Transition metal free synthesis of multifunctional thiomethylated-benzenes from aryl/heteroaryl/cyclopropyl methyl ketones

Article abstract of DOI:10.1016/j.tet.2020.131183

A base-promoted strategic synthesis of various functionalized thiomethylated-benzenes has been established from aryl/heteroaryl/cyclopropyl methyl ketone. We can directly access the thiomethylated-benzene nucleus embedded with diverse functional group by

Full text of DOI:10.1016/j.tet.2020.131183

Journal Pre-proof
Transition metal free synthesis of multifunctional thiomethylated-benzenes from aryl/
heteroaryl/cyclopropyl methyl ketones
Rahul Panwar, Ismail Althagafi, Shally, Ranjay Shaw, Amr Elagamy, Chandan Shah,
Pratik Yadav, Ramendra Pratap
PII:
S0040-4020(20)30318-5
https://doi.org/10.1016/j.tet.2020.131183
TET 131183
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 31 January 2020
Revised Date: 20 March 2020
Accepted Date: 4 April 2020
Please cite this article as: Panwar R, Althagafi I, Shally , Shaw R, Elagamy A, Shah C, Yadav P, Pratap
R, Transition metal free synthesis of multifunctional thiomethylated-benzenes from aryl/heteroaryl/
cyclopropyl methyl ketones, Tetrahedron (2020), doi: https://doi.org/10.1016/j.tet.2020.131183.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition
of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of
record. This version will undergo additional copyediting, typesetting and review before it is published
in its final form, but we are providing this version to give early visibility of the article. Please note that,
during the production process, errors may be discovered which could affect the content, and all legal
disclaimers that apply to the journal pertain.
© 2020 Published by Elsevier Ltd.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Transition metal free synthesis of
multifunctional thiomethylated-benzenes
from aryl/heteroaryl/cyclopropyl methyl
ketones
Leave this area blank for abstract info.
Rahul Panwar,a Ismail Althagafi,b Shally, a Ranjay Shaw,a Amr Elagamy,a Chandan Shah,a Pratik Yadavc and
Ramendra Pratapa
aDepartment of Chemistry, University of Delhi, North campus, Delhi, India-110007
bDepartment of Chemistry, Umm Al-Qura University, Makkah, Saudi Arabia
cKirori Mal College, University of Delhi, Delhi, India-110007
Ar
CS2, CH3I
O
SCH3
SCH3
High yield
Mild condition
Easily accessible precursor
Groups can be modified further
Ar
SCH3
Ar
Ar
CH3
O
NC
Ar
CH3
NH2
O

1
Tetrahedron
journal homepage: www.elsevier.com
Transition metal free synthesis of multifunctional thiomethylated-benzenes
from aryl/heteroaryl/cyclopropyl methyl ketones
Rahul Panwar,a Ismail Althagafi,b Shally, a Ranjay Shaw,a Amr Elagamy,a Chandan Shah,a Pratik Yadav,c
and Ramendra Pratapa
aDepartment of Chemistry, University of Delhi, North campus, Delhi, India-110007
bDepartment of Chemistry, Umm Al-Qura University, Makkah, Saudi Arabia
c Kirori Mal College, University of Delhi, Delhi, India-110007
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A base-promoted strategic synthesis of various functionalized thiomethylated-benzenes has been
established from acetophenones and cyclopropyl methyl ketone. We can directly access the
thiomethylated-benzene nucleus embedded with diverse functional group by the reaction of 3,3-
bis(methylthio)-1-arylprop-2-en-1-ones and 2-(1-aryl/cyclopropyl)ethylidene)malononitriles in
the presence of sodium hydride in THF at reflux temperature. These precursors are easily
accessible from aryl methyl ketones. Various functional groups like alkyl, aryl, nitrile, amine,
aroyl and thiomethyl can be directly installed to the benzene ring. The one-pot approach for the
construction of thiomethylated-benzene nucleus was also developed. The structure of the
synthesized compound was confirmed by X-ray crystallography.
Available online
Keywords:
Benzenes
malononitrile
Base
2009 Elsevier Ltd. All rights reserved
.
Reflux
1. Introduction
three steps and unsaturated ketones as a carbon nucleophile to
assemble benzene core via a formal [3+3] cycloaddition
reaction.7a This strategy was further utilized by Wang et al.
via [4+2] benzannulation7b and Ye and coworkers via [2+4]
annulation7c approach and both starting from enals and
unsaturated ketones. In early 2015, Lupton et al. described
another intramolecular NHC catalyzed strategy for the
synthesis of functionalized benzaldehydes.7d Chi and
coworkers subsequently developed an elegant NHC catalyzed
Benzene ring installed with various important functional
groups is omnipresent and privileged structural motifs. They
are found in a variety of natural products, pharmaceutical
compounds, advanced functional materials and various
organic ligands used for metal catalyzed chemistry.1
Therefore, development of efficient and new synthetic
methods toward multi-substituted benzenes have been paid
tremendous attention during recent years. Over the years,
electrophilic and nucleophilic aromatic substitution,
benzannulation reactions,2 transition-metal catalyzed cross-
coupling reactions,3a aryne intermediates3b and arylation via
C-H activation,3c were used as powerful tools to construct the
multi-substituted arenes.
Previous work
R1
O
R
O
i)
R1
R2
R2
O
O
H
R
NHC
R'
+
R'
R1
ii)
R1
Apart from these strategies various approaches have been
developed to construct the functioned benzene directly from
suitable precursors. Various diketones and enones have been
studied for the construction of multifunctional benzenes
through selective transformations under transition metal-free
conditions.4 Benzannulation was also carried out by using
Rhodium and Indium catalyzed reaction of enaminones.5 Very
recently N-heterocyclic carbenes (NHC) have emerged as an
efficient organocatalytic method to construct various multi-
substituted benzenes. To achieve these transformations,
various α,β-unsaturated electron deficient alkenes were
activated using NHCs followed by addition of carbon
nucleophile in the presence of oxidant and base. In the first
R3
Ar
R2
R3
R2
Ar
KOH
DMF
+
ArCOCH3
O
O
Ar
O
This work
iii)
2
2
R
NC
R
CN
O
O
S
NH2
O
CS2, CH3I
CH3
Ar
SCH3
NC
Ar
0-5 o
C
Ar
NaH/THF
reflux
H3CS
R
Scheme 1: Previous approaches versus this approach to construction
functionalized benzenes
6
report, Chi and coworkers used enals, readily prepared in

2
Tetrahedron
domino reaction triggered by a δ-LUMO activation of α, β-γ,
Table 1: Effect of base and solvent on the synthesis of 3aa
δ-diunsaturated enal for the formal [4+2] construction of
multi-substituted benzenes (Scheme 1, entry i).8 Very
recently, transition metal-free assembly of the benzene
skeleton from enaminodiones was established through self-
condensation.8 A new Rh(III)-catalyzed approach for the
S
S
NH2
O
NC
CN
Base/Solvent
Temp
O
NC
SMe
construction
of
multifunctional
benzenes
through
Me
regioselective [4+2] C-annulation was developed.8 We have
also established various ring transformation reactions for the
construction of benzene nucleus by reaction of various
functionalized 2-pyranones and carbon nucleophiles (Scheme
1, entry ii).9
2a
Solvent T (°C)
3a
Me
1a
Entry Base
t (h)
Yield
(%) 3
c
1
NEt3
NEt3
DMSO
DMSO
RTb
12
12
12
12
12
12
12
12
12
12
6
-
c
2
70
-
c
3
NaNH2 DMSO
NaNH2 DMSO
NaNH2 DMSO
NaNH2 DMF
RTb
-
Due to importance of suitably functionalized benzene nucleus,
we became interested in the development of new base-
promoted approach for their synthesis (Scheme 1, entry iii).
Ketene dithioacetals are well known for the strong synthetic
potential10 so we have further explored their synthetic
potential.
4
70
30
35
35
30
36
40
32
95
42
5
100
6
100
7
KOtBu
KOH
NaH
DMSO
DMSO
DMSO
DMF
100
8
100
2. Result and discussion
9
100
10
11
12
13
14
15
NaH
100
To start our study, we have synthesized the required
precursors 3,3-bis(methylthio)-1-arylprop-2-en-1-ones and 2-
(1-aryl)ethylidene)malononitriles by using earlier reported
procedures. 3,3-Bis(methylthio)-1-arylprop-2-en-1-ones were
synthesized by the reaction of functionalized acetophenones,
carbon disulphide and methyl iodide under basic conditions.11
The other precursor 2-(1-aryl)ethylidene)malononitriles was
also synthesized by the reaction of alky/aryl methyl ketone
and malononitrile in the presene of glacial acetic acid and
ammonium acetate in toluene under reflux condition.12-14
NaH
THF
Reflux
Reflux
Reflux
Reflux
Reflux
NaNH2 THF
Cs2CO3 THF
12
12
12
12
c
-
KOH
KOtBu
THF
THF
55
45
a] all reactions were performed by stirring 3,3-bis(methylthio)-1-phenylprop-
2-en-1-one (0.5 mmol), 2-(1-(p-tolyl)ethylidene)malononitrile (0.5 mmol)
and base (0.6 mmol) in solvent (5.0 mL) at different temperature; (b) Room
temperature was ranging from 30-35 oC, (c) both starting material left
unconsumed during the reaction.
CN
MeS
O
SMe
O
NC
Ar
CN
CS2,CH3I
CN
Ar
NaH/THF
0 oC
NH4OAc
Ar
2
1
Scheme 2: Synthesis of precursors 3,3-bis(methylthio)-1-arylprop-2-en-1-
ones (1) and 2-(1-aryl)ethylidene)malononitriles (2) [Compound 1 was
synthesized by stirring aryl methyl ketone (10.0 mmol), carbon disulphide (11
mmol), methyl iodide (20.0 mmol) and NaH (30.0 mmol) in dry THF (50.0
ml) at 0 oC; Compound 2 was synthesized by stirring malononitrile (48.0
mmol), ammonium acetate (9.60 mmol) and ketone (48.0 mmol) and acetic
acid (52.8 mmol) in toluene (30.0 ml) at reflux temperature]
NC
NH2
SMe
NC
NH2
SMe
NC
R2
NH2
SMe
O
R
H3C
R1
O
O
3a) R1= C6H5; 95%
3b) R1= 3-Br.C6H4; 87%
3j) R= H; 85%
3k) R= F; 89%
3l) R= Cl; 74%
3m) R= Br; 72%
3n) R= CH3O; 91%
3o) R= CH3; 77%
3p) R= C6H5;78%
3q) R2= 2,4-Cl2.C6H3; 68%
3r) R2= 3-Br.C6H4; 78%
3s) R2= 1-Naphthyl; 45%
3t) R2= 2-Naphthyl; 48%
3u) 3,4-(CH3O)2.C6H3; 78%
In order to optimize the reaction condition 3,3-
3c) R1= 4-CH3.C6H4; 86%
3d) R1= 4-CH3O.C6H4; 68%
3e) R1= 2-CH3O.C6H4; 95%
3f) R1= 1-Naphthyl; 52%
3g) R1= 3,4-(CH3O)2.C6H3; 64%
3h) R1= 2-furyl; 78%
bis(methylthio)-1-phenylprop-2-en-1-one
and
2-(1-(p-
tolyl)ethylidene)malononitrile was selected as model substrate.
We started the study using triethyl amine in DMSO at room
o
temperature and 70 C, but no product formation was observed
(Table 1, entries 1 and 2). Further trial was made by using
3i)R1=2-Thienyl; 80%
o
sodamide as base in DMSO at room temperature, 70 C and 100
oC and 30-35% product was obtained at higher temperature
(Table 1, entries 3-5). Then, we performed the reaction using
Scheme 3: Synthesis of various arylated benzenes 3 [Reactions were
performed by stirring 3,3-bis(methylthio)-1-arylprop-2-en-1-one ( 0.5 mmol),
2-(1-aryl)ethylidene)malononitrile (0.5 mmol) and sodium hydride (0.6
mmol) in THF (5.0 mL) at reflux temperature]
o
sodamide in DMF at 100 C and 35% of product was isolated
(Table 1, entry 6). We used potassium tert.-butoxide and KOH at
o
100 C and 30-36% product was formed (Table 1, entries 7,8).
Then, we used sodium hydride in DMSO and DMF at 100 oC and
40 and 32% product was isolated respectively (Table 1, entries 9
and 10). When reaction was performed in THF using sodium
hydride at reflux temperature, surprisingly 95% product was
isolated (Table 1, entry 11). We proposed that due to high
polarity of DMF, sodium hydride act as stronger base and cause
decomposition of precursor and therefore low yield was obtained
in DMF. From the entry 11, we concluded that THF act as the
best solvent for this reaction so tested the reactivity of some
other bases in THF, such as sodamide, cesium carbonate,
KOH and KOtBu but none of them provided better results
than sodium hydride (Table 1, entries 12-15). Thus, reaction
of 1 and 2 in THF in the presence of sodium hydride at reflux

