Novel process for the synthesis of class I antiarrhythmic agent (±)-cibenzoline and its analogs

Article abstract of DOI:10.1080/00397910802006388

Synthesis of (±)-cibenzoline and its analogs has been achieved by a simple sequence of reactions. The diaryl cyanoolefin intermediate 3 could be prepared by Knoevenagel condensation of benzophenone with ethylcyanoacetate to form the tetra-substituted olefin intermediate 2 followed by Krapcho deethoxycarbonylation or from β-hydroxynitrile intermediate 2' followed by the elimination of hydroxyl group respectively. The 2,2- diphenylcyclopropanecarbonitrile 4 was synthesized from intermediate 3 by cyclopropanation, which was converted to (±)-2-(2,2-diphenylcyclopropyl)- 2-imidazoline 5 by reaction with ethylenediamine in the presence of a catalytic amount of sulfur. Moreover, the obtained 2-imidazolines were smoothly oxidized to the corresponding imidazoles 6 in good to moderate yields. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802006388

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Novel Process for the Synthesis
of Class I Antiarrhythmic Agent
(±)-Cibenzoline and Its Analogs
Atul R. Gholap a , Vincent Paul a & Kumar V.
Srinivasan a
a Division of Organic Chemistry, Technology, National
Chemical Laboratory , Pune, India
Published online: 28 Aug 2008.
To cite this article: Atul R. Gholap , Vincent Paul & Kumar V. Srinivasan (2008)
Novel Process for the Synthesis of Class I Antiarrhythmic Agent (±)-Cibenzoline
and Its Analogs, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 38:17, 2967-2982, DOI:
10.1080/00397910802006388
To link to this article: http://dx.doi.org/10.1080/00397910802006388
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Synthetic Communications1, 38: 2967–2982, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802006388
Novel Process for the Synthesis of Class I
Antiarrhythmic Agent ( )-Cibenzoline
and Its Analogs
Atul R. Gholap, Vincent Paul, and Kumar V. Srinivasan
Division of Organic Chemistry, Technology, National Chemical Laboratory,
Pune, India
Abstract: Synthesis of (ꢀ)-cibenzoline and its analogs has been achieved by
a simple sequence of reactions. The diaryl cyanoolefin intermediate 3 could be
prepared by Knoevenagel condensation of benzophenone with ethylcyanoacetate
to form the tetra-substituted olefin intermediate 2 followed by Krapcho deethoxy-
carbonylation or from b-hydroxynitrile intermediate 20 followed by the elimi-
nation of hydroxyl group respectively. The 2,2-diphenylcyclopropanecarbonitrile
4 was synthesized from intermediate 3 by cyclopropanation, which was converted
to (ꢀ)-2-(2,2-diphenylcyclopropyl)-2-imidazoline 5 by reaction with ethylene-
diamine in the presence of a catalytic amount of sulfur. Moreover, the obtained
2-imidazolines were smoothly oxidized to the corresponding imidazoles 6 in good
to moderate yields.
Keywords: Benzophenone, cibenzoline, cyclopropanation, diaryl cyanoolefin
INTRODUCTION
Atrial fibrillation represents an important medical problem,[1] because
not only of increased incidence in the elderly population, but also it is a
major cause of embolic stroke. Atrial fibrillation is the most commonly
sustained cardiac arrhythmia and is a frequent reason for antiarrhythmic
therapy.[2] Numerous antiarrhythmic drugs have been developed and used
to treat arrhythmia, but clinical efficacy is often less than satisfactory.
Received December 17, 2007.
Address correspondence to Kumar V. Srinivasan, Division of Organic
Chemistry, Technology, National Chemical Laboratory, DR. Homi Bhabha
Road, Pune, 411008, India. E-mail: kumarv.srinivasan@gmail.com
2967

2968
A. R. Gholap, V. Paul, and K. V. Srinivasan
Scheme 1. Synthesis of cibenzoline and its analogs: reagents and conditions:
(i) CNCH2COOEt, HOAc=C6H6, b-alanine at reflux, 90 (ia) CH3CN, n-BuLi,
dry THF, ꢂ 80ꢁC, 2 h; (ii) NaCl, H2O, DMSO, 160–170ꢁC, 4 h; (iib) SOCl2, dry
pyridine, dry DCM, 0ꢁC to rt, 3 h; (iii) Me3S(O)I, NaH, DMSO, rt, 24 h;
(iv) sulfur, ethylenediamine, reflux, 4 h; (v) (diacetoxyiodo) benzene, K2CO3,
DMSO, rt, 48 h.
( ꢀ )-2-(2,2-diphenylcyclopropyl)-2-imidazoline 5a (Scheme 1) has been
clinically used as one of the class I antiarrhythmic agents.[3,4] This drug
relieves arrhythmia by restricting fast inward Naþ current and blocking
the slow inward Ca2 þ channel in myocytes.[5] It was shown that micromo-
lar concentrations of cibenzoline blocked the ATP-sensitive Kþ (KATP)
channel in excised membranes from rat heart and pancreatic b cells.[6–8]
Cibenzoline is marketed under the trade names Cipralan (Glaxo) and
Exacor (Monsanto).
To our knowledge, literature cites only six reports so far, including
four patents for the synthesis of cibenzoline from diphenyldiazo-
methane[9–13] and chiral cibenzoline from chiral 2,2-disubstituted cyclopro-
pylmethanols.[14] In the patented method, the synthesis of diphenyldiazo-
methane has been carried out by the oxidation of benzophenone
hydrazone with toxic reagents such as mercuric oxide or manganese diox-
ide, and a high temperature of about 200ꢁC was needed for the final
condensation process with ethylenediamine monotosylate. It is observed
that all the reported methods are cumbersome and expensive for a pro-
cess-scale preparation. They entail certain inconvenient reagents to handle,
such as an unstable diphenyldiazomethane and HgO. This article
describes our attempts to develop a novel and less hazardous synthetic
route amenable for scale-up operations. Herein we report an improved

