Magdalena Dolna1, Michał Nowacki1, Oksana Danylyuk2, Artur Brotons-Rufes3, Albert Poater3, Michał Michalak1. 1. Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland. 2. Institute of Physical Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland. 3. Institut de Química Computacional i Catàlisi and Departament de Química, Universitat de Girona, c/ M. Aurèlia Capmany 69, 17003 Girona, Catalonia, Spain.
Abstract
The direct catalytic alkynylation/dehydrative cyclization of 2-amino-3-trifluoroacetyl-pyridines on water was developed for the efficient synthesis of a broad range of fluorinated 1,8-naphthyridines from terminal alkynes. A novel N-heterocyclic carbene (NHC) ligand system that combines a π-extended acenaphthylene backbone with sterically bulky pentiptycene pendant groups was successfully utilized in a copper- or silver-mediated cyclization. Computational analysis of the reaction pathway supports our explanation of the different experimental conversions and yields for the set of copper and silver catalysts. The impact of steric hindrance at the metal center and the flexibility of substituents on the imidazole ring of the NHC on catalytic performance are also discussed.
The direct catalytic alkynylation/dehydrative cyclization of 2-amino-3-trifluoroacetyl-pyridines on water was developed for the efficient synthesis of a broad range of fluorinated 1,8-naphthyridines from terminal alkynes. A novel N-heterocyclic carbene (NHC) ligand system that combines a π-extended acenaphthylene backbone with sterically bulky pentiptycene pendant groups was successfully utilized in a copper- or silver-mediated cyclization. Computational analysis of the reaction pathway supports our explanation of the different experimental conversions and yields for the set of copper and silver catalysts. The impact of steric hindrance at the metal center and the flexibility of substituents on the imidazole ring of the NHC on catalytic performance are also discussed.
Naphthyridines are
a ubiquitous structural motif in modern medicinal
chemistry, as well as in organic synthesis and catalysis. Transition-metal
complexes of 1,8-naphthyridine-based ligands have been utilized in
many efficient catalytic processes. Among them, rhodium-,[1] iridium-,[2] ruthenium-,[3] copper-,[4] and nickel-catalyzed[5] reactions (Figure ) have gained attention in recent years for enabling
useful transformations. These heterocycles have also found widespread
application as scaffolds in supramolecular chemistry, for example,
as molecular tweezers,[6] highly selective
molecular receptors,[7] or in self-assembly
host–guest systems[8] (Figure ). Naphthyridine derivatives
are also a central point of interest in modern material science as
well as being utilized for the preparation of dye-sensitized solar
cells[9] and OLEDs.[10] Furthermore, 1,8-naphthyridines can act as powerful hydrogen bond
acceptors, which are often incorporated into pharmaceutical active
substances, such as voreloxin,[11] trovafloxacin,[12] and many other antifungal,[13] antibacterial,[14] antiviral,[15] anticancer,[16] or
antidepressant[17] compounds. Although fewer
in number, some natural products contain this motif; an example of
such is eucophylline, which has a partially reduced 1,8-naphthyridine
skeleton.[18]
Figure 1
Applications of naphthyridines
in catalysis, medicinal chemistry,
and materials science.
Applications of naphthyridines
in catalysis, medicinal chemistry,
and materials science.The biological activity
of naphthyridines or quinolines can be
modified by the incorporation of one or more fluorine atoms into its
structure. Synthesis of fluorinated naphthyridines has been demonstrated
many times (for selected examples, see Scheme ).[15,19] Although many methods
have been developed for direct fluorination of azaheterocycles,[20] direct functionalization of naphthyridine using
transition-metal-catalyzed processes remains challenging due to its
ability to strongly bind transition metals and suppress their catalytic
performance. Therefore, there is a need for a new and practical approach
to the synthesis of fluorinated naphthyridines.
Scheme 1
Friedländer
Reaction Leading to Fluorinated Naphthyridines
The classic Friedländer reaction between an ortho-amino aldehyde and an activated methylene compound
remains the most
obvious choice for the synthesis of many quinolines and naphthyridines.[21] In contrast, the fluorinated ortho-aminophenones present a challenge under classical conditions due
to the reactivity of the α-fluoroketone moiety, which can easily
undergo hydration or nucleophilic addition when a strong mineral acid
or base is used (Scheme ). It appears that fluorinated ortho-aminophenones
have been reported only by Strekowski in the late 90s with very limited
scope (seven examples) for quinoline synthesis.[22] Note that fluorinated ortho-aminophenones
derived from aminopyridine (2-amino-3-trifluoroacetyl-pyridines) have
not been utilized to prepare naphthyridines under those harsh conditions.We anticipated that a modified Friedländer reaction between
terminal alkynes and 2-amino-3-trifluoroacetyl-pyridines could provide
a milder synthetic route to useful naphthyridine derivatives. Our
previous work,[23] and that of others,[24] has demonstrated alkynylation catalyzed by copper
and silver NHC complexes on water. We reason that an appropriate combination
of steric and electronic tuning of the NHC ligand is critical to its
performance in catalysis and may be adapted for this reaction. In
particular, we observe a linear correlation between steric hindrance
of N-heterocyclic carbene ligands expressed as the percentage of buried
volume (%Vbur)[25] and the yield
resulting from direct catalytic alkynylation of trifluoromethyl ketones
leading to trifluoromethyl propargylic alcohols.[23b] Because increased steric hindrance and donor character
of the NHC ligand heavily influence the yield of the alkynylation
process, we hypothesize that a more electron-rich NHC ligand (than
standard IPr; Scheme ) equipped with a polyaromatic skeleton should positively impact
the alkynylation of pyridine-based ortho-aminophenones.
Scheme 2
NHC–Cu–Cl and NHC–Ag–Cl Complexes Used
for Optimization Studies for the Synthesis of the Naphthyridine Derivative 3a
Results and Discussion
To test our hypothesis, a series of NHC ligands 4a–h were prepared from several sterically hindered
aniline derivatives (for details, Scheme ). For the initial catalytic performance
test, unsubstituted 2-amino-3-trifluoroacetyl-pyridines (1a) and cyclopropyl acetylene 2a were selected (Scheme ). The optimization
studies were conducted at an elevated temperature on water with 2
mol % of catalyst and an equimolar amount of TMG (1,1,3,3-tetramethylguanidine).
Generally, silver and copper complexes 4a–d did not perform well under these conditions (Table , entries 1–4) providing
naphthyridine 3a in marginal yield. Extension of the
NHC ligand backbone by incorporating a rigid acenaphthylene subunit
is known to increase σ-donation[26] (this is an NHC–BIAN-type in reference to its bis(iminoacenaphthene)
precursor). The resulting formation of the more nucleophilic metal
acetylide had a beneficial effect on reactivity. In the series of
complexes with NHC ligands bearing a π-extended backbone (4e–h, Table , entries 5–8), copper complexes 4f and 4h performed better than silver ones 4e and 4g. Finally, complex 4h bearing
pentiptycene as the N-wingtip substituent was observed to be the superior
catalyst, providing naphthyridine 3a in a 64% isolated
yield. Further optimization proved that decreasing the amount of alkyne 2a to 1.2 equiv afforded product 3a with a comparable
yield of 50%, while increasing up to 2.2 equiv returned a lower yield
of 21% (Table , entries
12 and 13; for details on the optimization, see SI).
Scheme 5
Synthesis of NHC–Cu–Cl and NHC–Ag–Cl
Complexes and Selected Molecular Structure for Complexes 4a, 4b, 4e, and 4f
Thermal ellipsoids represent
50% probability; hydrogen atoms on carbon are omitted for clarity.
Table 1
Results of Optimization Studies for
the Synthesis of the Naphthyridine Derivative 3a
entry
2a (equiv)
NHCCuCl
time
(h)
temp. (°C)
conv. (%)a
yield (%)b
1
1.8
4a
19
120
95
4
2
1.8
4b
19
120
33
4
3
1.8
4c
19
120
79
13
4
1.8
4d
19
120
19
1
5
1.8
4e
19
120
88
10
6
1.8
4f
19
120
63
55
7
1.8
4g
19
120
89
2
8
1.8
4h
19
120
88
64
9
1.8
4h
1
120
18
<1
10
1.8
4h
19
100
10
<1
11
1.8
4h
19
80
5
1
12
1.2
4h
19
120
80
50
13
2.2
4h
19
120
87
21
Conversion based
on GC with durene
as the internal standard.
Yield based on GC from the calibration
curve.
Conversion based
on GC with durene
as the internal standard.Yield based on GC from the calibration
curve.To test our hypothesis,
a series of NHC ligands 4a–h were
prepared from several sterically hindered
aniline derivatives (for details, see Scheme ). For the initial catalytic performance
test, unsubstituted 2-amino-3-trifluoroacetyl-pyridines (1a) and cyclopropyl acetylene 2a were selected (Scheme ). The optimization
studies were conducted at an elevated temperature on water with 2
mol % of catalyst and an equimolar amount of TMG (1,1,3,3-tetramethylguanidine).
Generally, silver and copper complexes 4a–d did not perform well under these conditions (Table , entries 1–4), providing
naphthyridine 3a in marginal yield. Extension of the
NHC ligand backbone by incorporating a rigid acenaphthylene subunit
is known to increase σ-donation[26] (this is an NHC–BIAN-type in reference to its bis(iminoacenaphthene)
precursor). The resulting formation of the more nucleophilic metal
acetylide had a beneficial effect on reactivity. In the series of
complexes with NHC ligands bearing a π-extended backbone (4e–h, Table , entries 5–8), copper complexes 4f and 4h performed better than silver ones 4e and 4g. Finally, complex 4h bearing
pentiptycene as the N-wingtip substituent was observed to be the superior
catalyst, providing naphthyridine 3a in a 64% isolated
yield. Further optimization proved that decreasing the amount of alkyne 2a to 1.2 equiv afforded product 3a with a comparable
yield of 50%, while increasing up to 2.2 equiv returned a lower yield
of 21% (Table , entries
12 and 13; for details on the optimization, see SI, Table S1).With the optimal catalyst and reaction conditions
established,
the scope of the NHC–BIAN–CuCl-catalyzed naphthyridine
synthesis was investigated using a variety of terminal alkynes (Scheme ). Initially, a series
of phenylacetylene derivatives possessing electron-donating and electron-withdrawing
groups in the para position to the triple bond were
investigated. The desired heterocycles 3b–f were obtained with excellent yields of 65–92%. Rather
surprisingly, complex 4h catalyzed the reaction with
the substrate 4-CF3 phenylacetylene to give 3f. This stands in contrast to the findings in our previous work on
the alkynylation of nitrones in which phenylacetylene bearing electron-withdrawing
groups (NO2, TsO) appeared to be unreactive.[23a]
Scheme 3
Scope of NHC-Catalyzed Naphthyridine Synthesis
TBS-protected phenol was used
at the alkyne substrate. Deprotection of phenol moiety occurred under
the reaction conditions.
Scope of NHC-Catalyzed Naphthyridine Synthesis
TBS-protected phenol was used
at the alkyne substrate. Deprotection of phenol moiety occurred under
the reaction conditions.Alkyl-substituted
alkynes bearing functional groups such as an
amide (3g), an ester (3h), a piperidine
(3i), or an unprotected hydroxyl group (3j,k) were also tolerated. Further investigation demonstrated
that a common bioisostere of disubstituted benzene[27] could be directly attached to the naphthyridine core. A
sterically encumbered adamantane derivative (3l) was
obtained in a high yield of 58%, and a double Friedländer reaction
afforded a dinaphthyridine derivative with two heterocyclic subunits
connected via bicyclo[2.2.2]octane linker (3m). Finally,
the synthetic utility of the method was demonstrated by successfully
utilizing several structurally complex alkyne substrates derived from
biologically active compounds as well as natural products, further
supporting the excellent functional group tolerance of this methodology.
Thus, androstane, cholesterol, biotin, mycophenolic acid, quinolonic
acid, and sulfamethoxazole-derived alkynes afforded products 3q–v in excellent yields in the range
of 65–99%. It should be noted that no byproducts have been
detected despite the presence of functional groups that are potentially
reactive toward metal acetylides. These include 5-membered lactones
and cyclopropyl rings that can undergo ring opening, and enones or
ketone conjugate addition. Several of the substituents used are common
ligands able to coordinate with copper and potentially suppress its
catalytic activity such as the heterocycles tetrahydrofuran and oxazole
or amide, urea, and hydroxyl groups. However, these did not appear
to suppress the naphthyridine formation. Next, we examined whether
difluoromethyl ketone derivatives could be engaged in the Friedländer
reaction. These are potentially more challenging due to their slightly
acidic character. The incorporation of the CF2H group into
heterocycles has gained a lot of attention in medicinal chemistry[19a,28] due to their ability to act as lipophilic hydrogen bond donors,
modifying permeability, binding affinity, and bioavailability.[29] To our delight, difluoromethyl naphthyridines 3w–y were formed in high yields of around
80%. The method also demonstrated that ethynyl-substituted heterocycles
could provide the respective naphthyridines. Usually, coupling two
heterocyclic components is accomplished via a palladium-catalyzed
protocol; however, the required 2-substituted azaheterocycles (e.g.,
2-bromopyridine or its analogues) are challenging substrates.[30] The protocol developed here offers an alternative.
