Synthesis of (±)-trans-hexahydropyrrolo[3,4-d]oxazol-2-one and its derivatives by using N-(tert-butyloxycarbonyl)-3-pyrroline as precursor

Article abstract of DOI:10.1002/jhet.494

Synthetic method for the preparation of (±)-trans- hexahydropyrrolo[3,4-d]oxazol-2-one and its derivatives has been developed. By one route, an efficient preparation of these fused heterobicyclic moieties could be achieved, which are prepared by using N-(tert-butyloxycarbonyl)-3-pyrroline as precursor. These fused heterobicyclic systems could be useful to develop a series of 2-oxazolidinone analogues.

Full text of DOI:10.1002/jhet.494

1
392
Synthesis of (6)-trans-Hexahydropyrrolo[3,4-d]oxazol-2-one and
Its Derivatives by Using N-(tert-Butyloxycarbonyl)-3-pyrroline
as Precursor
Vol 47
a,b
Tammana Rajesh, Sambangi Polinaini Narayana Rao, Kopparthi Suresh,
a
a
a
Gutta Madhusudhan, * and Kagga Mukkanti
b
a
Department of Research and Development, Inogent Laboratories Private Limited, A GVK BIO
Company, Nacharam, Hyderabad, Andhra Pradesh 500 076, India
b
Centre for Pharmaceutical Sciences, Institute of Science and Technology, Jawaharlal Nehru
Technological University, Hyderabad, Andhra Pradesh 500 072, India
*
E-mail: madhusudhan.gutta@inogent.com or madhusudhan.gutta@yahoo.com
Received December 29, 2009
DOI 10.1002/jhet.494
Published online 27 August 2010 in Wiley Online Library (wileyonlinelibrary.com).
Synthetic method for the preparation of (6)-trans-hexahydropyrrolo[3,4-d]oxazol-2-one and its deriv-
atives has been developed. By one route, an efficient preparation of these fused heterobicyclic moieties
could be achieved, which are prepared by using N-(tert-butyloxycarbonyl)-3-pyrroline as precursor.
These fused heterobicyclic systems could be useful to develop a series of 2-oxazolidinone analogues.
J. Heterocyclic Chem., 47, 1392 (2010).
INTRODUCTION
urgent need for improved antibiotics that overcome bac-
terial resistance mechanisms. A particularly attractive
goal would be a next-generation oxazolidinone with
improved spectrum and binding affinity, while retaining
properties for good oral exposure and safety [7].
Diverse biological activities are encountered in fused
heterocyclic systems containing the pyrrolidine and 2-
oxazolidinone moieties [1]. In continuation of our inter-
est in this field of 2-oxazolidinones [2], it was thought
worthwhile to incorporate 2-oxazolidinone (2) to the 3-
pyrroline ring by using N-(tert-butyloxycarbonyl)-3-pyr-
roilne (1b) as a precursor for building of newly fused
heterobicyclic systems, (6)-trans-hexahydropyrrolo[3,4-
d]oxazol-2-one and its derivatives (3) (Fig. 1).
N-Substituted-3-pyrrolines are an important class of
compounds which exhibit biological activity and serve
as useful synthetic intermediates [3]. The alkene moiety
of 3-pyrroline can serves as a handle for various func-
tional group transformations.
Several SAR studies of the 2-oxazolidinones have dem-
onstrated a high tolerance for structural variation at the
4
-position of the phenyl ring [8], while the oxazolidinone
ring is essential for biological activity [9]. These fused
heterobicyclic systems could be useful to develop a series
of oxazolidinone analogues where the morpholine moiety
of linezolid could be replaced with these heterobicyclic
systems such as RWJ-416457 [10] (Fig. 2).