(
)-Cibenzoline and Its Analogs
2969
strategy for the synthesis of cibenzoline and its analogs from commercially
available benzophenone as starting material. Toxic reagents such as mer-
curic oxide and high temperature in the final condensation process are
avoided. The synthesis of the analogs has been carried out to create a
more potent and well-tolerated therapeutic.
RESULTS AND DISCUSSION
The synthesis of imidazoles 6a–c is outlined in Scheme 1. Thus benzo-
phenone 1a was converted to the tetra-substituted olefin 2a with
ethylcyanoacetate by Knoevenagel condensation.[15] The reported
procedure, which makes use of ammonium acetate as a catalyst, failed
to initiate the condensation of benzophenone and ethylcyanoace-
tate.[16] When a molar mixture of these components were heated to
reflux in the presence of b-alanine in a mixture of glacial acetic acid
and benzene for several hours, the formation of desired product 2a
was detected by gas chromatography (GC). The condensation reac-
tion reached equilibrium after 90 h with continuous removal of water
(Dean–Stark water trap). The rate of condensation was slow and was
further retarded if higher boiling solvents such as toluene and xylene
were used. The cyanoester 2 was isolated by column chromatography.
The deethoxycarbonylation of 2-cyano-2-alkenoates 2 to the unsatu-
rated nitriles 3 was carried out in good yields by Krapcho’s proto-
col[17] using wet dimethyl sulfoxide (DMSO) containing sodium
chloride. The synthesis of unsaturated nitriles 3 by the sequence of
Knoevenagel condensation followed by deethoxycarbonylation was
inconvenient because of the longer reaction time (90 h) and lower
yields (58–65%). To achieve higher yields and short reaction time,
synthesis of intermediate 3 was also carried out by an alternative
route as shown in Scheme 1. The intermediate 3 can be prepared by
starting from the substituted benzophenone. Acetonitrile was found
to undergo mainly ionization of an a-hydrogen with n-butyl lithium
in tetrahydrofuran, rather than an addition reaction involving the
nitrile group. The ionization of acetonitrile with n-butyl lithium in
tetrahydrofuran and its condensation with substituted benzophenone
was carried out at ꢂ80ꢁC to get the b-hydroxynitrile in just 2 h, fol-
lowed by the elimination of the hydroxyl group using thionyl
chloride and pyridine, which gave exclusively the compound 3. The
unsaturated nitrile 3 was cyclopropanated by the addition of tri-
methylsulfoxonium iodide and sodium hydride in dry DMSO at room
temperature to afford the 2,2-diphenylcyclopropanecarbonitriles 4 as
a mixture of diastereomers.

2970
A. R. Gholap, V. Paul, and K. V. Srinivasan
Table 1. Method for conversion of nitrile to 2-imidazoline
Entry
1
Conditions
Time (h)
12
Results
(i) Dry HCl=EtOH, 0ꢁC, (ii) Et3N,
ethylenediamine, MeOH, reflux[18]
CuCl=MeOH, ethylenediamine, reflux[19]
Ethylenediamine monotosylate 200ꢁC[12]
Ethylediamine, reflux
No expected product
2
3
4
5
24
10
12
4
No reaction
No expected product
No reaction
88% isolated yield
Ethylediamine, sulfur, reflux[20]
Attempts were made synthesize 4,5-dihydro-2-(2,2-diphenylcyclo-
propyl)-1H-imidazole 5a by the reaction of ethylenediamine with
2,2-diphenylcyclopropanecarbonitrile 4a using reported methods in
literature (Table 1).[18–20] Thus various methods (entries 1 to 4) as shown
in Table 1 were tried, which failed to convert the nitrile to 2-imidazoline.
Finally the conversion of the nitrile group to 2-imidazoline was achieved
by refluxing 4a with ethylenediamine in the presence of a catalytic
amount of sulfur. The plausible explanation[21–23] is that sulfur reacts
with the nitrile to produce a thioamide. The thioamide reacts with
ethylenediamine, which upon elimination of hydrogen sulfide and
ammonia produces the target molecule cibenzoline. The oxidation of
imidazoline to imidazole[24] derivative was carried out smoothly in good
yields using (diacetoxyiodo) benzene in the presence of K2CO3 in DMSO
at room temperature.
Recently Miura et al.[14] failed to synthesize cibenzoline analog from
9-fluorenone. However, using the methodology of our present article, we
have successfully synthesized the racemic analog of cibenzoline starting
from 9-fluorenone as shown in Scheme 2. The sterically hindered two
benzene rings of spiro (cyclopropane-1,90-fluorene)-2-carbonitrile 4d
fixed in the same plane can stereochemically hinder the formation of
the imidazoline ring. In our hands, however, 4d was easily converted to
the target molecule 5d by heating with ethylenediamine in the presence
of sulfur. Further, 5d was oxidized to 6d.

(
)-Cibenzoline and Its Analogs
2971
Scheme 2. Synthesis of cibenzoline analog: reagents and conditions: (i)
CNCH2COOEt, HOAc=C6H6, b-alanine at reflux, 90 h; (ia) CH3CN, n-BuLi,
dry THF, ꢂ 80ꢁC, 2 h; (ii) NaCl, H2O, DMSO, 160–170 ꢁC, 4 h; (iib) SOCl2, dry
pyridine, dry DCM, 0ꢁC to rt, 3 h; (iii) Me3S(O)I, NaH, DMSO, rt, 24 h; (iv) sulfur,
ethylenediamine reflux, 4 h; (v) (diacetoxyiodo) benzene, K2CO3, DMSO, rt, 48 h.
CONCLUSION
In summary, we have presented an efficient and simple four-step organic
transformation for the synthesis of cibenzoline and its analogs. The
synthesis of intermediate 3 via b-hydroxynitrile is more convenient with
higher yields. The nitrile group of intermediate 4 was easily converted
into the imidazoline ring in the presence of elemental sulfur as catalyst,
which is relatively less toxic among the commercially available sulfur
sources. We believe that this less hazardous and simple organic transfor-
mations makes the process amenable for scale-up operations.
EXPERIMENTAL
Melting points were recorded in open capillaries using a Buchi melting-
point B540 apparatus. Column chromatography was performed using
silica gel (60- to 120-mesh size), and thin-layer chromatography (TLC)
was carried out using aluminum sheets precoated with silica gel 60F254.
All solvents and chemicals used were reagent grade procured commercially
1
and used without further purification. H NMR and 13C NMR spectra
were recorded on a Bruker Avance DPX 200 spectrometer. Infrared spec-
tra were recorded with ATI Matt-son RS-1 FTIR spectrometer. Elemental
analysis was performed on Flash EA 1112 Thermo Finnigan instrument.

