Synthesis of polysubstituted 5-azaindoles via palladium-catalyzed heteroannulation of diarylalkynes

Article abstract of DOI:10.1021/jo200480h

A general and efficient procedure for the synthesis of functionalized 5-azaindoles through the catalyzed heteroannulation of 4-acetamido-3- iodopyridines and diarylalkynes is described. The reaction allows the preparation of a variety of substituted 2,3-d

Full text of DOI:10.1021/jo200480h

NOTE
pubs.acs.org/joc
Synthesis of Polysubstituted 5-Azaindoles via Palladium-Catalyzed
Heteroannulation of Diarylalkynes
Gꢀeraldine Calvet, Marion Livecchi, and Frꢀedꢀeric Schmidt*
Institut Curie, Centre de Recherche, 26 rue d0Ulm, Paris F-75248, France
CNRS, UMR 176, 26 rue d0Ulm, Paris F-75248, France
S Supporting Information
b
ABSTRACT: A general and efficient procedure for the syn-
thesis of functionalized 5-azaindoles through the catalyzed
heteroannulation of 4-acetamido-3-iodopyridines and diaryl-
alkynes is described. The reaction allows the preparation
of a variety of substituted 2,3-diaryl-5-azaindoles in good to
excellent yields.
zaindoles,1ꢀ3 also known as pyrrolopyridines or diazain-
denes, constitute an important class of heterocyclic compounds
We thus turned our attention to potentially more straightfor-
A
ward palladium-catalyzed processes, well-known for the synth-
esis of indole derivatives,30ꢀ32 starting from easily available
aminoiodo- or aminobromopyridines. Nevertheless, the tandem
Sonogashira/5-endo cyclization (Scheme 1, path c) does not
allow introducing the required aryl substituent in the 3 position
(R4).33,34 For these reasons, we decided to focus on the Larock
type heteroannulation with diarylalkynes (Scheme 1, path d).35
To the best of our knowledge, the single example reported in
literature shows a quite sluggish reactivity of a diarylacetylene
with 3-iodo-4-aminopyridine, the corresponding 3,4-diphenyl-5-
azaindole being obtained in low yield (22%).36 Another reported
application of Larock heteroannulation led to the formation
of tricyclic or tetracyclic 5-azaindoles.37,38 We wish to report
here an efficient and easy access to functionalized 5-azaindoles
through the heteroannulation of 3-iodo-4-acetamidopyridines
with diarylalkynes.
At the outset of our study, we investigated the reaction
of 4-acetamido-3-iodopyridine (1) and diphenylacetylene (2)
(5 equiv) with Pd(OAc)2 (5 mol %), a base (5 equiv), and an
additive (1 equiv) in DMF at 100 °C (Table 1) during 48 h.39
Using either LiCl or n-Bu4NCl as additives, several bases were
evaluated. No conversion or poor yields were observed when
potassium carbonate, potassium acetate, or sodium acetate were
used as base (Table 1, entries 1ꢀ5). Unexpectedly, although
usually poorly efficient for indole synthesis, sodium carbonate
proved to be the most efficient base,39 as the 5-azaindole 3 was
obtained in reasonable yields of 52% and 58%, respectively, with
n-Bu4NCl and LiCl (Table 1, entries 6 and 7). It is noteworthy
that, under the same reaction conditions, unprotected, mesy-
lated, and tosylated 3-iodo-4-aminoaminopyridines are comple-
tely unreactive, thus confirming the decisive influence of the
N-protecting group.40
possessing a broad range of biological activities. While acting as
indole isosteres, or as tryptophan and purine base analogues, the
extra nitrogen atom usually brings to these scaffolds a better
solubility and often a better bioavailability than their indole
counterparts. Recently, azaindoles have been established as very
promising candidates in the drug discovery of anthelmintic
agents,4 angiotensin inhibitors,5 dopamine D4 ligands,6 throm-
bin inhibitors,7 coagulation factors inhibitors (Xa, VIIa),8,9 kinase
inhibitors (p38, VEGFR, MK-2, Chk1, B-Raf),10ꢀ14 5-HT6 receptor
ligands,15,16 HIV-1 inhibitors,17 and CB2 agonists.18
Although many efficient synthetic strategies have been
devoted to the preparation of indole derivatives,19 the pre-
paration of their aza analogs remains particularly challenging
due to the electron-deficient nature of the pyridine ring. Among
the azaindole family, the 5-azaindoles are even more difficult
to synthesize.1ꢀ3 Almost all the methods currently employed
for the preparation of the indole core, such as the Madelung
reaction,20 the Fischer synthesis,21,22 the LeimbrugerꢀBatcho
reaction,23 the BischlerꢀNapieralski reaction,24 or the Hemets-
bergerꢀKnittel reaction,25,26 cannot be efficiently transposed to
5-azaindoles as they usually proceed with low yields and/or
cannot be generalized.
In our ongoing research project aiming at the evaluation of
2,3-diaryl-5-azaindoles (R4 = R5 = aryl) as kinase inhibitors, we
required a straightforward, efficient, and flexible access to these
structures. Very recently, some improved methods have been
reported for the synthesis of 5-azaindoles: on one hand, the [3 þ 2]
dipolar cycloaddition between nitriles and a 3,4-cyclopropano-
piperidine, followed by SeO2 oxidation (Scheme 1, path a),27
and, on the other hand, the zirconocene coupling of Si-tethered
diyne with three molecules of organonitriles (Scheme 1, path
b).28,29 However, neither of these methods were suitable for us as
they either require the synthesis of complex starting materials or
are not flexible enough.
