A general modular method of azaindole and thienopyrrole synthesis via Pd-catalyzed tandem couplings of gem-dichloroolefins

Article abstract of DOI:10.1021/jo070460b

(Chemical Equation Presented) A palladium-catalyzed reaction of gem-dichloroolefins and a boronic acid via a tandem intramolecular C-N and intermolecular Suzuki coupling process gave corresponding substituted azaindoles or thienopyrroles. This method is a

Full text of DOI:10.1021/jo070460b

A General Modular Method of Azaindole and Thienopyrrole
Synthesis Wia Pd-Catalyzed Tandem Couplings of
gem-Dichloroolefins
Yuan-Qing Fang, Josephine Yuen, and Mark Lautens*
DaVenport Chemistry Laboratories, Department of Chemistry, UniVersity of Toronto,
80 St. George Street, Toronto, Ontario, M5S 3H6, Canada
mlautens@chem.utoronto.ca
ReceiVed March 14, 2007
A palladium-catalyzed reaction of gem-dichloroolefins and a boronic acid via a tandem intramolecular
C-N and intermolecular Suzuki coupling process gave corresponding substituted azaindoles or
thienopyrroles. This method is a very modular protocol to synthesize all four isomers of azaindole and
two isomers of thienopyrroles in good to excellent yield.
Introduction
bition and antiproliferative behavior,5 selective potent dopamine
D4 antagonism,2 transforming growth factor (TGF)-â1 antago-
nism,6 antithrombotic and anticoagulant activity,7 NK1 receptor
antagonism,8 and MAP kinase p38 inhibition.9 Similarly,
thienopyrroles are biologically active as sPLA2 inhibitors,10
MCP-1 inhibitors,11 glycogen phosphorylase inhibitors,12 go-
nadotropin releasing hormone antagonists,13 and antiviral agents.14
Azaindoles and thienopyrroles are two very important families
of drug-like heteroaromatic structures that show diverse biologi-
cal activity.1 Compared to their bioisosteric indole structure,
they feature unique electronic properties. Moreover, the variable
position of the heteroatom existing in the four azaindole and
two stable thienopyrrole isomers increases the chance of suitable
binding in biological systems, increasing selectivity,2 as well
as improving bioavailability.3 For example, azaindole com-
pounds exhibit a broad spectrum of activity including tubulin-
inhibitory properties, antimitotic activity,4 protein kinase inhi-
(4) Mahboobi, S.; Pongratz, H.; Hufsky, H.; Hockemeyer, J.; Frieser,
M.; Lyssenko, A.; Paper, D. H.; Buergermeister, J.; Boehmer, F.-D.; Fiebig,
H.-H.; Burger, A. M.; Baasner, S.; Beckers, T. J. Med. Chem. 2001, 44,
4535.
(5) Wentzler, S.; El Ahmad, Y.; Filoche Romme, B.; Nemecek, C.; Venot,
C. (Aventis Pharma S. A., Fr.) Fr. Demande FR 2868422, 2005.
(6) (a) Maruyama, Y.; Hirabayashi, K.; Hori, K. (Nippon Shinyaku Co.,
Ltd., Japan) PCT Int. Appl. WO 03037862, 2003. (b) Jinnin, M.; Ihn, H.;
Tamaki, K. Mol. Pharmacol. 2006, 69, 597.
* Author to whom correspondence should be addressed. Phone: 416-978-
6083. Fax: 416-946-8185.
(1) Joule, J. A.; Mills, K. Heterocylic Chemistry, 4th ed.; Blackwell
Sciences: Oxford, UK, 2000; p 351.
(2) (a) Lo¨ber, S.; Hu¨bner, H.; Gmeiner, P. Bioorg. Med. Chem. Lett.
1999, 9, 97. (b) Curtis, N. R.; Kulagowski, J. J.; Leeson, P. D.; Ridgill, M.
P.; Emms, F.; Freedman, S. B.; Patel, S.; Patel, S. Bioor. Med. Chem. Lett.
1999, 9, 585. (c) Showell, G. A.; Emms, F.; Marwood, R.; O’Connor, D.;
Patel, S.; Leeson, P. D. Bioorg. Med. Chem. 1998, 6, 1.
(7) Bastian, J. A.; Fisher, M. J.; Harper, R. W.; Lin, H.-S.; McCowan,
J. R.; Sall, D. J.; Smith, G. F.; Takeuchi, K.; Wiley, M. R.; Zhang, M. (Eli
Lilly, Indianapolis) Eur. Pat. Appl. EP 997465, 2000.
(8) Cooper, L. C.; Chicchi, G. G.; Dinnell, K.; Elliott, J. M.; Holling-
worth, G. J.; Kurtz, M. M.; Locker, K. L.; Morrison, D.; Shaw, D. E.; Tsao,
K. L.; Watt, A. P.; Williams, A. R.; Swain, C. J. Bioorg. Med. Chem. Lett.
2001, 11, 1233.
(3) (a) Wang, T.; Zhang, Z.; Wallace, O. B.; Deshpande, M.; Fang, H.;
Yang, Z.; Zadjura, L. M.; Tweedie, D. L.; Huang, S.; Zhao, F.; Ranadive,
S.; Robinson, B. S.; Gong, Y.-F.; Ricarrdi, K.; Spicer, T. P.; Deminie, C.;
Rose, R.; Wang, H.-G. H.; Blair, W. S.; Shi, P.-Y.; Lin, P.-f.; Colonno, R.
