Cu(OTf)2-catalysed synthesis of structurally novel bicyclic 1,3-oxazines via condensation-dehydrazinative ring transformation cascades

Article abstract of DOI:10.3184/030823409X466753

The Cu(OTf)₂-catalysed expeditious synthesis of 1,3-oxazin-2-ones(thiones) from unprotected D-glucose and D-xylose in excellent yields is reported. Cu(OTf)₂ plays a dual role of a Lewis acid and an oxidant for dehydrazination, which

Full text of DOI:10.3184/030823409X466753

520 RESEARCH PAPER
AUGUST, 520–526
JOURNAL OF CHEMICAL RESEARCH 2009
Cu(OTf)2-catalysed synthesis of structurally novel bicyclic 1,3-oxazines
via condensation-dehydrazinative ring transformation cascades
Lal Dhar Singh Yadav*, Ankita Rai, Vijai Kumar Rai and Chhama Awasthi
Green Synthesis Laboratory, Department of Chemistry, University of Allahbad, Allahabad 211 002, India
The Cu(OTf)2-catalysed expeditious synthesis of 1,3-oxazin-2-ones(thiones) from unprotected D-glucose and
D-xylose in excellent yields is reported. Cu(OTf)2 plays a dual role of a Lewis acid and an oxidant for dehydrazination,
which is the cornerstone in the present investigation. The 1,3-oxazin-2-ones(thiones) serve as synthons for diversity
oriented synthesis of structurally distinct bicyclic 1,3-oxazin-2-ones(thiones), when subjected to Malaprade reaction,
followed by Cu(OTf)2-catalysed cyclisation with an appropriate traditional reagent such as phenylhydrazine,
amidines, hydroxylamine, or semi(thiosemi)carbazide.
Keywords: carbohydrates, copper(II) triflate, diversity oriented synthesis, 1,3-oxazines, solvent-free, microwaves
The use of biorenewable resources in organic synthesis is
a promising approach as it is in accord with sustainable
development. Carbohydrates are major raw materials for
organic chemicals with tailor-made industrial applications,
because they are inexpensive, accessible on a ton-scale and
have diverse chemical possibilities.1 Lewis acid catalysts have
been advantageously used in organic syntheses. Amongst
these, Cu(OTf)2 is an inexpensive, air and moisture stable
catalyst, which has been found useful for several catalytic
stereoselective transformations.2,3
The 1,3-oxazine nucleus features prominently in many
biologically important molecules.4-6 The most outstanding
of these, Sustiva (Efavirenz), a fused ring 1,3-oxazin-2-one
derivative, is a non-nucleoside reverse transcriptase inhibitor
(NNRTI) that has been approved by the FDA and is presently
in clinical use for the treatment of AIDS. 1,3-Oxazin-2-one
derivatives have also been recognised as chiral auxiliaries in
asymmetric synthesis.7 Furthermore, five- and six-membered
heterocycles containing a C=N bond are important structural
units in both natural products and synthetic pharmaceutical
targets. Half of the small molecule drugs receiving FDA
approval in 2005–06 contain at least one azole (five-membered)
or azine (six-membered) ring.8 Recently, Cu(OTf)2-catalysed
Biginelli type condensation has been reported for the synthesis
of 1,3-oxazin-2-ones.9
of various C=N bond-containing structurally novel five- and
six-membered bioactive heterocycles fused with biologically
potential 1,3-oxazine nucleus starting from unprotected
D-glucose/D-xylose 1 and N-phenylsemi(thiosemi)carbazide
2 (Scheme 1), which are attractive scaffolds to be utilised
for exploiting chemical diversity and generating a drug-like
library to screen for potential new leads.
To realise our idea, first we optimised the synthesis of 1,3-
oxazin-2-ones(thiones) 3, which are synthons for the present
diversity oriented synthesis (DOS). We tested several mineral
catalysts for the synthesis of compounds 3 and the best result
was obtained with montmorillonite K-10 clay affording 3 in
81–88% yields. Other mineral catalysts, namely, CeCl3.7H2O/
NaI, CeCl3.7H2O and acidic, neutral, or basic alumina were
far less effective resulting in either no reaction (in the case
of basic alumina) or relatively moderate yields (39–52%,
in case of CeCl3.7H2O CeCl3.7H2O/NaI), or too low yields
(12–23%, in case of silica gel, neutral and acidic alumina)
of compounds 4'. Compounds 4' on further treatment with
copper(II) sulfate on alumina support afforded the target 1,3-
oxazines 3 in 59–66% yields. Then, we turned our attention
to improve the yield and synthesise 3 in a one-pot procedure,
and we were successful in this effort by using Cu(OTf)2 as
catalyst. Thus, the present optimised one-step synthesis is
accomplished by microwave (MW) irradiation of an intimate
solvent-free mixture of D-glucose/D-xylose 1, N-phenylsemi
(thiosemi)carbazide 2 and Cu(OTf)2 (30 mol%) in an
open vessel under air. The reaction proceeds via domino
cycloisomerisation of in situ formed N-phenylsemi(thiosemi)
carbazones 4 to 4-hydrazino-1,3- oxazin-2-ones(thiones) 4'
and dehydrazination of compounds 4' to target oxazines 3 in
81–88% yields (Scheme 2). Here, Cu(OTf)2 plays a dual role
of a Lewis acid catalyst and an oxidant. Only 0.3 equivalent
In continuation of our quest for developing new solvent-
free microwave (MW)-assisted cyclisation processes,10-12
especially using carbohydrates as raw material,13,14 we
planned the synthesis and annulation of 1,3-oxazine ring with
five- and six-membered heterocycles containing a C=N bond.
Although many routes are well documented for the synthesis
of 1,3-oxazines fused with a benzene ring,15-22 this work
presents a new report on Cu(OTf)2-promted efficient synthesis
H
H
Ph
O
O
Ph
N
N
N
N
X
O
N
O
O(S)
H
O(S)
Ph
HO
H
CHO
(CHOH)n
CH2OH
H2NNHCNHPh
H
OH
N
(X = O, S)
Ph
N
Ph
N
H
2
O(S)
;
Ph
O
Ph
1,3-oxazin-2-
one(thione)
3
N
N
(CHOH)n-2
CH2OH
3
N
MW, Cu(OTf)2
n = 3,
n = 4,
D
-xylose
O(S)
H
O
H
O
N
O(S)
H
D
-glucose
OH
1
H
H
R
O
O
N
Ph
Ph
N
N
N
O(S)
O
O
O(S)
H
Scheme 1 Synthesis of bicyclic scaffolds from d-glucose and d-xylose.
* Correspondent. E-mail: ldsyadav@hotmail.com

JOURNAL OF CHEMICAL RESEARCH 2009 521
X
N.NH2
CHO
(CHOH)n
CH2OH
N
H2NNHCNHPh
HO
HO
N
HO
NH
NHPh
NHPh
(X = O, S)
NH
NHPh
2
X
OH
X
O
O
Cu(OTf)2, MW
n = 3, D-xylose
X
(CHOH)n-2
(CHOH)n-2
CH2OH
(CHOH)n-2
CH2OH
n = 4, D-glucose
H
CH2OH
1
4
NHNH2
N Ph
N=NH
N Ph
HO
Cu2+
-2H+
HO
HO
N Ph
X
-N2
O
X
O
X
O
(CHOH)n-2
(CHOH)n-2
CH2OH
4'
(CHOH)n-2
3a, X = O, n = 3
3b, X = S, n = 3
3c, X = O, n = 4
3d, X = S, n = 4
CH2OH
CH2OH
Scheme 2 Plausible mechanism for the formation of 1,3-oxazin-2-ones(thiones) 3 from d-glucose/d-xylose 1.
