Microwave-assisted flexible synthesis of 7-azaindoles

Article abstract of DOI:10.1021/jo060512h

7-Azaindoles are versatile building blocks, especially in medicinal chemistry, where they serve as bioisosteres of indoles or purines. Herein, we are presenting a robust and flexible synthesis of 1,3- and 1,3,6-substituted 7-azaindoles starting from nicot

Full text of DOI:10.1021/jo060512h

Microwave-Assisted Flexible Synthesis of 7-Azaindoles
Hartmut Schirok
Bayer HealthCare AG, Pharma Research, D-42096 Wuppertal, Germany
hartmut.schirok@bayerhealthcare.com
ReceiVed March 8, 2006
7-Azaindoles are versatile building blocks, especially in medicinal chemistry, where they serve as
bioisosteres of indoles or purines. Herein, we are presenting a robust and flexible synthesis of 1,3- and
1,3,6-substituted 7-azaindoles starting from nicotinic acid derivatives or 2,6-dichloropyridine, respectively.
Microwave heating dramatically accelerates the penultimate reaction step, an epoxide-opening-cyclization-
dehydration sequence. The functional group compatibility of the reaction is examined as well as the
application of the products in further functionalizations.
Introduction
known as efficient fluorescent chromophores in the UV/blue
region. They are able to bind to metal ions, thus providing the
potential to act as building blocks in supramolecular materials
for organic electroluminescent devices.11 However, the main
interest in the synthesis of 7-azaindoles has arisen in numerous
recent pharmacological programs in diverse therapeutic areas,
wherein they serve as bioisosteres of indole or purine ring
systems. The 7-azaindole scaffold was incorporated in antago-
nists of a variety of protein kinases,12 in antihistamines13 and
-dopamines,14 in analogues of melatonin,15 staurosporin,16 and
rebeccamycin,17 in antagonists of the corticotropin18 and the
gonadotropin19 releasing hormone, and in PPAR agonists.20
In nature, 7-azaindoles (1H-pyrrolo[2,3-b]pyridines) appear
only as submoieties in a very small number of alkaloids. To
these rare examples belong neocryptolepine1 (cryptotackieine2)
from the extracts of the West African plant Cryptolepis
sanguinolenta, the grossularines isolated from the tunicates
Dendrodoa grossularia3 and Polycarpa aurata,4 and mescen-
gricin from Streptomyces griseoflaVus,5 all containing an
R-carboline skeleton, as well as the variolins from the antarctic
sponge Kirkpatrickia Varialosa.6 Because of their biological
activity,7 these alkaloids were the objective of several synthetic
studies.8-10 In the field of material science, 7-azaindoles are
(8) Grossularines: (a) Achab, S.; Guyot, M.; Potier, P. Tetrahedron Lett.
1993, 34, 2127-2130. (b) Molina, P.; Fresneda, P. M.; Sanz, M. A.
Tetrahedron Lett. 1997, 38, 6909-6912. (c) Papamicae¨l, C.; Dupas, G.;
Que´guiner, G.; Bourguignon, J. Heterocycles 1998, 47, 991-1004. (d)
Molina, P.; Fresneda, P. M.; Sanz, M. A.; Foces-Foces, C.; Ramirez de
Arellano, M. C. Tetrahedron 1998, 54, 9623-9638. (e) Miyake, F. Y.;
Yakushijin, K.; Horne, D. A. Angew. Chem. 2005, 117, 3344-3346; Angew.
Chem., Int. Ed. 2005, 44, 3280-3282.
(9) Cryptotackieine: (a) Alajar´ın, M.; Molina, P.; Vidal, A. J. Nat. Prod.
1997, 60, 747-748. (b) Sundaram, G. S. M.; Venkatesh, C.; Syam Kumar,
U. K.; Ila, H.; Junjappa, H. J. Org. Chem. 2004, 69, 5760-5762. (c) Chen,
Y.-L.; Hung, H.-M.; Lu, C.-M.; Li, K.-C.; Tzeng, C.-C. Bioorg. Med. Chem.
2004, 12, 6539-6546.
(10) Variolins: (a) Anderson, R. J.; Morris, J. C. Tetrahedron Lett. 2001,
42, 8697-8699. (b) Molina, P.; Fresneda, P. M.; Delgado, S. J. Org. Chem.
2003, 68, 489-499. (c) Ahaidar, A.; Ferna´ndez, D.; Danelo´n, G.; Cuevas,
C.; Manzanares, I.; Albericio, F.; Joule, J. A.; AÄ lvarez, M. J. Org. Chem.
2003, 68, 10020-10029. (d) Mendiola, J.; Baeza, A.; Alvarez-Builla, J.;
Vaquero, J. J. J. Org. Chem. 2004, 69, 4974-4983. (e) Anderson, R. J.;
Hill, J. B.; Morris, J. C. J. Org. Chem. 2005, 70, 6204-6212. (f) Karpov,
A. S.; Merkul, E.; Rominger, F.; Mu¨ller, T. J. J. Angew. Chem. 2005, 117,
7112-7117; Angew. Chem., Int. Ed. 2005, 42, 6947-6951. (g) Fresneda,
P. M.; Delgado, S.; Francesch, A.; Manzanares, I.; Cuevas, C.; Molina, P.
J. Med. Chem. 2006, 49, 1217-1221.
(1) Cimanga, K.; De Bruyne, T.; Pieters, L.; Claeys, M.; Vlietinck, A.
Tetrahedron Lett. 1996, 37, 1703-1706.
(2) Sharaf, M. H. M.; Schiff, P. L., Jr.; Tackie, A. N.; Phoebe, C. H.,
Jr.; Martin, G. E. J. Heterocycl. Chem. 1996, 33, 239-243.
(3) (a) Moquin, C.; Guyot, M. Tetrahedron Lett. 1984, 5047-5048;
structure revised in (b) Moquin-Pattey, C.; Guyot, M. Tetrahedron 1989,
45, 3445-3450.
(4) Abas, S. A.; Hossain, M. B.; van der Helm, D.; Schmitz, F. J.; Laney,
M.; Cabuslay, R.; Schatzman, R. C. J. Org. Chem. 1996, 61, 2709-2712.
(5) Kim, J.-S.; Shin-ya, K.; Furihata, K.; Hayakawa, Y.; Seto, H.
Tetrahedron Lett. 1997, 38, 3431-3434.
(6) (a) Perry, N. B.; Ettouati, L.; Litaudon, M.; Blunt, J. W.; Munro, M.
H. G.; Parkin, S.; Hope, H. Tetrahedron 1994, 50, 3987-3992. (b) Perry,
N. B.; Ettouati, L.; Litaudon, M.; Blunt, J. W.; Munro, M. H. G.; Jameson,
G. B. Tetrahedron 1994, 50, 3993-4000.
(7) On the cytotoxicity of neocryptolepine and cryptolepine and deriva-
tives thereof, see: (a) Dassonneville, L.; Lansiaux, A.; Wattelet, A.; Wattez,
N.; Mahieu, C.; Van Miert, S.; Pieters, L.; Bailly, C. Eur. J. Pharm. 2000,
409, 9-18. (b) Jonckers, T. H. M.; van Miert, S.; Cimanga, K.; Bailly, C.;
Colson, P.; De Pauw-Gillet, M.-C.; van den Heuvel, H.; Claeys, M.;
Lemie`re, F.; Esmans, E. L.; Rozenski, J.; Quirijnen, L.; Maes, L.; Dommisse,
R.; Lemie`re, G. L. F.; Vlietinck, A.; Pieters, L. J. Med. Chem. 2002, 45,
3497-3508.
