Synthesis of 2,5-disubstituted 6-azaindoles from substituted aziridines via intramolecular cyclization

Article abstract of DOI:10.1021/ol301187s

A new and efficient preparation of pharmacologically and biologically important 2,5-disubstituted 6-azaindoles was achieved from cyclizations of aziridin-2-yl dipropargylic alcohols as adducts of two propargyl groups to ethyl 1-benzylaziridine-2-carboxylate. The sequential cyclizations include pyrrole formation and a novel base-catalyzed intramolecular acetylenic Schmidt reaction.

Full text of DOI:10.1021/ol301187s

ORGANIC
LETTERS
2012
Vol. 14, No. 12
3120–3122
Synthesis of 2,5-Disubstituted
6-Azaindoles from Substituted Aziridines
via Intramolecular Cyclization
Hogyu Lee,† Jun Hee Kim,† Won Koo Lee,*,† Jae-Hoon Jung,‡ and Hyun-Joon Ha*,‡
Department of Chemistry, Sogang University, Seoul 121-742, Korea, and Department of
Chemistry, Hankuk University of Foreign Studies, Yongin 449-791, Korea
wonkoo@sogang.ac.kr; hjha@hufs.ac.kr
Received May 1, 2012
ABSTRACT
A new and efficient preparation of pharmacologically and biologically important 2,5-disubstituted 6-azaindoles was achieved from cyclizations of
aziridin-2-yl dipropargylic alcohols as adducts of two propargyl groups to ethyl 1-benzylaziridine-2-carboxylate. The sequential cyclizations
include pyrrole formation and a novel base-catalyzed intramolecular acetylenic Schmidt reaction.
Azaindole structural units are found in natural marine
products, and the importance of their derivatives is re-
flected in biologically active compounds as indole
isosteres.1 Several strategies for azaindole synthesis have
been reported by Reissert, Batcho-Leimgrube, Hemetsberger-
Knitel, and Bartoli.2 However, these methods need im-
provement in terms of long reaction times, harsh reaction
conditions, and low yields. Yet, recently better preparatory
methods have come to light such as the Aza-Fischer
reaction;2 transition metal catalyzed cyclizations4 using
Pd, Ru, Zr, Ti, and Cu; and a dilithiation pathway.5
However, previous synthetic methods cannot provide
functionalized 6-azaindoles in high yields.
Compounds containing 6-azaindole show pharmacolo-
gical activity1,6 as HIV-1 inhibitors and have a character-
istic photophysical property.7 The synthetic routes for
these compounds are limited. Most azaindole syntheses
start from substituted pyridines to form a pyrrole unit.3À5,8
Here, we would like to propose a new efficient synthetic
route for the 2,5-substituted 6-azaindoles using an intra-
molecular pyrrole formation followed by a pyridine ring
formation via an intramolecular azide cyclization reaction
into the acetylenic unit.
We recently reported an efficient synthesis of 1,2,3,5-
substituted pyrroles from N-benzylaziridine-2-carboxylate
(1),9 which is a readily available starting material. The ester
1 was reacted with 2 equiv of various lithium acetylides to
† Sogang University.
(6) (a) Plewe, M. B.; Butler, S. L.; R. Dress, K.; Hu, Q.; Johnson,
T. W.; Kuehler, J. E.; Kuki, A.; Lam, H.; Liu, W.; Nowlin, D.; Peng, Q.;
Rahavendran, S. V.; Tanis, S. P.; Tran, K. T.; Wang, H.; Yang, A.;
Zhang, J. J. Med. Chem. 2009, 52, 7211–7219. (b) Wang, T.; Yin, Z.;
Zhang, Z.; Bender, J. A.; Yang, Z.; Johnson, G.; Yang, Z.; Zadjura,
L. M.; D’Arienzo, C. J.; DiGiugno Parker, D.; Gesenberg, C.; Yama-
naka, G. A.; Gong, Y.-F.; Ho, H.-T.; Fang, H.; Zhou, N.; McAuliffe,
B. V.; Eggers, B. J.; Fan, L.; Nowicka-Sans, B.; Dicker, I. B.; Gao, Q.;
Colonno, R. J.; Lin, P.-F.; Meanwell, N. A.; Kadow, J. F. J. Med. Chem.
