A novel Cu-assisted cycloisomerization of alkynyl imines: Efficient synthesis of pyrroles and pyrrole-containing heterocycles [9]

Full text of DOI:10.1021/ja0058684

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J. Am. Chem. Soc. 2001, 123, 2074-2075
Table 1. Cu-Assisted Synthesis of Pyrroles 2
A Novel Cu-Assisted Cycloisomerization of Alkynyl
Imines: Efficient Synthesis of Pyrroles and
Pyrrole-Containing Heterocycles
Alexander V. Kel’in, Anna W. Sromek, and
Vladimir Gevorgyan*
Department of Chemistry, UniVersity of Illinois at Chicago
845 West Taylor Street, Chicago, Illinois 60607-7061
ReceiVed December 11, 2000
Pyrroles are important heterocycles broadly used in material
science1 and found in naturally occurring and biologically
important molecules.2 Accordingly, substantial attention has been
paid to develop efficient methods for the synthesis of pyrroles.
Most known methods for the construction of the pyrrole ring
proceed via various types of cycloaddition or cycloisomerization
of acyclic precursors1,2a,3 and are most effective for forming 2,5-
di- or polysubstituted pyrroles. To the best of our knowledge,
there are no convenient methods for the formation of a mono-
substituted pyrrole ring.4 Herein we wish to report a novel,
general, and efficient method for the construction of 2-monosub-
stituted and 2,5-disubstituted pyrroles, as well as fused aromatic
heterocycles containing a pyrrole ring, via the Cu-assisted
cycloisomerization of readily available alkynyl imines.
First, it was found that N-butyl-substituted alkynyl imine 1a5
in the presence of CuI (30 mol %) in Et3N/DMA (1:7) at 110 °C
underwent cycloisomerization to give pyrrole 2a in 50% yield
(eq 1, Table 1, entry 1). Replacement of the n-butyl group at
nitrogen with the tert-butyl group dramatically increased the
efficiency of cycloisomerization providing the pyrrole 2b in 86%
yield (entry 2). Encouraged by this finding, we searched for
another, potentially deprotectable group. This would allow access
to synthetically more attractive N-unsubstituted pyrroles. We
found that the trityl6 and the 3-(ethylbutyryl)7 (EB) groups
perfectly serve these purposes: the corresponding alkynyl imines
underwent smooth cycloisomerization to give the pyrroles 2c and
2d8 in 91% and 93% yields, respectively (entries 3 and 4).
Naturally, most of our further cycloisomerization experiments
a Isolated yields.
were performed with easily deprotectable N-EB-substituted alky-
nyl imines. This method was found to be rather general with
respect to functional group compatibility: 5-pentenyl- (1e),
2-cyanoethyl- (1f), OTBS-methyl- (1g), and OTBS- (1h) substi-
tuted imines readily cycloisomerized to afford the corresponding
pyrroles 2e-h in reasonable to good yields (Table 1, entries 5-8).
In all of the above examples, the monosubstituted pyrroles were
synthesized from the alkynyl aldimines 1a-h. Alternatively, the
monosubstituted pyrroles 2i,j can be efficiently synthesized from
the corresponding propynyl ketimines 1i,j (entries 9 and 10).
Finally, the 2,5-disubstituted pyrrole 2k was prepared in 87% yield
from the ketimine 1k (entry 11).
Inspired by the successful cycloisomerization of acyclic alkynyl
imines to pyrroles, we attempted the cycloisomerization of the
cyclic alkynyl imines 3.9 We were pleased to find that 2-hexynyl
pyridine 3a in the presence of CuCl (50 mol %) at 130 °C
underwent smooth cycloisomerization to give the indolizine10 4a
in 91% yield (Table 2, entry 1). This approach proved to be
general for the synthesis of various types of fused N-containing
heteroaromatic compounds (eq 2, Table 2). Thus, a number of
(1) For most recent work, see: Lee, C.-F.; Yang, L.-M.; Hwu, T.-Y.; Feng,
A.-S.; Tseng, J.-C.; Luh, T.-Y. J. Am. Chem. Soc. 2000, 122, 4992, and
references therein.
(2) For a review see: (a) Gossauer, A. Pyrrole. In Houben-Weyl; Thieme:
Stuttgart, 1994; E6a/1, p 556. See also: (b) Boger, D. L.; Boyce, C. W.;
Labroli, M. A.; Sehon, C. A.; Jin, Q. J. Am. Chem. Soc. 1999, 121, 54. (c)
Furstner, A.; Weintritt, H. J. Am. Chem. Soc. 1998, 120, 2817. (d) Sayah, B.;
Pelloux-Leon, N.; Vallee, Y. J. Org. Chem. 2000, 65, 2824. (e) Liu, J.-H.;
Yang, Q.-C.; Mak, T. C. W.; Wong, H. N. C. J. Org. Chem. 2000, 65, 3587.
(3) For a review, see: (a) Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1
1999, 2849. See also: (b) Tarasova, O. A.; Nedolya, N. A.; Vvedensky, V.
Yu.; Brandsma, L.; Trofimov, B. A. Tetrahedron Lett. 1997, 38, 7241.
