Stereoselective addition of grignard reagents and lithium alkyls onto 3,5-disubstituted-1,3-oxazolidine-2,4-diones

Article abstract of DOI:10.1080/00397911.2011.609301

3-Benzyl-5-methyl-1,3-oxazolidine-3,4-diones react with Grignard reactants and with lithium alkyls to yield 4-substituted 3-benzyl-4-hydroxy-5-methyl-1,3- oxazolidine-2-ones. The reaction is stereoselective and follows Cram's rule.

Full text of DOI:10.1080/00397911.2011.609301

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Stereoselective Addition of Grignard
Reagents and Lithium Alkyls onto 3,5-
Disubstituted-1,3-oxazolidine-2,4-diones
Guido Galliani a , Bruno Rindone b , Ricardo Suarez-Bertoa c
Francesco Saliu b & Alberto Terraneo a
a Chorisis, Gerenzano, Italy
,
b Department of Environmental Sciences, University of Milano-
Bicocca, Milano, Italy
c LISA, Université de Paris XII, Créteil Cédex, France
Version of record first published: 13 Nov 2012.
To cite this article: Guido Galliani , Bruno Rindone , Ricardo Suarez-Bertoa , Francesco Saliu &
Alberto Terraneo (2013): Stereoselective Addition of Grignard Reagents and Lithium Alkyls onto 3,5-
Disubstituted-1,3-oxazolidine-2,4-diones, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 43:5, 749-757
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Synthetic Communications1, 43: 749–757, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.609301
STEREOSELECTIVE ADDITION OF GRIGNARD
REAGENTS AND LITHIUM ALKYLS ONTO
3,5-DISUBSTITUTED-1,3-OXAZOLIDINE-2,4-DIONES
Guido Galliani,1 Bruno Rindone,2 Ricardo Suarez-Bertoa,3
Francesco Saliu,2 and Alberto Terraneo1
1Chorisis, Gerenzano, Italy
2Department of Environmental Sciences, University of Milano-Bicocca,
Milano, Italy
3
´
´
´
LISA, Universite de Paris XII, Creteil Cedex, France
GRAPHICAL ABSTRACT
Abstract 3-Benzyl-5-methyl-1,3-oxazolidine-3,4-diones react with Grignard reactants and
with lithium alkyls to yield 4-substituted 3-benzyl-4-hydroxy-5-methyl-1,3-oxazolidine-2-
ones. The reaction is stereoselective and follows Cram’s rule.
Keywords Grignard; lithium alkyls; oxazolidinedione; stereoselectivity
INTRODUCTION
1,3-oxazolidine-2,4-diones are useful intermediates for the preparation of
biologically active compounds.[1–7] These compounds are hydrolyzed in alkaline con-
ditions by attack of the three available bonds, namely the amide C-N bond and the
two carbamate C-O and C-N bonds, depending on substrate and reaction con-
ditions. Scarce data on their reactivity with nucleophiles are available. Recently,
we found that 3,5-dialkyl-1,3-oxazolidine-2,4-diones (1) react with primary aliphatic
amines to give N-lactylureas (4) (Scheme 1, path a). Reactions are performed in sol-
ventless conditions and require a temperature of 80–90 ꢀC to proceed, with rates
being enhanced by microwaves.[8,9] The carbamate carbonyl is attacked by primary
Received April 29, 2011.
Address correspondence to Guido Galliani, Chorisis, srl, Via Roberto Lepetit 34, Gerenzano, Va
21040, Italy. E-mail: g.galliani@chorisis.it
749

750
G. GALLIANI ET AL.
Scheme 1. Reaction scheme of 3-substituted 5-methyl-1,3-oxazolidine-2,4-diones with primary aliphatic
amines. Only N-lactylureas (path a) are formed.
aliphatic amines and the bond broken during the reaction is the C-O bond. No
substantial amounts of the products from path b were found.