2009, 52, 7778–7787.
‡ Hankuk University of Foreign Studies.
(1) Badarau, E.; Putey, A.; Suzenet, F.; Joseph, B.; Bojarski, A.;
Finaru, A.; Guillaumet, G. J. Enzyme Inhib. Med. Chem. 2010, 25, 301–
305.
ꢀ
(2) (a) Popowycz, F.; Merour, J.-Y.; Joseph, B. Tetrahedron 2007, 63,
8689–8707. (b) Song, J. J.; Reeves, J. T.; Gallou, F.; Tan, Z.; Yee, N. K.;
Senanayake, C. H. Chem. Soc. Rev. 2007, 36, 1120.
(3) Jeanty, M.; Blu, J.; Suzenet, F.; Guillaumet, G. R. Org. Lett. 2009,
11, 5142–5145.
(7) Twine, S. M.; Murphy, L.; Phillips, R. S.; Callis, P.; Cash, M. T.;
Szabo, A. G. J. Phy. Chem. B 2002, 107, 637–645.
(4) (a) McLaughlin, M.; Palucki, M.; Davies, I. W. Org. Lett. 2006, 8,
3307–3310. (b) Huo, Z.; Yamamoto, Y. Tetrahedron Lett. 2009, 50,
3651–3653. (c) Xu, L.; Lewis, I. R.; Davidsen, S. K.; Summers, J. B.
Tetrahedron Lett. 1998, 39, 5159–5162. (d) Fang, Y.-Q.; Yuen, J.;
Lautens, M. J. Org. Chem. 2007, 72, 5152–5160.
(5) Song, J. J.; Tan, Z.; Gallou, F.; Xu, J.; Yee, N. K.; Senanayake,
C. H. J. Org. Chem. 2005, 70, 6512–6514.
(8) (a) Whelligan, D. K.; Thomson, D. W.; Taylor, D.; Hoelder, S. J.
J. Org. Chem. 2010, 75, 11–15. (b) Debenham, S. D.; Chan, A.; Liu, K.;
Price, K.; Wood, H. B. Tetrahedron Lett. 2005, 46, 2283–2285.
(9) Kim, J. H.; Lee, S. B.; Lee, W. K.; Yoon, D.-H.; Ha, H.-J.
Tetrahedron 2011, 67, 3553–3558.
r
10.1021/ol301187s
Published on Web 06/05/2012
2012 American Chemical Society

provide the corresponding dipropargylic alcohols 3 in high
yields. This time we were able to prepare 1,2,3,5-substi-
tuted pyrroles which have a 2-azidomethyl substituent and
various acetylenic substituents at the C-3 position via
regioselective aziridine ring opening10 by TMSN3, fol-
lowed by silver ion catalyzed intramolecular cyclization
(Scheme 1 and Table 1).
