Efficient Synthesis of Aminomethylated Pyrroloindoles
SCHEME 1. Copper-Catalyzed Domino Three-Component
Coupling and Cyclization
SCHEME 2. Multicomponent Tandem Cyclization
Reactions of 8
control the reactions by appropriate choice of the reaction
conditions as well as functionality of the substrates.
In recent years, we reported a direct synthesis of 2-(aminom-
ethyl)indoles 4 via copper-catalyzed domino three-component
coupling and cyclization reactions of ethynylaniline 1 (Scheme
1).6,7 This reaction would proceed through a Mannich-type three-
component reaction of 1 with paraformaldehyde 2 and a
secondary amine 3 through formation of copper acetylide 5 from
a terminal alkyne, followed by the copper-catalyzed intramo-
lecular hydroamination8 of the internal alkyne. Based on this
reaction, we designed a multicomponent tandem cyclization
reaction of 1,3-phenylenediamine bearing two terminal alkynes
or its pyridine congener (8) with 1 or 2 equiv of formaldehyde
and a secondary amine (Scheme 2). Three types of tricyclic
compounds 9-11 can be selectively synthesized from the
common substrates 8: (1) successive Mannich-type reactions
of 8 at both alkynes followed by tandem cyclization would give
bis-aminomethylated tricyclic compounds 9, (2) monocyclization
of 8 followed by a Mannich-type reaction and the second
cyclization would afford monoaminomethylated tricyclic com-
pounds 10, and (3) tandem cyclization of 8 without using a
Mannich-type reaction would yield 2,6-unsubstituted tricyclic
compounds 11. Herein, we report the copper-catalyzed selective
synthesis of pyrroloindole derivatives9 and dipyrrolopyridine
derivatives10 9-11 (X ) CH and X ) N, respectively) by a
controlled Mannich-type reaction-cyclization.
Results and Discussion
Synthesis of 2,6-Bis(aminomethyl)pyrroloindole Derivatives.
In our previous study on the three-component indole formation,
the intramolecular hydroamination required N-substituted ethy-
nylanilines.6 Therefore, we first investigated the pyrroloindole
formation from 4,6-diethynyl-1,3-phenylenediamines 12-14
having acetyl, tosyl, or mesyl groups on both of the nitrogen
atoms (Table 1).11 We found that this reaction is strongly
dependent on the substituents on the nitrogen atoms. When using
diacetamide 12, a Mannich adduct 18a was obtained without
producing the desired intramolecular hydroamination product
(entry 1). On the other hand, the reaction of ditosylamide 13
gave the desired product 16a in 34% yield along with a
monoaminomethylated pyrroloindole derivative 19a in 14%
yield (entry 2). Among the three substrates tested, dimesylamide
14 showed the most promising result to afford the desired
product 17a in 69% yield (entry 3). We then optimized the
reaction conditions using the dimesylamide 14. Lowering the
reaction temperature to 60 or 40 °C slightly decreased the yields
of 17a (entries 4 and 5). According to the previous report,8d,f
the counteranion of copper catalysts considerably affects the
reactivity of the alkyne toward intramolecular hydroamination.
Among the copper salts investigated [CuI, CuBr, CuCl, CuBr2
and Cu(OAc)2, entries 3 and 6-9], CuI afforded the highest
yield of 17a (entry 3). When using Cu(OAc)2, 25% yield of
monoaminomethylated pyrroloindole 20a was obtained (entry
9). These results suggest that Cu(OAc)2 more strongly activates
the alkyne toward the intramolecular hydroamination than the
copper halides. Finally, the best result was obtained when a
mixed solvent of toluene and dioxane (1:1) was used in the
reaction (85%, entry 10).
(6) Ohno, H.; Ohta, Y.; Oishi, S.; Fujii, N. Angew. Chem., Int. Ed. 2007, 46,
2295–2298.
(7) For related reactions, see: (a) Ohta, Y.; Oishi, S.; Fujii, N.; Ohno, H.
Chem. Commun. 2008, 835–837. (b) Ohta, Y.; Chiba, H.; Oishi, S.; Fujii, N.;
Ohno, H. Org. Lett. 2008, 10, 3535–3538.
(8) For representative examples, see: (a) Fujiwara, J.; Fukutani, Y.; Sano,
H.; Maruoka, K.; Yamamoto, H. J. Am. Chem. Soc. 1983, 105, 7177–7179. (b)
Sakamoto, T.; Kondo, Y.; Iwashita, S.; Nagano, T.; Yamanaka, H. Chem. Pharm.
Bull. 1988, 36, 1305–1308. (c) Ma, C.; Yu, S.; He, X.; Liu, X.; Cook, J. M.
Tetrahedron Lett. 2000, 41, 2781–2785. (d) Hiroya, K.; Itoh, S.; Ozawa, M.;
Kanamori, Y.; Sakamoto, T. Tetrahedron Lett. 2002, 43, 1277–1280. (e) Cacchi,
S.; Fabrizi, G.; Parisi, L. M. Org. Lett. 2003, 5, 3843–3846. (f) Hiroya, K.; Itoh,
S.; Sakamoto, T. J. Org. Chem. 2004, 69, 1126–1136. (g) Kamijo, S.; Sasaki,
Y.; Yamamoto, Y. Tetrahedron Lett. 2004, 45, 35–38. (h) Nishikawa, T.; Koide,
Y.; Kajii, S.; Wada, K.; Ishikawa, M.; Isobe, M. Org. Biomol. Chem. 2005, 3,
687–700. (i) Majumdar, K. C.; Mondal, S. Tetrahedron Lett. 2008, 49, 2418–
2420.
Using the optimized reaction conditions (Table 1, entry 10),
we next investigated the scope of this reaction using several
secondary amines (Table 2). The reactions using piperidine 3b
proceeded faster than diethylamine 3a to give 17b in excellent
yield (95%, entry 1). The presence of the removable allyl groups
did not affect the yield, although a prolonged reaction time was
(9) For examples of synthesis of pyrroloindole derivatives, see: (a) Ezquerra,
J.; Pedregal, C.; Lamas, C.; Barluenga, J.; Prez, M.; Garca-Martin, G. A.;
Gonzlez, J. M. J. Org. Chem. 1996, 61, 5804–5812. (b) Burling, S.; Field, L. D.;
Li, H. L.; Messerle, B. A.; Shasha, A. Aust. J. Chem. 2004, 57, 677–680. (c)
Schenck, L. W.; Sippel, A.; Kuna, K.; Frank, W.; Albert, A.; Kucklaender, U.
Tetrahedron 2005, 61, 9129–9139.
(10) For examples of the synthesis of dipyrrolo[2,3-b:3′,2′-e]pyridine deriva-
tives, see: (a) Rodriguez, A. L.; Koradin, C.; Dohle, W.; Knochel, P. Angew.
Chem., Int. Ed. 2000, 39, 2488–2490. (b) Karadin, C.; Dohle, W.; Rodriguez,
A. L.; Schmid, B.; Knochel, P. Tetrahedron 2003, 59, 1571–1587.
(11) For synthesis of the requisite substrates, see the Supporting Informa-
tion.
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