10.1021/jo060512h CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/20/2006
5538
J. Org. Chem. 2006, 71, 5538-5545

Synthesis of 7-Azaindoles
During the past decade, several 7-azaindole syntheses were
published, and they were reviewed by Me´rour.21 A recent and
very successful strategy, which has been applied in a couple of
variations, is based on the Pd-catalyzed Sonogashira coupling
of 2-amino-3-halogenopyridines to install the C3-C3a bond
(Figure 1, A), followed by an intramolecular cyclization to form
the five-membered ring (B). The cyclization has been ac-
complished with strong bases,22 iodine,23 copper iodide,24 or
palladium catalysts.25 The latter were also used in one-pot
procedures together with the preceding C-C coupling (C).26
A
synthesis following a similar approach comprises the Pd-
catalyzed annulation of 2-amino-3-iodopyridines with allyl
(11) See, for example: (a) Jia, W.-L.; Bai, D.-R.; McCormick, T.; Liu,
Q.-D.; Motala, M.; Wang, R.-Y.; Seward, C.; Tao, Y.; Wang, S. Chem.
Eur. J. 2004, 10, 994-1006. (b) Tani, K.; Sakurai, H.; Fujii, H.; Hirao, T.
J. Organomet. Chem. 2004, 689, 1665-1674. (c) Jia, W.-L.; Wang, R.-Y.;
Song, D.; Ball, S. J.; McLean, A. B.; Wang, S. Chem. Eur. J. 2005, 11,
832-842. (d) Zhao, S.-B.; Song. D.; Jia, W.-L.; Wang, S. Organometallics
2005, 24, 3290-3296.
(12) See the following examples. p38 MAP kinase inhibitors: (a) Henry,
J. R.; Rupert, K. C.; Dodd, J. H.; Turchi, I. J.; Wadsworth, S. A.; Cavender,
D. E.; Schafer, P. H.; Siekierka, J. J. Bioorg. Med. Chem. Lett. 1998, 8,
3335-3340. (b) Henry, J. R.; Rupert, K. C.; Dodd, J. H.; Turchi, I. J.;
Wadsworth, S. A.; Cavender, D. E.; Fahmy, B.; Olini, G. C.; Davis, J. E.;
Pellegrino-Gensey, J. L.; Schafer, P. H.; Siekierka, J. J. J. Med. Chem.
1998, 41, 4196-4198. (c) Expert Opin. Ther. Pat. 2005, 15, 227-232.
Rho Kinase inhibitors: (d) Ishizaki, T.; Uehata, M.; Tamechika, I.; Keel,
J.; Nonomura, K.; Maekawa, M.; Narumiya, S. Mol. Pharm. 2000, 57, 976-
983. GSK-3â inhibitors: (e) Kuo, G.-H.; Prouty, C.; DeAngelis, A.; Shen,
L.; O’Neill, 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.; Jolliffe, L.; Beavers, M. P.; Chen, X. J.
Med. Chem. 2003, 46, 4021-4031. (f) Zhang, H.-C.; Ye, H.; Conway, B.
R.; Derian, C. K.; Addo, M. F.; Kuo, G.-H.; Hecker, L. R.; Croll, D. R.;
Li, J.; Westover, L.; Xu, J. Z.; Look, R.; Demarest, K. T.; Andrade-Gordon,
P.; Damiano, B. P.; Maryanoff, B. E. Bioorg. Med. Chem. Lett. 2004, 14,
3245-3250.
FIGURE 1. Recent strategies for azaindole syntheses.
SCHEME 1. Retrosynthesis
acetate.27 7-Azaindoles were also obtained by carbolithiation
of vinyl pyridines (D, R′′ ) CH2R′′′).28 Other new developments
rely on the cyclization of (2-aminopyridin-3-yl)methylphospho-
nates (E),29 the intramolecular Hegedus-Mori-Heck reaction
of enamines30 or enaminones (F),31 the Hemetsberger-Knittel
reaction (G),32 or a Sommelet-Hauser type rearrangement of
azasulfonium salts (H, R′′ ) SR′′′).33
In the course of one of our own programs in medicinal
chemistry, we required a robust synthesis of 1,3-disubstituted
7-azaindoles 1, which would allow a general and rapid variation
of the N1-substituent R2 (Scheme 1). Former reports on an
indole synthesis starting from 2-(2-halogenophenyl)oxiranes34
(13) Fonquerna, S.; Miralpeix, M.; Page`s, L.; Puig, C.; Cardu´s, A.; Anto´n,
F.; Vilella, D.; Aparici, M.; Prieto, J.; Warrellow, G.; Beleta, J.; Ryder, H.
Bioorg. Med. Chem. Lett. 2005, 15, 1165-1167.
(14) (a) Kulagowski, J. J.; Broughton, H. B.; Curtis, N. R.; Mawer, I.
M.; Ridgill, M. P.; Baker, R.; Emms, F.; Freedman, S. B.; Marwood, R.;
Patel, S.; Patel, S.; Ragan, C. I.; Leeson, P. D. J. Med. Chem. 1996, 39,
1941-1942. (b) Lo¨ber, S.; Hu¨bner, H.; Gmeiner, P. Bioorg. Med. Chem.
Lett. 1999, 9, 97-102. (c) Oh, S.-J.; Lee, K. C.; Lee, S.-Y.; Ryu, E. K.;
Saji, H.; Choe, Y. S.; Chi, D. Y.; Kim, S. E.; Lee, J.; Kim, B.-T. Bioorg.
Med. Chem. 2004, 12, 5505-5513.
(15) (a) Guillard, J.; Larraya, C.; Viaud-Massuard, M.-C. Heterocycles
2003, 60, 865-877. (b) Larraya, C.; Guillard, J.; Renard, P.; Audinot, V.;
Boutin, J. A.; Delagrange, P.; Bennejean, C.; Viaud-Massuard, M.-C. Eur.
J. Med. Chem. 2004, 39, 515-526.
(16) Routier, S.; Ayerbe, N.; Me´rour, J.-Y.; Coudert, G.; Bailly, C.; Pierre´,
A.; Pfeiffer, B.; Caignard, D.-H.; Renard, P. Tetrahedron 2002, 58, 6621-
6630.
(17) (a) Hugon, B.; Pfeiffer, B.; Renard, P.; Prudhomme, M. Tetrahedron
Lett. 2003, 44, 4607-4611. (b) Messaoudi, S.; Anizon, F.; Pfeiffer, B.;
Golsteyn, R.; Prudhomme, M. Tetrahedron Lett. 2004, 45, 4643-4647. (c)
Messaoudi, S.; Anizon, F.; Pfeiffer, B.; Prudhomme, M. Tetrahedron 2005,
61, 7304-7316.
(18) Hodge, C. N.; Aldrich, P. E.; Wasserman, Z. R.; Fernandez, C. H.;
Nemeth, G. A. J. Med. Chem. 1999, 42, 819-832.
(19) Ujjainwalla, F.; Walsh, T. F. Tetrahedron Lett. 2001, 42, 6441-
6445.
(26) (a) Park, S. S.; Choi, J.-K.; Yum, E. K. Tetrahedron Lett. 1998, 39,
627-630. (b) Ujjainwalla, F.; Warner, D. Tetrahedron Lett. 1998, 39, 5355-
5358. (c) Curtis, N. R.; Kulagowski, J. J.; Leeson, P. D.; Ridgill, M. P.;
Emms, F.; Freedman, S. B.; Patel, S.; Patel, S. Bioorg. Med. Chem. Lett.
