2-Phenyl-4-bis(methylthio)methyleneoxazol-5-one: Versatile template for diversity oriented synthesis of heterocycles

Article abstract of DOI:10.1039/c1ob05495c

4-Bis(methylthio)methylene-2-phenyloxazol-5-one (1) has been shown to be a versatile template for the synthesis of novel heterocyclic scaffolds. The key protocol involves nucleophilic ring opening of 1 with various primary aliphatic, aromatic amines and diamines to give open-chain amide adducts which are transformed into 4-bis(methylthio)methylene-2-phenyl-1-alkyl/arylimidazol-5-(4H) -ones (5) in good yields in the presence of anhydrous NaOAc/AcOH. Similarly, the amide adducts 4h-i from 3,4-dimethoxyphenylethylamine and tryptamine undergo interesting rearrangement in the presence of POCl₃ to furnish 1-(2-phenyl-5-methylthio-4-thiazolyl)dihydroisoquinoline and β-carboline derivatives 8-9 in good yields. The amide adduct 14 from o-phenylenediamine on exposure to refluxing acetic acid or in the presence of Ag₂CO ₃ affords substituted 3H-1,5-benzodiazepinone, 2-(5-methylthio-2- phenyl-4-oxazolyl)-1H-benzimidazole and trisubstituted oxazole (15-17), whereas the bis-adduct from ethylenediamine yields ethylene bridge tethered bis-imidazole 23 and bis-oxazole 24 under similar reaction conditions. Probable mechanisms for the formation of various products have been suggested.

Full text of DOI:10.1039/c1ob05495c

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PAPER
2-Phenyl-4-bis(methylthio)methyleneoxazol-5-one: versatile template for
diversity oriented synthesis of heterocycles†‡
Vijayalaxmi Amareshwar,a Nimesh C. Mishrab and Hiriyakkanavar Ila*a
Received 29th March 2011, Accepted 11th May 2011
DOI: 10.1039/c1ob05495c
4-Bis(methylthio)methylene-2-phenyloxazol-5-one (1) has been shown to be a versatile template for the
synthesis of novel heterocyclic scaffolds. The key protocol involves nucleophilic ring opening of 1 with
various primary aliphatic, aromatic amines and diamines to give open-chain amide adducts which are
transformed into 4-bis(methylthio)methylene-2-phenyl-1-alkyl/arylimidazol-5-(4H)-ones (5) in good
yields in the presence of anhydrous NaOAc/AcOH. Similarly, the amide adducts 4h–i from
3,4-dimethoxyphenylethylamine and tryptamine undergo interesting rearrangement in the
presence of POCl3 to furnish 1-(2-phenyl-5-methylthio-4-thiazolyl)dihydroisoquinoline and b-carboline
derivatives 8–9 in good yields. The amide adduct 14 from o-phenylenediamine on exposure to refluxing
acetic acid or in the presence of Ag2CO3 affords substituted 3H-1,5-benzodiazepinone,
2-(5-methylthio-2-phenyl-4-oxazolyl)-1H-benzimidazole and trisubstituted oxazole (15–17), whereas
the bis-adduct from ethylenediamine yields ethylene bridge tethered bis-imidazole 23 and bis-oxazole 24
under similar reaction conditions. Probable mechanisms for the formation of various products have
been suggested.
moiety represents the main chromophore of green, blue and
Introduction
red fluorescent proteins (GFP, BFP, RFP).6,8 a-Methylene-
The imidazolone structural motif represents an important phar-
imidazolones also represent a highly electrophilic prosthetic group
for chemical and biochemical studies.9 Therefore, considerable
interest has been evoked for the synthesis of such class of
compounds in view of their broad range of biological activity
and synthetic applications.6,10
macophore present in several therapeutics displaying a broad
range of biological activity. In particular, imidazol-5-(4H)-one
and its derivatives play a unique role in drug discovery1 and
crop protection2 serving as privileged structures in combinatorial
chemistry.1d Thus, compounds containing the imidazol-5-(4H)-
one core are associated with antiviral (against both HSV and
HIV),1d anticonvulsant,3 immunosupressant,4 protein kinase C
(CDK-4) inhibitor,1a inflammation mediator,1b fungicidal and
herbicidal1d and COX-2 inhibitor activity.5 Some of these com-
pounds act as antagonists against various receptors6 such as
angiotensin II receptor, dopamine CGRP, b3-adrenergic and
GABAA receptors.6 Similarly, aplysinopsin, a naturally occurring
4-(indolylmethylene)-5-imidazolone derivative and its analogs dis-
play specific cytotoxicity for cancer cells,7a–c antileishmanial7d and
anti-infective7e activity, and affect neurotransmission.7a–b Addi-
tionally, several imidazolone derivatives are used as intermediates
in the synthesis of biologically active natural products including
imidazoles.6 Also, the 4-(aryl/heteroaryl)methyleneimidazolone
Our own interest in the synthesis of imidazolone derivatives
derives from our continued interest in the development of new
general synthetic methods for five- and six-membered hetero-
cycles using polarized ketene dithioacetals as versatile building
blocks.11–12 During the course of these studies, we have recently
reported synthetic applications of 4-bis(methylthio)methylene-2-
phenyloxazol-5-one (1) as a versatile template for the synthesis
of 2-phenyl-4,5-substituted oxazoles.13 The overall strategy in-
volves nucleophilic lactone ring opening of 1 by various oxygen
(alkoxides), nitrogen (amines) and carbon (Grignard reagents)
nucleophiles to give open-chain adducts 2 in high yields followed
by intramolecular 5-endo cyclization of 2 in the presence of silver
carbonate to furnish 2,4,5-substituted oxazoles 3 in excellent yields
(Scheme 1).13 Facile ring opening of 1 by various nucleophiles,
especially amines, further prompted us to envisage new synthetic
transformations based on these open-chain amide adducts such
as 4 leading to novel heterocycle scaffolds. We now report in
the present paper, nucleophilic ring opening of 1 by various
primary aliphatic/aromatic amines to 4 and their intramolecular
cyclodehydration to novel 4-bis(methylthio)methylene-2-phenyl-
1-alkyl/arylimidazol-5(4H)-ones 5 (Scheme 2). Synthetic trans-
formations and rearrangements of a few open chain amides
aNew Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific
Research, Jakkur, Bangalore 560064, India
bDepartment of Chemistry, Indian Institute of Technology, Kanpur 206016,
India. E-mail: hila@jncasr.ac.in
† Dedicated to Professor H. Junjappa on his 75th birthday.
