Base mediated synthesis of α-aminated aroyl/acetylnaphthalenes through [4+2] annulations

Article abstract of DOI:10.1016/j.tet.2014.09.089

We have developed a base promoted simple, efficient and alternative approach for the synthesis of 4-amino-3-aroyl//heteroaroyl/acetyl-2-methylsulfanyl-naphthalene-1-carbonitriles by reaction of easily accessible 3,3-bis(methylthio)-1-aryl/heteroaryl/acety

Full text of DOI:10.1016/j.tet.2014.09.089

Tetrahedron 70 (2014) 8879e8884
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Base mediated synthesis of a-aminated aroyl/acetylnaphthalenes
through [4þ2] annulations
Surjeet Singh a, Ismail Althagafi b, Pratik Yadav a, Rahul Panwar a, Abhinav Kumar c,
,
Ramendra Pratap a
*
a Department of Chemistry, University of Delhi, North Campus, Delhi 110007, India
b Department of Chemistry, Umm Alqra University, Makkah, Saudi Arabia
c Department of Chemistry, University of Lucknow, Lucknow, Uttar Pradesh 226009, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 May 2014
Received in revised form 27 September 2014
Accepted 29 September 2014
Available online 5 October 2014
We have developed a base promoted simple, efficient and alternative approach for the synthesis of 4-
amino-3-aroyl//heteroaroyl/acetyl-2-methylsulfanyl-naphthalene-1-carbonitriles by reaction of easily
accessible 3,3-bis(methylthio)-1-aryl/heteroaryl/acetylprop-2-en-1-one and 2-cyanomethyl-benzoni-
trile. Reaction of 1-(2-halo/methoxy-phenyl)-3,3-bis(methylthio)prop-2-en-1-one and 2-cyanomethyl-
benzonitrile under basic conditions also afforded 6-(methylthio)-7-oxo-7,12-dihydrobenzo[c]acridine-5-
carbonitrile along with usual product. Structure of the synthesized product has been confirmed by single
X-ray crystallography.
Keywords:
Naphthalene
Annulation
Ketenedithioacetal
Acridine
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
aromatic ketones,13 Pd-catalyzed carbonylative cross-coupling fol-
lowed by hydrogenation,14 Cu-catalyzed synthesis of aryl amines
Arylketones are well known for their use as a building block for
the synthesis of various pharmaceutical and biologically important
compounds.1 They are also in use for dye, fragrance and agro-
from aryl halides and ammonia.15 1-Amino-2-aroylnaphthalenes
were also synthesized by reaction of 1-amino-naphthalene-2-
carbonitrile and aryl magnesium halide (Grignard reagent).16 Ear-
lier literature procedures require expensive metal catalysts, harsh
reaction conditions and moisture sensitive reagents, which gave us
impetus to develop new protocol for synthesis of highly function-
alized 1-amino-2-aroyl-naphthalene.
chemical industries.2
a-Aminoaryl-arylketone and closely related
skeletons are reported as antitubulin agents3 and also exhibit better
anti-proliferative activity against human cancer cell than colchi-
cine.4 Functionalized
a-aminated-diarylketones were used as an
intermediate for synthesis of various natural products and bi-
ologically important compound, such as derivatives of quinazo-
lines,5 new class of homocamptothecins,6 2-(aminoalkyl)-
2,3,3a,8-tetrahydrodibenzo[c,f]isoazole[2,3-a]azepine derivatives,7
azaisoflavones,8 central benzodiazepine receptor9 and pyrazole
containing class of GluN2C/GluN2D selective antagonist.10 These
compounds were also used for the synthesis of various compounds
Recently, we have developed a new precursor 2-(1-cyano-
2,2-bis(methylthio)vinyl)benzonitrile for the synthesis of 1-amino-
2-aroyl/acetylnaphthalenes.
Reaction
of
2-(1-cyano-2,2-
bis(methylthio)vinyl)benzonitrile with various acetophenones/ac-
etone under basic conditions involves (5þ1) annulation to afford
1-amino-2-aroyl/acetylnaphthalenes in good to moderate yields
(Scheme 1).17
possessing electrochemical and photophysical properties.11
a-
Aminoaryl-arylketones were generally synthesized by Friedele-
Crafts acylation.12 For monoacylation, protection of amine group is
necessary and also requires excess of Lewis acid. In literature,
limited methodologies are available for synthesis of a-amino aryl-
ketones, such as Ru (II) catalyzed intermolecular ortho amidation of
2. Result and discussion
In search of an alternative route to achieve excellent yield, we
planned to use 3,3-bis(methylthio)-1-aryl/heteroaryl/acetylprop-
2-en-1-one as a precursor (Scheme 1).18 These precursors are well
explored by Ila and co-worker for the construction of polycyclic
aromatic system.19 The required precursor 3,3-bis(methylthio)-1-
aryl/heteroaryl/acetylprop-2-en-1-ones was synthesized by re-
action of various acetophenones, acetone or cyclopropylmethyl
* Corresponding author. Tel./fax: þ91 27666646; e-mail address: ramen-
drapratap@gmail.com (R. Pratap).
http://dx.doi.org/10.1016/j.tet.2014.09.089
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

8880
S. Singh et al. / Tetrahedron 70 (2014) 8879e8884
Recently established approach [5+1 annulation approach]
moderate yield (entry 3 and 4, Table 1). Further attempt was made
by using potassium hydroxide as a base in dimethyl sulfoxide
(DMSO) and afforded the product in excellent yield (94%) in 2 h
(entry 5, Table 1). This result encourages us to screen other bases in
DMSO. Then model reaction was performed in DMSO using sodium
hydride and sodamide as base and afforded 90% and 85% of the
desired product, respectively (entry 6 and 7, Table 1). Then reaction
of 1 and 2 was performed in DMSO in presence of KOH at 70 ꢀC for
1 h and obtained 88% of desired product. Reaction of 1 and 2 was
carried out by using excess of base (3 and 4 equiv) and observed the
lowering in yield (entry 9 and 10, Table 1), probably due to some
side reaction.
