Generation and reactivity of oxazolidinone derived N-acyl radicals

Article abstract of DOI:10.1055/s-1999-2913

The N-acyl(phenylseleno)oxazolidinone 5 was prepared (85% yield) by treatment of the lithium salt of oxazolidinone with triphosgene, followed by addition of benzeneselenol. Reduction of 5 with n-Bu₃SnH/AIBN gave the N- formyloxazolidinone 6 (99%) and reaction with allyltri-n-butylstannane gave 7 (89%). Bimolecular additions to various alkenes using the N-acyl radical derived from oxazolidinone 5 were also studied. Best results were obtained with electron rich olefins, such as enol ether derivatives. Eight such additions are reported, with yields ranging from 51-90%. Two prochiral substrates showed significant levels of diastereoselectivity in reactions with 5/Bu₃SnH.

Full text of DOI:10.1055/s-1999-2913

LETTER
1657
Generation and Reactivity of Oxazolidinone Derived N-Acyl Radicals
Gary E. Keck, Mark C. Grier
Department of Chemistry, University of Utah, Salt Lake City, Utah 84112, USA
Fax +1 (801) 581-7055; E-mail: keck@chemistry.utah.edu
Received 12 August 1999
Abstract: The N-acyl(phenylseleno)oxazolidinone 5 was prepared
(85% yield) by treatment of the lithium salt of oxazolidinone with
triphosgene, followed by addition of benzeneselenol. Reduction of
5 with n-Bu3SnH/AIBN gave the N-formyloxazolidinone 6 (99%)
and reaction with allyltri-n-butylstannane gave 7 (89%). Bimolecu-
Equation 2
lar additions to various alkenes using the N-acyl radical derived
from oxazolidinone 5 were also studied. Best results were obtained
with electron rich olefins, such as enol ether derivatives. Eight such
additions are reported, with yields ranging from 51-90%. Two
prochiral substrates showed significant levels of diastereoselectivi-
ty in reactions with 5/Bu3SnH.
firmed that, as expected, radical 2 could in fact be gener-
ated from 5 and, more importantly, that 2 was sufficiently
stable with respect to decarbonylation to function effec-
tively in bimolecular reactions. Thus, reduction of 5 gave
the N-formyloxazolidinone 6 in 99% yield, while the
allylation afforded 7 in 89% isolated yield (Eq 3).
Key words: radicals, radical reactions, acylations, stereoselectivity,
Lewis acids
In recent years, free radical based methodology has
played an increasingly inportant role in organic synthesis,
and many desirable features of such reactions are now ap-
preciated.1 One developmental thrust has been directed at
methodology which can preserve high levels of function-
ality in radical additions to unsaturated systems. Among
many conceptual approaches to this general problem, the
use of acyl radicals,2 a-alkoxy radicals,3 and acetal de-
rived radicals4 are of considerable interest. It occurred to
us that, in view of the many well known chemical trans-
formations of N-acyloxazolidinones developed to support
asymmetric aldol technology,5 additions of oxazolidinone
derived N-acyl radicals to various unsaturations could po-
tentially prove to be of utility in synthesis (Eq 1). We de-
scribe herein the first examples of the generation and
reactivity of such radicals.
Equation 3
Reactions of 5 with a variety of olefins were then investi-
gated. The standard reaction protocol eventually em-
ployed in each case utilized 5 (1.0 eq), tri-n-butyltin
hydride (1.5 eq), bis(tributyltin) (0.05 eq) or AIBN (0.1
eq), and an excess (5 eq) of olefin, with irradiation via a
200 W sunlamp during slow addition (over 12 h) of the tin
hydride as a solution in benzene (0.3 M overall). Several
trends were noted. The desired addition reactions pro-
ceeded very poorly (no isolable amounts of products de-
tected) with a,b-unsaturated esters such as benzylacrylate
or benzylcrotonate. In these cases, the reduction product
6 was isolated. Reaction with cyclopentenone did occur,
but in general, more electron rich olefins proved superior
in reactivity towards 2 (Table 1). Thus, addition to meth-
ylenecyclopentane was successful (76% isolated yield) as
was addition to a-methylstyrene (51%). Very good re-
sults were obtained with various enol ethers including
TBS silyl enol ethers. Reaction with n-butyl vinyl ether
afforded the desired addition product in 72% isolated
yield; similar results (77% yield) were obtained with the
endocyclic enol ether dihydrofuran. Additions to the TBS
enol ethers derived from pinacolone and acetophenone
provided excellent results (90% and 85% isolated yields,
respectively).
Equation 1
The N-acyl(phenylseleno)oxazolidinone 5 was chosen as
a potential precursor to radical 2 and was synthesized by
reaction of the lithium salt of oxazolidinone with triphos-
gene (0.5 eq), followed by addition of a solution of ben-
zeneselenol in pyridine (Eq 2).
Preliminary experiments to examine the potential of 5 as
a source of 2, and also to investigate the viability of 2 in
bimolecular free radical reactions, were performed by re-
duction of 5 with tri-n-butyltin hydride and allylation6 of
5 using allyltri-n-butylstannane. These experiments con-
Synlett 1999, No. 10, 1657–1659 ISSN 0936-5214 © Thieme Stuttgart · New York

