytic Cross-Coupling of Aryl Bromides
with Alkyl Sulfinates
A veclass="Chemical">ry class="Chemical">n class="Chemical">similar strategy to access ies">C(sp3) <hemical">span class="Chemical">radicals involves
the photoredox induced cleavage of alkyl oxalate 60–1, starting from the corresponding alcohols (see Scheme , see also Scheme ).[252] The rapid in situ formation of the oxalate
(without purification) was followed by the metallaphotoredox sequence
based on Ni catalysis, allowing to obtain the C(sp2)-C(sp3) coupling to give derivatives 60–3a–e in good yields.
Scheme 60
Coupling of Alkyl Oxalates with Aryl Bromides
Tclass="Disease">he advaclass="Chemical">ntage of tclass="Chemical">n class="Disease">he use of hemical">potassium and ammonium
<hemical">span class="Chemical">bis-catecholato
silicates relies in the smooth generation of unstabilized primary
and secondary alkyl radicals to be engaged in dual catalysis.[253,254] An example is the consecutive functionalization of bromo(iodo)arene 61–2 (Scheme , see also Scheme ) for the preparation of 61–4 where the radical (from 61–1) is trapped by Ni0 (stabilized by a phenanthroline
ligand). The synthesis of 61–3 can
be achieved in high yields on 10 mmol scale with reduced effect on
yield (75%) and selectivity (98%). The crude bromide 61–3 was further functionalized by a second Ni/photoredox
cross-coupling of the alkylsilicate 61–5, affording product 61–4 in 66%
yield.[255] The procedure was extended successfully
to alkyl triflates, tosylates and mesylates,[256] and to brominated borazaronaphthalene cores.[257] The latter approach was crucial to access previously unknown
isosteres of azaborines.
Scheme 61
Consecutive Functionalization of Bromo-Iodo
Arenes with bis-Catecholato
Silicates
Tclass="Disease">he actclass="Chemical">n class="Chemical">ion of a hemical">silyl radical
on an <hemical">span class="Chemical">alkyl bromide 62–1 forms an
alkyl radical that, again with the
help of a Ni based catalyst, reacted with aryl bromides 62–2 (Scheme , see also Scheme ). The scope of products 62–3 that can be obtained is varied and includes both aromatic
and heteroaromatic substrates, along with cycloalkanes of different
size.[71]
Scheme 62
Ir/Ni Complex Mediated
Coupling Between Alkyl and Aryl Bromides
A peclass="Chemical">culclass="Chemical">n class="Chemical">iar case is when theipso-substitution took place via a
hemical">radical rearrangement such as shown in Scheme .[258] Thus, the
<hemical">span class="Chemical">heteroaromatic sulfonamide 63–1 was
subjected to the Finkelstein reaction, obtaining the corresponding
iodide 63–2 that acted as the source
of radical able to induce a Smiles rearrangement via 63–5. Intermediate 63–5 has
lost its aromaticity; however, the radical has become tertiary, gaining
further stabilization from the ester group nearby. Restoration of
the aromaticity is followed by a presumable hydrogen atom transfer
to obtain compound 63–6 in 95% yield.[258]
Scheme 63
Photocatalyzed Smiles Rearrangement
Dual photoclass="Chemical">redox/<class="Chemical">n class="Chemical">span class="Chemical">nickel catalysis was successfully
applied to couple
β-trifluoroborato<hemical">span class="Chemical">ketones 64–1 with aryl bromides 64–2a–f (Scheme , see also Scheme ). Arylated compounds 64–3a–f were efficiently prepared with substituents
of different electronic nature on the aryl ring.[259]
Scheme 64
Photoredox/Nickel Dual Catalytic Coupling of β-Trifluoroboratoketones
with Aryl Bromides
<class="Chemical">spaclass="Chemical">n class="Cclass="Chemical">n class="Disease">hemical">Potassium tetrafluoroborate
salts have been applied to generate
secondary <hemical">span class="Chemical">alkyl radicals via Ir photocatalysis coupled with Ni.[260] However, they were found to be likewise suitable
for cross-coupling reactions devoted to the forging of quaternarycarbon centers (Scheme ) without the need of using reactive organometallic species.[261] In the adamantylation of bromides 65–1a–d better yields were obtained when the aryl ring was substituted with
electron-withdrawing groups.
Scheme 65
Adamantylation of Aryl Bromides
Anclass="Chemical">iclass="Chemical">nteclass="Chemical">n class="Chemical">reshemical">ting application of this synthetic
strategy is the functionalization
of <hemical">span class="Chemical">7-azaindole pharmacophores with cycloalkyl scaffolds to improve
the drug likeness of the azaindole core structure. Different potential
drug candidates (66–3a–c, Scheme ) were prepared via dual photocatalysis
in a flow setup varying the dimension and substitution of the ring.[262]
Scheme 66
Functionalization of 7-Azaindole Pharmacophores
in Flow
class="Chemical">Iclass="Chemical">n a class="Chemical">n class="Chemical">similar way, a hemical">DHP-functionalized
<hemical">span class="Chemical">cyclohexene 67–1 was used to generate
a secondary alkyl radical.
In this case, the authors promoted the oxidation of 67–1 by using the strongly oxidizing 4CzIPN photocatalyst.
Coupling with bromopyridine 67–2 gave
substituted pyridine 67–3 in moderate
yields (Scheme ,
see also Scheme ).[118]
Scheme 67
Coupling of DHP-Cyclohexene with Cyanobromopyridine
<class="Chemical">spaclass="Chemical">n class="Cclass="Chemical">n class="Disease">hemical">DHP-derivatives (68–1) may be
used in ipso-substitution reaction even in the absence of a photocatalyst
(Scheme ). Violet
light LED illumination directly excited <hemical">span class="Chemical">didehydropyridine 68–1, fueling electrons to the NiII species
which formed the catalytic competent Ni0 along with the
desired radical by the fragmentation of 68–1. Noteworthy, the alkyl
aromatic 68–3 was then formed where
the use of electron-withdrawing groups on the ring contributes to
the good yields of the process.[263]
Scheme 68
Photocatalyst-Free Activation of DHPs
Formation of a C(sp3)-C(sp) Bond
Cyanation
<class="Chemical">spaclass="Chemical">n class="Cclass="Chemical">n class="Disease">hemical">Alkyl radicals have been
used for the synthesis of <hemical">span class="Chemical">alkyl nitriles by using different cyanide
sources. The cyanation may be carried out in the presence of cyanide
anion as tetrabutyl ammonium salt (TBACN). The C–C bond formation
here may be carried out under very mild conditions by using the inexpensive
precatalyst CuI, starting from unactivated alkyl chlorides (e.g., 69–1a–c, Scheme ). Probably, a CuI-cyanide adduct
is the species that was excited and engaged an electron transfer reaction
with the alkyl halide to form a CuII-cyanide adduct. This
intermediate combines with the alkyl radical formed to release nitriles 69–2a–c. The CuI-halide complex formed
in the reaction restores the initial photocatalyst by exchange with
the cyanide anion.[264]
Scheme 69
CopperI-Mediated Synthesis of Nitriles
<class="Chemical">spaclass="Chemical">n class="Cclass="Chemical">n class="Disease">hemical">TMSCN was instead used for the remote δ-<hemical">span class="Species">C(sp3)-H
cyanation of alcohols under Ir/Cu-photocatalyzed conditions. The reduction
of an N-alkoxypyridinium salt generated an alkoxy
radical that upon intramolecular 1,5-HAT formed an alkyl radical that
is cyanated with the help of the copper catalyst.[265]
A typclass="Chemical">ical cyaclass="Chemical">natclass="Chemical">n class="Chemical">ion procedure, however, makes use
of hemical">tosyl cyanide
as cyana<hemical">span class="Chemical">ting agent. Thus, the radical obtained by oxidation of trifluoroborate 70–1a (by excited Acr+Mes)[266] or acid 70–1b (by riboflavin tetraacetateRFTA)[267] was trapped by tosyl cyanide to
afford nitrile 70–2 by a substitution
reaction (Scheme ).
