Convenient preparation of optically active cibenzoline and analogues from 3,3-diaryl-2-propen-1-ols

Article abstract of DOI:10.1016/j.tetasy.2009.08.024

(R)-(+)-Cibenzoline (95% ee) was synthesized in two steps from (+)-2,2-diphenylcyclopropylmethanol 3a (98% ee), which was oxidized with IBX in DMSO, followed by treatment with ethylenediamine in the presence of I₂ and K₂CO₃

Full text of DOI:10.1016/j.tetasy.2009.08.024

Tetrahedron: Asymmetry 20 (2009) 2065–2071
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Convenient preparation of optically active cibenzoline and analogues
from 3,3-diaryl-2-propen-1-ols
Naka Koyata a, Tsuyoshi Miura a, Yoko Akaiwa a, Hisashi Sasaki a, Rie Sato a, Takuya Nagai a,
Hirohisa Fujimori b, Takuya Noguchi b, Masayuki Kirihara b, Nobuyuki Imai a,
*
a Faculty of Pharmacy, Chiba Institute of Science, 15-8 Shiomi-cho, Choshi, Chiba 288-0025, Japan
b Department of Materials and Life Science, Shizuoka Institute of Science and Technology, 2200-2 Toyosawa, Fukuroi, Shizuoka 437-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 July 2009
Accepted 18 August 2009
Available online 14 September 2009
(R)-(+)-Cibenzoline (95% ee) was synthesized in two steps from (+)-2,2-diphenylcyclopropylmethanol 3a
(98% ee), which was oxidized with IBX in DMSO, followed by treatment with ethylenediamine in the
presence of I2 and K2CO3 in tBuOH. Compound (R)-(+)-3a (98% ee) was prepared by cyclopropanation
of 3,3-diphenyl-2-propen-1-ol 1 with Et2Zn and CH2I2 in the presence of a catalytic amount of (S)-2-
(methanesulfonyl)amino-1-(p-toluenesulfonyl)amino-3-phenylpropane 2, followed by esterification
with 3,5-dinitorobenzoyl chloride, recrystallization, and hydrolysis.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Commercially available cibenzoline, which is a medicine as a
class I antiarrhythmic agent,1 consists of four rings: a cyclopropane
containing a stereogenic carbon, two arene rings, and an imidazo-
line. A Simmons–Smith reaction is one of the most effective cyclo-
propane skeleton-forming procedures.2 Since the first reports
about the enantioselective Simmons–Smith cyclopropanation
catalyzed by C2-symmetrical disulfonamide-zinc or aluminum
complex by Kobayashi,3e,h–j Denmark has optimized conditions
for his method3d,f,g while Charette has developed another enantio-
selective catalytic cyclopropanation using 25 mol % of C2-symmet-
Ph
MsHN
2
NHTs
Ar
OH
Ar
OH
3 (51~76% ee)
*
Et2Zn, CH2I2 in CH2Cl2
at 0 oC for 24 h
1
Ar
Ar
The reaction of 3,3-diphenyl-2-propen-1-ol 1a with Et2Zn and
CH2I2 in the presence of 10 mol % of 2 afforded the corresponding
cyclopropane product 3a7 with 76% ee as indicated in entry 1 of
Table 1. The cyclopropanation of 3,3-diaryl-2-propen-1-ols substi-
tuted on the aromatic ring by electron-donating or electron-with-
drawing groups was then examined: the results from the
cyclopropanation of various 3,3-diaryl-2-propen-1-ols 1b–1f with
Et2Zn and CH2I2 in the presence of 10 mol % of 2 are collected in
Table 1. We selected methoxy and methyl substituents as represen-
tativeelectron-donatinggroups(see entries2 and3), trifluoromethyl
and chloro substituents as electron-withdrawing groups (see entries
4 and 5), and fluorenyl substituent for making the spiro-ring (see en-
try 6). The cyclopropanation of non-substituted allylic alcohol 1a
which can be converted to cibenzoline gave the highest ee among
these 3,3-diaryl-2-propen-1-ols 1a–1f. The reactions of the allylic
alcohols 1b and 1c (entries 2 and 3, respectively) substituted with
an electron-donating group afforded slightly lower enantioselectivi-
ties than those of the allylic alcohols 1d and 1e (entries 4 and 5,
respectively) substituted with an electron-withdrawing group. The
reactions of the allylic alcohol 1f (entry 6) substituted with a tricyclic
group also afforded slightly lower enantioselectivity than those of
the allylic alcohol 1a (entry 1) non-substituted on the aromatic ring.
rical titanium complex of (4R,5R)-2,2-diethyl-a,a,a’,a’-tetra-
phenyl-1,3-dioxane-4,5-dimethanol (Ti-TADDOLate).3c Then, we
have developed a catalytic enantioselective Simmons–Smith reac-
tion3a,b using the simple disulfonamides derived from
a-amino
acid. Recently, Katsuki has found a catalytic asymmetric Sim-
mons–Smith reaction using an Al Lewis acid/N Lewis base bifunc-
tional Al Salalen complex.4 We have also reported the convenient
synthesis of optically active cibenzoline and the analogues.5 Herein
we report the catalytic enantioselective cyclopropanation of 3,3-
diaryl-2-propen-1-ols 16 with Et2Zn and CH2I2 using a catalytic
amount
of
(S)-2-(methanesulfonyl)amino-1-(p-toluenesulfo-
nyl)amino-3-phenylpropane 2 and the synthesis of (R)-(+)-cibenz-
oline and analogues.
* Corresponding author. Tel./fax: +81 479 30 4610.
