Synthesis of 1-amino-2-aroyl/acetylnaphthalenes through a base mediated one pot inter and intramolecular C-C bond formation strategy

Article abstract of DOI:10.1039/c4ob00432a

A new precursor 2-(1-cyano-2,2-bis(methylthio)vinyl)benzonitrile has been synthesized by the reaction of 2-cyanomethylbenzonitrile, carbon disulfide and methyl iodide under basic conditions. The reaction of 2-(1-cyano-2,2- bis(methylthio)vinyl)benzonitrile with various functionalized aryl/heteroaryl methyl ketones or acetone under basic conditions afforded 4-amino-3-aroyl/ heteroaroyl/acetyl-2-methylsulfanylnaphthalene-1-carbonitriles in good yields through a (5C + 1C) annulation strategy; this involves sequential intermolecular, followed by intramolecular, C-C bond formation reactions. The structure of the product was confirmed by single crystal X-ray crystallography. This journal is

Full text of DOI:10.1039/c4ob00432a

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PAPER
Synthesis of 1-amino-2-aroyl/acetylnaphthalenes
through a base mediated one pot inter and
intramolecular C–C bond formation strategy†
Cite this: Org. Biomol. Chem., 2014,
12, 4730
Surjeet Singh,a Pratik Yadav,a Satya Narayan Sahu,a Ismail Althagafi,b Abhinav Kumar,c
Brijesh Kumar,d Vishnu Ji Ramc and Ramendra Pratap*a
A new precursor 2-(1-cyano-2,2-bis(methylthio)vinyl)benzonitrile has been synthesized by the reaction of
2-cyanomethylbenzonitrile, carbon disulfide and methyl iodide under basic conditions. The reaction of
2-(1-cyano-2,2-bis(methylthio)vinyl)benzonitrile with various functionalized aryl/heteroaryl methyl ketones
or acetone under basic conditions afforded 4-amino-3-aroyl/heteroaroyl/acetyl-2-methylsulfanyl-
naphthalene-1-carbonitriles in good yields through a (5C + 1C) annulation strategy; this involves sequen-
tial intermolecular, followed by intramolecular, C–C bond formation reactions. The structure of the
product was confirmed by single crystal X-ray crystallography.
Received 25th February 2014,
Accepted 16th April 2014
DOI: 10.1039/c4ob00432a
www.rsc.org/obc
Introduction
Ketenedithioacetals are known to be versatile precursors, for
their broad synthetic applications.1 Their synthetic utility
has been widely explored for the construction of various aro-
matic and heteroaromatic, along with nonaromatic, ring
systems of medicinal and synthetic importance.2 A large
variety of ketenedithioacetals are reported to have applications
in substitution, elimination and addition reactions;1 the syn-
thesis of various functionalized 2H-pyran-2-ones;3 partially
reduced coumarin;3 pyrazoles;3 oxazoles;3 thiophenes;3 pyri-
dines;3 pyrimidines3 and fluorescent4 compounds. The broad
synthetic potential of these synthons prompted us to further
investigate their chemistry.
Functionally loaded diaryl ketones are present as the struc-
tural motif in various synthetically and biologically important
molecules and natural products.5 α-Aminodiaryl ketones and
molecules embedded with these molecular skeletons find
applications as antitubulin agents, e.g. phenstatin I,6 hydroxy-
phenstatine6 (II) and 2-aminobenzophenone analogues (III).7
Fig. 1 The structures of phenstatin I, hydroxyphenstatine II, 2-amino-
benzophenone analogues III 3-substituted 6-aryl-4H-imidazo-[1,5-a]-
benzodiazepines and related compounds (IV–VI).
2-Amino-1-aroylnaphthalene and 2-hydroxy-1-aroylnaphthalene
also exhibit good anti-proliferative activity against human
cancer cells, comparable in potency to colchine (Fig. 1).8
3-Substituted 6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepines
(IV) and related compounds (V–VI) embedded with o-aminated
phenyl aryl ketones are reported to be central benzodiazepine
receptor (CBR) ligands, as shown in Fig. 1.9
An extensive literature survey concluded that very limited
methodologies are available for the synthesis of o-aminoaryl
aryl ketones (Scheme 1). 2-Aminobenzophenone analogues
have been prepared in three steps by Liou et al.7 The first
step was the synthesis of benzhydrol derivatives via the
coupling of (3,4,5-trimethoxyphenyl)magnesium bromide with
aDepartment of Chemistry, University of Delhi, North campus, Delhi, 110007, India.
E-mail: ramendrapratap@gail.com; Tel: +91 1127666646
bDepartment of Chemistry, Umm Alqra University, Makkah, Saudi Arabia
cDepartment of Chemistry, University of Lucknow, Lucknow, Uttar Pradesh 226009,
India
dDivision of SAIF, Central Drug Research Institute, Lucknow, Uttar Pradesh 226001,
India
†Electronic supplementary information (ESI) available: NMR spectra. Crystallo-
graphic and computational details and CIF file for 10b. CCDC 967742. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c4ob00432a
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Scheme 2 Synthesis of 2-(1-cyano-2,2-bis(methylthio)vinyl)benzonitrile.
be employed for the development of new molecular make-ups.
We wished to use carbon nucleophiles to replace the methylthio
group of 2-(1-cyano-2,2-bis(methylthio)vinyl)benzonitrile, fol-
lowed by utilization of the nitrile group at the ortho position in
the benzene ring for concomitant cyclization.
Taking into account the above concept, we used 2-(1-cyano-
2,2-bis(methylthio)vinyl)benzonitrile and acetophenone as
model substrates to screen various reaction conditions
(Table 1). We started the screening using sodium hydride in
THF, and isolated the desired compound with a 55% yield
upon reacting it for 20 hours at room temperature (entry 1).
