The modular synthesis of photoprecursors and their photoinduced cyclization into substituted 1-benzazocanes of two distinct topologies is described. The key step producing an extended polyheterocyclic system involves the photogeneration of azaxylylenes and their subsequent intramolecular cycloaddition with furan-containing pendants tethered either via the aniline nitrogen or through the carbonyl group containing arm. The primary photoproducts-secondary or tertiary anilines which are not acylated at the nitrogen atom-undergo facile acid-catalyzed or spontaneous ring-opening-ring-closing rearrangement to yield fused polyheterocyclic structures possessing a 2,6-epoxyazocane (or oxamorphan) core.
The modular synthesis of photoprecursors and their photoinduced cyclization into substituted 1-benzazocanes of two distinct topologies is described. The key step producing an extended polyheterocyclic system involves the photogeneration of n class="Chemical">azaxylylenes and their subsequent intramolecular cycloaddition with furan-containing pendants tethered either via the anilinenitrogen or through the carbonyl group containing arm. The primary photoproducts-secondary or tertiary anilines which are not acylated at the nitrogen atom-undergo facile acid-catalyzed or spontaneous ring-opening-ring-closing rearrangement to yield fused polyheterocyclic structures possessing a 2,6-epoxyazocane (or oxamorphan) core.
Nitrogen heterocycles are ubiquitous in
nature: a large number of biochemical pathways involve n class="Disease">N-heterocycles
as substrates, products, or coenzymes.[1] This ensures their prominence among top pharmaceuticals, with 23
out of the 50 top-selling drugs in the US in 2012 containing N-heterocycles.[2] It is not surprising that their methods of synthesis
and properties have long been a focus of sustained research efforts.[3] As a result, the methods for five- and six-membered
N-containing heterocycle preparation are countless and also diverse.[4] However, access to seven- and especially eight-membered
heterocycles remains challenging, mostly because these medium-sized
rings are less entropically favored. Such structures, their properties,
and methods of synthesis deserve closer examination and further development.
They either can be found in a number of bioactive molecules, for example
nakadomarin A and manzamine A, or are intermediates in their biosynthesis
(Figure 1).[5]
Figure 1
Some members
of mitomycinoid alkaloids and their congeners.
Some members
of mitomycinoid alkaloids and their congeners.The 1-benzazocine core is of particular interest: it can
serve as an important intermediate in the synthesis of mitomycinoid
n class="Chemical">alkaloids,[6] which are potent cytotoxins
as they can cross-link DNA, and exhibits a broad range of biological
activity, including potent anticancer activity.[7] Moreover, it has been suggested that the biochemistry of
several alkaloids of the mitomycine family, FR-66979 and FR-900482,
as well as their semisynthetic analogues, FK-973 and FK-317, can be
rationalized by invoking in vivo formation of the benzazocane intermediate
that starts a biochemical cascade.[8] Several
approaches to the synthesis of the benzazocine/benzazocane moiety
have been described, including ingenious examples of olefin metathesis,[9] Mizoroki–Heck reaction,[10] ring expansion,[11] cycloaddition,[12] and condensation[13] strategies. Most of these approaches, however, imply multistep synthesis;
therefore, the development of new short synthetic pathways to the
benzazocane scaffold is well justified.
The route to 1-benzazocanes
that is being developed in our laboratory is based on [4 + 4] cycloaddition
reactions of n class="Chemical">azaxylylenes—short-lived species generated via
excited-state intramolecular proton transfer, ESIPT,[14] in aromatic o-amino ketones and aldehydes.
Transient C-hydroxyazaxylylenes generated via ESIPT
have been observed in the past and characterized by time-resolved
photophysical methods.[14] However, they
were not trapped chemically, as any addition reaction would have to
compete with very fast back proton transfer. Alternative (i.e., non-ESIPT)
approaches to azaxylylenes require exotic precursors such as benzosultams
and benzoazetines and often occur under the harsh conditions of flash
vacuum pyrolysis;[15] thus, their utilization
in the synthesis of delicate complex organic architectures remains
very limited. An exception is Corey’s mild generation of azaxylylenes
via 1,4-dehydrochlorination of o-aminobenzyl chlorides.[16] However, azaxylylenes generated via nonphotochemical
methods exclusively undergo [4 + 2] cycloadditions, limiting the structural
scaffolds accessible via these reactions to quinolines. The [4 + 4]
cycloaddition path is not available for these ground-state reactions.
Another option—intramolecular reactions
of the ESIPT-generated n class="Chemical">azaxylylenes in their excited state which could
successfully compete with the wasteful back proton transfer—has
not been explored before our work. Recently we found that photogenerated
azaxylylenes can indeed react intramolecularly with
the appropriately tethered unsaturated pendants (Scheme 1).[17]
Scheme 1
Photogeneration of
Azaxylylenes and Their Intramolecular Cycloadditions
In this context, furans and other five-membered
heterocycles are particularly suitable as unsaturated pendants, because
they can participate in the cycloaddition reaction not only as ann class="Chemical">alkene component, leading to the products of [4 + 2] cycloadditions,
but also as a diene component, furnishing azacanes as the products
of [4 + 4] cycloadditions. Our initial studies with azaxylylenes and
furan as a pendant demonstrated predominant formation of the [4 +
4] products in a 3:1 or lower ratio to the [4 + 2] products in the
majority of cases. This scaffold diversity and complexity arising
in one step from the same photoprecursor is appealing from a diversity-oriented
synthesis (DOS) standpoint.
Although furan derivatives have
been employed in Diels–Alder reactions[18] both as 4π and less commonly as 2π[19] components, to the best of our knowledge there have not
been observations of the borderline behavior where both [4 + 4] and [4 + 2] reaction pathways are realized from the same
starting material under the same reaction conditions.[20] According to our recent experimental and theoretical mechanistic
study,[21] it is likely that the intramolecular
cycloaddition of n class="Chemical">azaxylylenes photogenerated via ESIPT occurs in a
stepwise manner in the triplet manifold, thus offering a rationale
for the formation of both [4 + 4] and [4 + 2] cycloadducts. From our
prior work we infer that the ratio of [4 + 4] to [4 + 2] products
is affected by the length of the tether between the azaxylylene precursor
and the nature of unsaturated pendants, with longer linkers often
favoring [4 + 4] products. The same bias toward [4 + 4] cycloaddition
was observed when the azaxylylenophile, i.e. a furan-based pendant,
was tethered via a carbonyl group, as in furanoyls. Also, in the past
we utilized ubiquitous amide bond forming coupling reactions to tether
unsaturated pendants to the photoactive o-amino ketone
core of the azaxylylene precursor.
