Efficient and divergent synthesis of functionalized cyclopropanes via iodoform reaction

Article abstract of DOI:10.1055/s-0031-1289693

Efficient and divergent one-pot synthesis of cyclopropyl amides and esters from readily available 1-acetylcyclopropanes via iodoform reaction based on the selection of reaction conditions is reported. A series of substituted cyclopropyl amides were synthe

Full text of DOI:10.1055/s-0031-1289693

PAPER
705
Efficient and Divergent Synthesis of Functionalized Cyclopropanes
via Iodoform Reaction
S
ynthesis of Funct
i
ionaliz
ng
Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. of China
Fax +86(431)85262676; E-mail: zhangningtum@gmail.com; E-mail: dwdong@ciac.jl.cn
Received 26 November 2011; revised 1 January 2012
O
O
Abstract: Efficient and divergent one-pot synthesis of cyclopropyl
amides and esters from readily available 1-acetylcyclopropanes via
iodoform reaction based on the selection of reaction conditions is
reported. A series of substituted cyclopropyl amides were synthe-
sized from 1-acetylcyclopropanes, iodine, and ammonia in water in
the presence of K2CO3 in good yields, whereas substituted cyclopro-
pyl esters were obtained from the reaction of 1-acetylcyclopropanes
with iodine and alcohols in the presence of DBU.
R1
R1
X
Me
2, 3
1
X = NH2, OR2
Scheme 1 Proposed synthetic approach for functionalized cyclo-
propanes
Key words: cyclopropanes, iodoform reaction, iodine, amide,
water
reaction of 1-acetylcyclopropanes under different condi-
tions. Herein, we wish to report our experimental results.
Iodoform reaction is an efficient tool for the conversion of
acetyl to carboxylic acid group under basic conditions.8
Recently, Cao and co-workers reported a modification of
classical iodoform reaction using water as a solvent, in
which they achieved efficient synthesis of primary
amides.8d In the present work, we investigated the iodo-
form reaction of the readily available acetylcyclopropanes
1.9 Thus, the reaction of 1-acetyl-N-phenylcyclopropane
carboxamide (1a) with iodine (3.0 equiv) and NH4OH
(3.0 equiv) in the presence of K2CO3 (4.0 equiv) was first
attempted in DMF at room temperature for 4.5 hours. The
reaction proceeded smoothly as monitored by TLC and
furnished a white solid after workup and purification by
column chromatography of the resulting mixture. The
product was identified as N-phenylcyclopropane-1,1-di-
carboxamide (2a) on the basis of the spectral and analyti-
cal data.
The overwhelming importance of cyclopropane deriva-
tives in organic synthesis has been recognized for their
presence in numerous natural products and synthetic or-
ganic compounds, such as chrysanthemates and cilastatin,
along with diverse bio-, physio-, and pharmacological ac-
tivities.1,2 Moreover, functionalized cyclopropanes are
widely utilized as versatile intermediates in organic trans-
formations to carbo- and heterocyclic systems. So far, ex-
tensive work has generated many approaches for the
synthesis of a variety of cyclopropanes, from either appro-
priately acyclic precursors,3–5 or the modification of the
preconstructed cyclopropane rings.6 Nevertheless, to
match the increasing scientific and practical demands, it is
still of great importance to develop simple and efficient
approaches for the construction of skeleton cyclopro-
panes, especially those with wide applicability to achieve
more elaborate and flexible substitution patterns.
The results encouraged us to exploit the feasibility of
preparation of cyclopropyl amides in water. The use of
water as a reaction medium in organic chemistry was re-
discovered in the 1980s in Breslow’s work, which showed
that a hydrophobic effect can strongly enhance the rates of
some organic reactions.10 Organic reactions in water with-
out the use of any organic solvent can also benefit from
the fact that water is an easily available, cheap, safe, and
environmentally benign solvent.8d,11,12 After a series of ex-
periments, including variation of reaction temperature,
base, and the feed ratio of iodine/base/NH4OH, the opti-
mal reaction conditions were obtained when the reaction
of 1a was performed with iodine (3.0 equiv) and NH4OH
(2.0 equiv) in the presence of K2CO3 (4.0 equiv) in water
at 60 °C, whereby the yield of 2a reached 88% (Table 1,
entry 1).
During the course of our studies on the synthesis and util-
ity of cyclopropanes based on b-oxo amides and their de-
rivatives,7 we developed one-pot synthesis of pyridin-
2(1H)-ones,7a spiro-fused pyrazolin-5-ones,7b spiro-fused
pyrazolin-5-one N-oxides,7c 1H-pyrazoles, and isox-
azoles.7d The important synthetic utility of functionalized
cyclopropanes and our continuing interest in the synthesis
of highly valuable carbo- and heterocycles prompted us to
exploit the synthesis of variable and novel cyclopropanes.
