Oxidative difunctionalization of 2-amino-4 H-pyrans in iodobenzene diacetate and N-chlorosuccinimide: Reactivity, mechanistic insights, and DFT calculations

Article abstract of DOI:10.1021/jo301801b

Oxidative difunctionalization of 2-amino-4H-pyrans was accomplished with iodobenzene diacetate (IBD) and N-chlorosuccinimide (NCS) reagents in alcoholic medium. 2-Amino-4H-pyrans undergo geminal dialkoxylation with the migration of an amino group (1a,b, 2

Full text of DOI:10.1021/jo301801b

Article
pubs.acs.org/joc
Oxidative Difunctionalization of 2‑Amino‑4H‑pyrans in Iodobenzene
Diacetate and N‑Chlorosuccinimide: Reactivity, Mechanistic Insights,
and DFT Calculations
Santhosh Reddy Mandha,† Manjula Alla,*,† Vittal Rao Bommena,† Jagadeesh Babu Nanubolu,‡
Santosh Kumar Lingala,§ and Soujanya Yarasi§
‡
§
†Crop Protection Chemicals, Laboratory of X-ray Crystallography, and Molecular Modelling Group, CSIR-Indian Institute of
Chemical Technology, Tarnaka, Hyderabad 500607, India
S
* Supporting Information
ABSTRACT: Oxidative difunctionalization of 2-amino-4H-pyrans
was accomplished with iodobenzene diacetate (IBD) and N-
chlorosuccinimide (NCS) reagents in alcoholic medium. 2-Amino-
4H-pyrans undergo geminal dialkoxylation with the migration of an
amino group (1a,b, 2a−i, 3a,b, and 4) in IBD, whereas with NCS
addition of both chlorine and alkoxy groups takes place across the
chromene double bond (6a−i).
Scheme 1. Catalyst-Free Construction of 2-Amino-4-aryl-
4H-benzo[h]chromene-3-carbonitrile Analogues
INTRODUCTION
■
Amino-4H-pyrans have long been attractive molecules for
medicinal chemists because of their diverse pharmacological
profile which includes antibacterial,1 fungicidal,2 mollusicidal,3
anticonvulsant,4 and antiviral5 activities. Amino-4H-pyrans are
isosters of 1,4-dihydropyridines.6 Annulated aminopyrans,
especially heterocyclic analogues of tacrine, are known
cholinesterase inhibitors finding applications in treatment of
Alzheimer’s disease.7 Among the fused aminopyrans, amino-
chromenes receive special attention as antiproliferative and
antiarthritic molecules.8 4-Aryl-4H-chromenes are known
apoptosis inducers by tubulin inhibition and vascular
disruption.9 Cyclization of the 7,8 positions of 4-aryl-4H-
chromenes has been established to lead to more potent
anticancer molecules.10
As part of an ongoing program on the design and synthesis of
new chemical entities incorporating a 4H-pyrans, we have
recently developed a clean method for synthesis of fused
pyrano[2,3-c]pyrazoles and evaluated their biological activity.11
Herein a construction of a series of diversely substituted 4-aryl-
4H-benzochromenes is envisaged.
aromatic aldehyde. Synthesis of 2-amino-2′-oxospiro[benzo[h]-
chromene-4,3′-indoline]-3-carbonitrile was carried out through
a reported method13 as it was not obtained in the green
protocol.
Various attempts to utilize both the amine and nitrile
functionalities for modifying the chromene skeleton as well
construction of heterocycles by employing aforesaid function-
alities were unsuccessful.14 Catalytic oxidative difunctionaliza-
tion of the chromene double bond was envisaged as a
reasonable synthetic transformation for obtaining vicinal
substitutions. Hypervalent iodine reagents such as iodobenzene
diacetate (IBD) are known for oxidative difunctionalization15 of
flavonoids, indoles, and pyrans, which would be a simple
protocol for obtaining diversely substituted amino-4H-pyrans.
During the course of the experiments, it was observed that
the reaction between 2-amino-4H-pyrans and IBD does not
proceed with dichloromethane as solvent. When methanol was
employed as the solvent, the reaction progressed instanta-
neously (Scheme 2). An intriguing product was formed, whose
RESULTS AND DISCUSSION
■
At the outset, 2-amino-4-aryl-4H-benzo[h]chromene-3-carbon-
itrile analogues12 were constructed by a catalyst-free protocol
via a one-pot, three-component condensation of malononitrile,
aromatic aldehyde, and 1-naphthol in water and ethanol (1:1)
medium (Scheme 1). The green protocol was found to be of
wide scope, and a number of aryl-substituted 2-amino-
chromenes were obtained by varying the substitutions on
Received: September 6, 2012
© XXXX American Chemical Society
A
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a
Scheme 2. IBD-Catalyzed Geminal Dialkoxylation with 1,2-
Migration of Amino Group
Table 1. Dialkoxylation of 2-Amino-4H-pyrans with IBD
b
entry
R
R1
product time (min) yield (%)
1
2
CH3
C6H5
C6H5
C6H5
1a
1b
2a
2b
2c
2d
2e
2f
15
20
15
15
15
10
15
20
15
15
20
20
20
300
80
78
78
84
74
85
77
74
78
72
70
72
70
60
C2H5
CH3
3
4
CH3
2-thienyl
4-CH3OC6H4
4-O2NC6H4
4-FC6H4
C6H5
5
CH3
6
CH3
7
CH3
PMR spectrum shows the presence of two signals correspond-
ing to −OCH3 protons at δ 3.8 and 3.4 ppm, respectively,
indicating the introduction of two methoxy groups. The amino
group, which is at δ 4.7 ppm in the starting material (2-amino-
4-phenyl-4H-benzo[h]chromene-3-carbonitrile), shifted to δ
1.7 ppm in the product. Dialkoxylation suggests the product is
not a result of mere oxidative difunctionalization. X-ray
crystallography data16 of the product shows a 1,2-migration
of amino group to the C12-carbon bearing nitrile group and
geminal dimethoxy groups installed at C13-carbon. From the
insights obtained through crystallographic data, the product 2a
(Figure 1) was assigned as 3-amino-2,2-dimethoxy-4-phenyl-
8
C2H5
C2H5
C2H5
(CH3)2CH
CH3
9
2-thienyl
4-ClC6H4
C6H5
2g
2h
2i
10
11
12
13
14
C6H5
3a
3b
4
C2H5
CH3
C6H5
a
All of the reactions were carried out using 2-amino-4H-pyrans (1
equiv) and IBD (1.1 equiv) in the presence of excess alcohol under rt
conditions. Yield of crude product.
b
Scheme 3. Plausible Mechanism of IBD-Catalyzed
Dialkoxylation of 2-Amino-4H-pyrans
Figure 1. Scope of products from diverse 2-aminopyran analogues.
2,3-dihydro-4H-benzo[h]chromene-3-carbonitrile. In order to
authenticate the phenomena, the dialkoxylation was repeated
with ethanol as the solvent. X-ray crystallography data of the
product show geminal diethoxy groups at C13 with 1,2-
migration of the amino group to a C12-carbon-bearing nitrile
group. Both compounds 2a and 2f crystallized in the centro
symmetric space group and are found to be racemic mixtures
(1:1) with configurations of R and S at C11 and C12,
respectively.
