Copper- and palladium-catalyzed amidation reactions for the synthesis of substituted imidazo[4,5-c]pyridines

Article abstract of DOI:10.1021/jo500064j

Imidazo[4,5-c]pyridines were synthesized in three steps utilizing a palladium-catalyzed amidation/cyclization strategy. N-Aryl substrates were synthesized using copper-catalyzed amidation of 3-amino-N-Boc-4-chloropyridine. Complementary protocols for the selective chlorination of imidazo[4,5-c] pyridines at the C2 and C7 positions were also developed.

Full text of DOI:10.1021/jo500064j

Article
pubs.acs.org/joc
Copper- and Palladium-Catalyzed Amidation Reactions for the
Synthesis of Substituted Imidazo[4,5‑c]pyridines
Robert J. Wilson, Adam J. Rosenberg, Lauren Kaminsky, and Daniel A. Clark*
Department of Chemistry, 1-014 Center for Science and Technology, Syracuse University, Syracuse, New York 13244, United States
S
* Supporting Information
ABSTRACT: Imidazo[4,5-c]pyridines were synthesized in three steps
utilizing a palladium-catalyzed amidation/cyclization strategy. N-Aryl
substrates were synthesized using copper-catalyzed amidation of 3-
amino-N-Boc-4-chloropyridine. Complementary protocols for the
selective chlorination of imidazo[4,5-c]pyridines at the C2 and C7 positions were also developed.
strategy provides access to substituted heterocycles that are
problematic to obtain selectively using other methods.8
INTRODUCTION
■
Imidazopyridines and derivatives thereof comprise an impor-
tant collection of biologically active molecules. Imidazopyridine
structures are present in druglike molecules ageladine A and 3-
deazaadenosine (Figure 1)1 and are recognized by the
RESULTS AND DISCUSSION
■
In order to explore a cross-coupling route to these molecules
the N-3 nitrogen of 3-amino-4-chloropyridine must first be
arylated or alkylated. Alkylation has previously been accom-
plished with 3-amino-2-chloropyridine by reductive amina-
tion,17 and N-aryl moieties were installed by Chan−Lam
coupling.18,19 However, in our hands, use of the corresponding
3-amino-4-chloropyridine provided the desired products in
poor yield. Due to these unexpected difficulties, we elected to
investigate known 4-chloro-3-N-Boc-pyridine (1)20 as an entry
into these analogous systems (Scheme 1). Base-mediated
Scheme 1. Substituted 3-Aminopyridines
Figure 1. Biologically active compounds containing imidazo[4,5-
c]pyridine core.
pharmaceutical industry as valuable bioisosteres.2 Imidazo[4,5-
c]pyridines (IPc) are currently being investigated for the
inhibition of hepatitis C virus replication,3,4 cyclin-dependent
kinase inhibitors (i.e., grossularine 1 and 2),5 and other
biologically relevant targets.6−15
Previously imidazopyridines have been prepared from the
appropriately substituted diaminopyridines; however, these
compounds can be difficult to obtain in a regiospecific fashion,
and mixtures often result.8 We recently reported a new route to
imidazo[4,5-b]pyridines (IPb) utilizing an amide cross-coupling
strategy starting from 3-amino-2-chloropyridine.16 This method
allowed for complete control of regioselectivity in the synthesis
of N-1 substituted IPb. Based on the success of this approach,
investigations shifted to the 3-amino-4-chloropyridines which
may be useful for the synthesis of the corresponding IPc. This
alkylation of the carbamate nitrogen provided N-alkyl and N-
benzyl products from the corresponding alkyl or benzyl halides,
and removal of the Boc group was accomplished by TFA in
DCM.
Cognizant that installation of N-aryl and N-heteroaryl
functionality by this strategy would not be practical, an
alternative approach was sought. Palladium-catalyzed amidation
was not explored due to the activated aryl chlorine present in 1.
Multiple unselective coupling events were envisioned, and these
competitive couplings would likely limit the substrate scope.
Therefore, copper-catalyzed couplings were examined to avoid
the aforementioned problems; however, new questions arose
Received: January 10, 2014
Published: February 6, 2014
© 2014 American Chemical Society
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a
about the ability of 1 to participate in copper-catalyzed
amidation. Basic pyridines are known to interfere with
amidation reactions, and pyridine itself is occasionally used as
a ligand.21 Undaunted by these precedents, we investigated
copper-catalyzed conditions for the desired N-aryl products.
Studies commenced with copper(I) iodide and diamine
ligands previously used for copper-catalyzed amidation (Table
1).22−25 None of the desired product (2h) was observed using
Table 2. Copper-Catalyzed Amidation Scope
a
Table 1. Copper-Catalyzed Amidation Optimization
b
b
entry
ligand
solvent
conversion (%)
yield (%)
c
1
2
3
4
5
6
7
DMEDA
DMEDA
DMEDA
EDA
L1
DMF
100
100
79
0
c
Tol
0
dioxane
dioxane
Tol
43
59
65
71
70
d
L1
dioxane
dioxane
dioxane
dioxane
dioxane
100
72
96
L2
trace
65
e
8
L1
100
77
f
9
L1
74
a
g
Reaction conditions: (1) 1 equiv of 1, 1.1 equiv of ArX, 10 mol % of
CuI, 20 mol % of L1, 2 equiv of K3PO4, 1,4-dioxane (0.5 M); (2) 25%
TFA in CH2Cl2. Isolated yield. Yield over two steps.
10
L1
19
19
a
Reaction conditions: 10 mol % of CuI, 20 mol % of ligand, 2 equiv of
b
c
b
c
base, 0.5 M. Using mesitylene as an internal standard. Decompo-
sition of 1 was observed. Isolated yield. 20 mol % of CuI, 40 mol %
of ligand. Cs2CO3 used as the base. K2CO3 used as the base.
DMEDA = N,N′-dimethylethylenediamine. EDA = ethylenediamine.
L1 = ( ) trans-1,2-diaminocyclohexane. L2 = ( ) N,N′-dimethyl-1,2-
diaminocyclohexane.
d
e
f
g
3l and 3m in 47% and 66% yield, respectively, over two steps.
The use of halopyridines as coupling partners did not adversely
affect the amidation or deprotection reactions as 3-bromopyr-
idine gave 2n in 88% and Boc deprotection afforded 3n in 89%
yield (entry 8).
With the desired N-substituted 3-amino-4-chloropyridine
substrates in hand, the palladium-catalyzed formation of the
desired IPc commenced. Substrate 3h (3-amino-N-phenyl-4-
chloropyridine) was chosen to evaluate conditions for the
synthesis of IPc (Figure 2, Table 3). The newly developed
Me3(OMe)-t-BuXPhos26 ligand was utilized in place of the
Me4-t-BuXPhos or t-BuBrettPhos ligands previously em-
ployed.16 This ligand performed well giving the desired IPc
N,N′-dimethylethylenediamine (DMEDA) as a ligand in either
DMF or toluene, although 79% conversion and 43% yield of 2h
was obtained in 1,4-dioxane (entries 1−3). Ethylenediamine
(EDA), a less encumbered ligand, gave 71% conversion and an
increased 59% yield of 2h (entry 4). The more rigid trans-1,2-
diaminocyclohexane gave similar results when the reaction was
carried out in toluene (entry 5); when 1,4-dioxane was utilized
complete conversion and 96% isolated yield of 2h was obtained
(entry 6). The more electron-rich N,N′-dimethyl analogue L2
gave moderate conversion (72%) but only a trace of 2h (entry
7). These results support Buchwald’s hypothesis that the
coupling of bulky secondary amides is aided by unencumbered
diamine ligands.23,24 Attempts to further improve the coupling
and shorten the reaction time by altering the base or increasing
the catalyst loading were unsuccessful (entries 8−10).
With optimized copper-amidation conditions elucidated, we
explored the substrate scope of the C−N coupling reaction
(Table 2). As shown previously, iodobenzene gave 96% yield of
2h, and Boc deprotection under acidic conditions provided 3h
in 97% yield (entry 1). Analogous conditions with 4-
iodotoluene gave 2i in 76% yield and 3i in 92% yield (entry
2). Aryl bromides were also effective substrates for the copper
amidation conditions. Electron-poor 4′-bromoacetophenone
and 4-bromotrifluorotoluene gave 2j in 90% and 2k in 79%,
respectively (entries 3 and 4). Electron-rich aryl bromides 4-
bromoanisole (entry 5) and 3,5-dimethylbromobenzene (entry
6) gave partial conversion for the amidation, and the crude
reaction mixtures were deprotected for ease of isolation to give
Figure 2. Ligand structures.
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The use of substituted amides under conditions optimized
for formamide only lead to the formation of dimer 7. Since
amides are less nucleophilic than anilines,30 substrate 3h must
out-compete the amide for binding to palladium, leading to a
facile dimerization. In the absence of amide under otherwise
identical reaction conditions, we also observed the formation of
7. This unwanted dimerization could be thwarted by increasing
the amount of amide from 1.5 to ≥5 equiv (Scheme 2). Using
these slightly modified conditions, C2-substituted IPc 5 and 6
could be obtained in 61% and 51% yields, respectively.
Table 3. Ligand Screen
a
entry
ligand
conversion (%)
yield (%)
b
1
2
3
4
5
6
7
8
Me3(MeO)-t-BuXPhos
cBRIDP
100
100
100
10
90
81
87
trace
0
BippyPhos
TrippyPhos
RuPhos
a
15
Scheme 2. Amide Scope
(t-Bu3PH)BF4
(Cy3PH)BF4
17
0
18
0
XantPhos
17
0
a
1
Determined by H NMR using mesitylene as an internal standard.
Isolated yield.
b
4h in 90% yield. The cBRIDP27 ligand developed by Takasago
afforded 81% yield, and Singer’s BippyPhos28 gave 87% yield of
the desired IPc 4h. TrippyPhos29 furnished only trace amounts
of 4h. No product was observed for other ligands, for example,
RuPhos, tri-tert-butylphosphine, tricyclohexylphosphine, and
XantPhos.
With useful palladium-catalyzed amidation conditions in
hand, attention turned to examining the reaction scope. As
illustrated in Table 4, benzyl derivitives 3a−e performed well
a
Conditions: 1 equiv of 3h, Pd (2 mol %), ligand (10 mol %), 2 equiv
of K3PO4, (a) 10 equiv of acetamide, (b) 5 equiv of furanamide, 0.2 M
t-BuOH, 110 °C, 4 h.
a
Table 4. Palladium-Catalyzed Amidation/Cyclization
We sought to demonstrate the utility of the IPc system by
further elaboration of the reaction products (Scheme 3).