RESULTS AND DISCUSSION
The oxazolidinone family represents one of only two
new chemical classes of antibiotics disclosed in the past
The literature survey of the titled compound reveals
the cis fusion of pyrrolidine and 2-oxazolidinone rings
for the preparation of (6)-cis- and (3aR,6aS)-hexahydro-
3-methylpyrrolo[3,4-d]oxazol-2-one only [11]. Further-
more, it is very important to find out a general method-
ology to synthesize (6)-trans-hexahydropyrrolo[3,
4-d]oxazol-2-one and its derivatives (3). The key chal-
lenge of the synthesis is the effective trans fusion of 2-
oxazolidinone ring using alkene moiety between 3 and 4
positions of 3-pyrroline (1a). We required a general
4
0 years [4]. Linezolid (Fig. 2), the first approved oxa-
zolidinone, demonstrates good activity against all major
pathogenic Gram-positive bacteria, including methicil-
lin-resistant Staphylococcus aureus (MRSAa), vancomy-
cin-resistant Enterococcus faecium (VREF), and penicil-
lin-resistant Streptococcus pneumoniae [5]. However,
not long after the commercial release of linezolid, oxa-
zolidinone resistant strains of MRSA and VREF began
to appear in the clinic [6], underscoring the increasingly
V
C
2010 HeteroCorporation

November 2010
Synthesis of (6)-trans-Hexahydropyrrolo[3,4-d]Oxazol-2-one and
Its Derivatives by Using N-(tert-Butyloxycarbonyl)-3-pyrroline as Precursor
1393
Scheme 1. Retrosynthetic analysis to prepare (6)-trans-3
Figure 1. Chemical structures of 3-Pyrroline (1a), N-Boc-3-pyrroline
1b), 2-oxazolidinone (2), and (6)-trans-hexahydropyrrolo[3,4-d]oxa-
zol-2-one and its derivatives (3).
(
Under basic conditions (NaOH), the bromohydrin
6)-7 was converted to the epoxide 8, followed by treat-
method for the preparation of these trans fused heterobi-
cyclic systems (3) which should be the most attractive
in terms of practical and economical. Based on retrosyn-
thetic analysis, we designed two synthetic routes to 3
and are shown in Scheme 1. Each synthetic route
includes a key intermediate amino alcohol (4) or azido
alcohol (5) which gives the targeted moieties (3).
To prepare these intermediates, N-(tert-butyloxycar-
bonyl)-3-pyrroline (1b) or cis-1,4-dichloro-2-butene (6)
are regarded as a common starting material. Recently,
(
ment with methylamine or benzylamine furnished the
desired intermediates 4a or 4b. However, the carbonyl
insertion between b-amino alcohol of 4b with various
0
reagents, such as N,N -carbonyldiimidazole (CDI),
diethyl carbonate or triphosgene in different reaction
conditions were not successful. Although in case of 4a,
after screening of several reaction conditions the
required 2-oxazolidinone 3a was obtained in low yield
(
36%) with triphosgene using N,N-diisopropylethylamine
ꢀ
1
b was prepared by us with high purity in large scale
(
in methanol, to remove the N-Boc protection, 3d was
DIPEA) as a base at 0 C. On treatment of 3a with HCl
starting from cis-1,4-dichloro-2-butene 6 via Del e´ pine
reaction [12] and subsequent in situ cyclization in the
presence of potassium carbonate (K CO ) followed by
obtained in good yield (Scheme 2).
On the other hand, 4b on protection with Boc O gives
2
3
2
N-Boc protection with di-tert-butyldicarbonate (Boc O)
2
the di-tert-boc protected compound which on further
treatment with mesyl chloride, tosyl chloride, or thionyl
chloride, the corresponding fused 2-oxazolidinone was
not achieved [14]. Thus, we have studied the scope of
this approach by opening of epoxy compound 8 with
different amines. We were not obtained the right results
on the formation of 2-oxazolidinone heterobicyclic sys-
tems using different methodologies, such as direct car-
bonyl insertion or tert-boc protection of the amines 4
followed by reaction with mesyl chloride or tosyl
chloride.
in methanol [3]. This is an efficient and commercial via-
ble synthetic method for N-(tert-butyloxycarbonyl)-3-
pyrroline.
