Radical cyclization of β-aminoacrylates: Synthesis of bicyclic pyrrolidine derivatives

Article abstract of DOI:10.1016/S0040-4039(00)00970-9

Radical cyclization of the β-aminoacrylate derived from 4-(2- bromoethyl)azetidin-2-one led to the stereoselective formation of a bicyclic β-lactam product, which may serve as a precursor for cis-2,5-disubstituted pyrrolidines. (C) 2000 Elsevier Science L

Full text of DOI:10.1016/S0040-4039(00)00970-9

Tetrahedron Letters 41 (2000) 5915±5916
Radical cyclization of b-aminoacrylates: synthesis of bicyclic
pyrrolidine derivatives
Eun Lee,* Sang Kyun Kim, Ji Young Kim and Jaehong Lim
School of Chemistry and Molecular Engineering, Seoul National University, Seoul 151-742, South Korea
Received 8 May 2000; revised 5 June 2000; accepted 9 June 2000
Abstract
Radical cyclization of the b-aminoacrylate derived from 4-(2-bromoethyl)azetidin-2-one led to the
stereoselective formation of a bicyclic b-lactam product, which may serve as a precursor for cis-2,5-
disubstituted pyrrolidines. # 2000 Elsevier Science Ltd. All rights reserved.
Radical cyclization of b-aminoacrylates was shown to be a useful method in the preparation of
azacyclic compounds.1 b-Aminoacrylates prepared from primary amines carrying secondary alkyl
groups were converted into pyrrolidine and piperidine derivatives, and a useful level of stereo-
control (ꢀ4:1) favoring trans-2,5-disubstituted pyrrolidine products was ascertained when the
methanesulfonamide substrates were employed.1a In our continuing search for stereoselective
conversions, we considered the use of b-lactam templates in radical cyclization reactions.
The known azetidin-2-one derivative 32 may be synthesized from the carboxylic acid 13 via the
homologous alcohol 2.4 Reaction of the azetidin-2-one 3 with ethyl propiolate in the presence of
tributylphosphine a€orded the b-aminoacrylate 4. Radical cyclization of 4 under the standard
high dilution conditions led to the formation of the novel bicyclic b-lactam 55 in 49% yield. An
epimeric product 6 was isolated in 3% yield along with the simple reduction product 4-ethyl-
azetidin-2-one (28%) (Scheme 1). The stereochemical assignment was con®rmed by comparing
proton NMR spectra of the N-benzyl derivatives of cis- and trans-2,5-bis(ethoxycarbonyl-
methyl)pyrrolidine, obtained from the reaction of 5 and 6 with sodium ethoxide in ethanol and
then with benzyl bromide in acetone in the presence of K2CO3. The benzylic methylene protons
exhibit a singlet signal (ꢀ 3.78) for the cis isomer and an AB quartet (ꢀ 3.64 and 3.85, J=14.3 Hz)
for the trans isomer.6
For further comparison studies, the b-aminoacrylate 8 was prepared from the known oxazo-
lidinone 7.7 Radical cyclization of 8 in the presence of tributylstannane and AIBN resulted in the
formation of an inseparable 3.3:1 mixture of the products 9 and 10 (Scheme 2). The mixture was
reacted with trimethylsilyl phenylselenide in toluene under re¯ux in the presence of a catalytic
* Corresponding author. Fax: +82-2-889-1568; e-mail: eunlee@snu.ac.kr
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00970-9

5916
Scheme 1. (a) (COCl)2, DCM; CH2N2, ether; Ag2O, MeOH, 55ꢁC, 90 min; (b) LAH, ether, 0ꢁC, 40 min; (c) CBr4,
Ph3P, TEA, DCM, rt, 4 h; (d) KF, AcOH, MeOH, 0ꢁC, 10 min; (e) 2.0 equiv. HCCCO2Et, 1.0 equiv. Bu3P, DCM, 0ꢁC
to rt, 90 min; (f) 1.1 equiv. Bu3SnH, 0.1 equiv. AIBN, benzene (0.025 M), re¯ux, 5 h (syringe pump, 4 h)
amount of ZnI2,1a and cis- and trans-2-(phenylseleno)methyl-5-(ethoxycarbonylmethyl)-
pyrrolidine thus produced were separated by ¯ash column chromatography. The benzylic
methylene protons of the N-benzyl derivatives exhibit an AB quartet at ꢀ 3.71 and 3.77 (J=14.2
Hz) for the cis isomer and an AB quartet at ꢀ 3.66 and 3.91 (J=14.4 Hz) for the trans isomer.
Scheme 2. (a) p-TsCl, pyridine, DCM; (b) HCCCO2Et, NMM, DCM, re¯ux; (c) LiBr, acetone, re¯ux; (d) 1.3 equiv.
Bu3SnH, 0.15 equiv. AIBN, benzene (0.025 M), re¯ux, 5 h (syringe pump, 4 h)
It is apparent from these studies that cis-2,5-disubstituted pyrrolidine derivatives may be
prepared with useful stereoselectivity when azetidinone and oxazolidinone templates are used in
the radical cyclization reactions of b-aminoacrylates, and they complement the results of earlier
studies in which trans-2,5-disubstituted pyrrolidine derivatives were obtained as major products.
Acknowledgements
This work was supported by a grant of the Korea Science and Engineering Foundation (98-
0501-05-01).
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