2972
A. R. Gholap, V. Paul, and K. V. Srinivasan
Procedure A: Ethyl 2-Cyano-3,3-diphenyl Acrylate (2a)
A mixture of benzophenone 1a (20.0 g, 110 mmol), ethyl cyanoacetate
(13.65 g, 121 mmol), and a catalytic amount of b-alanine (0.9 g) was refluxed
with separation of water with a Dean–Stark water trap in a mixed solvent of
benzene (100 ml) and glacial acetic acid (20 ml). Separation of water was
rapid during the first 2 h but became slower afterward. Azeotropic distil-
lation continued for a period of 90 h. Benzene was removed under reduced
pressure, and the crude product was dissolved in ethyl acetate and washed
with water. The ethyl acetate layer was separated, dried over Na2SO4, and
concentrated in vacuo to afford the residue, which was chromatographically
purified on silica gel using pet. ether=EtOAc (9.8:0.2) as eluꢁent to give 2a
ꢁ
1
(19.6g, 64%) as white solid, mp 97–99 C, lit.[25] 97.6–98.9 C. H NMR
(CDCl3, 200 MHz): d 1.15 (t, J ¼ 7.2Hz, 3H), 4.15 (q, J ¼ 7.2 Hz, 2H),
7.13–7.18 (m, 2H), 7.33–7.50 (m, 8H); 13C NMR (CDCl3, 50 MHz): d
13.4, 61.9, 103.8, 116.6, 127.9, 128.2, 129.0, 129.9, 130.1, 131.1, 138.0,
138.3, 162.4, 168.7; IR (KBr): 3020, 2220, 1958, 1731, 1558, 1445, 1368,
1246, 1111, 757 cmꢂ 1;. Anal. calcd. for C18H15NO2: C, 77.96; H, 5.45; N,
5.05. Found: C, 77.82; H, 5.62; N, 4.95. Compounds 2b, 2c, and 2d were
similarly synthesized by using this procedure.
Procedure B: 3,3-Diphenylacrylonitrile (3a)
A mixture of ethyl 2-cyano-3,3-diphenyl acrylate 2a (15 g, 54 mmol),
sodium chloride (0.949 g, 16.2 mmol), and H2O (0.584 g, 32.5 mmol) in
35 ml of DMSO was heated up to 160–170ꢁC for 4 h. After completion
of the reaction, the reaction mixture was partitioned between ethyl
acetate and water. The ethyl acetate layer was separated, dried over
Na2SO4, and concentrated under reduced pressure to afford the crude
residue, which was chromatographically purified on silica gel by using
pet.ether=EtOAc, (9.9:0.1) to afford the pure product 3a (8 g, 72%) as
1
colorless liquid. H NMR (CDCl3, 200 MHz): d 5.74 (s, 1H), 7.25–7.45
(m, 10H); 13C NMR (CDCl3, 50 MHz): d 94.8, 117.8, 128.40, 128.48,
128.5, 129.4, 129.9, 130.3, 136.9, 138.8, 163.0; IR (KBr): 3018, 2239,
1951, 1599, 1496, 1216, 1025, 880 cm ꢂ 1. Anal. calcd. for C15H11N: C,
87.77; H, 5.40; N, 6.82. Found: C, 87.89; H, 5.48; N, 6.71. Compounds
3b, 3c, and 3d were similarly synthesized by using this procedure.
Procedure C: 3-Hydroxy-3,3-Diphenylpropanenitrile (20a)
To a stirred solution of anhydrous THF (20 ml), n-butyl lithium in
hexane 1.6 M (13.4 ml, 21.46 mmol) was added at ꢂ80 ꢁC under an argon

(
)-Cibenzoline and Its Analogs
2973
atmosphere, followed by a solution of acetonitrile (1.02 ml, 19.51 mmol)
in THF (15 ml). After stirring the reaction mixture for 1 h at ꢂ80ꢁC,
benzophenone (3.55 g, 19.5 mmol) in anhydrous THF (20 ml) was added
to the resulting white suspension over a period of 5 min and stirred
ꢁ
further for 30 min at ꢂ80 C. The bath was removed after 30 min, and
the pale yellow solution was further stirred for 10 min after attaining
room temperature and then poured into an ice water–hydrochloric acid
mixture. The layers were separated, and the aqueous layer was extracted
with ethyl acetate. The organic layer was separated, dried over Na2SO4,
and concentrated in vacuo to obtain the residual crude product, which
was purified by column chromatography using pet. ether=EtOAc
(8.5ꢁ:1.5) as a eluent to obtain 20a (3.9 g, 90%); white solid, mp 141–
ꢁ
1
143 C, lit.[26] 142–143 C. H NMR (CDCl3, 200 MHz): d 2.80 (s, 1H),
3.28 (s, 2H), 7.31–7.43 (m, 10H); 13C NMR (CDCl3, 50 MHz): d 32.5,
76.4, 117.1, 125.7, 128.1, 128.6, 143.8; IR (KBr): 3390, 2269, 1884,
1683, 1449, 1378, 1189, 1055 cmꢂ 1. Anal. calcd. for C15H13NO: C,
80.69; H, 5.87; N, 6.27. Found: C, 80.60; H, 5.79; N, 6.38. Compounds
20b, 20c, and 20d were similarly synthesized using this procedure.
Procedure D: 3,3-Diphenylacrylonitrile (3a from 20a)
A solution of 3-hydroxy-3,3-diphenylpropanenitrile 20a (3.5 g, 15.69 mmol)
in dry CH2Cl2 (30 ml) was stirred under an atmosphere of argon. Dry
pyridine (1.50 ml, 18.52 mmol) was added, and the reaction mixture was
cooled to 0ꢁC using an ice–salt mixture. After 20 min, SOCl2 (1.27 ml,
17.42 mmol) was added dropwise at 0ꢁC over a period of 10 min and stirred
at room temperature for 3 h. After completion of reaction, ice–cold water
(10 ml) and CH2Cl2 (30 ml) was added to the reaction mixture. The CH2Cl2
layer was then washed with dilute HCl, water, and NaHCO3 (5%, 15 ml).
The organic layer was separated, dried over Na2SO4, and concentrated in
vacuo to afford the residue, which was chromatographically purified
on silica gel using pet.ether=EtOAc (9.9:0.1) as a eluent to afford the pro-
duct 3a as colorless liquid (2.79 g, 87%).
Procedure E: 2,2-Diphenylcyclopropanecarbonitrile (4a)
Sodium hydride (2.48 g, as 60% dispersion in mineral oil, 62.43 mmol) was
washed with dry hexane and suspended in anhydrous DMSO (40 ml) under
a nitrogen atmosphere. Trimethylsulfoxonium iodide (13.73 g, 62.43 mmol)
was added in portions to the heterogeneous reaction mixture, which
was stirred until the foaming subsided. The reaction was cooled to 0ꢁC,
and 3,3-diphenylacrylonitrile 3a (8 g, 39.02 mmol) dissolved in anhydrous