Reaction of 1b with N-bromosuccinimide (NBS) in
DMSO–H O at room temperature afforded the racemic
2
1
trans bromohydrin (7) [13]. The H NMR spectra of the
latter product revealed disappearance the triplet corre-
sponding to alkenyl protons at d 5.78 ppm, whereas
broad singlet for hydroxyl signal appeared at d 2.8 ppm
and also the mass spectrum showed in addition to mo-
þ
lecular ion peak, bromine isotopic peak (M þ2) at m/z
Finally, our attention was altered to another approach
Scheme 3). The major difference in this strategy is ring
2
68.
(
opening of epoxy compound 8 with sodium azide
instead of amines. In the previous approach, the alkyl
substituent on exo cyclic amine of 4 may hinders the
formation of 2-oxazolidinone ring due to steric factor.
Probably, by choosing alternative strategy, 2-oxazolidi-
none ring formation followed by alkylation, could be
succeeded due to lower steric factor. The epoxide 8 was
readily opened with sodium azide in AcOHAH O at
2
room temperature gave the corresponding azido alcohol,
(
6)-trans-5. The infra-red spectrum of 5 showed clearly
ꢁ
1
a new band at t ¼ 2096 cm for N group.
3
Azido alcohol (6)-5 on further treatment with phenyl
chloroformate using pyridine in dichloromethane at
room temperature yielded the phenyl carbonate 9. The
1
Figure 2. 2-Oxazolidinone antibacterials with different N-substitutents.
H NMR spectra of the latter product 9 divulged a
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1
394
T. Rajesh, S. P. N. Rao, K. Suresh, G. Madhusudhan, and K. Mukkanti
Vol 47
Scheme 2
multiplet at d 5.08–5.14 ppm due to deshielding of the
C AH signal attached to phenyl carbonate and also two
3
ꢁ
1
bands were appeared at m ¼ 1757, 1682 cm corre-
sponding to carbonyl (C ¼¼ O) groups in the infra-red
spectrum. Reduction of azide in phenyl carbonate (6)-9
could be achieved by hydrogenation (10% Pd/C, 20 psi,
methanol) gave the corresponding amine which under-
goes in situ cyclisation produced the required basic
fused heterobicyclic compound (6)-10. Whereas the
same reaction is performed in ethyl acetate instead of
methanol, in situ cyclisation was not occurred. The
spectral analysis of the latter product 10 showed the ab-
Figure 3. H–H interaction of compound 3c in NOE spectra (DMSO-
d6).
very slow and also observed the incompletion of the
reaction even at elevated temperatures. Finally, sulfonyla-
tion was achieved by the reaction of (6)-10 with tosyl
ꢀ
chloride using DIPEA in dichloromethane at 0 C.
Compounds 3a-c are well characterized by spectral
1
1
data. The H NMR spectrum of 3a-c showed the corre-
sence of phenyl protons in the H NMR spectrum and
disappearance of azido absorption band at m ¼ 2122
sponding alkylation peaks at N-3 site. Compound 3a-c
on N-tert-boc deprotection was achieved with HCl in
methanol afforded the targeted hexahydro-3-alkylpyrrolo
[3,4-d]oxazol-2-one 3e-f in high yield (Scheme 3). Com-
pounds 3d-f have been characterized by spectral and
elemental analyses.
ꢁ
1
cm
1
in addition, two bands were appeared at m ¼
ꢁ
1
749, 1694 cm
corresponding to carbonyl (C ¼¼ O)
groups in the infra-red spectrum. This heterobicyclic
compound (6)-10 was utilized to make derivatization
with various substituents at 2-oxazolidinone site.
Compound (6)-10 was alkylated with benzyl bromide
or iodomethane using sodium hydride (NaH) in N,N-
dimethylformamide (DMF) at 0 C gave the related tert-
butylhexahydro-3-alkyl-2-oxopyrrolo[3,4-d]oxazole-5-car-
boxylate, 3a-b. On the other hand, the alkylation of (6)-
The trans fusion of the two rings, pyrrolidine and 2-
oxazolidinone, was assigned by using NOESY studies.