Scheme 70
Cyanation of (a) Trifluoroborates and (b) Carboxylic Acids
A class="Chemical">related class="Chemical">n class="Chemical">RuII-photocatalyzed cyanation
employing Ts-CN
starhemical">ting from <hemical">span class="Chemical">alkyl trifluoroborates but requiring BI-OAc as a mild
oxidant has been likewise reported.[268]
An elegant way to foclass="Chemical">rge aclass="Chemical">n <class="Chemical">n class="Chemical">span class="Chemical">alkyl-CN bond required the photocatalyzed
elaboration of <hemical">span class="Chemical">cyanohydrines 71–1a–d. At
first, the interaction of the OH group with the sulfate anion (generated
by the decomposition of persulfate anion) allowed its oxidation by
a proton-coupled electron transfer (PCET) process promoted by an in situ formed IrIV species. Alkoxy radicals 71–2a–d were then formed and promoted a regioselective
cyanation of remote C(sp3)–H bonds by a 1,5-HAT
followed by cyano migration to form cyanoketones 71–3a–d (Scheme ).[269]
Scheme 71
Photocatalyzed Cyano Migration in Cyanohydrines
Alkynylation
Dclass="Chemical">irect alkyclass="Chemical">nylatclass="Chemical">n class="Chemical">ion
of photogenerated hemical">alkyl radicals could be accomplished utilizing a
reagent or catalyst that activates the <hemical">span class="Chemical">alkyne moiety, making it more
prone to the forging of a novel C(sp3)–C(sp) bond.
One of the first strategies that were employed made use of benziodoxole-functionalized
alkynes to promote the reaction with the alkyl radical.[270] A representative case is illustrated in Scheme . [Ru(bpy)3](PF6)2 promoted the alkyl radical formation
from trifluoroborate salt 72–1 that
upon addition onto the alkynyl derivatives 72–2a–d induced the alkynylation via the intermediacy of vinyl radicals 72–3a–d. This deboronative alkynylation strategy could
be performed in neutral DCM:water (1:1) at room temperature, giving
access to the alkynylation of primary, secondary, and tertiary derivatives.
To further prove the mildness of the conditions used, the authors
carried out the reaction in PBS at pH 7.4 in the presence of biomolecules
such as amino acids, but also single-stranded DNA and proteins (e.g.,
bovine serum albumin), obtaining satisfactory yields ranging from
68 to 86% of selectively alkynylated product.[270]
Scheme 72
Alkynylation of Alkyl Trifluoroborates
Tclass="Disease">heclass="Chemical">natuclass="Chemical">n class="Chemical">re of the substituents on the <span class="Chemical">alkynylbenziodoxole
reagent
were proved to determine the outcome of the alkynylation process.
The electron-rich compounds performed better in the photocatalyzed
transformation, both as <hemical">span class="Chemical">radical acceptor and oxidative quencher of
the RuII* photocatalyst.[271]
A class="Chemical">simclass="Chemical">n class="Chemical">ilar strategy to the one mentioned before consists in theIrIII-photoredox-catalyzed alkynylation of hemical">carboxylic acids 73–2 (see Scheme a, path a).[272,273] In this case
<hemical">span class="Chemical">benziodoxole derivatives 73–1 were
again used to activate the spcarbon of the alkyne to the radical
attack, affording good yields of products 73–3. Following these results, they developed a reaction to synthesize
ynones 73–4 utilizing the same reaction
conditions in the presence of gaseous CO (see Scheme a, path b and Section ). Gram-scale reactions and late-stage
functionalization of natural terpenoids such as ursolic acid (73–5, Scheme b) were likewise reported.[273]
Scheme 73
IrIII-Catalyzed Alkynylation of Carboxylic
Acids
<class="Chemical">spaclass="Chemical">n class="Cclass="Chemical">n class="Disease">hemical">Alkynyl sulfones were extensively
employed as alkynyla<hemical">span class="Chemical">ting reagents,
with a mechanism like the one described in Scheme . Alkynyl phenyl sulfone was used in combination
with N-acyloxyphthalimide derivatives as radical
precursors in a RuII-photocatalyzed reaction that gave
direct access to TIPS-substituted alkynes.[274]N-Phthalimidoyl oxalates and tolyl alkynyl sulfones
were found to be competent for the reaction (even for the preparation
of internal alkynes having quaternarycarbons),[275,276] the latter even in combination with pyridinium salts as radical
precursors.[277] The consecutive photoredox
decarboxylative coupling of doubly functionalized adipic acid derivatives
with alkynyl phenyl sulfones induced the cascade formation of interesting
cyclic derivatives with an exo double bond (Scheme ). In this case, compound 74–1 underwent two efficient consecutive photoredox
decarboxylative couplings leading first to alkyne 74–3 that it was subjected to radical cyclization to form radical 74–4 and
styrene 74–5 from it.[278] The authors reported the formation of five-membered
rings via the consecutive formation of two C–C bonds, along
with one example showing the application to the synthesis of six-membered
derivatives (31% yield).[278]
Scheme 74
Cascade
Double Alkynylation of Functionalized Adipic Acids
class="Chemical">Iclass="Chemical">n class="Chemical">n class="Chemical">rare instances hemical">alkynyl bromides could be used as hemical">sp
counterpart
in the <hemical">span class="Chemical">radical addition of alkyl derivatives obtained from the oxidative
decomposition of various Hantzsch esters under visible light conditions
promoted by 4CzIPN.[279]
Tclass="Disease">he veclass="Chemical">n class="Chemical">rsatility
of the photocatalytic method, however, allowed
to obtain functionalized hemical">alkynes star<hemical">span class="Chemical">ting from terminal alkynes (Scheme ). The first approach
involves the UV light induced cleavage of the C–I bond in iodide 75–1 (used in large excess) in basic aqueous
media. Addition of the cyclohexyl radical onto alkyne 75–2 followed by the incorporation of the iodine
atom gave vinyl iodide 75–3. The strong basic
conditions used (NaOtBu) coupled with heating (up
to 50 °C) favored an elimination of HI to yield the desired alkyne 75–4 under metal-free conditions (Scheme a).[280] Visible-light (450 nm) was used in the copper-catalyzed
coupling of an alkyl iodide (75–5) and again a terminal alkyne (75–6, Scheme b). The
success of the reaction was ascribed to the use of terpyridine ligand 75–8 that avoided the photoinduced copper-catalyzed
polymerization of the starting substrates. Probably, the reaction
started by the excitation of the first formed copper acetylide that
upon SET with 75–5 promoted the synthesis
of alkyne 75–7 in high yields.[281]
Scheme 75
Alkylation of Terminal Alkynes
Formation of a C(sp3)-Y Bond
C–B Bond
Boclass="Chemical">rylatclass="Chemical">n class="Chemical">ion of an
hemical">alkyl derivative to access differently substituted <hemical">span class="Chemical">boron containing
compounds can be carried out under mild conditions, employing different
photochemical approaches. Thus, the alkyl radical formed from an N-hydroxyphthalimide 76–1 (derived from dehydrocholic acid) may be trapped either by bis(pinacolato)diboron
(B2pin2) to give the corresponding alkylpinacolboronates 76–2 (Scheme , path a) or by tetrahydroxydiboron
(B2(OH)4) followed by treatment with KHF2 to give alkyl tetrafluoroborates (Scheme , path b).[282]
Scheme 76
Photocatalyzed Borylation of N-Hydroxyphthalimides
A vclass="Chemical">arclass="Chemical">n class="Chemical">iation of the previous methodology involves
theirradiation
of hemical">N-hydroxyphthalimide esters 77–2 in the presence of <hemical">span class="Chemical">B2cat2 (77–1) with the help of N,N-dimethylacetamide
(DMAc) as the solvent under uncatalyzed conditions (Scheme ). These components formed
a heteroleptic ternary complex able to be excited by blue light and
ultimately leading to the corresponding benzo[1,3,2]dioxaborole 77–4 that upon treatment with pinacol
and TEA released the desired pinacol boronic ester 77–3. The functionalization of a series of drugs
and natural products, such as pinonic acid and fenbufen were likewise
effective, underlying the broad scope and functional group tolerance
of the method.[283]
Scheme 77
Photocatalyst-Free
Borylation
Two class="Chemical">related appclass="Chemical">n class="Chemical">roaches were
later developed and involve theirradiation
of the ternary complex formed by differently substituted hemical">N-alkyl pyridinium salts, <hemical">span class="Chemical">B2cat2 and DMAc. The
reaction gave again pinacol boronic esters in what is considered a
deaminative protocol for the borylation of aliphatic primary amines
since the latter compounds were used for the synthesis of the pyridinium
salts.[284−286]
class="Chemical">Iclass="Chemical">nteclass="Chemical">n class="Chemical">reshemical">tingly, <hemical">span class="Chemical">2-iodophenyl thionocarbonates
were later adopted
as radical precursor for the preparation of boronic ester via photocatalyzed
reaction with B2cat2 (Scheme ).[95] The strategy
is based on the photoinduced reduction of compound 78–1 that upon iodide anion elimination formed
aryl radical 78–2 that underwent a 5-endo-trig cyclization
causing the release of benzo[d][1,3]oxathiol-2-one 78–3 and alkyl radical 78–4. Usual borylation
gave boronic ester 78–5 in 85% yield.
