An expeditious synthesis of benzoxazine-2-thione C-nucleosides via Cu(OTf)2-mediated dehydrazinative β-glycosylation

Article abstract of DOI:10.1080/15257770802458212

A novel expeditious synthetic protocol for 1,3-benzoxazine-2-thione C-nucleosides via Cu(OTf)2-mediated dehydrazinative β-glycosylation of 4-hydrazino-2H-benz[e]-1,3-oxazine-2-thiones with unprotected D-ribose is reported. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/15257770802458212

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An Expeditious Synthesis of
Benzoxazine-2-Thione c-Nucleosides Via
Cu(OTf)2-Mediated Dehydrazinative β-
Glycosylation
Lal Dhar S. Yadav a & Vijai K. Rai a
a Green Synthesis Lab, Department of Chemistry , University of
Allahabad , Allahabad, India
Published online: 26 Nov 2008.
To cite this article: Lal Dhar S. Yadav & Vijai K. Rai (2008) An Expeditious Synthesis of Benzoxazine-2-
Thione c-Nucleosides Via Cu(OTf)2-Mediated Dehydrazinative β-Glycosylation, Nucleosides,
Nucleotides and Nucleic Acids, 27:12, 1227-1237, DOI: 10.1080/15257770802458212
To link to this article: http://dx.doi.org/10.1080/15257770802458212
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Nucleosides, Nucleotides and Nucleic Acids, 27:1227–1237, 2008
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770802458212
AN EXPEDITIOUS SYNTHESIS OF BENZOXAZINE-2-THIONE
C-NUCLEOSIDES VIA Cu(OTf)2-MEDIATED DEHYDRAZINATIVE
β-GLYCOSYLATION
Lal Dhar S. Yadav and Vijai K. Rai
Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad, India
A novel expeditious synthetic protocol for 1,3-benzoxazine-2-thione C-nucleosides via Cu(OTf)2-
2
mediated dehydrazinative β-glycosylation of 4-hydrazino-2H-benz[e]-1,3-oxazine-2-thiones with
unprotected D-ribose is reported.
Keywords
1,3-Benzoxazine-2-thione C-nucleosides; unprotected D-ribose; non-
nucleoside reverse transcriptase inhibitor (NNRTI)
INTRODUCTION
Efavirenz (Sustiva), a benzoxazinone derivative, is a non-nucleoside
reverse transcriptase inhibitor (NNRTI) that has been approved by the U.S.
Food and Drug administration (FDA) and is presently in clinical use for
the treatment of AIDS. The strategy for the fight against HIV by developing
more efficacious drugs than Efavirenz has been the prime driving force for
ingenious benzoxazinone derivatizations.[1–6] Moreover, our interest in the
family of C-nucleosides also resides with the naturally occurring antibiotics.
Several of these have potent antiviral, anticancer and antitumour activity
and, as a result of C-C glycosidic linkage, they are resistant to enzymatic
hydrolysis which is the major factor in the degradation of N-nucleosides.[7]
The formation of C-C bond at the anomeric carbon, especially C-
glycosylation of bioactive heterocycles, is a field of increasing interest
in synthetic organic chemistry. The most common methods for the C-C
bond formation at the anomeric centre involve nucleophilic attack on the
Received 8 July y2008; accepted 20 August 2008.
We sincerely thank the Sophisticated Analytical Instrument Facility (SAIF), Punjab University,
Chandigarh, for providing microanalyses and spectra.
Address correspondence to Lal Dhar S. Yadav, Green Synthesis Lab, Department of Chemistry,
University of Allahabad, Allahabad-211 002, U. P., India. E-mail: ldsyadav@hotmail.com
1227

1228
L. D. S. Yadav and V. K. Rai
intrinsically electrophilic anomeric carbons.[8–11] In most cases, these pro-
cedures require specific, awkward reaction conditions and generally suffer
from low yields. Although microwave (MW)-assisted heterocyclisations have
gained significant interest for over a decade,[12,13] the first example of
MW-assisted solvent-free synthesis of nucleoside analogues was reported very
recently.[14]
Considering the above points and in pursuing our work on the devel-
opment of organic syntheses in solvent-free MW-assisted conditions,[15–19]
we present herein the first report on Cu(OTf)2-mediated dehydrazina-
tive β-glycosylation yielding benzoxazine-2-thione C-nucleosides. The key
element in our approach is the novel utilization of salicylaldehyde as a
bifunctional building block whose application to the construction of various
benzo-fused oxygen heterocycles of chemical and biological interest is well
documented.[20–23]
RESULTS AND DISCUSSION
1,3-Oxazine-2-thiones 4 were synthesized in 78–89% yields by MW irra-
diation of an intimate solvent-free mixture of salicylaldehydes 1, thiosemi-
carbazide 2, and Cu(OTf)2 (0.30 equivalent) in an open vessel under air.
