Concise synthesis of indole-fused 1,4-diazepines through copper(l)-catalyzed domino three-component coupling-cyclization-N-arylation under microwave irradiation

Article abstract of DOI:10.1021/ol801383b

(Chemical Equation Presented) Indole-fused benzo-1,4-diazepines were synthesized by copper-catalyzed domino three-component coupling-indole formation-N-arylation under microwave irradiation from a simple N-mesyl-2-ethynylaniline. This method was also applicable to the formation of heterocycle-fused 1,4-diazepines.

Full text of DOI:10.1021/ol801383b

ORGANIC
LETTERS
2008
Vol. 10, No. 16
3535-3538
Concise Synthesis of Indole-Fused
1,4-Diazepines through
Copper(I)-Catalyzed Domino
Three-Component
Coupling-Cyclization-N-Arylation
under Microwave Irradiation
Yusuke Ohta, Hiroaki Chiba, Shinya Oishi, Nobutaka Fujii,* and Hiroaki Ohno*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Sakyo-ku,
Kyoto 606-8501, Japan
hohno@pharm.kyoto-u.ac.jp; nfujii@pharm.kyoto-u.ac.jp
Received June 19, 2008
ABSTRACT
Indole-fused benzo-1,4-diazepines were synthesized by copper-catalyzed domino three-component coupling-indole formation-N-arylation
under microwave irradiation from a simple N-mesyl-2-ethynylaniline. This method was also applicable to the formation of heterocycle-fused
1,4-diazepines.
New methods that produce complex, useful molecules from
simpler materials in a single reaction vessel are important
challenges in modern synthetic chemistry. Tandem cataly-
sis,1,2 which involves several catalytic cycles within the same
medium to produce a desired product, is becoming increas-
ingly important for the economic and environmental accept-
ability of the process. Copper salts are efficient catalysts in
various transformations, including formation of carbon-
(1) For a recent review on concurrent tandem catalysis, see: (a) Wasilke,
J.-C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem. ReV. 2005, 105, 1001–
1020. See also: (b) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew.
(3) For reviews, see: (a) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem.
2002, 3221–3236. (b) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed.
2003, 42, 5400–5449. (c) Chemler, S. R.; Fuller, P. H. Chem. Soc. ReV.
2007, 36, 1153–1160. (d) Carril, M.; SanMartin, R.; Dom´ınguez, E. Chem.
Soc. ReV. 2008, 37, 639–647.
Chem., Int. Ed. 2006, 45, 7134–7186
.
(2) For representative examples, see: (a) Burk, M. J.; Lee, J. R.; Martinez,
J. P. J. Am. Chem. Soc. 1994, 116, 10847–10848. (b) Jeong, N.; Seo, S. D.;
Shin, J. Y. J. Am. Chem. Soc. 2000, 122, 10220–10221. (c) Bielawski, C. W.;
Louie, J.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 12872–12873. (d)
Son, S. U.; Park, K. H.; Seo, H.; Chung, Y. K.; Lee, S.-G. Chem. Commun.
2001, 2440–2441. (e) Sutton, A. E.; Seigal, B. A.; Finnegan, D. F.; Snapper,
M. L. J. Am. Chem. Soc. 2002, 124, 13390–13391. (f) Komon, Z. J. A.;
Diamond, G. M.; Leclerc, M. K.; Murphy, V.; Okazaki, M.; Bazan, G. C.
J. Am. Chem. Soc. 2002, 124, 15280–15285. (g) Dijk, E. W.; Panella, L.;
Pinho, P.; Naasz, R.; Meetsma, A.; Minnaard, A. J.; Feringa, B. L.
Tetrahedron 2004, 60, 9687–9693. (h) van As, B. A. C.; van Buijtenen, J.;
Heise, A.; Broxterman, Q. B.; Verzijl, G. K. M.; Palmans, A. R. A.; Meijer,
(4) For selected examples of tandem catalytic reaction using a copper
salt including two catalytic cycles, see: (a) Hiroya, K.; Itoh, S.; Ozawa,
M.; Kanamori, Y.; Sakamoto, T. Tetrahedron Lett. 2002, 43, 1277–1280.
(b) Kamijo, S.; Sasaki, Y.; Yamamoto, Y. Tetrahedron Lett. 2004, 45, 35–
38. (c) Li, K.; Alexakis, A. Tetrahedron Lett. 2005, 46, 8019–8022. (d)
Loones, K. T. J.; Maes, B. U. W.; Meyers, C.; Deruytter, J. J. Org. Chem.
2006, 71, 260–264. (e) Yuen, J.; Fang, Y.-Q.; Lautens, M. Org. Lett. 2006,
8, 653–656. (f) Zhang, L.; Malinakova, H. C. J. Org. Chem. 2007, 72, 1484–
1487. (g) Martin, R.; Laursen, C. H.; Cuenca, A.; Buchwald, S. L. Org.
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10.1021/ol801383b CCC: $40.75
Published on Web 07/11/2008
2008 American Chemical Society