In the current study we extend
the scope to azaxylylenes derived from n class="Chemical">o-amines, i.e. not amides, and also explore topological variations related
to the nature and the attachment point of the tether linking the photoactive
core with the unsaturated, mostly dienic, pendant. For cycloadditions
of ESIPT-generated azaxylylenes—in the context of DOS—it
is desirable not only to modulate the topology resulting from the
competing [4 + 2] and [4 + 4] photoinduced processes but also to take
advantage of the fact that a variety of additional (poly)cyclic moieties
can be installed in the photoproducts utilizing strategically chosen
linking groups and their attachment points. Our original topology
of tethering the furan-containing unsaturated pendant via the aniline
moiety of the photoprecursor was predicated on the simplicity of the
coupling reaction: i.e., the amide bond formation (Figure 2, top; the “south-bridged” topology).
In this paper we report an alternative approach to the assembly of
photoprecursors—via the ketone arm of the aromatic amino ketone
(Figure 2, bottom; the “north-bridged”
topology). This alternative linking offers access to new topologically
unique polyheterocyclic core structures.
Figure 2
Original “south-bridged”
and new “north-bridged” topology.
Original “south-bridged”
and new “north-bridged” topology.
Results and Discussion
The departure from the original south-bridged
topology is realized by linking the unsaturated pendant and the azaxylylene
precursor through the α n class="Chemical">carbon of the carbonyl group (Figure 2, north-bridged topology). Thus, this new scaffold
consists of a primary aromatic amine and an unsaturated pendant joined
through the α substitution in aminoacetophenone, which entails
differences in both stereo and electronic properties of the photoprecursors.
The synthetic route and the nature of the linker between the azaxylylene
precursor and the unsaturated pendant were deliberately chosen to
be attuned with a modular approach within the framework of diversity-oriented
synthesis.[22] The implemented pathway to
the photoprecursors comprises two simple steps: aldol condensation
of the o-furyl aromatic (or α-furyl vinyl)
carboxaldehyde followed by the conjugate (Michael) addition of a nucleophile
to the obtained α,β-unsaturated ketone. The starting aldehyde
can be prepared by the Suzuki reaction of 2-furanboronic acid with
the corresponding o- or β-halogen-substituted
aromatic or vinyl aldehyde. Thus, a diverse library of compounds can
be accessed through the variation of the following building blocks
and pendants: the polycyclic aldehyde obtained via the Suzuki reaction,
the Michael nucleophile, and aromatic or α substitution in o-aminoacetophenone.
The initial synthetic studies
were conducted using o-bromobenzaldehyde (1) as a starting material (Scheme 2). The Suzuki
coupling with n class="Chemical">furanboronic acid 2, catalyzed by 5 mol
% of PdCl2(PPh3)2, yielded aldehyde 3(23) (89%), which serves as the
carbonyl component in the subsequent aldol condensation[24] with o-aminoacetophenone (4), giving chalcone 5, a reactive Michael acceptor
for a variety of nucleophiles, including nitromethane,[25] diethyl malonic ester,[26] and phenylboronic acid,[27] in a Pd0-catalyzed reaction. Thus, the photoprecursors 6–8 are readily available in three simple steps
in moderate to good yields.
Scheme 2
Synthesis of the Initial Batch of
Photoprecursors
Similarly, heterocyclic
analogues 15 and 16 were prepared, starting
the sequence with 2-bromonicotinaldehyde (9) or 2-formyl-3-bromothiophene
(10) (Scheme 3). In both of these
cases, nitromethane was used as a Michael nucleophile.
Scheme 3
Access
to Photoprecursors Containing Heterocyclic Moieties
Further diversification of photoprecursors was
achieved by making use of vinyl carboxaldehydes 20–22 as starting materials. These n class="Chemical">aldehydes are readily obtained
via a variation of the Vilsmeier–Haack reaction[28] from commercially available cyclic ketones on
a multigram scale, using DMF and PBr3. In these cases,
the developed synthetic sequence of Suzuki coupling, followed by aldol
condensation and conjugate addition to chalcone, gives the photoprecursors 29–31 in good yields (Scheme 4).
Scheme 4
Synthesis of Alicyclic Derivatives
The photoprecursors, obtained
as described above, have an (n,π*) UV absorption maximum around
350 nm. Methanol was the solvent of choice for irradiation after a
few solvent optimization runs. Irradiations were carried out with
a Rayonet broad-band 300–400 nm UV source (RPR-3500 lamps).
Curiously, irradiation of the photoprecursors possessing the north-bridged
topology yielded exclusively the products of [4 + 4] addition: i.e.,
no [4 + 2] products were detected (Scheme 5 and Table 1).
Scheme 5
Intramolecular Cycloadditions of Photogenerated Azaxylylenes
Table 1
Primary
Photoproducts from the “North-Bridged” Photoprecursors
and Their Acid-Catalyzed Rearrangement
The stereochemistry of the primary [4 + 4] photoproducts
was assigned on the basis of their NMR spectra and the X-ray structure
of 34. We hypothesize that the [4 + 4] intramolecular
cycloaddition of the n class="Chemical">ESIPT-generated azaxylylene occurs via a transition
state (Figure 3), in which the stereochemistry
of folding of the α-(nitromethyl)ethylphenyl tether to form
a six-membered ring is biased by the nitromethyl group assuming the
shown pseudoequatorial conformation. The alternative folding, with
the nitromethyl assuming a pseudoaxial conformation, leads to a severe
steric clash and therefore is not expected to be a feasible reaction
channel.
Figure 3
Nitromethyl moiety biasing the folding of the furanyl tether in the
transition state, leading to the [4 + 4] intramolecular cycloadducts.
The ORTEP structure of 34 is shown with 50% thermal ellipsoids.
Nitromethyl moiety biasing the folding of the furanyl tether in the
transition state, leading to the [4 + 4] intramolecular cycloadducts.
The ORTEP structure of 34 is shown with 50% thermal ellipsoids.Another observation was that in
some cases primary photoproducts underwent a partial rearrangement,
similar to a carbohydrate transformation from a n class="Chemical">furanose to a pyranose
form. Further probing the stability of the primary photoproducts,
we subjected compound 34 to acidic conditions (1 vol
% of TFA in DCM), which resulted in a 100% conversion into the “pyranose”
form (Scheme 6). Presumably, such a rearrangement
is facilitated by the amino stabilization of the cation formed upon
the opening of the 2,5-dihydrofuran moiety. The initial step of it
is somewhat reminiscent of the rearrangement reported by Padwa and
co-workers,[29] except that in our case the
transient cation is captured by the benzylic hydroxy group, leading
to the formation of the unprecedented oxazobicyclo[3.3.1]nonadiene
or oxamorphan substructure.
