Asymmetric Friedel-Crafts alkylation of pyrroles with nitroalkenes using a dinuclear zinc catalyst

Article abstract of DOI:10.1021/ja711080y

The catalytic enantioselective and atom economic Friedel-Crafts alkylation of pyrroles with nitroalkenes under mild reaction conditions using a dinuclear zinc catalyst is reported. The versatility of the reaction is demonstrated by the conversion of a number of differentially substituted nitroalkenes with differentially substituted pyrroles. Tandem addition reactions to form 2,5-disubstituted pyrroles are also demsonstrated. All pyrrole alkylations have been carried out without using N-protecting groups, which also enhances the efficiency by which substituted pyrroles may be synthesized. The reactions result in good yields and excellent enantioselectivities. Copyright

Full text of DOI:10.1021/ja711080y

Published on Web 02/01/2008
Asymmetric Friedel-Crafts Alkylation of Pyrroles with Nitroalkenes Using a
Dinuclear Zinc Catalyst
Barry M. Trost* and Christoph Mu¨ller
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received December 13, 2007; E-mail: bmtrost@stanford.edu
Table 1. Reaction of Various Pyrroles with Nitroalkenesa
Since first reported in the year 1877,1 the Friedel-Crafts reaction
has gained substantial synthetic and industrial significance as an
immensely powerful tool to effect C-C bond-formations.2 Recently,
there have been studies conducted with the aim of developing
asymmetric and catalytic versions of this important transforma-
tion.3,4 Among the stereoselective alkylations of aromatic and
heteroaromatic compounds, reports about the use of pyrroles,
especially unprotected pyrroles, remain rare.5 Pyrroles are abundant
in natural products,6 medicinal agents,7 and a number of intermedi-
ates in multistep syntheses.8 Because of the relative instability of
pyrroles toward acidic environments, classical Friedel-Crafts
conditions are unsuitable for this class of compounds. Instead, mild
reaction conditions are required to implement a useful Friedel-
Crafts protocol for these substrates. Herein we report the use of
our dinuclear zinc bis-ProPhenol complex9 as an efficient catalyst
to conduct asymmetric Friedel-Crafts alkylations of unprotected
pyrroles with nitroalkenes, to prepare 2-substituted and 2,5-
disubstituted pyrroles with an asymmetric carbon atom in the
R-position. The nitro-compounds were chosen because of the strong
electron withdrawing character and the synthetic versatility of that
functional group.10 The bis-ProPhenol complex has previously been
used in a number of efficient, catalytic enantioselective transforma-
tions and has been applied successfully to a number of natural
product syntheses.11
To optimize the reaction conditions, pyrrole was reacted with
nitroalkene 2. The dinuclear zinc complex 1 was prepared as
previously reported by treating the bis-ProPhenol ligand with 2
equiv of Et2Zn in THF at room temperature.9 Our studies indicated
that an excess of 3 equiv of pyrrole leads to the highest yields and
stereoselectivities. A decrease of the catalyst loading below 10 mol
%, the use of toluene as solvent or an increase of the reaction
temperature resulted in lower yields and selectivities. As conditions
of choice, we used THF at room temperature and a catalyst loading
of 10 mol % in the presence of molecular sieves (4 Å).
To explore the scope of the reaction, various nitroalkenes were
reacted with pyrrole (Table 1). First, aromatic substituents were
used as R′ (entry 1-5). In all these cases, excellent enantioselec-
tivities were obtained, which ranged from 87% for the o-methoxy
substrate 5 to 97% for the tolyl substituted compound 2. The
position of the methoxy-substituent of compound 4 and 5 (ortho
vs para) did not affect either the reactivity or selectivity of the
reaction. An improvement of the yield was observed by using a
furanyl substituent (entry 6). This finding cannot be rationalized
by a simple coordination of the furan-oxygen atom of nitroalkene
7 to the dinuclear zinc complex, for the additional oxygen atoms
in substrates 12 and 13 give lower yields and selectivities (vide
infra). Compared to the furanyl-derived substrate 7, the thiophene
derived nitroalkene 8 gave a slightly increased enantioselectivity
of 97% (entry 7). In addition to the aromatic and heteroaromatic
substituents R′ presented above, entries 8-12 show examples for
alkyl substituents R′. The best result in these cases was obtained
for the cyclohexyl-substituted compound 9 (entry 8) which gave
an excellent yield and selectivity. Both branched and straight chain
a Reaction performed with (S,S)-complex 1 (10 mol %), pyrrole or pyrrole
derivative (3 equiv), nitroalkene (1 equiv) and molecular sieves (4 Å) in
THF at room temp. b Determined by chiral HPLC. c b.r.s.m. d Reaction
performed with the (R,R)-ligand and Et2Zn.
alkyl groups on the nitroalkene as in compounds 10 and 11 (entries
9 and 10) gave very high enantioselectivities.
As mentioned above, it was hoped that by introducing further
oxygen atoms into the nitroalkene, the yield could possibly be
enhanced like in the case of compound 7. Therefore, substrates 12
and 13 were prepared (entries 11 and 12). In both cases however,
the additional oxygen-atoms did not increase yield or selectivity.
Next, we examined the behavior of substituted pyrroles. These
substrates were prepared by direct addition reactions starting from
pyrrole. In combination with our Friedel-Crafts protocol, we were