E-mail address: nimai@cis.ac.jp (N. Imai).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.08.024

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N. Koyata et al. / Tetrahedron: Asymmetry 20 (2009) 2065–2071
Table 1
Cyclopropanation of 3,3-diaryl-2-propen-1-ols 1a–1f in the presence of 2a
Entry
1
Ar
Yield (%)
eeb (%)
Eluentc (%)
[a]
D
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
Ph
82
77
99
99
88
97
76
51
65
73
72
60
5
5
5
5
5
5
+115.9 (c 1.07, CHCl3)
+74.2 (c 1.04, CHCl3)
+101.7 (c 1.45, CHCl3)
+80.0 (c 1.41, CHCl3)
+100.4 (c 0.78, CHCl3)
+12.5 (c 1.12, CHCl3)
4-MeOC6H4
4-MeC6H4
4-CF3C6H4
4-ClC6H4
Fluorenyl
a
b
c
All reactions were carried out with 1 equiv of 3,3-diaryl-2-propen-1-ol 1, 0.1 equiv of 2, 2 equiv of Et2Zn, and 3 equiv of CH2I2 in anhydrous CH2Cl2.
Determined by HPLC analysis using Chiralcel OD.
The number indicates the concentration of iPrOH in hexane as an eluent on HPLC analysis for the determination of enantiomeric excess of the product.
converted under reduced pressure (2 mmHg) at 160 °C for 37 h
to (R)-(+)-cibenzoline 7a in 55% yield as shown in Scheme 1. These
Ph
2
results suggest that the absolute configurations of the compounds
MsHN
NHTs
Ph
OH
Ph
OH
3a, 4a, 5a, and 6a are R. The fluorenyl alcohol 3f, which is con-
nected at the ortho-position of each benzene ring in 3a, was con-
verted to the corresponding amide 6f in quantitative overall yield
in a similar manner to that described for the preparation of 6a as
indicated in Scheme 2. Amide 6f was not cyclized under reduced
pressure (2 mmHg) at 160 °C for 26 h and recovered in 52% yield
after silica gel column chromatograpy. It was found that the fluore-
nyl group of the amide 6f hinders the stereochemical formation of
the 2-imidazoline ring because the two benzene rings of 6f are
fixed at the same plane.
Et2Zn, CH2I2 in CH2Cl2
at 0 oC for 24 h
1g
(1S,2S)-3g (38% ee)
+24.1 (c 1.01, CHCl3)
Me
Me
trans-3-Phenylbut-2-enol 1g, which possesses different substitu-
ents on the 3-position, was converted to the corresponding cyclo-
propylmethanol 3g3c in 85% yield with a low enantiomeric excess,
unfortunately.
(R)-(+)-Cibenzoline 7a, the absolute configuration and specific
rotation of which were already known in the literature,1a was syn-
thesized from (+)-2,2-diphenylcyclopropylmethanol 3a as follows;
alcohol 3a was oxidized with 2-iodoxybenzoic acid (IBX) in
dimethylsulfoxide (DMSO) at rt for 3 h to afford the corresponding
aldehyde 4a, which was treated with NaClO2, H2O2, and NaH2PO4
in MeCN–H2O at rt for 30 min to give acid 5a. Acid 5a was con-
densed with ethylenediamine in the presence of benzotriazol-1-
yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP)
and Et3N in CH2Cl2 at rt for 5 h to give the corresponding amide
6a in quantitative overall yield from 3a. Then, the amide 6a was
Cyclopropylmethanols 3c, 3d, and 3e8 which are oriented with
methyl, trifluoromethyl, chloro groups at the para-position on the
benzene rings, were converted to the corresponding cibenzoline
analogues in a similar manner to that described for the preparation
of cibenzoline. All specific rotations of the amides 6a–6f, cibenzo-
line 7a, and analogues 7c–7e are summarized in Table 2.
The enantiomeric excess of (R)-(+)-cibenzoline 7a was checked
by HPLC analysis with a 80:15:5:0.1 mixture of hexane–ethanol–
O
OH
I
O
(IBX)
O
NaClO2, H2O2
Ph
NaH2PO4 in MeCN-H2O
Ph
OH
Ph
CHO
CO2H
in DMSO
Ph
Ph
Ph
3a
4a
5a
at rt for 30 min
at rt for 3 h
H
2 mmHg
H2NCH2CH2NH2
N
Ph
Ph
CONHCH2CH2NH2
at 160 oC for 37 h
in 55% yield
PyBOP, Et3N in CH2Cl2
at rt for 5 h
Ph
(R)-(+)-cibenzoline 7a
N
Ph
6a
in quantitative yield form 3a
Scheme 1. Synthesis of (R)-(+)-cibenzoline 7a from (+)-2,2-diphenylcyclopropylmethanol 3a.
*
OH
*
NaClO2, H2O2
IBX
CHO
NaH2PO4 in MeCN-H2O
at rt for 3 h
in DMSO
3f
4f
at rt for 2.5 h
*
*
CONHCH2CH2NH2
H2NCH2CH2NH2
CO2H
PyBOP, Et3N in CH2Cl2
at rt for 3 h
6f
5f
in quantitative yield form 3f
Scheme 2. Trial for the preparation of a cibenzoline analog 7f from (+)-cyclopropylmethanol 3f.

N. Koyata et al. / Tetrahedron: Asymmetry 20 (2009) 2065–2071
2067
Table 2
Synthesis of (R)-(+)-cibenzoline and analogues 7a and 7c–7f from (+)-2,2-diarylcyclopropylmethanols 3a–3f
NaClO2, H2O2
IBX
Ar
OH
3a-3f
Ar
Ar
Ar
*
*
*
*
CHO
CO2H
NaH2PO4 in MeCN-H2O
at rt
in DMSO
at rt
Ar
Ar
Ar
Ar
4a, 4c-4f
5a, 5c-5f
H
N
H2NCH2CH2NH2
2 mmHg
at 160 oC
Ar
*
CONHCH2CH2NH2
PyBOP, Et3N in CH2Cl2
at rt
N
Ar
6a, 6c-6f
cibenzoline and analogues 7a, 7c-7f
Cibenzoline and analogues 7
Entry
3
Ar
6
Yielda (%)
[
a
]
D
Yield (%)
[a
]
D
eeb (%)
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
Ph
quant.
0
quant.
89
55
quant.
