A practical method for the acylation of 2-imidazolidinone and 2-oxazolidinone chiral auxiliaries with 2-bromoacyl halides

Article abstract of DOI:10.1081/SCC-100106033

Optimised conditions for the acylation of (S)-4-(1-methyl-ethyl)-oxazolidin-2-one 4, (R)-4-phenyloxazolidin-2-one 5 and 4-(R), (5S)-1,5-dimethyl-4-phenylimidazolidin-2-one 3 with 2-bromoacyl halides were developed. For imidazolidin-2-one 3 the optimum con

Full text of DOI:10.1081/SCC-100106033

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A PRACTICAL METHOD FOR THE ACYLATION OF 2-
IMIDAZOLIDINONE AND 2-OXAZOLIDINONE CHIRAL
AUXILIARIES WITH 2- BROMOACYL HALIDES
Sara X. Candeias a , Kerry Jenkins b , A. S. C. Ribeiro a , Carlos A. M. Afonso c & Stephen
Caddick b
a Departamento de Química, Centro de Química Fina e Biotecnologia, Faculdade de
Ciências e Tecnologia , Universidade Nova de Lisboa , Caparica, 2825-114, Portugal
b The Chemistry Laboratory , Centre for Biomolecular Design and Drug Development
University of Sussex , Brighton, BN1 9QJ, UK
c Departamento de Química, Centro de Química Fina e Biotecnologia, Faculdade de
Ciências e Tecnologia , Universidade Nova de Lisboa , Caparica, 2825-114, Portugal
Published online: 20 Aug 2006.
To cite this article: Sara X. Candeias , Kerry Jenkins , A. S. C. Ribeiro , Carlos A. M. Afonso & Stephen Caddick (2001)
A PRACTICAL METHOD FOR THE ACYLATION OF 2-IMIDAZOLIDINONE AND 2-OXAZOLIDINONE CHIRAL AUXILIARIES WITH 2-
BROMOACYL HALIDES, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 31:21, 3241-3254, DOI: 10.1081/SCC-100106033
To link to this article: http://dx.doi.org/10.1081/SCC-100106033
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SYNTHETIC COMMUNICATIONS, 31(21), 3241–3254 (2001)
A PRACTICAL METHOD
FOR THE ACYLATION OF
2-IMIDAZOLIDINONE AND
2-OXAZOLIDINONE CHIRAL
AUXILIARIES WITH 2-
BROMOACYL HALIDES
Sara X. Candeias,1 Kerry Jenkins,2
A. S. C. Ribeiro,1 Carlos A. M. Afonso,1,
*
and Stephen Caddick2
1Departamento de Quımica, Centro de Quımica
Fina e Biotecnologia, Faculdade de Ciencias e
Tecnologia, Universidade Nova de Lisboa,
2825-114 Caparica, Portugal
2Centre for Biomolecular Design and Drug
Development, The Chemistry Laboratory,
University of Sussex, Brighton BN1 9QJ, UK
ABSTRACT
Optimised conditions for the acylation of (S )-4-(1-methyl-
ethyl)-oxazolidin-2-one 4, (R)-4-phenyloxazolidin-2-one 5 and
4-(R), (5S )-1,5-dimethyl-4-phenylimidazolidin-2-one 3 with
2-bromoacyl halides were developed. For imidazolidin-2-one
3 the optimum conditions require the use of the hindered bases
*Corresponding author. Fax: þ351 21 2948550; E-mail: cma@dq.fct.unl.pt
3241
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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3242
CANDEIAS ET AL.
2,6-di-t-butylpyridine or 2,6-lutidine in order to reduce the
ketene formation which has
O-acylation.
a strong preference for
INTRODUCTION
Oxazolidin-2-ones 11 and imidazolidin-2-ones 22 and 3 are efficient,
readily available chiral auxiliaries for organic synthesis. The (4R, 5S )-1,5-
dimethyl-4-phenylimidazolidin-2-one 3 is readily prepared from fusion of
(-)-ephedrine hydrochloride and urea.3 It is a useful chiral auxiliary for
numerous asymmetric transformations4 including aldol condensation,3c,4k
cycloaddition,4a,b alkylation,4a,d,e,f cross-coupling,4c,j cyclization,4g,h and
protonation.41 During the course of our studies on stereoselective dynamic
kinetic resolution of a-haloacyl imidazolidinones using a range of nitrogen
and carbon nucleophiles5 we required an efficient acylation of chiral auxili-
aries. The general reported method for acylation of 2-oxazolidinones
involves the reaction of the corresponding N-Li salt with acyl halides or
mixed anhydrides.1
For 2-imidazolidinone 3 other methods have been reported2a; includ-
ing coupling using N-trimethylsilyl,4f,6 N-Lithio,3c,4c–e,7 and N-magnesio8
salts with acyl halides or anhydrides. Alternatively reaction of 3 with acyl
halides has been successfully achieved in the absence of base4a or under basic
conditions using DABCO9a or N,N-dimethylaniline.9b,c The purpose of this
paper is to describe observations we have made regarding acylation reac-
tions of these chiral auxiliaries which have enabled us to identify optimised
conditions for such coupling reactions.
RESULTS
The coupling of oxazolidin-2-one auxiliaries 4 and 5 with 2-bromoacyl
halides using the reported method1 (method A) gave the desired products 6

