Catalytic asymmetric intramolecular aminopalladation: Enantioselective synthesis of vinyl-substituted 2-oxazolidinones, 2-imidazolidinones, and 2-pyrrolidinones

Article abstract of DOI:10.1021/ja017198n

A new catalytic asymmetric synthesis of five-membered nitrogen heterocycles is reported. This synthesis employs ferrocenyloxazoline palladacycles (FOP trifluoroacetate catalysts) 2 and 4 and proceeds by a catalytic cycle involving Pd(II) intermediates. Fo

Full text of DOI:10.1021/ja017198n

Published on Web 12/04/2001
Catalytic Asymmetric Intramolecular Aminopalladation: Enantioselective
Synthesis of Vinyl-Substituted 2-Oxazolidinones, 2-Imidazolidinones, and
2-Pyrrolidinones
Larry E. Overman* and Travis P. Remarchuk
Department of Chemistry, 516 Rowland Hall, UniVersity of California IrVine, California 92697-2025
Received September 29, 2001
A variety of useful reactions are catalyzed by Pd(II) complexes.1
Although the first example was described by Murahashi over 20
Table 1. Catalytic Asymmetric Synthesis of
3-Arylsulfonyl-4-vinyloxazolidin-2-ones (6a-e)
years ago,2 only within the past few years has the potentially rich
catalytic asymmetric chemistry of Pd(II) received wide attention.3
In 1999 we reported that ferrocenyloxazoline palladacycles 2 and
4 were excellent catalysts for asymmetric rearrangement of prochiral
allylic imidates to form enantioenriched allylic amides.4 Intramo-
lecular aminopalladation of the double bond is undoubtedly a central
event in this rearrangement,5 as it is in syntheses of numerous
nitrogen heterocycles.6 The use of ferrocenyloxazoline palladacycles
(FOP catalysts) 2 and 4 to catalyze the asymmetric synthesis of
five-membered nitrogen heterocycles is disclosed herein.
concentration (M)
catalyst (mol %)
product
yield (%)b
ee (%)b,c
1.0
2 (5.0)
2 (1.0)
2 (0.5)
2 (5.0)
(S)-6a
96
91
86
98
98
80
98
88
91
98
91
90
91
93
92
92
92
91
89
92
2.0
0.2
4 (5.0)
2 (5.0)
(R)-6a
6b
6c
6d
6e
a Reactions conducted in 1:1 CH2Cl2-MeNO2 at room temperature for
10-20 h; the starting (Z)-allylic carbamate was >98% isomerically pure.
b Mean of 2-4 experiments. d HPLC analysis using a Chiracel OD-H
column ((2%).
As summarized in Table 1, the efficient, highly enantioselective
conversion of 5a f (S)-6a can be accomplished under practical
conditions: substrate concentrations up to 2 M, reaction times at
room temperature of 10-20 h, and catalyst loadings as low as 0.5
mol %. Cyclization of 5a with the pseudoenantiomeric FOP
trifluoroacetate catalyst 4 delivered (R)-6a in similar high yield and
enantioselectivity. Contributing to the practicality of this method,
iodide-bridged dimers 1 and 3 are air- and moisture-stable pre-
catalysts, which are activated in situ by reaction with silver
trifluoroacetate.10 High yields and enantioselectivities were realized
in cyclizations of N-arylsulfonylcarbamates containing a range of
aryl substituents (Table 1). The lack of reaction of substrates such
as p-nitrophenylcarbamate 10 under identical conditions suggests
that a highly acidic nitrogen nucleophile is required.11 Also required
is the Z configuration of the starting allylic N-arylsulfonylcarbamate,
as the E stereoisomer of 5a was transformed extremely slowly at
room temperature (22% yield after 4 days, 5 mol % of 2) to give
(R)-6a of moderate enantiopurity (65% ee). The absolute config-
uration of (S)-6a was established by conversion to (S)-4-vinylox-
azolidin-2-one;12 the absolute configurations of 6b-6e were
assigned in analogy.
It is most convenient to form the allylic N-arylsulfonylcarbamate
in situ by reaction of an allylic alcohol with an arylsulfonyl
isocyanate. This modification is particularly useful with tertiary
allylic alcohols whose derived allylic N-arylsulfonylcarbamates are
prone to eliminate. Using this procedure, spirocyclic 4-vinylox-
azolidin-2-ones 13a and 13b were prepared in high enantiopurity
and good overall yield from cyclohexanone and N-tert-butoxyoxy-
carbonyl-4-piperidone (Scheme 1). To minimize competing ioniza-
tion of the tertiary allylic N-tosylcarbamate intermediate, the
cyclization step was carried out in CH2Cl2 using 5 mol % of the
FOP trifluoroacetate catalyst. The high enantioselectivity (97-99%
ee) realized in these reactions appears to be a general feature of
catalytic asymmetric cyclizations of tertiary allylic N-tosylcarbam-
We began by studying the formation of 4-vinyloxazolidin-2-ones
from readily available derivatives of (Z)-2-buten-1,4-diol (eq 1).7
To keep the leaving group and the anionic ligand of the catalyst
the same, the cyclization of allylic N-tosylcarbamate trifluoroacetate,
7, with FOP trifluoroacetate catalyst 2 (generated in situ by
deiodination of 1 with silver trifluoroacetate) was examined initially.
