Synthesis of fused-oxazines from cyclic ketoximes via α-nitrosoalkenes

Article abstract of DOI:10.13005/ojc/330238

Cyclic ketoximes having a α-methylene group on reaction with chloramine-T followed by treatment with triethylamine generate α-nitrosoalkenes via α-chloronitroso intermediates, which are further treated with alkenes to give fused-oxazines.

Full text of DOI:10.13005/ojc/330238

ISSN: 0970-020 X
CODEN: OJCHEG
2017, Vol. 33, No. (2):
Pg. 893-896
ORIENTAL JOURNAL OF CHEMISTRY
An International Open Free Access, Peer Reviewed Research Journal
www.orientjchem.org
Synthesis of Fused-Oxazines from Cyclic Ketoximes
Via a-Nitrosoalkenes
SANTOSH L. GAONKAR1,2* and K. M. LOKANATHA RAI2
1Department of Chemistry, Manipal Institute of Technology,
Manipal University, Manipal-576104, India.
2Department of Studies in Chemistry, University of Mysore,
Manasagangotri, Mysore-570 006, India.
*Corresponding author E-mail: gaonkarslg@rediffmail.com
http://dx.doi.org/10.13005/ojc/330238
(Received: March 03, 2017; Accepted: April 04, 2017)
ABSTRACT
Cyclic ketoximes having a a-methylene group on reaction with chloramine-T followed by
treatment with triethylamine generate a-nitrosoalkenes via a-chloronitroso intermediates, which are
further treated with alkenes to give fused-oxazines.
Keywords: Fused-oxazines, a-nitrosoalkenes, Chloramine-T.
INTRODUCTION
a a-methylene group and their cycloaddition
with dienophiles to yield fused-oxazines, which
are having huge synthetic applications2,3 and
biological use as therapeutic agents4-7. Generation
of a-nitrosoalkenes is quite difficult.Usually they are
reactive intermediates and unstable, hence they are
only generated in situ2.
1,2-Oxazine and their fused counterparts
received interest in these years due to their diverse
synthetic and pharmacological importance. 1,2-
Oxazine derivatives are useful synthetic building
blocks in heterocyclic chemistry. In our preceding
report1, we have disclosed the method to obtain
a-nitrosoalkenes from ketoximes having a-methylene
group and their cycloaddition with olefinic compounds
to 1,2-oxazines.a-Nitrosoalkenes behave like dienes
(4П-elecron component) in Hetero-Diels-Alder
reaction. Further to our research on oxazines and
their counterparts, we are reporting the synthesis
of a-nitrosoalkenes from cyclic ketoximes bearing
In our prior work chloramine-T was used
extensively for the synthesis of a-nitrosoolefins1,
azoalkenes8-9, nitrile oxides10, nitrile imines11
etc., which undergo cycloaddition with active
dienes yield bioactive heterocycles. During the
studies, cyclohexanone oxime was reacted with
chloramine-T formed a blue colour indicates the