of Cu(OTf)2 is sufficient to complete the reaction because
Cu(I) formed is oxidised to Cu(II) by air under the reaction
conditions. Along with dehydrazinative reactions using Cu(II)
reported in the literature, we report here its novel application
to dehydrazinative ring-transformation reactions leading to
1,3-oxazin-2-ones(thiones) 3.23-26
formation of hydrazine during the reaction as detected
by the p-dimethylaminobenzaldehyde method.28
All the chiral carbons in 3–6 have the same absolute
configuration as that of the corresponding carbons in their
precursor carbohydrates because they are not involved in
any bond breaking/formation. This fact is supported by
the observation that there was no change in the absolute
configuration of any chiral carbon of D-xylose or D-glucose
when an intimate solvent-free mixture of D-xylose or
D-glucose (1 mmol) and Cu(OTf)2 (0.3 mmol) was subjected
to MW irradiation at 90°C for 12 min, i.e. under the present
reaction conditions. The structures of all the synthesised
compounds were established on the basis of their IR, 1H NMR,
13C NMR and EIMS data. The stereochemistry of compounds
7–11 and 13 was established by 1H NMR spectroscopic
analysis and the coupling constant of 3.1 to 3.7 Hz for the ring
junction protons in 7–11 evidences that the rings are cis-fused,
whereas in compound 13, the coupling constant of 7.6–7.8 Hz
for the ring junction protons shows that the rings are trans-
fused. For sake of convenience, the relative stereochemistry at
the ring junction in each of the bicyclic 1,3-oxazines has been
depicted in Schemes 4 and 5.
The structure and relative stereochemistry was further
confirmed by NOE interaction experiments of all the
synthesised compounds. For example, 13.2% and 12.8%
NOEs were observed between 4a-H and 7a-H in compounds
9a and 10a, respectively, whereas 13.7%, 12.8% and 11.5%
NOEs were observed between 4a-H and 8a-H protons in
products 7a, 8a and 11a respectively. On the other hand, there
was no any measurable NOE present between 4a-H and 8a-H
in compound 13. These results reveal that 4a-H and 7a-H in
compounds 9 and 10; 4a-H and 8a-H in compounds 7, 8 and
11 are located on the same face of the molecule, that is, cis
The 1,3-oxazin-2-ones(thiones)
3 were subjected to
Malaprade reaction27 (Scheme 3) to afford aldehydes 5 and
6, which were converted into the target compounds 7–11
and 13 by judicious use of the reagents (Schemes 3–5). The
strategy for the envisaged solvent-free green synthesis of
1,3-oxazin-2-one(thione)-fused isoxazoles 9, pyrazoles 10
and pyrimidines 11 consisted of microwave irradiation of
an intimate solvent-free mixture of compound 5, Cu(OTf)2
and sodium acetate with hydroxylamine hydrochloride,
phenylhydrazine hydrochloride and amidines hydrochlorides
respectively, at 85°C for 7–12 min (Scheme 4). Isolation and
purification by recrystallisation from ethanol afforded 9, 10
and 11 in 77–94% yields (Table 1). Similarly, compounds 7
and 8 were synthesised in 82–92% yields (Table 1) by MW
irradiation of an intimate solvent-free mixture of Cu(OTf)2
and sodium acetate with hydroxylamine hydrochloride and
phenylhydrazine hydrochloride respectively, at 90°C for 8–
10 min (Scheme 3). The formation of compounds 7–11 may
be tentatively explained by acid-catalysed condensation of
hydroxylamine, phenylhydrazine or amidines with aldehydic
>C=O group of 5 and 6 followed by cyclodehydration of
the resulting condensation product (Schemes 3 and 4).
Furthermore, MW irradiation of a thoroughly mixed N-
phenylsemi(thiosemi)carbazones 12 and Cu(OTf)2 at 90°C for
8-10 min afforded compounds 13 in 90–93% yields (Table 1)
via cycloisomerisation-dehydrazination of 12 (Scheme 5).
The mechanism shown in Scheme 5 is supported by the
H
HO
O
Ph
X
O
H
O
aq. NaIO4
1 equiv
74-79%
OH
Ph
N
N
N
NH2OH.HCl
Ph
X
5
N
O
AcONa
Cu(OTf)2
MW
X
-H2O
HO
O
Ph
H
H
N
OH
O
OH
5a, X = O
5b, X = S
7a, X = O
X
O
OH
7b, X = S
(CHOH)n-2
Ph
N
H
H
H
Ph
HO
CH2OH
OH
Ph
N
Ph
X
PhNHNH2.HCl
aq. NaIO4
2 equiv
76-82%
N
N
N
Ph
H
3c, X = O
3d, X = S
5
N
X
AcONa
Cu(OTf)2
MW
O
-H2O
O
X
O
O
OH
6a, X = O
6b, X = S
8a, X = O
8b, X = S
OH
Scheme 3 Malaprade reaction to afford aldehydes 5 and 6 and formation of compounds 7 and 8 from 5.

522 JOURNAL OF CHEMICAL RESEARCH 2009
Ph
HO
H
O
N
OH
Ph
H
OH
PhNHNH2.HCl
NH2OH.HCl
Ph
Ph
X
H
N
N
N
X
O
-H2O
AcONa,
Cu(OTf)2
MW
AcONa,
Cu(OTf)2
MW
N
X
O
O
H
H
O
Ph
6a, X = O
6b, X = S
O
N
O
N
9a, X = O
X
PhC=NH
NH2.HCl
9b, X = S
Cu(OTf)2
MW
-H2O
Ph
N
H
N
H
H
H
OH
11a, R = Me, X = O
11b, R = Me, X = S
11c, R = Ph, X = O
11d, R = Ph, X = S
11e, R = NH2, X = O
11f, R = NH2, X = S
Ph
X
Ph
R
N
Ph
N
O
R
N
N
N
-H2O
N
N
10a, X = O
10b, X = S
X
O
X
O
H
Scheme 4 Routes for the formation of compounds 9–11 from compounds 6.
H
O
O
O
H2N
H
O
HO
H
Ph
X
.
H2N
HN
N
Cu(OTf)
Ph
X
NH2CONHNH2 HCl
2
Ph
X
N
HN
N
O
AcONa
Cu(OTf)2
MW
N
O
N
O
O
6a, X = O
6b, X = S
12
Ph
N
O
Ph
X
H
H
O
O
O
N
O
O
Ph
S
N
N
-NH2NH2
H2N:
O
H
N
O
X
13a, X = O
13b, X = S
O
NHNH2
NNH2
Scheme 5 Routes for the formation of compounds 13 via 12 from compounds 6.
Table 1 MW-assisted solvent-free synthesis of compounds 7–11 and 13 from aldehydes 5 and 6
Entry
1
Aldehydes 5 and 6
Time/mina
8
Compounds 7–11 and 13
Yield/%b,c
82
HO
O
H
Ph
Ph
O
N
N
N
O
O
O
O
H
H
H
O
O
OH
HO
H
5a
5b
5a
OH
7a
7b
H
Ph
Ph
N
N
O
O
N
N
N
N
2
3
8
9
88
91
S
S
O
O
O
OH
H
H
OH
HO
O
Ph
N
Ph
Ph
O
N
N
O
OH
H
H
OH
8a
HO
O
Ph
N
Ph
N
Ph
S
4
5
10
7
92
77
S
O
H
OH
O
5b
H
OH
8b
Ph
H
HO
Ph
O
O
O
N
N
H
N
N
O
O
O
O
6a
H
9a
Ph
H
HO
Ph
S
6
7
7
80
94
H
S
O
O
6b
6a
H
9b
Ph
Ph
N
HO
H
12
Ph
H
N
O
O
N
O
O
O
H
10a

JOURNAL OF CHEMICAL RESEARCH 2009 523
Table 1 Continued
Entry
Aldehydes 5 and 6
Time/mina
10
Compounds 7–11 and 13
Yield/%b,c
90
Ph
Ph
H
HO
Ph
N
8
H
N
N
S
O
O
S
6b
6a
O
H
10b
Ph
H
HO
Ph
O
Me
Me
N
9
8
9
N
83
85
H
O
O
N
O
O
O
H
11a
Ph
S
H
HO
Ph
S
N
10
N
H
O
N
O
6b
6a
H
H
11b
11c
Ph
O
HO
Ph
O
Ph
Ph
N
11
12
13
14
9
10
7
80
89
82
81
N
N
H
O
O
N
N
O
O
O
H
H
Ph
S
HO
Ph
S
N
H
O
6b
6a
6b
H
11d
11e
11f
Ph
HO
H
H
Ph
H2N
H2N
N
N
O
O
N
N
O
O
O
H
H
Ph
HO
Ph
N
8
N
H
S
O
O
S
O
N
H
Ph
O
HO
H
H
O
O
15
16
8
Ph
93
90
O
N
O
O
O
6a
H
13a
Ph
S
HO
H
H
O
O
10
Ph
N
O
N
O
O
S
6b
H
13b
aMicrowave irradiation time for the formation of products. bYield of isolated and purified products. cAll compounds gave C, H and
N analyses within 0.34% and satisfactory spectral (IR, 1H NMR, 13C NMR and EIMS) data.
