Facile synthesis of 3-alkyl-5-methyloxazolidine-2,4-diones and N-lactoyl-N,N′-dialkylureas

Article abstract of DOI:10.1080/00397911003707154

(Chemical Equation Presented) The reaction between aliphatic amines and propylene carbonate can be performed in solventless conditions under microwave irradiation, becoming nearly complete within 15 min of irradiation. Oxidation of the formed mixture of 2-hydroxyethylcarbamates gives 3,5-methylalkyl- oxazolidine-2,4-diones. These compounds can react further with aliphatic primary amines to give N-lactoylureas. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911003707154

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Facile Synthesis of 3-Alkyl-5-
methyloxazolidine-2,4-diones and N-
Lactoyl-N,N′-dialkylureas
Francesco Saliu a , Guido Galliani b , Marco Orlandi a , Bruno Rindone
a , Eeva-Liisa Tolppa a & Ricardo Suarez-Bertoa a
a Department of Environmental Science , University of Milan ,
Milan , Italy
b Chorisis , Gerenzano , Italy
Published online: 03 Mar 2011.
To cite this article: Francesco Saliu , Guido Galliani , Marco Orlandi , Bruno Rindone , Eeva-Liisa
Tolppa & Ricardo Suarez-Bertoa (2011) Facile Synthesis of 3-Alkyl-5-methyloxazolidine-2,4-diones
and N-Lactoyl-N,N′-dialkylureas, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 41:7, 956-962, DOI: 10.1080/00397911003707154
To link to this article: http://dx.doi.org/10.1080/00397911003707154
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Synthetic Communications1, 41: 956–962, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911003707154
FACILE SYNTHESIS OF 3-ALKYL-5-
METHYLOXAZOLIDINE-2,4-DIONES AND
N-LACTOYL-N,N’-DIALKYLUREAS
Francesco Saliu,1 Guido Galliani,2 Marco Orlandi,1
Bruno Rindone,1 Eeva-Liisa Tolppa,1 and
Ricardo Suarez-Bertoa1
1Department of Environmental Science, University of Milan, Milan, Italy
2Chorisis, Gerenzano, Italy
GRAPHICAL ABSTRACT
Abstract The reaction between aliphatic amines and propylene carbonate can be performed
in solventless conditions under microwave irradiation, becoming nearly complete within
15 min of irradiation. Oxidation of the formed mixture of 2-hydroxyethylcarbamates gives
3,5-methylalkyl-oxazolidine-2,4-diones. These compounds can react further with aliphatic
primary amines to give N-lactoylureas.
Keywords 3,5-Dialkyl-oxazolidine-2,4-diones; N-lactoyl-N,N0-dialkylureas; solventless
reaction
INTRODUCTION
N-Substitued oxazolidine-2,4-diones are important therapeutic agents and
scaffolds for the preparation of biologically active compounds.[1,2] For example,
3-methyloxazolidine-2,4-diones have analgesic and anticonvulsant properties, with lit-
tle or no hypnotic action.[3] Oxazolidine-2,4-diones can be prepared from a-halogeno
acids or a-halogenoureides, by hydrolysis of 2-imino-4-oxazolidinones or dialuric
acids, by oxidation of 2-thiooxo-4-oxazolidones, by condensation of esters of
a-hydroxy acids with urea, by condensation of amides of a-hydroxy acids with alkyl
carbonates or chloroformates, or by cyclization of urethans of a-hydroxy acids.[4]
However, the most efficient method for building 3-substituted oxazolidine-2,4-diones
Received December 9, 2009.
