Enecarbamates as imine surrogates: Nucleophilic addition of 1,3-dicarbonyl compounds to enecarbamates

Article abstract of DOI:10.1021/ol0620186

(Chemical Equation Presented) Novel Mannich-type reactions of 1,3-dicarbonyl compounds with enecarbamates have been developed. Stable and storable enecarbamates work as surrogates of aliphatic aldehyde-derived imines, which are known to be difficult to isolate and store.

Full text of DOI:10.1021/ol0620186

ORGANIC
LETTERS
2006
Vol. 8, No. 21
4923-4925
Enecarbamates as Imine Surrogates:
Nucleophilic Addition of 1,3-Dicarbonyl
Compounds to Enecarbamates
Shu¯ Kobayashi,* Tomas Gustafsson, Yusuke Shimizu, Hiroshi Kiyohara, and
Ryosuke Matsubara
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo,
The HFRE DiVision, ERATO, Japan Science and Technology Agency (JST),
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
skobayas@mol.f.u-tokyo.ac.jp
Received August 15, 2006
ABSTRACT
Novel Mannich-type reactions of 1,3-dicarbonyl compounds with enecarbamates have been developed. Stable and storable enecarbamates
work as surrogates of aliphatic aldehyde-derived imines, which are known to be difficult to isolate and store.
Nucleophilic addition to imines provides a facile synthetic
route to nitrogen-containing compounds, many of which are
of biological and chemical importance.1 Although there have
been many reports of addition reactions involving imines so
far,2 most of these have employed imines such as those
derived from aromatic aldehydes or ethyl glyoxylate. In
addition, imines bearing hydrogens at the R position are
known to isomerize readily to the corresponding enamines
and to be difficult to isolate and purify.3
catalytic asymmetric hydrogenation ractions.4 Recently we
have reported that enamides and enecarbamates can be used
as nucleophiles and that they react with several electrophiles
in the presence of Lewis acids.5 During these investigations,
we found that enamides and enecarbamates dimerize on
treatment with a strong Brønsted or Lewis acid such as
TfOH, Sc(OTf)3, or Cu(OTf)2 (Scheme 1).6 These results
Enamides and enecarbamates are stable under air and easy
to handle, and they have often been used as substrates in
Scheme 1. Self-Condensation of Enecarbamates
(1) (a) Kibayashi, C. Chem. Pharm. Bull. 2005, 53, 1375. (b) Joullie´,
M. M.; Richard, D. J. Chem. Commun. 2004, 2011.
(2) Reviews: (a) Denmark, S. E.; Nicaise, O. J.-C. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Heidelberg, 1999; pp 923-961. (b) Kleinmann, E. F. In
ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: New
York, 1991; Vol. 2, Chapter 4.1. (c) Arend, M.; Westermann, B.; Risch,
N. Angew. Chem., Int. Ed. 1998, 37, 1044. (d) Kobayashi, S.; Ishitani, H.
Chem. ReV. 1999, 99, 1069.
(3) To overcome this problem, a synthetic equivalent has been used. For
an example, see: (a) Coˆte´, A.; Boezio, A. A.; Charette, A. B. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5405. (b) Pearson, W. H.; Lindbeck, A. C.;
Kampf, J. W. J. Am. Chem. Soc. 1993, 115, 2622. (c) Ha, H.-J.; Ahn, Y.-
G. Synth. Commun. 1995, 25, 969. (d) Katritzky, A. R.; Rachwal, S.;
Hitchings, G. J. Tetrahedron 1991, 47, 2683.
indicate that enamides and enecarbamates isomerize to the
corresponding imines under acidic conditions and that imines
so formed are activated by acids to react with the second
10.1021/ol0620186 CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/21/2006

Scheme 2. Proposed Catalytic Cycle
Table 2. Catalytic Reactions of Enecarbamates 1 with
1,3-Dicarbonyl Compounds 2a
enamides and enecarbamates. We envisioned that the second
enamides and enecarbamates might be replaced by other
nucleophiles and that in that case enamides and enecarbam-
ates might work as aliphatic imine surrogates. Herein we
realize this idea, and would like to report the catalytic direct
Mannich-type reactions of 1,3-dicarbonyl compounds with
enecarbamates catalyzed by Cu(OTf)2 or Sc(OTf)3.
To prevent enamides and enecarbamates from dimerizing
under acidic conditions, it is necessary to use nucleophiles
that are more reactive than enamindes and enecarbamates
themselves. In general, however, most reactive nucleo-
philes such as metal-carbon nucleophiles are unstable under
Brønsted acidic conditions. A strategy to overcome this
problem is shown in Scheme 2. Nucleophiles would be
activated by a metal salt to form a Brønsted acid,7 which
could isomerize enamides and enecarbamates to iminium
Table 1. Screening of Metal Saltsa
a Reaction conditions: a solution of 1a (1.0 equiv) in the indicated solvent
was added to a suspension of 2a (1.5 equiv) and a metal salt (10 mol %)
in the indicated solvent over 12 h at room temperature. b In most cases,
diastereoselectivity is within a range of 1:1 and 1:2 except with 3d and 3e
(single diastereomer), 3g (4:1), and 3t (9:1).
entry
M(OTf)x
solvent
yield (%)
1
2
3
4
5
6
7
8
9
Cu(OTf)2
Cu(OTf)2
Sc(OTf)3
Sc(OTf)3
Sn(OTf)2
Sn(OTf)2
Yb(OTf)3
Bi(OTf)3
Zn(OTf)2
CuOTf
DCE
Tol
DCE
Tol
DCE
Tol
DCE
DCE
DCE
DCE
89
73
73
49
71
55
6
56
0
0
species. Iminium species would be reactive enough to
undergo nucleophilic additions by activated metal-containing
species to afford the desired adducts along with regeneration
of the metal salt.
On the basis of this scheme, we examined the reaction of
enecarbamates 1a8 with â-ketoester 2a.9 Several metal salts
10
a Reaction conditions: a solution of 1a (1.0 equiv) in the indicated solvent
was added to a suspension of 2a (1.5 equiv) and a metal salt (10 mol %)
in the indicated solvent over 12 h at room temperature.
(4) Gridnev, I. D.; Imamoto, T. Acc. Chem. Res. 2004, 37, 633 and
references therein.
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Org. Lett., Vol. 8, No. 21, 2006