J.; Meanwell, N. A. J. Med. Chem. 2003, 46, 4236. (b) Cooper, L. C.;
Chicchi, G. G.; Dinnell, K.; Elliott, J. M.; Hollingworth, G. J.; Kurtz, M.
M.; Locker, K. L.; Morrison, D.; Shaw, D. E.; Tsao, K. L.; Watt, A. P.;
Williams, A. R.; Swain, C. J. Bioorg. Med. Chem. Lett. 2001, 11, 1233.
(9) (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. (b) Henry, J. R.; Dodd, J. H. Tetrahedron Lett. 1998,
39, 8763. (c) Dodd, J. H.; Henry, J. R.; Rupert, K. (Ortho-McNeil
Corporation, Inc.) PCT Int. Appl. WO 9847899, 1998. (d) 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.
10.1021/jo070460b CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/09/2007
5152
J. Org. Chem. 2007, 72, 5152-5160

Azaindole and Thienopyrrole Synthesis
conditions and high functional group compatibility of Pd
chemistry. Compared to azaindoles, synthetic methods for
thienopyrroles are much more limited and include Friedel-
Crafts acylation followed by aromatization,29 reductive ketone
amine condensation,30 and aldol condensation,31 nitrene C-H
insertion cyclization using azides32 or nitrothiophene,33 intramo-
lecular Heck reaction,34 and a Rh(II)-mediated-Wolff rearrange-
ment-cyclization sequence.35 Again, these methods mostly suffer
from drawbacks including low yields or difficult access to the
starting materials. There are no previous reports of a single,
general method to produce all the possible isomers of azaindoles
and thienopyrroles.
In the context of developing rapid and efficient access to a
diverse family of indole compounds via a tandem Pd-catalyzed
C-N/C-C coupling or Cu-catalyzed double amidation of gem-
dihalovinylaniline systems,36 we sought to extend our methodol-
ogy to the synthesis of azaindoles and thienopyrroles. We report
herein our success in this endeavor leading to these important
families of molecules.
Synthetic routes to azaindoles or thienopyrroles are not always
straightforward since the most general and effective processes,
such as the Fischer indole method, often fail to give azaindoles
and thienopyrroles.15 Typical methods of azaindole synthesis
are Madelung-type cyclization,16 Gassman-type cyclization,17
Bartoli-type cyclization,18 intramolecular nitrene C-H insertion
cyclization,16a ketone amine condensation,19 electrophilic cy-
clization Via a Pictet-Spengler reaction,20 and Friedel-Crafts
type cyclization followed by dehydration.21 These traditional
methods suffer from low yields, limited reaction scope, and
harsh reaction conditions; hence, very few functional groups
are compatible.22 More recently, Pd-catalyzed alkynyl amine
formation/cyclization,23 Heck reaction,24 Larock-type annula-
tion,25 Ar-Pd-X-mediated cyclization of alkynyl amines,26
ring-opening of a spiro pyridone-cyclopropane followed by
cross-couplings,27 and a double Buchwald-Hartwig C-N
coupling28 show very attractive features which overcome the
shortcomings of traditional methods owing to the mild reaction
Results and Discussion
Solution for Catalyst Poisoning. Initial experiments showed
that the conditions we developed for indole synthesis (eq 1 in
Scheme 1) via a tandem C-N/Suzuki coupling of gem-
dibromovinylaniline 2 failed to give the desired 7-azaindole
product 3 (eq 2 in Scheme 1). Not only did the starting material
decompose under the reaction conditions, the starting material
(or the decomposed products) poisoned the catalyst in a control
experiment (eq 3 in Scheme 1). Attempts to synthesize 6-, 5-,
or 4-azaindoles under these conditions all failed to result in the
desired products.
(10) Beight, D. W.; Morin, J. M.; Sawyer, J. S.; Smith, E. C. R. (Eli
Lilly, Indianapolis) WO 2002012249, 2002.
(11) Barker, A. J.; Kettle, J. G.; Faull, A. W. (Zeneca Ltd, UK) WO
9940914, 1999.
(12) Birch, A. M.; Morley, A. D.; Stocker, A.; Whittamore, P. R. O.
(Astrazeneca) WO 2003074532, 2003.
There are only a few cases of C-N coupling between free
aminopyridines and aryl halides employing bidentate phosphine
ligands.37 Moreover, it is well-established that the free NH2
group in aminopyridines retards the Pd-catalytic cycle.38 Early
studies on Pd-catalyzed C-N coupling reactions using a
monodentate phosphine ligand showed that primary amines are
generally poor substrates due to formation of the aryl palladium
bis-amine complex, which failed to undergo reductive elimina-
tion.39 Therefore, formation of complex 4 from the gem-
(13) Arnould, J. C. (Astrazeneca) WO 2004018479, 2004.
(14) Attenni, B.; Hernando, J. I. M.; Malancona, S. N. F.; Ontoria Ontoria,
J. M.; Rowley, M. (Istituto di Ricerche di Biologia Molecolare P Angeletti
S.p.A., Italy) WO 2005023819, 2005.
(15) Molina, A.; Vaquero, J. J.; Garcia-Navio, J. L.; Alvarez-Builla, J.;
Pascual-Teresa, B.; Gago, F.; Rodrigo, M. M.; Ballesteros, M. J. Org. Chem.