894
formation of chloro-nitroso intermediate, which
GAONKAR & RAI, Orient. J. Chem., Vol. 33(2), 893-896 (2017)
13C NMR spectrum of all fused-oxazines
produces 1-nitroso-cyclohexene on treatment gave expected signals for the newly formed ring
with a base. With this achievement, we are now carbons. For instance, in fused-oxazine 4 (when
reporting a new method for the conversion of cyclic X=H) the peak due to C3 observed around d 54-67
ketoximes heaving an active methylene group into ppm while 4 (when X=CH3) seen around d 62-69 ppm
a-chloronitroso intermediates, which are appropriate and a new signal was observed around d 23-26 ppm
for in situ formation of a-nitrosoalkenes which acts indicative of the methyl group.The signal in oxazine
as dienes and undergo [4+2] cycloaddition with 4c at d 119 ppm is indicative of the CN group. The
dienophiles.
stable molecular ion peaks were seen in the Mass
spectrum which supports the structure of the newly
formed oxazines. The product formation further
confirmed by elemental analyses.1,2-Oxazines and
RESULTS AND DISCUSSIONS
Cyclic ketoximes having a a-hydrogen their fused counterparts are potentially very useful
atom on treatment with chloramine-T followed by heterocycles in synthetic chemistry, and act as useful
treatment with a base are oxidized to a-nitroso building blocks for the construction of complex and
alkenes which undergo Hetero-Diels-Alder reaction new heterocyclic compounds.
with olefinic compounds to produce fused-oxazines
in good yield.Typically, the reaction was performed by
In summary we have established that fused-
boiling an equimolar mixture of cyclic ketoxime and oxazines can be produced by the reaction of cyclic
chloramine-T in ethyl alcohol followed by addition of ketoximes having a a-methylene group with olefinic
a base and an alkene. Overall fused-1,2-oxazines compounds in the presence of chloramines-T and a
are synthesized in good yield as indicated in the base in good yield.
scheme 1.
EXPERIMENTAL
1HNMR, 13CNMR, Mass spectral analyses
and elemental analyses established the structure of
1H NMR and 13C NMR spectra were taken
the fused-oxazines synthesized. The cycloaddition at 400 MHz and 100 MHz respectively on Bruker
reaction was regioselective. Proton NMR spectrum Avance 400 spectrometer using DMSO-d6 or CDCl3 as
of fused-oxazine 4 (when X=H) showed dd around solvents andTMS as internal standard.The chemical
d 3.6-4.4 ppm which is due to H3 and triplet in the shifts are stated in d ppm downfield shift from TMS.
region d 1.70-1.90 ppm is the signal for H4.Where as Mass spectrum was recorded on a Finnigan 4021
in fused-oxazine 4 (when X=CH3), no signal observed mass spectrometer using ionizing energy of 35 ev.
for H3 in the above said region, while a new signal Elemental analyses were performed using Vario-EL
was appeared at d 1.69 ppm designates methyl group elemental analyzer. Reactions were checked for the
and H4 observed in the region d 1.70-1.90 ppm as completion by thin layer chromatography (TLC) on
doublet.
precoated silica gel plates using chloroform-ethyl
acetate (7:3) as eluent.
OH
N
z
O
O
Z
X
N
N
Representative process for the preparation of
3-Phenyl-4,4a,5,6,7,8-hexahydro-3H-benzo[c]
[1,2]oxazine 4a
chloramine-T
TEA
X
3 (a-d)
(a-d)
4
1
2
A mixture of cyclohexanone oxime 1 (1.0
Z
OH
N
O
Z
X
g, 8.85 mmol) and chloramine-T. 3H20 (2.51 g, 8.93
mmol) in ethyl alcohol (6 ml) were boiled for 1 hour.
The reaction mass was cooled to rt.and triethylamine
(1 ml) was added. The reaction mixture was further
stirred for 30 minutes at rt. 3a (0.94 g, 9.03 mmol)
dissolved in ethyl alcohol (3 ml) was then added to
the above reaction mass and was further boiled 2
hr. After the completion of the reaction, ethyl alcohol
O
N
N
chloramine-T
TEA
X
3 (a-d)
5
6
(a-d)
7
a
b
c
d
X =
H, Z= Ph
X =
X =
X =
, Z= Ph
CH3
H, Z= CN
H, Z= COOEt
Scheme 1