The information obtained from initial screening of the
reaction conditions mentioned above led to the establishment
of the best parameters for the conversion. The study was
extended by varying the 2-aminopyrans as well as readily
available alcoholic solvents. The dialkoxylation with 1,2-
migration of the amino group is facile in methanol, ethanol,
and isopropyl alcohol. However, the reaction does not proceed
in ethylene glycol and 2-chloroethanol. Yields and reactivity are
better in methanol when compared to both ethanol and
isopropyl alcohol. More importantly, the reaction is compatible
to various functional groups on the C11-phenyl ring. All of the
reactions proceed within a few minutes, and the corresponding
products are formed in excellent yields (Table 1).
formation of the aminoiodinane species is followed by
immediate attack of alcohol to form the aziridine ring. The
aziridine opens to a stable carbocation at the α-carbon. Attack
of alcohol as a nucleophile then occurs to yield the geminal
dialkoxylation product. Since the reaction is instantaneous,
none of the intermediates could be isolated. Density functional
theory (DFT) calculations were carried out to see the energy
profile of the reaction. From the energy profile in Figure 2 it is
evident that the transition state with a barrier of about 20 kcal/
mol involves the cleavage of acetic acid from IBD with proton
abstraction from methanol solvent molecule followed by
nucloephilic attack of the methoxy group leading to azridine
ring formation. The exothermicity of the reaction is found to be
due to highly stabilized aziridine ring, which further leads to
product formation.
In order to understand the role of IBD in transformation, a
routine investigation was performed on 2-amino-4-phenyl-4H-
benzo[h]chromene-3-carbonitrile with various iodine-contain-
ing oxidizing agents listed in Table 2. Iodine and [hydroxy-
(tosyloxy)iodo]benzene (HTIB) gave 2-oxo-4-phenyl-2H-
benzo[h]chromene-3-carbonitrile (5) as a sole product. 2-
Iodoxybenzoic acid (IBX) does not show any effect on 2-
aminochromene, whereas in the case of N-iodosuccinimide
(NIS) product 5 was observed in trace amounts. Perhaps
iodine(III)-mediated aziridination of the pyran ring is the
A thorough survey of literature revealed that the unusual
geminal dialkoxy addition with migration of amino group has
no precedence. Combining aspects of the experimental
findings, a plausible mechanism presented in Scheme 3. Initial
B
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the chemical shift of the amino group in the product was not
drastically different as in the case of the product obtained from
IBD reaction, indicating that migration of the amino group may
not have occurred. Further, the mass spectrum indicated the
presence of chlorine. The structure of the compound 6g
validated by X-ray crystallography18 gave conclusive evidence
that the chromene double bond is oxidatively difunctionalized
by the addition of chlorine and methoxy groups, leading to the
formation of 2-amino-3-chloro-2-alkoxy-4-aryl-2,3-dihydro-4H-
benzo[h]chromene-3-carbonitrile. Similar to the IBD case,
compound 6g crystallized in the centrosymmetric space group.
The compounds 6a−i are found to be racemic mixtures (1:1)
with a configuration of R,R,S at C11, C12, and C13, respectively.
The optimized reaction conditions were employed by
studying the reaction scope as well as generality by varying
the solvents and the phenyl ring substitutions as shown in
Table 3. The reaction proceeds instantaneously in methanol,
Table 3. Difunctionalization of 2-Amino-4H-pyrans with
NCS
Figure 2. Free energy profile for IBD-catalyzed geminal dialkoxylation
with 1,2-amino migration reaction as calculated in the gas phase by the
DFT method.
a
Table 2. Screening of Different Catalytic and Solvent
Systems for Difunctionalization of 2-amino-4-phenyl-4H-
a
benzo[h]chromene-3-carbonitrile
b
entry
R
R1
product time (min) yield (%)
1
2
CH3
CH3
CH3
CH3
CH3
CH3
C6H5
6a
6b
6c
6d
6e
6f
10
88
80
91
83
84
82
82
80
77
70
77
4-CH3C6H4
4-CH3OC6H4
4-FC6H4
10
3
10
4
10
5
4-O2NC6H4
2-Thienyl
4-ClC6H4
2-Thienyl
C6H5
10
6
10
7
C2H5
6g
6h
6i
overnight
overnight
overnight
overnight
15
8
C2H5
9
(CH3)2CH
CH3
10
11
7
4-BrC6H4
7a
a
All reactions were carried out using 2-amino-4H-pyrans (1 equiv) and
NCS (1.1 equiv) in the presence of excess alcohol under rt conditions.
b
Yield of crude product.
whereas it takes a longer time when ethanol or isopropyl
alcohol is used as a solvent. However, it stops at an
intermediate stage in the presence of methanol for 2-amino-
2′-oxospiro[benzo[h]chromene-4,3′-indoline]-3-carbonitrile to
afford 3-chloro-2-imino-2′-oxo-3,4-dihydrospiro[benzo[h]-
chromene-4,3′-indoline]-3-carbonitrile (7) with 70% yield.
The reactions with NCS also do not progress in alternative
non-nucleophilic solvents.
A plausible mechanism to corroborate with the experimental
observations is shown in Scheme 4. As is evident from the
proposed mechanism, a stepwise addition of chlorine at β-
carbon followed by the addition of alcohol across CNH
leaves no scope for NH2 migration. Since the addition is
a
All of the reactions are carried out by stirring under rt conditions and
open to air.
driving force for unusual migration of amino group. Such
iodine(III)-catalyzed aziridination has literature precedence in
some cyclic allylic carbamates.17
Notably different results were obtained when the oxidizing
reagent was N-chlorosuccinimide (NCS). Reacting 2-amino-
chromene with NCS in methanol gave addition of a single
methoxy group as indicated by the NMR spectrum. However,
C
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Scheme 4. Proposed Mechanism for Chloroalkoxylation of
2Aamino-4H-pyrans in the Presence of NCS and Alcohol
EXPERIMENTAL SECTION
■
General Methods. All reactions were performed under rt
conditions and open to air. Melting points were determined in open
1
capillary tubes and are uncorrected. H NMR (300 MHz, 400 MHz,
500 MHz) and 13C NMR (75, 125 MHz) spectra were recorded in
CDCl3 and DMSO-d6. Chemical shifts are given in δ values referenced
to the solvent. All of the yields mentioned in the experimental data are
of isolated crude products unless otherwise mentioned.
General Procedure for the Synthesis of 1a,b, 2a−i, 3a,b. To a
suspension of 2-amino-4H-pyran (1 mmol) in 5 mL of methanol (or
ethanol) was added IBD (1.1 mmol) with stirring at rt open to air. The
reaction mixture immediately became a clear solution followed by the
precipitation of product. The mixture was filtered and washed with the
corresponding alcohol to afford the desired product. The structures of
the products (2a and 2f) were assigned on the basis of spectral and X-
ray crystallographic data.