1996, 61, 5587.
(16) (a) Fisher, M. H.; Schwartzkopf, G., Jr.; Hoff, D. R. J. Med. Chem.
1972, 15, 1168. (b) Turner, J. A. J. Org. Chem. 1983, 48, 3401. (c) Lorenz,
R. R.; Tullar, B. F.; Koelsch, G. F.; Archer, S. J. Org. Chem. 1965, 30,
2531. (d) Hands, D.; Bishop, B.; Cameron, M.; Edwards, J. S.; Cottrell, I.
F.; Wright, S. H. B. Synthesis 1996, 877. (e) Song, J. J.; Tan, Z.; Gallou,
F.; Xu, J.; Yee, N. K.; Senanayake, C. H. J. Org. Chem. 2005, 70, 6512.
(17) Debenham, S. D.; Chan, A.; Liu, K.; Price, K.; Wood, H. B.
Tetradedron Lett. 2005, 46, 2283.
(29) Matteson, D. S.; Snyder, H. R. J. Am. Chem. Soc. 1957, 79, 3610.
(30) Gale, W. W.; Scott, A. N.; Snyder, H. R. J. Org. Chem. 1964, 29,
2160.
(31) Soth, S.; Farnier, M.; Paulmier, C. Can. J. Chem. 1978, 56, 1429.
(32) (a) Hemetsberger, H.; Knittel, D. Monatsh. Chem. 1972, 103, 194.
(b) Gairns, R. S.; Moody, C. J.; Rees, C. W. J. Chem. Soc., Chem. Commun.
1985, 1818.
(18) Zhang, Z.; Yang, Z.; Meanwell, M. A.; Kadow, J. F.; Wang, T. J.
Org. Chem. 2002, 67, 2345.
(19) Estel, L.; Marsais, F.; Que´guiner, G. J. Org. Chem. 1988, 53, 2740.
(20) Rousseau, J.-F.; Dodd, R. H. J. Org. Chem. 1998, 63, 2731.
(21) Dekhane, M.; Potier, P.; Dodd, R. H. Tetrahedron, 1993, 49, 8139.
(22) For a review, see: Hyaric, M.; Viera de Almeida, M.; Nora de
Souza, M. V. Quim. NoVa 2002, 25, 1165.
(33) Srinivasan, K.; Srinivasan, K. G.; Balasubramanian, K. K.; Swa-
minathan, S. Synthesis 1973, 313.
(23) KOt-Bu in NMP: (a) Koradin, C.; Dohle, W.; Rodriguez, A. L.;
Schmid, B.; Knochel, P. Tetrahedron 2003, 59, 1571. (b) Rodriguez, A.
L.; Koradin, C.; Dohle, W.; Knochel, P. Angew. Chem., Int. Ed. 2000, 39,
2488. (c) McLaughlin, M.; Palucki, M.; Davies, I. W. Org. Lett. 2006, 8,
3307. CuI in DMF: (d) Xu, L.; Lewis, I. R.; Davidsen, S. K.; Summers, J.
B. Tetrahedron Lett. 1998, 39, 5159.
(24) (a) Nazare´, M.; Schneider, C.; Lindenschmidt, A.; Will, D. W.
Angew. Chem., Int. Ed. 2004, 43, 4526. (b) Lachance, N.; April, M.; Joly,
M.-A. Synthesis 2005, 2571.
(25) (a) Ujjainwalla, F.; Warner, D. Tetrahedron Lett. 1998, 39, 5355.
(b) 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.
(34) Wensbo, D.; Annby, U.; Gronowitz, S. Tetrahedron 1995, 51, 10323.
(35) Lee, D. J.; Kim, K.; Park, Y. J. Org. Lett. 2002, 4, 873.
(36) (a) Fang, Y.-Q.; Lautens, M. Org. Lett. 2005, 7, 3549. (b) Yuen, J.;
Fang, Y.-Q.; Lautens, M. Org. Lett. 2006, 8, 653. (c) Fayol, A.; Fang, Y.-
Q.; Lautens, M. Org. Lett. 2006, 8, 4203. (d) Lautens, M.; Alberico, D.;
Bressy, C.; Fang, Y-Q.; Mariampillai, B.; Wilhelm, T. Pure. Appl. Chem.
2006, 78, 351.
(37) (a) Yin, J.; Zhao, M. M.; Huffman, M. A.; McNamara, J. M. Org.
Lett. 2002, 4, 3481. (b) Iwaki, T.; Yasuhara, A.; Sakamoto, T. J. Chem.
Soc. Perkin Trans. 1 1999, 1505.
(38) (a) Wagaw, S.; Buchwald, S. L. J. Org. Chem. 1996, 61, 7240. (b)
Billingsley, K. L.; Anderson, K. W.; Buchwald, S. L. Angew. Chem., Int.
Ed. 2006, 45, 3484.
(26) Cacchi, S.; Fabrizi, G.; Parisi, L. M. J. Comb. Chem. 2005, 7, 510.
(27) Zhang, X.; Kerr, M. A. Org. Lett. 2006, 8, 3777.
(28) Willis, M. C.; Brace, G. N.; Holmes, I. P. Angew. Chem., Int. Ed.
2005, 44, 403.
(39) (a) Widenhoefer, R. A.; Buchwald, S. L. Organometallics 1996,
15, 3534. (b) Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem. Soc.