Scheme 1 Reported methodologies versus our methodology.
various substituted 2-nitrobenzaldehydes, which, on oxidation We shifted to a polar solvent, DMF, in lieu of the THF in com-
with pyridinium dichromate (PDC), followed by nitro group bination of NaH, but little change was observed (entry 2). We
reduction, provided functionalized α-aminobenzophenones. also tested potassium hydroxide and sodamide in DMF under
Synthesis of α-aminonaphthophenones was also reported by similar reaction conditions and got better results in the case
Zhang et al.10 1-Amino-2-naphthonitrile, the required pre- of the potassium hydroxide than the sodamide. For further
cursor for the synthesis of α-aminonaphthophenones, has been improvement, we carried out the reaction in DMSO with KOH
synthesized by the regioselective cyanation of l-nitronaphtha- at room temperature, and surprisingly the reaction was com-
lene.11 The reaction of aryl magnesium halides with 1-amino- pleted in 2 hours with an 81% yield (entry 5). This result
2-naphthonitrile, followed by hydrolysis, provided the α-nitro- proves that DMSO is the best solvent for the screening of
naphthophenones. These, upon concomitant reduction, gave various bases. Probably, the presence of the CHO group in the
α-aminonaphthophenones in a poor overall yield.
DMF hindered the formation of the desired product, due to
Most of the previously reported methodologies required a
multistep reaction approach, the use of expensive reagents,
harsh reaction conditions, naphthyl ring-containing pre-
cursors and provided overall low yields.10,11 A 5 + 1 Annulation
strategy for the construction of various kind of nuclei has been
reported earlier.11 Zhang et al. have reported using the 5C +
1C/N cyclization strategy for the synthesis of benzene nuclei
from ketenedithioacetals.11b Liu and co-workers have also
used 5C + 1C cyclization for the synthesis of highly crowded
cyclohexenones.11 We have made the first attempt to syn-
thesize a naphthalene nucleus using the 5C + 1C cyclization
strategy.
Table 1 Optimization of reaction conditionsa
Entry
Base
Solvent
Tempc (°C)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
NaH
NaH
THF
DMF
DMF
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
RT
RT
RT
RT
RT
RT
RT
RT
60
20
20
20
20
2
2
2
2
2
1.5
2
2
55
65
70
26
81
70
70
65
65
55
70d
66e
KOH
NaNH2
KOH
NaH
NaNH2
NaOH
KOH
KOH
KOH
KOH
Results and discussion
We chose 2-(1-cyano-2,2-bis(methylthio)vinyl)benzonitrile as a
key synthetic precursor for the construction of multifunctional
naphthalene rings. This was synthesized by the reaction of
2-cyanomethylbenzonitrile, carbon disulfide and methyl iodide
under basic conditions (Scheme 2). We screened some alkaline
solvent combinations such as NaH–THF, K2CO3–DMF, NaOEt–
9
10
11
12
90
RT
RT
a All the reactions were carried out by using 3 (0.5 mmol), 4a
(0.55 mmol), a base (1.0 mmol) and 4.0 mL of solvent. b Yields
ethanol and KOtBu–THF for the synthesis of the desired pre- reported are after purification through column chromatography. c RT
is room temperature; this ranged from 25–30 °C. d The reaction was
cursor, and NaH–THF was found to be the best combination.
carried out using 3 equivalents of KOH (1.5 mmol) as a base. e The
An earlier report3 has shown that the methylthio group of
reaction was carried out using 4 equivalents of KOH (2.0 mmol)
ketenedithioacetals acts as an excellent leaving group, and can as a base.
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some side reactions with acetophenone. We screened sodium formation of product 7. It is likely that the bigger size of bromine
hydride, sodamide and sodium hydroxide in DMSO, but no prevents the nucleophilic attack of the methylthio group. The
base was better than potassium hydroxide (entries 6, 7 and 8). use of o-substituted acetophenone gave a low to moderate yield
We checked the influence of temperature using potassium of aryl naphthyl ketone, probably due to steric hindrance. We
hydroxide as a base in dimethyl sulfoxide, and no significant tried 2-hydroxyacetophenone as a nucleophile source and
results were obtained (entries 9 and 10). We also evaluated the ended up with a complex reaction mixture, but the use of
effect of an excess of potassium hydroxide on the reaction, and 2-allyloxyacetophenone yielded the desired product in a moderate
observed a lower yield of the desired product (entries 11 and yield. Apart from functionalized acetophenones, we also
12). We proposed that an excess amount of the base enhances used 2-acetylfuran and 2-acetylthiophene as nucleophile
the possibility of side reactions of the product, lowering the sources, and isolated the desired product in moderate yields.
yield. Thus, the stirring of one equivalent of 2-(1-cyano-2,2-bis- We successfully synthesized dinaphthyl ketone in a good yield,
(methylthio)vinyl)benzonitrile 3 with 1.1 equivalents of aryl using acetonaphthone as a nucleophile source. Interestingly,
methyl ketones 4 and two equivalents of potassium hydroxide we also used acetone as a nucleophile source and successfully
in DMSO at room temperature, followed by a proper work-up synthesized highly functionalized acetonaphthone, which is a
and purification, provided multifunctional naphthalenes 5 in very interesting precursor that is very difficult to synthesize by
good yields.
With these optimized reaction conditions, we synthesized
reported literature procedures.
In order to further enhance the scope of this reaction, we
various highly functionalized aryl naphthyl ketones (Scheme 3). planned to replace the methylthio group with a secondary
We used various acetophenones 4 containing electron donor amine, before the 5C + 1C annulations. We tested various reac-
and acceptor groups. It has been observed that the presence of tion conditions for the synthesis of 2-(1-cyano-2-(methylthio)-
these groups in the aryl ring negatively affects the yields of the 2-(pyrrolidin-1-yl)vinyl)benzonitrile, but failed to obtained a
desired product. Interestingly, we observed that the use of selective route to monoamination. The reaction of 2-(1-cyano-
p-chloro/fluoroacetophenone provides the desired product, 2,2-bis(methylthio)vinyl)benzonitrile and an excess of pyrroli-
4-amino-3-(4-chloro/fluoro-benzoyl)-2-(methylthio)-1-naphtho- dine at 30 °C yielded a mixture of 2-(1-cyano-2-(methylthio)-
nitrile, as
a major product and 4-amino-2-(methylthio)- 2-(pyrrolidin-1-yl)vinyl)benzonitrile as the major product and
3-(4-(methylthio)benzoyl)-1-naphthonitrile as a minor product, 2-(1-cyano-2,2-di(pyrrolidin-1-yl)vinyl)benzonitrile as the minor
by an unusual nucleophilic substitution of the fluoro/chloro product (Scheme 3). At 90 °C, the monoaminated product was
group in the aryl ring due to the in situ generation of a isolated in a 73% yield, while the continuation of the reaction
methylthio nucleophile. Meanwhile, the use of o/p-bromoaceto- for a longer time provided the diaminated product in excess.
phenone afforded only the desired product, without any Six-membered secondary amines yielded a major diaminated
product due to the more nucleophilic nature of nitrogen,
which was not a suitable precursor for the synthesis of
naphthalene.