Ethyl 3-amino-3-cyano-2,2-dimethoxy-6-methyl-4-phenyl-2,3-di-
hydro-4H-pyran-5-carboxylate (1a): yield 0.277 g (80%); mp 144−
145 °C; IR (neat, cm−1) 3379, 3315, 2982, 2232, 1705, 1646, 1116,
708; 1H NMR (300 MHz, CDCl3) δ 7.39−7.28 (m, 5H), 4.34 (s, 1H),
3.91−3.80 (m, 2H), 3.71 (s, 3H), 3.53 (s, 3H), 2.33 (d, J = 1.7 Hz,
3H), 1.6 (s, 2H), 0.68 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 166.7, 157.3, 136.4, 129.1, 128.5, 127.8, 120.7, 110.8, 105.7,
59.9, 56.1, 52.9, 50.9, 48.3, 18.2, 13.3. MS (ESI) m/z 369 (M + Na)+;
HRMS ESI (M + Na)+ m/z calcd for C18H22N2O5Na (M + Na)+
369.1420, found 369.1413.
stepwise, the intermediate 7a (where the reaction was carried
out in isopropyl alcohol) could be isolated and characterized.
Difunctionalization of 2-amino-4-phenyl-4H-benzo[h]-
chromene-3-carbonitrile in IBD as well as NCS was revisited
by executing the experiments in methanol-d4 (Scheme 5). In
Scheme 5. Deuterated Methanol Study
Ethyl 3-amino-3-cyano-2,2-diethoxy-6-methyl-4-phenyl-2,3-di-
hydro-4H-pyran-5-carboxylate (1b): yield 0.292 g (78%); mp 149−
151 °C; IR (neat, cm−1) 3399, 3328, 2978, 2230, 1702, 1636, 1095,
710; 1H NMR (300 MHz, CDCl3) δ 7.39−7.26 (m, 5H), 4.35 (s, 1H),
4.14−3.64 (m, 6H), 2.31 (d, J = 1.5 Hz, 3H), 1.60 (s, 2H), 1.35−1.26
(m, 6H), 0.67 (t, J = 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
166.8, 157.5, 136.6, 129.2, 128.4, 127.4, 120.8, 110.7, 105.4, 61.0, 59.9,
59.3, 56.3, 48.2, 18.3, 15.4, 15.0, 13.3; MS (ESI) m/z 397 (M + Na)+;
HRMS ESI (M + Na)+ m/z calcd for C20H26N2O5Na (M + Na)+
397.1733, found 397.1726.
both the cases, the crude products obtained after reaction were
subjected to spectral analysis. As expected, the PMR spectra
show the disappearance of −OCH3 signals. In the case of IBD,
PMR spectra of the product (8) show a broad singlet for one
proton at δ 1.78 ppm, and in the NCS case, spectra of the
product (9) showed a broad singlet for one proton at δ 2.75
ppm. They were both assigned as −NHD signals. When
subjected to D2O exchange in both cases, the −NHD signals
disappeared. The fact that the PMR chemical shifts of the
amino group (−NHD) vary in each case suggests that they are
not on identical carbons. From a mechanistic analysis of either
protocol, a loss of amino proton at initial stages of reaction and
a gain of proton from the alcohol is expected. The methanol-d4
experiments corroborate the proposed mechanism. Further,
both products were confirmed by mass spectrometry.
3-Amino-2,2-dimethoxy-4-phenyl-2,3-dihydro-4H-benzo[h]-
chromene-3-carbonitrile (2a): yield 0.281 g (78%); mp 188−190 °C;
1
IR (neat, cm−1) 3394, 3325, 2229, 1113, 720; H NMR (300 MHz,
CDCl3) δ 8.30−8.24 (m, 1H), 7.79−7.73 (m, 1H), 7.55−7.29 (m,
8H), 6.90 (d, J = 8.3 Hz, 1H), 4.82 (s, 1H), 3.96 (s, 3H), 3.48 (s, 3H),
1.72 (brs, 2H); 13C NMR (75 MHz, CDCl3) δ 145.2, 135.8, 133.6,
131.2, 128.7, 128.5, 127.6, 126.5, 126.1, 124.3, 121.9, 121.0, 120.9,
115.8, 111.2, 56.8, 53.6, 50.8, 50.6; MS (ESI): m/z 383 (M + Na)+;
HRMS ESI (M + Na)+ m/z calcd for C22H20N2O3Na (M + Na)+
383.1366, found 383.1358.
3-Amino-2,2-dimethoxy-4-(thiophene-2-yl)-2,3-dihydro-4H-
benzo[h]chromene-3-carbonitrile (2b): yield 0.307 g (84%); mp
176−178 °C; IR (neat, cm−1) 3399, 3317, 2225, 1120, 715; 1H NMR
(300 MHz, CDCl3) δ 8.28−8.22 (m, 1H), 7.79−7.72 (m, 1H), 7.54−
7.44 (m, 2H), 7.42−7.35 (m, 2H), 7.19 (d, J = 3.0 Hz, 1H), 7.12−7.08
(m, 1H), 7.02 (d, J = 8.3 Hz, 1H), 5.14 (s, 1H), 3.95 (s, 3H), 3.48 (s,
3H), 1.90 (brs, 2H); 13C NMR (75 MHz, CDCl3) δ 144.6, 137.8,
133.8, 129.9, 127.6, 127.0, 126.7, 126.6, 126.2, 126.1, 124.1, 121.9,
121.1, 120.6, 115.6, 111.2, 57.1, 53.5, 50.8, 46.7; MS (ESI) m/z 389
(M + Na)+; HRMS ESI (M + Na)+ m/z calcd for C20H18N2O3NaS (M
+ Na)+ 389.0930, found 389.0923.
CONCLUSION
■
In summary, oxidative difunctionalization of the chromene
double bond has been studied in alcoholic solvent medium in
the presence IBD as well as NCS. Addition of geminal dialkoxy
groups and 1,2-migration of −NH2 occur in the case of IBD via
an apparent intramolecular aziridination. In marked contrast,
the NCS mediated reaction results in an anticipated ddition of
chlorine and alkoxy groups across the chromene double bond
in a stepwise manner. Deuterated methanol experiments and
DFT calculations are supportive of the proposed mechanisms.
Studies of scope, application, and limitations of this unusual
protocol with amino migration on related systems are currently
under investigation.
3-Amino-2,2-dimethoxy-4-(4-methoxyphenyl)-2,3-dihydro-4H-
benzo[h]chromene-3-carbonitrile (2c): yield 0.288 g (74%); mp
1
188−189 °C; IR (neat, cm−1) 3394, 3330, 2231, 1512, 1115, 772; H
NMR (300 MHz, CDCl3) δ 8.28−8.23 (m, 1H), 7.77−7.72 (m, 1H),
7.55−7.15 (m, 5H), 6.97−6.87 (m, 3H), 4.76 (s, 1H), 3.94 (s, 3H),
3.83 (s, 3H), 3.47 (s, 3H), 1.71 (brs, 2H); 13C NMR (75 MHz,
CDCl3) δ 159.7, 145.1, 133.6, 132.2, 127.6, 126.5, 126.1, 124.3, 121.9,
121.0, 116.0, 114.1, 111.3, 56.9, 55.3, 53.5, 50.8, 49.9; MS (ESI) m/z
413 (M + Na)+; HRMS ESI (M + Na)+ m/z calcd for C23H22N2O4Na
(M + Na)+ 413.1471, found 413.1461.
