Expedient copper-free one-pot alkynylation-cyclization sequence for the preparation of 2-substituted 7-azaindoles

Article abstract of DOI:10.1055/s-0034-1379907

Abstract 2-Substituted 7-azaindoles are rapidly and efficiently prepared in a one-pot copper-free alkynylation-cyclization sequence starting from 2-aminopyridyl halides and terminal alkynes. Most importantly the amino nitrogen atom neither requires activation nor protection throughout the sequence.

Full text of DOI:10.1055/s-0034-1379907

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 1217–1221
letter
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T. Lessing et al.
Letter
Synlett
Expedient Copper-Free One-Pot Alkynylation–Cyclization
Sequence for the Preparation of 2-Substituted 7-Azaindoles
Timo Lessing
R2
R2
Br
Pd(PPh3)2Cl2, (1-Ad)2PBn·HBr
DBU, DMSO, 100 °C, 1–2 h
Fabian Sterzenbach
Thomas J. J. Müller*
R1
R1
+
N
then: KOt-Bu, DMSO, 100 °C, 0.25–1.1 h
N
N
NH2
H
rapid coupling-cyclization synthesis
in a one-pot fashion
19 examples (18–90%)
Institut für Organische Chemie und Makromolekulare Chemie,
Heinrich-Heine-Universität Düsseldorf, Universitätsstrasse 1,
40225 Düsseldorf, Germany
without amino protection
ThomasJJ.Mueller@uni-duesseldorf.de
Dedicated to Prof. Dr. Matthias M. Wagner on the
occasion of his 50th birthday
Received: 27.01.2015
Accepted after revision: 05.03.2015
Published online: 02.04.2015
and carbolithiation of N-protected vinylpyridines have
been reported.5 Just recently, the synthesis of 7-azaindoles
under acidic conditions has been communicated.6
DOI: 10.1055/s-0034-1379907; Art ID: st-2015-b0059-l
Encouraged by our recent contributions in consecutive
four-component syntheses of dihydropyridinones initiated
by Cu-free Pd-catalyzed alkynylation under mild condi-
tions,7 we report here a copper-free alkynylation of 3-bro-
mopyridine-2-amines 1 followed by subsequent cyclization
under basic conditions without the need for amino nitro-
gen protection in a one-pot fashion (Scheme 1). Most ad-
vantageously this approach allows for regiospecifically po-
sitioning the substitution pattern by directly employing un-
protected 5-substituted 3-bromopyridine amines 1 and
various terminal alkynes 2.
Abstract 2-Substituted 7-azaindoles are rapidly and efficiently pre-
pared in a one-pot copper-free alkynylation–cyclization sequence start-
ing from 2-aminopyridyl halides and terminal alkynes. Most important-
ly the amino nitrogen atom neither requires activation nor protection
throughout the sequence.
Key words 7-azaindoles, heterocycles, alkynylation, cyclization, one-
pot reaction
1H-Pyrrolo[2,3-b]pyridines, often referred to as 7-aza-
indoles, receive utmost attention in organic synthesis and
medicinal chemistry since they constitute a rare scaffold in
natural products that causes enormous biological activities.
7-Azaindoles are known to act as potent kinase inhibitors,
and many derivatives with this structural core have been
devised, synthesized, and studied for instance as efficacious
inhibitors of the Aurora B/C kinase, the IKK2 kinase, the Rho
kinase or the Abl/Src dual kinase, respectively.1
Although 7-azaindoles are isosteres of indoles, their
synthesis is often considerably more challenging, in partic-
ular since established routes such as Madelung-type reac-
tions or variations of the Fischer indole synthesis often fail
to give the desired azaindoles in good yields.2 Therefore and
due to their paramount importance in kinase inhibitor re-
search the development of new, efficient synthetic proto-
cols for their preparation has been actively pursued.3 The
most common approaches range from the protection and
subsequent deprotonation of 2-aminopicolines,4a,b to Sono-
gashira alkynylation of 2-aminopyridyl halides followed by
subsequent base-mediated cyclization with sodium hy-
dride or alkoxides, potassium phosphate, DBU, or triethyl-
amine, in many cases requiring protection of the amino ni-
trogen atom.4c–g In addition, microwave-assisted syntheses
R2
R2
Br
R1
R1
+
N
N
N
NH2
H
4
1
2
base-
mediated
Cu-free
alkynylation
R1
cyclization
R2
N
NH2
3
Scheme 1 General retrosynthetic approach to 2-substituted 7-azain-
doles 4
As a model system for developing and optimizing this
sequence we chose phenylacetylene (2a) as a terminal
alkyne. In initial attempts Pd(PPh3)2Cl2 and Pd(PPh3)4 be-
haved similarly in the coupling step. As a ligand, cataCXium®
ABn·HBr [di(1-adamantyl)benzylphosphonium bromide]
was superior to the also examined cataCXium® A·HI [di(1-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1217–1221

