2 Oxazolidinones

2-OXAZOLIDONES
MARTIN E. DYE"
AND DANIEL SWERN
Fels Research Institute and Department of Chemistry, Temple University, Philadelphia, Penneylvania 19188
Received June 88,1966
CONTENIW
I. Introduction and Nomenclature. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11. Preparation of Oxazolidones.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
B. From &Amino Alcohols. . . . . .
197
199
199
C. From 8-AminoalkylsulfurioAci
...........................................
206
D. From 8-Haloamines.. . . . . . . . .
E. From @-HaloAlcohols (Halohy
. . . . . . . . . . 206
F. From 1,2-Glycols. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
208
G. From 1,a-Dihalides. . . . . . . . . .
H. From Epoxides.. . . . . . . . . . . . .
I. From Cyclic Carbonates (2-Dioxolanones) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
213
J. From Acetylenic Compounds. . . . . . . . . . . . . . . . . . . . . . . .
K. From Urethans.. . . . . . . . . . . . . .
L. From ,%Hydroxy Isocyanates. .
M. From Acyloins (a-Ketols). . . . .
N. From Nitrenes .
......................................................
219
P. From P-Amino Chloroformates. . . .
...............
...........................
225
. . . . . . . . . . . . . . . . . . . 231
E. Formation of Molecular Complexes
C. Polarography. . .
........................................
D. DipoleMomenB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
V. Determination of 2-Oxaaolidones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
233
A. Drug and Other Biological Uses. . . .
IX. Addendum.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
I. INTRODUCTION
AND NOMENCLATURE
2-Oxazolidones (1), an important class of heterocyclic
compounds containing a five-membered ring, have not
been reviewed in detail. The related oxasolid~es,
which have a saturated five-membered ring containing
nonadjacent oxygen and nitrogen atoms, have been
reviewed (541, but their carbonyl-conta~ing counterparts, the 2-oxazolidones, have not. Cornforth (104)
has very briefly and incompletely covered the literature
(1)
NASA Predoctoral Fellow, Temple University.
236
on 2-oxazolidones up to 1956, but his latest reported

reference is l9s3* Though no conscious eff
has
been made here to include Cornforth's material, much
of it has crept in because of the necessity of organization*
The parent member of the series is variously referred
to as 2-oxazolidone, 2-oxazolidinone, oxazolid-2-one,
oxazolidin-2-one, oxazolidone-2, and oxazolidinone-2.
The numbering system starts with the most
negative element in the ring, oxygen, and assigns the
next most electronegative element, nitrogen, the lowest
197
MARTINE. DYENAND DANIELSWERN
198
TABLEI
ZOXAZOLIDONES
PREPARED
FROM ,%AMINOALCOHOLS
AND PHOSGENE
%
Empirical
formula
Ri
H
H
Ra
H
HOOC
R4
RI
H
H
H
Me
H
H
89
196-197 dec
H
H
H
H
H
161 (0.1)
51-52 (EtOAc-heDtane'l
4 1 4 2 (EtOAc-heitane)
53-54 (EtOAc-heptane)
trans, 99-100 (CHC4-pet. ether);
106-102; 100-110 (0.01)
..
255
&Nitro-Zfurfuryli- H
deneamino
B p (mm) or mp, O C
RI
(DLC~)
yield
Ref
60
26
464,545
283, 285,
50
95
90
92
80
50
50
50
357,358
62
205
377
c1
I
Structure
pOzNCe&CHn
m-MeCsH4
pMeCsH4
PhCHzOCO
H
H
H
H
H
Et
Et
Et
Et
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H'
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
H
H
H
H
H
H
H
H
H
H
i-Pr
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
GPr
H
Et
n-BU
Me
Ph
Ph
m-MeCeH4
pMeCeH4
H
H
H
H
H
H
H
H
H
H
H
Ph
H
H
Ph
H
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
~ M ~ C Q H ~ O C H Z -H
H
pMeOC6H4OCHz
H
o-MeOCeHdOCHz
H
2,4-MezCeHs0CHz
H
3,5-MezCsH80CH~
o-M~OCEH~OCHZ H
H
Ph
H
2,3,&Me*CsHZOCH2
H
o-MeOCeH4OCHz
H
Ph
H
PhOCHi
H
Ph
H
Ph
H
Ph
MP,OC
Ref
220-222 dec (70%

aq MeOH)
tetraacetyl deriv,
150-151
501
150
trans, 107-109 (EtO-pet. ether)
87-87.5 (EtOH-hexane)
171-173 (EtOAc-hexane)
73
358
426
50
109
109
50
12
12
44
12,322
12
325
325
325
325
12,325
73.5
98-100
..
..
..
12
12
12
106-107 (C6Hbhexane)
..
520
94-94.5 (isooctane)
115-116
71~(i-PrzO
50-50.5 (i-PrzO)
50-51
90-91 (i-PrzO)
80-81 (i-PrzO)
175-178 (0.1)
37-38.5 (i-PrzO )
71-72 (i-PrzO), 204-205 (0.08)
76-78 (i-PrzO)
trans, 159-160; cis, 188-189
154-155 (EtOAc)
186-188 (0.03) '
trans, 90; cis, 128
134.5-136.5
216 (EtOH)
189 (EtOH)
209 (EtOH)
82
85
45
59
40
52
96
325
325
325
325
325
325
325
12
325
325
325
262
325
325
262
592
109
109
109
...
101-102
73.5
79-81
128-129
141-142
121-123
215-220
116-117
Structure
H&-NH
HhOH
HAOH
LzoH
..
..
89
..
..
..
(EtOAc)
(HzO)
37
..
(0.12)
77.5-78.5 (i-PrzO), 180-195

(0.08)
H - - O >,=O
224
(EtOAcheptane)
122.5
43-44 (i-PrzO), 182-185 (0.15)
HOhH
123 (EhO)
(51% yield)
434
50
96
82
20
99
98
77
56
..
..
28
14
76
..
45
..
..
..
MP,'C
Ref
155-156
tetraacetyl deriv,
126-127
501
199
2-OXAZOLIDONES
TABLE
I (Continued)
4
&bo
Camphane Derivatives (224)
3
I
Me
% yield
Mp or bp (mm), C
82 (EbO-hexane)
193 (MeOH-EbO)
192-193
119 (EbO)
70
80
..
60
60
90
87
87
85
80
100
65
60
122
AcO
PhCHz0
H
c1
c1
c1
c1
H
H
H
AcO
c1
HO
AcO
Me0
Me0
practical number. A tautomeric form can also be

written when RI = H (2).
y?
RK- 6-ic-R~
R4
Rs-C
R3
-
\.
C-Rz
//
C
OH
2
A standard designation for substituents on the parent

oxazolidone ring has been adopted and used throughout,
with a few clearly marked exceptions. I n all preparative methods the nearest integral per cent yield is given
as reported by the authors cited or as calculated from
the data given wherever possible. Every effort has
been expended to include all references to December 31,
1965, but, in such an active field as that of 2-oxazolidones, it is expected that there will be certain unavoidable omissions.
11. PREPARATION
OF OXAZOLIDONES
A.
INTRODUCTION
2-Oxazolidones can be looked upon as a two-carbon

chain joined to a carbonyl group through oxygen on
one side and nitrogen on the other. Since most classification systems are purely arbitrary, the view we have
taken is that the carbon-carbon chain constitutes the
backbone of the molecule, and classification of the
numerous syntheses is made on this basis. I n view of
the numerous syntheses of 2-oxazolidones from compounds with vicinally substituted carbon atoms, such
a classification is very convenient.
i45 (0.07)
107 (hexane)
153-1 54
120.5 (EttO)
132 fEtlO-hexane)
254 dec-(MeOH-EtO)
84-85 (EtzO-hexane)
76-78, 110-120 (0.05)
48-50, 120-30 (0.15)
..
amino groups on adjacent carbon atoms (404). There

must be a t least one replaceable hydrogen atom in the
amino group. The phosgene has been supplied as a
gas (544, 545), in solution (50, 109, 283, 322, 520), or as
a complex with pyridine (464),with and without added
base (283, 501, 520) (Eq 1). The amino group would
be expected to exhibit greater nucleophilicity than the
hydroxyl, so that the first intermediate might? be
formulated as shown in E q 1. One author (50),
however, indicates primary reaction with the hydroxyl
group when the amine is adjacent to a carbonyl group.
RIR~C-CRZR~
A I
+ COClz
H NHRl
R~RR~C-CRZR~
FROM
One of the first reported and most general syntheses

utilized a carbon-carbon chain with hydroxyl and
(Eq 1)
NRI
II
Studies have shown that the addition of phosgene

does not alter the stereochemistry of the starting ma-
y/(:
COCl2
NaOH
OH
threo
trans
COClZ
/3-AMINOALCOHOLS
1. Using Phosgene (Table I)
R4RaC-CRzRa
dH ~ R I
Cl-C=o
NaOH
B.
OH
H
6
O
erythro
MARTINE. DYENAND DANIEL

SWERN
200
terial (262). Thus, threo- and erythro-p-amino alcohols

give trans- and cis4,5-disubstituted 2-oxazolidones,
respectively, each of which can be hydrolyzed to afford
the startingmaterial (Eq 2 and 3).
hydrazine (197, 388, 423, 528, 529, 565) (Eq 6). The
products are 3-amino-2-oxazolidones.
HOCHzCHzNHNH2
+ (EtO)zC--O
-C
CHP--CHe
I
2EtOH
2. Using Dialkyl Carbonates (Table 11)
Historically one of the earliest and certainly one of

the key synthetic methods for the preparation of 2oxazolidones is that of Homeyer (250). This is the
reaction of diethyl carbonate with a @-amino alcohol
catalyzed by basic substances, such as sodium methoxide, magnesium methoxide, potassium hydroxide, or
sodium carbonate. The reaction has wide scope and
synthetic utility.
Although the reaction might be looked upon as the
generation of carbon dioxide in situ with its subsequent
addition to the alcohol-amine system, accompanied by
the elimination of the elements of water (cf. next section), the evidence suggests that the reaction proceeds
in two stages (248) : first, the more nucleophilic nitrogen displaces ethoxide giving ethyl alcohol plus the ethyl
carbamate derivative (Eq 4a) ; second, cyclization
takes place with elimination of another mole of ethyl
alcohol (Eq 4b). Kinetic studies (526) have shown that
the reaction is third order, first order in ethyl carbonate
and second order in amino alcohol.
basa
R~NH-CR~R~-CR~RS
(Et0)sCO
OH
E t 0 -C-
II
f EtOH
NRl-CR2R3-CR4Ra
base
R~Rs-Y-C-R~R~
I
(Eq4a)
OH
R4R5y-CR2R3
I
EtOH
As a variant the cyclic carbonate, ethylene carbonate,

has been used (74, 121, 147, 560) giving ethylene glycol
in addition to the oxazolidone (Eq 5 ) .
LRsC-CRzRs
+ CHz-CHz
dH NHRi
l
A d
C/
R4RRsC-CRzRs
3.
Using Carbon Dioxide (Table 111)
Gaseous carbon dioxide has been used to produce

2-oxazolidones from ,&amino alcohols in a limited
number of cases described only in patents. The reactions are carried out with or without solvent at elevated
temperatures under pressure (Eq 7). The reaction
has the advantage of simplicity, but it has not been
widely studied.
RiNH-C&%--C(OH)hRs
+ COz
-C
RdR5C-CRzRa
I
NRI
\C/
0
(Eq 7 )
4. Using Urea (Table I V )

A more recent method for preparing 2-oxazolidones
from &amino alcohols utilizes urea as the other reactant. The reaction is carried out by fusion above
the melting point of the reactants. It has been suggested (96, 97) that the urea first decomposes to form
cyanic acid, which then reacts with the amino group to
form a 0-hydroxyethylurea derivative. This subsequently cyclizes with loss of ammonia to afford the
product (Eq 8). The 6-hydroxyethylurea can be
synthesized separately by reaction of the amino group
with an isocyanate. This product gives the 2-oxazolidone on heating (see next section).
RlNHCRzRaC(OH)LR6
+ (HzN)zCO
-+
AH NR1
O=dOCHzCH20H
b
R~R~C-CRIRS
+ HOCHzCHzOH
(Eq 5 )
8
Although the Rl-N bond is usually a carbon-nitrogen bond, it may also be a nitrogen-nitrogen bond.
The amino alcohol starting material is then a p-hydroxy-
It is reported that 2-oxazolidones are also obtained

from 0-amino alcohols and semicarbazones and even
semicarbazide itself (514). I n the cases reported the
oxazolidones obtained were unsubstituted on nitrogen.
The formation of a 2-oxazolidone, or the failure to
form one, has been used to determine the configuration
of the ephedrines (96). The determination of configuration depends on whether the hydroxyl group is
better situated for a displacement reaction or for con-
ZOXAZOLIDONES
~ X A Z O L I D O N E SPREPARED
Empirical
formula
201
TABLEI1
FROM &AMINO ALCOHOLS
AND DIALKYL
CARBONATES
%
RI
Ra
Itr
Rd
Ra
Bp (mm) or mp, OC
yield
CsHoNOa
CaHsNaOa
CrHiNOzCla
CrHiNOa
HaN
H
H
Me
H
HiN
HzN
HaN
HzN
H
ClCHzCHa
ICHaCHi
CHaCONH
H
Et
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
CLC
Me
93-94 (EtOH)
55-58 (EtOH-pet. ether)
95-95.5 (LI), 92 (I), 78 (0.5)
16-18.5 (CHClrpet. ether)
74
61
87-89 (CHCls), 90-91 (ligroin), 87

170-172 (3)
89-71 (EtOH), 70.5-71
93
125-125.5 (MeEO-EtOH)
111-113 (1)
15, 87-90 (1)
Et
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
HOCHiCHz
H
H
Me
H
HOCHn
H
H
H
H
184-188 (1)
115-116.5 (EtOH), 120 (EtOH-
H
HaN
HaN
HzN
HzN
HaN
H
H
Me
Et
H
MeSCHa
H
H
H
H
n-Pr
HOCHt
H
CiHiaNOz
CsHiNaOr
H
H
H
H
H
H
H
H
H
H
H
Et
H
H
H
H
109-110 (MezCO, then EtOH)

130-135 (10)
CI(CHm)r
I(CHn)a
MeaC=N
H
H
HzN
HzN
n-Bu
5-Nitro-2furfurylideneamino
HOCHz HOCHz
Me
Me
Me
H
H
H
Et
H
H
H
-0CMezOH
H
H
H
H
H
Me
H
H
H
n-Bu
H
H
H
H
H
H
H
CsHiaNOi
CsHirNOsCl
CaHiaNaOt
CsHisNsOa
CsHisNzOi
CsHirN90zI
H
H
HzN
HzN
H
MeaN +CHnCHz
H
H
H
H
H
C4HiNOs
CIHsNaOn
CbHtNiO,
CiHiNOzCl:
CsHsNOzCl
CsHBNOaI
CrHsNzOa
C~HBNOZ
CsHoNOa
H
HOCHz
H
ClCHx
H
H
H
Me
H
HOCHz
H
Me
H
HOCHz
H
H
ClCHz
H
H
...
50.3-50.5
156-157
137-138 (3)
...
...
...
...
...
CsHd
CsHoNOr
CsHioNzOa
CsHioNsOB
CkHoNOr
CeHioNOnCl
CaHioNOaI
CsHioNaO:
CsHiiNOs
CsHiiNO:
CeHizNzOi
n-Bu
H
H
...
...
...
...
184-185 (EtOAc)
158 (3)
...
110-115 (5)
133 (1.5)
135 (0.7)
...
...
98.2-99.3 (0.5), 94 (1)

256-257 (DMF)
CoHoNsOr
HzN
5-Nitro-2-furfurylideneamino
H
Ph
H
H
Ph
H
H
Me
38
70
34
...
...
...
...
95
88
...
...
...
...
45
20
62
...
62
...
...
...
...
...
46
42
...
...
147, 250,
328,580
195,389,528
74
48,371
48
13
205
195,205.389
205
195,227,389
481
121
121
529
158,250 382
250,560
158,250,371,
382
48,250
248,250,417
250
389
195,205,389
205
205
423
48 1
121
121
585
250
13
195,205,389
205
147,250
205, 274,
388,523
158,382
319
199
200,203,227
478
121
H
2-Me5-Cl-CeHaOCHz
N-Pyrrolidinomethyl
N-Morpholinomethyl
EtzNCHz
H
81-82
77
183-187 (2.5)
120 (i-PrOH)
51.5-53 (EtOH)
227
H
H
H
H
H
H
EtzNCHz
CICHa
H
H
Me
H
H
H
H
H
H
H
170-171, 138.5 (1.8)

