Heteroaromatic annulation studies on 10,11-dihydro-11-[bis(methylthio)methylene]dibenzoxepin-10-one: a facile access to novel dibenzoxepino[4,5]-fused heterocycles

Article abstract of DOI:10.1016/j.tet.2007.07.045

10,11-Dihydro-11-[bis(methylthio)methylene]dibenzoxepin-10-one has been shown to be a useful three carbon synthon for the efficient regiospecific annulation of a variety of five- (pyrazoles, isoxazoles, thiophene, and γ-lactone) and six-membered (pyrimidi

Full text of DOI:10.1016/j.tet.2007.07.045

Tetrahedron 63 (2007) 10067–10076
Heteroaromatic annulation studies on 10,11-dihydro-11-
[bis(methylthio)methylene]dibenzoxepin-10-one: a facile
access to novel dibenzoxepino[4,5]-fused heterocycles
*
Sarvesh Kumar, Hiriyakkanavar Ila and Hiriyakkanavar Junjappa
Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India
Received 19 March 2007; revised 18 June 2007; accepted 12 July 2007
Available online 19 July 2007
Dedicated to Professor Nouria A. Al-Awadi on her 55th birthday
Abstract—10,11-Dihydro-11-[bis(methylthio)methylene]dibenzoxepin-10-one has been shown to be a useful three carbon synthon for the
efficient regiospecific annulation of a variety of five- (pyrazoles, isoxazoles, thiophene, and g-lactone) and six-membered (pyrimidines, pyr-
idone and pyridines) heterocycles by cyclocondensation with heterobinucleophiles such as hydrazine, hydroxylamine, dimethylsulfonium
methylide, guanidine, thiourea, cyanoacetamide, and substituted b-lithioaminoacrylonitrile.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
dibenzoxepin-10-one 2 was selected as a model substrate for
our heteroannulation studies and the results are reported
herein.
A number of dibenzoxepine derivatives containing a fused
heterocyclic ring at the 4,5-position are known to display
a wide range of biological activity, and have proven to be
lead compounds for psychoactive drugs for the treatment
of anxiety disorder, depression, and in particular schizo-
phrenic psychoses.1,2 Thus, a few of the azepino- (maroxe-
pine, savoxepine),3 piperidino- (ORG 4428, beloxepin)1a,4
and pyrrolidino-fused (ORG 5222)1a,4 dibenzoxepine deriv-
atives are shown to be a new class of emerging potential
antianxiety and antidepressant agents, displaying improved
activity and tolerance in comparison to the existing classical
psychoactive drugs. Therefore, such dibenzoxepino-fused
heterocycles have attracted considerable attention from
both medicinal and synthetic organic chemists in recent
years because of their broad pharmacological applications
as indicated by large number of publications and patents in
this field.1,5 As a part of our ongoing research program on
aromatic and heteroaromatic annulation studies on a-oxoke-
tene dithioacetals as three carbon 1,3-electrophilic com-
ponents,6,7 we became interested in elaborating this strategy
for the synthesis of dibenzoxepino[4,5]-fused five- and
six-membered heterocycles in view of the unique biolog-
ical activity displayed by this class of compounds. The
corresponding 10,11-dihydro-11-[bis(methylthio)methylene]-
2. Results and discussion
The desired a-oxoketene dithioacetal 2 was prepared in high
yield by the treatment of 10,11-dihydrodibenzoxepin-10-
one 18 with sodium hydride and carbon disulfide in THF at
0 ꢀC followed by alkylation with methyl iodide (Scheme
1).9 The corresponding b-oxodithioester 3 was also synthe-
sized as a useful precursor for various heterocycles by react-
ing the ketone 1 with dimethyl trithiocarbonate in the
presence of NaH in refluxing benzene according to our ear-
lier reported procedure.10 Syntheses of dibenzoxepino[4,5]-
fused five-membered heterocycles were undertaken first
(Schemes 2–4). Thus, when 2 was reacted with hydrazine
hydrate in refluxing ethanol, the corresponding 3-(methyl-
thio)-2H-dibenzoxepino[4,5-c]pyrazole 4 was obtained in
73% yield (Scheme 2).11 Similarly, the treatment of the ke-
tene dithioacetal 2 with phenylhydrazine in the presence of
potassium tert-butoxide in refluxing tert-butanol furnished
3-(methylthio)-2-phenyldibenzoxepino[4,5-c]pyrazole 5 in
63% yield.12 The corresponding regioisomeric 3-(methyl-
thio)-1-phenyldibenzoxepin[4,5-d]pyrazole 6a could also
be prepared in good yield by treating b-oxodithioester 3
with phenylhydrazine in refluxing ethanol.12a The structures
and regiochemistry of products 5 and 6 were established
with the help of spectral and analytical data, and also by de-
sulfurization of the pyrazole 6a to the known dethiomethyl-
ated pyrazole 6b1a with Raney-Ni in refluxing ethanol.
Keywords: Heteroaromatic annulation; a-Oxoketene dithioacetal; Dibenz-
oxepine; Heterocycles.
* Corresponding author. Tel.: +91 512 2597870; fax: +91 512 2597436;
e-mail: hila@iitk.ac.in
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.045

10068
S. Kumar et al. / Tetrahedron 63 (2007) 10067–10076
MeS
S
SMe
O
SMe
CH2I2/Zn-Cu
1. NaH/CS2/THF/0 °C
2. MeI (2 equiv)/8 h
2
Et2O/Δ/6 h
O
O
O
2, 80%
10, 61%
O
O
H
O
SMe
S
S
SMe
1
MeS
SMe
NaH/C6H6/DMF/Δ/4 h
O
O
1. Me3SI/n-BuLi
THF/ -78 °C/N2
11
3, 84%
2
Me
H2C=S
Me
O
Scheme 1.
O
X
2. MeOH/aq. HCl/5 h
O
H
N
SMe
N
12a, X = SMe, 61%
12b, X = H, 91%
Raney-Ni
EtOH/Δ/2 h
.
NH2NH2 H2O
EtOH/Δ/6 h
O
Scheme 4.
4, 73%
Ph
N
2
The ketene dithioacetal 2 was next reacted with hydroxyl-
amine hydrochloride with a view to synthesize dibenzoxe-
pino-fused isoxazoles as shown in the Scheme 3.13 Thus,
when 2 was exposed to NH2OH$HCl in the presence of so-
dium ethoxide in refluxing ethanol, the product isolated was
characterized as 3-ethoxydibenzoxepino[4,5-c]isoxazole 7
in which the methylthio group was replaced by the ethoxy
group as observed earlier in our previous studies.9b On the
other hand, treatment of 2 with NH2OH$HCl in the presence
of a non-nucleophilic base such as barium hydroxide
afforded the corresponding 3-(methylthio)dibenzoxepino-
[4,5-c]isoxazole 8 in 86% yield.13 Similarly, the reaction
of 2 with NH2OH$HCl in the presence of sodium acetate–
acetic acid buffer furnished regioisomeric 3-(methylthio)-
dibenzoxepino[4,5-d]isoxazole 9 in good yield (Scheme 3).
These observations are in conformity with our earlier
report13 on the formation of regioisomeric isoxazoles under
varying pH conditions.
X
N
PhNHNH2/KOtBu
ButOH/Δ/10 h
O
5a, X=SMe, 63%
5b, X=H, 75%
Raney-Ni
EtOH/Δ/7 h
H
O
S
N
X
SMe
Ph
N
PhNHNH2
EtOH/Δ/7 h
O
O
3
6a, X = SMe, 69%
6b, X = H, 83%
Raney-Ni
EtOH/Δ/3 h
Scheme 2.
The ketene dithioacetal 2 was next subjected to treatment
with methylene iodide and Zn–Cu couple yielding the cor-
responding 1-(methylthio)thieno[3,4-d]dibenzoxepine 10
(61%), in line with our earlier observations on Simmons–
Smith reaction on a-oxoketene dithioacetals.14
O
OEt
N
NH2OH.HCl/NaOEt
EtOH/Δ/8 h
O
7, 72%
Interestingly, attempted preparation of dibenzoxepino-fused
methylthiofuran 11 by reacting ketene dithioacetal 2 with di-
methylsulfonium methylide followed by acid work-up15
yielded an unexpected product, which was characterized
as 3-(methylthio)-1,3-dihydro-1-oxo-furo-[3,4-d]dibenzoxe-
pine 12a, instead of 11 on the basis of its spectral and ana-
lytical data and also by Raney-Ni mediated desulfurization
of 12a to 12b (Scheme 4).
O
N
SMe
NH2OH.HCl/Ba(OH)2
2
EtOH/Δ/4 h
O
8, 86%
N
SMe
O
NH2OH.HCl/NaOAc
The probable mechanism for the formation of the lactone
12a from 2, which involves an oxidative step at some stage
of the transformation, is shown in Scheme 5. The initial
fused dihydrofuran intermediate A affords the furan 11 on
treatment with aqueous HCl. However, the furan 11 appears
AcOH/EtOH/C6H6/Δ
O
68 h
9, 68%
Scheme 3.

S. Kumar et al. / Tetrahedron 63 (2007) 10067–10076
10069
CN
SMe
O
to be unstable under the present reaction condition and un-
dergoes acid-induced hydration and subsequent oxidation
of the hydrated intermediate C to furnish the lactone 12a.
Our attempts to isolate furan 11 under varying conditions
were unsuccessful.