The reaction proceeds via domino cycloisomerization of in situ formed
N -phenylthiosemicarbazones 3 to 4-hydrazino-1,3-oxazine-2-thiones 3ꢁ and
dehydrazination of compounds 3ꢁ to target oxazines 4 (Scheme 1). Here,
Cu(OTf)2 plays a dual role of Lewis acid and oxidant. Only 0.30 equivalent
of Cu(OTf)2 is sufficient to complete the reaction because Cu(I) formed
is oxidized to Cu(II) by air under the reaction conditions and a redox
cycle is established. A plausible mechanism of dehydrazination of 3ꢁ into 4
using Cu(II) is depicted in Scheme 2. Although the present dehydrazinative
cyclization to afford 1,3-oxazine-2-thione 4 is our new finding, similar
dehydrazination reactions using Cu(II) have already been reported in the
literature.[24–27]
In our initial experiments for the synthesis of compounds 4, we used
CeCl3.7H2O/NaI as Lewis acid catalyst but compounds 3ꢁ rather than
compounds 4 were isolated in 73–87% yields. Compounds 3ꢁ on further
treatment with copper(II) sulfate on alumina support afforded the target
oxazines 4 in 55–67% yields. In order to improve the yields and synthesize
target 1,3-oxazine-2-thiones 4 expeditiously from salicylaldehydes 1 in a
one-pot procedure, we relied upon the significant advantages of Cu(OTf)2,
which acts not only as an efficient Lewis acid catalyst for cycloisomerization
of compounds 3 to 3ꢁ but also as copper(II) source for the desired
dehydrazination of 4-hydrazino-1,3-oxazin-2-thiones 3ꢁ to afford 4. Other
mineral catalysts, viz. CeCl3.7H2O, K-10 clay, and acidic, neutral, or basic
alumina were far less effective resulting in either no reaction (in the case of
basic alumina) or relatively moderate (36–50%, in case of CeCl3.7H2O, K-10

Synthesis of Benzoxazine-2-Thione C-Nucleosides
1229
R1
S
O
δ
R1
H
O
S
R2
H2NNHCNHAr
HO
S
δ
ArHN
ArHN
H
2
HN
R2
Cu(OTf)2, MW
HN
OH
R2
N
N
S
R1
1
3
H
R1
R1
R1
R1
S
ArHN
O
O
O
O
Cu2+
-2H+
S
S
HN
N
N
R2
Ar
R2
Ar
R2
R2
ArHN
N
NHNH2
N=NH
NNH2
3'
R1
O
S
N
-N2
Ar
R2
4
SCHEME 1 Tentative mechanism for the formation of 1,3-benzoxazine-2-thione4
clay) to low yields (12–21%, in case of silica gel, neutral and acidic alumina)
of compounds 3ꢁ.
After considerable experimentation, it was found that the envisaged
β-glycosylation of 4 was successful with the unprotected D-ribose 6 in the
presence of NaH/THF at 60◦C to give 4-β-D-ribofuranosyl-2H-benz[e]-1,3-
oxazine-2-thiones 9 in 75–87% yield. The formation of C-nucleosides 9
probably results with the initial generation of a carbanion 5 at the activated
benzylic carbon and its nucleophilic attack on the electrophilic anomeric
carbon of D-ribose 6 followed by cyclization as outlined in Scheme 3.
It has been shown that α,β-C-glycofuranoside analogues having an
activated methylene group adjacent to the anomeric carbon underwent
anomeric equilibration via an acyclic intermediate upon prolonged reaction
under basic conditions leading ultimately to one predominant thermody-
namically stable anomer.[28] The exclusive formation of the β-ribofuranosyl
stereoisomer 9 at 60◦C could be perceived from thermodynamic control
driven largely by steric interactions because of the bulky benzoxazinone
moiety. The critical structural assignments of the configurations at the
ribofuranosyl anomeric center of C-nucleosides 9 were made on the basis of
detailed analysis of 1H NMR spectra, NOE experiments,[29] and comparison
Cu(II)
Cu(II)
R1
RNH-NH2
RNH-NH2
RNHNH
RNH-NH2
H+
Cu(II)
RNH-NH
Cu(I)
O
S
3'
R
=
Ar
N
R2
Cu(II)
RNH-NH
R-H
R-N=NH
N2
H+
Cu(I)
4
SCHEME 2 Plausible mechanism for dehydrazination of 3ꢁ into 4

1230
L. D. S. Yadav and V. K. Rai
HO
HO OH
O
R1
OH
R1
NaH/THF
O
6
O
60 oC
-H2
S
O
NaH/THF
rt, 2 h, 60 oC
N
N
O
R2
Ar
R2
Ar
Na
4
5
R1
R1
R1
O
O
O
O
O
Ar
N
O
N
H
Ar
N
Ar
OH
R2
R2
R2
HO
O
OH
HO
HO
HO OH
HO OH
HO OH
9
8
7
R1
R2
Ar
R1
R2
Ar
4,9
4,9
a
b
c
d
e
f
H
H
Br
H
Cl
H
H
Br
H
Cl
H
H
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
g
h
i
Br
Br
Cl
Cl
Br
Br
Cl
Cl
j
SCHEME 3 Tentative mechanism for β-glycosylation of 1,3-benzoxzine-2-thione4
with appropriate reference data.[30–32] In fact, selective irradiation of the
H-1ꢁ signal of 9 significantly increased the intensity of the H-4ꢁ signal
(2.0–2.8%), while no intensity enhancement of the H-3ꢁ signal was ob-
served; this is consistent with the β-glycosidic linkage. Furthermore, the
ꢁ
ꢁ
ꢁ
ꢁ
comparison of J 1 ,2 values of 9 (J 1 ,2 = 5.4–5.8 Hz) with those of similar
ꢁ
ꢁ
systems in the literature (J 1 ,2 = 5.4–5.9 Hz) also supported a β-glycosidic
linkage.[30–32] These analyses permit assignment of compounds 9 as the
β-D-ribofuranoside anomer.