Although vinyloxazolidinone (S)-6a could be formed in up to 79%
ee (5 mol % catalyst, CH2Cl2, room temperature), the lability of
the allylic trifluoroacetate group made this synthesis impractical.
Bis-N-tosylcarbamate 8 also cyclized in CH2Cl2 at room temperature
in the presence of 5 mol % of 2 to provide (S)-6a (72% yield and
79% ee),8 comparable to the outcome achieved (95% yield and 78%
ee) in the cyclization of alcohol precursor 9. Cyclizations of allylic
N-tosylcarbamate acetate 5a were significantly better, providing
(S)-6a in 96% yield and 86% ee under similar conditions. Further
optimization showed that enantioselectivity was enhanced in more
polar solvents, a 1:1 mixture of CH2Cl2-MeNO2 being optimal in
terms of both yield and enantioselection (>95% yield and 91-
93% ee). Changing the anionic ligand by activating precatalyst 1
with other silver salts was also examined; however, all silver salts
screened provided catalysts that were less satisfactory than 2.9
9
12 VOL. 124, NO. 1, 2002 J. AM. CHEM. SOC.
10.1021/ja017198n CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1
Supporting Information Available: Preparation of representative
rearrangement substrates (5a, 12a, and 16), representative catalytic
asymmetric cyclizations (formation of (S)-6a, 13a, and 18), copies of
HPLC traces used to determine enantiopurity, and copies of H and
13C NMR spectra for all new compounds (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
1
References
(1) Tsuji, J. Palladium Reagents and Catalysts. InnoVations in Organic
Synthesis; Wiley: New York, 1995.
(2) (a) Hosokawa, T,; Miyagi, S.; Murahashi, S.-I.; Sonoda, A. J. Chem. Soc.,
Chem. Commun. 1978, 687-688. (b) Hosokawa, T.; Uno, T.; Inui, S.;
Murahashi, S.-I. J. Am. Chem. Soc. 1981, 103, 2318-2323.
(3) Allylic imidate rearrangements: (a) Calter, M.; Hollis, T. K.; Overman,
L. E.; Ziller, J.; Zipp, G. G. J. Org. Chem. 1997, 62, 1449-1456. (b)
Hollis, T. K.; Overman, L. E. Tetrahedron Lett. 1997, 38, 8837-8840.
(c) Uozumi, Y.; Kato, K.; Hayashi, T. Tetrahedron: Asymmetry 1998, 9,
1065-1072. (d) Cohen, F.; Overman, L. E. Tetrahedron: Asymmetry
1998, 9, 3213-3222. (e) Jiang, Y.; Longmire, J. M.; Zhang, X.
Tetrahedron Lett. 1999, 40, 1449-1450. (f) Leung, P.-H.; Ng, K.-H.; Li,
Y.; White, A. J. P.; Williams, D. J. Chem. Commun. 1999, 2435-2436
and refs 4 and 5a. Preparation of oxygen heterocycles: (g) Uozumi, Y.;
Kato, K.; Hayashi, T. J. Am. Chem. Soc. 1997, 119, 5063-5064. (h)
Uozumi, Y.; Kato, K.; Hayashi, T. J. Org. Chem. 1998, 63, 5071-5075.
(i) Uozumi, Y.; Kyota, H.; Kato, K.; Ogasawara, M.; Hayashi, T. J. Org.
Chem. 1999, 64, 1620-1625. (j) Zhang, Q.; Lu, X. J. Am. Chem. Soc.
2000, 122, 7604-7605. (k) Arai, M. A.; Kuraishi, M.; Arai, T.; Sasai, H.
J. Am. Chem. Soc. 2001, 123, 2907-2908 and ref 2. Other reactions: (l)
Hagiwara, E.; Fujii, A.; Sodeoka, M. J. Am. Chem. Soc. 1998, 120, 2474-
2475. (m) Mikami, K.; Hatano, M.; Terada, M. Chem. Lett. 1999, 55-
56. (n) El-Qisairi, A.; Hamed, O.; Henry, P. M. J. Org. Chem. 1998, 63,
2790-2791. (o) Stark, M. A.; Jones, G.; Richards, C. J. Organometallics
2000, 19, 1282-1291.
Scheme 2
Scheme 3
(4) Donde, Y.; Overman, L. E. J. Am. Chem. Soc. 1999, 121, 2933-2934.
(5) (a) Hollis, T. K.; Overman, L. E. J. Organomet. Chem. 1999, 576, 290-
299. (b) Overman, L. E. Angew. Chem., Int. Ed. Engl. 1984, 23, 579-
586.
(6) Hegedus, L. S. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: New York, 1991; Vol. 4, Chapter 3.1.