‡ Electronic supplementary information (ESI) available. See DOI:
10.1039/c1ob05495c
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Scheme 1
Scheme 2
from aromatic and aliphatic diamines to give novel heterocyclic
scaffolds have also been reported.
yield (48%) of imidazolone 5b under these conditions (Table 1,
entry 2), while no trace of 1-N-t-butylimidazolone 5c was isolated
on intramolecular cyclodehydration of the corresponding N-(t-
butylamino) adduct 4c (entry 3). In both of these reactions, the
4-bis(metylthio)methylene-5-oxazolone 1 was isolated in 38% and
60% yields, respectively (entries 2, 3). Apparently, the reaction
takes different course because of steric reasons yielding 1 by in-
tramolecular cyclization through the oxygen of the benzoylamino
group in 4b–c with concurrent elimination of bulkier amines as
the major pathway.
Results and discussion
The ketene dithioacetal 1 was prepared from N-benzoylglycine,
according to the modified procedure described in our previous
paper.13 Although we have reported earlier the reaction of a few
primary amines with 1 in refluxing ethanol in the presence of
a trace of acetic acid (entries 1 and 9, Table 1) to give the corre-
sponding open-chain amide adducts (4a and 4i), in our subsequent
optimization studies, we found that most of the primary aliphatic
amines smoothly react with 1 at room temperature in ethanol
affording the acyclic amide adducts 4 in excellent yields (4a, 4d–
i, Table 1, entries 1, 4–9). The only exceptions were structurally
crowded i-propyl and t-butyl amines which furnished the products
4b–c in lower yields under these conditions along with the ethyl
ester 6 as the side product formed by the ring opening of 1 by
ethoxide ion (Table 1 entries 2–3). However, changing to a non-
nucleophilic solvent such as THF afforded the amide adducts 4b–
c in high yields at room temperature (entries 2–3). On the other
hand, the aromatic amines remained unreacted with 1 at room
temperature in ethanol or THF and the amides 4j–l were obtained
in good yields only under refluxing ethanol in the presence of a
trace of acetic acid (Table 1, entries 10–12).
Intramolecular cyclodehydration of 4a to imidazolone-4-
dithioacetal 5a was next attempted in the presence of vari-
ous dehydrating agents (anhydrous ZnCl2, K2CO3/EtOH, dry
pyridine, anhydrous sodium acetate) and the best yield of 5a
(70%) was obtained when 4a was exposed to freshly fused flame
dehydrated sodium acetate in glacial acetic acid for 7 h (Table 1,
entry 1). Similarly, the other open-chain amides 4d–l from cyclic
aliphatic amines, benzylamine and aromatic amines underwent
smooth cyclodehydration under similar conditions furnishing
the novel 1-N-substituted 2-pheyl-4-bis(methylthio)methylene-
imidazol-5(4H)-ones 5d–l in overall good yields (Table 1, entries
4–12). The adduct 4b from i-propylamine, however, gave a low
We next examined Bischler–Napieralski-type cyclization
of open-chain amide adducts 4h and 4i from 3,4-
dimethoxyphenylethylamine and tryptamine, in the presence of
phosphorous oxychloride (Scheme 3). Since oxoketenedithioac-
etals are known to undergo partial hydrolysis to oxothioesters
in the presence of Lewis acids,14 we anticipated the formation of
imidazo[5,1-a]isoquinoline derivatives such as A and B (Chart 1)
through cascade dehydrative cyclization of 4h and 4i under these
conditions.15 However, when 4h was reacted with phosphorous
oxychloride (4 equiv.) in refluxing dioxane for 3 h, work-up of the
reaction mixture furnished two products, which were characterized
as the isoquinoline dithioester 7 (22%) and 6,7-dimethoxy-1-(5-
methylthio-2-phenyl-4-thiazolyl)-3,4-dihydroisoquinoline 8 (56%)
on the basis of spectral and analytical data. No trace of the desired
imidazo[5,1-a]isoquinoline A could be detected from the reaction
mixture (Scheme 3). Similarly, when open-chain amide adduct 4i
from tryptamine was exposed to POCl3 under identical conditions,
the only product isolated (65%) was identified as 1-(5-methylthio-
2-phenyl-4-thiazolyl)-4,9-dihydro-3H-b-carboline 9 (Scheme 3).