Received: March 4, 2011
Published: April 18, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo200480h J. Org. Chem. 2011, 76, 4734–4740
|

The Journal of Organic Chemistry
NOTE
Scheme 1. Recent Methods for 5-Azaindole Synthesis
Table 1. Optimization of the Heteroannulation Reaction
between 4-Acetamido-3-iodopyridine (1) and Diphenylace-
tylene (2)
entry
base
additive
catalyst
[1] M 2 (equiv) yield (%)
1
2
3
4
5
6
7
8
9
K2CO3 n-Bu4NCl Pd(OAc)2
K2CO3 LiCl Pd(OAc)2
n-Bu4NCl Pd(OAc)2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
3
2
1
3
2
1
0a
0a
KOAc
KOAc
24b
28b
30b
52b
58b
89b
83b
84b
99
LiCl
Pd(OAc)2
Pd(OAc)2
NaOAc LiCl
No conversion was observed when DMF was substituted by a
less polar solvent like toluene. The influence of the halide source
was then investigated. Pleasingly, when LiCl was substituted by
either LiBr or LiI the reaction was achieved in very good yield of
89% and 83%, respectively (Table 1, entries 8 and 9).41 We
pursued our studies by optimization of the palladium catalyst and
concentration of the aminopyridine. The use of PdCl2(PhCN)2
afforded the desired 5-azaindole 3 in good yield (84%), compar-
able to that obtained with Pd(OAc)2 (Table 1, entry 10). On the
other hand, a quantitative yield was obtained when using the
triphenylphosphine-stabilized palladium complex PdCl2(PPh3)2
(Table 1, entry 11). The substrate concentration also plays a
significant role in this process. The reaction was not complete
when the concentration was lower than 0.2 M (Table 1, entries
14 and 15) and degradation was observed when the concentra-
tion was higher than 0.5 M (Table 1, entry 13). We next
evaluated the impact of decreasing the stoichiometry of the
alkyne using either LiCl or LiBr as additives. Using 3 equiv of
alkyne 2, the desired 5-azaindole 3 was obtained in excellent
yields of 89% (LiCl) and 95% (LiBr) (Table 1, entries 16 and
19); the conversion became incomplete with a lower amount of
alkyne (Table 1, entries 17, 18, 20, and 21).
Na2CO3 n-Bu4NCl Pd(OAc)2
Na2CO3 LiCl
Na2CO3 LiBr
Na2CO3 LiI
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
10 Na2CO3 LiCl
11 Na2CO3 LiCl
12 Na2CO3 LiCl
13 Na2CO3 LiCl
14 Na2CO3 LiCl
15 Na2CO3 LiCl
16 Na2CO3 LiCl
17 Na2CO3 LiCl
18 Na2CO3 LiCl
19 Na2CO3 LiBr
20 Na2CO3 LiBr
21 Na2CO3 LiBr
PdCl2(PhCN)2 0.2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
0.2
0.5
1
96
29c
86b
62b
89b
42b
24b
95
0.1
0.05
0.2
0.2
0.2
0.2
0.2
0.2
80b
50b
a Starting material was recovered. b Incomplete conversion. c Partial
degradation was observed.
With these optimized reaction conditions in hand (Table 1,
entry 19), we next examined the reactivity of chlorine or bromine
substituted 3-iodo-4-(acetamido)pyridines 4ꢀ9 (Table 2).
When the substrate bore a chlorine in position 2, the correspond-
ing azaindole 10 was obtained in a good yield of 80% (Table 2,
entry 1), whereas a bromine in the same position led to an
incomplete conversion and afforded 11 in 42% yield (Table 2,
entry 2). 5- and 6-chloro-substituted substrates 6 and 8 led to
5-azaindoles 12 and 14 in good to excellent yields of 79% and
99%, respectively (Table 2, entries 3 and 5). Although 5- and
6-bromo compounds 7 and 9 were more slugglish to react, the
corresponding 5-azaindoles 13 and 15 were obtained in satisfac-
tory yields. In view of these results, it seems that chloro-
substituted acetamidopyridines are better substrates than their
bromo counterparts, which may be explained by a better
chemoselectivity during the palladium(0) oxidative addition.
Nonetheless, our reaction conditions allow the introduction of
chlorine or bromine in every positions of the pyridine ring,
thus opening the door to further functionalization of the
5-azaindole core through SNAr reactions or metal-catalyzed
coupling processes.42ꢀ44
electronic effects. When the aromatic rings possessed a chlorine
(16) or a methoxy group (17), the corresponding azaindoles
were obtained in good yields of 76% and 85%, respectively
(Table 3, entries 1ꢀ2). However, the use of the very electron-
deficient bis-nitroalkyne did not promote the desired hetero-
annulation, probably because of its poor ability to complex
palladium (Table 3, entry 3). Notably, we could combine the
use of chloro-substituted acetamidopyridines with the electron-
rich 1,2-bis(4-methoxyphenyl)alkyne and could obtain the cor-
responding functionalized 5-azaindoles 22 and 23 in good yields
(Table 3, entries 4 and 5).
Finally, in order to evaluate the regioselectivity of this process,
the reaction was carried out with unsymmetrical alkynes. The
desired 5-azaindoles were obtained with good yields of 77%,
89%, and 87% for the methoxymethyl, chlorine, and methoxy
groups, respectively (Table 4, entries 1ꢀ3). Similar to the use of
symmetrical alkynes, the substitution of an aromatic ring by a
nitro group was detrimental to the reaction (Table 4, entry 4). In
all cases, products were formed without any regioselectivity and
the azaindoles isolated as a mixture of both regioisomers.
In summary, we have developed a straightforward and efficient
access to functionalized 5-azaindoles through the palladium-
catalyzed heteroannulation of 3-iodoacetamidopyridines with
diarylalkynes. This process allows the preparation of a wide
We next turned our attention to the synthesis of azaindoles
with functionalized diarylacetylenes. For this study, alkynes
16ꢀ18 were prepared possessing either withdrawing or donating
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NOTE
Table 2. Heteroannulation Reaction between Halogenated
4-Acetamido-3-iodopyridines 4ꢀ9 and Diphenylacetylene (2)
Table 3. Heteroannulation Reaction between 4-Acetamido-
3-iodopyridines 1, 4, and 6 and Symmetrical Diarylacetylenes
16ꢀ18
entry
R1
Cl
R2
R3
product
yield (%)
76
1
2
3
4
5
H
H
H
Cl
H
H
H
H
H
Cl
19
20
21
22
23
OMe
NO2
OMe
OMe
85
a
46
66
a Starting material was recovered.