Scheme 3. Functionalization Reactions
b
entry
R
yield (%)
product
1
3a, CH2(C6H5)
3b, CH2(2,5-OMe-C6H3)
3c, CH2(3,5-OMe-C6H3)
3d, CH2(4-F-C6H4)
3e, CH2(4-Ph-C6H4)
3f, Me
84
85
52
75
75
58
85
90
89
87
91
80
90
86
4a
4b
4c
4d
4e
4f
2
3
4
5
6
7
3g, n-Pr
4g
4h
4i
8
3h, Ph
9
3i, 4-Me-Ph
10
11
12
13
14
3j, 4-Ac-Ph
4j
3k, 4-CF3-Ph
4k
4l
3l, 4-OMe-Ph
3m, 3,5-xylyl
4m
4n
3n, 3-pyridyl
a
Reaction conditions: 1 equiv of 3, Pd (1 mol %), ligand (5 mol %),
Selective deprotonation of 4h at C2 with LDA and quenching
the resulting lithiate with hexachloroethane produced com-
pound 8 in 85% yield. Alternatively, m-CPBA can be used to
oxidize 4h to pyridine-N-oxide 9 in 89% yield. Pyridine N-oxide
9 was subsequently treated with POCl3 at 120 °C for 2 h to
form aryl chloride 10 regioselectively in 84% yield.31 Thus, we
have demonstrated complementary regioselective chlorination
protocols to obtain functionalized chloro-IPc 8 and 10.
Additionally, treatment of 9 with TMSCN and triethylamine
in acetonitrile32 gave the Reissert−Henze product 11 in 89%
yield as a single regioisomer.
1.5 equiv of formamide, 1.5 equiv of K3PO4, 0.2 M t-BuOH, 110 °C, 4
h. Isolated yield.
b
(52−85% yield), with electron-donating, electron-withdrawing,
aryl, and fluorine substitution all being tolerated (entries 1−5).
Methyl (3f) and n-propyl (3g) substitution gave 4f in 58% and
4g in 85% yield, respectively (entries 6 and 7). The aryl-
substituted derivatives provided the cyclized products 4h−m in
excellent 80−91% yields, with both electron-poor and electron-
rich systems performing admirably (entries 8−13). Addition-
ally, bis-pyridine moiety 3n was well tolerated under the
reaction conditions giving 4n in 86% yield (entry 14).
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the starting material. The reaction was quenched by the addition of
H2O and diluted with EtOAc. The layers were separated, and the
aqueous layer was extracted with EtOAc. The combined organic layers
were washed with H2O and brine, dried over Na2SO4, filtered, and
concentrated in vacuo to give the crude alkylated product which was
used without further purification.
The crude alkylated substrate was dissolved in DCM (0.5 M) and
added to an oven-dried round-bottom flask equipped with a stir bar.
TFA (0.17−0.25 M) was added dropwise and the reaction stirred at
room temperature until TLC analysis indicated consumption of the
CONCLUSION
■
In summary, we have utilized copper-catalyzed conditions for
the arylation of 3-amino-4-chloropyridine 1 with aryl and
heteroaryl halides, providing a high-yielding and direct route to
monoarylated 3-amino-4-chloropyridines. Subsequent palladi-
um-catalyzed amidation produced imidazo[4,5-c]pyridines in
excellent yields using amide coupling partners. Further
functionalization of the IPc by halogenation and cyanation
was demonstrated yielding IPc primed for further manipulation.
starting material. The reaction was quenched with satd NaHCO3(aq)
,
and the layers were separated. The organic layer was dried over
Na2SO4, concentrated in vacuo, and applied to a silica gel column to
give the desired product.
EXPERIMENTAL SECTION
■
General Procedures. Unless otherwise indicated, all reactions
were conducted in oven (140 °C) or flame-dried glassware using
distilled and degassed solvents under a positive pressure of dry argon
with standard Schlenk techniques. All air-sensitive reagents were
stored in a glovebox containing dry argon gas. Dry tetrahydrofuran
(THF), toluene, acetonitrile (CH3CN), and methylene chloride
(DCM) were obtained by passing commercially available predried,
oxygen-free formulations through two activated alumina columns.
Stainless steel syringes or cannulae that had been oven-dried (140 °C)
and cooled under an argon atmosphere or in a desiccator were used to
transfer air- and moisture-sensitive liquids. Yields refer to chromato-
graphically and spectroscopically (1H NMR) homogeneous materials,
unless otherwise stated. Reactions were monitored by thin-layer
chromatography (TLC) carried out on precoated glass plates of silica
gel (0.25 mm) using the indicated solvent system. Visualization was
accomplished with ultraviolet light (254 nm) or by treatment with one
of the following solutions and carefully heating with a hot-air gun (450
°C): 10% phosphomolybdic acid in ethanol, 1% potassium
permanganate/7% potassium carbonate/0.5% sodium hydroxide
aqueous solution, or anisaldehyde in ethanol with 10% sulfuric acid.
Flash column chromatography was performed using silica gel (40−63
μm). All workup and purification procedures were carried out with
reagent grades solvents in air.
General Experimental A: Copper Coupling. To an oven-dried
Schlenk tube equipped with a stir bar were added copper(I) iodide (10
mol %), potassium phosphate (2 equiv), tert-butyl-4-chloropyridin-3-yl
carbamate 1 (1 equiv), and the haloarene (1.1 equiv) (if a solid). The
reaction tube was evacuated and refilled with Ar(g). ( )-trans-1,2-
Diaminocyclohexane (L1) (20 mol %) was added, followed by 1,4-
dioxane (0.5 M) and the haloarene (1.1 equiv) (if a liquid). The
reaction was degassed with three vacuum/Ar(g) purge cycles, equipped
with a coldfinger, and placed in a preheated 110 °C oil bath. The
reaction mixture was stirred for the time indicated, cooled to room
temperature, and diluted with EtOAc. The reaction mixture was then
filtered through a Celite plug, concentrated in vacuo, and applied to a
silica gel column eluted with the indicated solvent mixture(s) to give
the N-aryl product.
General Experimental B: Boc Deprotection. To an oven-dried
round-bottom flask equipped with a stir bar was added Boc-pyridine
2h−n (1 equiv) and DCM (0.5 M). The reaction was cooled to 0 °C
(ice−water bath), and trifluoroacetic acid (TFA) (0.17 M) was added.
The reaction was allowed to warm to room temperature and stirred
until TLC analysis indicated consumption of the starting material
(2h−n). The reaction was then poured into satd NaHCO3(aq) and
diluted with DCM, and the layers were separated. The aqueous layer
was extracted with DCM. The combined organic layers were dried
over sodium sulfate, decanted, and concentrated in vacuo to give the
desired deprotected product.
General Experimental C: Alkylation/Deprotection. To an
oven-dried round-bottom flask equipped with a stir bar were added
pyridine 1 (1 equiv) and DMF (0.5 M). The reaction mixture was
cooled to 0 °C (ice−water bath), and sodium hydride (60 wt % in
mineral oil) (1.5 equiv) was added in small portions over a period of
∼2 min. The reaction mixture was stirred for 1 h at 0 °C, at which time
the appropriate benzyl or alkyl halide (1.5 equiv) was added dropwise
as a solution in DMF. The reaction was allowed to warm to room
temperature and stirred until TLC analysis indicated consumption of
General Experimental D: Palladium Amidation of 3-Amino-
4-chloropyridines. To an oven-dried 25 mL Schlenk tube equipped
with a stirbar were added Pd2(dba)3·CHCl3 (1 mol %), Me3(OMe)t-
BuXPhos (5 mol %), K3PO4 (1.5 equiv), and pyridine 3 (1 equiv).
The reaction vessel was evacuated under vacuum and refilled with
Ar(g). t-BuOH (0.2 M) and formamide (1.5 equiv) were then added via
syringe, and the reaction mixture was degassed by three vacuum/Ar(g)
purge cycles. The reaction vessel was then equipped with a coldfinger
condenser, placed in a preheated 110 °C oil bath, and stirred for the
specified time. Upon consumption of pyridine 3 (as judged by TLC
analysis), the reaction mixture was allowed to cool to room
temperature. The reaction mixture was diluted with methanol and
passed through a Celite plug. The crude mixture was concentrated in
vacuo and applied to a silica gel column eluted with the indicated
solvent mixture(s) to give the desired product.
Pyridine 2h. Following general experimental procedure A: Copper-
(I) iodide (83 mg, 0.44 mmol), potassium phosphate (1.86 g, 8.74
mmol), pyridine 1 (1.0 g, 4.37 mmol), diamine L1 (0.11 mL, 0.87
mmol), iodobenzene (0.54 mL, 4.81 mmol), and 1,4-dioxane (0.5 M)
were combined and stirred for 18 h. Purification via flash column
chromatography, eluted with 30% EtOAc/hexanes, gave 1.28 g of
pyridine 2h (96%) as a light yellow solid: mp 85−87 °C; Rf = 0.39
1
(30% EtOAc/hexanes); H NMR (300 MHz, CDCl3) δ = 8.50 (s,
1H), 8.39 (d, J = 5.4 Hz, 1H), 7.39 (d, J = 5.1 Hz, 1H), 7.33−7.21 (m,
4H), 7.18−7.11 (m, 1H), 1.42 (s, 9H); 13C NMR (75.4 MHz, CDCl3)
δ = 152.8, 151.6, 148.9, 143.0, 141.3, 137.3, 128.9, 126.0, 125.6, 125.0,
82.1, 28.1; FT-IR (NaCl, thin film) ν = 2977, 2932, 1719, 1559, 1319,
1160, 691 cm−1. Anal. Calcd for C16H17ClN2O2: C, 63.05; H, 5.62; N,
9.19. Found: C, 63.29; H, 5.45; N, 9.39
Pyridine 2i. Following general experimental procedure A: Copper-
(I) iodide (43 mg, 0.22 mmol), potassium phosphate (955 mg, 4.50
mmol), pyridine 1 (500 mg, 2.18 mmol), diamine L1 (0.06 mL, 0.44
mmol), 4-iodotoluene (539 mg, 2.48 mmol), and 1,4-dioxane (0.5 M)
were combined and stirred for 22 h. Purification via flash column
chromatography, eluted with 20% EtOAc/hexanes, gave 540 mg of
pyridine 2i (76%) as an off-white solid: mp 98−100 °C; Rf = 0.64
1
(30% EtOAc/hexanes); H NMR (300 MHz, CDCl3) δ = 8.50 (s,
1H), 8.40 (d, J = 5.1 Hz, 1H), 7.40 (d, J = 5.4 Hz, 1H), 7.16−7.09 (m,
4H), 2.31 (s, 3H), 1.42 (s, 9H); 13C NMR (75.4 MHz, CDCl3) δ =
153.0, 151.6, 148.8, 142.9, 138.8, 137.5, 129.5, 125.7, 125.0, 82.0, 28.1,
21.0; FT-IR (NaCl, thin film) ν = 3036, 2979, 1715, 1554 cm−1. Anal.