195-198
138.8-137.8
92
118 (EtOH), 120-122.5 (CHCla)
258-259, 255-258
199-200
200,203
205,388
158,382
580,588
196,205,388
196,205,388
205
-(CHa)p
H
H
H
H
H
H
H
H
H
H
ICsHiiNaOa
CBHaNrOiCl
CoHoNOn
...
...
...
Ref
89
45
...
...
88.5
...
...
...
......
...
...
OIN&bMe)=N
133
CnHoNaOa
S-Nitro-2-furfurylideneamino
HOCHt
241-243
...
205,388
CoHiaNOd
201-202 (MerCO)
...
461
CoHaNOa
Cyclohexyl
33-34, 151-153 (4), 128-131
...
580,598
(0.5-1.0)
CoHirNaOs
CoHisNzOa
HiN
H
HOCHz
H
N-Piperidinomethyl
EtzNCHz H
CoHioNzOzI
MeaN +(CHz)s
128-129
51-54 (pentane), 205-210
(0.08)
123
H
H
H
H
5-Nitr0-2-furfurylideneamino
H
H
Me
Me
Me
Me
H
Et
H
H
Ph
H
Me
H
H
H
2,4,6-CLCsHaOCHz
2,4-ClnCsHaOCHs
H
Ph
H
Me
Et
H
H
H
H
H
H
H
H
H
128-130
79.6-80.0
145-148
152-153
143-144
215-218
142-143
O,di.JL(Me)=N
Me
120-122
1CioHsNOsCls
CioHoNOsClz
CioHiiNOz
CioHiiNaOs
44
54
...
...
200,203
481
121
...
...
...
...
319
319
158,382
250
205,388
205,388
205,388
205
...
205
82
...
202
TABLE
I1 (Continued)
Empirical
formula
CioHiiNaOsS
CiaHiiNaOrS
CioHiaNO4
CioHiaNOsCl
CioHisNOiCl
CioHi7N01
CiiHiiNOaF
CiiHiiNOsBr
CiiHiiNzOzCl
CiiHiiNsOsS
CiiHizNzOa
CiiHiaNOz
CiiHisNsOiS
CiiHisNaOz
CiiHisNOsCl
CiiHiaNaOa
CiiHzaNzOzI
CizHiaNOaCIi
CizHiaNaOsS
CizHisNOs
CizHisNOsCI
CizHisNOaBr
CizHisNO4
CizHisNOs
CizHisNaOs
CizHisNaOsS
CizHisNaOrS
CizHziNzOzI
CizHzsNiOz
CiaHisNOICl
CiaHisN4Os
CiaHirNOa
CisHirNOi
CiaHirNzOz
CisHirNaOsS
CisHirNsOrS
CuHisNO:
CirHisNzO:
C~HisN40,
C~HisN40s
Rz
OzNQ
CH=CHCHzNH
H
H
H
PhCHz
H
H
PhCH=N
PhCH=N
Me
HzN
Pr
MezC=N
EtaN +CHzCHzIEt
H
Et
Et
Et
Me
102
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
MeSCHz
MeSOzCHz
o-MeOCsH4OCHz
2-Pr-6-ClCsHaOCHz
2-PrO-B-C1CsHsOCHz
H
2-Me-4-FCsHaOCHz
2-Me-4-BrCaHaOCHz
ClCHz
CHz=CHSCHz
HOCHz
Ph
EtSOzCHz
PhMeNCHz
2-hle-3-CICsHsOCHz
N-hIorpholinomethy1
H
2,4-ClzCaHaOCHz
CHz=CHCHzSCHz
2,6-MezCsHaOCHz
PhOCHz
P-CIC~H~OCH~
p-BrCsHiOCHz
o-MeOCsH4OCHz
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
132-135
182 (HOAo)
195
140.5-142.0 (EtOH)
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Bu
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
BuzNCHz
3-C1-2-MeCsHaOCHz
4-Cl-3-MeCsHsOCHz
5-CI-Z-MeCsHaOCHz
N-Morpholinomethyl
Et
Et
Et
Et
Et
H
p-MeCsH4
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
PhCH=N
CIKHZONSOS
CiaHziNOs
CiaHziNO4
CisHzzNzOz
Et
n-Bu
n-Bu
n-Bu
o-MeCaH4OCHz
m-MeCaHdOCHz
p-MeCsHdOCHz
p-MeOCsH4OCHz
p-MeCsH4NHCHz
n-BuSCHz
n-BuSOzCHz
2,6-EtzCsHaOCHz
N-Morpholinyl
N-Piperidinomethyl
2-Me-N-morpholinomethyl
H
H
2,4-MezCsHaOCHz
H
H
3,5-MezCsHaOCHz
H
H
o-MeOCeH4OCHz
H
H
p-ClCsH4NHCHz
H
H
p-MeCsH4NHCHz
H
H
PhNHCHz
H
H
H
H
H
Ph
Ph
Ph
H
N-Piperidinomethyl H
N-Piperidinomethyl
H
H
(CHz=CHCHz)zNCHz
H
H
N-Morpholinomethyl
H
H
2,6-MeeN-morpholinomethyl
H
H
N-Me-N'-piperazinomethyl
H
H
2,3,5-MeaCaHzOCHz
H
H
o-M~OC~HIOCHZ
H
H
p-MeCeH4NHCHz
H
H
m-MeCaHiNHCHz
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
yield
...
H
H
H
CirHisNiOs
CisHioN40a
CisHzaNiOs
Ci~HziNzOzI
CisHiaNOz
Bp (mm) or mp, "C
2,6-(MeO)zCsHaOCHz
H
Bu
n-PrSCHx
i-PrSCHz
n-PrSOzCHz
i-PrSOzCHz
H
CisHisNzOi
Ci4HivNO~
CiiHioNzOzCl
C14HzoNzOz
Rs
H
5-N itro-2-furfurylideneamino
EtaN +(CHz)g
IHzN
Et
Et
Et
Et
Et
i-Pr
n-Bu
n-Pr
n-Bu
(PhCHz)MezN 'CHtCHd
H
H
H
CirHiaNOi
Ra
78-80 (pet. ether-CsHs)

...
...
...
...
...
...
...
91
...
117.5-118 (abs. EtOH)
150
138-138.5 (abs. EtOH)
92-92.5 (CsHspet. ether)
159
214-215
...
172-175 (1-2)
116
215-220 (0.12)
118
117.0-1 18.5
43-44 (i-PrzO), 182-185 (0.15)
116-117
122.5
77.5-78.5 (i-PrzO), 73-75, 180195 (0.08)
104-105, 117-1 18.5
150-151
194
148
170
158
180
131
152.5-153.5
110-111, 115-116
94-94.5 (isooctane)
77 (i-PrzO)
169.5-170.5 (EtOH) (D form)
208-209 (i-PrOH-MeNOz)
(L form)
50-50.5 (i-PrzO)
50-51
90-91 (i-PrzO)
80-81 (i-PrzO)
67-68 (ligroin-CsHs)
134
150
...
119.5-120.5 (ligroin-CsHs)
197-198 (EtOH)
174
...
...
...
...
...
89
...
...
...
75
...
20
...
...
77
99
98
73
...
...
...
...
...
...
.. .
...
...
85
82
45
..,
59
40
52
96
91
. ..
...
96
...
...
...
37-38.5 (i-PrzO)
71-72 (i-PrzO), 202-205 ( 01.08)
76-78 (i-PrzO)
94-96 (ligroin-CsHa)
74-76 (EtzO)
170
56
42
28
78
90
86
H
H
178.4-178.8
180-181 (EtOH)
98
H
H
H
151
169.5-170.5 (EtOH)
203
197
H
H
H
H
154-155 (EtOAc)
186-188 (0.03)
..
Ph
...
. ..
...
...
Ref
205
388
423
423
323
319
319
598
319
319
227
423
227
250
423
200
319
567
121
325
423
319
325
325
325
321
319,321
205,388
205,388
423
423
423
423
121
200
319,325
325
325
227
325
325
325
325
314
423
423
319
314
200
168
325
325,437
325
314
314
314
121
382
156,382
461
.. .
...
168
227
168
...
168
14
76
96
94
325
325
314
314
203
2-OXAZOLIDONES
TABLE
I1 (Continued)
Empirical
formula
CiaHzzNsOa
%
Rr
Ri
CisHzsNOr
CisHzaNzOa
CisHzaNzOa
Ci7HzsNO4
Ci7HsNsOs
H
n-Am
Ph
Cyclohexyl
5-Nitrc-2-furfurylideneamino
H
H
H
H
H
H
H
CiaHipNOi
CiaHzoNzOi
CiaHziNsOz
CIQHUN~OI
PhCHr
p-MeCsHc
HzN
Ph
H
H
H
H
H
H
H
H
R4
Ra
H
H
H
Rr
N-Et-N'-piperszinoH
methyl
3,4-Mez-N-piperazino- H
methyl
2,4-Mel-N-piperH
azinomethyl
2,6-(n-PrO)zC8HaOCHz H
p-MeCsHaNHCHz
H
n-BuzNCHz
H
o-MeOCsH4OCHz
H
N-n-Pr-"-piperH
azinomethyl
o-MeOCsHaOCHz
H
p-MeCsHdNHCHz
H
(PhCHz)zNCHz
H
n-BuPhNCHa
H
BP (mm) or mp, OC
yield
193
...
161-164
...
.. .
...
191-193
...
81-82 (ligroin-CsHs)
32-33 (EtzO-pet. ether)
68-69
184-185
92
59-59.5 (isooctane-EtrO)
157-158.5 (ligroin-CsHa)
163-1 65
214-216 (1.5)
70
87
87
...
...
...
64
. ..
106-108 (EtOH)
Ref
168
168
168
319,321
314
314
321
168
321,325
314
200-203
314
250
TABLEI11
WXAZOLJDONES
PREPARED
FROM @-AMINO
ALCOHOLS
AND CARBON
DIOXIDE
%
Empirical
formula4
RI
CaHsNOz
CsHsNOs
CdLNOz
C7HiaNOs
CdL"a
'R, = Ra = Rg = H.
R4
H
Me
Me
Me
Me
i-Pr
Et
CHaCH(0H)CHz
Et
densation with elimination of water after fusion

with urea (Eq 9 and 10).
Bp (mm) or mp, OC
yield
Ref
88-89 (CHC1,)
92 (1.5)
87 (1)
132-133 (0.2)
107 (1)
35
58
326
495
495
495
495
..
76
..
6. Use of Isocyanates (Table V )

Urea derivatives are obtained by reaction of @amino alcohols with organic isocyanates (588) or inorganic cyanates (205, 261). The substituted urea is
then cyclized by heating alone (588) or by heating in
the presence of urea (261) or with hydrochloric acid
(262). Ammonia or an amine is eliminated (Eq 11).
RaRsC(OH)C(NHRr)RzRa
H1N--C=O
RaR&-CR2Ra
AH NR1
from (+)-pseudoephedrine
CONHR
I
H
Me
Ph'
(Eq10)
e displacement
/NMe
HZN- C=O
II
from ( - )-ephedrine
One worker (425) claims to have produced 2-oxazolidone itself by first forming the @-hydroxyethylurea,
nitrosating, and then cyclizing.
'd
+ RNHa
(Eq11)
NRI
Use of Ethyl Chlorocarbonate

(Chloroformate) (Table V I )
Ethyl chlorocarbonate in the presence of bases,
such as sodium hydroxide, sodium ethoxide, sodium
acetate, and potassium carbonate, has been used to a
moderate extent to convert @-amino alcohols to 2oxazolidones. Evidence (166) points to primary reaction with the amino group, with elimination of HCI,
to form the N-carbethoxy derivative (P-hydroxyurethan). This subsequently cyclizes with loss of ethanol
(Eq 12).
6.
+ RNCO
R~R~C-CR~RI

SWERN
204
TABLEIV
B~XAZOLIDONES
PREPARED
FROM &AMINO
ALCOHOLS
AND UREAS
%
Empirical
formula
CaHsNOz
C4HdiOz
CsHeNOn
CsHsNOr
CaHoNO4
CTHiiNOz
CsH~N30e
CioHiiNOz
CiiHiaNOz
CigHi7NOz
CidIiaNOz
c1J31SNoz
RI
Ra
H
Me
H
H
H
H
H
H
5-Nitro-2-f urfurylideneamino
H
Me
H
H
H
H
H
Me
H
H
H
Me
H
HOCHz
HOCHz
H
H
Me
Me
H
H
Me
Ph
H
Ph
Bp (mm)or mp, O C
yield
Ref
R4
Rl
H
H
H
Me
H
Me
KOCH,
-(CH2)4H
H
H
Me
H
Me
H
H
H
H
H
H
H
Me
H
H
H
H
85-87 (CHCls)
83
...
180 (1.5)
20-22, 110-111 (0.1-0.2)
...
56.5-58 (EtOH-EbO)
13
79-82 (EtOHSkellysolve B )
53
73
115 (MeOH, then MezCO)
107-109 (EtOH)
69
trans, 100-102 (CHCla-pet. ether) 10
253-255
H
H
H
H
Me
H
H
H
Ph
Ph
Ph
i-Bu
i-Pr
Ph
Ph
Ph
H
H
Et
Me
H
H
Ph
H
123
Ra
...
...
...
...
50-52 (EtOSkellysolve B)
tTUn8, 159-160; C i s , 188-190
199-200 (EtOH)
trans, 90
251
251
57,251,481
97
97
251
251
357,358
101, 4
x
514,515.
96
83
60
83
73 ( t )
82
97
97
97
261!
97
261
...
TABLEV
BOXAZOLIDONES
PREPARED
FROM &AMINO
ALCOHOLS
AND ORQANIC
OR INORGANIC
CYANATES
ISOCYANATES
Empirical
formula"
R:
RI
R4
CaHSNOa
CsHiiNO2
CTHiiNOz
CsHiaNOz
CioHioNOoCl
Ci6HiaNOz
ClsHlaNOl
a
H
H
Me
H
Ph
Ph
O-C~C~H~OCHZ
Ph
Ph
BP (mm)
or
mp. 'C
90 (EtOH)
143-144 (2)
trans, 100-102;
Cis, 55-56
trans, 51-52;
cis, liquid
151 (EtOAc)
Cis, 188-190
trans, 90
5%
Ref
yield
..
53
..
..
..
..
..
62
..
290
588
357
357
357
357
44
261,262
261,262
R, = R3 = H.
- EtOH
+ ClCOOEt
-+
C''
II
Stereochemical studies have not been reported other

than that the ephedrines yield different oxazolidones
(166).
Use of Esters of Trichloroacetic

Acid (Table V r l )
One of the new methods for synthesizing 2-oxazolidones uses methyl or ethyl trichloroacetate as the
cyclizing reagents for @-aminoalcohols without the use
of added catalysts or elevated temperatures. One

proposed mechanism (305,306) suggests primary attack
(alcoholysis) by the alcohol function of the amino alcohol on the ester with displacement of methyl or ethyl
alcohol, then cyclization by internal nucleophilic
attack by nitrogen on the carbonyl carbon followed by
elimination of chloroform (Eq 13).
RiNHC%RsC(OH)R,Rs
+ CliCOOR
+
- ROH
[RiNHCRzRaC&RsOCOCCla]
7.
NR1
c''
tl
205
8-OXAZOLIDONES
TABLEVI
Z~XAZOLIDENES
PREPARED
FROM
RI
H
H
H
H
AMINO ALCOHOLSAND ETHYLCHLOROCARBONATE

( CHLOROFORMATE)
R;
H
OzNOCHz
HOCHz
H
Ri
R4
H
OzNOCHa
HOCHz
H
%
yield
Bp (mm) or mp, "C
H
H
H
i-Pr
87
106-107
109.5-110.7 (MeOH)
(D) 113-114 (C6Hs-ligroin,
then CsHe)
2-Furfurylideneamino H
H
H
173-174 (50% EtOH)
H
69-70.4
MeCOOCHz MeCOOCHz H
i-Bu
HOCHa
H
72-73, 121-122 (0.01)
Me
H
H
H
143-145 (EtOH)
PhCH=N
H
H
227-229
p-OzNCeHaCH=N
H
HOCHn
H
138-141
MegCCHz
Me
Ph
From ephedrine: 57-58,175Me
Me
H
177 (7-8); from pseudoephedrine: 56-56.5, 160 (6-9);
from isoephedrine: 72-73
H
119-120
HOCHz
p-ClCoHaCHz
Me
92-93
H
HOCHz
PhCHz
Me
H
148-150 (0.05)
HOCHz
Me
Me(CH2)s
H
48-49, 138-139 (0.01)
HOCHz
Me
EtzCHCHz
H
106-107
HOCHz
Me
PhCH(0H)CHz
132
HzNCOzCHz H
PhCHz
Me
N-Morpholiio- 206
5-Nitro-2-f urfuryliH
H
methyl
deneamino
H
132-134
p-MeOCaH4CHz
Me
HOCHz
N-Morpholino- 166-167
PhCH=N
H
H
methyl
136-139, 225-230 (0.02)
H
HOCHz
Me
60
Ref
68
..
562
60
60,90
376
90
444
53
85
90
351
141,205
..
..
..
444
60
351
166
80
351
351
351
351
351
351
32
..
..
86
..
..
..
90
..
351
32
..
351
TABLEVI1
Z~XAZOLIDONES
PREPARED
FROM CH MI NO ALCOHOLS
AND ESTERSOF TRICHLOROACETIC
ACID
%
Empirical
formula5
Rt
R4
CiaHioNzOa
CioHiiNOz
CioHiiNOs
CmHi8N20zCl
CiiHiiNO~Clz
CiiH1iN04
CiiHisNOz
CizHi5NOa
CizHi6NOc
CizHieN406
HOCHzCHz
2,6-ClzCeHsCHz
3,4-ChCeHsCHz
2,4-C1zCeHpCHz
o-ClCeHnCHz
p-ClCsHaCH2
p-OzNCeHaCHz
PhCHz
p-HOCeHaCH2
p-HsN +C6HaCHzCl2,4-C1zCeHsCHz
3,4-CHzOzCaHsCHz
p-MeCaHaCHz
p-EtOCeHaCHz
~,~-(M~O)ZC~H&H~
5-Nitro-Zfurfurylideneamino
CiaHi7NOz
CdigNOz
p-i-PrCeHaCHz
p+-BuCsHrCHz
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
N-Morpholinomethyl
H
H
CsHgNOs
CioHgNOzClz
CioHioNOzCl
Rz
Rg
Rg
yield
Ref
150-155 (0.25)
115.8-118.1
68.0-69.6
72.2-74.3
70.0-72.1
72.1-73.5
148.0-150.3
78.3-79.2
128.2-1 29.2
190.9-192.1
75.4-77.6
59.3-62.2
160-162 (0.03)
63.4-66.1
59.3-62.2
205-206 dec
92
57
84
79
75
48
90
40
52
..
102,299
306,518
306,518
306
306,518
306,518
306,518
306
306
306
518
306,518
306
306,518
306,518
312
47.5-49.1
170-175 (0.04)
59
87
306
306,518
O C
..
..
63
92
68
62
H.
Use of Miscellaneous Cyclizing