Table 2. Formation of 2,5-Diphenyl-6-azaindole
base
temp
time
(h)
yield
(%)
entry
(equiv)
solvent
(°C)
Table 1. Preparation of Substituted Pyrrole 4
1
2
3
4
5
À
toluene
DMF
140
140
140
140
140
48
8
failed
18
À
À
DMSO
DMSO
DMF
12
18
6
failed
49
KOH (5)
KOH (5)
87
yield of 3
yield of 4
The mechanism of this modified intramolecular azido
cyclization of 2-azidomethyl-substituted pyrroles 4 with a
hydroxide base to form 6-azaindoles 5 is proposed with the
intramolecular base-catalyzed Schmidt cyclization shown
in Scheme 1. The anionic nitrogen of the azide attacks the
acetylene to form a six-membered ring, and then deproto-
nation of the benzylic proton by the hydroxide base releases
nitrogen gas to promote aromatization. As far as we know,
this is the first example of 6-endo intramolecular acetylenic
Schmidt cyclization that is free from any metal catalyst.14
entry
R
(%)
(%)
1
2
3
4
5
6
7
phenyl
3a, 98
3b, 84
3c 85
4a, 92a
4b, 89a
4c, 92a
4d, 95a
4e, 80b
4f, 91a
4-methoxyphenyl
2-tolyl
4-fluorophenyl
pyridin-2-yl
3d, 94
3e, 91
3f, 91
3g, 76
6-methoxynaphthalen-2-yl
phenanthren-9-yl
c
À
a The reaction was carried out in CH3CN . b The reaction was carried out
in DCM . c The reaction was carried out in DCM/CH3CN. Not isolated.
With the 2-azidomethyl-substituted pyrroles, we carried
out intramolecular acetylenic Schmidt reactions11 for the
synthesis of azaindoles in various reaction conditions.
Unlike usual indolization reactions in the presence of a
pyrrole ring, pyrrole-fused pyridine cyclization methods to
provide azaindoles are rare12 and introducing various sub-
stituents in the azaindole ring is another challenging task.
In the reactions of modified intramolecular azido, cycli-
zation provides 6-azaindoles in high yield without using
metal catalysts (Table 2).13 When the reaction was carried
out without a base in DMSO and toluene, we could not
obtain any product (entries 1 and 3). But in DMF we
obtained the expected 6-azaindole in 18% yield (entry 2).
However, when we added a hydroxide base (KOH), the
cyclization reaction proceeded smoothly to provide the
corresponding azaindole (entries 4 and 5). After nitrogen
cyclization to the acetylenic unit, the deprotonation fol-
lowed by N2 elimination seemed to be the driving force to
form 2,5-substituted 6-azaindoles in both DMSO (49%)
and DMF (87%).
Scheme 1. Proposed Mechanism of 6-Azaindoles Formation
This synthetic method was used to introduce various
substituents on the 2- and 5-positions of 6-azaindoles. The
cyclization reactions provided 6-azaindoles with diverse
aryl groups bearing electron donors, electron acceptors,
and bulky substituents. In all cases, intramolecular cycliza-
tion was succeeded to provide 6-azaindoles 5aÀ5g in high
yields of 74À87% (Table 3).
We also prepared 6-azaindoles which have different
substituents on the 2- and 5-positions from heterosubsti-
tuted bispropargylic alcohols 3h, 3i, and 3j synthesized by
two successive alkylation processes using different acety-
lene reagents.
Low temperature alkynylations provided the correspond-
ing ketones 2 in good yields. Subsequent addition of one
more alkyne afforded tertiary bispropargylic alcohols 3h, 3i,
and 3j with two different substituents R1 and R2 (Table 4).
When pyrrole cyclization was carried out with the
tertiary alcohols containing two different acetylenic
(10) Stankovic, S.; D’hooghe, M.; Catak, S.; Eum, H.; Waroquier,
M.; Van Speybroeck, V.; De Kimpe, N.; Ha, H.-J. Chem. Soc. Rev. 2012,
41, 643–665.
(11) Gorin, D. J.; Davis, N. R.; Toste, F. D. J. Am. Chem. Soc. 2005,
127, 11260–11261.
(12) (a) Huo, Z.; Yamamoto, Y. Tetrahedron Lett. 2009, 50, 3651–
3653. (b) Dekhane, M.; Potier, P.; Dodd, R. H. Tetrahedron 1993, 49,
8139–8146. (c) Mahadevan, I.; Rasmussen, M. J. Heterocycl. Chem.
1992, 29, 359–367.