2974
A. R. Gholap, V. Paul, and K. V. Srinivasan
DMSO (20 ml) was added to the reaction mixture over a period of 20 min.
The reaction mixture was allowed to warm to room temperature with stir-
ring overnight. The crude reaction mixture was slowly poured into saturated
aqueous ammonium chloride, and the resulting mixture was further diluted
with ethyl acetate. The phases were separated, and the aqueous layer was
extracted several times with ethyl acetate. The combined organic fractions
were dried over Na2SO4 and concentrated in vacuo to obtain a crude pro-
duct, which was chromatographically purified on silica gel using pet. ether=
EtOAc (9.5:0.5) to afford 4a (4.68 g, 55%) as a white solid, mp 108–110 ꢁC,
ꢁ
1
lit.[27] 107–108 C. H NMR (CDCl3, 200MHz): d 1.78 (dd, J ¼ 5.5 Hz,
J ¼ 9.2 Hz, 1H), 2.01 (t, J ¼ 5.5Hz, 1H), 2.20 (dd, J ¼ 5.5 Hz, J ¼ 9.2 Hz,
1H), 7.20–7.46 (m, 10H); 13C NMR (CDCl3, 50MHz): d 12.0, 20.8, 38.0,
119.3, 127.2, 127.6, 127.7, 128.60, 128.66, 129.2, 138.3, 142.1; IR (KBr):
3058, 2213, 1662, 1592, 1494, 1445, 1355, 1251, 1078, 827cmꢂ1. Anal. calcd.
for C16H13N: C, 87.64; H, 5.98; N, 6.39; found: C, 87.48; H, 5.75; N, 6.45.
Compounds 4b, 4c, and 4d were synthesized similarly using this procedure.
Procedure F: 4,5-Dihydro-2-(2,2-Diphenylcyclopropyl)-1H-imidazole (5a)
A
mixture of 2,2-diphenylcyclopropanecarbonitrile 4a (0.790 g,
3.60 mmol) and sulfur (0.029 g, 0.90 mmol) in ethylenediamine (5 ml)
was refluxed with stirring for 4 h. After completion of the reaction, ethy-
lenediamine was removed under reduced pressure to obtain a yellow
solid, which was dissolved in CHCl3, and the organic layer was washed
with water and dried over anhydrous Na2SO4. A thick oily residue was
obtained after evaporation of solvent, which was chromatographically
purified on silica gel using CH3OH=Et3N (9.8:0.2) to afford a sticky pro-
duct, which was recrystallized from pet. ether 5a (0.830 g, 88%) as a white
solid; mp 100–102ꢁC, lit.[10]103–104ꢁC. 1H NMR (CDCl3, 200 MHz):
d 1.70 (dd, J ¼ 5.8 Hz, J ¼ 8.8 Hz, 1H), 2.10 (t, J ¼ 5.8 Hz, 1H), 2.66
(dd, J ¼ 5.8 Hz, J ¼ 8.8 Hz, 1H), 3.17–3.28 (m, 2H), 3.40–3.51 (m, 2H),
4.09 (s, 1H), 7.20–7.48 (m, 10H); 13C NMR (CDCl3, 50 MHz): d 19.7,
25.5, 37.6, 49.5, 126.3, 127.0, 127.4, 128.3, 128.4, 129.6, 140.3, 144.9,
166.1; IR (KBr): 3140, 2970, 2400, 2219, 1617, 1495, 1446, 930 cm ꢂ 1
.
Anal. calcd. for C18H18N2: C, 82.41; H, 6.92; N, 10.68. Found: C,
82.59; H, 6.74; N, 10.49. Compounds 5b, 5c, and 5d were synthesized
similarly using this procedure.
Procedure G: 2-(2,2-diphenylcyclopropyl)-1H-imidazole (6a)
To a mixture of 4,5-dihydro-2-(2,2-diphenylcyclopropyl)-1H-imidazole
5a (0.5 g, 1.90 mmol) and K2CO3 (0.290 g, 2.10 mmol) in DMSO