1658
G. E. Keck, M. C. Grier
LETTER
With two prochiral substrates, very intriguing observa- even more interesting result. In this case, the addition
tions were made regarding the potential for diastereose- product 11 (80% isolated yield) was again found to con-
1
lectivity in these reactions. Reaction with the TBS enol sist of essentially a single diastereomer as judged by H
ether derived from cyclopentanone afforded product 8 as and 13C NMR. Analysis by capillary VPC indicated a ca.
largely a single diastereomer by 1H and 13C NMR analy- 40:1 level of diastereoselectivity, but the separation ob-
sis, in 83% isolated yield (entry 7). Reductive removal of tained was not adequate for an accurate analysis. Carbo-
the oxazolidinone using LiBH4 gave the corresponding nyl reduction with lithium borohydride afforded the
primary alcohol 9; NMR analysis (methine protons at 4.35 corresponding alcohol 12, which gave a baseline separa-
and 3.90 d for the major and minor diastereomers) indicat- tion by capillary VPC, revealing a 30:1 level of diastereo-
ed a 14:1 mixture of isomers (Eq 4). Assignment of trans selectivity (Eq 5). Assignment of stereochemistry to the
stereochemistry to the major isomer was made by conver- major diastereomer as anti was made by removal of the
sion of alcohol 9 to 2-methylcyclopentanol and compari- TBS group from alcohol 12 followed by reaction with
1
son of H and 13C NMR data with those previously dimethoxypropane to give the 1,3-dioxane 13 which ex-
reported for the cis and trans isomers.7,8
hibited a 10.2 Hz coupling constant between the relevant
vicinal protons Ha and Hb.9
Table 1 Products & Yields for Reactions of 5 with Alkenes.
Equation 5
Preliminary experiments aimed at achieving asymmetric
induction in these reactions by the obvious strategy have
also been conducted using the Evans chiral oxazolidinone
derivatives 15 derived from L-phenylalanine.10 As ex-
pected, no selectivity was observed in the reaction of 14
with 15a in the absence of additives; at ~80oC a 1:1 mix-
ture of 16 and 17 was obtained in 89% yield (Table 2). It
was anticipated that the use of Lewis acids to complex and
rigidify the acyloxazolidinone at lower reaction tempera-
tures would be necessary to realize significant levels of di-
astereoselectivity.10 However, an unanticipated problem
was encountered in that the selenide 15a proved unreac-
tive at lower temperatures (~15oC) in the presence of
MgBr2•OEt2; at higher temperatures the silyl enol ether
substrate 14 suffered extensive decomposition. In an at-
tempt to utilize a more reactive radical precursor, the xan-
thate 15b was investigated (Eq 6). This material was
easily prepared along the lines previously employed by re-
action of lithiated (S)-benzyloxazolidinone with triphos-
gene followed by addition of commercially available
potassium O-ethylxanthate to give 15b in 95% yield. Re-
action with 14 in the presence of MgBr2•OEt2 as a chelat-
ing Lewis acid at ca 15 oC afforded predominantly the anti
products 16 and 17 with significant diastereoselectivity
(8:1), albeit in low (20%) isolated yield.11
Equation 4
Reaction with another prochiral substrate, the Z TBS enol
ether derived from propiophenone (entry 8) provided an
Equation 6
Synlett 1999, No. 10, 1657–1659 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Generation and Reactivity of Oxazolidinone Derived N-Acyl Radicals
1659
