Rhodium(I)-catalyzed [4+1] cycloaddition reactions of α, βunsaturated imines with terminal alkynes for the preparation of pyrrole derivatives

Article abstract of DOI:10.1002/anie.200904402

Rhodium vinylidene intermediates are characteristic for the title reaction (see scheme; coe = cyclooctene, cy = cyclohexyl). This reaction proceeds by the nucleophilic addition of the nitrogen atom of the imine to the rhodium vinylidene complex to give a zwitterionic intermediate, which undergoes intramolecular cyclization to afford the corresponding pyrrole.

Full text of DOI:10.1002/anie.200904402

Communications
DOI: 10.1002/anie.200904402
Cycloaddition Reactions
Rhodium(I)-Catalyzed [4+1] Cycloaddition Reactions of a,b-
Unsaturated Imines with Terminal Alkynes for the Preparation of
Pyrrole Derivatives**
Akio Mizuno, Hiroyuki Kusama, and Nobuharu Iwasawa*
Vinylidene complexes have attracted much attention for
being unique reactive intermediate and synthetically useful,
and characteristic reactions have been developed using
various kinds of transition-metal complexes.[1] One of the
main reactions involves the addition of heteroatom nucleo-
philes such as alcohols, carboxylates, and carbamates to give
anti-Markovnikov addition products.[1] However, the addition
showed somewhat lower activity compared to [{RhCl-
(coe)2}2]/PCy3.
The reaction is thought to proceed by the nucleophilic
addition of the nitrogen atom of the imine 1a to the carbene
carbon atom of the rhodium vinylidene complex A,[5] which is
generated in situ from the terminal alkyne, to afford a
zwitterionic intermediate B (Scheme 2). This intermediate
=
of the heteroatom of C X bonds to the vinylidene carbon
atom has rarely been achieved in spite of the high synthetic
potential of the zwitterionic intermediates that are pro-
duced.[2] Herein, we report
a
rhodium(I)-catalyzed
[4+1] cycloaddition reaction between a,b-unsaturated
imines and terminal alkynes for the preparation of syntheti-
cally useful, substituted pyrrole derivatives through the
addition of the imine nitrogen atom to rhodium vinylidene
intermediates.[3]
When a mixture of b-TMS-substituted a,b-unsaturated
imine 1a and 1-octyne (2a) was treated with a catalytic
amount of [{RhCl(coe)2}2] and PCy3 in toluene at 1108C for
nine hours, pyrrole 3a (a formal [4+1] cycloaddition prod-
uct)[4] was obtained in good yield (Scheme 1). In this reaction
[{RhCl(coe)2}2], as well as other phosphine ligands such as
PPh3, P(iPr)3, 1,4-bis(diphenylphosphanyl)butane (dppb), and
1,1’-bis(diphenylphosphanyl)ferrocene (dppf) showed almost
no activity. Also, [{RhOH(cod)}2] (cod = 1,5-cyclooctadiene),
[Rh(cod)2]BF4, and [{IrCl(coe)2}2] in the presence of PCy3 did
not show any activity either. Meanwhile, [{RhCl(cod)2}2]/PCy3
Scheme 2. Proposed reaction mechanism.
further undergoes intramolecular cyclization to generate
metalacyclic intermediate C. Finally, reductive elimination
proceeds to give the pyrrole 3a via enamine D through olefin
isomerization and desilylation[6] with regeneration of the
catalyst. The reaction of imine 1a with 1-deuterio-1-octyne
([D1]-2a) gave pyrrole [D1]-3a wherein deuterium (90%
incorporation) was introduced onto the carbon atom adjacent
to the pyrrole ring (Scheme 3). Furthermore, the isolated
[7]
= =
vinylidene complex [RhCl( C C(H)nHex)(PCy3)2] also
catalyzed the reaction under similar reaction conditions
(Scheme 4). These results are consistent with the proposed
mechanism shown in Scheme 2. Thus, by utilizing the rhodium
vinylidene complex, a novel [4+1] cycloaddition was realized
where the a,b-unsaturated imine and terminal alkyne carbon
atom constitute the pyrrole ring through a zwitterionic
intermediate.
Scheme 1. Rhodium(I)-catalyzed [4+1] cycloaddition reaction between
a,b-unsaturated imine 1a and terminal alkyne 2a. Bn=benzyl, coe=
cyclooctene, Cy=cyclohexyl, TMS=trimethylsilyl.
