A novel one-step synthesis of 2-substituted 6-azaindoles from 3-amino-4-picoline and carboxylic esters

Article abstract of DOI:10.1021/jo0506480

Dilithiation of 3-amino-4-picoline (1) was achieved with sec-BuLi at room temperature. Condensation of the resulting dianion (2) with carboxylic esters afforded a wide range of 2-substituted 6-azaindoles in good yields.

Full text of DOI:10.1021/jo0506480

A Novel One-Step Synthesis of
2-Substituted 6-Azaindoles from
3-Amino-4-picoline and Carboxylic Esters
FIGURE 1. Retrosynthetic analysis.
Jinhua J. Song,* Zhulin Tan, Fabrice Gallou,
Jinghua Xu, Nathan K. Yee, and Chris H. Senanayake
dine derivatives also proved useful for the synthesis of
substituted azaindoles.5 Hands et al. have developed a
convenient azaindole synthesis by reacting Weinreb
amides with the dianion of 3-tert-butoxycarbonylamino-
4-picoline or 4-tert-butoxycarbonylamino-3-picoline, fol-
lowed by Boc deprotection/cyclization.6 For example,
2-phenyl-6-azaindole was synthesized in two steps in 50%
overall yield from 3-tert-butoxycarbonylamino-4-picoline,
whose synthesis required two additional steps from
3-aminopyridine6 or one additional step from 3-amino-
4-picoline. Certain substituted azaindoles were obtained
via photostimulated SRN1 reaction between ketone eno-
lates and N-protected 2-amino-3-iodo-, 3-amino-4-iodo-,
or 4-amino-3-iodopyridines followed by acidic deprotec-
tion and cyclization.7 In a more recent report, 2-arylaza-
indoles were prepared in multiple steps from substituted
pyridines such as 3-nitro-4-[(E)-2-phenylethenyl]pyridine
via a series of reduction-oxidation reactions.8 The above
and other reported processes9 often require multiple-step
synthesis and suffer from limited generality and/or
unsatisfactory overall yields. Therefore, it is highly
desirable to investigate new strategies for azaindole
synthesis.
During the course of our search for a general and
practical method to prepare 2-substituted 6-azaindoles,
we considered the possibility of utilizing the commercially
available and inexpensive 3-amino-4-picoline (1)10 as a
direct building block, as indicated in the retrosynthetic
analysis in Figure 1. Our proposed reaction sequence
would involve the initial creation of the C-C bond
followed by cyclization and dehydration to give the
azaindole derivatives. We believe that this disconnection
represents one of the most efficient strategies for 6-aza-
indole formation since it does not necessitate the use of
protecting groups or any oxidation state adjustment. In
this paper, we wish to report a novel one-step synthesis
of 2-substituted 6-azaindoles via condensation of car-
boxylic esters with the dianion of 3-amino-4-picoline
(Figure 2).
Department of Chemical Development, Boehringer Ingelheim
Pharmaceuticals, Inc., 900 Old Ridgebury Road, P.O. Box
368, Ridgefield, Connecticut 06877-0368
jsong@rdg.boehringer-ingelheim.com
Received April 2, 2005
Dilithiation of 3-amino-4-picoline (1) was achieved with sec-
BuLi at room temperature. Condensation of the resulting
dianion (2) with carboxylic esters afforded a wide range of
2-substituted 6-azaindoles in good yields.
