Facile synthesis of aryl(het)cyclopropane catalyzed by palladacycle

Article abstract of DOI:10.1016/j.tet.2011.11.024

Sphos (2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′- biphenyl) adduct of cyclopalladated ferrocenylimine (IIe) exhibited highly catalytic activity for the Suzuki cross-coupling reaction of cyclopropylboronic acid with aryl(het) halides with 1 mol % catalyst loading. This process was applied to both of aryl and heteroaryl halides (Br and Cl), and made the various arylcyclopropane and heteroarylcyclopropane to be easily synthesized. A variety of substituents on the aryl halides, such as alkyl, acetyl, benzoyl, ether, formyl, carboxylate, methoxy, nitro and cyano were tolerated.

Full text of DOI:10.1016/j.tet.2011.11.024

Tetrahedron 68 (2012) 900e905
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Facile synthesis of aryl(het)cyclopropane catalyzed by palladacycle
,
,
a
a,
Min Zhang a b, Xiuling Cui a , Xiaopei Chen , Lianhui Wang b, Jingya Li b, Yusheng Wu b, Lifen Hou a,
*
Yangjie Wu a
,
*
a Henan Key Laboratory of Chemical Biology and Organic Chemistry, Key Laboratory of Applied Chemistry of Henan Universities, Department of Chemistry,
Zhengzhou University, Daxue Road 75#, Zhengzhou 450052, PR China
b Tetranov Biopharm, Inc. Zhengzhou 450052, PR China
a r t i c l e i n f o
a b s t r a c t
Sphos (2-dicyclohexylphosphino-20,60-dimethoxy-1,10-biphenyl) adduct of cyclopalladated ferrocenyli-
mine (IIe) exhibited highly catalytic activity for the Suzuki cross-coupling reaction of cyclopropylboronic
acid with aryl(het) halides with 1 mol % catalyst loading. This process was applied to both of aryl and
heteroaryl halides (Br and Cl), and made the various arylcyclopropane and heteroarylcyclopropane to be
easily synthesized. A variety of substituents on the aryl halides, such as alkyl, acetyl, benzoyl, ether,
formyl, carboxylate, methoxy, nitro and cyano were tolerated.
Article history:
Received 30 August 2011
Received in revised form 25 October 2011
Accepted 8 November 2011
Available online 19 November 2011
Keywords:
Palladacycle
Ó 2011 Elsevier Ltd. All rights reserved.
Suzuki cross-coupling
Cyclopropylboronic acid
Arylcyclopropane
1. Introduction
which can significantly lower the catalyst loading and improve the
reactivity with a broad scope of substrates.
The cyclopropyl group is an increasingly common structural
motif in pharmaceutically active molecules due to its unique steric,
electronic, conformational properties and its microsomal metabolic
stability.1 It is also the smallest cyclic alkyl group to be frequently
included as a substituent in medicinal chemistry for the structuree
activity relationship studies.2 Arylcyclopropane have been attrac-
tive for medicinal chemists particularly because its motif allows the
exploration of lipophilic binding pockets and the optimization of
hydrophobic interactions with a biological target.3 An impressive
number of synthetic methodologies for such structures have been
developed recently.4 Among, which, palladium catalyzed Suzuki
cross-coupling reaction between aryl halides or pseudohalides and
cyclopropylboronic acid or boronate has emerged particularly as an
effective tool.5 Such methodology overcomes the limitation of
Negishi reaction, Stille reaction and Kumada reaction, such as in-
ferior tolerance of functional groups, toxicity of the inorganic waste
and being of sensitive to the moisture. Pd catalysts derived from
electron-rich, bulky di, tri, or tetra-alkylphosphanes have led to
considerable progress in this area. However, high catalyst loading,
complicate and large excessive phosphine ligand, strong base and
harsh reaction condition are often required to attain satisfactory
results. There is still a need for more efficient catalystic system,
In our laboratory, we synthesized easily series of phosphine
adducts of cyclopalladated ferrocenylimines in large scale. They
were stable under air and could serve as efficient catalysts for
several cross coupling reactions, such as Heck reaction, borylation
reaction, Suzuki reaction, amination reaction, Sonogashra re-
action.6 Herein, we would like to disclose our work on screening
a series of phosphine adducts of cyclopalladated ferrocenylimine
IIaef (shown in Scheme 1) for the Suzuki cross-coupling of cyclo-
propylboronic acid with aryl(het) halides under mild conditions to
synthesize arylcyclopropane and heteroarylcyclopropane easily.
* Corresponding authors. Fax: þ86 371 67767753 (X.C.); fax: þ86 371 67766667
Scheme 1. Synthesis of phosphine adducts of cyclopalladated ferrocenylimine.
(Y.W.); e-mail addresses: cuixl@zzu.edu.cn (X. Cui), wyj@zzu.edu.cn (Y. Wu).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.11.024