In summary, we have developed a novel expeditious synthetic protocol
for benzoxazine-2-thione C-nucleosides via dehydrazinative β-glycosylation.
Furthermore, the Knoevenagel-type condensation presented in this paper
represents a very convenient method for the preparation of pure β-C-
glycosides in one step directly from the unprotected sugar and a compound
containing an activated methylene group.
EXPERIMENTAL
Melting points were determined by open glass capillary method and are
uncorrected. IR spectra in KBr were recorded on a Perkin-Elmer 993 IR
1
spectrophotometer. H NMR spectra were recorded on a Bruker WM-40 C
(400 MHz) FT spectrometer in DMSO-d6 using TMS as internal reference.
13C NMR spectra were recorded on the same instrument at 100 MHz
in DMSO-d6 and TMS was used as internal reference. Mass (EI) spectra

Synthesis of Benzoxazine-2-Thione C-Nucleosides
1231
were recorded on a JEOL D-300 mass spectrometer. Elemental analyses
were carried out in a Coleman automatic carbon, hydrogen and nitrogen
analyzer. A Chemical Laboratory Microwave Oven (Model; BP-310/50, 230
volt, 50 Hz power input) was used for all experiments. All chemicals used
were reagent grade and were used as received without further purification.
Silica gel-G was used for TLC.
3-Aryl-2H-benz[e]-1,3-oxazine-2-thiones 4; General Procedure
Thoroughly mixed salicylaldehyde 1 (when R1 = R2 = H; 0.12 g, 1.00
mmol), N -arylthiosemicarbazide 2 (when Ar = 4-ClC6H4; 0.20 g, 1.00 mmol)
and Cu(OTf)2 (0.11 g, 0.30 mmol) were taken in a 20 mL open vial and
subjected to MW irradiation for 7–12 minutes at 90◦C under air. After
completion of the reaction as indicated by TLC (hexane-AcOEt, 8:2, v/v),
the product was extracted with dichloromethane (3 × 25 mL), the extract
was filtered and the filtrate was evaporated under reduced pressure to
leave the crude product, which was recrystallized from ethanol to obtain
an analytically pure sample of 4 as yellowish needles.
4a: yellowish needles; m.p. 170–172◦C. IR (KBr): ν 3011, 1595, 1585,
1450 cm−1. 1H NMR (400 MHz, DMSO-d6): δ 6.56 (d, 1H, J = 13 Hz, axial
H of CH2), 6.63 (d, 1H, J = 13 Hz, equatorial H of CH2), 6.71–7.09 (m,
6Harom), 7.28–7.35 (m, 2Harom). 13C NMR (100 MHz, DMSO-d6): δ 64.5,
113.1, 114.5, 118.2, 120.5, 122.7, 128.5, 129.6, 130.5, 150.2, 166.2, 192.3.
EIMS m/z = 275, 277 (M+, M+ + 2). Anal. calcd for C14H10ClNOS: C, 60.98;
H, 3.66; N, 5.08. Found: C, 60.67; H, 3.91; N, 5.26.
4b: yellowish needles; m.p. 159–161◦C. IR (KBr): ν 3010, 1600, 1585,
1455 cm−1. 1H NMR (400 MHz, DMSO-d6): δ 6.53 (d, 1H, J = 13 Hz, axial
H of CH2), 6.65 (d, 1H, J = 13 Hz, equatorial H of CH2), 6.69–7.13 (m,
3Harom), 7.19–7.41 (m, 4Harom). 13C NMR (100 MHz, DMSO-d6): δ 64.2,
113.5, 114.7, 118.8, 120.6, 122.5, 128.1, 129.7, 130.2, 150.1, 166.4, 192.5.
EIMS m/z = 355 (M+). Anal. calcd for C14H9BrClNOS: C, 47.41; H, 2.56; N,
3.59. Found: C, 47.68; H, 2.71; N, 3.45.
4c: yellowish needles; m.p. 143–145◦C. IR (KBr): ν 3012, 1601, 1581,
1456 cm−1. 1H NMR (400 MHz, DMSO-d6): δ 6.55 (d, 1H, J = 13 Hz, axial
H of CH2), 6.64 (d, 1H, J = 13 Hz, equatorial H of CH2), 6.68–7.05 (m,
2Harom), 7.21–7.48 (m, 4Harom). 13C NMR (100 MHz, DMSO-d6): δ 64.2,
113.2, 114.1, 118.5, 120.2, 121.9, 128.2, 129.5, 130.3, 150.3, 166.2, 192.1.
EIMS m/z = 435 (M+). Anal. calcd for C14H8Br2ClNOS: C, 38.78; H, 1.86;
N, 3.23. Found: C, 38.44; H, 2.07; N, 2.91.
4d. yellowish needles; m.p. 149–151◦C. IR (KBr): ν 3011, 1598, 1580,
1455 cm−1. 1H NMR (400 MHz, DMSO-d6): δ 6.54 (d, 1H, J = 13 Hz, axial
H of CH2), 6.66 (d, 1H, J = 13 Hz, equatorial H of CH2), 6.75–7.11 (m,
3Harom), 7.19–7.39 (m, 4Harom). 13C NMR (100 MHz, DMSO-d6): δ 64.5,
113.0, 114.2, 118.4, 120.5, 122.2, 128.5, 129.2, 130.1, 150.2, 166.0, 192.2.