RESULTS AND DISCUSSION
In the search for additional data on the reactivity of 3,5-dialkyl-1,3-
oxazolidine-2,4-diones with nucleophiles, 3-benzyl-5-methyl-1,3-oxazolidine-2,4-
dione (5) (Scheme 2) was reacted with several carbon-centered nucleophiles. The
starting material was prepared by condensation of urea and ethyl lactate with
sodium ethoxide in ethanol, followed by N-alkylation (86% yield).[10]
With Grignard reagents and with lithium alkyls, the reaction product obtained
at low temperatures (ꢁ30 ꢀC) was identified as the cyclic adduct (6) (Scheme 2),
namely a 4-substituted 3-benzyl-4-hydroxy-5-methyl-1,3-oxazolidin-2-one, as a cou-
ple of enantiomers. The formation of the adduct at low temperature is an example of
stereoselective additions to carbonyls. The stereochemistry of the adducts is in line
with Cram’s rule,[11] the incoming group attacking carbonyl from the side of the
small group, hydrogen in this case, more preferably than on the side of the large
group, namely methyl in the present case.
Proofs of the structure are given by the following pieces of evidence:
1. Liquid chromatography–mass spectrometry (LC-MS) data of the purified
products, typical for adducts.
Scheme 2. Reaction of 3-benzyl-5-methyl-1,3-oxazolidine-3,4-diones with alkyl Grignard reactants and
with lithium alkyls at ꢁ30 ꢀC in THF.

2,4-OXAZOLIDINEDIONES AND C-NUCLEOPHILES
751
2. A hydrogen atom on a heteroatom is present (1 H in the 1H NMR spectrum in the
range of 4–5 ppm, disappearing upon treatment with D2O).
3. The amide carbonyl of the starting product, giving a signal at 172 ppm in the 13
C
NMR, disappears, whereas the carbamate carbonyl (at 158 ppm) is retained dur-
ing the reaction, unlike in the reaction with primary amines.
4. APT (attached proton test) 13C NMR spectrum shows that a quaternary sp3
carbon is formed, with a signal close to 82, according to the group attached
during the reaction.
5. The C-H carbon bearing the 5 methyl group is shifted in the 13C NMR spectrum
to a value close to 90 ppm, instead of 76 ppm of the starting material, as predicted
by 13C NMR simulation (ChemOffice 2005). Addition of the R group of the
metallorganic reagent onto the carbamate would not affect the signal. Figure 1
shows both simulated signals and those actually found for the adduct of 3-
benzyl-5-methyl-1,3-oxazolidine-2,4-dione with methyl magnesium bromide
(compound 9a of Table 1).
6. Correlation spectroscopy = nuclear overhauser effect spectroscopy (COSY=
NOESY) experiments on compound 9a (Table 1) indicate a long-range interac-
tion between the hydrogen atom at 4.35 ppm and the methyl group entered by
the addition of the Grignard reagent, resonating at 1.29 ppm. The interaction is
consistent with cis configuration of these groups (Fig. 2).
7. Compound 9a structure was confirmed by an independent synthesis on the
analogy of similar compounds obtained by reaction of 2-hydroxybutanone and
isocyanates.[12,13] Moreover, stereochemistry was confirmed as well, COSY=
NOESY experiments showing the same pattern described in these papers.
Figure 1. 13C NMR simulated spectra for the two possible adducts of MeMgBr onto carbonyl groups of
3-benzyl-5-methyl-1,3-oxazolidine-2,4-dione. A comparison with the spectrum actually found shows that
the Grignard reagent attacks the amide carbonyl.

752
G. GALLIANI ET AL.
Table 1. Reaction of 1,3-oxazolidine-2,4-diones (8) with either Grignard reagents or lithium alkyls to give
adducts (9)
Entry
R1
R2
R3
M
Yield (%)
a
b
c
c0
d
e
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Ethyl
MgBr
MgBr
MgBr
Li
76
80
58
47
64
64
57
n-Butyl
n-Butyl
Propynyl
Allyl
MgCl
MgBr
f
4-Ethoxy-2,4-dioxobut-1-yl (as a reaction product) Li
Structure 10 (as a reactant)
g
h
i
Benzyl
Benzyl
Methyl
n-Butyl Methyl
2-Methyl-1,3-dithian-2-yl
Li
44
62
83
75
MgBr
MgBr
MgBr
n-Pentyl Methyl
n-Hexyl Methyl
Ethyl
Allyl
j
Table 1 (entries a–g) reports the yields obtained after flash chromatography of the
crude reaction mixture, which contained only reaction product and starting material.