3-Amino-2,2-dimethoxy-4-(4-nitrophenyl)-2,3-dihydro-4H-
benzo[h]chromene-3-carbonitrile (2d): yield 0.344 g (85%); mp
198−199 °C; IR (neat, cm−1) 3384, 3314, 2233, 1520, 1351, 1110,
D
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801; 1H NMR (400 MHz, CDCl3) δ 8.35−8.23 (m, 3H), 7.78 (d, J =
7.4 Hz, 1H), 7.70−7.48 (m, 4H), 7.40 (d, J = 8.3 Hz, 1H), 6.74 (d, J =
8.3 Hz, 1H), 4.92 (s, 1H), 3.95 (s, 3H), 3.49 (s, 3H), 1.68 (brs, 2H);
13C NMR (75 MHz, CDCl3) δ 148.0, 145.3, 143.6, 133.7, 132.2, 127.7,
150.0, 145.6, 139.0, 135.5, 131.1, 128.6, 128.2, 127.1, 121.6, 120.8,
119.9, 111.5, 56.1, 53.2, 50.9, 50.8; MS (ESI) m/z 362 (M + H)+;
HRMS ESI (M + H)+ m/z calcd for C21H20N3O3 (M + H)+ 362.1499,
found 362.1492.
3-Amino-2,2-diethoxy-4-phenyl-2,3-dihydro-4H-pyrano[3,2-h]-
127.0, 126.5, 125.8, 124.2, 123.6, 122.4, 121.0, 120.0, 114.4, 111.1,
56.4, 53.5, 51.0, 50.6; MS (ESI) m/z 428 (M + Na)+; HRMS ESI (M
+ Na)+ m/z calcd for C22H19N3O5Na (M + Na)+ 428.1216, found
428.1208.
quinoline-3-carbonitrile (3b): yield 0.272 g (70%); mp 174−176 °C;
1
IR (neat, cm−1) 3399, 3330, 2231, 1122, 717; H NMR (300 MHz,
DMSO-d6) δ 8.96 (d, J = 3.9 Hz, 1H), 8.17 (d, J = 8.3 Hz, 1H), 7.68−
7.24 (m, 7H), 6.97 (d, J = 8.6 Hz, 1H), 4.87 (s, 1H), 4.39−4.19 (m,
2H), 4.04−3.90 (m, 1H), 3.84−3.70 (m, 1H), 1.93 (brs, 2H), 1.42 (t, J
= 6.9 Hz, 3H), 1.04 (t, J = 6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ
150.0, 146.0, 139.1, 135.9, 135.5, 131.2, 128.6, 128.4, 128.3, 127.3,
121.5, 121.0, 120.6, 120.0, 111.3, 61.4, 59.2, 56.4, 51.0, 15.5, 14.7; MS
(ESI) m/z 390 (M + H)+; HRMS ESI (M + H)+ m/z calcd for
C23H24N3O3 (M + H)+ 390.1812, found 390.1805.
3-Amino-2,2-dimethoxy-4-(4-fluorophenyl)-2,3-dihydro-4H-
benzo[h]chromene-3-carbonitrile (2e): yield 0.291 g (77%); mp
164−166 °C; IR (neat, cm−1) 3383, 3321, 2230, 1111, 819; 1H NMR
(300 MHz, CDCl3) δ 8.33−8.26 (m, 1H), 7.82−7.76 (m, 1H), 7.60−
7.30 (m, 5H), 7.13 (t, J = 8.3 Hz, 2H), 6.88 (d, J = 9.0 Hz, 1H), 4.84
(s, 1H), 3.97 (s, 3H), 3.48 (s, 3H), 1.66 (brs, 2H); 13C NMR (75
MHz, CDCl3) δ 164.5, 161.2, 145.2, 133.6, 132.8, 131.6, 127.6, 126.7,
126.2, 125.9, 124.3, 122.0, 121.0, 120.8, 115.8, 115.6, 111.2, 56.7, 53.5,
50.8, 49.9; MS (ESI) m/z 401 (M + Na)+; HRMS ESI (M + Na)+ m/z
calcd for C22H19N2O3FNa (M + Na)+ 401.1271, found 401.1263.
3-Amino-2,2-diethoxy-4-phenyl-2,3-dihydro-4H-benzo[h]-
chromene-3-carbonitrile (2f): yield 0.287 g (74%); mp 194−195 °C;
Experimental Procedure for the Synthesis of 3-Amino-2,2-
dimethoxy-2′-oxo-2,3-dihydrospiro[benzo[h]chromene-4,3′-
indoline]-3-carbonitrile (4). To a suspension of 2-amino-2′-
oxospiro[benzo[h]chromene-4,3′-indoline]-3-carbonitrile (0.339 g, 1
mmol) in 5 mL of methanol was added IBD (0.354 g, 1.1 mmol) with
stirring at room temperature open to air. The resulting clear solution
was allowed to stir at rt for 5 h. The solvent methanol from the
mixture was removed under vacuum followed by partitioning of the
reaction mixture between dichloromethane (2 × 15 mL) and water
(10 mL). The organic layers collected were dried over anhydrous
sodium sulfate and concentrated. The crude reaction mixture was
subjected to column chromatography on silica gel (ethyl acetate/
hexane 3:7) to afford the required product 4. Isolated yield of pure
product: 0.240 g (60%); mp 170−171 °C; IR (neat, cm−1) 3274, 2230,
1
IR (neat, cm−1) 3391, 3324, 2231, 1098, 710; H NMR (300 MHz,
CDCl3) δ 8.25−8.20 (m, 1H), 7.77−7.71 (m, 1H), 7.53−7.27 (m,
8H), 6.89 (d, J = 9.0 Hz, 1H), 4.82 (s, 1H), 4.35−4.23 (m, 2H), 4.02−
3.90 (m, 1H), 3.76−3.64 (m, 1H), 1.61 (brs, 2H), 1.46 (t, J = 7.5 Hz,
3H), 1.08 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 145.5,
136.1, 133.6, 131.2, 128.7, 128.4, 127.5, 126.6, 126.5, 126.0, 124.3,
121.6, 121.2, 121.1, 115.7, 111.1, 61.5, 59.1, 57.0, 50.6, 15.7, 14.9; MS
(ESI) m/z 411 (M + Na)+; HRMS ESI (M + Na)+ m/z calcd for
C24H24N2O3Na (M + Na)+ 411.1679, found 411.1669.
1
3-Amino-2,2-diethoxy-4-(thiophene-2-yl)-2,3-dihydro-4H-benzo-
1720, 1471, 1123, 752; H NMR (500 MHz, CDCl3) δ 8.40 (s, 1H),
[h]chromene-3-carbonitrile (2g): yield 0.307 g (78%); mp 152−154
8.32 (d, J = 7.6 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.60−7.51 (m, 2H),
7.41 (d, J = 8.6 Hz, 1H), 7.29−7.25 (m, 2H), 7.00−6.93 (m, 2H), 6.68
(d, J = 7.6 Hz, 1H), 3.89 (s, 3H), 3.59 (s, 3H), 2.78 (brs, 2H); 13C
NMR (75 MHz, CDCl3) δ 178.0, 145.6, 140.9, 134.0, 130.8, 129.8,
128.4, 127.7, 127.1, 126.5, 124.9, 124.5, 123.3, 122.8, 121.2, 118.7,
114.1, 111.9, 110.3, 59.1, 58.1, 53.6, 50.4; MS (ESI) m/z 424 (M +
Na)+; HRMS ESI (M + Na)+ m/z calcd for C23H19N3O4Na (M +
Na)+ 424.1267, found 424.1266.