+102.8 (c 1.03, MeOH)
—
+23.9 (c 1.38, MeOH)
+19.2 (c 1.27, MeOH)
+38.7 (c 1.39, MeOH)
+97.4 (c 1.63, MeOH)
55
—
43
46
50
0
+30.1 (c 1.12, MeOH)
—
+25.6 (c 0.64, MeOH)
+21.6 (c 0.75, MeOH)
+3.3 (c 0.67, MeOH)
—
15
—
17
20
1.2
—
4-MeOC6H4
4-MeC6H4
4-CF3C6H4
4-ClC6H4
Fluorenyl
a
Overall yields from the cyclopropylmethanols 3a–3f.
The enantiomeric excesses were determined by HPLC analysis with a 80:15:5:0.1 mixture of hexane–ethanol–isopropanol–diethylamine as an eluent using Chiralcel
b
OD.1a
isopropanol–diethylamine as an eluent using Chiralcel OD and
found to be 15% ee, which is lower than that (76% ee) of the start-
ing alcohol 3a. It is supposed that racemization proceeds under
cyclization of the amide 6a at the high reaction temperature. In or-
der to avoid racemization, an alternative route reported by Togo9
was examined. The aldehydes 4a and 4c–4e were reacted with eth-
ylenediamine in the presence of K2CO3 and I2 in tBuOH to afford
the corresponding 2-imidazoline derivatives 7a, 7c–7e in quantita-
tive yields as indicated in Table 3. No racemization was observed in
entries 1 and 3–6.
3. Conclusion
In conclusion, (S)-2-(methanesulfonyl)amino-1-(4-toluenesul-
fonyl)amino-3-phenylpropane 2 efficiently works as a catalyst in
the Simmons–Smith cyclopropanation of steric hindered allylic
alcohols such as 3,3-diaryl-2-propen-1-ols 1. In our procedure, it
is possible to prepare various chiral 3,3-disubstituted 2,3-meth-
ano-1-propanols 3 conveniently and to synthesize the correspond-
ing chiral cibenzoline analogues 7 including the imidazoline
derivatives. We are still working on the optimization of
a-amino
Even when using the fluorenyl type’s aldehyde 4f, which hin-
ders steric hinderance, the reaction proceeded to give the cibenzo-
line analogue 7f in 48% yield. The specific rotation (+186.4) is
completely different from that (+75.7) of cibenzoline, hence the
biological activity is very interesting.
Next, we tried to improve the enantiomeric purity of the alcohol
3a (76% ee) by recrystallization after the formation of the 3,5-dini-
trobenzoyl ester, followed by hydrolysis under basic conditions to
afford 98% ee of 3a.3a The alcohol 3a with 98% ee was converted to
the aldehyde 4a, which was then cyclized by Togo’s method
with ethylenediamine, (1R,2R)-1,2-diphenylethylenediamine, or
(1R,2R)-cyclohexanediamine to obtain the corresponding 2-imi-
dazolines 7a, 7h, and 7i, respectively, as described in Scheme 3
and Table 4.
acid-derived chiral disulfonamides for the catalytic enantioselec-
tive cyclopropanation of 3,3-diphenyl-2-propen-1-ol 1a.
4. Experimental
4.1. General
The 1H NMR spectra were measured with a Bruker Ultra-
shieldTM 400 Plus (400 MHz) spectrometer. The chemical shifts
are expressed in ppm downfield from tetramethylsilane (d = 0.00)
as an internal standard. Splitting patterns are indicated as s, sin-
glet; d, doublet; t, triplet; q, quartet; m, multiplet; and br, broad
signal. The high-resolution Mass spectra (HRMS) of the compounds
Table 3
Alternative synthesis of (+)-cibenzoline and analogues 7a and 7c–7f from the aldehydes 4a and 4c–4f
H
H2NCH2CH2NH2
N
Ar
Ar
*
*
CHO
I2, K2CO3 in tBuOH
Ar
Ar
N
at 70o for 3h
4a, 4c-4f
cibenzoline and analogues 7a, 7c-7f
Entry
4
Ar
4
Cibenzoline and analogues 7
Yield (%)
[
a
]
D
Yield (%)
[a
]
D
eea (%)
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
Ph
86
0
90
89
98
94
+112.4 (c 1.47, CHCl3)
—
+77.9 (c 1.37, CHCl3)
+86.4 (c 1.43, CHCl3)
+95.0 (c 0.65, CHCl3)
+125.5 (c 0.99, CHCl3)
quant.
—
quant.
quant.
quant.
48
+110.0 (c 1.12, MeOH)
—
+66.0 (c 0.90, MeOH)
+68.6 (c 1.18, MeOH)
+86.0 (c 0.97, MeOH)
+186.4 (c 0.34, CHCl3)
72
—
65
74
71
58
4-MeOC6H4
4-MeC6H4
4-CF3C6H4
4-ClC6H4
Fluorenyl
a
The enantiomeric excesses were determined by HPLC analysis with a 80:15:5:0.1 mixture of hexane–ethanol–isopropanol–diethylamine as an eluent using Chiralcel
OD.1a

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N. Koyata et al. / Tetrahedron: Asymmetry 20 (2009) 2065–2071
O2N
COCl
NO2
NO2
O
C
O2N
Ph
OH
Ph
O
Et3N, DMAP in THF
at rt for 3 h
Ph
Ph
3a (76% ee)
8a (76% ee)
NO2
O
C
EtONa
in EtOH
recrystallization
Ph
OH
Ph
Ph
O
from EtOAc and hexane
Ph
NO2
8a (98% ee)
3a (98% ee)
R
R'
H
N
IBX
H2N
NH2
Ph
Ph
R
CHO
4a
in DMSO
at rt
I2, K2CO3 in tBuOH
Ph
Ph
N
R'
at 70oC for 3h
7a = (R, R' = H): quantitative yield
7h = (R, R' = Ph): 99% yield
7i = (R, R' = -(CH2)4-): 65% yield
Scheme 3. Synthesis of the enantiopure (R)-(+)-cibenzoline and analogues 7a, 7h, and 7i via recrystallization of the ester 8a.