To demonstrate the trans fusion of the synthesized com-
pounds 3a-f, the example chosen for NOESY experi-
ments is 3c. Upon irradiation of H-6a of compound 3c,
ꢀ
1
similar conditions (NaH, DMF, 0 C), the reaction was
0 with p-toluenesulfonyl chloride was attempted under
led to enhancement of the H
-4, which suggested that both H-6a and H
b
b
-4 and no cross peak of
ꢀ
H
-4 are in
a
the same spatial arrangement in addition H-6a and H -4
a
Scheme 3
are in different special arrangement. Whereas irradiation
of H -4 revealed that H-3a and H -4 are in the same
a
a
spatial arrangement (strong enhancement of H-3a sig-
nal). This indicates trans fusion at the ring junction,
which was further confirmed by the very low NOE sig-
nal of H-3a upon irradiation of H -4 (Fig. 3). A similar
b
spectral phenomenon was also observed in case of com-
pound 9.
As a conclusion, a simple and straightforward method
was developed to synthesis (6)-trans-hexahydropyrrolo
[
3,4-d]oxazol-2-one and its derivatives. Further studies
on the application of these compounds to prepare a se-
ries of 2-oxazolidinone analogues where the morpholine
moiety of linezolid could be replaced with these
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2010
Synthesis of (6)-trans-Hexahydropyrrolo[3,4-d]Oxazol-2-one and
Its Derivatives by Using N-(tert-Butyloxycarbonyl)-3-pyrroline as Precursor
1395
heterobicyclic systems are actively underway in our
laboratories.
treated with benzylamine (47.2 g, 0.44 mol) and stirred at
ꢀ
ꢀ
6
5 C for 2 h, then cooled to 0 C. The resultant precipitates
were collected by filtration, washed with water and i-Pr O and
dried to afford 4b as white crystals in 60% yield relative to 1b
2
ꢀ
31.1 g), mp 140–141 C; H NMR (CDCl ): d 1.46 (s, 9H, t-
3
1
(
EXPERIMENTAL
butyl), 1.8 (br s, 2H, OH and NH) 3.10–3.30 (m, 3H, C A2H
2
and C
2
5
AH), 3.57–3.75 (m, 2H, C
3
AH and C AH), 3.82 (d,
5
N-(tert-Butyloxycarbonyl)-3-pyrroline (1b) was synthesized
in-house (purity >99%) [3]. All reagents and solvents used
were of commercial grade and were used as such, unless other-
H, NCH
2
APh), 4.1 (m, 1H, C AH), 7.21–7.38 (m, 5H, ArH);
4
þ
þ
ESI-MS: m/z (%) 291.2 (100, M ꢁ1), 293.2 (15, M þ1); IR
ꢁ1
(
KBr): m 3255 (OH), 1694 (C ¼¼ O) cm
.
ꢀ
wise specified. Reaction flasks were oven-dried at 200 C,
Preparation of (6)-trans-tert-butyl hexahydro-3-methyl-
-oxopyrrolo[3,4-d]oxazole-5-carboxylate, 3a. The amino
alcohol 4a (5.0 g, 0.023 mol) was dissolved in dichlorome-
flame-dried, and flushed with dry nitrogen prior to use. All
moisture and air-sensitive reactions were carried out under an
atmosphere of dry nitrogen. TLC was performed on Kieselgel
2
ꢀ
thane (30 mL) and the solution was cooled to 0 C. Triphos-
gene (8.23 g, 0.028 mol) was added followed by DIPEA (9.0
g, 0.07 mol) at 0 C. After 1 h, the mixture was washed with
6
0 F254 silica-coated aluminium plates (Merck) and visualized
by UV light (k ¼ 254 nm) or by spraying with a solution of
ninhydrin. Organic extracts were dried over anhydrous
Na SO . Flash chromatography was performed using Kieselgel
ꢀ
2 4
water, dried over anhydrous Na SO and then concentrated
2
4
under reduced pressure. The residue was purified by column
chromatography eluting with ethyl acetate: hexane (1:1) to
give 3a as colourless liquid in 36% yield.