Reagents with @-AminoAlcohols
a. Carbonyl Sulfide or Carbon
Monoxide and Sulfur (Table VIII)
Among the gaseous cyclizing reagents, both carbonyl
sulfide COS (35) and its equivalent, carbon monoxide
8.
Bp (mm) or mp,
and sulfur (20), have been used. I n both cases pressure is used along with methanol as solvent. I n the
case of carbonyl sulfide, the reaction is catalyzed by
cumene hydroperoxide, suggesting a free-radical r e
action. NOwork has been reported on the mechanism
or stereochemistry of the reaction, however. Only
206
2QXAZOLIDONES PREPARED
FROM
TABLE
VI11
8-hINO ALCOHOLSAND CARBONYL SULFIDE
RE
H
H
Et
HOCHz
R:
Mp, OC
yield
Method
Ref
H
H
H
HOCHe
...
23
90
cos
co + s
co + s
co + s
35
20
20
20
a few 2-oxazolidones have been prepared by this

method.
b.
CARBON MONOXIDE
AND SULFUR
OR
Carbon Tetrachloride
Two groups of workers have reported the use of

carbon tetrachloride as the cyclizing reagent for ephedrine. One group (256) obtained a small yield of 3,4dimethyl-5-phenyl-2-oxazolidone, mp 91-92 (EtOH),
using a sunlamp to bring about the reaction. They
also found that the yield could be increased by addition
of water.
The other group (415) carried out the reaction under
nitrogen in the presence of copper and oxygen. They
from
also obtained 3,4-dimethyl-5-phenyl-2-oxazolidone
ephedrine. It has been pointed out that carbon tetrachloride acts as a hydrogen acceptor to form hydrogen
chloride and chloroform. No mechanistic details
are known, and only one synthetic example is reported.
88-90
...
..
..
106-110
N,N-carbodiimidazole as the cyclizing reagent (Eq

15) (599).
VL-CIC~H~NHCH~CH~OH
C.
FROM P-AMINOALKYLSULFURIC
ACIDS (TABLE IX)
The feasibility of synthesizing 2-oxazolidones from

0-aminoalkylsulfuric acids using an inorganic carbonate
or bicarbonate in the presence of base as cyclizing reagent has been shown in a few cases. Both potassium
carbonate (118) and sodium bicarbonate (484,561) in
the presence of sodium hydroxide have been used.
c. Cyanogen Bromide and Base
TABLEIX
The p-amino alcohol, diethanolamine, has been

treated with BrCN and then potassium hydroxide to
yield a small amount of 3-(@-hydroxyethyl)-2-oxazolidone (331).
d. Carbon Bisulfide and Methyl Chloroformate
2-Oxazolidone has been prepared (470) by the reaction of @-aminoethanol first with carbon bisulfide
followed by methyl chloroformate. This yields the
2-thione which on treatment with aqueous potassium
permanganate is converted to the 2-oxazolidone (Eq 14).
I n the reviewers opinion the potassium permanganate
is unnecessary; the conversion of the thione to the 2oxazolidone is a hydrolytic process.
HOCH&HzNH*
+ CSz
-+
HOCHiCHzNHCSSH
ClCOnMs
KMnO4
HOCH2CHzNHCSSC02Me+ CHz- CH2d CH
NH
\C/
Hn0
*-I CH,
NH
\C/
8
(Eq 14)
e. N,N-Carbonyldiimidazole
There is only one literature report of the preparation of a 2-oxazolidone from a @-amino alcohol using
2-0XAZOLIDONES PREPARED
FROM ~ - h I N O A L K Y L s U L F U R I C
ACIDS AND INORGANIC
CARBONATES
BP (mm)
Empirical
formula
RI
CaHsNOz
CsHsNOI
CsHvNOz
HOCHzCHz
Ph
R2
Ra = R1
D.
FROM
01
mp, OC
yield
Ref
...
90
170 (0.5)
123
..
..
118,484,
561
484, 561
484,561
R5 = H.
P-HALOAMINES
(TABLE x)
Gabriel (189) was the first to prepare 2-oxazolidone.

He employed the reaction of silver carbonate with 0bromoethylamine hydrobromide. More recently, sodium carbonate or sodium bicarbonate in the presence
of sodium hydroxide has been used (27, 28, 407).
The reaction has had only limited study.
E.
FROM
0-HALO
ALCOHOLS
(HALOHYDRINS)
Only a modest amount of work has been reported

to date on the preparation of 2-oxazolidones from @halo alcohols. It seems worthwhile, however, to
classify the few examples in the literature on the basis
of the cyclizing reagent used in view of the ready availability of halohydrins and the cyclizing reagents employed.
207
2-OXAZOLIDONES
TABLEX
~-OXAZOLIDONES
PREPARED
FROM ~HALOAAUNES
AND INORQANIC
CARBONATES
Empirical
formulaa
CaHsNOz
CaHgNOzCl
CsHsNOa
CrHioNOzC1
RI
R4
Bp (mm) or mp, OC
H
ClCHzCHz
HOCHzCHz
C1(CH2)s
ClCH(Me)CH2
Cl(CHz)a
H
H
H
H
H
Me
90-91 (EtOH)
114 (0.3)
125-140 (0.1)
132-135 (0.5)
107-108 (0.5)
112-114 (0.1)
%
yield
Ref
..
189
27,28
28
27
27
27
95
..
82
84
50
TABLE
XI
ZOXAZOLIDONES
PREPARED
FROM HALO ALCOHOLS
AND UREA
%
yield
MP, 'C
R4
Ref
..
128-129 (EtOAc)
140.5-142 (EtOH)
124-125
125-126
129-1 32
o-MeCsH&CHt
o-MeOC&OCHs
3,5-(MeO)&~HpOcH2
2,3,5-MeGHzOCH2
3,4,5-Me3CsHzOCHz
44
323
427
427
427
..
..
60
..
TABLEXI1
ZOXAZOLIDONES
PREPARED
FROM &HALOALCOHOLS
AND URETHANS
R1
PhCH= N
CizHzs
%
yield
Ref
H
Me
142-143 (EtOH)
140.5-143.0
78
66
48 1
481
62
53
530
R4
H
Me
H
1. Use of Urea (Table X I )
Cyclization of p-halo alcohols with urea to form 2oxazolidones has been reported by several investigators
(44,323,427).
2.
MP, 'C
Ra
and proceeds first by transesterification followed by

cyclization (Eq 17).
RlNHCOOEt
+ HOCR4R&R2R3Br base_
Use of Sodium Cyanamide
Many years ago, Fromm and Honold (182) obtained

a derivative of 2-oxazolidone by the sequence shown in
Eq 16.
+ NazNCN
NaCl + NC-N(Na)CH2CH20H
ClCHtCHtOH
H+
p-MeCsHBOd21
NC-NHCHzCHzOH
n
0,,2-S02C.~H~Me-p
hydrolysis
On
p-SO&sHaMe-p
Use of Urethans (Table X I I )

Urethans have been used to cyclize p-halo alcohols
although examples are still limited. The reaction is
carried out in the presence of base, such as alcoholic
potassium hydroxide (530) and sodium ethoxide (481),
3.
ii
4. Use of Inorganic Cyanates (Table X I I I )

There are two references in the literature (44, 184)
to the reaction of inorganic cyanates with Bhalo
alcohols to form 2-oxazolidones. I n one (184) the reaction was carried out in dimethylformamide, with or
without the addition of iodide ion, and methyl sulfate.
I n the other (44), an epoxide ring was first opened
with aqueous hydrochloric acid to give the chlorohydrin which then underwent displacement of chloride
by cyanate ion (Eq 18). The intermediate isocyanate

SWERN
208
TAB^ XI11
ZOXAZOLIDONES
PREPARED
FROM &HALOALCOHOLSAND INORQANIC
CYANA~S
%
R4
Me
Rr
MP, O C
yield
Ref
H
H
79-80 (dioxane-EhO)
93
79
44
184
184
184
184
44
44
...
101-102 (dioxane)
-(CHz)r
Ph
o-C~C~H~OCH*
o-MeCsH&CHt
...
H
H
H
..
..
151 (EtOAc)
128-129 (EtOAc)
..
TABLEXIV
%OXAZOLIDONES
PREPARED
FROM &HALOETEANOLS
AND PHOSGENE
PLUS PRIMARY
AMINES
%
Empirical
formula"
CsHiNOzCl
C7HisNOe
CsHibNOe
CgHsNOzCl
CoHoNOz
C9H17"02
CioHiiNOz
CiJW":
CisHiiNOe
RI
Bp (mm) or mp, O C
yield
Ref
c1
n-CIH9
n-C&
o-C~C~HI
m-ClCsH4
P-ClCeH4
Ph
n-CJ3Ia
o-MeCBt
pMeCpR4
p-EtOCJ34
a-Naphthyl
122
132 (3)
145 (4)
185-188 (3), 192-194 (7)
53-54
121-122, 118.5-119.0 (EtOH)
82
70
68
82
73
80
176 (1)
180-185 (3)
91 (EtOH)
96 (EtOH-EtO)
130
82
66
66
66
5,66
66
5,66
4,379
66
5
5
4.5
...
cannot be isolated as it immediately undergoes ring

closure with the neighboring hydroxyl group.
HOCR~RsCFhR~Cl NCO-
-C
[HOCR4RsC&R:NCO]
&R&-CRaRa
C'
..
..
.-.
.
78
66
ethyl N-phenylcarbamate, which is cyclized by boiling

in potassium hydroxide solution (379) (Eq20).
(Eq 18)
AH
dl
6. Use of Cyanuric Acid

Cyanuric acid, the cyclic trimer of isocyanic acid,
HNCO, has been used to cyclize /3-chloroethanol in
basic medium (455). Hydrogen chloride is eliminated
to form the tris(hydroxyethy1) derivative, which on
heating collapses to 2-oxazolidone in high yield
0% 19).
HNA! &H
O
F.
1. Use of Urea (Table X V )
CICHzCHzOH,
aq, NaOH
HOCHzCH~'~HZCHzOH
FROM 1,2-GLYCOLS
H (Eq19)
N 0
CHzCHzOH
When 2 moles of urea are heated with 1 mole of a

1,2 glycol, 2-oxazolidones are obtained in fairly good,
but sometimes variable yields. The reaction has
received extensive study. The following mechanism
has been suggested (325) (Eq 21a-e).
A
6. Use of Phosgene plus Amines (Table X I V )

Another early method is the reaction of phosgene
and aniline with p-chloroethanol to produce p-chloro-
2HaCONH2 S SHNCO
&R&-CRsR,
AH AH
+ HNCO
+ 2NHa
&RsC-CRzRt
AH ACONHz
(Eq 21rt)
(Eq 21b)
209
2-OXAZOLIDONES
TABLEXV
ZOXAZOLIDONES
PREPAEZD
FROM ~,%GLYCOLB
AND UREA
RI
R4
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
H
H
2,4,6-ClrC~z0CHp
2,4ClzCsHaOCH2
o-ClCJ&OCHz
m-ClC'H4OCHz
pClC&OCHz
p-BrC&OCHz
PhOCHz
O-HOC~H~OCHZ
2-Md-FCsH:OCHz
3-Me4FCcHsOCH2
ZMe-5-ClCJbOCH2
ZMe3-ClCcH:OCHz
3-Md-ClCaaOCHI
2-Md-BrCasOCHz
3-Md-BrCa:OCHs
o-MeCaH.OCH2
m-MeCcH4OCH2
p-MeCdLOCH2
o-C~C&OCHI
m-ClC~40CHz
o-MeOC"4OCHa
H
H
Me
Me
H
H
H
Me
Me
H
H
II
H
Et
H
H
H
H
Et
H
H
Bp (mm) or mp, *C
91, 87-89 (CHCl:)
...
57
...
...
-NHs
3"
35
36
..
..
140.5-142.0 (EtOH); 141-143 (Hz0);

143-145 (95% EtOH)
121-123, 125.0-126.5 (EtOAc)
135-136 (EtOAc)
67
...
54
58
..
. I
48
50
..
..
73.5
116-117 (EtOAc)
121.5-123.0 (EtOAc), 220-225 (1.5)
104-105 (EtOAc), 220-235 (0.35)
72.5-75.0 (CSHa-EhO)
37
79
74
98-1 00, 105-1 06

104-105, 117.5-118.5 (EtOAc)
124-125 (EtOAc), 245-257 (0.15)
42
52
76
95.5-96.0 (i-Pr20)
* .
129-132
125-126 (EtOAc)
175-178 (0.1)
106-108
129-132 (EtOAc), 265-280 (0.15)
..
94
...
&Rsq-CRzRs
..
127-129, 124.5-125.5 (MeOH)

102-103, 225-240 (0.35)
131-131.5 (EtOAc)
79-81
...
RaRs$+yRiRs
..
104-104.5 (EtOAc)
124.0-125.5 (EtOAc)
135-137 (EtOAc)
...
...
...
...
260, 406
319
319,325
325
325
325
325
325
325
319
320
319,325
325
325
319
320
44,325
325
325
12
12
12, 321, 323,
325
12,325
325
320
12
325
325,437
319,325
12
12
12,260
319,324,325
325,437
319
320
320
319
437
325,437
12
260
325
42
48
76
59
47
49
20
...
Ref
..
128-130 (EtOAc)
147-148 (EtOAc)
96.5-97 (EtOAc)
143.5-146 (EtOAc)
153-154 (EtOAc)
120.5-122 (EtOAc)
84-86 (EtOAc)
...
Pr
H
H
H
H
Ra = Rs =e H.
0 RZ
-co*
R~R~C-CRZR~
R~R~C-CRZR~
I I
1 1
HO OCONHz
HO NH2
RdREC-CRzR,
HNCO 1-t R4RsCTRzRs
I I
H d NHCONHz
HO NHz
%
yield
...
...
139.5-141.5 (EtOAc)
62-63 (EtOAc), 235-255 (0.1)
...
2.
..
..
..
..
..
.-.
60
..
63
60
..
..
..
45
71
..
319
320
319
325
325
319
Use of Urethan (Table X V I )
Cyclization of 1,2-glycols to 2-oxazolidones has also

been effected by reaction with urethan in the presence
of bases, such as sodium ethoxide (300) and aluminum
isopropoxide (108) (Eq 22). Not much work has
been done on this reaction which has the advantage
of simplicity.
210
TABLEXVI
~ ~ X M O L I D O N E PREPARED
S
FROM G GLYCOLS
AND
URETHAN
%
Bp (mm) or mp, "C
Rd
o-MeCeH40CH~
O-M~OC~H~OCHZ
ZMe-4EtOCeHaOCHz
130-131 (EtOH)
145-146 (EtOH)
ZM~O-~-(M~CH=CH)C~H~OCHZ116-117
2-Me0-4-( CHZ==CHCHZ)C~H~OCH~
2-Me0-4-PrCeHaOCHz
O-PhCsHdOCHz
p-PhCeHaOCHz
109-1 10
103-104
99-100, 205-230 (0.1)
195-196
yield
Ref
..
..
59,105,300
59,300
108
108
108
108
108
108
..
..
..
..
48
..
H.
TABLEXVII
ZOXAZOLIDONES
PREPARED
FROM EPOXIDES
AND
Empirical
formulao
CaHsNOz
C~H~NOZ
%
RI
Rz
H
H
H
HOCHzCHz
HOCHzCHg
p-ClCsH4
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
(Me)b
(CHFCH)~
R, = Ra = H.
R4R&-C&Ra
AH AH
CYANURIC
ACID
Bp (mm) or mp, OC
R4
H
Me
C H A H
H
Me
H
H
(Me)b
(CHFCH)~
-( CH2)4(4Pentenyl)b
(4Pentenyl)b
85-87 (MeOH), 89-90, 130-140 (1-2)

111-113 (l), 113-118 (3)
41-44 (EtzO), 125-130 (0.1)
145-165 (1)
123-128 (0.1)
119-1 20
119-120 (THF-hexane)
81
87, 171-176 (3.5)
168-173 (0.3)
161-163 (0.15)
yield
Ref
90
111,179,311
111,311
310
177
177
134
134
134
134
134
134
..
..
,.,
..
..
..
..
..
.-.
...
Position of substituent in doubt.
+ EtOCONHt base_ RaRsC---CReRa
A AH
'C'
dl
\ /
(Eq22)
for the preparation of 2-oxazolidones in which R1 = H,

but when R1is a substituent group a different mechanism must apply (see section IIH2 below for the reaction of epoxides with organic isocyanates).
0
It
G.
FROM 1,z-DIHALIDES
A single patent (533) reports the preparation of 2oxazolidone, mp 88" [EtOH or (CH2C1)2]and bp 160170' (5 mm), in 39% yield by the high-temperature,
high-pressure reaction of 1,2-dichloroethane, ammonia,
and carbon dioxide. The ammonia is generated
in situ from ammonium sesquicarbonate.
H.
HNK NH
0 ; o
AA
+RzR3C-CCRaRs
FROM EPOXIDES
1. Use of Cyanuric Acid (Table X V I I )
2-Oxazolidones have been prepared by the reaction

of epoxides with cyanuric acid (s-triazinetrione).
Both heat and base are necessary for the success of the
reaction; dimethylformamide is a solvent of choice.
It has been suggested that the acidic hydrogens bonded
to the nitrogen atoms of cyanuric acid open the epoxide
ring to form a triply substituted isocyanurate with hydroxyl groups 0 to the ring as shown in the bracketed
formula below. Subsequently, 3 moles of 2-oxazolidone are formed by pyrolytic collapse of the cyanuric
acid ring (Eq 23). This mechanism readily accounts
--c
'0'
OH
Use of Organic Isocyanates (Table X V I I I )

and Inorganic Cyanates
The reaction of epoxides with organic isocyanates
has received much attention recently. The reaction
has been carried out in solvents, such as dimethylformamide, acetonitrile, dioxane, etc. (491) and without solvent (214). Catalysts employed are secondary
amines (592), tertiary amines (215), the halide salts
of amines (269), carboxylate anions (135), zinc
2.
211
2-OXAZOLIDONES
TABLE
XVIII
EPOXIDESAND ORQANICISOCYANATES
~ ~ X A Z O L I D O N E PREPARED
S
FROM
Empirical
formulaa
%
RI
R2
C6HsN02
C oH QNOI
Et
Ph
H
H
H
H
CioKiNOz
Ci8HisNO:
CisHieNOz
CiCHdOz
CieHi 6NO:
Ph
Ph
Ph
Cy clohexyl
PhCHz
Ph
H
(Me)*
H
H
H
H
Me
(Me)b
CHz=CHCHzOCHn
Ph
Ph
PhOCHz
CIOHZINOZ
CisHzsNOz
CzzHa4NOa
Cy clohexyl
Ph
~-CIZHZ~
H
H
H
PhOCHz
n-CloHzl
PhOCHz
~.--:;o'-~H~H~-~';H,-~~~~-'"~~~H;
CH2,0AOM,
'O&/CHI
RI = Ra = H.
Bp (mm) or mp,
R4
I-
Ref
yield
O C
129-130 (lo), 65-68 (0.15)