We took 2-(1-cyano-2-(methylthio)-2-(pyrrolidin-1-yl)vinyl)-
benzonitrile as a precursor and performed the reaction with
various functionalized aryl/heteroaryl methyl ketones, using
KOH as a base in DMSO at room temperature; we successfully
obtained naphthalene bearing a pyrrolidine group in lieu of
the methylthio group (Scheme 4).
Scheme 4 Synthesis
of
2-(1-cyano-methylsulfanyl-2-pyrrolidine-
1-yl-vinyl)-benzonitrile, 2-(1-cyano-methylsulfanyl-2,2-di-pyrrolidine-
1-yl-vinyl)-benzonitrile and 4-amino-3-aroyl/heteroaroyl/acetyl-2-pyrroli-
din-1-yl-1-carbonitriles.
Scheme 3 Synthesis of various 4-amino-3-aroyl/heteroaroyl/acetyl-2-
methylsulfanylnaphthalene-1-carbonitriles (5a–m and 7).
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Mechanistically, the reaction is possibly initiated by a presence of potassium hydroxide. The reaction containing
nucleophilic substitution at the C-2 of 2-(1-cyano-2,2-bis- acetone shows an additional peak at ∼5.98 ppm in comparison
(methylthio)vinyl)benzonitrile, by an in situ generated nucleo- to the mixture containing acetone-d6, which confirms that the
phile from acetophenone with the loss of the methylthio proton on the amino group comes from the methyl group of
group, which would lead to the formation of intermediate X aryl methyl ketone (see Fig. 1 in the ESI†).
(Scheme 5). In the presence of an excess of base, a carbanion
would be generated in the α position to the carbonyl group, X-ray structural analysis
which would attack intramolecularly at the nitrile group
The structure of one of the products, 4-amino-3-(4-methoxy-
present in the ortho position, forming intermediate Y (Path A).
benzoyl)-2-(pyrrolidin-1-yl)-1-naphthonitrile 10b, has been
Intermediate Y would undergo tautomerisation to yield the
confirmed by X-ray crystallography (Fig. 2).‡ Compound 10b
desired product. Mechanistically, there was also the possibility
of the formation of 2-pyranone (Path B), but the aryl naphthyl
ketone was regioselectively isolated. We propose that C–C
bond formation by an attack of the carbanion at the nitrile
group present in the aryl ring is more facile than C–O bond
formation, due to the reaction of the enolate oxygen with the
other nitrile group.
In order to prove the mechanism, we have made various
attempt to isolate the intermediate X, but failed. We per-
formed the reaction using a ketone/base ratio of 2 : 1, but we
got a mixture of products and the starting material, without
any trace of intermediate. We conclude that, as soon as inter-
mediate X forms in the reaction mixture, it immediately under-
goes cyclization due to the formation of an activated
methylene group, which is more reactive than the methyl
group and cannot be isolated. We have also attempted to
check whether the proton on the amino group is coming from
the methyl group of the aryl methyl ketone, or from the acidic
work-up. We performed two parallel reactions of 3 and
acetone-d6 and acetone in DMSO-d6 respectively, in the
ˉ
crystallized in the P1 space group, having two molecules in the
triclinic unit cell. The naphthalene and the anisole rings are
planar, and the dihedral angle between the planes formed by
the fused naphthalene and anisyl rings is 52.47°. The five-
membered pyrrolidine ring adopts a puckered half-chair con-
formation to relieve the strain resulting from the eclipsed
orientation of the hydrogens and substituents on the adjacent
carbon atoms. The proton H1b forms an intramolecular hydro-
gen bond with the carbonyl oxygen O1, having an H1b⋯O1
interaction length of 1.891 Å with a N1–H1b⋯O1 bond angle
of 138.35°.
The compound displayed an intermolecular N–H⋯NuC
interaction (Fig. 3) to form a one dimensional chain which
had an N⋯H interaction distance of 2.091 Å and an interaction
angle of 159.39° (symm. op. −1 + x, y, z). Quantum chemical
DFT calculations for the dimer held by the N–H⋯NuC inter-
action yielded an interaction energy of −8.18 kcal mol−1
.
Additionally, the atoms-in-molecules (AIM) theory calculations
indicated bond critical points between the H and N atoms,
which also confirm the presence of this interaction between
the two molecules (see ESI†). The values of electron density
(ρ) +0.019733; Laplacian (∇2ρbcp) +0.059176; bond ellipticity
(ε) +0.018129 and total energy density (H) +0.014103 at the bond
critical point indicated the real interaction. The bond ellipti-
city (ε) measuring the extent to which the density is preferen-
tially accumulated in a given plane of the bond path, indicated
that these N–H⋯NuC interactions are not cylindrically sym-
metrical in nature.
Fig. 2 ORTEP diagram of 10b at 30% probability with atom numbering
scheme. Only one molecule of the asymmetric unit comprised of two
molecules is presented.
ˉ
‡Crystal data for 10b (CCDC 967742): C23H21N3O2, FW = 371.43, triclinic, P1, a =
9.094(5) Å, b = 13.650(5) Å, c = 16.253(5) Å, α = 80.99(3), β = 85.10(3), γ = 72.87(4),
V = 1902.6(14) Å3, T = 298(2) K, Z = 4, μ, mm−1 = 0.084, dcalc, g cm−3 = 1.297,
R1 [I > 2σ(I)] = 0.0787, wR2 = 0.1529, R1 [all data] = 0.1815, wR2 = 0.2068, S = 1.010.
Scheme 5 Proposed mechanism for the synthesis of 4-amino-3-aroyl/
heteroaroyl/acetyl-2-methylsulfanylnaphthalene-1-carbonitriles.
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removed under reduced pressure. The mixture was poured
onto ice-water with vigorous stirring, and the obtained pre-
cipitate was filtered and dried under vacuum. The compound
was purified by recrystallization from 2% acetone in hexane.