General procedure for the preparation of 1,3-oxazin-2-ones(thiones)
3a–d
Thoroughly mixed D-xylose/D-glucose (1 mmol) 1, N-phenyl
to each other and thus confirming their cis stereochemistry.
Furthermore, the absence of any measurable NOE between 4a-
H and 8a-H along with their coupling constants (7.6–7.8 Hz)
indicates that these are trans to each other, which confirms the
trans stereochemistry of the compound 13.
In summary, we have developed a general, straightforward
diversity oriented green synthetic approach for stereoselective
synthesis of various 1,3-oxazin-2-one(thione)-fused heterocycles
containing C=N bond using D-glucose and D-xylose as
biorenewable resources under solvent-free microwave irradiation
conditions.
semicarbazide/thiosemicarbazide (1 mmol)
2
and Cu(OTf)2
(0.3 mmol) were taken in a 20 mL open vial and subjected to MW
irradiation for 2–4 min at 90°C under air. After completion of the
reaction as indicated by TLC, water (10 mL) was added to give the
crude product which was recrystallised from ethanol to obtain an
analytically pure sample of 3. The physical and spectra data of the
compounds 3a–d are as follows.
5-Hydroxy-6-(1,2-dihydroxyethyl)-3-phenyl-1,3-oxazin-2-one (3a):
Colourless solid; m.p. 154–156°C, yield 88%. [a]D20 + 79.1 (c 0.75,
EtOH). IR (KBr): 3399, 3010, 1698, 1605, 1581, 1456 cm-1.
1H NMR (DMSO-d6/TMS + D2O): d = 2.91 (dd, J4Ha,4Hb = 12.3 Hz,
J4Hb,5H=7.6Hz,1H,4-Hb),3.37(dd,J4Ha,4Hb=12.3Hz,J4Ha,5H=2.8Hz,
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 spectrophotometer. 1H 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 were recorded on a JEOL D-300
mass spectrometer. Elemental analyses were carried out in a Coleman
automatic carbon, hydrogen and nitrogen analyser. 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.
1 H, 4-Ha), 3.65 (dd, J2'Ha,
= 10.8 Hz, J1'H,2'Ha, = 4.8 Hz,
2'Hb
1 H, 2'Ha), 3.89 (dd, J2'Ha,2'Hb = 10.8 Hz, J1'H,2'Hb = 2.7 Hz, 1 H,
2'Hb), 4.01 (ddd, J1'H,6H = 6.1 Hz, J1'H,2'Ha, = 4.8 Hz, J1'H,2'Hb = 2.7 Hz,
1 H, 1'H), 4.23 (dd, J1'H,6H = 6.1 Hz, J5H,6H = 9.3 Hz, 1 H, 6H),
4.45 (ddd, J4Ha,5H = 2.8 Hz, J4Hb,5H = 7.6 Hz, J5H,6H = 9.3 Hz, 1 H,
5H), 7.05–7.72 (m, 5 Harom). 13C NMR (DMSO-d6/TMS): d = 63.1,
65.9, 69.3, 71.9, 75.3, 121.5, 128.7, 131.7, 133.4, 172.5. MS (FAB):
m/z = 254 [MH+]. Anal. Calcd for C12H15NO5: C, 56.91; H, 5.97;
N, 5.53. Found: C, 56.73; H, 5.85; N, 5.79%.
5-Hydroxy-6-(1,2-dihydroxyethyl)-3-phenyl-1,3-oxazine-2-thione
(3b): Colourless solid; m.p. 159–161°C, yield 85%. [a]D20 + 80.3 (c
0.75, EtOH). IR (KBr): 3392, 3009, 1599, 1579, 1458, 1052 cm-1.

524 JOURNAL OF CHEMICAL RESEARCH 2009
1H NMR (DMSO-d6/TMS + D2O): d = 2.95 (dd, J4Ha,4Hb = 12.3 Hz,
5-Hydroxy-2-oxo-3-phenyl-1,3-oxazine-6-carbaldehyde (6a):
Colourless solid; m.p. 129–130°C, yield 82%. [a]D20 + 73.7 (c 1.00,
EtOH). IR (KBr): 3391, 3006, 1718, 1693, 1605, 1585, 1455 cm-1.
1H NMR (DMSO-d6/TMS + D2O): d = 2.92 (dd, J4Ha,4Hb = 12.1 Hz,
J4Hb,5H = 7.7 Hz, 1 H, 4-Hb), 3.42 (dd, J4Ha,4Hb = 12.1 Hz, J4Ha,5H
= 2.8 Hz, 1 H, 4-Ha), 4.39 (ddd, J4Hb,5H = 7.7 Hz, J5H,6H = 9.3 Hz,
J4Ha,5H = 2.8 Hz, 1 H, 5H), 5.13 (d, J5H,6H = 9.3 Hz, 1 H, 6H), 7.01–
7.59 (m, 5 Harom), 9.81 (s, 1 H, CHO). 13C NMR (DMSO-d6/TMS):
d = 65.6, 69.1, 101.3, 122.7, 123.5, 129.1, 132.8, 171.4, 173.8. MS
(FAB): m/z = 222 [MH+]. Anal. Calcd for C11H11NO4: C, 59.73;
H, 5.01; N, 6.33. Found: C, 59.55; H, 5.13; N, 6.01%.
5-Hydroxy-3-phenyl-2-thioxo-1,3-oxazine-6-carbaldehyde(6b):
Colourless solid; m.p. 135–137°C, yield 76%. [a]D20 + 60.9 (c 1.30,
EtOH). IR (KBr): 3392, 3017, 1715, 1601, 1587, 1449, 1052 cm-1.
1H NMR (DMSO-d6/TMS + D2O): d = 2.89 (dd, J4Ha,4Hb = 12.1 Hz,
J4Hb,5H = 7.8 Hz, 1 H, 4-Hb), 3.39 (dd, J4Ha,4Hb = 12.1 Hz, J4Ha,5H
= 2.8 Hz, 1 H, 4-Ha), 4.38 (ddd, J4Hb,5H = 7.7 Hz, J5H,6H = 9.2 Hz,
J4Ha,5H = 2.8 Hz, 1 H, 5H), 5.12 (d, J5H,6H = 9.2 Hz, 1 H, 6H), 7.11–
7.65 (m, 5 Harom), 9.80 (s, 1 H, CHO). 13C NMR (DMSO-d6/TMS)
d = 65.8, 69.1, 101.5, 122.7, 123.5, 129.1, 132.8, 171.5, 173.8. MS
(FAB): m/z = 238 [MH+]. Anal. Calcd for C11H11NO3S: C, 55.68; H,
4.67; N, 5.90. Found: C,55.34; H, 4.73; N, 5.69%.