Address correspondence to Francesco Saliu, Department of Environmental Science, University of
Milano, Bicocca Milano, Milano 20126, Italy. E-mail: francesco.saliu@unimib.it
956

OXAZOLIDINEDIONES AND LACTOYLUREAS
957
involves the cyclization of N-substituted chloroacylcarbamates.[5] As a ‘‘greener’’
alternative, in our previous work we reported the possibility of proceeding via
the intramolecular cyclization of a carbamate salt, obtained by a 1,8-diazabicy-
clo[5.4.0]undec-7-enc (DBU)–mediated carbon dioxide fixation.[6]
Here, we describe a very efficient and easy procedure involving a microwave-
assisted solventless reaction between cyclic carbonates and primary amines, followed
by an oxidation, to give the corresponding 3,5-substituted oxazolidine-2,4-diones in
good yields. In addition, by reacting 3,5-substituted oxazolidine-2,4-diones under the
same conditions and with an equimolecular amount of primary amines, N-lactoyl-
N,N0-dialkylureas are formed in very good yields. These compounds represent useful
intermediates to prepare new molecules, particularly in pharmaceutical development,
with a special interest for peptidomimetic drugs.[7]
RESULTS AND DISCUSSION
We reacted 4-methyl-1,3-dioxolan-2-one (1) with an equimolecular amount of
primary amines in the absence of solvent and without any catalyst. The reaction tem-
perature was fixed at 85 ꢀC, to minimize overreaction of the products with unreacted
amines. The mixture of 2-hydroxyethylcarbamates 2 þ 3 was obtained with a ratio of
primary to secondary alcohols ranging from 1.16 to 1.52 (Scheme 1).
The transformation can be sped up by reacting the solventless mixture under
microwave irradiation. The reaction was nearly complete within 15 min of
irradiation and the ratio of primary to secondary alcohols ranged from 1.07 to
1.28 (Table 1).
The structures of 2-hydroxyethylcarbamates 2 þ 3 were determined by 1H, 13C,
and correlation spectroscopy (COSY) NMR, and the results are in good agreement
with literature data.[8]
The ratio of primary alcohol (2) to secondary alcohol (3) was evaluated by 1H
NMR analysis of the crude reaction mixture by integration of the doublet peaks at
1.06 ppm and 1.13 ppm, corresponding at methyl protons in structures 2 and 3
respectively, and by integration of the nitrogen proton of carbamate groups.
The oxidation of the mixture of 2-hydroxyethylcarbamates with the CrO3–
pyridine complex[9] gave the corresponding 3,5-dialkyl-oxazolidine-2,4-diones (4)
in 83–85% yield (Table 2).
Compound 4 is probably formed by oxidation of the primary alcohol (2) to the
corresponding aldehyde, which is further oxidized and cyclized to 4, and an equilib-
rium between the primary and secondary alcohol must be involved, because the
yields in compound 4 are larger than the molar fraction of the primary alcohol (2)
Scheme 1. Reaction of propylene carbonate with primary amines.

958
F. SALIU ET AL.
Table 1. Reaction of 4-methyl-1,3-dioxolan-2-one with amines
Time
(h)
Conversion
(%)
Primary
alcohol (2) (%)
Secondary
alcohol (3) (%)
Ratio
primary=secondary
Amine
Thermal
n-Pentylamine
6
12
7
98
95
96
96
59 (2a)
57 (2b)
51 (2c)
58 (2d)
39 (3a)
38 (3b)
44 (3c)
38 (3d)
1.51
1.50
1.16
1.52
Cyclohexylamine
Benzylamine
n-Hexylamine
Microwave assisteda
n-Pentylamine
6
0.25
0.25
0.25
91
98
91
(2a) 47
(2b) 54
(2d) 49
(3a) 44
(3b) 42
(3d) 42
1.07
1.28
1.17
Cyclohexylamine
n-Hexylamine
aIn a microwave oven at 200 W, 2450 MHz for 15 min.
Table 2. Chromic oxidation of alcohols 2 þ 3 to form 3-alkyl-5-
methyloxazolidindiones (4)
Amine in the mixture
2 þ 3
Isolated yield in 3-alkyl-5-methyl-
oxazolidine-2,4-dione (4) (%)
n-Pentylamine
Cyclohexylamine
Benzylamine
(4a) 83
(4b) 85
(4c) 83
present in the crude starting mixture. The oxidation should proceed faster with the
primary alcohol (2) than with the secondary alcohol (3), thus giving the correspond-
ing aldehyde and subsequently 4 as the main product, and not a ketone, which has
been recognized in only trace amounts. Investigations are in progress to verify this
mechanism, and results will be presented in a future paper.