Azaindoles constitute essential subunits in many phar-
maceutically important drug substances.1 In contrast to
a vast array of methods for indole synthesis,2 there are
a limited number of methodologies available for azaindole
formation.3 The often employed method involves a So-
nogashira coupling of a terminal alkyne with 4-tert-
butoxycarbonylamino-3-iodopyridine followed by depro-
tection/cyclization in situ or in a separate step.4 Palladium-
catalyzed heteroannulation of internal alkynes with
2-amino-3-iodo-, 3-amino-4-iodo-, or 4-amino-3-iodopyri-
(1) (a) Maignan, S.; Guilloteau, J.-P.; Choi-Sledeki, Y. M.; Becker,
M. R.; Ewing, W. R.; Pauls, H. W.; Spada, A. P.; Mikol, V. J. Med.
Chem. 2003, 46, 685. (b) Choi-Sledeski, Y. M.; Kearney, R.; Poli, G.;
Pauls, H.; Gardner, C.; Gong, Y.; Becker, M.; Davis, R.; Spada, A.;
Liang, G.; Chu, V.; Brown, K.; Collussi, D.; Leadley, R., Jr.; Rebello,
S.; Moxey, P.; Morgan, S.; Bentley, R.; Kasiewski, C.; Maignan, S.;
Guilloteau, J.-P.; Mikol, V. J. Med. Chem. 2003, 46, 681. (c) Marminon,
C.; Pierre, A.; Pfeiffer, B.; Perez, V. S.; Joubert, A.; Bailly, C.; Renard,
P.; Hickman, J.; Prudhomme, M. J. Med. Chem. 2003, 46, 609. (d) Kuo,
G.-H.; Prouty, C.; DeAngelis, A.; Shen, L.; O’Neil, D. J.; Shah, C.;
Connolly, P. J.; Murray, W. V.; Conway, B. R.; Cheung, P.; Westover,
L.; Xu, J. Z.; Look, R. A.; Demarest, K. T.; Emanuel, S.; Middleton, S.
A.; Jolloffe, L. J. Med. Chem. 2003, 46, 4021. (e) Kulagowski, J. J.;
Leeson, P. D. US patent, 5563152, 1991. (f) DiNinno, F. P.; Guthikonda,
R. N.; Meurer, L. C. US patent, 5532261, 1994. (g) Hunsch, W.;
Angerbauer, R.; Fey, P.; Bisschoff, H.; Bender, J.; Schmidt, D. US
patent, 5120782, 1991. (h) Patchett, A. A.; Mantlo, N. B.; Greenlee,
W. J. US patent, 5124335, 1991. (i) Scherlock, M. H.; Tom, W. C. US
patent, 5023265, 1990. (j) Anderson, P. L. US patent, 4751235, 1986.
(k) Fisher, M. H.; Schwartzkopf, G., Jr.; Hoff, D. R. J. Med. Chem.
1972, 15, 1168.
(2) (a) Sunberg, R. J. The Chemistry of Indoles; Academic Press:
New York, 1970. (b) Pindur, U.; Adam, R. J. Heterocycl. Chem. 1988,
25, 1.
(3) (a) Greenhill, J. V. In Comprehensive Heterocyclic Chemistry;
Kartritzky, A. R., Rees, C. W., Bird, C. W., Cheeseman, G. W. H., Eds.;
Pergamon: Oxford, UK, 1984; Vol. 4, p 497. (b) Yakhontov, L. N.;
Prokopov, A. A. Russ. Chem. Rev. 1980, 49, 428. (c) Yakhontov, L. N.
Russ. Chem. Rev. 1968, 37, 551. (d) Wilette, R. E. Adv. Heterocycl.
Chem. 1968, 9, 27.
(4) Xu, L.; Lewis, I. R.; Davidsen, S. K.; Summers, J. B. Tetrahedron
Lett. 1998, 39, 5159.
(5) (a) Ujjainwalla, F.; Walsh, T. F. Tetrahedron Lett. 2001, 42, 6441.
(b) Ujjainwalla, F.; Warner, D. Tetrahedron Lett. 1998, 39, 5355. (c)
Park, S. S.; Choi, J.-K.; Yum, E. K.; Ha, D.-C. Tetrahedron Lett. 1998,
39, 627.
(6) Hands, D.; Bishop, B.; Cameron, M.; Edwards, J. S.; Cottrell, I.
F.; Wright, S. H. B. Synthesis 1996, 877.
(7) Estel, L.; Marsais, F.; Queguiner, G. J. Org. Chem. 1988, 53,
2740.
(8) Kuzmich, D.; Mulrooney, C. Synthesis 2003, 11, 1671.
(9) Other methods: (a) Turner, J. A. J. Org. Chem. 1983, 48, 3401.
(b) Reference 1k. (c) Cadgan, J. I. G.; Cameron-Wood, M.; Mackie, R.