Experimental Procedure for the Synthesis of 2-Oxo-4-
phenyl-2H-benzo[h]chromene-3-carbonitrile (5). To a suspen-
sion of 2-amino-4-phenyl-4H-benzo[h]chromene-3-carbonitrile (0.298
g, 1 mmol) in 5 mL of ethanol was added iodine (0.279 g, 1.1 mmol),
and the resulting mixture was refluxed for 12 h. The solid formed was
filtered and washed with cooled ethanol to afford the required product
5 as yellow solid: yield 0.160 g (54%); mp 215−217 °C; IR (neat,
cm−1) 3439, 3332, 2924, 2223, 1720, 1536, 1355, 758; 1H NMR (500
MHz, CDCl3) δ 8.62 (d, J = 7.9 Hz, 1H), 7.90 (d, J = 7.1 Hz, 1H),
7.80−7.61 (m, 6H), 7.57−7.50 (m, 2H), 7.30 (d, J = 8.7 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 161.2, 152.1, 148.7, 136.4, 136.2, 131.1,
128.5, 128.3, 128.0, 125.7, 123.8, 123.3, 122.7, 121.9, 113.4, 113.1; MS
(ESI) m/z 298 (M + H)+; HRMS ESI (M + H)+ m/z calcd for
C20H12NO2 (M + H)+ 298.0862, found 298.0859.
General Procedure for the Synthesis of 6a−i. To a suspension
of 2-amino-4H-pyran (1 mmol) in 5 mL of methanol (or ethanol) was
added NCS (1.1 mmol) with stirring at room temperature open to air.
The resulting clear solution was stirred at room temperature until the
product precipitated. The reaction mixture was filtered and washed
with the corresponding alcohol to separate the desired product. The
structures of the products (6a−i) were assigned on the basis of the
spectral data. Further, the product 6g was confirmed by X-ray
crystallographic data.
1
°C; IR (neat, cm−1) 3391, 3320, 2230, 1115, 704; H NMR (500
MHz, CDCl3) δ 8.25 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 7.0 Hz, 1H),
7.56−7.48 (m, 2H), 7.45−7.37 (m, 2H), 7.27−7.20 (m, 1H), 7.15−
7.10 (m, 1H), 7.04 (d, J = 8.0 Hz, 1H), 5.21 (s, 1H), 4.36−4.27 (m,
2H), 4.01−3.93 (m, 1H), 3.75−3.67 (m, 1H), 1.98 (brs, 2H), 1.46 (t, J
= 7.0 Hz, 3H), 1.06 (t, J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
144.9, 138.1, 133.8, 129.8, 127.6, 127.0, 126.6, 126.5, 126.3, 126.0,
124.1, 121.7, 121.3, 120.8, 115.6, 111.1, 61.6, 59.2, 57.3, 46.6, 15.7,
14.9; MS (ESI) m/z 417 (M + Na)+; HRMS ESI (M + Na)+ m/z calcd
for C22H22N2O3NaS (M + Na)+ 417.1243, found 417.1233.
3-Amino-2,2-diethoxy-4-(4-chlorophenyl)-2,3-dihydro-4H-benzo-
[h]chromene-3-carbonitrile (2h): yield 0.303g (72%); mp 179−180
1
°C; IR (neat, cm−1) 3394, 3328, 2231, 1106, 806; H NMR (500
MHz, CDCl3) δ 8.26 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 7.0 Hz, 1H),
7.57−7.27 (m, 7H), 6.87 (d, J = 9.0 Hz, 1H), 4.84 (s, 1H), 4.34−4.26
(m, 2H), 4.01−3.93 (m, 1H), 3.75−3.67 (m, 1H), 1.74 (brs, 2H), 1.44
(t, J = 7.0 Hz, 3H), 1.05 (t, J = 7.0 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 145.5, 134.6, 134.4, 133.6, 132.5, 128.8, 127.5, 126.6, 126.2,
126.1, 124.3, 121.8, 121.1, 120.8, 115.2, 111.0, 61.4, 59.2, 56.8, 50.0,
15.6, 14.8; MS (ESI) m/z 445 (M + Na)+; HRMS ESI (M + Na)+ m/z
calcd for C24H23N2O3ClNa (M + Na)+ 445.1289, found 445.1282.
3-Amino-2,2-diisopropoxy-4-phenyl-2,3-dihydro-4H-benzo[h]-
chromene-3-carbonitrile (2i): yield 0.291 g (70%); mp 192−193 °C;
1
IR (neat, cm−1) 3395, 3334, 2229, 1115, 716; H NMR (300 MHz,
CDCl3) δ 8.24−8.17 (m, 1H), 7.82−7.75 (m, 1H), 7.61−7.30 (m,
8H), 6.93 (d, J = 8.6 Hz, 1H), 5.07−4.95 (m, 1H), 4.92 (s, 1H), 4.62−
4.49 (m, 1H), 1.67 (brs, 2H), 1.55 (d, J = 6.0 Hz, 3H), 1.46 (d, J = 6.2
Hz, 3H), 1.31 (d, J = 6.2 Hz, 3H), 0.75 (d, J = 6.0 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 146.0, 136.3, 133.6, 131.2, 128.7, 128.3, 127.6,
126.7, 126.4, 126.0, 124.4, 121.1, 121.0, 115.5, 111.3, 69.5, 66.0, 58.4,
50.5, 24.3, 23.7, 23.1; MS (ESI) m/z 439 (M + Na)+; HRMS ESI (M
+ Na)+ m/z calcd for C26H28N2O3Na (M + Na)+ 439.1992, found
439.1983.
2-Amino-3-chloro-2-methoxy-4-phenyl-2,3-dihydro-4H-benzo-
[h]chromene-3-carbonitrile (6a): yield 0.320 g (88%); mp 133−135
1
°C; IR (neat, cm−1) 3404, 3331, 2229, 1967, 1389, 1089, 723; H
3-Amino-2,2-dimethoxy-4-phenyl-2,3-dihydro-4H-pyrano[3,2-h]-
NMR (300 MHz, CDCl3) δ 8.35−8.29 (m, 1H), 7.83−7.77 (m, 1H),
7.64−7.34 (m, 8H), 6.81 (d, J = 8.6 Hz, 1H), 4.89 (s, 1H), 3.41 (s,
3H), 2.76 (brs, 2H); 13C NMR δ (75 MHz, CDCl3): 145.5, 136.2,
133.7, 131.4, 128.7, 128.4, 128.0, 127.6, 126.9, 126.4, 125.9, 124.5,
122.2, 121.4, 117.3, 116.0, 104.5, 68.8, 54.8, 52.9, 49.9; MS (ESI): m/z
quinoline-3-carbonitrile (3a): yield 0.260 g (72%); mp 228−229 °C;
1
IR (neat, cm−1) 3396, 3323, 2228, 1114, 776; H NMR (300 MHz,
CDCl3) δ 9.00 (dd, J = 2.2, 1.5 Hz, 1H), 8.10 (dd, J = 2.2, 1.5 Hz, 1H),
7.54−7.28 (m, 7H), 7.00 (d, J = 9.0 Hz, 1H), 4.88 (s, 1H), 3.94 (s,
3H), 3.51 (s, 3H), 1.83 (brs, 2H); 13C NMR (75 MHz, CDCl3) δ
E
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The Journal of Organic Chemistry
Article
365 (M + H)+, 348 (M − NH2)+; HRMS ESI (M + H)+ m/z calcd for
(300 MHz, CDCl3) δ 8.28 (d, J = 5.2 Hz, 1H), 7.80 (d, J = 5.1 Hz,
1H), 7.61−7.51 (m, 2H), 7.46−7.38 (m, 2H), 7.23−7.19 (m, 1H),
7.15−7.08 (m, 1H), 6.97 (d, J = 8.4 Hz, 1H), 5.20 (s, 1H), 4.06 (quin,
1H), 3.62 (quin, 1H), 2.77 (brs, 2H), 0.98 (t, J = 6.9 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 145.1, 138.2, 133.9, 129.5, 127.5, 127.0,
126.9, 126.3, 126.2, 125.6, 124.4, 122.1, 121.5, 117.0, 116.2, 104.4,
68.9, 58.5, 48.4, 14.9; MS (ESI) m/z 385 (M + H)+; HRMS ESI (M +
H)+ m/z calcd for C20H18N2O2SCl (M + H)+ 385.0772, found
385.0783.