O
HN
CN
H2N
t
t
NaO Bu/HO Bu/Δ/7 h
O
16, 50%
CN
SMe
SMe
SMe
O
Ο
SMe
H
2
Me
Me
H2C
S
Ph
aq. HCl/MeOH
-MeSH
2
N
1. MeCN/ BuLi
(1 equiv)/-78 °C
O
O
A
11
2. PhCN/-78 °C
3. Δ/10 h
CN
O
18, 60%
H
LiHN
Ph
SMe
H
HO
SMe
H
O
O
O
O
O
H
H
17
O
12a
Scheme 7.
C
B
Scheme 5.
furnished
4-ethoxy-2-(3-pyridyl)dibenzoxepino[4,5-d]-
pyrimidine 14b in 58% yield (Scheme 6). Cyclocondensa-
tion of 2 with thiourea using sodium ethoxide in refluxing
ethanol furnished the dimeric compound bis(4-ethoxy-
dibenzoxepino[4,5-d]pyrimidin-2-yl)disulfide 15 resulting
via oxidative dimerization of the initially formed 4-ethoxy-
2-mercaptodibenzoxepino[4,5-d]pyrimidine (Scheme 6).
Cyclocondensation of 2 with 1,3-heterobinucleophiles was
next examined with a view to synthesize dibenzoxepino-
fused six-membered heterocycles (Schemes 6 and 7).
Thus, heterocyclization of 2 with guanidine nitrate in the
presence of sodium hydride in DMF afforded the corre-
sponding
2-amino-4-(methylthio)dibenzoxepino[4,5-d]-
pyrimidine 13 in 80% yield.9 On the other hand, a similar
reaction when conducted in the presence of sodium ethoxide
in refluxing ethanol gave 2-amino-4-ethoxydibenzoxe-
pino[4,5-d]pyrimidine 14a (60%) in accordance with our
earlier reported alkoxypyrimidine synthesis from a-oxo-
ketene dithioacetals.9b Similarly, treatment of 2 with 2-(3-
pyridyl)amidine hydrochloride under identical conditions
The versatility of our heteroaromatic annulation strategy
was further demonstrated by the synthesis of a few pyrido-
fused dibenzoxepines as shown in Schemes 7 and 8. Thus,
the reaction of 2 with cyanoacetamide in the presence of
sodium tert-butoxide in tert-butanol afforded the highly
functionalized 3-cyano-4-(methylthio)-1H-dibenzoxepino-
[4,5-b]pyridine-2-one 16 in a moderate yield of 50%.16
Similarly, the cyclocondensation of 2 with b-phenyl-b-
lithioaminoacrylonitrile 17 (generated in situ according to
earlier reported method)17 yielded 4-(methylthio)-2-phenyl-
dibenzoxepino[4,5-b]pyridine-3-carbonitrile 18 in 60%
yield (Scheme 7). In another strategy for pyridine annula-
tion, the ketene dithioacetal 2 was subjected to conjugate ad-
dition–elimination with acetophenone enolate affording the
conjugate adduct 19, which in the presence of ammonium
acetate–acetic acid provided the corresponding 4-(methyl-
thio)-2-phenyldibenzoxepino[4,5-b]pyridine 20 in 63%
yield (Scheme 8).18
H2N
N
NH
N
SMe
.HNO3
H2N
NH2
NaH/DMF/Δ/20 h
O
13, 80%
R
N
N
2
NH
OEt
.HX
R
NH2
Ph
Ph
NaOEt/EtOH/Δ
O
O
O
SMe
N
SMe
14a R = NH2; X=NO3, 60%
14b R = 3-pyridyl; X=Cl, 58%
NH4OAc
PhCOCH3
NaH/DMF
2
AcOH/Δ/5 h
O
O
)
2
S
N
19, 83%
20, 63%
S
N
OEt
H2N
NH2
Scheme 8.
2
NaOEt/EtOH/Δ/7 h
O
Finally, we also investigated benzo- and naphtho-annulation
of 2 with allyl and benzyl Grignard reagents with a view to
synthesize [4,5]-benzo- and naphtho-fused dibenzoxepines,
as well as to show the generality and scope of our aromatic
15, 63%
Scheme 6.

10070
S. Kumar et al. / Tetrahedron 63 (2007) 10067–10076
annulation protocol.6b,19 Thus, 1,2-addition of 2 with either
allyl or methallyl magnesium halide followed by the cyclo-
aromatization of the resulting carbinol acetal in the presence
of BF3$OEt2 at reflux in benzene proceeded smoothly af-
fording the respective tribenzoxepine 21a or 21c in overall
good yield.20 1-(Methylthio)tribenzoxepine 21a was con-
verted into the parent 21b21 in 78% yield by reductive de-
thiomethylation with Raney-Ni (Scheme 9). Similarly, the
treatment of 2 with benzylmagnesium chloride under previ-
ously reported conditions afforded only 1,2-carbinol adduct,
which was transformed into the 5-(methylthio)naphtho[2,3-
d]dibenzoxepine 22a through BF3$OEt2 promoted cycloaro-
matization under standard reaction conditions.22 Subsequent
Raney-Ni dethiomethylation of 22a gave the parent 22b in
78% yield (Scheme 9).
Elemental analyses were carried out on an Elementar Vario
EL III analyzer.
Column chromatography was carried out using silica gel
(100–200 mesh). THF was distilled over sodium benzophe-
none ketyl prior to use. DMF was distilled over calcium
hydride and stored over molecular sieves. n-BuLi was pur-
chased from Aldrich company.
4.1.1. Synthesis of 10,11-dihydro-11-[bis(methylthio)-
methylene]dibenz[b,f]oxepin-10-one (2). To a stirred
suspension of NaH (60%, 0.2 g, 4.8 mmol) in dry DMF
(10 mL) under a nitrogen atmosphere was added dropwise a
DMF solution (10 mL) of 10,11-dihydro-dibenzoxepin-10-
one 1 (0.4 g, 1.9 mmol) and carbon disulfide (0.13 mL,
2.2 mmol) at 0 ꢀC. The resulting anion was stirred at the
same temperature for 30 min, followed by stirring at room
temperature overnight (12 h). Methyl iodide (0.9 mL,
3.8 mmol) was added dropwise at 0 ꢀC followed by stirring
of the reaction mixture at room temperature for 8 h (moni-
tored by TLC). The reaction mixture was poured into ice-
cold water (50 mL) and extracted with ethyl acetate
(3ꢁ20 mL). The combined organic extracts were washed
with water (3ꢁ40 mL), brine (1ꢁ30 mL), and dried over an-
hydrous Na2SO4. The solvent was evaporated under reduced
pressure and the crude product was recrystallized from hex-
ane–chloroform to yield 2 as yellow crystals (0.48 g, 80%);
Rf 0.2 (49:1 hexane–EtOAc); mp 132–133 ꢀC; IR cmꢂ1
(KBr): 3062, 2920, 1632, 1464, 1443, 1299; 1H NMR
(400 MHz, CDCl3): d 8.18 (dd, J¼8.04, 1.72 Hz, 1H,
ArH), 7.49 (ddd, J¼7.44, 7.44, 1.96 Hz, 1H, ArH), 7.45
(d, J¼7.32, 1H, ArH), 7.29–7.25 (m, 3H, ArH), 7.22–7.17
(m, 2H, ArH), 2.44 (s, 3H, SMe), 2.15 (s, 3H, SMe); 13C
NMR (100 MHz, CDCl3): d 183.7, 160.0, 156.6, 152.7,
137.4, 134.5, 131.4, 131.3, 130.1, 128.9, 127.4, 125.7,
124.2, 121.0, 120.7, 18.5, 17.9; MS m/z (%): 315 (M++1,
100), 314 (M+, 80), 267 (58). Anal. Calcd for C17H14O2S2:
C, 64.94%; H, 4.49%. Found: C, 64.83%; H, 4.57%.
R
R
X
MgCl/Et2O/THF
1.
2
2. BF3·OEt2/C6H6/Δ/3-4 h
O
21a, R = H; X = SMe, 64%
21b, R = X = H, 78%
Raney-N i
EtOH/Δ/7 h
21c, R = Me; X= SMe, 75%
X
1.
MgCl/Et2O/THF
2
2. BF3·OEt2/C6H6/Δ/4 h
O
22a, X = SMe, 52%
22b, X = H, 78%
Raney-Ni
EtOH/Δ/9 h
Scheme 9.
3. Conclusion
4.1.2. Synthesis of methyl(10,11-dihydro-10-oxodi-
benz[b,f]oxepine)-11-dithioate (3). A solution of ketone 1
(1.0 g, 4.8 mmol) in benzene (20 mL) was added dropwise
to a stirred suspension of NaH (60%, 0.48 g, 12.0 mmol)
and dimethyl trithiocarbonate (0.8 g, 5.7 mmol) in a solution
of benzene (40 mL) and DMF (4 mL) at reflux temperature
over a period of 40 min. After addition was over, the reflux-
ing was continued for 4 h (monitored by TLC). The reaction
mixture was cooled to room temperature and poured into
saturated aqueous ammonium chloride solution (40 mL).
The organic layer was separated and washed with water
(3ꢁ40 mL), brine (1ꢁ40 mL), and dried over anhydrous
Na2SO4. The solvent was evaporated under reduced pressure
and the crude product was purified by column chromato-
graphy over silica gel using hexane–EtOAc (24:1) as eluant
to give 3 as a viscous yellow liquid (1.2 g, 84%); Rf 0.6 (49:1
hexane–EtOAc); IR cmꢂ1 (neat): 2920, 1679, 1527, 1443,
In summary, overall work presented in this paper further
demonstrates the versatility of our heteroaromatic/aromatic
annulation protocol via a-oxoketene dithioacetal for gener-
ating a wide range of novel hitherto unreported condensed
polycyclic heteroaromatics, which cannot be prepared easily
by traditional classical methods. In view of the wide range of
biological activities displayed by dibenzoxepino-fused het-
erocycles, especially, as psychoactive drugs, these newly
synthesized heterocycles will prove useful for preliminary
pharmacological evaluations.