Calcd for C17H19ClN2O2: C, 64.05; H, 6.01; N, 8.79. Found: C, 64.12;
H, 6.04; N, 8.99.
Pyridine 2j. Following general experimental procedure A: Copper-
(I) iodide (43 mg, 0.22 mmol), potassium phosphate (955 mg, 4.5
mmol), pyridine 1 (500 mg, 2.18 mmol), diamine L1 (0.06 mL, 0.45
mmol), 4-trifluoromethylbromobenzene (0.35 mL, 2.48 mmol), and
1,4-dioxane (0.5 M) were combined and stirred for 22 h. Purification
via flash column chromatography, eluted with 20% EtOAc/hexanes,
gave 640 mg of pyridine 2j (79%) as a yellow oil: Rf = 0.69 (30%
EtOAc/hexanes); 1H NMR (600 MHz, CDCl3) δ = 8.50 (s, 1H), 8.48
(d, J = 5.4 Hz, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 5.1 Hz, 1H),
7.36 (d, J = 8.7 Hz, 2H), 1.43 (s, 9H); 13C NMR (150 MHz, CDCl3) δ
= 152.3, 151.6, 149.5, 144.3, 143.2, 136.5, 127.4 (q, JC−F = 32.7 Hz),
126.0 (q, JC−F = 3.6 Hz), 125.1, 124.6, 124.0 (q, JC−F = 272.8 Hz),
83.0, 28.0; 19F NMR (282.3 MHz, CDCl3) δ = −62.8; FT-IR (NaCl,
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thin film) ν = 2982, 1722, 1615, 1161 cm−1. Anal. Calcd for
C17H16ClF3N2O2: C, 54.77; H, 4.33; N, 7.51. Found: C, 54.69; H,
4.10; N, 7.27.
then 1-(chloromethyl)-4-fluorobenzene35 (432 mg, 3 mmol) was
added, and the reaction mixture was stirred for an additional 2 h.
Subsequent workup gave the crude alkylated product, which was
dissolved in DCM (5 mL) and TFA (1 mL) and stirred for 4 h.
Purification via flash column chromatography, eluted with 25%
EtOAc/hexane, gave 236 mg of pyridine 3d (50% over two steps)
as a pale yellow solid: mp 78−79 °C; Rf = 0.71 (50% EtOAc/hexanes);
1H NMR (300 MHz, CDCl3) δ = 7.98 (s, 1H), 7.90 (d, J = 5.1 Hz,
1H), 7.35−7.31 (m, 2H), 7.20 (d, J = 5.1 Hz, 1H), 7.08−7.02 (m,
2H), 4.61 (bs, NH), 4.43 (d, J = 5.4 Hz, 2H); 13C NMR (75 MHz,
Pyridine 2k. Following general experimental procedure A: Copper-
(I) iodide (42 mg, 0.22 mmol), potassium phosphate (929 mg, 4.38
mmol), pyridine 1 (500 mg, 2.18 mmol), diamine L1 (0.06 mL, 0.44
mmol), 4′-bromoacetophenone (480 mg, 2.41 mmol), and 1,4-dioxane
(0.5 M) were combined and stirred for 24 h. Purification via flash
column chromatography, eluted with 30% EtOAc/hexanes, gave 686
mg of pyridine 2k (90%) as a yellow oil: Rf = 0.27 (30% EtOAc/
hexanes); 1H NMR (300 MHz, CDCl3) δ = 8.45 (s, 1H), 8.43 (d, J =
5.4 Hz, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 5.4 Hz, 1H), 7.26
(d, J = 8.7 Hz, 2H), 2.50 (s, 3H), 1.43 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ = 196.9, 152.1, 151.6, 149.5, 145.4, 143.1, 136.5, 133.7,
129.1, 125.1, 123.9, 82.9, 28.0, 26.5; FT-IR (NaCl, thin film) ν = 2982,
1722, 1615, 1161 cm−1. Anal. Calcd for C18H19ClN2O3: C, 62.34; H,
5.52; N, 8.08. Found: C, 61.95; H, 5.28; N, 7.71.
Pyridine 2n. Following general experimental procedure A: Copper-
(I) iodide (42 mg, 0.22 mmol), potassium phosphate (929 mg, 4.38
mmol), pyridine 1 (500 mg, 2.18 mmol), diamine L1 (0.06 mL, 0.44
mmol), 3-bromopyridine (0.24 mL, 2.41 mmol), and 1,4-dioxane (0.5
M) were combined and stirred for 24 h. Purification via flash column
chromatography, eluted with 35% EtOAc/hexanes, gave 590 mg of
pyridine 2n (88%) as a yellow solid: mp 55−57 °C; Rf = 0.14 (30%
EtOAc/hexanes); 1H NMR (300 MHz, CDCl3) δ = 8.53 (s, 1H), 8.47
(d, J = 5.4 Hz, 1H), 8.47 (s, 1H), 8.40 (dd, J = 4.7, 1.4 Hz, 1H), 7.66
(d, J = 7.5 Hz, 1H), 7.45 (d, J = 5.4 Hz, 1H), 7.27 (dd, J = 8.3, 4.8 Hz,
1H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3) δ = 152.4, 151.5,
149.5, 146.6, 143.0, 137.9, 136.2, 132.3, 125.0, 123.3, 82.9, 29.9; FT-IR
(NaCl, thin film) ν = 2980, 1716 cm−1. Anal. Calcd for
C15H16ClN3O2: C, 58.92; H, 5.27; N, 13.74. Found: C, 58.94; H,
4.98; N, 14.01.
Pyridine 3b. Following general experimental procedure C: Pyridine
1 (228 mg, 1 mmol), DMF (4 mL), and sodium hydride (60 wt % in
mineral oil) (60 mg, 1.5 mmol) were combined and stirred for 1 h,
then 1-(chloromethyl)-2,5-dimethoxybenzene33 (224 mg, 1.2 mmol)
was added, and the reaction mixture was stirred for 14 h. Subsequent
workup gave the crude alkylated product, which was dissolved in DCM
(5 mL) and TFA (2.5 mL) and stirred for 4 h. Purification via flash
column chromatography, eluted with 20% EtOAc/hexanes, gave 174
mg of pyridine 3b (40% over two steps) as a light brown solid: mp
65−68 °C; Rf = 0.55 (5% MeOH/DCM); 1H NMR (300 MHz,
CDCl3) δ = 8.03 (s, 1H), 7.84 (d, J = 5.4 Hz, 1H), 7.14 (d, J = 5.4 Hz,
1H), 6.85−6.73 (m, 3H), 4.77 (bs, NH), 4.41 (d, J = 6.0 Hz, 2H) 3.81
(s, 3H) 3.71 (s, 3H); 13C NMR (75 MHz, CDCl3) δ = 153.6, 151.5,
140.5, 138.6, 134.1, 127.7, 127.0, 123.7, 115.2, 112.5, 111.3, 55.8, 55.7,
42.9; FT-IR (NaCl, thin film) ν = 3293, 2914, 1582 cm−1. Anal. Calcd
for C14H15ClN2O2: C, 60.33; H, 5.42; N, 10.05. Found: C, 60.73; H,
5.33; N, 9.68.
CDCl3) δ = 162.3 (d, JC−F = 244.5 Hz), 140.1, 139.0, 133.7 (d, JC−F
9 Hz), 133.5, 128.9 (d, JC−F = 8.25 Hz), 127.6, 123.8, 115.7 (d, JC−F
=
=
21.75 Hz), 46.9; 19F NMR (282.3 MHz, CDCl3) δ = [(−115.1)−
(−115.2)] (m); FT-IR (NaCl, thin film) ν = 3424, 1603 cm−1. Anal.
Calcd for C12H10ClFN2: C, 60.90; H, 4.26; N, 11.84. Found: C, 61.23;
H, 4.19; N, 12.02.
Pyridine 3e. Following general experimental procedure C: Pyridine
1 (457 mg, 2 mmol), DMF (4 mL), and sodium hydride (60 wt % in
mineral oil) (120 mg, 3 mmol) were combined and stirred for 1 h,
then 4-(chloromethyl)-1,1′-biphenyl36 (606 mg, 3 mmol) was added,
and the reaction mixture was stirred for an additional 2 h. Subsequent
workup gave the crude alkylated product, which was dissolved in DCM
(7 mL) and TFA (1 mL) and stirred for 4 h. Purification via flash
column chromatography, eluted with 25% EtOAc/hexanes, gave 240
mg of pyridine 3e (45% over two steps) as a pale yellow solid: mp 99−
101 °C; Rf = 0.5 (50% EtOAc/hexanes); 1H NMR (300 MHz, CDCl3)
δ = 8.06 (s, 1H), 7.91 (d, J = 5.1 Hz, 1H), 7.61−7.56 (m, 4H), 7.47−
7.41 (m, 4H), 7.38−7.32 (m, 1H), 7.21 (d, J = 4.8 Hz, 1H), 4.67 (t, J =
5.1 Hz, NH), 4.51 (d, J = 5.4 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ
= 140.7, 140.7, 140.3, 139.0, 137.0, 133.9, 128.9, 127.8, 127.7, 127.5,
127.1, 123.8, 47.4; FT-IR (NaCl, thin film) ν = 3417, 1579 cm−1. Anal.
Calcd for C18H15ClN2: C, 73.34; H, 5.13; N, 9.50. Found: C, 73.27; H,
4.88; N, 9.18.