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T. Lessing et al.
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adamantyl)butylphosphonium iodide]. The coupling with
catalytic amounts of Pd(PPh3)2Cl2 and cataCXium® ABn·HBr
as a ligand8 in acetonitrile finally furnished (phenyl-
ethynyl)pyridin-2-amine (3a) in 82% isolated yield (Scheme
2).
Pd(PPh3)2Cl2 (2.5 mol%)
(1-Ad)2PBn·HBr (5 mol%)
phenylacetylene (2a) (1.2 equiv)
DBU (3.0 equiv)
Br
DMSO, 100 °C, 1 h
Ph
N
H
then: KOt-Bu (2.5 equiv)
N
N
NH2
DMSO, 100 °C, 15 min
Pd(PPh3)2Cl2 (2.5 mol%)
Ph
4a (89%)
1a
(1-Ad)2PBn·HBr (5.0 mol%)
phenylacetylene (1.2 equiv)
DBU (3.0 equiv)
Br
Scheme 3 Representative Cu-free Pd-catalyzed alkynylation–cycliza-
tion sequence in a one-pot fashion for the preparation of 2-phenyl-1H-
pyrrolo[2,3-b]pyridine (4a)
MeCN, 90 °C, 4 h
N
NH2
N
NH2
3a (82%)
1a
With these conditions for the alkynylation–cyclization
sequence in hand several 2-substituted 7-azaindoles 4 from
3-bromopyridine-2-amines 1 and various (hetero)aromatic
and aliphatic terminal alkynes 2 as starting materials were
prepared (Scheme 4, Table 1). The structures of all com-
pounds were unambiguously assigned by spectroscopic
methods (1H NMR and 13C NMR, IR) and combustion analy-
sis or HRMS.
Scheme 2 Initial coupling conditions for the synthesis of 3-(phenyl-
ethynyl)pyridine-2-amine (3a) in acetonitrile
However, using Cs2CO3 or DBU as bases in the separate
cyclization step did not result in the desired 2-phenyl-1H-
pyrrolo[2,3-b]pyridine as cyclization product and only
starting material 3a was recovered. Therefore, for the devel-
opment of the one-pot process, potassium tert-butoxide
was used as a base and the solvent had to be changed to tol-
uene with substoichiometric amounts of 18-crown-6 as an
additive, finally giving rise to the isolation of the desired 2-
phenyl-1H-pyrrolo[2,3-b]pyridine (4a) in 74% yield. How-
ever, in a one-pot fashion at 100 °C the cyclization step
needed a reaction time of 24 hours to completion. Upon al-
tering the solvent to DMSO, due to its ability to form low
concentrations of the dimsyl anion in the presence of alkox-
ide bases, the cyclization step at 100 °C was complete with-
in 15 minutes and compound 4a was isolated in 89% yield
(Scheme 3).9
R2
Br
Pd(PPh3)2Cl2 (2.5 mol%)
(1-Ad)2PBn·HBr (5 mol%)
DBU (3.0 equiv), DMSO
100 °C, 1 h
R2
N
1
NH2
R1
then: KOt-Bu (2.5 equiv)
N
+
N
H
DMSO, 100 °C, 15 min
R1
4
2
Scheme 4 One-pot Cu-free Pd-catalyzed alkynylation–cyclization syn-
thesis of 2-substituted 7-azaindoles 4
Table 1 One-Pot Copper-Free Alkynylation–Cyclization Sequence for the Preparation of Substituted 7-Azaindoles 4
Entry
1
2-Aminopyridylhalide 1
Alkyne 2
Product
Yield (%)a
Ph
3-bromopyridine-2-amine (1a)
phenylacetylene (2a)
4a (89)
N
H
N
OMe
OMe
2
3
1a
1a
4-ethynyl-1,2-dimethoxybenzene (2b)
1-(tert-butyl)-4-ethynylbenzene (2c)
4b (84)
4c (90)
N
H
N
N
t-Bu
N
H
O
4
5
1a
1a
(prop-2-yn-1-yloxy)benzene (2d)
2-ethynylpyridine (2e)
4d (18)
4e (39)
N
H
N
N
N
H
N
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1217–1221