1232
L. D. S. Yadav and V. K. Rai
EIMS m/z = 309, 311 (M+, M++2). Anal. calcd for C14H9Cl2NOS: C, 54.21;
H, 2.92; N, 4.52. Found: C, 54.49; H, 2.78; N, 4.35.
4e. yellowish needles; m.p. 183–185◦C. IR (KBr): ν 3010, 1605, 1581,
1455 cm−1. 1H NMR (400 MHz, DMSO-d6): δ 6.59 (d, 1H, J = 13 Hz, axial
H of CH2), 6.67 (d, 1H, J = 13 Hz, equatorial H of CH2), 6.75–7.12 (m,
2Harom), 7.31–7.39 (m, 4Harom). 13C NMR (100 MHz, DMSO-d6): δ 64.3,
113.0, 114.4, 118.8, 120.2, 122.9, 129.0, 130.3, 135.5, 151.1, 166.5, 192.1.
EIMS m/z = 343, 345 (M+, M++2). Anal. calcd for C14H8Cl3NOS: C, 48.79;
H, 2.34; N, 4.06. Found: C, 49.03; H, 2.49; N, 4.31.
4f: yellowish needles; m.p. 170–180◦C. IR (KBr): ν 3010, 1603, 1587,
1
1450 cm−1. H NMR (400 MHz, DMSO-d6): δ 3.73 (s, 3H, OMe), 6.52 (d,
1H, J = 13 Hz, axial H of CH2), 6.68 (d, 1H, J = 13 Hz, equatorial H of
CH2), 6.70–7.11 (m, 6Harom), 7.18–7.35 (m, 2Harom). 13C NMR (100 MHz,
DMSO-d6): δ 53.5, 64.0, 113.2, 114.7, 118.5, 120.2, 122.7, 128.3, 129.5, 130.3,
150.5, 166.3, 192.3. EIMS m/z = 273 (M+). Anal. calcd for C15H13NO2S: C,
66.40; H, 4.83; N, 5.16. Found: C, 66.69; H, 4.58; N, 5.27.
4g: yellowish needles; m.p. 155–157◦C. IR (KBr): ν 3009, 1595, 1583,
1
1452 cm−1. H NMR (400 MHz, DMSO-d6): δ 3.76 (s, 3H, OMe), 6.53 (d,
1H, J = 13 Hz, axial H of CH2), 6.67 (d, 1H, J = 13 Hz, equatorial H of
CH2), 6.75–7.11 (m, 3Harom), 7.28–7.42 (m, 4Harom). 13C NMR (100 MHz,
DMSO-d6): δ 53.1, 64.3, 113.1, 114.0, 118.3, 120.1, 122.3, 128.2, 129.2, 130.5,
150.2, 166.4, 192.5. EIMS m/z = 351 (M+). Anal. calcd for C15H12BrNO2S:
C, 51.44; H, 3.45; N, 4.00. Found: C, 51.19; H, 3.61; N, 3.85.
4h: yellowish needles; m.p. 138–140◦C. IR (KBr): ν 3012, 1599, 1588,
1
1455 cm−1. H NMR (400 MHz, DMSO-d6): δ 3.75 (s, 3H, OMe), 6.51 (d,
1H, J = 13 Hz, axial H of CH2), 6.65 (d, 1H, J = 13 Hz, equatorial H of
CH2), 6.78–7.15 (m, 2Harom), 7.21–7.33 (m, 4Harom). 13C NMR (100 MHz,
DMSO-d6): δ 53.3, 64.2, 113.3, 114.3, 118.2, 120.4, 122.2, 128.5, 129.3, 130.2,
150.5, 166.1, 192.2. EIMS m/z = 331 (M+). Anal. calcd for C15H11Br2NO2S:
C, 41.98; H, 2.58; N, 3.26. Found: C, 42.32; H, 2.89; N, 3.39.
4i: yellowish needles; m.p. 163–165◦C. IR (KBr): ν 3010, 1605, 1579,
1
1449 cm−1. H NMR (400 MHz, DMSO-d6): δ 3.76 (s, 3H, OMe), 6.52 (d,
1H, J = 13 Hz, axial H of CH2), 6.68 (d, 1H, J = 13 Hz, equatorial H of
CH2), 6.71–7.09 (m, 3Harom), 7.15–7.34 (m, 4Harom). 13C NMR (100 MHz,
DMSO-d6): δ 53.8, 64.4, 113.5, 114.6, 118.7, 120.2, 122.5, 128.1, 129.2, 130.1,
150.8, 166.7, 192.3. EIMS m/z = 307 (M+). Anal. calcd for C15H12ClNO2S:
C, 58.92; H, 3.96; N, 4.58. Found: C, 58.59; H, 3.67; N, 4.87.
4j: yellowish needles; m.p. 134–136◦C. IR (KBr): ν 3010, 1600, 1582,
1
1452 cm−1. H NMR (400 MHz, DMSO-d6): δ 3.72 (s, 3H, OMe), 6.51 (d,
1H, J = 13 Hz, axial H of CH2), 6.66 (d, 1H, J = 13 Hz, equatorial H of
CH2), 6.79–7.11 (m, 2Harom), 7.28–7.39 (m, 4Harom). 13C NMR (100 MHz,
DMSO-d6): δ 53.5, 64.3, 113.2, 114.5, 118.6, 120.4, 122.4, 128.2, 129.5, 130.7,
150.6, 166.3, 192.7. EIMS m/z = 341 (M+). Anal. calcd for C15H11Cl2NO2S:
C, 52.95; H, 3.26; N, 4.12. Found: C, 52.71; H, 3.49; N, 3.95.