The ring of 3,5-dialkyloxazolidine-2,4-diones (4) can be further opened with
equimolecular amounts of a primary amine in solventless conditions and under
microvawe heating to give N-lactoyl-N,N0-dialkylureas (5) (Scheme 1) in satisfactory
yields, as shown in Table 3.
Table 3. Reaction of 3-alkyl-5-methyloxazolidin-2,4-diones (4) with amines to give N-lactoyl-N,N0-
dialkylureas (5) in solventless conditions
3-Alkyl-5-methyloxazolidine-2,
4-diones (4)
Isolated yield in N-lactoyl-N,
N0-dialkylurea (5) (%)
Reacting amine
(4a) R0 ¼ n-pentyl
(4a) R0 ¼ n-pentyl
(4a) R0 ¼ n-pentyl
(4b) R0 ¼ cyclohexyl
(4b) R0 ¼ cyclohexyl
(4b) R0 ¼ cyclohexyl
(4c) R0 ¼ benzyl
n-Pentylamine
Benzylamine
R0 ¼ n-pentyl; R00 ¼ n-pentyl (5a): 85
R0 ¼ n-pentyl; R00 ¼ benzyl (5b): 83
R0 ¼ n-pentyl; R00 ¼ cyclohexyl (5c): 59
R0 ¼ ciclohexyl; R00 ¼ n-pentyl (5d): 73
R0 ¼ cyclohexyl; R00 ¼ benzyl (5e): 59
R0 ¼ cyclohexyl; R00 ¼ cyclohexyl (5f): 55
R0 ¼ benzyl; R00 ¼ n-pentyl (5 g): 78
R0 ¼ benzyl; R00 ¼ benzyl (5 h): 62
Cyclohexylamine
n-Pentylamine
Benzylamine
Cyclohexylamine
n-Pentylamine
Benzylamine
(4c) R0 ¼ benzyl

OXAZOLIDINEDIONES AND LACTOYLUREAS
959
CONCLUSIONS
In conclusion, the reaction of 4-methyl-1,3-dioxolan-2-one and 3-alkyl-5-
methyl-oxazolidine-2,4-diones with amines, carried out in solventless conditions
under microwave irradiation, gave respectively 2-hydroxyethylcarbamates and
lactoylureas in satisfactory yields.
The oxidation of 2-hydroxyethylcarbamates affords 3-alkyloxazolidine-2,4-
diones in good yields.
EXPERIMENTAL
1
All chemicals were purchased from Aldrich or Fluka chemical companies. H
and 13C NMR were recorded on a Varian Mercury 400 instrument in CDCl3 or
dimethylsulfoxide (DMSO-d6). Chemical shifts were reported in parts per million (d),
relative to the internal standard of tetramethylsilane (TMS). Gas chromatography–
mass spectrometry (GC-MS) analyses were performed with a Hewlett Packard 5890
instrument equipped with a 5971A mass selective detector. Melting points were
determined in open glass capillaries using a Electrothermal melting-point apparatus
and are uncorrected. Infrared (IR) spectra in solutions were recorded on a Nicolet
Avatar 360 Fourier transform (FT)–IR spectrometer, using calcium fluoride cells
previously purged with N2. Elemental analyses were carried out on Perkin-Elmer ser-
ies II 2400 instrument. All reactions were monitored by thin-layer chromatography
(TLC). The reactions under microwave irradiation were carried out with a CEM
Discover Labmate instrument. Flash chromatography was performed on silica gel
(100–200 mesh). All products were purified through chromatographic column before
characterization.