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2-IMIDAZOLIDINONE AND 2-OXAZOLIDINONE
3243
and 7 in good yields and as approximately 1:1 mixtures of diastereomers10
(Table 1, entries 1, 2, 3 and 5). However application of this method to the
coupling of 2-imidazolidone 3 was less efficient, leading to products in
modest and variable yields (Table 2). Attempted coupling using the corre-
sponding N-Li salt of 3 with 2-bromoacyl bromides (entries 1 and 4–6) or
mixed anhydride (entry 3) following the reported method3c,4c–e,7 gave lower
yields (ꢀ 52%) of 8. However we found that by using 2-bromopropanoyl
chloride as electrophile, the coupling was more effective (entry 2, 77%) but
with the added complication of product contamination with the correspond-
ing a-chloropropanoyl derivative of 8e. We observed the chloride 8e as the
sole product using the DMAP/TEA method (entry 10). Attempts to improve
the procedure using magnesium or potassium salts were also ineffective
(entries 7 and 8, respectively) as were DABCO, triethylamine (TEA),
Table 1. Acylation of Oxazolidin-2-one Auxiliaries
2-Bromoacyl Halides
4
and
5
with

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3244
CANDEIAS ET AL.
Table 2. Acylation of Imidazolidin-2-one Auxiliary 3

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2-IMIDAZOLIDINONE AND 2-OXAZOLIDINONE
3245
4-(dimethylamino)pyridine (DMAP) or n-Bu4NI11 (entries 9 to 12).
However, we observed that the use of the hindered amine 2,6-di-t-butylpyri-
dine alone led to complete acylation (entry 13, method I) and similar results
could be obtained using the less expensive base 2,6-lutidine (entry 14,
method J). These methods were applied with success to the synthesis of
substrates 8a to 8d (entries 13 to 17). Under these general conditions the
acylation is equally effective at room12 or higher temperatures which can be
useful when coupling unreactive acyl chlorides (for example entry 18).
However the lutidine method is inferior to the existing n-BuLi method
for the coupling of 2-bromopropanoyl bromide with the oxazolidin-2-one
auxiliary 4 (Table 1, entries 4 and 3, respectively).
DISCUSSION
From these results it is apparent that coupling of the less reactive
oxazolidin-2-one auxiliary, requires prior formation of N-lithio salt.
Presumably the greater delocalization of the nitrogen atom lone pair4a
moderates its nucleophilicity and so the auxiliary is insufficiently nucleophi-
lic for reaction to take place effectively using an amine base. Acylation of
2-imidazolidinone 3 is successful under a much wider range of conditions;
however N-acylation with a-haloacyl halides appears to be successful only
when using a hindered amine base. It is interesting to note that reactions
involving 3 are characterised by excellent mass recoveries with a high
recovery of starting material. We noted that a simple experiment involving
treatment of 2-bromoacetyl bromide with triethylamine in dichloromethane
at low temperature13 and then 3 led to the isolation of mixture of 8a and an
unstable product whose NMR data were consistent with 9 (Scheme 1). This
compound undergoes hydrolysis to give exclusively the recovered auxiliary 3
and 2-bromoacetic acid. We suspect that this result indicates that the
O-acylated products may be the source of recovered auxiliary as opposed
to an inherent lack of reactivity of auxiliary 3. It would appear that the use
Scheme 1. 1) Et3N, DCM, À60ꢀC; 2) auxiliary 3, À60ꢀC; 3) SiO2 chromatography
or H2O work-up.

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3246
CANDEIAS ET AL.
of hindered base enables clean N-acylation to take place, presumably with-
out the intermediacy of O-acylated products.
In conclusion the results show that acylation of 2-imidazolidinone 3
with bromoacyl halides requires the use of a hindered base and that under
these optimised conditions excellent yields can be achieved. However these
reaction conditions cannot be used for related oxazolidinones which are
unreactive under these milder conditions. Coupling of these species requires
the use of organolithium reagents, presumably to effect auxiliary deproto-
nation with an enhancement of nucleophilicity.
EXPERIMENTAL
All glassware was oven dried and cooled in a desiccator (P2O5
desiccant) prior to use. Reaction solvents were pre-dried and distilled imme-
diately prior to use. Tetrahydrofuran (THF) was pre-dried over sodium wire
and distilled from sodium/benzophenone under a nitrogen atmosphere.
Dichloromethane (DCM), triethylamine (TEA) and 2,6-lutidine were dis-
tilled from calcium hydride powder under a nitrogen atmosphere.
Commerically supplied reagents were used as supplied except for acyl
halides which were distilled prior to use.
Flash column chromatography was carried out using Merck 60 silica
gel (70–240 mm). The non polar liquid phase was either distilled hexanes or
petroleum ether 40–60ꢁC boiling fraction unless otherwise stated. Pet30–40
refers to petroleum ether 30–40ꢁC boiling fractions which were distilled
prior to use. Other eluents were used as supplied. Thin layer chromatogra-
phy was carried out using Merck Kieselgel 60 F254 pre-coated, glass backed
plates. The plates were visualised using ultraviolet light (254 nm), KMnO4
solution, ninhydrin or iodine as appropriate.
1H NMR spectra were recorded on Bruker AMX 500, ARX 400, WM
360 or DPX 300 spectrometers. Chemical shifts are reported downfield
in parts per million (ppm) from a tetramethylsilane reference. 13C NMR
spectra were recorded on Bruker AMX 500, ARX 400 or DPX 300 spectro-
meters at 125 MHz, 100 MHz or 75 MHz respectively. Infra red (IR) spectra
were recorded on a Perkin-Elmer FT-IR 1720 spectrometer as thinly
dispersed films (from DCM) between sodium chloride plates unless other-
wise stated. Low resolution (EI/FAB) mass spectra were recorded using a
Fisons Autospec or Kratos mass spectrameter. High resolution accurate
mass determinations were carried out by the EPSRC National Mass
Spectrometry Service, University of Wales – Swansea, Singleton Park,
Swansea, Wales. Optical rotations were carried out using a Perkin-Elmer
241 or Optical Activity Mod. AA-1000 digital polarimeters with a cell path