2-(1-Cyano-2,2-bis-methylsulfanyl-vinyl)-benzonitrile 3
Yield: 90% (3.321 g); 0.42 Rf (20% ethylacetate–hexane), light
yellow solid, mp: 82–84 °C; IR (KBr): 2925, 2853, 2226,
Fig. 3 One dimensional chain held together by intermolecular
N–H⋯NuC interactions (symm. op. −1 + x, y, z).
1
2200 cm−1; H NMR (400 MHz, CDCl3): δ 2.41 (s, 3H, –SCH3),
2.64 (s, 3H, –SCH3), 7.43–7.49 (m, 2H, ArH), 7.61–7.66 (m, 1H,
ArH), 7.70 (d, J = 8.0 Hz, 1H, Ar-H); 13C NMR (100 MHz,
CDCl3): δ 18.0, 18.8, 107.1, 112.8, 116.9, 117.1, 129.1, 130.5,
133.2, 133.3, 137.8, 165.1; HRMS values (ESI) calculated for
C12H10N2S2, 247.0358 (M + H+); found for m/z, 247.0358.
Conclusion
In conclusion, we have developed an economical, metal-free
one-step (5 + 1) annulation strategy for the synthesis of
4-amino-3-aroyl/acetyl-2-methylsulfanyl/secamino-naphthalene-
1-carbonitriles. The precursor required for the synthesis of
4-amino-3-aroyl/acetylnaphthalenes is easily accessible in one
step, in moderate to good yields. This synthesis is also atomic-
ally economical. We have not used any harsh reaction con-
ditions and the structure was confirmed unambiguously by
X-ray crystallography.
General procedure for the synthesis of 4-amino-3-aroyl-2-methyl-
sulfanyl-naphthalene-1-carbonitrile
To a 25 mL RB flask, a mixture of 2-(1-cyano-2,2-bismethylsul-
fanyl-vinyl)-benzonitrile (0.5 mmol, 0.123 g), aryl/alkyl methyl
ketone (0.55 mmol), and powdered KOH (1 mmol, 0.056 g) in
dry DMSO (4.0 mL) was stirred at room temperature for 2 h
under dry conditions. After completion (monitored by TLC) of
the reaction, the mixture was poured onto ice-water with con-
stant stirring, followed by neutralization with 10% HCl. The
obtained precipitate was filtered off and dried. The crude
product was purified by silica gel column chromatography,
using 15% ethylacetate in hexane as an eluent.
Experimental section
General remarks
4-Amino-3-benzoyl-2-methylsulfanyl-naphthalene-1-carbo-
nitrile 5a. Yield: 81% (0.129 g); 0.28 Rf (20% ethylacetate–
hexane), light brown solid mp: 166–168 °C; IR (KBr): 3372,
We used commercially available reagents without purification.
1H and 13C NMR spectra were recorded on a 400 MHz NMR
and 100 MHz NMR spectrometer and CDCl3 was used as the
solvent. Chemical shifts are reported in parts per million shift
(δ-value) from (CDCl3) (δ 7.24 ppm for 1H) or based on the
middle peak of the solvent (CDCl3) (δ 77.00 ppm for 13C NMR)
as an internal standard. Signal patterns are indicated as
s, singlet; d, doublet; dd, double doublet; t, triplet; m, multiplet;
bs, broad singlet and bm, broad multiplet. Coupling constants
(J) are given in hertz (Hz). Infrared (IR) spectra were recorded
on a Perkin-Elmer AX-1 spectrophotometer and reported in
wave number (cm−1). High-resolution mass spectrometry
(HRMS) values reported show the peak for M + H+. Room
temperature ranged from 25–30 °C during the reactions.
1
2921, 2205, 1638, 1248, 763 cm−1; H NMR (400 MHz, CDCl3):
δ 2.35 (s, 3H, –SCH3), 5.37 (s, 2H, –NH2), 7.39–7.47 (m, 2H,
ArH), 7.53–7.63 (m, 2H, ArH), 7.69–7.76 (m, 3H, ArH), 7.84
(d, J = 8.0 Hz, 1H, ArH), 8.21 (d, J = 8.0 Hz, 1H, ArH); 13C NMR
(100 MHz, CDCl3): δ 20.5, 104.6, 117.2, 120.5, 121.6, 121.6,
126.0, 127.0, 128.7, 129.1, 130.0, 133.5, 134.5, 138.5, 140.6,
145.3, 196.8; HRMS values (ESI) calculated for C19H14N2OS,
319.0900 (M + H+); found for m/z, 319.0889.
4-Amino-3-(4-methyl-benzoyl)-2-methylsulfanyl-naphthalene-
1-carbonitrile 5b. Yield: 41% (0.068 g); 0.27 Rf (20% ethylace-
tate–hexane), light yellow, mp: 170–172 °C; IR (KBr): 3367,
2926, 2854, 2206, 1627, 1242, 752 cm−1 1H NMR (400 MHz,
;
CDCl3): δ 2.37 (s, 3H, –SCH3), 2.40 (s, 3H, –CH3), 5.27 (s, 2H,
–NH2), 7.21–7.25 (m, 2H, ArH), 7.53–7.61 (m, 1H, ArH), 7.63
(d, J = 8.0 Hz, 2H, ArH), 7.69–7.75 (m, 1H, ArH), 7.83 (d, J =
General procedure for the synthesis of 2-(1-cyano-2,2-
bismethylsulfanylvinyl)benzonitrile 3
To a well dried 100 mL RB flask was added THF (40.0 mL) and 8.0 Hz, 1H, ArH), 8.20 (d, J = 8.0 Hz, 1H, ArH); 13C NMR
sodium hydride [60% dispersion in mineral oil] (30.0 mmol, (100 MHz, CDCl3): δ 20.5, 21.7, 104.3, 117.3, 120.9, 121.6,
1.20 g), and this was cooled in an ice-bath. 2-Cyanomethyl- 125.9, 126.9, 129.3, 129.4, 129.9, 134.4, 135.7, 140.3, 144.8,
benzonitrile (15.0 mmol, 2.130 g) was added drop wise to the 145.0, 196.3; HRMS values (ESI) calculated for C20H16N2OS,
pre-cold basic solution. After complete addition, the reaction 333.1056 (M + H+); found for m/z, 333.1044.