Yields are not optimized. Reaction products were identified by infrared (IR),
1
LC-MS, and H and 13C NMR. The reaction seems to be of general application,
because compounds with different substitutions both in positions 3 and 5 give
analogous reaction products, as shown in Table 1, entries h, i, and j.
Reactions of 3-benzyl-5-methyl-1,3-oxazolidine-2,4-dione (5) with the same
carbon centered nucleophiles in refluxing tetrahydrofuran (THF) retained chemos-
electivity. In these conditions, however, stereoselectivity was lost. As a matter of fact,
Figure 2. NOESY shows a long-range interaction between the hydrogen atom and the methyl group in the
enantiopure couple obtained at ꢁ30 ꢀC.

2,4-OXAZOLIDINEDIONES AND C-NUCLEOPHILES
753
Scheme 3. Reaction of 3-benzyl-5-methyl-1,3-oxazolidine-3,4-diones with alkyl Grignard reactants and
with lithium alkyls at reflux in THF.
both diastereoisomers on position 4 were found (Scheme 3). Similar diastereoisomers
were described as well in the reaction of 2-hydroxybutanone with isocyanates.[12]
Moreover, both products converged to a single product in dehydrating condition
already described in the same paper, to give a 4-oxazolin-2-one.
The reaction of Grignard reagents and lithium alkyls with 3,5-disubstituted-
1,3-oxazolidine-2,4-diones at ꢁ30 ꢀC is a new entry to 3,4-substituted 4-hydroxy-
1,3-oxazolidin-2-ones, as an alternative method to published procedures.[13]
Advantages of this new method are a good control of stereochemistry and the possi-
bility of introducing different groups onto position 4.
EXPERIMENTAL
1
All chemicals were purchased from Aldrich or Fluka chemical companies. H
and 13C were recorded on a Varian Mercury 400 instrument in CDCl3. Chemical
shifts were reported in parts per million (d) relative to the internal standard of tetra-
methylsilane (TMS). Melting points were determined in open capillaries using an
Electrothermal melting-point apparatus and are uncorrected. All products where
analyzed by LC=MS (column Gemini C18, 5 micron, 4.6 ꢂ 150 mm, 80% ammonium
acetate 0.01 M pH 3.5, 20% acetonitrile, 30 ꢀC). Infrared spectra (IR) spectra in sol-
ution were recorded on a Nicolet Avatar 360 Fourier transform (FT-IR) spec-
trometer, using calcium fluoride cells previously purged with nitrogen. Elemental
analyses were carried out on a Perkin-Elmer series II 2400 instrument. All reactions
were monitored by thin-layer chromatography (TLC). Flash chromatography was
performed on silica gel (100–200 mesh).
Typical Procedure for Addition of Either Grignard Reagents or
Lithium Alkyks
4-Benzyl-5-methyl-1,3-oxazolidine-2,4-dione (2 g, 9.75 mmol) was dissolved in
40 mL of anhydrous THF. The solution was cooled at ꢁ40 ꢀC under nitrogen.
Methyl magnesium chloride 3 M (3.25 ml) in THF (9.75 mmol) was dropped into
the solution, keeping temperature below ꢁ30 ꢀC. Temperature was then raised from
ꢁ30 ꢀC to 5 ꢀC in 5 h, this final temperature being maintained for an additional hour.
After quenching with 200 mL of a saturated aqueous solution of ammonium chlor-
ide, the mixture was extracted with methylene chloride (2 ꢂ 200 mL). The combined
organic phases were washed with brine (100 mL), dried over anhydrous sodium

754
G. GALLIANI ET AL.
sulfate, filtered, and evaporated under reduced pressure. The residue was purified by
flash chromatography, eluting with n-hexane=ethyl acetate 4:1.