Recently, Colby, Bergman, and Ellman reported an
apparently similar combination of reactants and reagents to
[*] A. Mizuno, Dr. H. Kusama, Prof. Dr. N. Iwasawa
Department of Chemistry, Tokyo Institute of Technology
O-okayama, Meguro-ku, Tokyo 152-8551 (Japan)
Fax: (+81)3-5734-2931
E-mail: niwasawa@chem.titech.ac.jp
[**] This research was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science,
and Technology of Japan. A.M. was granted a Research Fellowship of
the Japan Society for the Promotion of Science for Young Scientists.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200904402.
Scheme 3. [4+1] Cycloaddition reaction using 1-deuterio-1-octyne ([D1]-
2a).
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Chemie
Table 1: [4+1] Cycloaddition reactions of imine 1a with several alkynes.
Entry
2
Alkyne
Yield of 3 [%][a]
1
2
2b
2c
56 (3b)
71[b] (3c)
Scheme 4. [4+1] Cycloaddition reaction using the isolated rhodium
vinylidene complex.
3
4
5
2d
2e
2 f
73[c] (3d)
70 (3e)
75 (3 f)
give dihydropyridines instead of pyrroles.[8] In their reaction,
À
C H bond activation took place at the b position to the imine
6
2g
66[d] (3g)
moiety, and subsequent alkyne insertion gave 1,3,5-azatrienes,
which underwent thermal electrocyclization and gave dihy-
dropyridines.[8]
[a] Yield of isolated product. [b] 15% of 1a was recovered. [c] 13% of 1a
was recovered. [d] 24% yield of 3g and 42% yield of its 3-TMS derivative
were obtained. TBS=tert-butyldimethylsilyl.
To evaluate the importance of the TMS group, a compar-
ison of the reactions using b-nonsubstituted derivative 4a and
b-silyl-substituted a,b-unsaturated imine 4b was carried out.
When nonsubstituted imine 4a was treated with [{RhCl-
(coe)2}2] and PCy3 in toluene at 1108C, the corresponding
pyrrole 5a was obtained in only 12% yield and pyridines 6
were obtained as the major products (Scheme 5). In contrast,
entries 2–5).[12] Furthermore, even trisubstituted pyrrole 8 f
could be obtained by using ketimine 7 f (Table 2, entry 6). The
preparation of substituted pyrroles is important because of
their high utility as medicinal agents[13] and functional
materials[14] etc., and this approach would be a concise
method for the preparation of such pyrroles in a catalytic
manner.[15]
In summary, we have developed a novel rhodium(I)-
catalyzed intermolecular [4+1] cycloaddition reaction of a,b-
unsaturated imines with terminal alkynes by utilizing the
addition of the imine nitrogen atom to the rhodium vinylidene
complex. This reaction demonstrates another utility of the
rhodium vinylidene complex as a reactive species. Also, the
reaction could be a useful method for the preparation of
substituted pyrroles with high tolerance of functional groups.
Efforts are currently underway to expand the scope of this
reaction and to clarify the mechanism more explicitly.
Scheme 5. [4+1] or [4+2] Cycloaddition reaction of imine 4a and 4b.
imine 4b, which has a TMS group at the b position, gave
pyrrole 5a as the only isolable product, albeit in low yield.
Table 2: [4+1] Cycloaddition reactions of several imines with 1-octyne.