Table 4. Heteroannulation Reaction between 4-Acetamido-
3-iodopyridine (1) and Unsymmetrical Diarylacetylenes
24ꢀ27
entry
alkyne
R
products
ratioa
yield (%)
1
2
3
4
24
25
26
27
CH2OMe
Cl
28a/28b
29a/29b
30a/30b
31a/31b
1/1
1/1
1/1
77
89
OMe
NO2
87
b
a Determined by 1H NMR spectroscopy. b Degradation of the reaction
mixture
a Isolated as a mixture with 5.
range of 5-azaindoles possessing various substituents on both the
pyridine and the pyrrole rings. The diversification of these
scaffolds through palladium-catalyzed cross-coupling reactions
is currently being evaluated. All the compounds prepared in this
study are currently being evaluated as kinase inhibitors, and their
biological activities will be reported in due course.
was hydrolyzed with lithium hydroxide (0.21 g, 5.07 mmol) in 6 mL of H2O/
THF 1:1 (v:v) for 30 min. When the hydrolysis was complete, the solution
was extracted with EtOAc (3 ꢁ 6 mL), and the combined organic layers were
dried over MgSO4 and concentrated under vacuum to yield 1.27 g (72%) of
the title compound as a white solid. Mp: 115 °C (recrystallized from a mixture
of EtOAc/heptane). Rf = 0.31 (EtOAc). 1H NMR (CDCl3, 300 MHz) δ
(ppm): 8.82 (s, 1H), 8.41 (d, J = 5.4 Hz, 1H), 8.34 (d, J = 5.4 Hz, 1H), 7.61
(brs,1H),2.29(s, 3H).13CNMR(CDCl3,75MHz) δ(ppm): 168.6, 157.1,
150.1, 144.7, 115.0, 87.2, 25.0. IR (NaCl, thin film) ν (cmꢀ1): 2921, 1704,
1572, 1496, 1399, 1302, 1237, 1012, 751. LRMS (ESþ): m/z = 263.0 ([M þ
H]þ, 100). HRMS (ESþ): calcd for C7H8N2OI [M þ H]þ: 262.9681,
found 262.9691.
N-(2-Chloro-3-iodopyridin-4-yl)acetamide (4). General pro-
cedure A for acetylation reaction: Under argon atmosphere, 4-amino-2-
chloro-3-iodopyridine (3.00 g, 11.76 mmol) was added to a stirred
solution of sodium hydride (3.02 g, 70.56 mmol) in THF (12 mL). After
5 min, acetyl chloride (5.00 mL, 70.56 mmol) was added, and the
’ EXPERIMENTAL SECTION
N-(3-Iodopyridin-4-yl)acetamide (1). Under an argon atmo-
sphere, acetic anhydride (0.77 mL, 6.74 mmol) and triethylamine
(1.41 mL, 10.11 mmol) were added to a solution of 4-amino-3-iodo-
pyridine (1.48 g, 6.74 mmol) in CH2Cl2 (13.5 mL). The mixture was then
stirred for 18 h at room temperature. After concentration under vacuum, the
crude product was purified by chromatography (silica gel, EtOAc/cyclo-
hexane 80:20 to 90:10) to give 1.58 g of a mixture of N-(3-iodopyridin-4-
yl)acetamide and N-acetyl-N-(3-iodopyridin-4-yl)acetamide. This fraction
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NOTE
solution was warmed to room temperature until completion. The mixture
was cooled at 0 °C, and then MeOH (5 mL) followed by H2O (5 mL)
were added. The aqueous layer was extracted with EtOAc (3 ꢁ 10 mL),
and the combined organic layers were concentrated under vacuum. The
fraction composed of N-(2-chloro-3-iodopyridin-4-yl)acetamide and N-
acetyl-N-(2-chloro-3-iodopyridin-4-yl)acetamide was hydrolyzed with
lithium hydroxide (0.33 g, 7.97 mmol) in 14 mL of H2O/THF 1:1 (v/v)
for 30 min. When the hydrolysis was complete, the solution was
extracted with EtOAc (3 ꢁ 30 mL), the combined organic layers were
dried over MgSO4, and concentrated under vacuum. The crude product
was purified by chromatography (silica gel, cyclohexane/EtOAc 50:50)
to give 1.79 g (51%) of the desired compound as a white solid. Mp:
149 °C (recrystallized from a mixture of EtOAc/heptane). Rf = 0.33
(EtOAc/cyclohexane 4/6). 1H NMR (CDCl3, 300 MHz) δ (ppm): 8.20
(d, J = 5.5 Hz, 1H), 8.15 (d, J = 5.5 Hz, 1H), 7.85 (br s, 1H), 2.27 (s,
3H). 13C NMR (CDCl3, 75 MHz) δ (ppm): 168.3, 155.1, 149.2,
147.8, 112.4, 88.9, 25.0. IR (NaCl, thin film) ν (cmꢀ1): 3300, 1680,
1560, 1493, 1348, 764, 750. LRMS (ESþ): m/z = 295.0 ([M þ H]þ, 64),
297.0 (22). HRMS (ESꢀ): calcd for C7H5N2OClI [M]ꢀ 294.9135,
found 294.9130.
N-(2-Bromo-3-iodopyridin-4-yl)acetamide (5). Compound 5
was prepared following the general procedure A with 387 mg (1.29
mmol) of 4-amino-2-bromo-3-iodopyridine. The crude product was
purified by chromatography (silica gel, cyclohexane/EtOAc 60:40) to
give 277 mg (63%) of compound 5 as a white solid. Mp: 170 °C
(recrystallized from a mixture of EtOAc/heptane). Rf = 0.27 (cyclo-
hexane/EtOAc: 6/4). 1H NMR (MeOD, 300 MHz) δ (ppm): 8.19 (d,
J = 5.4 Hz, 1H), 7.89 (d, J = 5.4 Hz, 1H), 2.25 (s, 3H). 13C NMR
(MeOD, 75 MHz) δ (ppm): 171.7, 151.1, 150.6, 150.1, 117.6, 97.1, 24.2.
IR (CH2Cl2), ν (cmꢀ1): 3361, 2932, 2857, 1718, 1558, 1488, 1343,
1242. LRMS (ESꢀ): m/z = 338.8 ([M ꢀ H]ꢀ, 100), 340.8 (67); HRMS
(ESþ): calcd for C7H7N2OBrI [M þ H]þ 340.8787, found 340.8802.