In the present work, we envisioned that under appropriate
conditions the readily available acetylcyclopropanes
could be converted into other cyclopropyl systems
(Scheme 1). As a result, we developed a facile one-pot
synthesis of cyclopropyl amides and esters via iodoform
To determine the scope of the iodoform reaction in water,
various cyclopropyl ketones 1 were subjected to the iden-
tical conditions, and some of the results are summarized
in Table 1. It was observed that the reactions of 1-acetyl-
SYNTHESIS 2012, 44, 705–710
Advanced online publication: 03.02.2012
DOI: 10.1055/s-0031-1289693; Art ID: F110811SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
2

706
D. Zhang et al.
PAPER
equiv) was performed in water at room temperature for
4.5 hours. Unfortunately, no reaction was observed as in-
dicated by TLC. When 1a, methanol (1.2 equiv), and io-
dine (3.0 equiv) reacted in CH2Cl2 (10 mL) in the presence
of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 4.0 equiv)
at 0 °C for 1 hour, a product was obtained, and character-
ized as methyl 1-(phenylcarbamoyl)cyclopropanecarbox-
ylate (3a) on the basis of the spectral and analytical data
(Table 2, entry 1). Under the identical conditions, a range
of reactions of 1-acetylcyclopropanes 1b–i bearing vari-
able aryl amide and benzoyl groups were carried out. As
shown in Table 2, the efficiency of the iodoform reaction
proved to be suitable to afford the corresponding substi-
tuted cyclopropyl esters 3b–i in good yields (Table 2, en-
tries 2–9). The versatility of the cyclopropyl ester
synthesis was evaluated by using other kind of alcohols,
such as EtOH and BnOH, as the reactants (Table 2, entries
10–12).
Table 1 Synthesis of Cyclopropyl Amides 2 from 1-Acetylcyclo-
propanes 1a
O
O
I2, NH4OH, K2CO3
H2O, 60 °C
R1
R1
H2N
R2
R2
1
2
Entry
1
1
R1
R2
H
2
Yield (%)b
1a
1b
1c
1d
1e
1f
1g
1h
1i
PhNHCO
2a
2b
2c
2d
2e
2f
88
80
82
79
71
62
65
83
76
74
82c
63d
2
4-MeC6H4NHCO
4-MeOC6H4NHCO
4-ClC6H4NHCO
2-MeC6H4NHCO
2-MeOC6H4NHCO
2-ClC6H4NHCO
2,4-Me2C6H3NHCO
PhCO
H
3
H
4
H
5
H
6
H
7
H
2g
2h
2i
Table 2 Synthesis of Cyclopropyl Esters 3 from 1-Acetylcyclopro-
panes 1a
8
H
O
O
9
H
R2OH, I2, DBU
CH2Cl2, 0 °C
R1
R1
R2O
10
11
12
1j
1k
1l
CO2Et
H
2j
3
1
PhNHCO
Me
Ph
2k
2l
Entry
1
1
R1
R2
3
Yield (%)b
PhNHCO
a Reaction conditions: 1 (1.0 mmol), I2 (3.0 mmol), NH4OH (2.0
mmol), K2CO3 (4.0 equiv), H2O (20 mL), 60 °C, 1.0–4.5 h.
b Isolated yield.
1a
1b
1c
1d
1e
1f
1g
1h
1i
PhNHCO
4-MeC6H4NHCO
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
3a
3b
3c
3d
3e
3f
3g
3h
3i
86
79
80
76
73
82
72
84
82
84
81
75
2
c For entry 11: cis-1k was used, cis-2k was obtained.
d For entry 12: trans-1l was used, trans-2l was obtained.
3
4-MeOC6H4NHCO
4-ClC6H4NHCO
2-MeC6H4NHCO
2-MeOC6H4NHCO
2-ClC6H4NHCO
2,4-Me2C6H3NHCO
PhCO
4
cyclopropanes 1b–h could proceed smoothly to afford the
corresponding substituted cyclopropyl amides 2b–h in
good yields (Table 1, entries 2–8). The efficiency of the
reaction proved to be suitable for substrates 1i and 1j bear-
ing benzoyl and ester groups, respectively (Table 1, en-
tries 9, 10). In the cases of substrates cis-1k and trans-1l
with a substituent on the cyclopropyl ring, the correspond-
ing cyclopropyl amides cis-2k and trans-2l were obtained
in moderate to good yields (Table 1, entries 11, 12).13 All
the results demonstrated the efficiency and synthetic in-
terest of the protocol with respect to 1-acetylcyclopro-
panes 1 bearing variable amide, benzoyl, and ester groups.