À
The TMS group is assumed to inhibit the C H activation
reaction at the b position to the imine moiety.[9,10]
The reaction of imine 1a with several terminal alkyne
derivatives was examined under the optimized reaction
conditions (Table 1). The reaction proceeded smoothly with
alkynes possessing a functional group such as silyl ether or
methoxycarbonyl group to give 2-subustituted pyrroles in
good yield (Table 1, entries 2 and 3). Notably, alkynes with a
more sensitive functional group such as nitrile, chloro, or
amino groups also reacted with 1a to give the corresponding
functionalized pyrroles in good yield (Table 1, entries 4–6).[6]
Next, we carried out the reaction using several imine
derivatives which have a Me substituent on the nitrogen atom
instead of a Bn group:[11] to do this we employed 1-octyne as
the alkyne counterpart (Table 2). In these cases, the yield of
pyrrole derivatives was somewhat improved by carrying out
the reaction in the presence of three equivalents each of NBu3
and H2O to suppress side reactions. Imine 7a, which is derived
from phenyl ketone, gave pyrrole 8a in good yield (Table 2,
entry 1). Ketimines 7b–7e with alkenyl, alkynyl, or heteroaryl
substituents were also employed and gave the corresponding
2,5-disubstituted pyrroles in reasonable yield (Table 2,
Entry
7 (E/Z)
R1
R2
Yield of 8 [%][a]
1
7a (1:3)
7b[e]
Ph
H
H
H
H
H
Me
72 (8a)
64 (8b)
50 (8c)
53 (8d)
62 (8e)
56 (8 f)
2[b]
3
C C(Me)2
propynyl
2-furyl
=
7c[f]
4[b]
5[b]
6[c,d]
7d (1:1)
7e (1:4)
7 f (1:2.5)
2-thienyl
Ph
[a] Yield of isolated product. [b] 3 equivalents of 1-octyne were used.
[c] The reaction was carried out without NBu3 at 1.0m. [d] 17% of imine
7 f was recovered. [e] Geometry of imine 7b was mostly E. [f] Geometry
of imine 7c could not be determined (but was mostly one isomer).
Experimental Section
General procedure: A degassed solution of a,b-unsaturated imine
(0.2 mmol) and terminal alkyne (0.40 mmol) in toluene (0.5 mL,
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Communications
0.4m) was added to [{RhCl(coe)2}2] (0.01 mmol, 10 mol% at Rh
Ed. Engl. 1985, 24, 406 – 408, and see the Supporting Information
for details.
atom) and PCy3 (0,04 mmol, 20 mol%). The reaction mixture was
kept in a closed system and was stirred for 9–24 h at 1108C before the
solvent was removed under reduced pressure to give the crude
product, which was purified by column chromatography on silica gel
to give the corresponding pyrrole derivative.
[8] a) D. A. Colby, R. G. Bergman, J. A. Ellman, J. Am. Chem. Soc.
2006, 128, 5604 – 5605; b) D. A. Colby, R. G. Bergman, J. A.
Ellman, J. Am. Chem. Soc. 2008, 130, 3645 – 3651; where internal
alkynes were employed in most cases and only one example was
reported for a terminal alkyne to give the corresponding
dihydropyridine in good yield. This type of transformation was
first reported by Odom and co-workers; c) C. Cao, Y. Li, Y. Shi,
A. L. Odom, Chem. Commun. 2004, 2002 – 2003.
Received: August 6, 2009
Published online: September 25, 2009
[9] Other imines, which have methyl or phenyl group instead of a
TMS group at the b position, did not give the corresponding
pyrroles (or pyridines). In the case of the imine with a phenyl
substituent, most of the starting material was recovered. In
contrast, the imine bearing a methyl group was mostly con-
sumed, but the reaction gave a complex mixture of unidentified
products. Thus, the presence of the TMS (or silyl) group is
essential for this reaction.
[10] Other silyl substituents at the b position gave the following
results. PhMe2Si: 65% (recovery 5%); TBS: 15% (recovery
58%). Bulkier silyl group retarded the reaction.
[11] When ketimines with a benzyl group on the nitrogen atom were
used as substrates, corresponding pyrroles were obtained in low
yield because of the competitive 1,5-hydride shift.
Keywords: a,b-unsaturated imines · cycloaddition · pyrroles ·
rhodium · terminal alkynes
.
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[6] In the crude products, 3-TMS derivatives were obtained in most
cases and the ratio of TMS derivative to protodesilylated
derivative depended on the reaction conditions and the nature
of the substrate. The protodesilylation reaction of TMS-sub-
stituted pyrrole usually proceeded smoothly during purification
by column chromatography on silica gel, however, 1-benzyl-2-
{(5-morpholino)pentyl}-3-(trimethylsilyl) pyrrole was isolated in
the reaction of morpholino derivative 2g.
[7] The vinylidene complex was prepared according to the proce-
dure for the preparation of similar rhodium(I) vinylidene
complexes. F. J. G. Alonso, A. Hꢁhn, J. Wolf, H. Otto, H.
Werner, Angew. Chem. 1985, 97, 401 – 402; Angew. Chem. Int.
8320 www.angewandte.org
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