A probable mechanism for the formation of products 7 and 8
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Table 1 Synthesis of 4-bis(methythio)methylene-1-alkyl/cycloalkyl/aryl-2-phenylimidazol-5-ones (5a–5l)
Entry
Primary amine
Reaction conditions
4
% Yield 4
5
% Yield 5d
1
2
3
4
EtNH2
i-PrNH2
t-BuNH2
a
b
b
a
4a
4b
4c
4d
85
5a
5b
5c
5d
70
80b (59)a
81b (30)a
78
48 (38)e
0 (60)e
67
5
6
a
a
4e
4f
75
78
5e
5f
65
64
7
8
PhCH2NH2
a
a
4g
4h
78
76
5g
5h
59
58
9
a
4i
85
5i
61
10
11
12
R2 = Me; R1 = R3 = H
R1 = R2 = MeO; R3 = H
R1 = R3 = H; R2 = OMe
c
c
c
4j
4k
4l
70
69
65
5j
5k
5l
58
65
64
Reaction conditions:a EtOH/RT/3–4 h. b THF/RT, 4 h for 4b, 24 h for 4c. c EtOH/gl. AcOH (catalytic)/D, 6–10h. d Yields of pure isolated compounds.
e Yield of 1.
Scheme 3
from 4h is shown in the Scheme 4. Thus 4h undergoes Bischler–
Napieralski-type cyclization in the presence of POCl3 to give
dihydroisoquinoline intermediate 10 having a substituted ketene
dithioacetal moiety at the 1-position. The intermediate 10 appears
to undergo further POCl3 assisted dethiomethylation through
intermediate 11 to give dithioester 7 which was isolated as the
minor product from cyclization of 4h. Subsequent intramolecular
cyclization of 7 in the presence of POCl3 furnishes the observed
product thiazole 8 through the intermediate 12 as depicted in
Scheme 4.16 The corresponding 1-(4-thiazolyl)-b-carboline9 is also
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formed from 4i through a similar mechanistic pathway (Schemes 3
and 4).
To further explore the versatility of 1 for the synthesis of novel
heterocycles, we investigated the reaction of diamines such as o-
phenylenediamine and ethylenediamine with 1 and the results are
summarized in Schemes 5–7. Thus, the ketene dithioacetal 1 was
reacted with o-phenylenediamine 13 (1 equiv.) in various solvents
like benzene, xylene and ethanol. The product isolated in varying
yields on prolonged refluxing was characterized as the open-chain
1 : 1 adduct 14 formed by nucleophile ring opening of 1 by one of
the amino groups of o-phenylenediamine (Scheme 5). The product
Chart 1
Scheme 4
Scheme 5
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14 was obtained in increased yield (65%) within shorter time (5 h)
when 1 was reacted with 13 in refluxing ethanol in the presence of
a trace of acetic acid (Scheme 5). Reaction of o-phenylenediamine
with 2 equivalents of 1 also yielded the open-chain anilide 14 (62%)
as the only product under these conditions without any trace
of bisadduct formed by ring opening of 1 by the second amino
group of 14. When the open-chain anilide 14 was subjected to
further transformation in refluxing acetic acid (5 h), work-up of the
reaction mixture yielded two products which were characterized
as the substituted 3H-1,5-benzodiazepinone 15 (45%) and 2-
(5-methylthio-2-phenyl-4-oxazolyl)-1H-benzimidazole 16 (56%)
on the basis of their spectral and analytical data (Scheme 5).
Intramolecular cyclization of 14 in the presence of silver carbonate
in refluxing acetonitrile13 furnished the N-(2-aminophenyl)-5-
(methylthio)-2-phenyloxazol-4-carboxamide 17 in 79% yield as
observed in our earlier studies (Scheme 5).13 Thermal cyclization
of 17 in refluxing glacial acetic acid also afforded the 2-(5-
methylthio-2-phenyl-4-oxazolyl)benzimidazole 16 in 74% yield
(Scheme 5). A probable mechanism for the formation of products
15–16 from the anilide adduct 14 is depicted in Scheme 6.
Thus, intramolecular 1,4-conjugate addition of the amino group
in 14 to the a-amidoketenedithioacetal moiety and subsequent
elimination of methylmercaptan yields the 1,5-benzodiazepinone
15 (route a), which exists exclusively in the tautomeric form 15
with no trace of 15A as evidenced by the presence of a one
proton signal at d 5.1 (d, 1H, J = 6 Hz) for HA in its 1H
NMR spectrum (Scheme 6).17 On the other hand, sequential in-
tramolecular dehydrative cyclization of 14 followed by elimination
of methylmercaptan through intermediates 19 and 20 yields 2-
(5-methylthio-2-phenyl-4-oxazolyl)benzimidazole 16 as the other
major product (route b, Scheme 6).
ilarly, 2-phenyl-5-(methylthio)-bisoxazol-4-carboxamide 24 was
obtained in high yield by intramolecular 5-endo cyclization of the
bisamide adduct 22 in the presence of silver carbonate (Scheme 7).