1999, 9, 585-588.
(27) Hong, C. S.; Seo, J. Y.; Yum, E. K.; Sung, N.-D. Heterocycles 2004,
63, 631-639.
(28) Cottineau, B.; O’Shea, D. F. Tetrahedron Lett. 2005, 46, 1935-
1938.
(29) Graczyk, P. Process for preparation of 7-azaindoles by cyclization
of 2-amino-3-pyridinylphosphine oxides or 3-pyridinylphosphonic acid
dialkyl esters with base, in particular t-BuOK. Patent WO 2004/013139,
February 12, 2004; Chem. Abstr. DN 140:163708.
(30) (a) Nazare´, M.; Schneider, C.; Lindenschmidt, A.; Will, D. W.
Angew. Chem. 2004, 116, 4626-4629; Angew. Chem., Int. Ed. 2004, 43,
4526-4528. (b) Lachance, N.; April, M.; Joly, M.-A. Synthesis 2005, 2571-
2577.
(31) Blache, Y.; Sinibaldi-Troin, M.-E.; Hichour, M.; Benezech, V.;
Chavignon, O.; Gramain, J.-C.; Teulade, J.-C.; Chapat, J.-P. Tetrahedron
1999, 55, 1959-1970.
(32) (a) Fresneda, P. M.; Molina, P.; Delgado, S.; Bleda, J. A.
Tetrahedron Lett. 2000, 41, 4777-4780. (b) Roy, P. J.; Dufresne, C.;
Lachance, N.; Leclerc, J.-P., Boisvert, M.; Wang, Z.; Leblanc, Y. Synthesis
2005, 2751-2757.
(20) Cai, Z.; Feng, J.; Guo, Y.; Li, P.; Shen, Z.; Chu, F.; Guo, Z. Bioorg.
Med. Chem. 2006, 14, 866-874.
(21) Review: (a) Me´rour, J.-Y.; Joseph, B. Curr. Org. Chem. 2001, 5,
471-506. A former review is given in: (b) Yakhontov, L. N.; Prokopov,
A. A. Russ. Chem. ReV. 1980, 49, 428-444.
(22) Koradin, C.; Dohle, W.; Rodriguez, A. L.; Schmid, B.; Knochel, P.
Tetrahedron 2003, 59, 1571-1587.
(23) Amjad, M.; Knight, D. W. Tetrahedron Lett. 2004, 45, 539-541.
(24) (a) Kumar, V.; Dority, J. A.; Bacon, E. R.; Singh, B.; Lesher, G.
Y. J. Org. Chem. 1992, 57, 6995-6998. (b) Pearson, S. E.; Nandan, S.
Synthesis 2005, 2503-2506.
(25) Cacchi, S.; Fabrizi, G.; Parisi, L. M. J. Comb. Chem. 2005, 7, 510-
512.
J. Org. Chem, Vol. 71, No. 15, 2006 5539

Schirok
SCHEME 3. Synthesis of Oxiranes 6 from
2,6-Dichloropyridine Using DoM Techniquea
inspired us to develop a similar 7-azaindole synthesis based on
the regioselective opening of a 2-chloro-3-oxiran-2-ylpyridine
2 by an amine 3,35 followed by a nucleophilic aromatic
substitution and subsequent dehydration yielding the desired
7-azaindoles 1. This retrosynthetic concept proved to be very
successful, and preliminary results were published recently.36
Herein, we are disclosing the full account of our discovery and
are presenting results obtained by microwave heating applied
to the synthesis.
a Reagents and conditions: (a) LDA, -78 °C; then RCOCH3, -78 °C
f rt. (b) HOAc/H2SO4 (3:1), reflux. (c) m-CPBA, DCM, rt.
Results
2-chloro- and 2-fluoropyridines. However, mixtures of regio-
isomeric products may be observed. For example, in the case
of 2,6-dichloropyridine 6 (Scheme 3), the lithiation occurs in
the 4-position when it is done under kinetic control, whereas
equilibrating conditions lead to the thermodynamically more
stable 3-derivative.43
In our hands, after lithiation of 2,6-dichloropyridine and
subsequent treatment with acetone, acetophenone, and trifluo-
roacetone, we obtained the corresponding tertiary alcohols 7a-
c, which as a result of their higher polarity could be separated
very easily by column chromatography from unconsumed
starting material, in yields of 70-85% (Scheme 3). The
undesired regioisomer was detected as a minor component in
some experiments, but separation was dispensable, since the
corresponding consecutive epoxide is unproductive in the ring-
forming step.
Synthesis of Epoxides 2. Our retrosynthetic concept required
effective syntheses of oxiranes 2. Their provenance mainly
depended on the accessibility of pyridines with a suitable
substitution pattern. We applied both the epoxidation of styrenes
4, as well as the Corey-Chaykovsky epoxide formation37 from
ketones 5 (Scheme 2).
SCHEME 2. Retrosynthesis of Epoxides 2
The elimination of the tertiary alcohols 7 to R-substituted
styrenes 4 was achieved in a 3:1 mixture of acetic and sulfuric
acid at reflux temperature for 30 min, smoothly producing the
elimination products in 85% up to quantitative yield. After basic
workup, the crude products needed no further purification and
were oxidized in high yields with m-CPBA to the epoxides 2,
which were isolated in high purity and used without purification.
The elimination to the styrene failed with the trifluoromethyl
analogue 7c. In this case the unaffected alcohol was re-isolated
even after heating it up to 120 °C in concentrated sulfuric acid
for 14 h. Other reagents such as thionyl chloride, thionyl
chloride/pyridine,44 or Burgess’ reagent failed as well. Since
we discovered a reliable alternative access to 3-trifluoromethyl-
7-azaindole,45 we did not perform further experiments with 7c.
The synthesis of the monochloro derivative 2d started from
2-chloro nicotinic acid chloride 8. The unoptimized iron-
catalyzed reaction46 with isobutylmagnesiumbromide afforded
the ketone 5b in 60% yield. Ketone 5b as well as the commercial
compound 5a were subjected to Corey-Chaykovsky epoxide
formation37 using trimethylsulfoniumiodide in THF and KOtBu
as base to afford the desired oxiranes 2c and 2d in high yields.
Azaindole Synthesis. The pivotal transformation of the
sequence leading to the 7-azaindole bicyclus consists of the
The ortho lithiation of fluoro- and chloroarenes based on the
acidifying effect of the halogen is a powerful method of
introducing functional groups to an aromatic nucleus,38 known
as directed ortho metalation (DoM), and we recently applied
this method in one of our drug discovery programs.39 As shown
in thorough investigations done mainly by Que´guiner40 and
Schlosser,41 lithium diisopropylamide42 promotes a hydrogen/
metal exchange at the 3-position adjacent to the halogen of
(33) Debenham, S. D.; Chan, A.; Liu, K.; Price, K.; Wood, H. B.
Tetrahedron Lett. 2005, 46, 2283-2285.
(34) (a) Tambute, A. C. R. Hebd. Seances Acad. Sci. Ser. C 1974, 278C,
1239-1242. (b) Fleming, I.; Woolias, M. J. Chem. Soc., Perkin Trans. 1
1979, 827-828. (c) Fleming, I.; Woolias, M. J. Chem. Soc., Perkin Trans.