Scheme 6
Bicyclo[4.2.1] to [3.3.1] Rearrangement
and the ORTEP Structure of 42
Shown with 50% thermal ellipsoids.
Bicyclo[4.2.1] to [3.3.1] Rearrangement
and the ORTEP Structure of 42
Shown with 50% thermal ellipsoids.This rearrangement
appears to be general for all the photoproducts in Table 1. It proceeds smoothly upon the addition of a catalytic
amount of acid or simply upon heating of the reaction mixture in DMSO.
The structures of the rearranged products were supported by n class="Chemical">NMR data.
Additionally the structures of photoproduct 34 and rearranged
product 40 were unambiguously determined by X-ray analysis. 1HNMR spectra of the rearranged products differ considerably
from the NMR spectra of nonrearranged compounds (Figure 4). In compound 34 the vinyl protons appear as
a doublet and a doublet of doublets with a common spin–spin
coupling constant of 5.6 Hz. After the rearrangement the vicinal coupling
constant of vinyl protons increases to 10.0 Hz, which is in keeping
with the proposed change in the molecule’s geometry. The experimental
NMR data were supported by our relativistic force field computations of proton spin–spin coupling constants,[30] with the predicted constants, shown in Figure 4, matching the experimental values very well.
Figure 4
Experimental
and calculated (in parentheses) proton spin–spin coupling constants
(in Hz) for primary and rearranged products exemplified by compounds 34 and 42.
Experimental
and calculated (in parentheses) proton spin–spin coupling constants
(in Hz) for primary and rearranged products exemplified by compounds 34 and 42.The only exception in this series was the rearrangement of
photoproduct 49, derived from tetralone-based precursor 48. The photoprecursor 48 was obtained as a mixture
of diastereomers. However, only one diastereomer of the photoproduct 49 is formed with an isolated yield of 27%. We hypothesize
that one of the diastereomers 48 is photoinactive due
to unfavorable folding of the tn class="Chemical">ether in the transition state. We were
unable to obtain an X-ray structure of the photoproduct and could
not assign its stereochemistry on the basis of NMR data.
During
column chromatography compound 49 isomerized on silica
gel into the [4 + 2] product 50. The structure of the
product was established on the basis of its n class="Chemical">1H NMR and
COSY spectra. Protons Ha, Hb, and Hc (Scheme 7) of the primary photoproduct 49 are characterized by the set of spin–spin coupling
constants typical of the series: 5.6 Hz for the vinylic Ha and Hb protons and 1.3 Hz for Hb and Hc (bridge). In contrast to both these experimental observations
and the spin–spin coupling constants observed for other compounds
possessing the [4.2.1] scaffold, the rearranged product 50 exhibited a set of much smaller constants: vinyl Jab = 2.4 Hz and Jac = 0.9
Hz. Such a distinctive set of values has been observed earlier for
[4 + 2] azaxylylene cycloaddition products and is supported by our
calculations. A plausible mechanism for such 1,3-allylic migration
is presented in Scheme 7 and involves protonation
of the amine, scission of the aminal C–N bond (i.e., not C–O
bond), and subsequent nucleophilic attack by aniline at C-3 of the
furan ring.
Scheme 7
Rearrangement of Tetralone-Derived 49
Computed J values
are given in parentheses.
Rearrangement of Tetralone-Derived 49
Computed J values
are given in parentheses.This outlier notwithstanding,
the north-bridged anilines, lacking acyl substitution at the n class="Chemical">nitrogen
atom, exclusively undergo a photoinduced intramolecular [4 + 4] cycloaddition,
with subsequent heat- or acid-catalyzed [4.2.1] → [3.3.1] rearrangement
yielding a polycyclic aminal possessing an oxamorphan core. We identified
a case in which this rearrangement occurs spontaneously during the
photolysis. Sulfide 52, which is readily synthesized
via the substitution in α-bromo-2′-nitroacetophenone 51 and a subsequent reduction of the nitro group with tin
chloride (Scheme 8) undergoes irradiation in
wet acetonitrile, yielding only the rearranged compound 54 as a single product. The [4 + 4] cycloadduct 53, which
is a presumed intermediate, could not be isolated. While we do not
have an X-ray structure for 54, the predicted NMR spectra
better match the syn stereochemical configuration of the hydroxy group.
The spontaneous [4.2.1] → [3.3.1] rearrangement without added
acid also provides circumstantial evidence for the syn configuration.
As we show below, the anti photoproducts do not undergo this rearrangement
in the absence of acids.
Scheme 8
Spontaneous Post-Photochemical Rearrangement
in Sulfide 52
The observed rearrangement into the pyranose form is clearly
facilitated by the fact that the aniline moiety is not acylated, resulting
in a more stable iminium ion (Scheme 6) as
the key intermediate in this rearrangement. Additional questions are
whether this lack of N-acylation (or further electron-donating alkyl
substitution on the nitrogen) possibly affects the [4 + 4] vs [4 +
2] partitioning of the primary photoproducts and also whether the
[4.2.1] → [3.3.1] transformation is unique to the north-bridged
architecture of the photoprecursors.We therefore revisited
the south-bridged structures, but instead of amide-forming coupling
of the n class="Chemical">furan pendant we explored reductive amination to furnishalkylated anilines, not anilides. First, we synthesized
the secondary amine 57, through the sequence of reductive
amination of 3-furylpropanal (56) with 2-aminophenylmethanol
(55) and the oxidation of the benzylic alcohol with MnO2 (Scheme 9).
Scheme 9
Typical Synthesis
of South-Bridged Alkylamines via Reductive Amination
Similar to the case for the previously studied
amides, photoprecursor 57 has a UV absorption band in
the range 320–350 nm. After screening the solvents n class="Chemical">methanol,
methanol–water, acetonitrile, acetonitrile–water, benzene,
and tert-butyl alcohol, we arrived at methanol as
the optimal medium for the initial photoinduced cycloaddition. Irradiation
of 57 with a Rayonet broad-band 300–400 nm UV
source is accompanied by a spontaneous [4.2.1] → [3.3.1] rearrangement,
yielding diastereomeric oxamorphans 65a (OH is syn to
the bridge oxygen) and 65b (anti) (Scheme 10). The structural assignment of the products was guided by
calculations of their proton spin–spin coupling constants.