carbon and carbon-nitrogen bonds.3 We postulated they
could play key parts in construction of complex nitrogen
heterocycles with important biological activities through
formation of multiple bonds.4
Indole and 1,4-benzodiazepine frameworks are useful
templates for drug discovery. Indole-fused 1,4-diazepine,5
found in various bioactive compounds, can also be an
attractive drug template. We recently reported a novel
copper(I)-catalyzed synthesis of 2-(aminomethyl)indoles via
a three-component coupling-cyclization reaction.6,7 This
indole formation prompted us to develop a novel method
for the synthesis of indole-fused tetracyclic compounds by
three-component indole formation and simultaneous copper-
catalyzed N-arylation (Scheme 1). We expected that a copper
catalyzed domino reactions, which involve the formation of
one carbon-carbon bond and three carbon-nitrogen bonds.
We chose N-mesyl-2-ethynylaniline 1a as a model sub-
strate because three-component indole formation requires
N-substituted ethynylanilines.6 Appropriate conditions were
initially investigated for one-pot, three-component indole
formation, deprotection of the mesyl group, and subsequent
N-arylation. A mixture of 1a, paraformaldehyde (2 equiv),
and secondary amine 2a (1.1 equiv) was treated with CuI (5
mol %) in toluene, and after indole formation was completed
(monitored by TLC), an additive for cleavage of the N-mesyl
group was introduced (Table 1).8 Addition of MeOK and
Table 1. Screening of Reaction Conditions Using Ethynylaniline
1a and Secondary Amine 2aa
Scheme 1. Copper(I)-Catalyzed Domino Three-Component
Coupling-Cyclization-N-Arylation Reaction
catalyst
entry (mol %) solvent
conditions additive conditions yieldc
Ab
(equiv)
Bb
(%)
1
2
3
4
5
6
7
8
9
CuI (5) toluene reflux
MeOK (6) reflux
1 h
t-BuOK (6) reflux
0.5 h
MeONa (6) reflux
3 h
MeONa (6) 80 °C
ligand (0.1)d 4 h
MeONa (6) reflux
3 h
43
6 h
CuI (5) toluene reflux
38
51
34
49
6 h
CuI (5) toluene reflux
6 h
CuI (5) toluene reflux
6 h
CuBr (5) toluene reflux
6 h
CuI (5) toluene MW, 170 °C MeONa (6) MW, 170 °C 64
20 min 20 min
CuI (5) dioxane MW, 170 °C MeONa (6) MW, 170 °C 81
20 min 20 min
CuI (1) dioxane MW, 170 °C MeONa (6) MW, 170 °C 77
20 min 20 min
CuI (2.5) dioxane MW, 170 °C MeONa (6) MW, 170 °C 88
20 min 20 min
salt could catalyze multiple transformations, including Man-
nich-type coupling of ethynylaniline derivative 1 with
formaldehyde and N-substituted o-halobenzylamine 2, indole
formation, and arylation of the indole nitrogen. In this paper,
we report direct access to indole-fused tetracyclic compounds
3 containing the 1,4-diazepine framework by copper(I)-