Scheme 78
Borylation of 2-Iodophenyl Thionocarbonates
C–N Bond
Dclass="Chemical">iveclass="Chemical">n class="Chemical">rse structural
motifs based on the C–N bond such as hemical">hydrazine and <hemical">span class="Chemical">hydrazide
cores were accessed by the photochemical addition of alkyl radicals
onto the N=N of azodicarboxylates. TBADT-photocatalyzed HAT
was applied to synthesize hydrazines by the coupling of cycloalkylradicals with diisopropyl azodicarboxylate (DIAD). A synthetically
challenging three component reaction can be achieved in the presence
of CO, allowing the synthesis of the corresponding hydrazides.[287]
Tclass="Disease">he C–H amclass="Chemical">n class="Chemical">ination can be smoothly
achieved even starhemical">ting from light <hemical">span class="Chemical">hydrocarbons, such as methane (79–1, Scheme ), with ditert-butylazodicarboxylate
(DBAD, 79–2) in the presence of CeIII salts. This inexpensive photocatalyst furnished the desired
product 79–3 in 63% yield, with a
turnover number up to 2900. The authors proposed a ligand-to-metal
charge transfer excitation between the cerium salt and trichloroethanol
as the source of alkoxy radicals that acted as hydrogen atom transfer
agents.[288]
Scheme 79
Photocatalyzed Amination
of Methane
<class="Chemical">spaclass="Chemical">n class="Cclass="Chemical">n class="Disease">hemical">Aminated alkanes can be obtained
by reac<hemical">span class="Chemical">ting aliphatic carboxylates
with DIAD making use of Acr+Mes as a photoredox catalyst.[289] A cerium catalyst was adopted for the generation
of several alkyl radicals starting from carboxylic acids, under basic
conditions, allowing for the functionalization of a broad range of
substrates, including natural products such as drugs like gemfibroxil
(80–2) and tolmetin (80–1, Scheme ).[290]
Scheme 80
Cerium-Catalyzed
Decarboxylative Amination
Tclass="Disease">heclass="Chemical">n class="Chemical">N=N bond of differently substituted hemical">azobenzenes (81–1a–e) can be functionalized on both <hemical">span class="Chemical">nitrogens
with a tandem N-methylation and N-sulfonylation, by cleavage of DMSO by UV irradiation of the Fenton
reagent (FeSO4/H2O2,Scheme ).[105]
Scheme 81
Tandem N-Methylation and N-Sulfonylation
of Azobenzenes
Syntclass="Disease">heclass="Chemical">n class="Chemical">sis of hemical">amides
can be achieved recurring to <hemical">span class="Chemical">copper photocatalysis.
Secondary alkyl bromide 82–1 could
be efficiently coupled with cyclohexane carboxyamide 82–2 in 90% yield using CuI in catalytic amounts
(Scheme a). The
authors were able to isolate the catalytic species (a copper–amidate
complex), formed by the assembly of four copper ions and four amides.[291]
Scheme 82
Photocatalyzed Synthesis of (a) Amides
and (b) Carbamates
Tclass="Disease">he same gclass="Chemical">n class="Chemical">roup reported
the functionalization of hemical">carbamates with
secondary <hemical">span class="Chemical">alkyl bromides by shifting the wavelength of irradiation
in the visible region by developing a tridentate carbazolide/bisphosphine
ligand 82–4 for the copper catalyst
thus able to prepare Boc-pregnenolone 82–5 in 90% yield (Scheme b).[292] A variation of this
protocol was applied to the synthesis of amines, using secondary unactivated
alkyl iodides and CuI/BINOL as the catalytic system.[293]
Seveclass="Chemical">ral class="Chemical">n class="Chemical">reagents can be used as an hemical">azide source to
synthesize synthetically
valuable C–N3 bonds. Tertiary aliphatic C–H
bonds can be selectively functionalized via Zhdankin <hemical">span class="Chemical">azidoiodane reagent 83–2. Visible light was used to excite
Ru(bpy)3Cl2 that cleaves the labile I–N3 bond, triggering the cascade of radical reactions that leads
to the product formation (Scheme ). The selectivity and compatibility of this reaction
with different groups is underlined by the conversion of the dipeptide 83–1 to 83–3 in 30% yield.[294] A related C–H
azidation was performed by using tosyl azide as an alternative azide
source with the help of 4-benzoylpyridine to promote the photocatalytic
C–H cleavage in various cycloalkanes.[295]
Scheme 83
Azidation of Tertiary Aliphatic C–H Bonds
Anotclass="Disease">heclass="Chemical">n class="Chemical">r example of the functionalization of
unactivated C–H
bonds is depicted in Scheme making use of hemical">tosyl azide 84–2. The reaction needs the intermediacy of an <hemical">span class="Chemical">oxygen radical center
on a phosphate group, previously oxidized by the action of the mesityl
acridinium photocatalyst 84–3. This allows the
C–H to C–N3 conversion in menthol benzoate 84–1 to give azide 84–4 in a satisfying yield, with a regioselectivity favoring
the more electron-rich tertiary position.[296]
Scheme 84
Photocatalyzed C–H to C–N3 Conversion
Tclass="Disease">he syclass="Chemical">ntclass="Chemical">n class="Disease">hesis of hemical">amines is undoubtedly more
challenging to be dealt
with, relying on <hemical">span class="Chemical">radical chemistry. However, several strategies were
developed to effectively forge this fundamental functional group.
A classic reaction for the synthesis of amine is the Curtius reaction
that has the drawback in handling of potentially dangerous azides.
A dual copper/photoredox catalytic approach mimicked this process
for the obtainment of N-protected amines from the N-hydroxyphthalimide ester of cholic acid triacetate 85–1 (Scheme , see also Scheme ). The alkyl radical was again formed by
CuI-photocatalyzed reduction of 85–1, but this recombine with the CuII–phthalimide
complex formed to release 85–2 (52%
yield) by a formal decarboxylation process. A great variety of functional
groups are compatible with this reaction including steroidal structures.[297]
Scheme 85
Decarboxylative C–N Coupling in
Cholic Acid Triacetate
A veclass="Chemical">ry class="Chemical">n class="Chemical">intereshemical">ting approach to synthesize β-amino<hemical">span class="Chemical">alcohols
from the unfunctionalized alcohol 86–1 relies on the introduction of a radical relay chaperone to direct
the C–H functionalization of the β position of the OH
group (Scheme ).