1996, 118, 7215. (c) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald,
S. L. Acc. Chem. Res. 1998, 31, 805.
J. Org. Chem, Vol. 72, No. 14, 2007 5153

Fang et al.
SCHEME 1
SCHEME 2
SCHEME 3
SCHEME 4
CCl2PPh3, generated from the reaction of PPh3 and dichloro-
carbene (generated in situ from the reaction of KOtBu and
chloroform).41 Although the literature protocol was effective,
the need to use freshly prepared KOtBu makes it less attractive.
Fortunately, freshly prepared KOtBu can be substituted by a
KOtBu‚HOtBu adduct, which was prepared by simply heating
commercially available t-BuOK in anhydrous t-BuOH followed
by removal of excess t-BuOH under vacuum. This white solid
adduct was stable at -20 °C for long periods of time without
deterioration in yield of the olefination.
Preparation of a variety of these substrates consisting of
different azaindole and thienopyrrole isomers following this
procedure is shown in Table 1. Alkylation of the BocNH
substrate (e.g., 11) followed by deprotection of the Boc group
gave the N-alkyl substrate.42
Synthesis of 7-Azaindole Derivatives. A range of 7-azain-
doles were prepared as shown in Table 2. Substrates with alkyl
substituents on the nitrogen produced successful reactions, with
the least bulky methylamine 19 being the most efficient
(Table 2, entry 2 vs 4). The Boc-protected amino substrate also
gave the desired product, albeit in lower yield (Table 2, entry
7). Both electron-rich and electron-poor boronic acids were
tolerated under these conditions. More interestingly, reaction
of the tetrasubstituted olefin substrate 20 gave the 2,3-disub-
stituted 7-azaindole in excellent yield, although prolonged
heating was required, which caused partial loss of the Boc group.
Compound 6b was subsequently converted into a transform-
ing growth factor (TGF)-â1 antagonist SIS3 (21), which was
dibromovinyl aminopyridine substrate 2 is presumably the cause
of catalyst poisoning (Scheme 2).
To avoid catalyst poisoning through bis-amine coordination
to palladium, we chose to introduce a substituent on the nitrogen.
In the event, the N-benzyl substrate 5 gave the desired N-benzyl-
7-azaindole 6 in good yield (74%) in the presence of phenyl-
boronic acid (1.5 equiv) under our previously described
conditions [(Pd(OAc)2 (3 mol %), S-Phos (6 mol %), K3PO4‚
H2O (3-5 equiv) in toluene at 100 °C] (Scheme 3). More
interestingly, further investigation revealed that the gem-
dichloroolefin substrate 7 gave a significantly improved yield
(90%). Therefore, we explored the scope of this reaction in the
synthesis of azaindole isomers using gem-dichlorovinyl sub-
strates.
Substrate Synthesis. The Ramirez olefination40 of aldehydes
which also bear an N-H group in the molecule (e.g., 8) typically
afforded gem-dibromovinyl products in moderate yield pre-
sumably due to the interference of the amide NH group
(Scheme 4). Conversely, preparation of gem-dichlorovinyl
substrates can be achieved with much better functional group
compatibility by reacting aldehydes or ketones with the ylid,
(41) (a) Speziale, A. J.; Marco, G. J.; Ratts, K. W. J. Am. Chem. Soc.
1960, 82, 1260. (b) Speziale, A. J.; Ratts, K. W. J. Am. Chem. Soc. 1962,
84, 854. (c) Speziale, A. J.; Ratts, K. W.; Bissing, D. E. Organic Synthesis;
Wiley: New York, Coll. Vol. 5, p 361.
(40) (a) Ramiraz, F.; Desal, N. B.; McKelvie, N. J. Am. Chem. Soc. 1962,
84, 1745. (b) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769.
(42) Krein, D. M.; Lowary, T. L. J. Org. Chem. 2002, 67, 4965.
5154 J. Org. Chem., Vol. 72, No. 14, 2007

Azaindole and Thienopyrrole Synthesis
TABLE 1. Preparation of gem-Dichloroolefins Using the Wittig
Reaction
TABLE 2. Synthesis of 7-Azaindoles
a Isolated yield.
were removed upon treatment with HCl, affording the 6-aza-
indole analogue 26 in quantitative yield, which was reported
by Merck as a KDR kinase inhibitor.
Synthesis of 5-Azaindoles. Initial attempts to form the
5-azaindole 27a using substrate 10 and 1.5 equiv of PhB(OH)2
were rather disappointing, giving a mixture of bis-Suzuki
coupling product 28 and the desired product 27a (Scheme 7).
We have not previously obtained the bis-coupled product and
speculate this reaction is due to the unique electron-withdrawing
character of the 4-pyridylamide 10.
In order to solve this problem, the first strategy was to protect
the pyridyl group as an N-oxide, thereby reversing the electronic
properties of the 4-pyridyl amide. After N-oxidation of the
substrate 10 using mCPBA, the tandem coupling reaction of
29 proceeded very well, giving the 5-azaindole 30 in good yield
(Scheme 8).