In our case, thiophene 3n and indole 3p derivatives
were obtained in high yields, whereas the benzophenone-derived alkyne
afforded product 3o in lower yields of 38%. To improve
the yield of the benzofuran-substituted naphthyridine 3o, we investigated whether this could be prepared via a novel tandem
catalytic alkynylation/double dehydrative cyclization from the salicylic
aldehyde derivative 2b (Scheme ). Indeed, naphthyridine 3o was
formed by this approach but with a lower yield of 25%.
Scheme 4
Tandem
Direct Catalytic Alkynylation/Double Dehydrative Cyclization
Finally, the robustness of the naphthyridines
synthesis was demonstrated
by the gram-scale synthesis of the octanol-substituted naphthyridine 3k. It should be noted that the 8-fold scale-up did not impact
the high yield (89% on a 0.5 mmol scale vs 92% on a 4.0 mmol scale)
and afforded 1.3 g of 3k in a single batch.
Synthesis of
NHC–BIAN-Type Complexes and Mechanistic
Considerations
The key to the successful implementation of
NHC metal catalysts in the development of a protocol for the synthesis
of fluorinated naphthyridines in water was the rational design of
the NHC ligand’s structure. We initially assumed that ligands
exhibiting strong σ-donor properties and possessing sterically
hindered N-wingtip substituents with additional electron-donating
functionality such as methoxy groups should be the best combination.
We were particularly interested in how the extension of the NHC backbone
would influence the ligand’s electronic properties and hence
the catalytic activity of its complex. An excellent example of how
structural modification of an NHC ligand can significantly influence
the catalytic activity of metal complexes is the IPr* ligand. This
sterically encumbered NHC ligand, developed by Nolan and co-workers,[31] had a profound effect on the development of
processes catalyzed by Pd, Rh, Ir, Cu, and Au complexes, demonstrating
remarkable catalytic performance in comparison to the commonly used
IPr ligand.[32]A set of carbene precursors
(7) were synthesized via bisimine (6) formation
and subsequent cyclization with chloromethyl ethyl ether (EOMCl; Scheme ). It should be noted that the aniline (5)- and
pentiptycene[33]-derived starting materials
are easily obtained on the multigram scale following literature procedures.
The respective imidazolium salts (7) were also prepared
in large quantities and isolated by precipitation from the reaction
mixture (for details, see the SI). Copper
and silver complexes of the NHC precursors (7) were prepared
using Nolan’s[34] and Lin’s[35] well-established procedures. These afforded
the pure complexes 4a–4h without
the need for chromatographic purification at any step (Scheme ). Complex 4h,
which appeared to be optimal for naphthyridine synthesis (vide infra), was successfully prepared on a large scale
(890 mg) without any reduction in yield (81%), underlining the scalability
of the developed method. The structures of complexes 4a, 4b, 4e, and 4f were unequivocally
confirmed by X-ray analysis. Unfortunately, all attempts to get monocrystals
of the pentiptycene derivatives 4g and 4h failed due to the poor solubility of the complex in organic solvents.
Synthesis of NHC–Cu–Cl and NHC–Ag–Cl
Complexes and Selected Molecular Structure for Complexes 4a, 4b, 4e, and 4f
Thermal ellipsoids represent
50% probability; hydrogen atoms on carbon are omitted for clarity.To shed some light on the structure–reactivity
relationship
of these NHC ligands, we investigated their electronic and steric
properties. First, we tried to estimate their σ-donor properties
by measuring the 13C{1H} NMR spectra of heteroleptic
gold complexes of the type [NHC(i-Pr2-bimy)Au]BF4, where i-Pr2-bimy is a 1,3-diisopropylbenzimidazolin-2-ylidene
NHC ligand. The original methodology developed by Huynh and co-workers[36] used the 13C{1H} NMR chemical
shift of the carbene carbon atom of palladium(II) NHC complexes of
the type trans-[PdBr2(i-Pr2-bimy)L]. If palladium complexes are not easily accessible,
heteroleptic gold(I) complexes [NHC1(i-Pr2-bimy)Au]X could be used instead.[37] Generally, a stronger donating ligand induces a downfield
shift in the 13C{1H} NMR signal of the carbene
atom of the probe, i.e., the i-Pr2-bimy
ligand. Thus, four heteroleptic gold(I) complexes, 11a–11d, were synthesized via a route employing
(i-Pr2-bimy)AuOAc.[37] The characteristic signal of the carbene i-Pr2-bimy ligand in [NHC1(i-Pr2-bimy)Au]X was assigned by HMBC analyses in each case
(Scheme ). It was
found that replacing the hydrogen atoms (complex 11a)
bonded to the imidazolium core with methyl groups (complex 11b) slightly increases the σ-donor character of the NHC ligand,
which is consistent with literature data for structurally similar
NHC ligands.[38] Complexes 11c and 11d bearing a polyaromatic acenaphthylene backbone
exhibited chemical shifts for the carbene carbon atom that were very
similar to complex 11b. It should be noted that Szostak
and others[26] have suggested that NHC–BIAN-type
ligands are stronger σ-donors and have better π-acceptor
character than the classical imidazolylidene NHCs, which is in accordance
with our assumption.
Scheme 6
Synthesis of Heteroleptic [NHC(i-Pr2-bimy)Au]BF4 Complexes and Comparison of
the 13C{1H} NMR Chemical Shifts of Their Carbene
Carbon
Considering that the electronic
properties of any NHC ligand used
will be difficult to determine, we reasoned that the steric properties
should be an important factor for catalytic activity. The steric bulk
of NHCs can be expressed by the percent buried volume (%Vbur), a general descriptor initially developed for NHCs[39] by Cavallo and co-workers,[25a] introduced for the first time in 2003 in a combined experimental/theoretical
work by Nolan, Cavallo, and co-workers.[25c] The calculated %Vbur values for the 4a–h series are 62.6% (4a), 56.5% (4b), 65.3% (4c), 58.4% (4d), 62.5% (4e), 58.7% (4f), 50.8% (4g), and
48.7% (4h). We were surprised to find that the best-performing
catalysts 4g and 4h had the lowest %Vbur in the series, despite having the bulkiest substituents.
In part, the reason is based on the rigidity imposed by the NHC backbone
in those systems, as well as in 4e and 4f.[40] Thus, the N-appended aryl rings on
the imidazole are sterically constrained and unable to rotate. Furthermore,
the interaction of the imidazole with the aryl rings pushes them up.[41] The most opened C–N–C angle between
the linking carbon atom of the NHC ligand increases from 121.0°
for 4a to 123.1 and 125.7° for 4g and 4h, respectively. In fact, the correlation between %VBur and the observed catalytic conversions and yields did not
result in any Pearson coefficients above 0.8. Worse correlations were
obtained for the silver complexes. However, selectively removing the
values of the most rigid species in the 4e–4g series, i.e., 4g and 4h, we increase
the R2 to 0.887. Also, removing 4e and 4f produces a greater increase to 0.985.
For the copper series, even though the agreement was good, removing 4e improves this to a near-perfect linear fit (R2 = 0.9997). However, with just three points, the statistical
significance remains low. And since the same reasoning is not applicable
to the silver series, no final judgment can be made.The disparity
between %Vbur values for the chloride
compounds (4a–h) with both metals,
copper and silver, hints that the series of NHC ligands are flexible.
The values for silver are 5% larger than for copper. Tied to the flexibility
of the substituents on the NHCs, the energy barrier of the rate-determining
step (rds) gives insight into the measurement of %Vbur,
i.e., the NHC that is maximally tensioned but stable in that tensioned
conformation. Thus, it is fundamental to also characterize the reaction
pathway.A plausible mechanistic cycle is depicted in Scheme . The catalytic process
commences with the
formation of the copper acetylide (a) proceeding via
a well-established π-activation mode. Within a minute of combining
the NHC–BIAN–CuCl complex with the terminal alkyne and
base (b), the formation of a yellow solid was observed.
The copper acetylide then undergoes 1,2-addition, producing a propargylic
alkoxide (c). It should be noted that the NHC ligand
plays a dual role in this process, forming a nucleophilic acetylide
and promoting a mononuclear intermediate, enabling the addition. The
mononuclear structure of the NHC copper acetylide was confirmed by
Jones and co-workers by X-ray crystallographic analysis of an IPrCuC≡CPh
complex.[42] The role of the NHC ligand was
further evidenced by the lack of formation of naphthyridine when the
reaction is attempted with a stoichiometric amount of polymeric copper
phenylacetylide (PhC≡CCu) (see
the SI). The last step of the catalytic
cycle involves the protonation of copper alkoxide by TMG hydrochloride,
regenerating the NHC–Cu–Cl catalyst. The propargylic
alcohol (d) then might undergo either spontaneous or
water-assisted dehydrative cyclization. Unfortunately, all experimental
attempts to isolate this intermediate have failed. To confirm the
beneficial role of copper in the 6-endo-dig cyclization step, preparation of 3z was undertaken
in D2O. This test reaction produced naphthyridine 3z in a virtually quantitative yield with 92% deuterium incorporation
into the aromatic ring (full proton–deuterium exchange was
also detected in the α position of the ester functionality; Scheme ).
Scheme 7
Plausible Catalytic
Cycle and Scheme of Deuterium-Labeled Experiment
We conducted DFT calculations, screening the whole reaction
pathway
(Scheme ) to find
out the rds and any other kinetically significant steps. First, the
reactant TMG is responsible for the deprotonation of the alkyne substrate,
not as a single moiety, i.e., TMG·HCl, but as separate ions,
the TMG·H+ cation and Cl– anion,
since the ionic scenario is more stable by 7.5 kcal/mol.[43] Therefore, the proton is readily replaced by
the cationic Cu–NHC moiety despite the large difference in
size. The intermediate a then sees amine b, although its metallic center is hardly affected and does not lose
the linear axis C–Cu–C until the transition state where
the C–C bond between the former alkyne and the keto group of
the 2-amino-3-trifluoroacetyl-pyridines is formed. This overcomes
an energy barrier of 25.4 kcal/mol calculated from the initial NHC–Cu–Cl
catalyst. Although the nitrogen of b has a favorable
interaction with the metal in the transition state, the resulting
intermediate c is in equilibrium with isomer c′ where the oxygen of the former ketone group coordinates to the copper
instead. The transition state where there is a Cu···O
interaction was also studied, but it is less favorable by 2.9 kcal/mol
(see Figure S6 for further details). For
the protonation of oxygen by the proton previously extracted by TMG,
an increase in a thermodynamic stability of 23.6 kcal/mol occurs in
the transition from c to d. A transition-state
energy barrier of 9.4 kcal/mol is determined for the cyclization forming
the C–N bond. Formation of g from f is assisted by a molecule of water, which facilitates proton transfer
from the positively charged nitrogen to the hydroxyl group, which
leaves as water in a condensation step. This step requires 8.3 kcal/mol
and leads to a thermodynamic stabilization of 34.8 kcal/mol. Again,
two water molecules facilitate the transfer of the remaining proton
in intermediate g from the nitrogen to the carbon attached
to the metal, with the following kinetic and thermodynamic energies
of 21.0 and 14.6 kcal/mol, respectively. This gives way to the release
of the organic product, exchanging it for a chloride anion and thus
closing the catalytic cycle. This step was also studied with one and
three water molecules resulting in higher kinetic costs of 14.9 and
1.4 kcal/mol, respectively.
Scheme 8
Reaction Mechanism of the NHC–Cu(I)-Catalyzed
Friedländer-Type
Annulation of 2-Amino-3-trifluoroacetyl-pyridines with a Terminal
Alkyne Using the Pentiptycene NHC Complex
Steps
assisted by a molecule
of water are shown in purple, with relative Gibbs energies in kcal/mol.
Reaction Mechanism of the NHC–Cu(I)-Catalyzed
Friedländer-Type
Annulation of 2-Amino-3-trifluoroacetyl-pyridines with a Terminal
Alkyne Using the Pentiptycene NHC Complex
Steps
assisted by a molecule
of water are shown in purple, with relative Gibbs energies in kcal/mol.The kinetic energy barrier of the rds for each
of the complexes
studied is compiled in Table along with the anterior and posterior intermediates. This
is not only to define the rds barrier but also to account for whether
the formation of the c′ isomer poses a problem
for reaction efficiency. Thermodynamics does not seem to indicate
anything, and therefore efforts must be based on kinetics, and understanding
the transition state of the rds is fundamental. Apart from observing
a significant difference of around 5 kcal/mol that explains the higher
conversions for the copper catalytic systems, results do not follow
a clear trend in any of the metal catalyst series. While there appears
to be a correlation (R2 = 0.707) between
this energy barrier and the conversion, it does not proceed to give
high product yields. Going into further detail, it is shown that the
ratio is maintained by copper complexes, with an acceptable correlation
(R2 = 0.736), indicating that the higher
the barrier, the lower the yield. Returning to %Vbur, the
combination of both variables, i.e., %Vbur and energy barrier,
only gave good agreement for the catalytic conversion values (R2 = 0.809). For copper complexes, the correlation
is good for yield (R2 = 0.819) and even
better for conversion (R2 = 0.953). Although
there are insufficient data to provide strong statistical significance,
it does suggest that a lower %Vbur may improve the reaction
studied and explain why the catalytic system 4g is the
best for this reaction. The steric maps in Figure represent another validation of this hypothesis.[44] Although there are two quadrants around the
metal center that are sterically hindered for the pentiptycene-based
NHC ligand system 4g, overall it is less hindered than
the other complexes. In fact, the other two quadrants are hardly affected
by the corresponding NHC ligand with values of 28.1 and 41.0%, thus
much lower compared to any of the other three systems (see Tables S2 and S3), as the least occupied quadrant
is 55.7, 59.9, and 54.3% for 4a, 4c, and 4d, respectively (see the SI for
further details).