mixture was stirred for one hour followed by the drop-wise
4-Amino-3-(4-methoxy-benzoyl)-2-methylsulfanyl-naphthalene-
addition of carbondisulphide (16.5 mmol, 0.995 mL) at 0–5 °C. 1-carbonitrile 5c. Yield: 48% (0.084 g); 0.24 Rf (20% ethyl-
The reaction mixture was further stirred for another hour fol- acetate–hexane), Brown solid, mp: 131–133 °C; IR (KBr): 3362,
lowed by the drop-wise addition of methyl iodide (33.0 mmol, 2933, 2207, 1630, 1594, 1259, 752 cm−1 1H NMR (400 MHz,
;
2.055 mL) over a period of 30 minutes. The reaction mixture CDCl3): δ 2.40 (s, 3H, –SCH3), 3.85 (s, 3H, –OCH3), 5.19 (s, 2H,
was stirred for one hour. After completion, excess THF was –NH2), 6.90 (d, J = 8.8 Hz, 2H, Ar-H), 7.54–7.62 (m, 1H, ArH),
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7.67–7.76 (m, 3H, ArH), 7.82 (d, J = 8.0 Hz, 1H, ArH), 8.20
4-Amino-2-methylsulfanyl-3-(thiophene-2-carbonyl)-naphthalene-
(d, J = 8.0 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3): δ 20.6, 55.5, 1-carbonitrile 5h. Yield: 61% (0.099 g); 0.31 Rf (30% ethylace-
104.4, 114.0, 117.3, 121.3, 121.5, 121.6, 126.0, 126.9, 129.8, tate–hexane), yellow solid mp: 173–175 °C; IR (KBr): 3362,
130.9, 131.8, 134.4, 140.2, 144.7, 164.2, 195.1; HRMS values 2929, 2207, 1624, 1271, 727 cm−1; H NMR (400 MHz, CDCl3):
1
(ESI) calculated for C20H16N2O2S, 349.1005 (M + H+); found for δ 2.47 (s, 3H, –SCH3), 5.24 (s, 2H, –NH2), 7.06–7.10 (m, 1H,
m/z, 349.0990.
ArH), 7.32–7.37 (m, 1H, ArH), 7.56–7.63 (m, 1H, ArH),
4-Amino-3-(4-bromo-benzoyl)-2-methylsulfanyl-naphthalene- 7.69–7.76 (m, 2H, ArH), 7.82 (d, J = 8.8 Hz, 1H, ArH), 8.21
1-carbonitrile 5d. Yield: 68% (0.135 g); 0.26 Rf (20% ethylace- (d, J = 8.0 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3): δ 20.9, 104.5,
tate–hexane); light yellow solid, mp: 152–154 °C; IR (KBr): 117.2, 121.2, 121.5, 121.6, 126.0, 127.0, 128.3, 130.0, 134.4,
3361, 2924, 2207, 1638, 1249, 749 cm−1 1H NMR (400 MHz, 134.8, 135.5, 140.2, 144.7, 145.1, 188.3; HRMS values (ESI)
;
CDCl3): δ 2.37 (s, 3H, –SCH3), 5.45 (s, 2H, –NH2), 7.51–7.69 calculated for C17H12N2OS2, 325.0464 (M + H+); found for m/z,
(m, 5H, ArH), 7.70–7.78 (m, 1H, ArH), 7.83 (d, J = 8.0 Hz, 1H, 325.0450.
ArH), 8.21 (d, J = 8.0 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3):
4-Amino-2-methylsulfanyl-3-(naphthalene-1-carbonyl)-naphtha-
δ 20.6, 104.7, 117.1, 119.6, 121.6, 121.6, 126.1, 127.2, 128.7, lene-1-carbonitrile 5i. Yield: 48% (0.088 g); 0.25 Rf (20% ethy-
130.2, 130.5, 132.0, 134.5, 137.5, 140.5, 145.6, 195.7; HRMS lacetate–hexane), orange solid, mp: 187–189 °C; IR (KBr): 3372,
1
values (ESI) calculated for C19H13BrN2OS, 397.0005 (M + H+); 2925, 2210, 1609, 1240, 759 cm−1; H NMR (400 MHz, CDCl3):
found for m/z, 396.9983.
δ 2.12 (s, 3H, –SCH3), 5.95 (s, 2H, –NH2), 7.22–7.35 (m, 2H,
4-Amino-3-(2-bromo-benzoyl)-2-methylsulfanyl-naphthalene- ArH), 7.55–7.71 (m, 4H, ArH), 7.90 (d, J = 8.0 Hz, 2H, ArH),
1-carbonitrile 5e. Yield 48% (0.095 g); 0.26 Rf (20% ethylace- 7.95 (d, J = 8.0 Hz, 1H, ArH), 8.19 (d, J = 8.0 Hz, 1H, ArH), 8.78
tate–hexane); yellow solid, mp: 188–190 °C; IR (KBr): 3369, (d, J = 8.0 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3): δ 20.3,
1
2925, 2211, 1609, 1245, 757 cm−1; H NMR (400 MHz, CDCl3): 104.9, 117.2, 121.1, 121.6, 121.8, 124.0, 126.0, 126.7, 127.1,
δ 2.23 (s, 3H, –SCH3), 6.56 (s, 2H, –NH2), 7.15–7.20 (m, 1H, 128.2, 128.5, 128.8, 130.3, 130.7, 133.1, 134.0, 134.6, 137.6,
ArH), 7.23–7.29 (m, 2H, ArH), 7.57–7.67 (m, 2H, ArH), 7.74 141.9, 146.8, 198.9; HRMS values (ESI) calculated for
(t, J = 7.7 Hz, 1H, ArH), 7.90 (d, J = 8.0 Hz, 1H, ArH), 8.17 (d, C23H16N2OS, 369.1056 (M + H+); found for m/z, 369.1038.
J = 8.8 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3): δ 20.4, 105.2,
4-Amino-2-methylsulfanyl-3-(naphthalene-2-carbonyl)-naphtha-
117.1, 118.0, 121.3, 121.8, 121.9, 126.1, 126.9, 127.2, 130.1, lene-1-carbonitrile 5j. Yield: 68% (0.125 g); 0.25 Rf (20% ethy-
130.8, 131.7, 134.2, 134.6, 142.4, 142.6, 148.9, 196.7; HRMS lacetate–hexane), yellow solid, mp: 192–193 °C; IR (KBr): 3372,
1
values (ESI) calculated for C19H13BrN2OS, 397.0005 (M + H+); 2925, 2208, 1617, 1291, 754 cm−1; H NMR (400 MHz, CDCl3):
found for m/z, 397.0007.