3
temperature provides the desired product in high yield and is
In order to perform the reaction at gram scale we have tried
the best reaction condition.
to synthesize compound 3a. Surprisingly, we need to replace
the base from NaH to KOH under similar reaction conditions,
but lower yield 54% was obtained. We proposed that
powdered KOH had better solubility than sodium hydride in
THF and therefore at large scale KOH works better but low
yield was obtained.
Then, we tested the generality of optimized reaction condition
and performed the reaction using 2-(1-p-tolyl-ethylidene)-
malononitrile and various ketene dithioacetals containing
differently functionalized aryl group and afforded the arylated
benzene in 52-95% yield. The presence of different functional
group in aryl ring of ketene dithioacetal affects the yield of
the product, but does not follow any specific trends. 3,3-
Bismethylsulfanyl-1-(pyridine/thiophen/furan-2-yl)-
Interestingly,
the
use
of
1-(halophenyl)-3,3
bismethylsulfanylpropenones as a precursor, provided the
product 5 in which halide group was replaced with the
methylthio group in addition to desired product (Scheme 4). If
we increase the duration of reaction, yield of product 5
increased. Mechanistically, compound 4 can be converted in 5
through ipso attack by in situ generated methylthio group at
position containing halide group followed by loss of halide to
afford the product 5.
propenones were also used as a precursor and good yields of
the desired product was isolated.
Further, treatment of 3, 3-bis-methylsulfanyl-1-phenyl-
propenone with differently functionalized 2-(1-aryl-
ethylidene)-malononitriles afforded the functionalized
benzenes in good yields. From these reactions, we observed
that presence of different functional group in aryl ring of 2-(1-
aryl-ethylidene)-malononitriles have no significant effect on
the yield of product under basic conditions. Apart from this,
we tested many other combinations of ketene dithioacetals
and 2-(1-aryl-ethylidene)-malononitriles under the same
reaction conditions and all of them provide the desired
product in moderate to good yields. It was interesting to note
that presence of naphthyl group in either starting materials
provides a lower yield probably due to electronic effect of
naphthyl ring.
To expand the scope of the reaction, we further synthesized
heteroaryl substituted benzenes. We have synthesized the
benzene functionalized with furan and thiophene in good
yield by using 2-(1-heteroaryl)ethylidene)malononitriles as a
precursor (Scheme 5).
We also planned to synthesize alkylated benzenes, but failed
due to low yields of corresponding alkylidine malononitrile
and various side reactions under basic conditions.
Interestingly, we have synthesized 2-(1-cyclopropyl-
ethylidene)-malononitrile as a precursor and used it for further
cyclization reaction. Treatment of ketene dithioacetal with 2-
(1-cyclopropyl-ethylidene)-malononitrile
under
basic
condition afforded cyclopropyl functionalized benzene in
good yields (Scheme 6). We observed low yield of the desired
product probably due to side reaction occurred under basic
conditions, such as abstraction of protons from cyclopropyl
ring or ring opening reaction. The cyclopropyl group can be
used for further modification to develop new molecular
entities.
NH2
O
MeS
O
SMe
NC
CN
NC
NaH, THF
Reflux
R1
SMe
Scheme 4: Synthesis of various arylated benzene using 1-(halophenyl)-3,3-
bismethylsulfanylpropenones.[Reactions were performed by stirring 3,3-
bis(methylthio)-1-arylprop-2-en-1-one (0.5 mmol), 2-(1-aryl)ethylidene)-
malononitrile (0.5 mmol) and sodium hydride (0.6 mmol) in THF (5.0 mL) at
reflux temperature]
R1
7
8
1
NH2
O
NH2
O
NH2
O
O
NC
NC
NC
Ar2
CN
Ar1
MeS
NC
NaH/THF
Reflux
Ar2
SMe
SMe
SMe
8a; 59%
Ar1
SMe
8b; 62%
2
6
1
NH2
O
NH2
O
NC
S
NC
O
NH2
O
NH2
O
NC
OMe
OMe
SMe
6b;76%
SMe
6a;84%
NC
SMe
8d; 50%
SMe
OMe
NH2
O
NH2
O
NC
O
NC
8c; 56%
SMe
O
Scheme 6: Synthesis of 2-amino-3-(arylcarbonyl)-6-cyclopropyl-4-
SMe
O
CH3
(methylthio)benzonitriles
S
CH3
6c;74%
6d;72%
In continuation, we became interested to develop the one-pot
approach for the synthesis of functionalized benzenes. In this
trial, we first performed the synthesis of ketene dithioacetal
by stirring the acetophenone, carbon disulphide and methyl
Scheme 5: Synthesis of various heteroaryl substituted benzenes 6.[Reactions
were performed by stirring 3,3-bis(methylthio)-1-arylprop-2-en-1-ones ( 0.5
mmol), 2-(1-aryl)ethylidene)malononitriles (0.5 mmol) and sodium hydride
(0.6 mmol) in THF (5.0 mL) at reflux temperature.]

4
Tetrahedron
3. X-ray structural analysis
iodide under basic condition. Formation of ketene
dithioacetal was monitored by TLC. Then 2-(1-
arylethylidene)-malononitriles and additional base was added
to the same pot and the reaction mixture was refluxed until the
reaction was completed. Usual work-up afforded the
functionalized benzenes in good yield. We have synthesized
some of the functionalized benzene in overall good yields
(Scheme 7).
The structure of the product 3a was confirmed by X-ray
crystallography (Fig. 1).15 Compound 3a was crystallized in
P-1 space group and contains two molecules in the triclinic
unit cell. Both the phenyl ring of biaryl was not in the same
plane. Both aryl rings of biaryl are planar and the dihedral
angle between the planes 34.69°.
MeS
O
SMe
NC
Ar
CN
O
NH2
O
CS2,CH3I
NC
Ar
NaH/THF
0oC
NaH/THF
Reflux
SMe
3
2
3a) Ar = p-Me.C6H4 = 67%
3l) Ar= C6H5; 70%
3m) Ar= 4-F.C6H4; 69%
3p) Ar= 4-CH3O.C6H4; 62%
3r) Ar = 4-Ph.C6H4 = 63%
Scheme 7: One-pot synthesis of highly functionalized benzenes
Fig.
1
Ortep diagram of 3-amino-4-benzoyl-4'-methyl-5-
methylsulfanyl-biphenyl-2-carbonitrile
Mechanistically, we propose that reaction is initiated by
Michael addition of carbanion generated from 2-(1-aryl-
ethylidene)-malononitrile on ketene dithioacetal 1 followed
by elimination of methanethiol to afford the intermediate A.
Further, in the presence of excess of base, carbanion
generated from intermediate A undergoes isomerization to
Conclusions
In summary, we have developed a simple and efficient
approach for the synthesis of highly functionalized
thiomethylated-benzenes under basic condition. Atom
economy of the reported reaction is very high. Various
functional groups such as aryl, heteroaryl, aroyl, heteroaroyl,
cyclopropyl, amino and nitrile group can be incorporated into
the benzene nucleus. This reaction does not require any
transition metal catalysts. We also successfully achieved one-
pot synthesis of functionalized thiomethylated-benzene from
acetophenones. We tried to understand the mechanistic
pathway, but not able to isolate the intermediate. All the
synthesized compounds are characterized by spectroscopic
techniques and one structure was confirmed by single crystal
X-ray.
afford intermediate enolate B. Enolate
B
undergoes
cyclization by involvement of nitrile group and carbon present
at α-position to a carbonyl group to provide intermediate C.
Intermediate C undergoes tautomerization to provide the
desired product.
To probe the mechanistic pathway, we tried to isolate the
intermediate A. For this purpose, we performed the reaction
under similar condition using low concentrations of base, but
only desired product 3 was isolated with the left starting
material. This result demonstrates that intermediate A
immediately converted to product due to presence of more
activated proton than compound 2.
Experimental section
O
General remarks: All the reactions were performed by using
commercially available reagents without any further purification.
The sodium hydride (60% dispered in oil) was washed with hexanes
to remove the oil before use. THF was dried over sodium under
K
O
NC
Ar1
CN
NC
Ar1
CN
CN
Ar2
Ar2
NaH
S
NC
Ar1
S
S
S
2
1
nitrogen atmosphere. H and 13C NMR spectra were recorded on a
1
-SCH3
O
400 MHz NMR and 100 MHz NMR spectrometer. To perform the
NMR spectroscopy, CDCl3 was used as solvent. Chemical shifts
values are reported as parts per million (δ-value) and for proton
NMR peak of CDCl3 (δ = 7.24 ppm for 1H) or the middle peak of the
CDCl3 in 13C NMR (δ 77.00 ppm) was used as an internal reference.
Characterization data shows signal patterns as s, singlet; d, doublet;
dd, double doublet; t, triplet; bs, broad singlet; m, multiplets.
Coupling constants (J) are given in hertz (Hz). During the period of
reaction, room temperature was ranging from 30-35 °C.
O
N
O K
Ar2
NC
Ar1
CN
NC
Ar1
C
Ar2
NC
Ar1
CN
Ar2
NaH
S
S
S
A
K
B
+H+
NH
O
NH2
O
NC
Ar1
NC
Ar1
Ar2
Ar2
SMe
H
General procedure for the synthesis of 3,3-bis(methylthio)-1-
arylprop-2-en-1-ones: To a vacuum dried RB flask sodium hydride
(30.0 mmol) was taken in dry THF (50.0 ml) and cooled to 0 oC over
ice bath. Then aryl methyl ketone (10.0 mmol) was added drop-wise
with constant stirring until the solution at low temperature. Reaction
mixture was stirred for 30 minutes. Then carbon disulphide (11
mmol) was added slowly and the mixture was again stirred for one
hour. Further, methyl iodide (20.0 mmol) was added drop-wise at 0
oC. Then reaction mixture was stirred for another 1 hour at room
SMe
3
C
Scheme 8: Proposed mechanistic pathway for the synthesis of highly
functionalized thiomethylated-benzenes