General Procedure for the Preparation of 2-Hydroxyethylcarbamates
2 þ 3
Cyclic carbonates (1) (0.1 mol) were mixed with 0.1 mol of amine, and the mix-
ture was stirred at 85 ꢀC for 10 h. The oily mixtures of hydroxyethylcarbamates
obtained were directly submitted to analysis. Alternatively, the reaction was per-
formed in the same conditions under microwave irradiation at 200 W, 2450 MHz
for 15 min, T < 85 ꢀC.
General Procedure for the Synthesis of 3-Alkyl-5-methyl-
oxazolidine-2,4-diones (4a–c)
Pyridine (4.8 mL) was dissolved in dichloromethane (100 mL). The solution was
cooled at 5 ꢀC, and then CrO3 (2.88 g) was added. The mixture was stirred 15 min at
5 ꢀC and allowed to reach room temperature. After 30 min, the mixture of adducts 2
and 3 (4.8 mmol), dissolved in dichloromethane (10 mL), was added. The mixture was
stirred for 15 min at room temperature; black tars were separated and extracted with
additional dichloromethane (5 ꢁ 40 mL), stirring for 10 min each time.
The pooled organic solutions were evaporated under reduced pressure, and the
oily residue was dissolved in toluene (50 mL) and again evaporated under reduced

960
F. SALIU ET AL.
pressure. The oily residue was filtered on silica gel (5 g) to remove metal traces,
eluting with dichloromethane (150 mL). The eluate was then evaporated under
reduced pressure.
1
5-Methyl-3-pentyl-oxazolidine-2,4-dione (4a). IR (neat): 1810, 1730. H
NMR (400 MHz, DMSO-d6) d: 0.95 (t, 3H), 1.20–1.40 (m, 4H), 1.40 (m, 2H), 1.50
(d, 3H), 3.00 (m, 2H), 4.80 (q, 1H, J ¼ 8 Hz). 13CNMR (100 MHz, DMSO-d6) d:
13.8, 15.8, 21.6, 28.3, 28.9, 40.1, 75.5, 155.1, 202.9. Mass (m=z): 185 (Mþ). Anal.
calcd. for C9H15NO3: C, 58.36; H, 8.16; N, 7.56; O, 25.91. Found: C, 58.54; H,
8.31; N, 7.82; O, 26.02.
3-Cyclohexyl-5-methyl-oxazolidine-2,4-dione (4b). IR (neat): 1810, 1730.
1H NMR (400 MHz, DMSO-d6) d: 1.25–1.60 (m, 11H aliphatic protons), 1.50
(d, 3H, CH3), 3.15 (m, 2H), 4.80 (q, 1H, J ¼ 8 Hz). 13C NMR (100 MHz, DMSO-d6)
d: 15.8, 24.5, 25.0, 32.5, 49.3, 74.6, 154.2, 202.9. Mass (m=z): 197 (Mþ). Anal. calcd.
for C10H15NO3: C, 60.90; H, 7.67; N, 7.10; O, 24.34. Found: C 60.80; H, 7.90; N, 7.20;
O, 24.12.
3-Benxyl-5-methyl-oxazolidine-2,4-dione (4c). Mp 74–75. IR (neat): 1810,
1
1730. H NMR (400 MHz, DMSO-d6) d: 1.50 (d, 3H), 4.58 (s, 2H), 4.80 (q, 1H,
J ¼ 8 Hz), 7.19–7.40 (m, 5H aromatic protons); 13CNMR (100 MHz, DMSO-d6) d:
15.8, 43.6, 74.6, 126.4, 126.6, 126.8, 127.3, 127.8, 128.2, 155.4, 202.8. Mass
(m=z): 205 (Mþ). Anal. calcd. for C11H11NO3: C, 64.38; H, 5.40; N, 6.83; O, 23.39.
Found: C, 64.20; H, 5.50; N, 6.72; O, 23.12.
General Procedure for the Synthesis of N-Lactoyl-N,N’-dialkylureas
(5a–h)
3-Alkyl-5-methyloxazolidine-2,4-dione (4) (20 mmol) were mixed with amine
(20 mmol) under nitrogen, and the resulting mixture was stirred at 100 ꢀC for 5 h,
cooled, and dissolved in dichloromethane (50 mL). The resulting solution was filtered
on silica gel (200 g), eluting with dichloromethane–ethyl acetate (3:1). Microwave
irradiation requires shorter times (20 min).
