Cinnamoylacetonitrile in heterocyclic synthesis, part 7 [1]. Simple synthesis of benzothiazepines, pyrones and oxazolopyridine

Article abstract of DOI:10.1515/znb-1999-0917

A facile synthesis of the entitled compounds is reported starting with cinnamonitrile.

Full text of DOI:10.1515/znb-1999-0917

Cinnamoylacetonitrile in Heterocyclic Synthesis, Part 7 [1].
Simple Synthesis of Benzothiazepines, Pyrones and Oxazolopyridine
Randa H. Swellem, Yehia A. Allam*, and Galal A. M.Nawwar
National Research Center, Dokki, Cairo, Egypt
* Reprint requests to Dr. Y. A. Allam
Z. Naturforsch. 54b, 1197-1201 (1999); received March 3, 1999
Cinnamoylacetonitrile, 2,4-Diarylbenzothiazepines, Dehydrogenation,
Tetra-chloro-o-benzoquinone, Acylation
A facile synthesis of the entitled compounds is reported starting with cinnamonitrile.
Introduction
system present in 3 disappeared and instead a new
aromatic multiplet was detected at <57.4-7.8 ppm
beside the coumarinyl H-4. Elemental analysis and
spectral data were also in full accord.
Cinnamoylacetonitriles are versatile reagents in
organic synthesis, their functional groups are pre-
sent in a special arrangement which permit simple
synthesis of a variety of heterocycles. We have pre-
viously reported their utility in the preparation of
pyridazines, pyrans, coumarins and condensed het-
erocycles [1-4]. In the present investigation, we
continue our study on cinnamoylacetonitrile aim-
ing to prepare the entitled ring systems.
Results and Discussion
Cinnamoylacetonitrile (1) reacted with o-
aminothiophenol in presence of HC1 catalysis to
give the 4-cyanoacetyldihydrobenzothiazepine (2).
It showed an A B X pattern attributable to the
benzothiazepine moiety as dds at
d 2.6 , d 3.0 and
ö
4.7 ppm along with the methylene protons
singlet at <5 4.5 ppm and a CN absorption at 2200
cm-1. Elemental analysis as well as the mass
spectral data showing a molecular formula com-
patible with C 17H 14N2S m/z (M +278) confirmed
the given structure together with its chemical be-
havior.
Thus, compound 2 reacted readily with salicylal-
dehyde to form the expected coumarin derivative
3 which lacked the CN absorption and a CO one
appeared instead at 1700 cm“1. It also revealed
coumarin H-4 at
d 8.0 ppm beside the other dihy-
drobenzothiazepine characteristics. Compound 3
could be easily dehydrogenated at room temper-
ature by tetrachloroquinone to give the corre-
sponding benzothiazepine (4a) and tetrachlorocat-
echol (5) [5]. In compound 4a, the aliphatic A BX
This simple method of dehydrogenation [6] en-
couraged us to test its validity on other dihydro-
benzothiazepines. So, the propenones 6a,b were
treated with o-aminothiophenol in presence of
HC1 as a catalyst, similar to (1), thus affording the
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1198
R. H. Swellem et al. ■Cinnamoylacetonitrile in Heterocyclic Synthesis, Part 7
corresponding dihydrobenzothiazepines (7a,b).
Compared to the Stephenes procedure [7], this
simple modification afforded compounds 7a,b
nearly as sole products. The structure of 7a was
The structures of 8 and 9, respectively, were de-
duced from their analytical and spectral data (cf.