MeS
SMe
NH2
O
O
CN
+
CN
R
R
CH3
SMe
CN
Yield 41-81%
Proposed alternative approach [4+2 annulation approach]
NH2
O
MeS
H
SMe
O
CN
CN
R
SMe
R
CN
Thus, stirring of an equimolar mixture of 3,3-bis(methylthio)-1-
Yield 65-94%
aryl/heteroaryl/acetylprop-2-en-1-one
and
2-
cyanomethylbenzonitrile 2 in DMSO using KOH as base for two
hours followed by required work-up provides the desired product
3-aroyl/acetyl-4-amino-2-(methylthio)-1-naphthonitriles in ex-
cellent yields. It was observed that various functional groups
present in phenyl ring of ketenedithioacetal adversely affect the
yield or product. We observed that reaction of 3,3-bis(methylthio)-
1-(4-acetylphenyl)prop-2-en-1-one with 2-cyanomethylbenz
onitrile 2 under similar conditions gave moderate yield of 3-(4-
acetylphenyl)-4-amino-2-(methylthio)-1-naphthonitrile probably
due to some side reactions of additional acetyl group in the phenyl
ring. Under optimized reaction conditions 3,3-bis(methylthio)-1-
(thiophen/furan-2-yl)prop-2-en-1-ones react with 2 and provides
excellent yield (91e92%) of the product (Table 2).
Scheme 1. (5þ1) versus (4þ2) annulations approach for synthesis of
a-amino-2-aroyl-
naphthalenes.
ketone and carbon disulphide and methyl iodide under basic con-
dition at low temperature (Scheme 2).18
MeS
SMe
O
NaH/THF
CS /
H3C
O
2 MeI
R
R
1
Scheme 2. Synthesis of 3,3-bis-methylsulfanyl-1aryl/heteroaryl/acetylprop-2-en-1-
one [Precursor was synthesized by reported literature procedure].18
Table 2
Synthesis
We have chosen 3,3-bis(methylthio)-1-phenylprop-2-en-1-one
1 and 2-cyanomethylbenzonitrile 2 as model substrate to screen
various reaction conditions (Table 1). We have started our in-
vestigation by stirring the mixture of 3,3-bis(methylthio)-1-
phenylprop-2-en-1-one 1 and 2-cyanomethylbenzonitrile 2 for
2 h in tetrahydrofuran (THF) in presence of sodium hydride and
obtained 65% of the desired product 3a (entry 1, Table 1). While use
of N,N-dimethylformamide (DMF) in lieu of THF provides 77% yield
(entry 2, Table 1). Then we have used potassium hydroxide and
sodamide as base in DMF separately and obtained the product in
of
a
variety
of
4-amino-3-aroyl/acetyl/heteroaroyl-2-
methylsulfanylnapthalene-1-carbonitrilesa,b,c
CN
CN
MeS
SMe
O
CN
2
SMe
R
KOH/DMSO
R
1
NH2
O
3
Entry
R
Yield (%)
3a
3b
3c
3d
3e
3f
3g
3h
3i
C6H5
94 (gram scale yield 91%)
87
85
84 (gram scale yield 82%)
72
50
Table 1
Optimization of reaction conditionsa
p-CH3$C6H4
p-OCH3$C6H4
p-Br$C6H4
m-Br$C6H4
p-Ac$C6H4
2-Furyl
2-Theinyl
1-Naphthyl
2-Naphthyl
CH3
CN
CN
CN
SMe
SMe
MeS
Base / Solvent
Time
91 (gram scale yield 86%)
NH2
3a
O
92
83
87
63
65
O
2
1
3j
3k
3l
Entry
Base
Solvent
Time (h)
Yieldb,c (%)
Cyclopropyl
1
2
3
NaH
THF
2
2
2
2
2
2
2
1
2
2
65
77
75
70
94
a
NaH
DMF
All reactions were performed by stirring 1 (1 mmol), 2 (1 mmol) and KOH
KOH
NaNH2
KOH
NaH
NaNH2
KOH
KOH
KOH
DMF
DMF
(2.0 mmol) in DMSO (5.0 mL) at room temperature for 2 h.
b
4
Yields are reported after recrystallisation or purification by column
5g
6
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
chromatography.
c
Room temperature was ranging between 25 and 30 ꢀC.
90
7
8
9
10
85
88d
89e
86f
Further scope of reaction was tested by using 4,4-bis(methylthio)
but-3-en-2-one
and
1-cyclopropyl-3,3-bis(methylthio)
a
All reactions performed by stirring 1 (1.0 mmol), 2 (1.0 mmol) and Base
prop-2-en-1-one as a precursor. Their reaction with 2 under basic
conditions provides corresponding product in moderate yields
(63e65%), probably due to some side reaction of acetyl or cyclo-
propyl group. The competence of the optimized reaction conditions
were checked on large scale (up to 2.0 gm) for the synthesis of var-
ious functionalized naphthalene and obtained in good yield
(82e91%).
(2.0 mmol) in 5.0 mL of solvent at room temperature.
Yields are reported after purification by recrystallization or column
chromatography.
b
c
Room temperature was ranging from 25 to 30 ꢀC.
Reaction was performed at 70 ꢀC.
d
e
3.0 equiv of KOH was used.
