Published on Web 01/27/2010

Nontraditional Reactions of Azomethine Ylides: Decarboxylative

Three-Component Couplings of r-Amino Acids
Chen Zhang and Daniel Seidel*
Department of Chemistry and Chemical Biology, Rutgers, The State UniVersity of New Jersey,
Piscataway, New Jersey 08854
Received December 20, 2009; E-mail: [email protected]

Decarboxylative reactions of R-amino acids with carbonyl resulting from the [3+2] cycloaddition of the intermediate azome-
compounds were first reported in 1862 in what is now known as thine ylide with excess benzaldehyde. Formation of the undesired
the Strecker degradation.1 The intermediacy of azomethine ylides compound 7 could be suppressed completely by delivering the
was first suggested by Rizzi2 and later established by Grigg who aldehyde slowly via syringe pump over 18 h. In this instance,
provided detailed insights into the mechanism of dipole formation.3 product 6a was isolated in excellent yield (91%). Additionally, trace
Inter- and intramolecular [3+2] cycloadditions of azomethine ylides amounts of a regioisomeric product were observed (Vide infra). The
are widely used in synthesis.4,5 Here we report a three-component scope of this reaction is summarized in Chart 1. Proline and other
decarboxylative R-functionalization of amino acids that involves a amino acids readily underwent three-component reactions with
new reaction pathway for azomethine ylides. aromatic or aliphatic aldehydes and different naphthol and indole
derivatives. In most cases, the desired regioisomer 6 was strongly
preferred over 6′. Interestingly, N-methyl indole, generally con-
sidered a stronger nucleophile as compared to unsubstituted
indole,15 did not participate in this reaction. A reaction with
sarcosine resulted in the exclusive formation of 6l′.
Chart 1. Reactions of Azomethine Ylides with Naphthols and
Indolesa,b

The potential of azomethine ylides to engage in nonpericyclic

reactions has not yet been evaluated to an appreciable extent. One
such reaction is that of proline with sterically congested 2-hydroxy-
acetophenones to form products 2 (R ) Me, X ) O, eq 1),
previously reported by Cohen.6 We recently reported the reaction
of aminobenzaldehydes (e.g., 1, R ) H, X ) NH) with proline as
part of a study on the formation of aminals via redox neutral
reactions between secondary amines and aminobenzaldehydes.7a
Subsequently, a related reaction was described by Dang and Bai.8
Concurrently, Li and co-workers reported interesting reactions of
N-benzylated amino acids (e.g., 3) with various nucleophiles (eq
2).9 These decarboxylative reactions require superstoichiometric
amounts of oxidant and a metal catalyst while giving rise to
synthetically useful products 4.10 Azomethine ylides, possibly bound
to a metal catalyst, were proposed as intermediates in this reaction.
Given our interest in developing redox-neutral transformations7,11
a
and due to the growing appreciation for redox economy,12 we were Reactions were performed on a 1 mmol scale. The aldehyde was added
intrigued by the idea of using in situ generated azomethine ylides via syringe pump over 18 h. The yields for the regioisomeric products are given
in related reactions with what would constitute nontraditional in parentheses. b 1.3 equiv of each, amino acid and aldehyde was used.
dipolarophiles (eq 3).13
In another set of experiments, we evaluated alkynes as nucleo-
philes in this process (Chart 2). Catalytic amounts of CuBr and
tetramethyl ethylenediamine (TMEDA) were employed to generate
copper acetylides which function as the active nucleophiles in this
process. As in the case of indoles and naphthols, no oxidant or
preformed N-alkylamino acid derivatives were required. Terminal
alkynes readily underwent decarboxylative coupling reactions with
We began our studies by evaluating the reaction between proline, proline and different benzaldehydes. Pipecolic acid and sarcosine
benzaldehyde, and
-naphthol (eq 4). Simple heating of a mixture were also viable substrates in this reaction, and good regioselec-
of the three components in toluene at reflux led to the formation of tivities were observed in most cases.16
the desired product 6a, albeit in only 40% yield. Not surprisingly, Nitroalkanes also engaged in reactions with azomethine ylides
1 (eq 6). Compounds 9 were isolated in moderate yields; only one
H NMR analysis of the crude reaction mixture indicated the
presence of significant quantities of the known compound 7,14 regioisomeric product was observed in each case.
1798 9 J. AM. CHEM. SOC. 2010, 132, 1798–1799 10.1021/ja910719x  2010 American Chemical Society
 COMMUNICATIONS
a
Chart 2. Reactions of Azomethine Ylides with Alkynes ions for Friedel-Crafts type alkylations, Mannich reactions, and
alkynylations. Widespread application of these and related reactions
is anticipated as they offer an opportunity for the rapid generation
of molecular complexity.
Acknowledgment. We thank the National Science Foundation
for support of this research (Grant CHE-0911192).

Supporting Information Available: Experimental procedures and

a
characterization data. This material is available free of charge via the
See footnote a in Chart 1. Internet at http://pubs.acs.org.

A proposed mechanism for the decarboxylative three component References

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of benzoic acid, reaction of N-methyl indole with proline and (16) After the submission of this manuscript, the formation of products 8 under
similar conditions was reported: Bi, H.-P.; Teng, Q.; Guan, M.; Chen, W.-
benzaldehyde gave rise to the formation of product 13 in 50% yield W.; Liang, Y.-M.; Yao, X.; Li, C.-J. J. Org. Chem. 2010 (DOI: 10.1021/
(eq 7).17 jo902319h).
In summary, we have introduced a new mode of reactivity for (17) The use of lower amounts of benzoic acid gave rise to lower yields.
azomethine ylides. The latter act as a convenient source for iminium JA910719X

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