Pyridine 3f. Following general experimental procedure C: Pyridine
1 (708 mg, 3.09 mmol), DMF (7 mL), and sodium hydride (60 wt %
in mineral oil) (223 mg, 5.57 mmol) were combined and stirred for 1
h, then iodomethane (0.58 mL, 9.28 mmol) was added, and the
reaction mixture was stirred for an additional 2 h. Subsequent workup
gave the crude alkylated product, which was dissolved in DCM (15
mL) and TFA (5 mL) and stirred for 4 h. Purification via flash column
chromatography, eluted with 20% EtOAc/hexanes, gave 174 mg of
pyridine 3f (40% over two steps) as a light brown solid: mp 54−55
1
°C; Rf = 0.42 (5% MeOH/DCM); H NMR (300 MHz, CDCl3) δ =
8.02 (s, 1H), 7.89 (d, J = 4.8 Hz, 1H), 7.17 (d, J = 5.1 Hz, 1H), 4.25
(bs, NH), 2.97 (d, J = 5.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ =
141.3, 138.5, 132.9, 127.4, 123.6, 30.2; FT-IR (NaCl, thin film) ν =
3293, 2914, 1582 cm−1. Anal. Calcd for C6H7ClN2: C, 50.54; H, 4.95;
N, 19.65. Found: C, 50.57; H, 5.18; N, 19.45.
Pyridine 3g. To an oven-dried 100 mL round-bottom flask
equipped with a stirbar were added 3-amino-4-chloropyridine (2.0 g,
15.6 mmol), EtOAc (24 mL), propionaldehyde (1.2 mL, 17.1 mmol),
and TFA (2.3 mL, 31.1 mmol). The reaction mixture was stirred for 5
min before sodium triacetoxyborohydride (3.95 g, 18.7 mmol) was
added in three portions over 2 min. The reaction mixture was stirred
for 15 min and judged complete by TLC analysis. The reaction
mixture was poured into 100 mL of satd NaHCO3(aq) and diluted with
EtOAc (25 mL). The layers were separated, and the aqueous layer was
extracted with EtOAc (25 mL). The combined organics were washed
with brine (25 mL), dried over MgSO4, filtered, concentrated in vacuo,
and applied directly to a silica gel column eluted with 30% EtOAc/
hexanes to give 2.05 g of pyridine 3g (77%) as yellow oil. Upon
cooling to −20 °C, this compound solidified to give a slightly yellow
Pyridine 3c. Following general experimental procedure C: Pyridine
1 (1.85 g, 8.09 mmol), DMF (33 mL), and sodium hydride (60 wt %
in mineral oil) (483 mg, 12.1 mmol) were combined and stirred for 1
h, then 1-(chloromethyl)-3,5-dimethoxybenzene34 (1.81 g, 9.71
mmol) was added, and the reaction mixture was allowed to stir
overnight. Subsequent workup gave the crude alkylated product, which
was dissolved in DCM (27 mL) and TFA (9 mL) and stirred for 3 h.
Purification via flash column chromatography, eluted with 30−70%
EtOAc/hexanes (20% gradient elution), gave 1.85 g of pyridine 3c
(82% over two steps) as an orange solid: mp 44−47 °C; Rf = 0.10
1
(30% EtOAc/hexanes); H NMR (300 MHz, CDCl3) δ = 8.00 (s,
1H), 7.89 (d, J = 5.1 Hz, 1H), 7.19 (d, J = 5.1 Hz, 1H), 6.52 (d, J = 2.4
Hz, 2H), 6.39 (t, J = 2.4 Hz, 1H), 4.64 (bs, 1H), 4.40 (d, J = 5.7 Hz,
2H), 3.79 (s, 6H); 13C NMR (75 MHz, CDCl3) δ = 161.2, 140.4,
140.2, 138.7, 133.7, 127.5, 123.7, 105.1, 99.2, 55.2, 47.6; FT-IR (NaCl,
thin film) ν = 3414, 2837, 1622, 1504, 1328, 1205, 1156, 1068 cm−1.
Anal. Calcd for C14H15ClN2O2: C, 60.33; H, 5.42; N, 10.05. Found: C,
60.62; H, 5.13; N, 10.22.
Pyridine 3d. Following general experimental procedure C: Pyridine
1 (457 mg, 2 mmol), DMF (4 mL), and sodium hydride (60 wt % in
mineral oil) (120 mg, 3 mmol) were combined and stirred for 1 h,
1
solid: mp 28−29 °C; Rf = 0.69 (5% MeOH/DCM); H NMR (300
MHz, CDCl3) δ = 8.01 (s, 1H), 7.84 (d, J = 5.1 Hz, 1H), 7.15 (d, J =
5.1 Hz, 1H), 4.18 (bs, 1H), 3.19 (m, 2H), 1.69 (sext, J = 7.5 Hz, 2H),
1.02 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ = 140.7,
138.3, 133.4, 127.4, 123.8, 45.2, 22.6, 11.6; FT-IR (NaCl, thin film) ν
= 2992, 2938, 1543, 1471, 973, 855, 691 cm−1. Anal. Calcd for
C8H11ClN2: C, 56.31; H, 6.50; N, 16.42. Found C, 56.66; H, 6.39; N,
16.65.
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Pyridine 3h. Following general experimental procedure B: Pyridine
2h (1.12 g, 3.67 mmol), DCM (7.3 mL), and TFA (2.45 mL) were
combined and stirred for 24 h to give 732 mg (97%) of pyridine 3h as
a tan microcrystalline solid: mp 107−109 °C; Rf = 0.39 (30% EtOAc/
hexanes); 1H NMR (300 MHz, CDCl3) δ = 8.56 (s, 1H), 8.02 (d, J =
5.1 Hz, 1H), 7.39−7.31 (m, 2H), 7.28 (d, J = 5.1 Hz, 1H), 7.21−7.17
(m, 2H), 7.15−6.95 (m, 1H), 5.98 (br s, 1H); 13C NMR (75.4 MHz,
CDCl3) δ = 141.2, 140.5, 138.0, 137.6, 130.0, 129.8, 124.4, 123.7,
120.6; FT-IR (NaCl, thin film) ν = 3106, 3031, 1596, 1560, 1496,
1406, 1328, 1233, 1075, 816, 755, 696 cm−1. Anal. Calcd for
C11H9ClN2: C, 64.56; H, 4.43; N, 13.69. Found: C, 64.86; H, 4.66; N,
13.86.
mmol), 5-bromo-m-xylene (0.17 mL, 1.2 mmol), and 1,4-dioxane (0.5
M) were combined and stirred for 29 h, cooled to room temperature,
diluted with EtOAc, filtered through a Celite plug, and concentrated in
vacuo. The crude mixture was dissolved in DCM (3 mL) and TFA
(1.5 mL) and stirred for 24 h. The reaction was poured into satd
NaHCO3(aq) and diluted with DCM, the layers were separated, and the
aqueous layer was extracted with DCM. The combined organic layers
were dried over Na2SO4, decanted, and concentrated in vacuo to give a
brown oil. Purification via flash column chromatography, eluted with
20% EtOAc/hexanes, gave 168 mg of pyridine 3m (66% over two
steps) as an off-white solid: mp 127−128 °C; Rf = 0.42 (30% EtOAc/
hexanes); 1H NMR (400 MHz, CDCl3) δ = 8.58 (s, 1H), 8.01 (s, 1H),
7.27 (d, J = 3.9 Hz, 1H), 6.81 (s, 2H), 6.74 (s, 1H), 5.88 (s, 1H), 2.30
(s, 6H); 13C NMR (100 MHz, CDCl3) δ = 140.9, 140.3, 139.6, 138.2,
137.7, 129.8, 125.5, 124.4, 118.3, 21.4; FT-IR (NaCl, thin film) ν =
3402, 1606, 1571, 1075 cm−1. Anal. Calcd for C13H13ClN2: C, 67.10;
H, 5.63; N, 12.04. Found: C, 67.17; H, 5.88; N, 11.93.
Pyridine 3i. Following general experimental procedure B: Pyridine
2i (436 mg, 1.4 mmol), DCM (3 mL), and TFA (1.5 mL) were
combined and stirred for 24 h to give 280 mg (92%) of pyridine 3i as a
1
yellow solid: mp 59−60 °C; Rf = 0.39 (30% EtOAc/hexanes); H
NMR (300 MHz, CDCl3) δ = 8.45 (s, 1H), 7.98 (d, J = 5.1 Hz, 1H),
7.25 (d, J = 5.1 Hz, 1H), 7.16 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz,
2H), 5.90 (br s, 1H), 2.34 (s, 3H); 13C NMR (75.4 MHz, CDCl3) δ =
140.5, 138.2, 137.6, 137.2, 133.7, 130.3, 129.3, 124.3, 121.5, 20.9; FT-
IR (NaCl, thin film) ν = 3401, 3233, 3030, 2920, 1571, 1517, 809
cm−1. Anal. Calcd for C12H11ClN2: C, 65.91; H, 5.07; N, 12.81. Found:
C, 65.76; H, 4.71; N, 12.55.
Pyridine 3n. Following general experimental procedure B: Pyridine
2n (168 mg, 0.55 mmol), DCM (2 mL), and TFA (1 mL) were
combined and stirred for 6 h to give 100 mg (89%) of pyridine 3n as a
1
yellow solid: mp 117−118 °C; Rf = 0.06 (30% EtOAc/hexanes); H
NMR (300 MHz, CDCl3) δ = 8.49 (s, 1H), 8.46 (d, J = 2.1 Hz, 1H),
8.29 (d, J = 4.5 Hz, 1H), 8.07 (d, J = 5.1 Hz, 1H), 7.48 (d, J = 5.1 Hz,
1H), 7.30 (d, J = 5.1 Hz, 1H), 7.24 (dd, J = 8.1, 4.8 Hz, 1H), 6.28 (br
s, 1H); 13C NMR (75.4 MHz, CDCl3) δ = 144.3, 142.4, 142.3, 138.5,
137.5, 136.7, 131.4, 126.4, 124.6, 124.0; FT-IR (NaCl, thin film) ν =
3172, 3042, 1588, 1326 cm−1. Anal. Calcd for C10H8ClN3: C, 58.41; H,
3.92; N, 20.43. Found: C, 58.36; H, 4.14; N, 20.39.
Pyridine 3j. Following general experimental procedure B: Pyridine
2j (520 mg, 1.4 mmol), DCM (3 mL) and TFA (1.5 mL) were
combined and stirred for 24 h to give 340 mg (89%) of pyridine 3j as a
1
yellow solid. Rf = 0.21 (30% EtOAc/hexanes); H NMR (600 MHz,
CDCl3) δ = 8.67 (s, 1H), 8.15 (d, J = 4.8 Hz, 1H), 7.55 (d, J = 8.4 Hz,
2H), 7.34 (d, J = 5.1 Hz, 1H), 7.14 (d, J = 8.7 Hz, 2H), 6.10 (s, 1H);
13C NMR (150 MHz, CDCl3) δ = 144.5, 143.3, 140.5, 135.9, 132.7,
127 (q, JC−F = 3.8 Hz), 124.7, 124.3 (q, JC−F = 271.0 Hz), 124.2 (q,
JC−F = 32.6 Hz), 117.6; 19F NMR (282.3 MHz, CDCl3) δ= −62.2; FT-
IR (NaCl, thin film) ν = 3249, 2988, 1616, 1111 cm−1. Anal. Calcd for
C12H8ClF3N2: C, 52.86; H, 2.96; N, 10.27. Found: C, 52.88; H, 2.98;
N, 10.07.