4. Experimental
4.1. General
1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were
recorded on Jeol JNM Lambda Spectrometer with CDCl3 or
DMSO-d6 as the solvent and TMS as an internal standard.
Melting points were measured using Mel-Temp apparatus
and are uncorrected. IR spectra were recorded on a Per-
kin–Elmer 1320 spectrometer. Mass spectra were recorded
on Jeol SX 102/DA-6000 Mass Spectrometer/Data System.
1
1219, 968; H NMR (400 MHz, CDCl3) (4:5 mixture of
keto–enol tautomers): d 8.12 (dd, J¼7.92, 1.84 Hz, 0.45H,
ArH, keto), 7.87 (dd, J¼8.16, 1.84 Hz, 0.55H, ArH, enol),
7.88–7.39 (m, 2.45H, ArH, keto+enol), 7.34–7.19 (m, 4H,
ArH, keto+enol), 7.11 (ddd, J¼8.06, 6.10, 2.39 Hz, 0.55H,
ArH, enol), 4.98 (s, 0.45H, CH, keto), 2.61 (s, 3ꢁ0.55H,
SMe, enol), 2.55 (s, 3ꢁ0.45H, SMe, keto); 13C NMR

S. Kumar et al. / Tetrahedron 63 (2007) 10067–10076
10071
(100 MHz, CDCl3): d 230.8, 222.3, 187.8, 163.9, 161.1,
160.0, 158.0, 156.6, 134.9, 133.9, 133.3, 131.8, 131.52,
130.56, 130.5, 129.5, 128.1, 127.9, 127.2, 126.4, 125.1,
124.9, 124.2, 124.0, 121.8, 121.6, 121.1, 120.9, 120.5,
29.7, 19.7, 19.3; MS m/z (%): 301 (M++1, 78), 300 (M+,
69), 299 (M+ꢂ1, 56), 267 (35), 253 (100), 252 (72). Anal.
Calcd for C16H12O2S2: C, 63.97%; H, 4.03%. Found: C,
64.06%; H, 4.07%.
7 h (monitored by TLC). The solvent was evaporated under
reduced pressure and the crude product was purified by col-
umn chromatography over silica gel using hexane–EtOAc
(24:1) as eluant to give 6a as a white solid (0.23 g, 69%);
Rf 0.4 (49:1 hexane–EtOAc); mp 172–173 ꢀC; IR cmꢂ1
1
(KBr): 1506, 1390, 1223, 764, 697; H NMR (400 MHz,
CDCl3): d 7.90 (dd, J¼7.46, 1.58 Hz, 1H, ArH), 7.46–7.22
(m, 10H, ArH), 6.90 (ddd, J¼7.50, 7.50, 1.32 Hz, 1H,
ArH), 6.77 (dd, J¼8.04, 1.48 Hz, 1H, ArH), 2.64 (s, 3H,
SMe); 13C NMR (100 MHz, CDCl3): d 157.1, 156.2,
145.7, 139.7, 137.9, 130.4, 129.1, 128.8, 128.6, 127.9,
127.8, 125.29, 125.27, 124.6, 122.7, 122.0, 121.3, 117.6,
15.3; MS m/z (%): 357 (M++1, 100), 356 (M+, 72). Anal.
Calcd for C22H16N2OS: C, 74.13%; H, 4.52%; N, 7.86%.
Found: C, 74.05%; H, 4.59%; N, 8.03%.
4.1.3. Synthesis of 3-(methylthio)-2H-dibenz[b,f]oxe-
pino[4,5-c]pyrazole (4). To a stirred solution of 2 (0.45 g,
1.5 mmol) in ethanol (20 mL), hydrazine hydrate (80%,
0.14 mL, 2.25 mmol) was added and the reaction mixture
was refluxed for 6 h (monitored by TLC). The solvent was
removed under reduced pressure and the residue was dis-
solved in chloroform (20 mL). The chloroform layer was
washed with water (2ꢁ20 mL), brine (1ꢁ30 mL), and dried
over anhydrous Na2SO4. The solvent was evaporated under
reduced pressure and the crude product was purified by col-
umn chromatography over silica gel using hexane–EtOAc
(9:1) as eluant to give 4 as a white solid (0.32 g, 73%); Rf
0.3 (9:1 hexane–EtOAc); mp 163–164 ꢀC; IR cmꢂ1 (KBr):
3257, 1524, 1445, 1240, 1135, 990, 938, 760, 737; 1H
NMR (400 MHz, CDCl3): 7.90 (dd, J¼7.68, 1.36 Hz, 1H,
ArH), 7.57 (d, J¼7.32, 1H, ArH), 7.32–7.23 (m, 4H, ArH),
7.19 (ddd, J¼7.88, 7.88, 1.64 Hz, 1H, ArH), 7.08 (ddd,
J¼6.96, 6.96, 2.20 Hz, 1H, ArH), 2.47 (s, 3H, SMe); 13C
NMR (100 MHz, CDCl3): d 157.3, 156.1, 130.6, 128.4,
127.7, 126.5, 125.3, 125.2, 124.0, 121.8, 121.7, 116.6,
17.0; MS m/z (%): 281 (M++1, 100), 280 (M+, 80), 234
(40). Anal. Calcd for C16H12N2OS: C, 68.55%; H, 4.31%;
N, 9.99%. Found: C, 68.71%; H, 4.28%; N, 10.02%.
4.1.6. Synthesis of 3-ethoxydibenz[b,f]oxepino[4,5-c]iso-
xazole (7). Hydroxylamine hydrochloride (0.28 g, 4 mmol)
was added to a stirred solution of sodium ethoxide
(6 mmol, prepared in situ from 0.14 g of sodium metal and
2 mL of ethanol) in ethanol (10 mL) at room temperature.
After 10 min, ketene dithioacetal 2 (0.31 g, 1.0 mmol) was
added at the same temperature and the reaction mixture
was refluxed for 8 h (monitored by TLC). Solvent was evap-
orated under reduced pressure and the residue was treated
with water (20 mL). Extraction was done with chloroform
(2ꢁ30 mL). The combined organic extracts were washed
with water (2ꢁ20 mL), brine (1ꢁ30 mL), and dried over
anhydrous Na2SO4. Solvent was removed under reduced
pressure and the crude product was purified by column chro-
matography over silica gel using hexane–EtOAc (9:1) as el-
uant to give a white solid (7) (0.20 g, 72%); Rf 0.5 (9:1
hexane–EtOAc); mp 149–150 ꢀC; IR cmꢂ1 (KBr): 2986,
1
4.1.4. Synthesis of 3-(methylthio)-2-phenyldibenz[b,f]-
oxepino[4,5-c]pyrazole (5a). A solution of a-oxoketene
1641, 1526, 1445, 1383, 1224, 1041, 752, 737; H NMR
(400 MHz, CDCl3): d 7.76 (dd, J¼7.56, 1.72 Hz, 1H,
ArH), 7.70 (dd, J¼7.58, 1.70 Hz, 1H, ArH), 7.47 (ddd,
J¼7.75, 7.75, 1.62 Hz, 1H, ArH), 7.34–7.19 (m, 5H, ArH),
4.51 (q, J¼7.08 Hz, 2H, OCH2), 1.54 (t, J¼7.08 Hz, 3H,
Me); 13C NMR (100 MHz, CDCl3): d 169.0, 164.3, 156.2,
155.0, 132.5, 129.3, 126.8, 126.15, 126.12, 125.4, 125.4,
122.6, 122.0, 121.8, 104.9, 66.3, 14.7; MS m/z (%): 280
(M++1, 72), 279 (M+, 100). Anal. Calcd for C17H13NO3:
C, 73.11%; H, 4.69%; N, 5.02%. Found: C, 73.29%; H,
4.64%; N, 5.07%.
dithioacetal
2
(0.2 g, 0.64 mmol), phenylhydrazine
(0.94 mL, 0.96 mmol), and ButOK (0.14 g, 1.28 mmol) in
ButOH (5 mL) was refluxed for 10 h (monitored by TLC)
with constant stirring. The reaction mixture was concen-
trated under reduced pressure and the residue was dissolved
in chloroform (30 mL). The chloroform layer was washed
with water (2ꢁ30 mL), brine (1ꢁ30 mL), and dried over an-
hydrous Na2SO4. Solvent was evaporated under reduced
pressure and the crude product was purified by column chro-
matography over silica gel using hexane–EtOAc (9:1) as el-
uant to give 5 as a white solid (0.14 g, 63%); Rf 0.6 (9:1
hexane–EtOAc); mp 172–173 ꢀC; IR cmꢂ1 (KBr): 1440,
4.1.7. Synthesis of 3-(methylthio)dibenz[b,f]oxepino-
[4,5-c]isoxazole (8). Hydroxylamine hydrochloride (0.28 g,
4 mmol) was added to a stirred suspension of Ba(OH)2
(1.03 g, 6 mmol) in 95% aqueous ethanol (10 mL) at room
temperature. Ketene dithioacetal 2 (0.31 g, 1.0 mmol) was
added and the reaction mixture was refluxed for 4 h (moni-
tored by TLC). Solvent was evaporated under reduced pres-
sure and the residue was treated with ice-cold water (20 mL).