4.0 equiv of KOH was used.
Bold row shows the best reaction conditions.
f
g

S. Singh et al. / Tetrahedron 70 (2014) 8879e8884
8881
Interestingly, reaction of 3,3-bis(methylthio)-1-(4-fluoro/chlor-
ophenyl)prop-2-en-1-ones and 2-cyanomethylbenzonitrile under
similar reaction conditions afforded 4-amino-2-(methylthio)-3-(4-
(methylthio)benzoyl)-1-naphthonitrile 4 along with usual product
4-amino-3-(4-fluoro/chlorobenzoyl)-2-(methylthio)-1-
naphthonitrile 3m and 3n. It is clear that product 4 was formed by
nucleophilic substitution reaction of fluoro/chloro group present in
phenyl ring by in situ generated methylthio nucleophile (Scheme
3). Mechanistically, reaction will initiate with ipso attack of meth-
ylthio nucleophile at carbon bearing fluoro or chloro group with
formation of intermediate X followed by loss of halide ion to afford
the product 4. Presence of bulky group in phenyl ring will not fa-
cilitate the ipso attack and so 3d don’t react with methylthio
nucleophile.
probable
intermediate
S.N
X
Temp
(oC)
Time
hrs
Yield 3
(%)
Yield 5 Yield 6
X
CN
(%)
(%)
SMe
O
X
S
1
2
F
F
RT
RT
100
RT
RT
100
RT
RT
100
RT
100
2
30
2
35(3o)
10(3o)
----
20
28
15
25
27
18
30
47
----
10
45
----
38
-X
X
NH2
SCH3
3
F
30
CN
CN
CN
CN
4
OMe
OMe
OMe
Cl
2
50(3p)
32(3p)
----
----
----
----
----
trace
trace
----
----
SMe
O
X
SMe
O
SMe
2
5
24
2
+
KOH/DMSO
O
6
NH2
NH2
7
2
73(3q)
55(3q)
----
MeS
SMe
1
4
3
3m) X=F; 50% and 4; 33%
3n) X=Cl; 57% and 4; 29%
8
Cl
24
2
9
Cl
Scheme 3. Synthesis of 4-amino-3-(4-chloro/fluorobenzoyl)-2-(methylthio)-1-
naphthonitrile 3m, 3n and 4-amino-2-(methylthio)-3-(4-(methylthio)benzoyl)-1-
naphthonitrile 4.
10
11
Br
2
65(3r)
----
Br
2
Scheme 4. Synthesis of 4-amino-3-(2-halo/methoxybenzoyl)-2-(methylthio)-1-naph
thonitrile 3oer, 4-amino-2-(methylthio)-3-(2-(methylthio)benzoyl)-1-naphthonitrile
5 and 6-(methylthio)-7-oxo-7,12-dihydrobenzo[c]acridine-5-carbonitrile 6.
In order to explore the effect of functional group at ortho posi-
tion of phenyl ring, we have chosen the precursors 1-(2-fluoro/
chloro/bromo/methoxy-phenyl)-3,3-bis(methylthio)prop-2-en-1-
ones,18 and performed the reaction under similar conditions. 1-(2-
Fluorophenyl)-3,3-bis(methylthio)-prop-2-en-1-one 1 on reaction
with 2 afforded two more products apart from usual product 3o.
One of the product isolated was 4-amino-2-(methylthio)-3-(2-
(methylthio)benzoyl)-1-naphthonitrile (yield, 20%) formed by nu-
cleophilic replacement of fluoro group by in situ generated meth-
ylthio nucleophile, and other product 6-(methylthio)-7-oxo-7,12-
dihydrobenzo[c]acridine-5-carbonitrile (yield, 15%) formed by
intramolecular CeN bond formation reaction from 3o under basic
conditions (Scheme 4). We have observed that, reaction of 1-(2-
methoxy group followed by loss of hydrogen halide or methanol to
afford 6 (Scheme 5).
H
O
SMe
CN
-HX
O
X
N
H
Base
SMe
Y
SMe
O
fluorophenyl)-3,3-bis(methylthio)prop-2-en-1-one with
2
at
CN
CN
100 ꢀC afforded mixture of 5 (yield, 30%) and 6 (yield, 27%) with
complete consumption of 3o. If reaction of other precursors 1-(2-
chloro/bromo/methoxy-phenyl)-3,3-bis(methylthio)prop-2-en-1-
ones was carried out under basic condition at room temperature,
DMSO / KOH
100 oC/ 30-45 Minutes
N
H
X
H2N
6
only
6-(methylthio)-7-oxo-7,12-dihydrobenzo[c]acridine-5-
Yield (%)
3
Entry
X
carbonitrile 6 also isolated along with usual product 3per. If
same reaction was performed at 100 ꢀC, exclusively formation of
product 6 occurs in moderate yield (38e47%).
In order to confirm the probable intermediate for 6, reaction was
carried out for 24e30 h at room temperature and it was observed
that amount of 3oer decrease with increase in concentration of 5
(only for entry 2, Scheme 4) and 6. This result concludes that re-
quired precursor for product 6 is 3oer rather than 5. To further
confirm the proposed route, we have stirred 3oer in DMSO using
KOH as a base for 30e45 min and obtained 6-(methylthio)-7-oxo-
6
71
68
68
74
F
Cl
Br
OCH3
1
2
3
4
Scheme 5. Proposed mechanism for the synthesis of 6-(methylthio)-7-oxo-7,12-
dihydrobenzo[c]acridine-5-carbonitrile 6 from 3.