N-(2-Chloro-5-iodopyridin-4-yl)acetamide (6). Compound 6
was prepared following the general procedure A with 501 mg (1.97
mmol) of 4-amino-2-chloro-5-iodopyridine. The crude product was
purified by chromatography (silica gel, cyclohexane/EtOAc 80:20 to
70:30) to give 366 mg (63%) of compound 6 as a white solid. Mp:
181 °C (recrystallized from a mixture of EtOAc/heptane). Rf = 0.24
(cyclohexane/EtOAc 6/4). 1H NMR (CDCl3, 300 MHz) δ (ppm): 8.55
(s, 1H), 8.40 (s, 1H), 7.62 (br s, 1H), 2.28 (s, 3H). 13C NMR (CDCl3,
75 MHz) δ (ppm): 168.7, 156.2, 153.0, 146.4, 114.8, 85.0, 25.2. IR
(NaCl, thin film) ν (cmꢀ1): 3284, 2924, 1679, 1555, 1480, 1350,
1261, 1101. LRMS (ESþ): m/z = 297.1 ([M þ H]þ, 13), 299.0 (31).
HRMS (ESþ): calcd for C7H7N2OClI [M þ H]þ 296.9292, found
296.9300.
7.04 (br s, 1H), 2.27 (s, 3H). 13C NMR (MeOD, 75 MHz) δ (ppm):
171.3, 157.3, 150.3, 146.9, 131.9, 99.5, 22.7. IR (CH2Cl2) ν (cmꢀ1):
3184, 1667, 1538, 1492, 1396, 1227. LRMS (ESþ): m/z = 296.9 ([M þ
H]þ, 100), 298.9 (34). HRMS (ESþ): calcd for C7H7N2OClI [M þ
H]þ 296.9292, found 296.9297.
N-(3-Bromo-5-iodopyridin-4-yl)acetamide (9). Compound 9
was prepared following the general procedure A with 1.08 g (3.62 mmol)
of 4-amino-3-bromo-5-iodopyridine. The crude product was purified by
chromatography (silica gel, cyclohexane/EtOAc 70:30 to 30:70) to give
553 mg (45%) of compound 9 as a white solid. Mp: 221 °C
(recrystallized from a mixture of EtOAc/heptane). Rf = 0.18
1
(cyclohexane/EtOAc: 6/4). H NMR (MeOD, 300 MHz) δ (ppm):
8.82 (s, 1H), 8.62 (s, 1H), 2.12 (s, 3H). 13C NMR (MeOD, 75 MHz) δ
(ppm): 171.3, 157.9, 152.9, 148.4, 122.4, 99.9, 22.8. IR (CH2Cl2) ν
(cmꢀ1): 3194, 1668, 1538, 1494, 1276. LRMS (ESþ): m/z = 340.8 ([M
þ H]þ,100), 342.8 (98). HRMS (ESþ): calcd for C7H7N2OBrI [M þ
H]þ 340.8787, found 340.8800.
2,3-Diphenyl-1H-pyrrolo[3,2-c]pyridine (3). General proce-
dure B for heteroannulation reaction: Under argon atmosphere, to a
solution of 4-acetamido-2-iodopyridine (86 mg, 0.32 mmol), PdCl2-
(PPh3)2 (11 mg, 0.016 mmol), lithium bromide (28 mg, 0.32 mmol),
and sodium carbonate (170 mg, 1.6 mmol) in anhydrous DMF (1.6 mL)
was added diphenylacetylene 2 (171 mg, 0.96 mmol). The mixture was
stirred at 100 °C for 48 h and then cooled to room temperature and
hydrolyzed with 2 mL of water. After extraction with EtOAc (3 ꢁ 4 mL),
the combined organic layers were dried over MgSO4 and concentrated
under vacuum. The purification of the residue by chromatography (silica
gel, methanol/EtOAc/cyclohexane 0:70:30 to 10:90:00) afforded 82 mg
(95%) of the 5-azaindole 3 as a white solid. Mp: 228 °C (recrystallized
from methanol). Rf = 0.28 (EtOAc/methanol: 9/1). 1H NMR (DMSO-
d6, 300 MHz) δ (ppm): 12.11 (s, 1H), 8.81 (s, 1H), 8.27 (d, J = 5.7 Hz,
1H), 7.45 (d, J = 5.7 Hz, 1H), 7.51ꢀ7.29 (m, 10H). 13C NMR (DMSO-
d6, 75 MHz) δ (ppm): 141.9, 140.9, 139.5, 135.0, 134.0, 131.6, 129.7
(2C), 128.7 (2C), 128.6 (2C), 128.4 (2C), 128.1, 126.5, 124.9, 112.6,
106.6. IR (CH2Cl2) ν (cmꢀ1): 3446, 3043, 1465, 1262, 752, 699. LRMS
(ESþ): m/z = 271.1 ([M þ H]þ, 100); HRMS (ESþ): calcd for
C19H15N2 [M þ H]þ 271.1235, found 271.1235.
4-Chloro-2,3-diphenyl-1H-pyrrolo[3,2-c]pyridine (10). Com-
pound 10 was prepared following the general procedure B with 1.00 g
(3.28 mmol) of N-(2-chloro-3-iodopyridin-4-yl)acetamide 4. The crude
product was purified by chromatography (silica gel, cyclohexane/EtOAc
90:10 to 70:30) to give 0.82 g (80%) of compound 10 as a yellow solid.
Mp: 249 °C. Rf = 0.29 (EtOAc/methanol 9/1). 1H NMR (DMSO-d6,
300 MHz) δ (ppm): 12.38 (s, 1H), 7.99 (d, J = 5.7 Hz, 1H), 7.45 (d, J =
5.7 Hz, 1H), 7.46ꢀ7.29 (m, 10H). 13C NMR (DMSO-d6, 75 MHz) δ
(ppm): 142.0, 140.9, 139.5, 136.5, 134.1, 131.7 (2C), 131.1, 128.4 (2C),
128.1 (3C), 127.8 (2C), 127.2, 121.6, 113.3, 107.0. IR (NaCl, thin film)
ν (cmꢀ1): 3640, 3056, 1444, 1260, 765, 750, 697. LRMS (ESþ): m/z =
305.1 ([M þ H]þ, 100), 307.1 (36). HRMS (ESþ): calcd for C19H14N2-
Cl [M þ H]þ 305.0846, found 305.0854.