C21H18N2O2Cl (M + H)+ 365.1051, found 365.1053.
2-Amino-3-chloro-2-methoxy-4-(4-methylphenyl)-2,3-dihydro-
4H-benzo[h]chromene-3-carbonitrile (6b): yield 0.302 g (80%); mp
135−137 °C; IR (neat, cm−1) 3421, 3345, 2231, 1901, 1391, 1084,
720; 1H NMR (500 MHz, CDCl3) δ 8.31 (d, J = 8.9 Hz, 1H), 7.79 (d,
J = 7.9 Hz, 1H), 7.58−7.18 (m, 7H), 6.83 (d, J = 8.9 Hz, 1H), 4.86 (s,
1H), 3.40 (s, 3H), 2.74 (brs, 2H), 2.40 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 145.4, 138.6, 133.7, 133.2, 131.2, 129.2, 128.8, 127.6, 126.8,
126.3, 126.0, 124.5, 122.2, 121.3, 117.5, 116.1, 104.5, 68.9, 54.4, 52.6,
49.8, 21.2; MS (ESI): m/z 379 (M + H)+, 362 (M − NH2)+; HRMS
ESI (M + H)+ m/z calcd for C22H20N2O2Cl (M + H)+ 379.1207,
found 379.1209.
2-Amino-3-chloro-2-methoxy-4-(4-methoxyphenyl)-2,3-dihydro-
4H-benzo[h]chromene-3-carbonitrile (6c): yield 0.319 g (81%); mp
134−136 °C; IR (neat, cm−1) 3417, 3345, 2230, 1899, 1383, 1088,
762; 1H NMR (500 MHz, CDCl3) δ 8.31 (d, J = 6.9 Hz, 1H), 7.79 (d,
J = 6.9 Hz, 1H), 7.61−7.28 (m, 5H), 6.95 (d, J = 8.0 Hz, 2H), 6.84 (d,
J = 9.2 Hz, 1H), 4.84 (s, 1H), 3.85 (s, 3H), 3.40 (s, 3H), 2.75 (brs,
2H); 13C NMR (75 MHz, CDCl3) δ 159.9, 145.4, 133.7, 132.4, 128.1,
127.6, 126.9, 126.3, 125.9, 124.5, 122.2, 121.4, 117.6, 116.2, 113.8,
104.5, 69.1, 55.3, 54.7, 52.2, 49.8; MS (ESI): m/z 395 (M + H)+, 376
(M − NH2)+; HRMS ESI (M + H)+ m/z calcd for C22H20N2O3Cl (M
+ H)+ 395.1157, found 395.1162.
2-Amino-3-chloro-2-isopropoxy-4-phenyl-2,3-dihydro-4H-benzo-
[h]chromene-3-carbonitrile (6i): yield 0.301 g (77%); mp 112−113
1
°C; IR (neat, cm−1) 3394, 3325, 2229, 1113, 720; H NMR (300
MHz, CDCl3) δ 8.32−8.26 (m, 1H), 7.81−7.75 (m, 1H), 7.59−7.35
(m, 8H), 6.80 (d, J = 8.6 Hz, 1H), 4.89 (s, 1H), 4.80−4.70 (m, 1H),
2.77 (brs, 2H), 1.24 (d, J = 6.2 Hz, 3H), 0.63 (d, J = 6.2 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 146.1, 136.5, 133.6, 131.6, 128.9, 128.6,
128.4, 127.5, 126.8, 126.2, 125.9, 124.6, 121.9, 121.6, 117.0, 116.2,
104.5, 69.3, 66.3, 54.6, 52.7, 23.9, 22.6; MS (ESI) m/z 393 (M + H)+,
376 (M − NH2)+; HRMS ESI (M + H)+ m/z calcd for C23H22N2O2Cl
(M + H)+ 393.1364, found 393.1369.
Experimental Procedure for the Synthesis of 3-Chloro-2-
imino-2′-oxo-3,4-dihydrospiro[benzo[h]chromene-4,3′-indo-
line]-3-carbonitrile (7). To a suspension of 2-amino-2′-oxospiro-
[benzo[h]chromene-4,3′-indoline]-3-carbonitrile (0.339 g, 1 mmol) in
5 mL of methanol was added NCS (0.146 g, 1.1 mmol) with stirring at
room temperature. The resulting clear brown solution was then
allowed to stir overnight. The precipitate formed was filtered and dried
to afford the desired product 7 as brown solid: yield 0.261 g (70%);
mp 242−244 °C; IR (neat, cm−1) 3426, 3349, 2233, 1936, 1347, 1086,
2-Amino-3-chloro-2-methoxy-4-(4-fluorophenyl)-2,3-dihydro-
4H-benzo[h]chromene-3-carbonitrile (6d): yield 0.317 g (83%); mp
120−122 °C; IR (neat, cm−1) 3429, 3356, 2234, 1903, 1392, 1088,
1
762; H NMR (300 MHz, CDCl3) δ 8.35−8.29 (m, 1H), 7.83−7.78
(m, 1H), 7.68−7.32 (m, 5H), 7.12 (t, J = 8.3 Hz, 2H), 6.79 (d, J = 8.3
Hz, 1H), 4.89 (s, 1H), 3.41 (s, 3H), 2.76 (brs, 2H); 13C NMR (75
MHz, CDCl3) δ 164.6, 161.3, 145.5, 133.8, 133.0, 132.1, 127.6, 127.0,
126.5, 125.6, 124.5, 122.4, 121.4, 117.0, 115.9, 115.5, 104.5, 68.7, 54.1,
52.3, 49.8; MS (ESI): m/z 383 (M + H)+, 366 (M − NH2)+; HRMS
ESI (M + H)+ m/z calcd for C21H17N2O2ClF (M + H)+ 383.0957,
found 383.0958.
1
762; H NMR (300 MHz, DMSO-d6) δ 11.08 (brs, 1H), 9.13 (brs,
1H), 8.33 (d, J = 7.5 Hz, 1H), 7.88−7.80 (m, 1H), 7.67−7.45 (m,
5H), 7.21 (t, J = 7.7 Hz, 1H), 7.14 (d, J = 7.7 Hz, 1H), 6.71 (d, J = 8.6
Hz, 1H); 13C NMR (75 MHz, CDCl3 + DMSO-d6) δ 172.0, 151.6,
145.6, 142.8, 133.5, 130.3, 126.8, 126.6, 126.1, 123.0, 122.9, 122.3,
122.0, 120.3, 112.1, 111.4, 110.5, 58.8, 48.7; MS (ESI) m/z 374 (M +
H)+; HRMS ESI (M + H)+ m/z calcd for C21H13N3O2Cl (M + H)+
374.0690, found 374.0696.