Both syn and anti products have a large vicinal coupling constant
between vinylic protons, Jcd = 9.8 Hz
(calculated 9.6 Hz) for the syn isomer and 10.0 Hz (calculated 9.9
Hz) for the anti isomer, indicative of oxabicyclo[3.3.1] scaffold
formation. There is, however, a significant difference in spin–spin
coupling for the α-hydroxy proton Hb: the syn isomer
has the large constant Jbc= 5.2 Hz (calculated 5.1 Hz) and a small constant Jab = 1.3 Hz (calculated 1.5 Hz); in contrast, the anti
isomer has a small constant Jbc = 1.7
Hz (calculated 2.0 Hz) and a large constant Jab = 5.9 Hz (calculated 5.9 Hz). The near-perfect match of
the experimental and calculated spin–spin coupling constants
leaves no doubt that the conversion of the primary photoproducts into
the 9-oxabicyclo[3.3.1]nonadiene compounds 65a,b occurs spontaneously at room temperature in these amines.
Scheme 10
Irradiation of Alkylamine 57
To test the scope of the reaction, additional secondary
amines were similarly synthesized. The reductive amination approach
is again amenable to the modular synthesis of photoprecursors, allowing
for access to diverse structures from various n class="Chemical">aldehydes and amines
used for the reductive amination. A heterocyclic (pyridine) moiety
was readily incorporated into photoprecursors 60 and 63, synthesized with 2-amino-3-pyridinylmethanol. Upon irradiation
both produced the desired photoproducts, which is, to the best of
our knowledge, the first example of azaxylylene generation from heterocyclic
precursors.
The modular synthesis of photoprecursors benefits
from the fact that the aldehydes obtained via Suzuki coupling (Schemes 2–4) and utilized to
assemble the north-bridged precursors via aldol condensation can also
be used in the reductive amination synthetic sequence, as exemplified
by the south-bridged photoprecursors 63 and 64. The matrix of synthesized photoprecursors and their respective
photoproducts is presented in Table 2.
Table 2
South-Bridged Alkylaminesa
The asterisk indicates that the yields for synthesis
of photoprecursors 57–61 and 63 are given over two steps: reductive amination and benzylic
alcohol oxidation.
The asterisk indicates that the yields for synthesis
of photoprecursors 57–61 and 63 are given over two steps: reductive amination and benzylic
alcohol oxidation.As it
is evident from Table 2, upon irradiation all
photoprecursors produced the rearranged oxabicyclo[3.3.1]nonadiene
core, supporting the mechanistic rationale that additional alkyl stabilization
of the transient n class="Chemical">iminium cation is needed for the spontaneous [4.2.1]
to [3.3.1] rearrangement. It should also be noted that, with the exception
of 65, the only isolated stereoisomer was that with the
OH group syn to the bridge oxygen. In the case of the tetralone-derived
photoproduct 70, the NMR-based structural assignment
was also supported by X-ray data. Introduction of halogen substitution
into the aromatic ring (58, 59) accelerates
the photochemical step, which is in keeping with our prior observations.[21] It also sets the product up for a subsequent
Suzuki coupling,[31] allowing for another
diversity input in the resulting [3.3.1] scaffold. The presence of
the Me–C* stereogenic center in the tether of photoprecursor 61 expectedly does not impose any diastereoselection in the
transition state of the primary photoinduced cycloaddition step and
leads to the formation of a 1:1 mixture of diastereomers (69a,b), which can be separated via column chromatography.
Diastereomers 69a,b both have the same syn
configuration of the hydroxy group but differ in the stereoconfiguration
of the methyl group in the pyrroline moiety.
Indanone-derived 73 was the only photoprecursor which did not undergo spontaneous
[4.2.1] to [3.3.1] rearrangement. Instead, we observed n class="Disease">dehydration
in the primary photoproduct 74 to yield indene 75 (Scheme 11). A plausible explanation
for this is that the [4.2.1] → [3.3.1] rearrangement in this
case is less energetically favorable. This hypothesis is corroborated
by our DFT calculations, which predict that generally the rearranged
bicyclo[3.3.1]nonadienes are 7–12 kcal/mol more stable than
the primary photoproducts possessing the bicyclo[4.2.1]nonadiene structure.
Even the tetralone-based 70 is 6.9 kcal/mol more stable
than its [4.2.1] precursor. However, in the indanone case the [4.2.1]
and the [3.3.1] structures are nearly (within 0.6 kcal/mol) energy
degenerate. An analysis of the experimental and predicted NMR spectra
of 75 does not leave any doubt of the correct structural
assignment. In the 5.0–6.0 ppm region of the NMR spectrum of
the photoproduct, in addition to the two expected alkenyl protons
(Jexp = 5.6 Hz, Jcalc = 5.5 Hz) and the allylic bridgehead proton (Jexp = 2.0, 1.2 Hz, Jcalc =
2.0, 1.3 Hz), there is an additional triplet with Jexp = 2.2 Hz (calculated dd, Jcalc = 2.4, 2.3 Hz), corresponding to the new vinyl proton of the indene
moiety.
Scheme 11
Spontaneous Dehydration of the Primary Photoproduct 74
In the majority of
the cases, as follows from Table 2, the photoinduced
cycloaddition is always followed by the spontaneous [4.2.1] →
[3.3.1] rearrangement, which is clearly accelerated by the lack of
acyl substitution on nitrogen. While the acyl linker explored in our
previous work should indeed retard the rate of this rearrangement,
we hypothesized that such acyl substitution should not necessarily
affect the position of the equilibrium between [4.2.1] and [3.3.1].
Our DFT B3LYP/6-311+G(d,p) calculations indeed revealed that this
equilibrium has a very similar 7–12 kcal/mol energy bias toward
the rearranged [3.3.1] products in the n class="Chemical">amido series. We therefore revisited the amide-derived photoproducts synthesized
earlier to test whether this rearrangement can be induced in the structures
with an electron-withdrawing acyl substituent on the nitrogen atom.
Indeed, we found that the heat- or acid-promoted [4.2.1] →
[3.3.1] rearrangement in this series is possible as well (Scheme 12). Moreover, as is illustrated by the rearrangement
of the ketopiperazine 82, the rearrangement is not limited
to three-atom tethers but occurs in photoproducts with four-atom linkers
as well.
Scheme 12
[4.2.1] → [3.3.1] Rearrangement in Amides
It is instructive that the
barrier for the [4.2.1] → [3.3.1] transformation in the absence
of acid catalysis is much higher for anti photoproducts to a point
that, while syn-76 photoproduct rearranges
in DMSO at 150 °C, there is no thermal reaction at all for the
anti photoproduct (Scheme 13).
Scheme 13
Thermal
Rearrangement: Anti vs Syn Reactivity
The versatility of the [4.2.1] → [3.3.1] transformation
in the syn photoproducts of the amido series is hard to underestimate.