δ 2.34 (s, 3H, –SCH3), 5.38 (s, 2H, –NH2), 7.47–7.53 (m, 1H,
3-(2-Allyloxy-benzoyl)-4-amino-2-methylsulfanyl-naphthalene- ArH), 7.55–7.66 (m, 2H, ArH), 7.75 (t, J = 7.3 Hz, 1H, ArH), 7.82
1-carbonitrile 5f. Yield: 60% (0.112 g); 0.37 Rf (40% ethylace- (d, J = 8.0 Hz, 1H, ArH), 7.85–7.90 (m, 2H, ArH), 7.90–7.96
tate–hexane), light yellow, mp: 165–167 °C; IR (KBr): 3372, (m, 2H, ArH), 8.07 (s, 1H, ArH), 8.25 (d, J = 8.0 Hz, 1H, ArH);
1
2929, 2208, 1610, 1240, 757 cm−1; H NMR (400 MHz, CDCl3): 13C NMR (100 MHz, CDCl3): δ 20.6, 104.7, 117.2, 120.8, 121.6,
δ 2.26 (s, 3H, –SCH3), 4.29–4.33 (m, 2H, –CH2–), 4.78–4.86 (dd, 121.7, 124.3, 126.1, 126.9, 127.0, 127.8, 128.8, 129.6, 130.0,
J = 1.4 Hz, 1H, CH), 4.96–5.06 (m, 1H, CH), 5.32–5.46 (m, 1H, 131.1, 132.4, 134.5, 135.8, 135.9, 140.6, 145.4, 196.7; HRMS
CH), 5.88 (s, 2H, –NH2), 6.85 (d, J = 8.0 Hz, 1H, ArH), 6.99 values (ESI) calculated for C23H16N2OS, 369.1056 (M + H+);
(t, J = 7.7 Hz, 1H, ArH), 7.38–7.47 (m, 1H, ArH), 7.56 (t, J = 7.7 Hz, found for m/z, 369.1033.
1H, ArH), 7.60–7.64 (m, 1H, ArH), 7.69 (t, J = 7.7 Hz, 1H, ArH),
3-Acetyl-4-amino-2-methylsulfanyl-naphthalene-1-carbonitrile
7.84 (d, J = 8.8 Hz, 1H, ArH), 8.15 (d, J = 8.8 Hz, 1H, ArH); 5k. Yield: 45% (0.058 g); 0.35 Rf (20% ethylacetate–hexane),
13C NMR (100 MHz, CDCl3): δ 20.2, 69.1, 104.2, 112.7, 117.4, light brown solid, mp: 140–142 °C; IR (KBr): 3373, 2925, 2854,
117.7, 120.7, 121.7, 122.0, 122.2, 125.9, 126.7, 129.9, 130.0, 2210, 1611, 1234, 757 cm−1; 1H NMR (400 MHz, CDCl3): δ 2.56
130.9, 131.8, 133.7, 134.3, 141.6, 146.1, 157.4, 196.0; HRMS (s, 3H, –SCH3), 2.70 (s, 3H, –CH3), 6.04 (s, 2H, –NH2),
values (ESI) calculated for C22H18N2O2S, 375.1162 (M + H+); 7.48–7.60 (m, 1H, ArH), 7.65–7.72 (m, 1H, ArH), 7.83 (d, J =
found for m/z, 375.1161.
8.8 Hz, 1H, ArH), 8.14 (d, J = 8.0 Hz, 1H, ArH); 13C NMR
4-Amino-3-(furan-2-carbonyl)-2-methylsulfanyl-naphthalene- (100 MHz, CDCl3): δ 20.7, 32.6, 104.5, 117.2, 120.9, 121.7,
1-carbonitrile 5g. Yield: 60% (0.092 g); 0.30 Rf (40% ethylace- 122.0, 126.0, 127.0, 130.3, 134.1, 140.5, 145.7, 204.1; HRMS
tate–hexane), dark green solid, mp: 196–98 °C; IR (KBr): 3371, values (ESI) calculated for C14H12N2OS, 257.0743 (M + H+);
1
2925, 2209, 1618, 1298, 756 cm−1; H NMR (400 MHz, CDCl3): found for m/z, 257.0730.
δ 2.46 (s, 3H, –SCH3), 5.46 (s, 2H, –NH2), 6.53–6.57 (dd, J =
4-Amino-3-(4-fluoro-benzoyl)-2-methylsulfanyl-naphthalene-
1.4 Hz, 1H, ArH), 7.03 (d, J = 3.6 Hz, 1H, ArH), 7.55–7.64 1-carbonitrile 5l. Yield: 52% (0.087 g); 0.30 Rf (20% ethylace-
(m, 2H, ArH), 7.69–7.76 (m, 1H, ArH), 7.83 (d, J = 8.0 Hz, 1H, ArH), tate–hexane), yellow solid, mp: 144–146 °C; IR (KBr): 3328,
1
8.19 (d, J = 8.05 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3): 2929, 2209, 1611, 1228, 757 cm−1; H NMR (400 MHz, CDCl3):
δ 20.0, 100.0, 112.9, 117.6. 119.5, 120.6, 121.4, 123.8, 124.4, δ 2.37 (s, 3H, –SCH3), 5.49 (s, 2H, –NH2), 7.10 (t, J = 8.79 Hz,
126.3, 130.2, 134.1, 139.2, 146.6, 148.6, 152.8, 182.1; HRMS 2H, ArH), 7.60 (t, J = 7.3 Hz, 1H, ArH), 7.70–7.78 (m, 3H, ArH),
values (ESI) calculated for C17H12N2O2S, 309.0692 (M + H+); 7.83 (d, J = 8.0 Hz, 1H, ArH), 8.21 (d, J = 8.8 Hz, 1H, ArH);
found for m/z, 309.0677.