(
)-Cibenzoline and Its Analogs
2975
(15 ml), diacetoxyiodo(benzene) (DIB) (0.614 g, 2.10 mmol) was added.
Then the mixture was stirred for 48 h at room temperature under an
argon atmosphere. After completion of the reaction, the reaction mixture
was diluted with sat. aq NaHCO3 and EtOAc and was stirred for 5 min.
The mixture was extracted with EtOAc. The organic layer was separated,
dried over Na2SO4, and concentrated in vacuo to obtain the residual
crude product, which was purified by column chromatography using
EtOAc=MeOH (9.9:0.1) as a eluent to afford ( ꢀ )-2-(2,2-diphenylcyclo-
propyl)-1H-imidazole 6a (0.357 g, 72%) as an off-white solid; mp 218–
ꢁ
1
220 C. H NMR (CDCl3=DMSO-d6, 200 MHz): d 1.76 (dd, J ¼ 5.5 Hz,
J ¼ 9.2 Hz, 1H), 2.31 (t, J ¼ 5.5 Hz, 1H), 2.85 (dd, J ¼ 5.5 Hz, J ¼
9.2 Hz, 1H), 6.71 (s, 2H), 7.05–7.36 (m, 10H), 7.75 (s, 1H); 13C NMR
(CDCl3=DMSO-d6, 50 MHz): d 18.2, 25.1, 37.8, 125.9, 126.1, 127.5,
127.7, 128.2, 130.1, 140.9, 144.7, 146.1; IR (KBr): 3365, 3140, 1581,
1496, 1462, 1377, 1077, 862 cm ꢂ 1. Anal. calcd. for C18H16N2: C, 83.05;
H, 6.19; N, 10.76. Found: C, 82.87; H, 6.24; N, 10.59. Compounds 6b,
6c, and 6d were synthesized similarly using this procedure.
Other Compounds
Ethyl 3,3-bis(4-Chlorophenyl)-2-cyanoacrylate (2b)
Compound 1b (20 g, 80 mmol) was reacted as described in procedure
A to give 2b as a white solid (18 g, 65%); mp 90–92ꢁC. 1H NMR
(CDCl3, 200 MHz): d 1.21 (t, J ¼ 7.1 Hz, 3H), 4.19 (q, J ¼ 7.1 Hz,
2H), 7.05–7.12 (m, 2H), 7.31–7.44 (m, 6H); 13C NMR (CDCl3,
50 MHz): d 13.7, 62.4, 104.6, 116.3, 128.6, 129.0, 130.6, 131.5, 136.2,
136.3, 136.9, 138.0, 162.0, 166.4; IR (cm ꢂ 1): 3020, 2219, 1911, 1732,
1590, 1490, 1247, 1215, 1093, 833 cm ꢂ 1. Anal. calcd. for C18H13Cl2
NO2: C, 62.45; H, 3.78; Cl, 20.48; N, 4.05. Found: C, 62.52; H,
3.84; Cl, 20.56; N, 4.22.
3,3-bis(4-Chlorophenyl)-3-hydroxypropanenitrile (20b)
Compound 1b (4 g, 16 mmol) was reacted as described in procedure C to
give 20b as a white solid (3.95 g, 85%); mp 115–117ꢁC. 1H NMR (CDCl3,
200 MHz): d 2.87 (s, 1H), 3.23 (s, 2H), 7.29–7.39 (m, 8H); 13C NMR
(CDCl3, 50 MHz): d 32.3, 75.6, 116.7, 127.1, 128.7, 134.2, 141.9; IR
(KBr) 3385, 2262, 1890, 1650, 1485, 1462, 1367, 1254, 1168, 1094 cmꢂ1
.
Anal. calcd. for C15H11Cl2NO: C, 61.67; H, 3.79; Cl, 24.27; N, 4.79.
Found: C, 61.80; H, 3.67; Cl, 24.39; N, 4.90.

2976
A. R. Gholap, V. Paul, and K. V. Srinivasan
3,3-bis(4-Chlorophenyl)acrylonitrile (3b)
Compound 2b (10 g, 28.90 mmol) was reacted as described in procedure B
to give 3b as a white solid (5.65 g, 71%). Compound 3b from 20b):
Compound 20b (3 g, 10.27 mmol) was reacted as describedꢁin procedure
1
D to give 3b as a white solid (2.54 g, 90%); mp 100–102 C. H NMR
(CDCl3, 200 MHz): d 5.73 (s, 1H), 7.19–7.25 (m, 2H), 7.34–7.47 (m,
6H); 13C NMR (CDCl3, 50 MHz): d 95.6, 117.3, 128.9, 129.0, 129.6,
130.8, 134.8, 136.3, 136.80, 136.87, 160.5; IR (KBr) 3019, 2216, 1909,
1590, 1494, 1403, 1253, 1093, 834 cmꢂ1. Anal. calcd. for C15H9Cl2N: C,
65.72; H, 3.31; Cl, 25.86; N, 5.11. Found: C, 65.80; H, 3.17; Cl, 25.75;
N, 5.24.
2,2-bis(4-Chlorophenyl) cyclopropanecarbonitrile (4b)
Compound 3b (8.5 g, 31.02 mmol) was reacted as described in procedure
ꢁ
1
E to give 4b as a white solid (4.65 g, 52%); mp 139–140 C. H NMR
(CDCl3, 200 MHz): d 1.82 (dd, J ¼ 5.5 Hz, J ¼ 9.2 Hz, 1H), 2.05
(t, J ¼ 5.5 Hz, 1H), 2.25 (dd, J ¼ 5.5 Hz, J ¼ 9.2 Hz, 1H), 7.18–7.39
(m, 8H); 13C NMR (CDCl3, 50 MHz): d 12.3, 20.9, 36.9, 118.8, 128.9,
129.0, 129.1, 130.5, 133.4, 134.0, 136.9, 140.1; IR (KBr) 3019, 2241,
1596, 1492, 1401, 1215, 758 cmꢂ1. Anal. calcd. for C16H11Cl2N: C,
66.69; H, 3.85; Cl, 24.61; N, 4.86. Found: C, 66.80; H, 3.62; Cl, 24.44;
N, 4.98.
2-(2,2-bis(4-Chlorophenyl)cyclopropyl)-4,5-dihydro-1H-imidazole (5b)
Compound 4b (0.7 g, 2.43 mmol) was reacted as described in procedure F
ꢁ
1
to give 5b as a white solid (0.684 g, 85%); mp 155–158 C. H NMR
(CDCl3, 200 MHz): d 1.62 (dd, J ¼ 5.5 Hz, J ¼ 9.0 Hz, 1H), 2.00 (t,
J ¼ 5.5 Hz, 1H), 2.46 (dd, J ¼ 5.5 Hz, J ¼ 9.0 Hz, 1H), 2.71 (brs, 1H),
3.15–3.27 (m, 2H), 3.38–3.50 (m, 2H), 7.13–7.29 (m, 10H); 13C NMR
(CDCl3, 50 MHz): d 19.5, 25.6, 36.4, 49.6, 128.5, 128.7, 130.9, 132.3,
132.9, 138.5, 143.1, 164.8; IR (KBr): 3153, 2974, 2400, 1621, 1493,
1215, 846 cmꢂ1. Anal. calcd. for C18H16Cl2N2: C, 65.27; H, 4.87; Cl,
21.41; N, 8.46. Found: C, 65.42; H, 4.71; Cl, 21.24; N, 8.54.
2-(2,2-bis(4-chlorophenyl)cyclopropyl)-1H-imidazole (6b)
Compound 5b (0.290 g, 0.87 mmol) was reacted as described in procedure
ꢁ
1
G to give 6b as a white solid (0.196 g, 68%); mp 224–226 C. H NMR