1 1979, 829-837.
(35) Very recently, the synthesis of 1-substituted 7-azaindoles by reaction
of anilines or amines with 2-chloro-3-(2-methoxyvinyl)pyridines has been
described: Dyck, B.; Grigoriadis, D. E.; Gross, R. S.; Guo, Z.; Haddach,
M.; Marinkovic, D.; McCarthy, J. R.; Moorani, M.; Regan, C. F.;
Saunders: J.; Schwaebe, M. K.; Szabo, T.; Williams, J. P.; Zhang, X.;
Bozigian, H.; Chen, T. K. J. Med. Chem. 2005, 48, 4100-4110. Also similar
to our approach, the reaction of 2-chloro-3-(1,2-dibromoethyl)quinoline with
p-aminobenzenesulphonamide in the synthesis of R-carbolines has been
reported: Murugesan, M.; Ramasamy, K.; Shanmugam, P. Z. Naturforsch.
B 1980, 35, 746-748. For the conversion of 2,4,6-trichloro-3-(2-chloroethyl)
pyridine to 5- and 7-azaindoles, see: Yakhontov, L. N.; Uritskaya, M. Y.;
Rubtsov, M. V. Chem. Heterocycl. Compd. Engl. Transl. 1965, 625-630.
(36) Schirok, H. Synlett 2005, 1255-1258.
(37) (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1962, 84, 3782-
3783. (b) Ciaccio, J. A.; Drahus, A. L.; Meis, R. M.; Tingle, C. T.; Smrtka,
M.; Geneste, R. Synth. Commun. 2003, 33, 2135-2143 and references
therein.
(38) (a) Marsais, F.; Que´guiner, G. Tetrahedron 1983, 39, 2009-2021.
(b) Sniekus, V. Chem. ReV. 1990, 90, 879-900. (c) Mongin, F.; Que´guiner,
G. Tetrahedron 2001, 57, 4059-4090. (d) Clayden, J. Organolithiums:
SelectiVity for Synthesis; Pergamon: Oxford, 2002.
(39) Alonso-Alija, C.; Michels, M.; Peilsto¨cker, K.; Schirok, H. Tetra-
hedron Lett. 2004, 45, 95-98.
(40) (a) Gu¨ngo¨r, T.; Marsais, F.; Que´guiner, G. J. Organomet. Chem.
1981, 215, 139-150. (b) Marsais, F.; Pineau, P.; Nivolliers, F.; Mallet,
M.; Turck, A.; Godard, A.; Que´guiner, G. J. Org. Chem. 1992, 57, 565-
573. (c) Rocca, P.; Marsais, F.; Godard, A.; Que´guiner, G. Tetrahedron
1993, 49, 49-64. (d) Weymeels, E.; Awad, H.; Bischoff, L.; Mongin, F.;
Tre´court, F.; Que´guiner, G.; Marsais, F. Tetrahedron 2005, 61, 3245-3249.
(41) (a) Schlosser, M.; Rausis, T. Eur. J. Org. Chem. 2004, 1018-1024.
(b) Schlosser, M.; Rausis, T.; Bobbio, C. Org. Lett. 2005, 7, 127-129. (c)
Bobbio, C.; Schlosser, M. J. Org. Chem. 2005, 70, 3039-3045.
(42) For a recent report on the deprotonation with lithium magnesates
see: Awad, H.; Mongin, F.; Tre´court, F.; Que´guiner, G.; Marsais, F.
Tetrahedron Lett. 2004, 45, 7873-7877.
(43) (a) Radinov, R.; Chanev, C.; Haimova, M. J. Org. Chem. 1991, 56,
4793-4796. (b) Mongin, F.; Tognini, A.; Cottet, F.; Schlosser, M.
Tetrahedron Lett. 1998, 39, 1749-1752. (c) Kelly, T. P.; Rodgers, T. R.;
Wright, C. J. Labelled Compd. Radiopharm. 2001, 44, 451-457. (d) Marzi,
E.; Bigi, A.; Schlosser, M. Eur. J. Org. Chem. 2001, 1371-1376.
(44) Rodrigues, I.; Bonnet-Delpon, D.; Be´gue´, J.-P. J. Org. Chem. 2001,
66, 2098-2103.
(45) Publication in preparation.
(46) Scheiper, B.; Bonnekessel, M.; Krause, H.; Fu¨rstner, A. J. Org.
Chem. 2004, 69, 3943-4349.
5540 J. Org. Chem., Vol. 71, No. 15, 2006

Synthesis of 7-Azaindoles
TABLE 1. Comparison of Conventional and Microwave Heating
SCHEME 4. Synthesis of Oxiranes 2 from Nicotinic Acid
Derivativesa
a Reagents and conditions: (a) Fe(acac)3 (0.03 equiv), iBuMgCl, THF,
-78 °C. (b) Me3S+I-, KOtBu, THF, 0 °C f rt.
SCHEME 5. Proposed Mechanism for 7-Azindole
Formation
reaction of epoxides 2 with primary amines. In preceding
experiments with 3-(2-methyloxiran-2-yl)pyridine and p-meth-
oxybenzylamine, 1-butanol was found to be an appropriate
solvent for the initiating epoxide opening and was preferred
over DMSO and DMF, whereas the results in dioxane, toluene,
pyridine, triethylamine and acetonitrile were clearly inferior.
The azaindole synthesis was therefore performed in 1-butanol
at 100-120 °C. Mechanistically, the first step is the regiose-
lective opening of the oxirane 2 to the amino alcohol 9, and
the second is the intramolecular nucleophilic aromatic substitu-
tion to the 3-hydroxyazaindoline 10 (Scheme 5). With the
reversed order, the high regioselectivity in the aromatic substitu-
tion step of the dichloro derivatives 2a and 2b could not be
explained.
We found that the speed of the reaction mainly depends on
the degree of substitution of the R-carbon next to the amine
nitrogen. Reactions with R-linear amines such as n-butyl, allyl-,
or benzylamine (Table 1, entries 1-5) are completed within
1-10 h. R-Branched amines such as cyclopentylamine reacted
significantly more slowly and required heating overnight (entry
6). Reactions with R-trisubstituted amines such as adamanty-
lamine were heated for several days (entry 7). However, the
yields of the outcoming azaindoles were still very high.
Presumably because of the insufficient nucleophilicity of
anilines, the reaction could not be expanded to obtain 1-arylated
7-azaindoles.
a After the given reaction time the solvent was removed in vacuo, ethanol
and hydrochloric acid were added, and the mixture was stirred overnight at
room temperature to complete the elimination of water.
significant impact on synthetic chemistry. The application of
microwave-assisted technology has proven to be beneficial in
a vast number of reactions examined during the past 2 decades,47
with the greatest benefit provided in the reduction of reaction
times under microwave conditions relative to times using
conventional heating.48 Microwave-assisted opening of epoxides
by amines are well precedented,49 including nucleophilic
aromatic aminations of 2-halopyridines.50 We therefore envis-
aged that the application of this heating technique could result
in a much faster and therefore more practical azaindole
formation, even when less reactive amines are used.
(47) (a) Lidstro¨m, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron
2001, 57, 9225-9283. (b) MicrowaVes in Organic Synthesis; Loupy, A.,
Ed.; Wiley-VCH: Weinheim, 2002. (c) Kappe, C. O. Angew. Chem. 2004,
116, 6408-6443; Angew. Chem., Int. Ed. 2004, 43, 6250-6284. (d) Kappe,
C. O.; Stadler, A. MicrowaVes in Organic and Medicinal Chemistry; Wiley-
VCH: Weinheim, 2005. (e) MicrowaVe-Assisted Organic Synthesis; Lid-
stro¨m, P., Tierney, J. P., Eds.; Blackwell Publishing: Oxford 2005.