Tables). Thus, the presence of the cyanomethyl
side arm in structure 2 could be utilized to prepare
confirmed by analytical, spectral data and analogy interesting derivatives, capable of further chemical
[7], Compounds 7a,b were then treated with o- transformations or cyclization reactions.
tetrachlorobenzoquinone under similar reaction
conditions as used for 3, to afford the aimed dehy-
dro-genated derivatives 4b,c together with tetra-
Continuing our investigation on the utility of
cinnamoylacetonitrile in heterocyclic synthesis, it
was acylated with 3,4,5-trimethoxyphenyl and 2,4-
chlorocatechol 5. Structures 4b,c were confirmed dichlorophenoxymethyl acid chlorides, respec-
by elemental and spectral data where their
NMR lacked the ABX system, present in 7a at
tively, in presence of sodium hydride, affording the
4-pyrone derivatives 10 in satisfactory yield. These
6
3.0, d 3.4 and
of 7a gave a molecular formula C19H14N20 3 S m/z
(M+350) while that of its dehydrogenated deriva- the acid chloride radical, while their mass spectra
d
5.5 ppm. Also, the mass spectrum compounds showed the pyrone H-5 beside the
aromatics of cinnamoacetonitrile (1 ) and those of
gave molecular weights equivalent to the acylated
structure minus 2H; these data beside elemental
tive 4b was compatible with Q gH ^^C ^S m/z
(M+348).
Compound 2 could be simply diazotized to af- analysis and IR confirmed the structure of 10. A
ford the newly prepared diazo derivative 8. Mean- similar reaction pathway was previously dis-
time, it was acylated readily using 2,4-dichloro- cussed [8],
phenoxymethyl
acid
chloride,
giving
the
Furthermore, compound 1, after nitrosation [9],
was treated with Sn/HCOOH (50%). The product
corresponding acyl derivative 9.
Table I. Physical data for the prepared compounds.
Compd
no.
Colour/
Yield%
Mol.Wt /
Mol. Formula
Analysis [%]
Calc./Found
M. p. [°C] /
Solvent of
crystallization
C
H
N
S
11.52
11.2
8.36
8.0
8.41
8.1
9.20
8.8
10.23
10.0
9.15
2
3
50
pale yellow
45
colourless
55
colourless
30
yellow
40
182
MeOH
228
dioxane
192
MeOH
182
MeOH
150
BuOH
180
MeOH
197
MeOH
154
MeOH
134-35
c 6h 6
150
73.35
73.1
75.17
75.0
75.57
75.3
65.50
65.3
80.47
80.3
65.12
64.8
72.22
72.1
62.37
62.2
69.41
69.2
61.31
61.1
70.95
70.8
67.28
67.0
5.07
4.9
4.47
4.2
3.96
3.6
3.47
3.3
4.82
4.5
4.03
4.0
4.74
4.5
3.77
3.5
4.72
4.5
2.98
2.7
5.41
5.3
4.70
4.4
10.06
9.7
3.65
3.4
3.67
3.3
8.04
7.8
4.47
4.2
8.00
7.8
14.65
14.3
5.82
5.6
3.85
3.5
c 17h 14n 2s
278.364
C24H17NO!S
383.451
c 24h 15n o 2s
381.431
C]9H 12N20 3S
348.374
C21H15NS
313.401
c 19H 14N 2o 3s
350.384
c 23H 18N 4s
382.464
c25h 18ci2n 2o 2s
481.384
c 2Ih I7n o 5
363.357
c 19h „ c i2n o 3
372.197
CnH I0N2O
186.21
C12H 10N2O2
214.22
4a
4b
4c
7a
8
reddish brown
50
yellow
60
yellow
60
pale yellow
20
yellow
60
pale yellow
55
colourless
60
pale yellow
45
colourless
8.38
8.0
6.66
6.3
-
-
-
-
-
-
-
9
10a
10b
11
13
14
3.76
3.4
MeOH
192
MeOH
220
MeOH
264
dioxane
15.05
14.8
13.05
12.7
13.20
12.9
-
-
3.80
3.6
C12H8N20 2
212.204
67.91
67.7
-
Satisfactory halogen analysis were obtained for compounds 9 and 10b.
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1199
R. H. Swellem et al. • Cinnamoylacetonitrile in Heterocyclic Synthesis, Part 7
Table II. Spectral data of the newly prepared compounds.
Compd.
No.