On one hand, the initial photoproducts are very stable at temperatures
varying from ambient to 70–80 °C. On the other, they undergo
a clean transformation in n class="Chemical">DMSO when heated to 140 °C, furnishing
the rearranged products with the oxamorphan core.
Conclusions
We have developed a versatile approach to the synthesis of bicyclic
1-benzoazocine structures of two distinct topologies. The method is
amenable to a straightforward modular synthesis of both south- and
north-bridged photoprecursors in three to four simple steps. Irradiation
of photoprecursors results in a significant growth of complexity,
giving a single primary photoproduct of the [4.2.1] oxabicyclic core
structure in the case of north-bridged primary n class="Chemical">amines and the [3.3.1]
oxabicyclic core structure as a result of spontaneous [4.2.1] →
[3.3.1] rearrangement in the case of secondary amines. The [4.2.1]
→ [3.3.1] transformation can be achieved either by heat or
under acid catalysis. The generality of this rearrangement was demonstrated
using the amides of the same topology as secondary amines.
Experimental Section
Commercial solvents were used as is, except for THF, which was
refluxed over and distilled from n class="Chemical">potassium benzophenone ketyl prior
to use. Common reagents were purchased from commercial sources and
used without additional purification, unless indicated otherwise.
NMR spectra were recorded at 25 °C on a 500 MHz spectrometer
in CDCl3 with TMS as an internal standard (unless noted
otherwise). Flash column chromatography was performed using 230–400
mesh silica gel.
General Procedure
for Vilsmeier–Haack Reaction
To a solution of N,N-dimethylformamide (2.40 mL, 30.6 mmol)
inchloroform (20 mL) at 0 °C was added phosphorus tribromide
(2.60 mL, 27.5 mmol). After 30 min the reaction mixture was warmed
to room temperature and a solution of ketone (10.2 mmol) in chloroform
(10 mL) added. The reaction mixture was heated to reflux for 3 h then
cooled to room temperature and poured onto ice–water (50 mL).
Solid sodium bicarbonate was added to neutralize the aqueous phase,
which was then separated and extracted with ether (3 × 75 mL).
The combined organic phases were washed with saturated NaHCO3 (100 mL) and brine (100 mL), dried over MgSO4, and concentrated
in vacuo.[28]
1-Bromo-2-formyl-1-cyclopentene[32] (20)
Following the general
procedure for the Vilsmeier–Haack reaction from 0.86 g (10.2
mmol) of cyclopentanone, 1.20 g (67%) of the title compound was obtained,
which was used without further purification. n class="Chemical">1H NMR (500
MHz, CDCl3): δ 9.93 (s, 1H), 2.93 (m, 2H), 2.56 (m,
2H), 2.04 (m, 2H). 13CNMR (126 MHz, CDCl3):
δ 189.3, 141.5, 140.0, 42.6, 29.3, 21.4.
1-Bromo-2-formyl-1-cyclohexene[32] (21)
Following the general
procedure for the Vilsmeier–Haack reaction from 1.00 g (10.2
mmol) of cyclohexanone, 1.08 g (56%) of the title compound was obtained,
which was used without further purification. n class="Chemical">1H NMR (500
MHz, CDCl3): δ 10.05 (s, 1H), 2.77 (m, 2H), 2.30
(m, 2H), 1.79 (m, 2H), 1.71 (m, 2H). 13CNMR (126 MHz,
CDCl3): δ 193.8, 143.6, 135.3, 38.8, 25.0, 24.3,
21.1.
1-Bromo-2-formyl-1-cycloheptene[33] (22)
Following the general procedure for the
Vilsmeier–Haack reaction reaction from 1.34 g (10.2 mmol) of
cycloheptanone, 0.87 g (42%) of the title compound was obtained, which
was used without further purification. n class="Chemical">1H NMR (500 MHz,
CDCl3): δ 9.95 (s, 1H), 3.04 (m, 2H), 2.52 (m, 2H),
1.82 (m, 2H), 1.69 (m, 2H), 1.48 (m, 2H). 13CNMR (126
MHz, CDCl3): δ 193.3, 148.3, 140.5, 44.3, 31.4, 25.7,
25.2, 24.8.
General Procedure for Suzuki Coupling
Under a nitrogen atmosphere, α-formyl aryl (or cycloalkyl)
halide (10 mmol), arylboronic acid (12 mmol), K2CO3 (30 mmol), and PdCl2(PPh3)2, (5 mol %, 350 mg) were suspended in DMF/H2O (15 mL/1.5
mL). The resulting solution was stirred at 110 °C until the completion
of the reaction. After it was cooled to room temperature, the resulting
mixture was filtered through a short path of silica gel. The filtrate
was then extracted several times with EtOAc/Et2O (1/1).
The combined organic layer was washed with brine (3 × 10 mL)
and dried over MgSO4. The reaction mixture was then concentrated
in vacuo, and the crude residue was purified by silica gel column
chromatography if necessary (petroleum ether/EtOAc) to afford the
coupling products.[23]
Following the general
procedure for Suzuki coupling from 2.40 g (13.71 mmol) of 20, 1.20 g (54%) of the title compound was obtained. 1HNMR (500 MHz, CDCl3): δ 10.61 (s, 1H), 7.60 (d, J = 1.6 Hz, 1H), 6.63 (d, J = 3.4 Hz, 1H),
6.53 (dd, J = 3.4, 1.8 Hz, 1H), 2.94 (m, 2H), 2.77
(m, 2H), 1.99 (p, J = 7.6 Hz, 2H). 13CNMR (126 MHz, CDCl3): δ 191.2, 151.0, 145.3, 144.8,
137.4, 114.0, 111.8, 36.0, 31.1, 21.7.
2-(Furan-2-yl)cyclohex-1-enecarbaldehyde[34] (24)
Following the general
procedure for Suzuki coupling from 1.20 g (6.34 mmol) of 21, 0.83 g (74%) of the title compound was obtained. 1HNMR (500 MHz, CDCl3): δ 10.14 (s, 1H), 7.55 (s, br,
1H), 6.54 (d, J = 3.3 Hz, 1H), 6.50 (m, 1H), 2.63
(m, 2H), 2.41 (m, 2H), 1.77 (m, 2H), 1.69 (m, 2H). 13CNMR (126 MHz, CDCl3): δ 193.5, 151.9, 144.1, 143.8,
135.8, 113.1, 111.5, 29.19, 23.0, 22.1, 21.4.