(
)-Cibenzoline and Its Analogs
2977
(CDCl3=DMSO-d6, 200 MHz): d 1.75 (dd, J ¼ 5.5 Hz, J ¼ 9.2 Hz, 1H),
2.31 (t, J ¼ 5.5 Hz, 1H), 2.87 (dd, J ¼ 5.5 Hz, J ¼ 9.2 Hz, 1H), 6.76 (s,
2H), 7.09 (s, 4H), 7.23 (s, 4H), 7.42 (s, 1H); 13C NMR (CDCl3=DMSO-
d6, 50 MHz): d 18.4, 25.1, 36.5, 127.8, 128.2, 129.4, 130.8, 130.9, 131.8,
139.4, 144.2, 144.4; IR (KBr): 3497, 3356, 1668, 1583, 1462, 1220,
1377, 861 cmꢂ1. Anal. calcd. for C18H14Cl2N2: C, 65.67; H, 4.29; Cl,
21.54; N, 8.51; Found: C, 65.79; H, 4.42; Cl, 21.34; N, 8.49.
Ethyl 2-Cyano-3,3-bis(4-fluorophenyl)acrylate (2c)
Compound 1c (20 g, 91.74 mmol) was reacted as describedꢁin procedure
1
A to give 2c as a white solid (16.7 g, 58%); mp 114–116 C. H NMR
(CDCl3, 200 MHz): d 1.20 (t, J ¼ 7.2 Hz, 3H), 4.18 (q, J ¼ 7.2 Hz, 2H),
7.04–7.19 (m, 6H), 7.38–7.45 (m, 2H); 13C NMR (CDCl3, 50 MHz):
d 13.7, 62.2, 103.8, 115.5 (d, J ¼ 22.0 Hz), 115.8 (d, J ¼ 22.0 Hz), 116.7,
131.5 (d, J ¼ 9.00 Hz), 132.6 (d, J ¼ 9.00 Hz), 134.1, 134.1, 134.2, 164.0
(d, J ¼ 252.4 Hz), 164.5 (d, J ¼ 252.4 Hz), 166.8; IR (KBr): 3010, 2225,
1931, 1605, 1513, 1250, 844 cmꢂ1. Anal. calcd. for C18H13F2NO2:
C, 69.01; H, 4.18; N, 4.47. Found: C, 68.90; H, 4.25; N, 4.62.
3,3-bis(4-Fluorophenyl)-3-hydroxypropanenitrile (20c)
Compound 1c (4 g, 18.34 mmol) was reacted as desꢁcribed in procedure C
to give 20c as a white solid (4.1 g, 86%); mp 98–100 C. 1H NMR (CDCl3,
200 MHz): d 2.82 (s, 1H), 3.24 (s, 2H), 7.00–7.12 (m, 4H), 7.31–7.42
(m, 4H); 13C NMR (CDCl3, 50 MHz): d 32.71, 75.68, 115.4 (d,
J ¼ 21.6 Hz), 116.9, 127.6 (d, J ¼ 8.4 Hz), 139.5 (d, J ¼ 3.3 Hz), 162.2
(d, J ¼ 248.1 Hz); IR (KBr): 3384, 2267, 1898, 1603, 1508, 1461, 1387,
1231, 1164, 1065 cmꢂ1. Anal. calcd. for C15H11F2NO: C, 69.49; H,
4.28; F, 14.66; N, 5.40. Found: C, 69.58; H, 4.12; N, 5.26.
3,3-bis(4-Fluorophenyl)acrylonitrile (3c)
Compound 2c (9 g, 28.75 mmol) was reacted as described in procedure B
to give 3c as a white solid (5.2 g, 75%). Compound 3c from 20c): Com-
pound 20c (3.8 g, 14.67 mmol) was reacted as described in procedure D
ꢁ
1
to give 3c as a white solid (3.0 g, 85%); mp 80–82 C. H NMR (CDCl3,
200 MHz) d 5.61 (s, 1H), 7.01–7.37 (m, 8H); 13C NMR (CDCl3, 50 MHz)
d 94.7, 115.7 (d, J ¼ 21.8 Hz), 115.7 (d, J ¼ 21.8 Hz), 117.5, 130.3 (d,
J ¼ 8.6 Hz), 131.5 (d, J ¼ 8.6 Hz), 133.7 (d, J ¼ 100.5 Hz), 133.7 (d,
J ¼ 100.5 Hz), 160.7, 163.5 (d, J ¼ 252.3 Hz), 164.0 (d, J ¼ 252.3 Hz);