J4Hb,5H = 7.6 Hz, 1 H, 4-Hb), 3.36 (dd, J4Ha,4Hb = 12.3 Hz, J4Ha,5H
=
2.7 Hz, 1 H, 4-Ha), 3.61 (dd, J2'Ha, 2'Hb = 10.8 Hz, J1'H,2'Ha, = 4.8 Hz,
1 H, 2'Ha), 3.91 (dd, J2'Ha, 2'Hb = 10.8 Hz, J1'H,2'Hb = 2.7 Hz, 1 H,
2'Ha), 4.05 (ddd, J1'H,6H = 6.1 Hz, J1'H,2'Ha, = 4.8 Hz, J1'H,2'Hb = 2.7 Hz,
1 H, 1'H), 4.21 (dd, J1'H,6H = 6.1 Hz, J5H,6H = 9.2 Hz, 1 H, 6H), 4.48
(ddd, J4Ha,5H = 2.7 Hz, J4Hb,5H = 7.6 Hz, J5H,6H = 9.2 Hz, 1 H, 5H),
7.03–7.78 (m, 5 Harom). 13C NMR (DMSO-d6/TMS): d = 63.5,
66.1, 69.2, 72.6, 75.5, 122.5, 127.8, 130.9, 131.9, 192.5. MS
(FAB): m/z = 270 [MH+]. Anal. Calcd for C12H15NO4S: C, 53.52;
H, 5.61; N, 5.20. Found: C, 53.86; H, 5.39; N, 5.85%.
5-Hydroxy-6-(1,2,3-trihydroxypropyl)-3-phenyl-1,3-oxazin-2-one
20
(3c): Colourless solid; m.p. 140–141°C, yield 86%. [a]D + 85.1
(c 0.75, EtOH). IR (KBr): 3395, 3007, 1692, 1601, 1583, 1455 cm-1.
1H NMR (DMSO-d6/TMS + D2O): d = 2.93 (dd, J4Ha,4Hb = 12.2 Hz,
J4Hb,5H = 7.8 Hz, 1 H, 4-Hb), 3.39 (dd, J4Ha,4Hb = 12.2 Hz, J4Ha,5H = 2.8 Hz,
1H, 4-Ha), 3.43(ddd, J2'H,3'Ha=4.5Hz, J1'H,2'H=5.9Hz, J2'H,3'Hb=2.8Hz,
1 H, 2'H), 3.67 (dd, J3'Ha,3'Hb = 10.3 Hz, J2'H,3'Ha = 4.5 Hz, 1 H, 3'Ha),
3.92 (dd, J3'Ha,3'Hb = 10.3 Hz, J2'H,3'Hb = 2.8 Hz, 1 H, 3'Hb), 3.99 (dd,
J1'H,6H = 9.1 Hz, J1'H,2'H = 5.9 Hz, 1 H, 1'H), 4.19 (dd, J1'H,6H = 9.1 Hz,
J5H,6H = 9.4 Hz, 1 H, 6H), 4.51 (ddd, J4Ha,5H = 2.8 Hz, J4Hb,5H = 7.8 Hz,
J5H,6H = 9.4 Hz, 1 H, 5H), 7.11–7.81 (m, 5 Harom). 13C NMR (DMSO-
d6/TMS): d = 63.5, 66.3, 69.1, 71.7, 72.5, 75.6, 121.7, 124.5, 129.5,
131.8, 172.5. MS (FAB): m/z = 284 [MH+]. Anal. Cald for C13H17NO6:
C, 55.12; H, 6.05; N, 4.94. Found: C, 55.41; H, 6.26; N, 4.85%.
5-Hydroxy-6-(1,2,3-trihydroxypropyl)-3-phenyl-1,3-oxazine-2-
thione(3d):Colourlesssolid;m.p.156–158°C,yield81%.[a]D20+72.9
(c 0.50, EtOH). IR (KBr): 3395, 3008, 1607, 1581, 1453, 1055 cm-1.
1H NMR (DMSO-d6/TMS + D2O): d = 2.92 (dd, J4Ha,4Hb = 12.2 Hz,
J4Hb,5H = 7.5 Hz, 1 H, 4-Hb), 3.33 (dd, J4Ha,4Hb = 12.2 Hz,
J4Ha,5H = 2.7 Hz, 1 H, 4-Ha), 3.41 (ddd, J2'H,3'Ha = 4.5 Hz, J1'H,2'H
= 5.9 Hz, J2'H,3'Hb = 2.7 Hz, 1 H, 2'H), 3.66 (dd, J3'Ha,3'Hb = 10.5 Hz,
J2'H,3'Ha = 4.5 Hz, 1 H, 3'Ha), 3.89 (dd, J3'Ha,3'Hb = 10.5 Hz, J2'H,3'Hb
= 2.7 Hz, 1 H, 3'Hb), 3.97 (dd, J1'H,6H = 9.1 Hz, J1'H,2'H = 5.9 Hz,
1 H, 1'H), 4.18 (dd, J1'H,6H = 9.1 Hz, J5H,6H = 9.3 Hz, 1 H, 6H), 4.49
(ddd, J4Hb,5H = 7.5 Hz, J5H,6H = 9.3 Hz, J4Ha,5H = 2.7 Hz, 1 H, 5H),
7.09–7.83 (m, 5 Harom). 13C NMR (DMSO-d6/TMS): d = 63.1,
65.7, 69.5, 71.5, 72.7, 75.4, 123.5, 126.3, 130.8, 133.2, 192.8. MS
(FAB): m/z = 300 [MH+]. Anal. Calcd for C13H17NO5S: C, 52.16; H,
5.72; N, 4.68. Found: C, 51.93; H, 5.85; N, 4.47%.
General procedure for the preparation of 4-hydroxy-1,2-oxazino-,
pyridazino-1,3-oxazin-6-ones(thiones) 7, 8
An intimate solvent-free mixture of 5 (1 mmol), sodium acetate
(1 mmol), and hydroxylamine hydrochloride (1 mmol), or
phenylhydrazine hydrochloride (1 mmol) in the presence of
Cu(OTf)2 (0.3 mmol) was taken in a 20 mL vial and subjected
to MW irradiation at 80°C for 7–12 min to get the crude product
which was extracted with dichloromethane (3 ¥ 10 mL). The extract
was filtered, the filtrate was evaporated under reduced pressure
and the residue thus obtained was recrystallised from ethanol to
obtain an analytically pure sample of compounds 7 and 8 as a
white solid. The physical and spectra data of the compounds 7
and 8 are as follows.
4,4a,8,8a-Tetrahydro-4-hydroxy-7-phenyl-[1,2]oxazino[6,5-e]
[1,3]oxazin-6(7H)-one (7a): Colourless solid; m.p. 141–143°C.
[a]D20 + 33.5 (c 1.20, EtOH). IR (KBr): 3395, 3007, 1694, 1637, 1599,
1
1585, 1457 cm-1. H NMR (DMSO-d6/TMS + D2O): d = 2.93 (dd,
J4Ha,4Hb = 12.5 Hz, J4Hb,4aH = 7.6 Hz, 1 H, 4-Hb), 3.53 (dd, J4Ha,4Hb
= 12.5 Hz, J4Ha,4aH = 2.8 Hz, 1 H, 4-Ha), 3.75 (dd, J8H,8aH = 9.1 Hz,
J7H,8H = 6.5 Hz, 1 H, 8H), 4.01 (ddd, J4Hb,4aH = 7.6 Hz, J4aH,8aH
= 3.1 Hz, J4Ha,4aH = 2.8 Hz, 1 H, 4aH), 4.31 (dd, J8H,8aH = 9.1 Hz,
General procedure for Malaprade reaction to afford aldehydes 5, 6
A solution of sodium periodate (1 mmol) in water (8 mL) was
added dropwise with stirring to a well stirred ice-cold solution
of 1,3-oxazin-2-one(thione) 3 (1 mmol) in ethanol (15 mL). The
reaction mixture was further stirred for 2–3 h at room temperature.
After completion of reaction, as indicated by TLC, solvent was
evaporated under reduced pressure to get solid residue which was
extracted with ethyl acetate (3 ¥ 10 mL). The extract was filtered
and filtrate was the concentrated under the reduced pressure to leave
the crude product, which on recrystallisation from ethanol afforded
pure compounds 5 as white solid. The procedure followed for 6 was
exactly the same, except that in this case 2 mmol of sodium periodate
was used instead of 1 mmol of sodium periodate for 5. The physical
and spectra data of the compounds 5a,b and 6a,b are as follows.