2-(Furan-2-yl)cyclohept-1-enecarbaldehyde
(25)
Following the general procedure for Suzuki
coupling from 2.10 g (10.3 mmol) of 22, 1.08 g (55%)
of the title compound was obtained. 1HNMR (500 MHz, CDCl3): δ 9.97 (s, 1H), 7.57 (dd, J = 1.8,
0.6 Hz, 1H), 6.55 (d, J = 3.4 Hz, 1H), 6.51 (dd, J = 3.4, 1.8 Hz, 1H), 2.81 (m, 2H), 2.65 (m, 2H), 1.85 (m,
2H), 1.70 (dt, J = 11.6, 6.1 Hz, 2H), 1.52 (p, J = 6.0 Hz, 2H). 13CNMR (126 MHz, CDCl3): δ 192.6, 151.9, 150.5, 144.7, 141.8, 114.8, 111.7, 33.9,
32.2, 26.0, 25.9, 25.3.
2-(Furan-2-yl)benzaldehyde[35] (3)
Following the general procedure
for Suzuki coupling from 0.92 g (4.97 mmol) of 2-bromobenzaldehyde
(1), 0.76 g (89%) of the title compound was obtained. 1HNMR (500 MHz, CDCl3): δ 10.41 (s, 1H),
8.00 (m, 1H), 7.71 (m, 1H), 7.65 (m, 2H), 7.47 (m, 1H), 6.66 (m, 1H),
6.59 (dd, J = 3.4, 1.8 Hz, 1H). 13CNMR
(126 MHz, CDCl3): δ 192.4, 151.1, 144.0, 133.6, 133.4,
133.1, 128.4, 128.1, 128.0, 111.9, 111.3.
2-(Furan-2-yl)nicotinaldehyde[36] (11)
Following the general
procedure for Suzuki coupling from 0.92 g (4.97 mmol) of nicontinaldehyde
(9), 0.52 g (60%) of the title compound was obtained. 1HNMR (500 MHz, CDCl3): δ 10.72 (d, J = 0.8 Hz, 1H), 8.82 (dd, J = 4.6, 1.8
Hz, 1H), 8.28 (dd, J = 7.9, 1.8 Hz, 1H), 7.71 (dd, J = 1.7, 0.8 Hz, 1H), 7.35 (m, 1H), 7.23 (dd, J = 3.5, 0.7 Hz, 1H), 6.66 (dd, J = 3.5, 1.8 Hz,
1H). 13CNMR (126 MHz, CDCl3): δ 191.9,
153.4, 150.0, 152.6, 145.3, 136.2, 128.2, 122.3, 113.8, 112.4.
3-(Furan-2-yl)thiophene-2-carbaldehyde[37] (12)
Following the general
procedure for Suzuki coupling from 1.00 g (5.23 mmol) of 3-bromo-thiophene-2-carbaldehyde
(10), 0.84 g (90%) of the title compound was obtained. 1HNMR (500 MHz, CDCl3): δ 10.50 (d, J = 1.2 Hz, 1H), 7.68 (dd, J = 5.1, 1.2
Hz, 1H), 7.60 (dd, J = 1.8, 0.7 Hz, 1H), 7.36 (m,
1H), 6.80 (dd, J = 3.4, 0.6 Hz, 1H), 6.57 (dd, J = 3.4, 1.8 Hz, 1H). 13CNMR (126 MHz, CDCl3): δ 184.6, 149.7, 143.9, 137.4, 134.2, 128.5, 127.5,
112.0, 110.8.
General Procedure for Aldol Condensation
Procedure A.[24]
2′-Aminoacetophenone (10 mmol, 1 equiv) was added to a solution
of the corresponding n class="Chemical">aldehyde (10 mmol, 1 equiv) in EtOH (10 mL) containing
NaOH (0.3 of a pellet), and the mixture was stirred at 5 °C for
8 h. The precipitate was filtered, washed with EtOH and then with
water, and finally dried under vacuum to yield a product pure enough
for subsequent transformations.
Procedure B.[38]
Ethanolic solutions (10 mL) of equimolar
amounts of 2′-aminoacetophenone (2.8 mmol), the corresponding
aldehyde, and 20% aqueous NaOH (0.5 mL, 2.5 mmol) were heated to reflux
for 10–20 min. After the mixture was cooled, the precipitate
was filtered off, washed with EtOH and then with water, and finally
dried under vacuum.
Following the general procedure A for aldol
condensation from 0.34 g (1.97 mmol) of 3, 0.26 g (42%)
of the title compound was obtained. 1Hn class="Chemical">NMR (500 MHz, CDCl3): δ 7.89 (m, 2H), 7.53 (dd, J = 1.8,
0.7 Hz, 1H), 7.44 (m, 1H), 7.33 (m, 2H), 7.22 (dd, J = 8.3, 7.3 Hz, 1H), 6.63 (s, 2H), 6.58 (d, J =
8.3 Hz, 1H), 6.54 (dd, J = 3.4, 0.7 Hz, 1H), 6.49
(m, 2H), 2.92 (m, 2H), 2.87 (m, 2H). 13CNMR (126 MHz,
CDCl3): δ 190.2, 152.1, 151.8, 145.0, 142.3, 137.1,
135.3, 134.5, 132.7, 130.6, 129.7, 128.3, 126.8, 126.4, 115.9, 115.6,
115.0, 111.9, 110.8, 30.4, 27.1.
Procedure for Addition
of Phenyl Boronic Acid to Enones.[27]
Enone (1.0 mmol), arylboronic acid (2.0 mmol), Pd2(dba)3 (5 mol %, 0.05 mmol), PPh3 (10 mol %, 0.10 mmol),
Cs2CO3 (1.0 mmol, 0.32 g), and CHCl3 (0.01 mL) in toluene (2 mL) were heated to 80 °C for 24 h.
The mixture was concentrated and purified via chromatography.
Following the procedure for addition of
boronic acids from 0.27 g (0.93 mmol) of 5, 0.18 g (53%)
of the title compound was obtained. n class="Chemical">1H NMR (500 MHz, CDCl3): δ 7.81 (dd, J = 8.4, 1.4 Hz, 1H),
7.61–7.55 (m, 1H), 7.54–7.49 (m, 1H), 7.31–7.23
(m, 6H), 7.18 (dd, J = 13.1, 7.1 Hz, 3H), 6.69–6.61
(m, 2H), 6.52–6.43 (m, 2H), 6.19 (s, 2H), 5.42 (dd, J = 8.2, 6.4 Hz, 1H), 3.82 (dd, J = 17.1,
8.4 Hz, 1H), 3.65 (dd, J = 17.1, 6.2 Hz, 1H). 13CNMR (126 MHz, CDCl3): δ 199.7, 153.4,
150.4, 144.0, 142.2, 142.1, 134.2, 130.9, 130.5, 129.4, 128.4, 128.3,
128.3, 127.9, 126.3, 126.1, 118.0, 117.3, 115.7, 111.2, 108.8, 45.3,
41.8. HRMS (ESI): calcd for C25H22NO2+ (MH+) 368.1645, found 368.1650.
Procedure
for Addition of Diethyl Malonate.[26]
To a solution of 1 mmol of chalcone and 5 mL of diethyl malonate
in 25 mL of ethanol was added 0.25 g of sodium in 2.5 mL of ethanol,
the mixture was refluxed for 2 h, quenched with NH4Cl,
and extracted with ether, and the extract was dried over Na2SO4, concentrated, and chromatographed.