4.2.2. 2,2-Bis(4-methylphenyl)cyclopropylmethanol, 3c
Table 4
Colorless oil; 99% yield; ½a D24
¼ þ101:7 (c 1.45, CHCl3); 65% ee;
ꢁ
The 2-imidazoline derivatives 7a, 7h, and 7i from the aldehyde 4a
1H NMR (400 MHz, CDCl3) d 1.20 (1H, dd, J = 4.8, 8.8 Hz), 1.30
(1H, br s), 1.33 (1H, t, J = 4.8 Hz), 1.95 (1H, m), 2.28 (3H, s), 2.30
(3H, s), 3.35 (1H, t, J = 10.9 Hz), 3.48 (1H, t, J = 10.9 Hz), 7.04 (2H,
d, J = 8.2 Hz), 7.10 (2H, d, J = 7.9 Hz), 7.12 (2H, d, J = 8.2 Hz), 7.25
(2H, d, J = 7.9 Hz); 13C NMR (100 MHz, CDCl3) d 17.7, 20.9, 21.0,
27.5, 34.9, 63.9, 127.8, 129.0, 129.3, 129.8, 135.5, 136.2, 138.3,
143.6; HRMS (ESI-TOF): Calcd for C18H20ONa (M+Na)+: 275.1406,
Found: 275.1389.
Entry
7
Yield (%)
[a]
D
1
2
3
7aa
7h
7i
quant.
99
65
+154.4 (c 1.40, MeOH)
+152.5 (c 1.00, MeOH)
+177.1 (c 0.71, MeOH)
a
The enantiomeric excess (95% ee) was determined by HPLC analysis with a
80:15:5:0.1 mixture of hexane–ethanol–isopropanol–diethylamine as an eluent
using Chiralcel OD.1a
4.2.3. 2,2-Bis(4-trifluoromethylphenyl)cyclopropyl-methanol, 3d
Colorless oil; 99% yield; ½a D24
ꢁ
¼ þ80:0 (c 1.41, CHCl3); 73% ee; 1H
with a high molecular weight were recorded using a Waters LCT
Premier (ESI-TOF-MS) spectrometer. Unless otherwise noted, all
experiments were carried out under an argon atmosphere. For thin
layer chromatographic (TLC) analyses, Merck precoated TLC plates
(Silica Gel 60 F254, Art 5715) were used.
NMR (400 MHz, CDCl3) d 1.37 (1H, dd, J = 5.2, 9.0 Hz), 1.43 (1H, t,
J = 5.2 Hz), 1.44 (1H, br s), 2.04 (1H, m), 3.29 (1H, dd, J = 8.2,
11.4 Hz), 3.57 (1H, dd, J = 6.0, 11.4 Hz), 7.31 (2H, d, J = 8.1 Hz),
7.52 (4H, s), 7.59 (2H, d, J = 8.2 Hz); 13C NMR (100 MHz, CDCl3) d
1
1
18.2, 28.2, 35.5, 63.3, 124.08 (q, JC–F = 272 Hz), 124.11 (q, JC–F
=
3
3
272 Hz), 125.5 (q, JC–F = 3.6 Hz), 125.7 (q, JC–F = 3.8 Hz), 128.1,
4.2. Typical procedure for Simmons–Smith cyclopropanations
2
2
128.7(q, JC–F = 32.4 Hz), 129.4 (q, JC–F = 32.6 Hz), 130.8, 144.4,
149.3; HRMS (ESI-TOF): Calcd for C18H14F6ONa (M+Na)+:
383.0841, Found: 383.0871.
To a colorless clear solution of the sulfonamide 2 (38 mg,
0.5 mmol, 0.1 equiv) and
1 (1 mmol, 1 equiv) in anhydrous
CH2Cl2 (7.5 mL) was added dropwise at ꢀ40 °C a solution of
4.2.4. 2,2-Bis(4-chlorophenyl)cyclopropylmethanol, 3e8
Et2Zn in hexane (1.05 M, 0.95 mL, 1 mmol, 2 equiv) and CH2I2
Yellow oil; 88% yield; ½a D24
ꢁ
¼ þ100:4 (c 0.78, CHCl3); 72% ee; 1H
(121 lL, 1.5 mmol, 3 equiv). After stirring for 3 h at 0 °C, the col-
NMR (400 MHz, CDCl3) d 1.26 (1H, dd, J = 5.1, 9.0 Hz), 1.28 (1H, br
s), 1.32 (1H, t, J = 5.1 Hz), 1.95 (1H, m), 3.29 (1H, m), 3.54 (1H, m),
7.13 (2H, d, J = 8.6 Hz), 7.21 (2H, d, J = 8.6 Hz), 7.29 (4H, s); 13C
NMR (100 MHz, CDCl3) d 18.0, 27.8, 34.6, 63.4, 128.5, 128.8,
129.1, 131.5, 132.0, 132.7, 139.2, 144.3.
orless suspension was quenched at the temperature with Et3N
(0.3 mL), diluted with Et2O (70 mL), washed with brine
(20 mL), and dried over MgSO4. The crude product was chro-
matographed on silica gel with a 1:10 mixture of EtOAc and hex-
ane to afford 3.
4.2.5. 2,2-Fluorenylcyclopropylmethanol, 3f
4.2.1. 2,2-Bis(4-methoxyphenyl)cyclopropylmethanol, 3b
Pale brown oil; 97% yield; ½a D24
¼ þ12:5 (c 1.12, CHCl3); 60% ee;
ꢁ
24
Pale yellow oil; 77% yield; [a] D = +74.2 (c 1.04, CHCl3); 51% ee;
1H NMR (400 MHz, CDCl3) d 1.32 (1H, br s), 1.73 (1H, dd, J = 5.2,
7.4 Hz), 1.95 (1H, dd, J = 5.2, 9.0 Hz), 2.26 (1H, m), 3.91 (1H, dd,
J = 8.7, 12.1 Hz), 4.10 (1H, dd, J = 6.2, 12.1 Hz), 7.02 (1H, d,
J = 7.0 Hz), 7.22–7.39 (5H, m), 7.80 (1H, d, J = 7.0 Hz), 7.84 (1H, d,
J = 7.5 Hz); 13C NMR (100 MHz, CDCl3) d 21.7, 33.5, 61.9, 118.5,
119.7, 120.3, 121.1, 126.1, 126.4, 126.6, 127.1, 139.0, 141.1,
144.1, 148.1; HRMS (ESI-TOF): Calcd for C16H14ONa (M+Na)+:
245.0937, Found: 245.0891.