2-Hydroxy-2-(5-hydroxy-2-oxo-3-phenyl-1,3-oxazin-6-yl)
acetaldehyde (5a): Colourless solid; m.p. 101–102°C, yield 79%.
J4aH,8aH = 3.1 Hz, 1 H, 8aH), 7.12–7.61 (m, 5 Harom), 7.56 (d, J7H,8H
=
6.5 Hz, 1 H, 7H). 13C NMR (DMSO-d6/TMS): d = 65.3, 68.5, 70.2,
76.5, 121.8, 123.9, 128.8, 130.5, 162.2, 172.8. MS (FAB): m/z = 249
[MH+]. Anal. Calcd for C12H12N2O4: C, 58.06; H, 4.87; N, 11.29.
Found: C, 57.83; H, 4.55; N, 11.09.
4,4a,8,8a-Tetrahydro-4-hydroxy-7-phenyl-[1,2]oxazino[6,5-e]
[1,3]oxazine-6(7H)-thione (7b): Colourless solid; m.p. 128–
20
130°C. [a]D + 38.9 (c 1.00, EtKH). IR (OBr): 3391, 3013,
1634, 1602, 1581, 1456, 1057 cm-1. 1H NMR (DMSO-d6/TMS
+ D2O): d = 2.92 (dd, J4Ha,4Hb = 12.3 Hz, J4Hb,4aH = 7.6 Hz,
1 H, 4-Hb), 3.51 (dd, J4Ha,4Hb = 12.3 Hz, J4Ha,4aH = 2.5 Hz, 1 H, 4-Ha),
3.81 (dd, J8H,8aH = 9.1 Hz, J7H,8H = 6.6 Hz, 1 H, 8H), 3.98 (ddd,
J4Hb,4aH = 7.6 Hz, J4aH,8aH = 3.1 Hz, J4Ha,4aH = 2.5 Hz, 1 H, 4aH),
4.35 (dd, J8H,8aH = 9.1 Hz, J4aH,8aH = 3.1 Hz, 1 H, 8aH), 7.08–7.79 (m,
5 Harom), 7.61 (d, J7H,8H = 6.6 Hz, 1 H, 7H). 13C NMR (DMSO-d6/
TMS): d = 65.5, 68.9, 71.2, 76.3, 123.5, 128.2, 130.1, 131.8, 162.5,
193.5. MS (FAB): m/z = 265 [MH+]. Anal. Calcd for C12H12N2O3S:
C, 54.53; H, 4.58; N, 10.60. Found: C, 54.84; H, 4.75; N, 10.49%.
4,4a,8,8a-Tetrahydro-4-hydroxy-1,7-diphenyl-1H-pyridazino
[3,4-e][1,3]oxazin-6(7H)-one (8a): Colourless solid; m.p. 167–
20
[a]D + 69.3 (c 0.60, EtOH). IR (KBr): 3393, 3008, 1717, 1695,
1602, 1583, 1451 cm-1. 1H NMR (DMSO-d6/TMS + D2O): d = 2.91
(dd, J4Ha,4Hb = 12.5 Hz, J4Hb,5H = 7.5 Hz, 1 H, 4-Hb), 3.43 (dd,
J4Ha,4Hb = 12.5 Hz, J4Ha,5H = 2.6 Hz, 1 H, 4-Ha), 4.41 (dd, J1'H,6H
=
5.9 Hz, J5H,6H = 9.5 Hz, 1 H, 6H), 4.52 (ddd, J4Hb,5H = 7.5 Hz, J5H,6H
= 9.5 Hz, J4Ha,5H = 2.6 Hz, 1 H, 5H), 4.85 (d, J1'H,6H = 5.9 Hz, 1 H,
1'H), 7.11–7.69 (m, 5 Harom), 9.83 (s, 1 H, CHO). 13C NMR (DMSO-
d6/TMS): d = 66.1, 69.0, 77.5, 85.9, 121.7, 122.9, 129.9, 132.5, 171.1,
173.7. MS (FAB): m/z = 252 [MH+]. Anal. Calcd for C12H13NO5:
C, 57.37; H, 5.22; N, 5.58. Found: C, 57.13; H, 5.41; N, 5.62%.
2-Hydroxy-2-(5-hydroxy-3-phenyl-2-thioxo-1,3-oxazin-6-
yl)acetaldehyde (5b): Colourless solid; m.p. 119–121°C, yield 74%.
[a]D20 + 78.2 (c 0.60, EtOH). IR (KBr):3390, 3009, 1720, 1602, 1579,
20
169°C. [a]D + 48.5 (c 1.00, EtOH). IR (KBr): 3395, 3011, 1698,
1631, 1604, 1587, 1451 cm-1. 1H NMR (DMSO-d6/TMS + D2O):
d = 2.98 (dd, J4Ha,4Hb = 12.3 Hz, J4Hb,4aH = 7.8 Hz, 1 H, 4-Hb), 3.53
(dd, J4Ha,4Hb = 12.3 Hz, J4Ha,4aH = 2.5 Hz, 1 H, 4-Ha), 3.95 (dd, J8H,8aH
=
9.1 Hz, J7H,8H = 6.3 Hz, 1 H, 8H), 4.23 (ddd, J4Hb,4aH = 7.8 Hz, J4aH,8aH
= 3.7 Hz, J4Ha,4aH = 2.5 Hz, 1 H, 4aH), 4.59 (dd, J8H,8aH = 9.1 Hz,
J4aH,8aH = 3.7 Hz, 1 H, 8aH), 7.08–7.79 (m, 10 Harom), 7.62 (d, J7H,8H
= 6.3 Hz, 1 H, 7H). 13C NMR (DMSO-d6/TMS): d = 62.1, 66.0, 70.8,
77.3, 121.2, 123.8, 125.3, 126.8, 128.8, 129.7, 131.2, 133.5, 161.8,
172.3. MS (FAB): m/z = 324 [MH + ]. Anal. Calcd for C18H17N3O3: C,
66.86; H, 5.30; N, 13.00. Found: C, 66.61; H, 5.18; N, 12.89%.
4,4a,8,8a-Tetrahydro-4-hydroxy-1,7-diphenyl-1H-pyridazino
[3,4-e][1,3]oxazine-6(7H)-thione (8b): White solid; m.p. 181–
183°C. [a]D20 + 53.2 (c 0.75, EtOH). IR (KBr): 3388, 3008, 1634,
1
1457, 1055 cm-1. H NMR (DMSO-d6/TMS + D2O): d = 2.95 (dd,
J4Ha,4Hb = 12.5 Hz, J4Hb,5H = 7.5 Hz, 1 H, 4-Hb), 3.40 (dd, J4Ha,4Hb
= 12.5 Hz, J4Ha,5H = 2.7 Hz, 1 H, 4-Ha), 4.39 (dd, J1'H,6H = 5.5 Hz,
J5H,6H = 9.3 Hz, 1 H, 6H), 4.55 (ddd, J4Hb,5H = 7.5 Hz, J5H,6H = 9.3 Hz,
J4Ha,5H = 2.7 Hz, 1 H, 5H), 4.82 (d, J1'H,6H = 5.5 Hz, 1 H, 1'H), 7.08–
7.64 (m, 5 Harom), 9.82 (s, 1 H, CHO). 13C NMR (DMSO-d6/TMS):
d = 66.3, 69.1, 77.2, 85.8, 122.2, 123.4, 128.9, 130.7, 171.5, 193.4.
MS (FAB): m/z = 268 [MH+]. Anal. Calcd for C12H13NO4S: C, 53.92;
H, 4.90; N, 5.24. Found: C, 54.17; H, 4.79; N, 5.51%.

