Diastereoselective Enolsilane Coupling Reactions

Full text of DOI:10.1021/jo971050y

5680
J . Org. Chem. 1997, 62, 5680-5681
Sch em e 1
Dia ster eoselective En olsila n e Cou p lin g
Rea ction s
Scott J . Miller* and Christopher D. Bayne
Merkert Chemistry Center, Department of Chemistry, Boston
College, Chestnut Hill, Massachusetts 02167-3860
Received J une 11, 1997
Reliable C-C bond forming processes that proceed
under mild conditions are of significance in organic
synthesis. Diastereoselective bond constructions are
particularly important, as they allow for efficient syn-
thesis of stereochemically complex molecules. Coupling
of enolates is a conceptually attractive process for these
goals because their generation is reasonably well under-
stood (eq 1).1 However, traditional approaches to enolate
coupling involve formation of enolates with a strong base,
followed by oxidative dimerization induced by high valent
metal salts (e.g., Cu(OAc)2 or TiCl4).2 As a result of the
harsh conditions, yields and diastereoselectivities often
suffer, and the substrate scope is frequently limited.
Alternatively, enolates have been coupled by sigmatropic
rearrangement. Magedov3 and Endo4 independently
reported that under anionic conditions diacyl hydrazines
and hydroxylamines rearrange to afford succinic dia-
mides (eq 2); rearrangement is apparently driven by the
cleavage of a weak N-N bond. Yet, yields and diaste-
reoselectivities are generally poor, and various byprod-
ucts are formed under these conditions. Herein, we
report a mild intramolecular coupling of bis(enolsilanes)
that leads to succinimide heterocycles (eq 3). In the
present study, use of a Lewis acid and a mild base not
only renders the rearrangement of unactivated substrates
feasible, but also introduces an alternative reactivity
pattern wherein a different product is obtained.
Ch a r t 1. P r ep a r a tion of Hyd r a zid e Su bstr a tes
An attractive feature of the present process is that
hydrazide preparation is straightforward. Thus, sym-
metrical and unsymmetrical N,N′-diacylhydrazines (1a -
h ) are readily made by sequential acylation of N,N′-
dimethylhydrazine (Chart 1). In cases where one of the
substituents is an azide, the bromoacetate derivative
serves as the precursor; azide displacement subsequently
produces the hydrazide in good yield. (See Supporting
Information for details.)
Table 1 illustrates a wide range of substrates that
undergo efficient rearrangement with moderate to excel-
lent selectivity (2:1 to >20:1). Both symmetrical and
unsymmetrical hydrazides rearrange efficiently, support-
ing the notion that the reaction is intramolecular. Rear-
rangement of both aliphatic- (1a -c) and aryl-substituted
substrates (1d ) demonstrates that activating groups are
not required to enhance substrate acidity. In addition,
R-alkoxy-substituted substrates rearrange to form the
(2) For representative examples, see: (a) Ito, Y.; Konoike, T.;
Harada, T.; Saegusa, T. J . Am. Chem. Soc. 1975, 97, 2912-2914. For
more recent representative contributions, see (b) Matsumura, Y.;
Nishimura, M.; Hiu, H.; Watanabe, M.; Kise, N. J . Org. Chem. 1996,
61, 2809-2812. (c) Paquette, L. A.; Bzowej, E. I.; Branan, B. M.;
Stanton, K. J . J . Org. Chem. 1995, 60, 7277-7283. (d) Porter, N. A.;
Su, Q.; Harp, J . J .; Rosenstein, I. J .; McPhail, A. T. Tetrahedron Lett.
1993, 34, 4457-4460.
(3) Magedov, I. V.; Smushkevich, Y. I. J . Chem. Soc., Chem.
Commun. 1990, 1686-1687.
(4) (a) Endo, Y.; Shudo, K. Tetrahedron Lett. 1991, 32, 4517-4520.
(b) Endo, Y.; Shudo, K. Heterocycles 1992, 33, 91-95. (c) Uchida, T.;
Endo, Y.; Hizazate, S.; Shudo, K. Chem. Pharm. Bull. 1994, 42, 419-
421. (d) Endo, Y.; Uchida, T.; Hizazate, K.; Shudo, K. Synthesis 1994,
1096-1105.
(5) For reviews of hetero-[3,3]-rearrangements, see: (a) Blechert,
S. Synthesis 1989, 71-82. (b) Ziegler, F. E. Chem. Rev. 1988, 88, 1423-
1452. (c) Overman, L. E. Angew. Chem., Int. Ed. Engl. 1984, 23, 579-
586.
(6) Representative procedure (substrates 1a -f): To a cold (-78 °C)
solution of the N,N′-diacylhydrazine in dichloromethane (0.2 M) is
added TMSOTf (4.0 equiv) followed by Et3N (4.0 equiv). The reaction
mixture is then warmed to room temperature and stirred for 12-24
h. The reaction mixture is then applied directly to a silica gel column,
which is eluted with the appropriate EtOAc/hexane solvent system.
Modification for substrates 1g and 1h : The reactions were quenched
by addition of saturated NaHCO3 solution. The organic layer was then
vigorously stirred for 10 min in the presence of 1 N HCl. Concentration
of the aqueous layer then afforded the pure cyclic hydrazide salt (5a
and 5b). See Supporting Information for details.
