Nontraditional reactions of azomethine ylides: Decarboxylative three-component couplings of α-amino acids

Article abstract of DOI:10.1021/ja910719x

(Formula Presented) New reactions of azomethine ylides with nontraditional dipolarophiles are reported. Azomethine ylides, formed in situ via decarboxylative condensations of α-amino acids with aldehydes, undergo reactions with naphthols, indoles, alkynes

Full text of DOI:10.1021/ja910719x

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: seidel@rutchem.rutgers.edu
Decarboxylative reactions of R-amino acids with carbonyl
resulting from the [3+2] cycloaddition of the intermediate azome-
thine ylide with excess benzaldehyde. Formation of the undesired
compound 7 could be suppressed completely by delivering the
aldehyde slowly via syringe pump over 18 h. In this instance,
product 6a was isolated in excellent yield (91%). Additionally, trace
amounts of a regioisomeric product were observed (Vide infra). The
scope of this reaction is summarized in Chart 1. Proline and other
amino acids readily underwent three-component reactions with
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′.
compounds were first reported in 1862 in what is now known as
the Strecker degradation.1 The intermediacy of azomethine ylides
was first suggested by Rizzi2 and later established by Grigg who
provided detailed insights into the mechanism of dipole formation.3
Inter- and intramolecular [3+2] cycloadditions of azomethine ylides
are widely used in synthesis.4,5 Here we report a three-component
decarboxylative R-functionalization of amino acids that involves a
new reaction pathway for azomethine ylides.
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
and due to the growing appreciation for redox economy,12 we were
intrigued by the idea of using in situ generated azomethine ylides
in related reactions with what would constitute nontraditional
dipolarophiles (eq 3).13
a Reactions were performed on a 1 mmol scale. The aldehyde was added
via syringe pump over 18 h. The yields for the regioisomeric products are given
in parentheses. b 1.3 equiv of each, amino acid and aldehyde was used.
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
proline and different benzaldehydes. Pipecolic acid and sarcosine
were also viable substrates in this reaction, and good regioselec-
tivities were observed in most cases.16
We began our studies by evaluating the reaction between proline,
benzaldehyde, and ꢀ-naphthol (eq 4). Simple heating of a mixture
of the three components in toluene at reflux led to the formation of
the desired product 6a, albeit in only 40% yield. Not surprisingly,
1H NMR analysis of the crude reaction mixture indicated the
presence of significant quantities of the known compound 7,14
Nitroalkanes also engaged in reactions with azomethine ylides
(eq 6). Compounds 9 were isolated in moderate yields; only one
regioisomeric product was observed in each case.
9
1798 J. AM. CHEM. SOC. 2010, 132, 1798–1799
10.1021/ja910719x  2010 American Chemical Society