13C NMR (100 MHz, CDCl3): δ 20.5, 104.6, 115.6 (d, JC−F
=
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22.0 Hz), 117.1, 120.1, 121.6, 126.6, 127.1, 130.1, 131.8 (d, JC–F
9.6 Hz), 134.4, 134.8, 134.9, 140.4, 145.3, 166.0 (d, JC–F
=
=
(m, 1H, ArH), 7.78 (d, J = 8.0 Hz, 1H, ArH), 7.96 (d, J = 8.0, 1H,
ArH); 13C NMR (100 MHz, CDCl3): δ 25.5, 25.8, 48.7, 51.2, 69.2,
253.9 Hz), 195.2; HRMS values (ESI) calculated for 113.7, 120.5, 121.8, 122.5, 126.2, 130.6, 141.9, 155.5, 157.1.
C19H13FN2OS, 337.0805 (M + H+); found for m/z, 337.0789.
4-Amino-3-(4-chloro-benzoyl)-2-methylsulfanyl-naphthalene-
General procedure for the synthesis of 4-amino-3-aroyl-
2-pyrrolidin-1-yl-naphthalene-1-carbonitriles
1-carbonitrile 5m. Yield: 48% (0.085 g); 0.31 Rf (20% ethylace-
tate–hexane), orange solid, mp: 135–137 °C; IR (KBr): 3377,
A mixture of 2-(1-cyano-2-methylsulfanyl-2-pyrrolidine-1-yl-
2925, 2210, 1620, 1261, 757 cm−1; H NMR (400 MHz, CDCl3): vinyl)-benzonitrile (0.5 mmol, 0.134 g), ketone (0.55 mmol),
δ 2.37 (s, 3H, –SCH3), 5.42 (s, 2H, –NH2), 7.39 (d, J = 8.8 Hz, and powdered KOH (1 mmol, 0.056 g) in dry DMSO (4.0 mL)
2H, ArH), 7.57–7.67 (m, 3H, ArH), 7.71–7.77 (m, 1H, ArH), 7.83 was stirred at room temperature for 2 h. After completion
(d, J = 8.8 Hz, 1H, ArH), 8.21 (d, J = 8.0 Hz, 1H, ArH); 13C NMR (monitored by TLC) of the reaction, the mixture was poured
(100 MHz, CDCl3): δ 20.5, 104.4, 117.1, 119.6, 121.6, 121.6, onto ice-water with constant stirring, followed by neutraliz-
126.0, 127.1, 129.0, 130.2, 130.4, 134.4, 136.9, 139.9, 140.4, ation with 10% HCl. The obtained precipitate was filtered,
145.6, 195.6; HRMS values (ESI) calculated for C19H13ClN2OS, dried and purified by silica gel column chromatography, using
1
353.0510 (M + H+); found for m/z, 353.0490.
20% ethylacetate–hexane as an eluent.
4-Amino-2-methylsulfanyl-3-(4-methylsulfanyl-benzoyl)-naphtha-
4-Amino-3-benzoyl-2-pyrrolidin-1-yl-naphthalene-1-carbonitrile
lene-1-carbonitrile 7. Yield: 30% (0.055 g); 0.30 Rf (30% ethyl- 10a. Yield: 72% (0.123 g); 0.32 Rf (20% ethylacetate–hexane),
acetate–hexane), yellow solid, mp: 137–139 °C; IR (KBr): 3375, brown solid, mp: 192–194 °C; IR (KBr): 3325, 2925, 2855, 2192,
1
1
2919, 2206, 1636, 1248, 755 cm−1; H NMR (400 MHz, CDCl3): 1608, 1256, 755 cm−1; H NMR (400 MHz, CDCl3): δ 1.32–1.37
δ 2.40 (s, 3H, –SCH3), 2.50 (s, 3H, –SCH3), 5.28 (s, 2H, –NH2), (m, 4H, –CH2–), 3.39–3.45 (m, 4H, –CH2–), 6.42 (s, 2H, –NH2),
7.20–7.26 (m, 2H, ArH), 7.56–7.68 (m, 3H, ArH), 7.70–7.77 7.31–7.39 (m, 3H, ArH), 7.44–7.51 (m, 1H, ArH), 7.54–7.65
(m, 1H, ArH), 7.83 (d, J = 8.8 Hz, 1H, ArH), 8.22 (d, J = 8.8 Hz, (m, 3H, ArH), 7.73 (d, J = 8.0 Hz, 1H, ArH), 8.03 (d, J = 8.0 Hz,
1H, ArH); 13C NMR (100 MHz, CDCl3): δ 14.6, 20.6, 104.4, 117.2, 1H, ArH); 13C NMR (100 MHz, CDCl3): δ 25.2, 51.8, 109.2,
120.7, 121.5, 124.9, 126.0, 127.0, 129.6, 129.9, 134.3, 134.4, 118.7, 120.4, 121.6, 123.7, 124.8, 128.0, 128.7, 130.6, 132.2,
140.3, 145.0, 147.1, 195.6; HRMS values (ESI) calculated for 136.7, 139.9, 149.2, 153.4, 197.0; HRMS values (ESI) calculated
C20H16N2OS2, 365.0777 (M + H+); found for m/z, 365.0780.
for C22H19N3O, 342.1601 (M + H+); found for m/z, 342.1601.
4-Amino-3-(4-methoxy-benzoyl)-2-pyrrolidin-1-yl-naphthalene-
1-carbonitrile 10b. Yield: 45% (0.083 g); 0.31 Rf (20% ethyl-
General procedure for the synthesis of 2-(1-cyano-
2-methylsulfanyl-2-pyrrolidine-1-yl-vinyl)-benzonitrile
acetate–hexane), light yellow, mp: 197–199 °C; IR (KBr): 3351,
1
A
mixture of 2-(1-cyano-2,2-bismethylsulfanyl-vinyl)-benzo- 2924, 2191, 1594, 1251, 763 cm−1; H NMR (400 MHz, CDCl3):
nitrile (1 mmol, 0.246 g) and pyrrolidine (as a solvent, 5.0 mL) δ 1.42–1.47(m, 4H, –CH2–), 3.44–3.50 (m, 4H, –CH2–), 3.83 (s,
was stirred at a temperature of 90 °C for 1 h. After completion 3H, –OCH3), 6.17 (s, 2H, –NH2), 6.84 (d, J = 8.8 Hz, 2H, ArH),
(monitored by TLC) of the reaction, the mixture was poured 7.29–7.35 (m, 1H, ArH), 7.57–7.63 (m, 3H, ArH), 7.70 (d, J =
onto ice-water with constant stirring, followed by neutraliz- 8.0 Hz, 1H, ArH), 8.03 (d, J = 8.8 Hz, 1H, ArH); 13C NMR
ation with 10% HCl. The obtained precipitate was filtered off (100 MHz, CDCl3): δ 25.4, 51.9, 55.4, 82.8, 109.3, 113.3, 118.7,
and dried over Na2SO4. The crude product contained both 120.6, 121.6, 123.5, 124.7, 130.4, 131.2, 132.0, 136.6, 148.5,
mono- and diaminated product. This was purified by silica gel 153.1, 163.1, 195.8; HRMS values (ESI) calculated for
column chromatography, using 20% ethylacetate–hexane as an C23H21N3O2, 372.1707 (M + H+); found for m/z, 372.1684.