M. Zhang et al. / Tetrahedron 68 (2012) 900e905
901
Table 2
2. Results and discussion
2.1. Screening of catalysts
Screening of bases and solvents for Suzuki cross-coupling of cyclopropylboronic acid
with 3-bromoacetophenonea
O
O
Br
1 mol% IIe, Base
Solvent, 100oC
To evaluate the activity of the cyclopalladated ferrocenylimines
IIaef (Scheme 1), the coupling of cyclopropylboronic acid with 3-
bromoacetophenone was initially chosen as a model reaction in
toluene at 100 ꢀC in the presence of 1 mol % catalyst and
K3PO4$7H2O as base. As shown in Table 1, palladacycles IIa, IIb, IIc,
IId and IIf gave 75%, 90%, 45%, 40% and 72% yields, respectively
(Table 1, entries 1e5), and compound IIe gave 94% yield (Table 1,
entry 6). To compare the catalytic activity, the palladium catalysts
derived from Pd(OAc)2 and Pd2(dba)3$CHCl3 with phosphine ligand
Le was used as a catalyst instead of IIe under the same reaction
conditions. Pd(OAc)2$Le and Pd2(dba)3$CHCl3$Le gave 60% and 62%
yields, respectively (Table 1, entries 7 and 8). Therefore, palladacycle
IIe was chosen as a catalyst for the following study. The yield was
decreased when the catalyst loading was reduced from 1 mol % to
0.5 mol % (Table 1, entry 6 vs 9), while the reaction was not signif-
icantly improved when temperature increased from 100 ꢀC to 110 ꢀC
(Table 1, entry 6 vs 10). No desired product was obtained when
reaction temperature was 50 ꢀC and 25 ꢀC even after the reaction
time was prolonged from 3 h to 24 h (Table 1, entries 11 and 12).
B(OH)2
Entry
Base
Solvent
Temp (ꢀC)
Yieldb (%)
1
2
3
4
5
6
7
8
9
Na2CO3
K2CO3
CsCO3
NaOH
Toluene/water
Toluene/water
Toluene/water
Toluene/water
Toluene/water
Toluene/water
Toluene/water
DMF/water
100
100
100
100
100
100
100
140
100
43
70
86
81
84
76
94
57
44
KOH
tBuONa
K3PO4$7H2O
K3PO4$7H2O
K3PO4$7H2O
Dioxane/water
a
Reaction conditions: 0.25 mmol 3-bromoacetophenone, 1 mol % IIe, 2.0 equiv
cyclopropylboronic acid, 3 equiv base, solvent 2 mL, 3 h.
b
Isolated yield.
K3PO4$7H2O, 1 mol % complex IIe, toluene/H2O (20/1) as solvent,
100 ꢀC, under nitrogen), the scope of the substrates for the Suzuki
cross-coupling reaction of cyclopropylboronic acid was investigated.
As shown in Table 3, the catalyst IIe exhibited highly efficient in the
Suzuki cross-coupling of cyclopropylboronic acid with aryl bromides
substituted by electron-withdrawing groups, such as acetyl, benzoyl,
formyl, carboxylate, nitro and nitrile, affording the desired product in
good to excellent yields (Table 3, entries 1e9). 1-Bromonaphthalene
and electron-rich aryl bromide, such as 1-bromo-3-
methoxybenzene, gave 57% and 46% yields, respectively (Table 3,
entries 10 and 11). The cross-coupling of the cyclopropylboronic acid
with heteroaromatic bromides including pyridines and thiophene
was also tested. The desired products were obtained up to 86% yield
(Table 3, entries 12e17), among which, 5-bromo-N,N-dimethyl-2-
Table 1
Screening of catalysts for the Suzuki cross-coupling of cyclopropylboronic acid with
3-bromoacetophenonea
O
O
Br
Catalyst, K3PO4.7H2O
Toluene, T
B(OH)2
Entry
Catalyst
Ligand
Temp (ꢀC)
Time (h)
Yieldc (%)
1
2
3
4
5
6