Table 2
Relative Gibbs Energies (in kcal/mol)
of the C–C Bond Formation between the Alkyne and 2-Amino-3-trifluoroacetyl-pyridine
Catalyzed by the Metal Catalysts
system
cat
a
a + b → c
c
c′
4a
0.0
5.9
27.3
14.4
–0.7
4b
0.0
5.8
20.7
13.5
5.7
4c
0.0
8.2
30.5
10.2
0.9
4d
0.0
9.6
25.8
16.3
6.5
4e
0.0
6.1
24.9
15.9
7.7
4f
0.0
8.6
19.6
16.1
0.2
4g
0.0
7.5
25.4
4.1
–5.1
4h
0.0
9.8
19.6
9.4
5.4
Figure 2
Steric maps of the xy plane for copper
systems 4a, 4c, 4e, and 4g (centered
on the metal, z axis defined by the CNHC, xz plane containing any of the N atoms of the
imidazole ring; curves are given in Å).
Steric maps of the xy plane for copper
systems 4a, 4c, 4e, and 4g (centered
on the metal, z axis defined by the CNHC, xz plane containing any of the N atoms of the
imidazole ring; curves are given in Å).
Conclusions
A
practical and scalable method for the synthesis of fluorinated
naphthyridines has been developed based on a modified Friedländer
reaction between terminal alkynes and fluorinated ortho-aminophenones, catalyzed by NHC–BIAN–Cu–Cl
complexes on water. Utilizing a unique NHC ligand that combines the
steric bulk of pentiptycene pendant groups with the π-extended
backbone of acenaphthylene was crucial for the successful development
of a direct catalytic alkynylation/dehydrative cyclization sequence.
The established method accommodates a variety of terminal alkynes
including those derived from natural sources or biologically active
substances. In addition, mechanistic studies and computational calculations
unveil the whole reaction pathway identifying the rds to be that of
the C–C bond formation between the alkyne and fluorinated 2-amino-3-fluoroacetyl-pyridines.
It was possible to describe in detail that the magnitude of the largest
barrier was significantly lower for silver systems. Further, to explain
the different performances of the eight studied systems, a correlation
analysis of variables was done to explain the different conversions
and experimental yields. This enabled the observation of certain trends
linking the variables of steric congestion at the metal center, by
means of the steric index %Vbur, and also the energy barrier
of the rds. DFT calculations also revealed the fundamental role of
water as a proton shuttle in two steps.
Experimental
Section
General Remarks
NMR spectra were recorded in CDCl3 or DMSO-d6 solutions (unless
indicated otherwise); chemical shifts are quoted on the δ scale,
ppm, with the solvent signal as the internal standard (CHCl3, 1H NMR 7.26 ppm; CDCl3, 13C{1H} NMR 77.00 ppm, DMSO-d6 2.50
ppm, 13C{1H} NMR 39.40 ppm, 13C{1H} NMR CD3OD 49.00 ppm). High-resolution mass spectra
(HR MS) were taken using the EI technique or electrospray ionization
(ESI). Column chromatography was performed on Merck silica gel 60,
230–400 mesh. TLC was performed on aluminum sheets, Merck 60F
254. Anhydrous solvents were obtained by distillation over CaH2 (CH2Cl2) or Na/benzophenone (THF, hexane,
MTBE, toluene). Air-sensitive reactions were performed in flame-dried
glassware under an atmosphere of argon. Organic extracts were dried,
and solvents were evaporated in a rotary evaporator.Reagents
were used as they were purchased unless otherwise indicated. Alkynes 2a, 2c, S1–5, S9, S11 and S21, and S23–25 were commercially available and
used as received. Aminophenones 1a(23c) and 1b(23c) and alkynes S6,[23c]S8,[45]S10,[46]S14,[47]S19,[48]S2,[49] and S22(50) were prepared
according to the literature procedure (for details, see the SI, Schemes S1–S3). The names of compounds
were generated using ACD Lab Name 12.0 software. Complexes 7a(23c) and 4b(23c) were synthesized according to the literature procedure.
Synthesis of N-Heterocyclic Carbene Precursors Containing Chloride
Anion
2,6-Bis(diphenylmethyl)-4-methoxyaniline (5a)[51] and pentiptycene-derived bisimine[33]6d were synthesized according to
the literature procedure.
The compound was synthesized according
to the modified literature procedure.[52] To a two-necked round-bottom flask were charged with 2,6-dibenzhydryl-4-methoxyaniline
(5a) (2.0 g, 4.39 mmol, 2.0 equiv), butano-2,3-dione
(0.2 mL, 2.19 mmol, 1.0 equiv), p-TSA (15.1 mg, 0.09
mmol, 2 mol %), and toluene (50 mL). The resulting solution was heated
at 80 °C for 24 h. Then, the flask was equipped with the Dean–Stark
apparatus and heated to reflux for 3 days. Then, the solvent was evaporated
and the residue was treated with MeOH (40 mL). The resulting yellow
solid was washed with MeOH (3 × 5 mL) and dried under high vacuum
to give 6b as a yellow solid (990.9 mg, 23%). 1H NMR (200 MHz, CDCl3) δ 7.35–6.90 (m, 40H),
6.42 (s, 4H), 5.16 (s, 4H, CPh2), 3.53 (s, 6H, OC3), 1.15 (s, 6H, N=CC3). Spectral data are in agreement with those reported.[52]
The compound was synthesized according
to the modified literature procedure.[53] To a suspension of acenaphthoquinone (350.0 mg, 1.91 mmol) in glacial
AcOH (30 mL) were added ZnCl2 (230.0 mg, 2.20 mmol, 1.0
equiv) and 2,6-dibenzhydryl-4-methoxyaniline (2.0 g, 4.39 mmol, 2.3
equiv). The resulting mixture was heated at 120 °C under an atmosphere
of argon for 16 h. Thus, the formed zinc/bisimine complex was filtered,
washed with AcOH (3 × 3 mL) and Et2O (3 × 10
mL), and subjected to decomplexation.The resulting solid was
suspended in DCM (27 mL), and potassium oxalate (809.0 mg) in water
(4 mL) was added and stirred at rt for an additional 1 h. The resulting
orange solution was extracted with DCM (2 × 10 mL), and the combined
organic extracts were washed with water (3 × 10 mL), dried over
MgSO4, and evaporated to give 6c as an orange
solid (1.33 g, 66%). 1H NMR (400 MHz, CDCl3)
δ 7.51 (d, J = 8.2 Hz, 2H), 7.17–7.02
(m, 20H), 6.90–6.80 (m, 10H), 6.69 (s, 4H), 6.67–6.58
(m, 12H), 6.16 (d, J = 7.2 Hz, 2H), 5.71 (s, 4H,
CAr2), 3.66 (s, 6H,
OC3). Spectral data
are in agreement with those reported.[53]Salt 7b was synthesized according to a modified
literature
procedure.[53] A 50 mL sealed tube was charged
with bisimine 6b (1.0 g, 1.0 mmol) and CH3CH2OCH2Cl (3.0 mL, 32.40 mmol, 32.4 equiv)
and heated at 100 °C (temp. of oil bath) for 16 h. Then, the
reaction mixture was evaporated, and the residue was chromatographed
on silica (5% MeOH/DCM) to give a light brown solid (978.3 mg, 93%).
mp > 260 °C (decomposition, analytical sample was precipitated
from a mixture of DCM/Et2O); 1H NMR (400 MHz,
CDCl3) δ 12.40 (s, 1H, NCN), 7.42–6.85 (m, 40H), 6.67 (s, 4H), 5.12 (s, 4H,
CPh2), 3.59 (s, 6H,
OC3), 0.67 (s, 6H,
C3); 13C{1H} NMR (100 MHz, CDCl3) δ 160.6 (NHN), 142.8, 141.6, 140.3, 129.8, 129.4,
128.5, 127.2, 126.6, 123.5, 115.7, 77.2, 55.1 (OH3), 51.5 (HPh2), 7.2 (H3); HR MS (ESI TOF) m/z calcd
for C71H61N2O2 [M –
Cl]+: 973.4733; found: 973.4724.Salt 7c: A 50 mL sealed ampule was charged with bisimine 6c (940.0 mg, 0.89 mmol) and CH3CH2OCH2Cl (4.1 mL, 44.5 mmol, 50.0 equiv) and heated at 100 °C
(temp. of oil bath) for 16 h. Then, the reaction mixture was evaporated,
and the residue was treated with Et2O (10 mL). The resulting
solid was filtered and washed with water (2 × 50 mL) to give
a yellow solid (618.9 mg, 63%). mp 311.0–312.0 °C (analytical
sample was precipitated from a mixture of DCM/Et2O); 1H NMR (400 MHz, CDCl3) δ 13.13 (s, 1H, NCN), 7.60 (d, J =
8.2 Hz, 2H), 7.29–7.13 (m, 18H), 7.03–6.94 (m, 6H),
6.78–6.56 (m, 22H), 6.26 (d, J = 7.0 Hz, 2H),
5.31 (s, 4H, CPh2),
3.61 (s, 6H, OC3); 13C{1H} NMR (100 MHz, CDCl3) δ
161.0 (NHN), 143.1, 141.5, 140.5,
137.8, 129.7, 129.4, 129.2, 128.7, 128.6, 128.3, 128.1, 126.8, 126.7,
124.7, 123.0, 122.2, 115.7, 55.3 (OH3), 51.8 (HPh2); HR MS (ESI TOF) m/z calcd for C79H61N2O2 [M – Cl]+: 1069.4733; found: 1069.4744.Salt 7d was synthesized
according to the modified
literature procedure.[33] A 50 mL sealed
tube was charged with pentiptycene-derived bisimine 6d(33) (648.2 mg, 0.59 mmol) and CH3CH2OCH2Cl (4.0 mL, 43.3 mmol, 73.2 equiv) and
heated at 80 °C (temp. of oil bath) for 16 h. Then, the reaction
mixture was evaporated with Et2O (10 mL). The resulting
solid was filtered, washed with Et2O (3 × 10 mL),
and further purified by chromatography on silica (DCM, 5% MeOH/DCM)
to give a yellow solid (285.2 mg, 42%). 1H NMR (400 MHz,
CD2Cl2) δ 8.23 (d, J =
8.2 Hz, 2H), 8.07 (s, 1H, NCN),
7.57–7.42 (m, 10H), 7.32 (d, J = 7.3 Hz, 4H),
7.24 (d, J = 7.2 Hz, 4H), 7.13–6.99 (m, 8H),
6.98–6.88 (m, 6H), 6.87–6.79 (m, 4H), 6.01 (d, J = 7.0 MHz, 8H, CAr3), 4.19 (s, 6H, OC3). Spectral data are in agreement with those reported.[33]
Synthesis of N-Heterocyclic Carbene Precursors
Containing Tetrafluoroborate
Anion
The experimental protocol for the anion exchange (from
chloride to tetrafluoroborate) developed by Nolan[51] was implemented in all cases described below.Salt 10a was synthesized according to the modified literature
procedure.[51] To a suspension of salt 7a (200.0 mg, 0.20 mmol, 1.0 equiv) in a mixture of THF (330
μL) and H2O (6 mL), 48% HBF4(aq) (29.0
μL, 0.30 mmol, 1.5 equiv) was added and stirred at rt for 16
h (the progress of the reaction was monitored by TLC, 7aRf = 0.26, 10aRf = 0.53, 10% MeOH/DCM). Then, the reaction
mixture was extracted with DCM (3 × 5 mL), and the combined organic
extracts were dried over Na2SO4 and evaporated.