Compound 5a. Mp 62–63. IR (neat): 3312, 1721, 1684, 1650. 1H NMR
(400 MHz, DMSO-d6) d: 0.83 (m, 6H), 1.24–1.37 (m, 12H), 1.40 (d, 3H), 2.92 (m,
2H), 3.03 (m, 2H), 4.83 (qd, 1H), 7.78 (NH); 13C NMR (100 MHz, DMSO-d6) d:
14.2, 18.3, 22.1, 29.0, 38.7, 40.4, 69.3, 154.5, 170.2. Mass (m=z): 272, 186, 158, 144,
130, 114, 98, 85. Anal. calcd. for C14H28N2O3: C, 61.73; H, 10.36; N, 10.28; O,
17.62. Found: C, 61.60; H, 10.43; N, 10.35; O, 17.51.
Compound 5b. Mp 76–77. IR (neat): 3310, 1720, 1682, 1651. 1H NMR
(400 MHz, DMSO-d6) d: 0,83 (m, 3H), 1.25–1.37 (m, 4H), 1.39 (d, 3H), 1.41 (dd,
2H), 2.92 (m, 2H), 4.30 (d, 2H) 4.85 (qd, 1H), 7.19–7.38 (m, 5H), 8.42 (NH);
13CNMR (100 MHz DMSO-d6) d: 14.2, 18.3, 22.1, 29.0, 38.7, 42.4, 69.3, 126.5,
128.2, 139.3, 155.1, 170.2. Mass (m=z): 292 (Mþ) 206, 179, 161, 133, 106, 91. Anal.
calcd. for C16H24N2O3: C, 65.73; H, 8.27; N, 9.58; O, 16.42. Found: C, 65.89; H,
8.11; N, 9.43; O, 16.55.

OXAZOLIDINEDIONES AND LACTOYLUREAS
961
Compound 5c. IR (neat): 3311, 1720, 1682, 1652. 1H NMR (400 MHz,
DMSO-d6) d: 0.83 (td, 3H), 1.04–1.68 (m, 16H), 1.40 (d, 3H), 2.92 (m, 2H), 3.60
(m, 1H), 4.83 (qd, 1H), 7.80 (NH); 13C NMR (100 MHz, DMSO-d6) d: 14.2, 18.3,
=
22.2, 24.1, 25.9, 29.0, 31.0, 40.4, 49.0, 69.3, 155.0 (C O), 168.2. Mass (m=z): 284
(Mþ, 1%), 203 (16%), 186 (42%), 171 (6%), 159 (54%), 130 (100%), 114 (39%), 102
(18%). Anal. calcd. for C15H28N2O3: C, 63.35; H, 9.92; N, 9.85; O, 16.88. Found:
C, 63.37; H, 9.76; N, 9.95; O, 16.64.
Compound 5d. IR (neat): 3310, 1722, 1684, 1650. 1H NMR (400 MHz,
DMSO-d6) d: 0.83 (td, 3H), 1.04–1.65 (m, 16H), 1.39 (d, 3H), 2.93 (m, 2H), 3.29
(m, 1H), 4.83 (qd, 1H), 7.80 (NH); 13C NMR (100 MHz, DMSO-d6) d:14.2, 18.3,
22.8, 23.9, 25.5, 31.1, 40.4, 47.7, 69.3, 156.0, 170.1. Mass (m=z): 284 (Mþ, 1%),
198 (15%), 171 (34%), 159 (22%), 142 (100%), 126 (23%), 114 (36%), 98 (12%),
83 (42%). Anal. calcd. for C15H28N2O3: C, 63.35; H, 9.92; N, 9.85; O, 16.88.
Found: C, 63.43; H, 9.81; N, 9.92; O, 16.78.