5
temperature. After completion of the reaction, excess of THF was
removed under reduced pressure and ice was added to the reaction
mixture and obtained precipitate was filtered, dried and recrystallized
with cold hexane to isolate the desired product.10,11
same mixture. The reaction bath was transferred to oil bath and
refluxed till completion of the reaction. After completion of reaction,
excess of THF was removed under reduced pressure followed by
addition of ice water. Reaction mixture was neutralized by dilute
HCl and obtained precipitate was filtered and dried. The crude
product was purified on silica gel column chromatography by using
20% EtOAc in hexane as an eluent.
General procedure for the synthesis of 2-(1-arylethylidene)-
malononitriles: To a vacuum dried RB flask malononitrile (3.17 g,
48.0 mmol, 1 equiv), ammonium acetate (0.740 g, 9.60 mmol, 0.2
equiv) and ketone (48.0 mmol, 1 equiv) was added. To the mixture
acetic acid (3.0 ml, 52.8 mmol, 1.1 equiv) and toluene (30.0 ml) was
added. The round-bottom was fitted with a Dean-Stark apparatus and
reaction mixture was refluxed for 1-2 h. The reaction mixture was
cooled to room temperature and diluted with toluene (50.0 mL). The
organic layer was washed with saturated sodium bicarbonate solution
(50.0 mLx3) and water (50.0 mLx2). The organic layer was dried
with MgSO4 and concentrated under vacuum and resulting solid was
recrystallized in ethanol to isolate the compound.12-14
3-Amino-4-benzoyl-4'-methyl-5-(methylthio)-[1,1'-biphenyl]-
2-carbonitrile (3a): To a vacuum dried RB flask 3,3-bis(methylthio)-
1-phenylprop-2-en-1-one (0.5 mmol, 0.112 g) and 2-(1-(p-
tolyl)ethylidene)malononitrile (0.5 mmol, 0.091 g) was placed. Then
sodium hydride (0.6 mmol, 0.0144 g) was added, followed by addition
of THF (5.0 ml). The reaction mixture was refluxed for 6 hours. After
completion of the reaction, excess of THF was removed under reduced
pressure followed by the addition of ice water. Reaction mixture was
neutralized by diluting HCl and obtained precipitate was filtered and
dried. The crude product was purified on silica gel column
chromatography by using 20% EtOAc in hexane as an eluent. Yield
95% (170 mg); light yellow solid; mp 150-152 °C; IR (KBr): 3395,
2210, 1645 cm-1; 1H NMR (400 MHz, CDCl3): δ 2.36 (s, 3H, -SMe),
2.43 (s, 3H, -CH3), 4.89 (s, 2H, -NH2), 6.69 (s, 1H, ArH), 7.31 (d, J
= 8 Hz, 2H, ArH), 7.49 (t, J = 8 Hz, 4H, ArH), 7.62-7.66 (m, 1H,
ArH), 7.87 (d, J = 8 Hz, 2H, ArH); 13C NMR (100 MHz, CDCl3): δ
16.5, 21.3, 93.9, 115.9, 117.1, 120.9, 128.3, 128.9, 129.4, 129.6,
134.2, 135.2, 137.0, 139.2, 144.8, 147.2, 148.4, 196.5. HRMS (ESI):
calculated for C22H19N2OS, 359.1213 (MH+), found: m/z, 359.1214.
General procedure for the synthesis of multifunctional
benzenes: To a vacuum dried RB flask 3,3-bis(methylthio)-1-
arylprop-2-en-1-ones
(0.5
mmol)
and
2-(1-
aryl)ethylidene)malononitriles (0.5 mmol) was placed. Then sodium
hydride (0.6 mmol) was added followed by addition of THF (5.0
mL). The reaction mixture was refluxed till completion of the
reaction. After completion of reaction, excess of THF was removed
under reduced pressure followed by addition of ice water. Reaction
mixture was neutralized by dilute HCl and obtained precipitate was
filtered and dried. The crude product was purified on silica gel
column chromatography by using 20% EtOAc in hexane as an
eluent.
3-Amino-4-(3-bromobenzoyl)-4'-methyl-5-(methylthio)-[1,1'-
biphenyl]-2-carbonitrile (3b): To a vacuum dried RB flask 1-(3-
bromophenyl)-3,3-bis(methylthio)prop-2-en-1-one (0.5 mmol, 0.151 g)
and 2-(1-(p-tolyl)ethylidene)malononitrile (0.5 mmol, 0.091 g) was
placed. Then sodium hydride (0.6 mmol, 0.0144 g) was added,
followed by addition of THF (5.0 ml). The reaction mixture was
refluxed till completion of the reaction. After completion of the
reaction, excess of THF was removed under reduced pressure followed
by the addition of ice water. Reaction mixture was neutralized by
diluting HCl and obtained precipitate was filtered and dried. The crude
product was purified on silica gel column chromatography by using
20% EtOAc in hexane as an eluent. Yield 87% (190 mg); light yellow
General procedure for the synthesis of multifunctional
cyclopropylated benzenes: To a vacuum dried RB flask 3,3-
bis(methylthio)-1-arylprop-2-en-1-ones (0.5 mmol) and 2-(1-
cyclopropylethylidene)malononitrile (0.5 mmol) was placed. Then
sodium hydride (1.0 mmol) was added, followed by addition of THF
(5.0 ml). The reaction mixture was refluxed till completion of the
reaction. After completion of the reaction, excess of THF was
removed under reduced pressure followed by the addition of ice
water. Reaction mixture was neutralized by diluting HCl and
obtained precipitate was filtered and dried. The crude product was
purified on silica gel column chromatography by using 20% EtOAc
in hexane as an eluent.
solid; mp: 148-150 °C; IR (KBr): 3471, 2208, 1691 cm-1; H NMR
1
(400 MHz, CDCl3): δ 2.37 (s, 3H, -SMe), 2.43 (s, 3H, -CH3), 5.00 (s,
2H, -NH2), 6.69 (s, 1H, ArH), 7.31-7.33 (m, 2H, ArH), 7.36 (t, J = 8
Hz, 1H, ArH), 7.49 (d, J = 8 Hz, 2H, ArH), 7.73-7.76 (m, 2H, ArH),
7.98-7.99 (m, 1H, ArH); 13C NMR (100 MHz, CDCl3): δ 16.6, 21.3,
94.1, 116.1, 117.0, 119.9, 123.1, 128.1, 128.3, 129.5, 130.4, 132.1,
135.0, 136.8, 139.1, 139.3, 145.0, 147.6, 148.7, 195.2. HRMS (ESI):
calculated for C22H18BrN2OS, 437.0318, (MH++2); found: m/z,
439.0326.
General procedure for the gram scale synthesis of
multifunctional benzenes: To a vacuum dried 100 ml RB flask 3,3-
bis(methylthio)-1-phenylprop-2-en-1-one (6.0 mmol) and 2-(1-(p-
tolyl)ethylidene)malononitrile (6.0 mmol) was placed. Then
potassium hydroxide (9.0 mmol) was added, followed by addition of
THF (60 ml). The reaction mixture was refluxed till completion of
the reaction. After completion of the reaction, excess of THF was
removed under reduced pressure followed by the addition of ice
water. Reaction mixture was neutralized by diluting HCl and
obtained precipitate was filtered and dried. The crude product was
purified on silica gel column chromatography by using 20% EtOAc
in hexane as an eluent.
3-Amino-4'-methyl-4-(4-methylbenzoyl)-5-(methylthio)-[1,1'-
biphenyl]-2-carbonitrile (3c): To a vacuum dried RB flask 3,3-
bis(methylthio)-1-(p-tolyl)prop-2-en-1-one (0.5 mmol, 0.119 g) and 2-
(1-(p-tolyl)ethylidene)malononitrile (0.5 mmol, 0.091 g) was placed.
Then sodium hydride (0.6 mmol, 0.0144 g) was added, followed by
addition of THF (5.0 ml). The reaction mixture was refluxed till
completion of the reaction. After completion of the reaction, excess of
THF was removed under reduced pressure followed by the addition of
ice water. Reaction mixture was neutralized by diluting HCl and
obtained precipitate was filtered and dried. The crude product was
purified on silica gel column chromatography by using 20% EtOAc in
hexane as an eluent. Yield 86% (160 mg); light yellow solid; mp:
General procedure for one-pot synthesis of multifunctional
benzenes (3): To a vacuum dried RB flask sodium hydride (3.0
o
mmol) was taken in dry THF (10.0 mL) and cooled to 0 C over the
ice bath. Then aryl methyl ketone (1.0 mmol) was added drop-wise
o
with constant stirring to the solution at 0 C. Reaction mixture was
stirred for 10 minutes. Then carbon disulphide (1.1 mmol) was added
slowly and mixture was again stirred for half hours. Then methyl
iodide (2.0 mmol) was added drop-wise at 0 oC and reaction mixture
was stirred for another hour at room temperature. Completion of
reaction was monitored by TLC and then sodium hydride (1.0 mmol)
and 2-(1-aryl)ethylidene)malononitriles (1.0 mmol) was added to the
170-172 °C; IR (KBr): 3427, 2208, 1698 cm-1; H NMR (400 MHz,
1
CDCl3): δ 2.35 (s, 3H, -SMe), 2.41 (s, 3H, -CH3), 2.42 (s, 3H, -CH3),
4.79 (s, 2H, -NH2), 6.66 (s, 1H, ArH), 7.28 (t, J = 8 Hz, 4H, ArH ),
7.46 (d, J = 8 Hz, 2H, ArH), 7.76 (d, J = 8 Hz, 2H, ArH); 13C NMR
(100 MHz, CDCl3): δ 16.4, 21.3, 21.9, 93.8, 115.9, 117.2, 121.3,

6
Tetrahedron
128.3, 129.4, 129.7, 129.8, 134.3, 135.3, 139.2, 144.5, 145.5,
148.4, 196.3. HRMS (ESI): calculated for C26H21N2OS, 409.1369
147.0, 148.1, 196.0. HRMS (ESI): calculated for C23H21N2OS,
(MH+); found: m/z, 409.1361.
373.1369 (MH+); found: m/z, 373.1367.
3-Amino-4-(3,4-dimethoxybenzoyl)-4'-methyl-5-(methylthio)-
[1,1'-biphenyl]-2-carbonitrile (3g): To a vacuum dried RB flask 1-
(3,4-dimethoxyphenyl)-3,3-bis(methylthio)prop-2-en-1-one (0.5 mmol,
0.142 g) and 2-(1-(p-tolyl)ethylidene)malononitrile (0.5 mmol, 0.091 g)
was placed. Then sodium hydride (0.6 mmol, 0.0144 g) was added,
followed by addition of THF (5.0 ml). The reaction mixture was refluxed
till completion of the reaction. After completion of the reaction, excess of
THF was removed under reduced pressure followed by the addition of
ice water. Reaction mixture was neutralized by diluting HCl and
obtained precipitate was filtered and dried. The crude product was
purified on silica gel column chromatography by using 20% EtOAc in
hexane as an eluent. Yield 64% (134 mg); light yellow solid, mp: 155-
3-Amino-4'-methoxy-4-(4-methylbenzoyl)-5-(methylthio)-
[1,1'-biphenyl]-2-carbonitrile (3d): To a vacuum dried RB flask 1-
(4-methoxyphenyl)-3,3-bis(methylthio)prop-2-en-1-one (0.5 mmol,
0.127 g) and 2-(1-(p-tolyl)ethylidene)malononitrile (0.5 mmol, 0.091
g) was placed. Then sodium hydride (0.6 mmol, 0.0144 g) was added,
followed by addition of THF (5.0 ml). The reaction mixture was
refluxed till completion of the reaction. After completion of the
reaction, excess of THF was removed under reduced pressure followed
by the addition of ice water. Reaction mixture was neutralized by
diluting HCl and obtained precipitate was filtered and dried. The crude
product was purified on silica gel column chromatography by using
20% EtOAc in hexane as an eluent. Yield 68% (132 mg); light yellow
1
157 °C; IR (KBr): 3322, 2210, 11698 cm-1; H NMR (400 MHz,
1
solid; mp: 165-167 °C; IR (KBr): 3369, 2210, 1728 cm-1; H NMR
CDCl3): δ 2.32 (s, 3H, -SMe), 2.46 (s, 3H, -CH3), 3.89 (s, 3H, -
OMe), 3.97 (s, 3H, -OMe), 6.82 (s, 1H, ArH), 6.85-6.87 (m, 1H,
ArH), 6.92-6.94 (m, 1H, ArH), 7.14 (d, J = 4 Hz, 2H, ArH), 7.35 (d,
J = 12 Hz, 2H, ArH), 7.61 (d, J = 8 Hz, 1H, ArH); 13C NMR (100
MHz, CDCl3): δ 17.7, 21.3, 55.9, 56.0, 105.9, 110.6, 112.9, 121.6,
121.9, 122.1, 123.6, 128.8, 129.5, 131.7, 135.3, 139.2, 147.2, 147.4,
148.5 149.5, 149.7, 161.8. HRMS (ESI): calculated for
C24H23N2O3S, 419.1424 (MH+); found: m/z, 419.1423.
(400 MHz, CDCl3): δ 2.38 (s, 3H, -SMe), 2.43 (s, 3H, -CH3), 3.89 (s,
3H, -OMe), 4.77 (s, 2H, -NH2), 6.68 (s, 1H, ArH), 6.95-7.00 (m, 2H,
ArH), 7.25-7.32 (m, 2H, ArH), 7.46- 7.50 (m, 2H, ArH), 7.86-7.88,
(m, 2H, ArH); 13C NMR (100 MHz, CDCl3): δ 16.2, 21.3, 55.6, 93.7,
114.2, 115.7, 117.2, 128.3, 129.4, 129.6, 129.7, 132.2, 135.3, 139.1,
144.3, 146.8, 148.0, 164.6, 194.6. HRMS (ESI): calculated for
C23H21N2O2S, 389.1318 (MH+); found: m/z, 389.1326.
3-Amino-4-(2-methoxybenzoyl)-4'-methyl-5-(methylthio)-[1,1'-
biphenyl]-2-carbonitrile (3e): To a vacuum dried RB flask 1-(2-
methoxyphenyl)-3,3-bis(methylthio)prop-2-en-1-one (0.5 mmol, 0.127
g) and 2-(1-(p-tolyl)ethylidene)malononitrile (0.5 mmol, 0.091 g) was
placed. Then sodium hydride (0.6 mmol, 0.0144 g) was added,
followed by addition of THF (5.0 ml). The reaction mixture was
refluxed till completion of the reaction. After completion of the
reaction, excess of THF was removed under reduced pressure followed
by the addition of ice water. Reaction mixture was neutralized by
diluting HCl and obtained precipitate was filtered and dried. The crude
product was purified on silica gel column chromatography by using
3-Amino-4-(furan-2-carbonyl)-4'-methyl-5-(methylthio)-[1,1'-
biphenyl]-2-carbonitrile (3h): In a vacuum dried RB flask 1-(furan-
2-yl)-3,3-bis(methylthio)prop-2-en-1-one (0.5 mmol, 0.107 g) and 2-
(1-(p-tolyl)ethylidene)malononitrile (0.5 mmol, 0.091 g) was placed.
Then sodium hydride (0.6 mmol, 0.0144 g) was added, followed by
addition of THF (5.0 ml). The reaction mixture was refluxed till
completion of the reaction. After completion of the reaction, excess of
THF was removed under reduced pressure followed by the addition of
ice water. Reaction mixture was neutralized by diluting HCl and
obtained precipitate was filtered and dried. The crude product was
purified on silica gel column chromatography by using 20% EtOAc in
hexane as an eluent. Yield 78% (136 mg); light yellow solid, mp:
20% EtOAc in hexane as an eluent. Yield 95% (184 mg); light yellow
1
1
solid; mp: 180-182 °C; IR (KBr): 3359, 2208, 1726 cm-1; H NMR
(400 MHz, CDCl3): δ 2.29 (s, 3H, -SMe), 2.40 (s, 3H, -SMe), 3.78
(s, 3H, -OMe), 5.46 (s, 2H, -NH2), 6.57 (s, 1H, ArH), 6.95 (d, J = 8
Hz, 1H, ArH), 7. 00 (t, J = 8Hz, 1H, ArH), 7.27 (d, J = 8 Hz, 2H,
ArH), 7.44-7.57 (m, 4H, ArH). 13C NMR (100 MHz, CDCl3): δ 16.7,
21.2, 56.4, 93.6, 112.0, 115.5, 120.7, 121.9, 128.2, 128.7, 129.3,
130.8, 131.2, 132.4, 134.3, 135.3, 139.2, 147.2, 149.5, 159.0, 195.4.
HRMS (ESI): calculated for C23H21N2O2S, 389.1318 (MH+); found:
m/z, 389.1326.
160-162 °C; IR (KBr): 3561, 3459, 2210, 1665 cm-1; H NMR (400
MHz, CDCl3): δ 2.42 (s, 6H, -SMe, -CH3), 4.93 (s, 2H, -NH2), 6.60-
6.61 (m, 1H, ArH), 6.70 (s, 1H, ArH),7.23-7.30 (m, 1H, ArH), 7.31
(d, J = 8 Hz, 2H, ArH), 7.47 (d, J = 8 Hz, 2H, ArH), 7.70 (s, 1H,
ArH); 13C NMR (100 MHz, CDCl3): δ 16.7, 21.3, 94.0, 113.0, 116.5,
117.0, 120.5, 121.4, 128.3, 129.4, 135.2, 139.3, 145.0, 147.5, 148.2,
148.4, 152.4, 182.7. HRMS (ESI): calculated for C20H17N2O2S,
349.1005 (MH+); found: m/z, 349.1008.
3-Amino-4'-methyl-5-(methylthio)-4-(thiophene-2-carbonyl)-
[1,1'-biphenyl]-2-carbonitrile (3i): To a vacuum dried RB flask
3,3-bis(methylthio)-1-(thiophen-2-yl)prop-2-en-1-one (0.5 mmol,
0.115 g) and 2-(1-(p-tolyl)ethylidene)malononitrile (0.5 mmol, 0.091
g) was placed. Then sodium hydride (0.6 mmol, 0.0144 g) was
added, followed by addition of THF (5.0 ml). The reaction mixture
was refluxed till completion of the reaction. After completion of the
reaction, excess of THF was removed under reduced pressure
followed by the addition of ice water. Reaction mixture was
neutralized by diluting HCl and obtained precipitate was filtered and
dried. The crude product was purified on silica gel column
chromatography by using 20% EtOAc in hexane as an eluent. Yield
80% (146 mg); light yellow solid, mp: 165-167 °C; IR (KBr): 3473,
2208, 1612 cm-1; 1H NMR (400 MHz, CDCl3): δ 2.41 (s, 3H, -SMe),
2.43 (s, 3H, -CH3), 4.80 (s, 2H, -NH2), 6.70 (s, 1H, ArH), 7.15 (t, J
= 8 Hz, 1H, ArH), 7.31(d, J = 8 Hz, 2H, ArH), 7.47 (d, J = 8 Hz,
2H, ArH), 7.61-7.62 (m, 1H, ArH), 7.79-7.80 (m, 1H, ArH); 13C
NMR (100 MHz, CDCl3): δ 16.5, 21.3, 93.9, 116.1, 117.0, 121.6,
128.3, 128.6, 129.4, 129.5, 135.2, 135.8, 136.4, 139.2, 143.6, 144.3,
147.147.8, 187.9. HRMS (ESI): calculated for C20H17N2OS2,
365.0777 (MH+); found: m/z, 365.0775.
4-(1-Naphthoyl)-3-amino-4'-methyl-5-(methylthio)-[1,1'-
biphenyl]-2-carbonitrile (3f): To a vacuum dried RB flask 3,3-
bis(methylthio)-1-(naphthalen-1-yl)prop-2-en-1-one (0.5 mmol, 0.137
g) and 2-(1-(p-tolyl)ethylidene)malononitrile (0.5 mmol, 0.091 g) was
placed. Then sodium hydride (0.6 mmol, 0.0144 g) was added,
followed by addition of THF (5.0 ml). The reaction mixture was
refluxed till completion of the reaction. After completion of the
reaction, excess of THF was removed under reduced pressure followed
by the addition of ice water. Reaction mixture was neutralized by
diluting HCl and obtained precipitate was filtered and dried. The crude
product was purified on silica gel column chromatography by using
20% EtOAc in hexane as an eluent. Yield 53% (108 mg); light yellow
solid, mp: 175-177 °C; IR (KBr): 3469, 2208, 1660 cm-1; H NMR
1
(400 MHz, CDCl3): δ 2.31 (s, 3H, -SMe), 2.42 (s, 3H, -CH3), 4.94 (s,
2H, -NH2), 6.71 (s, 1H, ArH), 7.30 (d, J = 8 Hz, 2H, ArH ), 7.49-
7.55 (m, 3H, ArH), 7.61 (t, J = 8Hz, 1H, ArH), 7.87-7.99 (m, 4H,
ArH), 8.31 (s, 1H, ArH); 13C NMR (100 MHz, CDCl3): δ 16.4, 21.3,
93.8, 115.9, 117.1, 121.0, 124.2, 126.9, 127.8, 128.3, 128.9, 129.0,
129.4, 129.8, 132.2, 132.5, 134.2, 135.2, 136.5, 139.2, 144.8, 147.1,