JOURNAL OF CHEMICAL RESEARCH 2009 525
1599, 1581, 1455, 1049 cm-1. 1H NMR (DMSO-d6/TMS + D2O):
d = 2.99 (dd, J4Ha,4Hb = 12.4 Hz, J4Hb,4aH = 7.8 Hz, 1 H, 4-Hb), 3.57
(dd, J4Ha,4Hb = 12.4 Hz, J4Ha,4aH = 2.7 Hz, 1 H, 4-Ha), 3.93 (dd,
J8H,8aH = 9.1 Hz, J7H,8H = 6.3 Hz, 1 H, 8H), 4.18 (ddd, J4Hb,4aH = 7.8 Hz,
(dd, J4Ha,4Hb = 12.3 Hz, J4Hb,4aH = 7.5 Hz, 1 H, 4-Hb), 3.51 (dd,
J4Ha,4Hb = 12.3 Hz, J4Ha,4aH = 2.7 Hz, 1 H, 4-Ha), 3.76 (ddd, J4Hb,4aH
= 7.7 Hz, J4aH,8aH = 3.7 Hz, J4Ha,4aH = 2.7 Hz, 1 H, 4aH), 4.55 (dd,
J8H,8aH = 8.5 Hz, J4aH,8aH = 3.7 Hz, 1 H, 8aH), 7.11–7.83 (m, 5 Harom),
7.62 (d, J8H,8aH = 8.5 Hz, 1 H, 8-H). 13C NMR (DMSO-d6/TMS): d =
50.9, 55.3, 71.8, 79.5, 121.5, 123.1, 129.5, 132.8, 161.8, 162.5, 172.2.
MS (FAB): m/z = 244 [MH+]. Anal. Calcd for C13H13N3O2: C, 64.19;
H, 5.39; N, 17.27. Found: C, 64.01; H, 5.53; N, 17.41%.
4,4a-Dihydro-6-methyl-3-phenyl-3H-pyrimido[4,5-
e][1,3]oxazine-2(8aH)-thione (11b): Colourless solid; m.p. 112–
114°C. [a]D20 + 59.3 (c 1.10, EtOH). IR (KBr): 3015, 1637, 1601,
1585, 1458, 1055 cm-1. 1H NMR (DMSO-d6/TMS + D2O): d = 1.61
(s, 3 H, Me), 2.99 (dd, J4Ha,4Hb = 12.5 Hz, J4Hb,4aH = 7.8 Hz, 1 H,
4-Hb), 3.58 (dd, J4Ha,4Hb = 12.5 Hz, J4Ha,4aH = 2.7 Hz, 1 H, 4-Ha),
3.80 (ddd, J4Hb,4aH = 7.8 Hz, J4aH,8aH = 3.7 Hz, J4Ha,4aH = 2.7 Hz,
1 H, 4aH), 4.56 (dd, J8H,8aH = 8.5 Hz, J4aH,8aH = 3.7 Hz, 1 H, 8aH),
7.09–7.71 (m, 5 Harom), 7.61 (d, J8H,8aH = 8.5 Hz, 1 H, 8H). 13C NMR
(DMSO-d6/TMS): d = 51.1, 55.7, 65.7, 72.1, 122.5, 123.8, 128.9,
130.1, 161.5, 162.2, 192.5. MS (FAB): m/z = 260 [MH+]. Anal. Calcd
for C13H13N3OS: C, 60.21; H, 5.05; N, 16.20. Found: C, 59.98; H,
5.29; N, 16.03%.
J4aH,8aH = 3.7 Hz, J4Ha,4aH = 2.7 Hz, 1 H, 4aH), 4.61 (dd, J8H,8aH
=
9.1 Hz, J4aH,8aH = 3.7 Hz, 1 H, 8aH), 7.11–7.87 (m, 10 Harom), 7.61
(d, J7H,8H = 6.3 Hz, 1 H, 7H). 13C NMR (DMSO-d6/TMS): d = 62.5,
65.4, 71.2, 76.9, 122.8, 123.9, 125.4, 127.9, 128.8, 130.2, 131.5,
132.8, 162.2, 192.8. MS (FAB): m/z = 340 [MH+]. Anal. Calcd for
C18H17N3O2S: C, 63.70; H, 5.05; N, 12.38. Found: C, 63.42; H, 5.29;
N, 12.58%.
General procedure for preparation of isoxazolo-, pyrazolo-, pyrimido-
1,3-oxazin-2-ones(thiones) 9–11
An intimate solvent-free mixture of 6 (1 mmol), sodium acetate
(1 mmol), and hydroxylamine hydrochloride (1 mmol), or
phenylhydrazine hydrochloride (1 mmol), or acetamidine/-
benzamidine/guanidine hydrochloride (1 mmol) in the presence
of Cu(OTf)2 (0.3 mmol) was taken in a 20 mL vial and subjected
to MW irradiation at 80°C for 7–12 min to get the crude product
which was extracted with dichloromethane (3 ¥ 10 mL). The
extract was filtered, the filtrate was evaporated under reduced
pressure and the residue thus obtained was recrystallised from
ethanol to obtain an analytically pure sample of compounds 9,
10, or 11 as a white solid. The physical and spectra data of the
compounds 9–11 are as follows.
7,7a-Dihydro-6-phenyl-3aH-isoxazolo[5,4-e][1,3]oxazin-
5(6H)-one (9a): Colourless solid; m.p. 182–184°C. [a]D20 + 29.5
(c 0.75, EtOH). IR (KBr): 3011, 1692, 1635, 1605, 1581, 1451 cm-1.
1H NMR (DMSO-d6/TMS + D2O): d = 3.01 (dd, J4Ha,4Hb = 12.3 Hz,
J4Hb,4aH = 7.6 Hz, 1 H, 4-Hb), 3.57 (dd, J4Ha,4Hb = 12.3 Hz, J4Ha,4aH
= 2.5 Hz, 1 H, 4-Ha), 3.81 (ddd, J4Hb,4aH = 7.6 Hz, J4aH,7aH = 3.3 Hz,
J4Ha,4aH = 2.5 Hz, 1H,4aH),5.09(dd,J7aH,7H=8.9Hz,J4aH,7aH=3.3Hz,
1 H, 7aH), 7.08–7.69 (m, 5 Harom), 7.63 (d, J7aH,7H = 8.9 Hz, 1 H,
7-H). 13C NMR (DMSO-d6/TMS): d = 65.3, 67.9, 75.1, 122.5, 124.5,
126.8, 130.5, 161.8, 172.5. MS (FAB): m/z = 219 [MH+]. Anal. Calcd
for C11H10NO3: C, 60.55; H, 4.62; N, 12.84. Found: C, 60.79; H,
4.51; N, 12.50%.
7,7a-Dihydro-6-phenyl-3aH-isoxazolo[5,4-e][1,3]oxazine-
5(6H)-thione (9b): Colourless solid; m.p. 168–170°C. [a]D20 + 38.3
(c 0.70, EtOH). IR (KBr): 3013, 1638, 1602, 1587, 1455, 1057 cm-1.
1H NMR (DMSO-d6/TMS + D2O): d = 3.05 (dd, J4Ha,4Hb = 12.3 Hz,
J4Hb,4aH = 7.7 Hz, 1 H, 4-Hb), 3.56 (dd, J4Ha,4Hb = 12.3 Hz, J4Ha,4aH
= 2.5 Hz, 1 H, 4-Ha), 3.83 (ddd, J4Hb,4aH = 7.7 Hz, J4aH,7aH = 3.3 Hz,
J4Ha,4aH = 2.5 Hz, 1H,4aH),5.10(dd,J7aH,7H=8.8Hz,J4aH,7aH=3.3Hz,
1 H, 7aH), 7.03–7.71 (m, 5 Harom), 7.66 (d, J7aH,7H = 8.8 Hz, 1 H,
7H). 13C NMR (DMSO-d6/TMS): d = 65.5, 68.5, 74.9, 123.1, 125.8,
127.9, 131.3, 162.3, 192.5. MS (FAB): m/z = 235 [MH+]. Anal. Calcd
for C11H10N2O2S: C, 56.39; H, 4.30; N, 11.96. Found: C, 56.65; H,
4.19; N, 12.11%.
