Carbon dioxide as a carbonylating agent in the synthesis of 2-oxazolidinones, 2-oxazinones, and cyclic ureas: Scope and limitations

Article abstract of DOI:10.1021/jo100268n

Carbon dioxide can be used as a convenient carbonylating agent in the synthesis of 2-oxazolidinones, 2-oxazinones, and cyclic ureas. The transient carbamate anion generated by treating a primary or secondary amine group in basic media can be activated with phosphorylating agents such as Diphenylphosphoryl azide (DPPA) and Diphenyl chlorophosphate (DPPCl) but also with other types of electrophiles such as SOCl₂, TsCl, or AcCl. The intramolecular trapping of the activated carbamate by a hydroxyl group leads to the formation of 2-oxazolidinones or 2-oxazinones in good to excellent yields. This methodology was successfully applied to the synthesis of cyclic ureas up to 7-membered rings from the corresponding diamines.

Full text of DOI:10.1021/jo100268n

pubs.acs.org/joc
Carbon Dioxide as a Carbonylating Agent in the Synthesis of
2-Oxazolidinones, 2-Oxazinones, and Cyclic Ureas:
Scope and Limitations
ꢀ
Jairo Paz, Carlos Perez-Balado, Beatriz Iglesias, and Luis Munoz*
~
´
ꢀ
´
Departamento de Quımica Organica, Facultade de Quımica, Universidade de Vigo
Campus Universitario, 36310 Vigo, Spain
lmunoz@uvigo.es
Received February 19, 2010
Carbon dioxide can be used as a convenient carbonylating agent in the synthesis of 2-oxazolidinones,
2-oxazinones, and cyclic ureas. The transient carbamate anion generated by treating a primary or
secondary amine group in basic media can be activated with phosphorylating agents such as
Diphenylphosphoryl azide (DPPA) and Diphenyl chlorophosphate (DPPCl) but also with other
types of electrophiles such as SOCl2, TsCl, or AcCl. The intramolecular trapping of the activated
carbamate by a hydroxyl group leads to the formation of 2-oxazolidinones or 2-oxazinones in good to
excellent yields. This methodology was successfully applied to the synthesis of cyclic ureas up to
7-membered rings from the corresponding diamines.
Introduction
an industrial scale. As a result of its unique properties and
ready availability, CO2 has emerged as an attractive source
of carbon that has found numerous applications.1 Among
these, the successful use of CO2 as a carbonylating agent in
the synthesis of dialkyl carbonates and ester carbamates has
shown that carbon dioxide is a convenient alternative to the
highly toxic phosgene derivatives.2 Despite the advantages of
CO2 as a carbonyl source, only a few reports on the synthesis
of 2-oxazolidinones from amino alcohols and CO2 have been
published to date. To the best of our knowledge, Kodaka and
co-workers reported the first synthesis of 2-oxazolidinones
The continuing search for safe, environmentally friendly,
and inexpensive reagents is one of the driving forces in
organic chemistry and has contributed a great deal to the
development of efficient synthetic routes that are feasible on
(1) For selected reviews and articles, see: (a) Kobayashi, K.; Kondo, Y.
Org. Lett. 2009, 11, 2035. (b) Sakakura, T.; Choi, J.-C.; Yasuda, H. Chem.
Rev. 2007, 107, 2365. (c) Arakawa, H.; Aresta, M.; Armor, J. N.; Barteau, M.
A.; Beckman, E. J.; Bell, A. T.; Bercaw, J. E.; Creutz, C.; Dinjus, E.; Dixon,
D. A.; Domen, K.; DuBois, D. L.; Eckert, J.; Fujita, E.; Gibson, D. H.;
Goddard, W. A.; Goodman, D. W.; Keller, J.; Kubas, G. J.; Kung, H. H.;
Lyons, J. E.; Manzer, L. E.; Marks, T. J.; Morokuma, K.; Nichoras, K. M.;
Periana, R.; Que, L.; Rostrup-Nielson, J.; Sachtler, W. M. H.; Schmidt, L.
D.; Sen, A.; Somorjai, G. A.; Stair, P. C.; Stults, B. R.; Tumas, W. Chem. Rev.
2001, 101, 953. (d) Gibson, D. H. Chem. Rev. 1996, 96, 2063. (e) Braunstein,
P.; Matt, D.; Nobel, D. Chem. Rev. 1988, 88, 747.
(2) (a) McGhee, W.; Riley, D. J. Org. Chem. 1995, 60, 6205. (b) Shi, M.;
ꢀ
Shen, Y. M. Helv. Chim. Acta 2001, 84, 3357. (c) Perez, E. R.; da Silva, M. O.;
Costa, V. C.; Rodrigues-Filho, U. P.; Franco, D. W. Tetrahedron Lett. 2002,
43, 4091. (d) Chaturvedi, D.; Ray, S. Monatsh. Chem. 2006, 137, 127.
DOI: 10.1021/jo100268n
r
Published on Web 04/13/2010
J. Org. Chem. 2010, 75, 3037–3046 3037
2010 American Chemical Society

Paz et al.
JOCArticle
SCHEME 1
TABLE 1. Screening of Phosphorylating Agents
entry
1
phosphorylating agent
yield (%)
78a
diphenylphosphoryl azide (150 mol %),
NaN3 (300 mol %)
2
3
4
5
6
diphenylphosphoryl azide (100 mol %)
diphenyl chlorophosphate (100 mol %)
diethyl chlorophosphate (100 mol %)
diphenyl cyanophosphonate (150 mol %)
diethyl cyanophosphonate (100 mol %)
75a
82a
55a
87a
86b
aIsolated yield. bDetermined by 1H NMR spectroscopy.
SCHEME 2
from 1,2-amino alcohols and carbon dioxide under
Mitsunobu conditions in 1993.3 Almost at the same time,
Kubota et al. published a slightly modified procedure that
involved the use of a combination of triphenylphosphine and
CCl4.4 In 2000, Feroci’s group described the carbonylation
of 1,2-amino alcohols in the presence of an electrogenerated
base, CO2, and tosyl chloride to give 2-oxazolidinones in
good to moderate yields.5 In 2004, Dinsmore and Mercer
established the scope of the CO2-carbonylation under
Mitsunobu conditions and explored the stereochemical issues
associated with this transformation, in which the inversion
of configuration of the carbon bearing the oxygen was obser-
ved.6 Very recently, our group has reported the preparation
of 2-oxazolidinones under mild conditions from 1,2-amino
alcohols in the presence of CO2 and diverse phosphorus
electrophiles.7 We wish to report here a full account of our
research into the synthesis of 2-oxazolidinones with carbon
dioxide and several types of electrophiles. The stereochemical
outcome of the reaction has been studied, and our synthetic
strategy has been further expanded to include the preparation
of 2-oxazinones and cyclic ureas.
It is well-known that primary and secondary amines are
in equilibrium with carbamate anions 1 in the presence of
carbon dioxide under basic conditions. The generation of these
anionic species is responsible for the trapping of CO2 by these
amines, which usually requires the presence of an additional
base. Nonprotic amines such as DBU (1,8-diazabicyclo[5.4.0]-
undec-7-ene), DBN (1,5-diazabicyclo[4.3.0]non-5-ene), penta-
alkyl guanidines, or Et3N have been utilized for this purpose.
These carbamate anions are versatile species that can be used in
the synthesis of a variety of carbonylated products such as
alkyl carbamates 2,8 dialkyl ureas 3,9 carbamoyl azides 4,10 and
carbamoyl cyanides 511 (Scheme 1). The results of our investiga-
tions into the synthesis of carbamoyl azides 410 suggested that in
the presence of a phosphorus electrophile, a carbamate anion
can be eventually transformed into an activated carbonyl
species, which in turn could behave as an acylating agent in
the presence of an appropriate nucleophile. According to this
proposal, 2-oxazolidinones could be easily obtained from 1,2-
amino alcohols, CO2, and a phosphorylating agent under
basic conditions.
Results and Discussion
The conditions developed by our group for the prepara-
tion of carbamoyl azides were initially assayed with norephe-
drine 6i as a readily available 1,2-amino alcohol (Table 1).