116 (THF-hexane), 118-121, 119.8120.2 (dioxane), 121-122, 196 (2)
79.5-81.5 (EtOH)
81-83
176 (0.06)
95-96 (pet. ether)
210-220 (0.4)
134.5-1 36.5, 137-1 38 (CsHe), 233-234
(0.5)
147.0-147.5 (pet. ether), 200-202 (0.2)
68.5-69.7 (pet. ether)
62 (EtOH), 231-232 (0.2)
26
92
96
25
64
269,398,491
135,214-216,
269,398, 491
269,491
398
214
214
214
215,479,
491,592
214
269
214
137.5 (EtOH, then C'Ht)
53
49 1
175-185
91
452
64
..
76
90
39
88
Position of substituent in doubt.
chloride, ferric chloride, and lithium chloride. Catalysts are not essential, however (398). This reaction
has been used to prepare condensation polymers from
diepoxides and diisocyanates (452). The poly(2oxazolidones) are high melting.
A suggested mechanism using halide ion catalysis
is formulated in E q 24 (491). If an isocyanate trimer
is employed, it may dissociate to the monomeric isocyanate under the reaction conditions.
Only two reports could be found (407, 534) on the

preparation of a 2-oxazolidone by reaction of an inorganic cyanate (KNCO) with an epoxide (epichlorohydrin). This is the earliest known 2-oxazolidone
synthesis. The position of the substituent on the 2oxazolidone ring has been questioned. The product,
mp 105", has been reported as 4- or 5-chloromethyl2-oxazolidone (407,534).
Use of Isothiocyanates (Table X I X )

The preparation of 2-oxazolidones directly from
epoxides and isothiocyanates has been reported by
two groups (164, 169). Triethylamine, tetraethylammonium bromide (164), and lithium chloride (169)
have been used as catalysts.
A proposed mechanism is given in Eq 25. It suggests the formation of an intermediate 2-oxazolidine
thione which is hydrolyzed to the product.
Xe
R ~ R ~ C , - ~ R Z R -~+
xI
R~R~C-CRZR~
00
4. Use of Urea and Substituted Ureas (Table X X )

Urea has been used to cyclize epoxides to 2-oxazolidones (Eq 26). Little work appears to have been done
RiNHCONR'R"
R~R~C-CRZR,~
'd
3.
II
0
(Es 26)
MARTIN
E. DYENAND DANIEL
SWERN
2 12
TABLEXIX
EPOXIDESAND
m X A Z O L l D O N E S PREPARED FROM
IBOTHIOCYANATES
Empirical
formulaa
Ri
Rd
Bp (mm) or mp, O C
yield
Ref
CpHoNOz
CioHioNOzCl
CioHiiNOz
GEH~SNOI
Ph
Ph
Ph
Ph
H
ClCHz
Me
PhOCHi
121 (CHzClrpet. ether)

103
81.5
137-138 (CH2Clz-pet. ether)
60
85
45
164,169
164
164
169
&
25
& = H.
TABLEXX
~ X A Z O L I D O N E SPREPARED
FROM
EPOXIDESAND UREA
Ri
R4
Bp (mm) or mp, OC
Ref
H
H
H
H
Ph
H
PhOCHz
o-MeCJ3,OCHz
o-MeOCJI,OCHz
PhOCHi
89 (EtOH)
124, 225-227 (5)
125-127 ( C H C l & r o i n )
140.5-142.0 (EtOH)
394
393
44
323
263
...
TABLEXXI
ZOXAZOLIDONES
PREPARED
FROM EPOXIDES
AND URETHAN
OR SUBSTITUTED
URETE~ANS
Empirical
formulaa
Ri
R4
CSH~NZOS
CioHioNOsCl
CiiH iaN 0I
CiiHiaNO4
5-Nitro-Zfurfurylideneemino
H
H
H
&lCsH4OCH2
o-MeCsH4OCHz
o-MeOCdLOCH,
CinHisNOa
CiaHisNzOs
CisHwNOsC1
C1&4N206
CisHisNOa
Ci.rHi.rNOa
CirrHioNOd
~,~-M~zC&OCHZ
PhOCHa
PhOCHp
PhOCHa
PhOCHt
PhOCHz
PhOCHz
5Y$!pOnNCJI4
:
Ph
pMeCsI4
pEtOCslIc
BR (mm) or mp, O C
146.9-151.O(EtOAo)
128-129 (EtOH)
140.5-142.0 (EtOH)
141.4-141.9 (H2O)
115-116 (EiOH)
158-162 (MeCO)
162-163 (MeeCO)
139-140 (MeCO)
149-151 (MeZCO)
131-133 (MegCO)
yield
Ref
*..
391
328
44
323,328
...
...
...
...
...
...
...
100
...
9 . .
328
263
263
263,264
263,264
263
263
StNCtUre
264
on this reaction. The reaction is carried out without

solvent or catalyst a t high temperatures.
5. Use of Urethans (Table X X I )
Urethan and substituted urethans have also been
used to react with epoxides. A small amount of nu-
185-187
264
206-210
264
cleophilic catalyst seems to be necessary, such as potassium hydroxide (44, 323), tertiary amines (263, 328),
quaternary ammonium salts (263), and betaine (328).
A suggested mechanism (263) requires the catalyst
to open the epoxide ring, and the urethan then displaces the nucleophile (Nu) forming an N-(&hydroxy-
213
2-OXAZOLIDONES
ethy1)urethan which cyclizes with loss of alcohol
(Eq 27).
[:*
CH2-CH2
-+
Nu
RiNHCOOR
I
&Rs -CR2Ra
base
(-~u:)
i
00
Use of Cyanamide
A small amount of 2-oxazolidone is reported to be
formed from ethylene oxide and cyanamide (331)
(Eq 28). Cyanogen bromide and diethanolamine are
claimed to react similarly.
6.
HzNCN
+ 2CHaCHz
NC-N(CHnCH*OH)z
Q, ,&Ph
C
II
0
[->NPh
-+.
RCH-CH2
CHz-CHn
I
RCH-CHz
(165) (Eq32)
0, ,N-Ph
C
It
0
minor product
I.
Y . Use of Cyanide Ion

An oxazolidone is reported to be produced by reaction of sodium cyanide in ethanol with an epoxide
(Eq 29) (323).
1. C N -
o-MeOCsH~OCH~CH-CHz
2. HnO-HC1
o-MeOCoH~OCH2-CH-CH2
I
NH
0
C
/
(Eq 29)
li
8. Use of Dithiolanes and Oxathiolanes (Table X X I I )

Russian workers (164, 165) have reported that fivemembered heterocycles containing oxygen and sulfur
in various combinations react with epoxides to yield
2-oxazolidones (Eq 30-32). There is no indication
of mechanism, and the conditions of the reaction are
not clear; in some cases either triethylamine or tetraethylammonium bromide serves as catalyst.
TABLEXXII
2QXAZOLIDONES PRZIPARED ACCORDING
TO EQ 32
%
Empirical
formula
Mp, OC
yield
Ref
CsHsNOn
CioHioN02C1
CioHiiNOz
H
ClCHz
Me
120
103
81.5
63
51
51
165
165
165
FROM CYCLIC CARBONATES (2-DIOXOLANONES)
1. Use of Isocyanates (Table X X I I I )

I n contrast to the reaction of P-amino alcohols with
organic carbonates, in which the two-carbon-atom
((backbone of the oxazolidone is supplied by the
alcohol, 2-oxazolidones can also be prepared by reaction of a cyclic carbonate with an isocyanate, in which
case the backbone is supplied by the carbonate.
Both inorganic salts, such as lithium chloride (214),
zinc chloride, stannous chloride, sodium hydroxide,
sodium carbonate, and potassium carbonate (226),
and tertiary amines, such as pyridine (216) and Nmethylmorpholine (548, 549), have been used as catalysts.
One group of workers (548, 549) has suggested that
an intermediate is formed a t slightly elevated temperatures (about 70) reported to be a molecular complex
of the isocyanate and the carbonate. This complex
can be recrystallized and exhibits a sharp melting point.
When heated, it decomposes, carbon dioxide is evolved,
and a 2-oxazolidone is formed. When the reaction is
carried out in one stage a t the higher temperature, no
appreciable complex formation is noted.
I n a tracer study of the reaction (329), it has been
found that approximately 90% of the carbon dioxide
evolved comes from the ethylene carbonate and 10%
from transformed isocyanate. Accordingly, the mechanism shown in Eq 33a-e has been suggested.
214
TABLEXXIII
PREPARED
FROM CYCLIC
CARBONATES
AND ISOCYANATES
ZOXAZOLIDONES
%
Empirical
formula"
Ra
Ri
CiHiaNOz
CsHsNOzCl
CoHoNOz
n-4Ho
p-c1csH4
Ph
H
H
H
H
H
H
CoHiaNOz
Ci,H11N02
Cyclohexyl
p-MeC6H4
PhCHz
Ph
Cy clohexyl
PhCHz
p-EtOCsH4
p-EtOcOcsH~
p-EtOCOC8H4
n-ClzHzs
n-Cl2H~s
Ph
H
H
H
H
H
H
H
H
H
H
H
PhOCHz
H
H
H
Me
Me
Me
H
H
Me
H
Me
H
Ci4HaNOz
CiiHiaN02
CiiHiaNOs
Ci2HirNOt
Ciz&6N04
CiaHd02
CisHaiNOz
Ci7Hi~Noa
Bp (mm) or mp,
R4
q=+-&y?F
yield
O C
95
63
30
94
96
26
78
98
91
54
48
88
216
548,550
214216,226,
548-550
214,215
548,550
214
214,216,548
214
214
548
214,215
214,215
214
214
215,216
syrupy
..
550
91
70
92
CH,--CHs
OI \ y N
Ref
122-124 (18)
116-117
117-119 (EtOH), 121-122, 196
(2)
33-33.4
90
79-80
79-81, 81-82, 141-142 (0.4)
3940
122-124 (0.2)
95-96
109.5
97-98
167-168 (0.25)
36-37
137-138, 233-234 (0.5)
RI
Rs = H.
2.
Use of Formamide (Table X X I V )
2-Oxazolidones have been prepared by refluxing

cyclic carbonates with formamide (456). Carbon dioxide is eliminated. The mechanism is unclear (Eq
34); in all cases a methylene group is attached to one
carbon atom of the carbonate "backbone." The
methylene group is converted into a methyl group.

R~R&-C=CH~
A A
C
'/
+-- COa
HCONHa
R4R6C-CH-CHs
C
'/
NH
(Eq 34)
2-OXAZOLIDONES
TABLE XXIv
Use of Ammonium Carbonate and

Potassium Cyanide (Table X X V )
The preparation of 2-oxazolidones in high yields by
reaction of cyclic carbonates with ammonium carbonate
and potassium cyanide at SO" has been reported (457,
455).
3.
2-OXAZOLIDONES PREPARED FROM CYCLIC CARBONATES

AND FORMAMIDE
Empirical
formulaa
R4
Rs
C6H1lNO~
Me
C7H13N02
CgHlsNOz
Me
Et
-(CHz)j-
C9H19N02
hIe
CiiHigNOz
a R i = Rz
Me
i-Bu
-(CH2)7=
215
Bp (mm) or mp, "C
Ref
60-62 (EtzO-pet. ether),

114-119 (0.1)
129-130 (0.3)
110-111 (EtOAc), 155167 (0.1)
39-41 (pet. ether), 139146 (0.1)
108 (0.25)
456
456
456
J.
FROM ACETYLENIC COMPOUNDS
456
1. Acetylenic Alcohols plus Isocyanates (Table X X V Z )
456
Acetylenic alcohols react with isocyanates to form

substituted 4-methylene-2-oxazolidones (Eq 35) Cycli-
H ; R3 = CHI.
TABLEXXV
2-OXAZOLIDONES PREPARED
Ri
H.
FROM
CYCLIC CARBONATES AND AMMONIUMCARBONATE
Rz
Rs
R4
R6
NC
NC
HzNCO
NC
NC
NC
NC
NC
HzNCO
HzNCO
HzNCO
HzNCO
NC
NC
NC
HzNCO
NC
NC
NC
NC
NC
HzNCO
NC
NC
HzNCO
NC
HiNCO
NC
NC
NC
HzNCO
NC
H2NCO
NC
Me
HOCHz
Me
Me
hIe
Me
Me
MeOCHz
Me
Me
Me
Me
Me
HOCHz
Me
Me
Me
MenC(OH)CEC
MeOCHz
EtzNCHz
Me
Me
Me
Me
Me& (0H)C-CCHt
PhCHz
PhCHz
CHz===CH(CHz)z
hle
b-(N-hlorpholino )ethyl
Me
Me
Me
Me
iMe
Me
Me
Me
Ale
Me
Me
Me
Me
Me
Me
Me
NC
Me
Me
Me
Me
Me
OHCCHZ
RleOCO
Et
MeOCHz
Me
Et
MeOCHz
i-Pr
bIezC(0H)
-(CH2)5-(CH2)6i-Bu
-(CH2)5cy-Pyridyl
Ne
-(CHz)r
Ale
Ph
Ph
(CHZ)73-Methyl-3-pentenyI
Rle
Me
Me
-(CH2)5EhN(CHd3
-(CHz)5Et2N(CH&
-(CHz)ii-(CHz)ii4,8-Dimethyl-3,7nonadienyl
4,8,12-Trimethyltridecyl
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ale
Me
Me
Me
AND POT.4SSIUM
CYANIDE
MP, O C
106-107 (EtOAc-pet. ether)

110-112
207-209 (HzO)
...
135-137
88-89
135-136
224-226 (EtOH)
205-206 (MeOH)
192-194 (EtOH)
189-191 (as HOAc)
133-134
240-249
8&83
253-254 (HOAc)
143-144.5
21G211
152-153
...
139.5-140.5
217-219 (malonic ester)
106.5-107.5
82-83
211-213 (DMF-HzO)
149
226-227 (THF-pet. ether)
133.5-135.5
Oil
133-134
156-158
25&260 (N-methylpyrrolidone)
...
Ref
458
458
457
458
458
458
458
458
457
457
457
457
458
458
458
457
458
458
458
458
458
457
458
458
458
457
457
458
458
458
457
458
457
458
458
283 dec (malonic ester-HOAc)
457
281-285 dec (HOAc-MeOH)
457

SWERN
2 16
TABLEXXVI
4-METHYLENE-2-OXAZOLIDONES PREPARED FROM
ACETYLENIC
ALCOHOLSAND ISOCYANATES
%
Empirical
formulaa
Ri
RI
Rr
Bp (mm) or mp, OC
yield
Ref
CsHisNOz
C9HxNOz
CioHTNOzClz
CioH9NOz
Et
Et
3,4-ClzCijHs
Ph
Me
Me
H
H
Me
Et
H
H
70
60
93
96
47 1
471
504
83,471,503,504
CizHiiNOzClz
CizHizNOzCl
CizHiiNOzCl
CinHiaNOzCl
63
CiaHiaNOzCl
CisHisNOzCL
CisHisNOzCl
CiaHnNOz
3,4ClzCsHs Me
Me
m-C1CsH4
Me
Me
Me
Me
Ph
~ , ~ - C ~ Z CE~t H ~ Me
2,5-ClzCsHs
Me
Et
3,4-C12CsH8
Me
Et
p-C1CsH4
Me
Et
-(CHz)s3,4-ClzCsHs
-(CHz)sm-ClCSHp
Ph
-(CHz)s-
60
67
89
89
83,504
83
83,471
471,504
47 1
83
471
504
504
83,471,477,504
CzzHn9NOz
Ph
72-74 (0.3-0.6)
87-91 (1.2-1.5)
152-153
94-97 (CHC18-isooctane); 97.297.7 (MeOH), 97.5-98.0
134.2-135.1, 140.2-140.8
102.0-102.5
130-133 (EtOH), 131.5-132.0
87-89 (pet. ether), 88.1-88.9
134-135 (1,2-dimethoxyethane)
88.6-88.8
112-119 (EtnO)
161.5-162.1
142-143
166-168 (EtOH), 167.1-167.6
(pet. ether), 168.9-170.0
129-130 (pet. ether)
..
477
..
83
Me
R:12CH2
Q-izm
150.8-15 1.6 (hexane)
..
90
90
50
..
0
a
R2RI = methylene.
TABLEXXVII
~ A L K Y G ~ X A Z O L I DPREPARED
ONES
FROM 4-ALKYLIDENE-2-OXAZOLIDONESBY
RI
3,4clzce
Ph
CioH9NOzCls
CioHiiNOz
R s = & = R6
R2
MP,OC
yield
Ref
Me
Me
88.7-89.5 (MeOH)
49-50 (EtzO)
73
66
504
R ~ R s C ~ G C HRiNCO
I
504
H.
zation is effected by bases, such as sodium methoxide

(471) and pyridine (83), or merely by heating (504).
Pyridine is a convenient solvent for the reaction.
(3H
CATALYTIC HYDROGENATION
%
Empirical
formula
R~R~C-CECH
R ~ R s C ~ E C H RiNHs
-+
and pressures in the presence of catalytic amounts of

copper salts (133) (Eq 36).
+ COz Cu salts &RbC-C=CHz

__f
AH
NRI
d
8
C-NRi
R~RSC-C=CHZ
I
(Eq 35)
8
Hydrogenation of 4-alkylidene-2-oxazolidones using
palladium on carbon as catalyst yields 4-alkyl-2-oxazolidones (504) (Table XXVII).
2. Acetylenic Alcohols Plus Amines
and Carbon Dioxide (Table X X V I I I )

5,5-Disubstituted 4-methylene-2-oxazolidones are obtained by the reaction of acetylenic alcohols with
amines and carbon dioxide a t elevated temperatures
(Eq36)
3. Acetylenic Amines And Carbon