7,7a-Dihydro-1,6-diphenylpyrazolo[3,4-e][1,3]oxazin-5(1H,
3aH,6H)-one (10a): Colourless solid; m.p. 140–142°C. [a]D20 + 61.9
(c 1.00, EtOH). IR (KBr): 3009, 1695, 1631, 1608, 1577, 1449 cm-1.
1H NMR (DMSO-d6/TMS + D2O): d = 2.98 (dd, J4Ha,4Hb = 12.2 Hz,
J4Hb,4aH = 7.7 Hz, 1 H, 4-Hb), 3.51 (dd, J4Ha,4Hb = 12.2 Hz, J4Ha,4aH
= 2.7 Hz, 1 H, 4-Ha), 3.80 (ddd, J4Hb,4aH = 7.7 Hz, J4aH,7aH = 3.1 Hz,
J4Ha,4aH = 2.7 Hz, 1H,4aH),4.99(dd,J7aH,7H=9.1Hz,J4aH,7aH=3.1Hz,
1 H, 7aH), 7.11–7.83 (m, 10 Harom), 7.61 (d, J7aH,7H = 9.1 Hz, 1 H,
7H). 13C NMR (DMSO-d6/TMS): d = 65.1, 66.9, 75.3, 121.8, 122.5,
124.5, 126.9, 128.4, 129.3, 131.5, 132.3, 161.9, 173.2. MS (FAB):
m/z = 294 [MH+]. Anal. Calcd for C17H15N3O2: C, 69.61; H, 5.15; N,
14.33. Found: C, 69.47; H, 5.31; N, 14.18%.
4,4a-Dihydro-3,6-diphenyl-3H-pyrimido[4,5-e][1,3]oxazin-
2(8aH)-one (11c): Colourless solid; m.p. 138–140°C. [a]D20 + 61.7
(c 0.90, EtOH). IR (KBr): 3009, 1692, 1634, 1605, 1579, 1459 cm-1.
1H NMR (DMSO-d6/TMS + D2O): d = 3.01 (dd, J4Ha,4Hb = 12.5 Hz,
J4Hb,4aH = 7.8 Hz, 1 H, 4-Hb), 3.50 (dd, J4Ha,4Hb = 12.5 Hz, J4Ha,4aH
= 2.4 Hz, 1 H, 4-Ha), 3.75 (ddd, J4Hb,4aH = 7.8 Hz, J4aH,8aH = 3.7 Hz,
J4Ha,4aH = 2.4 Hz, 1 H, 4aH), 4.51 (dd, J8H,8aH = 8.9 Hz, J4aH,8aH
=
3.7 Hz, 1 H, 8aH), 7.19–7.85 (m, 10 Harom), 7.63 (d, J8H,8aH = 8.9 Hz,
1 H, 8H). 13C NMR (DMSO-d6/TMS): d = 55.1, 65.9, 71.5, 121.5,
123.5, 125.5, 127.8, 128.9, 129.5, 130.2, 131.8, 161.9, 163.1, 172.5.
MS (FAB): m/z = 306 [MH+]. Anal. Calcd for C18H15N3O2: C, 70.81;
H, 4.95; N, 13.76. Found: C, 70.47; H, 4.79; N, 13.83%.
4,4a-Dihydro-3,6-diphenyl-3H-pyrimido[4,5-e][1,3]oxazine-
20
2(8aH)-thione (11d): Colourless solid; m.p. 115–117°C. [a]D
+
69.1 (c 0.75, EtOH). IR (KBr): 3008, 1631, 1601, 1579, 1459, 1051
cm-1. 1H NMR (DMSO-d6/TMS + D2O): d = 2.95 (dd, J4Ha,4Hb
=
12.4 Hz, J4Hb,4aH = 7.5 Hz, 1 H, 4-Hb), 3.52 (dd, J4Ha,4Hb = 12.4 Hz,
J4Ha,4aH = 2.5 Hz, 1 H, 4-Ha), 3.78 (ddd, J4Hb,4aH = 7.5 Hz, J4aH,8aH
= 3.7 Hz, J4Ha,4aH = 2.5 Hz, 1 H, 4aH), 4.55 (dd, J8H,8aH = 9.1 Hz,
J4aH,8aH = 3.7 Hz, 1 H, 8aH), 7.21–7.83 (m, 10 Harom), 7.65 (d, J8H,8aH
= 9.1 Hz, 1 H, 8H). 13C NMR (DMSO-d6/TMS): d = 55.7, 65.6, 71.8,
122.2, 123.8, 124.9, 126.5, 127.4, 128.5, 130.1, 132.5, 161.3, 162.6,
193.1. MS (FAB): m/z = 322 [MH+]. Anal. Calcd for C18H15N3OS: C,
67.27; H, 4.70; N, 13.07. Found: C, 67.51; H, 4.59; N, 13.23%.
6-Amino-4, 4a-dihydro-3-phenyl-3H-pyrimido[4, 5-
e][1,3]oxazin-2(8aH)-one (11e): Colourless solid; m.p. 184–
186°C. [a]D20 + 59.5 (c 0.75, EtOH). IR (KBr): 3010, 1692, 1633,
1601, 1583, 1450 cm-1. 1H NMR (DMSO-d6/TMS + D2O): d = 2.96
(dd, J4Ha,4Hb = 12.7 Hz, J4Hb,4aH = 7.5 Hz, 1 H, 4-Hb), 3.53 (dd,
J4Ha,4Hb = 12.7 Hz, J4Ha,4aH = 2.5 Hz, 1 H, 4-Ha), 3.81 (ddd, J4Hb,4aH
= 7.5 Hz, J4aH,8aH = 3.4 Hz, J4Ha,4aH = 2.5 Hz, 1 H, 4aH), 4.52 (dd,
J8H,8aH = 8.8 Hz, J4aH,8aH = 3.4 Hz, 1 H, 8aH), 7.04–7.69 (m, 5 Harom),
7.62 (d, J8H,8aH = 8.8 Hz, 1 H, 8H). 13C NMR (DMSO-d6/TMS): d =
55.1, 65.8, 72.0, 122.8, 123.9, 128.5, 131.9, 162.1, 162.9, 172.8. MS
(FAB): m/z = 245 [MH+]. Anal. Calcd for C12H12N4O2: C, 59.01; H,
4.95; N, 22.94. Found: C, 59.28; H, 5.03; N, 22.71%.
6-Amino-4,4a-dihydro-3-phenyl-3H-pyrimido[4,5-e][1,3]
oxazine-2(8aH)-thione (11f): Colourless solid; m.p. 203–205°C.
[a]D20 + 65.0 (c 0.60, EtOH). IR (KBr): 3009, 1637, 1597, 1579,
1
1451, 1055 cm-1. H NMR (DMSO-d6/TMS + D2O): d = 2.98 (dd,
J4Ha,4Hb = 12.7 Hz, J4Hb,4aH = 7.6 Hz, 1 H, 4-Hb), 3.49 (dd, J4Ha,4Hb
7,7a-Dihydro-1,6-diphenylpyrazolo[3,4-e][1,3]oxazine-
5(1H,3aH,6H)-thione (10b): Colourless solid; m.p. 188–190°C.
[a]D20 + 65.8 (c 1.20, EtOH). IR (KBr): 3342, 1633, 1596, 1582, 1451,
= 12.7 Hz, J4Ha,4aH = 2.8 Hz, 1 H, 4-Ha), 3.79 (ddd, J4Hb,4aH =
7.6 Hz, J4aH,8aH = 3.4 Hz, J4Ha,4aH = 2.8 Hz, 1 H, 4aH), 4.49 (dd,
J8H,8aH = 8.5 Hz, J4aH,8aH = 3.4 Hz, 1 H, 8aH), 7.11–7.75 (m, 5 Harom),
7.61 (d, J8H,8aH = 8.5 Hz, 1 H, 8H). 13C NMR (DMSO-d6/TMS):
d = 55.7, 66.2, 71.9, 123.2, 125.9, 128.9, 130.8, 161.7, 163.3, 192.6.