(13) (a) Niu, Y.-N.; Yan, Z.-Y.; Gao, G.-L.; Wang, H.-L.; Shu,
X.-Z.; Ji, K.-G.; Liang, Y.-M. J. Org. Chem. 2009, 74, 2893–2896.
(b) Huo, Z.; Yamamoto, Y. Tetrahedron Lett. 2009, 50, 3651–3653.
(14) The intramolecular acetylenic Schmidt cyclization was first
reported in ref 11, which was a gold(II)-catalyzed 5-exo process.
Org. Lett., Vol. 14, No. 12, 2012
3121

Table 3. Preparation of 2,5-Disubstituted 6-Azaindoles (5) from
Pyrroles (4)
Table 5. Regioselective Formation of Pyrroles 4 and 6-Azain-
doles 5 from Aziridin-2-yl Bispropargylic Alcohols 3
yield of 5
entry
R
(%)
1
2
3
4
5
6
7
phenyl
5a, 87
5b, 84
5c, 74
5d, 84
5e, 75
5f, 78
4-methoxyphenyl
2-tolyl
4-fluorophenyl
pyridin-2-yl
yield of 4 yield of 5
entry
R2
(%)
(%)
R/β
6-methoxynaphthalen-2yl
phenanthren-9-yl
1
2
3
4-(dimethylamino)phenyl
4-methoxyphenyl
4-tolyl
4h, 84
4i, 84
4j, 82
5h, 70
5i, 71
5j, 79
100:0
83:17
77:23
5g, 76a
a Three-step yield.
Table 4. Preparation of Bispropargylic Alcohols
entry
R2
yield of 3 (%)
Figure 1. NOE interaction of 6-azaindole 5h.
1
2
3
4-(dimethylamino)phenyl
4-methoxyphenyl
4-tolyl
3h, 75
3i, 84
3j, 88
Scheme 2. Cleavage of the N-Benzyl Substituent
substituents, the regioselectivity of the cyclization was
controlled by the electronic character of the alkynic bond.
It was observed that only one pyrrole product 4 hr was
obtained when we had a strongly electron-donating 4--
(dimethylamino)phenyl substituent and a strongly elec-
tron-withdrawing 3,5-difluorophenyl (Table 5, entry 1).
However, as the difference between EDG and EWG
became smaller, i.e. from 4-(dimethylamino)phenyl to
4-methoxyphenyl and 4-tolyl, the regioselectivity between
R and β in the cyclization became poorer, i.e. 83:17 and
77:23 (Table 5). Regioselectivity of the pyrrole formation
was controlled by the electronic character of the triple
bond. A silver cation activates the comparably electron-
rich acetylene between two substituents. As a consequence
the pyrrole formation proceeds regioselectively toward the
triple bond containing an electron-donating substituent.
The structure of the 6-azaindole 5h was confirmed by
NOE experiments (Figure 1). These data confirm the
structure of the 6-azaindole 5h and also show that intra-
molecular pyrrole cyclization occurred selectively to more
electron-rich acetylenic systems.
The N-benzyl group originating from aziridine was easily
removed with t-BuOK to provide 6-azaindole 6, which has a
free pyrrole unit in high yield (Scheme 2).15
In conclusion, 2,5-disubstituted 6-azaindoles were efficiently
synthesized in high yields by an intramolecular azido cycliza-
tion reaction to the acetylenic group of azidomethyl substituted
pyrroles which were prepared from substituted aziridines.
Acknowledgment. The authors are grateful for the finan-
cial support from the National Research Foundation of Korea
(NRF-2010-0005538 and NRF-2009-0081956 for W.K.L.
and NRF-2010-0008424 and NRF-2011-0012379 for H.J.H.).
Supporting Information Available. Experimental details
and copies of 1H and 13C spectra for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(15) Haddach, A. A.; Kelleman, A.; Deaton-Rewolinski, M. V.
Tetrahedron Lett. 2002, 43, 399–402.
The authors declare no competing financial interest.
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