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2-IMIDAZOLIDINONE AND 2-OXAZOLIDINONE
3247
length of 10 cm or 5 cm respectively. Melting points were carried out on a
Gallenkamp melting point apparatus and are uncorrected.
Typical Procedures for Coupling Using Method
A (N-Li Anion/Acyl Halide)
Preparation of (20RS,4S)-3-(20-Bromopropanoyl)-4-
(1-methylethyl)-Oxazolidin-2-one, 6b; Table 1, Entry 1)
To the stirred solution of (S )-4-(1-methylethyl)-oxazolidin-2-one, 4
(246 mg, 1.90 mmol) in THF (2 ml) at ꢂ78ꢁC under argon, was added
n-butyllithium (1.4 M in hexanes, 1.6 ml, 2.24 mmol, 1.2 eq). After 70 min
was added dropwise a solution of (2RS )-bromopropanoyl bromide (0.26 ml,
2.5 mmol, 1.3 eq) in THF (2.4 ml). After 5 h the reaction mixture was
allowed to reach room temperature. The crude mixture was diluted with
dichloromethane (5 ml), washed with aqueous saturated NaHCO3 solution
(5 ml) and the aqueous phase was extracted with ethyl acetate (2 ꢃ 10 ml).
The combined organic phase was washed with water (10 ml), dried with
MgSO4 and removed the solvent under reduced pressure. The product
was purified by column chromatography (SiO2, hexane/EtOAc 95/5 to
90/10; EtOAc) to afford 6b14 (281 mg, 56%) as a white solid, diastereomer
mixture, and recovered 4 (27.5 mg, 11%).
Preparation of (20RS,4S)-3-(20-Bromobutanoyl)-4-
(1-methylethyl)-Oxazolidin-2-one, 6c; Table 1,
Entry 3, Method A)
The product was purified by column chromatography (SiO2, hexane/
EtOAc, 95/5 to 80/20; EtOAc) to afford 6c (368 mg, 68%) as a clear colour-
less viscous oil, diastereomer mixture.
Diastereomer 6c of Rf(hexane/AcOEt 7/3) 0.58: [a]D þ 73.6 Æ 0.1ꢁ
(c. 1.2, CHCl3); IR (film): 2974, 2940, 2883 (C-H); 1787, 1707 (C¼O);
1
1389 (C-N); 1208 (C-O) cmꢂ1; H NMR 400 MHz (CDCl3); d 5.594 (1H, t,
J ¼ 7.1, CH3CH2CHBr-), 4.458 (1H, ddd, J ¼ 2.7, 4.0, 8.2, >NCH<), 4.337
(1H, t, J ¼ 8.2, 9.1, one of -OCH2-), 4.237 (1H, dd, J ¼ 2.7, 9.1, one of -
OCH2-), 2.377 (1H, m, -CH(CH3)2), 2.166 (1H, ddq, J ¼ 7.1, 7.3, 14.0, one
of CH3CH2CHBr-), 2.055 (1H, ddq, J ¼ 7.1, 7.3, 14.0, one of
CH3CH2CHBr-), 1.043 (3H, t, J ¼ 7.3, CH3CH2CHBr-), 0.931 (3H, d,
J ¼ 7.0, one of -CH(CH3)2), 0.880 (3H, d, J ¼ 6.9, one of -CH(CH3)2);
13C NMR 100 MHz (CDCl3): d 169.12, 153.27 (>C¼O); 63.64 (>CHCH2O-);