K.; Searle, R. J. G. J. Chem. Soc. 1965, 4831. (d) Davis, M. L.;
Wakefield, B. J.; Wardell, J. A. Tetrahedron 1992, 48, 939. (e) Kumar,
V.; Dority, J. A.; Bacon, E. R.; Singh, B.; Lesher, G. Y. J. Org. Chem.
1992, 57, 6995. (f) Zhang, Z.; Yang, Z.; Meanwell, N. A.; Kadow, J. F.;
Wang, T. J. Org. Chem. 2002, 67, 2345.
(10) 3-Amino-4-picoline is commercially available in bulk from
multiple sources.
10.1021/jo0506480 CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/01/2005
6512
J. Org. Chem. 2005, 70, 6512-6514

literature where the 2-phenyl-6-azaindole was synthe-
sized in only 50-70% yield over multiple synthetic
steps.6,8
Presumably a cascade of transformations took place
in this one-step construction of 2-phenyl-6-azaindole
(Figure 2). Addition of the C-anion to the carbonyl group
of the ester furnished the tetrahedral intermediate that
fragmented into the ketone, which in turn was trapped
immediately by the neighboring N-Li. Dehydration
completed the azaindole formation. It is noteworthy that
no secondary addition of the dianion to the intermediate
ketone was observed. Normally this is an unavoidable
side reaction when organolithium reagents are added to
esters.12 It is reasonable to speculate that the facile
cyclization of the N-Li into the putative ketone pre-
vented the secondary addition side reaction. Therefore,
the use of Weinreb amides is not required for the present
methodology.6
The scope of this new method was explored by using a
wide range of carboxylic esters (Table 1). It can be seen
that simple aromatic esters (entries 1 to 4) gave azaindole
products in very good yields. An aryl bromide is compat-
ible with the reaction conditions and no Br-Li exchange
was observed. Esters derived from furan and thiophene
carboxylic acids also condensed smoothly with the di-
anion to afford the corresponding azaindoles. In reactions
with enolizable esters (methyl acetate and methyl â-phen-
ylpropionate), the dianion acted as a typical nucleophile,
not a base, to furnish the desired 2-alkyl-6-azaindoles.
The strong nucleophilicity of the dianion was also evident
in its successful reactions with sterically demanding
substrates such as methyl pivalate and ethyl admantane-
1-carboxylate, although warming up to -30 °C was
required for a complete conversion in these cases.
Thioester (entry 11) was found to be suitable for this
transformation. Finally, we have shown that the con-
densation of the dianion with a lactone substrate was also
successful (entry 12).
In summary, we have developed conditions for direct
dilithiation of unprotected 3-amino-4-picoline. Condensa-
tion of the resulting dianion with various carboxylic
esters afforded 2-substituted 6-azaindoles in good yields
in a single step. It is noteworthy that no protecting group
or oxidation state adjustment is necessary in this one-step
synthesis. Considering its simplicity, demonstrated gen-
erality, and the ready availability of the starting materi-
als, we believe that this methodology will find wide
applications in the synthesis of 6-azaindole-containing
compounds.
FIGURE 2. Proposed reaction pathway.
Our studies started with the dilithiation11 of 3-amino-
4-picoline. Hands et al. have reported that the dilithiation
of 3-tert-butoxycarbonylamino-4-picoline could be readily
achieved by treatment with n-BuLi at -20 °C for 30 min.6
However, without an anion-stabilizing protecting group
such as acyl or Boc on the 3-amino group,6 dilithiation
of the naked 3-amino-4-picoline was challenging. Treat-
ment of 3-amino-4-picoline with 3 equiv of n-BuLi at room
temperature led to only 25% dilithiation as determined
by a deuterium-labeling experiment. The use of t-BuLi
at 0 °C increased the dilithiation to 45%. However,
significant side reaction between t-BuLi and the pyridine
ring occurred at this temperature. When 3-amino-4-
picoline was treated with 3 equiv of s-BuLi in THF at
room temperature for 3 h, an orange-colored slurry was
formed. Upon quenching with MeOH-d4, 70% deuterium
incorporation was detected at the methyl position. Other
solvents such as hexane, DME, and ether were found to
be less effective.