Conclusion
In summary, we have further demonstrated in the present
paper the synthetic versatility of 4-bis(methylthio)methylene-2-
phenyloxazol-5-one (1) for preparation of a variety of novel
heterocyclic compounds. The protocols involve nucleophilic ring
opening of 1 with various primary aliphatic/aromatic amines
or diamines and subsequent transformations of the resulting
amide adducts to either 4-bis(methylthio)methylene-2-phenyl-
1-alkyl/arylimidazol-5(4H)-one 5 (via cyclodehydration) or to
other novel heterocycles under appropriate conditions involving
mechanistically interesting rearrangements. It should be noted
that 2-substituted 4-bis(methylthio)methyleneimidazol-5-ones are
virtually unexplored in the literature, except for one report,18 and
further work to examine their synthetic applications as well as
their potential biological activity are in progress.
Experimental
General
1H NMR and 13C NMR spectra were recorded on a Bruker
400 MHz spectrometer and Jeol JNM Lambda and Jeol ECX-
500 MHz (100 MHz, 400 MHz and 500 MHz) spectrometers with
CDCl3or DMSO-d6 as solvent. Chemical shifts are expressed in
parts per million (d) using residual solvent protons as internal
standards (d 7.26 for CDCl3 and d 2.50 for DMSO-d6 in 1H, d 77.0
for CDCl3 and d 40.45 for DMSO-d6 in 13C). Coupling constants
(J) are reported in Hertz (Hz). Splitting patterns are designated
as s (singlet), d (doublet), t (triplet), m (multiplet). MALDI
(matrix assisted laser desorption ionisation) mass spectra were
recorded on a Bruker Daltonics Ultrafelx II TOF/TOF. HRMS
(ESI) were recorded on Waters Micromass Q-TOF Premier Mass
Spectrometer. Infrared spectra were recorded with Bruker IFS 66
v/S and Perkin Elmer 1320 spectrometers. Melting points were
Finally, we also studied the nucleophilic ring opening of 1 with
ethylenediamine 21 as shown in Scheme 7. Thus, treatment of
21 with either one or two equivalents of 1 in ethanol at room
temperature provided only the bis-adduct 22 formed by attack
of the more basic two amino groups on two molecules of 1
(Scheme 7). Intramolecular cyclodehydration of 22 in the presence
of anhydrous sodium acetate in refluxing acetic acid afforded the
ethylene bridge tethered bis-imidazolone 23 in 55% yield. Sim-
Scheme 6
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Scheme 7
recorded using Mel-Temp apparatus (capillary method) and are
uncorrected. Thin layer chromatography (TLC) analyses were
performed on aluminium backed plates with a 0.2 mm layer of
Kieselgel 60 F254 (Merck) and were visualized by UV (254 nm) and
iodine indicator where appropriate. Unless otherwise indicated,
all starting materials were obtained from commercial suppliers
and used without further purification. Acetonitrile was dried over
(MALDI/TOF): m/z calcd for C22H26N2O4S2 [M + Na]+ 469.1232;
found 469.1801.
N -(3-(2-(2-Benzamido-3,3-bis(methylthio)acrylamido)ethyl-
amino)-1,1-bis(methylthio)-3-oxoprop-1-en-2-yl)benzamide (22).
The bis adduct 22 was prepared as described above for 4a–i by
using two equivalents of ketene dithioacetal 1 (200 mg, 0.75
mmol) and one equivalent of ethylenediamine (0.024 ml, 0.37
mmol). White solid, yield: 150 mg (69%), mp 202–203 ◦C. Rf 0.3
(MeOH/DCM: 0.5/9.5). nmax (KBr)/cm-1 1284, 1513, 1649, 3300,
˚
P2O5 and stored over 4 A molecular sieves. THF was distilled over
sodium benzophenoneketyl. Silica gel (100–200 mesh) was used
for column chromatography.
4-(Bis(methylthio)methylene)-2-phenyloxazol-5(4H)-one (1)
was prepared according to the procedure reported in our previous
paper.13
1
3334. H NMR dH (400 MHz, CDCl3) 2.31 (6H, s, 2 ¥ SCH3),
2.36 (6H, s, 2 ¥ SCH3), 3.69–3.71 (4H, m, CH2–CH2), 7.32–7.36
(4H, m, ArH) 7.39 (2H, br s, 2 ¥ NH), 7.46–7.49 (2H, m, ArH),
7.60–7.63(4H, d, J = 8.4 Hz, ArH), 8.31(2H, br s, 2 ¥ NH). 13C
NMR dC (400 MHz, CDCl3) 16.4, 17.9, 37.9, 123.2, 127.2, 128.5,
132.3, 132.7, 137.1, 164.1, 164.2. MS (MALDI/TOF): m/z calcd
for C26H30N4O4S4 [M + Na]+ 613.1047; found 613.2230.