While this approach solved the problem of reactivity, it added
extra N-oxidation and deoxygenation steps if the azaindole is
the desired product. Our second approach was to reduce the
number of equivalents of the arylboronic acid from 1.5 to 1.2
and also to investigate the use of other phosphine ligands to
slow down the rate of the Suzuki step. Buchwald’s family of
biphenyl phosphine ligands allow for fine-tuning by varying
the substituent on the second phenyl ring, which may help to
facilitate C-N bond formation.
a Isolated yield. b After HCl treatment.
identified as a drug candidate for the treatment of systematic
sclerosis or scleroderma (Scheme 5).6 Iodination of 7-azaindole
6b using NIS afforded the 3-iodo-7-azaindole 22 in excellent
yield (95%), and Heck reaction between 22 and the acrylamide
23 under microwave irradiation gave the desired product 21 in
excellent yield (90%).
Synthesis of 6-Azaindole Derivatives. We next examined
the efficiency of 6-azaindole formation using the Boc-protected
chloro substrate 14 and various boronic acids. Under these
conditions, aryl boronic acids with electron-donating, electron-
withdrawing groups, or ortho substituents were tolerated. A
2-pentenyl azaindole 24g, which can be further functio-
nalized, was prepared using an alkenyl boronic acid in good
yield (Table 3, entry 7). Heteroaryl boronic acids such as
3-thienyl boronic and quinolinyl boronic acid were also suc-
cessfully applied to the synthesis of 6-azaindoles (Table 3,
entries 6 and 8).
The Boc-protected azaindole can be deprotected under acidic
conditions, for example treatment of 24d with TFA gave 25 in
good yield (Scheme 6). Both Boc and methyl groups in 24h
Indeed, the reaction was much cleaner with 1.2 equiv of PhB-
(OH)2 (Table 4, entry 1). All the ligands shown in Figure 1
J. Org. Chem, Vol. 72, No. 14, 2007 5155

Fang et al.
SCHEME 5. Synthesis of a SIS3 Inhibitor
TABLE 3. The Scope of 6-Azaindole Synthesis
SCHEME 8
SCHEME 9
SCHEME 10
a Isolated yield.
SCHEME 6
SCHEME 11
SCHEME 12
SCHEME 7
Synthesis of 4-Azaindoles. Attempts to synthesize 4-azain-
dole 32 from substrate 31 were plagued by formation of a
complex mixture of products (Scheme 9), probably due to
formation of the vinylpalladium species 33 wherein coordination
to the pyridyl nitrogen retards the C-N bond formation.
Variation in ligand and other conditions failed to reverse this
behavior.
Under these circumstances, it was necessary to protect the
pyridyl nitrogen as the N-oxide, and following oxidation of
31 with mCPBA, 34 successfully underwent a tandem coupling
to afford the desired N-oxy-4-azaindole 35a and 35b in
good to excellent yield (Scheme 10). In addition, the Cbz group
was completely deprotected under the reaction conditions.
Deoxygenation of N-oxy-4-azaindole 35a to give 2-phenyl
were effective and X-Phos was the best, affording the desired
product 27a in 87% yield. Evaluation of a number of electron-
poor, electron-rich, hindered, and heterocyclic arylboronic acids
showed that this strategy is effective for a wide range of boronic
acids (Table 4, entries 5-8). It was found that electron-rich
boronic acids (Table 4, entry 6) were less effective than electron
poor boronic acids (Table 4, entry 5), because rapid Suzuki
coupling in the former case resulted in bis-arylated coupling
product. In some cases, the original S-Phos ligand was more
effective than X-Phos (Table 4, entry 8).
5156 J. Org. Chem., Vol. 72, No. 14, 2007

Azaindole and Thienopyrrole Synthesis
FIGURE 1. Buchwald’s biphenylphosphine ligands.
TABLE 4. Synthesis of 5-Azaindoles
a Isolated yield.
4-azaindole (36) was performed in good yield using PCl3
(Scheme 11).
Additional support for the relative rates was obtained by
isolation of the monoaryl intermediate 40, which was possible
since the C-N coupling was very slow when X-Phos was used
as the ligand. (Scheme 13). Subjecting 40 to the reaction
conditions using S-Phos for a longer period of time in the
absence of boronic acid gave the desired azaindole 27e in high
yield (Scheme 13). It is also possible that the change in ligand
may lead to a change in the relative rates of the two steps
(Suzuki versus C-N coupling).
The mechanism of thienopyrrole synthesis from substrate
16 or 17 is consistent with our results with azaindoles. The reac-
tion between 16 and hindered o-tolyl boronic acid at 100 °C
for 18 h gave only 6% of the desired thieno[2,3-b]pyrrole 38d
(Scheme 14). The major product formed was a mono arylated
intermediate 41. Subjecting the isolated intermediate 41 to a
higher catalyst loading (7%) and in the presence of stronger
base Cs2CO3 gave 2-o-tolyl thienopyrrole 38d in good yield.
The same product distribution was observed for the isomeric
substrate 17 when treated with 4-methoxycarbonylphenylboronic
acid (Scheme 15). With 3% catalyst loading, a mixture of 42
(57%) and the desired product 37d (12%) was obtained even
after prolonged heating, presumably due to deactivation of the
catalyst. However, with 5% catalyst loading, both the intermedi-
ate 42 and the original substrate 17 underwent complete
conversion to the desired product 37d.
Synthesis of Thienopyrroles. Subjecting Boc-protected
aminothiophene 16 or 17 to the reaction conditions afforded
the Boc-protected thienopyrrole 37 or 38 (Table 5). Thiophene
substrates with either a free NH2 or N-alkyl failed to give the
desired thienopyrroles due to the instability of these substrates.