IR (cm *)
'H NMR-
d (ppm)
2200 (CN ), 1620 (C=N)
2.6 (dd, Jvic = 10Hz, Jgem= 15Hz, 1H, methylene H-axial), 3.0 (dd, Jvic =
6Hz, Jgem = 15Hz, 1H, methylene H-equatorial), 4.5 (s,2H,CH2CN), 4.7
(dd, Jvic} = 10Hz, Jvic2 = 6Hz, lH.methine H), 7.0-7.5 (m,9H,C6H5 and
benzothiazepine H-6 to H-9).
1700 ( CO )
2.4 (dd,Jvic = 10Hz, Jgem = 15Hz, 1H, methylene H-axial), 3.1 (dd,Jvic =
6Hz,Jgem = 15Hz, 1H, methylene H-equatorial), 4.4 (dd, Jvici = 10Hz,
Jvic2= 6Hz, 1H, methine H), 6.7-7.6 (m, 13H, C6H5, benzothiazepine H-
6 to H-9 and coumarin H-5 to H-8), 8.0 (s, 1H, coumarin H-4).
7.4-7.8 (m, 14H, C6H5, coumarin H-5 to H-8, benzothiazepine H-3 and
H-6 to H-9), 8.1 (s,lH, coumarin H-4).
4a
4b
6.6-6.8 (m, 2H, furan H-4, H-3), 7.0-8.1 (m, 10H, C6H4, benzothiazepine
H-3 , H-6 to H-9 and furan H-5).
4c
7a
6.9-8.0 (m, 15H, 2C6H5, benzothiazepine H-3, H-6 to H-9).
3.0 (dd, Jvic= 10Hz, Jgem = 15Hz, 1H, methylene H-axial), 3.4 (dd,Jvic=
6Hz, Jgem= 15Hz, 1H, methylene H equatorial), 5.5 (dd, Jvicl = 10Hz,
Jvic2 = 6Hz, 1H, methine H), 6.7 (dd, 1H, furanH-4), 7.1-8.0 (m, 10H,
C6H4, benzothiazepine, H-6 to H-9, furan H-3 and H-5).
2.7 (dd, Jvic = 10Hz, Jgem = 15Hz, 1H, methylene H-axial), 3.2 (dd,Jvic =
6Hz, Jgem = 15Hz, 1H, methylene H-equatorial), 5.1 (dd, Jvici= 10Hz,
Jvic2= 6Hz, 1H, methine H), 7.2-7.6 (m,14H,2C6H5and benzo-thiazepine
H-6 to H-9), 14.6 (s,lH,NH).
1640 (C=N)
3100-2800 (NH and ring
stretching), 2200 (CN)
2200 (CN), 1650 (CO)
2.9 (dd, Jvic = 10Hz, Jgem = 15Hz, 1H, methylene H-axial), 3.1 (dd, Jvic =
6Hz, Jgem = 15Hz, 1H, methylene H-equatorial), 4.9 (dd, Jvicl = 10Hz,
Jvic2= 6Hz, 1H, methine H), 5.4 (s, 2H, phenoxy-methylene), 7.1-7.7 (m,
12H, benzothiazepine H-6 to H-9,C6HSand C6H3), 12.4 (s,lH ,OH).
3.7-3.8 (2s,9H, 30CH3), 7.1 (s,2H,C6H2), 7.3-7.6 (m,6H,C6H5and pyron
H-5).
10a
2200 (CN), 1685 (CO)
10b
11
2200 (CN), 1680 (CO)
3100-2800 (NH and OH),
2200 (CN)
5.4 (s, 2H, phenoxy CH2), 7.4-7.7 (m, 9H, C6H5, C6H3 and pyron H-5).
3.2 (m, 2H, pyrrolidine CH2), 5.1 (s, 1H, NH), 6.1(m, lH, pyrrolidine H-
5), 7.4-7.6 (m,5H, C6H5), 8.5 (s, lH,OH).