ORDER
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3248
CANDEIAS ET AL.
59.15 (>NCH<); 45.83 (CH3CH2CHBr-); 28.60 (-CH(CH3)2); 27.86
(CH3CH2CHBr-); 17.92, 14.73 (-CH(CH3)2); 11.84 (CH3CH2CHBr-); MS
(EI) m/z 277 (6%, Mþ), 234 ð23%; Mþ -ECHðCH3Þ2Þ, 198 ð87%; Mþꢂ EBrÞ,
149 (63%, CH3CH2CHBrCOþ), 130 (51%), 121 (45%, CH3CH2CHBrþ), 85
(82%), 69 (100%), 55 (65%), 41 (92%), 27 (47%).
25
Diastereomer 6c of Rf(hexane/AcOEt 7/3) 0.49: ½aꢄD þ56.0 Æ 02ꢁ (c.
1.4, CHCl3); IR (film): 2974, 2940, 2883 (C-H); 1787, 1707 (C¼O); 1389
(C-N); 1208 (C-O) cmꢂ1 1H NMR 400 MHz (CDCl3): d 5.543 (1H, t,
;
J ¼ 7.2, CH3CH2CHBr-), 4.476 (1H, ddd, J ¼ 3.6, 3.8, 8.8, >NCH<),
4.293 (1H, t, J ¼ 8.8, 9.1, one of -OCH2-), 4.227 (1H, dd, J ¼ 3.6, 9.1, one
of -OCH2-), 2.379 (1H, m, -CH(CH3)2), 2.103 (1H, ddq, J ¼ 7.2, 7.3, 14.0,
one of CH3CH2CHBr-), 2.018 (1H, ddq, J ¼ 7.2, 7.3, 14.0, one of
CH3CH2CHBr-), 1.005 (3H, t, J ¼ 7.3, CH3CH2CHBr-), 0.920 (3H, d,
J ¼ 6.9, one of -CH(CH3)2), 0.911 (3H, d, J ¼ 7.1, one of -CH(CH3)2);
13C NMR 100 MHz (CDCl3):
d
169.03, 152.91 (>C¼O); 63.29
(>CHCH2O-); 58.18 (>NCH<); 45.58 (CH3CH2CHBr-); 27.81
(-CH(CH3)2); 26.93 (CH3CH2CHBr-); 17.72, 14.65 (-CH(CH3)2);
11þ.84 (CH3CH2CHBr-); MS (EI ) m/z 279 (53%, Mþ), 234 (3%,
þ
M -ECH(CH3)2), 198 ð67%; M - BrÞ, 149 (55%, CH3CH2 CHBrCOþ),
.
130 (52%), 121 (49%, CH3CH2CHBrþ), 85 (71%), 70 (67%), 49 (80%),
41 (100%), 27 (75%).
Preparation of (20RS,4R)-3-(20-Bromopropanoyl)-4-
phenyloxazolidin-2-one, 7b (Table 1, Entry 2)
To the stirred solution of (R)-4-phenyloxazolidin-2-one, 5 (903 mg,
5.53 mmol) in THF (8.5 ml) at ꢂ78ꢁC under argon, was added n-butyl-
lithium (1.6 M in hexanes, 4.2 ml, 6.72 mmol). After 1.5 h HMPA (0.50 ml,
2.87 mmol) was added and then was added dropwise a solution of (2RS )-
bromopropanoyl chloride (1.23 g, 7.16 mmol) in THF (1.5 ml). After 4 h the
reaction mixture was quenched with aqueous saturated NaHCO3 solution
(5 ml) extracted with EtOAc (4 ꢃ 15 ml). The combined organic phase was
washed with water (3 ꢃ 10 ml), dried with MgSO4 and removed the solvent
under reduced pressure. The product was purified by column chromatogra-
phy (SiO2, Pet/Et2O 4:1 to 2:1) to afford 7b (1.2 g, 72%) as white crystalline
solids, diastereomer mixture.
25
Diastereomer 7b of Rf ¼ 0.57 Pet/EtOAc (2:1): m.p. 131–133ꢁC; ½aꢄD
ꢂ90.0ꢁ (c ¼ 0.84, CHCl3); IR (film): 3547, 3381, 3048, 2996, 2918, 1965,
1785, 1698, 1495, 1474, 1456, 1376, 1302, 1257, 1198, 1182, 1123, 1093,
1068, 1040, 1025, 997, 970, 944, 922, 821, 768, 759, 731, 703 cmꢂ1; 1H NMR
360 MHz (CDCl3): d 7.43–7.30 (5H, m, Ph), 5.73 (1H, q, J ¼ 6.7 Hz,