Imidate radicals can be accessed via the photodecomposition of PhI(OAc)2. A transient sp2N-centered radical
is generated from 86–2, which allows
a 1,5-hydrogen atom transfer. A source of iodine promotes the formal
transfer of an iodineradical to the β-position to the imidate,
followed by cyclization to obtain 86–3 which can be promptly hydrolyzed to 86–4. The nature of the substituents on acetimidate 86–2 may affect the overall yield.[298]
Scheme 86
Radical Relay Chaperone Strategy Driven
by the Photodecomposition
of PhI(OAc)2
Dclass="Chemical">irect cclass="Chemical">n class="Chemical">ross-coupling between hemical">alkyl carboxylic acids and <hemical">span class="Chemical">nitrogen
nucleophiles can be achieved by dual copper/photoredox catalysis through
iodonium activation. The scope of the transformation is broad and
applicable to a diverse array of nitrogen nucleophiles such as heterocycles,
amides, sulfonamides, and anilines to give the corresponding C–N
coupling product in excellent yields on short time scales (5 min to
1 h). The high regioselectivity obtained in late stage functionalization
of complex pharmaceuticals such as Skelaxin 87–2 (to give 87–3 in 90% yield
from 87–1, Scheme , see also Scheme ) gave an idea of the importance of the
approach.[299]
Scheme 87
Late Stage Functionalization
of Skelaxin
class="Chemical">Simclass="Chemical">n class="Chemical">ilar strategies
were explored for the synthesis of hemical">amines via
<hemical">span class="Species">C(sp3)–N cross-coupling combining a copper catalyst
and the action of a photoredox catalyst by using anilines[300] or benzophenone imines[301] as nitrogen source. Hydroxylamines were instead formed
under photoorganocatalytic conditions by reaction of carboxylic acids
and nitrosoarenes.[302]
C–O Bond
Tclass="Disease">he C–O boclass="Chemical">nd
foclass="Chemical">n class="Chemical">rmation is without doubt a prerogative of polar chemistry. However,
there are examples of photochemically driven reactions making use
of an hemical">alkyl radical for the introduction of different <hemical">span class="Chemical">oxygen-containing
functional groups. In Scheme , the nonenolizable ester 88–1 is transformed into 88–2 via a
photochemically promoted decarboxylation of the NPhth-ester (see also Scheme ) in the presence
of Hantzsch ester to yield a tertiary radical. The intermediate is
promptly quenched by TEMPO, affording 88–2 in 91% yield, in a multigram scale reaction.[303]
Scheme 88
Decarboxylative Oxygenation of Phthalimide
Esters
A class="Chemical">simclass="Chemical">n class="Chemical">ilarreaction was employed
to synthesize hemical">alkyl aryl ethers,
given their importance in medicinal and agricultural chemistry. A
tandem photoredox and <hemical">span class="Chemical">copper catalysis approach allows the decarboxylative
coupling of alkyl N-hydroxyphthalimide esters (NHPI)
with phenols (89–2Scheme ). Various NHPI esters of
different drugs and natural products easily underwent a late-stage
decarboxylative etherification. As an example, the chlorambucil derivative 89–1 was converted into the corresponding
2-MeO phenyl ether 89–3 in 49% yield.[304]
Scheme 89
Decarboxylative C(sp3)-O Cross-Coupling
Followclass="Chemical">iclass="Chemical">ng a class="Chemical">n class="Chemical">similar strategy, hemical">carboxylates are
converted into <hemical">span class="Chemical">alcohols
via a photocatalytic decarboxylative hydroxylation mediated by the
mesityl acridinium salt. In this case, molecular oxygen is used as
the oxidant, to promote the formation of the desired C–O bond.
Since the reactions gave mainly a mixture of ketones and hydroperoxides,
reduction in situ by sodium borohydride allowed the
synthesis of alcohols in good yields.[305] A decarboxylative hydroxylation may be carried out with the intermediacy
of Barton esters that upon irradiation in oxygen-saturated toluene
followed by treatment with P(OEt)3 afforded an alcohol
intermediate for the total synthesis of Crotophorbolone.[306] The more challenging oxidation of unactivated
alkanes to alcohols or ketones can be achieved through a photoelectrochemical
approach, as testified by the C–H bond activation of cyclohexane
to prepare a mixture of cyclohexanone and cyclohexanol (the so-called
KA oil) with high partial oxidation selectivity (99%) and high current
utilization ratio (76%). The highest current ratio was obtained illuminating
the solution with 365 nm wavelength.[307] Decatungstate photocatalysis was efficiently applied to oxidize
activated and unactivated C–H bonds. Taking advantage of a
microflow reactor setup, a late stage regioselective CH2/C=O conversion in several natural compounds, such as artemisinin 90–1 to form artemisitone-9 90–2 was readily pursued even in a 5 mmol scale
(Scheme ).[308]
Scheme 90
Late Stage Regioselective Carbonylation
of Artemisinin
C-Halogen
Bond
<class="Chemical">spaclass="Chemical">n class="Cclass="Chemical">n class="Disease">hemical">Halogenation of <hemical">span class="Chemical">alkanes
through a radical reaction under UV irradiation is one of the core
pathways to chemically activate a paraffin. Industrially, chlorine
gas is used to functionalize methane. A major drawback of the classical
chain reaction using either Cl2 or Br2 under
direct irradiation is the formation of di or polyhalogenated products.
The application of microflow technology in combination with visible
light irradiation (with an absorption maximum in the near UV at ca.
350 nm) allowed the monobromination of different alkanes with molecular
bromine. High selectivity for the monobrominated compound and excellent
overall yields (between 60 and 99%) could be achieved for secondary
and tertiary alkanes, along with primary benzylic positions.[309]
Chloclass="Chemical">rclass="Chemical">n class="Chemical">ination with molecularhemical">chlorine,
on the other hand, suffers from the low yields of the reaction, typically
around 50%, from the high concentrations of <hemical">span class="Chemical">HCl generated in the process
and from the toxicity of the chlorine gas itself. However, when Cl2 was generated by mixing NaClO with HCl and the chlorination
took place under flow conditions, efficient C–H to C–Cl
conversion resulted.[310,311] A photochemical alternative
using NaCl as chlorine source was developed.[312] In the reaction, Cl2 was formed in situ by oxidation of the chloride anion with oxone. The monochlorination
of cyclohexane 91–1 to give 91–2 could be obtained in 93% isolated
yield thus overcoming the limitation of the classical chlorination
process with chlorine gas (Scheme , see also Scheme ).
Scheme 91
Photoinduced Monochlorination of Cyclohexane
Fluoclass="Chemical">rclass="Chemical">n class="Chemical">ination is essential to modern medicinal
chemistry, both as
a viable way to insert radiotracers or to deactivate specific degradation
pathways in drugs. Photochemistry is a reliable tool to achieve the
fluorination of C–H bonds, following different strategies.
Excited hemical">TBADT may formed a <hemical">span class="Chemical">radical intermediate (from unactivated
alkanes) that abstracts the fluorine atom from the labile N–F
bond of the fluorinating agent N-fluorobenzenesulfonimide
(NFSI). An N-centered radical resulted which closes
the radical cycle oxidizing the reduced photocatalyst. Acetate 92–1 was fluorinated in 40% yield following
this procedure to yield 92–2 (Scheme ). The reaction
applied to sclareolide, however, was not selective and gave a mixture
of fluorinated regioisomers (68% overall yield).[313]
Scheme 92
TBADT-Catalyzed Fluorination of Alkanes
Followclass="Chemical">iclass="Chemical">ng a class="Chemical">n class="Chemical">similarreaction scheme, hemical">uranyl
<hemical">span class="Chemical">acetate was employed
in combination with NFSI to promote the fluorination of secondary
alkanes but poorly on the benzylic positions. Indeed, in the absence
of an aromatic scaffold, the excited U=O abstract a hydrogen
atom through HAT, while the presence of an aromatic ring deactivated
the excited state of the catalyst via exciplex formation preventing
the fluorination to occur.[314] Acetophenone
in its excited state promoted the hydrogen abstraction of secondary
alkanes, with the advantage that a common CFL housebulb can be used
to promote an efficient conversion, using Selectfluor as the fluoride
source.[315] In this case, the authors irradiated
the tail of the n-π* absorption band of the ketone which can
be found in the visible region due to the high concentration of the
photocatalyst present in solution. N-Alkyl phthalimides
having an alkyl chain linked to the nitrogen was fluorinated by using
Selectfluor under photocatalyst-free conditions. An exciplex was supposed
to be formed between the reagents and it was proposed that the C–F
bond formation took place concomitantly with hydrogen atom abstraction
with the nitrogenradical of the fluorinating agent.[316]
A class="Chemical">coclass="Chemical">nclass="Chemical">n class="Chemical">siderable regioselectivity in the fluorination
reaction can
be achieved using hemical">carboxylates as <hemical">span class="Chemical">alkyl radical precursors and again
Selectfluor as a fluorinating reagent. The reaction is possibly initiated
by reduction of Selectfluor 93–2 by
means of Ir[dF(CF3)ppy]2(dtbbpy)PF6. Fluorination of different carboxylic acids can be achieved in a
very high yields (between 70 and 99%), and 93–1 was readily converted into 93–3 in 90% yield (Scheme ).[317] In case of unactivated
primary substrates, a prolonged irradiation (12–15 h) was mandatory
to achieve a high conversion of the substrate.