Thus, diphenylphosphoryl azide (DPPA) was added drop-
wise to a CO2-saturated solution of norephedrine 6i in
acetonitrile at -40 °C containing 1,1,3,3-tetramethyl-2-phenyl-
guanidine (PhTMG) as a base and NaN3. The expected
4-methyl-5-phenyloxazolidin-2-one 7i was isolated in 78%
yield (Table 1, entry 1). Encouraged by this preliminary result,
we directed our attention toward the key role of the phosphor-
ylating agent and the nature of the intermediates involved in the
reaction. Although the addition of NaN3 was necessary for the
synthesis of carbamoyl azides in good yields, we found that the
2-oxazolidinone 7i was obtained in nearly the same yield when
the reaction was performed with DPPA in the absence of NaN3
(Table 1, entry 2). The use of related phosphates as carbonyl
activating agents also proved effective in the formation of the
2-oxazolidinone. Diphenyl chlorophosphate (DPPCl), the most
inexpensive reagent in the series, afforded 7i in 82% yield
(Table 1, entry 3), whereas diethyl chlorophosphate (DEPCl)
gave 7i in only moderate yield (Table 1, entry 4). In this case,
(3) Kodaka, M.; Tomohiro, T.; Okuno, H. J. Chem. Soc., Chem. Com-
mun. 1993, 81.
(4) Kubota, Y.; Kodaka, M.; Tomohiro, T.; Okuno, H. J. Chem. Soc.,
Perkin Trans. 1 1993, 5.
(5) Casadei, M. A.; Feroci, M.; Inesi, A.; Rossi, L.; Sotgiu, G. J. Org.
Chem. 2000, 65, 4759.
(6) Dinsmore, C. J.; Mercer, S. P. Org. Lett. 2004, 6, 2885.
ꢀ
~
(7) Paz, J.; Perez-Balado, C.; Iglesias, B.; Munoz, L. Synlett 2009, 395.
(8) (a) McGhee, W.; Riley, D.; Christ, K.; Pan, Y.; Parnas, B. J. Org.
Chem. 1995, 60, 2820. (b) Ion, A.; Van Doorslaer, C.; Parvulescu, V.; Jacobs,
P.; De Vos, D. Green Chem. 2008, 10, 111.
(9) Ion, A.; Parvulescu, V.; Jacobs, P.; De Vos, D. Green Chem. 2007, 9,
158.
ꢀ
ꢀ
~
a-Egido, E.; Fernandez-Suarez, M.; Munoz, L. J. Org. Chem.
~
´
(11) Garcıa-Egido, E.; Paz, J.; Iglesias, B; Munoz, L. Org. Biomol. Chem.
2009, 7, 3991.
(10) Garcı
´
2008, 73, 2909.
3038 J. Org. Chem. Vol. 75, No. 9, 2010

Paz et al.
JOCArticle
TABLE 2. Synthesis of 2-Oxazolidinones
yield (%)
entry
R1
R2
X
6
7
DPPA
DPPCl
AcCl
1
2
3
Ph
Bn
i-Pr
H
H
H
OH
OH
OH
a (2R)
b (2R)
c (2S)
a (4R)
b (4R)
c (4S)
80a
75a
75a
95b
97b
97b
94b
89b
86a
97b
4
5
6
7
t-Bu
s-Bu
H
H
H
H
OH
OH
OH
OH
d (2S)
d (4S)
74a
85a
94b
92b
76a
e (2S,3S)
f (2S)
g (2S)
e (4S,1’S)
f (4S)
g (4S)
1H-indol-3-ylmethyl
CO2Et
73a
94b
73a
82b
8
9
CO2Et
Me
Me
Ph
OH
OH
h (2S,3R)
i (1S,2R)
h (4S,5R)
i (4R,5S)
78a
96b
94a
96b
96a
97b
75a
97b
95a
73a
10
11
CO2Me
CO2Et
H
H
SH
SH
j (2R)
k (2R)
j (4R)
k (4R)
aPhTMG as a base (100-200 mol %). bEt3N as a base (200-250 mol %).
TABLE 3. Screening of Electrophiles
besides the 2-oxazolidinone, the phosphoramide 8 was isolated
(Scheme 2). Apparently, the ethoxy substituents render DEPCl
more reactive than DPPCl and the formation of the phosphor-
amide 8 competes with the generation of the carbamate anion 1
under the reaction conditions. Although diphenyl cyanopho-
sphonate is quite effective in the synthesis of 7i (87% yield,
Table 1, entry 5), it is not commercially available. Finally,
diethyl cyanophosphonate also led to the 2-oxazolidinone 7i
in good yield (Table 1, entry 6). However, the cost and the
commercial technical grade12 make this phosphonate of little
interest for synthetic purposes.
Having discovered that diphenylphosphoryl azide (DPPA)
or diphenyl chlorophosphate (DPPCl) enabled the efficient
carbonylation of norephedrine with CO2 to give the corre-
sponding 2-oxazolidinone, we continued our study by assaying
other 1,2-amino alcohols in order to study the scope of this
methodology.13 As shown in Table 2, the 2-oxazolidinones
derived from primary amines were obtained in good yields
regardless of the nature of the substituents. Even in the presence
of the secondary amino group of the tryptophan derivative 6f,
the 2-oxazolidinone 7f was obtained in 92% yield (Table 2,
entry 6). 1,2-Amino thiols derived from cysteine (6j and 6k) also
underwent carbonylation to afford the corresponding 2-thiox-
azolidinones 7j and 7k in yields similar to those of the 2-
oxazolidinones (entries 10 and 11). The initial conditions for
the formation of the 2-oxazolidinones involved the use of
DPPA (120 mol %) and PhTMG (100-120 mol %) as a base
and acetonitrile at -40 °C. In an attempt to develop a more
versatile system, we explored different reaction conditions. In
our experience, the use of PhTMG as a base is crucial for the
reactivity of some carbamate anions.10,11 However, we found
that in the synthesis of 2-oxazolidinones PhTMG can be
advantageously replaced by DBN or by the readily available
Et3N (200 mol %). This change even led to improved yields in
some cases (see Table 2, entries 1-3 and 7-9). In some other
entry
electrophile
SOCl2
MsCl
conditions
yield (%)
1
2
3
4
PhTMG (100 mol %)
PhTMG (200 mol %)
Et3N (200 mol %)
Et3N (200 mol %)
88
68
81
92
TsCl
4-nitrobenzenesulfonyl
chloride (pNsCl)
Tf2O
AcCl
AcBr
ClCO2Et
5
6
7
8
Et3N (200 mol %)
Et3N (200 mol %)
PhTMG (200 mol %)
PhTMG (200 mol %)
88
97
94
86
cases, we encountered problems regarding the solubility of
certain 1,2-amino alcohols in acetonitrile at low temperature.
In these cases, CH2Cl2 was used as a solvent to obtain a
homogeneous reaction medium.14 This switch of solvent appa-
rently did not affect the course of the reaction and gave the
corresponding 2-oxazolidinones in the same range of yields
(75-95%). To complete our survey, we tried other types of
electrophiles that could play the role of DPPA or DPPCl as
carbonyl activating agents. We were delighted to find that the
carbonylation of norephedrine 6i can be successfully performed
with a variety of sulfur and carbon electrophiles (Table 3).
Among these carbonyl activating agents, acetyl chloride (AcCl)
was especially suitable for our purposes.
It can be seen from Table 2 that the use of AcCl gave the
2-oxazolidinones 7 in comparable or even better yields than with
the phosphorus electrophiles. The simplicity and efficiency of the
new conditions were exemplified by the preparation of the 2-oxa-
zolidinone derived from norephedrine 6i on a 2 g scale using
CO2, Et3N as a base, and acetyl chloride in CH2Cl2 (91% yield).
The carbonylation of N-alkyl 1,2-amino alcohols 8 gave
the corresponding N-alkyl-2-oxazolidinones 9 in good yields
(12) Diethyl cyanophosphonate was purchased from Sigma-Aldrich as a
technical grade reagent with 90% purity.
(13) DPPA can be quantitatively prepared from DPPCl by treatment with
an excess of NaN3; see the Supporting Information.
(14) See the Supporting Information for details.