1H NMR (400 MHz, CDCl3) d 1.18 (1H, dd, J = 4.8, 8.8 Hz), 1.26 (1H,
t, J = 4.8 Hz), 1.89 (1H, m), 3.33 (1H, dd, J = 7.9, 11.5 Hz), 3.47 (1H,
dd, J = 6.3, 11.5 Hz), 3.73 (3H, s), 3.76 (3H, s), 6.77 (2H, d, J = 8.8 Hz),
6.82 (2H, d, J = 8.8 Hz), 7.15 (2H, d, J = 8.8 Hz), 7.27 (2H, d,
J = 8.8 Hz); 13C NMR (100 MHz, CDCl3) d 17.7, 27.5, 34.2, 55.1,
55.2, 63.8, 113.6, 113.8, 128.8, 130.8, 133.5, 138.9, 157.7, 158.1;
HRMS (ESI-TOF): Calcd for C18H20O3Na (M+Na)+: 307.1305, Found:
307.1338.

N. Koyata et al. / Tetrahedron: Asymmetry 20 (2009) 2065–2071
2069
4.2.6. (1S,2S)-(+)-2-Methyl-2-phenylcyclopropyl-methanol, 3g3c
4.4. Typical procedure for oxidation of the aldehydes 4 into the
carboxylic acids 5
Colorless oil; 85% yield; ½a D27
ꢁ
¼ þ24:1 (c 1.01, CHCl3); 38% ee; 1H
NMR (400 MHz, CDCl3) d 0.60 (1H, dd, J = 5.0, 5.5 Hz), 1.14 (1H, dd,
J = 5.0, 9.0 Hz), 1.39–1.45 (1H, m), 1.45 (3H, s), 1.65 (1H, br s), 3.70
(1H, dd, J = 8.6, 11.5 Hz), 3.90 (1H, dd, J = 6.4, 11.5 Hz), 7.15–7.31
(5H, m); 13C NMR (100 MHz, CDCl3) d 18.7, 20.5, 24.8, 27.8, 63.6,
125.8, 127.2, 128.3, 147.6; HRMS (ESI-TOF): Calcd for C11H14ONa
(M+Na)+: 185.0937, Found: 185.0917.
To a colorless clear solution of aldehyde 4 and NaH2PO4
(0.3 equiv) in MeCN (4 mL) and H2O (0.4 mL) were added 35%
H2O2 (1.1 equiv) and a solution of NaClO2 (1.5 equiv) in H2O
(2 mL) at 0 °C. After stirring for 30 min at room temperature, sat-
urated Na2SO3 aq (1 mL) was added to the reaction mixture. Next,
1 M HCl was added, and the reaction mixture was adjusted to pH
3. The reaction mixture was extracted three times with AcOEt.
The combined AcOEt layers were washed with brine, dried over
anhydrous MgSO4, and evaporated. The obtained the crude car-
4.3. Typical procedure for oxidation of alcohols 3 into the
aldehydes 4
boxylic acid
purification.
5 was used in the next step without further
To a solution of alcohol 3 in dimethylsulfoxide (DMSO, 2 mL)
was added 2-iodoxybenzoic acid (IBX, 4 equiv) at room tempera-
ture. After stirring for 3 h at room temperature, EtOAc (10 mL)
was added to the reaction mixture. The suspension was filtered.
To the filtrate was added half brine, extracted three times with
AcOEt. The combined AcOEt layers were washed with brine, dried
over anhydrous MgSO4, and evaporated. The crude product was
chromatographed on silica gel with a 5:1 mixture of EtOAc and
hexane to afford the aldehyde 4.
4.5. Typical procedure of the carboxylic acids 5 into the amides 6
To a colorless clear solution of carboxylic acid 5 in anhydrous
CH2Cl2 (2 mL) were added ethylenediamine (20 equiv), triethyl-
amine (3 equiv), and benzotriazol-1-yloxytripyrrolidinophospho-
nium hexafluorophosphate (PyBOP; 1.2 equiv) at room temper-
ature. After stirring for 5 h at room temperature, water (2 mL)
was added to reaction mixture. Then, 1 M NaOH was added,
and the reaction mixture was adjusted to pH 10. The reaction
mixture was extracted three times with AcOEt. The combined
AcOEt layers were washed with brine, dried over anhydrous
MgSO4, and evaporated. The crude product was chromatographed
on silica gel with a 7:3:0.5 mixture of CHCl3, MeOH, and H2O to
afford the amine 6.
4.3.1. 2,2-Bis(4-methylphenyl)cyclopropanecarbox-aldehyde, 4c
Colorless oil; 90% yield; ½a D27
ꢁ
¼ ꢀ77:9 (c 1.37, CHCl3); 1H NMR
(400 MHz, CDCl3) d 1.83 (1H, dd, J = 5.2, 8.4 Hz), 2.21 (1H, t,
J = 5.2 Hz), 2.28 (3H, s), 2.30 (3H, s), 2.49 (1H, ddd, J = 5.2, 6.8,
8.4 Hz), 7.05–7.13 (6H, m), 7.27 (2H, m), 8.67 (1H, d, J = 6.8 Hz);
13C NMR (100 MHz, CDCl3) d 20.3, 20.9, 21.1, 36.8, 40.4, 127.2,
129.3, 129.6, 129.8, 136.6, 136.7, 137.1, 141.3, 200.8; HRMS
(ESI-TOF): Calcd for C18H18ONa (M+Na)+: 273.1250, Found:
273.1258.