Scheme 93
Regioselective Fluorination
of Carboxylates
Anclass="Chemical">iclass="Chemical">nteclass="Chemical">n class="Chemical">reshemical">ting case
is the fluorination of compounds having the
MOM group to direct the <hemical">span class="Chemical">halogenation event. In this case, the PC oxidized
an imidine base (DBN) that acted as hydrogen atom abstractor of the
dioxolanyl group in compound 94–1 (Scheme ). The
resulting α,α-dioxy radical 94–2 released an alkyl radical (upon formiate loss) that was
fluorinated by Selectfluor. This metal-free approach again used visible
light and is particularly successful when applied to tertiary alkylethers to give sterically hindered alkyl fluorides (e.g., 94–3).[318]
Scheme 94
DBN-Mediated
HAT in C–F Bond Formation
class="Chemical">Iclass="Chemical">nteclass="Chemical">n class="Chemical">reshemical">tingly, fluorination of <hemical">span class="Chemical">carboxylates with Selectfluor was
also reported to occur under heterogeneous photocatalytic conditions,
using titania as photocatalyst to promote the oxidation of the carboxylate
anion.[319] Fluorination and chlorination
of nitriles and ketones could be obtained starting from oximes, using
Selectfluor and NCS as halogen sources, respectively. With this methodology,
γ-functionalization of ketones and a complex photoinduced ring-opening/halogenation
of oximes via the intermediacy of an iminyl radical was pursued. The
C=N moiety of the reagent (e.g., 95–1) was preserved in the products (95–2a,b) in its oxidized nitrile form (Scheme ). Several natural products could be functionalized
following this methodology, such as androsterone (95–3a,b) and camphor (95–4a,b) derivatives (Scheme , see also Scheme ).[320]
Scheme 95
Ring-Opening Halogenation of Oximes
<class="Chemical">spaclass="Chemical">n class="Cclass="Chemical">n class="Disease">hemical">Alcohols were converted into their corren class="Disease">hemical">sponding
<hemical">span class="Chemical">pyruvates that
upon irradiation in the presence of an IrIII photocatalyst
with blue LEDs released an alkyl radical prone to be chlorinated by
2,2,2-trichloroacetate as the chlorine atom source. A series of secondary
and tertiary chlorides could be obtained in good to excellent yields.[321]
Anclass="Chemical">Ir-based photocatalyst was used to
pclass="Chemical">n class="Chemical">romote bromination of hemical">carboxylic
acid (96–1) with <hemical">span class="Chemical">bromomalonate as
brominating agent (Scheme ).[322] The acids used in this work
were likewise converted into the corresponding alkyl chlorides and
iodides in the presence of the corresponding N-halosuccinimides.[322]
Scheme 96
Bromomalonate as Brominating Agent
A <class="Chemical">spaclass="Chemical">n class="Cclass="Chemical">n class="Disease">hemical">radical relay strategy was employed to synthesize
<hemical">span class="Chemical">gem-diiodides
through successive intramolecular 1,5-HAT processes and iodine trapping.
Indeed, the excitation with visible light of an N–I imidate
group, formed in situ from the reaction of a trichloroacetimidate
with PhI(OAc)2 as an iodine source, allowed the synthesis
of a small library of gem di-I compounds in good yields. As an example,
the cholic acid derivative 97–1 has
been converted to its corresponding di-iodo derivative 97–2 in 71% yield (Scheme ). Moreover, the authors could also achieve
a dibromination using NaBr and TBABr and visible light, while only
monochlorination is reported when NaCl, TBACl, and UV light were adopted.[323]
Scheme 97
Gem di-Iodination of a Cholic Acid Derivative
C–S or C–Se
Bonds
<class="Chemical">spaclass="Chemical">n class="Cclass="Chemical">n class="Disease">hemical">Alkyl
<hemical">span class="Chemical">radicals were sparsely used for the unusual introduction of a SCF2X (X = F, H) or an SAr moiety in an organic compound. The
introduction of a SCF2X group has recently sparked attention
due to the remarkable hydrogen donor nature of the group when X =
H, making it the lipophilic surrogate for OH or NH groups.[324] On the other hand, the trifluoromethylthio
group increases the metabolic stability and the lipophilicity of drugs.
One stclass="Chemical">rategy foclass="Chemical">n class="Chemical">r theintroduction of a hemical">SCF2X group is
the photocatalyzed (by IrIII PC) oxidation of <hemical">span class="Chemical">alkyl carboxylates
via visible light irradiation in the presence of PhthN-SCF2H (98–2) as the sulfur donor. Indeed, 98–1 was converted into 98–3 in high yields (Scheme ). The reaction was sustained by the stability
of the imidyl radical liberated in the process, that was able to promote
a chain reaction oxidizing a further carboxylate group. Indeed, the
quantum yield for the reaction was found to be 1.7.[325] Bis-methyltiolation was observed in different cases, possibly
due to HAT triggered by an intermediate of the reaction, presumably
PhthN• and following transfer of SCF2X from the reactant. To avoid the formation of byproducts either
mesitylene or 3-(methyl) toluate were added as sacrificial hydrogen
donors.
Scheme 98
Difluorothiomethylation of Carboxylic Acids
Anclass="Chemical">iclass="Chemical">nteclass="Chemical">n class="Chemical">reshemical">ting follow-up for this methodology
from the same group
made use of the <hemical">span class="Chemical">hydrogen atom transfer process previously reported
as detrimental for the reaction yield. In fact, when using an aryl
carboxylate instead of an aliphatic one, the carboxyl radical that
is formed upon electron transfer with the excited Ir catalyst is now
stable enough to act as a hydrogen abstractor, selectively targeting
secondary or tertiary H in alkyl chains. Also, in this case, PhthN-SCF2X acted as the sulfur source. The conversion of ambroxide 99–1 to its trifluorothiomethyl derivative 99–2 proceeded with 95% yield (Scheme ).[326]
Scheme 99
Trifluoromethylthiolation of Ambroxide
A photocatalyst-fclass="Chemical">ree decclass="Chemical">n class="Chemical">arboxylative arylthiation
took place by
mixing an hemical">N-acyloxyphthalimide (e.g., 100–2) in the presence of an <hemical">span class="Chemical">aryl thiol (100–1) under basic conditions (by Cs2CO3) upon visible light irradiation. In this case, a SET
between 100–1 and 100–2 caused the formation of 100–2 along with thiyl
radical 100–3 (that easily dimerized to disulfide 100–4). Trapping of the resulting cyclohexyl radical (by loss
of PhthN from 100–2) with 100–4 afforded alkylaryl sulfide 100–5 in 89% yield (Scheme ).[327]
Scheme 100
Arylthiation
of N-Acyloxyphthalimides
Tclass="Disease">he most wclass="Chemical">n class="Chemical">idely used reaction for the C–S bond
synthesis
requires theincorporation of hemical">sulfur dioxide by using <hemical">span class="Chemical">DABSO (DABCO(SO2)2) as its surrogate as depicted in Scheme .[328] Thus, excited mesityl acridinium salts promoted
the oxidation of an alkyl-BF3K salt that generated a nucleophilic
radical able to react with DABSO. The sulfonyl radical intermediate
formed has been employed in a three-component reaction with electron
poor olefins (e.g., a vinyl piridine 101–1, Scheme a)[329] or an alkyne (phenyl acetylene, Scheme b),[330] affording alkyl sulfone (101–2) or (E)-vinyl sulfone (101–3), respectively.