As illustrated in Scheme 1, treatment of N,N′-dialkyl-
N,N′-diacylhydrazines (1) with 4 equiv of TMSOTf and
4 equivalents of Et3N results in the formation of N-meth-
yl-2,3-disubstituted succinimides 2. It is plausible that
hydrazide 1 is first converted to the bis(enolsilane) 3,
which undergoes diastereoselective bond formation
through a neutral [3,3]-sigmatropic rearrangement to
afford bis(imine) 4.5 Cyclization and expulsion of a
methylamine equivalent then lead to the formation of
succinimide 2.6
(1) (a) Mekelburger, H. B.; Wilcox, C. S. In Comprehensive Organic
Syntheis:Additions to C-X π-Bonds; Trost, B. M., Fleming, I., Heath-
cock, C. H., Eds.; Pergamon: New York, 1991; Part 2, pp 99-131. (b)
Heathcock, C. H. In Asymmetric Synthesis; Morrison, J . D., Ed.;
Academic Press: New York, 1984; vol. 3, Chap. 2. (c) Evans, D. A.;
Nelson, J . V.; Taber, T. R. Top. Stereochem. 1982, 13, 1-115.
S0022-3263(97)01050-5 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 17, 1997 5681
Ta ble 1. Su bstr a tes P r ep a r ed by [3,3]-Rea r r a n gem en t
F igu r e 1. 400 MHz 1H NMR spectrum of reaction mixture
after 10 min (25 °C).
â-elimination of N2 to afford a silylated glyoxalate-imine
intermediate 6 (eq 4).10 This scenario suggests that
intramolecular aldol addition is responsible for C-C bond
formation to provide the â-substituted aspartic acid
derivative.
The origin of the observed diastereoselectivity is not
certain at the present time and must await further
studies to be completely understood. Nonetheless, in
cases where we observe high trans selectivity, we expect
that the [3,3]-rearrangement proceeds through a chair-
like transition state.11 In these instances, enolsilane
geometries are projected to be mutually Z, as shown for
structure 7. Attempts to observe this intermediate in the
reaction by 1H NMR spectroscopy have yielded the
following information (Figure 1). Exposure of 1c to the
reaction conditions yields a reaction mixture in which two
dominant enol protons can be observed in approximately
a 2:1 ratio. While the multiplicity of each proton allows
a definitive assignment of each to the coupling moieties
A and B, we have not been able to establish rigorously
the individual enolate geometries. These and other
mechanistic studies are in progress.
Ta ble 2. F or m a tion of Cyclic Hyd r a zid es
In summary, we have described a facile coupling of enol
silanes linked through a N-N bond. Attractive features
of the reaction include the following: (i) facile synthesis
of substrates for the coupling process; (ii) diastereose-
lective C-C bond formation under the influence of
TMSOTf and Et3N; (iii) in situ cyclization to form trans-
disubstituted succinimide products. In addition, a new
reaction of azidoacetate derivatives is presented that
results in a stereochemically defined â-substituted cyclic
aspartic acid-derived hydrazide. Studies directed toward
the development of enantioselective variants of this
process and their application in natural products syn-
thesis are underway.
corresponding heterocycles (1e and 1f). In all cases, the
trans-disubstituted product constitutes the major dias-
teromer.7,8
To extend the utility of the present method to the
preparation of N-substituted heterocycles, we examined
the rearrangement of azide-substituted hydrazides (1g
and 1h ). These substrates exhibit a different reactivity
pattern wherein C-C bond formation occurs without
rupture of the hydrazide N-N bond to afford the derived
six-membered ring product (5a and 5b, Table 2). In these
cases, the trans-substituted products are obtained exclu-
sively.9 With the azide-substituted compounds, we pos-
tulate that formation of the bis(enolsilane) is followed by
Ack n ow led gm en t. The National Science Founda-
tion is acknowledged for financial support (CHE-
9612563).
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for all compounds and experimental details for their
preparation (10 pages).
J O971050Y
(9) In this case, stereochemical assignment was made based on the
large coupling constants observed for the vicinal protons. See Sup-
porting Information for details.
(10) Conversion of R-azido carbonyl compounds to the corresponding
diketones by a related mechanism has been reported. See: (a) Edwards,
O. E.; Purushothaman, K. K. Can. J . Chem. 1964, 42, 712-716. (b)
Manis, P. A.; Rathke, M. W. J . Org. Chem. 1980, 45, 4952-4954.
(11) (a) Doering, W. v. E.; Roth, W. R. Angew. Chem., Int. Ed. Engl.
1963, 2, 115-122. (b) Reference 7 and references cited therein.
(7) For a review highlighting selectivity issues in [3,3]-sigmatropic
rearrangements, see: Enders, D.; Knopp, M.; Schiffers, R. Tetrahe-
dron: Asymmetry 1996, 7, 1847-1882.
(8) The relative stereochemical relationships were established on
the basis of the characteristically smaller coupling constant between
the C3 and C4 methine protons in the trans-products. For example,
see: Tschappat, K. D.; Crider, A. M.; Hassan, M. N.; Fahn, S. J .
Heterocycl. Chem. 1987, 24, 673-676.