Synthesis of Benzoxazine-2-Thione C-Nucleosides
1233
3-Aryl-4-β-D-ribofuranosyl-3,4-dihydro-2H-benz[e]-1,3-oxazine-2-
thiones 9; General
Procedure
To a suspension of 1,3-benzoxazine-2-thione 4 (when Ar = 4-ClC6H4,
R1 = R2 = H; 0.28 g, 1.00 mmol) in THF (10 mL) was added slowly a
suspension of sodium hydride (0.12 g, 5.00 mmol) in THF (10 mL) with
stirring at room temperature. After the addition was completed and the
evolution of hydrogen gas (effervescence) had ceased, the reaction mixture
was stirred at 60◦C for 45 minutes and then cooled to room temperature.
Next, D-ribose (0.30 g, 2.00 mmol) was added to it and further stirred for
4–5 hours at 60◦C. After completion of the reaction as indicated by TLC
(hexane/AcOEt, 9:1, v/v), glacial acetic acid (2.0 mL) was added followed
by water (10 mL) and the product was extracted with dichloromethane
(3 × 25 mL). The extract was filtered and the filtrate was evaporated
under reduced pressure to leave the crude product, which was recrystallized
from ethanol to obtain an analytically pure sample of 9 as yellowish
powder.
9a. Yellowish powder; m.p. 229–231◦C. [α]D:[27] + 46.4 o (c 1.5, MeOH).
IR (KBr): ν 3391, 3013, 1605, 1585, 1456 cm−1. 1H NMR (400 MHz, DMSO-
d6): δ 3.53 (ddd, 1H, J = 3.4, 5.3, 11.6 Hz, Ha-5ꢁ), 3.61 (ddd, 1H, J = 3.4,
5.7, 11.6 Hz, Hb-5ꢁ), 4.05 (ddd, 1H, J = 4.2, 3.5, 3.4 Hz, H-4ꢁ), 4.37 (dd,
1H, J = 5.6, 6.4 Hz, H-1ꢁ), 4.49 (ddd, 1H, J = 4.6, 5.6, 6.8 Hz, H-2ꢁ), 4.67
(ddd, 1H, J = 4.6, 5.2, 6.8 Hz, H-3ꢁ), 5.15 (dd, 1H, J = 5.3, 5.7 Hz, OH-5ꢁ),
5.31 (d, 1H, J = 5.2 Hz, OH-3ꢁ), 5.58 (d, 1H, J = 5.6 Hz, OH-2ꢁ), 6.55 (d,
1H, J = 6.4 Hz, H-4), 6.75–7.05 (m, 6Harom), 7.21–7.38 (m, 2Harom). 13C
NMR (100 MHz, DMSO-d6): δ 37.5, 62.2, 72.8, 73.3, 76.6, 78.3, 83.5, 113.2,
114.5, 119.0, 121.5, 122.9, 130.3, 132.0, 151.8, 166.5, 192.2. MS m/z (FAB,
NBA) 408 [MH+]. Anal. calcd for C19H18ClNO5S: C, 55.95; H, 4.45; N, 3.43.
Found: C, 56.21; H, 4.69; N, 3.27.
9b. Yellowish powder; m.p. 205–207◦C. [α]D:[27] + 46.8 o (c 1.5, MeOH).
IR (KBr): ν 3390, 3009, 1602, 1581, 1450 cm−1. 1H NMR (400 MHz, DMSO-
d6): δ 3.55 (ddd, 1H, J = 3.4, 5.3, 11.6 Hz, Ha-5ꢁ), 3.60 (ddd, 1H, J = 3.4,
5.7, 11.6 Hz, Hb-5ꢁ), 4.08 (ddd, 1H, J = 4.2, 3.5, 3.4 Hz, H-4ꢁ), 4.34 (dd, 1H,
J = 5.6, 6.4 Hz, H-1ꢁ), 4.47 (ddd, 1H, J = 4.6, 5.6, 6.8 Hz, H-2ꢁ), 4.68 (ddd,
1H, J = 4.6, 5.2, 6.8 Hz, H-3ꢁ), 5.18 (dd, 1H, J = 5.3, 5.7 Hz, OH-5ꢁ), 5.30
(d, 1H, J = 5.2 Hz, OH-3ꢁ), 5.55 (d, 1H, J = 5.6 Hz, OH-2ꢁ), 6.56 (d, 1H,
J = 6.4 Hz, H-4), 6.69–7.08 (m, 3Harom), 7.18–7.35 (m, 4Harom). 13C NMR
(100 MHz, DMSO-d6): δ 38.2, 62.5, 72.8, 73.5, 76.6, 78.7, 83.8, 113.2, 114.9,
119.9, 121.2, 122.5, 130.1, 131.5, 152.0, 166.5, 192.3. MS m/z (FAB, NBA)
486 [MH+]. Anal. calcd for C19H17BrClNO5S: C, 46.88; H, 3.52; N, 2.88.