3-Benzyl-3H-imidazo[4,5-c]pyridine (4a).37 Following general
procedure D: Pyridine 3a (88 mg, 0.4 mmol), Pd2(dba)3·CHCl3
(4.14 mg, 0.004 mmol), Me3(OMe)-tert-butyl-XPhos26 (10 mg, 0.02
mmol), K3PO4 (128 mg, 0.6 mmol), and formamide (0.024 mL, 0.6
mmol) were combined with 2 mL of tert-butyl alcohol in a 25 mL
Schlenk tube. After 4 h, TLC analysis indicated the reaction was
complete. The reaction mixture was cooled to rt, filtered through
Celite, concentrated in vacuo, and purified on a silica gel column,
eluted with 3% MeOH/DCM, to give 70 mg of pyridine 4a (84%) as a
light brown solid: mp 134−135 °C (lit.37 133−136 °C); Rf = 0.4 (5%
Pyridine 3k. Following general experimental procedure B: Pyridine
2k (440 mg, 1.27 mmol), DCM (3 mL), and TFA (1.5 mL) were
combined and stirred for 24 h to give 280 mg (89%) of pyridine 3k as
1
1
MeOH/DCM); H NMR (400 MHz, CDCl3) δ = 8.75 (s, 1H), 8.45
a yellow solid: mp 115−116 °C; Rf = 0.12 (30% EtOAc/hexanes); H
(d, J = 5.7 Hz, 1H), 8.08 (s, 1H), 7.75 (dd, J = 5.7 Hz, 1H), 7.40−7.34
(m, 3H), 7.25−7.21 (m, 2H), 5.44 (s, 2H).
NMR (300 MHz, CDCl3) δ = 8.72 (s, 1H), 8.17 (d, J = 5.1 Hz, 1H),
7.93 (d, J = 8.7 Hz, 2H), 7.36 (d, J = 5.1 Hz, 1H), 7.11 (d, J = 8.7 Hz,
2H), 6.22 (br s, 1H), 2.56 (s, 3H); 13C NMR (75.4 MHz, CDCl3) δ =
196.6, 146.0, 143.8, 141.3, 135.5, 133.3, 131.2, 130.7, 124.9, 116.6,
26.5; FT-IR (NaCl, thin film) ν = 3247, 3172, 3049, 1667, 1604, 1565,
813 cm−1. Anal. Calcd for C13H11ClN2O: C, 63.29; H, 4.49; N, 11.36.
Found: C, 63.31; H, 4.14; N, 11.71.
3-(2,5-Dimethoxybenzyl)-3H-imidazo[4,5-c]pyridine (4b). Follow-
ing general procedure D: Pyridine 3b (111 mg, 0.4 mmol), Pd2(dba)3·
CHCl3 (4 mg, 0.004 mmol), Me3(OMe)-tert-butyl-XPhos26 (10 mg,
0.02 mmol), K3PO4 (128 mg, 0.6 mmol), and formamide (0.024 mL,
0.6 mmol) were combined with 2 mL of tert-butyl alcohol in a 25 mL
Schlenk tube. After 6.5 h, TLC analysis indicated the reaction was
complete. The reaction mixture was cooled to rt, filtered through
Celite, concentrated in vacuo, and purified on a silica gel column,
eluted with 3% MeOH/DCM, to give 92 mg of pyridine 4b (85%) as a
Pyridine 3l. Following general experimental procedure A: Copper-
(I) iodide (20 mg, 0.11 mmol), K3PO4 (465 mg, 2.18 mmol), pyridine
1 (250 mg, 1.09 mmol), diamine L1 (27 μL, 0.22 mmol), 4-
bromoanisole (0.15 mL, 1.2 mmol), and 1,4-dioxane (0.5 M) were
combined and stirred for 29 h, cooled to room temperature, diluted
with EtOAc, filtered through a Celite plug, and concentrated in vacuo.
The crude mixture was dissolved in DCM (3 mL) and TFA (1.5 mL)
and stirred for 24 h. The reaction was poured into satd NaHCO3(aq)
and diluted with DCM, and the layers were separated. The aqueous
layer was extracted with DCM, and the combined organic layers were
dried over Na2SO4, decanted, and concentrated in vacuo to give a
brown oil. Purification via flash column chromatography, eluted with
20% EtOAc/hexanes, gave 120 mg of pyridine 3l (47% over two steps)
as a brown solid: mp 59−60 °C; Rf = 0.24 (30% EtOAc/hexanes); 1H
NMR (300 MHz, CDCl3) δ = 8.26 (s, 1H), 7.94 (d, J = 5.1 Hz, 1H),
7.24 (d, J = 5.1 Hz, 1H), 7.16 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 9.0 Hz,
2H), 5.82 (br s, 1H), 3.82 (s, 3H); 13C NMR (75.4 MHz, CDCl3) δ =
157.1, 140.0, 139.3, 136.3, 132.7, 128.4, 124.9, 124.2, 115.1, 55.7; FT-
IR (NaCl, thin film) ν = 3234, 3041, 2933, 2835, 1513, 1244 cm−1.
Anal. Calcd for C12H11ClN2O: C, 61.41; H, 4.72; N, 11.94. Found: C,
61.48; H, 4.97; N, 11.67.
1
light brown solid: mp 125 °C dec; Rf = 0.25 (5% MeOH/DCM); H
NMR (300 MHz, CDCl3) δ = 8.83 (d, J = 0.6 Hz, 1H), 8.38 (d, J = 5.4
Hz, 1H), 8.06 (s, 1H), 7.65 (dd, J = 5.7 Hz, 0.9 Hz, 1H), 6.79 (app d, J
= 1.5 Hz, 2H), 6.73 (app t, J = 1.5 Hz, 1H), 5.32 (s, 2H), 3.75 (s, 3H),
3.68 (s, 3H); 13C NMR (75.4 MHz, CDCl3) δ = 153.6, 151.5, 138.8,
146.3, 141.8, 133.9, 131.8, 123.7, 116.2, 115.0, 114.1, 111.7, 55.8, 55.8,
45.0; FT-IR (NaCl, thin film) ν = 2968, 2936, 2878, 1650, 1610, 1492,
1461, 1383, 1309, 1264, 1211, 907, 826 cm−1. Anal. Calcd for
C15H15N3O2: C, 66.90; H, 5.61; N, 15.60. Found: C, 66.79; H, 5.24;
N, 15.59.
3-(3,5-Dimethoxybenzyl)-3H-imidazo[4,5-c]pyridine (4c). Follow-
ing general procedure D: Pyridine 3c (110 mg, 0.4 mmol), Pd2(dba)3·
CHCl3 (4 mg, 0.004 mmol), Me3(OMe)-tert-butyl-XPhos26 (10 mg,
0.02 mmol), K3PO4 (128 mg, 0.6 mmol), and formamide (0.024 mL,
0.6 mmol) were combined with 2 mL of tert-butyl alcohol in a 25 mL
Schlenk tube. After 19 h, TLC analysis indicated the reaction was
complete. The reaction mixture was cooled to rt, filtered through
Celite, concentrated in vacuo, and purified on a silica gel column,
eluted with 1−5% MeOH/DCM (2% gradient elution), to give 54 mg
of pyridine 4c (52%) as an orange solid: mp 98−100 °C; Rf = 0.20
Pyridine 3m. Following general experimental procedure A:
Copper(I) iodide (20 mg, 0.11 mmol), K3PO4 (465 mg, 2.18
mmol), pyridine 1 (250 mg, 1.09 mmol), diamine L1 (27 μL, 0.22
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1
(5% MeOH/DCM); H NMR (300 MHz, CDCl3) δ = 8.69 (s, 1H),
δ = 149.0, 145.8, 141.9, 133.5, 131.7, 115.2, 47.4, 23.4, 11.4; FT-IR
(NaCl, thin film) ν = 2969, 2880, 1655, 1609, 1492, 1460, 1383, 1309,
1264, 1211, 1166, 1126, 1027, 906, 825 cm−1. Anal. Calcd for
C9H11N3: C, 67.06; H, 6.88; N, 26.07. Found: C, 67.10; H, 6.99; N,
26.06.
8.39 (d, J = 5.7 Hz, 1H), 8.01 (s, 1H), 7.65 (dd, J = 5.7 Hz, 1.2 Hz,
1H), 6.35 (t, J = 2.1 Hz, 1H), 6.28 (d, J = 2.1 Hz, 2H), 5.28 (s, 2H),
3.66 (s, 6H); 13C NMR (75 MHz, CDCl3) δ = 161.4, 149.0, 145.8,
142.1, 136.7, 133.9, 115.1, 105.5, 100.0, 55.4, 49.5; FT-IR (NaCl, thin
film) ν = 3482, 2799, 1644, 1455, 1374, 1159, 1067 cm−1. Anal. Calcd
for C15H15N3O2: C, 66.90; H, 5.61; N, 15.60. Found: C, 66.80; H,
5.69; N, 15.63.