Compound 5e. Mp 67–68. IR (neat): 3312, 1721, 1682, 1650. 1H NMR
(400 MHz, DMSO-d6) d: 1.39 (d, 3H), 1.04–1.70 (m, 10H), 3.29 (m, 1H), 4.30 (d,
2H), 4.85 (qd, 1H), 7.18–7.37 (m, 5H), 8.41 (t, 1H); 13C NMR (100 MHz, DMSO-d6)
d: 18.3, 24.0, 25.5, 31.0, 42.3, 47.7, 69.3, 126.5, 128.2, 139.3, 155.0, 170.0. Mass (m=z):
305 (Mþ, 1%), 179 (15%), 161 (100%), 142 (34%), 133 (42%), 106 (44%), 91 (85%).
Anal. calcd. for C16H22N2O3: C, 66.18; H, 7.64; N, 9.65; O, 16.53. Found: C,
66.23; H, 7.55 N, 9.81; O, 16.39.
Compound 5f. Mp 64–65. IR (neat): 3310, 1720, 1683, 1651; 1H NMR
(400 MHz, DMSO-d6) d: 1.39 (d, 3H), 1.13–1.80 (m, 20H), 3.29 (m, 2H), 4.83 (qd,
1H), 8.4 (t, 1H); 13C NMR (100 MHz, DMSO-d6) d: 18.3, 22.8, 23.9, 25.5, 31.1,
47.7, 49.0, 69.3, 156.0, 170.1. Mass (m=z): 296 (Mþ, 1%), 215 (4%), 207 (5%), 198
(11%), 171 (38%), 153 (4%), 142 (50%), 126 (22%), 97 (57%), 83 (100%). Anal. calcd.
for C16H28N2O3: C, 64.83; H, 9.52; N, 9.45; O, 16.19. Found: C, 64.69; H, 9.56; N,
9.41; O, 16.26.
Compound 5g. Mp 68–69. IR (neat): 3311, 1720, 1683, 1650. 1H NMR
(400 MHz, DMSO-d6) d: 0.83 (t, 3H), 1.25–1.37 (m, 6H), 1.40 (d, 3H), 2.93 (m,
2H), 4.27 (s, 2H), 4.85 (qd, 1H), 7.20–7.39 (m, 5H), 7.80 (NH); 13C NMR
(100 MHz, DMSO-d6) d: 14.2, 18.3, 22.2, 29.0, 40.1, 40.4, 69.3, 126.5, 128.2, 139.3,
155.9, 170.1. Mass (m=z): 292 (Mþ, 1%), 179 (10%), 161 (38%), 150 (9%), 133
(43%), 118 (4%), 106 (26%), 91 (100%). Anal. calcd. for C16H24N2O3: C, 65.73;
H, 8.27; N, 9.58; O, 16.42. Found: C, 65.78; H, 8.31; N, 9.54; O, 16.40.
Compound 5h. Mp 93–94. IR (neat): 3310, 1721, 1682, 1650. 1H NMR
(400 MHz, DMSO-d6) d :1.40 (d, 3H), 4.27 (s, 2H), 4.30 (d, 2H), 4.86 (qd, 1H),
7.19–7.40 (m, 10H), 8.42 (NH); 13C NMR (100 MHz, DMSO-d6) d: 18.3, 40.1,
42.3, 69.4, 126.6, 128.2, 139.3, 155.1, 170.2. Mass (m=z): 206 (Mþ, 7%), 179 (14%),
159 (7%), 150 (47%), 133 (44%), 114 (22%), 105 (26%), 91 (100%). Anal. calcd. for
C16H18N2O3: C, 67.12; H, 6.34; N, 9.78; O, 16.76. Found: C, 67.24; H, 6.19; N,
9.84; O, 16.59.

962
F. SALIU ET AL.
ACKNOWLEDGMENTS
We thank CEM Srl. (Innovators in Microwave Technology) for providing
us with the instrumentation for microwave irradiation and Mr. Umberto Vallone,
Mr. Andrea Rota, and our student Luca Gabrielli for help in performing the
experiments.
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