Probably, formation of 3 is initiated with nucleophilic sub-
stitution of either methylthio group by attack of carbanion gener-
ated in situ from 2-cyanomethylbenzonitrile to afford 2-(1-cyano-
2-(methylthio)-4-oxo-4-arylbut-2-enyl)benzonitrile. Under basic
7,12-dihydrobenzo[c]acridine-5-carbonitrile
(Scheme 5). Mechanistically, reaction initiates with intramolecular
nucleophilic attack of amino group at carbon bearing halogen or
6 in 68e74% yield

8882
S. Singh et al. / Tetrahedron 70 (2014) 8879e8884
condition 2-(1-cyano-2-(methylthio)-4-oxo-4-arylbut-2-enyl)ben-
zonitrile will loss the proton and enolate forms, which can exist as
either E-isomer (intermediate C) or Z-isomer (intermediate A).
Formation of isolated product can be described by using Z-isomer
enolate. Reaction involves Z-isomer and enolate attack through
carbon at CN-2, with formation of intermediate B. Intermediate B
on tautomerization, provides the desired product 3 (Scheme 6). We
proposed that regioselectively, sterically less hindered and ther-
modynamically more stable Z enolate forms as an intermediate to
afford the desired product. In order to prove the mechanistic route,
we attempted to isolate the proposed intermediate, but failed.
Reaction was performed by using low equivalent of base to avoid
the cyclization of proposed intermediate A, but desired product and
left starting material obtained. On the basis of these experiments,
we concluded that, as soon as enolate forms, it undergoes cycliza-
tion through CN-2 immediately to afford 3.
there is no intramolecular hydrogen bonding between 1ꢀ amine
and the carbonyl oxygen O1 exist.
3. Conclusions
In conclusion, we have developed a metal free, simple and
highly efficient one pot [4þ2] cycloaromatization route for the
synthesis of 4-amino-3-aroyl/heteroaroyl/acetyl-2-methylsulfanyl-
naphthalene-1-cabonitriles. This reaction is atom economic and
requires very mild reaction condition. This reaction involves one
pot inter and intramolecular CeC bond formation reaction. This
reaction provides excellent yield in comparison with recently
established 5þ1 annulations approach for their synthesis. All the
required precursors are easily accessible. This reaction has been
performed on gram scale with excellent yield successfully. In many
cases, column chromatographic purification was not required.
Along with desired product, formation of 4-amino-2-(methylthio)-
3-(4-(methylthio)benzoyl)-1-naphthonitrile, 4-amino-2-(methyl-
thio)-3-(2-(methylthio)benzoyl)-1-naphthonitrile and 6-(methyl-
thio)-7-oxo-7,12-dihydrobenzo[c]acridine-5-carbonitrile are also
an exciting result.
CN-2
CN CN
CN-1
NC
MeS
H
SMe
O
CN
H
NC
SMe
O
KOH
CN
R
4. Experimental
4.1. General
R
KOH
NC
SMe
K
NC
SMe
Commercial available reagent and solvent purchased by sigma
Aldrich and Alfa Aesar and used without further purification, IR
spectra were recorded on a PerkineElmer AX-1 spectroscopy in
wave number (cmꢁ1). The 1H NMR (400 MHz) and 13C NMR
(100 MHz) recorded in CDCl3 solution with reference of tetrame-
thylsilane and coupling constant J reported in Hertz, internal signal
patterns reported as a m, multiplet; dd double doublet; t, triplet;
d, doublet; s, singlet. Mass spectra was performed by ESIMS
spectrometer.
NC
NC
SMe
OK
K
NC
E-isomer
X
R
R
O
O
CN
C
R
CN
NH
CN
CN
Z-isomer
SMe
SMe
O
SMe
OK
H
O
H
Intensity data for the yellow coloured crystal of 3n was collected
at 298(2) K on a OXFORD CrysAlis diffractometer system equipped
N
R
NH2
R
R
A
ꢀ
B
with graphite monochromated Mo K
a
radiation
l
¼0.71073 A. The
3
final unit cell determination, scaling of the data, and corrections for
Lorentz and polarization effects were performed with CrysAlis
RED.21 The structures were solved by direct methods (SHELXS-
97)22 and refined by a full-matrix least-squares procedure based on
F2.23
Scheme 6. Mechanistic approach synthesis for 4-amino-3-aryl-2- methylsulfanyl-
naphthalene-1-cabonitriles.
2.1. X-ray structural analysis
The structure of one of the products 3n has been confirmed by
X-ray crystallography (Fig. 1).20 The compound 3n crystallize in P
21/c space group having eight molecules in the monoclinic unit cell.
The two fused rings of the naphthalene are almost planer with
dihedral angle of 3.48ꢀ between them. The fused naphthalene and
the chlorophenyl rings are perpendicular with respect to each other
and the dihedral angle between the planes formed by the naph-
thalene and the chlorophenyl rings is 82.44ꢀ and due to this fact,
4.2. General procedure for the synthesis of 4-amino-3-aroyl-
2-(methylthio)-naphthalene-1-carbonitrile (3aer, 4, 5 and 6)
A
mixture of 1-aryl/alkyl-3,3-bis-methylsulfanyl-propenone
(1.0 mmol), 2-cyanomethyl-benzonitrile (1 mmol, 142.0 mg), and
powdered KOH (2 mmol, 112.0 mg) in dry DMSO (5 mL) was stirred
at room temperature for 2 h. Completion of reaction was monitored
by TLC. After completion, reaction mixture was poured onto ice-
water with constant stirring and then neutralized with 10% HCl.