Found: C, 46.52; H, 3.77; N, 3.02.
9c. Yellowish powder; m.p. 195–197◦C. [α]D:[27] + 43.9 o (c 1.5, MeOH).
1
IR (KBr): ν 3390, 3011, 1603, 1586, 1449 cm−1. H NMR (400 MHz,

1234
L. D. S. Yadav and V. K. Rai
DMSO-d6): δ 3.52 (ddd, 1H, J = 3.4, 5.3, 11.6 Hz, Ha-5ꢁ), 3.64 (ddd, 1H,
J = 3.4, 5.7, 11.6 Hz, Hb-5ꢁ), 4.09 (ddd, 1H, J = 4.2, 3.5, 3.4 Hz, H-4ꢁ), 4.33
(dd, 1H, J = 5.6, 6.5 Hz, H-1ꢁ), 4.48 (ddd, 1H, J = 4.6, 5.6, 6.8 Hz, H-2ꢁ), 4.65
(ddd, 1H, J = 4.6, 5.2, 6.8 Hz, H-3ꢁ), 5.21 (dd, 1H, J = 5.3, 5.7 Hz, OH-5ꢁ),
5.29 (d, 1H, J = 5.2 Hz, OH-3ꢁ), 5.56 (d, 1H, J = 5.6 Hz, OH-2ꢁ), 6.53 (d,
1H, J = 6.5 Hz, H-4), 6.71–7.05 (m, 2Harom), 7.21–7.35 (m, 4Harom). 13C
NMR (100 MHz, DMSO-d6): δ 38.0, 62.1, 72.5, 73.4, 76.3, 78.5, 83.5, 113.1,
114.5, 119.7, 121.1, 122.2, 130.7, 131.2, 152.9, 166.2, 192.1. MS m/z (FAB,
NBA) 566 [MH+]. Anal. calcd for C19H16Br2ClNO5S: C, 40.34; H, 2.85; N,
2.48. Found: C, 40.59; H, 2.99; N, 2.31.
9d. Yellowish powder; m.p. 211–213◦C. [α]D:[27] + 44.4 o (c 1.5, MeOH).
IR (KBr): ν 3389, 3010, 1601, 1583, 1452 cm−1. 1H NMR (400 MHz, DMSO-
d6): δ 3.56 (ddd, 1H, J = 3.4, 5.3, 11.6 Hz, Ha-5ꢁ), 3.62 (ddd, 1H, J = 3.4,
5.7, 11.6 Hz, Hb-5ꢁ), 4.07 (ddd, 1H, J = 4.2, 3.5, 3.4 Hz, H-4ꢁ), 4.35 (dd, 1H,
J = 5.5, 6.4 Hz, H-1ꢁ), 4.51 (ddd, 1H, J = 4.6, 5.5, 6.8 Hz, H-2ꢁ), 4.67 (ddd,
1H, J = 4.6, 5.2, 6.8 Hz, H-3ꢁ), 5.19 (dd, 1H, J = 5.3, 5.7 Hz, OH-5ꢁ), 5.33
(d, 1H, J = 5.2 Hz, OH-3ꢁ), 5.59 (d, 1H, J = 5.6 Hz, OH-2ꢁ), 6.55 (d, 1H,
J = 6.4 Hz, H-4), 6.70–7.12 (m, 3Harom), 7.19–7.35 (m, 4Harom). 13C NMR
(100 MHz, DMSO-d6): δ 38.5, 62.5, 72.2, 73.1, 76.2, 78.2, 83.7, 113.5, 114.3,
120.2, 121.5, 122.7, 129.9, 131.3, 152.5, 166.1, 192.5. MS m/z (FAB, NBA) 444
[MH+]. Anal. calcd for C19H17Cl2NO5S: C, 51.59; H, 3.87; N, 3.17. Found:
C, 51.32; H, 3.65; N, 3.39.
9e. Yellowish powder; m.p. 256–258◦C. [α]D:[27] + 46.9 o (c 1.5, MeOH).
IR (KBr): ν 3393, 3010, 1588, 1455 cm−1. δ 3.48 (ddd, 1H, J = 3.7, 5.4, 11.6
Hz, Ha-5ꢁ), 3.65 (ddd, 1H, J = 3.7, 5.8, 11.6 Hz, Hb-5ꢁ), 4.08 (ddd, 1H, J =
4.1, 3.7, 3.7 Hz, H-4ꢁ), 4.49 (dd, 1H, J = 5.5, 6.4 Hz, H-1ꢁ), 4.56 (ddd, 1H, J =
4.5, 5.5, 6.9 Hz, H-2ꢁ), 4.74 (ddd, 1H, J = 4.1, 5.1, 6.9 Hz, H-3ꢁ), 5.16 (dd, 1H,
J = 5.4, 5.8 Hz, OH-5ꢁ), 5.32 (d, 1H, J = 5.1 Hz, OH-3ꢁ), 5.61 (d, 1H, J = 5.5
Hz, OH-2ꢁ), 6.58 (d, 1H, J = 6.4 Hz, H-4), 6.82–7.01 (m, 2Harom), 7.29–7.43
(m, 4Harom). 13C NMR (100 MHz, DMSO-d6): δ 38.1, 62.5, 72.5, 73.8, 76.5,
78.4, 83.7, 113.5, 114.8, 119.8, 120.6, 122.7, 130.1, 131.6, 152.5, 166.7, 192.5.