Ethyl benzoate was first selected for investigation of
the reaction with the dianion of 3-amino-4-picoline
(Figure 2). Under the initial reaction conditions (6 equiv
of ethyl benzoate, -78 °C to room temperature, 15 h),
the desired 2-phenyl-6-azaindole was formed along with
a large amount of amide (ca. 25%). Apparently, the amide
byproduct was derived from nitrogen attack on the ester.
To increase the C/N selectivity of the condensation
reaction, we carefully studied reaction temperature,
reaction time, and stoichiometry. It was found that the
reaction was very rapid at -78 °C. If used as the limiting
reagent, ethyl benzoate was completely consumed within
30 min at this temperature. We have further determined
that excellent C/N selectivity could be achieved as long
as the reaction mixture is maintained at <-30 °C. With
use of the optimized conditions, 2-phenyl-6-azaindole was
formed in 91% HPLC assay yield (88% isolated yield)
with minimal formation of the amide byproduct (<1%).
This result compares favorably with those reported in the
Experimental Section
General procedures: All reactions were performed in oven-
dried glassware under nitrogen with magnetic stirring. All
commercial reagents were used as received. Flash chromatog-
raphy was performed with 230-400 mesh silica gel.
Representative procedure: 3-Amino-4-picoline (1.32 g,
12.0 mmol) was dissolved in anhydrous THF (44 mL) in a dry
flask under nitrogen. The solution was cooled to -78 °C and a
solution of s-BuLi (1.4 M in cyclohexane, 26 mL, 36.0 mmol) was
added in 10 min. The solution was warmed to room temperature,
stirred at that temperature for 3 h, and cooled to -78 °C. Ester
(11) For reviews on lateral lithiation reactions, see: (a) Clark, R.
D.; Johangir, A. Organic Reactions; John Wiley & Sons: New York,
1995; Vol. 47, p 1. (b) Snieckus, V. Chem. Rev. 1990, 90, 879. (c) Beak,
P.; Snieckus, V. Acc. Chem. Res. 1982, 15, 306.
(12) Larock, R. C. Comprehensive Organic Transformations, 2nd ed.;
Wiley-VCH, New York, 1999; pp 1191-1192.
J. Org. Chem, Vol. 70, No. 16, 2005 6513

TABLE 1. 6-Azaindole Synthesis via Dianion of
3-Amino-4-picoline
solution was warmed to room temperature and stirred for 1 h.
A half-saturated NH4Cl aqueous solution (30 mL) was added
and the organic residue was extracted with MTBE (3 × 50 mL).
The combined organic extract was dried over MgSO4 and filtered.
Solvents were evaporated under vacuum. The crude product
mixture was purified by silica gel chromatography to give
product in yields specified in Table 1.
For detailed experimental procedures and copies of 1H NMR
spectra for all isolated compounds 3 to 14, see the Supporting
Information.
Characterization data for 2-thiophen-3-yl-1H-pyrrolo-
[2,3-c]pyridine (8): mp 247-249 °C. IR (cm-1) 3230, 3212, 1266,
730. 1H NMR (DMSO-d6, 400 MHz) δ 11.95 (s, 1H), 8.72 (s, 1H),
8.08 (d, J ) 5.32 Hz, 1H), 8.04 (m, 1H), 7.70 (m, 2H), 7.48 (d, J
) 5.32 Hz, 1H), 6.85 (d, J ) 1.00 Hz, 1H). 13C NMR (DMSO-d6,
125 MHz) δ 136.2, 135.5, 131.8, 131.2, 130.8, 125.5, 124.2, 120.0,
112.3, 95.8. HRMS calcd for the [M + 1]+ 201.0480, found
201.0491.
Characterization data for 2-phenethyl-1H-pyrrolo[2,3-
c]pyridine (10): mp 172-173 °C. IR (cm-1) 3451, 3227, 1459,
1
1266, 822, 741, 699. H NMR (DMSO-d6, 400 MHz) δ 11.50 (s,
1H), 8.62 (s, 1H), 8.01 (d, J ) 5.28 Hz, 1H), 7.38 (d, J ) 5.32
Hz, 1H), 7.27 (m, 4H), 7.19 (m, 1H), 6.24 (s, 1H), 3.05 (m, 4H).