The precipitate obtained was filtered, washed with water and dried
over dry sodium sulfate. Many compounds were purified by re-
crystallization in dry methanol. Some compounds were purified
through column chromatography using 15% ethylacetate in hexane
as an eluent. Characterization data for some of the synthesized
compounds are reported earlier.17
4.2.1. 4-Amino-3-(3-bromobenzoyl)-2-(methylthio)-1-naphthonitrile
(3e). A mixture of 1-(3-bromophenyl)-3,3-bis(methylthio)prop-2-
en-1-one (301.0 mg, 1.0 mmol), 2-cyanomethyl-benzonitrile
(142.0 mg, 1.0 mmol), and powdered KOH (112.0 mg, 2.0 mmol) in
dry DMSO (5.0 mL) was stirred at room temperature for 2 h. After
completion, reaction mixture was poured onto ice-water with
Fig. 1. ORTEP diagram of 3n at 30% probability with atom numbering scheme. Only
one molecule of the asymmetric unit comprising of two molecules is presented and
water molecules have been omitted for clarity.

S. Singh et al. / Tetrahedron 70 (2014) 8879e8884
8883
constant stirring followed by neutralization with 10% HCl. The
precipitate obtained was filtered, washed with water, dried and
purified through column chromatography using 15% ethylacetate in
hexane as an eluent to obtain 82% (323.0 mg) of 3e. Brown solid, Rf
(20% ethylacetateehexane) 0.25, mp: 161e163 ꢀC; IR (KBr): 3367,
20%) and 6-(methylthio)-7-oxo-7,12-dihydrobenzo[c]acridine-5-
carbonitrile (yield, 15%) was also isolated along with usual product
3o; Rf (20% ethylacetateehexane) 0.28, yellow solid, mp:
190e192 ꢀC; IR (KBr): 3375, 2927, 2210, 1606, 1274 cmꢁ1 1H NMR
;
(400 MHz, CDCl3):
d 2.30 (3H, s, eSeCH3), 6.05 (2H, br s, eNH2),
2922, 2206,1609,1236 cmꢁ1; 1H NMR (400 MHZ, CDCl3):
d
2.35 (3H,
7.04e7.11 (1H, m, ArH), 7.15e7.20 (1H, m, ArH), 7.43e7.62 (3H, m,
ArH), 7.70e7.76 (1H, m, ArH), 7.87 (1H, d, J¼8.0 Hz, ArH), 8.17 (1H, d,
s, eSeCH3), 5.53 (2H, br s, eNH2), 7.28 (1H, t, J¼8.0 Hz, ArH),
7.53e7.63 (2H, m, ArH), 7.64e7.69 (1H, m, ArH), 7.70e7.77 (1H, m,
ArH), 7.83e7.88 (2H, m, ArH), 8.20 (1H, d, J¼8.0 Hz, 1H, ArH); 13C
J¼8.0 Hz, ArH); 13C NMR (100 MHz, CDCl3):
d 20.3, 104.5, 116.5 (d,
JCeF¼22.0 Hz), 117.1, 120.0, 121.8, 121.9, 124.2 (d, JCeF¼3.8 Hz), 126.1,
127.0, 129.0 (d, JCeF¼9.6 Hz), 130.5, 130.5, 134.1 (d, JCeF¼8.6 Hz),
134.5, 141.6, 146.8, 160.7 (d, JCeF¼262.2 Hz), 193.7; HRMS (ESI) cal-
culated for C19H13FN2OS, 337.0805 (MHþ); found for m/z, 337.0805.
NMR (100 MHz, CDCl3): d 20.5, 104.5, 117.1, 119.2, 121.6, 121.7, 122.9,
126.0, 127.1, 127.6, 130.1, 130.3, 131.5, 134.5, 136.1, 140.5, 140.7, 145.9,
195.4; HRMS (ESI) calculated for C19H13BrN2OS, 397.0005 (MHþ);
found for m/z, 397.0003.
4.2.5. 4-Amino-3-(2-methoxybenzoyl)-2-(methylthio)-1-
naphthonitrile (3p). A mixture of 1-(2-methoxyphenyl)-3,3-
bis(methylthio)prop-2-en-1-one (254.0 mg, 1.0 mmol), 2-
cyanomethyl-benzonitrile (142.0 mg, 1.0 mmol), and powdered
KOH (112.0 mg, 2.0 mmol) in dry DMSO (5.0 mL) was stirred at
room temperature for 2 h. After completion, reaction mixture was
poured onto ice-water with constant stirring followed by neutral-
ization with 10% HCl. The precipitate obtained was filtered, washed
with water, dried and purified through column chromatography
using 20% ethylacetate in hexane as an eluent to obtain 50%
(174.0 mg) of 3p along with 6-(methylthio)-7-oxo-7,12-
dihydrobenzo[c]acridine-5-carbonitrile (yield, 18%); Rf (20% ethyl-
acetateehexane) 0.23, yellow solid, mp: 179e181 ꢀC; IR (KBr):
4.2.2. 3-(4-Acetylbenzoyl)-4-amino-2-(methylthio)-1-naphthonitrile
(3f). A mixture of 1-(4-acetylphenyl)-3,3-bis(methylthio)prop-2-
en-1-one (266.0 mg, 1.0 mmol), 2-cyanomethyl-benzonitrile
(142.0 mg, 1.0 mmol), and powdered KOH (112.0 mg, 2.0 mmol) in
dry DMSO (5.0 mL) was stirred at room temperature for 2 h. After