J. Org. Chem. Vol. 75, No. 9, 2010 3039

Paz et al.
JOCArticle
TABLE 4. Synthesis of N-Alkyl-2-oxazolidinones
yield (%)
entry
R1
R2
R3
R4
8
9
DPPA
DPPCl
1
2
3
4
5
6
Bn
Bn
i-Pr
s-Bu
Me
H
H
H
H
H
H
Ph
H
H
H
H
H
Ph
a (2S)
b (2S,3S)
c (2S)
d
e (2S)
f (2S)
a (4S)
b (4S,1’S)
c (4S)
d
e (4S)
f (4S)
84a
97b
3-phenylpropyl
1,3-diphenylprop-2-yl
i-Bu
83b
95b
94b
96b
49a
1H-indol-3-ylmethyl
-(CH2)3-
98a
94b
7
8
9
Et
i-Bu
Me
CO2Et
CO2Et
Me
Me
Me
Ph
H
H
H
g (2S,3R)
h (2S,3R)
i (1S,2S)
g (4S,5R)
h (4S,5R)
i (4S,5S)
77 b
70 b
72a
78b
79a
aPhTMG as a base (120 mol %). bEt3N as a base (200 mol %).
TABLE 5. N-Alkyl-2-oxazolidinones Derived from Norephedrine
when DPPA or DPPCl were used as carbonyl activating
agents (Table 4). However, the yields were only moderate
when the reaction was performed with AcCl. This drop in
yield is explained by the formation of undesired byproducts,
which seems to indicate that acetyl chloride is too reactive for
this type of substrate and other reaction pathways must
compete with the formation of the 2-oxazolidinone. The
noncommercial N-alkyl derivatives were prepared in a
straightforward manner from the unsubstituted 1,2-amino
alcohols by condensation of the primary amine group with
the corresponding aldehyde or ketone and subsequent reduc-
tion of the intermediate imine.14,15 The bulkiness of the
N-alkyl chain had little effect on the carbonylation of
unsubstituted or C2-substituted 1,2-amino alcohols (entries
1-5, Table 4). Conversely, steric hindrance does seem to
have a detrimental effect on C1,C2-disubstituted 1,2-amino
alcohols, as evidenced by the lower yields of 2-oxazolidi-
nones 9g-i (entries 6-9, Table 4). Although in these cases
the anticipated 2-oxazolidinones were isolated as a single
isomer, in the case of N-alkyl 1,2-amino alcohols derived
from norephedrine (i.e., 10a-f) a mixture of syn and anti
diastereoisomers was surprisingly obtained (Table 5). The
expected syn-2-oxazolidinones 11 were still the major pro-
ducts, with ratios from 4/1 to >98/2, but the anti 2-oxazo-
lidinones 12 also appear as a result of the inversion of
configuration at the oxygen-bearing center. The relative
and absolute configurations were established by comparison
of the spectroscopic data of 11a and 12a with data reported
in the literature.16 Such an inversion of configuration was
also observed by Dinsmore and Mercer in the carbonylation
of N-alkyl 1,2-amino alcohols with CO2 under Mitsunobu
conditions.6 The use of 18O isotopically marked carbon
yield (%)
DPPA
syn/anti
ratioc
entry
R
10
2-oxazolidinones
1
2
3
4
5
6
Me
Et
i-Pr
i-Bu
neopentyl
Bn
a
b
c
d
e
f
11a þ 12a
11b þ 12b
11c þ 12c
11d þ 12d
11e þ 12e
11f þ 12f
88b
86b
69a
83b
70a
67a
4:1
6:1
5:1
4:1
>98:2
4:1
aPhTMG as a base (120 mol %). bEt3N as a base (200 mol %).
cDetermined by 1H NMR spectroscopy.
dioxide enabled the authors to show that the inversion takes
place through nucleophilic substitution of the oxygen
(presumably transformed into a good leaving group) of the
1,2-amino alcohol by the oxygen of the carbamate anion.
According to this rationale, the ring closure of the oxazoli-
dinone ring could follow two different pathways.
In the case of retention of configuration, the activated
carbamate group undergoes nucleophilic attack of the hydroxyl
oxygen, and in the case of inversion, the oxygen of the amino
alcohol undergoes nucleophilic substitution (Scheme 3). Two
factors seem to favor the inversion pathway for the (1R,2S)-
norephedrine derivatives: (i) the oxygen-bearing center (C1) is
an activated benzylic position and (ii) the steric interactions
between the methyl and the phenyl groups (13) during the ring-
closure step should penalize the retention pathway. This
would explain why in the case of pseudoephedrine 8i
(1S,2S) only the 2-oxazolidinone 9i with retention of con-
figuration is found (Table 4). Interestingly, the syn/anti
ratio was found to be dependent on the nature of the alkyl
group bound to the amino nitrogen as can be seen from the
results in Table 5. For groups such as methyl, ethyl,
isopropyl, isobutyl, and benzyl (entries, 1, 2, 3, 4, and 6)
(15) (a) Chen, L.; Wiemer, D. F. Tetrahedron Lett. 2002, 43, 2705. (b)
Parrott, R. W., II; Hitchcock, S. R. Tetrahedron: Asymmetry 2008, 19, 19. (c)
Hitchcock, S. R.; Davis, R. A.; Richmond, D. M.; Dore, D. D.; Kuschel, S.
L.; Vaughn, J. F.; Wolfe, J. A.; Hamaker, C. G.; Casper, D. M.; Dingle, J. J.
Heterocycl. Chem. 2008, 45, 1265. (d) Parrott, R. W., II; Hamaker, C. G.;
Hitchcock, S. R. J. Heterocycl. Chem. 2008, 45, 873. (e) Effenberger, F.;
€
Gutterer, B.; Jager, J. Tetrahedron: Asymmetry 1997, 8, 459. (f) Borch, R. F.;
Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc. 1971, 93, 2897.
1
the syn/anti ratio determined by H NMR spectroscopy
(16) The relative and absolute configurations were established by com-
parison of the spectroscopic data of samples of 11a and 12a described in the
literature. Claridge, T. D. W.; Davies, S. G.; Polywka, M. E. C.; Roberts, P.
M.; Russell, A. J.; Savory, E. D.; Smith, A. D. Org. Lett. 2008, 23, 5433.
varies between 6/1 and 4/1. However, for the neopentyl
group (entry 5), the syn 2-oxazolidinone 11e is the major
product (syn/anti >98/2). This result is difficult to explain
3040 J. Org. Chem. Vol. 75, No. 9, 2010

Paz et al.
JOCArticle
SCHEME 3
TABLE 6. Carbonylation Using SO2Cl2 as the Activating Agent
entry
R1
R2
Me
Me
CO2Et
R3
1,2-amino alcohol
2-oxazolidinones
yield (%)
Ret/Inv ratioc
1
2
3
H
Me
H
Ph
Ph
Me
6i (1S,2R)
8i (1S,2S)
6h (2S,3R)
7i (4R,5S) þ 15 (4R,5R)
9i (4S,5S) þ 16 (4S,5R)
7h (4S,5R) þ 17 (4S,5S)
68b
34b
44a
1:10
1:4
1:3.6
aPhTMG as a base (120 mol %). bEt3N as a base (200 mol %). cDetermined by 1H NMR spectroscopy.
SCHEME 4
only in terms of steric hindrance, taking into account the
bulkiness of the aforementioned N-alkyl groups.
presence of SO2Cl2.17 A more efficient activation of the
hydroxyl group, instead of the carbamate anion, must
account for the bias for the inversion pathway in this case.
In order to assess the mechanistic aspects of the carbonyl
activation mediated by DPPA, the carbonylation of several
N-alkyl-1,2-amino alcohols was monitored by TLC, and the
presence of a reaction intermediate was found. This inter-
mediate disappeared completely during the workup and
purification. Despite its short life, the intermediate was
separated by flash chromatography and the 31P NMR
spectrum was recorded. A transient signal was observed at
around -20 ppm, and this disappeared rapidly, while a
signal at around -10 ppm increased in intensity; this latter
value is typical for diphenyl hydrogen phosphate 25.18 The
1H NMR spectrum of this fraction showed the presence of
the expected 2-oxazolidinone and a phosphorus derivative.