7
3-Amino-4-benzoyl-5-(methylthio)-[1,1'-biphenyl]-2-carbonitrile
(3j): To vacuum dried RB flask 3,3-bis(methylthio)-1-
followed by addition of THF (5.0 ml). The reaction mixture was
a
refluxed till completion of the reaction. After completion of the
reaction, excess of THF was removed under reduced pressure followed
by the addition of ice water. Reaction mixture was neutralized by
diluting HCl and obtained precipitate was filtered and dried. The crude
product was purified on silica gel column chromatography by using
20% EtOAc in hexane as an eluent. Yield 72% (152 mg); light yellow
phenylprop-2-en-1-one (0.5 mmol, 0.112 g) and 2-(1-
phenylethylidene)malononitrile (0.5 mmol, 0.084 g) was placed.
Then sodium hydride (0.6 mmol, 0.0144 g) was added, followed by
addition of THF (5.0 ml). The reaction mixture was refluxed till
completion of the reaction. After completion of the reaction, excess
of THF was removed under reduced pressure followed by the
addition of ice water. Reaction mixture was neutralized by diluting
HCl and obtained precipitate was filtered and dried. The crude
product was purified on silica gel column chromatography by using
20% EtOAc in hexane as an eluent. Yield 85% (146 mg); light
solid, mp: 170-172 °C; IR (KBr): 3409, 2208, 1635 cm-1; H NMR
1
(400 MHz, CDCl3): δ 2.41 (s, 3H, -SMe), 4.89 (s, 2H, -NH2), 6.66 (s,
1H, ArH), 7.36-7.40 (m, 1H, -ArH), 7.47-7.54 (m, 4H, ArH), 7.60-
7.62 (m, 1H, ArH), 7.65-7.69 (m, 1H, ArH), 7.87 (d, J = 8 Hz, 2H,
ArH); 13C NMR (100 MHz, CDCl3): δ 16.4, 93.7, 115.8, 121.6,
122.8, 127.2, 129.0, 129.6, 130.3, 131.3, 132.1, 134.4, 140.1, 145.1,
145.4, 148.3, 196.3. HRMS (ESI): calculated for C21H16BrN2OS,
423.01461 (MH++2); found: m/z, 425.01459.
1
yellow solid, mp: 140-142 °C; IR (KBr): 3345, 2210, 1625 cm-1; H
NMR (400 MHz, CDCl3): δ 2.37 (s, 3H, -SMe), 4.89 (s, 2H, -NH2),
6.70 (s, 1H, ArH), 7.43-7.55 (m, 5H, ArH), 7.57-7.59 (m, 2H, ArH),
7.62-7.66 (m, 1H, ArH), 7.88 (d, J = 8 Hz, 2H, ArH); 13C NMR (100
MHz, CDCl3): δ 16.6, 93.8, 115.9, 117.1, 121.6, 128.6, 128.9, 129.0,
129.3, 129.7, 134.4, 136.8, 138.0, 144.8, 147.4, 148.5, 196.6.
HRMS (ESI): calculated for C21H17N2OS, 345.1056 (MH+); found:
m/z, 345.1059.
3-Amino-4-benzoyl-4'-methoxy-5-(methylthio)-[1,1'-
biphenyl]-2-carbonitrile (3n): To a vacuum dried RB flask 3,3-
bis(methylthio)-1-phenylprop-2-en-1-one (0.5 mmol, 0.112 g) and 2-1-
(4-methoxyphenyl)ethylidene)malononitrile (0.5 mmol, 0.099 g) was
placed. Then sodium hydride (0.6 mmol, 0.0144 g) was added,
followed by addition of THF (5.0 ml). The reaction mixture was
refluxed till completion of the reaction. After completion of the
reaction, excess of THF was removed under reduced pressure followed
by the addition of ice water. Reaction mixture was neutralized by
diluting HCl and obtained precipitate was filtered and dried. The crude
product was purified on silica gel column chromatography by using
20% EtOAc in hexane as an eluent. Yield 91% (170 mg); light yellow
3-Amino-4-benzoyl-4'-fluoro-5-(methylthio)-[1,1'-biphenyl]-2-
carbonitrile (3k): To a vacuum dried RB flask 3,3-bis(methylthio)-1-
phenylprop-2-en-1-one (0.5 mmol, 0.112 g) and 2-(1-(4-
fluorophenyl)ethylidene)malononitrile (0.5 mmol, 0.093 g) was placed.
Then sodium hydride (0.6 mmol, 0.0144 g) was added, followed by
addition of THF (5.0 ml). The reaction mixture was refluxed till
completion of the reaction. After completion of the reaction, excess of
THF was removed under reduced pressure followed by the addition of
ice water. Reaction mixture was neutralized by diluting HCl and
obtained precipitate was filtered and dried. The crude product was
purified on silica gel column chromatography by using 20% EtOAc in
hexane as an eluent. Yield 89% (161 mg); light yellow solid, mp:
solid, mp: 120-122 °C; IR (KBr): 3427, 2208, 1603 cm-1; H NMR
1
(400 MHz, CDCl3): δ 2.34 (s, 3H, -SMe), 3.85 (s, 3H, -OMe), 4.88
(s, 2H, -NH2), 6.65 (s, 1H, ArH), 6.99-7.01 (m, 2H, ArH), 7.45-7.53
(m, 4H, ArH), 7.59-7.63 (m, 1H, ArH), 7.85 (d, J = 8 Hz, 2H, ArH);
13C NMR (100 MHz, CDCl3): δ 16.4, 55.3, 93.7, 114.1, 115.8, 117.2,
120.6, 128.9, 129.5, 129.7, 130.3, 134.1, 137.0, 144.7, 146.8, 148.4,
160.3, 196.4. HRMS (ESI): calculated for C22H19N2O2S, 375.1162
(MH+); found: m/z, 37.1164.
1
145-147 °C; IR (KBr): 3579, 2210, 1648 cm-1; H NMR (400 MHz,
CDCl3): δ 2.37 (s, 3H, -SMe), 4.90 (s, 2H, -NH2), 6.60 (s, 1H, ArH),
7.17-7.22 (m, 2H ArH), 7.48-7.52 (m, 2H, ArH), 7.54-7.58 (m, 2H,
ArH), 7.64 (t, J = 8 Hz, 1H, ArH), 7.87 (d, J = 4 Hz, 2H); 13C NMR
(100 MHz, CDCl3): δ 16.6, 94.0, 116.1, (d, J = 20 Hz), 117.0, 121.4,
129.3 (d, J = 60 Hz), 130.4, 130.5, 134.2, 134.3, 134.4, 137.0, 145.1,
146.2, 148.5, 163.3 (d, J = 250 Hz), 196.4. HRMS (ESI): calculated
for C21H16FN2OS, 363.0962 (MH+); found: m/z, 363.0964.
3-Amino-4-benzoyl-4'-methyl-5-(methylthio)-[1,1'-biphenyl]-2-
carbonitrile (3o): To a vacuum dried RB flask 3,3-bis(methylthio)-1-
phenylprop-2-en-1-one (0.5 mmol, 0.112 g) and 2-(1-(p-
tolyl)ethylidene)malononitrile (0.5 mmol, 0.122 g) was placed. Then
sodium hydride (0.6 mmol, 0.0144 g) was added, followed by addition of
THF (5.0 ml). The reaction mixture was refluxed till completion of the
reaction. After completion of the reaction, excess of THF was removed
under reduced pressure followed by the addition of ice water. Reaction
mixture was neutralized by diluting HCl and obtained precipitate was
filtered and dried. The crude product was purified on silica gel column
chromatography by using 20% EtOAc in hexane as an eluent. Yield
95% (170 mg); light yellow solid; mp: 150-152 °C; IR (KBr): 3395,
3-Amino-4-benzoyl-4'-chloro-5-(methylthio)-[1,1'-biphenyl]-2-
carbonitrile (3l): To a vacuum dried RB flask 3,3-bis(methylthio)-1-
phenylprop-2-en-1-one (0.5 mmol
,
0.112 g) and 2-(1-(4-
chlorophenyl)ethylidene)malononitrile (0.5 mmol, 0.101 g) was
placed. Then sodium hydride (0.6 mmol, 0.0144 g) was added,
followed by addition of THF (5.0 ml). The reaction mixture was
refluxed till completion of the reaction. After completion of the
reaction, excess of THF was removed under reduced pressure followed
by the addition of ice water. Reaction mixture was neutralized by
diluting HCl and obtained precipitate was filtered and dried. The crude
product was purified on silica gel column chromatography by using
20% EtOAc in hexane as an eluent. Yield 74% (140 mg); light yellow
2210, 1645 cm-1; H NMR (400 MHz, CDCl3): 1H NMR (400 MHz,
1
CDCl3): δ 2.36 (s, 3H, -SMe), 2.43 (s, 3H, -CH3), 4.89 (s, 2H, -NH2),
6.69 (s, 1H, ArH), 7.31 (d, J = 8 Hz, 2H, ArH), 7.49 (t, J = 8 Hz,
4H, ArH), 7.62-7.66 (m, 1H, ArH), 7.87 (d, J = 8.0 Hz, 2H, ArH);;
13C NMR (100 MHz, CDCl3); δ 16.3, 22.0, 93.8, 115.8, 117.1, 121.2,
128.3, 129.4, 129.7, 129.8, 134.3, 135.3, 139.1, 144.5, 145.5, 147.0,
148.1, 196.0.. HRMS (ESI): calculated for C22H19N2OS, 359.1213
(MH+); found: m/z, 359.1214.
3-Amino-4-benzoyl-5-(methylthio)-[1,1':4',1''-terphenyl]-2-
carbonitrile (3p): To a vacuum dried RB flask 3,3-bis(methylthio)-
1-phenylprop-2-en-1-one (0.5 mmol, 0.112 g) and 2-(1-([1,1'-
biphenyl]-4-yl)ethylidene)malononitrile (0.5 mmol, 0.122S g) was
placed. Then sodium hydride (0.6 mmol, 0.0144 g) was added,
followed by addition of THF (5.0 ml). The reaction mixture was
refluxed till completion of the reaction. After completion of the
reaction, excess of THF was removed under reduced pressure
followed by the addition of ice water. Reaction mixture was
neutralized by diluting HCl and obtained precipitate was filtered and
dried. The crude product was purified on silica gel column
chromatography by using 20% EtOAc in hexane as an eluent. Yield
1
solid, mp: 130-132 °C; IR (KBr): 3571, 2210, 1660 cm-1; H NMR
(400 MHz, CDCl3): δ 2.36 (s, 3H, -SMe), 4.87 (s, 2H, -NH2), 6.64 (s,
1H, ArH, 7.45-7.51 (m, 6H, ArH), 7.63 (t, J = 8 Hz, 1H, ArH), 7.85
(d, J = 8 Hz, 2H, ArH); 13C NMR (100 MHz, CDCl3): δ 16.4, 93.7,
115.8, 116.7, 121.4, 129.0, 129.0, 129.6, 129.8, 134.3, 135.4, 136.5,
136.8, 145.1, 145.8, 148.4, 196.3. HRMS (ESI): calculated for
C21H16ClN2OS, 379.0666 (MH+); found: m/z, 379.0668.
3-Amino-4-benzoyl-4'-bromo-5-(methylthio)-[1,1'-biphenyl]-
2-carbonitrile (3m): To a vacuum dried RB flask 3,3-bis(methylthio)-
1-phenylprop-2-en-1-one (0.5 mmol, 0.112 g) and 2-(1-(4-
bromophenyl)ethylidene)malononitrile (0.5 mmol, 0.123 g) was
placed. Then sodium hydride (0.6 mmol, 0.0144 g) was added,