The residue was washed with n-pentane (3 × 10
mL) and dried under high vacuum to give a white solid (171.2 mg, 83%). 1H NMR (400 MHz, CDCl3) δ 10.44 (br s, 1H,
NCN), 7.34–7.00 (m, 32H),
6.87–6.80 (m, 8H), 6.50 (s, 4H), 5.60 (s, 2H), 5.10 (s, 4H,
CPh2), 3.53 (s, 6H,
OC3). Spectral data
are in agreement with those reported.[51]Salt 10b: To a suspension of salt 7b (300.0
mg, 0.29 mmol, 1.0 equiv) in a mixture of THF (0.5 mL) and H2O (9 mL), 48% HBF4(aq) (43.5 μL, 0.45 mmol, 1.5
equiv) was added and stirred for 16 h (the progress of the reaction
was monitored by TLC, 7bRf = 0.05, 10bRf = 0.32,
5% MeOH/DCM). Then, the reaction mixture was extracted with DCM (3
× 5 mL), and the combined organic extracts were dried over Na2SO4, filtered, and evaporated to give salt 12b as a light brown solid (310.0 mg, 98%). mp > 300 °C
(decomposition, analytical sample was precipitated from a mixture
of DCM/n-pentane); 1H NMR (400 MHz, CDCl3) δ 9.90 (s, 1H, NCN), 7.40–6.88 (m, 40H), 6.66 (br s, 4H), 4.94 (s, 4H, CPh2), 3.60 (s, 6H, OC3), 0.73 (s, 6H, C3); 13C{1H} NMR (100 MHz, CDCl3) δ 160.9 (NHN), 142.9, 141.3, 140.6, 137.7, 130.5, 129.6,
129.2, 128.7, 127.4, 127.0, 123.4, 115.9, 55.2 (OH3), 51.7 (HPh2), 7.5 (H3); 19F NMR (376 MHz, CDCl3) δ
−150.9 (×2); HR MS (ESI TOF) m/z calcd
for C71H61N2O2 [M –
BF4]+: 973.4733; found: 973.4733.Salt 10c: To a suspension of salt 7c (200.0
mg, 0.18 mmol, 1.0 equiv) in THF (0.3 mL) and H2O (6 mL),
48% HBF4(aq) (26.1 μL, 0.27 mmol, 1.5 equiv) was
added and stirred at rt for 16 h (the progress of the reaction was
monitored by TLC, 7cRf =
0.22, 10cRf = 0.50, 5% MeOH/DCM).
Then, the reaction mixture was extracted with DCM (5 × 5 mL),
and the combined organic extracts were dried over Na2SO4, filtered, and evaporated to give salt 12c as
a yellow solid (170.1 mg, 81%). mp > 360 °C (decomposition,
analytical
sample was precipitated from a mixture of DCM/n-pentane); 1H NMR (400 MHz, CDCl3) δ 9.97 (s, 1H, NCN), 7.70 (d, J =
8.3, 2H), 7.21–7.13 (m, 8H), 7.11–7.05 (m, 2H), 7.04–6.93
(m, 12H), 6.82–6.62 (m, 24H), 6.35 (d, J =
7.0 Hz, 2H), 5.13 (s, 4H, CPh2), 3.63 (s, 6H, OC3); 13C{1H} NMR (50 MHz, CDCl3) δ 161.1 (NHN), 143.0,
141.0, 140.7, 138.1, 129.5, 129.3, 129.2, 128.6, 128.4, 128.2, 127.1,
126.8, 124.4, 123.3, 121.9, 115.6, 55.3 (OH3), 51.8 (HAr2); 19F NMR (376 MHz, CDCl3)
δ −150.1, −150.2; HR MS (ESI TOF) m/z calcd for C79H61N2O2 [M – BF4]+: 1069.4733; found: 1069.4733.Salt 10d: To a suspension of salt 7d (200.0
mg, 0.17 mmol, 1.0 equiv) in a mixture of THF (0.30 mL) and H2O (6 mL), 48% HBF4(aq) (25.1 μL, 0.26 mmol,
1.5 equiv) was added, and the reaction mixture was stirred at rt for
16 h (the progress of the reaction was monitored by TLC, 7dRf = 0.25, 10dRf = 0.45, 5% MeOH/DCM). Then, the reaction mixture
was extracted with DCM (4 × 5 mL), and the combined organic extracts
were dried over Na2SO4 and evaporated. The residue
was treated with n-pentane (10 mL), stirred for 5
min, filtered, and dried under high vacuum to give 10d as a yellow solid (175.0 mg, 84%). mp > 350 °C (decomposition,
analytical sample was precipitated from a mixture of DCM/n-pentane); 1H NMR (400 MHz, CDCl3) δ
8.16 (d, J = 8.0 MHz, 2H), 7.83 (s, 1H, NCN), 7.56–7.33 (m, 9H), 7.32–7.13
(m, 9H), 7.12–6.68 (m, 18H), 5.96 (s, 4H, CAr3), 5.74 (s, 4H, CAr3), 4.19 (s, 6H, OC3); 13C{1H}
NMR (100 MHz, CDCl3) δ 152.7 (NHN), 144.4, 144.0, 143.7, 143.4, 141.5, 139.1, 135.1, 131.6,
126.1, 126.0, 125.8, 125.7, 125.4, 124.2, 124.0, 123.7, 121.8, 120.3,
63.1 (OH3), 49.5 (HAr3), 48.2 (HAr3); 19F NMR (376 MHz,
CDCl3) δ −150.8 (×2); HR MS (ESI TOF) m/z calcd for C83H53N2O2 [M – BF4]+: 1109.4107; found:
1109.4117.
Synthesis of N-Heterocyclic Carbene Copper(I)
Complexes
Complex 4a was synthesized according
to the literature
procedure.[23c]13C{1H} NMR (50 MHz, CD2Cl2) δ 181.6 (NN), 160.6, 143.4, 143.2, 142.9,
130.1, 130.0, 129.8, 129.1, 129.0, 127.3, 127.2, 124.0, 115.3, 55.7,
52.0. 13C{1H} NMR data are in agreement with
those reported. However, the authors did not record a carbene atom
in the 13C NMR spectrum. A prolonged acquisition time was
required, at least 24 h (the equally long acquisition time was also
needed for the other copper(I) and silver complexes).Complex 4c: A 20 mL screw cap vial was charged with salt 7b (150.0 mg, 0.15 mmol), CuCl (18.3 mg, 0.19 mmol, 1.2 equiv),
and K2CO3 (42.6 mg, 0.31 mmol, 2.0 equiv). Then,
the vial was transferred to a glovebox and anhydrous acetone (10.5
mL) was added. The resulting suspension was heated at 60 °C in
an aluminum heating block (thermocouple was inserted into a separate
vial filled with silicon oil) for 16 h. Then, the reaction mixture
was filtered through a pad of Celite 545 (washing with acetone), and
the solvent was evaporated. The residue was chromatographed on silica
(1% acetone/DCM); however, some impurities have been still observed.
The crude complex was dissolved in a minimal volume of DCM (1 mL)
and precipitated with n-pentane (16 mL, precipitation
was repeated twice) to give a light brown solid (82.5 mg, 50%). mp
> 300 °C (decomposition, DCM/n-pentane);
IR
(KBr) 3058, 3024, 2926, 2838, 1642, 1599, 1493, 1469, 1445 cm–1; 1H NMR (400 MHz, CD2Cl2) δ 7.30–6.95 (m, 40H), 6.70 (s, 4H), 5.27 (s,
4H, CAr2), 3.64 (s,
6H, OC3), 0.67 (s,
6H, C3); 13C{1H} NMR (50 MHz, CD2Cl2) δ
186.7, 160.6, 143.9, 142.8, 141.8, 139.6, 130.1, 130.1, 129.9, 129.2,
128.9, 128.6, 128.5, 127.7, 127.1, 127.0, 126.9, 124.4, 122.2, 115.5,
55.8 (OH3), 52.2 (HAr2) (despite prolonged
drying under high vacuum, residual signals of n-pentane
were detected). HR MS (ESI TOF) m/z calcd for C71H60CuClN2O2Na [M + Na]+: 1093.3537; found: 1093.3538.Complex 4e: A 4 mL screw cap vial was charged with
salt 7c (150.0 mg, 0.14 mmol), CuCl (16.6 mg, 0.17 mmol,
1.2 equiv), and K2CO3 (38.7 mg, 0.28 mmol, 2.0
equiv). Then, the vial was transferred to a glovebox, anhydrous acetone
(1.5 mL) was added, and the resulting suspension was heated at 60
°C for 16 h in an aluminum heating block (thermocouple was inserted
into a separate vial filled with silicon oil). Then, the solvent was
evaporated, and the residue was treated with MeOH (5 mL) and centrifugated
(6000 rpm, 15 min). The mother liquid was removed by Pasteur pipette,
and thus, the obtained solid was treated with MeOH (11 mL) and centrifugated
(6000 rpm, 15 min). The mother liquid was removed by Pasteur pipette,
and the solid was treated with MeOH, and the suspension was transferred
to a round-bottom flask. Then, the solvent was evaporated and the
residue was dried under high vacuum to give a yellow solid (81.0 mg,
51%). mp > 351 °C (decomposition, analytical sample was precipitated
from a mixture of DCM/n-pentane); IR (KBr) 3083,
3058, 3024, 2932, 2838, 1598, 1584, 1493, 1468, 1446 cm–1; 1H NMR (400 MHz, CD2Cl2) δ
7.55 (d, J = 8.4 Hz, 2H), 7.20–6.55 (m, 46H),
6.19 (d, J = 6.9 Hz, 2H), 5.44 (br s, 4H, CAr2), 3.67 (s, 6H, OH3); 13C{1H} NMR (100 MHz, CD2Cl2) δ 160.1,
143.4, 142.3, 141.3, 139.2, 129.6, 129.3, 128.7, 128.4, 128.0, 127.2,
126.6, 126.4, 123.9, 121.7, 115.0, 55.2 (OH3), 51.6 (HAr2); HR MS m/z (APCI TOF) calcd for
C79H60CuN2O2 [M –
Cl]+: 1131.3951; found: 1131.3942.Complex
4g: A 20 mL screw cap vial was charged with
salt 7d (191.0 mg, 0.17 mmol), CuCl (19.8 mg, 0.20 mmol,
1.2 equiv), and K2CO3 (46.0 mg, 0.33 mmol, 2.0
equiv). Then, the vial was transferred to a glovebox and anhydrous
acetone (10 mL) was added, and the reaction mixture was heated at
60 °C in an aluminum heating block (thermocouple was inserted
into a separate vial filled with silicon oil). After 16 h, the solvent
was evaporated and the residue was treated with MeOH (11 mL), centrifugated
(6000 rpm, 10 min), and the mother liquid was removed by means of
Pasteur pipette. The crude complex was treated with an additional
portion of MeOH (11 mL) and centrifugated (6000 rpm, 10 min). After
the removal of the mother liquid, complex 4g was transferred
to a flask and dried under high vacuum to give a yellow-olive solid
(174.9 mg, 87%).The same procedure was repeated on a 1 g scale
using salt 7d (1 g, 0.87 mmol), CuCl (103.7 mg, 1.05
mmol, 1.2 equiv),
K2CO3 (240.5 mg, 1.74 mmol, 2.0 equiv), and
acetone (40 mL). The reaction mixture was heated to reflux for 48
h (while the formation of a yellow solid was observed). The reaction
mixture was diluted with MeOH (30 mL) and centrifugated (6000 rpm,
15 min), and the mother liquid was removed by means of Pasteur pipette.
The residue was treated with MeOH (40 mL) and centrifugated (6000
rpm, 15 min). After the removal of the solvent by Pasteur pipette,
the resulting solid was suspended in MeOH, transferred to a round-bottom
flask, and evaporated to give a yellowish solid (890.0 mg, 81%). mp
> 300 °C (decomposition, DCM/n-pentane);
IR
(KBr) 3065, 3019, 2967, 2829, 1711, 1602, 1479, 1459 cm–1; 1H NMR (400 MHz, CD2Cl2) δ
7.85 (d, J = 8.3 Hz, 2H), 7.54–7.46 (m, 8H),
7.42 (d, J = 7.1 Hz, 4H), 7.12–6.90 (m, 14H),
6.84–6.71 (m, 8H), 6.20 (d, J = 7.0 Hz, 2H),
5.97 (s, 4H, CAr3),
5.47 (s, 4H, CAr3),
4.19 (s, 6H, OC3); 13C{1H} NMR (50 MHz, CD2Cl2) δ 186.3, 152.0, 145.7, 145.0, 144.9, 144.8, 144.3, 141.9,
139.8, 138.3, 131.2, 130.2, 129.2, 127.9, 126.4, 126.2, 125.6, 125.4,
125.2, 124.6, 124.3, 124.3, 124.3, 123.6, 63.7, 50.9, 48.8, 31.2 (spectra
of the suspension has been recorded due to poor solubility of complex 4h in CD2Cl2); HR MS (ESI TOF) m/z calcd for C83H52CuN2O2 [M – Cl]+: 1171.3325; found: 1171.3312.
Synthesis of N-Heterocyclic Carbene Silver Complexes
Complex 4b:[54] A flame-dried
Schlenk was charged with salt 7a (313.7 g, 0.319 mmol)
and Ag2O (44.4 mg, 0.0192 mmol, 0.6 equiv). Then, anhydrous
DCM (20 mL) was added and stirred at rt for 36 h (Schlenk tube was
protected from light by an aluminum foil). Then, the reaction mixture
was passed through a pad of silica (washing with 5% MTBE/hexane).