Synthesis of open chain amides 4a–l
Typical procedure. A solution of 1 (200 mg, 0.75 mmol) and
the corresponding aliphatic amine (0.75 mmol) in absolute ethanol
(10 ml) or dry THF (10 ml) was stirred at room temperature for 3–
7 h (monitored by TLC), the solvent was evaporated under vacuum
and the residue was triturated with diethyl ether to give a colorless
solid, which was purified by crystallizing with ethyl acetate.
Synthesis of anilides 4j–l and 14
A solution of ketene dithioacetal 1 (200 mg, 0.75 mmol) and the
corresponding aromatic amine (0.75 mmol) in absolute ethanol
(10 ml) in the presence of a catalytic amount of acetic acid (0.05 ml)
was refluxed for 4–5 h with constant stirring (monitored by TLC)
and the reaction mixture was worked up as described above for
4a–i.
N -(3-(3,4-Dimethoxyphenethylamino)-1,1-bis(methylthio)-3-
oxoprop-1-en-2-yl)benzamide (4h). White solid, yield: 255 mg
(76%), mp 154–155 ◦C. Rf 0.35 (MeOH/DCM: 0.2/9.8). nmax
(KBr)/cm-1 1258, 1509, 1629, 1652, 3191, 3348. 1H NMR dH
(400 MHz, CDCl3) 2.23 (3H, s, SCH3), 2.33(3H, s, SCH3), 2.92
(2H, t, J = 8 Hz, CH2), 3.74 (2H, t, J = 8 Hz, NCH2), 3.85 (3H, s,
OCH3), 3.86 (3H, s, OCH3), 6.18 (1H, br s, NH), 6.79 (1H, d,
J = 8 Hz, ArH), 6.82 (1H, dd, J1 = 8 Hz, J2 = 2 Hz, ArH), 6.85
(d, J = 1.6 Hz, ArH), 7.45–7.57 (3H, m, ArH), 7.85 (2H, d, J =
8 Hz, ArH), 8.38 (1H, s, NH). 13C NMR dC (400 MHz, CDCl3)
16.3, 17.7, 34.7, 41.1, 55.9, 56.0, 111.4, 112.2, 120.8, 124.3, 127.5,
128.8, 131.6, 132.4, 133.0, 136.6, 147.6, 149.0, 164.0, 164.2. MS
N -(1-(2-Aminophenylcarbamoyl)-2,2-bis-(methylthio)vinyl)-
benzamide (14). Pale yellow solid, yield: 185 mg (65%), mp 164–
165 ◦C. Rf 0.4 (MeOH/DCM: 2/8). nmax (KBr)/cm-1 1475, 1511,
1
1628, 1666, 3312, 3361, 3406. HNMR dH (400 MHz, DMSO-
d6) 2.36 (3H, s, SCH3), 2.38 (3H, s, SCH3), 5.08 (2H, br s, NH2),
6.53 (1H, dd, J1 = 7.6 Hz, J2 = 1.2 Hz, ArH), 6.67 (1H, d, J =
8 Hz, ArH), 6.95 (2H, dd, J1 = 8.0 Hz, J2 = 1.2 Hz, ArH), 7.08
(1H, d, J = 7.6 Hz, ArH), 7.51–7.63 (3H, m, ArH), 7.95 (2H,
d, J = 8.4 Hz, ArH), 9.5 (1H, br s, NH), 9.77 (1H, br s, NH).
5798 | Org. Biomol. Chem., 2011, 9, 5793–5801
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1
13CNMR dC (400 MHz, DMSO-d6) 16.1, 16.7, 115.0, 115.5, 122.2,
126.7, 126.9, 127.5, 127.7, 128.5, 132.1, 133.0, 135.5, 144.2, 163.0,
164.6. MS (MALDI/TOF): m/z calcd for C19H20N2O3S2 [M +
Na]+ 411.0813; found 411.0513.
(KBr)/cm-1 1025, 1121, 1249, 1445, 1513, 1558, 1595, 1686. H
NMR dH (400 MHz, CDCl3) 2.67 (3H, s, SCH3), 2.91 (3H, s,
SCH3), 3.77 (3H, s, OCH3), 3.89 (3H, s, OCH3), 6.69 (2H, m,
ArH), 6.85 (1H, d, J = 8.0 Hz, ArH), 7.29 (3H, m, ArH), 7.50 (2H,
d, J = 7.5 Hz, ArH). 13C NMR dC (100 MHz, CDCl3) 18.4, 20.1,
56.0, 110.8, 111.1, 119.9, 127.4, 128.2, 128.5, 128.7, 130.7, 133.0,
148.8, 149.3, 153.0, 157.8, 163.8. MS (MALDI/TOF): m/z calcd
for C20H20N2O3S2 [M + H]+ 401.0994; found 401.1556.