8
Tetrahedron
78% (164 mg); light yellow solid, mp: 190-192 °C; IR (KBr):
129.6, 131.1, 133.6, 134.3, 135.8, 136.8, 144.5, 146.0, 147.9, 196.5.
HRMS (ESI): calculated for C25H19N2OS, 395.1213 (MH+); found:
m/z, 395.1215.
3579, 2208, 1648 cm-1; 1H NMR (400 MHz, CDCl3): δ 2.38 (s, 3H, -
SMe), 4.92 (s, 2H, -NH2), 6.75 (s, 1H, ArH), 7.39-7.41 (m, 1H,
ArH), 7.46-7.52 (m, 4H, ArH), 7.62-7.68 (m, 5H, ArH), 7.71-7.74
(m, 2H, ArH), 7.88-7.90 (m, 2H, ArH); 13C NMR (100 MHz,
CDCl3): δ 16.4, 93.8, 116.0, 117.0, 121.2, 127.1, 127.4, 127.7, 128.8,
128.9, 129.6, 134.2, 136.9, 140.2, 142.0, 144.9, 146.7, 148.4, 196.4.
HRMS (ESI): calculated for C27H21N2OS, 421.1369 (MH+); found:
m/z, 421.1372.
2-Amino-3-benzoyl-4-(methylthio)-6-(naphthalen-2-
yl)benzonitrile (3t): To a vacuum dried RB flask 3,3-bis(methylthio)-
1-phenylprop-2-en-1-one (0.5 mmol, 0.112 g) and 2-(1-(naphthalen-2-
yl)ethylidene)malononitrile (0.5 mmol, 0.109 g) was placed. Then
sodium hydride (0.6 mmol, 0.0144 g) was added, followed by addition
of THF (5.0 ml). The reaction mixture was refluxed till completion of
the reaction. After completion of the reaction, excess of THF was
removed under reduced pressure followed by the addition of ice water.
Reaction mixture was neutralized by diluting HCl and obtained
precipitate was filtered and dried. The crude product was purified on
silica gel column chromatography by using 20% EtOAc in hexane as
an eluent.Yield 48% (95 mg); light yellow solid, mp: 178-180 °C; IR
3-Amino-4-benzoyl-2',4'-dichloro-5-(methylthio)-[1,1'-
biphenyl]-2-carbonitrile (3q): To a vacuum dried RB flask 3,3-
bis(methylthio)-1-phenylprop-2-en-1-one (0.5 mmol, 0.112 g) and 2-
(1-(2,4-dichlorophenyl)ethylidene)malononitrile (0.5 mmol, 0.118 g)
was placed. Then sodium hydride (0.6 mmol, 0.0144 g) was added,
followed by addition of THF (5.0 ml). The reaction mixture was
refluxed till completion of the reaction. After completion of the
reaction, excess of THF was removed under reduced pressure followed
by the addition of ice water. Reaction mixture was neutralized by
diluting HCl and obtained precipitate was filtered and dried. The crude
product was purified on silica gel column chromatography by using
20% EtOAc in hexane as an eluent. Yield 68% (140 mg); light yellow
solid, mp: 133-135 °C; IR (KBr): 3473, 2210, 1658-1; 1H NMR (400
MHz, CDCl3): δ 2.35 (s, 3H, -SMe), 4.83 (s, 2H, -NH2), 6.61 (s, 1H,
ArH), 7.33-7.35 (m, 1H, ArH), 7.37-7.40 (m, 1H, ArH), 7.50-7.53
(m, 2H, ArH) 7.56-7.56 (m, 1H, -ArH), 7.66 (t, J = 8 Hz, 1H, ArH),
7.88 (d, J = 8 Hz, 2H, -ArH); 13C NMR (100 MHz, CDCl3): δ 16.4,
95.3, 116.0, 116.6, 122.0, 127.4, 129.0, 129.6, 130.0, 131.5, 134.4,
135.4, 135.7, 136.6, 143.4, 144.8, 147.8, 196.2. HRMS (ESI):
calculated for C21H15Cl2N2OS, 413.0277 (MH+); found: m/z,
413.0279.
(KBr): 3469, 2210, 1665 cm-1; H NMR (400 MHz, CDCl3): δ 2.39
1
(s, 3H, -SMe), 4.93 (s, 2H, -NH2), 6.81 (s, 1H, ArH), 7.49-7.58 (m,
5H, ArH), 7.63-7.70 (m, 2H, ArH), 7.89-7.92 (m, 2H, ArH), 7.93-
7.97 (m, 1H, ArH), 7.99 (s, 1H, ArH), 8.06 (s, 1H, ArH); 13C NMR
(100 MHz, CDCl3): δ 16.5, 94.1, 116.3, 121.1, 125.9, 126.7, 126.9,
127.7, 128.0, 128.4, 128.6, 129.0, 129.6, 133.0, 133.3, 134.3, 135.4,
136.9, 147.1, 148.5, 196.5. HRMS (ESI): calculated for C25H19N2OS,
395.1213(MH+); found: m/z, 395.1215.
3-Amino-4-benzoyl-3',4'-dimethoxy-5-(methylthio)-[1,1'-
biphenyl]-2-carbonitrile (3u): To a vacuum dried RB flask 3,3-
bis(methylthio)-1-phenylprop-2-en-1-one (0.5 mmol, 0.112 g) and 2-1-
(3,4-dimethoxyphenyl)ethylidene)malononitrile (0.5 mmol, 0.114 g)
was placed. Then sodium hydride (0.6 mmol, 0.0144 g) was added,
followed by addition of THF (5.0 ml). The reaction mixture was
refluxed till completion of the reaction. After completion of the
reaction, excess of THF was removed under reduced pressure followed
by the addition of ice water. Reaction mixture was neutralized by
diluting HCl and obtained precipitate was filtered and dried. The crude
product was purified on silica gel column chromatography by using
20% EtOAc in hexane as an eluent. Yield 78% (147 mg); light yellow
3-Amino-4-benzoyl-3'-bromo-5-(methylthio)-[1,1'-biphenyl]-2-
carbonitrile (3r): To a vacuum dried RB flask 3,3-bis(methylthio)-1-
phenylprop-2-en-1-one (0.5 mmol, 0.112 g) and 2-(1-(3-
bromophenyl)ethylidene)malononitrile (0.5 mmol, 0.123 g) was
placed. Then sodium hydride (0.6 mmol, 0.0144 g) was added,
followed by addition of THF (5.0 ml). The reaction mixture was
refluxed till completion of the reaction. After completion of the
reaction, excess of THF was removed under reduced pressure followed
by the addition of ice water. Reaction mixture was neutralized by
diluting HCl and obtained precipitate was filtered and dried. The crude
product was purified on silica gel column chromatography by using
20% EtOAc in hexane as an eluent. Yield 78% (165 mg); light yellow
solid, mp: 153-155 °C; IR (KBr): 3317, 2210, 1697 cm-1; H NMR
1
(400 MHz, CDCl3): δ 2.40 (s, 3H, -SMe), 3.95 (s, 3H, -OMe), 3.99
(s, 3H, -OMe), 4.92 (s, 2H, -NH2), 6.70 (s, 1H, ArH), 6.99 (d, J = 8
Hz, 1H, ArH), 7.12-7.17 (m, 2H, ArH), 7.47-7.51 (m, 2H, ArH),
7.61-7.65 (m, 1H, ArH), 7.87 (d, J = 4 Hz, 2H, ArH); 13C NMR (100
MHz, CDCl3): δ 16.5, 55.9, 56.0, 93.8, 111.1, 111.6, 115.9, 117.2,
120.8, 121.1, 128.9, 129.5, 130.6, 134.1, 137.0, 144.7, 146.9, 148.4,
148.8, 149.8, 196.4. HRMS (ESI): calculated for C23H21N2O3S,
405.1267 (MH+); found: m/z, 405.1271.
solid, mp: 148-150°C; IR (KBr): 3409, 2208, 1635 cm-1; H NMR
1
(400 MHz, CDCl3): δ 2.41 (s, 3H, -SMe), 4.89 (s, 2H, -NH2), 6.66 (s,
1H, ArH), 7.36-7.40 (m, 1H, -ArH), 7.47-7.54 (m, 4H, ArH), 7.60-
7.62 (m, 1H, ArH), 7.65-7.69 (m, 1H, ArH), 7.87 (d, J = 8 Hz, 2H,
ArH); 13C NMR (100 MHz, CDCl3): δ 16.4, 93.7, 115.8, 116.5,
121.6, 122.8, 127.2, 129.0, 129.6, 130.3, 131.3, 132.1, 134.4, 136.7,
140.1, 145.1, 145.4, 148.3, 196.3. HRMS (ESI): calculated for
C21H16BrN2OS, 425.0161 (MH+); found: m/z, 425.0158.
3-Amino-4-(2-chlorobenzoyl)-4'-methyl-5-(methylthio)-[1,1'-
biphenyl]-2-carbonitrile (4a): To a vacuum dried RB flask 1-(2-
chlorophenyl)-3,3-bis(methylthio)prop-2-en-1-one (0.5 mmol, 0.129 g)
and 2-(1-(p-tolyl)ethylidene)malononitrile (0.5 mmol, 0.091 g) was
placed. Then sodium hydride (0.6 mmol, 0.0144 g) was added,
followed by addition of THF (5.0 ml). The reaction mixture was
refluxed till completion of the reaction. After completion of the
reaction, excess of THF was removed under reduced pressure followed
by the addition of ice water. Reaction mixture was neutralized by
diluting HCl and obtained precipitate was filtered and dried. The crude
product was purified on silica gel column chromatography by using
20% EtOAc in hexane as an eluent. Yield 65% (127 mg); light yellow
2-Amino-3-benzoyl-4-(methylthio)-6-(naphthalen-1-
yl)benzonitrile (3s): To a vacuum dried RB flask 3,3-bis(methylthio)-
1-phenylprop-2-en-1-one (0.5 mmol, 0.112 g) and 2-(1-(naphthalen-1-
yl)ethylidene)malononitrile (0.5 mmol, 0.109 g) was placed. Then
sodium hydride (0.6 mmol, 0.0144 g) was added, followed by addition
of THF (5.0 ml). The reaction mixture was refluxed till completion of
the reaction. After completion of the reaction, excess of THF was
removed under reduced pressure followed by the addition of ice water.
Reaction mixture was neutralized by diluting HCl and obtained
precipitate was filtered and dried. The crude product was purified on
silica gel column chromatography by using 20% EtOAc in hexane as
an eluent. Yield 45% (89 mg); light yellow solid, mp: 178-180°C; IR
solid, mp: 185-187 °C; IR (KBr): 3511, 3341, 2210, 1660 cm-1; H
1
NMR (400 MHz, CDCl3): δ 2.30 (s, 3H, -SMe), 2.42 (s, 3H, -CH3),
6.07 (s, 2H, -NH2), 6.56 (s, 1H, ArH), 7.29 (s, 1H, ArH), 7.31-7.35
(m, 2H, ArH), 7.44-7.45 (m, 2H, ArH), 7.46 (s, 2H, ArH), 7.48 (s,
1H, ArH); 13C NMR (100 MHz, CDCl3): δ 17.0, 21.3, 93.8, 115.4,
117.1, 118.7, 126.9, 128.2, 129.4, 130.5, 130.7, 132.4, 132.6, 135.0,
139.3, 139.5, 148.1, 148.7, 151.2, 195.3. HRMS (ESI): calculated for
C22H18ClN2OS, 393.0823 (MH+); found: m/z, 393.0826.
(KBr): 3469, 2210, 1665 cm-1; H NMR (400 MHz, CDCl3): δ 2.31
1
(s, 3H, -SMe), 4.87 (s, 2H, -NH2), 6.74 (s, 1H, ArH), 7.50-7.60 (m,
6H, ArH), 7.66 (t, J = 8 Hz, 1H, ArH), 7.73 (d, J = 8 Hz, 1H, ArH) ,
7.93-7.97 (m, 4H, ArH); 13C NMR (100 MHz, CDCl3): δ 16.2, 96.1,
116.3, 117.2, 121.3, 125.1, 126.2, 126.7, 127.0, 128.5, 129.0, 129.3,