13C NMR (DMSO-d6, 125 MHz) δ 144.2, 141.4, 138.1, 133.6,
133.5, 128.7, 128.6, 126.3, 114.2, 98.5, 98.4, 34.8, 29.8. HRMS
calcd for the [M + 1]+ 223.1229, found 223.1238.
Characterization data for 2-adamantan-1-yl-1H-pyr-
rolo[2,3-c]pyridine (12): mp 216-219 °C. IR (cm-1) 3462, 3234,
3053, 2987, 2910, 2852, 1571, 1466, 1266, 822, 733. 1H NMR
(DMSO-d6, 400 MHz) δ 11.31 (s, 1H), 8.57 (s, 1H), 7.96 (d, J )
5.28 Hz, 1H), 7.34 (d, J ) 5.32 Hz, 1H), 6.13 (d, J ) 1.52 Hz,
1H), 2.03 (s, 3H), 1.94 (s, 6H), 1.72 (m, 6H). 13C NMR (DMSO-
d6, 125 MHz) δ 153.9, 153.8, 138.0, 133.8, 133.7, 133.6, 132.5,
114.4, 95.1, 95.0, 42.0, 36.7, 36.6, 34.1, 28.2. HRMS calcd for
the [M + 1]+ 253.1699, found 253.1711.
Characterization data for 2-furan-2-yl-1H-pyrrolo[2,3-
c]pyridine (13): mp 214-216 °C. IR (cm-1) 3235, 3204, 1610,
1
1567, 1532, 1266, 1015. H NMR (DMSO-d6, 400 MHz) δ 12.04
(s, 1H), 8.70 (s, 1H), 8.06 (d, J ) 5.48 Hz, 1H), 7.83 (d, J ) 1.76
Hz, 1H), 7.47 (dd, J ) 0.96, 4.96 Hz, 1H), 7.02 (d, J ) 3.32 Hz,
1H), 6.74 (s, 1H), 6.66 (dd, J ) 1.76, 3.32 Hz, 1H). 13C NMR
(DMSO-d6, 100 MHz) δ 146.5, 144.0, 137.3, 133.4, 133.2, 133.1,
133.0, 114.6, 112.2, 108.5, 96.9. HRMS calcd for the [M + 1]+
185.0709, found 185.0718.
Characterization data for 1-naphthalen-2-yl-3-(1H-pyr-
rolo[2,3-c]pyridin-2-yl)propan-1-ol (14): mp 73-76 °C. IR
(cm-1) 3235, 1266. 1H NMR (DMSO-d6, 400 MHz) δ 11.65 (s,
1H), 8.64 (s, 1H), 8.03 (d, J ) 5.56 Hz, 1H), 7.90 (m, 4H), 7.55
(d, J ) 8.56 Hz, 1H), 7.51 (m, 3H), 6.33 (s, 1H), 5.53 (d, J ) 4.28
Hz, 1H), 4.78 (m, 1H), 2.89 (m, 2H), 2.14 (m, 2H) .13C NMR
(DMSO-d6, 125 MHz) δ 143.7, 136.5, 133.2, 132.6, 132.3, 128.1,
128.0, 127.8, 126.4, 125.9, 124.9, 124.4, 114.4, 98.7, 72.0, 71.9,
38.4, 24.6, 24.3. HRMS calcd for the [M + 1]+ 303.1491, found
303.1499.
Supporting Information Available: Detailed experi-
mental procedures and copies of 1H NMR spectra for com-
pounds 3 to 14 as well as 1H NMR data for known compounds
3-7, 9, and 11. This material is available free of charge via
the Internet at http://pubs.acs.org.
a Isolated yield (HPLC assay yields in parentheses).
(4.8 mmol) was added and the resulting mixture was stirred at
-78 °C for 1 h. Methanol (20 mL) was added in 5 min and the
JO0506480
6514 J. Org. Chem., Vol. 70, No. 16, 2005