a After the reaction with 2-ethynylaniline 1a, paraformaldehyde (2 equiv),
and secondary amine 2a (1.1 equiv) was completed on TLC, additives were
introduced. b MW ) microwave irradiation. c Isolated yields. d Ligand )
(()-trans-N,N′-dimethylcyclohexane-1,2-diamine.
(5) (a) Maryanoff, B. E.; Nortey, S. O.; Gardocki, J. F. J. Med. Chem.
1984, 27, 1067–1071. (b) Ho, C. Y.; Hageman, W. E.; Persico, F. J. J. Med.
Chem. 1986, 29, 1118–1121. (c) Suzuki, H.; Shinpo, K.; Yamazaki, T.;
Niwa, S.; Yokoyama, Y.; Murakami, Y. Heterocycles 1996, 42, 83–86. (d)
Sasaki, S.; Ehara, T.; Sakata, I.; Fujino, Y.; Harada, N.; Kimura, J.;
Nakamura, H.; Maeda, M. Bioorg. Med. Chem. Lett. 2001, 11, 583–585.
(e) Kau, T. R.; Schroeder, F.; Ramaswamy, S.; Wojciechowski, C. L.; Zhao,
J. J.; Roberts, T. M.; Clardy, J.; Sellers, W. R.; Silver, P. A. Cancer Cell
2003, 4, 463–476. (f) Ennis, M. D.; Hoffman, R. L.; Ghazal, N. B.; Olson,
R. M.; Knauer, C. S.; Chio, C. L.; Hyslop, D. K.; Campbell, J. E.; Fitzgerald,
L. W.; Nichols, N. F.; Svensson, K. A.; McCall, R. B.; Haber, C. L.; Kagey,
M. L.; Dinh, D. M. Bioorg. Med. Chem. Lett. 2003, 13, 2369–2372. (g)
Ducker, C. E.; Griffel, L. K.; Smith, R. A.; Keller, S. N.; Zhuang, Y.; Xia,
Z.; Diller, J. D.; Smith, C. D. Mol. Cancer Ther. 2006, 5, 1647–1659. (h)
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C.; Wang, B.; Cavender, D.; Murray, W. V. Bioorg. Med. Chem. Lett. 2007,
17, 326–331.
heating of the reaction mixture under reflux for 1 h promoted
the desired arylation of the indole nitrogen to afford the
expected tetracyclic compound 3a9 in ca. 43% yield (entry
1). t-BuOK was less effective, leading to ca. 38% yield of
3a (entry 2). These runs furnished tetracyclic compound 3a
containing some impurities that were not easily removed,
but the reaction with MeONa under reflux for 3 h gave pure
3a in 51% yield after column chromatography (entry 3).
(8) One portion addition of all the reactants including the alkoxide at
the beginning of the reaction caused decomposition of the starting material.
(9) For patent information including a related tetracyclic compound, see:
Ivashchenko, A. V.; Ilyin, A. P.; Kysil, V. M.; Trifilenkov, A. S.;
Tsirulnikov, S. A.; Shkirando, A. M.; Churakova, M. V.; Lomakina, I. O.;
Potapov, V. V.; Zamaletdinova, A. I.; Tkachenko, S. Y.; Kravchenko, D. V.;
Khvat, A. V.; Okun, I. M.; Kyselev, A. S. PCT Int. Appl. 2007,
WO2007117180.
(6) Ohno, H.; Ohta, Y.; Oishi, S.; Fujii, N. Angew. Chem., Int. Ed. 2007,
46, 2295–2298
.
(7) For a related isoquinoline formation, see: (a) Ohta, Y.; Oishi, S.;
Fujii, N.; Ohno, H. Chem. Commun. 2008, 835–837
.
3536
Org. Lett., Vol. 10, No. 16, 2008