2978
A. R. Gholap, V. Paul, and K. V. Srinivasan
IR (KBr) 3027, 2215, 1943, 1602, 1495, 1237, 1160, 843 cmꢂ1. Anal.
calcd. for C15H9F2N: C, 74.68; H, 3.76; F, 15.75; N, 5.81. Found: C,
74.51; H, 3.89; N, 5.75.
2,2-bis(4-Fluorophenyl)cyclopropanecarbonitrile (4c)
Compound 3c (8 g, 31.19 mmol) was reacted as descrꢁibed in proꢁcedure
1
E to give 4c as a white solid (4.24 g, 50%); mp 97–99 C, lit[15] 95 C. H
NMR (CDCl3, 200 MHz): d 1.77 (dd, J ¼ 5.5 Hz, J ¼ 9.2 Hz, 1H), 1.99
(t, J ¼ 5.5 Hz, 1H), 2.19 (dd, J ¼ 5.5 Hz, J ¼ 9.2 Hz, 1H), 6.94–7.10 (m,
4H), 7.18–7.25 (m, 2H), 7.36–7.43 (m, 2H); 13C NMR (CDCl3,
50 MHz): d 12.3, 21.0, 36.8, 115.6 (d, J ¼ 21.6 Hz), 115.9 (d, J ¼ 21.6 Hz),
Hz), 119.1, 129.3 (d, J ¼ 8.3 Hz), 130.9 (d, J ¼ 8.3 Hz), 136.2 (d,
J ¼ 158.9 Hz), 136.2 (d, J ¼ 158.9 Hz), 161.8 (d, J ¼ 247.3 Hz), 162.1
(d, J ¼ 247.3 Hz); IR (KBr): 3019, 2240, 1889, 1661, 1602, 1512, 1219,
1159, 837, 758 cmꢂ1. Anal. calcd. for C16H11F2N: C, 75.28; H, 4.34; F,
14.88; N, 5.49. Found: C, 75.36; H, 4.20; N, 5.35.
2-(2,2-bis(4-Fluorophenyl)cyclopropyl)-4,5-dihydro-1H-imidazole (5c)
Compound 4c (0.8 g, 3.12 mmol) was reacted as described in procedure F
ꢁ
1
to give 5c as a white solid (0.841 g, 90%); mp 112–115 C. H NMR
(CDCl3, 200 MHz): d 1.61 (dd, J ¼ 5.8 Hz, J ¼ 9.0 Hz, 1H), 1.96 (t,
J ¼ 5.8 Hz, 1H), 2.46 (dd, J ¼ 5.8 Hz, J ¼ 9.0 Hz, 1H), 3.14–3.24 (m,
2H), 3.37–3.49 (m, 2H), 6.89–7.03 (m, 4H), 7.18–7.38 (m, 4H); 13C
NMR (CDCl3, 50 MHz): d 19.6, 25.5, 36.2, 49.9, 115.1 (d, J ¼ 21.4 Hz),
Hz), 115.2 (d, J ¼ 21.4 Hz), 128.9 (d, J ¼ 8.0 Hz), 131.0 (d, J ¼ 8.0 Hz),
138.3 (d, J ¼ 227.7 Hz), 138.4 (d, J ¼ 227.7 Hz), 161.2 (d, J ¼ 246.3),
161.6 (d, J ¼ 246.3 Hz), 165.1; IR (KBr): 3150, 2924, 1594, 1510, 1461,
1377, 1223, 1158, 830 cmꢂ1. Anal. calcd. for C18H16F2N2: C, 72.47; H,
5.41; F, 12.74; N, 9.39. Found: C, 72.52; H, 5.60; N, 9.22.
2-(2,2-bis(4-Fluorophenyl)cyclopropyl)-1H-imidazole (6c)
Compound 5c (0.180 g, 0.60 mmol) was reacted as described in procedure
ꢁ
1
G to give 6c as a white solid (0.126 g, 71%); mp 224–226 C. H NMR
(CDCl3=DMSO-d6, 200 MHz): d 1.66 (dd, J ¼ 5.8 Hz, J ¼ 9.2 Hz, 1H),
2.15 (t, J ¼ 5.8 Hz, 1H), 2.79 (dd, J ¼ 5.8 Hz, J ¼ 9.2 Hz, 1H), 6.67 (s,
2H), 6.75 (d, J ¼ 8.8 Hz, 2H), 6.86 (t, J ¼ 8.8 Hz, 2H), 7.01–7.08 (m,
2H), 7.17–7.24 (m, 2H); 13C NMR (CDCl3=DMSO-d6, 50 MHz): d
17.4, 24.0, 35.4, 113.6 (d, J ¼ 24.1 Hz), 114.0 (d, J ¼ 24.1 Hz), 128.5 (d,