completion, reaction mixture was poured onto ice-water with
constant stirring and neutralized with 10% HCl. The precipitate
obtained was filtered, washed with water, dried and purified
through column chromatography using 30% ethylacetate in hexane
as an eluent to obtain 50% (180.0 mg) of 3f; Rf (40% ethyl-
acetateehexane) 0.37, light yellow solid, mp: 160e162 ꢀC; IR (KBr):
3369, 2924, 2208, 1624, 1259 cmꢁ1
;
1H NMR (400 MHz, CDCl3):
d
2.33 (3H, s, eSeCH3), 2.61 (3H, s, eCOeCH3), 5.65 (2H, br s,
3367, 2923, 2206, 1600, 1276 cmꢁ1
;
1H NMR (400 MHz, CDCl3):
eNH2), 7.55e7.65 (1H, m, ArH), 7.72e7.79 (3H, m, ArH), 7.87 (1H, d,
J¼8.8 Hz, ArH), 7.98 (2H, d, J¼8.8 Hz, ArH), 8.21 (1H, d, J¼8.8 Hz,
d
2.27 (3H, s, eSeCH3), 3.67 (3H, s, eOeCH3), 5.93 (2H, br s, eNH2),
6.84e6.98 (2H, m, ArH), 7.39e7.49 (2H, m, ArH), 7.52e7.60 (1H, m,
ArH), 7.66e7.74 (1H, m, ArH), 7.86 (1H, d, J¼8.7 Hz, ArH), 8.14e8.19
ArH); 13C NMR (100 MHz, CDCl3):
d 20.6, 26.8, 104.7, 117.0, 119.2,
121.7,121.7,126.1,127.2,128.5,129.0,130.4,134.6,140.0,140.8,142.6,
(1H, m, AreH); 13C NMR (100 MHz, CDCl3):
d 20.2, 55.8, 104.1, 111.8,
146.2, 196.3, 197.3; HRMS (ESI) calculated for
C
21H16N2O2S,
117.4,120.3,121.5, 121.7, 121.9, 125.9,126.8,129.7, 130.0, 130.8,133.8,
134.2, 141.8, 146.3, 158.6, 196.0; HRMS (ESI) calculated for
C
361.1005 (MHþ); found for m/z, 361.0981.
20H16N2O2S, 349.1005 (MHþ); found for m/z, 349.1005.
4.2.3. 4-Amino-3-(cyclopropanecarbonyl)-2-(methylthio)-1-
naphthonitrile (3l). A mixture of 1-cyclopropyl-3,3-bis(methylthio)
prop-2-en-1-one (188.0 mg, 1.0 mmol), 2-cyanomethyl-benzoni-
trile (142.0 mg, 1.0 mmol), and powdered KOH (112.0 mg,
2.0 mmol) in dry DMSO (5.0 mL) was stirred at room temperature
for 2 h. Completion of reaction was monitored by TLC. After com-
pletion, reaction mixture was poured onto ice-water with constant
stirring followed by neutralization with 10% HCl. The precipitate
obtained was filtered, washed with water, dried and purified
through column chromatography using 15% ethylacetate in hexane
as an eluent to obtain 65% (183.0 mg) of 3l; Rf (20% ethyl-
acetateehexane) 0.32, Brown solid, mp: 166e168 ꢀC; IR (KBr):
4.2.6. 4-Amino-3-(2-chlorobenzoyl)-2-(methylthio)-1-naphthonitrile
(3q). A mixture of 1-(2-chlorophenyl)-3,3-bis(methylthio)prop-2-
en-1-one (257.0 mg, 1.0 mmol), 2-cyanomethyl-benzonitrile
(142.0 mg, 1.0 mmol), and powdered KOH (112.0 mg, 2.0 mmol) in
dry DMSO (5.0 mL) was stirred at room temperature for 2 h. After
completion, reaction mixture was poured onto ice-water with
constant stirring followed by neutralization with 10% HCl. The
precipitate obtained was filtered, washed with water, dried and
purified through column chromatography using 15% ethylacetate in
hexane as an eluent to obtain 73% (257.0 mg) of 3q; Rf (20% eth-
ylacetateehexane) 0.29, yellow solid, mp: 174e176 ꢀC; IR (KBr):
3363, 2925, 2204, 1642, 1241 cmꢁ1
;
1H NMR (400 MHz, CDCl3):
3351, 2923, 2205, 1608, 1277 cmꢁ1
;
1H NMR (400 MHz, CDCl3):
d
1.05e1.14 (2H, m, eCH2e), 1.31e1.37 (2H, m, eCH2e), 2.56 (3H, s,
d
2.22 (3H, s, eSeCH3), 6.51 (2H, br s, eNH2), 7.19e7.25 (2H, m,
eSeCH3), 2.59e2.68 (1H, s, eCHe), 5.94 (2H, br s, eNH2), 7.51e7.58
(1H, m, ArH), 7.65e7.73 (1H, m, ArH), 7.81 (1H, d, J¼8.5 Hz, ArH),
ArH), 7.32e7.38 (1H, m, ArH), 7.39e7.45 (1H, m, ArH), 7.56e7.63
(1H, m, ArH), 7.70e7.7 (1H, m, ArH), 7.90 (1H, d, J¼8.0 Hz, ArH), 8.15
8.14 (1H, d, J¼8.5 Hz, ArH); 13C NMR (100 MHZ, CDCl3):
d
13.9, 20.4,
(1H, d, J¼8.0 Hz, ArH); 13C NMR (100 MHz, CDCl3):
d 20.3, 105.1,
24.3, 103.8, 117.3, 120.8, 121.7, 121.8, 126.0, 126.8, 130.2, 134.1, 141.4,
145.5, 206.0; HRMS (ESI) calculated for C16H14N2OS, 283.0900
(MHþ); found for m/z, 283.0905.