4.5.1. N-(2-Aminoethyl)-2,2-diphenylcyclopropane-carboxamide,
6a
4.3.2. 2,2-Bis(4-trifluoromethylphenyl)cyclopropane-carboxal-
dehyde, 4d
Pale yellow oil; quantitative yield; ½a D21
¼ þ102:8 (c 1.03,
ꢁ
MeOH); 1H NMR (400 MHz, CD3OD) d 1.50 (1H, dd, J = 5.0,
8.2 Hz), 2.16 (1H, dd, J = 5.0, 5.9 Hz), 2.53 (1H, dd, J = 5.9, 8.2 Hz),
2.73 (2H, m), 3.23 (2H, t, J = 6.2 Hz), 7.12–7.36 (10H, m); 13C
NMR (100 MHz, CD3OD) d 19.4, 31.0, 38.6, 40.2, 41.1, 127.5,
127.9, 128.7, 129.3, 129.4, 130.9, 142.0, 146.6, 173.6; HRMS
(ESI-TOF): Calcd for C18H21N2O (M+H)+: 281.1648, Found:
281.1654.
Colorless oil; 89% yield; ½a D27
ꢁ
¼ ꢀ86:4 (c 1.43, CHCl3); 1H NMR
(400 MHz, CDCl3) d 1.93 (1H, dd, J = 5.5, 8.5 Hz), 2.34 (1H, t,
J = 5.5 Hz), 2.65–2.70 (1H, m), 7.34 (2H, d, J = 8.2 Hz), 7.52 (2H, d,
J = 8.2 Hz) 7.55 (2H, d, J = 8.2 Hz) 7.62 (2H, d, J = 8.2 Hz), 8.80 (1H,
d, J = 6.2 Hz); 13C NMR (100 MHz, CDCl3) d 20.3, 36.4, 40.3, 123.80
1
1
3
(q, JC–F = 272 Hz), 123.84 (q, JC–F = 272 Hz), 125.9 (q, JC–F
=
3
2
3.7 Hz), 126.1 (q, JC–F = 3.7 Hz), 127.8, 129.6 (q, JC–F = 32.8 Hz),
2
130.2 (q, JC–F = 32.7 Hz), 130.5, 142.4, 146.7, 198.7; HRMS
4.5.2. N-(2-Aminoethyl)-2,2-bis(4-methylphenyl)-cyclopropane-
(ESI-TOF): Calcd for C18H12F6ONa (M+Na)+: 381.0685, Found:
381.0703.
carboxamide, 6c
Colorless oil; quantitative yield; ½a D21
¼ þ23:9 (c 1.38, MeOH);
ꢁ
1H NMR (400 MHz, CD3OD) d 1.42 (1H, dd, J = 4.8, 8.2 Hz), 2.08
(1H, dd, J = 4.8, 5.9 Hz), 2.23 (3H, s), 2.25 (3H, s), 2.46 (1H, dd,
J = 5.9, 8.2 Hz), 2.74 (2H, m), 3.21 (2H, t, J = 6.2 Hz), 7.02 (2H, d,
J = 8.0 Hz), 7.05 (2H, d, J = 8.2 Hz), 7.15 (2H, d, J = 8.2 Hz), 7.20
(2H, d, J = 8.0 Hz); 13C NMR (100 MHz, CD3OD) d 19.3, 20.9, 21.1,
31.2, 39.4, 40.3, 41.4, 128.5, 129.8, 129.9, 130.7, 137.0, 137.4,
139.1, 143.9, 173.2; HRMS (ESI-TOF): Calcd for C20H25N2O
(M+H)+: 309.1961, Found: 309.2000.
4.3.3. 2,2-Bis(4-chlorophenyl)cyclopropanecarbox-aldehyde, 4e
Yellow solid; 98% yield; Mp 88–89 °C; ½a D27
¼ ꢀ95:0 (c 0.65,
ꢁ
CHCl3); 1H NMR (400 MHz, CDCl3)
d 1.84 (1H, dd, J = 5.4,
8.4 Hz), 2.24 (1H, t, J = 5.4 Hz), 2.52–2.57 (1H, m), 7.14 (2H, d,
J = 8.6 Hz), 7.25 (2H, d, J = 8.6 Hz), 7.30 (4H, s), 8.73 (1H, d,
J = 6.4 Hz); 13C NMR (100 MHz, CDCl3) d 20.3, 36.5, 39.7, 128.7,
128.9, 129.3, 131.3, 133.1, 133.7, 137.4, 141.9, 199.5; HRMS
(ESI-TOF): Calcd for C16H12Cl2ONa (M+Na)+: 313.0157, Found:
313.0202.
4.5.3. N-(2-Aminoethyl)-2,2-bis(4-trifluoromethyl-phenyl)cyclo-
propanecarboxamide, 6d
4.3.4. 2,2-Fluorenylcyclopropanecarboxaldehyde, 4f
Colorless oil; 89% yield; ½a D21
ꢁ
¼ þ19:2 (c 1.27, MeOH); 1H NMR
Yellow oil; 94% yield; ½a D27
ꢁ
¼ ꢀ125:2 (c 0.99, CHCl3); 1H NMR
(400 MHz, CD3OD) d 1.63 (1H, dd, J = 5.5, 8.3 Hz), 2.22 (1H, t,
J = 5.5 Hz), 2.65 (1H, dd, J = 5.5, 8.3 Hz), 2.81(2H, t, J = 6.3 Hz),
3.26 (2H, t, J = 6.3 Hz), 7.54 (8H, m); 13C NMR (100 MHz, CD3OD)
(400 MHz, CDCl3) d 2.30 (1H, dd, J = 5.5, 8.3 Hz), 2.66 (1H, dd,
J = 5.5, 7.4 Hz), 2.90 (1H, ddd, J = 4.1, 7.4, 8.3 Hz), 7.09 (1H, d,
J = 7.5 Hz), 7.27–7.43 (5H, m), 7.81 (1H, d, J = 6.5 Hz), 7.82 (1H, d,
J = 7.6 Hz), 9.70 (1H, d, J = 4.1 Hz); 13C NMR (100 MHz, CDCl3) d
20.6, 39.7, 40.4, 118.8, 120.0, 120.2, 122.7, 127.0, 127.3, 127.4,
139.8, 141.0, 141.9, 145.6, 197.0; HRMS (ESI-TOF): Calcd for
C16H12ONa (M+Na)+: 243.0780, Found: 243.0762.