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2-IMIDAZOLIDINONE AND 2-OXAZOLIDINONE
3249
-COCH(Br)CH3), 5.44 (1H, dd, J ¼ 8.5 Hz, >NCH(Ph)CH2-), 4.78 (1H, t,
J ¼ 8.7 Hz, -OCHAHBCH <), 4.36 (1H, dd, J ¼ 8.9 Hz, -OCHAHBCH <),
1.77 (3H, d, J ¼ 6.8 Hz, -CH(Br) CH3); 13C NMR 75.5 MHz (CDCl3): d
169.5, 153.2, 139.1, 129.7, 129.4, 126.4, 70.6, 58.6, 39.1, 21.0; MS (EI )
m/z: 297 (Mþ), 218 (Mþ -Br), 162, (Mþ-COCH(Br)CH3), 149, 104, 91, 77;
HRMS (EI ): C12H12BrNO3 (Mþ); calcd. 297.0001; found 297.0001.
Diastereomer 7b of Rf ¼ 0.39 Pet/EtOAc (2:1): m.p. 134.7–136.7ꢁC;
25
½aꢄD ꢂ54.8ꢁ (c ¼ 1.06, CHCl3); IR (film): 3040, 2976, 1785, 1765, 1706, 1494,
1471, 1459, 1390, 1367, 1329, 1257, 1229, 1204, 1086, 1061, 1041, 1000, 982,
936, 779, 758, 749, 699 cmꢂ1; 1H NMR 360 MHz (CDCl3): d 7.44–7.36 (5H,
m, Ph), 5.76 (1H, q, J ¼ 6.7 Hz, -COCH(Br)CH3), 5.47 (1H, dd, J ¼ 9.0 Hz,
>NCH(Ph)CH2-), 4.74 (1H, t, J ¼ 9.0 Hz, -OCHAHBCH<), 4.28 (1H, dd,
J ¼ 9.0 Hz, -OCHAHBCH<), d 1.77 (3H, d, J ¼ 6.8 Hz, -CH(Br)CH3);
13C NMR 75.5 MHz (CDCl3): d 169.3, 153.2, 138.0, 129.7, 129.4, 126.3,
70.4, 58.3, 38.9, 20.4; MS (EI) m/z: 297 (Mþ), 246, 218 (Mþ -Br), 162,
(Mþ-COCH(Br)CH3), 149, 104, 91, 77; HRMS (EI ):. C12H12BrNO3
(Mþ); calcd. 297.0001; found 297.0001.
Preparation of (4S,5R)-2-(20-Bromoethanoyl)-3,4-
dimethyl-5-phenylimidazolidin-2-one 8a (Table 2, Entry 1)
To the stirred solution of (4R,5S)-1,5-dimethyl-4-phenylimidazolidin-
2-one 3 (408 mg, 2.14 mmol) in THF (6 ml) at ꢂ7ꢁC under argon, was added
n-butyllithium (1.5 M in hexanes, 1.65 ml, 2.39 mmol, 1.1 eq). After 15 min.
the mixture was cooled to ꢂ78ꢁC and was added dropwise 2-bromoethanoyl
bromide (225.0 ml, 2.58 mmol), 1.2 eq). After 30 min. the reaction mixture
was allowed to reach room temperature. The crude mixture was diluted with
dichloromethane (5 ml), washed with aqueous saturated NH4Cl solution
(5 ml) and the aqueous phase was extracted with ethyl acetate (3 ꢃ 10 ml).
The combined organic phase was washed with water (10 ml), dried with
MgSO4 and removed the solvent under reduced pressure. The product
was purified by column chromatography (SiO2, hexane/EtOAc 95/5 to
4/6; EtOAc) to afford (4S,5R)-2-(20-dibromoethanoyl)-3,4-dimethyl-5-phe-
nylimidazolidin-2-one 10 (42 mg, 5%), 8a (163 mg, 24%) and recovered 3
(236 mg, 58%).
25
10: Rf(hexane/AcOEt, 6/4) 0.42; m.p. 155–156ꢁC (Et2O); ½aꢄD
ꢂ121.3 Æ 0.1ꢁ (c. 1.4, CHCl3); IR (KBr): 3046 (C-H Ar); 2980, 2901
(C-H); 1733, 1718, 1703 (C ¼ O); 1371 (C-N) cmꢂ1; H NMR 400 MHz
1
(CDCl3): d 7.636 (1H, s, -CHBr2), 7.351–7.302 (3H, m, Ar), 7.165–7.145
(2H, m, Ar), 5.324 (1H, d, J ¼ 8.6, PhCH <), 3.989 (1H, dq, J ¼ 6.6, 8.6,
CH3CH <), 2.860 (3H, s, CH3N <), 0.815 (3H, d, J ¼ 6.6, CH3CH <);