117.1, 118.4, 121.8, 121.9, 126.0, 126.4, 127.1, 129.9, 130.8, 130.8, 131.7,
132.6, 134.6, 140.5, 142.4, 148.6, 196.0; HRMS (ESI) calculated for
C
19H13ClN2OS, 353.0510 (MHþ); found for m/z, 353.0510.
4.2.4. 4-Amino-3-(2-fluorobenzoyl)-2-(methylthio)-1-naphthonitrile
(3o). A mixture of 1-(2-fluorophenyl)-3,3-bis(methylthio)prop-2-
en-1-one (242.0 mg, 1.0 mmol), 2-cyanomethyl-benzonitrile
(142.0 mg, 1.0 mmol), and powdered KOH (112.0 mg, 2.0 mmol) in
dry DMSO (5.0 mL) was stirred at room temperature for 2 h. After
completion, reaction mixture was poured onto ice-water with con-
stant stirring and neutralized with 10% HCl. The precipitate obtained
was filtered, washed with water, dried and purified through column
chromatography using 15% ethylacetate in hexane as an eluent to
obtain 35% (117.0 mg) of 3o. Two other products 4-amino-2-
4.2.7. 4-Amino-2-(methylthio)-3-(2-(methylthio)benzoyl)-1-
naphthonitrile (5). A mixture of 1-(2-fluorophenyl)-3,3-
bis(methylthio)prop-2-en-1-one (242.0 mg, 1.0 mmol), 2-
cyanomethyl-benzonitrile (142.0 mg, 1.0 mmol), and powdered
KOH (112.0 mg, 2.0 mmol) in dry DMSO (5.0 mL) was stirred at
100 ꢀC for 2 h. After completion, reaction mixture was poured onto
ice-water with constant stirring and neutralized with 10% HCl. The
precipitate obtained was filtered, washed with water, dried and
purified through column chromatography using 20% ethylacetate in
hexane as an eluent to obtain 30% (109.0 mg) of 5 along with 6-
(methylthio)-7-oxo-7,12-dihydrobenzo[c]acridine-5-carbonitrile
(methylthio)-3-(2-(methylthio)benzoyl)-1-naphthonitrile
(yield,

8884
S. Singh et al. / Tetrahedron 70 (2014) 8879e8884
2. (a) Surburg, H.; Panten, J. Common Fragrance and Flavor Materials, 5th ed.;
Wiley-VCH: Weinheim, Germany, 2006; (b) Frank, H. G.; Stadelhofer, J. W. In-
dustrial Aromatic Chemistry; Springer: Berlin, 1988.
3. Liou, J. P.; Chang, C. W.; Song, J. S.; Yang, Y. N.; Yeh, C. F.; Tseng, H. Y.; Lo, Y. K.;
Chang, Y. L.; Chang, C. M.; Hsieh, H. P. J. Med. Chem. 2002, 45, 2556.
4. Reddy, G. R.; Kuo, C.-C.; Tan, U.-K.; Coumar, M. S.; Chang, C.-Y.; Chiang, Y.-K.; Lai,
M.-J.; Yeh, J.-Y.; Wu, S.-Y.; Chang, J.-Y.; Lion, J.-P.; Hsieh, H.-P. J. Med. Chem. 2008,
51, 8163.
5. (a) Yan, Y.; Zhang, Y.; Feng, C.; Zha, Z.; Wang, Z. Angew. Chem. 2012, 51, 8077; (b)
Yan, Y.; Wang, Z. Chem. Commun. 2011, 9513; (c) Zhang, J.; Zhu, D.; Yu, C.; Wan,
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P.; Zhang, W. Eur. J. Med. Chem. 2010, 45, 2726.
(yield, 27%); Rf (20% ethylacetateehexane) 0.24, yellow solid, mp:
200e202 ꢀC; IR (KBr): 3367, 2924, 2206, 1630, 1247 cmꢁ1; 1H NMR
(400 MHz, CDCl3):
d 2.33 (3H, s, eSeCH3), 2.51 (3H, s, eSeCH3),
4.88 (2H, br s, eNH2), 6.99e7.99 (1H, m, ArH), 7.20e7.26 (1H, m,
ArH), 7.37 (1H, d, J¼8.2 Hz, ArH), 7.43e7.49 (1H, m, ArH), 7.55e7.63
(1H, m, ArH), 7.68e7.76 (1H, m, ArH), 7.85 (1H, d, J¼8.2 Hz, ArH),
8.19 (1H, d, J¼8.2 Hz, ArH); 13C NMR (100 MHz, CDCl3):
d 15.6, 20.3,
104.6, 117.2, 120.6, 121.6, 121.7, 123.4, 125.0, 126.0, 127.0, 130.1, 131.8,
132.5, 134.5, 136.0, 141.1, 143.1, 146.0, 196.8; HRMS (ESI) calculated
for C20H16N2OS2, 365.0777 (MHþ); found for m/z, 365.0775.
7. Andres, J. I.; Alcazar, J.; Alonso, J. M.; Diaz, A.; Fernandez, J.; Gil, P.; Iturrino, L.;
Matesanz, E.; Meert, T. F.; Megens, A.; Sipido, V. K. Bioorg. Med. Chem. Lett. 2002,
12, 249.
8. Jin, G. H.; Ha, S. K.; Park, H. M.; Kang, B.; Kim, S. Y.; Kim, H. D.; Ryu, J. H.; Jeon, R.
Bioorg. Med. Chem. Lett. 2008, 18, 4092.