The crude complex was dissolved in a minimal volume of DCM (6 mL)
and crashed with n-pentane (28 mL). The resulting
white solid was filtered, washed with n-pentane (3
× 10 mL), and dried under high vacuum to give 4b (285.6 mg, 82%). All manipulations with complex 4b were
carried out in air without any precaution. Complex 4b was stored under air for more than 24 months in the fridge in a
glass vial without any decomposition, as judged by 1H NMR. 1H NMR (400 MHz, CD2Cl2) δ 7.27–7.18
(m, 26H), 7.04–6.91 (m, 16H), 6.60 (m, 4H), 5.98 (br d, J = 1.9 Hz, 2H), 5.15 (s, 4H), 3.59 (s, 6H); 13C{1H} NMR (50 MHz, CD2Cl2) δ
185.8 (dd, JC-Ag = 248.3, 17.9
Hz, NN), 160.7, 143.3, 143.3,
142.7, 130.4, 130.3, 130.0, 129.8, 129.3, 129.1, 127.4, 127.3, 124.5,
124.3, 115.5, 55.7, 52.0. Spectral data are in agreement with those
reported.[54]Complex 4d: A Schlenk tube was charged with salt 7b (250.0 mg,
0.26 mmol) and Ag2O (36.0 mg, 0.15 mmol, 0.6 equiv), and
anhydrous DCM (6.3 mL) was added. The resulting suspension was stirred
at 55 °C (temp. of oil bath) for 16 h. Then, the reaction mixture
was filtered through a pad of Celite 545 (washing with DCM, 2 ×
10 mL), and the solvent was evaporated. The residue was purified by
chromatography on silica (1% acetone/DCM). Thus, the obtained crude
complex 4d was dissolved in a minimal volume of DCM (1
mL) and crashed with n-pentane (6.5 mL), filtered,
and dried under high vacuum to give a light brown solid (137.9 mg,
48%). All manipulations with complex 4d were carried
out in air without any precaution. Complex 4d was stored
under air for more than 15 months in the fridge in a glass vial without
any decomposition, as judged by 1H NMR. mp > 300 °C
(decomposition, DCM/n-pentane); IR (KBr) 3058, 3024,
2928, 2839, 1598, 1492, 1469, 1446 cm–1; 1H NMR (400 MHz, CD2Cl2) δ 7.27–7.19
(m, 12H), 7.11–7.00 (m, 20H), 6.98–6.92 (m, 8H), 6.67
(s, 4H), 5.16 (s, 4H, CAr2), 3.61 (s, 6H, OC3), 0.77 (s, 6H, C3); 13C{1H} NMR (50 MHz, CD2Cl2) δ 182.3 (dd, JC-Ag = 251.5, 18.1 Hz, NN),
18.1 Hz, 160.4, 143.8, 143.3, 142.1, 130.3, 130.2, 129.9, 129.8, 129.4,
129.3, 129.2, 129.1, 129.0, 127.5, 127.3, 127.2, 115.8, 55.7 (OH3), 51.8 (HAr2), 8.8(H3); HR MS (ESI TOF) m/z calc
for C71H60AgN2O2 [M –
Cl]+: 1079.3706; found: 1079.3724.Complex
4f: A flame-dried Schlenk tube was charged
with salt 7c (150.0 mg, 0.14 mmol) and Ag2O (19.5 mg, 0.08 mmol, 0.6 equiv). Then, anhydrous DCM (3.5 mL) was
added and the resulting suspension was stirred at rt for 16 h. Then,
the reaction mixture was filtered through a pad of Celite 545 (washing
with DCM, 2 × 10 mL), and the solvent was evaporated. The crude
complex was treated with MeOH (ca. 12 mL), centrifugated (6000 rpm,
15 min), and the mother liquid was removed by means of Pasteur pipette.
The crude complex was treated with an additional portion of MeOH (11
mL) and centrifugated (6000 rpm, 15 min). After the removal of the
mother liquid, complex 4f was transferred to a flask
and dried under high vacuum to give a bright yellow solid (82.1 mg,
50%). mp > 336 °C (decomposition, analytical sample was precipitated
from a mixture of DCM/n-pentane); IR (KBr): 3082,
3060, 3024, 3000, 2840, 1598, 1582, 1493, 1469, 1447 cm–1; 1H NMR (500 MHz, CD2Cl2) δ
7.58 (d, J = 8.3 Hz, 2H), 7.10–7.00 (m, 14H),
6.95–6.88 (m, 8H), 6.85–6.75 (m, 20H), 6.71 (s, 4H),
6.24 (d, J = 6.9 Hz, 2H), 5.36 (s, 4H, CAr2), 3.66 (s, 6H, OC3); 13C{1H}
NMR (50 MHz, CD2Cl2) δ 190.8 (dd, JC-Ag = 251.1, 18.2 Hz, NN), 160.7, 143.8, 142.6, 142.0, 140.2, 140.0,
130.1, 129.8, 129.4, 129.1, 128.6, 127.9, 127.2, 127.0, 124.3, 124.3,
122.3, 115.6, 55.8 (OH3), 52.1 (HAr2); HR
MS (APCI TOF) m/z calcd for C79H60AgN2O2 [M]•+: 1175.3706;
found: 1175.3713. 1H NMR confirmed the presence of a residual
amount of n-pentane after rigorous drying under high
vacuum overnight.Complex 4h was synthesized according
to a modified
literature procedure.[33] A flame-dried Schlenk
was charged with salt 7d (219.5 mg, 0.19 mmol) and Ag2O (132.2 mg, 0.57 mmol, 6.0 equiv). Then, anhydrous DCM (10
mL) was added and the resulting suspension was stirred at rt for 16
h. The reaction mixture was filtered through a pad of Celite 545,
washing with 10% MeOH/DCM (CAUTION: silver complex 4h is poorly soluble), and solvents were evaporated. The resulting
complex was filtered through a pad of silica (DCM, 10% MeOH/DCM),
the solvent was evaporated, and the residue was dissolved in a minimal
volume of 10% MeOH/DCM (16 mL) and precipitated with n-pentane (24 mL) to give a bright yellow solid (116.0 mg, 48%). mp
> 300 °C (decomposition, MeOH/DCM/n-pentane);
IR (KBr) 3648, 3064, 3018, 2966, 2828, 1730, 1602, 1479, 1459 cm–1; 1H NMR (400 MHz, CD2Cl2) δ 7.89 (d, J = 8.2 Hz, 2H), 7.55–7.48
(m, 8H), 7.37 (d, J = 7.2 Hz, 4H), 7.15–6.91
(m, 14H), 6.86–6.75 (m, 8H), 6.30 (d, J =
7.0 Hz, 2H), 5.99 (s, 4H, CAr3), 5.46 (s, 4H, CAr3), 4.21 (s, 6H, OC3); 13C{1H} NMR (100 MHz, CD2Cl2) δ 151.6, 145.1, 144.5, 144.2, 143.7, 141.3,
137.8, 128.8, 127.4, 126.1, 125.9, 125.7, 125.0, 124.3, 124.1, 123.9,
123.7, 123.3, 116.6, 63.2 (OH3), 50.3, 48.3; HR MS (ESI TOF) m/z calcd
for C83H52AgN2O2 [M –
Cl]+: 1215.3080; found: 1215.3101. Carbene carbon atom
has not been recorded due to poor solubility of complex 4h in CD2Cl2.
Synthesis of Gold(I) Complexes
Complex 8: A 4 mL screw cap vial was charged with
NHC precursor (300.0 mg,
1.1 mmol), AuCl·Me2S (312.0 mg, 1.1 mmol, 1.0 equiv),
and K2CO3 (152.0 mg, 1.1 mmol, 1.0 equiv). Then,
the vial was transferred to a glovebox, and anhydrous acetone was
added (2 mL). The resulting suspension was vigorously stirred at 60
°C for 16 h. Then, the solvent was evaporated, and the residue
was filtered through a pad of silica (washing with DCM, 2 × 5
mL). The resulting solution was evaporated and dried under high vacuum
to give complex 8 as a white solid (438.7 mg, 92%). 1H NMR (400 MHz, CDCl3) δ 7.67–7.62
(m, 2H), 7.40–7.34 (m, 2H), 5.51 (sept, J =
7.0 Hz, 2H), 1.74 (d, J = 7.0 Hz, 12H). The spectral
data are in agreement with those reported[55] (known compound CAS: 953820-59-2).Complex 9 was
prepared according to the literature procedure.[56] Gold(I) complex 8 (50.0 mg, 0.12 mmol) and
AgOAc (23.4 mg, 0.14 mmol, 1.2 equiv) were placed in a flame-dried
Schlenk flask. Then, anhydrous DCM (12 mL) was added and the resulting
mixture was stirred for 1 h at rt (Schlenk tube was protected from
light by an aluminum foil). The resulting suspension was passed through
a pad of Celite 545, and the solvent was evaporated and dried under
high vacuum to give a white solid (39.5 mg, 72%). 1H NMR
(400 MHz, CDCl3) δ 7.66–7.58 (m, 2H), 7.38–7.30
(m, 2H), 5.56–5.43 [m, 2H, NC(CH3)2], 2.10 (s, 3H, C3), 1.76 and 1.75 and 1.73 (s, 12H,
C3). The spectra data
are in agreement with those reported.[56]Complex 11a: To a solution of NHC·BF4 salt 10a (83.4 mg, 0.08 mmol) in anhydrous acetone
(30 mL), gold(I) complex 9 (37.0 mg, 0.08 mmol, 1.0 equiv)
was added and stirred at 80 °C (temp. of aluminum heating block)
for 48 h. The solvent was evaporated, dissolved in a minimal volume
of DCM, and crashed with n-pentane to give complex 11a as a creamy solid (110.3 mg, 95%). mp 216.0–218.0
°C (DCM/n-pentane); 1H NMR (600 MHz,
CDCl3) δ 7.70–7.66 (m, 2H), 7.50–7.46
(m, 2H), 7.19–7.11 (m, 32H), 6.87–6.83 (dd, 8H), 6.68
(s, 4H), 5.49 (s, 2H), 5.34 (s, 4H, CAr2), 4.47 [sept, J = 7.0 Hz,
2H, NC(CH3)2], 3.67 (s, 6H, OC3), 1.18 (d, J = 7.0 Hz, 12H, C3); 13C{1H} NMR (125 MHz,
CDCl3) δ 188.4 (NCH), 186.4 (Nar), 161.2, 143.9, 142.8, 142.6, 133.1, 130.2, 129.4,
129.4, 129.3, 128.1, 128.0, 125.8, 124.8, 115.3, 114.2, 56.2 (OH3), 54.5 [H(CH3)2], 52.8 (HAr2), 22.7 (H3); 19F NMR (376 MHz, CDCl3) δ −154.5 (×2); HR MS (ESI TOF) m/z calcd for C82H74AuN4O2 [M – BF4]+: 1343.5477; found: 1343.5482.Complex 11b: To a solution of NHC·BF4 salt 10b (46.3 mg, 0.04 mmol) in anhydrous acetone
(20 mL), gold(I) complex 9 (20.0 mg, 0.04 mmol, 1.0 equiv)
was added and the resulting mixture was heated to 80 °C for 24
h. Then, the solvent was evaporated and the residue was chromatographed
on silica (DCM, 5% MeOH/DCM) to give a light brown solid (28.1 mg,
44%). Purification of complex 11b appeared to be difficult
due to decomposition observed. mp > 300 °C (decomposition,
DCM/n-pentane); 1H NMR (600 MHz, CDCl3); δ 7.44–7.39 (m, 2H), 7.25–7.19 (m,
2H), 7.04–6.89
(m, 20H), 6.85–6.69 (m, 20H), 6.58 (s, 4H), 5.24 (s, 4H, CAr2), 4.10 [sept, J = 7.0 Hz, 2H, NCb(CH3)2], 3.50 (s, 6H, OC3), 1.00 (s, 6H, Ca3), 0.86 (d, J = 7.0 Hz, 12H, C3); 13C{1H} NMR (125 MHz, CDCl3)
δ 186.9 (Nar), 185.4 (NCH), 160.8, 144.5, 143.3, 141.2,
133.1, 131.2, 130.4, 130.0, 129.9, 129.4, 129.3, 128.5, 128.1, 127.9,
125.7, 116.6, 115.8, 114.6, 56.3 (OH3), 55.1, 52.8, 22.2; 19F NMR (376 MHz, CDCl3) δ −153.7, −153.8; HR MS (ESI TOF) m/z calcd for C84H78AuN4O2 [M – BF4]+: 1371.5790;
found: 1371.5786.Complex 11c: To a solution of
NHC·BF4 salt 10c (50.5 mg, 0.04 mmol)
in anhydrous acetone
(10 mL), gold(I) complex 9 (20.0 mg, 0.04 mmol, 1.0 equiv)
was added and stirred at 80 °C for 48 h. Then, the solvent was
evaporated, and the residue was chromatographed on silica (DCM, 5%
MeOH/DCM) to give a yellow solid (65.4 mg, 96%). mp > 300 °C
(decomposition, analytical sample was precipitated from a mixture
of DCM/n-pentane); 1H NMR (600 MHz, CDCl3) δ 7.69–7.64 (m, 2H), 7.47–7.42 (m, 2H),
7.32 (d, J = 8.2, 2H), 7.12 (br d, J = 7.4, 8H), 7.02–6.92 (m, 12H), 6.84 (s, 4H), 6.79–6.61
(m, 22H), 5.74 (d, J = 6.9 Hz, 2H), 5.60 (s, 4H,
CAr2), 4.42 [sept, J = 7.0 Hz, 2H, NC(CH3)2], 3.74 (s, 6H, OC3), 1.19 (d, J = 7.0 Hz, 12H,
C3); 13C{1H} NMR (125 Hz, CDCl3) δ 192.5 (NCH), 186.8 (NAr), 161.0, 144.7, 142.8,
140.8, 140.4, 133.1, 130.0, 129.7, 129.3, 129.0, 128.6, 128.5, 128.2,
127.9, 127.7, 126.8, 125.8, 123.0, 122.7, 115.5, 114.7, 56.3 (OH3), 55.3 [NC(CH3)2], 53.2 (CAr2), 22.3 (H3); 19F NMR (376 MHz, CDCl3) δ −154.5 (×2); HR MS (ESI TOF) m/z calcd for C92H78AuN4O2 [M – BF4]+: 1468.5869; found: 1468.5852.Complex 11d: To a solution of NHC·BF4 salt 10d (112.3 mg, 0.09 mmol) in anhydrous acetone
(12 mL), gold(I) complex 9 (43.0 mg, 0.09 mmol, 1.0 equiv)
was added and stirred for 24 h at 80 °C. Then, DCM (20 mL) was
added, and the resulting green solid (impurities) was filtered. Then,
the solution was evaporated and dried under high vacuum to give a
yellow solid (143.7 mg, 98%). mp > 300 °C (decomposition,
analytical
sample was precipitated from a mixture of DCM/n-pentane); 1H NMR (600 MHz, CDCl3) δ 8.04 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 7.3 Hz, 4H),
7.49 (d, J = 7.2 Hz, 4H), 7.34–7.21 (m, 10H),
7.08–7.03 (m, 4H), 6.90 (d, J = 7.1 Hz, 4H),
6.87–6.82 (m, 4H), 6.81–6.75 (m, 4H), 6.65 (d, J = 7.0 Hz, 2H), 6.42 (t, J = 7.3, 7.2
Hz, 4H), 6.01 (s, 4H, CAr3), 5.44 (s, 4H, CAr3), 4.26 (s, 6H, OC3), 3.70–3.62 [m, 2H, NC(CH3)2], 0.21 (d, J = 6.8 Hz, 12H, C3); 13C{1H} NMR (125 MHz, CDCl3)
δ 192.1 (NCH), 186.5 (NAr), 152.4,
145.4, 144.5, 144.3, 142.2, 139.8, 138.7, 132.5, 131.1, 130.7, 130.6,
128.5, 126.9, 126.8, 126.0, 125.6, 125.1, 125.0, 124.9, 124.8, 124.7,
124.6, 123.6, 112.7, 64.2 (OH3), 52.3 [H(CH3)2], 51.2 (CAr3), 48.9 (CAr3), 21.8 (H3); 19F NMR (376 MHz, CDCl3) δ −153.8,
−153.9; HR MS (ESI TOF) m/z calcd for C96H70AuN4O2 [M – BF4]+: 1507.5164; found: 1507.5171.