Scheme 101
Sulfonylation of
(a) Styrenes and (b) Alkynes
Alteclass="Chemical">rclass="Chemical">natclass="Chemical">n class="Chemical">ively, hemical">alkyl iodides can be used to react with
<hemical">span class="Chemical">olefins
decorated with EWGs and DABSO to generate a broad range of alkyl sulfones.[331] A very similar strategy was implemented by
the same authors using differently substituted Hantzsch esters as
alkyl radical precursors, upon irradiation in the presence of Eosin
Y.[332] In the latter case, the sulfonyl
radical added onto vinyl azides and, after releasing of molecular
nitrogen, an imidyl radical resulted which reacted with the reduced
photocatalyst, forming an anion that is easily protonated. After a
tautomeric equilibrium, (Z)-2-(alkylsulfonyl)-1-arylethen-1-amines
were formed, with good regioselectivity and complete control over
the configuration of the double bond.[332]
<class="Chemical">spaclass="Chemical">n class="Cclass="Chemical">n class="Disease">hemical">Cyclobutanone oximes can be reduced via photocatalytic means
in
the presence of Ir<hemical">span class="Chemical">(dtbbpy)(ppy)2PF6 to form
γ-cyanoalkyl radicals after radical fragmentation. In this process,
a vinyl sulfone was used having the dual role of radical acceptors
and SO2 source, allowing the synthesis of β-ketosulfones
or allylsulfones through a radical transfer mechanism.[333]
C–H Bond
Clasclass="Chemical">sical <class="Chemical">n class="Chemical">span class="Chemical">radical
reductive de<hemical">span class="Chemical">halogenation is one of the most successful reactions based
on tin chemistry.[21] Photocatalysis and
photochemistry propose a milder and more environmentally friendly
alternative to this process, via different strategies. As an example, fac-Ir(ppy)3 was used to convert alkyl iodides 102–1 into their corresponding alkyl radicals
using Hantzsch ester or HCO2H as the hydrogen atom source
for the HAT process that drives the reaction to the formation of 102–2 (Scheme ). The authors optimized their procedure
by using tributylamine as the sacrificial electron donor to reduce
the oxidized form of the catalyst and restore the catalytic cycle.[334] A variation of this protocol using p-toluenethiol, DIPEA, and fac-Ir(mppy)3 was used to synthesize D-albucidin.[335]
Scheme 102
Photocatalyzed Reduction of Alkyl Iodides
Otclass="Disease">heclass="Chemical">n class="Chemical">r catalytic systems were proved to be competent
in thereduction
of hemical">halides. In particular, unactivated <hemical">span class="Chemical">aryl and alkyl bromides could
be reduced using [Ir(ppy)2(dtbbpy)]PF6 in combination
with TTMSS as a reducing agent. The mild conditions typical of the
reaction were critical to obtain both the mono and the bis reduction
of a gem-dibromocyclopropane in a selective fashion.[336]
<class="Chemical">spaclass="Chemical">n class="Cclass="Chemical">n class="Disease">hemical">Alkyl iodides and <hemical">span class="Chemical">bromides were reduced under metal-free
conditions
via irradiation of 4-carbazolyl-3-(trifluoromethyl)-benzoic acid as
the photocatalyst and 1,4 cyclohexadiene as sacrificial hydrogen donor.[337] The reduction of C–X bonds to C–H
bonds can take place under photocatalyst-free conditions by PET reactions
between the halide and an amine as sacrificial reductant. In this
way, adamantane was obtained in 95% yield by photochemical reduction
of 1-bromoadamantane.[338] Borohydride-mediated
radical photoreduction of alkyl halides (iodides, bromides, and chlorides)
is another valuable tool for the formation of a C–H bond.[339]
Tclass="Disease">he C–H boclass="Chemical">nd foclass="Chemical">n class="Chemical">rmation could be
achieved via a hydrodecarboxylation
of hemical">carboxylic acids. In fact, <hemical">span class="Chemical">carboxylic acid 103–1 could be reduced in 97% yield to 103–2 by generating the corresponding carboxyl radical through
excitation of an acridinium photocatalyst with 450 nm LEDs, in the
presence of 10% mol of (PhS)2 (Scheme ). The authors achieved good yields in
the decarboxylation of different carboxylic acids. Most notably they
succeeded in the double reduction of doubly substituted malonic acids,
although with the necessity of longer irradiation times and higher
catalyst loading to compensate for the increased amount of substrate
to be reduced.[340]
Scheme 103
Hydrodecarboxylation
of Carboxylic Acids
Tclass="Disease">he challeclass="Chemical">ngclass="Chemical">n class="Chemical">ing
reduction of hemical">alcohols to the correhemical">sponding <hemical">span class="Chemical">alkane
can take place via functionalization of the OH group to form an O-thiocarbamate. This compound is the substrate of a photocatalyzed
Barton-McCombie deoxygenation in combination with Ir(ppy)3 and DIPEA under an oxidative quenching. Accordingly, the xylofuranose
derivative 104–1 was cleanly reduced
to 104–2 in 70% yield by maintaining
the benzoyl group in position 5 (Scheme ).[93] The reaction
was studied mostly on secondary alcohol derivatives being another
interesting alternative to the usual tin-mediated reaction.[22]
Scheme 104
Reduction of a Xylofuranose Derivative
An alteclass="Chemical">rclass="Chemical">natclass="Chemical">n class="Chemical">ive pathway to reduce the hydroxy
function required
a more sophisticated functionalization of thehemical">OH group making use
of two consecutive photochemical reactions. Conduc<hemical">span class="Chemical">ting the reaction
in CBr4 under UVA irradiation, the hydroxy groups of a
series of primary alcohols were converted into their bromides and
then subjected to a one-pot photoreduction mediated by the dimeric
gold complex[Au2(dppm)2]Cl2 in the
presence of DIPEA.[341]
Formation of a Ring
Three/Four-Membered Rings
class="Chemical">Iclass="Chemical">n thclass="Chemical">n class="Chemical">is
last section, selected examples will be given when a photogenerated
hemical">alkyl radical is used for the construction of a ring. Scheme shows one example of formation
of a three-membered ring. <hemical">span class="Chemical">1,1-Disubstituted cyclopropanes 105–3a–d were obtained through the addition of an alkyl radical (from silicate 105–1) onto homoallylic tosylates 105–2a–d. The trick here is a radical/polar
crossover process where the reduction of the benzyl radical adducts
to benzyl anions (by SET with the reduced form of the photoorganocatalyst
4-CzIPN) followed by intramolecular substitution gave the three-membered
ring (Scheme ).[342] The versatility of the method was demonstrated
by using alkyl trifluoroborates or 4-alkyldihydropyridines as radical
precursors and a good tolerance of various functional groups.
Scheme 105
Synthesis of 1,1-Disubstituted Cyclopropanes
A class="Chemical">related appclass="Chemical">n class="Chemical">roach was adopted for theconstruction of
hemical">cyclobutanes.[102] Here, the <hemical">span class="Chemical">alkyl radical
was formed by easily
oxidizable electron-rich alkyl arylboronate complexes and added to
an iodide-tethered alkene such as methyl 5-iodo-2-methylenepentanoate.