13
14
3400-3200 (NH2), 1710 (CO)
7.2 (d, J = 15H, 1H, olefinic H-l), 7.4-7.6 (m,5H, C6H5), 8.0 (d, J = 15Hz,
1H. olefinic H-2), 8.7 (s, 1H, oxazole H-2).
7.4-7.6 (m, 5H, C6H5), 8.2 (s,lH, oxazolopyridine H-2), 8.4 (s, 1H, oxazo-
lopyridine H-5), 11.6 (s,lH, NH).
3300 (NH), 1690 (CO)
was obtained with
a
molecular formula
obtained gave a molecular formula C11H 10N2O
m/z (M+186); it showed OH, CN and NH absorp-
C12H 10N2O2 m/z (M+214). It lacked the CN ab-
tions together with two signals at
6.1 (1H) ppm. Accordingly, the pyrrolidinone
structure of 11 was assigned to this product.
d 3.2 (2H) and sorption, detected in the parent oxime, and
d
showed CO and NH2 absorptions at 1710 and
3400-3200 cm-1. WTiile its !H NMR revealed two
When the same reaction was repeated using doublets at <57.2 and
d 8.0 ppm, similar to those
98% HCOOH instead of 50%, a different product present in the parent oxime and attributed to the
olefinic protons. So, the cinnamoyloxazole struc-
ture 13 was given to this product. This could be
explained via initial reduction to form the 2-
aminopentenenitrile, followed by its formylation
n h 2
c
n
rA
') oxim e
t
jj) Sn
h^JLcN
HNCHO
12
Ä
form ation
9 8 % HCOOH
P
h
V
R
NaH
to afford the intermediate 12 which undergoes in-
tracyclization via its enol form and the CN group
to the final isolable product 13. While in presence
of 50% HCOOH, the reduction step is followed
by intracyclization (NH2 group and olefinic double
bond) to form 11. The structure of 13 was also
13
ii) Sn
OCHj
Ph
10a,R = — < ^ ~ ^ -0CH 3
Q=<^~^NH
o c h 3
N~0
b ,R
=
^
0 ^
I
^
CI
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1200
R. H. Swellem et al. ■Cinnamoylacetonitrile in Heterocyclic Synthesis, Part 7
(m.p. and mixed m.p. of its diacetate derivative,
184° [5]).
confirmed chemically: it was refluxed in dioxane
affording a new compound for which structure 14
was given, based on analytical and spectral data.
Thus, it showed the pyridooxazole H-2 and H-5
2-Phenyl-4-[l-(phenyldiazo)cyanomethyl]-2,3-H-
benzothiazepine (8)
at
d 8.2 and (3 8.4 ppm, respectively, and its mass
The phenyl diazonuim chloride was added to a
cooled mixture of (2) (0.01 mole, 2.78 g) and so-
dium acetate trihydrate (5 g) in dimethylformam-
ide (30 ml) with stirring for 30 min; water was then
added and the precipitate was filtered off and crys-
tallized.
spectral data are also in full accord.
Experimental
Melting points are uncorrected and were taken
on Electrothermal 9100 apparatus. IR spectra
were recorded on Carl Zeiss spectrophotometer
instrument model “UR 10” using KBr. 'H NMR
spectra were determined on a Jeol 270 MHz in-
strument using tetramethylsilane as an internal
standard. Mass spectra (MS) were recorded on a
Finigan SSQ 7000 mass spectrometer. Microanaly-
sis were performed by the Central Service Labora-
tory at Cairo University.
2-Phenyl-4-(3-hydroxy-3-2,4-dichlorophenoxy-
methylacrylonitrile-2-yl)-2,3-H-benzothiazepine
(9) and 2-aryl-3-cyano-6-phenylpyran-4ones
(10a,b)
To a solution of each of compounds 1 or 2 (0.01
mole) in dry tetrahydrofuran (20 ml) in presence
of sodium hydride (0.01 mole) at room temper-
ature (25 °C), a solution of the appropriate acid
chloride (0.01 mole) in dry tetrahydrofuran
(10 ml) was dropped over with stirring for '/•>h,
then the salt formed was filtered off and the or-
ganic layer was treated with 1ml 50% HC1 and
partially concentrated. The precipitate, thus
formed, was collected and crystallized.