N-(2-Bromo-5-iodopyridin-4-yl)acetamide (7). Compound 7
was prepared following the general procedure A with 363 mg (1.21
mmol) of 4-amino-2-bromo-5-iodopyridine. The crude product was
purified by chromatography (silica gel, cyclohexane/EtOAc 80:20 to
60:40) to give 210 mg (51%) of compound 7 as a white solid. Mp:
202 °C (recrystallized from a mixture of EtOAc/heptane). Rf = 0.32
(cyclohexane/EtOAc 6/4). 1H NMR (CDCl3, 300 MHz) δ (ppm): 8.57
(s, 1H), 8.54 (s, 1H), 7.59 (br s, 1H), 2.29 (s, 3H). 13C NMR (CDCl3,
75 MHz) δ (ppm): 168.6, 156.6, 146.0, 143.3, 118.4, 85.9, 25.1. IR
(CH2Cl2) ν (cmꢀ1): 3283, 1676, 1549, 1341, 1277, 1091. LRMS (ESþ):
m/z = 340.9 ([M þ H]þ, 100), 342.9 (96). HRMS (ESþ): calcd for
C7H7N2OBrI [M þ H]þ 340.8787, found 340.8781.
4-Bromo-2,3-diphenyl-1H-pyrrolo[3,2-c]pyridine (11). Com-
pound 11 was prepared following the general procedure B with 78 mg
(0.23 mmol) of N-(2-bromo-3-iodopyridin-4-yl)acetamide 5. The crude
product was purified by chromatography (silica gel, cyclohexane/EtOAc
90:10 to 70:30) to give 34 mg (42%) of compound 11 in mixture with
starting material. The yield was evaluated by NMR. Rf = 0.24
(cyclohexane/EtOAc: 6/4). 1H NMR (DMSO-d6, 300 MHz) δ
(ppm): 12.37 (s, 1H), 7.95 (d, J = 5.4 Hz, 1H), 7.46 (d, J = 5.4 Hz,
1H), 7.37ꢀ7.27 (m, 10H). 13C NMR (DMSO-d6, 75 MHz) δ (ppm):
150.0, 141.2, 140.9, 137.5, 134.8, 133.8, 133.0 (2C), 132.0, 129.3 (2C),
129.0 (2C), 128.6 (2C), 128.2, 124.6, 114.8, 108.1. IR (CH2Cl2) ν
(cmꢀ1): 3442, 3049, 1557, 1440, 1262, 755, 701. LRMS (ESþ): m/z =
349.0 ([M þ H]þ, 43), 351.0 (99). HRMS (ESþ): calcd for
C19H14N2Br [M þ H]þ 349.0340, found 349.0356.
N-(3-Chloro-5-iodopyridin-4-yl)acetamide (8). Compound 8
was prepared following the general procedure A with 1.84 g (7.22 mmol)
of 4-amino-3-chloro-5-iodopyridine. The crude product was purified by
chromatography (silica gel, cyclohexane/EtOAc 60:40 to 20:80) to give
1.39 g (65%) of compound 8 as a white solid. Mp: 204 °C (recrystallized
from a mixture of EtOAc/heptane). Rf = 0.17 (cyclohexane/EtOAc 6/
4). 1H NMR (CDCl3, 300 MHz) δ (ppm): 8.85 (s, 1H), 8.56 (s, 1H),
4737
dx.doi.org/10.1021/jo200480h |J. Org. Chem. 2011, 76, 4734–4740

The Journal of Organic Chemistry
NOTE
6-Chloro-2,3-diphenyl-1H-pyrrolo[3,2-c]pyridine (12). Com-
pound 12 was prepared following the general procedure B with 100 mg
(0.34 mmol) of N-(2-chloro-5-iodopyridin-4-yl)acetamide 6. The crude
product was purified by chromatography (silica gel, cyclohexane/EtOAc
90:10 to 70:30) to give 81 mg (79%) of compound 12 as a yellow solid.
Mp: 262 °C. Rf = 0.55 (cyclohexane/EtOAc: 6/4). 1H NMR (DMSO-d6,
300 MHz) δ (ppm): 12.22 (s, 1H), 8.54 (s, 1H), 7.47ꢀ7.39 (m, 11H).
13C NMR (DMSO-d6, 75 MHz) δ (ppm): 141.9, 141.5, 141.0, 136.4,
133.3, 131.0, 129.5 (2C), 128.8 (2C), 128.6 (2C), 128.4, 128.3 (2C),
126.8, 124.6, 112.6, 105.6. IR (NaCl, thin film) ν (cmꢀ1): 3062, 1600,
1459, 1268, 1061, 765, 696, 614. LRMS (ESþ): m/z = 305.1 ([M þ
H]þ, 100), 307.1 (33); HRMS (ESþ): calcd for C19H14N2Cl [M þ H]þ
305.0846, found 305.0858.
6-Bromo-2,3-diphenyl-1H-pyrrolo[3,2-c]pyridine (13). Com-
pound 13 was prepared following the general procedure B with 80 mg
(0.23 mmol) of N-(2-bromo-5-iodopyridin-4-yl)acetamide 7. The crude
product was purified by chromatography (silica gel, cyclohexane/EtOAc
90:10 to 70:30) to give 49 mg (60%) of compound 13 as a yellow solid.
Mp: 238 °C. Rf = 0.52 (cyclohexane/EtOAc: 6/4). 1H NMR (DMSO-d6,
300 MHz) δ (ppm): 12.22 (s, 1H), 8.52 (s, 1H), 7.57 (s, 1H), 7.45ꢀ7.36
(m, 10H). 13C NMR (DMSO-d6, 75 MHz), δ (ppm): 141.6, 141.5,
136.3, 133.2, 132.0, 131.0, 129.6 (2C), 128.8 (2C), 128.6 (2C), 128.5,
128.4 (2C), 126.8, 124.9, 112.5, 109.4. IR (CH2Cl2) ν (cmꢀ1): 3442,
2928, 1556, 1460, 1268, 1049, 765, 696. LRMS (ESþ): m/z = 349.0 ([M
þ H]þ, 100), 351.0 (100). HRMS (ESþ): calcd for C19H14N2Br [M þ
H]þ 349.0340, found 349.0348.