With the aim of verifying whether a mixed anhydride could
be the intermediate, the secondary amine 18, bearing a
A more striking case of the inversion of configuration was
observed during the carbonylation of norephedrine 6i in the
presence of different electrophiles. When SO2Cl2 was utilized
as an electrophile, a mixture of diastereomeric 2-oxazolidi-
nones was found (Table 6) in which the product due to
inversion of configuration (15) was the major one with a 7i:15
ratio of 1:10. When other 1,2-disubstituted amino alcohols
were assayed (8i and 6h), we again found a mixture enriched
in the product arising from inversion of configuration.
Although the yields and the diastereomeric ratios are mod-
est, the reactivity of SO2Cl2 does not appear to be affected by
the substitution of the amino group or the nature of the
substituent at C1, which means that the stereochemical
outcome of the reaction can be potentially tuned as a
function of the electrophile used. It has been reported that
1,2-amino alcohols afford aziridines in excellent yields in the
(17) (a) Kuyl-Yeheskiely, E.; Lodder, M.; Van der Marel, G. A.; Van
Boom, J. H. Tetrahedron Lett. 1992, 33, 3013. (b) Pilkington, M.; Wallis, J.
D. J. Chem. Soc., Chem. Commun. 1993, 1857.
(18) Nilsson, J.; Kraszewski, A.; Stawinski, J. J. Chem. Soc., Perkin
Trans. 2 2001, 2263.
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JOCArticle
SCHEME 5. Mechanistic Proposal
SCHEME 6
SCHEME 7
methoxy group instead of a hydroxyl function, was sub-
mitted to the carbonylation conditions with DPPA
(Scheme 4). In this case, a mixture of the mixed anhydride
19 (62%) and the carbamoyl azide 20 (33%) was obtained.
The 31P NMR spectrum of 19 showed a characteristic peak at
-19.6 ppm, which is very close to the value displayed by the
transitory intermediate observed previously. A further experi-
ment with the N-benzylated carbamoyl azide 2119 showed that
the participation of a carbamoyl azide as an intermediate is
unlikely, since the ring closure of 21 in the presence of 200 mol %
of PhTMG is a slow reaction that takes 4 days to reach
completion (Scheme 4). These observations taken together seem
to support the involvement of a transient mixed anhydride in the
carbonylation with DPPA. This anhydride should serve to
activate the carbonyl group and would undergo the ring closure
to give the 2-oxazolidinone (Scheme 5).
In order to explore the synthetic scope of our methodol-
ogy, we next turned our attention to the carbonylation of
other types of substrates. We first tried the carbonylation of
1,3-amino alcohols to give the corresponding 2-oxazinones.
When 3-amino-2,2-dimethylpropanol 26 was treated with
CO2, PhTMG, and DPPA in acetonitrile, a mixture of the
carbamoyl azide 27 (63% yield) and the phosphorylated
carbamoyl azide 28 (13% yield) was obtained (Scheme 6).
Although under these conditions the expected 2-oxazinone
was not found, the carbamoyl azide 27 easily underwent the
ring closure in the presence of NaH as base to afford
quantitatively the 2-oxazinone 30. Assuming that a more
reactive system was required to proceed to the formation of
the 2-oxazinone in a single step, we performed the reaction
with acetyl chloride as the activating agent. Fortunately,
under these conditions the 2-oxazinone 30 was isolated in
96% yield (Scheme 6). Presumably, the transient mixed
anhydride 29 is reactive enough to undergo the ring-closure,
whereas the postulated carbamoyl phosphate formed with
DPPA is less reactive and evolves toward the formation of
the carbamoyl azides 27 and 28. Nevertheless, in substrates
such as the 2-aminomethylphenol derivatives 31 and 32,20
the carbonylation took place on using DPPA as the electro-
phile (Scheme 7), which indicates that the conformational
rigidity as well as the higher acidity of the phenol moiety
must contribute to the successful carbonylation with DPPA.
(20) The amino alcohols 31 and 32 were prepared by condensation of 2-
hydroxybenzaldehyde with n-butylamine and isopropylamine, respectively,
and subsequent reduction of the corresponding imines with NaBH4.
(19) The carbamoyl azide 21 was isolated in 25% yield from the carbo-
nylation reaction of the N-benzylated norephedrine 10f with DPPA.
3042 J. Org. Chem. Vol. 75, No. 9, 2010

Paz et al.
JOCArticle
TABLE 7. Carbonylation of Diamines
entry
n
R1
R2
R3
Me
R4
H
R5
35
36
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
0
0
0
0
0
0
0
0
1
1
1
2
3
3
0
H
H
H
H
Bn
H
H
Bn
i-Pr
Bn
a
b (1S,2S)
c (1S,2S)
d (1S,2S)
a
b
c
d
e
f
g
h
i
86
73
96
91
85
93
86
91
94
92
87
73
-(CH2)4-
-(CH2)4-
-(CH2)4-
H
H
H
H
H
H
H
H
H
H
H
H
e
f
g
h
i
j
k
l
cyclohexyl
cyclohexyl
1,3-diphenylprop-2-yl
1,3-diphenylprop-2-yl
H
i-Pr
Bn
H
Bn
H
H
Bn
Bn
Bn
H
H
-Ph-a
j
k
l
3-pentyl
Bn
Bn
Bn
-(CH2)2-
-Ph-b
H
H
H
H
H
H
H
H
CO2Et
H
m
n (2S)
o
a35j is 2-(aminomethyl)aniline. b35k is a derivative of 2-(aminomethyl)aniline.
Finally, we studied the carbonylation of diamines to
afford the corresponding cyclic ureas. Although this trans-
formation has been classically carried out with phosgene or
phosgene derivatives, these reactions lead to considerable
amounts of bis-carbamoyl derivatives, which explains the
modest yields of the cyclic ureas.21 Since our methodology
involves the initial formation of an ionic carbamate with
CO2, we thought that the unlikely formation of a bis-ionic
carbamate should favor the formation of ureas over other
byproducts. Much to our delight, our assumption was con-
firmed when the carbonylation of diamines was performed
with PhTMG as base and DPPA as the carbamate activating
agent in either acetonitrile or dichloromethane. The results
in Table 7 show that 1,2-diamines gave the corresponding
5-membered cyclic ureas in good yields regardless of the
substitution of one or both amino groups (Table 7, entries
1-8). 6-Membered cyclic ureas were obtained in good yields
when 1,3-diamines were used as substrates (entries 9-11), and
even the 7-membered cyclic urea 36l was also synthesized (entry
12). However, these conditions failed to afford 8-membered
ureas (entries 13-14) and the bicyclic urea derived from 1,4-
piperazine (entry 15). In the latter case, the bis-carbamoyl azide
37 was obtained. The use of 200 mol % of PhTMG and DPPA
led to the isolation of 37 in 81% yield (Scheme 8).
2-oxazolidinones, 2-oxazinones, and cyclic ureas. Activation
of the transient carbamate anion generated by treating a
primary or secondary amine group in basic media can be
effected with phosphorylating agents such as DPPA and
DPPCl, as well as with other types of electrophiles such as
SOCl2, TsCl, or AcCl. The intramolecular trapping of the
activated carbamate by a hydroxyl group leads to the
formation of 2-oxazolidinones or 2-oxazinones in good to
excellent yields. Although the formation of the 2-oxazolidi-
nones takes place with full retention of configuration for
a variety of N-alkyl 1,2-amino alcohols, we found that the
N-alkyl derivatives of norephedrine undergo partial inversion of
configuration at C1 and that this is dependent on the nature of
the alkyl group at the amino function. Interestingly, the com-
pounds arising from inversion of configuration at C1 become
the major products when SO2Cl2 is utilized as an electrophile.
This methodology was also successfully applied to the synthesis
of cyclic ureas with up to 7-membered rings.