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Table 1 (continued)
Entry
2-Aminopyridylhalide 1
Alkyne 2
Product
Yield (%)a
Me
n-Bu
6
3-bromo-5-methylpyridin-2-amine (1b)
1-hexyne (2f)
4f (79)
N
H
N
7
8
1a
1b
1a
1b
1b
but-3-yn-1-ol (2g)
4g (22)b
4h (79)
4i (51)
4j (64)
4k (73)
N
N
H
Me
Ph
2a
N
H
N
OMe
9
1-ethynyl-4-methoxybenzene (2h)
N
N
H
Me
t-Bu
10
11
2c
N
H
N
Me
OMe
2h
N
H
N
OMe
OMe
OMe
12
1a
5-ethynyl-1,2,3-trimethoxybenzene (2i)
4l (40)
N
N
H
OMe
OMe
OMe
Me
13
14
1b
1a
2i
4m (55)
4n (68)
N
H
N
F
1-ethynyl-2-fluorobenzene (2j)
N
H
N
Cl
t-Bu
15
16
3-bromo-5-chloropyridin-2-amine (1c)
2c
4o (86)
4p (37)
N
N
N
H
Cl
OMe
1c
2h
N
H
17
1a
1-ethynylnaphthalene (2k)
4q (70)
N
H
N
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Table 1 (continued)
Entry
2-Aminopyridylhalide 1
Alkyne 2
Product
Yield (%)a
F3C
Ph
18
3-bromo-5-(trifluoromethyl)pyridin-2-amine (1d) 2a
4r (66)
N
H
N
N
F3C
t-Bu
19
1d
2c
4s (54)
N
H
a Yields are the isolated yields after column chromatography.
b The synthetic procedure differed from the general procedure in that 3.4 equiv of KOt-Bu were used.
In summary, we have disclosed a practical, efficient and
rapid novel Cu-free Pd-catalyzed alkynylation–cyclization
sequence in a one-pot fashion, furnishing 2-substituted and
2,5-disubstituted 7-azaindoles in good yields dispensing
with protection of the amino nitrogen at any time in the se-
quence. Further studies employing this novel access to sub-
stituted 7-azaindoles in complex molecules’ syntheses are
currently underway.
(2) (a) Lorenz, R. R.; Tullar, B. F.; Koelsch, C. F.; Archer, S. J. Org.
Chem. 1965, 30, 2531. (b) Herbert, R.; Wibberley, D. G. J. Chem.
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(3) For a review summarizing syntheses, see: Mérour, J.-Y.; Routier,
S.; Suzenet, F.; Joseph, B. Tetrahedron 2013, 69, 476.
(4) (a) Fang, Y.-Q.; Yuen, J.; Lautens, M. J. Org. Chem. 2007, 72, 5152.
(b) Parcerisa, J.; Romero, M.; Pujol, M. D. Tetrahedron 2008, 64,
500. (c) Kurhade, S.; Rajopadhyay, V.; Avaragolla, S. V.; Koul, S.;
Ramaiah, P. A.; Bhuniya, D. Tetrahedron Lett. 2014, 55, 2415.
(d) Rodriguez, A. L.; Koradin, C.; Dohle, W.; Knochel, P. Angew.
Chem. Int. Ed. 2000, 39, 2488; Angew. Chem. 2000, 112, 2607.
(e) de Mattos, M. C.; Alatorre-Santamaría, S.; Gotor-Fernández,
V.; Gotor, V. Synthesis 2007, 2149. (f) Harcken, C.; Yancey, W.;
Thomson, D.; Riether, D. Synlett 2005, 3121. (g) Majumdar, K. C.;
Mondal, S. Tetrahedron Lett. 2007, 48, 6951.
Acknowledgment
The authors cordially thank the Fonds der Chemischen Industrie (sti-
pend for T.L.) for financial support.
(5) (a) Carpita, A.; Ribecai, A.; Stabile, P. Tetrahedron 2010, 66,
7169. (b) Schirok, H. J. Org. Chem. 2006, 71, 5538. (c) Cottineau,
B.; O’Shea, D. F. Tetrahedron Lett. 2005, 46, 1935. (d) Cottineau,
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(6) Leboho, T. C.; van Vuuren, S. F.; Michael, J. P.; de Koning, C. B.
Org. Biomol. Chem. 2014, 12, 307.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379907.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
(7) (a) Nordmann, J.; Müller, T. J. J. Synthesis 2014, 46, 522.
(b) Nordmann, J.; Müller, T. J. J. Org. Biomol. Chem. 2013, 11,
6556. (c) Nordmann, J.; Breuer, N.; Müller, T. J. J. Eur. J. Org.
Chem. 2013, 4303.
(8) (a) Goehrlich, J. R.; Schmutzler, R. Phosphorus, Sulfur Silicon
Relat. Elem. 1995, 102, 211. (b) Beller, M.; Hein, M.; Tewari, A.;
Zapf, A. Synthesis 2004, 935.
(9) Typical Procedure for the Synthesis of 2-Phenyl-1H-pyr-
rolo[2,3-b]pyridine (4a): In a flame-dried Schlenk tube under
nitrogen atmosphere, 3-bromopyridine-2-amine (1a; 173 mg,
1.00 mmol), Pd(PPh3)2Cl2 (17.5 mg, 0.025 mmol), and (1-
Ad)2PBn·HBr (22.6 mg, 0.050 mmol) were dissolved in anhyd
DMSO (1.50 mL). Phenylacetylene (2a; 122 mg, 1.20 mmol) and
DBU (457 mg, 3.00 mmol) were added via syringe and the reac-
tion mixture was stirred in a preheated oil bath at 100 °C until
complete conversion of compound 1a (monitored by TLC). Then,
KOt-Bu (281 mg, 2.5 mmol) and anhyd DMSO (1.00 mL) were
added and the mixture was stirred at 100 °C until completion of
the reaction (monitored by TLC). After cooling to r.t., de-ionized
H2O (2.00 mL) was added and the aqueous layer was extracted
three times with EtOAc. The combined organic phases were first
washed twice with de-ionized H2O and then dried with anhyd
Na2SO4. The solvents were removed under reduced pressure.
The residue was adsorbed onto Celite® and purified by column
References and Notes
(1) For the recent development and synthesis of several kinase
inhibitors, see, for example: (a) Chowdhury, S.; Sessions, E. H.;
Pocas, J. R.; Grant, W.; Schroter, T.; Lin, L.; Ruiz, C.; Cameron, M.
D.; Schurer, S.; LoGrasso, P.; Bannister, T. D.; Feng, Y. Bioorg.
Med. Chem. Lett. 2011, 21, 7107. (b) Liddle, J.; Bamborough, P.;
Barker, M. D.; Campos, S.; Cousins, R. P.; Cutler, G. J.; Hobbs, H.;
Holmes, D. S.; Ioannou, C.; Mellor, G. W.; Morse, M. A.; Payne, J.
J.; Pritchard, J. M.; Smith, K. J.; Tape, D. T.; Whitworth, C.;
Williamson, R. A. Bioorg. Med. Chem. Lett. 2009, 19, 2504.
(c) Adams, J. L.; Burgess, J. L.; Chaudhari, A. M.; Copeland, R. A.;
Donatelli, C. A.; Drewry, D. H.; Fisher, K. E.; Hamajima, T.;
Hardwicke, M. A.; Huffman, W. F.; Koretke-Brown, K. K.; Lai, Z.
V.; McDonald, O. B.; Nakamura, H.; Newlander, K. A.;
Oleykowski, C. A.; Parrish, C. A.; Patrick, D. R.; Plant, R.; Sarpong,
M. A.; Sasaki, K.; Schmidt, S. J.; Silva, D. J.; Sutton, D.; Tang, J.;
Thompson, C. S.; Tummino, P. J.; Wang, J. C.; Xiang, H.; Yang, J.;
Dhanak, D. J. Med. Chem. 2010, 53, 3973. (d) Chevé, G.; Bories,
C.; Fauvel, B.; Picot, F.; Tible, A.; Daydé-Cazals, B.; Loget, O.;
Yasri, A. Med. Chem. Commun. 2012, 3, 788.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1217–1221