Reaction with the Lithium Derivative of the Sodium Enolate of
Methyl Acetoacetate (Table 1, Entry f)
Methylacetoacetate (1.8 mL, 17 mmol) was added dropwise in a suspension of
0.41 g of sodium hydride (17 mmol) in 200 mL of dry THF at ꢁ15 ꢀC under a nitro-
gen atmosphere. The mixture was stirred for 40 min, and then 6.8 mL of 2.5 M butyl
lithium in THF (17 mmol) were added dropwise at the same temperature. A solution
of 2.0 g of 4-benzyl-5-methyl-1,3-oxazolidine-2,4-dione in 30 mL of dry THF was
added at ꢁ15 ꢀC. The mixture was allowed to reach 0 ꢀC during 2 h, and then it
was worked up as in the general procedure.
Reaction with the Lithium Derivative of 2-Methyl-1,3-dithiane
(Table 2, Entry g)
0.93 mL of 2.5 M butyl lithium in THF (10 mmol) were added dropwise into a
solution of 2-ethyl-1,3-dithiane (1.5 mL, 12.5 mmol) in 100 mL of dry THF at ꢁ20 ꢀC
under an argon atmosphere. After stirring for 30 min at the same temperature, a sol-
ution of 2.0 g of 4-benzyl-5-methyl-1,3-oxazolidine-2,4-dione in 30 mL of dry THF
was added dropwise at ꢁ20 ꢀC. The mixture was allowed to reach 20 ꢀC. Workup
was done as in the general procedure.
Spectroscopic Data for Reaction Products (Table 1)
Compound 9a. Mp: 65 ꢀC. IR (KBr): 3275, 1718, 1702, 1640 cmꢁ1. MS: 222
(Mþ þ 1).1H NMR: d ¼ 7.33 (t, J ¼ 2.4 Hz, 4H), 7.26 (d, J ¼ 2.8 Hz, 1H), 4.50 (AB,
13
J ¼ 16.0, 1H), 4.47 (AB, J ¼ 16.0 Hz, 1H), 4.35 (q, J ¼ 8.0 Hz, 1H), 4.08 (s, 1H),
=
1.41 (d, J ¼ 8.0 Hz, 3H), 1.29 (s, 3H). C NMR: d ¼ 158.8 (C O), 138.3 (C),
129.1 (CH), 128.1 (CH), 128.0 (CH), 88.5 (CH), 80.6 (C), 43.8 (CH2), 24.2 (CH3),
13.1 (CH3). Anal. calcd. for C12H15NO3: C, 65.13%; H, 6.85%; N, 6.33%. Found:
C, 64.97%; H, 6.80%, N, 6.27%.
Compound 9b. Mp: 57 ꢀC IR: 3280, 1720, 1702, 1645 cmꢁ1. MS: 236
(Mþ þ 1).1H NMR: d ¼ 7.28–7.18 (m, 5H), 4.39 (AB, J ¼ 16.0 Hz, 1H), 4.35 (AB,
J ¼ 16.0 Hz, 1H), 4.41 (s, 1H), 4.37 (q, J ¼ 6.8 Hz, 1H), 1.65 (ddd, J ¼ 7.6, 14.4,
22.0 Hz, 1H), 1.48 (ddd, J ¼ 7.6, 12.0, 22.0 Hz, 1H), 1.35 (d, J ¼ 6.8 Hz, 3H), 0.63
13
=
(t, J ¼ 7.6 Hz, 3H). C NMR: d ¼ 159.1 (C O), 138.4 (C), 128.8 (CH), 127.9
(CH), 127.6 (CH), 90.7 (CH), 78.5 (C), 43.9 (CH2), 30.7 (CH2), 14.6 (CH3), 8.0
(CH3). Anal. calcd. for C13H17NO3: C, 66.35%; H, 7.30%; N, 5.95%. Found: C,
66.46%; H, 7.41%; N, 5.91%.