Experimental Section
General Experimental Procedure A for the Reductive Alkyla-
tion of Amines. (2S,3S)-2-(Benzylamino)-3-methylpentan-1-ol
(8b). A solution of L-isoleucinol (500 mg, 4.27 mmol, 100 mol
%) and benzaldehyde (680 mg, 6.41 mmol, 150 mol %) in EtOH
(20 mL) was stirred for 12 h at 25 °C. The reaction mixture was
cooled to 0 °C, and NaBH4 (323 mg, 8.54 mmol, 200 mol %) was
added portionwise with stirring at 0 °C for 1.5 h. The solvents
were removed under reduced pressure, the residue was dissolved
in 1 M aq NaOH (50 mL) and then extracted with AcOEt. The
organic layer was washed with brine and dried over Na2SO4, and
the solvents were removed under reduced pressure. The crude
material was purified by flash chromatography (silica gel,
AcOEt/CH2Cl2 1:3fAcOEt) to give the title compound 8b
SCHEME 8
1
(823 mg, 93% yield) as a yellowish oil. H NMR (400 MHz,
Conclusions
CDCl3): δ 7.4-7.2 (m, 5H), 3.84 (d, J = 12.8 Hz, 1H), 3.73 (d,
J = 12.8 Hz, 1H), 3.63 (dd, J = 10.6, 4.1 Hz, 1H), 3.36 (dd, J =
10.6, 7.6 Hz, 1H), 2.61 (ddd, J = 7.6, 5.8, 4.1 Hz, 1H), 2.29 (br s,
1.65H), 1.68 (m, 1H), 1.47 (dqd, J = 13.4, 3 ꢀ 7.4, 4.6 Hz, 1H),
1.21 (m, 1H), 0.93 (t, J = 2 ꢀ 7.4 Hz, 3H), 0.88 (d, J = 6.9 Hz,
3H) ppm. 13C NMR (100 MHz, CDCl3): δ 140.3, 128.4, 128.1,
127.0, 62.0, 60.1, 51.2, 35.1, 26.2, 14.3, 11.7 ppm. FT-IR (NaCl):
In summary, we have shown that carbon dioxide can be
used as a convenient carbonylating agent in the synthesis of
(21) Thomas, E. W.; Nishizawa, E. E.; Zimmermann, D. C.; Williams, D.
J. J. Med. Chem. 1989, 32, 228.
J. Org. Chem. Vol. 75, No. 9, 2010 3043

Paz et al.
JOCArticle
ν 3328, 3061, 3028, 2960, 2926, 2875, 1598, 1457, 1378 cm-1
.
125.9, 72.4, 56.2 ppm. FT-IR (NaCl): ν 3246, 3152, 3026, 1736,
1711 cm-1. [R]24D: -50 (c 1.76, CHCl3). MS (EIþ): m/z 163 ([M]þ,
27), 162 (11), 133 (58), 105 (51), 104 (100), 69 (31). HRMS (EIþ):
calcd for C9H9NO2 163.0633, found 163.0639.
[R]26D: þ18 (c 1.00, CHCl3). MS (ESIþ): m/z 208 ([M þ H]þ,
100), 139 (12), 117 (20). HRMS (ESIþ): calcd for C13H22NO
208.1696, found 208.1701.
2-(1,3-Diphenylpropan-2-ylamino)ethanol (8d). 1H NMR (400
MHz, CDCl3): δ 7.4-7.3 (m, 4H), 7.3-7.2 (m, 6H), 3.53 (m,
2H), 3.12 (p, J = 4 ꢀ 6.6 Hz, 1H), 2.92 (br s, 2H), 2.9-2.6 (m,
6H) ppm. 13C NMR (100 MHz, CDCl3): δ 138.8, 128.9, 128.1,
125.9, 60.4 (2C), 48.4, 40.3 ppm. MS (EIþ): m/z 255 ([M]þ, 1),
165 (99), 164 (100), 146 (99), 132 (20), 131 (16), 130 (28), 129 (31),
120 (82), 119 (41), 118 (38), 117 (86), 115 (23), 105 (70), 104 (20),
103 (76), 92 (18), 91 (99), 78 (15), 77 (54), 65 (80). HRMS (EIþ):
calcd for C17H21NO 255.1623, found 255.1622.
(S)-4-tert-Butyloxazolidin-2-one (7d). Procedure A (DPPA):
Following the general procedure, (S)-2-amino-3,3-dimethylbu-
tan-1-ol 6d (210 mg, 1.79 mmol, 100 mol %), PhTMG (370 mg,
1.93 mmol, 108 mol %), and DPPA (0.38 mL, 1.79 mmol, 100
mol %) in CH3CN (10 mL) cooled initially to -40 °C afforded,
after flash chromatography (silica gel, AcOEt/hexane 1:3 to
1:2), the title compound 7d (190 mg, 74% yield) as a colorless
solid. Procedure A (DPPCl): Following the general procedure,
(S)-2-amino-3,3-dimethylbutan-1-ol 6d (170 mg, 1.45 mmol,
100 mol %), PhTMG (555 mg, 2.90 mmol, 200 mol %), and
DPPCl (0.45 mL, 2.17 mmol, 150 mol %) in CH3CN (10 mL)
cooled initially to -40 °C afforded, after flash chromatography
(silica gel, AcOEt/hexane 1:1.5), the title compound 7d (176 mg,
General Experimental Procedures for the Synthesis of 2-Ox-
azolidinones. Procedure A (phosphorus electrophiles): A solu-
tion of the 1,2-amino alcohol (100 mol %) and the base
(100-150 mol %) in CH3CN or CH2Cl2 was cooled to the
indicated initial temperature using H2O/ice, ice/NaCl, or acet-
one/CO2 cooling baths and was saturated with CO2 by bubbling
CO2 gas through the solution for 5-10 min. The phosphorus
electrophile (100-200 mol %) was added dropwise over 5-
20 min. The solution was stirred at the same temperature for an
additional 15-20 min and was allowed to reach room tempera-
ture slowly and stirred overnight under a CO2 atmosphere. The
reaction mixture was concentrated to dryness, and the residue
was dissolved in CHCl3 (20 mL) and washed with a 10%
aqueous Na2CO3 saturated with NaCl (1ꢀ). The aqueous
solution was further extracted with CHCl3 (1ꢀ), and the com-
bined organic layers were washed with 10% aqueous HCl
saturated with NaCl (1ꢀ). The final aqueous layer was extracted
with CHCl3 (1ꢀ), the combined organic layers were dried over
Na2SO4, and the solvents were removed under reduced pressure.
The crude reaction mixture was purified by flash chromatogra-
phy on silica gel to give the corresponding oxazolidinone.
Procedure B (carbon and sulfur electrophiles): A solution of
the 1,2-amino alcohol (100 mol %) and the base (200-250 mol
%) in CH3CN or CH2Cl2 cooled to the indicated initial tem-
perature using H2O/ice, ice/NaCl, or acetone/CO2 cooling baths
was saturated with CO2 by bubbling CO2 gas through the
solution for 5-10 min. The electrophile (100 mol %) was added
dropwise, and the solution was stirred at the same temperature
for an additional 5 min. The cooling bath was then removed, and
the mixture was stirred for 30-40 min under a CO2 atmosphere.
The reaction mixture was concentrated to dryness, and the crude
product was purified by flash chromatography on silica gel to
give the corresponding oxazolidinone.
1
85% yield) as a colorless solid. H NMR (400 MHz, CDCl3):
δ 7.43 (br s, 1H), 4.29 (t, J = 2 ꢀ 9.0 Hz, 1H), 4.11 (dd, J = 9.0,
5.8 Hz, 1H), 3.53 (ddd, J = 9.0, 5.8, 0.8 Hz, 1H), 0.83 (br s, 9H)
ppm. 13C NMR (100 MHz, CDCl3): δ 160.8, 66.3, 61.4, 33.1,
24.5 ppm. FT-IR (NaCl): ν 3238, 3136, 2963, 2874, 1736 cm-1
.
[R]25D: þ12 (c 1.80, CHCl3). MS (EIþ): m/z 143 ([M]þ, 1), 88 (5),
87 (100), 86 (21), 85 (14). HRMS (EIþ): calcd for C7H13NO2
143.0946, found 143.0947.
(S)-4-[(1H-Indol-3-yl)methyl]oxazolidin-2-one (7f). Procedure
A (DPPCl): Following the general procedure, (S)-tryptophanol
6f (211 mg, 1.11 mmol, 100 mol %) was treated with Et3N
(0.31 mL, 2.22 mmol, 200 mol %) and DPPCl (0.28 mL, 1.33
mmol, 120 mol %) in CH3CN (15 mL) cooled initially to -40 °C.