(4) For formation of the 2-monosubstituted pyrrole ring from γ-keto
aldehydes or related precursors, see: (a) Reference 2a. See also: (b) Gadzhily,
R. A.; Fedoseev, V. M.; Dzhafarov, V. G. Chem. Heterocycl. Compd. 1990,
26, 874. (c) Engel, N.; Steglich, W. Angew. Chem., Int. Ed. 1978, 17, 676.
For syntheses of 2-monosubstituted pyrroles via acylation-reduction or
alkylation of pyrrole see, for example: (d) Garrido, D. O. A.; Buldain, G.;
Frydman, B. J. Org. Chem. 1984, 49, 2619. (e) Muchowski, J. M.; Solas, D.
R. J. Org. Chem. 1984, 49, 203.
(5) For preparation of 1, see Supporting Information (SI).
(6) For deprotection of the N-Tr-group in pyrroles, see: Chadwick, D. J.;
Hodgson, S. T. J. Chem. Soc., Perkin Trans. 1 1983, 93.
(7) For deprotection of the analogous group from pyrroles, see: Roder,
E.; Wiedenfeld, H.; Bourauel, T. Liebigs Ann. Chem. 1985, 1708.
(8) 2d was deprotected into the corresponding N-H pyrrole quantitatively
via retro-Michael protocol. See SI for details.
heterocyclic alkynyl substrates, such as pyridines (entries 1-3),
quinoline (entry 4), isoquinoline (entry 5), pyrimidine (entry 6),
10.1021/ja0058684 CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/08/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 9, 2001 2075
Table 2. Cu-Assisted Synthesis of Fused Heterocycles 4
Scheme 1
not conflict with the proposed base-induced deprotonation-
protonation sequence (Scheme 1). Furthermore, the cycloisomer-
ization of 1j in the presence of decanal provided 2j along with
17% of the trapping product 11 (eq 3), thus supporting possible
involvement of an anionic intermediate of type-9 in the above
cycloisomerization reaction (Scheme 1).13 As a further demonstra-
tion of the synthetic utility of this novel cycloisomerization
methodology, we describe its application for an expeditious
synthesis of (() monomorine 15 (eq 4).14 The shortest synthesis
of (()15 known involves six steps from noncommercially
available starting material.14b We found that (()15 can now be
synthesized efficiently in three steps, in 47% overall yield, from
the commercially available bromopyridine 12. Thus, 12 was
quantitatively converted into the alkynylpyridine 13, which
underwent the cycloisomerization to give the indolizine 14 in 63%
yield. Catalytic hydrogenation of 14 gave (() monomorine 15 in
74% yield (eq 4).
a Isolated yields.
and thiazole (entry 7), effectively participated in the cycloisomer-
ization to give the corresponding fused heteroaromatic compounds
4 (eq 2, Table 2).
As a working hypothesis, we propose the following mecha-
nism: first, 5 would undergo a base-induced propargyl-allenyl
isomerization to form 6; next, coordination of copper to the
terminal double bond of the allene (intermediate 7) would make
it subject to intramolecular nucleophilic attack to produce a
zwitterion 8.11 The latter would isomerize into the more stable
zwitterionic intermediate 9, which would transform to the pyrrole
10 (Scheme 1). In fact, the following observations provide certain
support for the proposed mechanism. Significant deuterium loss,
which occurred during the cycloisomerization of 5 into pyrrole
10,12 rules out possible involvement of “clean” H-shifts and does
In conclusion, a novel, general, and efficient method, the Cu-
assisted cycloisomerization of alkynyl imines into the pyrrole ring,
has been developed. The generality and synthetic usefulness of
this methodology was demonstrated in the efficient synthesis of
pyrroles, various types of fused heteroaromatic compounds, and
the expeditious synthesis of (() monomorine 15.
Acknowledgment. The support of the National Science Foundation
and the Petroleum Research Fund, administrated by the American
Chemical Society, is gratefully acknowledged.
(9) Cyclic alkynyl imines 3 were readily prepared by the Sonogashira
protocol. For the original reference, see: Sonogashira, K.; Tohda, Y.; Hagihara,
N. Tetrahedron Lett. 1975, 4467.
(10) 1,2-Unsubstituted indolizines are not available using common ap-
proaches, such as Tschitschibabin reaction. For the most comprehensive review,
see: Behnisch, R.; Behnisch, P.; Eggenweiler, M.; Wallenhorst, T. Indolizine.
In Houben-Weyl; Thieme: Stuttgart, 1994; StuE6a/2a, p 323.
(11) A similar step has been proposed for the silver-assisted cycloisomer-
ization of the allenyl ketones into furans, see: Marshall, J. A.; Bartley, G. S.
J. Org. Chem. 1994, 59, 7169.
Supporting Information Available: Experimental details (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
JA0058684
(13) A control experiment revealed no acylation reaction of 2j with decanal
under the same reaction conditions.
(14) For a review on the syntheses of monomorine and related idolizidine
alkaloids, see: (a) Jefford, C. W. Current Org. Chem. 2000, 4, 205. For the
most efficient synthesis of (()monomorine, see: (b) Jefford, C. W.; Tang,
Q.; Zaslona, A. HelV. Chim. Acta 1989, 72, 1749.
(12) A control experiment confirmed that 10 did not undergo any detectable
change in the isotope composition upon the above-mentioned reaction
conditions.