2.4-Disubstituted-2,3-H-benzothiazepines (2) and
(7a,b)
Each of compounds 1, (6a,b) (0.01 mole) was
refluxed with o-aminothiophenol (0.01 mole,
1.25 g) in methanol (30 ml) for 10 minutes. Then,
conc HC1 (5 drops) was added and the solution
cooled. The precipitate formed was collected and
crystallized.
2-Cyano-5-phenylpyrrolidin-3-one (11) and
5-amino-4-cinnamoyloxazole (13)
4-(3-Coumarinyl)-2-phenyl-2,3-H-
Compound 1 was nitrosated to prepare the oxi-
minocinnamoylacetonitrile as reported [9]. Then,
to the oxime (0.01 mole, 2.0 g) in 50% or 98%
formic acid (30 ml), Sn (0.01 mole, 1.2 g) was
added portionwise at 60 °C over Vi h and stirring
was kept for further 6 h at the same temperature.
The solution was then left overnight at room tem-
perature. A precipitate was formed and found to
be a mixture of the product with inorganic residu-
als. So, it was boiled in methanol, filtered while
hot and the filtrate was cooled and left to precipi-
tate. The product obtained was then filtered off
and crystallized.
benzothiazepine (3)
A mixture of 2 (0.01 mole, 2.89 g) with an equi-
molar amount of salicylaldehyde was refluxed in
methanol (30 ml) in presence of piperidine (3
drops) for 6 h. After partial concentration, the
precipitate obtained was collected and crystallized.
2.4-DiaryIbenzothiazepines (4a-c)
Tetrachloro-o-benzoquinone (0.01 mole, 2.45 g)
was added while stirring at room temperature to
a solution of each of benzothiazepines (2), (7a,b),
(0.01 mole) in dry ether (100 ml). After few hours,
the separated solid was collected by filtration,
washed with ether, dried and recrystallized. The
original ethereal mother liquor was extracted with
a 10% aqueous sodium hydroxide solution, the ex-
tract acidified with cold dilute HC1, and the pre-
cipitate obtained proved to be tetrachlorocatechol
4-Oxo-6-phenyloxazolo[4,5-b]pyridine (14)
Compound 13 (0.01 mole, 2.14 g) was refluxed
in dioxane (25 ml) for 6 h. The solution was par-
tially concentrated and the precipitate collected
and crystallized.
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R. H. Swellem et al. • Cinnamoylacetonitrile in Heterocyclic Synthesis, Part 7
1201
[1] G. A. M. Nawwar, R. H. Swellem, L. M. Chabaka,
Heterocycles 38, (No.l), 71 (1994).
[2] G. Heinisch. W.Holzer, G. A. M. Nawwar, J. Hetero-
cycl. Chem. 23, 93 (1986).
[6]G. A. M. Nawwar, B. M. Haggag, El-S. M. A. Ya-
kout, Z. Naturforsch. 47b. 1639 (1992).
[7] Wm. D. Stphenes, L. Field, J. Org. Chem. 24, 1576
(1959).
[8]M. Augustin, G. Jahreis, W. D. Rudorf, Synthesis
472 (1977).
[3] G. A. M. Nawwar, Bull. N. R. C.Egypt 18 (No.3),
163 (1993).
[4] G. A. M. Nawwar, R. H. Swellem, L. M. Chabaka,
Coll. Czech. Chem. Commun. 59 (7), 136 (1994).
[5] Th. Zincke, Fr. Küster, Chem. Ber. 21, 2729 (1888).
[9] G. A. M. Nawwar, S. A. Osman, K. A. M. El-Bay-
ouki, G. E. M. Elgemeie, M. H. Elnagdi, Heterocy-
cles 23 (No. 12), 2983 (1985).
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