Single-Crystal
X-ray Diffraction
The crystals were
embedded in the inert perfluoropolyalkylether (viscosity 1800 cSt;
ABCR GmbH) and mounted using Hampton Research Cryoloops. The crystals
were flash-cooled to 100.0(1) K in a nitrogen gas stream and kept
at this temperature during the experiments. The X-ray data were collected
on a SuperNova Agilent diffractometer using Mo Kα radiation
(λ = 0.71073 Å) or Cu Kα radiation (λ = 1.54184
Å). The data were processed with CrysAlisPro.[57] Structures were solved by direct methods and refined using
SHELXL[58] under WinGX.[59] The figures were prepared using X-seed.[60]
Crystal Data for 4a
(C69H56N2O2AgCl)·2(CH2Cl2), Mr = 1258.3, colorless prisms,
orthorhombic, space group , a = 19.2621(2), b = 24.6506(5), c = 25.2385(3) Å, V = 11983.8(3) Å3, Z = 8, ρcalc = 1.39 g
cm–3, μ(Mo Kα) = 0.61 mm–1, θmax = 26.3°, 32 921 reflections measured,
12 236 unique, 760 parameters, R = 0.041, w = 0.093 (R = 0.062, w = 0.106 for all data), GooF = 1.01.
CCDC 2143426.
Crystal Data for 4b
(C69H56N2O2CuCl)·2(CH2Cl2), Mr = 1214.0,
colorless prisms,
monoclinic, space group 21/, a = 15.8854(3), b = 18.7151(2), c = 20.2401(2) Å,
β = 94.392(1)°, V = 5999.6(1) Å3, Z = 4, ρcalc = 1.34 g
cm–3, μ(Mo Kα) = 0.63 mm–1, θmax = 26.3°, 47 930 reflections measured,
12 250 unique, 732 parameters, R = 0.047, w = 0.118 (R = 0.059, w = 0.126 for all data), GooF = 1.02.
CCDC 2143425.
Crystal Data for 4e
(C79H60N2O2CuCl)·2(CH2Cl2), Mr = 1338.1,
yellow plates,
orthorhombic, space group , a = 19.0302(2), b = 24.2764(2), c = 29.9917(4) Å, V = 13855.7(3) Å3, Z = 8, ρcalc = 1.28 g
cm–3, μ(Cu Kα) = 2.59 mm–1, θmax = 66.6°, 79 445 reflections measured,
12 219 unique, 850 parameters, R = 0.059, w = 0.146 (R = 0.073, w = 0.157 for all data), GooF = 1.01.
CCDC 2143428.
Crystal Data for 4f
(C79H60N2O2AgCl)·3(CH2Cl2), Mr = 1467.4,
yellow prisms,
orthorhombic, space group , a = 19.2448(1), b = 24.1491(2), c = 29.9815(4) Å, V = 13933.7(2) Å3, Z = 8, ρcalc = 1.40 g
cm–3, μ(Mo Kα) = 0.61 mm–1, θmax = 27.5°, 209 158 reflections
measured, 15 937 unique, 849 parameters, R = 0.041, w = 0.097 (R = 0.055, w = 0.107 for all data),
GooF = 1.08. CCDC 2143427.
Synthesis of Alkynes
1-Benzofuran-2-carbaldehyde
(S26)
To a
solution of benzofuran (2.3 mL, 21.2 mmol) in anhydrous THF (100 mL),
cooled to −78 °C, n-BuLi (10.5 mL, 25.4
mmol, 2.5 M in hexane) was added dropwise. After 1 h, anhydrous DMF
(3.3 mL, 42.3 mmol, 2.0 equiv) was added dropwise, and the reaction
mixture was allowed to warm to rt within 16 h. Then, the reaction
mixture was quenched with sat. solution of NH4Cl (100 mL),
and the aqueous phase was extracted with EtOAc (3 × 20 mL). The
combined organic extracts were dried over MgSO4 and evaporated.
The residue was chromatographed on silica (10% EtOAc/hexane–100%
EtOAc, Combi-Flash, 40 g column) to give S26 as a yellow
solid (2.7 g, 87%). 1H NMR (200 MHz, CDCl3)
δ 9.86 (s, 1H), 7.80–7.69 (m, 1H), 7.66–7.44 (m,
3H), 7.40–7.25 (m, 1H). Spectral data are in agreement with
those reported.[61]
2-(2,2-Dibromoethyl)-1-benzofuran
(S27)
The compound was synthesized according
to a modified literature procedure.[62] To
a solution of aldehyde S26 (2.7
g, 18.0 mmol) in anhydrous DCM (50 mL), CBr4 (12.0 g, 36.0
mmol, 2.0 equiv) was added in one portion. Then, the reaction mixture
was cooled to 0 °C, and PPh3 (19.0 g, 72.0 mmol, 4.0
equiv) was added in portions. Then, the reaction mixture was stirred
at 0 °C for 2 h and quenched with water (40 mL). The aqueous
phase was separated and extracted with DCM (2 × 40 mL). The combined
organic extracts were dried over Na2SO4 and
evaporated. The residue was chromatographed on silica (hexane) to
give S27 as a white solid (2.0 g, 37%). 1H
NMR (400 MHz, CDCl3) δ 7.62–7.58 (m, 1H),
7.54–7.52 (m, 1H), 7.48–7.43 (m, 1H), 7.36–7.31
(m, 1H), 7.30–7.28 (m, 1H), 7.27–7.21 (m, 1H). Spectral
data are in agreement with those reported.[62]
2-Ethynyl-1-benzofuran (S12)
The compound
was synthesized according to the modified literature procedure.[62] To a solution of dibromide S27 (2.0
g, 6.6 mmol) in anhydrous MeCN (16 mL), DBU (3.9 mL, 26.4 mmol, 4.0
equiv) was added and stirred at rt for 16 h. Then, the reaction mixture
was cooled to 15 °C and quenched with 5% HCl (10 mL). After 5
min of vigorous stirring, the aqueous phase was extracted with a mixture
of EtOAc/hexane (2 × 50 mL, EtOAc/hexane = 1/1, v/v). The combined
organic extracts were washed with water (1 × 100 mL), dried over
Na2SO4, and evaporated. The residue was chromatographed
on silica (hexane, Combi-Flash, 40 g column) to give alkyne S12 as a brown oil (211.0 mg, 22%). 1H NMR (400
MHz, CDCl3) δ 7.60–7.53 (m, 1H), 7.49–7.43
(m, 1H), 7.38–7.32 (m, 1H), 7.28–7.22 (m, 1H), 7.02–7.00
(m, 1H), 3.49 (s, 1H); 13C{1H} NMR (100 MHz,
CDCl3) δ 154.8, 137.7, 127.2, 125.9, 123.4, 121.4,
112.6, 111.4, 83.6, 74.1. Spectral data are in agreement with those
reported.[62]
The compound was synthesized
according
to the modified literature procedure.[63] A 24 mL stainless ball milling vessel was charged with iodonium
salt S28 (925.3 mg, 2.16 mmol, 1.2 equiv), AuCl (8.4
mg, 0.036 mmol, 2 mol %), 1-methylindole (236 μL, 1.80 mmol),
and grinding balls (five stainless still balls, diameter 9 mm). The
ball milling vessel was placed in a Retsch PM100 ball mill (500 rpm,
99 min). The crude reaction mixture was dissolved in Et2O (20 mL) and diluted with water (50 mL). The aqueous phase was extracted
with Et2O (2 × 20 mL), and the combined ethereal extracts
were washed with NaOH (0.1 M, 2 × 50 mL), sat. soln of citric
acid (1 × 50 mL), brine (1 × 50 mL), dried over MgSO4, and evaporated. The residue was chromatographed on silica
(30% EtOAc/hexane) to give S29 as a green solid (416.0
mg, 93%). 1H NMR (400 MHz, CDCl3) δ 7.73
(br d, J = 7.7 Hz, 1H), 7.35–7.23 (m, 3H),
7.23–7.16 (m, 1H), 3.77 (s, 3H), 1.17 (br s, 18H). Spectral
data are in agreement with those reported.[63]
3-Ethynyl-1-methyl-1H-indole (S13)
A solution of indole derivatives S29 (295.9
mg, 0.95 mmol) was dissolved in anhydrous DCM (1.0 mL), and Bu4NF in THF (0.95 mL, 0.95 mmol, 1.0 equiv, 1.0 M in THF) was
added. The reaction mixture was stirred at rt for 4 h, and an additional
portion of Bu4NF in THF (0.95 mL, 0.95 mmol) was added,
and the reaction mixture was left for 16 h with stirring at rt. Then,
solvents were evaporated, and the residue was chromatographed on silica
(1–2% EtOAc/hexane) to give alkyne S13 as a green
oil (112.1 mg, 76%). 1H NMR (400 MHz, CDCl3)
δ 7.76–7.72 (m, 1H), 7.34–7.24 (m, 3H), 7.23–7.18
(m, 1H), 3.78 (s, 3H), 3.21 (s, C≡C–H, 1H). Spectral
data are in agreement with those reported.[64]
1-Benzoylpiperidine-4-carboxylic Acid (S31)
The compound was synthesized according to a slightly modified literature
procedure.[65] A solution of isonipecotic
acid (S30) (3.23 g, 25.0 mmol) was added to a mixture
of THF (25 mL) and water (25 mL), and K2CO3 (10.4
g, 75.0 mmol, 3.0 equiv) was added and cooled to 0 °C. Then,
BzCl (2.9 mL, 25.0 mmol, 1 equiv) was added dropwise, and the cooling
bath was removed and stirred overnight at rt. The reaction mixture
was acidified with 5% HClaq (up to pH = 1–2), saturated
with solid NaCl, and extracted with EtOAc (4 × 50 mL). The combined
organic phases were dried with Na2SO4 and concentrated.