Experimental Procedure for the Synthesis of 4-(4-Bromo-
phenyl)-3-chloro-2-imino-2,3-dihydro-4H-benzo[h]chromene-
3-carbonitrile (7a). To a suspension of 2-amino-4-(4-bromophenyl)-
4H-benzo[h]chromene-3-carbonitrile (0.376 g, 1 mmol) in 5 mL of
isopropyl alcohol was added NCS (0.146 g, 1.1 mmol) and the mixture
stirred at room temperature for 15 min. The reaction mixture became
a clear solution followed by the precipitation of solid product. The
precipitate was filtered and dried to afford the desired product 7a as a
white solid: yield 0.316 g (77%); mp 164−165 °C; IR (neat, cm−1)
3283, 2536, 2109, 1692, 1259, 907, 762; 1H NMR (300 MHz, CDCl3)
δ 8.50 (s, 1H), 8.29 (d, J = 7.5 Hz, 1H), 7.88 (d, J = 6.7 Hz, 1H),
7.70−7.59 (m, 3H), 7.47 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 8.3 Hz, 1H),
7.07 (d, J = 8.3 Hz, 2H), 4.78 (s, 1H); 13C NMR (75 MHz, CDCl3) δ
153.2, 134.3, 133.9, 132.5, 130.6, 128.0, 127.7, 127.3, 125.6, 125.0,
123.9, 122.8, 121.0, 114.0, 56.2, 54.7; MS (ESI) m/z 411 (M)+;
HRMS ESI (M + H)+ m/z calcd for C20H13N2OClBr (M + H)+
410.9899, found 410.9920.
Experimental Procedure for the Synthesis of Compounds 8
and 9. Synthesis of compounds 8 and 9 are similar to that of the
compounds 2a and 6a, respectively. However, the deuterated
methanol (CD3OD) was used as solvent instead of methanol.
Compound 8. To a suspension of 2-amino-4-phenyl-4H-benzo[h]-
chromene-3-carbonitrile (0.089 g, 0.3 mmol) in 1 mL of methanol-d4
was added IBD (0.106g, 0.33 mmol) with stirring at room
temperature. A clear solution immediately formed followed by the
precipitation of product. The mixture was filtered to afford the desired
product: yield 0.078 g (72%); mp 189−191 °C; IR (neat, cm−1) 3395,
3326, 2536, 2127, 2076, 1384, 1130, 765; 1H NMR (300 MHz,
CDCl3) δ 8.34−8.28 (m, J = 7.5 Hz, 1H), 7.82−7.76 (m, 1H), 7.59−
7.27 (m, 8H), 6.92 (d, J = 8.3 Hz, 1H), 4.86 (s, 1H), 1.78 (brs, 1H).
13C NMR (125 MHz, CDCl3) δ 145.2, 137.4, 135.8, 133.6, 131.3,
2-Amino-3-chloro-2-methoxy-4-(4-nitrophenyl)-2,3-dihydro-4H-
benzo[h]chromene-3-carbonitrile (6e): yield 0.343 g (84%); mp
142−144 °C; IR (neat, cm−1) 3426, 3349, 2233, 1936, 1347, 1086,
1
762; H NMR (500 MHz, CDCl3) δ 8.34−8.25 (m, 3H), 7.86−7.39
(m, 6H), 6.69 (d, J = 8.8 Hz, 1H), 5.04 (s, 1H), 3.41 (s, 3H), 2.78
(brs, 2H); 13C NMR (75 MHz, CDCl3) δ 148.3, 145.7, 143.7, 133.9,
132.3, 127.7, 127.3, 126.8, 125.1, 124.6, 123.6, 123.1, 122.8, 121.4,
115.7, 115.6, 104.5, 67.9, 54.3, 52.8, 50.0; MS (ESI) m/z 410 (M +
H)+, 393 (M-NH2)+; HRMS ESI (M + H)+ m/z calcd for
C21H17N3O4Cl (M + H)+ 410.0902, found 410.0903.
2-Amino-3-chloro-2-methoxy-4-(thiophene-2-yl)-2,3-dihydro-4H-
benzo[h]chromene-3-carbonitrile (6f): yield 0.303 g (82%); mp
126−128 °C; IR (neat, cm−1) 3430, 3343, 2225, 1969, 1347, 1085,
1
764; H NMR (300 MHz, CDCl3) δ 8.34−8.28 (m, 1H), 7.84−7.78
(m, 1H), 7.63−7.51 (m, 2H), 7.45 (d, J = 9.0 Hz, 1H), 7.41 (d, J = 5.2
Hz, 1H), 7.22 (d, J = 3.7 Hz, 1H), 7.14−7.09 (m, 1H), 6.97 (d, J = 8.3
Hz, 1H), 5.18 (s, 1H), 3.41 (s, 3H), 2.76 (brs, 2H); 13C NMR (75
MHz, CDCl3) δ 144.9, 138.1, 133.9, 129.6, 127.6, 127.0, 126.4, 126.3,
125.6, 124.4, 122.3, 121.4, 117.0, 116.1, 104.5, 68.7, 50.4, 49.9, 48.5;
MS (ESI) m/z 371 (M + H)+, 354 (M-NH2)+; HRMS ESI (M + H)+
m/z calcd for C19H16N2O2ClS (M + H)+ 371.0615, found 371.0621.
2-Amino-3-chloro-2-ethoxy-4-(4-chlorophenyl)-2,3-dihydro-4H-
benzo[h]chromene-3-carbonitrile (6g): yield 0.337 g (82%); mp
155−157 °C; IR (neat, cm−1) 3412, 3336, 2055, 1900, 1348, 1087,
764; 1H NMR (300 MHz, CDCl3) δ 8.29 (d, J = 7.9 Hz, 1H), 7.80 (d,
J = 6.9 Hz, 1H), 7.60−7.28 (m, 7H), 6.78 (d, J = 7.9 Hz, 1H), 4.90 (s,
1H), 4.05 (quin, 1H), 3.62 (quin, 1H), 2.77 (brs, 2H), 0.98 (t, J = 6.9
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 145.8, 134.9, 134.8, 133.7,
132.8, 128.7, 128.2, 127.6, 127.0, 126.4, 125.6, 124.6, 122.3, 121.5,
116.6, 116.0, 104.3, 68.7, 58.5, 54.1, 52.3, 14.9; MS (ESI) m/z 413 (M
+ H)+, 396 (M-NH2)+; HRMS ESI (M + H)+ m/z calcd for
C22H19N2O2Cl2(M + H)+ 413.0818, found 413.0820.
2-Amino-3-chloro-2-ethoxy-4-(thiophene-2-yl)-2,3-dihydro-4H-
benzo[h]chromene-3-carbonitrile (6h): yield 0.307 g (80%); mp
119−121 °C; IR (neat, cm−1) 3427, 3350, 1392, 1086, 752; 1H NMR
130.2, 128.7, 128.5, 127.6, 126.5, 126.4, 126.1, 124.3, 121.8, 121.0,
F
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120.9, 115.8, 111.2, 56.7, 50.6; MS (ESI) m/z 367 (M)+; HRMS ESI
(M)+ m/z calcd for C22H13D7N2O3 (M)+ 367.1907, found 367.1925.