Dioxide (Table X X I X )
4,4-Disubstituted 5-methylene-2-oxazolidones are obtained bv the reaction of carbon dioxide with acetylenic
amines at elevated pressures and temperatures in the
presence of copper salts (131) (Eq 37). Tetrahydrofuran is the solvent of choice; catalytic quantities of
tertiary amines increase the yield of oxazolidone.
HCGC-CRZR~
NHRi
cos
CHFC-CRZRI
d\ / NR1
(Eq 37)
217
2-OXAZOLIDONES
TABLEXXVIII
5,5-DISUBSTITUTED 4-METHYLENE-2-OXAZOLIDONES PREPARED FROM ACETYLENICALCOHOLS
PLUS AMINES AND
CARBON
DIOXIDE(133)
Ri
Me
HOCHeCH2
i-Pr
Me
n-Bu
CHFC (Me)CH (Me)
n-Bu
i-Pr
Cyclohexyl
PhCHz
~-Bu
PhCHz
Bp (mm) or mp, OC
RS
Me
Me
Me
R4
Me
Me
Me
94 (15)
71-73 (EtOAc), 128-130 (0.6)
66-69, 110-114 (21)
58-60, 118-120 (1)
-(CHz hMe
Me
Me
...
Me
Me
Et
88-90 (0.3)
89-93 (0.5)
89, 138-141 (1)
68, 140 (0.6)
32-34, 118-121 (0.9)
36-38, 118 (0.3)
79-80 (HOAC)
-(CHz)r
Me
Me
Me
Me
-(CHz16-(CH2)5-
115-117 (HOAc)
RzRa
methylene.
TABLEXXIX
q,&DISUBSTITUTED .!i-METHYLENE-%OXAZOLIDONES PREPARED

FROM ACETYLENIC
AMINESAND CARBON
DIOXIDE(131)
Empirical
formulao
C8HlaNOz
CgHiaNOz
C9HllNO2
CloHliNOz
CiiHiiN02
CiiHi7NOz
C13H21N0~
a
RI
i-Pr
H
i-Pr
n-Bu
PhCHz
Et
n-Bu
Rz
Ra
Me
H
-(CH2)5Me
Me
Me
Me
H
H
-(CHz)j-(CH2)6-
BP (mm)
or mp, O C
67 (0.3)
112
125-127 (EtOAc)
102 (1.5)
37
110 (0.01)
130 (0.15)
R4RaC-CRzRs
a,
RX
/NR1
X-~RRaR3-CR4R5-O-C-?lRRl
?
1
I
R4R6= methylene.
R2R3C-CR4Ra
x-2' R bN1010
R;/
K.
h'
FROM URETHANS
N-R cleavage
The cyclization of appropriately substituted urethans

to form 2-oxazolidones has received much study, presumably because the already existing sequence of nitrogen-carbonyl carbon-oxygen linkages is suitably
set up for ring closure. The large number of reported
cyclizations can be divided into those carried out (a)
pyrolytically without catalysts, (b) with alkaline catalysts, and (c) with acid catalysts. I n the ring closures,
either the carbonyl oxygen or the nitrogen serves as
the nucleophilic species for displacement (Eq 38 or 39,
respectively). I n Eq 38 the displacement of X occurs
on the carbon atom /3 to the urethan linkage with oxygen-alkyl cleavage. I n Eq 39 the displacement occurs
with nitrogen-alkyl cleavage (normally either R or R1 =
H), and alkaline catalysts are usually present. A
mechanism involving intermediate carbonium ions
RZR~C-CR~RS
I I
RX
has also been suggested (341) but does not appear as

likely as the ones suggested.
1. Pyrolytic Cyclizations (Table XXX)
If X (Eq 38 and 39) is suffciently labile, merely heating the urethan brings about cyclization. Only one case
is reported of nitrogen-alkyl cleavage among the purely
pyrolytic cyclizations (42). When oxygen-alkyl cleavage occurs, X can be iodine (140), bromine (297), chlorine (286,368), or even the amino group (142). In oxy-
R~ARTIS E. DYENAND DANIELSWERX
215
TABLE
R1
Ra
H
H
H
H
H
Me
H
H
H
Et
H
H
H
H
Rle
H
H
H
Et
Me
H
H
Ph
H
H
H
H
Ph
8-SUBSTITUTED URETHANS
R4
Ra
B p (mm) or mp, 'C
...
H
H
H
ClCHz
H
31e
H
H
H
BrCHzCHz
H
BrCHa
H
Et
H
H
Me
H
H
ClCHz
-(CHz)r
H
CgHgNOz
xxx
BY PYROLYSIS O F
103-106 (Hz0)
109-111 (2), 136-137 (5)
155-160 (11)
107 (C&)
180-190
109 (0.15)
152-154
trans, 100-102 (CHCI3-pet. ether);

cis, 55-56 (EtnO-pet. ether)
trans, 51-52 (EtOAc-pet. ether);
cis, 110-115 (0.02)
-(CHz)r
H
H
H
...
...
H
Ph
H
90-91 (CHClB-CeHe)
136
%
yield
50
80
90
Poor
70
...
90
Poor
...
...
...
...
...
...
95
45
...
Ref
543
286
286,368,543
368
286
13
543
368
286
13
358
230,358
358
358
42,286
543
230
Name
Cholestano [3p,2p-b]-2-oxazolidone
cis-Tetralino [2,l-b]-2-oxazolidone
cis-Indano [ 2,l-b]-2-oxazolidone
0
227
141
160
230
230
230
Rg = H.
gen-alkyl cleavage, the process is similar to an 5x2 reaction and hence is stereospecific (Eq 38) (230). This can
be seen from the perspective diagram 3. I n the case
of a p-halocyclohexane carbamate in the trans-diaxial
configuration, rearward attack by carbonyl oxygen on
the carbon bearing halogen yields an oxazolidone with
a cis ring fusion, cis-cyclohexano [b]-2-oxazolidone.
fl
OCONHPh
=
=
Me, mp 281-283', 84% yield

H, mp 269-272', 74% yield
@--OR
H
CX
2. Alkaline Cyclizations (Table X X X I )
Alkaline cyclizations of urethans have received

wide attention. As Table XXXI shows, yields are
generally fairly good. A variety of bases have been
used : alcoholic potassium hydroxide (279, 380, 420,
531), aqueous potassium hydroxide (277, 341), sodium
hydroxide (23, 497), sodium ethoxide (116, 119, 120,
122, 123, 367, 395), sodium methoxide (163, 403),
trimethylamine (117, 366), triethylamine (492), diethylamine (396), potassium (459), and fused urea
(318). Only two groups of workers (318, 359) report
alkaline cyclizations via oxygen-alkyl cleavage.
There is one example (353) of a cyclization of a urethan under basic conditions involving no loss of a
group.
3. Acidic Cyclizations (Table X X X I I )
There are only a few cases of cyclizations carried out

under acidic conditions. The proton is required to
satisfy some structural feature in the molecule and
may also be required for initiating the reaction as the
starting materials employed are benzylurethans. Both
thionyl chloride and phosphorus pentoxide have also
been reported as cyclizing reagents in the cyclization of
p-hydroxyethyl carbamates (X = OH) (3) (100).
L.
FROM @-HYDROXY ISOCYANATES

(TABLE XXXIII)
2-Oxazolidones have been prepared from p-hydroxyamides by way of the Hofmann reaction and from phydroxyacylazides by way of the Curtius reaction.
These two types of reactions are conveniently considered together, as they both proceed through a
common intermediate, the isocyanate (171). The production of the oxazolidone can be formulated as in
Eq 40.
2-OXAZOLIDONES
219
HONO
The formation of 2-oxazolidones has been used to

prove stereochemical configuration (590, 611) (Eq 41).
OH
- H20
Ht
+ R~R~C-C=CH~
R~R~c-&-cH~
NRI
NRI
RaRsC-CHMe
I
6
C
'/
ll
threo
trans
pH
R4
;
(Eq 43)
NR1
Rz
2.HONO
1.H2"H2,
(Eq41b)
2. Use of Potassium Cyanide and

Amrnonium Carbonate (Table X X X V )
a-Ketols (acyloins) have been converted into 2oxazolidones by reaction with potassium cyanide and
ammonium carbonate (Eq 44) (235). The reaction
OH
erythro
0
cis
4
R4RaC-CRz
dH
KCN
----f
(NH~zCOI
(a-KETOLS)
1. Use of Isocyanates (Table X X X I V )
2-Oxazolidones have been prepared by the reaction

of isocyanates with acyloins (Eq 42) (148). The product is then dehydrated and catalytically hydrogenated
(Eq 43)
NH
R4RsC-CCHs
dH
+ RlNCO
RdRsC-CCHa
C''
I
I
KR~
I1
(Eq 42)
product can be hydrolyzed with 4-5 N hydrochloric

acid to the corresponding carboxylic acid. The acid
can either be esterified directly or it can be treated
with thionyl chloride followed by methanol to give the
corresponding carbomethoxy derivative.
(TABLEXXXVI)
2-Oxaxolidones are reported to be products of the
intramolecular insertion of a nitrene into a carbonhydrogen bond (Eq 45) (482). The nitrenes are produced by pyrolysis or photolysis of an azide; the reaction is reported to go in 45-75y0 yields.
s.
OH
\C'
M. FROM ACYLOINS
TCONH, (Eq 44)
RdR6C-
FROM NITRENES
A~ARTIN E. DYENAND DANIEL

SWERN
TABLEXXXI
2-OXAZOLIDONES PREPARED BY ALKALINE-CATALYZED
CYCLIZATION
OF
URETHANS
%
R2
Ri
R4
Bp (mm)or mp, OC
H
HzN
H
Me
Me
H
CH-CH
ClCHzCHz
MezN
CHFCHCH~
H
n-Bu
t-Bu
H
H
HOOC
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
i-Pr
H
H
H
M~zN(CHZ)S
3,4-ClzCeHa
2-HO-3-NOz-5-ClCeHz
m-ClCsH4
p-ClCsHa
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
ClCHz
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
ClCHz
Me
H
ClCHz
o-ClCsHaOCHz
H
H
H
H
H
H
H
H
H
H
H
H
H
H
ClCHz
154-155 (alc)
3-Cl-6104-104.5, 200 (0.1)
MeCsH3OCHz
Me
67.5
o-MeCsH&CH~
125.6-126.5
H
94-95
o-M~OCEH~OCHZ
140-144, 220-225 (0.1)
H
110
131-132 ( d ~ )
ClCHz
H
129.5-130.0
Me
134
8-Naphthyloxy193.0-193.6
methyl
Ph
131
Ph
129
H
H
H
H
p-MeCbH4
H
p-EtOCeHa
H
p-EtOCOCeHd
PhCHzNHCO
a-Naphthyl
8-Naphthyl
H
n-Ci2Hzs
1-Anthraquinonyl
H
H
H
H
H
H
H
H
H
90
70 (EtOH), 34
118
71 (HCl salt)
208 dec (MeCl salt)
89-90 (0.04)
100-105 (1.3)
122-124 (1)
72 (EtzO)
...
113-114 ( d form)
122 (4)
94 (2)
246-247, 255-256
117, 177 (hygroscopic)
79
53.0-53.5
120.9-121.5, 122.5
142-147 (0.01)
139.8-140.6
186
154.5
110
118 (C~HIJ),
121-122
126.5
114
73-78 (ligroin)
108
151
141-143
79.5-80.0
125-130 (0.001), 170 (4)
94.3-95.0
90.5-91.0
77-77.6
109-110
171 (n-BuOH) (hygroscopic) (HC1 salt)
yield
.. .
.. ,
...
..
.. .
...
. ..
..
.. .
.. .
...
. ..
93
...
92
.. .
97
.. .
86
95
...
96
97
.. .
62 (EtOH)
226:5
.
Ref
459
119,170
448
*
128
123
367
... 23
72
23
87
116.
Poor 420.
* . 375
80
395
62
395
83
170,4CR,
566
120,122
.. . 380
*
497
95
279,341
92
279,341,
395
76
341
96
341
.. * 497
95
395
97
395
95
395,492
. . * 497
93
279
94
279
... 277
95
277,279
. . . 36
566
96
123,341
80
341,395
78
341
70
341,395
72
341
93
341
. . . 122
52
85
122
276
318
279
36
341
36,318
395
276
341
279
36
279
279
369
531
395
2-OXAZOLIDONES
22 1
TABLE
XXXI (Continued)
Empirical
formula"
CI~HIENZO~
Ri
Ra
R4
Ph
PhNHCOOCHs
%
yield
Bp (mm)or mp, OC
. ..
...
Structure
Ref
265
107
80
395
175
62
395
253
68
395
. ..
96 (MeOH)
n
n
n
n
n
=
=
=
=
=
238 (HOAc)
169 (HOAc)
193.5 (HOAc)
138 (HOAc)
130-131 (HOAc)
O
l
2
4
8
47
78
72
26
82
163
117,366
117,366
366
117,366
366
TABLEXXXII
GLUCOPYRANO8IDO-2-OXAZOLIDONES PREPARED BY
ACID-CATALYZED
CYCLIZATION
7%
R
R'
R"
MP, OC
HOCHg
H
Ph
PhCHeOCHa
H
H
NaCHe
CHIC0
Ph
MeSOaCHz
CHaCO
Ph
PhCHtOCHz
CHaCO
CHsCO
PhCHzOCHz
CHsCO
CHsCO
3-(5-Nitro-2-furfurylideneamino)-2-oxazolidone~
a
H
H
H
H
H
CHaCO
yield
..
114
114 (MeOHi-PrOH)
90
177
147 (MeOH-4-PrOH)
99-100 (THFi-PrOH)
256-257 dec (DMF)
80
88
...
..
..
..
Ref
210
211
210
210
211
211
100
Although not a glucopyranoside, this compound is included here because of its method of preparation.
least in the case of pyrolytic generation. Another

study (600) has confirmed that in the case of a pyrolytically produced nitrene there is 100% retention of configuration in the G H insertion reaction.
0. FROM
Recent studies have shown that, when the carbon

that becomes C-4 in the oxazolidone ring is optically
active, the optical activity is retained (482). It is
concluded that the cyclization takes place in a one-step
process and that the nitrene is in the singlet state, a t
(0-HYDROXYALKYL)SEMICARBAZIDES
2-Oxazolidones are obtained by refluxing a solution

of a P-hydroxyalkylsemicarbazide with acid (Eq 46)
(195, 198). 3-Amino-2-oxazolidone, mp 69-71 O (EtOH)
HC1
&RaC--CR*Ra
I
~6 T;T-NH~
H2N--C/
RIR&-CR%RZ
I
6
C'
T;T-NH~
I/
(Eq 46)

SWERN
TABLEXXXIII
BY W A Y O F
R2
Rs
H
H
H
H
H
H
H
H
Me0
H
H
i-Bu
Et
H
H
H
H
H
Et
H
i-Pr
H
H
H
H
Ph
H
H
H
H
H
Ph
H
H
H
H
H
H
H
H
H
H
H
H
Ri
CURTIUS AND HOFMANN

REACTIONS
R4
Me
RE
Bp (mm) or mp, " C
H
Me
H
H
H
H
...
56.8-58 (alc-EtO)
(1) 113-114 (CeH,)
130-140 (0.2)
160-170 (0.6)
256-257 (DMF)
%
yield
,
Ref
28
30
93
462
97
375,376
386
386
1,219
13
. ..
H
H
101.0-102.4
137-139
89-90 (HzO), 88-90 (alcSkellysolve B)
82
40
50
381
386
21,97
103-104
72
209
110
131
118-120
135
...
...
...
434
434
434
434
...
209
100
72
91
93
25
463
97
386
55
55
434
434
434
434
434
219
37
37
37
462
386
7
-(CHz)5-
-(CH&CHhle-(CHZ)&HMe(CHz)z-(CHz)aCHMeCHz-(CHy)zCH (OMe)(CHz)zH
( 7 0 .
...
...
OH (trans)
H
H
Ph
H
H
H
2,5- (Me0)tCeHa
H
2,5-(MeO)~CsH3
2,5-(EtO)nCsH3
trans-2-Decahydronaphthyl
cis-2-Decahydronaphthyl
Ph
Ph
H
H
Me
H
H
138
146-147 (EtOH)
78-79
108-109 (EtOH)
202-203 (BuOH)
120
103
109
148
127
251-256
( d l ) 184 (Hz0)
( d ) 157 (HzO)
(1) 157 (Hz0)
( d l ) 126-127 (MeOH)
80-81
( d l ) cis, 134-135
(CaHsEhO)
107 ( C a n )
139-140
159 ( C a s )
86.5 (C&-hexane)
165 and 200
140 and 207
PhOCONH
H
Ph
H
H
H
H
H
H
H
H
PhCHzCONH
H
H
H
PhCHzOCONH H
Et
Ph
H
MeOCHt
H
H
H
H
H
H
Ph
H
H
H
H
i-Pr
H
H
H
H
Ph
...
...
75
611
H
H
H
H
H
H
Ph
Ph
H
H
H
H
200 (EtOH)
cis, 193.5-194.5; trans,
161-162
178-179
H
H
Ph
PhCHz H
H
106-107
H
p-PhCHzOC&
H
145-146 (EtOH)
H
m-PhCH2OCaa
H
106-107 (EtOH)
H
2-PhCHz0-5-MeCaHs H
150-150.5 (CeHe-hexane)
161 (MeOH)
H
3,4-(Me0)~CeH&Hz
3,4(MeO)~CsHaCHz
63
62
76
76
86
386
386
55
55
22
472
( d ) 233-235 (MeOH), (1)