Compound 9c. Mp: 51 ꢀC. IR (KBr): 3260, 1722, 1695, 1650 cmꢁ1. MS: 264
(Mþ þ 1).1H NMR: d ¼ 7.36–7.25 (m, 5H), 4.46 (AB, J ¼ 16.0 Hz, 1H), 4.42 (AB,
J ¼ 16.0 Hz, 1H), 4.44 (q, J ¼ 6.4 Hz, 1H), 4.39 (s, 1H), 1.72–1.44 (overlapping,
2H), 1.41 (d, J ¼ 6.4 Hz, 3H), 1.29–1.04 (m, 2H), 1.00–0.87 (m, 2H), 0.70 (t,
13
=
J ¼ 7.2 Hz, 3H). C NMR: d ¼ 159.1 (C O), 138.3 (C), 128.7 (CH), 128.2 (CH),

2,4-OXAZOLIDINEDIONES AND C-NUCLEOPHILES
755
127.6 (CH), 90.6 (CH), 78.6 (C), 43.9 (CH2), 37.2 (CH2), 25.8 (CH2), 22.8 (CH2),
14.4 (CH3), 13.9 (CH3). Anal. calcd. for C15H21NO3: C, 68.40%; H, 8.05%; N,
5.32%. Found: C, 68.23%; H, 8.20%; N, 5.21%.
Compound 9d. Mp: 61 ꢀC. IR (KBr): 2295, 2231, 1730, 1715 cmꢁ1. MS: 246
(Mþ þ 1).1H NMR: d ¼ 7.36–7.25 (m, 5H), 4.46 (AB, J ¼ 16.0 Hz, 1H), 4.42 (AB,
J ¼ 16.0 Hz, 1H), 4.44 (q, J ¼ 6.4 Hz, 1H), 4.39 (s, 1H), 1.72–1.44 (overlapping,
2H), 1.41 (d, J ¼ 6.4 Hz, 3H), 1.29–1.04 (m, 2H), 1.00–0.87 (m, 2H), 0.70 (t,
13
=
=
J ¼ 7.2 Hz, 3H). C NMR: d ¼ 157.3 (C O), 137.6 (C O), 128.8 (CH), 128.4
(CH), 127.8 (CH), 84.9 (C), 83.6 (C), 81.0 (CH), 75.1 (C), 45.1 (CH2), 12.9 (CH3),
3.6 (CH3). Anal. calcd. for C14H15NO3: C, 68.54%; H, 6.18%; N, 5.71%. Found:
C, 68.67%; H, 6.10%; N, 5.78%.
Compound 9e. Oil. IR (KBr): 3250, 1731, 1697, 1644 cmꢁ1. MS: 248
(Mþ þ 1).1H NMR: d ¼ 7.37–7.25 (m, 5H), 5.47 (dd, J ¼ 7.2, 17.2 Hz, 1H),
5.04–4.96 (overlapping, 2H), 4.50 (AB, J ¼ 16.0 Hz, 1H), 4.46 (AB, J ¼ 16.0 Hz,
1H), 4.61 (s, 1H), 4.46 (q, J ¼ 6.0 Hz, 1H), 2.50–2.21 (overlapping, 2H), 1.39 (d,
13
=
J ¼ 6.0 Hz, 3H). C NMR: d ¼ 157.3 (C O), 137.6 (C), 131.5 (CH), 128.8 (CH),
128.4 (CH), 127.8 (CH), 120.0 (CH2), 89.7 (CH), 78.8 (C), 44.0 (CH2), 42.6 (CH2),
14.1 (CH3). Anal. calcd. for C14H17NO3: C, 68.03%; H, 6.88%; N, 5.67%. Found:
C, 67.89%; H, 7.01%; N, 5.52%.
Compound 9f. Mp: 69 ꢀC. IR (KBr): 3875, 1746,1713, 1695, 1660 cmꢁ1. MS:
336 (Mþ þ 1).1H NMR: d ¼ 7.38–7.28 (m, 5H), 5.11 (s, 1H), 4.54 (AB, J ¼ 16.0 Hz,
1H), 4.49 (AB, J ¼ 16.0 Hz, 1H), 4.53 (q, J ¼ 6.5 Hz, 1H), 3.70 (t, j ¼ 6.5 Hz, 2H),
3.05 (q, J ¼ 6.5 Hz, 3H), 2.80 (AB, J ¼ 16.9 Hz, 1H), 2.77 (AB, J ¼ 16.9 Hz, 1H),
13
=
=
1.42 (d, J ¼ 6.5 Hz, 3H). C NMR: d ¼ 202.5 (C O, ketone), 167.2 (C O, ester),
=
158.0 (C O, carbamate), 137.8 (C), 129.3 (CH), 129.2 (CH), 128.2 (CH), 88 (CH),
79.7 (C), 52.9 (CH2), 49.8 (CH2), 49.3 (CH2), 44.2 (CH2), 14.3 (2 CH3). Anal. calcd.
for C17H21NO6: C, 60.88%; H, 6.32%; N, 4.18%. Found: C, 60.78%; H, 6.39%; N,
4.31%.