It should be noted that the richness of the functionality, for
example, cyclopropane moiety and amide group of the cy-
clopropyl amides of type 2 obtained may render them ex-
tremely versatile as synthons in other organic
transformations. For example, the primary amide group is
very reactive group, which can be easily converted into
the cyano group,14 and a variety of ring-opening and ring-
enlargement reactions of the functionalized cyclopro-
panes, for their well-known ‘unsaturated’ character, may
lead to novel carbo- and heterocycles.7,15
5
6
7
8
9
10
11
12
1i
PhCO
3j
3k
3l
1e
2-MeC6H4NHCO
2-MeC6H4NHCO
Et
1e
Bn
a Reaction conditions: 1 (1.0 mmol), R1OH (1.2 mmol), I2 (3.0 mmol),
DBU (4.0 mmol), CH2Cl2 (10 mL), 0 °C, 1.0–6.0 h.
b Isolated yield.
Further, we were interested in the utilization of cyclopro-
pyl amides 2 under Vilsmeier conditions.16 The reaction
of 2a with Vilsmeier reagent, POCl3–DMF (1.5 equiv),
was performed at 0 °C for 2 hours, which furnished a
white solid. The product was characterized as 1-cyano-N-
phenylcyclopropanecarboxamide (4a) on the basis of its
spectral and analytical data (83% yield). When the reac-
tion was conducted with 3.0 equivalents of Vilsmeier re-
agent at 0 °C, the reaction could be completed within 30
To extend its scope of the reaction, we subsequently ex-
amined the iodoform reaction of 1-acetyl-1-carbamoylcy-
clopropanes 1 in alcohol. Thus, the reaction of 1a with
iodine (3.0 equiv), K2CO3 (4.0 equiv), and methanol (1.0
Synthesis 2012, 44, 705–710
© Thieme Stuttgart · New York

PAPER
Synthesis of Functionalized Cyclopropanes
707
7.10 (t, J = 7.5 Hz, 1 H), 7.33 (t, J = 7.5 Hz, 2 H), 7.57 (d, J = 7.5
Hz, 2 H), 10.06 (s, 1 H).
minutes and the yield of 4a reached 92% (Table 3, entry
1). Some of the selected cyclopropyl amides 2 were sub-
jected to the identical conditions, and the corresponding 13C NMR (100 MHz, CDCl3): d = 12.7, 22.1, 26.2, 27.7, 42.3, 120.2
(2 C), 124.2, 128.9 (2 C), 138.1, 165.1, 206.9.
1-cyanocyclopropanes 4 were obtained in good to high
yields (Table 3, entries 2–7).
Anal. Calcd for C13H15NO2: C, 71.87; H, 6.96; N, 6.45. Found: C,
71.64; H, 6.89; N, 6.49.
Table 3 Synthesis of Cyanocyclopropanes 4 from Cyclopropyl
Amides 2 under Vilsmeier Conditions
trans-1-Acetyl-N,2-diphenylcyclopropanecarboxamide (trans-
1l)
O
N
POCl3, DMF
0 °C
Yield: 109 mg (39%); white solid; mp 125–127 °C.
R
C
R
1H NMR (300 MHz, CDCl3): d = 1.60 (s, 3 H), 2.20 (dd, J = 8.0, 5.5
Hz, 1 H), 2.53 (dd, J = 9.0, 5.0 Hz, 1 H), 3.40 (t, J = 9.0 Hz, 1 H),
7.12 (t, J = 7.5 Hz, 1 H), 7.26–7.37 (m, 7 H), 7.62 (d, J = 7.5 Hz, 2
H), 10.73 (s, 1 H).
H2N
2
4
Entry
2
R
4
Time (h) Yield (%)b
13C NMR (100 MHz, CDCl3): d = 21.0, 30.1, 38.2, 41.9, 120.2 (2
C), 124.2, 127.8, 128.8 (2 C), 128.9 (2 C), 129.4 (2 C), 135.1, 138.1,
166.7, 208.0.
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2i
PhNHCO
4a
4b
4c
4d
4e
4i
2.0
1.5
2.0
2.5
1.0
1.5
1.5
92
90
87
83
89
86
82
4-MeC6H4NHCO
Anal. Calcd for C18H17NO2: C, 77.40; H, 6.13; N, 5.01. Found: C,
77.61; H, 6.09; N, 5.06.
4-MeOC6H4NHCO
4-ClC6H4NHCO
2-MeC6H4NHCO
PhCO
Substituted Cyclopropyl Amides; N-Phenylcyclopropane-1,1-
dicarboxamide (2a); Typical Procedure
To a solution of K2CO3 (553 mg, 4.0 mmol) in H2O (25 mL) was
added 1a (203 mg, 1.0 mmol), I2 (761 mg, 3.0 mmol), and NH4OH
(25%, 0.38 mL, 2.0 mmol). The mixture was stirred at 60 °C for 2.0
h (TLC monitoring; eluent: PE–EtOAc, 1:1). After completion, the
reaction mixture was cooled down to r.t. and poured slowly into sat.
aq Na2S2O3 (50 mL), and extracted with EtOAc (3 × 20 mL). The
combined organic phases were washed with H2O (3 × 20 mL), dried
(MgSO4), filtered, and concentrated in vacuo. The crude product
was purified by flash chromatography (silica gel, PE–EtOAc, 1:1)
to give 2a as a white solid; yield: 180 mg (88%); mp 106–107 °C.