Instead of the aqueous workup, the reaction mixture was
concentrated to dryness and the residue was purified by flash
chromatography (silica gel, AcOEt/hexane 2:1) to give the title
compound 7f (221 mg, 92% yield) as a colorless solid. 1H NMR
(400 MHz, DMSO-d6): δ 10.94 (br s, 1H), 7.80 (br s, 1H), 7.55
(m, 1H), 7.36 (dt, J = 8.1, 2 ꢀ 0.9 Hz, 1H), 7.23 (d, J = 2.4 Hz,
1H), 7.08 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 7.00 (ddd, J = 8.0, 7.0,
1.1 Hz, 1H), 4.29 (t, J = 2 ꢀ 8.3 Hz, 1H), 4.10 (m, 1H), 3.99 (dd,
J = 8.3, 5.4 Hz, 1H), 2.95 (dd, J = 14.4, 4.9 Hz, 1H), 2.84 (dd,
J = 14.4, 7.5 Hz, 1H) ppm. 13C NMR (100 MHz, DMSO-d6): δ
158.7, 136.1, 127.4, 123.7, 121.0, 118.4, 118.1, 111.4, 108.8, 68.6,
51.9, 30.3 ppm. FT-IR (NaCl): ν 3402, 3292, 3055, 3008, 2973,
2912, 1740 cm-1. [R]28D: þ4 (c 2.60, MeOH). MS (ESIþ): m/z
239 ([M þ Na]þ, 100), 217 ([M þ H]þ, 60). HRMS (ESIþ): calcd
for C12H13N2O2 217.0971, found 217.0970.
(4R,5S)-4-Methyl-5-phenyloxazolidin-2-one (7i). Procedure A
(DPPA): Following the general procedure, (1S,2R)-norephe-
drine 6i (210 mg, 1.39 mmol, 100 mol %), PhTMG (290 mg, 1.52
mmol, 109 mol %), and DPPA (0.30 mL, 1.39 mmol, 100 mol %)
in CH3CN (10 mL) cooled initially to -40 °C afforded, after
flash chromatography (silica gel, AcOEt/hexane 1:4 to 1:2), the
title compound 7i (185 mg, 75% yield) as a colorless solid.
Procedure A (DPPCl): Following the general procedure,
(1S,2R)-norephedrine 6i (200 mg, 1.32 mmol, 100 mol %),
PhTMG (300 mg, 1.57 mmol, 119 mol %), and DPPCl (0.27
mL, 1.32 mmol, 100 mol %) in CH3CN (10 mL) cooled initially
to -40 °C afforded, after flash chromatography (silica gel,
AcOEt/hexane 1:2 to 1:1), the title compound 7i (192 mg, 82%
yield) as a colorless solid. Procedure A (DPPCl): Following the
general procedure, (1S,2R)-norephedrine 6i (150 mg, 0.99
mmol, 100 mol %), Et3N (0.28 mL, 1.98 mmol, 200 mol %),
and DPPCl (0.25 mL, 1.19 mmol, 120 mol %) in CH3CN (15
mL) cooled initially to -40 °C afforded, after flash chromato-
graphy (silica gel, AcOEt/hexane 1.5:1), the title compound 7i
(168 mg, 96% yield) as a colorless solid. Procedure B (AcCl):
Following the general procedure, (1S,2R)-norephedrine 6i (110
mg, 0.73 mmol, 100 mol %), PhTMG (280 mg, 1.46 mmol, 200
mol %), and AcCl (0.05 mL, 0.73 mmol, 100 mol %) in CH3CN
(R)-4-Phenyloxazolidin-2-one (7a). Procedure A (DPPA): Fol-
lowing the general procedure, (R)-phenylglycinol 6a (150 mg,
1.09 mmol, 100 mol %), PhTMG (250 mg, 1.31 mmol, 120
mol %), and DPPA (0.23 mL, 1.09 mmol, 100 mol %) in
CH3CN (10 mL) cooled initially to -40 °C afforded, after flash
chromatography (silica gel, AcOEt/hexane 1:4 to 1:2), the title
compound 7a (143 mg, 80% yield) as a colorless solid. Procedure
A (DPPCl): Following the general procedure, (R)-phenylglyci-
nol 6a (110 mg, 0.80 mmol, 100 mol %), Et3N (0.22 mL, 1.60
mmol, 200 mol %), and DPPCl (0.20 mL, 0.96 mmol, 120
mol %) in CH3CN (12 mL) cooled initially to -40 °C afforded,
after flash chromatography (silica gel, AcOEt/hexane 1:5 to
1:2), the title compound 7a (124 mg, 95% yield) as a colorless
solid. Procedure B (AcCl): Following the general procedure
(R)-phenylglycinol 6a (120 mg, 0.87 mmol, 100 mol %), Et3N
(0.30 mL, 2.18 mmol, 250 mol %), and AcCl (0.06 mL, 0.87 mmol,
100 mol %) in CH3CN (12 mL) cooled initially to -40 °C afforded,
after flash chromatography (silica gel, AcOEt/hexane 1.5:1), the
1
title compound 7a (133 mg, 94% yield) as a colorless solid. H
NMR (400 MHz, CDCl3): δ 7.4-7.3 (m, 5H), 6.67 (br s, 1H), 4.94
(m, 1H), 4.69(t, J= 2ꢀ 8.7 Hz, 1H), 4.13 (dd, J=8.6, 7.0Hz, 1H)
ppm. 13C NMR (100 MHz, CDCl3): δ 160.1, 139.5, 129.0, 128.6,
3044 J. Org. Chem. Vol. 75, No. 9, 2010

Paz et al.
JOCArticle
(10 mL) cooled initially to -40 °C afforded, after flash chro-
matography (silica gel, AcOEt/hexane 1.5:1), the title com-
pound 7i (124 mg, 96% yield) as a colorless solid. Procedure B
(AcCl): Following the general procedure, (1S,2R)-norephedrine
6i (110 mg, 0.73 mmol, 100 mol %), Et3N (0.21 mL, 1.46 mmol,
200 mol %), and AcCl (0.05 mL, 0.73 mmol, 100 mol %) in
CH3CN (15 mL) cooled initially to -40 °C afforded, after flash
chromatography (silica gel, AcOEt/hexane 1.5:1), the title com-
pound 7i (126 mg, 97% yield) as a colorless solid. Procedure B
(AcCl): Following the general procedure, (1S,2R)-norephedrine
6i (110 mg, 0.73 mmol, 100 mol %), Et3N (0.21 mL, 1.46 mmol,
200 mol %), and AcCl (0.05 mL, 0.73 mmol, 100 mol %) in
CH3CN (15 mL) cooled initially to -40 °C afforded, after flash
chromatography (silica gel, AcOEt/hexane 1.5:1), the title com-
pound 7i (126 mg, 97% yield) as a colorless solid. Procedure B
(AcBr): Following the general procedure, (1S,2R)-norephedrine 6i
(100 mg, 0.66 mmol, 100 mol %), Et3N (0.18 mL, 1.32 mmol,
200 mol %), and AcBr (0.05 mL, 0.66 mmol, 100 mol %) in
CH3CN (10 mL) cooled initially to -40 °C afforded, after flash
chromatography (silica gel, AcOEt/hexane 1:1.5), the title com-
pound 7i (110 mg, 94% yield) as a colorless solid. Procedure B
(SOCl2): Following the general procedure, (1S,2R)-norephedrine 6i
(100 mg, 0.66 mmol, 100 mol %), PhTMG (250 mg, 1.32 mmol,
200 mol %), and SOCl2 (0.05 mL, 0.66 mmol, 100 mol %) in
CH3CN (10 mL) cooled initially to -40 °C afforded, after flash
chromatography (silica gel, AcOEt/hexane 1:1.5 to 1:1), the title
compound 7i (103 mg, 88% yield) as a colorless solid. Procedure B
(pNsCl): Following the general procedure, (1S,2R)-norephedrine 6i
(100 mg, 0.66 mmol, 100 mol %), PhTMG (250 mg, 1.32 mmol,
200 mol %), and a solution of p-NsCl (210 mg, 0.66 mmol, 100
mol %) in CH3CN (2 mL) in CH3CN (10 mL) cooled initially to
-40 °C afforded, after flash chromatography (silica gel, AcOEt/
hexane 1:1), the title compound 7i (153 mg, 92% yield) as a
colorless solid. 1H NMR (400 MHz, CDCl3): δ 7.5-7.2 (m, 5H),
7.05 (br s, 1H), 5.72 (d, J = 8.1 Hz, 1H), 4.25 (m, 1H), 0.83 (d, J =
6.6 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ 159.8, 134.8,
128.2, 128.1, 125.7, 80.8, 52.2, 17.2 ppm. FT-IR (NaCl): ν 3240,
2980, 1756 cm-1. [R]24D: þ176 (c 0.82, CHCl3). MS (EIþ): m/z 178
(33), 177 ([M]þ, 8), 107 (100), 79 (41). HRMS (EIþ): calcd for
C10H11NO2 177.0790, found 177.0792.