9
3-Amino-4'-methyl-5-(methylthio)-4-(2-(methylthio)benzoyl)-
[1,1'-biphenyl]-2-carbonitrile (5a): To a vacuum dried RB flask 1-
(2-chlorophenyl)-3,3-bis(methylthio)prop-2-en-1-one (0.5 mmol,
0.128 g) and 2-(1-(p-tolyl)ethylidene)malononitrile (0.5 mmol, 0.091
g) was placed. Then sodium hydride (0.6 mmol, 0.0144 g) was added,
followed by addition of THF (5.0 ml). The reaction mixture was
refluxed till completion of the reaction. After completion of the
reaction, excess of THF was removed under reduced pressure followed
by the addition of ice water. Reaction mixture was neutralized by
diluting HCl and obtained precipitate was filtered and dried. The crude
product was purified on silica gel column chromatography by using
20% EtOAc in hexane as an eluent. Yield 25% (51 mg); light yellow
0.121 g) and 2-(1-(p-tolyl)ethylidene)malononitrile (0.5 mmol,
0.091 g) was placed. Then sodium hydride (0.6 mmol, 0.0144 g) was
added, followed by addition of THF (5.0 ml). The reaction mixture
was refluxed till completion of the reaction. After completion of
reaction, excess of THF was removed under reduced pressure
followed by the addition of ice water. Reaction mixture was
neutralized by diluting HCl and obtained precipitate was filtered and
dried. The crude product was purified on silica gel column
chromatography by using 20% EtOAc in hexane as an eluent. Yield
26 % (41 mg); light yellow solid, mp: 160-162 °C; IR (KBr): 3360,
2208, 1610 cm-1; 1H NMR (400 MHz, CDCl3): δ 1H NMR (400
MHz, CDCl3): δ 2.35 (s, 3H, -SMe), 2.41 (s, 3H, -SMe), 2.51 (s, 3H,
-CH3), 4.80 (s, 2H, -NH2), 6.66 (s, 1H, ArH), 7.24 (d, J = 4 Hz, 2H,
ArH ), 7.27-7.30 (m, 2H, ArH), 7.44-7.46 (m, 2H, ArH), 7.76 (d, J =
8 Hz, 2H, ArH); 13C NMR (100 MHz, CDCl3): δ 14.8, 16.4, 21.3,
93.9, 115.9, 117.1, 121.1, 125.0, 128.3, 129.4, 130.0, 130.1, 135.3,
139.2, 144.4, 147.0, 147.9, 148.2, 195.2. HRMS (ESI): calculated for
C23H21N2OS2, 405.1090 (MH+); found: m/z, 405.1097.
1
solid, mp: 180-182 °C; IR (KBr): 3365, 2208, 1603 cm-1; H NMR
(400 MHz, CDCl3): δ 2.32 (s, 3H, -SMe), 2.41 (s, 3H, -SMe), 2.50
(s, 3H, -CH3), 5.10 (s, 2H, -NH2), 6.62 (s, 1H, ArH), 7.13 (t, J = 8
Hz, 1H, ArH), 7.28 (d, J = 8 Hz, 2H, ArH), 7.36-7.38 (m, 1H, ArH),
7.45-7.47 (m, 2H, ArH), 7.49-7.55 (m, 2H, ArH); 13C NMR (100
MHz, CDCl3): δ 15.7, 16.5, 21.2, 93.8, 115.8, 117.1, 121.0, 123.7,
128.3, 129.4, 129.5, 132.4, 133.1, 134.6, 135.2, 139.2, 143.4, 145.5,
147.4, 149.0, 196.3. HRMS (ESI): calculated for C23H21N2OS2,
405.1090 (MH+); found: m/z, 405.1089.
3-Amino-4-(4-chlorobenzoyl)-4'-methyl-5-(methylthio)-[1,1’-
biphenyl]-2-carbonitrile (4d): To a vacuum dried RB flask 1-(4-
chlorophenyl)-3,3-bis(methylthio)prop-2-en-1-one (0.5 mmol, 0.129
g) and 2-(1-(p-tolyl)ethylidene)malononitrile (0.5 mmol, 0.091 g)
was placed. Then sodium hydride (0.6 mmol, 0.0144 g) was added,
followed by addition of THF (5.0 ml). The reaction mixture was
refluxed till completion of the reaction. After completion of the
reaction, excess of THF was removed under reduced pressure
followed by the addition of ice water. Reaction mixture was
neutralized by diluting HCl and obtained precipitate was filtered and
dried. The crude product was purified on silica gel column
chromatography by using 20% EtOAc in hexane as an eluent. Yield
61% (120 mg); light yellow solid, mp: 144-146 °C; IR (KBr): 3471,
2210, 1660 cm-1; 1H NMR (400 MHz, CDCl3): δ 2.35 (s, 3H, -SMe),
2.41 (s, 3H, -CH3), 4.92 (s, 2H, -NH2), 6.66 (s, 1H, ArH), 7.29 (d, J
= 8 Hz, 2H, ArH ), 7.43-7.47 (m, 4H, ArH), 7.77-7.99 (m, 2H, ArH);
13C NMR (100 MHz, CDCl3): δ 15.7, 21.3, 94.0, 115.9, 116.9, 120.2,
128.3, 129.2, 129.5, 130.9, 135.1, 135.4, 139.2, 140.5, 144.7, 147.4,
148.5, 195.2. HRMS (ESI): calculated for C22H18ClN2OS, 393.0823
(MH+); found: m/z, 339.0828.
3-Amino-4-(2-bromobenzoyl)-4'-methyl-5-(methylthio)-[1,1'-
biphenyl]-2-carbonitrile (4b): To a vacuum dried RB flask 1-(2-
bromophenyl)-3,3-bis(methylthio)prop-2-en-1-one (0.5 mmol, 0.151
g) and 2-(1-(p-tolyl)ethylidene)malononitrile (0.5 mmol, 0.091 g)
was placed. Then sodium hydride (0.6 mmol, 0.0144 g) was added,
followed by addition of THF (5.0 ml). The reaction mixture was
refluxed till completion of the reaction. After completion of the
reaction, excess of THF was removed under reduced pressure
followed by the addition of ice water. Reaction mixture was
neutralized by diluting HCl and obtained precipitate was filtered and
dried. The crude product was purified on silica gel column
chromatography by using 20% EtOAc in hexane as an eluent. Yield
67% (146 mg); light yellow solid, mp: 182-184°C; IR (KBr): 3471,
2208, 1694 cm-1; 1H NMR (400 MHz, CDCl3): δ 2.23 (s, 3H, -SMe),
2.35 (s, 3H, -CH3), 6.06 (s, 2H, -NH2), 6.48 (s, 1H, ArH), 7.23 (d, J
= 8 Hz, 2H, ArH), 7.28-7.30 (m, 2H, ArH), 7.35-7.37 (m, 1H, ArH),
7.40 (d, J = 8 Hz, 2H, ArH), 7.57-7.59 (m, 1H, ArH); 13C NMR (100
MHz, CDCl3): δ 16.5, 21.3, 93.9, 115.8, 117.1, 121.0, 123.8, 125.2,
128.3, 129.4, 132.5, 133.1, 134.6, 135.3, 139.3, 143.4, 145.5, 147.4,
149.0, 196.3. HRMS (ESI): calculated for C22H18BrN2OS, 437.0318
(MH+); found: m/z, 437.0319.
3-Amino-4-(4-bromobenzoyl)-4'-methyl-5-(methylthio)-[1,1'-
biphenyl]-2-carbonitrile (4e): To a vacuum dried RB flask 1-(4-
bromophenyl)-3,3-bis(methylthio)prop-2-en-1-one (0.5 mmol, 0.151
g) and 2-(1-(p-tolyl)ethylidene)malononitrile (0.5 mmol, 0.091 g)
was placed. Then sodium hydride (0.6 mmol, 0.0144 g) was added,
followed by addition of THF (5.0 ml). The reaction mixture was
refluxed till completion of the reaction. After completion of the
reaction, excess of THF was removed under reduced pressure
followed by the addition of ice water. Reaction mixture was
neutralized by diluting HCl and obtained precipitate was filtered and
dried. The crude product was purified on silica gel column
chromatography by using 20% EtOAc in hexane as an eluent. Yield
72% (157 mg); light yellow solid, mp: 143-145 °C; IR (KBr): 3473,
2210, 1658 cm-1; 1H NMR (400 MHz, CDCl3): δ 2.27 (s, 3H, -SMe),
2.40 (s, 3H, -CH3), 4.88 (s, 2H, -NH2), 6.60 (s, 1H, ArH), 7.18-7.25
(m, 2H, ArH), 7.40 (d, J = 8 Hz, 2H, ArH), 7.54-7.56 (m, 2H, ArH),
7.63-7.66 (m, 2H, ArH); 13C NMR (100 MHz, CDCl3): δ 16.4, 21.3,
94.0, 115.9, 117.0, 120.1, 128.3, 129.2, 129.5, 131.0, 132.2, 135.1,
135.9, 139.3, 144.8, 147.5, 148.5, 195.5. HRMS (ESI): calculated for
C22H18BrN2OS, 437.0318 (MH+); found: m/z, 437.0317.
3-Amino-4-(4-fluorobenzoyl)-4'-methyl-5-(methylthio)-[1,1'-
biphenyl]-2-carbonitrile carbonitrile (4c): To a vacuum dried RB
flask 1-(4-fluorophenyl)-3,3-bis(methylthio)prop-2-en-1-one (0.5
mmol, 0.121 g) and 2-(1-(p-tolyl)ethylidene)malononitrile (0.5 mmol,
0.091 g) was placed. Then sodium hydride (0.6 mmol, 0.0144 g) was
added followed by addition of THF (5.0 mL). The reaction mixture
was refluxed till completion of the reaction. After completion of the
reaction, excess of THF was removed under reduced pressure followed
by the addition of ice water. Reaction mixture was neutralized by
diluting HCl and obtained precipitate was filtered and dried. The crude
product was purified on silica gel column chromatography by using
20% EtOAc in hexane as an eluent. Yield 65% (122 mg); light yellow
1
solid, mp: 145-147 °C; IR (KBr): 3579, 2208, 1648 cm-1; H NMR
(400 MHz, CDCl3): δ 2.37 (s, 3H, -SMe), 2.43 (s, 3H, -CH3), 4.89 (s,
2H, -NH2), 6.68 (s, 1H, ArH), 7.13-7.18 (m, 2H, ArH), 7.31 (d, J = 8
Hz, 2H, ArH), 7.47 (d, J = 8 Hz, 2H, ArH), 7.88-7.91 (m, 2H, ArH);
13C NMR (100 MHz, CDCl3): δ 16.4, 21.3, 94.1, 116.0 (d, J = 10
Hz), 116.3, 117.0, 120.6, 126.4, 128.3, 129.5, 132.3 (d, J = 10 Hz),
135.2, 139.3, 144.7, 147.3, 148.4, 166.4 (d, J = 270 Hz), 194.8.
HRMS (ESI): calculated for C22H18FN2OS, 377.1118 (MH+); found:
m/z, 377.1114.
3-Amino-4-(2-chlorobenzoyl)-4'-methoxy-5-(methylthio)-[1,1'-
biphenyl]-2-carbonitrile (4f): To a vacuum dried RB flask 1-(2-
chlorophenyl)-3,3-bis(methylthio)prop-2-en-1-one (0.5 mmol, 0.129 g)
and 2-(1-(4-methoxyphenyl)ethylidene)malononitrile (0.5 mmol, 0.099
g) was placed. Then sodium hydride (0.6 mmol, 0.0144 g) was added,
followed by addition of THF (5.0 ml). The reaction mixture was refluxed
3-Amino-4'-methyl-5-(methylthio)-4-(4-(methylthio)benzoyl)-
[1,1'-biphenyl]-2-carbonitrile (5b): To a vacuum dried RB flask 1-
(4-fluorophenyl)-3,3-bis(methylthio)prop-2-en-1-one (0.5 mmol,