1H NMR (300 MHz, CDCl3): d = 1.39–1.43 (m, 2 H), 1.77–1.81 (m,
2 H), 5.65 (br s, 2 H), 7.11 (t, J = 7.5 Hz, 1 H), 7.32 (t, J = 7.5 Hz,
2 H), 7.55 (d, J = 9.0 Hz, 2 H), 10.46 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 17.7 (2 C), 29.1, 120.5 (2 C),
124.4, 129.6 (2 C), 139.3, 168.9, 174.8.
2j
CO2Et
4j
a Reaction conditions: 2 (1.0 mmol), POCl3 (3.0 mmol), DMF (5 mL),
0 °C, 0.5–2.0 h.
b Isolated yield.
In summary, an efficient and divergent one-pot synthesis
of functionalized cyclopropanes 2 and 3 from readily
available 1-acetylcyclopropanes 1 via iodoform reaction
based on the selection of reaction conditions is reported.
Moreover, synthetic transformation of cyclopropyl
amides 2 provided an alternative synthetic approach to cy-
anocyclopropanes 4. These protocols for functionalized
Anal. Calcd for C11H12N2O2: C, 64.69; H, 5.92; N, 13.72. Found: C,
cyclopropanes are associated with readily available start- 64.84; H, 5.83; N, 13.79.
ing materials, mild conditions, high yields, and potential
N-(p-Tolyl)cyclopropane-1,1-dicarboxamide (2b)
Yield: 175 mg (80%); white solid; mp 140–141 °C.
utility of the products.
IR (KBr): 3338, 3072, 2920, 2798, 1656, 1589, 1544, 1411, 1112,
1031, 968, 810 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.38–1.42 (m, 2 H), 1.73–1.77 (m,
2 H), 2.31 (s, 3 H), 5.77 (br s, 2 H), 7.12 (d, J = 8.0 Hz, 2 H), 7.41
(d, J = 8.5 Hz, 2 H), 10.23 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 16.9 (2 C), 20.4, 28.1, 119.7,
119.8, 129.1 (2 C), 132.5, 136.1, 167.9, 174.1.
All reagents were purchased from commercial sources and used
without treatment, unless otherwise indicated. The products were
purified by column chromatography over silica gel. Petroleum ether
(PE) refers to a hydrocarbon mixture with a boiling range of 60–
90 °C. 1H NMR and 13C NMR spectra were recorded at 300 (or 400)
MHz and 75 (or 100) MHz, respectively, with TMS as internal stan-
dard at 25 °C. IR spectra (KBr) were recorded on a FTIR spectro-
photometer in the range of 400–4000 cm–1.
Anal. Calcd for C12H14N2O2: C, 66.04; H, 6.47; N, 12.84. Found: C,
66.23; H, 6.53; N, 12.72.
1-Acetyl-1-carbamoylcyclopropanes 1
Cyclopropanes 1a–l were prepared according to a known literature
procedure.9 Products 1a–j are known compounds; their analytical
and spectral data are in good agreement with those reported in the
literature.9 The data for the new derivatives cis-1k and trans-1l are
given below.
N-(4-Methoxyphenyl)cyclopropane-1,1-dicarboxamide (2c)
Yield: 192 mg (82%); yellowish solid; mp 159–161 °C.
1H NMR (300 MHz, CDCl3): d = 1.39–1.43 (m, 2 H), 1.73–1.77 (m,
2 H), 3.79 (s, 3 H), 5.77 (br s, 2 H), 6.85 (d, J = 9.0 Hz, 2 H), 7.44
(d, J = 9.0 Hz, 2 H), 10.16 (s, 1 H).
cis-1-Acetyl-2-methyl-N-phenylcyclopropanecarboxamide (cis-
1k)
Yield: 91 mg (42%); white solid; mp 87–89 °C.
1H NMR (300 MHz, CDCl3): d = 1.29 (d, J = 3.0 Hz, 3 H), 1.68–
1.72 (m, 1 H), 1.84–1.96 (m, 1 H), 1.98–2.02 (m, 1 H), 2.11 (s, 3 H),
13C NMR (100 MHz, DMSO-d6): d = 16.8 (2 C), 28.3, 55.3, 114.0
(2 C), 121.6 (2 C), 131.8, 155.6, 168.0, 174.1.
Anal. Calcd for C12H14N2O3: C, 61.53; H, 6.02; N, 11.96. Found: C,
61.46; H, 6.07; N, 12.08.
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D. Zhang et al.
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N-(4-Chlorophenyl)cyclopropane-1,1-dicarboxamide (2d)
Yield: 189 mg (79%); yellowish solid; mp 154–155 °C.