Extraction was done with chloroform (2ꢁ30 mL). The com-
bined organic extracts were washed with water (2ꢁ30 mL),
brine (1ꢁ30 mL), and dried over anhydrous Na2SO4. Sol-
vent was evaporated under reduced pressure and the crude
product was purified by column chromatography over silica
gel using hexane–EtOAc (19:1) as eluant to give 8 as a white
solid (0.24 g, 86%); Rf 0.4 (49:1 hexane–EtOAc); mp 100–
101 ꢀC; IR cmꢂ1 (KBr): 1442, 1391, 1251, 1216, 1041,
758; 1H NMR (400 MHz, CDCl3): d 7.83 (dd, J¼7.70,
1.58 Hz, 1H, ArH), 7.63 (dd, J¼8.18, 0.86 Hz, 1H, ArH),
1
1194, 773, 749; H NMR (400 MHz, CDCl3): d 8.08 (dd,
J¼7.56, 1.72 Hz, 1H, ArH), 7.88 (dd, J¼7.80, 1.24 Hz,
1H, ArH), 7.68 (d, J¼8.08 Hz, 2H, ArH), 7.52 (t,
J¼7.56 Hz, 2H, ArH), 7.47 (t, J¼6.08 Hz, 1H, ArH),
7.37–7.28 (m, 4H, ArH), 7.26–7.18 (m, 2H, ArH), 2.10 (s,
3H, SMe); 13C NMR (100 MHz, CDCl3): d 157.8, 156.9,
148.2, 139.3, 132.8, 130.1, 128.9, 128.5, 128.2, 127.5,
126.1, 125.3, 125.2, 121.8, 121.3, 120.7, 18.6; MS m/z
(%): 357 (M++1, 100), 356 (M+, 80). Anal. Calcd for
C22H16N2OS: C, 74.13%; H, 4.52%; N, 7.86%. Found: C,
74.08%; H, 4.58%; N, 7.79%.
4.1.5. Synthesis of 3-(methylthio)-1-phenyldibenz[b,f]ox-
epino[4,5-d]pyrazole (6a). A solution of b-oxodithioester
3 (0.28 g, 0.93 mmol) and phenylhydrazine (0.13 mL,
1.34 mmol) in absolute ethanol (10 mL) was refluxed for

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S. Kumar et al. / Tetrahedron 63 (2007) 10067–10076
7.44 (ddd, J¼7.81, 7.81, 1.61 Hz, 1H, ArH), 7.34–7.29 (m,
3H, ArH), 7.27–7.20 (m, 2H, ArH), 2.72 (s, 3H, SMe); 13C
NMR (100 MHz, CDCl3): d 162.0, 159.5, 157.5, 156.0,
132.1, 129.3, 128.3, 128.1, 125.6, 125.5, 122.6, 122.3,
121.9, 112.5, 14.8; MS m/z (%): 282 (M++1, 100), 281
(M+, 87). Anal. Calcd for C16H11NO2S: C, 68.31%;
H, 3.94%; N, 4.98%. Found: C, 68.27%; H, 3.86%; N,
5.07%.
4.1.10. Synthesis of 3-(methylthio)-1,3-dihydro-1-oxo-
furo[3,4-d]dibenz[b,f]oxepine (12a). n-BuLi (1.6 M in hex-
ane, 0.96 mL, 1.54 mmol) was added dropwise at ꢂ15 ꢀC to
a stirred suspension of trimethylsulfonium iodide (0.26 g,
1.54 mmol) in dry THF (15 mL) under a nitrogen atmo-
sphere. The reaction mixture was stirred at the same temper-
ature for 15 min for the generation of the dimethylsulfonium
methylide, and then it was cooled to ꢂ78 ꢀC and solution of
2 (0.40 g, 1.28 mmol) in dry THF (5 mL) was added drop-
wise over a period of 5 min. The reaction mixture was fur-
ther stirred at ꢂ78 ꢀC for 1 h and then slowly warmed to
room temperature over a period of 2 h. It was then quenched
with water (0.5 mL), washed with brine (2ꢁ20 mL), and
dried over anhydrous Na2SO4. Solvent was removed under
reduced pressure below 30 ꢀC to give the unstable dihydro-
furan derivative. This was dissolved in methanol (5 mL) and
treated with HCl (2 M, 0.2 mL). The reaction mixture was
stirred at room temperature for 5 h (monitored by TLC)
and then neutralized with saturated aqueous Na2CO3 solu-
tion (5 mL). Extraction was done with chloroform
(2ꢁ20 mL). The combined organic extracts were washed
with water (1ꢁ20 mL), brine (1ꢁ20 mL), and dried over an-
hydrous Na2SO4. Solvent was evaporated under reduced
pressure and the crude product was purified by column chro-
matography over silica gel using hexane–EtOAc (9:1) as el-
uant to give 12a as a white solid (0.23 g, 61%); Rf 0.2 (49:1
hexane–EtOAc); mp 152–153 ꢀC; IR cmꢂ1 (KBr): 1752,
4.1.8. Synthesis of 3-(methylthio)dibenz[b,f]oxepino[4,5-d]-
isoxazole (9). To a stirred solution of 2 (0.31 g, 1 mmol)
in benzene (10 mL) and glacial AcOH (10 mL) at room tem-
perature was added a solution of NaOAc (0.28 g, 3.4 mmol)
and NH2OH$HCl (0.28 g, 4 mmol) in water (1 mL). The
mixture was made homogeneous by the addition of ethanol
(5 mL) and refluxed for 68 h (monitored by TLC). Reaction
mixture was evaporated to dryness under reduced pressure
and the residue was dissolved in chloroform (40 mL). The
organic layer was washed with water (2ꢁ20 mL), brine
(1ꢁ20 mL), and dried over anhydrous Na2SO4. Solvent
was removed under reduced pressure and the crude product
was purified by column chromatography over silica gel
using hexane–EtOAc (3:1) as eluant to give 9 as a white
powder (0.19 g, 68%); Rf 0.5 (4:1 hexane–EtOAc); mp 114–
115 ꢀC; IR cmꢂ1 (KBr): 2925, 1600, 1446, 1228, 758,
734; 1H NMR (400 MHz, CDCl3): d 7.75 (dd, J¼7.82,
1.46 Hz, 1H, ArH), 7.72 (dd, J¼7.68, 1.60 Hz, 1H, ArH),
7.49 (ddd, J¼7.90, 7.90, 1.34 Hz, 1H, ArH), 7.38–7.29 (m,
3H, ArH), 7.27–7.22 (m, 2H, ArH), 2.74 (s, 3H, SMe); 13C
NMR (100 MHz, CDCl3): d 164.1, 158.6, 156.7, 155.7,
132.6, 129.7, 126.70, 126.69, 125.6, 125.5, 122.8, 122.25,
122.21, 121.9, 121.5, 14.0; MS m/z (%): 282 (M++1, 100),
281 (M+, 75). Anal. Calcd for C16H11NO2S: C, 68.31%;
H, 3.94%; N, 4.98%. Found: C 68.22%; H, 4.06%; N, 4.96%.
1
1487, 1442, 1217, 1102, 965, 766; H NMR (400 MHz,
CDCl3): d 8.02 (d, J¼7.56 Hz, 1H, ArH), 7.51 (t,
J¼7.82 Hz, 1H, ArH), 7.42 (t, J¼7.68 Hz, 1H, ArH), 7.34
(d, J¼7.80 Hz, 1H, ArH), 7.30 (d, J¼8.04 Hz, 1H, ArH),
7.26–7.22 (m, 3H, ArH), 7.46 (s, 1H, ArH), 2.01 (s, 3H,
SMe); 13C NMR (100 MHz, CDCl3): d 169.6, 158.4,
157.4, 154.1, 133.7, 131.8, 128.1, 127.5, 125.6, 125.4,
125.3, 124.4, 123.8, 122.4, 121.4, 82.9, 10.5; MS m/z (%):
297 (M++1, 83), 296 (M+, 47), 249 (100). Anal. Calcd for
C17H12O3S: C, 68.90%; H, 4.08%. Found: C, 68.93%; H,
4.04%.