10
Tetrahedron
till completion of the reaction. After completion of the reaction,
by the addition of ice water. Reaction mixture was neutralized by
diluting HCl and obtained precipitate was filtered and dried. The crude
product was purified on silica gel column chromatography by using
20% EtOAc in hexane as an eluent. Yield 76% (133 mg); light yellow
excess of THF was removed under reduced pressure followed by the
addition of ice water. Reaction mixture was neutralized by diluting HCl
and obtained precipitate was filtered and dried. The crude product was
purified on silica gel column chromatography by using 20% EtOAc in
hexane as an eluent. Yield 62% (128 mg); light yellow solid, mp: 133-
135°C; IR (KBr): 3471, 2208, 1660 cm-1; 1HNMR (400MHz,
CDCl3): δ 2.29 (s, 3H, -SMe), 3.85 (s, 3H, -OMe), 6.07 (s, 2H, -
NH2), 6.52 (s, 1H, ArH), 6.99 (d, J = 8 Hz, 2H, ArH ), 7.30-7.44 (m,
4H, ArH), 7.51 (d, J = 8 Hz, 2H, ArH); 13C NMR (100 MHz,
CDCl3): δ 16.5, 55.3, 93.7, 114.1, 115.6, 117.3, 120.7, 123.7, 125.1,
129.7, 130.4, 132.5, 133.1, 134.6, 143.4, 145.5, 147.0, 149.0, 160.3,
196.3. HRMS (ESI): calculated for C22H18ClN2O2S, 409.0772
(MH+); found: m/z, 409.0775.
solid, mp: 156-158 °C; IR (KBr): 3685, 2212, 1648 cm-1; H NMR
1
(400 MHz, CDCl3): δ 2.39 (s, 3H, -SMe), 4.95 (s, 2H, -NH2), 6.81 (s,
1H, ArH), 7.18 (t, J = 8 Hz, 1H, ArH), 7.46- 7.47 (m, 1H, ArH), 7.50
(d, J = 8 Hz, 2H, ArH), 7.62-7.67 (m, 2H, ArH), 7.85-7.87 (m, 2H,
ArH); 13C NMR (100 MHz, CDCl3): δ 16.5, 92.5, 115.6, 126.4,
127.5, 128.0, 128.2, 128.4, 128.9, 129.5, 130.2, 134.2, 136.9, 139.0,
139.3, 148.8, 196.2. HRMS (ESI): calculated for C19H15N2OS2,
351.0620 (MH+); found: m/z, 351.0616.
2-Amino-6-(furan-2-yl)-3-(4-methoxybenzoyl)-4-
(methylthio)benzonitrile (6c): To a vacuum dried RB flask 1-(4-
methoxyphenyl)-3,3-bis(methylthio)prop-2-en-1-one (0.5 mmol, 0.127
g) and 2-(1-(furan-2-yl)ethylidene)malononitrile (0.5 mmol, 0.079 g)
was placed. Then sodium hydride (0.6 mmol, 0.0144 g) was added,
followed by addition of THF (5.0 ml). The reaction mixture was refluxed
till completion of the reaction. After completion of the reaction, excess of
THF was removed under reduced pressure followed by the addition of
ice water. Reaction mixture was neutralized by diluting HCl and
obtained precipitate was filtered and dried. The crude product was
purified on silica gel column chromatography by using 20% EtOAc in
hexane as an eluent. Yield 74% (137 mg); light yellow solid, mp:
3-Amino-4'-methoxy-5-(methylthio)
(methylthio)benzoyl)-[1,1'-biphenyl]-2-carbonitrile (5c): To
vacuum dried RB flask 1-(2-chlorophenyl)-3,3-bis(methylthio)prop-2-
en-1-one (0.5 mmol, 0.128 g) and 2-(1-(4-
-4-(2-
a
methoxyphenyl)ethylidene)malononitrile (0.5 mmol, 0.099 g) was
placed. Then sodium hydride (0.6 mmol, 0.0144 g) was added,
followed by addition of THF (5.0 ml). The reaction mixture was
refluxed till completion of the reaction. After completion of the
reaction, excess of THF was removed under reduced pressure followed
by the addition of ice water. Reaction mixture was neutralized by
diluting HCl and obtained precipitate was filtered and dried. The crude
product was purified on silica gel column chromatography by using
20% EtOAc in hexane as an eluent. Yield 25% (53 mg); light yellow
1
149-151 °C; IR (KBr): 3395, 2208, 1674 cm-1; H NMR (400 MHz,
CDCl3): δ 2.40 (s, 3H, -SMe), 3.89 (s, 3H, -OMe), 4.82 (s, 2H, -
NH2), 6.80 (s, 1H, ArH), 6.95-6.96 (m, 1H, ArH), 6.97-6.97 (m, 1H,
ArH), 7.16-7.18 (m, 1H, ArH), 7.44-7.46 (m, 1H, ArH), 7.64-7.65
(m, 1H, ArH), 7.84-7.85 (m, 2H, ArH); 13C NMR (100 MHz,
CDCl3): δ 16.2, 55.6, 92.4, 114.2, 115.4, 117.2, 121.7, 127.3, 127.8,
128.2, 129.5, 132.2, 138.7, 139.4, 144.7, 148.4, 164.7, 194.3. HRMS
(ESI): calculated for C20H17N2O3S, 365.0954 (MH+); found: m/z,
365.0957.
1
solid, mp: 170-180 °C; IR (KBr): 3473, 2208, 1604 cm-1; H NMR
(400 MHz, CDCl3): δ 2.32 (s, 3H, -SMe), 2.49 (s, 3H, -SMe), 3.85
(s, 3H, -OMe), 5.12 (s, 2H, -NH2), 6.60 (s, 1H, ArH), 6.99 (d, J = 8
Hz, 3H, ArH ), 7.13 (t, J = 8 Hz, 1H, ArH), 7.37 (d, J = 8 Hz, 1H,
ArH), 7.51 (d, J = 8 Hz, 3H, ArH); 13C NMR (100 MHz, CDCl3): δ
15.6, 16.5, 55.3, 93.7, 114.1, 115.6, 117.3, 120.7, 123.7, 125.1,
129.7, 130.4, 132.5, 133.1, 134.6, 143.4, 145.5, 147.0, 149.0, 160.3,
196.3. HRMS (ESI): calculated for C23H21N2O2S2, 421.1039 (MH+);
found: m/z, 421.1040.
2-Amino-3-(4-methoxybenzoyl)-4-(methylthio)-6-(thiophen-2-
yl)benzonitrile (6d): To
a
vacuum dried RB flask 1-(4-
methoxyphenyl)-3,3-bis(methylthio)prop-2-en-1-one (0.5 mmol, 0.127 g)
and 2-(1-(thiophen-2-yl)ethylidene)malononitrile (0.5 mmol, 0.087 g) was
placed. Then sodium hydride (0.6 mmol, 0.0144 g) was added, followed
by addition of THF (5.0 ml). The reaction mixture was refluxed till
completion of the reaction. After completion of the reaction, excess of
THF was removed under reduced pressure followed by the addition of ice
water. Reaction mixture was neutralized by diluting HCl and obtained
precipitate was filtered and dried. The crude product was purified on silica
gel column chromatography by using 20% EtOAc in hexane as an eluent.
Yield 72 % (137 mg); light yellow solid, mp: 149-151 °C; IR (KBr):
3395, 2208, 1674 cm-1; 1H NMR (400 MHz, CDCl3): δ 2.40 (s, 3H, -
SMe), 3.89 (s, 3H, -OMe), 4.82 (s, 2H, -NH2), 6.80 (s, 1H, ArH),
6.95-6.96 (m, 1H, ArH), 6.97-6.97 (m, 1H, ArH), 7.16-7.18 (m, 1H,
ArH), 7.44-7.46 (m, 1H, ArH), 7.64-7.65 (m, 1H, ArH), 7.84-7.85
(m, 2H, ArH); 13C NMR (100 MHz, CDCl3): δ 16.2, 55.6, 92.4,
114.2, 115.4, 117.2, 121.7, 127.3, 127.8, 128.2, 129.5, 132.2, 138.7,
139.4, 144.7, 148.4, 164.7, 194.3. HRMS (ESI): calculated for
C20H17N2O2S2, 381.0726 (MH+); found: m/z, 381.0729.
2-Amino-3-benzoyl-6-(furan-2-yl)-4-(methylthio)benzonitrile
(6a): To a vacuum dried RB flask 3,3-bis(methylthio)-1-phenylprop-2-
en-1-one
(0.5
mmol,
0.112
g)
and
2-(1-(furan-2-
yl)ethylidene)malononitrile (0.5 mmol, 0.079 g) was placed. Then
sodium hydride (0.6 mmol, 0.0144 g) was added, followed by addition
of THF (5.0 ml). The reaction mixture was refluxed till completion of
the reaction. After completion of the reaction, excess of THF was
removed under reduced pressure followed by the addition of ice water.
Reaction mixture was neutralized by diluting HCl and obtained
precipitate was filtered and dried. The crude product was purified on
silica gel column chromatography by using 20% EtOAc in hexane as
an eluent. Yield 84% (140 mg); light yellow solid, mp: 158-160 °C;
1
IR (KBr): 3454, 2208, 1629 cm-1; H NMR (400 MHz, CDCl3): δ
2.42 (s, 3H, -SMe), 4.95 (s, 2H, -NH2), 6.58-6.59 (m, 1H, ArH), 7.14
(s, 1H, ArH), 7.37 (d, J = 4 Hz, 1H, ArH), 7.46-7.50 (m, 2H, ArH),
7.58-7.64 (m, 2H, ArH), 7.82-7.84 (m, 2H, ArH); 13C NMR (100
MHz, CDCl3): δ 16.5, 89.1, 111.5, 112.0,112.4, 117.4, 120.6, 128.9,
129.5, 134.1, 134.3, 137.1, 143.6, 145.4, 148.8, 149.5, 196.3. HRMS
(ESI): calculated for C19H15N2O2S, 335.0849 (MH+); found: m/z,
335.0854.
2-Amino-3-benzoyl-6-cyclopropyl-4-(methylthio)benzonitrile
(8a ): To a vacuum dried RB flask 3,3-bis(methylthio)-1-phenylprop-2-
en-1-one(0.5
mmol,
0.112
g)
and
2-(1-
2-Amino-3-benzoyl-4-(methylthio)-6-(thiophen-2-
cyclopropylethylidene)malononitrile (0.5 mmol, 0.066 g) was placed.
Then sodium hydride (0.6 mmol, 0.0144 g) was added, followed by
addition of THF (5.0 ml). The reaction mixture was refluxed till
completion of the reaction. After completion of the reaction, excess of
THF was removed under reduced pressure followed by the addition of ice
water. Reaction mixture was neutralized by diluting HCl and obtained
precipitate was filtered and dried. The crude product was purified on silica
gel column chromatography by using 20% EtOAc in hexane as an eluent.
yl)benzonitrile (6b): To
a
vacuum dried RB flask 3,3-
bis(methylthio)-1-phenylprop-2-en-1-one (0.5 mmol, 0.112 g) and 2-
(1-(thiophen-2-yl)ethylidene)malononitrile (0.5 mmol, 0.087 g) was
placed. Then sodium hydride (0.6 mmol, 0.0144 g) was added,
followed by addition of THF (5.0 ml). The reaction mixture was
refluxed till completion of the reaction. After completion of the
reaction, excess of THF was removed under reduced pressure followed