7-Chloro-2,3-diphenyl-1H-pyrrolo[3,2-c]pyridine (14). Com-
pound 14 was prepared following the general procedure B with 82 mg
(0.28 mmol) of N-(3-chloro-5-iodopyridin-4-yl)acetamide 8. The crude
product was purified by chromatography (silica gel, cyclohexane/EtOAc
90:10 to 70:30) to give 85 mg (99%) of compound 14 as a yellow solid.
Mp: 210 °C. Rf = 0.34 (cyclohexane/EtOAc: 6/4). 1H NMR (DMSO-d6,
300 MHz) δ (ppm): 12.40 (s, 1H), 8.70 (d, J = 1.8 Hz, 1H), 8.29 (d, J =
1.8 Hz, 1H), 7.50ꢀ7.35 (m, 10H). 13C NMR (DMSO-d6, 75 MHz) δ
(ppm): 140.3, 139.1, 137.0, 136.6, 133.3, 130.8, 129.6 (2C), 129.3 (2C),
128.8 (2C), 128.4, 128.3 (2C), 126.8, 126.2, 114.1, 113.6. IR (CH2Cl2)
ν (cmꢀ1): 3430, 2927, 1716, 1462, 1266, 1230, 756, 708. LRMS (ESþ):
m/z = 305.0 ([M þ H]þ, 100), 307.0 (37); HRMS (ESþ): calcd for
C19H14N2Cl [M þ H]þ 305.0846, found 305.0856.
128.3 (2C), 128.2, 127.5 (2C), 123.2, 122.4, 89.3, 89.2, 74.2, 58.1. IR
(CH2Cl2) ν (cmꢀ1): 2929, 1510, 1263, 1098,732, 718, 736. LRMS
(MALDI): m/z = 222.1 (Mþ, 100). HRMS (MALDI): calcd for
C16H14O [M]þ 222.1039, found 222.1037.
Alkynes 16,45 17,46 18,47 25,48 26,49 and 2750 were prepared as
previously described.
2,3-Bis(4-chlorophenyl)-1H-pyrrolo[3,2-c]pyridine(19). Com-
pound 19 was prepared following the general procedure B with 81 mg
(0.3 mmol) of N-(3-iodopyridin-4-yl)acetamide 1 and 222 mg (0.9
mmol) of 1,2-bis(4-chlorophenyl)ethyne 16. The crude product was
purified by chromatography (silica gel, cyclohexane/EtOAc/methanol
30:70:0 to 0:90:10) to give 77 mg (76%) of compound 19 as a yellow
solid. Mp: 227 °C. Rf = 0.33 (EtOAc/methanol 9/1). 1H NMR (DMSO-
d6, 300 MHz) δ (ppm): 12.15 (s, 1H), 8.78 (s, 1H), 8.27 (d, J = 4.2 Hz,
1H), 7.52ꢀ7.39 (m, 9H). 13C NMR (DMSO-d6, 75 MHz) δ (ppm):
142.8, 142.1, 140.4, 135.0, 133.9, 133.5, 132.3 (3C), 131.1 (3C), 129.9
(2C), 129.8 (2C), 125.4, 112.6, 107.6. IR (CH2Cl2) ν (cmꢀ1): 3444,
2929, 1464, 1262, 751, 708. LRMS (ESþ): m/z = 339.1 ([M þ H]þ,
100), 341.1 (73). HRMS (ESþ): calcd for C19H13N2Cl2 [M þ H]þ
339.0456, found 339.0466.
2,3-Bis(4-methoxyphenyl)-1H-pyrrolo[3,2-c]pyridine (20).
Compound 20 was prepared following the general procedure B with 124
mg (0.47 mmol) of N-(3-iodopyridin-4-yl)acetamide 1 and 336 mg
(1.41 mmol) of 1,2-bis(4-methoxyphenyl)ethyne 17. The crude product
was purified by chromatography (silica gel, cyclohexane/EtOAc/metha-
nol 30:70:0 to 0:90:10) to give 132 mg (85%) of compound 20 as a
yellow solid. Mp: 212 °C. Rf = 0.24 (EtOAc/methanol: 9/1). 1H NMR
(DMSO-d6, 300 MHz) δ (ppm): 11.85 (s, 1H), 8.69 (s, 1H), 8.19 (d, J =
3.9 Hz, 1H), 7.42ꢀ7.29 (m, 5H), 7.00ꢀ6.95 (m, 4H), 3.79 (s, 3H), 3.78
(s, 3H). 13C NMR (DMSO-d6, 75 MHz) δ (ppm): 159.0, 157.8, 141.5,
140.5, 139.1, 134.5, 130.7 (2C), 129.5 (2C), 126.2 (2C), 125.2, 124.0
(2C), 114.2, 114.1, 111.2, 106.4, 55.1, 55.0. IR (CH2Cl2) ν (cmꢀ1):
3449, 2966, 1521, 1499, 1466, 1262, 1178, 1033, 736, 722. LRMS
(ESþ): m/z = 331.2 ([M þ H]þ, 100). HRMS (ESþ): calcd for
C21H19N2O2 [M þ H]þ 331.1447, found 331.1463.
4-Chloro-2,3-bis(4-methoxyphenyl)-1H-pyrrolo[3,2-c]-
pyridine (22). Compound 22 was prepared following the general
procedure B with 184 mg (0.62 mmol) of N-(2-chloro-3-iodopyridin-4-
yl)acetamide 4 and 443 mg (1.26 mmol) of 1,2-bis(4-methoxyphe-
nyl)ethyne 17. The crude product was purified by chromatography
(silica gel, cyclohexane/EtOAc 80:20 to 60:40) to give 104 mg (46%) of
compound 22 as a yellow solid. Mp: 210 °C. Rf = 0.19 (cyclohexane/
7-Bromo-2,3-diphenyl-1H-pyrrolo[3,2-c]pyridine (15). Com-
pound 15 was prepared following the general procedure B with 110 mg
(0.32 mmol) of N-(3-bromo-5-iodopyridin-4-yl)acetamide 9. The crude
product was purified by chromatography (silica gel, cyclohexane/EtOAc
90:10 to 70:30) to give 89 mg (79%) of compound 15 as a yellow solid.