3-(4-Fluorobenzyl)-3H-imidazo[4,5-c]pyridine (4d). Following
general procedure D: Pyridine 3d (95 mg, 0.4 mmol), Pd2(dba)3·
CHCl3 (4 mg, 0.004 mmol), Me3(OMe)-tert-butyl-XPhos26 (10 mg,
0.02 mmol), K3PO4 (128 mg, 0.6 mmol), and formamide (0.024 mL,
0.6 mmol) were combined with 2 mL of tert-butyl alcohol in a 25 mL
Schlenk tube. After 4 h, TLC analysis indicated the reaction was
complete. The reaction mixture was cooled to rt, filtered through
Celite, concentrated in vacuo, and purified on a silica gel column,
eluted with 3% MeOH/DCM, to give 68 mg of pyridine 4d (75%) as a
pale yellow solid: mp 107−110 °C; Rf = 0.31 (5% MeOH/DCM); 1H
NMR (300 MHz, CDCl3) δ = 8.65 (d, J = 0.6 Hz, 1H), 8.39 (d, J = 5.4
Hz, 1H), 8.00 (s, 1H), 7.66 (dd, J = 5.7, 0.9 Hz, 1H), 7.18−7.13 (m,
2H), 7.09−6.96 (m, 2H), 5.34 (s, 2H); 13C NMR (75 MHz, CDCl3)
δ= 162.7 (d, JC−F = 246.75 Hz), 149.1, 145.7, 142.2, 133.7, 131.5,
3-Phenyl-3H-imidazo[4,5-c]pyridine (4h). Following general pro-
cedure D: Pyridine 3h (82 mg, 0.4 mmol), Pd2(dba)3·CHCl3 (4 mg,
0.004 mmol), Me3(OMe)-tert-butyl-XPhos26 (10 mg, 0.02 mmol),
K3PO4 (128 mg, 0.6 mmol), and formamide (0.024 mL, 0.6 mmol)
were combined with 2 mL of tert-butyl alcohol in a 25 mL Schlenk
tube. After 6.5 h, TLC analysis indicated the reaction was complete.
The reaction mixture was cooled to rt, filtered through Celite,
concentrated in vacuo, and purified on a silica gel column, eluted with
3% MeOH/DCM, to give 70 mg of pyridine 4h (85%) as a light
1
brown solid: mp 149−150 °C; Rf = 0.26 (EtOAc); H NMR (300
MHz, CDCl3) δ = 8.91 (s, 1H), 8.46 (d, J = 5.7 Hz, 1H), 8.19 (s, 1H),
7.72 (dd, J = 5.4 Hz, 0.6 Hz, 1H), 7.61−7.41 (m, 5H); 13C NMR (75.4
MHz, CDCl3) δ = 149.1, 144.8, 142.5, 135.4, 134.2, 131.4, 130.3,
128.7, 123.8, 115.2; FT-IR (NaCl, thin film) ν = 3177, 1597, 1503,
1480, 1304, 1233, 761, 696 cm−1. Anal. Calcd for C12H9N3: C, 73.83;
H, 4.65; N, 21.52. Found: C, 73.80; H, 4.90; N, 21.28.
3-(p-Tolyl)-3H-imidazo[4,5-c]pyridine (4i). Following general
procedure D: Pyridine 3i (87 mg, 0.4 mmol), Pd2(dba)3·CHCl3 (4
mg, 0.004 mmol), Me3(OMe)-tert-butyl-XPhos26 (10 mg, 0.02 mmol),
K3PO4 (128 mg, 0.6 mmol), and formamide (0.024 mL, 0.6 mmol)
were combined with 2 mL of tert-butyl alcohol in a 25 mL Schlenk
tube. After 6 h, TLC analysis indicated the reaction was complete. The
reaction mixture was cooled to rt, filtered through Celite, concentrated
in vacuo, and purified on a silica gel column, eluted with 4% MeOH/
DCM, to give 72 mg of pyridine 4i (86%) as a light brown solid: mp
130.4 (d, JC−F = 3.45 Hz), 129.2 (d, JC−F = 7.95 Hz), 116.3 (d, JC−F
=
21.75 Hz), 115.1, 48.8; 19F NMR (282.3 MHz, CDCl3) δ= −113.0
(m); FT-IR (NaCl, thin film) ν = 1608 cm−1. Anal. Calcd for
C13H10FN3: C, 68.71; H, 4.44; N, 18.49. Found: C, 68.54; H, 4.36; N,
18.32.
Imidazo[4,5-c]pyridine (4e). Following general procedure D:
Pyridine 3e (95 mg, 0.4 mmol), Pd2(dba)3·CHCl3 (4 mg, 0.004
mmol), Me3(OMe)-tert-butyl-XPhos26 (10 mg, 0.02 mmol), K3PO4
(128 mg, 0.6 mmol), and formamide (0.024 mL, 0.6 mmol) were
combined with 2 mL of tert-butyl alcohol in a 25 mL Schlenk tube.
After 4.5 h, TLC analysis indicated the reaction was complete. The
reaction mixture was cooled to rt, filtered through Celite, concentrated
in vacuo, and purified on a silica gel column, eluted with 4% MeOH/
DCM, to give 86 mg of pyridine 4e (75%) as an off-white solid: mp
1
108−109 °C; Rf = 0.33 (5% MeOH/DCM); H NMR (600 MHz,
CDCl3) δ = 8.90 (s, 1H), 8.48 (d, J = 5.7 Hz, 1H), 8.17 (s, 1H), 7.74
(dd, J = 5.7 Hz, 0.6 Hz, 1H), 7.40−7.36 (m, 4H), 2.43 (s, 3H); 13C
NMR (150 MHz, CDCl3) δ= 149.1, 145.0, 142.6, 139.1, 134.3, 133.0,
131.7, 131.0, 123.9, 115.3, 21.2; FT-IR (NaCl, thin film) ν = 3051,
2924, 1518, 1480, 821 cm−1. Anal. Calcd for C13H11N3: C, 74.62; H,
5.30; N, 20.08. Found: C, 74.66; H, 5.54; N, 19.97.
1
189−191 °C; Rf = 0.34 (5% MeOH/DCM); H NMR (300 MHz,
CDCl3) δ = 8.76 (s, 1H), 8.46 (d, J = 5.7 Hz, 1H), 8.07 (s, 1H), 7.73
(dd, J = 5.7, 1.2 Hz, 1H), 7.58−7.51 (m, 4H), 7.45−7.26 (m, 5H),
5.44 (s, 2H); 13C NMR (75 MHz, CDCl3) δ = 149.1, 145.8, 142.2,
141.8, 140.1, 133.9, 133.4, 131.6, 128.9, 127.9, 127.8, 127.7, 127.1,
115.1, 49.2; FT-IR (NaCl, thin film) ν = 1602 cm−1. Anal. Calcd for
C19H15N3: C, 79.98; H, 5.30; N, 14.73. Found: C, 79.96; H, 5.56; N,
14.39.
3-(4-(Trifluoromethyl)phenyl)-3H-imidazo[4,5-c]pyridine (4j). Fol-
lowing general procedure D: Pyridine 3j (108 mg, 0.4 mmol),
Pd2(dba)3·CHCl3 (4 mg, 0.004 mmol), Me3(OMe)-tert-butyl-XPhos26
(10 mg, 0.02 mmol), K3PO4 (128 mg, 0.6 mmol), and formamide
(0.024 mL, 0.6 mmol) were combined with 2 mL of tert-butyl alcohol
in a 25 mL Schlenk tube. After 6 h, TLC analysis indicated the reaction
was complete. The reaction mixture was cooled to rt, filtered through
Celite, concentrated in vacuo, and purified on a silica gel column,
eluted with 4% MeOH/DCM, to give 96 mg of pyridine 4j (91%) as a
pale yellow solid: mp 166−167 °C; Rf = 0.30 (5% MeOH/DCM); 1H
NMR (600 MHz, CDCl3) δ = 8.97 (s, 1H), 8.52 (d, J = 5.7 Hz, 1H),
8.25 (s, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 5.7 Hz, 1H), 7.69
(d, J = 8.4 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ = 149.4, 144.4,
3-Methyl-3H-imidazo[4,5-c]pyridine (4f).38 Following general
procedure D: Pyridine 3f (57 mg, 0.4 mmol), Pd2(dba)3·CHCl3 (4
mg, 0.004 mmol), Me3(OMe)-tert-butyl-XPhos26 (10 mg, 0.02 mmol),
K3PO4 (128 mg, 0.6 mmol), and formamide (0.024 mL, 0.6 mmol)
were combined with 2 mL of tert-butyl alcohol in a 25 mL Schlenk
tube. After 5 h, TLC analysis indicated the reaction was complete. The
reaction mixture was cooled to rt, filtered through Celite, concentrated
in vacuo, and purified on a silica gel column, eluted with 4% MeOH/
DCM, to give 31 mg of pyridine 4f (58%) as a pale yellow solid: mp
95−97 °C; Rf = 0.17 (5% MeOH/DCM); 1H NMR (300 MHz,
CDCl3): δ = 8.80 (d, J = 0.6 Hz, 1H), 8.42 (d, J = 5.4 Hz, 1H), 7.91 (s,
1H), 7.65 (dd, J = 5.7 Hz, 0.9 Hz, 1H), 3.89 (s, 3H); 13C NMR (75
MHz, CDCl3) δ = 148.7, 146.2, 142.0, 133.2, 132.3, 114.9, 31.5.
3-Propyl-3H-imidazo[4,5-c]pyridine (4g). Following general pro-
cedure D: Pyridine 3e (68 mg, 0.4 mmol), Pd2(dba)3·CHCl3 (4 mg,
0.004 mmol), Me3(OMe)-tert-butyl-XPhos26 (10 mg, 0.02 mmol),
K3PO4 (128 mg, 0.6 mmol), and formamide (0.024 mL, 0.6 mmol)
were combined with 2 mL of tert-butyl alcohol in a 25 mL Schlenk
tube. After 6.5 h, TLC analysis indicated the reaction was complete.
The reaction mixture was cooled to rt, filtered through Celite,
concentrated in vacuo, and purified on a silica gel column, eluted with
3% MeOH/DCM, to give 55 mg of pyridine 4e (85%) as a light brown
143.1, 138.5, 133.9, 131.0, 130.8 (q, JC−F = 33.3 Hz), 127.8 (q, JC−F
=
3.7 Hz), 123.9, 123.5 (q, JC−F = 272.9 Hz), 115.5; 19F NMR (282.3
MHz, CDCl3) δ = −63.0; FT-IR (NaCl, thin film) ν = 3056, 1606,
1334, 1106 cm−1. Anal. Calcd for C13H8F3N3: C, 59.32; H, 3.06; N,
15.96. Found: C, 59.04; H, 2.77; N, 15.67.
Imidazo[4,5-c]pyridine (4k). Following general procedure D:
Pyridine 3k (98 mg, 0.4 mmol), Pd2(dba)3·CHCl3 (4 mg, 0.004
mmol), Me3(OMe)-tert-butyl-XPhos26 (10 mg, 0.02 mmol), K3PO4
(128 mg, 0.6 mmol), and formamide (0.024 mL, 0.6 mmol) were
combined with 2 mL of tert-butyl alcohol in a 25 mL Schlenk tube.