895
GAONKAR & RAI, Orient. J. Chem., Vol. 33(2), 893-896 (2017)
was removed under vacuum and the residue left
behind was extracted with chloroform (2 X 20 ml).
The combined chloroform extract was washed with
H20 (15 ml), with dilute NaOH solution (210 ml) and
dried over anhydrous magnesium sulfate.Chloroform
was removed under vacuum and the oily mass left
behind was purified by column chromatography
(CHCl3:EtOAc, 8:2) to give 4a as a pale yellow oily
product to yield 1.25 g (66%); 1HNMR (CDCl3, 400
MHz): d 1.24-1.31 (m, 4H, 2 X -CH2), 1.45-1.55
(m, 5H, 2 X -CH2 and -CH), 1.89 (t, 2H, -CH2), 4.61
(dd, 1H, J= 9.7 Hz & 2.5 Hz, -CH), 7.31 (s, 5H, ArH);
13C NMR (CDCl3): d 24.4, 26.8, 29.5, 30.9, 32.6,
35.4, 81.2, 125.1, 128.4, 141.9, 162.5; MS (relative
abundance) m/z:215 (M+,8%), 138, 120, 95 (100%),
77. C, H and N. Calcd. for C14H17NO: C, 78.10;
H, 7.96; N, 6.51 %. Found: C, 78.19; H, 8.04; N,
6.43 %.
26.1, 29.2, 30.7, 31.5, 32.9, 34.2, 74.6, 125.9,
128.5, 129.0, 139.1, 162.2;MS (relative abundance)
m/z: 229 (M+, 12%), 152, 134, 95 (100%), 77. C, H
and N. Calcd. for C15H19NO: C, 78.56; H, 8.35; N,
6.11 %. Found: C, 78.50; H, 8.41; N, 6.03%.
4,4a,5,6,7,8-Hexahydro-3H-benzo[c][1,2]oxazine-
3-carbonitrile 4c
The product was synthesized from 1
(1.0g,8.85mmol),3c(0.48g,9.05mmol),chloramine-
T.3 H20 (2.51 g, 8.93 mmol) and TEA as a yellow
oily product to yield 1.03 g (71%); 1H NMR CDCl3:
d 1.28-1.34 (m, 4H, 2XCH2), 1.42-1.51 (m, 5H, 2XCH2
and CH), 2.12-2.17 (m, 2H, CH2), 4.69 (dd, 1H, CH);
13C NMR (CDCl3): d d 23.2, 26.1, 30.9, 31.3, 34.3,
35.5, 70.3, 118.2, 162.2; MS (relative abundance)
m/z: 164 (M+, 13%), 163, 136, 95 (100%), 69. C,
H and N. Calcd. for C9H12N2O: C, 65.83; H, 7.37; N,
17.06 %. Found: C, 65.89; H, 7.30; N, 17.11 %.
3-Methyl-3-phenyl-4,4a,5,6,7,8-hexahydro-3H-
benzo[c][1,2]oxazine 4b
4,4a,5,6,7,8-Hexahydro-3H-benzo[c][1,2]oxazine-
3-carboxylic acid ethyl ester 4d
The product was synthesized from 1
(1.0g,8.85mmol),3b(1.06g,8.98mmol), chloramine-
T.3 H20 (2.51 g, 8.93 mmol) and TEA to give yellow
oily product to yield 1.31 g (65%); 1H NMR CDCl3:
d 1.26-1.35 (m, 4H, 2XCH2), 1.45-1.55 (m, 5H,
2XCH2 and CH), 1.71 (s, 3H, CH3), 1.93 (d, 2H,
CH2), 7.41 (s, 5H, ArH); 13C NMR (CDCl3): d 23.6,
The product was synthesized from 1
(1.0 g, 8.85 mmol), 3d (0.90 g, 9.0 mmol), chloramine-
T.3 H20 (2.51 g, 8.93 mmol) andTEA as a pale yellow
oily product to yield 0.48 g (72%); 1H NMR CDCl3:
d 1.29 (t, 3H, CH3), 1.35-1.44 (m, 8H, CH2), 1.55-161
(m, 1H, CH), 2.22 (t, 2H, CH2), 4.28 (dd, 1H, CH),
4.69 (q, 2H, CH2); 13C NMR CDCl3: d 12.6, 27.3, 29.4,
30.8, 33.0, 35.3, 61.1, 83.2, 163.2, 174.3;MS (relative
abundance) m/z: 211 (M+, 22%), 166 (100%), 138,
95, 71. C, H and N. Calcd. for C11H17NO3: C, 62.54;
H, 8.11; N, 6.63 %. Found: C, 62.48; H, 8.19; N,
6.56 %.
2
1
N
O
3
a
8
4
8
4a
3-Phenyl-3,4,4a,5,6,7-hexahydro-cyclopenta[c]
[1,2]oxazine 7a
5
7
6
The product was synthesized from 5 (1.0 g,
10.10 mmol), 3a (1.07 g, 10.28 mmol), chloramine-
T.3 H20 (2.85 g, 10.15 mmol) and TEA to give a pale
yellow oily product to yield 0.48 g (64%); 1H NMR
CDCl3: d 1.33 (t, 2H, CH2), 1.46-1.55 (m, 5H, 2XCH2
and CH), 2.01 (t, 2H, CH2), 4.42 (dd, 1H, CH), 7.39
(s, 5H, ArH);13C NMR CDCl3: d 26.2, 27.9, 32.6, 36.5,
41.2, 78.4, 125.8, 128.9, 129.2, 140.1, 161.0; MS
(relative abundance) m/z: 201 (M+, 11%), 124, 120,
81 (100%), 77. C, H and N. Calcd. for C13H15NO: C,
77.58; H, 7.51; N, 6.96 %. Found: C 77.48; H, 7.59;
N, 6.91%.
4b
2
O
1
N
a
N
3
8
4
8
4a
5
7
6
4c