and solvents were screened, and the results are summarized
in Table 1. Of the metal salts used, Cu(OTf)2 and Sc(OTf)3
were revealed to be the most promising catalysts, 10 mol %
of each metal salt affording the desired Mannich-type product
in 89% and 73% yield, respectively. 1,2-Dichloroethane
(DCE) and toluene (Tol) were found to be appropriate
solvents. The reaction at 0 °C gave a yield lower than that
of the reaction at room temperature. In all cases, slow
addition of enecarbamate 1a was conducted over 12 h, rapid
mixing of all substrates directly giving a lower yield due to
fast dimerization of the enecarbamate.
Having established optimal conditions, we then studied
substrate scope of the reaction (Table 2). Enecarbamates
reacted with various â-ketoesters, â-ketoamide, and 1,3-
diketones smoothly to afford the corresponding adducts in
high yields. In general, Cu(OTf)2 gave high yields, whereas
Sc(OTf)3 provided better results in some other cases.
Interestingly, a difference of reactivity between (E)- and (Z)-
enecarbamates was observed (entry 10 vs 12). (Z)-Enecar-
bamate is more reactive than (E)-enecarbamate, which is
rationalized by considering the higher free energy of (Z)-
enecarbamate at ground state (due to steric repulsion), leading
to easy isomerization to reactive iminium species. It is noted
that the Boc protecting group (enecarbamate 1b) is tolerant
in this reaction.
In summary, we have developed novel Mannich-type
reactions of 1,3-dicarbonyl compounds with enecarbamates.
Lewis acids such as Cu(OTf)2 and Sc(OTf)3 promoted this
reaction to provide the adducts in good yields. The proposed
mechanism involves coordination of the metal salt first to
the 1,3-dicarbonyl compound to generate a metal enolate and
a strong Brønsted acid, which converts an enecarbamate to
the corresponding labile iminium species. This reaction
constitues a formal addition of 1,3-dicarbonyl compounds
to aliphatic aldehyde-derived imines, which are generally
unstable and difficult to isolate. Further investigations into
an asymmetric version of the developed reaction, as well as
application to the synthesis of biologically active compounds,
are in progress.
(5) (a) Matsubara, R.; Nakamura, Y.; Kobayashi, S. Angew. Chem., Int.
Ed. 2004, 43, 1679. (b) Matsubara, R.; Nakamura, Y.; Kobayashi, S. Angew.
Chem. Int. Ed. 2004, 43, 3258. (c) Matsubara, R.; Vital, P.; Nakamura, Y.;
Kiyohara, H.; Kobayashi, S. Tetrahedron 2004, 60, 9769. (d) Fossey, J. S.;
Matsubara, R.; Vital, P.; Kobayashi, S. Org. Biomol. Chem. 2005, 3, 2910.
(e) Matsubara, R.; Kawai, N.; Kobayashi, S. Angew. Chem., Int. Ed. 2006,
45, 3814.
(6) CuF2, CuOAc, and CoCl2 promoted isomerization of enecarbamates.
Isomerization and further self-condensation occurred when BiCl3, Nd(OTf)3,
Ce(OTf)3‚H2O, Zn(OTf)2, and AgSbF6 were employed. Isomerization can
be suppressed by using appropriate ligands. For example, fast isomerization
and dimerization of enecarbamate occurred when we used Cu(OTf)2,
whereas no isomerization was observed when a complex prepared from
Cu(OTf)2 and diphenylethylenediamine ligand was employed.
(7) A similar reaction mechanism was reported in palladium enolate
chemistry. Sodeoka, M.; Hamashima, Y. Bull. Chem. Soc. Jpn. 2005, 78,
941 and references therein.
Acknowledgment. This work was partially supported by
a Grant-in-Aid for Scientific Research from Japan Society
of the Promotion of Sciences (JSPS).
Supporting Information Available: Experimental details
for the reported reaction. This material is available free of
charge via the Internet at http://pubs.acs.org.
(8) Mecozzi, T.; Petrini, M. Synlett 2000, 73 and references therein.
(9) Recent examples of direct Mannich-type reactions using 1,3-
dicarbonyl compounds. (a) Ting, A.; Lou, S.; Schaus, S. E. Org. Lett. 2006,
8, 2003. (b) Tillman, A. L.; Ye, J. X.; Dixon, D. J. Chem. Commun. 2006,
1191. (c) Terada, M.; Sorimachi, K.; Uraguchi, D. Synlett 2006, 133.
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