IR (KBr): 3381, 3302, 3194, 1659, 1541, 1440, 1324, 1246, 756,
694 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.37–1.41 (m, 2 H), 1.81–1.86 (m,
2 H), 5.48 (br s, 2 H), 7.28 (d, J = 9.0 Hz, 2 H), 7.52 (d, J = 9.0 Hz,
2 H), 10.84 (s, 1 H).
1H NMR (300 MHz, CDCl3): d = 1.42–1.46 (m, 2 H), 1.64–1.68 (m,
2 H), 5.66 (br s, 1 H), 5.86 (br s, 1 H), 7.47 (t, J = 7.5 Hz, 2 H), 7.59
(t, J = 7.0 Hz, 1 H), 7.93 (d, J = 7.0 Hz, 2 H).
13C NMR (100 MHz, DMSO-d6): d = 16.9 (2 C), 28.6, 121.4 (2 C),
127.2, 128.7 (2 C), 137.5, 168.3, 173.8.
13C NMR (125 MHz, DMSO-d6): d = 13.8 (2 C), 34.8, 128.3 (2 C),
128.4 (2 C), 132.8, 136.7, 171.7, 195.9.
Anal. Calcd for C11H11ClN2O2: C, 55.36; H, 4.65; N, 11.74. Found:
C, 55.71; H, 4.59; N, 11.63.
Anal. Calcd for C11H11NO2: C, 69.83; H, 5.86; N, 7.40. Found: C,
69.68; H, 5.91; N, 7.49.
N-(o-Tolyl)cyclopropane-1,1-dicarboxamide (2e)
Yield: 155 mg (71%); yellowish solid; mp 123–124 °C.
cis-2-Methyl-N-phenylcyclopropane-1,1-dicarboxamide (cis-
2k)
Yield: 179 mg (82%); white solid; mp 142–145 °C.
IR (KBr): 3346, 1767, 1670, 1548, 1447, 1173, 758 cm–1.
IR (KBr): 3434, 3348, 3122, 1639, 1548, 1456, 1413, 1166, 960,
752 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.39–1.43 (m, 2 H), 1.79–1.83 (m,
2 H), 2.34 (s, 3 H), 5.68 (br s, 2 H), 7.07 (t, J = 6.0 Hz, 1 H), 7.20
(t, J = 6.0 Hz, 2 H), 7.93 (d, J = 8.0 Hz, 1 H), 10.51 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 17.8, 18.0 (2 C), 27.1, 121.8,
124.1, 126.4, 128.3, 130.4, 136.8, 168.1, 175.3.
1H NMR (400 MHz, CDCl3): d = 1.21 (d, J = 5.5 Hz, 3 H), 1.43–
1.46 (m, 1 H), 1.61–1.69 (m, 2 H), 5.69 (br s, 1 H), 6.59 (br s, 1 H),
7.12 (t, J = 7.0 Hz, 1 H), 7.32 (t, J = 8.0 Hz, 2 H), 7.54 (d, J = 8.0
Hz, 2 H), 9.20 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 13.8, 19.4, 22.1, 36.6, 119.8
(2 C), 123.4, 128.5 (2 C), 139.0, 166.4, 172.4.
Anal. Calcd for C12H14N2O2: C, 66.04; H, 6.47; N, 12.84. Found: C,
65.88; H, 6.41; N, 12.91.
Anal. Calcd for C12H14N2O2: C, 66.04; H, 6.47; N, 12.84. Found: C,
66.21; H, 6.53; N, 12.78.
N-(2-Methoxyphenyl)cyclopropane-1,1-dicarboxamide (2f)
Yield: 145 mg (62%); yellowish solid; mp 174–176 °C.
trans-N,2-Diphenylcyclopropane-1,1-dicarboxamide (trans-2l)
Yield: 177 mg (63%); yellow solid; mp 182–183 °C.
IR (KBr): 3419, 3276, 2962, 2839, 1650, 1600, 1541, 1465, 1413,
1232, 1114, 1029, 738 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.52–1.57 (m, 2 H), 1.60–1.65 (m,
2 H), 3.92 (s, 3 H), 5.50 (br s, 1 H), 6.88–6.91 (m, 1 H), 6.93–6.98
(m, 1 H), 7.04–7.09 (m, 1 H), 8.27–8.30 (m, 1 H), 9.62 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 18.0 (2 C), 27.2, 56.0, 111.1,
119.8, 120.6, 123.8, 127.8, 148.6, 167.8, 175.1.
1H NMR (300 MHz, CDCl3): d = 1.80 (dd, J = 8.0, 6.0 Hz, 1 H),
2.32 (dd, J = 9.0, 6.0 Hz, 1 H), 3.23 (t, J = 8.0 Hz, 1 H), 5.30 (br s,
2 H), 7.11 (t, J = 7.0 Hz, 1 H), 7.26–7.36 (m, 7 H), 7.60 (d, J = 8.0
Hz, 2 H), 10.53 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 15.4, 32.7, 38.6, 119.6 (2 C),
123.5, 126.8, 127.8 (2 C), 128.7 (2 C), 128.9 (2 C), 135.5, 138.5,
167.1, 169.6.