Preparation of (6)-trans-tert-butyl 3-azido-4-hydroxy
pyrrolidine-1-carboxylate, 5. To a stirred mixture of 1b (150
g, 0.89 mol), DMSO (1050 mL) and H O (55 mL), NBS
6
0 brand silica gel (230–400 mesh). The melting points were
determined in an open capillary tube using a B u¨ chi B-540
melting point instrument and were uncorrected. The IR spectra
were obtained on a Nicolet 380 FTIR instrument (neat for
liquids and as KBr pellets for solids). NMR spectra were
recorded with a Varian 300 MHz Mercury Plus Spectrometer
2
ꢀ
(188.3 g, 1.06 mol) was gradually added over 30 min at 0 C.
After stirring at room temperature for 2 h, water (1225 mL)
1
13
at 300 MHz ( H) and at 75 MHz ( C). Chemical shifts were
given in ppm relative to trimethylsilane. Mass spectra were
recorded on Waters quattro premier XE triple quadrupole spec-
trometer using either electron spray ionisation (ESI) or atmos-
pheric pressure chemical ionization (APCI) technique.
was added and the mixture was extracted with AcOEt (3 ꢂ
500 mL). The organic layer was washed with saturated NaCl,
dried over anhydrous Na SO4 and then concentrated under
2
reduced pressure to give crude 7 as oil. To this crude 7, aque-
ous NaOH (1N, 1110 mL, 1.11 mol) was added at room tem-
perature. After 1 h, the reaction mixture was extracted with
AcOEt (3 ꢂ 500 mL). The organic layer was washed with sat-
urated NaCl solution, dried over anhydrous Na SO and then
Preparation of (6)-trans-tert-butyl 3-bromo-4-hydroxy
pyrrolidine-1-carboxylate, 7 [13]. To a stirred solution of 1b
(
60 g, 0.355 mol), DMSO (420 mL) and H O (22 mL), NBS
2
75.3 g, 0.423 mol) was gradually added over 30 min at 0 C.
ꢀ
(
After stirring at room temperature for 2 h, water (490 mL)
2
4
concentrated under reduced pressure to give compound 8 as
oil.
was added and the mixture was extracted with AcOEt (3 ꢂ
200 mL). The organic layer was washed with brine, dried over
anhydrous Na SO and the solvent removed under vacuum to
To a solution of sodium azide (274 g, 4.21 mol) and water
1250 mL), compound 8 was added at room temperature. To
2
4
(
1
leave a crude 7 as oil in 99.6% yield (94.0 g); H NMR
this solution, acetic acid (350 mL) was slowly added at room
temperature over 40 min. After the reaction mixture was
stirred at room temperature for 24 h, the mixture was extracted
with AcOEt (3 ꢂ 500 mL). The organic layer was washed
with saturated sodium bicarbonate followed by saturated NaCl
solution, dried over anhydrous Na SO and then concentrated
(
CDCl
3
): d 1.47 (s, 9H, t-butyl), 2.8 (br s, 1H, OH), 3.36–3.45
(
m, 1H, C AH), 3.62–3.96 (m, 2H, C AH and C AH), 3.98–
5
5
2
4
.14 (m, 1H, C AH), 4.15–4.20 (m, 1H, C AH), 4.40–4.48
2
3
þ
(
(
m, 1H, C
þ
4
AH); APCI-MS: m/z (%) 266.0 (90, M þ1), 268.0
þ
88, M þ2), 533.1 (100, 2M þ3); IR (neat): m 3387 (OH),
ꢁ
1
.
2
4
1
655 (C ¼¼ O) cm
Preparation of (6)-trans-tert-butyl 3-hydroxy-4-(methyl
amino)pyrrolidine-1-carboxylate, 4a. A mixture of crude 7
47.0 g, 0.177 mol) and aqueous NaOH (1N, 222 mL, 0.222
under reduced pressure to give 5 as pale yellow color oil (162
g). This pale yellow color oil compound was proceeded to
1
next step without further purification; H NMR (CDCl
3
): d
(
1
.47 (s, 9H, t-butyl), 2.75 (br s, 1H, OH), 3.23–3.54 (m, 2H,
mol) was stirred at room temperature for 1 h. The mixture was
treated with 40% methylamine-water (182 mL, 2.344 mol) and
stirred at room temperature for 15 h. After evaporation of the
C AH and C AH), 3.56–3.80 (m, 2H, C AH and C AH),
3.90–4.01 (m, 1H, C
2
5
2
5
3
AH), 4.20–4.30 (m, 1H, C
4
AH); ESI-
þ
solvent, the residue was triturated with i-Pr O to give 4a as
MS: m/z (%) 229 (100, M þ1); IR (neat): m 3419 (OH), 2096
2
ꢁ
1
white crystals in 71% yield relative to 1b (27.2 g), mp 98–
(N
3
), 1668 (C ¼¼ O) cm
.