In general, electron-poor boronic acids worked well, while
electron-rich boronic acids often gave mixtures of the desired
product and bis-arylated byproduct. The reaction with hindered
boronic acids such as o-tolyl boronic acid resulted in a very
low yield. Depending on the boronic acid, some fine-tuning
using Buchwald’s biphenyl family of phosphine ligands (Figure
1) was required to obtain good yields (Table 5, entry 7-9).
The easiest and cleanest way of removing the Boc-protecting
group is by using NaOMe in anhydrous methanol and THF
(Scheme 12).
Mechanism of Tandem Reactions in Azaindole and
Thienopyrrole Syntheses. Our mechanistic studies for indole
synthesis revealed that intramolecular C-N bond formation is
faster than C-C bond formation for gem-dibromovinylaniline
1.43 However, the formation of bis-arylated product 28 in the
5-azaindole series (Scheme 7) suggests that in these circum-
stances, the Suzuki reaction is faster than the C-N bond
formation.
From these studies, it is most likely that 4-, 6-, and
7-azaindole formation may follow the same mechanism, in
(43) Fang, Y.; Lautens, M. Unpublished results.
J. Org. Chem, Vol. 72, No. 14, 2007 5157

Fang et al.
TABLE 5. The Scope of Thienopyrrole Synthesis
a Isolated yield.
SCHEME 13
SCHEME 14
which Suzuki coupling occurs prior to C-N coupling. However,
other possibilities such as initial C-N formation or competing
mechanisms cannot be excluded.
the best of our knowledge, this is the first general method that
is suitable for preparing all the stable azaindole and thienopy-
rrole isomers, which is potentially beneficial for the pharma-
ceutical industries since it can be applied to library synthesis
owing to large numbers of commercially available boronic
acids.44
Conclusion
We have extended the methodology of tandem C-N/Suzuki
couplings toward the synthesis of azaindoles and thienopyrroles
using gem-dichlororovinyl-pyridine or thiophene substrates. To
(44) There were over 640 commercially available aryl boronic acids by
early 2004.
5158 J. Org. Chem., Vol. 72, No. 14, 2007

Azaindole and Thienopyrrole Synthesis
SCHEME 15
hexanes to afford an oil (0.197 g, 84%), which was used directly
in the next step. To a solution of the methylated aldehyde (0.183
g, 0.77 mmol) and CBr4 (0.389 g, 1.17 mmol) was added a solution
of PPh3 (0.613 g, 2.34 mmol) in DCM (∼1 mL) at 0 °C for 15 min
before warmed to rt. The mixture was poured into a Na2CO3
solution, extracted with Et2O (2 × 5 mL), washed with brine (5
mL), dried over Na2SO4. After removal of solvent, the crude
material was filtered through a short column, eluting with 33%
EtOAc in hexane containing 1% Et3N to afford a yellow oil. The
oil was added into a solution of HCl (3 M, 10 mL), heated to 75
°C for 30 min, cooled to rt, then neutralized with solid K2CO3.
After extraction with Et2O, the organic layers were dried over Na2-
SO4, chromatographed with 20% EtOAc in hexane to afford 18 as
a yellow oil (0.160 g, 71% in 2 steps). IR (neat, cm-1): 3305,
2942, 1593, 1517, 1394, 1268. 1H NMR (400 MHz, CDCl3) δ 8.16
(1H, dm, Jd ) 5.1 Hz), 7.49 (1H, dm, Jd ) 7.5 Hz), 7.15 (1H, s),
6.62 (1H, dd, J ) 7.5, 5.5 Hz), 4.42 (1H, br), 3.04 (3H, d, J ) 4.0
Hz). 13C NMR (100 MHz, CDCl3) δ 155.5, 148.1, 137.1, 132.3,
116.9, 112.3, 95.0, 29.0 HRMS (ESI) calcd for C8H9Br2N2 ([M +
H]+) 290.9126. Found: 290.9126.
Experimental Section
[3-(2,2-Dichlorovinyl)pyridin-2-yl]carbamic Acid tert-Butyl
Ester (11). Preparation of KOtBu‚HOtBu: A mixture of KOtBu
(56 g), HOtBu (46 g), and anhydrous n-heptane (100 mL) was
heated to 115 °C (reflux) for 1 h. n-Heptane was distilled off at a
bath temperature of 115 °C. The mixture was cooled to rt, and the
residual HOtBu was removed under vacuum (0.3 mmHg) for 1 h
to yield a white powder (90.5 g, 97%).