4.1.9. Synthesis of 1-(methylthio)thieno[3,4-d]dibenz
[b,f]oxepine (10). A solution of CH2I2 (0.2 mL, 2.5 mmol)
in dry ether (5 mL) was added dropwise to a stirred suspen-
sion of Zn–Cu couple (activated by heating in oven at 100 ꢀC
for 10 h) (0.4 g, 3.0 mmol) in dry ether (20 mL) at reflux
temperature under a nitrogen atmosphere. After 1 h, a solu-
tion of 2 (0.31 g, 1.0 mmol) in dry THF (10 mL) was added
dropwise at reflux temperature and refluxing was continued
for 6 h (monitored by TLC). The reaction mixture was
cooled to room temperature and the organic layer was
decanted. The residue was washed with chloroform
(2ꢁ20 mL). The combined organics were washed with water
(1ꢁ20 mL), brine (1ꢁ20 mL), and dried over anhydrous
Na2SO4. Solvent was evaporated under reduced pressure
and the crude product was purified by column chromato-
graphy over silica gel using hexane–EtOAc (24:1%) as elu-
ant to give 10 as a white solid (0.18 g, 61%); Rf 0.7 (19:1
hexane–EtOAc); mp 83–84 ꢀC; IR cmꢂ1 (KBr): 1438,
4.1.11. Synthesis of 2-amino-4-(methylthio)dibenz[b, f]-
oxepino[4,5-d]pyrimidine (13). To a stirred suspension
of NaH (60%, 0.12 g, 3 mmol) in dry DMF (30 mL) at
room temperature under a nitrogen atmosphere, was added
guanidine nitrate (0.18 g, 1.5 mmol). After 10 min, a solu-
tion of ketene dithioacetal 2 (0.31 g, 1.0 mmol) in dry
DMF (5 mL) was added dropwise and the reaction mixture
was heated at 100 ꢀC for 20 h (monitored by TLC). The re-
action mixture was cooled to room temperature and poured
into ice-cold water (30 mL). Extraction was done with ethyl
acetate (3ꢁ30 mL). The combined organic extracts were
washed with water (3ꢁ30 mL), brine (1ꢁ30 mL), and dried
over anhydrous Na2SO4. Solvent was evaporated under re-
duced pressure and the crude product was purified by col-
umn chromatography over silica gel using hexane–EtOAc
as eluant (7:3) to give 13 as a white solid (0.25 g, 80%);
Rf 0.33 (4:1 hexane–EtOAc); mp 216–217 ꢀC; IR cmꢂ1
(KBr): 3493, 3300, 3188, 1626, 1538, 1448, 1212, 760; 1H
NMR (400 MHz, CDCl3): d 7.98 (dd, J¼8.18, 1.82 Hz,
1H, ArH), 7.78 (d, J¼8.08 Hz, 1H, ArH), 7.41 (ddd,
J¼7.74, 7.74, 1.82 Hz, 1H, ArH), 7.31–7.23 (m, 4H, ArH),
7.18–7.14 (m, 1H, ArH), 5.28 (br s, 2H, NH2), 2.50 (s, 3H,
SMe); 13C NMR (100 MHz, CDCl3): d 170.9, 161.1, 160.0
(2C), 158.5, 131.9, 130.8, 130.5, 130.3, 129.6, 126.7,
1
1235, 1196, 1100, 782, 740; H NMR (400 MHz, CDCl3):
d 7.86 (dd, J¼7.94, 1.10 Hz, 1H, ArH), 7.52 (dd, J¼7.56,
0.96 Hz, 1H, ArH), 7.44 (s, 1H, ArH), 7.36–7.29 (m, 4H,
ArH), 7.25–7.21 (m, 1H, ArH), 7.20–7.16 (m, 1H, ArH),
2.48 (s, 3H, SMe); 13C NMR (100 MHz, CDCl3): d 157.7,
157.3, 139.1, 136.5, 134.4, 130.9, 129.3, 129.0, 128.4,
127.5, 125.4, 124.7, 122.4, 121.4, 121.2, 21.30; MS m/z
(%): 297 (M++1, 50), 296 (M+, 100). Anal. Calcd for
C17H12OS2: C, 68.89%; H, 4.08%. Found: C, 69.01%; H,
4.14%.

S. Kumar et al. / Tetrahedron 63 (2007) 10067–10076
10073
125.3, 124.3, 121.0, 120.6, 118.9, 13.9; MS m/z (%): 308
(M++1, 100), 307 (M+, 32). Anal. Calcd for C17H13N3OS:
C, 66.43%; H, 4.26%; N, 13.67%. Found: C, 66.52%; H,
4.33%; N, 13.56%.
temperature. After 5 min, ketene dithioacetal 2 (0.31 g,
1.0 mmol) was added and the reaction mixture was refluxed
for 7 h (monitored by TLC). The solvent was evaporated un-
der reduced pressure and the residue was treated with ice-
cold water (20 mL). It was then extracted with chloroform
(3ꢁ20 mL). The combined organic extracts were washed
with water (3ꢁ20 mL), brine (1ꢁ30 mL), and dried over an-
hydrous Na2SO4. Solvent was evaporated under reduced
pressure and the crude product was purified by column chro-
matography over silica gel using hexane–EtOAc (7:3) as el-
uant to yield 15 as a yellow solid (0.61 g, 63%); Rf 0.70 (1:1
hexane–EtOAc); mp 184–185 ꢀC; IR cmꢂ1 (KBr): 1532,
1377, 1334, 1217, 1022, 767; 1H NMR (400 MHz,
CDCl3): d 7.88 (br d, J¼6.84 Hz, 2H, ArH), 7.60 (d,
J¼7.56 Hz, 2H, ArH), 7.36–7.32 (m, 2H, ArH), 7.25–7.05
(m, 10H, ArH), 4.46–4.42 (m, 2H, OCH), 4.45–4.42 (m,
2H, OCH), 1.17 (t, J¼6.94 Hz, 6H, Me); 13C NMR
(100 MHz, CDCl3): d 166.8, 166.5, 161.2, 161.0, 159.9,
132.2, 131.4, 130.6, 130.3, 129.8, 125.4, 124.8, 124.4,
121.0, 120.5, 113.7, 63.7, 14.1; MS m/z (%): 643 (M++1,
78), 206 (100). Anal. Calcd for C36H26N4O4S2: C,
67.27%; H, 4.08%; N, 8.72%. Found: C, 67.25%; H,
4.22%; N, 8.70%.
4.1.12. General procedure for the synthesis of 14a and
14b. Guanidine nitrate or 3-pyridyl amidine hydrochloride
(1.2 mmol) was added to a stirred solution of sodium ethox-
ide (2.4 mmol, prepared in situ from 0.058 g of sodium
metal and 2 mL of ethanol) in ethanol (10 mL) at room
temperature. After 5 min, ketene dithioacetal 2 (0.31 g,
1.0 mmol) was added and the reaction mixture was refluxed
for 5–12 h (monitored by TLC). The solvent was evaporated
under reduced pressure and the residue was treated with ice-
cold water (20 mL). It was then extracted with chloroform
(3ꢁ20 mL). The combined organic extracts were washed
with water (2ꢁ20 mL), brine (1ꢁ30 mL), and dried over an-
hydrous Na2SO4. Solvent was evaporated under reduced
pressure and the crude product was purified by column chro-
matography over silica gel using hexane–EtOAc (7:3) as
eluant to give 14a or 14b.
4.1.12.1. 2-Amino-4-ethoxydibenz[b,f]oxepino[4,5-d]-
pyrimidine (14a). White solid (0.18 g, 60%); Rf 0.3 (4:1
hexane–EtOAc); mp 183–184 ꢀC; IR cmꢂ1 (KBr): 3480,
3304, 3177, 1632, 1566, 1539, 1468, 1408, 1338, 1244; 1H
NMR (400 MHz, CDCl3): d 7.93 (dd, J¼7.80, 1.72 Hz,
1H, ArH), 7.70 (dd, J¼7.94, 1.70 Hz, 1H, ArH), 7.40
(ddd, J¼8.13, 7.25, 1.77 Hz, 1H, ArH), 7.29–7.21 (m, 4H,
ArH), 7.14 (ddd, J¼7.38, 7.38, 1.84 Hz, 1H, ArH), 5.21
(br s, 2H, NH2), 4.57–4.49 (m, 1H, OCH), 4.39–4.31 (m,
1H, OCH), 1.38 (t, J¼7.08 Hz, 3H, Me); 13C NMR
(100 MHz, CDCl3): d 167.4, 161.5, 161.0, 160.9, 159.2,
131.6, 131.4, 131.0, 130.0, 128.5, 126.0, 125.2, 124.2,
120.7, 120.5, 107.8, 62.6, 14.3; MS m/z (%): 306 (M++1,
100), 305 (M+, 50), 278 (30). Anal. Calcd for
C18H15N3O2: C, 70.81%; H, 4.95%; N, 13.76%. Found: C,
70.60%; H, 4.92%; N, 13.81%.
4.1.14. Synthesis of 3-cyano-4-(methylthio)-1H-di-
benz[b,f]oxepino[4,5-b]pyridin-2-one (16). To a stirred
suspension of NaOtBu (0.23 g, 2.4 mmol) in ButOH
(10 mL) at room temperature, cyanoacetamide (0.067 g,
0.8 mmol) was added. After 10 min, ketene dithioacetal 2
(0.25 g, 0.8 mmol) was added and the reaction mixture
was refluxed for 7 h (monitored by TLC). The solvent was
evaporated under reduced pressure to give the salt of pyri-
done 16, which was dissolved in water (10 mL) followed
by acidification with dilute HCl (5 mL, 5%). Extraction
was done with chloroform (3ꢁ30 mL). The combined or-
ganic extracts were washed with water (2ꢁ30 mL), brine
(1ꢁ30 mL), and dried over anhydrous Na2SO4. Solvent
was evaporated under reduced pressure and the crude prod-
uct was purified by column chromatography over silica gel
using hexane–EtOAc (1:1) as eluant to afford 16 as a yellow
solid (0.13 g, 50%); Rf 0.5 (3:7 hexane–EtOAc); mp
>280 ꢀC decomposes; IR cmꢂ1 (KBr): 2220, 1638, 1484,
4.1.12.2. 4-Ethoxy-2-(3-pyridyl)dibenz[b,f]oxepino-
[4,5-d]pyrimidine (14b). White solid (0.21 g, 58%); Rf
0.2 (4:1 hexane–EtOAc); mp 143–144 ꢀC; IR cmꢂ1 (KBr):
1
1
2987, 1583, 1531, 1403, 1371, 1249, 1026, 760; H NMR
1443, 1219, 747; H NMR (400 MHz, DMSO-d6): d 7.76
(400 MHz, CDCl3): 9.76 (s, 1H, ArH), 8.82 (d, J¼8.04 Hz,
1H, ArH), 8.72 (br d, J¼3.92 Hz, 1H, ArH), 8.20 (dd,
J¼7.80, 1.48 Hz, 1H, ArH), 7.82 (d, J¼7.32 Hz, 1H,
ArH), 7.48 (ddd, J¼7.69, 7.69, 1.54 Hz, 1H, ArH), 7.43
(dd, J¼7.96, 4.76 Hz, 1H, ArH), 7.38–7.29 (m, 4H, ArH),
7.21 (ddd, J¼8.04, 6.2, 2.42 Hz, 1H, ArH), 4.78–4.74 (m,
1H, OCH), 4.64–4.60 (m, 1H, OCH), 1.50 (t, J¼6.96 Hz,
3H, Me); 13C NMR (100 MHz, CDCl3): d 166.6, 161.3,
160.6, 160.1, 159.7, 151.1, 149.8, 135.5, 133.0, 132.1,
131.6, 130.8, 130.6, 129.9, 125.3, 125.1, 124.4, 123.3,
121.0, 120.6, 115.6, 63.3, 14.3; MS m/z (%): 368 (M++1,
100), 105 (58). Anal. Calcd for C23H17N3O2: C, 75.19%;
H, 4.66%; N, 11.44%. Found: C, 75.31%; H, 4.58%; N,
11.56%.