1
d 19.8, 31.1, 39.5, 40.4, 41.2, 125.6 (q, JC–F = 271 Hz), 125.7 (q,
1JC–F = 271 Hz), 126.3 (q, JC–F = 3.7 Hz), 126.5 (q, JC–F = 3.7 Hz),
3
3
2
2
129.6, 129.9 (q, JC–F = 32.0 Hz), 130.2 (q, JC–F = 32.0 Hz), 131.7,
145.8, 150.1, 172.1; HRMS (ESI-TOF): Calcd for C20H19F6N2O
(M+H)+: 417.1396, Found: 417.1385.

2070
N. Koyata et al. / Tetrahedron: Asymmetry 20 (2009) 2065–2071
4.5.4. N-(2-Aminoethyl)-2,2-bis(4-chlorophenyl)-cyclopropan-
2.29 (1H, t, J = 6.2 Hz), 2.69 (1H, dd, J = 6.2, 8.7 Hz), 3.35 (2H, m),
3.51 (2H, m), 7.57 (8H, m); 13C NMR (100 MHz, CD3OD) d 19.7,
ecarboxamide, 6e
Pale yellow oil; 55% yield; ½a D23
ꢁ
¼ þ38:7 (c 1.39, MeOH); 1H
25.1, 39.6, 125.6 (q, JC–F = 271 Hz), 126.5 (q, JC–F = 3.7 Hz), 126.6
1
3
3
2
2
NMR (400 MHz, CD3OD) d 1.49 (1H, dd, J = 5.0, 8.3 Hz), 2.12 (1H,
dd, J = 5.0, 6.0 Hz), 2.51 (1H, dd, J = 6.0, 8.3 Hz), 2.62 (2H, t,
J = 6.4 Hz), 3.14 (2H, m), 7.28 (8H, m); 13C NMR (100 MHz, CD3OD)
d 19.5, 31.3, 38.5, 42.0, 42.8, 129.4, 129.5, 130.4, 132.5, 133.4,
133.7, 140.4, 145.1, 171.8; HRMS (ESI-TOF): Calcd for C18H19Cl2N2O
(M+H)+: 349.0869, Found: 349.0869.
(q, JC–F = 3.7 Hz), 129.5, 130.2 (q, JC–F = 32.7 Hz), 130.7 (q, JC–F =
32.7 Hz), 131.9, 144.7, 149.4, 168.2; HRMS (ESI-TOF): Calcd for
C20H17F6N2 (M+H)+: 399.1290, Found: 399.1302.
4.7.4. 2-(2,2-Bis(4-chlorophenyl)cyclopropyl)imidazoline 7e
Colorless oil; quantitative yield; ½a D24
¼ þ86:0 (c 0.97, MeOH);
ꢁ
71% ee; 1H NMR (400 MHz, CD3OD) d 1.88 (1H, dd, J = 6.3,
8.6 Hz), 2.28 (1H, t, J = 6.3 Hz), 2.76 (1H, dd, J = 6.3, 8.6 Hz), 3.53
(2H, m), 3.71 (2H, m), 7.30 (2H, d, J = 8.9 Hz), 7.34 (2H, d,
J = 8.9 Hz), 7.37 (4H, s); 13C NMR (100 MHz, CD3OD) d 20.0, 23.7,
40.7, 46.2, 129.9, 130.1, 130.4, 132.4, 134.2, 135.0, 138.5, 143.3,
170.0; HRMS (ESI-TOF): Calcd for C18H17Cl2N2 (M+H)+: 331.0763,
Found: 331.0769.
4.5.5. N-(2-Aminoethyl)-2,2-fluorenylcyclopropane-carbox-
amide, 6f
Colorless oil; quantitative yield; ½a D23
¼ þ97:4 (c 1.63, MeOH);
ꢁ
1H NMR (400 MHz, CD3OD) d 2.07 (1H, dd, J = 5.0, 8.1 Hz), 2.38
(1H, dd, J = 5.0, 8.1 Hz), 2.73 (2H, m), 2.79 (1H, t, J = 8.1 Hz), 3.25
(2H, m), 7.14 (1H, d, J = 7.3 Hz), 7.21 (1H, t, J = 7.5 Hz), 7.31 (3H,
m), 7.46 (1H, d, J = 7.8 Hz), 7.80 (2H, t, J = 7.5 Hz); 13C NMR
(100 MHz, CD3OD) d 20.1, 35.4, 37.3, 40.3, 41.2, 120.1, 120.7,
120.9, 123.3, 127.6, 127.8, 127.9, 128.3, 140.8, 142.2, 144.3,
148.2, 171.2; HRMS (ESI-TOF): Calcd for C18H19N2O (M+H)+:
279.1492, Found: 279.1488.
4.7.5. 2-(2,2-Fluorenylcyclopropyl)imidazoline 7f
Colorless solid; 48% yield; Mp 151–166 °C; ½a D27
¼ þ186:4 (c
ꢁ
0.34, CHCl3); 58% ee; 1H NMR (400 MHz, CD3OD) d 2.11 (1H, dd,
J = 5.1, 8.6 Hz), 2.50 (1H, dd, J = 5.1 J = 7.4 Hz), 2.57 (1H, t,
J = 8.0 Hz), 3.46–3.57 (2H, m), 3.59–3.74 (2H, m), 4.76 (1H, br s),
7.07 (2H, d, J = 7.5 Hz), 7.23–7.46 (5H, m), 7.82 (2H, d, J = 7.5 Hz);
13C NMR (100 MHz, CD3OD) d 20.3, 27.9, 29.7, 35.1, 49.1, 118.6,
119.9, 120.0, 121.3, 126.8, 126.9, 127.1, 139.8, 140.6, 143.3,
146.7, 164.2; HRMS (ESI-TOF): Calcd for C18H17N2 (M+H)+:
261.1386, Found: 261.1376.