(48) Lidstro¨m, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron
2001, 57, 9225-9283.
(49) (a) Alikhani, V.; Beer, D.; Bentley, D.; Bruce, I.; Cuenoud, B. M.,
Fairhurst, R. A.; Gedeck, P.; Haberhuer, S.; Hayden, C.; Janus, D.; Jordan,
L.; Lewis, C.; Smithies, K.; Wissler, E. Bioorg. Med. Chem. Lett. 2004,
14, 4705-4710. (b) Lindsay, K. B.; Pyne, S. G. Tetrahedron Lett. 2004,
60, 4173-4176.
(50) Narayan, S.; Seelhammer, T.; Gawley, R. E. Tetrahedron Lett. 2004,
45, 757-759.
The intermediate tertiary alcohol 10 formed during the process
was labile, and spontaneous dehydratization occurred to a certain
degree. Frequently, acid catalysis was required to drive the
dehydration to completion.
Considering the protracted reaction times required, particu-
larly with sterically more demanding amines, we were intrigued
with the possibility of accelerating the azaindole formation.
Microwave-assisted organic synthesis (MAOS) has had a
J. Org. Chem, Vol. 71, No. 15, 2006 5541

Schirok
TABLE 2. 7-Azaindoles from 2,6-Dichloro-3-oxiranyl-pyridines
a Isolated yields. b The reaction was performed in methanol to prevent transesterification.
5542 J. Org. Chem., Vol. 71, No. 15, 2006

Synthesis of 7-Azaindoles
SCHEME 6. Synthesis of 1jja
TABLE 3. Suzuki-Miyaura Couplings with 6-Chloro-7-azaindoles
a Reagents and conditions: (a) 1-butanol, MW 200 °C, 30 min.
SCHEME 7. Suzuki-Miyaura Coupling with
6-Chloro-7-azaindolesa
a Reagents and conditions: (a) ArB(OH)2 (2.0 equiv), NaHCO3 (3.0
equiv), PdCl2(dppf)×CH2Cl2 (0.05 equiv), DME/H2O (3:1), 115 °C.
The conditions we applied in a focused microwave oven were
similar to the ones we operated with in the conventional
procedure: the oxirane and amine were dissolved in 1-butanol
and heated in a sealed tube, however, to a higher temperature.
The reduction of reaction times was dramatic, both with the
mono- and the dichloropyridines. As expected, the latter proved
to be more reactive, and therefore 150 °C was chosen for the
monochloro derivative and 200 °C for the dichloro derivative.
Reactions with benzylic and linear aliphatic amines that took
several hours by conventional heating were speeded up to 10-
40 min (Table 1, entries 1-5). With cyclopentylamine, the
reaction time was shortened from 16 h by conventional heating
to 30 min, and in the case of adamantylamine from 3 days to
2.5 h. Unexpectedly, no addition of acid was reqired for the
final dehydration of 10. Probing the hypothesis that a simple
thermal effect could be responsible for this phenomenon, test
reactions were heated in sealed tubes to similar temperatures
as in the microwave oven, but with clearly inferior results.
The compatibility with several functional groups was next
examined. Alkenes are well tolerated and offer the possibility
of later functionalization (Table 1, entry 4). Since the reactions
are done in butanol, primary and secondary alcohols (Table 2,
entries 8, 14, 23) are compatible, as well as, to a certain extent,
phenols (entry 9). Other functionalities, such as tertiary amines,
were also tolerated (entry 6). Primary diamines may be used,
and dependent on the stoichiometry of the reagents, the product
with one amino function can be isolated (entry 7). However,
monoprotected diamines offer a selective two-step process for
the same target molecules (entry 25). Nitrogen may also be
introduced as a nitro group (entry 18). If one amino function is
less nucleophilic, e.g., as a result of steric hindrance, the reaction
may also be highly selective (entry 24). For the same reason,
unprotected anilines or indoles are tolerated in the amino
component (entries 26 and 27). Alternatively, with excess
oxirane present, all primary amino functions of a polyamino
component react in good overall yield (Scheme 6). To a certain
degree, carboxylic esters and acids are also compatible with
the transformation (Table 2, entries 10 and 11). 3-Aminopro-
pionitrile decomposed under the reaction conditions. The
sterically encumbered tritylamine did not react at all. Ammonia
itself reacted in the desired fashion; however, byproducts were
found originating from the primary amine formed in the epoxide
opening with ammonia (data not shown).
Suzuki-Miyaura Coupling with 6-Chloro-7-azaindoles.
Halogenated 7-azaindoles are versatile building blocks for
further derivatizations. Recently, we reported on the nucleophilic
substitution of activated 4-chloro- and 4-nitro-7-azaindoles,51
and on the Pd-catalyzed C-O and C-N coupling of 4-iodo-
7-azaindoles.52 With unsubstituted 6-chloro-7-azaindole, the
Suzuki-Miyaura-type cross-coupling with boronic acids has
been reported in medium yields.53 With the N1-substituted
(51) Figueroa-Pe´rez, S.; Bennabi, S.; Schirok, H.; Thutewohl, M.
Tetrahedron Lett. 2006, 47, 2069-2072.
(52) Thutewohl, M.; Schirok, H.; Bennabi, S.; Figueroa-Pe´rez, S.
Synthesis 2006, 629-632.
(53) Allegretti, M.; Arcadi, A.; Marinelli, F.; Nicolini, L. Synlett 2001,
5, 609-612.
J. Org. Chem, Vol. 71, No. 15, 2006 5543

Schirok
obtained after treatment of the crude product with petroleum ether
and suction filtration, as pale tan crystals in 71% yield. H NMR
6-chloro-7-azaindoles 1 and using PdCl2(dppf)×CH2Cl2 as
catalyst in a dimethoxyethan/water mixture and sodium bicar-
bonate as base, we obtained the desired 6-arylated coupling
products in high to almost quantitative yields (Scheme 7, Table
3).
1
(400 MHz, DMSO-d6): δ 1.91 (s, 3H), 6.07 (s, 1H), 7.21-7.32
(m, 5H), 7.65 (d, J ) 8.2 Hz, 1H), 8.42 (d, J ) 8.2 Hz, 1H). 13C
NMR (125 MHz, DMSO-d6): δ 27.4, 73.3, 123.1, 126.1, 126.7,
127.7, 140.3, 141.8, 145.5, 146.8, 147.2. HRMS calcd for C13H11-
Cl2NO + [H+], 268.0291; found, 268.0289. The filtrate contained
an additional 8% of the desired product accompanied by the
symmetric regioisomer, which could be separated by HPLC. 1-(2,6-
Dichloropyridin-4-yl)-1-phenylethanol: 1H NMR (300 MHz,
DMSO-d6): δ 1.86 (s, 3H), 6.22 (s, 1H), 7.22-7.36 (m, 3H), 7.45-
7.50 (m, 2H), 7.54 (s, 2H).