Anal. Calcd for C12H14N2O3: C, 61.53; H, 6.02; N, 11.96. Found: C,
61.81; H, 6.08; N, 11.83.
Anal. Calcd for C17H16N2O2: C, 72.84; H, 5.75; N, 9.99. Found: C,
72.68; H, 5.84; N, 9.94.
N-(2-Chlorophenyl)cyclopropane-1,1-dicarboxamide (2g)
Yield: 155 mg (65%); yellowish solid; mp 160–162 °C.
Substituted Cyclopropyl Esters 3; Methyl 1-(Phenylcarbam-
oyl)cyclopropanecarboxylate (3a); Typical Procedure
IR (KBr): 3434, 3346, 3095, 3035, 1645, 1591, 1544, 1440, 1301,
1166, 1035, 962, 750 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.47–1.51 (m, 2 H), 1.77–1.82 (m,
2 H), 5.77 (br s, 2 H), 7.02–7.07 (m, 1 H), 7.22–7.28 (m, 1 H), 7.37–
7.40 (m, 1 H), 8.29–8.33 (m, 1 H), 10.72 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 18.7 (2 C), 26.9, 122.2, 123.0,
124.9, 127.8, 129.2, 135.3, 168.6, 175.2.
To a solution of 1a (203 mg, 1.0 mmol) in CH2Cl2 (10 mL) was add-
ed MeOH (0.049 mL, 1.2 mmol), I2 (761 mg, 3.0 mmol), and DBU
(609 mg, 4.0 mmol) under stirring at 0 °C. The mixture was stirred
for 1 h at 0 °C (TLC monitoring; eluent: PE–EtOAc, 3:1). After
completion, the reaction mixture was poured slowly into sat. aq
Na2S2O3 (50 mL), and extracted with EtOAc (3 × 20 mL). The com-
bined organic phases were washed with H2O (3 × 20 mL), dried
(MgSO4), filtered, and concentrated in vacuo. The crude product
was purified by chromatography (silica gel, PE–EtOAc, 4:1) to give
3a as a yellow solid, yield: 189 mg (86%); mp 54–55 °C.
Anal. Calcd for C11H11ClN2O2: C, 55.36; H, 4.65; N, 11.74. Found:
C, 55.29; H, 4.54; N, 11.86.
1H NMR (400 MHz, CDCl3): d = 1.64–1.67 (m, 2 H), 1.80–1.83 (m,
2 H), 3.74 (s, 3 H), 7.08 (t, J = 7.5 Hz, 1 H), 7.32 (t, J = 7.5 Hz, 2
H), 7.58 (d, J = 8.0 Hz, 2 H), 10.83 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 20.7 (2 C), 26.4, 52.4, 120.0 (2
C), 124.0, 128.8 (2 C), 138.0, 166.6, 174.3.
N-(2,4-Dimethylphenyl)cyclopropane-1,1-dicarboxamide (2h)
Yield: 193 mg (83%); white solid; mp 130–131 °C.
IR (KBr): 3367, 3184, 3033, 2916, 2794, 1650, 1589, 1541, 1409,
1218, 1027, 1180, 970, 765 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.40–1.44 (m, 2 H), 1.76–1.80 (m,
2 H), 2.29 (s, 6 H), 5.68 (br s, 2 H), 6.99 (d, J = 6.5 Hz, 2 H), 7.74
(d, J = 9.0 Hz, 1 H), 10.16 (s, 1 H).
Anal. Calcd for C12H13NO3: C, 65.74; H, 5.98; N, 6.39. Found: C,
65.57; H, 5.90; N, 6.55.
13C NMR (75 MHz, DMSO-d6): d = 18.4, 18.6 (2 C), 21.2, 27.7,
122.6, 127.4, 129.1, 131.6, 133.8, 134.9, 168.7, 175.9.
Methyl 1-(p-Tolylcarbamoyl)cyclopropanecarboxylate (3b)
Yield: 184 mg (79%); white solid; mp 120–121 °C.
Anal. Calcd for C13H16N2O2: C, 67.22; H, 6.94; N, 12.06. Found: C,
67.06; H, 6.98; N, 12.11.
IR (KBr): 3273, 1709, 1599, 1545, 1444, 1354, 1202, 1153, 974,
822, 721, 519 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.60–1.67 (m, 2 H), 1.79–1.83 (m,
2 H), 2.31 (s, 3 H), 3.73 (s, 3 H), 7.12 (d, J = 8.0 Hz, 2 H), 7.46 (d,
J = 8.0 Hz, 2 H), 10.75 (s, 1 H).
1-Benzoylcyclopropanecarboxamide (2i)
Yield: 144 mg (76%); white solid; mp 169–171 °C.