(7) For examples of preparing nitrogen heterocycles by aminopalladation-
deoxypalladation reactions using achiral Pd(II) catalysts, see: Hirai, Y.;
Watanabe, J.; Nozaki, T.; Yokoyama, H.; Yamaguchi, S. J. Org. Chem.
1997, 62, 776-777 and references therein.
(8) Similar moderate enantioselection (77% ee in the best case) was reported
earlier by Hayashi and Ito for cyclizations of bis-N-arylcarbamates of (Z)-
2-buten-1,4-diol with Pd(0) catalysts having (hydroxyalkyl)ferrocenyl-
diphosphine ligands: Hayashi, T.; Yamamoto, A.; Ito, Y. Tetrahedron
Lett. 1988, 29, 99-102.
ates with FOP trifluoroacetate catalysts, as 14 was converted to
vinyloxazolidin-2-one 15 of 96% ee under identical conditions.13-15
Enantioenriched 2-pyrrolidinones and 2-imidazolidinones can be
prepared in similar fashion (Scheme 2). The absolute configuration
of pyrrolidinone 19 was secured by converting this product to the
unnatural enantiomer of the powerful GABA inhibitor vigabatrin
20,16 whereas the absolute configuration of 18 was secured by
single-crystal X-ray analysis.14
At least two general mechanisms can be considered for these
catalytic asymmetric cyclization reactions (Scheme 3).17 In one,
the new C-N bond would be formed by aminopalladation of the
alkene (30 f 32). In the other, it would be formed by insertion of
the alkene into the Pd-N bond of 31.18 Alternative pathways
involving η3-allyl species and palladacyclic Pd(II) and Pd(IV)
intermediates, or a conventional Pd(0)/Pd(II) catalytic cycle (the
Pd(0) catalyst being some degradation product of the original
palladacycle),19 are unlikely.20
In summary, a new catalytic asymmetric synthesis of five-
membered nitrogen heterocycles was developed. This synthesis
employs palladacyclic Pd(II) catalysts and likely proceeds by a
novel mechanism. We anticipate additional applications of FOP
catalysts and other chiral Pd(II) complexes for catalytic asymmetric
construction of heterocycles and carbocycles.
Acknowledgment. We thank NSF (CHE-9726471) for financial
support, Drs. J. Greaves and J. Mudd for mass spectrometric
analyses, and Dr. J. Ziller for X-ray analyses. NMR and mass
spectra were determined at UCI with instruments purchased with
the assistance of NSF and HIH.
(9) The following silver salts were examined: AgOAc, AgOBz, AgOTf,
AgBF4, AgSbF6, AgCB11H6Br6, and Ag(acac).
(10) In situ IR monitoring of this ligand exchange in CH2Cl2 indicated that 4
equiv of Ag(OCOCF3) were required to fully transform 1 into 2. Control
experiments established that 5a (0.4 M in 1:1 CH2Cl2-MeNO2) was
unchanged when exposed at room temperature to 30 mol % of Ag-
(OCOCF3) for 18 h.
(11) pKa ≈ 5, see: Schaaf, T. K.; Hess, H.-J. J. Med. Chem. 1979, 22, 1340-
1346.
(12) Yoo, S.-E.; Lee, S. H. J. Org. Chem. 1994, 59, 6968-6972.
(13) The absolute configuration of 15 was determined by X-ray crystal-
lography;14 13a and 13b were assigned by analogy.
(14) Absolute configuration was assigned by analysis of the anomalous
dispersion using the Rogers’s η parameter, see: Flack, H. D. Acta
Crystallogr. 1983, A39, 876-881.
(15) The acetyl regioisomer of 14, (Z)-4-acetoxy-4-methyl-2-penten-1-ol
analogue, gave 3-tosyl-4-(2-methylpropenyl)-oxazolidin-2-one in 95%
yield, albeit in 25% ee, under similar conditions.
(16) For the state-of-the art in catalytic asymmetric synthesis of this agent,
see: Trost, B. M.; Bunt, R. C.; Lemoine, R. C.; Calkins, T. L. J. Am.
Chem. Soc. 2000, 122, 5968-5976.
(17) These mechanisms are undoubtedly oversimplified. The enantioselective
step could involve interaction with a catalyst dimer; the FOP acetyl-
acetonate catalyst, although kinetically competent for the 5a f 6a
conversion, delivers 6a as a racemate.
(18) Cowan, R. L.; Trogler, W. C. J. Am. Chem. Soc. 1989, 111, 4750-4761.
(19) Poli, G.; Giambastiani, G.; Pacini, B. Tetrahedron Lett. 2001, 42, 5179-
5182
(20) Evidence for this conclusion includes: (1) FOP catalysts are more reactive
when they contain nondonor anionic ligands (RCO2-, TsO-, NO3-, BF4-).
(2) The reactions reported here take place under acidic conditions (added
HOAc, 1-5 equiv has negligible effect on rate or ee). (3) Stereoisomeric
alkene substrates cyclize in the presence of 2 to give enantiomeric
4-vinyloxazolidin-2-one products, whereas both alkene stereoisomers give
the same 4-vinyloxazolidin-2-one enantiomer in related Pd(0)-catalyzed
cyclization reactions.8
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