IIa
IIb
IIc
IId
IIf
IIe
d
d
d
d
d
d
Le
Le
d
d
d
d
100
100
100
100
100
100
100
100
100
110
25
3
3
3
3
3
3
3
3
3
75
90
45
40
72
94
75
60
62d
93
d
pyridinamine,
5-bromo-2-pyridinamine
and
5-bromo-2-
phenylpyridine were smoothly transformed to the desired products
in 80%, 83% and 86% yields, respectively (Table 3, entries 14e16).
Methylboronic and allyl boronate also could be suitable coupling
partner with aryl bromide to provide desired products in 85 and 76%
yields, respectively (entry 18 and 19).
7b
8b
9
10
11
12
Pd(OAc)2
Pd2(dba)3$CHCl3
IIe
IIe
IIe
IIe
Aryl chloride is one kind of interesting substrates due to being
cheaper and commercially available. However, to the best of our
knowledge, there are only two reports of the cross-coupling of
cyclopropylboronic acid with aryl(het) chlorides,5c,7and complicate
phosphine was required. Thus, we turned our attention to the
aryl(het) chlorides 4 for the palladacycle-catalyzed Suzuki reaction
with cyclopropylboronic acid (shown in Table 4). Under the
optimized reaction conditions, aryl chlorides with electron-
withdrawing group, such as acetyl, formyl, nitro and cyano, could
converted smoothly into the desired products (Table 4, entries
1e6). 2-Chloronitrobenzene only gave 45% yield (Table 4, entry 4 vs
5). Perhaps large bulk in aryl chloride affected the yields. Two Cl
atoms in 2,4-dichlorobenzaldehyde could be replaced by cyclo-
propyl at the same time and 2,4-dicyclopropylbenzaldehyde was
obtained in 68% yield (Table 4, entry 6). 2-Chloro-6-phenylpyrazine
was also a suitable substrate and gave 87% yield (Table 4, entry 7).
3
24
24
50
d
a
Reaction conditions: 0.25 mmol 3-bromoacetophenone, 1 mol % [Pd], 2.0 equiv
cyclopropylboronic acid, 3 equiv K3PO4$7H2O, toluene/H2O¼2 mL/100
mL, 3 h,
100 ꢀC.
b
[Pd]/Le¼1:1.
c
Isolated yield.
d
[Pd] (0.5 mol %).
2.2. Screening of reaction parameters
The coupling of cyclopropylboronic acid with 3-bromoace-
tophenone was also chosen as a model reaction to screen differ-
ent reaction parameters including bases, solvents by fixing 1 mol %
loading of catalyst IIe. It was found that both of base and solvent
played critical role on the catalytic efficiency. Na2CO3 only gave 43%
yield (Table 2, entry 1). 70%, 86%, 81%, 84% and 76% yields were
t
obtained when K2CO3, CsCO3, NaH, KOH and BuONa was used as
a base, respectively (Table 2, entries 2e6). K3PO4$7H2O was found
to be the best base and provided the isolated yield of 94% (Table 2,
entry 7). Mixture of toluene with water (20/1, v/v) was proved to be
superior to DMF and dioxane (Table 2, entries 8 and 9).
3. Conclusion
In summary, we have developed SPhos adduct of cyclo-
palladated ferrocenylimine (IIe) as an efficient catalyst for Suzuki
cross-coupling reaction of cyclopropylboronic acid with a wide
range of aryl, heteroaryl halides to synthesize the arylcyclopropane
and heteroarylcyclopropane. This reaction system could tolerate
various functional groups, and was applied to both of bromides and
activated chlorides.
2.3. Scope of substrates
Under the optimized reaction conditions (1 equiv of aryl
(het) bromides, 2.0 equiv cyclopropylboronic acid, 3.0 equiv