Compound 9g. Oil. IR (KBr): 3280, 1712, 1688, 1640 cmꢁ1. MS: 326
(Mþ þ 1).1H NMR: d ¼ 7.46 (d, J ¼ 7.3 Hz, 2H), 7.33 (dd, J ¼ 7.1, 7.7 Hz, 2H),
7.28(d, J ¼ 7.3 Hz, 1H), 4.93 (AB, J ¼ 15.7, 1H), 4.91 (AB, J ¼ 15.7,1H), 4.83 (q,
J ¼ 6.4 Hz, 1H), 3.77 (s, 1H), 3.42 (ddd, J ¼ 7.4, 10.4, 13.6 Hz, 1H), 3.18 (ddd,
J ¼ 7.6, 10.8, 13.8 Hz, 1H), 2.71 (ddd, J ¼ 3.4, 6.7, 8.3 Hz, 1H), 2.63 (ddd, J ¼ 3.2,
5.3, 8.9 Hz, 1H), 1.47 (d, J ¼ 6.4 Hz, 3H), 1.42 (s, 3H);13C NMR: d ¼ 158.5
(C¼O), 138.9 (C), 128.8 (CH), 128.2 (CH), 97.5 (C), 78.2 (CH), 46.1 (C), 29.3
(CH2), 28.9 (CH2), 25.6(CH3), 24.8 (CH2), 16.7(CH3). Anal. calcd. for
C15H19NO3S2: C, 55.35%; H, 5.90%; N, 4.30%; S, 19.71%. Found: C, 55.19%; H,
5.73%; N, 4.21%; S, 19.56%.
Compound 9h. Mp: 47 ꢀC IR (KBr): 3264, 1720, 1695. MS: 264 (Mþ þ 1).1H
NMR: d ¼ 7.35 (d, J ¼ 4.0 Hz, 2H), 7.32–7.27 (m, 3H), 4.52 (AB, J ¼ 16.0, 1H), 4.48
(AB, J ¼ 16.0, 1H), 4.19 (q, J ¼ 4.0 Hz, 1H), 4.03 (s, 1H), 1.87–1.83 (m, 1H),
1.73–1.70 (m, 1H), 1.47–1.44 (m, 1H), 1.42–1.38 (overlapping, 3H), 1.32 (s, 3H),
13
=
0.93 (t, J ¼ 7.2 Hz, 3H); C NMR: d ¼ 158.9 (C O), 138.5 (C), 129.0 (CH), 128.0
(CH), 127.8 (CH), 88.6 (CH), 84.7 (C), 43.9 (CH2), 28.4 (CH2), 28.1 (CH2), 24.8

756
G. GALLIANI ET AL.
(CH3), 22.9 (CH2), 14.3 (CH3). Anal. calcd. for C15H21NO3: C, 68.40%; H, 8.05%; N,
5.32%. Found: C, 68.54%; H, 7.84%; N, 5.42%.
Compound 9i. Oil. IR (KBr): 3260, 1732, 1710, 1650 cmꢁ1. MS: 216
(Mþ þ 1).1H NMR: d ¼ 4.61 (s, 1H), 4.60 (q, J ¼ 6.8 Hz, 1H), 3.34 (t, J ¼ 7.6 Hz,
13
2H), 1.75–1.69 (m, 2H), 1.58 (5, J ¼ 6.8 Hz, 3H), 1.48–0.91 (overlapping, 6H),
=
0.89–0.87 (overlapping, 6H); C NMR: d ¼ 157.5 (C O), 83.7 (CH), 80.9 (C),
42.1 (CH2), 31.8 (CH2), 29.0 (CH2), 27.0 (CH2), 18.2 (CH2), 14.4 (CH3), 13.0
(CH3), 13.0 (CH3). Anal. calcd. for C11H21NO3: C, 61.35%; H, 9.85%; N, 6.51%.