MS (FAB): m/z = 261 [MH+]. Anal. Calcd for C12H12N4OS: C, 55.37;
H, 4.65; N, 21.52. Found: C, 55.59; H, 4.39; N, 21.42%.
1053 cm-1. 1H NMR (DMSO-d6/TMS + D2O): d = 2.99 (dd, J4Ha,4Hb
=
12.5 Hz, J4Hb,4aH = 7.7 Hz, 1 H, 4-Hb), 3.55 (dd, J4Ha,4Hb = 12.2 Hz,
J4Ha,4aH = 2.8 Hz, 1 H, 4-Ha), 3.79 (ddd, J4Hb,4aH = 7.7 Hz,
J4aH,7aH = 3.5 Hz, J4Ha,4aH = 2.8 Hz, 1 H, 4aH), 5.02 (dd, J7aH,7H
= 9.1 Hz, J4aH,7aH = 3.5 Hz, 1 H, 7aH), 7.18–7.89 (m, 10 Harom),
7.66 (d, J7aH,7H = 9.1 Hz, 1 H, 7H). 13C NMR (DMSO-d6/TMS):
d = 65.1, 66.2, 75.3, 121.5, 122.7, 123.9, 125.2, 127.3, 128.9, 130.0,
131.5, 161.5, 193.1. MS (FAB): m/z = 310 [MH+]. Anal. Calcd for
C17H15N3OS: C, 66.00; H, 4.89; N, 13.58. Found: C, 66.26; H, 4.97;
N, 13.45%.
General Procedure forpreparation of 1,3-oxazino[6,5-e][1,3]
oxazine-2,6-dione(6-thioxo-2-one) 13
Thoroughly mixed aldehyde 6 (2 mmol), semicarbazide hydro-
chloride (2 mmol), sodium acetate (2 mmol), and Cu(OTf)2
(0.6 mmol) were taken in a 20 mL vial and subjected to microwave
irradiation at 90°C for 8–10 min to afford crude product which was
extracted with dichloromethane (3 ¥ 20 mL). The extract was filtered
and the filtrate was evaporated under reduced pressure to leave the
product which was recrystallised from ethanol to obtain analytically
4,4a-Dihydro-6-methyl-3-phenyl-3H-pyrimido[4,5-e][1,3]
20
oxazin-2(8aH)-one (11a): Colourless solid; m.p. 124–126°C. [a]D
+ 55.7 (c 0.75, EtOH). IR (KBr): 3012, 1695, 1633, 1607, 1583, 1455
cm-1. 1H NMR (DMSO-d6/TMS + D2O): d = 1.58 (s, 3 H, Me), 2.95

526 JOURNAL OF CHEMICAL RESEARCH 2009
2
3
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Yakugaku Zasshi, 1984, 104, 659; Chem. Abstr., 1985, 102, 6344 m.
E. Testa, L. Fontanella, G. Cristiani and G. Gallo, J. Org. Chem., 1959,
24, 1928.
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U.S. 3.821.215; Chem. Abstr., 1975, 82, 49951r.
T.R. Abbas, J.I.G. Cadogan, A.A. Doyle, I. Gosney, P.K.G. Hodgson.
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pure sample of 13. The physical and spectra data of the compounds
13a,b are as follows.
4,4a-Dihydro-3-phenyl-[1,3]oxazino[6,5-e][1,3]oxazine-2,6
4
5
6
7
20
(3H,8aH)-dione (13a): Colourless solid; m.p. 179–181°C. [a]D
+
49.3(c0.85,EtOH).IR(KBr):3391,3011,1692,1601,1581,1455cm-1.
1H NMR (DMSO-d6/TMS + D2O): d = 3.05 (dd, J4Ha,4Hb = 12.7 Hz,
J4Hb,4aH = 7.3 Hz, 1 H, 4-Hb), 3.70 (dd, J4Ha,4Hb = 12.7 Hz, J4Ha,4aH
= 2.8 Hz, 1 H, 4-Ha), 4.62 (ddd, J4Hb,4aH = 7.3 Hz, J4aH,8aH = 7.8 Hz,
J4Ha,4aH = 2.8 Hz, 1H,4aH),4.81(dd,J8H,8aH=6.8Hz,J4aH,8aH=7.8Hz,
1 H, 8aH), 7.05–7.71 (m, 5 Harom), 7.56 (d, J8H,8aH = 6.8 Hz, 1 H,
8H). 13C NMR (DMSO-d6/TMS): d = 65.9, 66.5, 77.5, 122.9, 124.6,
128.1, 130.5, 161.7, 172.1, 173.2. MS (FAB): m/z = 247 [MH+]. Anal.
Calcd for C12H10N2O4: C, 58.54; H, 4.09; N, 11.38. Found: C,58.79;
H, 4.18; N, 11.55%.
8
9
http://www.centrewatch.com/patient/drugs/drugdirectories.htmL.
A.R. Jagdale, A.S. Paraskar and A. Sudalai, Indian J. Chem. B Org., 2008,
47B, 1091.
10 L.D.S. Yadav and V.K. Rai, Tetrahedron, 2006, 62, 8029.
11 L.D.S. Yadav, S. Yadav and V.K. Rai, Green Chem. 2006, 8, 455.
12 L.D.S. Yadav, A. Rai, V.K. Rai and C. Awasthi, Tetrahedron, 2008,
64, 1420.
13 L.D.S. Yadav, C. Awasthi, V.K. Rai and A. Rai, Tetrahedron Lett., 2007,
48, 4899.
14 L.D.S. Yadav, A. Rai, V.K. Rai and C. Awasthi, Synlett, 2007, 1905.
15 A. Klash, K. Koristek, J. Polis and J. Kosmrlj, Tetrahedron, 2000,
56, 1551.
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Commun., 2000, 65, 1262.
6,7,8,8a-Tetrahydro-7-phenyl-6-thioxo-[1,3]oxazino[6,5-e][1,3]
20
oxazin-2(4aH)-one (13b): Colourless solid; m.p. 166–168°C. [a]D
+ 53.8 (c 1.20, EtOH). IR (KBr): 3392, 3009, 1693, 1605, 1585, 1449,
1055 cm-1. 1H NMR (DMSO-d6/TMS + D2O): d = 3.01 (dd, J4Ha,4Hb
= 12.7 Hz, J4Hb,4aH = 7.3 Hz, 1 H, 4-Hb), 3.73 (dd, J4Ha,4Hb = 12.7 Hz,
J4Ha,4aH = 2.5 Hz, 1 H, 4-Ha), 4.58 (ddd, J4Hb,4aH = 7.3 Hz, J4aH,8aH
= 7.6 Hz, J4Ha,4aH = 7.6 Hz, 1 H, 4aH), 4.79 (dd, J8H,8aH = 6.8 Hz,
J4aH,8aH = 7.6 Hz, 1 H, 8aH), 7.02–7.75 (m, 5 Harom), 7.59 (d, J8H,8aH
= 6.8 Hz, 1 H, 8H). 13C NMR (DMSO-d6/TMS): d = 65.7, 66.3, 77.3,
122.7, 125.9, 130.2, 132.5, 162.3, 172.3, 192.7. MS (FAB): m/z = 263
[MH+]. Anal. Calcd for C12H10N2O3S: C, 54.95; H, 3.84; N, 10.68.
Found: C, 54.61; H, 3.97; N, 10.42%.
17 L. Waxman and P.L. Darke, Antivir. Chem. Chemother., 2000, 11, 1.
18 A.S. Girgis, Pharmazie, 2000, 426.
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We sincerely thank the DST, Govt. of India, for financial
support (DST File No.SR/S1/OC—65/2006) and SAIF, CDRI,
Lucknow, for providing microanalyses and spectra.
21 K. Thomas, Tetrahedron, 2005, 61, 3091.
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Received 12 April 2009; accepted 8 June2009
Paper 09/0528 doi: 10.3184/030823409X466753
Published online: 10 August 2009
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