ꢀ
1
1
1
2
1
(
(
00 C; H NMR (DMSO-d
H, C AH), 2.43 (s, 3H, CH
H, C AH and C AH), 3.51 (br s, 2H, OH, and NH), 4.0 (m,
6
): d 1.40 (s, 9H, t-butyl), 2.38 (dd,
Preparation of (6)-trans-1-(tert-butoxycarbonyl)-4-azido
pyrrolidin-3-yl phenyl carbonate, 9. To a solution of 5 (50
2
3
), 3.1 (dd, 1H, C AH), 3.2 (m,
5
g, 0.22 mol) in dichloromethane (500 mL), pyridine (50 mL)
ꢀ
2
5
H, C AH), 4.17 (m, 1H, C AH); ESI-MS: m/z (%) 161
was added at 0 C. To this mixture, phenyl chloroformate (41
ꢀ
4
3
þ
100), 217 (85, M þ1); IR (KBr): m 3309 (OH), 2972, 1694
g, 0.262 mol) was slowly added at 0 C over 1 h. After the
reaction mixture was stirred at room temperature for 6 h, the
mixture was washed with water (250 mL) followed by satu-
ꢁ
1
C ¼¼ O) cm
Preparation of (6)-trans-tert-butyl 3-(benzylamino)-4-
hydroxypyrrolidine-1-carboxylate, 4b. A mixture of crude 7
47.0 g, 0.177 mol) and aqueous NaOH (1N, 222 mL, 0.222
mol) was stirred at room temperature for 1 h. The mixture was
.
2 4
rated NaCl solution, dried over anhydrous Na SO and then
concentrated under vacuum. The residue was triturated with
n-heptane and filtered to give 9 as a white solid in 80% yield
(
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1
396
T. Rajesh, S. P. N. Rao, K. Suresh, G. Madhusudhan, and K. Mukkanti
Vol 47
ꢀ
1
1
(
61 g), mp 92–94 C; H NMR (CDCl
butyl), 3.42–3.80 (m, 4H, C A2H and C
H, C AH), 5.08–5.14 (m, 1H, C
3
): d 1.43 (s, 9H, t-
A2H), 4.20–4.24 (m,
AH), 7.18–7.42 (m, 5H,
standing in the refrigerator converted to semi-solid); H NMR
(DMSO-d ): d 1.4 (s, 9H, t-butyl), 2.4 (s, 3H, CH ), 3.05–3.1
(m, 1H, C AH), 3.22–3.33 (m, 2H, C AH and C AH), 3.52–
3.61 (m, 1H, C AH), 3.7–3.73 (m, 1H, C AH), 4.8–4.83 (m,
2
5
6
3
1
4
1
3
4
6
4
3
ArH); C NMR (CDCl ): d 153.9, 150.7, 129.6, 126.4, 120.8,
3
6
3a
8
0.4, 79.7, 78.9, 63.1, 62.3, 49.4, 49.0, 48.9, 48.5, 28.4; ESI-
þ
1H, C AH), 7.4–7.45 (m, 2H, ArH), 7.78–7.80 (m, 2H, ArH);
6a
13
MS: m/z (%) 349.28 (100, M þ1); IR (KBr): m 2122 (N
3
),
C NMR (CDCl
80.4, 79.5, 78.1, 56.6, 55.7, 55.2, 50.0, 49.1, 48.5, 28.3, 21.5;
3
): d 154.5, 154.1, 143.8, 136.6, 129.8, 127.1,
ꢁ
1
1
757 (C ¼¼ O), 1682 (C ¼¼ O) cm
.