Summary
In conclusion, we have developed an expedient and short
7-azaindole synthesis, based on an epoxide-opening-cyclization-
dehydration mechanism. Several functional groups such as
alcohols, phenols, esters, acids, and nitro groups and less reactive
amino functions including anilines are compatible with the
reaction conditions. Applying microwave heating, the reaction
can be completed within 3 h or less even with slowly reacting
amines. Chlorination at the 6-position allows for derivatization
of this position through the palladium-catalyzed Suzuki-
Miyaura coupling, giving 6-arylated dervatives in almost
quantitative yield. Facile access to the desired epoxides, which
do not require thorough purification, as well as the robustness
of the ring-forming step, make this synthetic route a valuable
synthetic tool and amenable to parallel synthesis.
2-(2,6-Dichloropyridin-3-yl)-1,1,1-trifluoropropan-2-ol (7c).
The title compound was synthesized analogously to 7a from
dichloropyridine (6.00 g, 27.0 mmol) and trifluoroacetone (6.81 g,
60.8 mmol). The crude product was triturated with cyclohexane,
and the product was collected by suction filtration in 73% yield.
1H NMR (300 MHz, DMSO-d6): δ 1.95 (s, 3H), 7.12 (br. s, 1H),
7.66 (d, J ) 8.3 Hz, 1H), 8.32 (d, J ) 8.3 Hz, 1H). 13C NMR (125
MHz, DMSO-d6): δ 21.8, 73.0 (q, 2JC,F ) 29.6 Hz), 123.4, 125.5
1
(q, JC,F ) 287 Hz), 133.1, 143.1, 147.2, 148.6. HRMS calcd for
C8H6Cl2FNO, 258.9779; found, 258.9773.
2,6-Dichloro-3-isopropenylpyridine (4a). The alcohol 7a (4.40
g, 21.4 mmol) was dissolved in 21 mL of acetic acid, and 7.0 mL
of concentrated sulfuric acid was added. The mixture was heated
to reflux for 30 min. It was poured into ice water, basified with
concentrated sodium hydroxide solution, and extracted with dichlo-
romethane. The organic layer was dried over sodium sulfate and
evaporated to yield 3.50 g (84%) of the title compound as a yellow
oil. 1H NMR (300 MHz, DMSO-d6): δ 2.06 (dd, J ) 1.3, 0.9 Hz,
3H), 5.08 (m, 1H), 5.38 (dq, J ) 1.5, 1.3 Hz, 1H), 7.56 (d, J ) 7.9
Hz, 1H), 7.82 (d, J ) 7.9 Hz, 1H). 13C NMR (125 MHz, DMSO-
d6): δ 22.6, 118.7, 123.8, 137.5, 140.6, 142.1, 146.7, 147.5. HRMS
calcd for C8H7Cl2N, 186.9956; found, 186.9956.
Experimental Section
1-(2-Chloropyridin-3-yl)-3-methylbutan-1-one (5b). Iron(III)-
acetylacetonate (30 mg, 0.09 mmol) and 2-chloronicotinoyl chloride
(500 mg, 2.84 mmol) were dissolved in degassed THF (20 mL)
and cooled to -78 °C. A solution of isobutylmagnesium bromide
(2 M in THF, 1.85 mL, 3.69 mmol) was added. After being stirred
for 15 min at -78 °C, the reaction was quenched with saturated
aqueous ammonium chloride solution. The mixture was extracted
three times with tert-butyl methyl ether. The combined organic
layers were dried over sodium sulfate, and the solvent was
evaporated. The residue was purified by preparative HPLC to yield
335 mg (60%) of a yellow oil. 1H NMR (300 MHz, DMSO-d6): δ
0.94 (d, J ) 6.6 Hz, 6H), 2.10 (tsept, J ) 7.0, 6.6 Hz, 1H), 2.86
(d, J ) 7.0 Hz, 2H), 7.56 (dd, J ) 7.6, 4.9 Hz, 1H), 8.12 (dd, J )
7.6, 1.9 Hz, 1H), 8.53 (dd, J ) 4.9, 1.9 Hz, 1H). 13C NMR (125
MHz, DMSO-d6): δ 22.1, 24.1, 50.6, 123.2, 135.2, 138.1, 145.5,
151.2, 201.4. HRMS calcd for C10H12ClNO + [H+], 198.0681;
found, 198.0673.
2,6-Dichloro-3-(1-phenylvinyl)pyridine (4b). Analogously to
1
4a, the title compound was obtained from 7b in 98% yield. H
NMR (300 MHz, DMSO-d6): δ 5.39 (s, 1H), 6.02 (s, 1H), 7.23-
7.28 (m, 2H), 7.30-7.40 (m, 3H), 7.66 (d, J ) 7.9 Hz, 1H), 7.90
(d, J ) 7.9 Hz, 1H). 13C NMR (125 MHz, DMSO-d6): δ 118.6,
124.1, 126.2, 128.5, 128.9, 135.8, 138.1, 143.8, 143.9, 148.2, 148.3.
HRMS calcd for C13H9Cl2N, 249.0112; found, 249.0104.
2,6-Dichloro-3-(2-methyloxiran-2-yl)pyridine (2a). Styrene 4a
(4.10 g, 21.8 mmol) was dissolved in dichloromethane (120 mL),
and m-CPBA (10.7 g, 43.6 mmol) was added in portions. The
mixture was stirred overnight, diluted with dichloromethane and
extracted three times with cold NaOH solution (1 N). The organic
layer was dried over sodium sulfate, and the solvent was evaporated
2-(2,6-Dichloropyridin-3-yl)propan-2-ol (7a). A solution of
diisopropylamine (12.5 mL, 89.2 mmol) in 240 mL of THF was
cooled to -78 °C. n-Butyllithium in hexane (55.8 mL of a 1.6 M
solution, 89.2 mmol) was added, and the mixture was warmed to
0 °C for 30 min. Subsequently, the mixture was cooled to -78 °C
again, and a solution of 2,6-dichloropyridine (12.0 g, 81.1 mmol)
in THF (30 mL) was added. After 2 h at this temperature, acetone
(8.94 mL, 122 mmol) was added, while the internal temperature
rose to -50 °C. The mixture was stirred for 0.5 h at -78 °C and
was then warmed to room temperature. It was poured into a cold
ammonium chloride solution and extracted three times with ethyl
acetate. The combined organic layers were washed with brine and
dried over sodium sulfate. The solvent was removed under reduced
pressure, and the residue was purified by column chromatography
(dichloromethane, then dichloromethane/methanol 25:1) to yield
14.9 g (89%) of the title compound as a yellow oil. The 1H NMR
spectrum revealed a 5% content of the regioisomeric compound,
which was not separated. 1H NMR (400 MHz, DMSO-d6): δ 1.59
(s, 6H), 5.58 (s, 1H), 7.57 (d, J ) 8.3 Hz, 1H), 8.23 (d, J ) 8.3
Hz, 1H). 13C NMR (125 MHz, DMSO-d6): δ 28.3, 70.0, 123.3,
1
to yield the epoxide as yellow oil (3.60 g, 81% yield). H NMR
(300 MHz, DMSO-d6): δ 1.59 (s, 3H), 2.85 (d, J ) 4.9 Hz, 1H),
3.07 (d, J ) 4.9 Hz, 1H), 7.59 (d, J ) 7.9 Hz, 1H), 7.94 (d, J )
7.9 Hz, 1H). 13C NMR (125 MHz, DMSO-d6): δ 21.4, 53.8, 56.1,
123.7, 135.2, 141.0, 147.2, 148.0. HRMS calcd for C8H7Cl2NO,
202.9905; found, 202.9895.