The residue was treated with hexane to precipitate pure acid S31 as a white solid (4.14 g, 71%). 1H NMR (400
MHz, CDCl3) δ 11.09 (bs, 1H, CO2), 7.43–7.35 (m, 5H, ArH), 4.50 (bs, 1H), 3.74 (bs, 1H), 3.15–3.01 (m, 2H),
2.65–2.56 (m, 1H), 2.12–1.83 (m, 2H), 1.74 (bs, 2H).
Spectral data are in agreement with those reported.[66]
The compound was synthesized according
to a slightly modified literature procedure.[67] To a vigorously stirred suspension of 1-benzoylpiperidine-4-carboxylic
acid (S31) (1.50 g, 6.43 mmol, 1.0 equiv), hydroxyimidate S32 (1.94 g, 6.43 mmol, 1.0 equiv), and DMAP (78.6 mg, 0.64
mmol, 10 mol %) in DCM (60 mL), DIC (1.1 mL, 7.07 mmol, 1.2 equiv)
was added dropwise and stirred for 17 h. The mixture was concentrated,
filtered, and the solid was washed with DCM. The combined filtrates
were concentrated, and the solid was precipitated using n-pentane to give a pale yellow solid (3.32 g, 71%). This amide was
used without further purification in the next step (purification by
column chromatography on silica has failed; decomposition was observed). 1H NMR (400 MHz, CDCl3) δ 7.44–7.37
(m, 5H), 4.43 (bs, 1H), 3.83 (bs, 1H), 3.31–3.22 (m, 2H), 3.11–3.01
(m, 1H), 2.29–1.81 (m, 4H). Spectral data are in agreement
with those reported.[67]
1-Benzoyl-4-ethynylpiperidine
(S7)
The
compound was prepared according to the literature procedure.[67] A round-bottom flask was charged with NiCl2·6H2O (188.3 mg 0.79 mmol, 20 mol %) and 4,4′-dimethoxy-2-2′-bipyridine
(171.3 mg, 0.79 mmol, 20 mol %), and dry DMF (20 mL) was added and
stirred till the mixture became a homogeneous green solution. In another
flask was prepared 1.0 M ZnCl2/LiCl in THF by dissolving
ZnCl2 (1.35 g, 9.90 mmol, 2.5 equiv) and LiCl (420 mg,
9.90 mmol, 2.5 equiv) in 10 mL of THF. After cooling to rt, ethynylmagnesium
bromide (19.8 mL, 9.90 mmol, 2.5 equiv, 0.5 M THF solution) was added
dropwise to a flask containing (4-MeOByPy)·NiCl2 complex,
and the resulting solution was stirred at rt for 30 min (until it
became homogeneous).Another flask, charged with ester S33 (2.04 g, 3.96 mmol), was evacuated and backfilled with
argon. Then, the premixed nickel/ligand and ethynyl zinc chloride
solution were added in succession. After stirring at rt for 15 h,
1.0 M HClaq (40 mL) and Et2O (50 mL) were added.
The layers were separated, and the aqueous layer was further extracted
with Et2O (50 mL), AcOEt (2 × 50 mL), and DCM (2 ×
50 mL). The combined organic extracts were washed with brine (1 ×
100 mL), dried with Na2SO4, and evaporated.
The crude product was chromatographed on silica (10–50% EtOAc/hexane),
and the resulting solid was treated with DCM (10 mL) and stirred for
1 h at rt. The solid impurities were filtered and washed with DCM
(1 × 5 mL). The filtrates were evaporated to give a white solid
(0.55 g, 65%). 1H NMR (400 MHz, DMSO-d6) δ 7.57–7.23 (m, 5H), 3.95 (bs, 1H), 3.46
(bs, 1H), 3.34–3.07 (m, 2H), 2.98 (s 1H), 2.70 (s, 1H), 1.79
(bs, 2H), 1.50 (br s, 2H). Spectral data are in agreement with those
reported.[68]
To a suspension of 6-chloro-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic
acid (S34) (2.25 g, 8.0 mmol) in toluene (20 mL), (COCl)2 (1.0 mL, 12.0 mmol, 1.5 equiv) and catalytic amount of DMF
(2 drops) were added. The resulting reaction mixture was heated at
40 °C for 3 h. The reaction mixture was cooled to rt, and the
resulting solid was filtered, washed with toluene (2 × 10 mL),
and dried in vacuo to give acid chloride S35 as a light
yellow solid (2.39 g). Acid chloride S35 was used in
the next step without further purification.
To a solution of hept-6-yne-1-ol (1.1
g, 9.6 mmol, 1.2 equiv) and Et3N (1.3 mL, 9.6 mmol, 1.2
equiv) in DCM (20 mL), cooled to 0 °C, acid chloride S35 (2.4 g, 8.0 mmol) was added in portions. Then, the reaction mixture
was stirred for 16 h at rt and diluted with water. The aqueous phase
was extracted with DCM (2 × 20 mL), dried over Na2SO4, and evaporated. The residue was chromatographed on
silica (5% EtOAc/DCM) to give a light yellow solid, which was further
purified by crystallization from mixture benzene/n-heptane (1.65 g). 1H NMR indicated some impurities, and
ester S15 was chromatographed on silica (1% MeOH/DCM)
to give pure S15 as a white solid (1.53 g, 51%). mp 150–153
°C (n-heptane/DCM); 1H NMR (400 MHz,
CDCl3) δ 8.54–8.47 (m, 1H), 8.13 (dd, J = 9.1, 4.8 Hz, 2H), 7.97 d, (J = 5.9
Hz, 1H), 4.30 (t, J = 6.8 Hz, 2H, C2O), 3.51–3.39 [m, 1H, NC(CH2)], 2.27–2.14
(m, 2H, C2), 1.95–1.89
(m, 1H, CH2CC), 1.84–1.72
(m, 2H, C2), 1.66–1.48
(m, 4H, C2), 1.41–1.30
(m, 2H, C2), 1.19–1.09
(m, 2H, C2); 13C{1H} NMR (100 MHz, CDCl3) δ
172.7, 165.2, 155.7 (d, JCF = 249.2 Hz),
148.9, 137.3 (d, JCF = 2.1 Hz), 128.7
(d, JCF = 5.8 Hz), 127.0 (d, JCF = 20.2 Hz), 119.1, 113.9 (d, JCF = 22.7 Hz), 110.8, 84.4, 68.5, 65.0, 34.9, 28.3, 28.2, 25.2,
18.4, 8.4; 19F NMR (376 MHz, CDCl3) δ
−118.0. HR MS (ESI TOF) m/z calcd for C20H19ClFNO3Na [M + Na]+: 398.0935; found: 398.0927.
Hex-5-ynoyl Chloride (S37)
To a solution
of hex-5-ynoic acid (S36) (2.0 mL, 18.2 mmol) in THF
(20 mL), oxalyl chloride (2.4 mL, 27.2 mmol) and one drop of DMF were
added. The resulting solution was stirred for 2 h at rt. Then, the
solvent and excess of oxalyl chloride were evaporated, and the crude
product was twice evaporated with DCM (2 × 5 mL) to give acid
chloride S37, which was used in the next step without
further purification.
To a precooled (−40 °C) solution
of 4-amino-N-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide S38 (3.5 g, 14.0 mmol, 1.0 equiv) in anhydrous pyridine (40
mL), a solution of crude 5-pentynoic chloride (18.2 mmol, 1.3 equiv)
in DCM (12 mL) was added dropwise. The cooling bath was removed, and
the suspension was stirred for 18.5 h at rt. The reaction mixture
was diluted with water (100 mL) and extracted with DCM (3 × 40
mL). The combined organic phases were washed with 5% HClaq (3 × 100 mL) and sat. NaHCO3aq (1 × 100 mL,
NaHCO3 appeared to be a strong enough base to deprotonate
sulfonamide). The aqueous phase was washed with DCM (1 × 40 mL,
organic phase was disposed of) and acidified with 10% HClaq. The precipitated solid was washed with water (1 × 50 mL) and
DCM (1 × 20 mL). The aqueous solution was washed with DCM (4
× 40 mL). The combined organic phases were dried with Na2SO4 and evaporated. The crude product and that
described above were combined and boiled with EtOAc giving a white
solid (1.66 g, 34%). mp 204.0 °C (decomposition, AcOEt); 1H NMR (400 MHz, CD3OD) δ 7.84–7.79
(m, 2H), 7.75–7.71 (m, 2H), 6.10 (s, 1H), 2.53 (t, J = 7.5 Hz, C2), 2.30 (s, 3H, C3) overlapping 2.29–2.24 (m, 3H, C2 and CCH), 1.92–1.83 (m, 2H,
CH2); 13C{1H} NMR (100
MHz, CD3OD) 174.1, 171.9, 159.4, 144.6, 135.3, 129.3, 120.4,
96.5, 84.1, 70.3, 36.6, 25.3, 18.6, 12.2. HR MS (ESI TOF) m/z calcd for C16H17N3O4SNa [M + Na]+: 370.0837; found:
370.0835.
The compound was synthesized according
to the modified literature procedure.[69] To the solution of mycophenolic acid (S40) (2.0 g,
12.5 mmol) and TBSCl (11.3 g, 74.9 mmol) in dry DMF (20 mL), imidazole
(6.8 g, 99.9 mmol) was added portionwise, and the reaction mixture
was stirred at rt for 2.5 h. Then, the solution was cooled to 0 °C,
and water (60 mL) was slowly added followed by Et2O (120
mL). The ethereal phase was separated and washed with water (5 ×
40 mL). Every aqueous phase was washed with the same portion of Et2O (1 × 50 mL). The combined organic phases were dried
over Na2SO4, and the solvent was evaporated.
Crude S41 was used in the next step without further purification.
Silyl ether S41 was
dissolved in THF (20 mL), and water (20 mL) and AcOH (20 mL) were
added. The resulting solution was stirred at rt for 1.5 h. Then, the
reaction mixture was diluted with water (60 mL) and Et2O (120 mL), and the organic phase was separated and washed with water
(5 × 40 mL). Every aqueous phase was extracted with the same
portion of Et2O (1 × 50 mL). The combined organic
phases were dried over Na2SO4, and the solvents
were evaporated. The residue was purified by chromatography on silica
(DCM, 3% MeOH/DCM) to give a white powder (5.55 g, ∼100%). 1H NMR (400 MHz, CDCl3) δ 5.20 (t, J = 5.2 Hz, 1H, C=CH), 5.06
(s, 2H, OCH2Ar), 3.73 (s, 3H, ArOCH3), 3.38 (d, J = 6.4 Hz,
2H, ArCH2CH=C), 2.44–2.37
(m, 2H, CH2), 2.32–2.25 (m,
2H, CH2), 2.14 (s, 3H, ArCH3), 1.75 (s, 3H, C=CCH3), 1.02 [s, 9H, SiC(CH3)3], 0.23 (s, 6H, Si(CH3)2]. Spectral data are in agreement with those reported.[69]
To
a suspension of biotin (500 mg, 2.21 mmol) in anhydrous DMF (20 mL),
HOBt·H2O (338.4 mg, 3.32 mmol, 1.5 equiv) was added
in one portion at rt. After 15 min, EDC·HCl (635.5 mg, 3.32 mmol,
1.5 equiv) was added, and the reaction mixture was stirred for an
additional 15 min (all solids have been dissolved). Then, alcohol
(426.0 μL, 433.8 mg, 4.42 mmol) and DMAP (540.0 mg, 4.42 mmol,
2.0 equiv) were added and stirred for 16 h at rt. Then, the reaction
mixture was diluted with water (100 mL) and brine (100 mL) and extracted
with EtOAc (3 × 30 mL). The combined organic extracts were washed
with brine (2 × 50 mL), dried over Na2SO4, and evaporated. The residue was chromatographed on silica (EtOAc/5%
MeOH/EtOAc) to give an ester S16 as a waxy solid (611.5
mg, 90%). [a]D29 = 49.5 (c = 1.0, DCM); 1H NMR 50 MHz, CDCl3) δ 6.18 (br s, 2H), 4.56–4.41
(m, 1H), 4.35–4.21 (m, 1H), 4.13–3.98 (m, 2H), 3.22–3.04
(m, 1H), 2.97–2.62 (m, 3H), 2.41–2.12 (m, 4H), 1.98–1.92
(m, 1H), 1.85–1.28 (m, 11H); 13C{1H}
NMR (50 MHz, CDCl3) δ 173.7, 164.1–163.7 (m),
83.8, 68.7, 63.7, 62.0, 60.1, 55.4, 40.4, 33.8, 28.3, 28.1, 27.6,
24.8, 24.7, 18.0. HR MS (EI EBE double focusing geometry mass analyzer) m/z calcd C16H24N2O3SNa [M + Na]+: 347.1405; found: 347.1403.