(d, J¼7.80 Hz, 1H, ArH), 7.62–7.56 (m, 2H, ArH), 7.45–
7.40 (m, 3H, ArH), 7.33 (t, J¼7.58 Hz, 1H, ArH), 7.24–
7.20 (m, 1H, ArH), 2.32 (s, 3H, SMe); 13C NMR
(100 MHz, DMSO-d6): d 160.1, 159.4, 133.7, 131.9,
130.7, 130.4, 126.1, 125.7, 125.1, 121.0, 120.7, 115.7,
18.7; MS m/z (%): 333 (M++1, 100). Anal. Calcd for
C19H12N2O2S: C, 68.66%; H, 3.64%; N, 8.43%. Found: C,
68.71%; H, 3.59%; N, 8.36%.
4.1.15. Synthesis of 4-(methylthio)-2-phenyldibenz[b,f]-
oxepino[4,5-b]pyridine-3-carbonitrile (18). To a stirred
solution of freshly distilled acetonitrile (0.1 mL, 1.9 mmol)
in dry THF (5 mL), n-BuLi (1.3 mL, 1.9 mmol) was added
dropwise at ꢂ78 ꢀC under a nitrogen atmosphere. After
10 min, a solution of benzonitrile (0.19 mL, 1.9 mmol) in
dry THF (5 mL) was added dropwise at the same tempera-
ture. The reagent was stirred for 30 min followed by the
dropwise addition of the solution of ketene dithioacetal 2
(0.40 g, 1.28 mmol) in dry THF (10 mL) at the same temper-
ature. Reaction mixture was warmed to room temperature
4.1.13. Synthesis of bis(4-ethoxydibenz[b,f]oxepino-
[4,5-d] pyrimidin-2-yl)disulfide (15). Thiourea (0.11 g,
1.5 mmol) was added to a stirred solution of sodium ethox-
ide (3.0 mmol, prepared in situ from 0.069 g of sodium
metal and 1 mL of ethanol) in ethanol (10 mL) at room

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S. Kumar et al. / Tetrahedron 63 (2007) 10067–10076
over a period of 2 h followed by refluxing for 10 h (moni-
tored by TLC). Reaction mixture was cooled to room tem-
perature and poured into saturated ammonium chloride
solution (20 mL). Extraction was done with chloroform
(3ꢁ30 mL). The combined organic extracts were washed
with water (2ꢁ20 mL), brine (1ꢁ20 mL), and dried over an-
hydrous Na2SO4. Solvent was removed under reduced pres-
sure and the crude product was purified by column
chromatography over silica gel using hexane–EtOAc (9:1)
as eluant to give 18 as white solid (0.30 g, 60%); Rf 0.5
(9:1 hexane–EtOAc); mp 214–215 ꢀC; IR cmꢂ1 (KBr):
2218, 1512; 1H NMR (400 MHz, CDCl3): d 8.26 (dd,
J¼7.70, 1.58 Hz, 1H, ArH), 8.06–8.03 (m, 2H, ArH), 7.78
(dd, J¼7.82, 1.46 Hz, 1H, ArH), 7.56–7.48 (m, 3H, ArH),
7.48–7.23 (m, 6H, ArH), 2.23 (s, 3H, SMe); 13C NMR
(100 MHz, CDCl3): d 161.2, 160.5, 159.7, 155.1, 153.8,
137.0, 132.3, 131.7, 131.6, 131.5, 130.8, 130.3, 129.3,
128.5, 127.7, 125.5, 125.2, 121.1, 120.5, 116.9, 108.9,
18.8; MS m/z (%): 393 (M++1, 100), 392 (M+, 50). Anal.
Calcd for C25H16N2OS: C, 76.51%; H, 4.11%; N, 7.14%.
Found: C, 76.44%; H, 4.12%, N, 7.28%.
4.2. General procedure for the cycloaromatization of 10,
11-dihydro-11-[bis(methylthio)methylene]dibenz[b,f]-
oxepin-10-one (2) with allyl, methallyl, and benzyl
Grignard reagents: synthesis of benzo-(21a,c) and
naphtho-(22a) fused dibenz[b,f]oxepines
A solution of ketene dithioacetal 2 (0.6 g, 2 mmol) in dry
THF (20 mL) was added dropwise at 0 ꢀC to a stirred solution
of allyl/methallyl/benzyl magnesium chloride [halide
(10 mmol) and magnesium turnings (0.2 g, 8 mmol)] in dry
ether (30 mL) under a nitrogen atmosphere and the reaction
mixturewas further stirred at room temperature for 2 h (mon-
itored by TLC). It was then poured into saturated aqueous
NH4Cl solution (30 mL) and extracted with chloroform
(2ꢁ40 mL). The combined organic extracts were washed
with water (2ꢁ30 mL), brine (1ꢁ30 mL), and dried over an-
hydrous Na2SO4. Solvent was evaporated under reduced
pressure to afford the crude carbinols as viscous liquids.
The crude carbinols were dissolved in dry benzene (30 mL)
followed by addition of BF3$OEt2 (0.5 mL, 4.0 mmol) drop-
wise at 0 ꢀC. The reaction mixture was then refluxed for 3–
4 h (monitored by TLC). It was then cooled to room temper-
ature, poured into saturated aqueous NaHCO3 solution
(20 mL), and extracted with chloroform (2ꢁ30 mL). The
combined organic extracts were washed with water
(2ꢁ30 mL), brine (1ꢁ30 mL), and dried over anhydrous
Na2SO4. Solvent was evaporated under reduced pressure
and the crude product was purified by column chromato-
graphy over silica gel using hexane–EtOAc as eluant (49:1).
4.1.16. Synthesis of 4-(methylthio)-2-phenyldibenz[b,f]-
oxepino[4,5-b]pyridine (20). A solution of acetophenone
(0.15 mL, 1.28 mmol) in dry DMF (5 mL) was added drop-
wise to a stirred suspension of NaH (60%, 0.07 g, 1.8 mmol)
in dry DMF (5 mL) at 0 ꢀC under a nitrogen atmosphere. The
anion was further stirred at the same temperature for 45 min.
A solution of 2 (0.4 g, 1.28 mmol) in dry DMF (5 mL) was
added dropwise at 0 ꢀC and the reaction mixture was further
stirred at room temperature for 8 h (monitored by TLC). The
reaction mixture was poured into saturated aqueous ammo-
nium chloride solution (20 mL) and extracted with ethyl ace-
tate (3ꢁ40 mL). The combined organic extracts were
washed with water (3ꢁ20 mL), brine (1ꢁ30 mL), and dried
over anhydrous Na2SO4. Solvent was evaporated under re-
duced pressure to yield the adduct 19 (0.40 g, 80%), which
was used directly for the cyclization step.
4.2.1. 1-(Methylthio)tribenz[b,d,f]oxepine (21a). Color-
less liquid (0.37 g, 63%); Rf 0.47 (49:1 hexane–EtOAc);
IR cmꢂ1 (neat): 2920, 1204, 746; 1H NMR (400 MHz,
CDCl3): d 7.76 (dd, J¼7.32, 0.96 Hz, 1H, ArH), 7.59 (dd,
J¼7.58, 1.46 Hz, 1H, ArH), 7.43–7.36 (m, 3H, ArH),
7.34–7.31 (m, 3H, ArH), 7.28 (dd, J¼5.98, 1.58 Hz, 1H,
ArH), 7.26–7.15 (m, 2H, ArH), 2.40 (s, 3H, SMe); 13C
NMR (100 MHz, CDCl3): d 161.0, 160.7, 138.2, 137.6,
135.0, 132.6, 132.3, 129.7, 129.5, 129.4, 129.3, 128.0,
126.5, 126.1, 125.3, 123.8, 120.7, 120.4, 17.4; MS m/z
(%): 291 (M++1, 86), 290 (M+, 100), 275 (50), 244 (83).
Anal. Calcd for C19H14OS: C, 78.59%; H, 4.86%. Found:
C, 78.48%; H, 4.90%.