Synthesis 2012, 44, 705–710
© Thieme Stuttgart · New York

PAPER
Synthesis of Functionalized Cyclopropanes
709
13C NMR (100 MHz, CDCl3): d = 20.6 (2 C), 20.8, 26.4, 52.4, 120.1
(2 C), 129.4 (2 C), 133.6, 135.6, 166.5, 174.4.
Anal. Calcd for C12H12ClNO3: C, 56.81; H, 4.77; N, 5.52. Found: C,
56.98; H, 4.74; N, 5.48.
Anal. Calcd for C13H15NO3: C, 66.94; H, 6.48; N, 6.00. Found: C,
66.78; H, 6.53; N, 6.08.
Methyl 1-[(2,4-Dimethylphenyl)carbamoyl]cyclopropanecar-
boxylate (3h)
Yield: 208 mg (84%); yellowish solid; mp 93–94 °C.
Methyl 1-[(4-Methoxyphenyl)carbamoyl]cyclopropanecarbox-
ylate (3c)
Yield: 199 mg (80%); white solid; mp 105–107 °C.
1H NMR (300 MHz, CDCl3): d = 1.63–1.67 (m, 2 H), 1.79–1.82 (m,
2 H), 3.73 (s, 3 H), 3.79 (s, 3 H), 6.86 (d, J = 7.5 Hz, 2 H), 7.49 (d,
J = 7.5 Hz, 2 H), 10.70 (s, 1 H).
1H NMR (300 MHz, CDCl3): d = 1.64–1.68 (m, 2 H), 1.80–1.84 (m,
2 H), 2.28 (s, 3 H), 2.34 (s, 3 H), 3.73 (s, 3 H), 6.99 (d, J = 7.0 Hz,
1 H), 7.01 (s, 1 H), 7.86 (d, J = 8.0 Hz, 1 H), 10.67 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 17.7, 20.4 (2 C), 20.6, 26.3, 52.2,
121.6, 126.8, 127.9, 130.7, 133.6, 133.8, 166.3, 174.2.
13C NMR (100 MHz, CDCl3): d = 20.4 (2 C), 26.2, 52.3, 55.3, 113.9
(2 C), 121.6 (2 C), 131.3, 156.1, 166.3, 174.3.
Anal. Calcd for C14H17NO3: C, 68.00; H, 6.93; N, 5.66. Found: C,
68.12; H, 6.87; N, 5.70.
Anal. Calcd for C13H15NO4: C, 62.64; H, 6.07; N, 5.62. Found: C,
62.85; H, 6.21; N, 5.67.
Ethyl 1-(o-Tolylcarbamoyl)cyclopropanecarboxylate (3k)
Yield: 200 mg (81%); yellowish solid; mp 66–69 °C.
Methyl 1-[(4-Chlorophenyl)carbamoyl]cyclopropanecarboxy-
late (3d)
Yield: 193 mg (76%); yellow solid; mp 115–116 °C.
1H NMR (400 MHz, CDCl3): d = 1.28 (t, J = 7.0 Hz, 3 H), 1.65–
1.67 (m, 2 H), 1.80–1.83 (m, 2 H), 2.38 (s, 3 H), 4.21 (q, J = 7.0 Hz,
2 H), 7.03 (t, J = 8.0 Hz, 1 H), 7.19 (t, J = 7.0 Hz, 2 H), 8.03 (d, J =
8.0 Hz, 1 H), 10.79 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 13.9, 17.9, 20.6 (2 C), 26.5, 61.4,
121.6, 124.1, 126.4, 127.9, 130.2, 136.5, 166.7, 173.9.
IR (KBr): 3279, 1707, 1664, 1593, 1537, 1441, 1398, 1198, 829,
708, 501 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.66–1.70 (m, 2 H), 1.79–1.83 (m,
2 H), 3.74 (s, 3 H), 7.28 (d, J = 9.0 Hz, 2 H), 7.54 (d, J = 9.0 Hz, 2
H), 10.91 (s, 1 H).
Anal. Calcd for C14H17NO3: C, 68.00; H, 6.93; N, 5.66. Found: C,
68.16; H, 6.99; N, 5.61.
13C NMR (100 MHz, CDCl3): d = 20.8 (2 C), 26.4, 52.5, 121.2 (2
Benzyl 1-(o-Tolylcarbamoyl)cyclopropanecarboxylate (3l)
Yield: 232 mg (75%); white solid; mp 86–87 °C.
C), 128.8 (2 C), 136.7, 166.8, 174.3.
Anal. Calcd for C12H12ClNO3: C, 56.81; H, 4.77; N, 5.52. Found: C,
56.62; H, 4.72; N, 5.59.