C O M M U N I C A T I O N S
Chart 2. Reactions of Azomethine Ylides with Alkynesa
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
characterization data. This material is available free of charge via the
Internet at http://pubs.acs.org.
a See footnote a in Chart 1.
References
A proposed mechanism for the decarboxylative three component
coupling reaction is outlined in Figure 1. Condensation of proline
with an aldehyde results in the formation of oxazolidin-5-one 10,
a known intermediate in the subsequent decarboxylative formation
of the azomethine ylide 11.3d Protonation of the dipole by the
pronucleophile H-Nu results in the formation of ion pairs 12 or
12′ which then collapse into products 5 or 5′. A concerted pathway
for the direct transformation of 11 into 5 or 5′ cannot be ruled out
for certain substrates. This proposed mechanism readily explains
the formation of the two regioisomers and suggests that the
regioselectivity of this reaction depends on the charge distribution
in the azomethine ylide 11, in addition to potential steric factors.
R-groups with electron-withdrawing character appear to stabilize
dipoles with a higher partial negative charge in the benzylic position.
This favors protonation of the benzylic position and ultimately leads
to the formation of regioisomer 5, in accordance with what was
observed for the m-Cl-phenyl bearing product 6b. In contrast,
azomethine ylides bearing aromatic R-groups with electron-donating
character gave rise to the formation of an increased amount of the
regioisomer 5′, which was the case for the p-MeO-phenyl bearing
substrate 6f. However, even in the latter case, regioisomer 5 was
still formed predominantly.
(1) (a) Strecker, A. Liebigs Ann. Chem. 1862, 123, 363. (b) Scho¨nberg, A.;
Moubasher, R. Chem. ReV. 1952, 50, 261.
(2) Rizzi, G. P. J. Org. Chem. 1970, 35, 2069.
(3) For examples, see: (a) Grigg, R.; Thianpatanagul, S. J. Chem. Soc., Chem.
Commun. 1984, 180. (b) Grigg, R.; Aly, M. F.; Sridharan, V.; Thianpa-
tanagul, S. J. Chem. Soc., Chem. Commun. 1984, 182. (c) Ardill, H.; Grigg,
R.; Sridharan, V.; Surendrakumar, S.; Thianpatanagul, S.; Kanajun, S.
J. Chem. Soc., Chem. Commun. 1986, 602. (d) Grigg, R.; Idle, J.;
McMeekin, P.; Vipond, D. J. Chem. Soc., Chem. Commun. 1987, 49. (e)
Grigg, R.; Kilner, C.; Sarker, M. A. B.; Orgaz de la Cierva, C.; Dondas,
H. A. Tetrahedron 2008, 64, 8974.
(4) For selected reviews, see: (a) Padwa, A., Ed. 1,3-Dipolar Cycloaddition
Chemistry, Vol. 1; Wiley: New York, NY, 1984; p 817. (b) Padwa, A.,
Ed. 1,3-Dipolar Cycloaddition Chemistry, Vol. 2.; Wiley: New York, NY,
1984; p 704. (c) Padwa, A.; Pearson, W. H. Synthetic Applications of 1,3-
Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural
Products; Wiley: Chichester, U.K., 2002; Vol. 59, p 940. (d) Na´jera, C.;
Sansano, J. M. Curr. Org. Chem. 2003, 7, 1105. (e) Coldham, I.; Hufton,
R. Chem. ReV. 2005, 105, 2765. (f) Pandey, G.; Banerjee, P.; Gadre, S. R.
Chem. ReV. 2006, 106, 4484.
(5) Azomethine ylides are known to engage in 1,5- or 1,7-electrocyclizations:
(a) Arany, A.; Bendell, D.; Groundwater, P. W.; Garnett, I.; Nyerges, M.
J. Chem. Soc., Perkin Trans. 1999, 1, 2605. (b) Nyerges, M.; Pinter, A.;
Viranyi, A.; Blasko, G.; Toke, L. Tetrahedron 2005, 61, 8199. (c) Nyerges,
M.; Toth, J.; Groundwater, P. W. Synlett 2008, 1269.
(6) Cohen, N.; Blount, J. F.; Lopresti, R. J.; Trullinger, D. P. J. Org. Chem.
1979, 44, 4005.
(7) (a) Zhang, C.; De, C. K.; Mal, R.; Seidel, D. J. Am. Chem. Soc. 2008, 130,
416. (b) Murarka, S.; Zhang, C.; Konieczynska, M. D.; Seidel, D. Org.