Preparation of tert-butyl hexahydro-2-oxopyrrolo[3,4-d]
ꢁ
1
IR (neat): m 2973, 1753 (C ¼¼ O), 1690 (C ¼¼ O) cm ; ESI-MS:
þ
oxazole-5-carboxylate, 10. A solution of 9 (20 g, 0.057) in
methanol (200 mL) was treated with palladium carbon (2 g,
m/z (%) 193.14 (100), 383.26 (45, M þ1).
General procedure for the preparation of hexahydro-3-
alkylpyrrolo[3,4-d]oxazol-2-one, 3d-f. To a solution of 3a-c
(0.003 mol) in methanol (10 mL), 10% HCl in methanol (2.2
1
0% palladium content) and hydrogenated at 20 psi for 10 h.
The reaction mixture was filtered and concentrated in vacuum.
The residue was purified by column chromatography eluting
with ethyl acetate: hexane (2:1) to give tert-butyl hexahydro-2-
ꢀ
mL, 0.006 mol) was added slowly at 10 C. The reaction mix-
ture was stirred at room temperature for 4–5 h. The solvent
was removed under reduced pressure and the residue is diluted
with saturated sodium bicarbonate solution. The mixture is
extracted with dichloromethane, washed with saturated NaCl
solution and dried over anhydrous Na SO . The solvent was
oxopyrrolo[3,4-d]oxazole-5-carboxylate (10) as a colorless oil
): d 1.38 (s, 9H, t-
1
in 62% yield (8.1 g), H NMR (CDCl
3
butyl), 3.56–3.61 (m, 1H, C
C A2H and C AH) 4.80–4.96 (m, 1H, C AH), 8.02 (br s,
1
2
4
AH), 3.65–3.78 (m, 4H, C AH,
4
6
3a
6a
þ
2
4
H, NH); ESI-MS: m/z (%) 229.2 (100, M þ1); IR (neat): m
removed under vacuum and the obtained residue was purified
by column chromatography eluting with ethyl acetate: hexane
(2:1) to give 3d-f.
ꢁ
1
972 (NH), 1749 (C ¼¼ O), 1694 (C ¼¼ O) cm
.
General procedure for the preparation of tert-butyl hexa
hydro-3-alkyl-2-oxopyrrolo[3,4-d]oxazole-5-carboxylate, 3a-
b. To a solution of 10 (1.0 g, 0.0044 mol) in DMF (30 mL),
sodium hydride (0.5 g, 60% dispersion in mineral oil) was
added in one portion at room temperature. After 1 h, benzyl
bromide or iodomethane (0.0044 mol) was added in a drop
wise fashion. The reaction was left to stir for 5–8 h at room
temperature. The reaction mixture was then poured into ice
Hexahydro-3-methylpyrrolo[3,4-d]oxazol-2-one,
compound was obtained as yellow color liquid in 92% yield;
3d. This
1
H NMR (CDCl ): d 2.8 (s, 3H, CH ), 3.12–3.25 (m, 4H,
3
3
C
6
A2H and C
4
A2H), 4.21–4.26 (m, 1H, C3aAH), 4.81–4.86
(m, 1H, C6aAH), 6.0 (br s, 1H, NH); IR (neat): m 3223 (NH),
ꢁ
1
þ
1690 (C ¼¼ O) cm ; ESI-MS: m/z (%) 143.10 (100, M þ1).
Anal. Calcd. for C H N O : C 50.69; H 7.09; N 19.71.
6
10 2 2
(
20 mL) and the aqueous phase was extracted with dichloro-
methane (3 ꢂ 20 mL). The combined dichloromethane layer
was washed with water and dried over anhydrous Na SO . The
Found: C 50.42; H 6.88; N 19.92.