Anhydrous NH4OAc (0.24 g, 3.12 mmol) was added to a so-
lution of adduct 19 (0.39 g, 1.04 mmol) in glacial acetic acid
(10 mL) and the reaction mixture was refluxed for 5 h (mon-
itored by TLC). It was then cooled, poured into ice-cold
water (40 mL), and extracted with chloroform (3ꢁ30 mL).
The combined organic extracts were washed with water
(3ꢁ30 mL), brine (1ꢁ30 mL), and dried over anhydrous
Na2SO4. Solvent was removed under reduced pressure and
the crude product was purified by column chromatography
over silica gel using hexane–EtOAc (9:1) as eluant to yield
20 as a white solid (0.24 g, 63%); Rf 0.13 (19:1 hexane–
EtOAc); mp 189–190 ꢀC. IR cmꢂ1 (KBr): 3045, 1552,
1198, 761; 1H NMR (400 MHz, CDCl3): d 8.25 (dd,
J¼7.56, 1.72 Hz, 1H, ArH), 8.14 (d, J¼7.08 Hz, 2H, ArH),
7.78 (d, J¼7.80 Hz, 1H, ArH), 7.59 (s, 1H, ArH), 7.51 (t,
J¼7.20 Hz, 2H, ArH), 7.45 (t, J¼7.20 Hz, 1H, ArH), 7.42–
7.37 (m, 3H, ArH), 7.32–7.24 (m, 2H, ArH), 7.21–7.17 (m,
1H, ArH), 2.54 (s, 3H, SMe); 13C NMR (100 MHz,
CDCl3): d 161.2, 160.6, 155.1, 152.3, 151.0, 138.5, 131.9,
131.6, 131.3, 130.9, 130.3, 129.4, 129.1, 128.7, 127.5,
127.2, 125.3, 124.1, 121.2, 120.2, 114.8, 16.0; MS m/z (%):
368 (M++1, 100), 367 (M+, 75), 352 (25), 341 (44). Anal.
Calcd for C24H17NOS: C, 78.45%; H, 4.66%; N, 3.81%.
Found: C, 78.54%; H, 4.64%; N, 3.77%.
4.2.2. 3-Methyl-1-(methylthio)tribenz[b,d,f]oxepine
(21c). Colorless liquid (0.46 g, 75%); Rf 0.57 (49:1 hex-
1
ane–EtOAc); IR cmꢂ1 (neat): 1438, 1203, 748; H NMR
(400 MHz, CDCl3): d 7.72 (dd, J¼7.80, 1.96 Hz, 1H,
ArH), 7.57 (dd, J¼7.80, 1.48 Hz, 1H, ArH), 7.33–7.27 (m,
3H, ArH), 7.26 (dd, J¼6.24, 1.60 Hz, 1H, ArH), 7.20–7.12
(m, 4H, ArH), 2.44 (s, 3H, SMe), 2.38 (s, 3H, Me); 13C
NMR (100 MHz, CDCl3): d 160.66, 160.64, 137.9, 137.8,
137.4, 132.6, 132.3, 129.56, 129.49, 129.44, 129.3, 127.9,
127.3, 127.0, 125.3, 123.8, 120.6, 120.4, 21.4, 17.4; MS
m/z (%): 304 (M+, 100), 258 (70). Anal. Calcd for C20H16OS:
C, 78.91%; H, 5.30%. Found: C, 78.98%; H, 5.27%.
4.2.3. 5-(Methylthio)naphtho[2,3-d]dibenz[b,f]oxepine
(22a). Colorless solid (0.35 g, 52%); Rf 0.3 (49:1 hexane–
EtOAc); mp 167–168 ꢀC; IR cmꢂ1 (KBr): 1481, 1444,
1181, 751; 1H NMR (400 MHz, CDCl3): d 8.76 (d,
J¼8.32 Hz, 1H, ArH), 8.0 (s, 1H, ArH), 7.92 (d,
J¼7.80 Hz, 1H, ArH), 7.75 (d, J¼7.70 Hz, 2H, ArH), 7.63

S. Kumar et al. / Tetrahedron 63 (2007) 10067–10076
10075
(ddd, J¼7.69, 7.69, 1.53 Hz, 1H, ArH), 7.55 (ddd, J¼7.45,
7.45, 0.97 Hz, 1H, ArH), 7.37–7.28 (m, 4H, ArH), 7.26–
7.17 (m, 2H, ArH), 2.09 (s, 3H, SMe); 13C NMR
(100 MHz, CDCl3): d 161.2, 161.2, 135.3, 134.6, 134.3,
134.1, 133.2, 132.7, 131.2, 129.6, 129.5, 129.4, 129.3,
128.7, 127.2, 127.2, 126.6, 125.5, 123.9, 120.4, 120.3,
19.8; MS m/z (%): 341 (M++1, 80), 340 (M+, 100), 294
(63). Anal. Calcd for C23H16OS: C, 81.14%; H, 4.74%.
Found: C, 81.08%; H, 4.69%.
3.42 Hz, 2H, ArH), 7.56 (dd, J¼7.22, 1.24 Hz, 2H, ArH),
7.48 (dd, J¼5.86, 3.42 Hz, 2H, ArH), 7.36–7.29 (m, 4H,
ArH), 7.24 (ddd, J¼8.72, 6.60, 2.20 Hz, 2H, ArH); 13C
NMR (100 MHz, CDCl3): d 160.1, 136.5, 132.8, 129.6,
129.3, 128.0, 125.5, 120.8; MS m/z (%): 245 (M++1, 94),
244 (M+, 100). Anal. Calcd for C18H12O: C, 88.50%; H,
4.95%. Found: C, 88.62%; H, 5.02%.
4.3.5. Naphtho[2,3-d]dibenz[b,f]oxepine (22b). White
solid (0.23 g, 78%); Rf 0.4 (99:1 hexane–EtOAc); mp 139–
140 ꢀC; IR cmꢂ1 (KBr): 3052, 1231, 759; 1H NMR
(400 MHz, CDCl3): d 8.08 (s, 2H, ArH), 7.94 (dd, J¼6.22,
3.30 Hz, 2H, ArH), 7.72 (dd, J¼7.56, 0.96 Hz, 2H, ArH),
7.53 (dd, J¼6.36, 3.16 Hz, 2H, ArH), 7.38–7.33 (m, 4H,
ArH), 7.30–7.26 (m, 2H, ArH); 13C NMR (100 MHz,
CDCl3): d 160.3, 134.7, 132.9, 132.8, 130.0, 129.3, 128.4,
127.8, 126.5, 125.6, 120.8; MS m/z (%): 295 (M++1, 92),
294 (M+, 100). Anal. Calcd for C22H14O: C, 89.77%; H,
4.79%. Found: C, 89.80%; H, 4.81%.
4.3. General procedure for Raney-Ni dethiomethylation
of 5a, 6a, 12a, 21a, and 22a
Raney-Ni (W2, five times by weight) was added to an etha-
nolic solution (10 mL) of appropriate substrates 5a, 6a,
12a, 21a, and 22a (1.0 mmol), and the suspension was
heated under reflux for 2–9 h (monitored by TLC). Reaction
mixture was filtered through a sintered glass funnel and the
residue was washed with hot ethanol (3ꢁ5 mL). The filtrate
was concentrated under reduced pressure and the crude
product was purified by column chromatography over silica
gel using hexane–EtOAc (49:1) as eluant.
Acknowledgements
4.3.1. 2-Phenyldibenz[b,f]oxepino[4,5-c]pyrazole (5b).
White solid (0.232 g, 75%); Rf 0.4 (98:2 hexane–EtOAc);
mp 133–134 ꢀC; IR cmꢂ1 (KBr): 3060, 2923, 1501, 1449,
S.K. thanks CSIR, New Delhi for junior and senior research
fellowships. Financial assistance under DST and CSIR pro-
jects is also acknowledged.
1
1204, 760; H NMR (400 MHz, CDCl3): d 8.09 (s, 1H,
ArH), 7.89 (dd, J¼7.58 Hz, 1.46, 1H, ArH), 7.74
(dd, J¼8.08, 0.96 Hz, 2H, ArH), 7.43–7.37 (m, 3H, ArH),
7.31–7.14 (m, 6H, ArH), 7.10 (ddd, J¼7.39, 7.39, 1.38 Hz,
1H, ArH); 13C NMR (100 MHz, CDCl3): d 157.3, 156.3,
148.4, 139.8, 130.1, 129.5, 128.7, 127.6, 127.3, 126.8,
126.1, 125.3, 123.9, 122.0, 121.7, 120.4, 119.2; MS m/z
(%): 310 (M++1, 100). Anal. Calcd for C21H14N2O: C,
81.27; H, 4.55; N, 9.03%. Found: C, 81.29; H, 4.50; N,
9.11%.
References and notes
1. (a) Olivera, R.; SanMartin, R.; Churruca, F.; Dominguez, E.
J. Org. Chem. 2002, 67, 7215 and references therein; (b)
SanMartin, R.; Olivera, R.; Churrucka, F.; Tellitu, I.;
Dominguez, E. Trends Heterocycl. Chem. 2003, 9, 259; (c)
Mercep, M.; Mesic, M.; Pesic, D. WO 2003099822, 2003;
(d) Peggy Paduraru, M.; Wilson, P. D. Org. Lett. 2003, 5, 4911.
2. Review: Missir, A.; Limban, C.; Stecoza, C.; Morusciag, L.;
Chirita, I. Farmacia (Bucharest) 1998, 46, 17.