4.6. Typical procedure for cyclization of the amides 6 into (R)-
(+)-cibenzoline and analogs 7
Amide 6 was heated at 160 °C under vacuum (2 mmHg) for
37 h. The crude product was chromatographed on silica gel with
a 8:2:0.2 mixture of CHCl3, MeOH, and Et3N to afford (R)-(+)-
cibenzoline and analogues.
4.7.6. (4R,5R,1’R)-2-(2,2-Diphenylcyclopropyl)-4,5-diphenyl-2-
imidazoline 7h
4.7. Typical procedure for cyclization of the aldehydes 4 into
(R)-(+)-cibenzoline and analogues 7
Yellow oil; 99% yield; ½a D27
ꢁ
¼ ꢀ152:5 (c 1.00, MeOH); 1H NMR
(400 MHz, CDCl3) d 1.63 (1H, dd, J = 5.2, 8.7 Hz), 2.34 (1H, dd,
J = 5.2, 6.2 Hz), 2.69 (1H, dd, J = 6.2, 8.7 Hz), 4.30 (1H, br s), 4.68
(1H, br s), 6.60 (1H, br s), 7.17–7.52 (20H, m); 13C NMR
(100 MHz, CDCl3) d 18.8, 25.0, 38.3, 77.2, 126.5, 126.6, 127.0,
127.8, 128.4, 128.5, 128.8, 130.2, 140.3, 143.1, 145.3, 163.7; HRMS
(ESI-TOF): Calcd for C30H27N2 (M+H)+: 415.2169, Found: 415.2203.
To a solution of the aldehyde 4 (1 equiv) in tBuOH (5 mL) was
added a diamine (1.1 equiv). After stirring for 30 min at rt, K2CO3
(3 equiv) and I2 (1.25 equiv) were added to the mixture. The sus-
pension was stirred for 3 h at 70 °C under an argon atmosphere,
quenched at the temperature with satd Na2SO3 (4 mL), extracted
with AcOEt (3 ꢂ 200 mL), washed with sat. NaHSO3 (20 mL) and
brine (20 mL), and dried over Na2SO4. The crude product was pure
enough without purification.
4.7.7. (4R,5R,1’R)-2-(2,2-Diphenylcyclopropyl)-4,5-cyclohexanimi-
dazoline 7i
Yellow solid; 65% yield; Mp 155–165 °C; ½a D27
¼ ꢀ177:1 (c 0.71,
ꢁ
MeOH); 1H NMR (400 MHz, CDCl3) d 1.07–1.35 (4H, m), 1.53 (1H,
dd, J = 5.3, 8.8 Hz), 1.58–1.73 (2H, m), 1.94–2.07 (2H, m), 2.19
(1H, t, J = 5.7 Hz), 2.53 (1H, dd, J = 6.3, 8.8 Hz), 2.49–2.63 (4H, m),
3.12 (1H, br s), 7.16–7.30 (10H, m); 13C NMR (100 MHz, CDCl3) d
18.6, 24.8, 25.8, 30.5, 37.5, 69.1, 126.5, 126.7, 128.07, 128.11,
128.5, 129.5, 140.1, 145.0, 166.2; HRMS (ESI-TOF): Calcd for
C22H25N2 (M+H)+: 317.2012, Found: 317.1969.
4.7.1. (R)-(+)-Cibenzoline 7a1
Colorless oil; quantitative yield; ½a D24
¼ þ110:0 (c 1.12, MeOH);
ꢁ
72% ee; 1H NMR (400 MHz, CD3OD) d 1.58 (1H, dd, J = 5.4, 8.6 Hz),
2.09 (1H, dd, J = 5.4, 6.3 Hz), 2.43 (1H, dd, J = 6.3, 8.6 Hz), 3.20 (2H,
m), 3.37 (2H, m), 7.11–7.38 (10H, m); 13C NMR (100 MHz, CD3OD)
d 19.5, 25.2, 30.8, 39.9, 48.9, 127.6, 128.1, 128.8, 129.3, 129.5,
131.0, 141.4, 146.4, 168.9; HRMS (ESI-TOF): Calcd for C18H19N2
(M+H)+: 263.1543, Found: 263.1540.
Acknowledgments
4.7.2. 2-(2,2-Bis(4-methylphenyl)cyclopropyl)-imidazoline 7c
This work was supported in part by Ajinomoto Award in Syn-
thetic Organic Chemistry, Japan and by Grants-in-Aid for Scientific
Research (C) (No. 18590014) from the Japan Society for the Promo-
tion of Science. This work was performed through the Scientific Re-
search Project by CIS (Chiba Institute of Science).
Colorless oil; quantitative yield; ½a D23
¼ þ66:0 (c 0.90, MeOH);
ꢁ
65% ee; 1H NMR (400 MHz, CD3OD) d 1.61 (1H, dd, J = 5.9,
8.6 Hz), 2.08 (1H, t, J = 5.9 Hz), 2.25 (3H, s), 2.28 (3H, s), 2.46 (1H,
dd, J = 5.9, 8.6 Hz), 3.29 (2H, m), 3.46 (2H, m), 7.04 (2H, d,
J = 8.1 Hz), 7.09 (2H, d, J = 8.0 Hz), 7.15 (2H, d, J = 8.1 Hz), 7.23
(2H, d, J = 8.0 Hz); 13C NMR (100 MHz, CD3OD) d 19.7, 21.0, 21.1,
25.1, 39.6, 48.5, 128.5, 129.9, 130.0, 130.8, 137.3, 137.9, 138.3,
143.4, 169.3; HRMS (ESI-TOF): Calcd for C20H23N2 (M+H)+:
291.1856, Found: 291.1863.
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