(
)-Cibenzoline and Its Analogs
2979
J ¼ 8.0 Hz), 130.8 (d, J ¼ 8.0 Hz), 138.60 (d, J ¼ 253.5 Hz), 138.65 (d,
J ¼ 253.5 Hz), 143.5, 159.6 (d, J ¼ 242.8); IR (KBr): 3356, 3152, 1595,
1583, 1511, 1462, 1377, 1233, 1106, 832 cmꢂ1. Anal. calcd. for C18H14
F2N2: C, 72.96; H, 4.76; F, 12.82; N, 9.45. Found: C, 73.12; H, 4.55;
N, 9.28.
Ethyl 2-Cyano-2-(9H-fluoren-9-ylidene)acetate (2d)
Compound 1d (20 g, 111.1 mmol) was reacted as described in procedure
ꢁ
1
A to give 2d as a orange solid (17.7 g, 58%); mp 97–99 C. H NMR
(CDCl3, 200 MHz): d 1.45 (t, J ¼ 7.2 Hz, 3H), 4.48 (q, J ¼ 7.2 Hz, 2H),
7.17–7.58 (m, 6H), 8.00 (d, J ¼ 8.0 Hz, 1H), 8.55 (d, J ¼ 8.0 Hz, 1H);
13C NMR (CDCl3, 50 MHz): d 13.9, 62.9, 99.6, 116.3, 119.9, 126.2,
127.8, 128.1, 128.5, 132.7, 134.3, 135.3, 141.9, 142.1, 154.7, 162.4; IR
(KBr): 3020, 2211, 1960, 1732, 1584, 1450, 1248, 1155, 857 cmꢂ1. Anal.
calcd. for C18H13NO2: C, 78.53; H, 4.76; N, 5.09. Found: C, 78.45; H,
4.58; N, 4.95.
2-(9-Hydroxy-9H-fluoren-9-yl)acetonitrile (20d)
Compound 1d (4 g, 22.2 mmol) was reacted as describedꢁin procedure C
to give 20d as a white solid (4.3 g, 87%); mp 98–100 C, lit.[28] 97.5–
98.5ꢁC. 1H NMR (CDCl3, 200 MHz): d 2.37 (s, 1H), 2.96 (s, 2H),
7.32–7.48 (m, 4H), 7.65–7.74 (m, 4H); 13C NMR (CDCl3, 50 MHz): d
29.2, 78.1, 116.7, 120.3, 123.5, 128.4, 130.0, 138.8, 145.7; IR (KBr):
3370, 2257, 1608, 1451, 1063, 942, 862 cmꢂ1. Anal. calcd. for
C15H11NO: C, 81.43; H, 5.01; N, 6.33. Found: C, 81.62; H, 5.14; N,
6.28.
2-(9H-Fluoren-9-ylidene)acetonitrile (3d)
Compound 2d (9 g, 32.72 mmol) was reacted as described in procedure B
to give 3d as a yellow solid (4.78 g, 72%). Compound 3d from 20d):
Compound 20d (4 g, 18.09 mmol) was reacted as described in procedure
D to giꢁve 3d as a yellow solid (3.38 g, 92%); mp 110–112ꢁC; lit.[28]
1
109–111 C. H NMR (CDCl3, 200 MHz): d 6.07 (s, 1H), 7.23–7.64 (m,
7H), 8.39 (d, J ¼ 7.5 Hz, 1H); 13C NMR (CDCl3, 50 MHz): d 88.3,
117.3, 120.06, 120.12, 121.4, 125.1, 127.7, 128.2, 131.60, 131.67, 134.7,
136.2, 140.4, 141.7, 153.2; IR (KBr): 3017, 2213, 1715, 1601, 1451,
1078, 820. Anal. calcd. for C15H9N: C, 88.64; H, 4.46; N, 6.89. Found:
C, 88.60; H, 4.58; N, 6.95.

2980
A. R. Gholap, V. Paul, and K. V. Srinivasan
Spiro(cyclopropane-1,90-fluorene)-2-carbonitrile (4d)
Compound 3d (9 g, 44.33 mmol) was reacted as described in procedure E
to give 4d as a white solid (5.19 g, 54%); mp 107–109ꢁC. 1H NMR
(CDCl3, 200 MHz): d 1.79 (dd, J ¼ 5.5 Hz, J ¼ 9.2 Hz, 1H), 2.02 (t,
J ¼ 5.5 Hz, 1H), 2.22 (dd, J ¼ 5.5 Hz, J ¼ 9.2 Hz, 1H), 7.28–7.46 (m,
8H); 13C NMR (CDCl3, 50 MHz): d 12.1, 20.9, 38.1, 119.3, 127.2,
127.6, 127.8, 129.2, 138.8, 142.2; IR (KBr): 3024, 2232, 1655, 1461,
1377, 759 cmꢂ1. Anal. calcd. for C16H11N: C, 88.45; H, 5.10; N, 6.45.
Found: C, 88.27; H, 5.38; N, 6.61.
2-(Spiro(cyclopropane-1,90-flurene)-2-yl)-4,5-dihydro-1H-imidazole (5d)
Compound 4d (1 g, 4.60 mmol) was reacted as described in procedure F
to give 5d as a white solid (1.07 g, 90%); mp 97–99ꢁC. 1H NMR (CDCl3,
200 MHz): d 1.65 (dd, J ¼ 5.4 Hz, J ¼ 9.0 Hz, 1H), 1.98 (t, J ¼ 5.4 Hz,
1H), 2.57 (dd, J ¼ 5.4 Hz, J ¼ 9.0 Hz, 1H), 3.09–3.25 (m, 2H), 3.34–3.46
(m, 2H), 7.15–7.43 (m, 8H); 13C NMR (CDCl3, 50 MHz): d 19.6, 25.5,
37.5, 49.6, 126.2, 126.9, 127.4, 128.2, 128.3, 129.6, 140.4, 144.9, 166.0;
IR (KBr): 3135, 2925, 1954, 1617, 1463, 1377, 1283, 899 cmꢂ1. Anal.
calcd. for C18H16N2: C, 83.05; H, 6.19; N, 10.76. Found: C, 83.21; H,
6.04; N, 10.62.
2-(Spiro(cyclopropane-1,90-flurene)-2-yl)-1H-imidazole (6d)
Compound 5d (0.165 g, 0.63 mmol) was reacted as described in procedure
ꢁ
1
G to give 6d as a white solid (0.114 g, 70%); mp 219–221 C. H NMR
(CDCl3=DMSO-d6, 200 MHz): d 1.80 (dd, J ¼ 5.5 Hz, J ¼ 9.2 Hz, 1H),
2.26 (t, J ¼ 5.5 Hz, 1H), 2.92 (dd, J ¼ 5.5 Hz, J ¼ 9.2 Hz, 1H), 6.74 (s,
2H), 7.10–7.22 (m, 5H), 7.29–7.37 (m, 3H); 13C NMR (CDCl3=DMSO-
d6, 50 MHz): d 18.1, 25.1, 37.7, 125.9, 126.1, 127.5, 127.7, 128.2, 130.0,
140.9, 144.7, 146.1; IR (KBr): 3460, 3356, 1668, 1582, 1496, 1461,
1377, 861 cmꢂ1. Anal. calcd. for C18H14N2: C, 83.69; H, 5.46; N, 10.84.
Found: C, 83.54; H, 5.67; N, 10.76.
ACKNOWLEDGMENT
We acknowledge the Director of National Chemical Laboratory for
in-house project funding. A. R. G. thanks Council of Scientific and
Industrial Research, New Delhi, for the award of a senior research
fellowship.

(
)-Cibenzoline and Its Analogs
2981
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