3. (a) Bischoff, S. Novel Antipsychotic Drugs; Meltzer:
New York, NY, 1992; pp 117–134; (b) Storni, A. Actual
Chim. Ther. 1989, 16, 143; (c) Review: Zimmermann, K.;
Waldmeier, P. C.; Tatton, W. G. Pure Appl. Chem. 1999, 71,
2039.
4.3.2. 1-Phenyldibenz[b,f]oxepino[4,5-d]pyrazole (6b).1a
White solid (0.257 g, 83%); mp 174–175 ꢀC (lit. mp 171–
173; H NMR (400 MHz, CDCl3): d 8.06 (s, 1H, ArH),
1
7.57 (d, J¼7.08 Hz, 1H, ArH), 7.52–7.21 (m, 10H, ArH),
6.95–6.92 (m, 1H, ArH), 6.81 (d, J¼7.80 Hz, 1H,
ArH); 13C NMR (100 MHz, CDCl3): d 156.5, 155.9,
139.9, 137.9, 136.3, 130.2, 129.2, 128.7, 128.6, 127.9,
127.1, 125.5, 125.6, 125.1, 122.9, 122.7, 122.3, 121.5, 120.3.
4. (a) Prinssen, E. P.; Koek, W.; Kleven, M. S. Eur. J. Pharmacol.
2000, 388, 57; (b) Miguel-Hidalgo, J. J. Drugs 2000, 2, 85; (c)
Andree, B.; Halidin, C.; Vrijmoed-De Vries, M.; Farde, L.
Psychopharmacology 1997, 131, 339.
4.3.3. 1,3-Dihydro-1-oxo-furo[3,4-d]dibenz[b,f]oxepine
(12b). White solid (0.228 g, 91%); Rf 0.20 (19:1 hexane–
EtOAc); mp 181–182 ꢀC.; IR cmꢂ1 (KBr): 1753, 1443,
5. (a) Martin, L. L.; Setescak, L. L. U.S. Patent 4,576,960, 1986;
Chem. Abstr. 1986, 104, 224840; (b) Cherkofsky, S. C.;
Sharpe, T. R. U.S. Patent 4,198,421, 1980; Chem. Abstr.
1980, 93, 71783; (c) Kumazawa, T.; Ohsima, E.; Obase, H.
JP 61152673, 1987; Chem. Abstr. 1987, 106, 4904; (d)
Bracaccio, G.; Lettiere, G.; Monforte, P.; Larizza, A.
Farmaco 1982, 37, 711; (e) Zimmermann, K.; Roggo, S.;
Betschart, C. WO 9745422, 1997; Chem. Abstr. 1998, 128,
61439; (f) Jinno, S.; Okita, T. Heterocycles 1999, 51, 303;
(g) Yamashita, S.; Takeo, J.; Jinno, S.; Kogure, Y.; Onuki,
H.; Okita, T.; Hata, J.; Fukuda, Y.; Ohtsuka, N. WO
9725985, 1997; Chem. Abstr. 1997, 127, 149089; (h) Jinno,
S.; Okita, T.; Ohtsuka, N.; Yamashita, S.; Hata, J.; Takeo, J.
WO 0075127, 2000; Chem. Abstr. 2001, 134, 29329; (i)
Nakazawa, H.; Ando, K.; Kuge, Y.; Sugaya, T.; Kasai, M.;
Tomioka, S. JP 06306070; Chem. Abstr. 1995, 122, 160492;
1
1221; H NMR (400 MHz, CDCl3): d 8.04 (dd, J¼8.04,
1.48 Hz, 1H, ArH), 7.55–7.7.51 (m, 1H, ArH), 7.43 (ddd,
J¼7.70, 7.70, 1.38 Hz, 1H, ArH), 7.34 (d, J¼8.04 Hz, 1H,
ArH), 7.28–7.22 (m, 4H, ArH), 5.25 (s, 2H, CH); 13C
NMR (100 MHz, CDCl3): d 171.7, 158.1, 157.0, 154.9,
133.7, 131.4, 127.9, 126.0, 125.63, 125.60, 125.2, 124.1,
123.9, 122.5, 121.4, 68.8; MS m/z (%): 251 (M++1, 100),
250 (M+, 63). Anal. Calcd for C16H10O3: C, 76.79%; H,
4.03%. Found: C, 76.71%; H, 4.05%.
4.3.4. Tribenz[b,d,f]oxepine (21b).21 White solid (0.18 g,
75%); Rf 0.5 (49:1 hexane–EtOAc); mp 113–114 ꢀC (lit.
mp 115–116 ꢀC); IR cmꢂ1 (KBr): 3060, 1482, 1427, 1207,
733; 1H NMR (400 MHz, CDCl3): d 7.62 (dd, J¼5.86,

10076
S. Kumar et al. / Tetrahedron 63 (2007) 10067–10076
(j) Kanamaru, T.; Hida, T.; Muroi, M. EP 342665, 1989; Chem.
Abstr. 1990, 113, 5954.
12. (a) Peruncheralathan, S.; Khan, T. A.; Ila, H.; Junjappa, H.
J. Org. Chem. 2005, 70, 10030; (b) Peruncheralathan, S.;
Yadav, A. K.; Ila, H.; Junjappa, H. J. Org. Chem. 2005, 60,
9644.
13. Purkayastha, M. L.; Ila, H.; Junjappa, H. Synthesis 1989, 20.
14. (a) Bhat, L. N.; Thomas, A.; Ila, H.; Junjappa, H. Tetrahedron
1992, 48, 10377; (b) Thomas, A.; Singh, G.; Ila, H.; Junjappa,
H. Tetrahedron Lett. 1989, 30, 3093.
6. Reviews: (a) Ila, H.; Junjappa, H.; Mohanta, P. K. Progress in
Heterocyclic Chemistry; Gribble, G. W., Gilchrist, T. L.,
Eds.; Pergamon: Oxford, 2001; Vol. 13, Chapter 1, pp 1–24;
(b) Junjappa, H.; Ila, H.; Asokan, C. V. Tetrahedron 1990, 46,
5423.
7. Recent papers on heteroaromatic annulation: (a) Panda, K.;
Venkatesh, C.; Ila, H.; Junjappa, H. Eur. J. Org. Chem. 2005,
2045; (b) Peruncheralathan, S.; Khan, T. A.; Ila, H.;
Junjappa, H. Tetrahedron 2004, 60, 3457; (c) Panda, K.;
Siddiqui, I.; Mahata, P. K.; Ila, H.; Junjappa, H. Synlett 2004,
449; (d) Mahata, P. K.; Venkatesh, C.; Syam Kumar, U. K.;
Ila, H.; Junjappa, H. J. Org. Chem. 2003, 68, 3966; (e)
Panda, K.; Suresh, J. R.; Ila, H.; Junjappa, H. J. Org. Chem.
2003, 68, 3498; (f) Mahata, P. K.; Syam Kumar, U. K.;
Sriram, V.; Ila, H.; Junjappa, H. Tetrahedron 2003, 59, 2631;
(g) Suresh, J. R.; Syam Kumar, U. K.; Ila, H.; Junjappa, H.
Tetrahedron 2001, 57, 781; (h) Basaveswara Rao, M. V.;
Syam Kumar, U. K.; Ila, H.; Junjappa, H. Tetrahedron 1999,
55, 11563.
15. (a) Okazaki, R.; Negishi, Y.; Inamoto, N. J. Chem. Soc., Chem.
Commun. 1982, 1055; (b) Okazaki, R.; Negishi, Y.; Inamoto,
N. J. Org. Chem. 1984, 49, 3819.
16. (a) Rastogi, R. R.; Kumar, A.; Ila, H.; Junjappa, H. J. Chem.
Soc., Perkin Trans. 1 1978, 549; (b) Rastogi, R. R.; Ila, H.;
Junjappa, H. J. Chem. Soc., Chem. Commun. 1975, 645.
17. Gupta, A. K.; Ila, H.; Junjappa, H. Tetrahedron 1990, 46, 3703.
18. (a) Barun, O.; Patra, P. K.; Ila, H.; Junjappa, H. Tetrahedron
Lett. 1999, 40, 3797; (b) Potts, K. T.; Cipullo, M. J.; Ralli, P.;
Theodoridis, G. J. Am. Chem. Soc. 1981, 103, 3585.
19. Reviews: (a) Ila, H.; Junjappa, H.; Barun, O. J. Organomet.
Chem. 2001, 624, 34; (b) Junjappa, H.; Ila, H. Phosphorous,
Sulfur Silicon Relat. Elem. 1994, 95, 35.
8. Ueda, I.; Sato, Y.; Maeno, S.; Umio, S. Chem. Pharm. Bull.
1975, 23, 2223.
20. Singh, G.; Ila, H.; Junjappa, H. Tetrahedron Lett. 1984, 25,
5095.
9. (a) Chauhan, S. M. S.; Junjappa, H. Synthesis 1974, 880; (b)
Chauhan, S. M. S.; Junjappa, H. Tetrahedron 1976, 32, 1779.
10. Singh, G.; Bhattacharjee, S. S.; Ila, H.; Junjappa, H. Synthesis
1982, 693.
21. Neale, A. J.; Rawlings, T. J.; McCall, E. B. Tetrahedron 1965,
21, 1299.
22. (a) Balu, M. P.; Singh, G.; Ila, H.; Junjappa, H. Tetrahedron
Lett. 1986, 27, 117; (b) Rao, C. S.; Balu, M. P.; Ila, H.;
Junjappa, H. Tetrahedron 1991, 47, 3499.
11. Chauhan, S. M. S.; Junjappa, H. Synthesis 1975, 798.