244-246 (MeOH)
...
505
Name
4-Dihydrolysergylamido-2-oxazolidone
H
H
H
H
Ph
Me
H
H
p-MeOCeH,
H
m-MeOCeHr
H
-CHzCHMeCH2CHPvIeCH2-CHzCHMeCHMe(CHz)r
-(CHz)$HEtCHz-(CHZ)&MezCHz-( cHZ)7H
H
H
H
H
H
H
H
H
H
H
H
H
H
PhCHzCHeN
H
M L
H
H
H
H
H
H
H
H
H
H
H
Ph
H
...
*..
...
...
...
...
78
77
73
95
89
60
...
74
...
...
...
...
.. .
41
386
41
257
434
434
223
2-OXAZOLIDONES
TABLE
XXXIII (Continued)
%
Name or structure
Bp (mm) or mp, O C
yield
..
( d ) 268-270 (Me2CO), ( I )
Ref
505
280 (NeOH)
Ph--S A N C H . C H . o > T
U
0
rl
OK"-"
0
194-196
...
8-Hydroxy-6-sulfonaphth-2-yl
7-Hydroxynaphth-1-yl
5-Hydroxy-l,7-disulfonaphth-2-y1
8-Hydroxy-3,6-disulfonaphth-2-yl
218-219 (Hz0)
...
...
I
...
14
333
...
.. .
...
...
...
...
498
498
498
498
498
498
TABLEXXXIV
2-OXAZOLIDONES PREP.4RED
FROM ISOCYAN.4TES .4ND
ACYLOINS(148)
%
Rz
Ri
p-ClCBH4
Ra
-CHz4HzMe
hfe
Me
hle
-CH*-
Ph
p-ClCeH4
p-ClCsH4
Ph
Ph
p-ClCBH4
H
HO
H
HO
R4
Rs
Me
Me
Me
hle
Me
Me
Et
Me
Me
Me
Me
Me
Me
Me
yield
MP, 'C
98-99 (MeOH)
94-95 (pet. ether, then EtOH)
65
68
...
..
..
...
86
98-99 (MeOH)
..
...
..
...
TABLEXXXV
Empirical
formulaa
C7HiiNO4
C&zNz03
CsHi3NOa
CsHirNzOs
CsHisNO4
CsHisNzOo
CioHisNOa
CioHieNnOi
CiC"7NO4
CioHi8NzOa
CiiHi7NO4
CnHi9NOa
CizHiaN04
CizHi4NzOs
(1
R1 = H ; RZ = Me.
CsHsNOz
C4H7NOz
CsHsNOz
CsHliNOz
OR1
H.
ACYLOINS
AND POTASSIUM CYANIDE PLUS
Rs
R4
R1
HOCO
HzNCO
HOCO
MeOCO
HzNCO
HOCO
HzKCO
HOCO
HzNCO
HOCO
HOCO
HzNCO
HzNCO
MeOCO
hleOCO
HOCO
HzNCO
Me
Me
Ale
Me
Me
Et
Et
Me
Me
Et
Me
Et
Et
Et
AMMONlUM
206-207
208-209
206-207
99-100
224-226
177-179
175-177
205-206
253-254
186-187'
195-196'
192-194b
176-17Bb
129-131
89-90
198-199
222-224
i-BU
i-BU
i-BU
i-BU
-(CHzh-
i-BU
Ph
Ph
Me
hl e
Me
%
yield
MP, 'G
-(CHz)r-(CHz)aMe
Me
Me
Me
CARBONATE (235)
74
34
80
58
31
66
72
73
79
74
69
39
19
33
69
72
24
* Diastereoisomers.
2-OXAZOLIDONES BY
Empirical
formulaa
FROM
RS
H
H
H
Et
TABLEXXXVI
INTRAMOLECULAR INSERTION OF NITRENES
INTO
CARBON-HYDROGEN
BOND
oc
RI
RI
Rs
Mp,
H
H
H
Me
H
Me
Me
H
H
H
Me
H
...
..
..
80-81
75
68
...
...
yield
Ref
296
296
295,296,431
482,600

SWERN
224
TABLEXXXVII
2-OXAZOLIDONES FROM 2-OXAZOLINES AND WATER
%
I
RI
RI
pC1C'HiCOOCHz
pMeCdH&OOCHl
p-MeOCJ14COOCHn
3,4,5-(Me0)8CJl~COOCHp
PhCOOCHz
Me
Me
Me
Me
H
MP, 'C
R4
H
H
H
H
Ph
yield
..
117
169 (HzO)
86 (1120)
144-145 (H;O)
87-87.5 (EtOH-hexane)
..
..
..
4
Ref
441,442
441,442
441
441,442
426
TABLE XXXVIII
2-OXAZOLIDONES FROM 2-IMINOOXAZOLlnl NEB
Empirical
formula"
RI
5-Ni tro-2furfurylideneamino
5-Nitro-Zfurfurylideneamino
3- (5-Nitro-2-fury1)acrylideneamino
PhNHCS
pMeCONHC&&3On
Me
CHFCHCHZNHCS
PhNHCS
CsH7NsOs
CoHgNaOr
(195), and 3-amino-4,4-dimethyl-2-oxaxolidone,

bp 130135" (10 mm), are reported to have been prepared in
this way.
P.
FROM
Rt
R4
MP, O C
Ref
H
H
Me
H
H
H
Me
H
H
Me
H
H
Me
H
Ph
Bu
PhCHzSCHa
PhCHzSCH1
253-256
245-248
199-200
270
114 (EtOH)
175
154
154
154
154
183
272
176
154
183
183
H
H
RIRaC-CRaR3
RdRsC-CRzRa
I
O\ JN
194
59 (EtOH)
107 (EtOH)
0-AMINO
CHLOROFORMATES
2-Oxaxolidone is obtained by heating an amino

chloroformate with aqueous potassium hydroxide
(Eq 47) (231). This is the sole example of the reaction.
KOH. O$
H20:2yk
\o
/
y=o
R CCl
CI-C-OCHZCHZNH~
It
H~c-C-CH~
OIN
,"
Fi
-NHn
O\
(Eq 47)
R3
H~c-C-CH~
I I
mp 90"
bp 152"(0.4mm)
)o
0 N-C=O
//
C
8 / \
Q. FROM OXAZOLTNES A N D
HzO R
OXAZOLINONES (TABLE XXXVII)
Hf shift,
H-0
I n one case (477), an oxazolinone was reduced to an

oxaxolidone with hydrogen at atmospheric pressure
and room temperature employing a palladium-oncarbon catalyst (Eq 48).
HZ
CH==CMe
A A-P~
\C'
d
-+Pd-C
CHz-CH-Me
(Eq48)
A-Ph
\C/
mp 5252.5' (EtzO)
Another special reaction type is the conversion of 2amino- or 2-alkyl-2-oxaxolines to 2-oxaxolidones by

refluxing in water (Eq49 and 50) (426,441,442).
R.
FROM 2-IMINOOXAZOLIDINES
(TABLE XXXVIII)
2-Iminooxazolidines are converted to 2-oxazolidones

by hydrolysis with sulfuric or nitrous acid (154, 176)
(Eq 51)
ZOXAZOLIDONES
225
TABLEXXXIX
2-OXAZOLIDONES (MISCELLANEOUS)
%
Empirical
formula
CaH7NOz
CsHsN20zSCl
CiiH1rN0a
CisHsoNzO4
C2iHisNOz
R4
MP,'C
R1
R1
RI
H
4C1-3-(HzNSOz)CeH~
Me
Me
MezN(CH2)20C0
MeZN(CH~)zOCO
MezNCH2CHa
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
MegN(CH~)20CO
MezN(CHz)zOCO
MezN(CH&OCO
MezN(CH&OCO
MeZN(CH~)ZOCO
MezN(CH2)2NHC0
MezN(CHz)zOCO
Me2N(CH&OCO
Me2N(CH2)20C0
MezN (CHz),OCO
Me.N (CHZ)ZOCO
EtaN (CH2)zOCO
Me
Me
p-MeOC6H4CHz
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
PhOCHzCHz
Me
Ph
MezN(CHz)zOCO
MezN(CHz)zOCO
a-Naphthylmethylene
Me
trans-2-Decahydronaphthyl
cis-2-Decahydronaphthyl
Ph
R1
Me
H
m-MeOCeH4
p-MeOCcH4
N-Morpholinomethyl
-(CHz)dCHCl-(CHz)5Ph
H
H
H
H
H
. I .
182-183
oily
72-75
205-206 (MeZCO)
...
H
-(CH2)4CHMe-(CH2)&HMe(CHz)z-(CHz)aCHMeCHz-(CHz)2CH(OMe)(CHz)2-( CH2)aCH(0Me)-(CHz)3CHMeCHz-(CH.)r
-CH~CHMeCHzCHMeCHz-CH&HMeCHMe(CHz)z-(CHk)zCHEt(CHz)z-(CHz)zCMe2(CH~)~-(CHz)3CHMeCHzm-PhCHzOCeH4
H
p-PhCHzOCJIa
H
Ph
H
90
..
..
..
..
70
75
51
54
60
77
434
cis, 117-118
trans, 120-125
55
57
609
609
125-126
..
334
182-183
..
334
...
...
...
...
...
...
...
65-66 (EtOH)
101-102
Cis
trans
cis, 55-57
trans, 113-115
...
55
72
57
50
67
89
61
42
40
34
70
82
75
75
73
56
50
Ref
280
280
527
527
374
434
434
609
609
434
434
434
434
434
434
434
434
434
434
434
434
527
527
609
609
609
609
434
HCl salt, 205 (EtOH)

(cis)
(trans)
H
H
yield
..
Structure
0 vS-R
I/
H +-H20
RdRsC--CRzRa
I
I
0
NRi
C'
RIR~C-CRZR~
NRI
C'
I1
NH
S.
T.
(Eq 51)
FROM 2-IMINO-1,3-DIOXOLANE
The literature cites one case (217) of a 2-phenylimino1,3-dioxolane rearranging to form a 2-oxazolidone when
treated with lithium chloride (Eq 52)
MISCELLANEOUS (TABLE XXXIX)
There are a number of preparations of 2-oxazoIidones

given in the literature in which the method of cyclization or the starting material, or both, is unclear.
These miscellaneous preparations are placed together
in Table XXXIX, although some of the compounds
may be listed in earlier tables if their preparation has
been clearly described.
111. REACTIONS
O F 2-OXAZOLIDONES
A.
DECOMPOSITION AND RING-OPENING REACTIONS
1.
Reactions with Bases
a. With Hydroxylic Bases

Hydrolysis with sodium hydroxide or potassium hydroxide yields a p-amino alcohol (Eq 53). These

SWERN
226
R~RGC-CR~R~
d\
OH +
+ cO3*-
R~RGC-CRZR~
NRl
A '
(Eq 53)
Reaction with hydrazine yields a semicarbazide

(607). The reaction proceeds in 90% yield in the case
of cis-4-methyl-5-phenyl-2-oxazolidoneand is reported
to be stereospecific (Eq 57).
H NHRi
CI
hydrolyses are commonly carried out in aqueous

(5, 21, 212, 332, 610) or alcoholic (5, 479, 589) systems,
although potassium hydroxide in dioxane has also been
used (211). Generally, alkaline hydrolyses have been
used to prove structure or to establish stereochemistry
(5,21, 107,209-212,221,235,325,479,609).
An interesting decomposition occurs when an amidesubstituted 2-oxazolidone is attacked by aqueous base
(Eq 54) (235).
0
R I R . & G C R ~11 -/*
T H ~ H10_
OH'
ASAH
R, Rs
f0
R3-CHCOOH
NH3
COS'- (Eq54)
2"
b. With Lithium Aluminum Hydride

Reduction of 2-oxazolidones with lithium aluminum
hydride yields the corresponding p-amino alcohols
(321,325,376,608). The reaction is stereospecific (608).
c. With Nitrogenous Bases and Ammonia
When 2-oxazolidones are attacked by equimolar
amounts of primary aliphatic amines, the major
product is an N,N'-disubstituted urea (370, 371)
(Eq 55)
RIR~C-CR~R~
C''
NRI
I
+ RNHz
d. With Hydrazine
R4RbC-CRtR3
bH
(Eq 55)
I!JR1
L o
I
NHR
When aromatic primary amines or araliphatic amines

are used, such as benzylamine, the products of ring
opening are an N,N'-disubstituted urea and a 2imidazolidone.
When 2-oxazolidone itself is treated with aqueous
ammonia, 0-aminoethyl carbamate is the product
(Eq 56) (536).
e. Alkaline Decomposition of
N-Nitr0~0-2-0xazolidone~
The pioneering work was done by Gabriel (190) who
observed that iT-nitroso-2-oxazolidone on heating
with strong base gave acetylene, carbon dioxide, nitrogen, and water. Later investigators found that Nnitrosooxazolidones substituted in the 5-position yielded
a mixture of products including acetylenes, ketones,
aldehydes, and vinyl ethers (156,351,383,384).
When the N-nitroso-2-oxazolidone was substituted
a t the 4-position, reaction with hydroxide ion yielded
aldehydes, alcohols, and carbonates (156,382).
With p-anisidine or p-phenetidine, the products of
decomposition of N-nitroso-2-oxazolidone were 2p-anisyl- (or phenetidyl-) aninoethyl N-p-anisyl-(or
phenetidyl-) carbamate and N,N'-di-p-anisyl- (or phenetidyl-) ethylenediamine, plus carbon dioxide, nitrogen,
and traces of acetaldehyde and acetylene (342).
With benzylamine in ethanol, N-nitroso-Boxazolidone yielded ethylene glycol bis-N-benzylcarbamate,
2-benzylaminoethyl N-benzylcarbamate, 2-hydroxyethyl N-benzylcarbamate, and N,N'-dibenzylethylenediamine, together with traces of benzyl alcohol
(99)*
6. Reactions with Acids

When concentrated or dilute aqueous hydrochloric
acid is used to decompose 2-oxazolidones, the products
are hydrochlorides of 0-amino alcohols (28, 41, 55, 224,
257, 283, 357, 419, 527, 598) ; with anhydrous gaseous
hydrogen chloride, the product is the hydrochloride
of ap-chloramine (56,515,559).
3. Pyrolytic Decomposition
H2C- CH2
a. N-Nitroso-2-oxazolidones
Pyrolysis of N-nitroso-substituted oxazolidones
has given evidence of evolution of carbon dioxide,
carbon monoxide, and nitrogen. The chief nongaseous
products are the parent oxazolidone, as well as aldehydes and ketones in smaller amounts (156, 382, 591).
Other studies suggest that acetylenes and ethylenes
are also formed (385).
2-OXAZOLIDOKES
b.
Other 2-Oxazolidones
When 2-oxazolidone itself is heated, carbon dioxide

is evolved and polyethylenimine is formed (110, 278,
486, 518). If, however, an amine, such as triethanolamine (51G), or a polyamide (486) is present, polymerization is prevented and a smooth decomposition
into ethylenimine and carbon dioxide ensues.
IT-Dodecyl-2-oxazolidone heated in vacuo evolves
carbon dioxide and affords a polymer (531). NAmino-2-oxasolidone heated to 175 forms polyethylenehydrasine and evolves carbon dioxide (167). Other
N-substituted 2-oxazolidones are believed to produce
low molecular weight polymers of the corresponding
ethylenimine upon pyrolysis (396).
Only one study of the kinetics of pyrolytic decarboxylation of 2-oxazolidones is reported (397). Apparently the fission of the nitrogen-carbon bond of the
urethan group is the rate-determining step.
227
Kitration has been accomplished with nitric acid in

both sulfuric acid (GO, 90) and acetic anhydride (90).
The nitro group has been reduced to the amine electrolytically (195), by hydrogenation in the presence of
platinum oxide in acid medium (195, 2 0 3 , and by
reaction TTith zinc and hydrochloric acid (425).
4. Reaction with Carbonyl Compounds

(Table X L I I I )
2-Oxazolidones react with carbonyl compounds in
the presence of added amine in a manner analogous to
the RIannich reaction (34) (Eq 58). I n the absence
of added amine, a second molecule of oxazolidone serves
I
as the amine (Eq 58, RRSH = OCOCH2CH2S-).

In one recorded instance a hydroxy compound is produced (57).
RaRsC-CR2RS
1
+ RRC=O + RRNH
4. Miscellaneous Decompositions
4-iLIethyl4-hydroxymethyl-2-oxazolidone on treatment with phosgene in dioxane is reported to yield the
carbamate (417).
B.
SUBSTITUTION ON THE RING
C
\
1. Alkylation at Nitrogen (Table X L )
II
Alkylation at the ring nitrogen has been effected in

various ways, but usually under basic conditions, thus
attesting to the acidity of the hydrogen atom attached
to the endocyclic nitrogen. Alkylations have been
carried out in the presence of potassium carbonate
(532), sodium hydroxide, sodium methoxide, sodium
hydride, sodium metal (12, 97, 419, 535, SlO), and
potassium (38). The alkylating agents have been
chlorides (97, 468, 532, 610), bromides (12, 535),
iodides (419, 478), sulfates (55, 209, 472), and even
olefins (38,326).
Another group of alkylations at nitrogen utilizes
ethers as the alkylating agents, together with such
catalysts as benzoic acid with mercuric acetate (576),
benzyl alcohol with mercuric acetate (5SGa), mercuric
acetate alone (5SG), sulfuric acid (413)) and hydrochloric and sulfuric acids (241).
The sodio derivative of substituted 2-oxazolidones

reacts with phosphorus oxychloride in dimethylformamide under nitrogen to give substituted phosphorus
compounds of the following type (112)
2. Acylation and Carbanzylation

at Nitrogen (Table X L I )
The endocyclic nitrogen has been acylated in both
acidic (309) and basic (250) media. Carbamylation
has been effected by reaction with phosgene in basic
medium, followed by reaction with ammonia (97).
R = H , Me or Et
3. Nitrosation, Nitration, and

Amination at Nitrogen (Table X L I I )
Xitrosation has been carried out with nitrous acid
(156, 381, 382, 425) and nitrosyl chloride (133, 382).
5. Reaction with Aryl Isocyanates

(Table X L I V )
Reaction of substituted 2-oxazolidones with aryl

isocyanates in the presence of pyridine or triethylamine
yields 2-oxazolidone-3-carbanilides (Eq 59) (487).
R4R&-CR*Ra
I
I
0
NH
C/
+ ArNCO
R4RsC-CR2Rs
I
o
C
/
I1
TS-CONHA~
I1
(Eq 59)
6. Reaction with Phosphorus Compounds
C.
REACTIOKS O F GROUPS ON THE RING
Although many reactions do not involve the 2oxazolidone ring itself, they are included here for the
sake of completeness.
MARTINE. DYENAXD DAKIELSWERN

TABLEXL
N-ALKYLATED
2-OXAZOLIDONES
%
Ri
RZ
CHFCH
HOCHzCHz
NCCH=CH
HC=CCH2
NCCH2CHz
CH2=CH
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
Me
HCECCHZ
CH?=CHCHz
CHFCH
CHFCHCHP
CHFCHCH~
hf e
Me
PhCHz
Me
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Et
Et
Me
Et
EtlNCHy
H
Ph
Me
H
H
H
H
Me
Et
H
H
H
Me
Isoamyl
CHI=CH
Me
Me
Me
Me
CHeCHCHz
Et
Me
Me
Me
Me
Me
Et
p-N-Pyrrolidinoethyl
p-N-Morpholinoethyl
Me
Me
8-N-Piperidinoethyl
Me
H
H
H
H
H
H
H
Rs
R4
BP (mm) or mp, O C
76.5-78.0 (0.5),
90-96 (1-2)
68-69 (0.39-0.40)
Oil
78-81 (1.3)
105-108 (2.5)
128-132 (24)
35-36 (EtOH-HzO)
80 (0.4)
82-90 (0.7)
Ref
yield
28
..
, .
..
93
86
51
.
..
,
45
..
..
586, 586a
332
468
535
326
38,413,586,
586a
97
535
539
586
539
539
97
478
532
97
92-94 (0.3)
HI salt, 160.5-161.5
78
68
68
110-115 (0.029)
72
209
RIe
H
H
H
H
H
Me
H
Et
H
H
H
H
H
H
102- 104 (0.3)