11
Yield 59 % (91 mg); light yellow solid, mp: 149-151 °C; IR (KBr):
3395, 2208, 1674 cm-1; 1H NMR (400 MHz, CDCl3): δ 0.82-0.86 (m,
2H), 1.13-1.18 (m, 2H), 2.18-2.24 (m, 1H), 2.30 (s, 3H, -CH3), 4.83
(s, 2H, -NH2), 6.19 (s, 1H, ArH), 7.46 (t, J = 8 Hz, 2H, ArH),
7.59.7.62 (m, 1H, ArH), 7.79 (d, J = 8 Hz, 2H, ArH); 13C NMR (100
MHz, CDCl3): δ 9.6, 15.0, 16.8, 95.9, 111.1, 116.4, 120.2, 128.6,
129.6, 134.0, 137.4, 144.7, 148.0, 150.1, 196.6; HRMS (ESI):
calculated for C18H17N2OS, 309.1506 (MH+); found: m/z, 309.1073.
110.4, 110.4, 111.0, 112.3, 116.9, 120.9, 125.8, 130.0, 147.5,
149.6, 154.5, 194.9. HRMS (ESI): calculated for C20H21N2O3S,
369.1267 (MH+); found: m/z, 369.1275.
Acknowledgements
RP, S and CS thanks UGC, New Delhi for providing research
fellowship. RS thanks CSIR for providing fellowship. AE thanks
DBT-TWAS for providing research fellowship. RP thanks CSIR,
New Delhi (No. 02(0286)/16/EMR-II) and ICMR, New Delhi
(BIC/12(03)/2014) for research funding. We also acknowledge the
USIC, Delhi University for providing instrumentation facility.
2-Amino-6-cyclopropyl-3-(4-methylbenzoyl)-4-
(methylthio)benzonitrile (8b ): To a vacuum dried RB flask 3,3-
bis(methylthio)-1-(p-tolyl)prop-2-en-1-one (0.5 mmol, 0.119 g) and 2-(1-
cyclopropylethylidene)malononitrile (0.5 mmol, 0.066 g) was placed.
Then sodium hydride (0.6 mmol, 0.0144 g) was added, followed by
addition of THF (5.0 ml). The reaction mixture was refluxed till
completion of the reaction. After completion of the reaction, excess of
THF was removed under reduced pressure followed by the addition of ice
water. Reaction mixture was neutralized by diluting HCl and obtained
precipitate was filtered and dried. The crude product was purified on silica
gel column chromatography by using 20% EtOAc in hexane as an eluent.
Yield 61 % (100 mg); light yellow solid, mp: 149-151 °C; IR (KBr):
3395, 2208, 1674 cm-1; 1H NMR (400 MHz, CDCl3): δ 0.81-0.82 (m,
2H), 1.12-1.14 (m, 2H), 2.15-2.22 (m, 1H). 2.29 (s, 3H, -CH3), 2.40
(s, 3H, -SMe), 4.73 (s, 2H, -NH2), 6.17 (s, 1H, ArH), 7.24 (d, J =
8Hz, 2H, ArH), 7.68 (d, J 8Hz, 2H, ArH); 13C NMR (100 MHz,
CDCl3): δ 9.5, 14.9, 16.7, 22.0, 96.2, 111.0, 117.0, 120.7, 129.7,
129.8, 134.7, 144.7, 145.3, 147.8, 149.8, 196.1; HRMS (ESI):
calculated for C19H19N2OS, 323.1213 (MH+); found: m/z, 323.1220.
4. References and notes
Electronic Supporting Information: 1H and 13C spectra of the
entire synthesized compound are provided in ESI.
1. A) D.A. Horton, G.T. Bourne, M.L. Smythe, The combinatorial
synthesis of bicyclic privileged structures or privileged
substructures, Chem. Rev. 103 (2003) 893; b) G. Bringmann, C.
Günther, M. Ochse, O. Schupp, S. Tasler, Biaryls in Nature: A
Multifaceted Class of Stereochemically, Biosynthetically, and
Pharmacologically Intriguing Secondary Metabolites (Springer-
Verlag, New York, 2001); c) M.C. Kozlowski, B.J. Morgan, E.C.
Linton, Total synthesis of chiral biaryl natural products by
asymmetric biaryl coupling, Chem. Soc. Rev. 38 (2009) 3193.
2. A)
K. Tanaka, Transition-metal-catalyzed enantioselective
[2+2+2] cycloadditions for the synthesis of axially chiral biaryls,
Chem. Asian. J. 4 (2009) 508; b) T.W. Wallace, Biaryl synthesis
with control of axial chirality, Org. Biomol. Chem. 4 (2006) 3197.
3. A) Metal-Catalyzed cross coupling reactions (Eds.: F. Diederich,
P. J. Stang), Wiley-VCH, New York, 1998, b) J.A.G. Lόpez, M.F.
Greaney, Synthesis of biaryls using aryne intermediates, Chem.
Soc. Rev. 45 (2016) 6766; c) L. Ackermann, R. Vicente, A.R.
Kapdi, Transition metal-catalyzed direct arylations of (hetero)
arenes through C-H bond breaking, Angew. Chem. 121 (2009)
9976; Transition metal-catalyzed direct arylations of (hetero)
arenes through C-H bond breaking, Angew. Chem. Int. Ed. 48
(2009) 9792.
4. A) T.N. Poudel, R.J.I. Tamargo, H. Cai, Y.R. Lee, Recent
progress in transition-metal-free, base mediated benzannulation
reactions for the synthesis of diverse range of aromatic and
heteroaromatic compounds, Asian J. Org. Chem. 7 (2018) 985; b)
T.N. Poudel, Y. R. Lee, Transition metal-free benzannulation for
diverse and polyfunctionalized biaryl formation, Org. Lett. 17
(2015) 2050; c) H. Chen, F. Xie, J. Gong, Y. Hu, Domino reaction
of functionalized 2-hydroxybenzophenones form electron-
deficient chromones and 1,3-dicarbonyl compound, J. Org. Chem.
76 (2011) 8495. (d) S.M.B. Maezono, T.N. Poudel, Y.R. Lee,
One-pot construction of sterically challenging and diverse
polyarylphenoles via transition metal-free benzannulation and
their potent in vitro antioxidant activity, Org. Biomol. Chem. 15
(2017) 2052; e) Q. Gao, X.C. Tan, Y.M. Pan, H.S. Wang, Y.
Liang, Palladium catalyzed formation of phenolic compounds by
the reaction of carbonyl compounds with carbon dioxide, Chem.
Commun. 48 (2012) 12080. (f) W.M. Shu, K.L. Zheng, J.R. Ma,
A.X. Wu, Transition metal-free multicomponent benzannulation
reactions for the construction of polysubstituted benzene
derivatives, Org. Lett. 17 (2015) 5216.
2-Amino-6-cyclopropyl-3-(4-methoxybenzoyl)-4-
(methylthio)benzonitrile (8c): To a vacuum dried RB flask 1-(4-
methoxyphenyl)-3,3-bis(methylthio)prop-2-en-1-one (0.5 mmol, 0.127 g)
and 2-(1-cyclopropylethylidene)malononitrile (0.5 mmol, 0.066 g) was
placed. Then sodium hydride (0.6 mmol, 0.0144 g) was added, followed
by addition of THF (5.0 ml). The reaction mixture was refluxed till
completion of the reaction. After completion of the reaction, excess of
THF was removed under reduced pressure followed by the addition of ice
water. Reaction mixture was neutralized by diluting HCl and obtained
precipitate was filtered and dried. The crude product was purified on silica
gel column chromatography by using 20% EtOAc in hexane as an eluent.
Yield 56% (95 mg); light yellow solid, mp: 149-151 °C; IR (KBr):
3395, 2208, 1674 cm-1; 1H NMR (400 MHz, CDCl3): δ 0.79-0.83 (m,
2H), 1.10-1.15 (m, 2H), 2.13-2.21 (m, 1H), 2.30 (s, 3H, -SMe), 3.86
(s, 3H, OMe), 4.68 (s, 2H, -NH2), 6.17 (s, 1H, ArH), 6.89-6.92 (m,
2H, ArH), 7.76-7.78 (m, 2H, ArH); 13C NMR (100 MHz, CDCl3): δ
9.4, 14.7, 16.7, 55.6, 96.0, 110.9, 114.2, 116.8, 120.8, 130.0, 132.2,
144.4, 147.6, 149.6, 164.6, 194.8; HRMS (ESI): calculated for
C19H19N2O2S, 339.1162 (MH+); found: m/z, 339.1166.
2-Amino-6-cyclopropyl-3-(3,4-dimethoxybenzoyl)-4-
(methylthio)benzonitrile (8d): To a vacuum dried RB flask 1-(3,4-
dimethoxyphenyl)-3,3-bis(methylthio)prop-2-en-1-one (0.5 mmol, 0.142
g) and 2-(1-cyclopropylethylidene)malononitrile (0.5 mmol, 0.066 g) was
placed. Then sodium hydride (0.6 mmol, 0.0144 g) was added, followed
by addition of THF (5.0 ml). The reaction mixture was refluxed till
completion of the reaction. After completion of the reaction, excess of
THF was removed under reduced pressure followed by the addition of ice
water. Reaction mixture was neutralized by diluting HCl and obtained
precipitate was filtered and dried. The crude product was purified on silica
gel column chromatography by using 20% EtOAc in hexane as an eluent.
Yield 56% (95 mg); light yellow solid, mp: 149-151 °C; IR
(KBr): Yield 72 % (137 mg); light yellow solid, mp: 149-151 °C;
IR (KBr): 3395, 2208, 1674 cm-1; 1H NMR (400 MHz, CDCl3): δ
0.79-0.85 (m, 2H), 1.10-1.15 (m, 2H), 2.15-2.20 (s, 1H, -CH2)
2.31 (S, 3H, -SMe), 3.91 (s, 6H), 4.65 (s, 2H, -NH2), 6.18 (s, 1H,
ArH), 6.80-6.89 (m, 1H, ArH), 7.50-7.56 (m, 1H, ArH). 13C
NMR (100 MHz, CDCl3): δ 9.4, 15.0, 16.6, 56.1, 96.0, 110.1,
5. a) H. Cai, L. Xia, Y.R. Lee, Regioselective construction of diverse
and multifunctionalized 2-hydroxybenzophenones for sun
protection by indium(III)- catalyzed benzannulation, Chem.
Commun. 52 (2016) 7661; (b) Y. Zhao, Q. Zheng, C. Yu, Z. Liu,
D. Wang, J. You, G. Gao, Rh(III)-catalyzed regioselective C-H
[4+2] C-annulation of vinyl enaminones with alkynes to form
polysubstituted salicylaldehydes, Org. Chem. Front. 5 (2018)
2875.
6. (a) J. Mahatthananchai, J.W. Bode, On the mechanism of N-
heterocyclic carbene –catalyzed reactions involving acyl azoliums,
Acc. Chem. Res. 47 (2014) 696; b) M.N. Hopkinson, C. Richter,
M. Schedler, F. Glorius, An overview of N-heterocyclic carbenes,
Nature. 510 (2014) 485; c) D.M. Flanigan, F.R. Michailidis, N.A.
White, T. Rovis, Organocatalytic reactions enabled by N-
heterocyclic carbenes, Chem. Rev. 115 (2015) 9307.
7. a) T. Zhu, P. Zheng, C. Mou, S. Yang, B.A. Song, Y.R. Chi,
Benzene construction via organocatalytic formal [3+3]
cycloaddition reaction, Nat. Commun. 5 (2014) 5027; b) Q. Jia, J.
Wang, N-heterocyclic carbene- catalyzed convenient benzonitrile
assemble, Org. Lett. 18 (2016) 2212; c) C.L. Zhang, Z.H. Gao, Z.

12
Tetrahedron
Q. Liang, S. Ye, N-heterocyclic-carbene catalyzed synthesis of
0.93 Å + Uiso(H) = 1.2Ueq(C) for aromatic H atoms, and with
C−H = 0.97 Å + Uiso(H) = 1.2Ueq(C) for methylene H atoms.
Crystal data: CCDC No: 1857029; C22 H18 N2 O S; Mr =
358.44, crystal system: triclinic; space group P-1, a = 9.1224(8) Å,
b = 10.0199(10) Å, c = 11.1240(8) Å, α = 74.343(8)°, β =
67.093(8)°, γ = 80.916(8)°, V = 900.25(15) Å3, Z = 2, ρcalcd =
1.322 Mg/m3 g cm-3, μ = 0.193 mm-1, F(000) = 376, R1 = 0.0472
and wR2 = 0.1313 for I>2σ(I) and 226 parameters, R1= 0.0606
and wR2 = 0.1417, gof = 0.904 for all data.
multi-substituted benzenes from enals and α-cyano-β-
methylenones, Adv. Synth. Catal. 358 (2016) 2862; d) L. Candish,
A. Levens, D. W. Lupton , N-heterocyclic carbene catalysed redox
isomerization of esters to functionalized benzaldehydes, Chem.
Sci. 6 (2015) 2366.
8. a) T. Zhu, C. Mou, B. Li, M. Smetankova, B.A. Song, Y.R. Chi,
N-heterocyclic carbene catalyzed δ-carbon LUMO activation of
unsaturated aldehydes, J. Am. Chem. Soc. 137 (2015) 5658; b)
Y. Zhao, Q. Zheng, C. Yu, Z. Liu, D. Wang, J. Youa, G. Gao,
Rh(III)-catalyzed regioselective C-H [4+2] C-annulation of vinyl
enaminones with alkynes to form polysubstituted salicylaldehydes
Org. Chem. Front. 5 (2018) 2875; c) D.L. Obydennov, E.V.
Chernyshova, V.Y. Sosnovskikh, Self-condensation of
enaminodionens as a method for benzene ring construction:
synthesis of diacyl-substituted phenols and catechols, J. Org.
Chem. 84 (2019) 6491.
9. a) R. Pratap, V.J. Ram, 2H-pyran-2-ones and their annelated
analogs as multifaceted building blocks for the fabrication of
diverse heterocycles, Tetrahedron, 73 (2017) 2529; b) P. Yadav,
R. Shaw, A. Elagamy, A. Kumar, R. Pratap, Base controlled
diverse reactivity of allyl cyanide for synthesis of multi-
substituted benzenes, Org. Biomol. Chem. 16 (2018) 5465; c) P.
Yadav, R. Shaw, R. Panwar, S. N. Sahu, A. Kumar, R. Pratap A
base-mediated 6-exo-trig versus 6-exo-dig carbocyclization
strategy for the synthesis of functionalized biaryls compunds,
Asian J. Org. Chem. 6 (2017) 1394.
10. a) L. Pan, X. Bi, Q. Liu, Recent developments of ketene
dithioacetals chemistry, Chem. Soc. Rev. 42 (2013) 1251; b) L.
Pan, Q. Liu, [5+1] Annulation strategy based on alkenoyl ketene
dithioacetals and analogues, Synlett. 8 (2011) 1073; c) R.K.
Dieter, α-oxo ketene dithioacetals and related compounds:
versatile three carbon synthons Tetrahedron. 42 (1986) 3029; d)
H. Junjappa, H. Ila, C. V. Asokan, α-oxo ketene –S,S-, N-S- and
N,N –acetals: Versatile intermediates in organic synthesis,
Tetrahedron. 46 (1990) 5423; e) M. Kolb, Ketene dithioacetals in
organic synthesis: Recent developments, Synthesis. 3 (1990) 171;
f) H. Ila, H. Junjapp, O. Barun, Studies on regeoselective of
benzylic oganometallics to α-oxo ketene dithioacetals in our
aromatic annelation protocol, J. Organometal. Chem. 624 (2001)
34.
11. a) H.S.P. Rao, S. Shivakumar, Condensation of α-Aroylketene
dithioacetals and 2-hydroxybenzaldehydes results in facile
synthesis of a combinatorial library of 3-aroylcoumarins, J. Org.
Chem. 71 (2006) 8715; b) G.K. Verma, R.K. Verma, G. Shukla,
N. Anugula, A. Srivastava, M. S. Singh, One-pot straight forward
approach to 2,3 disubstituted benzo/naphtho[b]furans via domino
annulation of α-oxo ketene dithioacetals and 1,4-
benzo/naphthoquinone mediated by AlCl3 at room temperature
Tetrahedron, 69 (2013) 6612; c) S. Singh, I. Althagafi, P. Yadav,
R. Panwar, A. Kumar, R. Pratap, Base mediated synthesis of α-
aminated aroyl/acetylnaphthalenes through [4+2] annulations,
Tetrahedron 70 (2014) 8879.
12. a) R. Ashley, S.B. Longstreet, B. Campbell, F. Gupton, D. Tyler
McQuade, Improved synthesis of mono-and disubstituted 2-
halonicotinonitriles form alkylidene malononitriles, Org. Lett., 15
(2013) 5298.
13. D.T. Mowry, New compounds, 1-phenylethylidenemalononitrile,
J. Am. Chem. Soc. 65 (1943) 991.
14. X. Gao, C. A, Di, Y. Hu, X. Yang, H. Fan, F. Zhang, Y. Liu, H.
Li, D. Zhu, Core-expanded naphthalne diimides fused with 2-
(1,3-dithiol-2-ylidene)malonitrile groups for high-peformance ,
ambient –stable, solution processed n-channel organic thin film
transistors, J. Am. Chem. Soc 132 (2010) 3697
15. Crystal data for C22H18N2OS: A white crystal (0.240 x 0.220 x
0.200 mm3) was mounted on a capillary tube for indexing and
intensity data collection at 298(2) K on an Oxford Xcalibur
Sapphire3 CCD single-crystal diffractometer (MoKα radiation, λ =
0.71073 Å). Routine Lorentz and polarization corrections were
applied, and an absorption correction was performed using the
ABSCALE 3 program [CrysAlis Pro software system, Version
171.34; Oxford Diffraction Ltd., Oxford, U.K., 2011]. Patterson
methods were used to locate the heavy metal atoms (SHELXS-
86), and the remaining atoms were located from successive
Fourier maps (SHELXL-97). All the non-hydrogen atoms were
refined anisotropically; hydrogen atoms were located at calculated
position using a riding model. All hydrogen atoms were calculated
after each cycle of refinement using a riding model, with C−H =

Declaration of interests
x
☐The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests:
Ramendra Pratap
Corresponding Author