General procedure for the synthesis of 4-bis(methylthio)methylene-
1-alkyl/aryl-2-phenyl-imidazol-5-(4H)-ones 5a–b, 5d–l and 23
from 4a–b, 4d–l and 22
4-(Bis(methylthio)methylene)-1-(2-(4-(bis(methylthio)methyl-
ene)-5-oxo-2-phenyl-4,5-dihydroimidazol-1-yl)ethyl)-2-phenyl-1H-
imidazol-5-(4H)-one (23). Yellow solid, yield: 103 mg (55%), mp
199–200 ◦C. Rf 0.6 (MeOH/DCM: 0.5/9.5). nmax (KBr)/cm-1
A suspension of the respective open-chain amide or anilide (0.45
mmol) and freshly fused anhydrous sodium acetate (150 mg, 1.8
mmol) in glacial acetic acid (10 ml) was heated under reflux with
stirring for 10–15 h (monitored by TLC). The reaction mixture was
poured into ice-cold water (20 ml) and neutralized with saturated
NaHCO3 solution (25 ml) and extracted with dichloromethane (3
¥ 50 ml). The organic layer was washed with water (2 ¥ 50 ml)
and saturated NaCl solution (50 ml), dried over Na2SO4 and
concentrated under reduced pressure to give crude residue which
was purified by column chromatography over silica gel using
hexane–ethyl acetate as eluent.
1
1461, 1666, 2854, 2922. H NMR dH (400 MHz, CDCl3) 2.59
(6H, s, 2 ¥ SCH3), 2.79 (6H, s, 2 ¥ SCH3), 4.02 (4H, s, CH2–CH2),
7.41–7.45 (6H, m, ArH), 7.51–7.53 (4H, m, ArH). 13C NMR dC
(100 MHz, CDCl3). 18.2, 19.7, 40.3, 128.3, 128.7, 129.0, 130.6,
135.3, 154.2, 155.6, 164.7. MS (MALDI/TOF): m/z calcd for
C26H26N4O2S4 [M + H]+ 555.1917; found 555.2283.
General procedure for POCl3 induced cyclization of 4h and 4i
4-(Bis(methylthio)methylene)-1-ethyl-2-phenyl-1H-imidazol-5-
(4H)-one (5a). Yellow solid, yield: 132 mg (70%), mp 86–88 ◦C.
Rf 0.6 (EtOAc/hexane: 3/7). nmax (KBr)/cm-1 1444, 1492, 1547,
To a solution of 4h or 4i (0.47 mmol) in dry dioxane (10 ml),
POCl3 (0.16 ml, 1.82 mmol) was added drop-wise and the reaction
mixture was refluxed for 3–6 h (monitored by TLC). It was
then slowly poured over ice-cold water (20 ml), neutralized with
saturated NaHCO3 (25 ml), extracted with EtOAc (4 ¥ 50 ml).
The organic layer was washed with water (2 ¥ 75 ml) and saturated
NaCl solution (75 ml), dried over Na2SO4 and concentrated under
reduced pressure to give crude residue, which was purified by
column chromatography over silica gel using hexane–ethyl acetate
as eluent.
1
1665. H NMR dH (400 MHz, CDCl3) 1.18 (3H, t, J = 7.0 Hz,
CH3), 2.61 (3H, s, SCH3), 2.78 (3H, s, SCH3), 3.77 (2H, q, J =
7.0 Hz, CH2), 7.42–7.47 (3H, m, ArH), 7.64–7.66 (2H, m, ArH).
13C NMR dC (100 MHz, CDCl3) 14.5, 18.2, 19.6, 36.8, 128.1, 128.7,
129.7, 130.6, 134.7, 155.0, 155.7, 164.7. MS (MALDI/TOF): m/z
calcd for C14H16N2OS2 [M + H]+ 293.0782; found 293.1055.
4-(Bis(methylthio)methylene)-1-(3,4-dimethoxyphenethyl)–2-
phenyl-1H-imidazol-5-(4H)-one (5h). Yellow solid, yield: 110 mg
(58%), mp 153–154 ◦C. Rf 0.2 (EtOAc/hexane: 2/8). nmax
(KBr)/cm-1 1027, 1261, 1495, 1513, 1678. 1H NMR dH (400 MHz,
CDCl3) 2.64 (3H, s, SCH3), 2.79 (3H, s, SCH3), 2.78 (2H, t, J =
4.8 Hz, CH2), 3.74 (3H, s, OCH3), 3.82 (3H, s, OCH3), 3.98 (2H, t,
J = 7.6 Hz, NCH2), 6.46 (1H, d, J = 2 Hz, ArH), 6.50 (1H, dd, J =
8 Hz, J = 2 Hz, ArH), 6.67 (1H, d, J = 8 Hz, ArH), 7.39–7.48 (5H,
m, ArH). 13C NMR dC (100 MHz, CDCl3) 18.4, 19.7, 34.5, 43.4,
55.7, 56.0, 111.3, 111.9, 120.8, 128.2, 128.5, 130.0, 130.3, 130.4,
135.0, 147.8, 149.0, 155.3, 156.0, 165.0. MS (MALDI/TOF): m/z
calcd for C22H24N2O3S2 [M + H]+ 429.1306; found 429.1461.