Synthesis of Fluorinated Naphthyridines
General Procedure 1 (GP1)
A 4 mL screw
cap vial was charged with aminophenone 1a,b (0.5 mmol), alkyne (0.6 mmol, 1.2 equiv), and complex 4a–h (0.005 mmol, 2 mol %). Then, the solution of TMG (N,N,N′,N′-tetramethylguanidine, 1.25 μL,
2 mol %) in degassed water (2 mL) was added. The resulting biphasic
mixture was stirred at 120 °C in an aluminum heating block (thermocouple
was inserted in a separate vial filled with silicon oil M350) for
the indicated time (usually 19 h) with vigorous stirring. Then, the
reaction mixture was diluted with brine and extracted with EtOAc (3×)
or DCM (3×). The combined organic extracts were dried over Na2SO4, evaporated, and the residue was chromatographed
on silica (unless indicated otherwise) using an appropriate eluting
system to afford the product.
The title compound was obtained according
to GP1 using
aminophenone 1a (570.4 mg, 3.0 mmol), alkyne 2a (280.0 μL, 3.6 mmol, 1.2 equiv), complex 4h (62.7
mg, 0.1 mmol, 2 mol %), TMG (7.5 μL, 0.1 mmol, 2 mol %), and
water (10 mL). The resulting reaction mixture was heated at 120 °C
for 16 h. Then, the reaction mixture was diluted with EtOAc (5 mL),
and the aqueous phase was separated and extracted with EtOAc (3 ×
5 mL). The combined organic extracts were washed with brine (1 ×
5 mL), dried over Na2SO4, and evaporated. The
residue was chromatographed on silica (20% EtOAc/hexane, Combi-Flash,
40 g column) to give 3a as a yellow solid (127.9 mg,
18%). 1H NMR (400 MHz, CDCl3) δ 9.10 (dd, J = 4.2, 1.8 Hz, 1H), 8.44–8.37 (m, 1H), 7.68 (s,
1H), 7.49 (dd, J = 8.2, 4.2 Hz, 1H), 2.35–2.22
(m, 1H), 1.52–1.36 (m, 2H), 1.28–1.12 (m, 2H). Spectral
data are in agreement with those reported.[23c] For details on optimization studies, see Table S1 in the SI.
The compound was obtained according to
GP1 using aminopyridine 1a (95.0 mg, 0.50 mmol, 1.0 equiv),
alkyne S1 (66.0 μL, 0.60 mmol, 1.2 equiv), copper(I)
complex 4h (12.1 mg, 0.01 mmol, 2 mol %), and TMG (1.25
μL, 0.01 mmol,
2 mol %) in water (2 mL). Then, the reaction mixture was diluted with
brine (2 mL) and extracted with EtOAc (3 × 1 mL). The residue
was chromatographed on silica (15% EtOAc/hexane) to give naphthyridine 3b as an orange solid (113.3 mg, 83%). To test the remarkable
effect of the NHC ligand on the course of direct catalytic alkynylation/dehydrative
cyclization, a polymeric (PhC≡C–Cu) (generated prior to use) was reacted with aminophenone 1a on water in the presence of TMG (or without an external
base) at 120 °C. Unfortunately, the formation of product 3a has not been detected. mp 154.0–155.0 °C (n-heptane); 1H NMR (400 MHz, CDCl3) δ 9.26–9.18 (m, 1H), 8.55–8.46 (m, 1H), 8.37–8.27
(m, 3H), 7.64–7.49 (m, 4H); 13C{1H} NMR
(100 MHz, CDCl3) δ 159.8, 156.4, 154.5, 137.3, 136.2
(q, JCF = 31.9 Hz), 133.3 (q, JCF = 2.0 Hz), 130.8, 129.0, 127.8, 123.0 (q, JCF = 273.3 Hz), 122.8, 116.9, 116.7 (q, JCF = 5.1 Hz); 19F NMR (376 MHz, CDCl3) δ −60.9; HR MS (EI EBE double focusing geometry
mass analyzer) m/z calcd C15H9F3N2 [M]•+: 274.0718; found:
274.0714.
The compound was obtained according to
GP1 using aminopyridine 1a (95.0 mg, 0.50 mmol), alkyne 2c (84.1 mg, 0.6 mmol, 1.2 equiv), copper(I) complex 4h (12.1 mg, 0.01 mmol, 2 mol %), and a solution of TMG (1.25
μL, 0.01 mmol, 2 mol %) in water (2 mL). The resulting reaction
mixture was heated at 120 °C for 19 h. Then, the reaction mixture
was extracted with EtOAc (4 × 1 mL). The residue was chromatographed
on silica (30–40% EtOAc/hexane) to give ester 3h as a light yellow oil (155.9 mg, 99%). 1H NMR (200 MHz,
CDCl3) δ 9.25–9.14 (m, 1H), 8.55–8.40
(m, 1H), 7.71 (s, 1H), 7.60 (dd, J = 8.5, 4.3 Hz,
1H), 4.14 (q, J = 7.2 Hz, 2H, CO2C2CH3), 3.18
(t, J = 7.3 Hz, 2H), 2.55–2.40 (m, 2H), 2.38–2.20
(m, 2H), 1.26 (t, J = 7.1 Hz, 3H). Spectral data
are in agreement with those reported.[23c]
The compound was obtained according to
GP1 using aminopyridine 1b (898.0 g, 4.0 mmol), alkyne S9 (740.0 mg, 4.8 mmol, 1.2 equiv), copper(I) complex 4h (97.0 mg, 0.08 mmol, 2 mol %), and a solution of TMG (10
μL, 0.08 mmol, 2 mol %) in water (16 mL). The glass pressure
ampoule, attached to the Schlenk line, was charged with copper(I)
complex and aminopyridine 1b and then evacuated and backfilled
with argon three times. A solution of TMG in water and alkyne S9 were added, the ampoule was closed, and the reaction mixture
was heated at 120 °C in an oil bath for 19 h. Then, the reaction
mixture was saturated with solid NaCl and extracted with EtOAc (6
× 25 mL) and then with DCM (6 × 25 mL). The combined organic
extracts were evaporated, dried over Na2SO4,
and the residue was chromatographed on silica (30–50% EtOAc/hexane,
then 3% MeOH/DCM) to give 3k as a beige solid (1.33 g,
92%). mp 136–139 °C (n-heptane/DCM); 1H NMR (400 MHz, CDCl3) δ 9.07 (br s, 1H),
8.41 (br s, 1H), 7.69 (br s, 1H), 3.63 (t, J = 6.6
Hz, C2OH, 2H), 3.63
(t, J = 7.7 Hz, ArC2, 2H), 1.95–1.85 (m, 2H, C2), 1.61–1.51 (m, 2H, C2) overlapping 1.62–1.28
(m, 9H, 4 × C2, 1 × O). 13C{1H} NMR (50 MHz, CDCl3) δ 166.9, 154.7–153.9
(m), 153.4, 134.9 (q, J = 32.2 Hz), 131.6, 130.7–129.9
(m), 122.8 (J = 273.6 Hz), 121.1–120.1 (m),
116.6 (q, J = 5. 0 Hz), 63.0, 39.4, 32.8, 29.4, 29.3
(×2), 29.1, 25.7 (not all of the characteristic quartets have
been precisely detected); 13C{1H} NMR spectrum
could not be recorded at higher temperature due to the low solubility
also at higher temp.; attempts to record the spectrum in DMSO-d6 or toluene-d8 failed
for the same reason); 19F NMR (376 MHz, CDCl3) δ −61.1; HR MS (EI EBE double focusing geometry mass
analyzer) m/z calcd for C17H20ClF3N2ONa [M + Na]+: 383.1114; found:
383.1116.
The compound was obtained according to
GP1 using
aminopyridine 1a (95.0 mg, 0.50 mmol), alkyne S11 (59.1 μL, 0.60 mmol, 1.2 equiv), copper(I) complex 4h (12.1 mg, 0.01 mmol, 2 mol %), and a solution of TMG (1.25 μL,
0.01 mmol, 2 mol %) in water (2 mL). The reaction mixture was heated
at 120 °C for 19 h. Then, it was diluted with brine and extracted
with EtOAc (5 × 1 mL). The combined organic extracts were dried
over Na2SO4 and evaporated. The residue was
chromatographed on silica (30% EtOAc/hexane, Combi-Flash) to give
a light orange solid (117.0 mg, 83%). mp 178.0–179.0 °C
(precipitation from n-pentane/DCM); 1H
NMR (400 MHz, CDCl3) δ 9.17 (br s, 1H), 8.45 (br
d, J = 8.2 Hz 1H), 8.27 (br d, J = 2.0 Hz, 1H), 8.12 (s, 1H), 7.98 (d, J = 4.9 Hz,
1H), 7.60–7.50 (m, 1H), 7.48–7.43 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 156.6, 155.7,
154.7–154.4 (m), 140.8, 133.2, 128.8–128.4 (m), 117.2–117.0
(m), 116.9–116.7 (m) (none of the characteristic quartets have
been detected due to broadening of signals); 19F NMR (376
MHz, CDCl3) δ −61.1; HR MS (EI EBE double
focusing geometry mass analyzer) m/z calcd for C13H7F3N2S
[M]•+: 280.0282; found: 280.0283.
The compound was obtained according to
GP1 using aminopyridine 1a (95.0 mg, 0.50 mmol), alkyne S12 (85.3 mg, 0.60 mmol, 1.2 equiv), copper(I) complex 4h (12.1 mg, 0.01 mmol, 2 mol %), and a solution of TMG (1.25
μL, 0.01 mmol, 2 mol %) in water (2 mL). Then, the reaction
mixture was heated to 120 °C for 19 h, diluted with brine, and
extracted with EtOAc (4 × 1 mL). The residue was chromatographed
on silica (15–25% EtOAc/hexane, Combi-Flash, 24 g column) to
give naphthyridine 3o as a brown solid (59.9 mg, 38%).The compound was obtained according to
GP1 using aminopyridine 1a (95.0 mg, 0.50 mmol), 2-(prop-2-yn-1-yloxy)benzaldehyde 2b (85.3 mg, 0.60 mmol, 1.2 equiv), copper(I) complex 4h (12.1 mg, 0.01 mmol, 2 mol %), and a solution of TMG (1.25
μL, 0.01 mmol, 2 mol %) in water (2 mL). The reaction mixture
was heated to 120 °C for 19 h. Then, it was diluted with brine
and extracted with DCM (4 × 1 mL). The residue was chromatographed
on silica (20% EtOAc/hexane, Combi-Flash, 12 g column) to give naphthyridine 3o as a brown solid (27.7 mg, 25%). Prolonged reaction time
(41 h) afforded product 3o with a slightly lower 18%
yield. mp 200–207 °C (precipitation from n-pentane/DCM); 1H NMR (400 MHz, CDCl3) δ
9.24–9.16 (m, 1H), 8.55–8.40 (m, 2H), 7.92 (s, 1H),
7.72 (br d, J = 7.7 Hz, 1H), 7.66–7.52 (m,
2H), 7.48–7.36 (m, 1H), 7.35–7.18 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 156.4, 155.9,
154.8, 153.4, 151.9, 136.5 (q, JCF = 32.4
Hz), 133.4 (q, JCF = 1.9 Hz), 128.6, 126.6,
123.7, 122.9, 122.8 (q, JCF = 273.1 Hz),
122.5, 117.4 (q, JCF = 1.0 Hz), 116.2
(q, JCF = 5.2 Hz), 111.8, 108.9; 19F NMR (376 MHz, CDCl3) δ −61.0; HR
MS (EI EBE double focusing geometry mass analyzer) m/z calcd for C17H9F3N2O
[M]•+: 314.0667; found: 314.0667.
Authors: Steven D Karlen; Horacio Reyes; R E Taylor; Saeed I Khan; M Frederick Hawthorne; Miguel A Garcia-Garibay Journal: Proc Natl Acad Sci U S A Date: 2010-08-05 Impact factor: 11.205
Authors: Yu Zhou; Jiang Wang; Zhanni Gu; Shuni Wang; Wei Zhu; José Luis Aceña; Vadim A Soloshonok; Kunisuke Izawa; Hong Liu Journal: Chem Rev Date: 2016-01-12 Impact factor: 60.622
Authors: Joel M Smith; Tian Qin; Rohan R Merchant; Jacob T Edwards; Lara R Malins; Zhiqing Liu; Guanda Che; Zichao Shen; Scott A Shaw; Martin D Eastgate; Phil S Baran Journal: Angew Chem Int Ed Engl Date: 2017-08-01 Impact factor: 15.336
Authors: Jiang Wang; María Sánchez-Roselló; José Luis Aceña; Carlos del Pozo; Alexander E Sorochinsky; Santos Fustero; Vadim A Soloshonok; Hong Liu Journal: Chem Rev Date: 2013-12-03 Impact factor: 60.622
Figure 1
Scheme 1
Scheme 2
Scheme 5
Scheme 3
Scheme 4
Scheme 6
Scheme 7
Scheme 8
Figure 2