1H NMR (400 MHz, CDCl3): d = 1.69–1.71 (m, 2 H), 1.82–1.85 (m,
2 H), 2.37 (s, 3 H), 5.18 (s, 2 H), 7.03 (t, J = 8.0 Hz, 1 H), 7.19 (t,
J = 6.0 Hz, 2 H), 7.33 (d, J = 8.0 Hz, 2 H), 7.39 (d, J = 6.0 Hz, 3 H),
8.01 (d, J = 8.0 Hz, 1 H), 10.73 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 18.0, 20.9 (2 C), 26.6, 67.0,
121.8, 124.3, 126.5, 128.0 (2 C), 128.6, 128.7 (2 C), 130.2, 134.9,
136.4, 166.5, 173.8.
Methyl 1-(o-Tolylcarbamoyl)cyclopropanecarboxylate (3e)
Yield: 170 mg (73%); white solid; mp 83–84 °C.
IR (KBr): 3282, 1715, 1587, 1553, 1144, 972, 854, 716, 598, 488
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.66–1.69 (m, 2 H), 1.81–1.85 (m,
2 H), 2.39 (s, 3 H), 3.74 (s, 3 H), 7.03 (t, J = 7.5 Hz, 1 H), 7.20 (t,
J = 6.0 Hz, 2 H), 8.04 (d, J = 6.0 Hz, 1 H), 10.77 (s, 1 H).
Anal. Calcd for C19H19NO3: C, 73.77; H, 6.19; N, 4.53. Found: C,
73.54; H, 6.14; N, 4.56.
13C NMR (100 MHz, CDCl3): d = 18.0, 20.8 (2 C), 26.5, 52.4,
121.7, 124.3, 126.6, 128.0, 130.3, 136.5, 166.6, 174.5.
Substituted Cyclopropanecarbonitriles 4; 1-Cyano-N-phenyl-
cyclopropanecarboxamide (4a); Typical Procedure
The Vilsmeier reagent was prepared by adding POCl3 (460 mg, 3.0
mmol) dropwise to anhyd DMF (5 mL) under stirring at 0 °C. The
mixture was then stirred for 10–15 min at 0 °C. To the above
Vilsmeier reagent was added 2a (204 mg, 1.0 mmol) as a solution
in DMF (5 mL). The mixture was stirred for 0.5 h (TLC monitoring,
eluent: PE–EtOAc, 7:1), poured into brine (50 mL), and extracted
with CH2Cl2 (3 × 20 mL). The combined organic phases were
washed with H2O (3 × 20 mL), dried (MgSO4), filtered, and con-
centrated in vacuo. The crude product was purified by flash chroma-
tography (silica gel, PE–Et2O, 4:1) to give 4a as a white solid; yield:
171 mg (92%).
Anal. Calcd for C13H15NO3: C, 66.94; H, 6.48; N, 6.00. Found: C,
67.16; H, 6.40; N, 6.05.
Methyl 1-[(2-Methoxyphenyl)carbamoyl]cyclopropanecarbox-
ylate (3f)
Yield: 204 mg (82%); yellow solid; mp 93–96 °C.
1H NMR (300 MHz, CDCl3): d = 1.63–1.67 (m, 2 H), 1.79–1.82 (m,
2 H), 3.75 (s, 3 H), 3.96 (s, 3 H), 6.92 (t, J = 7.5 Hz, 2 H), 7.04 (t,
J = 7.5 Hz, 1 H), 8.34 (d, J = 7.5 Hz, 1 H), 11.19 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 20.4 (2 C), 26.7, 52.2, 55.8,
109.9, 120.0, 120.7, 123.5, 127.9, 148.5, 166.3, 173.6.
Cyanocyclopropanes 4 are known compounds; their analytical data
are in good agreement with those reported in the literature.17
Anal. Calcd for C13H15NO4: C, 62.64; H, 6.07; N, 5.62. Found: C,
62.41; H, 6.14; N, 5.57.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Methyl 1-[(2-Chlorophenyl)carbamoyl]cyclopropanecarboxy-
late (3g)
Yield: 183 mg (72%); yellowish solid; mp 77–79 °C.
1H NMR (300 MHz, CDCl3): d = 1.69–1.73 (m, 2 H), 1.81–1.84 (m,
2 H), 3.77 (s, 3 H), 7.03 (t, J = 8.0 Hz, 1 H), 7.22 (t, J = 7.0 Hz, 1
H), 7.40 (d, J = 8.0 Hz, 1 H), 8.37 (d, J = 8.0 Hz, 1 H), 11.33 (s, 1
H).
13C NMR (100 MHz, CDCl3): d = 21.0 (2 C), 26.7, 52.5, 121.8,
123.3, 124.3, 127.3, 129.0, 135.2, 166.9, 173.7.
Acknowledgment
Financial support of this research by the National Natural Science
Foundation of China (20872136 and 21172211) is greatly acknow-
ledged.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 705–710

710
D. Zhang et al.
PAPER
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Synthesis 2012, 44, 705–710
© Thieme Stuttgart · New York