Mp: 248 °C. Rf = 0.37 (cyclohexane/EtOAc: 6/4). 1H NMR (DMSO-d6,
300 MHz) δ (ppm): 12.28 (s, 1H), 8.72 (s, 1H), 8.37 (s, 1H), 7.49ꢀ7.32
(m, 10H). 13C NMR (DMSO-d6, 75 MHz) δ (ppm): 141.5, 140.7,
138.1, 137.0, 133.3, 130.8, 129.6 (2C), 129.4 (2C), 128.8 (2C), 128.4,
128.3 (2C), 126.8, 126.1, 113.7, 102.7. IR (CH2Cl2) ν (cmꢀ1): 3428,
2929, 1716, 1462, 1267, 756, 697. LRMS (ESþ): m/z = 349.0 ([M þ
H]þ, 100), 351.0 (100); HRMS (ESþ): calcd for C19H14N2Br [M þ
H]þ 349.0340, found 349.0348.
1
EtOAc 6/4). H NMR (DMSO-d6, 300 MHz) δ (ppm): 12.21 (br s,
1H), 7.95 (d, J = 5.6 Hz, 1H), 7.41 (d, J = 5.6 Hz, 1H), 7.30 (d, J = 8.2 Hz,
2H), 7.21 (d, J = 8.2 Hz, 2H), 6.94 (d, J = 9.2 Hz, 2H), 6.91 (d, J = 9.2 Hz,
2H), 3.79 (s, 3H), 3.73 (s, 3H). 13C NMR (DMSO-d6, 75 MHz) δ (ppm):
159.0, 158.2, 141.7, 140.7, 139.1, 136.4, 132.8 (2C), 129.3 (2C), 126.2,
123.5, 121.5, 113.9 (2C), 113.2 (2C), 111.8, 106.7, 55.1, 54.9. IR (CH2Cl2)
ν (cmꢀ1): 3444, 2963, 1614, 1496, 1441, 1248, 1102, 1032, 760, 744.
LRMS (ESꢀ): m/z = 363.1 ([M-H]ꢀ, 100), 365.1 (34); HRMS (ESꢀ):
calcd for C21H16N2O2Cl [M ꢀ H]ꢀ 363.0900, found 363.0915.
6-Chloro-2,3-bis(4-methoxyphenyl)-1H-pyrrolo[3,2-c]-
pyridine (23). Compound 23 was prepared following the general
procedure B with 734 mg (2.48 mmol) of N-(2-chloro-5-iodopyridin-4-
yl)acetamide 6 and 1.97 g (7.44 mmol) of 1,2-bis(4-methoxyphe-
nyl)ethyne 17. The crude product was purified by chromatography
(silica gel, cyclohexane/EtOAc 80:20 to 70:30) to give 595 mg (66%) of
compound 23 as a yellow solid. Mp: 119 °C. Rf = 0.36 (cyclohexane/
EtOAc: 6/4). 1H NMR (DMSO-d6, 300 MHz) δ (ppm): 12.04 (br s,
1H), 8.46 (s, 1H), 7.44ꢀ7.23 (m, 4H), 7.39 (s, 1H), 7.02ꢀ6.89 (m, 4H),
3.77 (s, 6H). 13C NMR (DMSO-d6, 75 MHz) δ (ppm): 160.1, 158.9,
142.5, 142.2, 141.5, 136.9, 131.6 (2C), 130.5 (2C), 126.5, 126.0, 124.4,
115.2 (2C), 115.0 (2C), 112.2, 106.3, 56.0, 55.9. IR (CH2Cl2) ν
(cmꢀ1): 3444, 2930, 1611, 1464, 1217, 1178, 1030, 832. LRMS
1-(Methoxymethyl)-4-(phenylethynyl)benzene (24). Under
argon atmosphere, ethynylbenzene (250 μL, 2.3 mmol) was added to a
mixture of 1-iodo-4-(methoxymethyl)benzene (538 mg, 2.2 mmol),
PdCl2(PPh3)2 (15 mg, 0.02 mmol), CuI (17 mg, 0.88 mmol), and
triethylamine (445 μL, 3.3 mmol) in anhydrous THF (5.5 mL). The
mixture was stirred at room temperature until the reaction was complete
and then filtered over Celite and concentrated under vacuum. The crude
product was purified by chromatography (silica gel, pentane/Et2O 95:5)
to give 455 mg (94%) of compound 24 as a yellow oil. Rf = 0.29
1
(cyclohexane/EtOAc: 95/5). H NMR (CDCl3, 300 MHz) δ (ppm):
7.58ꢀ7.53 (m, 4H), 7.39ꢀ7.26 (m, 5H), 4.48 (s, 2H), 3.42 (s, 3H). 13C
NMR (CDCl3, 75 MHz), δ (ppm): 138.4, 131.6 (2C), 131.5 (2C),
4738
dx.doi.org/10.1021/jo200480h |J. Org. Chem. 2011, 76, 4734–4740

The Journal of Organic Chemistry
NOTE
(ESþ): m/z = 365.0 ([M þ H]þ, 100), 367.0 (36). HRMS (ESþ): calcd
for C21H18N2O2Cl [M þ H]þ 365.1057, found 365.1065.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: frederic.schmidt@curie.fr.