2,6-Dichloro-3-(2-phenyloxiran-2-yl)pyridine (2b). The title
compound was prepared from 4b analogously to 2a in 88% yield.
1H NMR (300 MHz, DMSO-d6): δ 3.36 (d, J ) 4.9 Hz, 1H), 3.48
(d, J ) 4.9 Hz, 1H), 7.17-7.24 (m, 2H), 7.31-7.39 (m, 3H), 7.68
(d, J ) 8.1 Hz, 1H), 8.16 (d, J ) 8.1 Hz, 1H). 13C NMR (125
MHz, DMSO-d6): δ 56.1, 58.9, 123.8, 126.1, 128.2, 128.4, 133.1,
137.2, 142.6, 148.7, 148.8. HRMS calcd for C13H9Cl2NO, 265.0061;
found, 265.0054.
2-Chloro-3-(2-methyloxiran-2-yl)pyridine (2c). Trimethylsul-
foniumiodide (6.82 g, 33.4 mmol) was dissolved in THF (175 mL),
and the solution was cooled to 0 °C. Potassium tert-butylate (3.95
g, 33.4 mmol) was added, and the mixture was stirred for 5 min.
Freshly distilled 3-acetyl-2-chloropyridine (4.00 g, 25.7 mmol) was
added to the suspension, and the reaction was stirred at room
temperature overnight. It was filtrated and washed with brine and
then dried over sodium sulfate, and the solvent was evaporated to
140.3, 142.7, 145.9, 146.4. HRMS calcd for C7H6Cl2NO [M+
CH3], 189.9826; found, 189.9823.
-
1-(2,6-Dichloropyridin-3-yl)-1-phenylethanol (7b). The title
compound was synthesized analogously to 7a from dichloropyridine
(4.00 g, 27.0 mmol) and acetophenone (3.9 g, 32.4 mmol). It was
5544 J. Org. Chem., Vol. 71, No. 15, 2006

Synthesis of 7-Azaindoles
1
yield the title compound (4.06 g, 89% yield) as a yellow oil. H
NMR (300 MHz, DMSO-d6): δ 1.60 (s 3H), 2.84 (d, J ) 4.9 Hz,
1H), 3.07 (d, J ) 4.9 Hz, 1H), 7.46 (dd, J ) 7.4, 4.6 Hz, 1H), 7.90
(dd, J ) 7.4, 1.6 Hz, 1H), 8.39 (dd, J ) 4.6, 1.6 Hz, 1H). 13C
NMR (125 MHz, DMSO-d6): δ 21.7, 53.9, 56.5, 123.3, 135.7,
137.9, 148.2, 149.0. HRMS calcd for C8H8ClNO, 168.0216; found,
168.0216.
J ) 7.6 Hz, 1H), 7.91 (dd, J ) 7.7, 1.5 Hz, 1H), 8.26 (dd, J ) 4.7,
1.5 Hz, 1H), 10.85 (br. s, 1H). 13C NMR (125 MHz, DMSO-d6):
δ 9.42, 25.9, 44.0, 107.3, 110.9, 111.3, 114.6, 118.2, 120.3, 120.9,
122.7, 126.2, 126.6, 127.0, 136.1, 142.1, 147.0. HRMS calcd for
C18H17N3, 275.1422; found, 275.1424.
3-Isobutyl-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine (1ii).
The title compound was synthesized following method B (200 °C,
30 min) in 56% yield. 1H NMR (400 MHz, DMSO-d6): δ 0.88 (d,
J ) 6.5 Hz, 6H), 1.89 (dsept, J ) 6.9, 6.5 Hz, 1H), 2.54 (d, J )
6.9 Hz, 2H), 3.69 (s, 3H), 5.35 (s, 2H), 6.85 (d, J ) 8.6 Hz, 2H),
7.05 (dd, J ) 7.8, 4.7 Hz, 1H), 7.18 (d, J ) 8.6 Hz, 2H), 7.33 (s,
1H), 7.93 (dd, J ) 7.8, 1.5 Hz, 1H), 8.22 (dd, J ) 4.7, 1.5 Hz,
1H). 13C NMR (125 MHz, DMSO-d6): δ 22.4, 28.9, 33.9, 46.3,
55.0, 112.1, 113.9, 115.0, 120.2, 126.4, 127.1, 128.7, 130.6, 142.3,
147.1, 158.5. HRMS calcd for C19H22N2O, 294.1732; found,
294.1731.
2-Chloro-3-(2-isobutyloxiran-2-yl)pyridine (2d). The com-
1
pound was prepared from 5b analogously to 2c in 99% yield. H
NMR (300 MHz, DMSO-d6): δ 0.83 (d, J ) 6.6 Hz, 3H), 0.91 (d,
J ) 6.6 Hz, 3H), 1.33-1.60 (m, 2H), 2.12 (dd, J ) 14.2, 5.3 Hz,
1H), 2.79 (d, J ) 4.9 Hz, 1H), 3.02 (d, J ) 4.9 Hz, 1H), 7.46 (dd,
J ) 7.6, 4.7 Hz, 1H), 7.90 (dd, J ) 7.6, 1.9 Hz, 1H), 8.39 (dd, J
) 4.7, 1.9 Hz, 1H). 13C NMR (125 MHz, DMSO-d6): δ 22.8, 23.2,
24.9, 42.9, 52.5, 58.7, 123.1, 134.6, 138.6, 148.5, 149.1. MS (DCI)
calcd for C11H14ClNO, 211; found, 211.9 [M + H+].
Synthesis of 7-Azaindoles. General Procedure. Method A. The
epoxide and the amine (1-2 equiv) were dissolved in 1-butanol (
mL/mmol epoxide), and the mixture was heated for the given
reaction time to 110 °C (higher temperatures were achieved in
sealed pressure tubes). The solvent was evaporated, the residue was
treated with ethanol (3 mL/mmol epoxide), and concentrated
hydrochloric acid (1 mL) was added. The reaction was stirred
overnight, then diluted with water, basified with diluted NaOH
solution, and extracted with ethyl acetate. The organic layer was
dried over sodium sulfate, and the solvent was evaporated. The
crude product was purified by column chromatography on silica
gel or by HPLC.
2-(3-Methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)-N,N-bis[2-(3-methyl-
1H-pyrrolo[2,3-b]-pyridin-1-yl)ethyl]ethanamine (1jj). The title
compound was synthesized following method B (200 °C, 30 min)
1
with 4 equiv of the epoxide in 69% yield. H NMR (300 MHz,
DMSO-d6): δ 2.18 (s, 9H), 2.88 (t, J ) 6.2 Hz, 6H), 4.05 (t, J )
6.2 Hz, 6H), 6.88 (s, 3H), 7.02 (dd, J ) 7.7, 4.7 Hz, 3H), 7.88 (dd,
J ) 7.7, 1.5 Hz, 3H), 8.19 (dd, J ) 4.7, 1.5 Hz, 3H). 13C NMR
(125 MHz, DMSO-d6): δ 9.37, 41.6, 53.3, 107.1, 114.6, 120.2,
126.5, 126.6, 142.0, 147.0. HRMS calcd for C30H33N7 + [H+],
492.2871; found, 492.2886.
Suzuki-Miyaura Reactions with 6-Chloro-7-azaindoles. Gen-
eral Procedure. A degassed mixture of dimethoxyethane and water
(3.5:1, 4 mL/mmol azaindole) was added under argon to 6-chloro-
7-azaindole, boronic acid (2 equiv), PdCl2(dppf)×CH2Cl2 (0.05
equiv), and sodium bicarbonate (3 equiv). The mixture was heated
in a sealed pressure tube to 115 °C for 3 h. Subsequently, the layers
were separated and the organic layer was evaporated. The residue
was separated by HPLC to yield the coupling product.