A mixture of
chalcone (0.3 mmol) and n class="Chemical">nitromethane (1.5 mmol) in DMSO (1 mL) in
the presence of MS 4 Å (100 mg) was stirred at room temperature
under an argon atmosphere. After 12 h, the reaction mixture was quenched
with a phosphate buffer (pH 7, 20 mL). The organic materials were
extracted with ethyl acetate and dried over anhydrous MgSO4. If necessary, the product was purified with flash chromatography.
Procedure D.[25b]
To a mixture
of chalcone (0.3 mmol) and nitromethane (1 mL) in DMSO (5 mL) was
added 0.3 mmol of tBuOK. After 12 h at room temperature the reaction
mixture was quenched with saturated aqueous NH4Cl. The
organic materials were extracted with ethyl acetate and dried over
anhydrous MgSO4. If necessary, the product was purified
with flash chromatography.
Following general procedure D for addition
of nitromethane from 0.24 g (0.76 mmol) of (E)-1-(2-aminophenyl)-3-(2-(furan-2-yl)phenyl)prop-2-en-1-one,
0.11 g (38%) of the title compound was obtained as a mixture of diastereomers
that could not be separated. 1HNMR (500 MHz, CDCl3): δ 7.52 (m, 2H), 7.43 (d, J = 3.8
Hz, 2H), 7.36 (m, 1H), 7.17 (m, 1H), 6.59 (d, J =
3.3 Hz, 1H), 6.51 (m, 2H), 6.40 (m, 3H), 5.23 (m, 1H), 4.88 (dd, J = 13.1, 9.4 Hz, 1H), 4.56 (td, J = 9.7,
4.6 Hz, 1H), 2.76 (m, 1H), 2.69 (m, 2H), 1.80 (m, 1H), 1.64 (dtd, J = 13.6, 8.2, 5.1 Hz, 1H). HRMS (ESI): calcd for C22H21N2O4+ (MH+) 377.1496, found 377.1494.
General Procedure for Reductive
Amination
To a solution of substituted aniline (1 mmol) inMeOH (10 mL) at 0 °C was added NaOAc (2 equiv), glacial acetic
acid (4 equiv), the corresponding aldehyde (1.5 equiv), and NaCNBH3 (1.1 equiv). The solution was warmed slowly to room temperature
over 1 h. The mixture was then filtered through a plug of silica gel
and washed with 1% glacial acetic acid in ethyl acetate. The solution
was then washed with brine, dried (Na2SO4),
and concentrated to afford the crude material, which was then purified
with flash chromatography.
General Procedure for Oxidation
with MnO2
Benzylic alcohol (1 equiv) was dissolved
inDCM, 7 equiv of MnO2 was added, and the mixture was
stirred overnight and then filtered through a plug of Celite, concentrated,
and purified using flash chromatography.
2-((3-(Furan-2-yl)propyl)amino)benzaldehyde
(57)
(1) (2-((3-(Furan-2-yl)propyl)amino)phenyl)methanol
was prepared following the general procedure for reductive amination
from 0.60 g (4.46 mmol) of 2-aminophenylmethanol with a yield of 0.78
g (73%) and used without further purification in the next step. 1HNMR (500 MHz, CDCl3): δ 7.35 (dd, J = 1.8, 0.8 Hz, 1H), 7.25 (td, J = 7.9,
1.6 Hz, 1H), 7.09 (dd, J = 7.6, 1.6 Hz, 1H), 6.68
(m, 2H), 6.32 (dd, J = 3.1, 1.9 Hz, 1H), 6.05 (m,
1H), 4.68 (s, 2H), 3.24 (t, J = 7.0 Hz, 2H), 2.80
(t, J = 7.4 Hz, 2H), 2.04 (p, J =
7.2 Hz, 2H). 13CNMR (126 MHz, CDCl3): δ
155.4, 147.6, 141.0, 129.7, 129.2, 124.2, 116.3, 110.6, 110.2, 105.1,
64.9, 42.8, 27.7, 25.6.(2) Following the general procedure
for benzylic alcohol oxidation from 0.78 g (3.37 mmol) of (2-((3-(furan-2-yl)propyl)amino)phenyl)methanol,
0.51 g (66%) of the title compound was obtained. 1HNMR
(500 MHz, CDCl3): δ 9.84 (s, 1H), 8.40 (s, 1H), 7.49
(d, J = 7.6 Hz, 1H), 7.41 (t, J =
7.8 Hz, 1H), 7.35 (s, 1H), 6.70 (m, 2H), 6.32 (s, 1H), 6.06 (m, 1H),
3.31 (m, 2H), 2.79 (t, J = 7.4 Hz, 2H), 2.06 (p, J = 7.2 Hz, 2H). 13CNMR (126 MHz, CDCl3): δ 193.9, 155.0, 150.7, 141.1, 136.7, 135.8, 118.4, 114.8,
110.8, 110.2, 105.4, 41.6, 27.4, 25.4. HRMS (ESI): calcd for C14H16NO2+ (MH+)
230.1176, found 230.1176.
A 2.24 g portion of 2-bromo-2′-nitroacetophn class="Chemical">enone
(51; 9.2 mmol) was dissolved in 30 mL of dichloromethane
along with 1.08 g of 2-furylmercaptan (9.2 mmol) and 1.48 g of dry
pyridine (18.4 mmol), and the reaction mixture was stirred for 1 h
before it was quenched with 5% HCl solution (10 mL). The aqueous layer
was then extracted with dichloromethane (2 × 20 mL), and the
organic layers were combined and dried over anhydrous sodium sulfate.
The organic layer was then concentrated to give 2.50 g (98%) of 1-(2-nitrophenyl)-2-(furan-2-ylmethylthio)ethanone.