General Procedure for the Preparation of gem-Dichlorovinyl
Substrates. To a round-bottomed flask was charged KOtBu‚HOtBu
(1.86 g, 10 mmol) and powdered PPh3 (2.62 g, 10 mmol), and the
flask was purged with argon for 10 min. After n-heptane (15 mL)
was added, the mixture was cooled to 0 °C with an ice bath. To
the vigorously stirred mixture, a solution of chloroform (1.19 g,
10 mmol) in n-heptane (5 mL) was added dropwise in such rate
that the internal temperature was maintained under 3 °C. After
addition, the mixture was stirred for an additional 30 min. The
mixture was concentrated to about 10 mL under high vacuum at
rt. To the mixture at 0 °C, 2-BocNH-3-pyridinecarboxaldehyde
(1.11 g, 5 mmol) was added in one portion followed by dry benzene
(3 mL), and the resulting mixture was stirred at 0 °C for 1 h and
then at rt overnight. The reaction was quenched with NH4Cl solution
(20 mL), and extracted with DCM (3 × 20 mL). H2O2 (10%, 1
mL) was added to the combined organic layers, and the mixture
was stirred for 30 min. After partition, the organic layer was washed
with Na2SO3 (10 mL), H2O (50 mL), brine (20 mL), and dried
over MgSO4. The crude material was further purified by flash
chromatography on silica gel (33% EtOAc in hexanes) to afford
the desired product as a white solid (1.24 g, 86%). mp 151-152
°C. IR (CHCl3, cm-1): 3415, 2981, 1731, 1576, 1489, 1438, 1369,
1-Methyl-2-phenyl-1H-pyrrolo[2,3-b]pyridine (6b). General
Procedure for the Tandem Coupling. To a mixture of the gem-
dibromoolefin (87.6 mg, 0.30 mmol), phenylboronic acid (55 mg,
0.45 mmol) and K3PO4‚H2O (350 mg, 0.15 mmol) was added a
solution of Pd(OAc)2 (2.3 mg, 0.010 mmol) and S-Phos (8.2 mg,
0.020 mmol) in toluene (3 mL). The resulting mixture was heated
at 100 °C for 2 h and cooled to rt. Saturated NaHCO3 solution was
added, and the mixture was extracted with Et2O (3 × 10 mL), dried
over Na2SO4, and concentrated in Vacuo. The crude material was
purified using chromatography eluting with 25% EtOAc in hexane
1
to afford the product as a white solid (52.6 mg, 84%). H NMR
1
1154. H NMR (400 MHz, CDCl3) δ 8.38 (1H, dd, J ) 4.9, 1.7
(400 MHz, CDCl3) δ 8.35 (1H, dd, J ) 4.8, 1.5 Hz), 7.90 (1H, dd,
J ) 7.7, 1.5 Hz), 7.56-7.54 (2H, m), 7.50-7.47 (2H, m), 7.45-
7.40 (1H, m), 7.08 (1H, dd, J ) 7.7, 4.6 Hz), 6.52 (1H, s), 3.88
(3H, s).
The general procedure for the tandem coupling was followed
using 19 (63 mg, 0.31 mmol), phenylboronic acid (55 mg,
0.45 mmol), K3PO4‚H2O (350 mg, 0.15 mmol), and a solution of
Pd(OAc)2 (2.3 mg, 0.010 mmol) and S-Phos (8.2 mg, 0.020 mmol)
in PhMe (3 mL). The reaction mixture was heated at 100 °C for
3 h. The crude material was purified using chromatography eluting
with 25% EtOAc in hexanes to afford the product as a white solid
(62 mg, 96%).
Hz), 7.94 (1H, ddd, J ) 7.7, 1.8, 0.7 Hz), 7.71 (1H, br), 7.14 (1H,
dd, J ) 7.7, 4.8 Hz), 6.85 (1H, s), 1.51 (9H, s). 13C NMR (100
MHz, CDCl3) δ 152.7, 149.1, 148.3, 138.5, 125.0, 123.9, 123.2,
120.4, 81.5, 28.3. HRMS (ESI) calcd for C12H14N2O2NaCl2 ([M +
Na]+) 311.0324. Found: 311.0331.
[3-(2,2-Dibromovinyl)-pyridin-2-yl]methylamine (18). To a
mixture of 2-BocNH-3-pyridinecarboxaldehyde (0.222 g, 1 mmol)
and DMF (3 mL) was added MeI (0.178 g, 1.25 mmol) dropwise
at 0 °C. NaH (0.052 g, 60% mineral oil, 1.35 mmol) was added in
three portions over 15 min, and the resulting yellowish suspension
was stirred for an additional 60 min. The mixture was warmed to
rt, and quenched with NaHCO3 (10 mL) and H2O (10 mL). The
mixture was extracted with Et2O (3 × 10 mL), and the combined
organic layers were washed with H2O (10 mL), NaHCO3 (10 mL),
brine (10 mL), and dried over Na2SO4. The crude material was
further purified by flash chromatography using 25% EtOAc in
2-Phenylpyrrolo[2,3-c]pyridine-1-carboxylic Acid tert-Butyl
Ester (24a). The general procedure for the tandem coupling was
followed using 14 (86.7 mg, 0.30 mmol), 2-phenylboronic acid
(55 mg, 0.45 mmol), K3PO4‚H2O (350 mg, 0.15 mmol), and a
J. Org. Chem, Vol. 72, No. 14, 2007 5159

Fang et al.
solution of Pd(OAc)2 (2.3 mg, 0.010 mmol) and S-Phos (8.2 mg,
0.020 mmol) in PhMe (3 mL). The reaction mixture was heated at
100 °C for 3 h. The crude material was purified using chromatog-
raphy eluting with 33% EtOAc in hexane to afford product as a
white solid (77 mg, 87%). mp 108-109 °C. IR (neat, cm-1): 2979,
1734, 1433, 1349, 1326, 1149. 1H NMR (400 MHz, CDCl3) δ 9.48
(1H, s), 8.42 (1H, d, J ) 5.3 Hz), 7.45 (1H, dd, J ) 5.3, 1.1 Hz),
7.43-7.40 (5H, m), 6.54 (1H, s), 1.36 (9H, s). 13C NMR (100 MHz,
CDCl3) δ 149.5, 144.0, 142.4, 137.8, 134.6, 134.3, 133.9, 129.0,
128.5, 128.1, 114.9, 108.8, 84.7, 27.7. HRMS (ESI) calcd for
C18H19N2O2 ([M + H]+) 295.1441. Found: 295.1450.