(E)-Methyl-2-benzamido-2-(6,7-dimethoxy-3,4-dihydroisoqui-
nolin-1(2H)-ylidene)ethanedithioate (7). Yellow solid, yield:
◦
40 mg (22%), mp 123–124 C. Rf 0.4 (EtOAc/hexane: 2/8). nmax
(KBr)/cm-1 1027, 1261, 1454, 1516, 1641, 3423. 1H NMR dH
(400 MHz, CDCl3) 2.66 (3H, s, SCH3), 2.97 (2H, t, J = 6.8 Hz,
CH2), 3.80 (3H, s, OCH3), 3.85 (2H, t, J = 6.8 Hz, NCH2), 3.87
(3H, s, OCH3), 6.76 (1H, br s, NH), 6.81 (2H, d, J = 1.2 Hz, ArH),
7.44 (3H, m, ArH), 7.95 (2H, m, ArH), 9.84 (1H, br s, NH). 13C
NMR dC (400 MHz, CDCl3) 16.5, 36.0, 45.1, 56.0, 111.7, 112.1,
120.8, 122.8, 126.1, 126.2, 128.7, 130.3, 130.4, 148.1, 149.2, 149.2,
159.6, 202.2. HRMS (ESI): m/z calcd for C21H22N2O3S2 [M + Na]+
437.0970; found 437.0964.
4-(Bis(methylthio)methylene)-1-(2-(1H -indol-3-yl)ethyl)-2-
phenyl-1H-imidazol-5-(4H)-one (5i). Yellow solid, yield: 115 mg
(61%), mp 113–114 ◦C. Rf 0.4 (EtOAc/hexane: 4/6). nmax
6,7-Dimethoxy-1-(5-methylthio-2-phenyl-4-thiazolyl)-3,4-dihy-
droisoquinoline (8). Yellow solid, yield: 99 mg (56%), mp 146–
147 ◦C. Rf 0.3 (EtOAc/hexane: 2/8). nmax (KBr)/cm-1 1067, 1148,
1
(KBr)/cm-1 1107, 1443, 1489, 1562, 1657, 1671, 3322. H NMR
d
H (400 MHz, CDCl3) 2.65 (3H, s, SCH3), 2.79 (3H, s, SCH3), 3.04
1
(2H, t, J = 7.6 Hz, CH2), 4.04 (2H, t, J = 7.6 Hz, NCH2), 6.90 (1H,
d, J = 2 Hz, ArH), 7.01 (1H, dd, J1 = 8 Hz, J2 = 1.2 Hz, ArH),
7.15 (1H, dd, J1 = 8 Hz, J2 = 1.2 Hz, ArH), 7.29–7.38 (4H, m,
ArH), 7.41–7.49 (3H, m, ArH), 7.97 (1H, br s, NH). 13C NMR dC
(100 MHz CDCl3) 18.4, 19.7, 24.8, 42.6, 111.0, 112.2, 118.6, 119.5,
122.1, 122.2, 127.2, 128.1, 128.6, 130.0, 130.3, 135.2, 136.2, 155.5,
155.7, 165.1. MS (MALDI/TOF): m/z calcd for C22H21N3OS2 [M
+ H]+ 408.1204; found 408.1448.
1279, 1439, 1557. H NMR dH (400 MHz, CDCl3) 2.59 (3H, s,
SCH3), 2.75 (2H, t, J = 7.2 Hz, CH2), 3.84 (3H, s, OCH3), 3.92
(2H, t, J = 7.2 Hz, NCH2), 3.94 (3H, s, OCH3), 6.74 (1H, s, ArH),
7.39–7.44 (3H, m, ArH), 7.56 (1H, s, ArH), 7.91 (2H, d, J = 8 Hz,
ArH). 13C NMR dC (400 MHz, CDCl3) 21.00, 26.0, 47.3, 56.0,
56.1, 110.0, 112.1, 121.4, 126.0, 129.0, 129.8, 132.2, 133.6, 138.7,
147.1, 149.2, 150.9, 160.3, 163.2. HRMS (ESI): m/z calcd for
C21H20N2O2S2 [M + H]+ 397.1044; found 397.1046.
4-(Bis(methylthio)methylene)-1-(3,4-dimethoxyphenyl)-2-phe-
nyl-1H-imidazol-5-(4H)-one (5l). Yellow solid, yield: 124 mg
(65%), mp 158–160 ◦C. Rf 0.3 (EtOAc/hexane: 4/6). nmax
1-(5-Methylthio-2-phenyl-4-thiazolyl)-4,9-dihydro-3H-b-car-
boline (9). Yellow solid, yield: 110 mg (63%), mp 173–174 ◦C.
Rf 0.45 (EtOAc/hexane:2/8). nmax (KBr)/cm-1 1103, 1233, 1407,
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1511, 3128. 1H NMR dH (400 MHz, CDCl3) 2.66 (3H, s, SCH3),
3.00 (2H, t, J = 8.0 Hz, CH2), 4.20 (2H, t, J = 8.0 Hz, NCH2), 7.14
(1H, dd, J1 = 8.0 Hz, J2 = 0.8 Hz, ArH), 7.29 (1H, dd, J1 = 8.0 Hz,
J2 = 0.8 Hz, ArH), 7.46–7.55 (4H, m, ArH), 7.63 (1H, d, J = 8 Hz,
ArH), 7.93 (2H, d, J = 8 Hz, ArH), 10.38 (1H, br s, NH). 13C
NMR dC (400 MHz, CDCl3) 19.4, 20.6, 48.6, 112.2, 116.8, 119.8,
119.9, 124.2, 125.4, 126.0, 128.2, 129.2, 130.1, 133.2, 136.2, 140.9,
145.5, 153.4, 162.5. HRMS (ESI): m/z calcd for C21H17N3S2 [M +
H]+ 376.0942; found 376.0943.