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3250
CANDEIAS ET AL.
13C NMR 100 MHz (CDCl3): d 162.68, 154.23 (>C¼O); 134.97, 128.61,
128.47, 126.90 (Ar); 59.86 (PhCH<); 54.01 (CH3CH<); 35.32 (-CHBr2);
28.32 (>NCH3); 14.96 (>CH H3); MS (EI ) m/z: 390 (40%, Mþ),
311 ð41%; Mþ -EBr), 189 (46%, Mþ-COCHBr2), 175 (64%), 149 (57%),
132 (100%), 77 (70%), 58 (94%), 42 (89%); HRMS (EI ): Found: Mþ,
387.9432; C13H14Br2N2O2 calcd. 387.9422.
25
8a: Rf(hexane/AcOEt 6/4) 0.29; m.p. 79–80ꢁC (Et2O); ½aꢄD
(C-H); 1737, 1728, 1687 (C¼O); 1362 (C-N) cmꢂ1
ꢂ82.8 Æ 0.2ꢁ (c. 1.3, CHCl3); IR (KBr): 3061, 3032 (C-H Ar); 2975, 2928
;
1H NMR 400 MHz
(CDCl3): d 7.343–7.262 (3H, m, Ar), 7.160–7.140 (2H, m, Ar), 5.288 (1H,
d, J ¼ 8.6, PhCH<), 4.609 (1H, d, J ¼ 11.8, one of -CH2Br), 4.533 (1H, d,
J ¼ 11.8, one of -CH2Br), 3.941 (1H, dq, J ¼ 6.6, 8.6, CH3CH<), 2.832
(3H, s, CH3N<), 0.795 (3H, d, J ¼ 6.6, CH3CH<); 13C NMR 100 MHz
(CDCl3); d 165.04, 154.87 (>C¼O); 135.62, 128.41, 128.15, 126.81 (Ar);
59.37 (PhCH <); 53.98 (CH3CH<); 28.72 (-CH2Br); 28.10 (>NCH3);
14.78 (>CHCH3); MS (EI ) m/z: 310 (17%, Mþ), 231 ð43%; Mþ -EBr),
189 (42%, Mþ-COCH2Br), 175 (31%), 132 (100%), 77 (65%), 56 (47%),
42 (93%); HRMS (EI ): Found: Mþ, 310.0317; C13Hl5BrN2O2 calcd.
310.0317.
Typical Procedure for Coupling Using Method F
(DMAP/TEA/acyl Halide,Table 2,Entry 10)
To a stirred solution of (4R,5S)-1,5-dimethyl-4-phenylimidazolidin-2-
one 3 (498 mg, 2.62 mmol) in DCM (5 ml), under argon atmosphere at room
temperature, was added triethylamine (0.44 ml, 3.16 mmol). (2RS )-bromo-
propanoyl chloride (0.40 ml, 3.97 mmol) was added dropwise. After 26 h the
crude mixture was diluted with dichloromethane (5 ml), washed with aqu-
eous saturated NH4Cl solution (5 ml) and the aqueous phase was extracted
with dichloromethane (4 ꢃ 10 ml). The combined organic phase was washed
with water (10 ml), dried with MgSO4 and removed the solvent under
reduced pressure. The product was purified by column chromatography
(SiO2, Pet/EtOAc 6 : 1 to 1 : 1, EtOAc) to afford (20RS,4S,5R)-1-(20-chlor-
opropanoyl)-3,4-dimethyl-5-phenylimidazolidin-2-one 8e (464 mg, 63.0%) as
white solids, diastereomer mixture and recovered 3 (41 mg, 8.3%).
(20S,4S,5R)-1-(20-Chloropropanoyl)-3,4-dimethyl-5-phenylimidazoli-
25
din-2-one, 20S-8e: Rf ¼ 0.54 Pet./EtOAc (2 : 1); m.p. 187–189ꢁC (dec.); ½aꢄD
ꢂ69.0ꢁC (c ¼ 0.99, CHCl3); IR (film): 2935, 2357, 1723, 1695, 1652, 1558,
1495, 1447, 1426, 1377, 1334, 1290, 1262, 1203, 1063, 961, 862, 808, 790, 750,
1
703, 669 cmꢂ1; H NMR 300 MHz (CDCl3): d 7.33–7.18 (3H, m, 3ArH),
7.09–7.03 (2H, m, 2ArH), 5.87 (1H, q, J ¼ 6.7 Hz, -COCH(Cl)CH3),

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2-IMIDAZOLIDINONE AND 2-OXAZOLIDINONE
3251
5.21 (1H, d, J ¼ 8.5 Hz, >NCH(Ph)CH<), 3.89 (1H, m, >NCH(CH3)
CH<), 2.77 (3H, s, > NCH3), 1.53 (3H, d, J ¼ 6.8 Hz, -CH(Cl)CH3), 0.72
(3H, d, J ¼ 6.7 Hz, > CHCH3); 13C NMR 75.5 MHz (CDCl3): d 169.3,
155.3, 136.5, 129.1, 128.7, 127.2, 60.2, 54.4, 52.1, 28.5, 21.4, 15.3; MS
(EI ) m/z: 280 (Mþ), 245 (Mþ-Cl), 199, 189 (Mþ-COCH(Cl)CH3), 175,
132, 91, 77, 42; HRMS (EI ): C14H17ClN2O2 (Mþ); calcd. 280.0979; found
280.0979.
(20R,4S,5R)-1-(20-Chloropropanoyl)-3,4-dimethyl-5-phenylimidazoli-
25
din-2-one, 20R-8e: Rf ¼ 0.22 Pet./EtOAc (2 : 1); m.p. 167–168ꢁC; ½aꢄD ꢂ62.3ꢁ
(c ¼ 1.50, CHCl3); IR (film): 2979, 1729, 1694, 1424, 1393, 1311, 1289, 1260,
1111, 1062, 995, 963, 863, 757, 701, 677 cmꢂ1; 1H NMR 300 MHz (CDCl3): d
7.26–7.05 (5H, m, Ph), 5.86 (1H, q, J ¼ 6.7 Hz, -COCH(Cl)CH3), 5.23 (1H,
d, J ¼ 8.8 Hz, >NCH(Ph)CH<), 3.80 (1H, m, >NCH(CH3)CH<), 2.74
(3H, s, >NCH3), 1.53 (3H, d, J ¼ 6.7 Hz, -CH(Cl)CH3), 0.69 (3H, d,
J ¼ 6.4 Hz, >CHCH3); 13C NMR 75.5 MHz (CDCl3): d 168.5, 154.7,
135.5, 128.5, 128.2, 127.7, 59.2, 53.9, 50.9, 28.3, 20.1, 15.1; MS (EI ) m/z:
280 (Mþ), 245 (Mþ -Cl), 189 (Mþ -COCH(Cl)CH3), 175, 132, 91, 77, 57, 42;
HRMS (EI ): C14H17ClN2O2 (Mþ); calcd. 280.0979; found 280.0979.
Preparation of (4S,5R)-3,4-Dimethyl-5-phenyl-1-
propanoylimidazolidin-2-one 8f (Method J,Table 2,Entry 18)
To a stirred solution of (4R, 5S)-1,5-dimethyl-4-phenylimidazolidin-2-
one 3 (496 mg, 2.61 mmol), in THF (5.0 ml), and 2,6-lutidine (340.0 ml,
2.92 mmol, 1.1 eq) under argon atmosphere at 60ꢁC (oil bath temperature),
was added dropwise propanoyl chloride (360.0 ml, 4.14 mmol, 1.6 eq). After
4 h the crude mixture was cooled to room temperature, diluted with
dichloromethane (5 ml), washed with aqueous saturated NH4Cl solution
(5 ml) and the aqueous phase was extracted with ethyl acetate (2 ꢃ 10 ml).
The combined organic phase was washed successively with aqueous HCl
solution (7.5%, 10 ml) and water (10 ml), dried with MgSO4 and removed
the solvent under reduced pressure. The product was purified by column
chromatography (SiO2, Pet/EtOAc 7/3; EtOAc) to afford 8f (585 mg,
91%).3c
Observation of O-acylation on (4R, 5S)-1,5-dimethyl-4-phenylimidazo-
lidin-2-one 3: To a stirred solution of triethylamine (206 ml, 1.47 mmol) in
DCM (2.0 ml), under argon atmosphere at ꢂ60ꢁC, was added dropwise
bromoacetyl bromide (116 ml, 1.34 mmol). After 15 min, a solution of
(4R, 5S)-1,5-dimethyl-4-phenylimidazolidin-2-one 3 (255 mg, 1.34 mmol) in
DCM (2.0 ml) was added dropwise (5 min). After 20 min the reaction
mixture was allowed to warm to room temperature and the solvent was