0.80 mmol, 100 mol %), Et3N (0.22 mL, 1.60 mmol, 200 mol %),
and DPPCl (0.20 mL, 0.96 mmol, 120 mol %) in CH3CN (12 mL)
cooled initially to -40 °C afforded, after flash chromatography
(silica gel, AcOEt/hexane 1:3 to 1:2), the title compound 9d (214mg,
1
95% yield) as a colorless oil. H NMR (400 MHz, CDCl3): δ
7.4-7.1 (m, 10H), 4.23 (tt, J = 2 ꢀ 9.1, 2 ꢀ 6.2 Hz, 1H), 4.1-3.9
(m, 2H), 3.3-3.1 (m, 2H), 3.01 (dd, J = 14.1, 9.1 Hz, 2H), 2.94 (dd,
J = 14.1, 6.2 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ 157.5,
137.8, 128.7, 128.4, 126.5, 61.7, 56.5, 42.3, 38.1 ppm. FT-IR (NaCl):
ν 3086, 3061, 3027, 3002, 2951, 2919, 2858, 1746, 1602 cm-1. MS
(ESIþ): m/z 304 ([M þ Na]þ, 37), 282 ([M þ H]þ, 100). HRMS
(ESIþ): calcd for C18H20NO2 282.1489, found 282.1496.
(S)-1,1-Diphenyltetrahydropyrrolo[1,2-c]oxazol-3(1H)-one (9f).
Procedure A (DPPA): Following the general procedure, (S)-
diphenyl(pyrrolidin-2-yl) methanol 8f (170 mg, 0.67 mmol, 100
mol %), PhTMG (180 mg, 0.94 mmol, 140 mol %), and DPPA
(0.17 mL, 0.80 mmol, 120 mol %) in CH2Cl2 (15 mL) cooled
initially to -40 °C afforded, after flash chromatography (silica gel,
AcOEt/hexane 1:8 to 1:4), the title compound (92 mg, 49% yield)
as a colorless solid. Procedure A (DPPCl): Following the general
procedure, (S)-diphenyl(pyrrolidin-2-yl) methanol 8f (139 mg,
0.55 mmol, 100 mol %), PhTMG (210 mg, 1.10 mmol, 200 mol
%), and DPPCl (0.17 mL, 0.82 mmol, 150 mol %) in CH2Cl2
(12 mL) cooled initially to -40 °C afforded, after flash chromato-
graphy (silica gel, AcOEt/hexane 1:5), the title compound (151 mg,
98% yield) as a colorless solid. Procedure A (DPPCl): Following
the general procedure, (S)-diphenyl(pyrrolidin-2-yl)methanol 8f
(157 mg, 0.62 mmol, 100 mol %), Et3N (0.17 mL, 1.24 mmol,
200 mol %), and DPPCl (0.15 mL, 0.74 mmol, 120 mol %) in
CH2Cl2 (15 mL) cooled initially to -40 °C afforded, after flash
chromatography (silica gel, AcOEt/hexane 1:5), the title compound
1
(163 mg, 94% yield) as a colorless solid. H NMR (400 MHz,
CDCl3):δ7.6-7.5 (m, 2H), 7.4-7.2 (m, 8H), 4.56 (dd, J= 10.5, 5.5
Hz, 1H), 3.73 (dt, J = 11.2, 2 ꢀ 8.1 Hz, 1H), 3.24 (ddd, J = 11.2,
9.7, 3.7 Hz, 1H), 2.05-1.79 (m, 2H), 1.73 (m, 1H), 1.12 (m, 1H)
ppm. 13C NMR (100 MHz, CDCl3): δ 160.3, 143.2, 140.1, 128.4,
128.2 (2ꢀ), 127.6, 125.8, 125.3, 85.7, 69.1, 45.9, 28.8, 24.7 ppm. FT-
IR (NaCl): ν 3060, 3030, 2974, 2903, 1754 cm-1. [R]26D: -211 (c
1.44, CHCl3). MS (EIþ): m/z 279 ([M]þ, 12), 165 (55), 146 (35), 105
(65), 81 (45), 69 (100). HRMS (EIþ): calcd for C18H17NO2
279.1259, found 279.1266.
(S)-3-Benzyl-4-isopropyloxazolidin-2-one (9a). Procedure A
(DPPA): Following the generalprocedure, (S)-2-(benzylamino)-
3-methylbutan-1-ol 8a (160 mg, 0.83 mmol, 100 mol %),
PhTMG (200 mg, 1.05 mmol, 126 mol %), and DPPA (0.20
mL, 0.91 mmol, 110 mol %) in CH3CN (20 mL) cooled initially
to -40 °C afforded, after flash chromatography (silica gel,
AcOEt/hexane 1:8 to 1:4), the title compound 9a (154 mg,
(4R,5S)-3-Isopropyl-4-methyl-5-phenyloxazolidin-2-one (11c)
and (4R,5R)-3-Isopropyl-4-methyl-5-phenyloxazolidin-2-one (12c).
Procedure A (DPPA): Following the general procedure, a mixture
of (1S,2R)-2-(isopropylamino)-1-phenylpropan-1-ol 10c (130 mg,
0.67 mmol, 100 mol %), PhTMG (170 mg, 0.89 mmol, 133 mol %),
and DPPA (0.29 mL, 1.34 mmol, 200 mol %) in CH2Cl2 (20 mL)
was cooled to -30 °C for 20 h. CO2 was bubbled through the
solution for 20 min, and the mixture was stirred and allowed to
warm to room temperature slowly over 14 h. Flash chromatogra-
phy (silica gel, AcOEt/hexane 1:10 to 1:5) gave a fraction contain-
ing diastereoisomers 11c and 12c in a 5:1 ratio (101 mg, 69% yield).
These compounds were finally separated by HPLC (AcOEt/
hexane 1:4). (4R,5S)-3-Isopropyl-4-methyl-5-phenyloxazolidin-2-
one (11c): 1H NMR (400 MHz, CDCl3): δ 7.4-7.2 (m, 5H), 5.53
(d, J = 7.9 Hz, 1H), 4.11 (m, 1H), 3.95 (sept, J = 6 ꢀ 6.9 Hz, 1H),
1.35 (d, J = 6.9 Hz, 3H), 1.31 (d, J = 6.8 Hz, 3H), 0.81 (d, J = 6.5
Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ 156.8, 135.1, 128.4,
128.2, 126.0, 78.8, 54.4, 45.9, 21.6, 19.9, 16.9 ppm. FT-IR (NaCl): ν
3033, 2980, 2938, 2880, 1733 cm-1. [R]24D: þ109 (c 0.72, CHCl3).