3333, 3427. 1H NMR dH (400 MHz, CDCl3) 2.71 (3H, s, SCH3),
3.96 (2H, br s, NH2), 6.82–6.86 (2H, m, ArH), 7.07 (1H, dd, J1 =
8.8 Hz, J2 = 1.6 Hz, ArH), 7.44 (1H, d, J = 8.0 Hz, ArH), 7.49–7.51
(3H, m, ArH), 8.02–8.04 (2H, m, ArH), 8.75 (1H, br s, NH). 13
C
NMR dC (400 MHz, CDCl3) 15.2, 118.0, 119.5, 124.0, 125.0, 126.3,
126.4, 127.0, 129.0, 131.0, 131.4, 140.5, 151.7, 159.3, 160.2.MS
(MALDI/TOF): m/z calcd for C17H15N3O2S [M + H]+ 326.0973;
found 325.9872 and [M +Na]+ 348.0784; found 347.0891.
5-(Methylthio)-N -(2-(5-(methylthio)-2-phenyloxazole-4-car-
boxamido)ethyl)-2-phenyloxazole-4-carboxamide
(24). White
Rearrangement of 14 in refluxing glacial AcOH
solid, yield: 141 mg (70%), mp 214–215 ◦C. Rf 0.4 (MeOH/DCM:
0.5/9.5). nmax (KBr)/cm-1 1247, 1569, 1646, 3291. 1H NMR
dH (400 MHz, CDCl3) 2.66 (6H, 2 ¥ SCH3), 3.69–3.71 (4H, m,
CH2–CH2), 7.36 (2H, br s, 2 ¥ NH), 7.46 (6H, m, ArH), 7.99 (4H,
m, ArH). 13C NMR dC (400 MHz CDCl3) 14.6, 15.2, 39.3, 126.2,
126.3, 126.5, 128.9, 129.0, 130.8, 131.7, 150.7, 160.3, 161.8. MS
(MALDI/TOF): m/z calcd for C24H22N4O4S2 [M + H]+ 495.1160;
found 495.1255.
A solution of 14 (200 mg, 0.52 mmol) in glacial acetic acid (10 ml)
was refluxed for 5 h (monitored by TLC). The reaction mixture
was poured in to ice-cold water (20 ml), neutralized with saturated
NaHCO3 solution (25 ml) and extracted with dichloromethane (3
¥ 50 ml). The organic layer was washed with water (2 ¥ 50 ml)
and saturated NaCl (50 ml), dried over Na2SO4 and concentrated
under reduced pressure to give viscous residue, which was purified
by column chromatography over silica gel using hexane and ethyl
acetate as eluent.
Acknowledgements
N-(4-Methylthio-2-oxo-2,3-dihydro-1H-benzo[b][1,4]diazepin-
3-yl)-benzamide (15). White solid, yield: 78 mg (45%), mp 209–
110 ◦C. Rf 0.3 (MeOH/DCM: 2/8). nmax (KBr)/cm-1 1586, 1654,
1689, 3264. 1H NMR dH (400 MHz, CDCl3) 2.43 (3H, s, SCH3),
5.12 (1H, d, J = 6.4 Hz, (NCH (HA in 15), 7.03 (1H, d, J = 8 Hz,
ArH), 7.20 (1H, dd, J1 = 7.2 Hz, J2 = 1.6 Hz, ArH), 7.3 (1H, dd, J1 =
7.2 Hz, J2 = 1.6 Hz, ArH), 7.43 (1H, d, J = 8 Hz, ArH), 7.48–7.59
(4H, m, 3 ArH and 1 NH), 7.83 (1H, br s, NH), 7.92 (2H, d, J =
7.2 Hz, ArH). 13C NMR dC (400 MHz, CDCl3) 13.7, 57.0, 122.0,
126.0, 126.4, 126.7, 127.6, 127.8, 129.0, 132.4, 133.4, 140.0, 164.4,
165.7, 167.2. MS (MALDI/TOF): m/z calcd for C17H15N3O2S [M
+ Na]+ 348.0783; found 348.0245.
We thank the Jawaharlal Nehru Centre for Advanced Scientific
Research for research associateship to VA and Indian National
Science Academy (INSA), New Delhi for INSA Senior Scientist
position to HI.
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White solid, yield: 92 mg (56%), mp 183–184 ◦C. Rf 0.5
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Silver carbonate-induced cyclization of 14 and 22: synthesis of
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N-(2-Aminophenyl)-5-(methylthio)-2-phenyloxazol-4-carboxa-
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5800 | Org. Biomol. Chem., 2011, 9, 5793–5801
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Org. Biomol. Chem., 2011, 9, 5793–5801 | 5801
©