However, changing the length of the chain in the haloalkyl alkenes
led to the synthesis of three-, five-, six-, and seven-membered rings.[102]
Five-Membered Rings
Fclass="Chemical">ive-membeclass="Chemical">n class="Chemical">red
ring is one of the privileged structures accessible via photogenerated
hemical">alkyl radicals. A common approach is the cyclization onto an <hemical">span class="Chemical">alkyne
to form an exocyclic double bond as exemplified in Scheme . In most cases, an alkylhalide is reduced by an excited photocatalyst and the resulting radical
cyclizes in a 5-exo dig fashion to form the desired
alkene. When using a dimeric gold complex 106–5 the reaction of alkyl bromide 106–1 generates diester 106–2 in 93% yield (Scheme a).[343] Cyclopentanes were likewise
formed starting from an unactivated alkyl iodide that underwent an
intramolecular radical closure by using a strong reductant in the
excited state (Ir(ppy)2(dtb-bpy)PF6). The iodine
atom, however, was incorporated in the final product forming an alkenyliodide.[344] The same metal-based photocatalyst
was effective to induce a visible light-promoted preparation of five-membered
heterocycles (Scheme b). The cyclization step was applied on a Ueno–Stork
reaction starting from 2-iodoethyl propargyl ethers (e.g., 106–3a,b) to construct a tetrahydrofuran ring (in 106–4a,b).[345] The examples described in Scheme required an
amine as a sacrificial donor. However, amines can be used as efficient
reducing agents by a PET reaction with excited alkynyl halides. The
resulting photocyclization may then be carried out under metal-free
conditions and in a flow photomicroreactor providing the preparation
of five-membered rings in a 4 g scale.[346]
Scheme 106
Metal-Photocatalyzed Synthesis of Cyclopentanes from Alkyl
Halides
Tclass="Disease">he de<class="Chemical">n class="Chemical">span class="Chemical">halogenation/cyclization
strategy was explored even under
heterogeneous conditions by using <hemical">span class="Chemical">platinum nanoparticles on titania
(PtNP@TiO2) as the photoredox catalyst. The pyrrolidine
scaffold was then obtained by reaction of N-(2-iodoethyl)-4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide under irradiation
(DIPEA as sacrificial donor).[347]
As an alteclass="Chemical">rclass="Chemical">natclass="Chemical">n class="Chemical">ive, a biphasic system may be adopted (Scheme ). In fact, a
hemical">polyisobutylene-tagged fac-Ir(ppy)3 complex
(Ir(ppy)2(PIB-ppy)) soluble in <hemical">span class="Chemical">heptane was prepared. The
substrate 107–1 along with the reagents
were soluble in a MeCN phase. However, heating at 85 °C allowed
the two phases to mix. Preparation of tetrahydrofuran derivative 107–2 was then accomplished in continuous
flow in a satisfying yield with an automatic recovery and reuse of
the catalyst (Scheme ).[348]
Scheme 107
Photocatalyzed
Synthesis of Tetrahydrofurans in Flow
<class="Chemical">spaclass="Chemical">n class="Cclass="Chemical">n class="Disease">hemical">Alkyl N-hydroxyphthalimide esters were
used as
<hemical">span class="Chemical">alkylation reagents in the functionalization of alkenoic acid 108–2 (Scheme ). The alkyl radical added onto the double
bond, and the resulting benzyl radical was oxidized to a benzyl cation
readily trapped by water and cyclization of the resulting hydroxy
acid gave alkyl-substituted lactones 108–3a–e in moderate yields.[349]
Scheme 108
Photocatalyzed
Lactonization of Alkenoic Acids
<class="Chemical">spaclass="Chemical">n class="Cclass="Chemical">n class="Disease">hemical">Alkyl N-hydroxyphthalimide esters were
exploited
for the photocatalyzed (by a RuII complex) <hemical">span class="Chemical">alkylation of N-arylacrylamides that caused the cyclization of the adduct
radical onto the phenyl ring to afford 3,3-dialkyl substituted oxindoles.[350] Moreover, the same radical precursors have
been used for the derivatization of alkynylphosphine oxides under
metal- and oxidant-free conditions to form benzo[b]phospholes in very good yields.[351]
A fclass="Chemical">ive-membeclass="Chemical">n class="Chemical">red ring may be accessed via late-stage ies">C(sp3)-H functionalization in <hemical">span class="Chemical">N-chlorosulfonamides 109–1 (Scheme a). The IrIII-photocatalyzed
reduction of 109–1 induced the elimination
of the chloride anion along the formation of a N-centered
radical prone to abstract a hydrogen atom from a remote position to
afford an alkyl radical. Oxidation of this radical to the cation followed
by incorporation of the chloride anion gave the corresponding chloride 109–2 that upon treatment with solid NaOH
formed pyrrolidine 109–3 by an intramolecular
nucleophilic substitution.[352] The mildness
of the process allowed the application onto biologically important
(−)-cis-myrtanylamine and (+)-dehydroabietylamine derivatives.
Scheme 109
Photochemically Induced Synthesis of Pyrrolidines
A class="Chemical">related class="Chemical">n class="Chemical">intramolecularhemical">1,5-HAT transfer was
induced in <hemical">span class="Chemical">N-tosyl amides 109–4a–e. In this
case, the haloamide is formed in situ by iodination
by reaction of 109–4a-e with iodine (obtained
by oxidation of iodide anion by PhI(OAc)2). The excess
of iodine allowed for tuning the amount of iodine released in solution
by forming the triiodide anion. Then, visible light irradiation of
the mixture induced the cyclization to give N-tosylpyrrolidines 109–5a–e (Scheme b).[353]
Evenpclass="Chemical">rclass="Chemical">n class="Chemical">imary nonactivated sp3-hybridized positions were
functionalized again by a remote intramolecularhemical">radical <hemical">span class="Chemical">1,5-hydrogen
abstraction in γ-bromoamides to produce several γ-lactones
in a one-pot fashion.[354] Trifluoroethyl
amides were found useful as the directing group increasing the efficiency
of the hydrogen abstraction process.
class="Chemical">It class="Chemical">n class="Chemical">is also possible to
incorporate more than one heteroatom in
thering starhemical">ting from <hemical">span class="Chemical">benzyl amine 110–2 and unactivated bromides 110–1a–e (Scheme ). Compound 110–2 incorporates CO2 (with
the help of the base TBD), and the resulting carbamate underwent attack
by an alkyl radical photogenerated by reaction of 110–1a–e and an excited Pd0 photocatalyst (Pd(PPh3)4). Ring closing yielded valuable 2-oxazolidinones 110–3a–e under very mild conditions and easy scalability.[355]
Scheme 110
Three-Component Synthesis of 2-Oxazolidinones
Six-Membered or Larger
Rings
Dclass="Chemical">iffeclass="Chemical">n class="Chemical">rent
approaches were devised to form a six-membered ring even cointaining
heteroatoms. A hemical">cyclohexane ring was constructed by ring opening of
an <hemical">span class="Chemical">iminyl radical by IrIII-photocatalyzed reduction of
a 3-phenyl O-acyl oxime (e.g., 111–1) to give radical 111–2 that upon addition onto unsaturated esters 111–3a–e and ensuing cyclization led to cyanoalkylated
1,2,3,4-tetrahydrophenanthrenes (111–4a–e, Scheme ).[356]
Scheme 111
Photocatalyzed Preparation of 1,2,3,4-Tetrahydrophenanthrenes
class="Chemical">Six-membeclass="Chemical">n class="Chemical">red rings have been likewise obtained
by ring expansion
inhemical">cycloalkanone derivatives. This expansion was caused by the photocatalyzed
decarboxylation of α-(ω-carboxy<hemical">span class="Chemical">alkyl) β-keto esters,
followed by an exo-trig cyclization of the resulting
radical onto the carbonyl group that ultimately led to the one-carbon
expanded cycloalkanones by β-cleavage.[357]
class="Chemical">Reductclass="Chemical">n class="Chemical">ion of indoles having an unactivated hemical">haloalkane chain
is
a useful approach to construct a ring. As an example, <hemical">span class="Chemical">bromo derivatives 112–1a,b were reduced by a AuI photocatalyst
and radical cyclization onto the heteroaromatic ring afforded 6,7,8,9-tetrahydropyrido[1,2-a]indoles 112–2a,b in excellent yield
(Scheme a).[358] Interestingly, changing the reaction conditions
and starting from N-(2-iodoethyl)indoles 112–3a,b in place of 112–1a,b in the presence of Michael
acceptors 112–4a–c caused a dearomatizative
tandem [4 + 2] cyclization to deliver tri- and tetracyclic benzindolizidines 112–5aa–bc with high diastereoselectivity and
yield (Scheme b).[359]
Scheme 112
Intramolecular
C–C Bond Formation in Indoles
Tclass="Disease">he <class="Chemical">n class="Chemical">span class="Chemical">phenanthridine core is one of the elective scaffolds
to be
prepared by using a cyclization step induced by photogenerated <hemical">span class="Chemical">alkyl
radicals. Scheme illustrated a representative case where an alkyl radical added onto
a vinyl azide 113–2, and after nitrogen
loss the resulting iminyl radicals 113–3a-c yielded phenanthridines 113–4a-c by ring closure.[360] The method has several
advantages including metal-free conditions (a dye as a POC) an excellent
functional group tolerance and a broad substrate scope.