able to gain access to 2,5-disubstituted pyrroles in a simple two-
step sequence (eq 1). For these transformations, we used the furanyl-
nitroalkene 7 and the iso-propyl-nitroalkene 10 as examples for an
aromatic and a noncyclic, aliphatic substituent R′, respectively
9
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10.1021/ja711080y CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Proposed Catalytic Cycle
the efficiency by which substituted pyrroles may be synthesized.
Further investigations concerning the scope of the dinuclear zinc
complex are under way in our group.
Acknowledgment. We thank the National Science Foundation
and the National Institutes of Health (NIH-13598) for their generous
support of our programs. C.M. thanks the Deutscher Akademischer
Austausch Dienst (DAAD) for a postdoctoral fellowship.
Supporting Information Available: Experimental procedures and
characterization data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
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(entries 13-16). We were pleased to observe that the MVK-derived
compound 14 and the phenylvinyl ketone-derived substrate 15 both
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nitroalkene 7. In the case of nitroalkene 10 however, only pyrrole
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609-612.
To rationalize the observed results, we propose a mechanism
that involves the deprotonation of pyrrole by precatalyst 1 ac-
companied by the formation of 1 equiv of ethane (Scheme 1). The
nitroalkene coordinates to this catalyst and undergoes the alkylation
reaction. The catalytic cycle is closed by a proton exchange with
an incoming pyrrole to release the product and reform the active
catalyst.
The absolute stereochemistry of the products was determined
by comparison with a literature known compound, 17.12 This was
accomplished by an oxidation-esterification procedure in analogy
to the oxidative cleavage-esterification of furans.13 In the first step,
pyrrole 16 was oxidized to the derived carboxylic acid, which then
was converted into the known methyl ester 17 (eq 2).
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Chem., Int. Ed. 2005, 44, 5664-5667. (b) Garg, N. K.; Caspi, D. D.;
Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 5970-5978. (c) Dhawan, R.;
Arndtsen, B. A. J. Am. Chem. Soc. 2004, 126, 468-469. (d) Donohoe, T.
J.; Sintim, H.; Sisangia, L.; Harling, J. D. Angew. Chem., Int. Ed. 2004,
43, 2293-2296.
(9) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003-12004.
(10) For a review about Michael Additions to nitroalkenes, see: Berner, O.
M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 1877-1894. For
examples of Friedel-Crafts reactions of indoles with nitroalkenes, see:
(a) Bandini, M.; Garelli, A.; Rovinetti, M.; Tommasi, S.; Umani-Ronchi,
A. Chirality 2005, 17, 522-529. (b) Zhuang, W.; Hazell, R. G.; Jorgensen,
K. A. Org. Biomol. Chem. 2005, 3, 2566-2571. (c) Fleming, E. M.;
McCabe, T.; Connon, S. J. Tetrahedron Lett. 2006, 47, 7037-7042. (d)
Singh, P. K.; Bisai, A.; Singh, V. K. Tetrahedron Lett. 2007, 48, 1127-
1129. (e) Sui, Y.; Liu, L.; Zhao, J. L.; Wang, D.; Chen, Y. J. Tetrahedron
2007, 63, 5173-5183.
(11) For aldol reactions, see: (a) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000,
122, 12003-12004. (b) Trost, B. M.; Ito, H.; Silcoff, E. R. J. Am. Chem.
Soc. 2001, 123, 3367-3368. (c) Trost, B. M.; Silcoff, E. R.; Ito, H. Org.
Lett. 2001, 3, 2497-2500. (d) Trost, B. M.; Fettes, A.; Shireman, B. T.
J. Am. Chem. Soc. 2004, 126, 2660-2661. (e) Trost, B. M.; Shin, S. H.;
Sclafani, J. A. J. Am. Chem. Soc. 2005, 127, 8602-8603. For Mannich
reactions, see: (f) Trost, B. M.; Terrell, L. R. J. Am. Chem. Soc. 2003,
125, 338-339. (g) Trost, B. M.; Jaratjaroonphong, J.; Reutrakul, V. J.
Am. Chem. Soc. 2006, 128, 2778-2779. For nitroaldol reactions, see: (h)
Trost, B. M.; Yeh, V. S. C. Angew. Chem., Int. Ed. 2002, 41, 861-863.
For desymmetrizations, see: (i) Trost, B. M.; Mino, T. J. Am. Chem.
Soc. 2003, 125, 2410-2411. For alkynylations of aldehydes, see: (j) Trost,
B. M.; Weiss, A. H.; von Wangelin, A. J. J. Am. Chem. Soc. 2006, 128,
8-9. For applications in natural product synthesis, see: (k) Trost, B. M.;
Yeh, V. S. C. Org. Lett. 2002, 4, 3513-3516. (l) Trost, B. M.; Yeh, V.
S. C.; Ito, H.; Bremeyer, N. Org. Lett. 2002, 4, 2621-2623. (m) Trost,
B. M.; Frederiksen, M. U.; Papillon, J. P. N.; Harrington, P. E.; Shin, S.;
Shireman, B. T. J. Am. Chem. Soc. 2005, 127, 3666-3667. (n) Trost, B.
M.; Weiss, A. H. Org. Lett. 2006, 8, 4461-4464.
By comparison of the optical rotation, the absolute stereochem-
istry of the prepared compound was thus determined to be of the
S-configuration. The catalytic cycle depicted in Scheme 1 also nicely
accounts for this absolute configuration.
In conclusion, we have demonstrated the use of dinuclear zinc
bis-ProPhenol complex 1 in an atom economic Friedel-Crafts
reaction of unprotected pyrroles with a variety of differently
substituted nitroalkenes to give both mono- and disubstituted
pyrroles. The reactions shown gave excellent stereoselectivities in
most cases. Tandem atom economic addition reactions to form 2,5-
disubstituted pyrroles were also demonstrated. Further the avoidance
of using N-protecting groups in pyrrole alkylations also enhances
(12) Liu, H.; Xu, J.; Du, D.-M. Org. Lett. 2007, 9, 4725-4728.
(13) The oxidation was reported for furans in: Kohler, F.; Gais, H.-J.; Raabe,
G. Org. Lett. 2007, 9, 1231.
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