4.3. 6-(Methylthio)-7,12-dihydrobenzo[c]acridine-5-carbon-
itrile (6)
9. Anzini, M.; Valenti, S.; Braile, C.; Cappelli, A.; Vomero, S.; Alcaro, S.; Ortuso, F.;
Marinelli, L.; Limongelli, V.; Novellino, E.; Betti, L.; Giannaccini, G.; Lucacchini,
A.; Daniele, S.; Martini, C.; Ghelardini, C.; Mannelli, L. D. C.; Giorgi, G.; Mascia,
M. P.; Biggio, G. J. Med. Chem. 2011, 54, 5694.
This product was isolated during the synthesis of 3oer. This
product was also synthesized by stirring 3oer (0.5 mmol) in DMSO
(4.0 mL) using KOH (56.0 mg, 1.0 mmol) as a base at 100 ꢀC for
30e45 min. After completion, reaction mixture was poured onto
ice-water with constant stirring followed by neutralization with
10% HCl. The precipitate obtained was filtered, washed with water,
dried and purified through column chromatography using 30%
ethylacetate in hexane as an eluent to obtain 68e74% of 6; Rf (40%
ethylacetateehexane) 0.30, yellow solid, mp: 274e276 ꢀC; IR (KBr):
10. Acker, T. M.; Khatri, A.; Vance, K. M.; Slabber, C.; Bacsa, J.; Snyder, J. P.; Traynelis,
S. F.; Liotta, D. C. J. Med. Chem. 2013, 56, 6434.
11. Jiang, P.; Zhao, D.-D.; Yang, X.-L.; Zhu, X.-L.; Chang, J.; Zhu, H.-J. Org. Biomol.
Chem. 2012, 10, 4704.
12. (a) Furstner, A.; Voigtlander, D.; Schrader, W.; Giebel, D.; Reetz, M. T. Org. Lett.
2001, 3, 417; (b) Fillion, E.; Fishlock, D.; Wilsily, A.; Goll, J. M. J. Org. Chem. 2005,
70, 1316.
13. Bhanuchandra, M.; Yadav, M. R.; Rit, R. K.; Kuram, M. R.; Sahoo, A. K. Chem.
Commun. 2013, 5225.
3325, 2925, 2206, 1624, 1274 cmꢁ1
2.67 (3H, s, eSeCH3), 7.36 (1H, s, ArH), 7.74e8.17 (6H, m, ArH),
8.84e8.90 (1H, m, ArH), 11.79 (1H, br s, eNHe); 13C NMR (100 MHz,
DMSO): 20.6, 104.1, 115.9, 117.3, 118.3, 121.5, 123.2, 123.5, 123.8,
;
1H NMR (400 MHz, DMSO):
14. Niu, J. R.; Huo, X.; Zhang, F. W.; Wang, H. B.; Zhao, P.; Hu, W. Q.; Ma, J.; Li, R.
d
ChemCatChem 2013, 5, 349.
15. Thakur, K. G.; Ganapathy, D.; Sekar, G. Chem. Commun. 2011, 5076.
16. Zhang, W.; Koehler, K. F.; Harris, B.; Skolnick, P.; Cook, J. M. J. Med. Chem. 1994,
37, 745.
d
124.4, 125.5, 127.3, 131.5, 133.0, 133.4, 139.0, 141.5, 148.3, 175.4;
HRMS (ESI) calculated for C19H12N2OS, 317.0743 (MHþ); found for
m/z, 317.0743.
17. Singh, S.; Yadav, P.; Sahu, S. N.; Althagafi, I.; Kumar, A.; Kumar, B.; Ram, V. J.;
Pratap, R. Org. Biomol. Chem. 2014, 12, 4730.
18. Rao, H. S. P.; Shivakumar, S. J. Org. Chem. 2006, 71, 8715; (b) Verma, G. K.;
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2011028864 A1 20110310, 2011.
Acknowledgements
Authors thank Council of Scientific and Industrial Research
(CSIR, New Delhi) and Department of Science and Technology (DST,
New Delhi) Delhi for financial support. S.S. thank Council of Sci-
entific and Industrial Research (CSIR, New Delhi) and P.Y. and S.N.S.
thank University Grants Commission (UGC, New Delhi) for research
fellowship. Authors thank University of Delhi for providing re-
search funding and instrumentation facility.
19. Nandi, S.; Panda, K.; Suresh, J. R.; Ila, H.; Junjappa, H. Tetrahedron 2004, 60,
3663.
20. Crystal data for 3n (CCDC 999668): C19H13ClN2OS, FW¼368.82, Monoclinic, P
ꢀ
ꢀ
ꢀ
b
21/c, a¼18.1345(7) A, b¼7.6901(3) A, c¼26.7377(14) A,
¼99.348(4)ꢀ, V¼3679.
3
ꢀ
2(3) A , T¼298(2) K, Z¼8,
m
, mmꢁ1¼0.335, dcalc, g cmꢁ3¼1.332, R1 [I>2
(I)]¼0.
s
0834, wR2¼0.2137, R1 [all data]¼0.1068, wR2¼0.2282, S¼1.145. ‘CCDC contains
the supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif’.
Supplementary data
21. CrysAlis CCD, RED version 1.711.13, copyright 1995e2003, Oxford Diffraction
Poland Sp.
1H and 13C spectra of the entire synthesized compound are
provided in ESD. Supplementary data related to this article can be
found at http://dx.doi.org/10.1016/j.tet.2014.09.089.
22. Sheldrick, G. M. SHELXS97, Program for Crystal Structure Solution; University of
€
€
Gottingen: Gottingen, Germany, 1997.
23. Sheldrick, G. M. SHELXL97, Program for Crystal Structure Refinement; University
€
€
of Gottingen: Gottingen, Germany, 1997.
References and notes
1. Kimpe, N. D.; Keppens, M.; Froncg, G. Chem. Commun. 1996, 635.