79.5-80.5
79-81
75
25
75 (Et2O)
78
H
H
H
H
H
H
Me
Me
Ph
O-CIC~H~OCHI
m-ClCeH4OCHz
p-MeOCsH40CHz
m-MeOCeH40CH~
Me
Ph
Ph
nt-MeCeH40CH2
o-MeOCaH40CH,
p-hfeOCeH40CHz
3,4-(MeO)zCaHa
o-MeOCeH40CHz
Ph
97
586
12
12
55
55
539
589
97
12
12
12
419
12
610
Me
Ph
cis, 86-89; trans, 60-62
H
H
H
101-102 (EtOH)
6 5 4 6 (dil EtOH)
cas, 95-96; trans, 49-52
76
80
.,
55
55
610
118-120 (ELO-MeOH)
96
472
168-169 (i-PrOH)
..
30
223.5
54
241
576
Me
H
H
Me
H
3,4- (Me0)~CeHa
...
...
141-142 (0.25)
73.5
72.5-75 (CeHe-EtzO)
...
...
175-178 (0.1)
trans, 126-128
..
..
..
..
.
..
44
78
..
..
..
..
..
..
..
610
Structure
Me
198-199 (Me&O)
229
2-OXAZOLIDONES
TABLEXLI
N-ACYLATED
AND CARBAMYLATED 2-OXAZOLIDONES
%
RI
Rz
Ra
R4
Rs
MeCO
CHFCH
HzNCO
MeCO
EtOCO
HzNCO
MeaCCO
HzNCO
H2NCO
MeCO
Me2CHCH2C0
HzNCO
HzNCO
HzNCO
MeCO
H
H
H
H
H
H
H
Me
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
Me
H
H
H
H
H
H
Me
Me
Me
Me
Et
Me
Pr
Ph
Pr
Me
Ph
Ph
Ph
Ph
H
H
Me
Me
Me
Et
Me
H
H
H
Me
Me
Et
Ph
Ph
yield
MP, 'C
..
Ref
118-120 (EtOHj
42.5-44 (EtOH-Skellysolve B)
54-55.5 (EtrO-Skellysolve B)
82-84 (CaHa-Skellysolve B)
80-81 (Skellysolve B)
102-105 (EtOH)
132.5-133.5 (EtOH)
29.5-30 (Skellysolve B)
49.5-51 (Skellysolve B)
113-114 (EtOH)
112-113 (CsH6-Skellysolve 3)
181-185 (EtOH)
142-143 (EtOH)
54
63
68
76
250
309
97
97
97
97
97
97
97
97
97
97
97
97
97
99-100 (THFi-Pr20)
88
211
69-70 (Skellysolve B-EGO)
14
48
75
79
78
48
55
67
80
70
Structure
MeC
TABLEXLII
N-NITROSO-,
N-NITRO-,AND N-hlN0-2-OXAZOLIDONES
%
Rz
Ri
ON
Rs
Rk
R:
H
H
H
OzNOCHz
H
Me
H
Me
Me
H
H
ON
ON
H
H
H
0zNOCHz
H
Me
Et
Me
Me
H
H
-(CHz)sPh
H
MeCOOCHz
H
H
Ph
H
H
Ph
H
H
MeCOOCH2
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
Me
Me
H
H
H
H
H
H
H
H
Et
Et
-(CH2)5H
H
H
H
I1
Ph
H
H
-(CHZ)6Ph
Me
H
H
Ph
Et
Ph
Ph
Ph
H
ON
ON
Ph
Ph
Ph
Ph
H
Ph
OzN
HzN
0zN
ON
ON
ON
0zN
HzN
ON
ON
ON
ON
ON
OzN
ON
ON
ON
ON
1. Reaction of N-Amino Groups
a. Reaction with Carbonyl Compounds

and Carbonyl Precursors (Table XLV)
Heating N-amino-2-oxazolidones with carbonyl compounds in a solvent produces Schiff bases (275, 301,
418, 522, 524) (Eq 60). I n only one case was a catalyst used (ZnC12)(418).
Besides the free carbonyl compounds, the diacetate
(234, 307, 402) and the oxime (204) have been used.
H
H
Bp (mm) or mp,
100
Ref
yield
OC
383,425
195
195,425
60
383
156,382
156,382
201
201
383
381,383
156,382
156,382
383
90
383
383
156,382
383
383
383
383
156,382
383
* .
...
..
55
30
71
70
84
69-71 (EtOH)
122-123
87.9-89.8
95.8-96.4
110 (1)
...
..
..
130-135 (10)
...
*.
82.5-83.2
107.5-108.5
83.8-84.6
76.5-77.5
97.1-97 .8
82.6-83.5
116.5-1 17.4
84.6-86.0
94
99
80
77
107.5-108.5
eruthro, 115.2-117.5
threo, 106.5-108.0
100.2-101.0
115.8-1 17.5
92
89
91
91
91
..
93
97
98
*.
Reactions have also been conduced on benzylideneamino (142), methyleneamino (234, 402), and acetylamino derivatives (234) of the oxaxolidone.
R4RsC-CRzRa
I
+ RiCH=O
-.+
R~R~C-CRZR~
I
b
C'
N-N-CHR~
/I
230
TABLEXLIII
REACTION
PRODUCTS O F 2-OXAZOLIDONES WITH C.4RBONYL
/O
Substitution a t 3-position
Bp (mm) or mp, O C
ChCCH(0H)
MezNCHz
N-Pyrrolidinomethyl
EtzNCHz
BuzNCHz
PhCHzN(Me,)CHz
R4RsC-CRzR3
01
134-136 (CC14)
90 (0.2)
123 (0.2)
107 (0.2)
130-132 (0.4)
152
RzR~C-CR~R~
yield
Ref
57
34
34
34
34
34
so80
..
A d
N1-CH-
RI
\C/
/I
0
Empiricd
formulaC
COMPOUNDS
m
Empirical
formula"
\C/
8
%
Mp,
R4
H
Me
H
H
H
Me
H
H
H
H
H
H
H
o c
yield
H
H
clsc
OCH
Me
Me
CHz=CH
Et
MeCH=CH
Zfuryl
99-100 (EtOAc)
91
129-134 (HzO)
197 dec
152-155
195.5-198.5 (MeOH)
Oil
123-1 26
55
Ph
PhCH=CH
96-98
125-127 (MeOH)
128
Oil
i38- 141
n-Bu
..
93
..
..
Ref
258
2.58
_.
~
258
258
258
258
258
258
258
258
258
258
258
TABLE
XLIV
2-OXAZOLIDONES AND ARYLISOCYANATES (487)
2-OXAZOLIDONE-3-CARBANILIDES FROM
%
R4
RE
MP, 'C
yield
H
H
H
H
Me
H
H
H
Me
Me
H
Me
Et
Me
114-115
130-132
139-140
143-144
152-153
113-114
138-139
82
40
76
50
69
57
37
195-1 97
Structure
b.
Other Reactions (Table XLVI)
Reaction of the N-amino group with potassium thiocyanate gives substituted thioureas (150, 151). With
acetic anhydride acetamides are obtained (233) and
with acid chlorides other amides result (453).
2. Elimination Reactions to
Produce N-Vinyl Groups
N-~-Chloroethyl-2-oxazolidone has been dehydrohalogenated with sodium oxide in benzede (23) or with
potassium &butoxide (218) to give N-vinyl-2-oxazolidone: mp 15", bp 70" (0.1 mm), 100-105" (1.3 mm).
Pyrolysis of N-(p-acetoxyethyl)-2-oxazolidone (299)
eliminates acetic acid, also giving the N-vinyl derivative in 71% yield.
Heating di(2-oxazolidon-3-y1)methylmethane under
reduced pressure alone oi- in the presence of catalysts,
such as aluminum chloride or zinc chloride, gives
vinyl-2-oxazolidone in 42y0 yield (259). The same decomposition has been effected with zinc oxide or with
y-collidine (573) on the 5-methyl-2-oxazolidone derivative to give the corresponding N-vinyl compounds.
3. Reactions of N-Vinyl Groups
N-Vinyl-2-oxazolidones undergo addition and polymerization reactions. Thus Diels-Alder reaction with
231
2-OXAZOLIDONES
hexachlorocyclopentadiene yields the adducts shown in

Eq 61 (438).
c1
Rn
0 NCH=CHz
0 NCH=CHz
\ /
C
IIII
0
++
"'e1
c1
c1
C1
c1
E.
FORMATION O F MOLECULAR COMPLEXES
2-Oxazolidones form molecular complexes with the

halogens (84, 193, 213, 541, 572), with IBr (541),
with sulfur trioxide (480), and with 5-nitro-Zfuraldehyde (202). The sulfur trioxide complex (480) can
be used as a sulfonation reagent for compounds sensitive to oxidation. The complex with 5-nitro-2-furaldehyde has a characteristic ultraviolet absorption at
310 mp.
IV. PHYSICAL
CHEMISTRY
AND PROPERTIES
A.
PROPERTIES
In general, 2-oxazolidones are stable solids (104,

109). The parent compound is water soluble and
forms an essentially neutral solution.
Benzenesulfonamide and p-toluenesulfonamide have
The five-membered ring is not readily reduced by
been added to the N-vinyl group (Eq 62) (242).
sodium in alcohol. It can be nitrated with nitric acidsulfuric acid mixtures, and it is not attacked by phosI
h
M
e
phorus
trichloride (109). Its basicity
is so slight that
0 NCH=CHz + H2NSOzCeHdR
w
neither hydrochlorides nor picrates can be isolated.
I1
It does not react with bromine (250).
R = H, mp 172-174'
R = Me, mp 219-221'
R = Et, mp 153.0-153.5"
mMe
0, ,N-CHNHSO&JHIR
(Eq62)
CH3
=
=
H, mp 145-148 (93% yield)

p-Me, mp 151-153' (91% yield)
Poly(S-vinyl-2-oxazolidone) is formed in 98% yield

by polymerization of the monomer with azobis(isobutyronitrile) as initiator (299).
N-Vinyl-2-oxazolidone reacts with 2-oxazolidone to
yield N,N'-ethylidenebis(2-oxazolidone) (299). The
N-vinyl derivative is sensitive to aqueous acids,
yielding 2-oxazolidone readily (299).
4. Miscellaneous Reaction Products

A miscellaneous group of reaction products is listed
in Table XLVII.
D. O T H E R REACTIONS O F THE R I N G
I n an early paper (191), it is reported that 2-oxazolidone reacts with aniline to form water, 3-phenyl-2oxazolidone, mp 124O , and l-phenyl-2-imidazolidone,
mp 157-158". More recent papers (193, 340) describe
the synthesis of 1-benzyl-2-imidazolidone in 17% yield
from 2-oxazolidone and benzylamine.
Reaction of N-substituted 2-oxazolidones with organic isocyanates yields N,N'-disubstituted 2-imidazolidones (Eq 63) (31). The reaction is catalyzed by
lithium chloride and is accompanied by evolution of
carbon dioxide.
0,,NRi
RNCO
RN, ,NRi
90
SPECTRAL CHARACTERISTICS
1. Infrared
0
R
R
B.
COz
(Eq63)
A number of studies have been published on the infrared characteristics of 2-oxazolidones (223, 344, 345,
421, 422). A larger number of papers have reported
characteristic infrared bands of the 2-oxazolidone ring
incidental to other work (50, 111, 240, 256, 275, 304,
386, 441, 442, 471, 477, 592). The carbonyl absorption is generally of fairly high energy, usually falling in
the range 1740-1810 cm-' and very often at wavenumbers above 1760 cm-'. I n addition it is reported
that the 2-oxazolidone ring has a characteristic absorption band a t 1029-1059 cm-' (421,422). Unpublished
work in this laboratory has shown that 2-oxazolidone
and other 2-oxazolidones with no substituent group on
nitrogen show a weak doublet in the 3200-3500-cm-'
region, suggesting that they may exist as a mixture of
keto and enol forms.
Ultraviolet
Most activity has centered about the pharmaceutically important nitrofurans and compounds related
to them chemically (153, 159-161, 202, 327). Ultraviolet data have been reported for a 2-oxazolidone
moiety attached to a steroidal nucleus (353).
2.
3. Nuclear Magnetic Resonance

There is a paucity of nuclear magnetic resonance
data, though a few fairly detailed analyses have been
made (255, 353, 482, 504). One study used nmr to
establish the configuration of the diastereomeric 2oxazolidone derivatives of the ephedrines (255).

SWERN
232
TABLEXLV
SCHIFF BASESFROM
N-hINO-2-OXAZOLIDONES AND CARBONYL COMPOUNDS

%
Ri
Mp OC
R4
yield
Ref
..
H
H
H
H
96 (MeOH)
179-182 (MeOH)
191-193 (MeOH)
230, 246-248, 254-256 (iPrOH)
88
90
96
188-189 (aq EtOH)
..
233,402
524
524
71,93,142,204,
234,307,402,
424,425,443,
558
85
220-222 dec (EtOH)
..
85
159-162
90
275
H
H
138-140 (50% MeOH)

227-229 (MeNOz)
71
58
524
275
H
H
246-248 deo
195-200 (MeNOz)
..
61
301
275
H
H
164-166.5 (EtOH)
212-214 (MeN02)
96
20
418
275
121 (EtOH)
..
275
N-Morpholinomethyl
N-Morpholinomethyl
N-Morpholinomethyl
N-Morpholinomethyl
200-202
209-210
204-206
164-165
84
80
522
522
208,522
522
As above
5-Methyl-2-furfurylideneamino
MezNCHz
N-Morpholiiomethyl
N-Morpholinomethyl
2 16-217
230-232
182-183 (MeOH)
93
199
199
522
O PJJcH,cH=cHcH=N
MelNCH2
120.5-121.5
..
199
N-Pyrrolidinomethy1
211-212
..
199
N-Morpholinomethyl
N-Morpholinomethyl
N-Morpholinomethyl
N-Morpholinomethyl
N-Morpholimomethyl
N-Morpholinomethyl
N-Morpholinomethyl
N-Morpholinomethyl
N-Pipendinomethyl
170- 172
122-123 (50% MeOH)
138-139 (50% MeOH)
129-130 (50% MeOH)
150-151 (50a/, MeOH)
195-198 (MezCO)
181-182 (MeOH)
174-175 (MeOH)
197-198 (EtOH)
..
o-C~C~H~CH=N
p-ClCeH4CH=N
o-BrCJI&H=N
p-BrCeH&H=N
p-ICeHdCH=N
p-OzNCeHdCH=N
~-OZNCBH*CH=N
82
53
76
84
60
95
95
199
522
522
522
522
522
522
522
203
02N
N-Morpholinomethyl
N-Morpholinomethyl
N-Morpholinomethyl
N-Morpholinomethyl
202-205
195-196
168-169
191-192
152-153
N-Morpholinomethyl
N-Morpholinomethyl
176-176.5 (CsH&PrOH)
149-1 50
o-MeOC,H40
182-184
CHFN
5-Bromo-2-furfurylideneamino
5-Iodo-2-furfurylideneamino
5-Chloromethyl-2-furfurylideneamino
5-Methyl-2-fur fur ylideneamho
5(6-Nitrovinyl)-2-furf urylideneamino
O2NJJL=CBrCH=N
5-Aldehydo-2-furfurylideneamino
02N&kH=CHCMe=N
5(8-Nitro-6-methylviny1)furfurylideneamino
5-Ethoxymethyl-2-f urfurylideneamino
5-Bromo-2-furfurylideneamino
5-Iodo-2-furfurylideneamho
ZFurfurylideneamino
02NJ J L H = C H C H = N
0 % ~
0
CH=CHCH=N
O& 4 A C H 2 C H = C H C H = N
(MeOH)
(Me2CO)
(EtOH), 206-208
(MeOH)
dec
(dioxane)
(MeOH)
(MeOH)
(50% MezCO)
..
84
..
..
..
225,301
68
68
87
522
522
522
..
70
225
522
..
301
233
2-OXAZOLIDONES
TABLE
XLV (Continued)
%
Empirical
formula"
Ci7HzzN106
' Rz
Rs
Rs
Mp OC
R4
R1
N-Piperidinomethyl
Bu~NCH~
151-152
152.5-153.5 (EtOH)
Ref
yield
..
..
199
203
H.
TABLE
XLVI
MISCELLANEOUS N-SUBSTITUTED
2-OXAZOLIDONES
%
Empirical
formula'
Ri
Ra
117
182-183 (MeOH-EtZO)
215-216 (MeOH-EtzO)
yield
..
..
..
Ref
233
453
453
H.
Rs
C.
POLAROGRAPHY
Most, if not all, of the polarographic work has

been on theN -(2-furfurylideneamino)-2-oxazolidone
system because of its pharmaceutical importance.
Much effort has been expended to discover methods
for its determination in a large variety of media (29,
181,327,510413,563,564).
D.
DIPOLE MOMENTS
A few publications have appeared on the dipole moment of 2-oxazolidone and N-acetyl-2-oxazolidone
(172, 173, 304). It has been concluded that a dipolar
structure contributes about 21% to the experimentally
found dipole moment (5.04 f 0.05 D).
v.
MP, 'C
H
MeCONH
~-HzNSOZ-~-C~C~H$~ONH H
~ - H ~ N S O Z - ~ - C I C ~ H ~ C O N H Me
CsHsNzOa
CioHioNaOsC1S
CiiHizNs06Cls
' R2
R4
DETERMINATION
O F 2-OXAZOLIDONES
Most work has been directed toward the determination of a few medicinally useful compounds in
various media. An infrared method has been developed for determining 2-oxazolidone (1l l). A titrimetric method employing silver nitrate has been reported for determining 5-methyl-2-oxazolidone (111).
Among the methods used to determine 2-oxazolidone derivatives are : spectrophotometric (69, 245,
359, 507, 553, 612), colorimetric (46, 69, 157, 244, 372,
508), reaction with indole (372), chromatographic
(69, 316), and methods based on the formation of a
phenylhydrazone (79, 236). Oxazolidones have been
analyzed in feeds (18, 19, 46, 79, 308, 315-317, 359,
509), urine (372), plasma (SO), milk (106), chicken
tissues (236), mixtures of pharmaceuticals (553, 612),
and in the presence of impurities (245).
VI. STEREOCHEMISTRY
Several of the earlier studies centered about establishing the configuration of ephedrine (96, 176, 514,
590). The assignment of configuration depended on
synthesis of 2-oxazolidones from a semicarbazide (514),
a P-amino alcohol plus urea (96), a P-hydroxyhydrazide
plus nitrous acid (590), and an involved synthesis producing a 2-iminooxazolidone and its subsequent hydrolysis to a 2-oxazolidone (176).
A later scheme helped establish the configuration of
monosaccharides. It utilized the stereospecific conversion of p-amino alcohols to 2-oxazolidones by reaction with diethyl carbonate (227). Japanese workers
(261, 262) cyclized p-amino alcohols with urea and also
with phosgene in order to assign configurations to the
starting material. 2-Oxazolidones have been used to
study the difference in rate of intramolecular migration
in N-benzoylated derivatives of ephedrine and pseudoephedrine (589). Part of the proof of the absolute
configuration of rotenone depended upon the formation of known derivatives of 2-oxazolidone (375).
A study of the threo and erythro forms of threonine
employed a synthesis of 2-oxazolidones from p-amino
alcohols and phosgene together with acidic and basic
hydrolyses (284).
French workers (358) obtained the hexahydrobenzo2-oxazolidones containing both cis and trans ring fusions.
VII. APPLICATIONS
Many uses have been suggested for the 2-oxazolidones. These cannot be discussed in detail here and
will only be summarized.
A.
DRUGS AND OTHER BIOLOGICAL USES
1. Furazolidme
Considerable work has been done on Furazolidone

or 3-(5-nitro-2-furfurylideneamino)-Boxazolidone(alternate name, N-(5-nitro-2-furfurylidene)-3-amino-2oxazolidone) .
The effect of Furazolidone on poultry has been
studied extensively (49, S7, 98, 103, 114, 130, 178,
185, 273, 338, 339, 427, 433, 440, 445, 483, 502, 606)
with respect to growth, reproduction, and hatchability.
Toxicity to poultry has been studied (136, 194) as