896
GAONKAR & RAI, Orient. J. Chem., Vol. 33(2), 893-896 (2017)
3-Methyl-3-phenyl-3,4,4a,5,6,7-hexahydro- C, 63.98; H, 6.71; N, 18.65 %. Found: C, 63.90;
cyclopenta[c][1,2]oxazine 7b
H, 6.77; N, 18.69 %.
The product was synthesized from 5 (1.0 g,
10.1 mmol), 3b (1.20 g, 10.16 mmol), chloramine-T.3 2-Phenyl-3, 4, 4a, 5, 6, 7-hexahydro-2H-
H20 (2.85 g, 10.15 mmol) andTEA to give yellow oily cyclopenta[c]pyridazine-3-carboxylic acid ethyl
product to yield 0.48 g (67%); 1H NMR CDCl3: d 1.34 ester 7d
(t, 2H, CH2), 1.48-1.55 (m, 4H, 2XCH2), 1.64 (s, 3H,
The product was synthesized from 5 (1.0 g,
CH3), 1.64-1.68 (m, 1H, CH), 1.98 (d, 2H, CH2), 7.35 10.1 mmol), 3d (1.03 g, 10.30 mmol), chloramine-T.3
(s, 5H, ArH);13C NMR CDCl3: d 24.2, 26.4, 33.3, 36.3, H20 (2.85 g, 10.15 mmol) and TEA as a yellow oily
38.9, 79.2, 125.3, 128.4, 128.8, 140.7, 162.3; MS mass to yield 0.48 g (68%); 1H NMR CDCl3: d 1.29
(relative abundance) m/z: 215 (M+, 9%), 138, 134, (t, 3H, CH3), 1.39-1.52 (m, 6H, 3XCH2), 1.55-1.63
81 (100%), 77. C, H and N. Calcd. for C14H17NO: C, (m, 1H, CH), 1.954-2.01 (m, 2H, CH2), 4.29 (dd, 1H,
78.10; H, 7.96; N, 6.51 %. Found: C, 78.19; H, 7.90; CH), 4.73 (q, 2H, CH2); 13C NMR CDCl3: d 14.3, 21.3,
N, 6.58%.
26.2, 30.8, 31.2, 33.9, 35.6, 61.2, 84.2, 161.2, 173.6;
MS (relative abundance) m/z: 197 (M+, 11%), 197,
3,4,4a,5,6,7-hexahydro-cyclopenta[c][1,2] 152 (100%), 124, 116, 81, 71. C, H and N. Calcd.
oxazine-3-carbonitrile 7c
for C10H15NO3: C, 60.90; H, 7.67; N, 7.10 %. Found:
The product was synthesized from 5 (1.0 g, C, 60.99; H, 7.60; N, 7.06 %.
10.1 mmol), 3c (0.55 g, 10.37 mmol), chloramine-T.3
H20 (2.85 g, 10.15 mmol) and TEA as pale brown
oily product to yield 0.48 g (69%); 1H NMR CDCl3:
d 1.39 (t, 3H, CH2), 1.51-1.60 (m, 5H, 2XCH2 and CH),
CONCLUSION
We have established a simple and effective
1.99 (t, 2H, CH2), 4.79 (dd, 1H, CH);13C NMR CDCl3: method for the synthesis of fused-oxazines from
d 22.2, 27.8, 32.9, 37.6, 41.1, 71.2, 118.3, 161.5; cyclic ketoximes by Heter-Diels-Alder cycloaddition
MS (relative abundance) m/z: 150 (M+, 10%), 149, of in situ generated a-nitroso olefins with various
122, 81 (100%), 69.C, H and N.Calcd.for C8H10N2O: alkenes.
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