Hexahydro-3-benzylpyrrolo[3,4-d]oxazol-2-one,
3e. This
compound was obtained as yellow color liquid in 89% yield;
2
4
1
solvent was removed under vacuum and the obtained residue
was purified by column chromatography eluting with ethyl ac-
etate: hexane (1:1) to give corresponding 2-oxazolidinone.
tert-Butyl hexahydro-3-methyl-2-oxopyrrolo[3,4-d]oxazole-
H NMR (CDCl
3 4
): d 3.07–3.34 (m, 1H, C AH), 3.36–3.61 (m,
2H, C AH and C AH), 3.63–3.78 (m, 2H, C AH and C AH),
6
4
6
3a
4.5 (s, 2H, NCH APh), 4.68–4.72 (m, 1H, C AH), 7.16–7.28
2
6a
ꢁ
1
(m, 5H, ArH); IR (neat): m 3310 (NH), 1692 (C ¼¼ O) cm
;
þ
5
-carboxylate, 3a. This compound was obtained as colorless
1
ESI-MS: m/z (%) 219.09 (100, M þ1). Anal. Calcd. for
liquid in 66% yield; H NMR (CDCl ): d 1.46 (s, 9H, t-butyl),
C H N O : C 66.04; H 6.47; N 12.84. Found: C 66.32; H
12 14 2 2
3
3
.20–3.30 (m, 1H, C AH), 3.4–3.7 (m, 4H, C AH, C A2H
6.27; N 12.51.
Hexahydro-3-tosylpyrrolo[3,4-d]oxazol-2-one, 3f. This com-
pound was obtained as yellow color liquid in 87% yield (upon
4
4
6
and C3aAH), 3.82 (s, 3H, CH
3
), 4.8 (m, 1H, C6aAH); ESI-MS:
þ
m/z (%) 243.15 (100, M þ1); IR (neat): m 2975, 1695 (C ¼¼ O),
ꢁ
1
.
1
long standing in the refrigerator converted to semi-solid); H
1
423 cm
tert-Butyl hexahydro-3-benzyl-2-oxopyrrolo[3,4-d]oxazole-
NMR (DMSO-d ): d 2.4 (s, 3H, CH ), 2.43–2.77 (m, 1H,
6
3
5-carboxylate, 3b. This compound was obtained as pale yellow
color liquid in 55% yield; H NMR (CDCl
C AH), 2.95–3.0 (dd, 1H, C AH), 3.1–3.3 (m, 2H, C AH and
4
6
6
1
3
): d 1.46 (s, 9H, t-
C AH), 3.58–3.60 (m, 1H, C AH), 4.81–4.84 (m, 1H,
4
3a
butyl), 3.1–3.37 (m, 1H, C AH), 3.39–3.63 (m, 2H, C AH,
C AH), 7.26–7.33 (d, 2H, ArH), 7.75–7.78 (d, 2H, ArH); IR
4
6
6a
ꢁ
1
and C
2
4
AH), 3.6–3.82 (m, 2H, C
6
AH, and C3aAH), 4.56 (s,
(neat): m 3305 (NH), 1694 (C ¼¼ O) cm ; ESI-MS: m/z (%)
þ
H, NCH APh), 4.8 (m, 1H, C6aAH), 7.26–7.35 (m, 5H,
2
2
H 5.00; N 9.92. Found: C 51.35; H 4.88; N 9.71.
83.10 (100, M þ1). Anal. Calcd. for C H N O S: C 51.05;
12 14 2 4
13
ArH); C NMR (CDCl ): d 154.7, 137.7, 128.5, 127.8, 127.7,
3
1
4
2
27.6, 83.7, 82.9, 79.4, 71.5, 55.5, 54.5, 51.8, 51.4, 50.5, 49.5,
8.6, 28.4; ESI-MS: m/z (%) 319 (100, M þ1); IR (neat): m
þ
ꢁ
1
Acknowledgments. The authors acknowledge Inogent Labora-
tories Private Limited (A GVK BIO Company) for their support
and encouragement throughout this study.
973, 1690 (C ¼¼ O), 1409 cm
.
Preparation of tert-butyl hexahydro-2-oxo-3-tosylpyrrolo
3,4-d]oxazole-5-carboxylate, 3c. To a solution of 10 (1.0 g,
.0044 mol) in dichloromethane (30 mL), DIPEA (1.7 g, 0.013
[
0
mol) was added in one portion at room temperature. p-Toluene
sulfonyl chloride (1.0 g, 0.005 mol) was slowly added to the
reaction mixture at 0 C. After 2 h, the reaction mixture was
diluted with water. The organic layer was washed with water
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