Scheme 113
Photocatalyzed
Synthesis of Functionalized Phenanthridines
An alteclass="Chemical">rclass="Chemical">natclass="Chemical">n class="Chemical">ive way to prepare hemical">phenanthridines is by having
recourse
to photoredox gold catalysis employing <hemical">span class="Chemical">bromoalkanes as alkyl radical
source. In this case, radicals attack a biaryl isonitrile thus forming
a sp2-hybridized radical that readily cyclizes upon the
pendant arene.[361] Aryl isocyanides (e.g., 114–2a–d) were largely used for the construction
of heterocycles such as pyrrolo[1,2-a]quinoxalines 114–4a–d. PhenyliodineIII dicarboxylate 114–1 was used for the incorporation of
the cyclohexyl group both in batch and flow under IrIII-photocatalyzed conditions (Scheme , see also Scheme ).[362]
Scheme 114
Photoredox
Preparation of Pyrrolo[1,2-a]quinoxalines
Tclass="Disease">he photocatalyzed class="Chemical">n class="Chemical">insertion of hemical">SO2 into an unactivated
<hemical">span class="Species">C(sp3)-H bond was designed to prepare 1,2-thiazine 1,1-dioxide
derivatives under uncatalyzed conditions. In fact, visible light irradiation
of the complex between an electron-poor O-aryl oxime
and DABCO·(SO2)2 releases an iminyl radical
that upon 1,5-HAT, SO2 incorporation and cyclization gave
the hoped-for heterocycle in a satisfying yield.[363]
class="Chemical">Iclass="Chemical">n class="Chemical">n class="Chemical">rare instances a ring larger than six may be constructed.
By
using the approach depicted in Scheme , it was possible to pursue a late stage
functionalization on hemical">ursolic acid (a compound having excellent pharmaceutical
activity). Accordingly, the <hemical">span class="Chemical">NHPI ester of ursolic acid acetate (115–2) underwent a radical addition cascade
by a photocatalyzed reaction with acrylamide-tethered styrene (115–1) with the intermediacy of radical 115–3.
As a result, the benzazepine unit was incorporated in the end compound 115–4 combining two privileged bioactive
scaffolds.[364]
Scheme 115
Late Stage Functionalization
of Ursolic Acid
Conclusions and Outlook
Thclass="Chemical">is class="Chemical">n class="Chemical">review provides a concise and
up-to-date selection of modern
methods to generate hemical">alkyl radicals via photochemistry and photocatalysis.
The effort and interest of the chemical community in developing and
applying these new methods is witnessed by the rapid increase in the
number of articles devoted to this topic that appeared in the literature
in the last two decades. Indeed, the rediscovery of photocatalysis
and the re<hemical">span class="Chemical">naissance of visible light-driven processes have contributed
to elevate radical chemistry from the isolated (yet efficient) niche
of the tyrannical organotin compounds to a vast plethora of methodologies
that relies on more environmental benign compounds. The facile synthesis
of the precursors necessary for these transformations, along with
the readily available setups (a vast number of reactions can occur
by simple irradiation with visible LEDs), made radical chemistry approachable,
appointing the photon as the agent of this revolutionary democracy.
Photocatalyclass="Chemical">sis has class="Chemical">n class="Chemical">reached the stage of maturity; however, we are
still far from the statement of Ciamician envisioning “industrial
colonies without smoke [···] forests of glass tubes
[···]; inside of these will take place the photochemical
processes that hitherto have been the guarded secret of the plants,
but that will have been mastered by ies">human industry which will know
how to make them bear even more abundant fruit than nature, for nature
is not in a hurry and mankind is”.[365] New practical methods and theoretical assumptions are needed to
foster the revolution that has just started. A promising approach
makes use of the upconversion of reductants to generate strongly reductive
hemical">species, but the method was not applied so far to <hemical">span class="Chemical">alkyl radicals.[366] This phenomenon can be exploited, for example,
if the reaction of a radical anion R to give P is less exoergonic (see the ΔG value in Figure A) than its neutral counterpart (ΔG, referred to R → P conversion).
The difference between these two free energies defines the upconversion
energy (ΔGup = ΔG – ΔG). The high quantum yields associated with the transformation
of R into P in Figure A (Φ = 44) were attributed to the presence
of electrocatalytic cycles propagated by P, which is able to transfer an electron
to the reactant, closing the catalytic cycle. This phenomenon is attributed
to P being a
better reductant than R, due to the diminished conjugation (Figure A).
Figure 4
(A) Upconversion of the
reducing power of the intermediates in
a photocatalytic/photoinitiated cyclization. (B) Two pathways to employ
the photoelectrocatalytic strategy: either promoting a single electron
transfer with photocatalysis first and a second one with electrocatalysis
or vice versa.
(A) Uclass="Chemical">pcoclass="Chemical">nveclass="Chemical">n class="Chemical">rsion of thereducing power of theintermediates in
a photocatalytic/photoinitiated cyclization. (B) Two pathways to employ
the photoelectrocatalytic strategy: either promo<span class="Chemical">ting a single electron
transfer with photocatalysis first and a second one with electrocatalysis
or vice versa.
Tclass="Disease">heclass="Chemical">novel appclass="Chemical">n class="Chemical">roach granted by
the merging of homogeneous photocatalysis
with electrocatalysis (see Figure B) is surfacing as the new challenge in this constantly
evolving topic.[367−369]
Joclass="Chemical">iclass="Chemical">nclass="Chemical">n class="Chemical">ing the almost unlimited potential
of these two interchangeable
fields of research would open unprecedented scenarios in chemical
synthesis, allowing one to tweak thereactivity of intermediates and
excited state species at will, walking on the path carved by theinstitution
of the photon democracy.
Authors: Christopher C Nawrat; Christopher R Jamison; Yuriy Slutskyy; David W C MacMillan; Larry E Overman Journal: J Am Chem Soc Date: 2015-08-31 Impact factor: 15.419
Authors: Elizabeth M Dauncey; Sara P Morcillo; James J Douglas; Nadeem S Sheikh; Daniele Leonori Journal: Angew Chem Int Ed Engl Date: 2017-12-04 Impact factor: 15.336
Authors: Feng Zhu; Eric Miller; Wyatt C Powell; Kelly Johnson; Alexander Beggs; Garrett E Evenson; Maciej A Walczak Journal: Angew Chem Int Ed Engl Date: 2022-06-23 Impact factor: 16.823
Figure 1
Figure 2
Figure 3
Scheme 1
Scheme 2
Scheme 3
Scheme 4
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Scheme 6
Scheme 7
Scheme 8
Scheme 9
Scheme 10
Scheme 11
Scheme 12
Scheme 13
Scheme 14
Scheme 15
Scheme 16
Scheme 17
Scheme 18
Scheme 19
Scheme 20
Scheme 21
Scheme 22
Scheme 23
Scheme 24
Scheme 25
Scheme 26
Scheme 27
Scheme 28
Scheme 29
Scheme 30
Scheme 31
Scheme 32
Scheme 33
Scheme 34
Scheme 35
Scheme 36
Scheme 37
Scheme 38
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Scheme 40
Scheme 41
Scheme 42
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Scheme 44
Scheme 45
Scheme 46
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Scheme 48
Scheme 49
Scheme 50
Scheme 51
Scheme 52
Scheme 53
Scheme 54
Scheme 55
Scheme 56
Scheme 57
Scheme 58
Scheme 59
Scheme 60
Scheme 61
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Scheme 63
Scheme 64
Scheme 65
Scheme 66
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Scheme 70
Scheme 71
Scheme 72
Scheme 73
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Scheme 77
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Scheme 81
Scheme 82
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Scheme 84
Scheme 85
Scheme 86
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Scheme 88
Scheme 89
Scheme 90
Scheme 91
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Scheme 94
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Scheme 99
Scheme 100
Scheme 101
Scheme 102
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Scheme 104
Scheme 105
Scheme 106
Scheme 107
Scheme 108
Scheme 109
Scheme 110
Scheme 111
Scheme 112
Scheme 113
Scheme 114
Scheme 115
Figure 4