Lett. 2009, 11, 129. (c) Zhang, C.; Murarka, S.; Seidel, D. J. Org. Chem.
2009, 74, 419. (d) Murarka, S.; Deb, I.; Zhang, C.; Seidel, D. J. Am. Chem.
Soc. 2009, 131, 13226.
(8) Zheng, L.; Yang, F.; Dang, Q.; Bai, X. Org. Lett. 2008, 10, 889.
(9) (a) Bi, H.-P.; Zhao, L.; Liang, Y.-M.; Li, C.-J. Angew. Chem., Int. Ed.
2009, 48, 792. (b) Bi, H.-P.; Chen, W.-W.; Liang, Y.-M.; Li, C.-J. Org.
Lett. 2009, 11, 3246.
(10) Metal catalyzed decarboxylative couplings have recently emerged as
valuable synthetic tools. For examples, see: (a) Myers, A. G.; Tanaka, D.;
Mannion, M. R. J. Am. Chem. Soc. 2002, 124, 11250. (b) Rayabarapu,
D. K.; Tunge, J. A. J. Am. Chem. Soc. 2005, 127, 13510. (c) Goossen,
L. J.; Deng, G.; Levy, L. M. Science 2006, 313, 662.
Figure 1. Proposed mechanism for the reaction of azomethine ylides with
pronucleophiles.
(11) For selected examples of recent contributions by others, see: (a) Polonka-
Balint, A.; Saraceno, C.; Luda´nyi, K.; Be´nyei, A.; Matyus, P. Synlett 2008,
2846. (b) Trost, B. M.; Livingston, R. C. J. Am. Chem. Soc. 2008, 130,
11970. (c) Yeom, H.-S.; Lee, J.-E.; Shin, S. Angew. Chem., Int. Ed. 2008,
47, 7040. (d) McQuaid, K. M.; Sames, D. J. Am. Chem. Soc. 2009, 131,
402. (e) Vadola, P. A.; Sames, D. J. Am. Chem. Soc. 2009, 131, 16525. (f)
Ruble, J. C.; Hurd, A. R.; Johnson, T. A.; Sherry, D. A.; Barbachyn, M. R.;
Toogood, P. L.; Bundy, G. L.; Graber, D. R.; Kamilar, G. M. J. Am. Chem.
Soc. 2009, 131, 3991. (g) Shikanai, D.; Murase, H.; Hata, T.; Urabe, H.
J. Am. Chem. Soc. 2009, 131, 3166. (h) Tobisu, M.; Nakai, H.; Chatani,
N. J. Org. Chem. 2009, 74, 5471. (i) Frank, E.; Schneider, G.; Kadar, Z.;
Woelfling, J. Eur. J. Org. Chem. 2009, 3544. (j) Mahoney, S. J.; Moon,
D. T.; Hollinger, J.; Fillion, E. Tetrahedron Lett. 2009, 50, 4706. (k) Mori,
K.; Ohshima, Y.; Ehara, K.; Akiyama, T. Chem. Lett. 2009, 38, 524. (l)
Han, S. B.; Kim, I. S.; Han, H.; Krische, M. J. J. Am. Chem. Soc. 2009,
131, 6916.
The mechanism depicted in Figure 1 provides a satisfying
explanation for the failure of N-methylindole to engage in this
reaction. If the protonation of dipole 11 is indeed a prerequisite
for nucleophilic attack, the scope of this reaction might be extended
to other nucleophiles simply by addition of an acid promoter. The
latter could serve to protonate dipole 11, form an iminium ion
related to 12, and subsequently react with nucleophiles that would
otherwise fail to add to azomethine ylides. Indeed, in the presence
of benzoic acid, reaction of N-methyl indole with proline and
benzaldehyde gave rise to the formation of product 13 in 50% yield
(eq 7).17
(12) (a) Burns, N. Z.; Baran, P. S.; Hoffmann, R. W. Angew. Chem., Int. Ed.
2009, 48, 2854. (b) Newhouse, T.; Baran, P. S.; Hoffmann, R. W. Chem.
Soc. ReV. 2009, 38, 3010.
(13) For an excellent review on the R-functionalization of amines, see: Campos,
K. R. Chem. Soc. ReV. 2007, 36, 1069.
(14) Orsini, F.; Pelizzoni, F.; Forte, M.; Destro, R.; Gariboldi, P. Tetrahedron
1988, 44, 519.
(15) Lakhdar, S.; Westermaier, M.; Terrier, F.; Goumont, R.; Boubaker, T.; Ofial,
A. R.; Mayr, H. J. Org. Chem. 2006, 71, 9088.
(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.-
W.; Liang, Y.-M.; Yao, X.; Li, C.-J. J. Org. Chem. 2010 (DOI: 10.1021/
jo902319h).
(17) The use of lower amounts of benzoic acid gave rise to lower yields.
In summary, we have introduced a new mode of reactivity for
azomethine ylides. The latter act as a convenient source for iminium
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