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3252
CANDEIAS ET AL.
evaporated under reduced pressure. Diethyl ether (10 ml) was added, the
mixture was vigorously stirred, filtered and the solid was washed again
with diethyl ether (5 ml). The combined ethereal solution was evaporated
under reduced pressure to give 291 mg of amorphous yellow solid; mixture
2 : 8 of 8a and proposed O-acylation structure 9 on basis of 1H NMR.
1
Partial spectral data assigned to 9: IR (Film): 1705, 1665 cmꢂ1; H NMR
400 MHz (CDCl3): d 4.82 (d, J ¼ 8.7, PhCH <), 3.84 (s, -CH2Br), 2.74
(s, CH3N<), 0.74 (d, J ¼ 6.6, CH3CH<); 13C NMR 100 MHz (CDCl3):
d 170.4, 163.4, 27.0. The above residue was dissolved in a mixture of
water (5 ml) and THF (5 ml), and stirred at room temperature. After 15 h,
the solution was partioned between diethyl ether (20 ml), and aqueous satu-
rated NaHCO3 solution (15 ml) and the aqueous phase was extracted with
diethyl ether (2 ꢃ 20 ml). The combined organic phase was dried with
MgSO4 and removed the solvent under reduced pressure to give 3
(204 mg, 79%). The aqueous phase was acidified with hydrochloric acid
ð37%; pH ꢅ 1Þ, saturated with NaCl and extracted with diethyl ether
(3 ꢃ 20 ml). The combined organic phase was dried with MgSO4 and
removed the solvent under reduced pressure to give bromoacetic acid
(88 mg, 47%).
ACKNOWLEDGMENTS
This work was supported by the Fundacao para a Ciencia e
Tecnologia (FCT, project PRAXIS XXI PCEX/C/QUI/53/96 and a Ph.D
grant for S.X.C., Ref. PRAXIS XXI/BD/4024/94). Financial support from
EPSRC, GlaxoWellcome, SmithKline Beecham, AstraZeneca and Novartis
is gratefully acknowledged.
REFERENCES
1. a) Evans, D.A.; Kim, A.S.; Ed.; Coates, R.M.; Denmark, S.E.
Handbook of Reagents for Organic Synthesis: Reagents, Auxiliaries,
and Catalysts for C-C Bond Formation, John Wiley and Sons LTD,
1999, 91. b) Ager, D.J.; Prakash, I.; Schaad, D.R. Aldrichimica Acta
1997, 30, 3–12.
2. a) Roos, G.H.P.S. Afr. J. Chem. 1998, 51, 7–24, review. b) Kim, T.H.;
Lee, G.-J. Tetrahedron Lett. 2000, 41, 1505–1508.
3. a) Close, W.J. J. Org. Chem. 1950, 15, 1131–1134. b) Roder, H.;
Helmchen, G.; Peters, E.-M.; Peters, K.; Schnering, H.-G. Angew.