Compound 9. To a suspension of 2-amino-4-phenyl-4H-benzo[h]-
chromene-3-carbonitrile (0.089 g, 0.3 mmol) in 1 mL of methanol-d4
was added NCS (0.044 g, 0.33 mmol) and the mixture stirred at room
temperature until the product precipitated. The reaction mixture was
then filtered to afford the desired product: yield 0.088 g (80%); mp
126−128 °C; IR (neat, cm−1) 3405, 3332, 2544, 2245, 2075, 1383,
1130, 764; 1H NMR (300 MHz, CDCl3) δ 8.34−8.29 (m, 1H), 7.82−
7.77 (m, 1H), 7.61−7.28 (m, 8H), 6.81 (d, J = 9.0 Hz, 1H), 4.89 (s,
1H), 2.75 (brs, 1H); 13C NMR (75 MHz, CDCl3) δ 145.5, 136.2,
133.7, 131.4, 128.7, 128.5, 128.0, 127.6, 126.9, 126.4, 125.9, 124.5,
122.2, 121.3, 117.3, 116.1, 104.4, 68.7, 54.7, 52.9; MS (ESI) m/z 369
(M + H)+, 351 (M − HD)+. Anal. Calcd for C21H13D4N2O2Cl: C,
68.38; H, 5.74; N, 7.59. Found: C, 68.27; H, 5.71; N, 7.64.
(10) Kemnitzer, W.; Drewe, J.; Jiang, S.; Zhang, H.; Zhao, J.; Crogan-
Grundy, C.; Xu, L.; Lamothe, S.; Gourdeau, H.; Denis, R.; Tseng, B.;
Kasibhatla, S.; Cai, S. X. J. Med. Chem. 2007, 50, 2858.
(11) Mandha, S. R.; Siliveri, S.; Alla, M.; Bommena, V. R.;
Bommineni, M. R.; Balasubramanian, S. Bioorg. Med. Chem. Lett.
2012, 22, 5272.
(12) (a) Solhy, A.; Elmakssoudi, A.; Tahir, R.; Karkouri, M.; Larzek,
M.; Bousmina, M.; Zahouily, M. Green Chem. 2010, 12, 2261.
(b) Kumar, D.; Reddy, V. B.; Mishra, B. G.; Rana, R. K.; Nadagouda,
M. N.; Varma, R. S. Tetrahedron 2007, 63, 3093.
(13) Al-Omran, F.; El-Ghamry, I.; Elnagdi, M. H. Org. Prep. Proc. Int.
1998, 30, 363.
(14) El-Agrody, A. M.; Emam, H. A.; El-Hakim, M. H.; Abd El-latif,
M. S.; Fakery, A. H. J. Chem. Res. 1997, 320.
(15) (a) Roizen, J. L.; Harvey, M. E.; Du Bois, J. Acc. Chem. Res.
2012, 45, 911. (c) Beaumont, S.; Pons, V.; Retailleau, P.; Dodd, R. H.;
Dauban, P. Angew. Chem., Int. Ed. 2010, 49, 1634. (d) Moriarty, R. M.;
Prakash, O. Acc. Chem. Res. 1986, 19, 244.
(16) CCDC 878374 (2a) and 878375 (2f) contain the
supplementary crystallographic data for this paper. These data can
be obtained free of charge at www.ccdc.cam.ac.uk/conts/retrieving.
html (or from the Cambridge Crystallographic Data Centre).
(17) (a) Padwa, A.; Stengel, T. Org. Lett. 2002, 4, 2137. (b) Silva, L.
F.; Pons, Olofsson, B. Nat. Prod. Rep. 2011, 28, 1722.
ASSOCIATED CONTENT
■
S
* Supporting Information
Atom coordinates and absolute energies, H and 13C NMR
1
spectra for all compounds, and X-ray data for compounds 2a,
2f, and 6g (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
(18) CCDC 878376 (6g) contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge at www.
ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crys-
tallographic Data Centre).
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: manjula@iict.res.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Director, IICT, and Head, Crop Protection
Chemicals Division, for the facilities. S.R.M. thanks the Council
of Scientific and Industrial Research (CSIR), India, for financial
support.
REFERENCES
■
(1) (a) Kidwai, M.; Saxena, S.; Khan, M. K. R.; Thukral, S. S. Bioorg.
Med. Chem. Lett. 2005, 15, 4295. (b) Khafagy, M. M.; El-Wahas, A. H.
F. A.; Eid, F. A.; El-Agrody, A. M. II Farmaco 2002, 57, 715. (c) Eid, F.
A.; El-Wahab, A. H. F. A.; Ali, G. A. M. E.; Khafagy, M. M. Acta Pharm.
2004, 54, 13.
(2) (a) Al-Haiza, M. A.; Mostafa, M. S.; El-Kady, M. Y. Molecules
2003, 8, 275. (b) Nakib, T. A.; Bezjak, V.; Rashid, S.; Fullam, B.;
Meegan, M. J. Eur. J. Med. Chem. 1991, 26, 221.
(3) (a) Abdelrazek, F. M.; Metz, P.; Kataeva, O.; Jager, A.; El-
Mahrouky, S. F. Arch. Pharm. 2007, 340, 543. (b) Abdelrazek, F. M.;
Metz, P.; Metwally, N. H.; El-Mahrouky, S. F. Arch. Pharm. 2006, 339,
456.
(4) Joshi, C.; Jain, R.; Sharma, K. J. Indian Chem. Soc. 1988, 65, 202.
(5) Smith, P. W.; Sollis, S. L.; Howes, P. D.; Cherry, P. C.; Starkey, I.
D.; Cobley, K. N.; Weston, H.; Scicinski, J.; Merritt, A.; Whittington,
A.; Wyatt, P.; Taylor, N.; Green, D.; Bethell, R.; Madar, S.; Fenton, R.
J.; Morley, P. J.; Pateman, T.; Beresford, A. J. Med. Chem. 1998, 41,
787.
(6) (a) Martinez-Grau, A.; Marco, J. Bioorg. Med. Chem. Lett. 1997, 7,
3165. (b) Meguro, K.; Aizawa, M.; Sohda, T.; Kawamatsu, Y.;
Nagaoka, A. Chem. Pharm. Bull. 1985, 33, 3787.
(7) (a) Marco-Contelles, J.; Leon, R.; Rios, C.; Garcia, A. G.; Lopez,
M. G.; Villarroya, M. Bioorg. Med. Chem. 2006, 14, 8176. (b) Leon, R.;
Marco-Contelles, J.; Garcia, A. G.; Villarroya, M. Bioorg. Med. Chem.
2005, 13, 1167.
(8) Smith, C. W.; Bailey, J. M.; Billingham, M. E. J.; Chandrasekhar,
S.; Dell, C. P.; Harvey, A. K.; Hicks, C. A.; Kingston, A. E.; Wishart, G.
N. Bioorg. Med. Chem. Lett. 1995, 5, 2783.
(9) Panda, D.; Singh, J. P.; Wilson, L. J. Biol. Chem. 1997, 272, 7681.
G
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