Found: C, 61.50%; H, 10.01%; N, 6.65%.
Compound 9j. Oil. IR (KBr): 3306, 1727, 1705, 1642 cmꢁ1. MS: 242
(Mþ þ 1).1H NMR: d ¼ 5.76 (ddt, J ¼ 7.2, 9.6, 16.1 Hz, 1H), 5.20–5.16 (overlapping,
2H), 4.39 (s, 1H), 4.39 (q, J ¼ 6.5 Hz, 1H), 3.20 (t, J ¼ 7.5 Hz, 2H), 2.63–2.57 (ABX,
jAB ¼ 14.3 Hz, 1H), 2.46–2.40 (ABX, jAB ¼ 14.3 Hz, 1H), 2.01–1.98 (m, 1H),
1.68–1.58 (m, 1H), 1.38–1.30 (overlapping, 9H), 0.91 (t, J ¼ 6.7 Hz, 3H);13C NMR:
=
d ¼ 158.5 (C O), 131.9 (CH), 120.1 (CH2), 89.6 (CH), 78.5 (C), 42.3 (CH2), 40.9
(CH2), 29.7 (CH2), 29.5 (CH2), 22.7 (CH2), 14.4 (CH3), 14.2 (CH3). Anal. calcd.
for C13H23NO3: C, 64.68%; H, 9.62%; N, 5.80%. Found: C, 64.61%; H, 9.45%; N,
5.91%.
Typical Example of Reaction at Reflux
3-Benzyl-5-methyl-1,3-oxazolidine-2,4-dione (2.0 g, 9.75 mmol) were dissolved
in 40 mL of anhydrous THF, and 3.25 mL of methyl magnesium chloride 3 M in
THF (9.75 mmol) were dropped into the solution blanketed with nitrogen, keeping
temperature below 10 ꢀC. Temperature was then raised to reflux and maintained
at such temperature for 3 h. After quenching with 200 mL of a saturated aqueous sol-
ution of ammonium chloride, the mixture was extracted with methylene chloride
(2 ꢂ 200 mL). The combined organic phases were washed with brine (100 mL), dried
over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The
residue was purified by flash chromatography, eluting with n-hexane = ethyl acetate
4:1. In addition to 0.9 g of the product obtained at ꢁ30 ꢀC, 1.1 g of its isomer were
recovered, showing the following spectroscopic data: mp: 59 ꢀC, IR: 3380 (broad),
1
1723, 1655, 1620 cmꢁ1; MS: 222 (Mþ þ 1); H NMR: d ¼ 7.36–7.25 (m, 5H), 4.56
(AB, J ¼ 15.6 Hz, 1H), 4.40 (AB, J ¼ 15.6 Hz, 1H), 4.49 (q, J ¼ 6.6 Hz, 1H), 3.71
13
=
(broad, 1H), 1.31 (d, J ¼ 6.6 Hz, 2H), 1.27 (s, 3H); C NMR: d ¼ 166.5 (C O),
=
138.0 (C O), 128.7 (CH), 127.5 (CH), 89.4 (C), 82.2 (CH), 43.4 (CH2), 20.9
(CH3), 16.8 (CH3). Anal. calcd. for C12H15NO3: C, 65.13%; H, 6.85%; N, 6.33%.
Found: C, 65.03%; H, 6.69% N, 6.42%.
Typical Dehydration Procedure
The crude mixture obtained from 3-benzyl-5-methyl-1,3-oxazolidine-2,4-dione
and methyl magnesium chloride in refluxing THF was heated in dimethylsulfoxide at
80 ꢀC for 12 h to give a single product, corresponding to the dehydrated product,
namely 3-benzyl-4,5-dimethyl-4-oxazolin-2-one. Yield (after workup): 77%. Oil,
1
MS: 203 (Mþ); H NMR: 1.82 (s, 3H), 2.02 (s, 3H), 4.72 (s, 2H), 7.36–7.24 (m,

2,4-OXAZOLIDINEDIONES AND C-NUCLEOPHILES
757
5H). Anal. calcd. for C12H13NO2: C, 70.90%; H, 6.46%; N, 6.89%. Found: C,
70.77%; H, 6.52% N, 7.02%.
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