formation using several 2-ethynylanilines 1a-d and second-
ary amines 2b-d (Table 2). Whereas the reaction of
2-ethynylaniline 1a, paraformaldehyde, and 2-bromobenzy-
lamine 2b bearing a smaller N-substituent under standard
conditions gave the corresponding indole-fused benzodiaz-
epine 3b in relatively low yield (51%, entry 1), the reaction
using 2c or 2d, carrying a removable nitrogen substituent
such as benzyl and allyl groups, proceeded smoothly to give
3c and 3d in 83% and 81% yields, respectively (entries 2
and 3). Ethynylaniline 1b bearing a methoxycarbonyl group
at the para-position of the amino group, gave a poor result
to afford 3e (23% yield), along with a complex mixture of
unidentified products (entry 4).11 Anilines 1c and 1d with a
p-trifluoromethyl or methyl group, respectively, were good
substrates for this copper-catalyzed reaction sequence (entries
5 and 6). The reaction with ethynylaniline 1e containing a
trifluoromethyl group at the meta position gave a moderate
yield of 3h (53% yield, entry 7). Thus, the copper-catalyzed
synthesis of indole-fused benzodiazepine was applicable to
various N-substituted o-bromobenzylamines and 2-ethyny-
lanilines with an electron-donating or electron-withdrawing
group.
Table 2. Construction of Tetracyclic Compounds Using
Substituted Ethynylanilines and o-Bromobenzylaminesa
Synthesis of tetracyclic compounds containing a heterocycle-
fused 1,4-diazepine was investigated (Scheme 2). By em-
Scheme 2
.
Direct Synthesis of Pyridine- or Thiophene-Fused
Tetracyclic Compounds
a All reactions were conducted with ethynylaniline 1, paraformaldehyde
(2 equiv), and secondary amine 2 (1.1 equiv) in the presence of CuI (2.5
mol %) in 1,4-dioxane at 170 °C for 20-40 min under microwave
irradiation. After the indole formation was completed on TLC, MeONa (6
equiv) was added and the mixture was heated at 170 °C for 20 min under
microwave irradiation. b Isolated yields.
Simultaneous addition of racemic trans-N,N′-dimethylcy-
clohexane-1,2-diamine, an efficient ligand for CuI-catalyzed
intermolecular N-arylation of indoles,10 was not effective for
the present formation of 1,4-diazepine (34%, entry 4).
Replacement of CuI by CuBr slightly decreased the yield of
3a (49%, entry 5). Microwave-assisted conditions at 170 °C
for the formation of indole and diazepine improved the
overall yield to 64% (entry 6). Investigation of the reaction
solvent and loading of the catalyst (entries 6-9) revealed
that 2.5 mol % of CuI in dioxane most effectively produced
3a in 88% yield within 40 min (entry 9).
ploying the secondary amines 4 and 6 involving a pyridine
and thiophene moiety, respectively, the reaction directly
delivered the desired pyridine- and thiophene-fused tetracy-
clic compounds 5 and 7 in 71% and 56% yields, respectively.
From these observations, this copper-catalyzed formation of
tetracyclic compounds allows the synthesis of indole-fused
1,4-diazepines containing another heterocyclic ring system.
In conclusion, we developed a novel method for the
preparation of fused indoles by copper-catalyzed domino
three-component coupling-indole formation-N-arylation.
Starting from simple 2-ethynylanilines and o-bromobenzy-
lamines, complex indole-fused tetracyclic compounds were
Having established optimal conditions (Table 1, entry 9),
we examined the scope of this indole-fused benzodiazepine
(11) Since the formation 2-(aminomethyl)indole using 1b and 2d
proceeded efficiently (quantitative yield), deprotection conditions using
MeONa caused undesired side reactions.
(10) Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 11684–11688.
Org. Lett., Vol. 10, No. 16, 2008
3537

easily and directly synthesized in a single reaction vessel.
This is the first example of copper-catalyzed one-pot reaction
including three catalytic cycles and formation of four bonds.
Further studies for construction of other heterocyclic ring
systems as well as development of novel drug templates
using this method are underway.
Program. Y.O. is grateful to Research Fellowships of the
Japan Society for the Promotion of Science (JSPS) for Young
Scientists. Appreciation is expressed to Fundamental Studies
in Health Sciences of the National Institute of Biomedical
Innovation (NIBIO).
Supporting Information Available: A General experi-
mental procedure and 1H and 13C NMR spectra for all indole-
fused 1,4-diazepines (3a-h, 5, and 7). This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was supported by a Grant-
in-Aid for Encouragement of Young Scientists (A) (H.O.)
from the Ministry of Education, Culture, Sports, Science and
Technology of Japan, and Targeted Proteins Research
OL801383B
3538
Org. Lett., Vol. 10, No. 16, 2008