This was then dissolved in 100 mL of ethanol along with 5.23 g of
tin(II) chloride (27.0 mmol) and heated to 70 °C under a nitrogen
atmosphere for 2 h. Saturated sodium bicarbonate solution was added
slowly until the solution reached pH 8, giving a thick milky white
emulsion. This was filtered through a pad of Celite, and the filtrate
was extracted with EtOAc (3 × 100 mL). The organic phase was
washed with brine (2 × 50 mL) and then dried over anhydrous sodium
sulfate. The solvent was removed under reduced pressure, and the crude
product was purified by flash chromatography to give 1.76 g (78%)
of the title compound. 1HNMR (500 MHz, CDCl3): δ 7.67 (dd, J = 8.2, 1.0 Hz, 1H), 7.40
(dd, J = 1.8, 0.7 Hz, 1H) 7.30 (dt J = 8.4, 1.3 Hz 1H), 6.69 (d, J = 8.4 Hz, 1H), 6.15
(dt J = 8.2, 1.0, 1H) 6.37–6.26 (m, 4H), 3.85
(s, 2H), 3.83 (s, 2H). 13CNMR (126 MHz, CDCl3): δ 196.7, 151.1, 150.7, 142.4, 134.8, 131.4, 117.5, 116.3,
115.8, 110.4, 108.4, 37.6, 28.5. HRMS (ESI): calcd for C13H14NO2S+ (MH+) 248.0740, found 248.0743.
General Procedure for Photochemical Reactions
A 4 mmol
portion of the photoprecursor was dissolved in 200 mL of methanol,
and the solution was degassed and irradiated with RPR-3500 until the
reaction was complete.
A 0.31 g
portion of 52 was dissolved in 50 mL of acetonitrile
(5% n class="Chemical">H2O by volume) and irradiated in a Pyrex reaction vessel
in a Rayonet reactor equipped with RPR-3500 UV lamps (broad-band 300–400
nm UV source with peak emission at 350 nm) for 2 h. The solution was
concentrated under reduced pressure and purified via flash chromatography,
with a yield of 0.28 g (89%). 1HNMR (500 MHz, CDCl3): δ 8.32 (dd, J = 8.1, 1.3 Hz, 1H),
7.24, (dt, J = 8.1, 1.5 Hz, 1H), 6.97 (dt, J = 8.1, 1.3 Hz, 1H), 6.76, (dd, J = 8.0,
1.2 Hz, 1H), 6.31 (d, J = 9.8 Hz, 1H), 5.63 (dd, J = 9.8, 3.2 Hz, 1H), 5.50 (ddd, J = 5.0,
3.4, 0.6 Hz, 1H), 4.60–4.55 (m, 1H), 3.38 (d, J = 9.8 Hz, 1H), 3.07 (m, 2H), 2.91 (d, J = 9.8 Hz,
1H), 2.85 (t, J = 1.4 Hz, 1H). 13CNMR
(126 MHz, CDCl3): δ 196.7, 151.1, 150.7, 142.4, 134.8,
131.4, 117.5, 116.3, 115.8, 110.4, 108.4, 37.6, 28.5. HRMS (ESI):
calcd for C13H14NO2S (MH+) 248.0740, found 248.0739.
General Procedure for Acid-Induced
Rearrangemen
The photoproducts were dissolved in 5 mL of
dichloromethane, 0.05 mL of trifluoroacetic was added, and the reaction
mixture was stirred until the reaction was complete. The reaction
mixture was then concentrated and purified by flash chromatography.
Yields are summarized in Table 1.
An approximately
0.1–0.3 M solution of the photoprecursors in acetonitrile was
irradiated in Pyrex or glass reaction vessels in a Rayonet reactor
equipped with RPR-3500 UV lamps (broad-band 300–400 nm UV source
with peak emission at 350 nm) until the reaction was complete.
From 203 mg (1.34 mmol)
of 73, following the general procedure for irradiation
of amines 120 mg (67%) of the title compound was obtained upon chromatography. n class="Chemical">1H NMR (500 MHz, CDCl3): δ 7.11 (m, 1H), 6.88
(m, 1H), 6.56 (d, J = 8.2 Hz, 1H), 6.10 (dd, J = 5.6, 2.0 Hz, 1H), 6.04 (t, J = 2.1
Hz, 1H), 5.75 (dd, J = 5.6, 1.2 Hz, 1H), 5.62 (s,
1H), 3.68 (m, 1H), 3.52 (m, 1H), 3.37 (m, 2H), 2.39 (m, 2H), 2.17
(m, 1H), 2.01 (m, 1H). 13CNMR (126 MHz, CDCl3): δ 148.6, 146.5, 139.6, 134.5, 129.4, 128.9, 126.2, 121.7,
113.8, 113.6, 105.0, 80.9, 50.1, 38.7, 37.5, 22.1. HRMS (ESI): calcd
for C16H16NO+ (MH+) 238.1226,
found 238.1232.
General Procedure for the Rearrangement of
Amides
A solution of the photoproduct in DCM (15 mL) was
treated with 0.5 mL of n class="Chemical">TFA; when the reaction was complete as monitored
by NMR, the reaction mixture was concentrated and purified using flash
chromatography.
Authors: Olga A Mukhina; W Cole Cronk; N N Bhuvan Kumar; M Chandra Sekhar; Anunay Samanta; Andrei G Kutateladze Journal: J Phys Chem A Date: 2014-06-24 Impact factor: 2.781
Authors: Lisa A Marcaurelle; Eamon Comer; Sivaraman Dandapani; Jeremy R Duvall; Baudouin Gerard; Sarathy Kesavan; Maurice D Lee; Haibo Liu; Jason T Lowe; Jean-Charles Marie; Carol A Mulrooney; Bhaumik A Pandya; Ann Rowley; Troy D Ryba; Byung-Chul Suh; Jingqiang Wei; Damian W Young; Lakshmi B Akella; Nathan T Ross; Yan-Ling Zhang; Daniel M Fass; Surya A Reis; Wen-Ning Zhao; Stephen J Haggarty; Michelle Palmer; Michael A Foley Journal: J Am Chem Soc Date: 2010-11-10 Impact factor: 15.419
Authors: Christina Despotopoulou; Richard C Bauer; Arkady Krasovskiy; Peter Mayer; Jeffrey M Stryker; Paul Knochel Journal: Chemistry Date: 2008 Impact factor: 5.236
Authors: Olga A Mukhina; Dmitry M Kuznetsov; Teresa M Cowger; Andrei G Kutateladze Journal: Angew Chem Int Ed Engl Date: 2015-06-30 Impact factor: 15.336
Figure 1
Scheme 1
Figure 2
Scheme 2
Scheme 3
Scheme 4
Scheme 5
Figure 3
Scheme 6
Figure 4
Scheme 7
Scheme 8
Scheme 9
Scheme 10
Scheme 11
Scheme 12
Scheme 13