eluent for the monoaminated product and 25% ethyl acetate
in hexane as an eluent for the diaminated product.
4-Amino-3-(furan-2-carbonyl)-2-pyrrolidin-1-yl-naphthalene-
1-carbonitrile 10c. Yield: 57% (0.094 g); 0.21 Rf (20% ethylace-
2-(1-Cyano-2-methylsulfanyl-2-pyrrolidine-1-yl-vinyl)-benzo- tate–hexane), orange solid, mp: 170–172 °C; IR (KBr): 2926,
nitrile 8: 2-(1-cyano-2-methylsulfanyl-2-pyrrolidine-1-yl-vinyl)- 2225, 1618, 1227, 757 cm−1 1H NMR (400 MHz, CDCl3):
;
benzonitrile 8. Yield: 73% (0.196 g); red, 0.32 Rf (20% ethylace- δ 1.62–1.67 (m, 4H, –CH2–), 3.58–3.64 (m, 4H, –CH2–), 6.23
tate–hexane), mp: 191–193 °C; IR (KBr) 2924, 2853, 2220, 2181, (s, 2H, –NH2), 6.45–6.48 (dd, J = 2.2 Hz, 1H, ArH), 6.91 (d, J =
1
1514, 1252, 761 cm−1; H NMR (400 MHz, CDCl3): δ 1.83–1.93 2.9 Hz, 1H, ArH), 7.26–7.33 (m, 1H, ArH), 7.52–7.62 (m, 2H,
(bm, 4H, –CH2–), 2.56 (s, 3H, –SCH3), 3.10–3.60 (bm, 4H, ArH), 7.68 (d, J = 8.8 Hz, 1H, ArH), 8.00 (d, J = 8.8 Hz, 1H,
–CH2–), 7.15–7.22 (m, 1H, ArH), 7.45–7.58 (m, 3H, ArH); ArH); 13C NMR (100 MHz, CDCl3): δ 25.7, 52.2, 82.3, 108.0,
13C NMR (100 MHz, CDCl3): δ 18.9, 25.3, 52.6, 111.7, 118.0, 112.1, 117.8, 118.3, 120.7, 121.6, 123.4, 124.7, 130.7, 137.0,
122.1, 125.7, 129.6, 132.6, 132.8, 141.4, 165.6; HRMS values 146.2, 148.7, 152.7, 153.6, 183.5; HRMS values (ESI) calculated
(ESI) calculated for C15H15N3S, 270.1059 (M + H+); found for for C20H17N3O2, 332.1394 (M + H+); found for m/z, 332.1396.
m/z, 270.1059.
4-Amino-2-pyrrolidin-1-yl-3-(thiophene-2-carbonyl)-naphtha-
2-(1-Cyano-2,2-di-pyrrolidine-1-yl-vinyl)-benzonitrile 9. Yield: lene-1-carbonitrile 10d. Yield: 58% (0.101 g); 0.30 Rf (20%
10% (0.029 g); 0.30 Rf (10% ethylacetate–hexane), light red, ethylacetate–hexane), yellow solid, mp: 171–173 °C; IR (KBr):
mp: 120–122 °C; IR (KBr): 2925, 2869, 2181, 1537, 1295, 756, 3349, 2925, 2854, 2190, 1597, 1253, 759 cm−1
;
1H NMR
1
cm−1; H NMR (400 MHz, CDCl3): δ 1.92–2.00 (m, 8H, –CH2–), (400 MHz, CDCl3): δ 1.57–1.67 (m, 4H, –CH2–), 3.59–3.65
3.76–3.87 (m, 8H, –CH2–), 7.00–7.08 (m, 1H, ArH), 7.40–7.50 (m, 4H, –CH2–), 6.09 (s, 2H, –NH2), 6.99–7.04 (m, 1H, ArH),
4736 | Org. Biomol. Chem., 2014, 12, 4730–4737
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7.27–7.36 (m, 2H, ArH), 7.56–7.62 (m, 2H, ArH), 7.68 (d, J =
8.0 Hz, 1H, Ar-H), 8.02 (d, J = 8.0 Hz, 1H, ArH); 13C NMR
(100 MHz, CDCl3): δ 25.6, 52.2, 82.5, 109.0, 118.3, 120.6, 121.6,
123.4, 124.6, 127.6, 130.5, 133.0, 133.3, 136.8, 145.3, 148.0,
152.2, 188.5; HRMS values (ESI) calculated for C20H17N3OS,
348.1165 (M + H+); found for m/z, 348.1147.
4 F. V. Singh, M. Dixit, S. Chaurasia, R. Raghunandan,
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Acknowledgements
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6110.
RP thanks the Council of Scientific and Industrial Research
(CSIR, New Delhi) [Project no. 02(0080)/12/EMR-II], the Univer-
sity Grants Commission (UGC, New Delhi) [Project no. 42–274/
2013], the Department of Science and Technology (DST, New
Delhi) [Project no. SB/FT/CS-049/2012] and the University of
Delhi, Delhi [R & D Grant] for financial support. SS thanks the
Council of Scientific and Industrial Research (CSIR, New
Delhi), and PY and SNS thank the University Grants Commis-
sion (UGC, New Delhi) for the research fellowship. AK is grate-
ful to DST, New Delhi for funding in project SB/FT/CS-018/
2012. The authors thank the University of Delhi for providing
research funding and instrumentation facilities.
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