MS m/z (FAB, NBA) 475 [MH+]. Anal. calcd for C19H16Cl3NO5S: C, 47.87;
H, 3.38; N, 2.94. Found: C, 47.58; H, 3.53; N, 3.09.
9f. Yellowish powder; m.p. 221–223◦C. [α]D:[27] + 47.8 o (c 1.5, MeOH).
IR (KBr): ν 3391, 3012, 1607, 1580, 1457 cm−1. 1H NMR (400 MHz, DMSO-
d6): δ 3.53 (ddd, 1H, J = 3.4, 5.3, 11.6 Hz, Ha-5ꢁ), 3.61 (ddd, 1H, J = 3.4,
5.7, 11.6 Hz, Hb-5ꢁ), 3.75 (s, 3H, OMe), 4.06 (ddd, 1H, J = 4.2, 3.5, 3.4 Hz,
H-4ꢁ), 4.34 (dd, 1H, J = 5.8, 6.4 Hz, H-1ꢁ), 4.53 (ddd, 1H, J = 4.6, 5.8, 6.8
Hz, H-2ꢁ), 4.63 (ddd, 1H, J = 4.6, 5.2, 6.8 Hz, H-3ꢁ), 5.24 (dd, 1H, J = 5.3,
5.7 Hz, OH-5ꢁ), 5.32 (d, 1H, J = 5.2 Hz, OH-3ꢁ), 5.54 (d, 1H, J = 5.6 Hz,
OH-2ꢁ), 6.57 (d, 1H, J = 6.4 Hz, H-4), 6.68–7.13 (m, 6Harom), 7.22–7.41 (m,
2Harom). 13C NMR (100 MHz, DMSO-d6): δ 38.1, 53.5, 62.2, 72.6, 73.6, 76.5,
78.3, 83.5, 113.2, 114.5, 120.1, 121.3, 122.5, 130.3, 131.0, 152.3, 166.7, 192.2.

Synthesis of Benzoxazine-2-Thione C-Nucleosides
1235
MS m/z (FAB, NBA) 404 [MH+]. Anal. calcd for C20H21NO6S: C, 59.54; H,
5.25; N, 3.47. Found: C, 59.79; H, 5.58; N, 3.31.
9g. Yellowish powder; m.p. 238–240◦C. [α]D:[27] + 42.3 o (c 1.5, MeOH).
IR (KBr): ν 3390, 3011, 1601, 1583, 1449 cm−1. 1H NMR (400 MHz, DMSO-
d6): δ 3.57 (ddd, 1H, J = 3.4, 5.3, 11.6 Hz, Ha-5ꢁ), 3.63 (ddd, 1H, J = 3.4,
5.7, 11.6 Hz, Hb-5ꢁ), 3.74 (s, 3H, OMe), 4.05 (ddd, 1H, J = 4.2, 3.5, 3.4 Hz,
H-4ꢁ), 4.31 (dd, 1H, J = 5.4, 6.3 Hz, H-1ꢁ), 4.50 (ddd, 1H, J = 4.6, 5.4, 6.8
Hz, H-2ꢁ), 4.62 (ddd, 1H, J = 4.6, 5.2, 6.8 Hz, H-3ꢁ), 5.17 (dd, 1H, J = 5.3,
5.7 Hz, OH-5ꢁ), 5.31 (d, 1H, J = 5.2 Hz, OH-3ꢁ), 5.52 (d, 1H, J = 5.6 Hz,
OH-2ꢁ), 6.51 (d, 1H, J = 6.3 Hz, H-4), 6.62–7.11 (m, 3Harom), 7.21–7.41 (m,
4Harom). 13C NMR (100 MHz, DMSO-d6): δ 38.3, 53.9, 62.4, 72.5, 73.3, 76.1,
78.6, 83.3, 113.6, 114.2, 120.3, 121.2, 123.2, 130.2, 131.5, 152.9, 166.5, 192.4.
MS m/z (FAB, NBA) 482 [MH+]. Anal. calcd for C20H20BrNO6S: C, 49.80;
H, 4.18; N, 2.90. Found: C, 49.61; H, 4.05; N, 3.17.
9h. Yellowish powder; m.p. 248–250◦C. [α]D:[27] + 45.1 o (c 1.5, MeOH).
IR (KBr): ν 3392, 3013, 1599, 1581, 1450 cm−1. 1H NMR (400 MHz, DMSO-
d6): δ 3.54 (ddd, 1H, J = 3.4, 5.3, 11.6 Hz, Ha-5ꢁ), 3.61 (ddd, 1H, J = 3.4,
5.7, 11.6 Hz, Hb-5ꢁ), 3.79 (s, 3H, OMe), 4.01 (ddd, 1H, J = 4.2, 3.5, 3.4 Hz,
H-4ꢁ), 4.32 (dd, 1H, J = 5.6, 6.4 Hz, H-1ꢁ), 4.49 (ddd, 1H, J = 4.6, 5.6, 6.8
Hz, H-2ꢁ), 4.60 (ddd, 1H, J = 4.6, 5.2, 6.8 Hz, H-3ꢁ), 5.21 (dd, 1H, J = 5.3,
5.7 Hz, OH-5ꢁ), 5.34 (d, 1H, J = 5.2 Hz, OH-3ꢁ), 5.51 (d, 1H, J = 5.6 Hz,
OH-2ꢁ), 6.50 (d, 1H, J = 6.4 Hz, H-4), 6.67–7.15 (m, 2Harom), 7.18–7.39 (m,
4Harom). 13C NMR (100 MHz, DMSO-d6): δ 38.2, 53.1, 62.3, 72.4, 73.5, 76.7,
78.1, 83.6, 113.4, 114.6, 119.5, 121.6, 123.3, 130.1, 131.8, 151.8, 166.3, 192.2.