Table 2 Products and Yields For Reactions of 14.
(5) (a) Evans, D. A. Aldrichim. Acta. 1982, 15, 23. (b) Yan, T.-H.;
Tan, C.-W.; Lee, H.-C.; Lo, H.-C.; Hung, T.-Y. J. Am. Chem.
Soc. 1993, 115, 3301, and references cited therein.
(6) (a) Keck, G. E.; Yates, J. B. J. Org. Chem. 1982, 47, 3590.
(b) Keck, G. E.; Yates, J. B. J. Am. Chem. Soc. 1982, 104,
5829. (c) Keck, G. E.; Enholm, E. J.; Yates, J. B.; Wiley, M.
R. Tetrahedron 1985, 41, 4079. (d) Keck, G. E.; Kachensky,
D. F.; Enholm, E. J. J. Org. Chem. 1985, 50, 3590.
(7) Canonne, P.; Bernatchez, M. J. Org. Chem. 1987, 52, 4025.
(8) The stereochemical outcome for the reaction described in
entry 7 of Table 1 suggests a late, product-like transition state
with significant pyramidalization at the radical center,
presumably to minimize steric interactions between the
acyloxazolidinone and OTBS groups.
(9) (a) The stereochemical outcome for the reaction described in
entry 8 of Table 1 may be rationalized by an extension of
stereochemical models set forth independently by Hart9b,c and
by Porter, Giese, and Curran:9d
The reactions described herein extend the known chemis-
try of acyl radicals to bimolecular processes utilizing syn-
thetically versatile N-acyloxazolidinones. Reactions with
acyclic enol ethers provide a radical based synthesis of
materials commonly envisioned as "aldol products" via an
alternative bond construction. Further studies on the reac-
tions of such radicals, particularly with respect to investi-
gations of asymmetric methodology, are in progress.12
References and Notes
(1) (a) Curran, D. P. Synthesis 1988, 417-439, 489-513.
(b) Curran, D. P. In Comprehensive Organic Chemistry, Trost,
B., Fleming, I., Eds.; Pergamon: New York; 1992; Vol. 4,
Chapters 4.1 and 4.2. (c) Jasperse, C. P.; Curran, D. P.; Fevig,
T. L. Chem. Rev. 1991, 91, 1237.
(2) (a) Elad, D.; Rokach, J. J. Org. Chem. 1964, 29, 1855.
(b) Curran, D. P.; Liu, H. J. Org. Chem. 1991, 56, 3463.
(c) Bachi, M. D.; Bosch, E.; Denenmark, D.; Girsh, D. J. Org.
Chem. 1992, 57, 6803. (d) Boger, D. L.; Mathvink, R. J. J.
Org. Chem. 1992, 57, 1429. (e) Crich, D.; Chen, C.; Hwang,
J. T.; Yuan, H.; Papadatos, A.; Walter, R. I. J. Am. Chem. Soc.
1994, 116, 8937. (f) Evans, P. A.; Roseman, J. D. Tetrahedron
Lett. 1995, 36, 31.
(b) Hart, D. J.; Huang, H.-C.; Krishnamurthy, R.; Schwartz, T. J.
Am. Chem. Soc. 1989, 111, 7507. (c) Hart, D. J.;
Krishnamurthy, R. J. Org. Chem. 1992, 57, 4457. (d) Porter,
N. A.; Giese, B.; Curran, D. P. Acc. Chem. Res. 1991, 24, 296.
(10) For recent leading references on the use of Lewis acids in free
radical reactions, see: (a) Sibi, M. P.; Ji, J.; J. Org. Chem.
1997, 62, 3800. (b) Guindon, Y.; Rancourt, J. J. Org. Chem.
1998, 63, 6554.
(11) The structural assignment made for these materials is based
upon independent synthesis.
(12) Financial assistance provided by the NIH and by Pfizer, Inc. is
gratefully acknowledged.
(3) (a) Ogura, K.; Kayano, A.; Sumitani, N.; Akazome, M.;
Fujita, M. J. Org. Chem. 1995, 60, 1106. (b) Garner, P. P.;
Cox, P. B.; Klippenstein, S. J. J. Am. Chem. Soc. 1995, 117,
4183. (c) Keck, G. E.; Tafesh, A. M. Synlett 1990, 257.
(4) (a) Nishida, A.; Nishida, M.; Yonemitsu, O. Tetrahedron Lett.
1990, 31, 7035. (b) Keck, G. E.; Kordik, C. P. Tetrahedron
Lett. 1993, 34, 6875.
Article Identifier:
1437-2096,E;1999,0,10,1657,1659,ftx,en;S05199ST.pdf
Synlett 1999, No. 10, 1657–1659 ISSN 0936-5214 © Thieme Stuttgart · New York