SWERN
234
TABLEXLVII
MISCELLANEOUS
REACTION
PRODUCTS
Empirical
formula
CaHsNOz
CaHtNzOz
CdHiNOa
CsHsNOzCl
C7HioNOsClzP
CiHiiNOz
C7HiiNOt
CsHiNsOs
CsHgNaOa
CsHizNOzCl
CoHioNz0~S
CoHisNOiClz
CoHirNOtSP
CoHirNOsCliP
CoHisNOz
CioHsNiOsS
CioHioNOsCl
CioHloNOrBr
CioHiiNOa
CioHisNOz
CioHisN02Clx
CioHnNOa
CioHieNOzS
CiiHizNOaCI
CiiHisNOs
CiiHisNOd
CiiHiaNOsS
CiiHisNOzClr
CizHizNOaCla
CizHiaNOaClz
CizHwNOzCIS
CizHisNOa
CizHisNOi
CizHisNOsS
CizHiiNOzClx
CisHioNOs
%
Ri
H
HzN
H
H
(MeO)zP(O)OC(=CCIz)
Me
MeCOO(CHz)z
5-Amino-2-furfurylideneamino
CICHzCHz
P-HzNCOH~SOZ
i-Pr
(EtO)iP(S)CHzCHa
(EtO)zP(O)C(=CCIz)
i-Pr
H
H
H
R:
H
H
H
ClCHz
H
R4
H
H
H
H
H
H
H
Me0
H
H
Me
H
H
H
Me
H
Me
H
H
Me
H
-CHH
H
H
H
H
H
-CHr
H
-CCIaH
H
H
H
-cHP
H
H
H
H
H
H
H
R, Bp (mm) or mp, OC
H
H
H
H
H
Me
H
H
H
Me
H
Me
H
H
Me
H
89-9 1
...
...
58-62, 98 (1)
52-54 (hexane-EtzO)
254-255 (MeNOz)
64-68
...
44-46, 96-98 (1.8)

188-192 (0.005)
...
87-9 1
173 (EtOH)
H
H
H
H
H
H
H
p-MeC8HtSOzOCHr
-cc1PH
H
H
H
H
H
H
H
pMeCsHiSOzOCHz
H
H
H
H
H
H
H
H
Me
o-CICOHIOCHZ
H
p-BrCsH4OCHz
H
PhOCHz
H
( CHz)sMe
Me
Me
Me
H
H
o-ClCaH4OCHz
Me
H
o-MeCsH4OCHi
PhOCHz
Me
m-MeOCsHdOCHz H
p-MeOCsHtOCHz H
o-MeOCsH4OCHz H
H
H
Et
Me
H
Me
H
Me
H
Me
H
Me
H
Me
hle
o-MeCsHdOCHz
o-MeOCsHdOCHx Me
o-MeOCsH4OCHz H
H
H
-(CHz)sH
H
H
H
H
p-MeCsH&OiOCHt
Me
H
H
H
Et
H
p-i-PrCsHdOCHz
H
o - M ~ O C ~ H I O C H SH
o-MeOCeHdOCHs E t
H
H
Ph
H
(a-cis)54
Ph
H
O - M ~ O C I H ~ O C HH~
Me
H
(a-tram, HCI salt) 167

(&cis, HCI salt) 151
57-58
180-200 (0.1)
Me
Bu
Bu
CHa(CHz)4SCHzCHz
H
H
H
H
H
H
H
Bu
2,4,5-ClaCeH~0CHzCHr
2,4-ClzCsHsOCHzCHz
3,4-CLCsHiOCHzCHq
p-ClCeH&CHzCHz
PhOCHzCHr
H
H
Me
H
i-Pr
Ra
-CHp
-CCI-CH-
-cch-
H
H
H
H
H
H
H
H
151-152.5
120-121
76-78
32-38, 118-120 (1)
112-114 (1)
134-136 (0.1)
135-137
120-122
112.5-114
121-123
103.5
139-141
...
117-119 (0.6)
76-79
200 (0.1)
188-208 (0.3)
...
...
99-101
88-90
72.5-75.0
155-157
>300
02N
CiaHiiNOa
CiaHiiNO4
CirHnNOsS
CisHmNzO4
CiiHzzNzO~
CiaHioNOc
Ci8HsNOzS
H
Et
H
H
MezN(CHz)zOCO
MezN(CHz)aOCO
PhCHz
CHs(CHz)iSCH&Hr
Structure or name
Me
H
H
H
H
H
120-122
175-178 (0.1)
...
...
yield
Ref
70 50,462,463
80 443
. 463
.. 13
466
75
132
95 299
83 247,346,373
30
153
132
. . 272
. . 132
. . 102
.
446
.
132
. 150
.
..
..
.
.
..
..
..
..
..
..
96
..
..
..
..
..
..
..
..
13
60
31
96
50
..
..
..
.,
..
..
..
..
..
..
..
..
..
..
84
13
13
13
13
303
303
303
13
239
476
~CH,O-cellulose
NH
OC
,/
13
13
13
132
132
132
239
13
13
13
13
13
13
13
132
239
239
239
239
239
13
13
13
13
132
152
ll
0
Poly(N-allyl-5-methyI-2-oxazolidone)
Compounds of the following type of uncertain structure
115
..
539
240
well as the usefulness of the drug against ornithosis

(113), typhoid (92, 313), Salmonella-type infections
(47, 72, 298, 416, 454, 475), leucocytozoon infection
(6), and respiratory diseases in fowl (400). Its effectiveness in the control of trypanosoma infection in
mice (70) , furunculosis in trout (428-430), treatment
of hog plague virus (192), influence on the growth of

pigs (432, 554), and control of pathogenic microorganisms in animals (281) has been studied. It is
reported to be efficacious in infectious synovitis (473,
474), coccidiosis infections (33, 67, 343) , trichonomas
infect,ions (253, 447, 493), and paratyphoid infections
235
2-OXAZOLIDONES
(8). It is reported to be effective when included in

animal feeds (14, 16, 552), as a nutritive preparation
for fish breeding (268), as an antibacterial (9, 243, 254,
330, 603, 604), as an inhibitor of the growth of Histomonas meleagmdes (252), to prevent pregnancy in mice
(267), and to treat infectious putrefactive diseases in
bees (378). Its effect on the excretion of B vitamins
in the urine (266) has been studied. It has been suggested as a radioprotectant drug in man (220), for
treating gastroenteritis in nursing infants (145), and
for the therapy of lambliasis (62).
Many of these studies deal with Furazolidone in
combination with other drugs; some deal with comparative studies (128). Since this substance is of
such importance, many methods for producing it have
been used. These have been treated in the appropriate sections dealing with the preparation of 2oxazolidones. Additionally, there have been several
studies that deal with the manufacturing aspects of
producing Furazolidone, rather than with the chemical
aspects (246,451,525).
6. Furaltadone
N- (5- nitro- 2- furfury1idene)-3- amino- 5(N- morpho linomethyl)-2-oxazolidone is known as Furaltadone or

Furoxone. Though it has not been studied as extensively as Furazolidone, Furaltadone has been proposed
as an antibacterial (73, 271, 469, 556, 605), and, more
specifically, against staphylococcus infections (186,
287, 288, 390). Its effectiveness against mastitis
(17, 436) and as an enzyme inhibitor (115) has been
studied. Its influence on gastric secretion (355),
facility of placental transfer (77), pharmacological
properties (124, 337), distribution in the rat (76),
and its value as a food additive (15) have been investigated. There has been a critical evaluation of the
clinical and laboratory studies of Furaltadone (336)
and several papers dealing with its manufacture (302,
490,521).
3. Methoxadone
While the two substances discussed above find
their major uses in controlling infection, 5-(o-methoxyphenoxymethyl)-2-oxazolidone, or Methoxadone or
Mephenoxalone, is used as a psychopharmacological
(187) or neuropharmacological (208) compound. Its
toxicity (51, Sol), pharmacological activity (89, 95,
349, 601), metabolic fate (356), adrenolytic action (a),
synergistic action with morphine, codeine, and the like
(174), effect on reproduction (500), and its effect on
blood pressure and behavioral responses (3) have been
studied.
4. Other Substances
The medicinal properties of a number of other derivatives of 2-oxazolidone have been studied. Their anti-
bacterial (1, 45, 68, 71, 83, 86, 151, 168, 203, 242, 293,
301, 354, 423, 443, 444, 506, 557, 566, 572, 593), antimicrobial (10, 142, 197, 199, 200, 388, 391, 402, 418,
572), antiseptic (206), antibiotic (20, 63, 94, 234),
antimetabolic (52, SS), antimitotic (546, 547), antianthelmintic (151,239,241,242,576), antiinflammatory
(303), antipyretic (4, 20, 518), anticonvulsant (20,
97, 319, 324), and antiprotozoal (175) activities have
been studied. Their effect on reproduction (411),
toxicity (401, 405), vasomotor effects (82), lymphatic
transport (78), metabolic degradation (292, 409) , and
excretion (416) have been reported. They have been
suggested as chemotherapeutic agents (347, 414, 435),
as growth promotors (53, 207, 408), as skeletal muscle
relaxants (318, 322, 323, 350), as hypotensives (155),
and as effective against organisms causing enteriocolitus (294) , Trichomonas vaginalis (450), pig ascarides
(4S7), and hepatic cirrhosis (449). They have been
found to have analgesic activity (20, 175, 303, 518),
t o inhibit swelling (43), and t o serve as central nervous
system relaxants (300, 335) , central nervous system depressants (108, 320), vasoconstrictors (527), tranquilizers (12), and strychnine antagonists (321).
They have been suggested as fungicides (131, 132,
239, 241, 242, 468), insecticides (102, 112, 132, 239,
241, 242), herbicides (132, 133, 239,438, 468, 487, 595),
parasiticides (150, 576), nematicides (239, 468), and
germicides (213, 275). They have been found effective
in plant growth retardation (456, 582)) as defoliating
agents (61, 311), and as growth stimulants (58, 64).
B.
POLYMERS
Derivatives of 2-oxazolidone have been polymerized

(11, 24, 39, 40, 125-127, 139, 140, 143, 144, 146, 149,
158, 222, 237, 289, 291, 394, 460, 485, 489, 494, 519,
537, 539,440,542,570,571,577,578,580,583485,587,
594, 596, 597) and copolymerized (25, 26, 65, 91, 129,
131, 138, 188, 228, 229, 238, 270, 291, 348, 352, 360365, 412, 467, 488, 499, 517, 538, 569, 574, 577, 579).
In this connection, two studies report reactivity ratios
for copolymers containing 2-oxazolidone derivatives
(65,229).
The polymers have been suggested for many uses:
fibers (362, 365), tablet coatings (270, 519, 594), lubricant additives (91, 180, 291), cigarette filters (488,
537), ore clarification (517), rust inhibition (131),
as components of photographic emulsions (125, 127,
146, 289), drilling muds (129), and hydraulic cements
(569), as dye assistants for textiles (139, 158, 585),
as dye-stripping compositions (539, 583), in the prevention of interfilamentary sticking (489) and bleeding
of dyes (584), in hair-setting compositions (542), in
propellants (540), in beverage clarification (539, 578),
as water-soluble polymers (11, 140, 237, 580), in emulsification of silicone oils (348), and in preparations of
thermoplastic foams (494).

SWERN
236
C.
MISCELLANEOUS
Derivatives of 2-oxazolidone have been suggested

for the following uses: blowing agents (460), paper
impregnation (596), extraction of hydrocarbons (387,
446, 496), solvents for polymers (311, 581), plasticizers
(20, 81, 134, 239, 398), beverage clarification (162),
metal coating (439), corrosion inhibition (133, 535),
emulsifiers (239), bleaches (572), flame retarders
(112), crease-resistance in textiles (112, 232), antistatic
treatment of fibers (555), dyeing aids (137, 399, 602))
laundering aids (568)) waterproofing for textiles (551),
sulfonation reagents (480), nitrating reagents (249),
source of polyethylene polyamine (394), formation
of polyester amides (392), and as a monoamine oxidase
inhibitor (282).
ACKNOTYLEDGMENT.--Martin
E. Dyen was supported
partially under a Training Grant Award 520-831 from
the National Aeronautics and Space Administration,
This work was also supported in part by Public Health
Service Research Grants No. CA-07803 and CA07174 of the National Cancer Institute.
vm
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244
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246

SWERN
IX. ADDENDUM
I n the period from January 1,1966, to May 23,1966,

the following references have come to our attention.
The designations in parentheses refer to the related
section or sections in the present paper.
It is noteworthy that Hickner and Bolme claim to
have alkylated the 2-oxazolidone ring at nitrogen by
use of alkylene oxides in the presence of strong base.
This is the first reported instance of such a reaction.
Gulbins and Hamann report the synthesis of 2-oxazolidones from cyclic ethylene carbonates and aromatic
amines or diacyl-substituted ureas. I n both cases
lithium chloride catalyzes the reaction; in the former
case, potassium or sodium hydroxide may also be used.
I n two patents Ham reports the synthesis of 2-oxazolidones by rearrangement of 2-alkoxy-2-oxazolines in
inert solvents with catalytic amounts of alkyl halides.
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(A23) Tousignant, W. F., and Sovich, R. C., U. S. Patent
3,226,372 (Dec 28, 1965); Chem.Abstr., 64,8187 (1966)
(IIIB1, 11%).
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C h .Abstr., 64,15812 (1966) (IIB1).
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C'hem. Abstr., 64, 9731 (1966) (IIH1).

2 Oxazolidinones

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2-OXAZOLIDONES

AND DANIEL SWERN

I. Introduction and Nomenclature. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

P. From P-Amino Chloroformates. . . .

E. Formation of Molecular Complexes

A. Drug and Other Biological Uses. . . .

NASA Predoctoral Fellow, Temple University.

on 2-oxazolidones up to 1956, but his latest reported

MARTINE. DYENAND DANIELSWERN

220-222 dec (70%

77.5-78.5 (i-PrzO), 180-195

Camphane Derivatives (224)

practical number. A tautomeric form can also be

A standard designation for substituents on the parent

2-Oxazolidones can be looked upon as a two-carbon

amino groups on adjacent carbon atoms (404). There

One of the first reported and most general syntheses

Studies have shown that the addition of phosgene

1. Using Phosgene (Table I)

MARTINE. DYENAND DANIEL

terial (262). Thus, threo- and erythro-p-amino alcohols

2. Using Dialkyl Carbonates (Table 11)

Historically one of the earliest and certainly one of

As a variant the cyclic carbonate, ethylene carbonate,

Using Carbon Dioxide (Table 111)

Gaseous carbon dioxide has been used to produce

4. Using Urea (Table I V )

It is reported that 2-oxazolidones are also obtained

87-89 (CHCls), 90-91 (ligroin), 87

109-110 (MezCO, then EtOH)

98.2-99.3 (0.5), 94 (1)

170-171, 138.5 (1.8)

33-34, 151-153 (4), 128-131

MARTINE. DYENAND DANIELSWERN

Bp (mm) or mp, "C

78-80 (pet. ether-CsHs)

densation with elimination of water after fusion

6. Use of Isocyanates (Table V )

Use of Ethyl Chlorocarbonate

MARTINE. DYENAND DANIEL

Stereochemical studies have not been reported other

Use of Esters of Trichloroacetic

of added catalysts or elevated temperatures. One

AMINO ALCOHOLSAND ETHYLCHLOROCARBONATE

Bp (mm) or mp, "C

Use of Miscellaneous Cyclizing

MARTINE. DYENAND DANIELSWERN

a few 2-oxazolidones have been prepared by this

Two groups of workers have reported the use of

N,N-carbodiimidazole as the cyclizing reagent (Eq

ACIDS (TABLE IX)

The feasibility of synthesizing 2-oxazolidones from

c. Cyanogen Bromide and Base

The p-amino alcohol, diethanolamine, has been

HOCH2CHzNHCSSC02Me+ CHz- CH2d CH

ACIDS AND INORGANIC

Gabriel (189) was the first to prepare 2-oxazolidone.

Only a modest amount of work has been reported