MS m/z (FAB, NBA) 562 [MH+]. Anal. calcd for C20H19Br2NO6S: C, 42.80;
H, 3.41; N, 2.50. Found: C, 42.55; H, 3.63; N, 2.72.
9i. Yellowish powder; m.p. 224–226◦C. [α]D:[27] + 46.8 o (c 1.5, MeOH).
IR (KBr): ν 3389, 3013, 1602, 1585, 1455 cm−1. 1H NMR (400 MHz, DMSO-
d6): δ 3.57 (ddd, 1H, J = 3.4, 5.3, 11.6 Hz, Ha-5ꢁ), 3.63 (ddd, 1H, J = 3.4,
5.7, 11.6 Hz, Hb-5ꢁ), 3.72 (s, 3H, OMe), 4.03 (ddd, 1H, J = 4.2, 3.5, 3.4 Hz,
H-4ꢁ), 4.29 (dd, 1H, J = 5.4, 6.4 Hz, H-1ꢁ), 4.47 (ddd, 1H, J = 4.6, 5.4, 6.8
Hz, H-2ꢁ), 4.61 (ddd, 1H, J = 4.6, 5.2, 6.8 Hz, H-3ꢁ), 5.18 (dd, 1H, J = 5.3,
5.7 Hz, OH-5ꢁ), 5.29 (d, 1H, J = 5.2 Hz, OH-3ꢁ), 5.50 (d, 1H, J = 5.6 Hz,
OH-2ꢁ), 6.53 (d, 1H, J = 6.4 Hz, H-4), 6.63–7.09 (m, 3Harom), 7.21–7.38 (m,
4Harom). 13C NMR (100 MHz, DMSO-d6): δ 38.4, 53.3, 62.0, 72.3, 73.1, 76.8,
78.5, 83.8, 113.2, 114.0, 119.9, 121.4, 122.9, 130.3, 131.3, 152.5, 166.8, 192.5.
MS m/z (FAB, NBA) 438 [MH+]. Anal. calcd for C20H20ClNO6S: C, 54.86;
H, 4.60; N, 3.20. Found: C, 55.02; H, 4.39; N, 2.93.
9j. Yellowish powder; m.p. 260–262◦C. [α]D:[27] + 48.5 o (c 1.5, MeOH).
1
IR (KBr): ν 3391, 3012, 1605, 1580, 1453 cm−1. H NMR (400 MHz,
DMSO-d6): δ 3.56 (ddd, 1H, J = 3.4, 5.3, 11.6 Hz, Ha-5ꢁ), 3.65 (ddd, 1H,
J = 3.4, 5.7, 11.6 Hz, Hb-5ꢁ), 3.77 (s, 3H, OMe), 4.02 (ddd, 1H, J = 4.2,
3.5, 3.4 Hz, H-4ꢁ), 4.34 (dd, 1H, J = 5.8, 6.4 Hz, H-1ꢁ), 4.50 (ddd, 1H, J

1236
L. D. S. Yadav and V. K. Rai
TABLE 1 Synthesis of products 4 and 9
Time
Time
Product
(minutes)a
Yield(%)b,c
product
(hours)d
Yield(%)b,c
4a
4b
4c
4d
4e
4f
4g
4h
4i
7
8
8
10
12
10
9
7
11
10
78
87
89
79
88
85
80
86
85
79
9a
9b
9c
9d
9e
9f
9g
9h
9i
3
5
3
4
4
5
5
3
4
5
75
87
85
76
86
85
81
87
87
77
4j
9j
aMicrowave irradiation time at 90◦C.
bYield of isolated and purified products.
cAll compound gave C, H, and N analyses within 0.34% and satisfactory spectral (IR,
1H NMR, 13C NMR, and EIMS) data.
dTime for oil-bath heating at 60◦C.
= 4.6, 5.8, 6.8 Hz, H-2ꢁ), 4.63 (ddd, 1H, J = 4.6, 5.2, 6.8 Hz, H-3ꢁ), 5.22
(dd, 1H, J = 5.3, 5.7 Hz, OH-5ꢁ), 5.32 (d, 1H, J = 5.2 Hz, OH-3ꢁ), 5.51
(d, 1H, J = 5.6 Hz, OH-2ꢁ), 6.56 (d, 1H, J = 6.4 Hz, H-4), 6.68–7.12 (m,
2Harom), 7.19–7.42 (m, 4Harom). 13C NMR (100 MHz, DMSO-d6): δ 38.0,
53.4, 62.4, 72.8, 73.7, 76.3, 78.8, 83.5, 113.1, 114.3, 120.2, 121.0, 122.8, 129.8,
131.6, 152.4, 166.5, 192.3. MS m/z (FAB, NBA) 472 [MH+]. Anal. calcd for
C20H19Cl2NO6S: C, 50.86; H, 4.05; N, 2.97. Found: C, 50.63; H, 4.26; N,
3.17 (Table 1).
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