After 4 h, TLC analysis indicated the reaction was complete. The
reaction mixture was cooled to rt, filtered through Celite, concentrated
in vacuo, and purified on a silica gel column, eluted with 4% MeOH/
DCM, to give 83 mg of pyridine 4k (87%) as a pale yellow solid: mp
1
199−201 °C; Rf = 0.33 (5% MeOH/DCM); H NMR (600 MHz,
CDCl3) δ= 8.99 (s, 1H), 8.51 (d, J = 5.7 Hz, 1H), 8.26 (s, 1H), 8.18
(d, J = 8.7 Hz, 2H), 7.76 (dd, J = 5.7 Hz, 0.9 Hz, 1H), 7.65 (d, J = 8.7
Hz, 2H), 2.65 (s, 3H); 13C NMR (150 MHz, CDCl3) δ = 196.3, 149.3,
144.3, 143.0, 139.1, 136.8, 134.0, 130.9, 130.5, 123.3, 115.4, 26.6; FT-
IR (NaCl, thin film) ν = 1677, 1601, 1353, 816 cm−1. Anal. Calcd for
1
solid: mp 75−78 °C; Rf = 0.22 (5% MeOH/DCM); H NMR (300
MHz, CDCl3) δ = 8.85 (s, 1H), 8.43 (d, J = 5.7 Hz, 1H), 7.98 (s, 1H),
7.69 (dd, J = 5.4 Hz, 0.9 Hz, 1H), 4.21 (t, J = 6.9 Hz, 2H), 1.95 (sext, J
= 7.2 Hz, 2H), 0.95 (t, J = 7.2 Hz, 3H); 13C NMR (75.4 MHz, CDCl3)
2209
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Article
C14H11N3O: C, 70.87; H, 4.67; N, 17.71. Found: C, 70.50; H, 4.76; N,
17.43.
2926, 1596, 1501, 1392, 822 cm−1. Anal. Calcd for C13H11N3: C,
74.62; H, 5.30; N, 20.08. Found: C, 74.77; H, 5.32; N, 19.85.
2-(Furan-2-yl)-3-phenyl-3H-imidazo[4,5-c]pyridine (6). To an
oven-dried 50 mL Schlenk tube were added pyridine 3h (82 mg, 0.4
mmol), Pd2(dba)3CHCl3 (8 mg, 0.008 mmol), Me3(OMe)-t-
BuXPhos26 (20 mg, 0.04 mmol), K3PO4 (170 mg, 0.8 mmol), and
furanamide (222 mg, 2.0 mmol); the reaction vessel was sealed,
evacuated under vacuum, and purged with Ar(g). t-BuOH (2.0 mL) was
added, and the reaction mixture was degassed with three vacuum/Ar(g)
purge cycles, equipped with a coldfinger condenser, and placed in a
preheated 110 °C oil bath. After 5 h, TLC analysis indicated the
complete consumption of pyridine 3h. The reaction mixture was
cooled to rt, filtered through Celite, concentrated in vacuo, and
purified on a silica gel column, eluted with 2% MeOH/DCM, to give
53 mg of pyridine 6 (51%) as a yellow solid: mp 153−155 °C; Rf =
3-(4-Methoxyphenyl)-3H-imidazo[4,5-c]pyridine (4l). Following
general procedure D: Pyridine 3l (93 mg, 0.4 mmol), Pd2(dba)3·
CHCl3 (4 mg, 0.004 mmol), Me3(OMe)-tert-butyl-XPhos26 (10 mg,
0.02 mmol), K3PO4 (128 mg, 0.6 mmol), and formamide (0.024 mL,
0.6 mmol) were combined with 2 mL of tert-butyl alcohol in a 25 mL
Schlenk tube. After 6.5 h, TLC analysis indicated the reaction was
complete. The reaction mixture was cooled to rt, filtered through
Celite, concentrated in vacuo, and purified on a silica gel column,
eluted with 3% MeOH/DCM, to give 69 mg of pyridine 4l (77%) as a
pale yellow solid: mp 105−106 °C; Rf = 0.30 (5% MeOH/DCM); 1H
NMR (300 MHz, CDCl3) δ = 8.86 (s, 1H), 8.49 (d, J = 5.7 Hz, 1H),
8.14 (s, 1H), 7.75 (d, J = 5.4 Hz, 1H), 7.42 (d, J = 8.7 Hz, 2H), 7.08
(d, J = 9.0 Hz, 2H), 3.88 (s, 3H); 13C NMR (75.4 MHz, CDCl3) δ =
159.9, 149.0, 145.2, 142.5, 134.3, 132.1, 128.3, 125.7, 115.5, 115.2,
55.8; FT-IR (NaCl, thin film) ν = 2839, 1517, 1253 cm−1. Anal. Calcd
for C13H11N3O: C, 69.32; H, 4.92; N, 18.66. Found: C, 69.44; H, 5.05;
N, 18.75.
1
0.21 (5% MeOH/DCM); H NMR (400 MHz, CDCl3) δ = 8.47 (s,
1H), 8.47 (d, J= 5.6 Hz, 1H), 7.72 (dd, J = 5.6, 1.2 Hz, 1H), 7.63−7.59
(m, 3H), 7.50 (dd, J=1.2, 0.8 Hz, 1H), 7.45−7.41 (m, 2H), 6.37 (dd, J
= 3.6, 1.6 Hz, 1H), 6.29 (dd, J= 3.6, 0.4 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ = 147.9, 146.6, 145.2, 144.3, 143.7, 142.9, 135.4,
134.7, 133.6, 130.2, 130.0, 127.6, 114.2, 111.8; FT-IR (NaCl, thin film)
ν = 3049, 2924, 2222, 1591, 1502, 1416, 1267, 905, 819 cm−1. Anal.
Calcd for C16H11N3O: C, 73.55; H, 4.24; N, 16.08. Found: C, 73.48;
H, 4.28; N, 15.94.
5,10-Diphenyl-5,10-dihydrodipyrido[3,4-b:3′,4′-e]pyrazine (7).
Pyridine 3h (82 mg, 0.4 mmol), Pd2(dba)3·CHCl3 (4 mg, 0.004
mmol), Me3(OMe)-tert-butyl-XPhos26 (10 mg, 0.02 mmol), and
K3PO4 (128 mg, 0.6 mmol), were combined with 2 mL of tert-butyl
alcohol in a 25 mL Schlenk tube. The reaction mixture was degassed
with three vacuum/Ar(g) purge cycles, equipped with a coldfinger
condenser, and placed in a preheated 110 °C oil bath. After 16.5 h, the
reaction mixture was cooled to rt, filtered through Celite, concentrated
in vacuo, and purified on a silica gel column, eluted with 5% MeOH/
DCM, to give 26 mg of pyrazine 7 (39%) as a yellow solid: mp 168−
170 °C; Rf = 0.05 (10% i-PrOH/DCM); 1H NMR (400 MHz,
CD3OD) δ = 7.68 (d, J= 1.5 Hz, 1H), 7.48 (dd, J= 6.8, 1.5 Hz, 1H),
7.21−7.17 (m, 2H), 7.05−7.02 (m, 2H), 6.86−6.83 (m, 1H), 6.38 (d,
J= 6.8 Hz, 1H); 13C NMR (100 MHz, CD3OD) δ = 173.0, 143.4,
136.4, 134.9, 130.7, 122.9, 119.8, 119.3, 113.1; FT-IR (NaCl, thin film)
ν = 2928, 2858, 1625, 1590, 1458, 1173, 824 cm−1. Anal. Calcd for
C22H16N4: C, 78.55; H, 4.79; N, 16.66. Found: C, 78.28; H, 4.84; N,
16.75;
3-(3,5-Dimethylphenyl)-3H-imidazo[4,5-c]pyridine (4m). Follow-
ing general procedure D: Pyridine 3m (93 mg, 0.4 mmol), Pd2(dba)3·
CHCl3 (4 mg, 0.004 mmol), Me3(OMe)-tert-butyl-XPhos26 (10 mg,
0.02 mmol), K3PO4 (128 mg, 0.6 mmol), and formamide (0.024 mL,
0.6 mmol) were combined with 2 mL of tert-butyl alcohol in a 25 mL
Schlenk tube. After 4 h, TLC analysis indicated the reaction was
complete. The reaction mixture was cooled to rt, filtered through
Celite, concentrated in vacuo, and purified on a silica gel column,
eluted with 4% MeOH/DCM, to give 80 mg of pyridine 4m (90%) as
a pale yellow solid: mp 144−146 °C; Rf = 0.33 (5% MeOH/DCM);
1H NMR (400 MHz, CDCl3) δ = 8.96 (s, 1H), 8.51 (d, J = 5.4 Hz,
1H), 8.19 (s, 1H), 7.77 (d, J = 5.6 Hz, 1H), 7.14 (s, 3H), 2.43 (s, 6H);
13C NMR (100 MHz, CDCl3) δ = 149.2, 144.9, 142.6, 140.5, 135.4,
134.6, 131.6, 130.5, 121.7, 115.3, 21.5; FT-IR (NaCl, thin film) ν =
3060, 2919, 1602, 1494, 1231 cm−1. Anal. Calcd for C14H13N3: C,
75.31; H, 5.87; N, 18.82. Found: C, 75.64; H, 5.59; N, 18.66.
3-(Pyridin-3-yl)-3H-imidazo[4,5-c]pyridine (4n). Following general
procedure D: Pyridine 3n (95 mg, 0.4 mmol), Pd2(dba)3·CHCl3 (4
mg, 0.004 mmol), Me3(OMe)-tert-butyl-XPhos26 (10 mg, 0.02 mmol),
K3PO4 (128 mg, 0.6 mmol), and formamide (0.024 mL, 0.6 mmol)
were combined with 2 mL of tert-butyl alcohol in a 25 mL Schlenk
tube. After 5 h, TLC analysis indicated the reaction was complete. The
reaction mixture was cooled to rt, filtered through Celite, concentrated
in vacuo, and purified on a silica gel column, eluted with 4% MeOH/
DCM, to give 67 mg of pyridine 4n (86%) as a yellow solid: mp 138−
2-Chloro-3-phenyl-3H-imidazo[4,5-c]pyridine (8). Chloride 8 was
prepared following a literature procedure.39 To an oven-dried 25 mL
Schlenk tube were added pyridine 4h (49 mg, 0.25 mmol) and 1.0 mL
of THF. The reaction mixture was cooled to −78 °C (CO2/acetone
bath), lithium diisopropylamide (2.0 M in THF, 0.19 mL) was added
dropwise, and the reaction mixture was allowed to stir for 1 h.