2-(4-(Methoxymethyl)phenyl)-3-phenyl-1H-pyrrolo[3,2-c]-
pyridine (28a) and 3-(4-(Methoxymethyl)phenyl)-2-phenyl-
1H-pyrrolo[3,2-c]pyridine (28b). Compounds 28a and 28b were
prepared following the general procedure B with 101 mg (0.37 mmol)
of N-(3-iodopyridin-4-yl)acetamide 1 and 247 mg (1.11 mmol) of
1-(methoxymethyl)-4-(phenylethynyl)benzene 24. The crude product
was purified by chromatography (silica gel, cyclohexane/EtOAc/metha-
nol 30:70:0 to 0:90:10) to give 90 mg (77%) of an inseparable mixture of
compounds 28a and 28b. Rf = 0.27 (EtOAc/methanol: 9/1). 1H NMR
(DMSO-d6, 300 MHz), δ (ppm): 12.00 (br s, 2H), 8.76 (s, 1H), 8.75
(s, 1H), 8.23 (d, J = 5.7 Hz, 2H), 7.47ꢀ7.31 (m, 20H), 4.44 (s, 1H), 4.41
(s, 1H), 3.33 (s, 3H), 3.30 (s, 3H). 13C NMR (DMSO-d6, 75 MHz),
δ (ppm): 141.8, 141.7, 140.8, 139.4, 138.2, 136.5, 135.0, 134.8, 133.9,
133.0, 132.0, 131.6, 131.5, 131.4, 130.7, 129.6 (2C), 129.4 (2C), 128.8
(2C), 128.6 (2C), 128.4 (2C), 128.2 (2C), 128.1, 128.0 (2C), 127.7
(2C), 126.5, 124.8, 112.5, 112.3, 106.6 (2C), 73.5, 73.2, 57.6 (2C). IR
(CH2Cl2) ν (cmꢀ1): 3446, 2929, 1466, 1262, 1099, 756, 719. LRMS
(ESþ): m/z = 315.2 ([M þ H]þ, 100); HRMS (ESþ): calcd for
C21H19N2O [M þ H]þ 315.1497, found 315.1492.
’ ACKNOWLEDGMENT
G.C. thanks the Association pour la Recherche sur le Cancer
(ARC) for a postdoctoral grant. We thank Dr. J.-C. Florent and
Dr. P. Belmont for fruitful discussions and Delphine Naud-
Martin for technical assistance.
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Comer, D. D.; Dalrymple, S. A.; Dunten, P.; Lafargue, J.; Lovejoy, B.;
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2-(4-Chlorophenyl)-3-phenyl-1H-pyrrolo[3,2-c]pyridine
(29a) and 3-(4-Chlorophenyl)-2-phenyl-1H-pyrrolo[3,2-c]-
pyridine (29b). Compounds 29a and 29b were prepared following
the general procedure B with 82 mg (0.31 mmol) of N-(3-iodopyridin-4-
yl)acetamide 1 and 195 mg (0.92 mmol) of 1-chloro-4-(phenylethynyl)-
benzene 25. The crude product was purified by chromatography (silica
gel, cyclohexane/EtOAc/methanol 30:70:0 to 0:90:10) to give 84 mg
(89%) of an inseparable mixture of compounds 29a and 29b. Rf = 0.33
1
(EtOAc/methanol: 9/1). H NMR (DMSO-d6, 300 MHz) δ (ppm):
12.08 (br s, 2H), 8.78 (s, 1H), 8.76 (s, 1H), 8.25 (d, J = 5.4 Hz, 2H),
7.47ꢀ7.34 (m, 20H). 13C NMR (DMSO-d6, 75 MHz) δ (ppm): 141.9,
141.7, 141.0, 140.9, 139.4, 135.4, 133.7, 133.6, 132.9, 132.8, 132.0, 131.5,
131.3 (2C), 131.1, 130.4, 130.0 (2C), 129.6 (2C), 128.9 (2C), 128.8
(3C), 128.7 (3C), 128.5 (2C), 128.3, 126.7, 124.7, 124.5, 113.1, 111.2,
106.7 (2C). IR (CH2Cl2) ν (cmꢀ1): 3444, 3043, 1503, 1464, 1265,
1094, 831, 732, 717. LRMS (ESþ): m/z = 305.1 ([M þ H]þ, 100), 307.1
(82). HRMS (ESþ): calcd for C19H14N2Cl [M þ H]þ 305.0846, found
305.0855.
2-(4-Methoxyphenyl)-3-phenyl-1H-pyrrolo[3,2-c]pyridine
(30a) and 3-(4-methoxyphenyl)-2-phenyl-1H-pyrrolo[3,2-c]-
pyridine (30b). were prepared following the general procedure B
with 97 mg (0.36 mmol) of N-(3-iodopyridin-4-yl)acetamide 1 and
225 mg (1.08 mmol) of 1-methoxy-4-(phenylethynyl)benzene 26. The
crude product was purified by chromatography (silica gel, cyclohexane/
EtOAc/methanol 30:70:0 to 0:90:10) to give 94 mg (87%) of an
inseparable mixture of compounds 30a and 30b. Rf = 0.28 (EtOAc/
methanol: 9/1). 1H NMR (DMSO-d6, 300 MHz) δ (ppm): 11.93 (br s,
1H), 11.91 (br s, 1H), 8.72 (s, 2H), 8.21 (d, J = 3.9 Hz, 2H), 7.62ꢀ7.28
(m, 16H), 6.98 (d, J = 7.5 Hz, 2H), 6.95 (d, J = 7.8 Hz, 2H), 3.78 (s, 3H),
3.77 (s, 3H). 13C NMR (DMSO-d6, 75 MHz) δ (ppm): 160.0, 158.9,
142.7, 142.3, 141.6, 141.5, 140.2, 136.0, 135.4, 135.1, 134.3, 132.9, 132.6,
132.4, 132.3, 131.7 (2C), 130.6, 130.5, 129.7 (3C), 129.5 (3C), 129.2
(2C), 128.9, 127.3, 126.9, 125.9, 124.7, 115.2, 115.0, 113.3, 112.5, 107.4
(2C), 56.1, 55.9. IR (CH2Cl2) ν (cmꢀ1): 3446, 2964, 1515, 1466, 1261,
1034, 836, 756, 717. LRMS (ESþ): m/z = 301.2 ([M þ H]þ, 100).
HRMS (ESþ): calcd for C20H17N2O [M þ H]þ 301.1341, found
301.1347.
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’ ASSOCIATED CONTENT
S
Supporting Information.
1H NMR and 13C NMR
b
spectra of all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
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