Method B. The reaction was run similar to method A, but
microwave heating to the given temperature for the indicated time
was used. Distinct from method A, no acid was added.
1-Benzyl-6-chloro-3-methyl-1H-pyrrolo[2,3-b]pyridine (1a).
The title compound was synthesized following method A (110 °C,
5 h) in 66% yield. Following method B (150 °C, 20 min) it was
isolated in 60% yield. 1H NMR (400 MHz, DMSO-d6): δ 2.25 (s,
3H), 5.37 (s, 2H), 7.13 (d, J ) 8.1 Hz, 1H), 7.20 (d, J ) 7.1 Hz,
2H), 7.24-7.33 (m, 3H), 7.38 (s, 1H), 8.01 (d, J ) 8.1 Hz, 1H).
13C NMR (125 MHz, DMSO-d6): δ 9.37, 46.9, 108.9, 114.7, 119.2,
126.8, 127.1, 127.3, 128.5, 130.2, 138.0, 143.1, 146.0. HRMS calcd
for C15H13ClN2, 256.0767; found, 256.0770.
1-(4-Methoxybenzyl)-3-methyl-1H-pyrrolo[2,3-b]pyridine (1c).
The title compound was synthesized following method A (110 °C,
9 h) in 82% yield. Following method B (150 °C, 40 min) it was
isolated in 72% yield. 1H NMR (400 MHz, DMSO-d6): δ 2.24 (s,
3H), 3.69 (s, 3H), 5.32 (s, 2H), 6.85 (d, J ) 8.6 Hz, 2H), 7.06 (dd,
J ) 7.8, 4.7 Hz, 1H), 7.20 (d, J ) 8.6 Hz, 2H), 7.32 (s, 1H), 7.92
(dd, J ) 7.8, 1.2 Hz, 1H), 8.24 (dd, J ) 4.7, 1.2 Hz, 1H). 13C
NMR (125 MHz, DMSO-d6): δ 9.40, 46.1, 54.9, 107.9, 113.7,
114.8, 120.3, 125.9, 126.7, 128.7, 130.5, 142.3, 147.0, 158.4. HRMS
calcd for C16H16N2O, 252.1263; found, 252.1252.
1-Benzyl-6-(3,5-difluorophenyl)-3-methyl-1H-pyrrolo[2,3-b]-
pyridine (11c). The title compound was prepared from 1a following
the general procedure in 99% yield. 1H NMR (400 MHz, DMSO-
d6): δ 2.28 (s, 3H), 5.50 (s, 2H), 7.20-7.33 (m, 6H), 7.46 (s, 1H),
7.80 (d, J ) 8.2 Hz, 1H), 7.89 (m, 2H), 8.05 (d, J ) 8.2 Hz, 1H).
2
13C NMR (125 MHz, DMSO-d6): δ 9.45, 46.8, 103.3 (t, JC,F
)
26.1 Hz), 108.5, 109.0 (dd, 2JC,F ) 20.3 Hz, 4JC,F ) 6.1 Hz), 112.2,
120.5, 127.3, 127.4, 127.87, 127.91, 128.4, 138.5, 143.4 (t, 3JC,F
9.6 Hz), 146.2 (t, JC,F ) 3.0 Hz), 146.8, 162.8 (dd, JC,F ) 245
Hz, JC,F ) 13.5 Hz). HRMS calcd for C21H16F2N2: 334.1282;
)
4
1
3
found, 334.1285.
[2-(1-Cyclopentyl-3-phenyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-
phenyl]methanol (11g). The title compound was prepared from
1
1f following the general procedure in 99% yield. H NMR (400
MHz, DMSO-d6): δ 1.67-1.79 (m, 2H), 1.86-2.07 (m, 4H), 2.14-
2.24 (m, 2H), 4.68 (d, J ) 5.6 Hz, 2H), 5.18-5.26 (m, 2H), 7.27
(t, J ) 7.4 Hz, 1H), 7.36-7.48 (m, 5H), 7.54 (d, J ) 7.3 Hz, 1H),
7.66 (d, J ) 7.3 Hz, 1H), 7.78 (d, J ) 7.4 Hz, 2H), 8.08 (s, 1H),
8.38 (d, J ) 8.2 Hz, 1H). 13C NMR (125 MHz, DMSO-d6): δ
23.6, 32.1, 54.8, 61.3, 113.6, 116.3, 116.7, 124.4, 125.7, 126.2,
126.6, 127.6, 127.7, 128.4, 128.8, 129.6, 134.6, 139.0, 140.3, 146.9,
151.5. HRMS calcd for C25H24N2O, 368.1889; found, 368.1886.
1-(1-Adamantyl)-6-chloro-3-phenyl-1H-pyrrolo[2,3-b]pyri-
dine (1g). The title compound was synthesized following method
A (120 °C, 72 h) in 84% yield. Following method B (200 °C, 2.5
1
h) it was isolated in 85% yield. H NMR (400 MHz, DMSO-d6):
δ 1.97 (m, 6H), 2.24 (br. s, 3H), 2.49 (6H under DMSO-signal),
7.21 (d, J ) 8.3 Hz, 1H), 7.27 (m, 1H), 7.44 (m, 2H), 7.70 (d, J )
7.1 Hz, 2H), 7.93 (s, 1H), 8.31 (d, J ) 8.3 Hz, 1H). 1H NMR (300
MHz, CDCl3): δ 1.76-1.91 (m, 6H), 2.28 (br. s, 3H), 2.54 (d, J
) 2.6 Hz, 6H), 7.08 (d, J ) 8.3 Hz, 1H), 7.27 (tt, J ) 7.4, 1.5 Hz,
1H), 7.40-7.45 (m, 2H), 7.51 (s, 1H), 7.54-7.59 (m, 2H), 8.08
(d, J ) 8.3 Hz, 1H). 13C NMR (125 MHz, DMSO-d6): δ 29.1,
35.6, 40.7, 57.5, 113.0, 115.6, 117.8, 124.0, 125.9, 126.4, 128.8,
130.8, 134.1, 141.4, 146.2. HRMS calcd for C23H23ClN2, 362.1550;
found, 362.1542.
Acknowledgment. We thank Dr. P. Schmitt, C. Streich, and
D. Bauer for recording NMR spectra and helpful discussions.
In addition we are grateful to M. Stoltefuss, G. Wiefel-
Hu¨bschmann and S. Brauner for HRMS measurements.
Supporting Information Available: Experimental methods and
compound data for 1b,d-f,h-z,aa-gg and 11a-b,d,f,h-j. 1H and
13C NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
1-[2-(1H-Indol-3-yl)ethyl]-3-methyl-1H-pyrrolo[2,3-b]pyri-
dine (1hh). The title compound was synthesized following method
1
B (200 °C, 30 min) in 66% yield. H NMR (300 MHz, DMSO-
d6): δ 2.24 (s, 3H), 3.19 (dd, J ) 7.7, 7.6 Hz, 2H), 4.48 (dd, J )
7.7, 7.6 Hz, 2H), 6.96-7.14 (m, 4H), 7.32-7.36 (m, 2H), 7.61 (d,
JO060512H
J. Org. Chem, Vol. 71, No. 15, 2006 5545