Hexachloroethane (89 mg, 0.375 mmol) was added as a solution in
THF (0.25 mL), and the reaction mixture was warmed to rt over 45
min. The reaction was quenched by the addition of a saturated
aqueous solution of ammonium chloride (4 mL), diluted with 5 mL of
water, and poured into 10 mL of EtOAc. The layers were separated,
and the aqueous layer was extracted with EtOAc (3 × 5 mL). The
combined organic layers were dried over magnesium sulfate, filtered,
concentrated in vacuo, and purified on a silica gel column, eluted with
5% MeOH/DCM, to afford 48 mg of chloride 8 (84%) as a yellow
1
140 °C; Rf = 0.57 (4% MeOH/DCM); H NMR (600 MHz, CDCl3)
δ = 8.94 (s, 1H), 8.88 (d, J = 2.4 Hz, 1H), 8.78 (dd, J = 4.8 Hz, 1.2 Hz,
1H), 8.55 (d, J = 5.4 Hz, 1H), 8.23 (s, 1H), 7.91 (ddd, J = 8.0 Hz, 2.4
Hz, 1.2 Hz, 1H), 7.80 (d, J = 5.4 Hz, 1H), 7.58 (dd, J = 8.0 Hz, 4.8 Hz,
1H); 13C NMR (150 MHz, CDCl3) δ= 150.2, 149.4, 145.3, 144.5,
143.3, 133.8, 132.5, 131.4, 131.4, 124.8, 115.6; FT-IR (NaCl, thin film)
ν = 3351, 3058, 2928, 1496, 1249 cm−1. Anal. Calcd for C11H8N4: C,
67.34; H, 4.11; N, 28.55. Found: C, 67.40; H, 4.15; N, 28.21.
2-Methyl-3-phenyl-3H-imidazo[4,5-c]pyridine (5). To an oven-
dried 50 mL Schlenk tube were added pyridine 3h (82 mg, 0.4 mmol),
Pd2(dba)3CHCl3 (8 mg, 0.008 mmol), Me3(OMe)tBuXPhos26 (20
mg, 0.04 mmol), K3PO4 (170 mg, 0.8 mmol), and acetamide (236 mg,
4.0 mmol); the reaction vessel was sealed, evacuated under vacuum,
and purged with Ar(g). t-BuOH (2.0 mL) was added, and the reaction
mixture was degassed with three vacuum/Ar(g) purge cycles, equipped
with a coldfinger condenser, and placed in a preheated 110 °C oil bath.
After 4 h, TLC analysis indicated the complete consumption of
pyridine 3h. The reaction mixture was cooled to rt, filtered through
Celite, concentrated in vacuo, and purified on a silica gel column,
eluted with 2% MeOH/DCM, to give 51 mg of pyridine 5 (61%) as a
1
solid: mp 110 °C dec; Rf = 0.40 (5% MeOH/DCM); H NMR (400
MHz, CDCl3) δ = 8.58 (s, 1H), 8.52 (d, J= 5.7 Hz, 1H), 7.68 (dd, J =
6.9, 0.9 Hz, 1H), 7.66−7.60 (m, 3H), 7.49−7.45 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ = 146.8, 144.4, 143.0, 134.1, 133.6, 133.2, 130.1,
130.0, 126.9, 114.0; FT-IR (NaCl, thin film) ν = 1638, 1498, 1437,
1366, 1285 cm−1. Anal. Calcd for C12H8ClN3: C, 62.76; H, 3.51; N,
18.30. Found: C, 62.94; H, 3.67; N, 18.66.
3-Phenyl-3H-imidazo[4,5-c]pyridine 5-Oxide (9). To a flame-dried
25 mL round-bottom flask containing a stir bar were added pyridine
4h (150 mg, 0.77 mmol) and chloroform (16 mL). After complete
dissolution, m-CPBA (85%, 390 mg, 1.93 mmol) was added as a single
portion, and the reaction mixture was warmed to 45 °C for 2 h. The
reaction mixture was cooled to rt, concentrated in vacuo, and then
1
yellow solid: mp 104−107 °C; Rf = 0.26 (5% MeOH/DCM); H
NMR (400 MHz, CDCl3) δ = 8.50 (s, 1H), 8.42 (d, J = 5.6 Hz, 1H),
7.63−7.53 (m, 4H), 7.39−7.36 (m, 2H), 2.53 (s, 3H); 13C NMR (100
MHz, CDCl3) δ = 155.0, 147.9, 142.6, 135.2, 134.3, 133.3, 130.3,
129.5, 126.8, 113.9, 14.5; FT-IR (NaCl, thin film) ν = 3407, 3048,
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The Journal of Organic Chemistry
Article
purified on a silica gel column, eluted with 10% MeOH/DCM, to
afford 145 mg of N-oxide 9 (89%) as a white powder: mp 174−175
°C; Rf = 0.02 (EtOAc); 1H NMR (400 MHz, CDCl3) δ = 8.56 (d, J =
1.0 Hz, 1H), 8.17 (s, 1H), 8.14 (dd, J = 6.9, 1.6 Hz, 1H), 7.65 (d, J =
6.9 Hz, 1H), 7.57−7.52 (m, 2H), 7.50−7.46 (m, 1H) 7.41−7.39 (m,
2H); 13C NMR (100 MHz, CDCl3) δ = 146.2, 141.9, 135.7, 134.4,
132.1, 130.6, 129.5, 124.6, 123.7, 117.0; FT-IR (NaCl, thin film) ν =
3379, 1506, 1463, 1446, 1204 cm−1. Anal. Calcd for C12H9N3O: C,
68.24; H, 4.29; N, 19.89. Found: C, 67.93; H, 4.50; N, 19.56.
(3) Puerstinger, G.; Paeshuyse, J.; Heinrich, S.; Mohr, J.; Schraffl, N.;
De Clercq, E.; Neyts, J. Bioorg. Med. Chem. Lett. 2007, 17 (18), 5111−
5114.
(4) Vliegen, I.; Paeshuyse, J.; De Burghgraeve, T.; Lehman, L. S.;
Paulson, M.; Shih, I. H.; Mabery, E.; Boddeker, N.; De Clercq, E.;
Reiser, H.; Oare, D.; Lee, W. A.; Zhong, W.; Bondy, S.; Purstinger, G.;
Neyts, J. J. Hepatol. 2009, 50 (5), 999−1009.
(5) Schneider, C.; Goyard, D.; Gueyrard, D.; Joseph, B.; Goekjian, P.
G. Eur. J. Org. Chem. 2010, 2010 (34), 6665−6677.
4-Chloro-3-phenyl-3H-imidazo[4,5-c]pyridine (10). To a 25 mL
Schlenk tube containing a stir bar were added N-oxide 9 (42 mg, 0.2
mmol) and 0.2 mL of POCl3. The reaction mixture was heated in a
120 °C oil bath for 2 h and then cooled to rt. The reaction mixture was
diluted with 5 mL of H2O and made basic with 1.5 mL of ammonium
hydroxide. The aqueous layer was extracted with DCM (3 × 10 mL),
and the combined organic layers were dried over MgSO4, filtered,
concentrated in vacuo, and then purified on a silica gel column, eluted
with 10% MeOH/DCM, to afford 38 mg of chloride 10 (84%) as an
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1
off-white solid: mp 148−151 °C; Rf = 0.50 (5% MeOH/DCM); H
NMR (300 MHz, CDCl3) δ = 8.27 (d, J = 5.5 Hz, 1H), 8.10 (s, 1H),
7.73 (d, J = 5.7 Hz, 1H), 7.57−7.53 (m, 3H), 7.46−7.43 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ = 150.9, 147.1, 141.5, 134.9, 134.3, 129.7,
129.1, 128.7, 127.7, 115.0; FT-IR (NaCl, thin film) ν = 3054, 1605,
1556, 1240, 980, 821 cm−1. Anal. Calcd for C12H8ClN3: C, 62.76; H,
3.51; N, 18.30. Found: C, 62.54; H, 3.66; N, 18.26.
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3-Phenyl-3H-imidazo[4,5-c]pyridine-4-carbonitrile (11). To an
oven-dried 15 mL pressure tube containing a stir bar were added N-
oxide 9 (53 mg, 0.25 mmol), acetonitrile (0.5 mL), Et3N (0.05 mL,
0.375 mmol), and trimethylsilyl cyanide (0.11 mL, 0.9 mmol). The
reaction vessel was sealed with a Teflon screw cap and heated in an oil
bath at 110 °C for 12 h. The reaction mixture was cooled to rt, diluted
with 10 mL of DCM, and washed with 10 mL of NaHCO3 (satd aq).
The organic layer was dried over MgSO4, filtered, concentrated in
vacuo, purified on a silica gel column, and eluted with 5% MeOH/
DCM to afford 49 mg of nitrile 11 (89%) as an off-white solid: mp
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Dempster, M.; Fradera, X.; Gillespie, J.; Andrews, F.; Boucharens, S.;
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1
179−181 °C; Rf = 0.50 (5% MeOH/DCM); H NMR (400 MHz,
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CDCl3) δ = 8.63 (d, J = 5.6 Hz, 1H), 8.24 (s, 1H), 8.02 (d, J = 5.6 Hz,
1H), 7.66−7.63 (m, 3H), 7.52−7.50 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ = 150.1, 147.9, 143.4, 133.5, 133.4, 130.7, 130.0, 127.1,
119.2, 117.4, 114.2; FT-IR (NaCl, thin film) ν = 3115, 3057, 2222,
1595, 1501, 1222 cm−1. Anal. Calcd for C13H8N4: C, 70.90; H, 3.66;
N, 25.44. Found: C, 70.81; H, 3.59; N, 25.07.
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ASSOCIATED CONTENT
* Supporting Information
■
(16) Rosenberg, A. J.; Zhao, J.; Clark, D. A. Org. Lett. 2012, 14 (7),
1764−1767.
S
Experimental procedures and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: daclar01@syr.edu.
■
(20) Lach, F.; Koza, P. ACS Comb. Sci. 2012, 14 (9), 491−495.
(21) Billingsley, K. L.; Anderson, K. W.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2006, 45 (21), 3484−3488.
Notes
The authors declare no competing financial interest.
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Chem. Soc. 2001, 123 (31), 7727−7729.
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ACKNOWLEDGMENTS
■
We thank Syracuse University for generous financial support of
this research. We thank the Chisholm and Totah research
groups for sharing of chemicals, use of instrumentation, and
helpful discussions. Prof. John Chisholm is thanked for
reviewing this manuscript.
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