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chromatography on a SNAP 100 g cartridge (EtOAc–n-hexane
33%) using a Biotage SP-1 flash chromatography purification
system to give pure compound 4a as a colorless solid; yield: 173
mg (89%); mp 204.3 °C; Rf 0.54 (EtOAc–n-hexane, 1:1). IR (ATR):
1456 (m), 1281 (m), 750 (s), 685 (m), 675 (m), 648 (m), 625 (m)
Hz, 1 H), 12.94 (br s, 1 H). 13C NMR (150 MHz, CDCl3): δ = 97.4
(CH), 116.1 (CH), 122.4 (Cquat), 126.0 (CH), 128.2 (CH), 128.7
(CH), 129.0 (CH), 132.5 (Cquat), 139.7 (Cquat), 142.1 (CH), 150.1
(Cquat). MS (EI+, 70 eV): m/z (%) = 195 (14), 194 (100) [M]+, 193
(14), 192 (6), 167 (7), 166 (8), 139 (5), 97 (7), 91 (8). Anal. Calcd
for C13H10N2 (194.2): C, 80.39; H, 5.19; N, 14.42. Found: C, 80.16;
H, 4.92; N, 14.21.
1
cm–1. H NMR (600 MHz, CDCl3): δ = 6.79 (s, 1 H), 7.10 (dd, J =
4.8, 7.7 Hz, 1 H), 7.40 (t, J = 7.4 Hz, 1 H), 7.52 (t, J = 7.6 Hz, 2 H),
7.92 (d, J = 7.8 Hz, 2 H), 7.96 (d, J = 7.7 Hz, 1 H), 8.31 (d, J = 4.8
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1217–1221

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