MS (EIþ): m/z 219 ([M]þ, 14), 204 (92), 160 (91), 132 (11), 118.06
(44), 117 (53), 105 (38), 85 (73), 91 (55), 77 (34), 70 (100). HRMS
(EIþ): calcd for C13H17NO2 219.1259, found 219.1268. (4R,5R)-3-
Isopropyl-4-methyl-5-phenyloxazolidin-2-one (12c): 1H NMR (400
MHz, CDCl3): δ 7.4-7.3 (m, 5H), 4.87 (d, J = 6.5 Hz, 1H), 3.97
(sept, J = 6 ꢀ 6.9 Hz, 1H), 3.69 (p, J = 4 ꢀ 6.2 Hz, 1H), 1.42 (d,
J = 6.2 Hz, 3H), 1.30 (d, J = 6.9 Hz, 3H), 1.27 (d, J = 6.9 Hz, 3H)
ppm. 13C NMR (100 MHz, CDCl3): δ 157.0, 138.5, 128.8, 128.8,
1
84% yield) as a yellowish oil. H NMR (400 MHz, CDCl3): δ
7.4-7.2 (m, 5H), 4.88 (d, J = 15.2 Hz, 1H), 4.18 (t, J = 2 ꢀ 9.0
Hz, 1H), 4.08 (dd, J = 8.9, 5.9 Hz, 1H), 4.01 (d, J = 15.2 Hz,
1H), 3.57 (m,1H), 2.08 (m, 1H), 0.88 (d, J = 6.9 Hz, 3H), 0.84 (d,
J = 7.0 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ 158.6,
135.7, 128.6, 127.9, 127.7, 62.6, 58.0, 45.7, 26.9, 17.4, 13.9 ppm.
FT-IR (NaCl): ν 3062, 3031, 2963, 2929, 2877, 1748 cm-1
.
[R]24D: -25 (c 1.68, CHCl3). MS (EIþ): m/z 219 ([M]þ, 7), 176
(31), 92 (6), 91 (100), 65 (6). HRMS (EIþ): calcd for C13H17NO2
219.1259, found 219.1267. MS (ESIþ): m/z 242 ([M þ Na]þ, 97),
220 ([M þ H]þ, 100). HRMS (ESIþ): calcd for C13H17NO2Na
242.1152, found 242.1159.
3-(1,3-Diphenylpropan-2-yl)oxazolidin-2-one (9d). Procedure
A (DPPA): Following the general procedure, 2-(1,3-diphenyl-
propan-2-ylamino)ethanol 8d (204 mg, 0.80 mmol, 100 mol %),
Et3N (0.22 mL, 1.60 mmol, 200 mol %), and DPPA (0.21 mL,
0.96 mmol, 120 mol %) in CH3CN (12 mL) cooled initially to
-40 °C afforded, after flash chromatography (silica gel, AcOEt/
hexane 1:3), the title compound 9d (211 mg, 94% yield) as a
colorless oil. Procedure A (DPPCl): Following the general
procedure, 2-(1,3-diphenylpropan-2-ylamino)ethanol 8d (204 mg,
J. Org. Chem. Vol. 75, No. 9, 2010 3045

Paz et al.
JOCArticle
125.6, 82.0, 58.6, 45.8, 21.4, 20.4, 19.5 ppm. FT-IR (NaCl) ν 3064,
3034, 2974, 2934, 2878, 1747 cm-1. [R]24D: -10 (c 0.26, CHCl3).
MS (EIþ): m/z 219 ([M]þ, 8), 204 (68), 160 (100), 132 (9), 118 (42),
117 (32), 105 (23), 91 (30), 85 (21), 70 (53). HRMS (EIþ): calcd for
C13H17NO2 219.1259; found 219.1257.
DPPA (0.38 mL, 1.78 mmol, 110 mol %) in CH3CN (30 mL)
cooled initially to -40 °C to afford, after flash chromatography
(silica gel, MeOH/CH2Cl2 1:20), the title compound 36a (139
mg, 86% yield) as a colorless solid. 1H NMR (400 MHz,
CDCl3): δ 5.93 (d, J = 8.5 Hz, 1H), 5.82 (d, J = 7.5 Hz, 1H),
3.84 (m, 1H), 3.53 (t, J = 2 ꢀ 8.5 Hz, 1H), 3.00 (t, J = 2 ꢀ 7.6 Hz,
1H), 1.18 (d, J = 6.2 Hz, 3H) ppm. 13C NMR (100 MHz,
CDCl3): δ 164.7, 48.3, 48.0, 21.1 ppm. IR (NaCl): ν 3208, 3105,
3080, 2967, 2929, 2862, 1698 cm-1. MS (EIþ): m/z 100 ([M]þ,
21), 85 ([M(-NH2)]þ, 100). HRMS (EIþ): calcd for C4H8N2O
100.0637, found 100.0636.
1,3-Dibenzyl-1,3-diazepan-2-one (36l). Following the general
procedure, N,N0-dibenzylbutane-1,4-diamine 35l (99 mg, 0.37
mmol, 100 mol %) was treated with PhTMG (121 mg, 0.63
mmol, 170 mol %) and DPPA (0.08 mL, 0.37 mmol, 100 mol %)
in CH2Cl2 (20 mL) cooled initially to -35 °C to afford, after
flash chromatography (silica gel, AcOEt/hexanes 1:4), the title
compound 36l (80 mg, 73%) as a pale yellow oil. 1H NMR (400
MHz, CDCl3): δ 7.5-7.2 (m, 10H), 4.55 (s, 4H), 3.20 (m, 4H),
1.54 (m, 4H) ppm. 13C NMR (100 MHz, CDCl3): δ 164.7, 138.8,
128.3, 128.2, 126.9, 53.5, 48.7, 26.3 ppm. IR (NaCl): ν 3060,
3028, 2932, 2856, 1635 cm-1. MS (ESIþ): m/z 317 ([M þ Na]þ,
100), 295 ([M þ H]þ, 15), 227 (4). HRMS (ESIþ): calcd for
C19H23N2O 295.1805, found 295.1805.
Synthesis of 2-Oxazinones. 5,5-Dimethyl-1,3-oxazinan-2-one
(30). Procedure B (with AcCl): Following the general procedure
for the synthesis of 2-oxazolidinones, the 1,3-amino alcohol 26
(130 mg, 1.26 mmol, 100 mol %) was treated with Et3N (0.44
mL, 3.15 mmol, 250 mol %), AcCl (0.09 mL, 1.26 mmol, 100 mol
%), and CO2 in CH3CN (15 mL). The reaction mixture was
concentrated to dryness, and the resulting crude material was
purified by flash chromatography (silica gel, AcOEt), to give the
title compound 30 (156 mg, 96% yield) as a colorless solid. 1H
NMR (400 MHz, CDCl3): δ 6.85 (br s, 1H), 3.86 (br s, 2H), 3.00
(br s, 2H), 1.03 (s, 6H) ppm. 13C NMR (100 MHz, CDCl3): δ
154.3, 76.0, 51.4, 27.7, 22.5 ppm. IR (NaCl): ν 3295, 2973, 2938,
2878, 1705, 1665 cm-1. MS (EIþ): m/z 129 ([M]þ, 100), 84 (12),
82 (4), 73 (6), 71 (4), 70 (18), 68 (7). HRMS (EIþ): calcd for
C6H11N1O2 129.0790, found 129.0789.
General Procedure for the Synthesis of Cyclic Ureas. A solu-
tion of the diamine (100 mol %) and the base (100-200 mol %)
in CH3CN or CH2Cl2 cooled to the indicated initial temperature
using H2O/ice, ice/NaCl, or acetone/CO2 cooling baths was
saturated with CO2 by bubbling CO2 gas through the solution
for 5-10 min. DPPA (100-120 mol %) was added dropwise
over 5-20 min, and the solution was stirred at the same
temperature for an additional 15-20 min. The reaction mixture
was allowed to warm to room temperature slowly and stirred
overnight under a CO2 atmosphere. The reaction mixture was
concentrated to dryness, and the residue was purified by flash
chromatography to give the corresponding cyclic urea. (()-4-
Methylimidazolidin-2-one (36a): Following the general proce-
dure, propane-1,2-diamine 35a (120 mg, 1.62 mmol, 100 mol %)
was treated with PhTMG (340 mg, 1.78 mmol, 110 mol %) and
Acknowledgment. Financial support from the Xunta de
ꢀ
Galicia and Ministerio de Educacion y Ciencia is gratefully
acknowledged.
Supporting Information Available: Experimental proce-
dures and characterization data for those compounds not
included in the Experimental Section and copies of 1H and 13
C
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
3046 J. Org. Chem. Vol. 75, No. 9, 2010