ORDER
REPRINTS
2-IMIDAZOLIDINONE AND 2-OXAZOLIDINONE
3253
Chem. Int. Ed. Eng. 1984, 23, 898–899. c) Drewes, S.E.; Malissar,
D.G.S.; Roos, G.H. Chem. Ber. 1993, 126, 2663–2673.
4. a) Clark, W.M.; Bender, C. J. Org. Chem. 1998, 63, 6732–6734
and references cited therein. b) Roos, G.H.P.; Balasubramaniam, S.
Tetrahedron: Asymm. 1998, 9, 923–926. c) Durandetti, M.;
Perichon, J.; Nedelec, J.-Y. J. Org. Chem. 1997, 62, 7914–7915.
d) Guillena, G.; Najera, C. Tetrahedron: Asymm. 1998, 9,
1125–1129; ibid 3935–3938. e) Heerden, P.S.; Bezuidenhoudt, B.C.B.;
Ferreira, D. Tetrahedron 1997, 53, 6045–6056. f ) Versteeg, M.;
Bezuidenhoudt, B.C.B.; Ferreira, D. Tetrahedron 1999, 55,
3365–3376. g) Cardillo, G.; Gentilucci, L.; Bastardas, I.R.; Tolomelli,
A. Tetrahedron 1998, 54, 8217–8222. h) Cardillo, G.; Gentilucci, L.;
Tolomelli, A. Chem. Commun. 1999, 167–168. i) Palomo, C.;
Aizpurua, J.M.; Mielgo, A.; Linden, A. J. Org. Chem. 1996, 61,
9186–9195. j) Langer, T.; Illich, M.; Helmchen, G. Synlett 1996,
1137–1138. k) Powers, T.S.; Shi, Y.; Wilson, K.J.; Wulff, W.D.
J. Org. Chem. 1994, 59, 6882–6884. l) Fehr, C.; Galinho, J. J. Am.
Chem. Soc. 1988, 110, 6909–6911.
5. a) Caddick, S.; Jenkins, K.; Treweeke, N.; Candeias, S.X.; Afonso,
C.A.M. Tetrahedron Lett. 1998, 39, 2203–2206. b) Caddick, S.;
Jenkins, K. Tetrahedron Lett. 1996, 37, 1301–1304.
6. Versteeg, M.; Bezuidenhoudt, B.C.B.; Ferreira, D.; Swart, K.J.
J. Chem. Soc. Chem. Commun. 1995, 1317–1318.
7. a) Heerden, P.S.; Bezuidenhoudt, B.C.B.; Ferreira, D. Tetrahedron
Lett. 1997, 38, 1821–1824. b) Orena, M.; Porzi, G.; Sandri, S.
Tetrahedron Lett. 1992, 33, 3797–3800. c) Cardillo, G.; Orena, M.;
Romero, M.; Sandri, S. Tetrahedron 1989, 45, 1501–1508.
d) Cardillo, G.; D’Amico, A.; Orena, M.; Sandri, S. J. Org. Chem.
1988, 53, 2354–2356.
8. a) Bongini, A.; Cardillo, G.; Mingardi, A.; Tomasini, C. Tetrahedron:
Asymm. 1996, 7, 1457–1466. b) Cardillo, G.; Gentilucci, L.; Tomasini,
C.; Castejon-Bordas, M.P.V. Tetrahedron: Asymm. 1996, 7, 755–762.
c) Amoroso, R.; Cardillo, G.; Sabatino, P.; Tomasini, C.; Trere, A.
J. Org. Chem. 1993, 58, 5615–5619.
9. a) Kriel, K.N.; Emslie, N.D.; Roos, G.H.P. Tetrahedron Lett. 1997,
38, 109–110. b) Anand, R.C.; Singh, V. Tetrahedron 1993, 49,
6515–6520. c) Melnyk, O.; Stephan, E.; Pourcelot, G.; Cresson, P.;
Tetrahedron 1992, 48, 841–850.
10. The a-bromo-acyl-oxazolidin-2-one diasteriomers epimerise at ꢂ4ꢁC in
less than a week while the corresponding a-bromoacyl-imidazolidin-2-
one diasteriomers are stable at room temperature.

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11. Other attempts using 2-bromopropanoyl bromide or chloride and
DMAP/TEA (Method F), DABCO/Cu?9a or NTMS gave a complex
mixture of products. Using 2-bromopropanoic acid and DCC/DMAP
coupling method no acylation was observed and the auxiliary 3 was
recovered in 71%.
12. The acylation of 3 with 2-bromobutanoyl bromide/2,6-lutidine
(Method J) at room temperature gave 8c in 88% and recovered 3 in 7%.
13. The formation of halogenated ketenes via triethylamine dehydrogena-
tion of acid halides at low termperature is well known: a) Tidwell, T.T.
Ketenes, John Wiley and Sons LTD, 1995, chapter 3. b) Schaumann, E.;
Scheiblich, S. Methoden der Organischen Chemie, Thieme Verlag,
Stuttgart, 1993, vol. E15, pp. 2353–2530. c) Brady, W. Tetrahedron
1981, 37, 2949–2966.
14. Ito, Y.; Sasaki, A.; Tamoto, K.; Sunagawa, M.; Terashima, S.
Tetrahedron 1991, 47, 2801–2820.
15. Iseki, K.; Asada, D.; Takahashi, M.; Nagai, T.; Kobayashi, Y.
Tetrahedron: Asymmetry 1996, 7, 1205–1215.
16. Spectral data of compounds 8b, 8c and 8d will appear in a manuscript
in preparation on dynamic kinetic resolution studies on these
substrates.
Received in the UK November 8, 2000

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