84%). mp 222-225 °C. IR (neat, cm-1): 1602, 1493, 1429, 1249.
1H NMR (400 MHz, DMSO) δ 11.87 (1H, s), 8.68 (1H, s), 8.04
(1H, d, J ) 5.3 Hz), 7.85 (1H, d, J ) 8.6 Hz), 7.44 (1H, d, J )
5.7 Hz), 7.06 (1H, d, J ) 8.3 Hz), 6.82 (1H, s), 3.80 (3H, s). 13C
NMR (100 MHz, DMSO) δ 159.6, 141.5, 138.2, 134.1, 133.8,
133.0, 127.2, 123.8, 114.5, 114.1, 96.6, 55.3, 55.2. HRMS (ESI):
calcd for C14H13N2O ([M + H]+) 225.1022. Found: 225.1013.
3-(1H-Pyrrolo[2,3-c]pyridin-2-yl)-1H-quinolin-2-one (26). 24h
(30 mg, 0.08 mmol) was dissolved in a HCl solution (3 M, 2 mL)
and heated to 80 °C for 13 h. The reaction was cooled to rt and
basified to ∼pH 9 by the careful addition of solid K2CO3. The
reaction was diluted with water then extracted using CHCl3 (6 ×
20 mL). The combined organic layers were concentrated and then
purified using chromatography eluting with 10%f20% MeOH/
EtOAc to give the product as a bright yellow solid (21 mg, 100%).
mp >290 °C. IR (neat, cm-1): 3256, 2355, 1667, 1157. 1H NMR
(400 MHz, DMSO) δ 12.29 (1H, s), 12.0 (1H, s), 8.89 (1H, s),
8.69 (1H, s), 8.09 (1H, d, J ) 4.9 Hz), 7.77 (1H, d, J ) 7.7 Hz),
7.57 (1H, tm, Jt ) 8.3 Hz), 7.52 (1H, d, J ) 5.3 Hz), 7.40 (1H, d,
J ) 8.1 Hz), 7.31 (1H, d, J ) 0.9 Hz), 7.27 (1H, t, J ) 7.3 Hz).
13C NMR (100 MHz, DMSO) δ 160.5, 138.0, 137.2, 136.5, 135.1,
133.5, 131.7, 130.9, 128.2, 122.5, 121.6, 119.2, 115.0, 114.2, 100.3,
100.3. HRMS (EI): calcd for C16H11N3O ([M]+) 261.0902.
Found: 261.0901.
5-(4-Fluorophenyl)thieno[2,3-b]pyrrole-6-carboxylic Acid tert-
Butyl Ester (38b). The general procedure for the tandem coupling
was followed using 16 (58.9 mg, 0.20 mmol), 4-fluorophenylboronic
acid (33.6 mg, 0.24 mmol), K3PO4‚H2O (230 mg, 1.0 mmol), Pd-
(OAc)2 (2.3 mg, 0.01 mmol), and DavePhos (7.9 mg, 0.02 mmol).
The reaction mixture was heated in PhMe (2 mL) at 100 °C for
13.5 h. The crude material was purified using chromatography
eluting with 3.5% EtOAc in hexanes to give the product as a white
solid (51.4 mg, 81%). The single-crystal suitable for X-ray
crystallographic determination was obtained by slow evaporation
of an Et2O solution in a freezer. mp 114-115 °C. IR (neat, cm-1):
1
2980, 1753, 1724, 1504, 1369, 1316, 1161, 1140, 1123. H NMR
(500 MHz, CDCl3) δ 7.40-7.37 (2H, m), 7.09-7.05 (2H, m), 7.02
(1H, AB, J ) 5.4 Hz), 6.99 (1H, AB, J ) 5.4 Hz), 6.45 (1H, s),
1.46 (9H, s). 13C NMR (125 MHz, CDCl3) δ 162.6 (JC-F
)
Acknowledgment. This work is supported by NSERC
(Canada), Merck Frosst, and the University of Toronto. Y.-Q.F.
thanks the Ontario Government and the University of Toronto
for financial support in the form of postgraduate scholarships
(OGS).
247 Hz), 149.0, 138.8, 136.2, 131.4 (JC-F ) 8.2 Hz), 130.5, 130.4
(JC-F ) 3.4 Hz), 121.8, 117.4, 114.8 (JC-F ) 22 Hz), 108.8, 84.9,
28.1. 19F NMR (288 MHz, CDCl3) δ -114.4. HRMS (EI): calcd
for C17H16NO2SF ([M]+) 317.0886. Found: 317.0878.
2-(4-Methoxyphenyl)-1H-pyrrolo[2,3-c]pyridine (25). Trifluo-
roacetic acid (0.1 mL) was added to a solution of 24d (24 mg,
0.074 mmol) in DCM (0.5 mL) at rt. The reaction was stirred for
4 h at rt and then diluted with DCM and basified to pH 10 using
2 M NaOH. H2O was added and the layers were separated. The
organic layer was washed with brine, dried over Na2SO4, filtered,
and concentrated to give the product as a pale brown solid (14 mg,
Supporting Information Available: Experimental procedure
and characterization data for rest of the substrates and products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO070460B
5160 J. Org. Chem., Vol. 72, No. 14, 2007