902
M. Zhang et al. / Tetrahedron 68 (2012) 900e905
Table 3
Palladium-catalyzed coupling reactions of cyclopropylboronic acid with aryl bromidesa
IIe, K3PO4·7H2O
Br
B(OH)2
toluene/H2O, 100 oC, Time
R
R
3
1
2
Entry
1
Aryl bromide
Product
Time (h)
Yieldb (%)
H3COC
H3COC
3
8
94
Br
1a
3a
H3COC
Br
H3COC
2
3
95
90
1b
3b
Br
3
O
1c
O
3c
H3COOC
H3COOC
Br
4
5
8
6
92
91
3d
1d
NC
Br
NC
1e
CN
3e
CN
Br
6
7
8
6
8
8
73
96
65
3f
1f
O2N
Br
O2N
3g
1g
NO2
NO2
Br
1h
3h
Br
9
10
88
F
F
NO2
1i
NO2
3i
10
11
5
57
46
57
Br
1j
3j
H3CO
H3CO
4.5
Br
1k
3k
Br
12
8
N
N
1l
3l

M. Zhang et al. / Tetrahedron 68 (2012) 900e905
903
Table 3 (continued )
Entry
Aryl bromide
Product
Time (h)
Yieldb (%)
Br
13
14
15
16
8
52
80
83
86
N
N
1m
3m
Br
Br
6
6
N
N
N
N
N
1n
1o
3n
H2N
H2N
N
3o
Br
4.5
N
N
1p
3p
NC
NC
17
18
10
62
85
Br
S
3q
S
1q
H3COC
Br
H3COC
8
8
1r
3r
3s
H3COC
Br
H3COC
19
76
1s
a
Conditions: (hetero)aryl halides: 0.25 mmol, 1 mol % IIe, cyclopropylboronic acid: 0.5 mmol, K3PO4$7H2O: 0.75 mmol, toluene/H2O¼2 mL/100
m
L, 100 ꢀC, nitrogen.
b
Isolated yield.
4. Experimental section
4.3. Characterization
4.1. General conditions
4.3.1. 1-Acetyl-3-cyclopropylbenzene(3a)9. 1H
NMR
(CDCl3,
400 MHz, ppm):
d
7.71 (d, J¼7.45 Hz, 1H), 7.66 (s, 1H), 7.33 (t,
1H NMR and 13C NMR spectra were recorded on a Bruker DPX-
400 spectrometer with CDCl3 as the solvent and TMS as an in-
ternal standard. High-resolution mass spectra were measured on
a Waters Q-Tof MicroÔ spectrometer. Aryl(het) halides and ligands
were used as received. Palladacycle IIaeIIe6c and cyclo-
propylboronic acid8 were prepared according to literature.
J¼7.56 Hz, 1H), 7.25 (d, J¼7.80 Hz, 1H), 2.58 (s, 3H), 1.94 (m, 1H),
0.99 (m, 2H), 0.71 (m, 2H). GCeMS, (EI): [Mþ]: 160.0.
4.3.2. 1-Acetyl-4-cyclopropylbenzene (3b)10
400 MHz, ppm):
.
1H NMR (CDCl3,
7.84 (d, J¼8.06 Hz, 2H), 7.12 (d, J¼8.06 Hz, 2H),
d
2.56 (s, 3H), 1.94 (m, 1H), 1.06 (m, 2H), 0.78 (m, 2H). GCeMS, (EI):
[Mþ]: 160.4.
4.2. General experimental procedure
4.3.3. 1-Benzoyl-4-cyclopyropylbenzene (3c)11. 1H NMR (CDCl3,
400 MHz, ppm):
d
7.77 (d, J¼7.38 Hz, 2H), 7.72 (d, J¼8.2 Hz, 2H),
Potassium phosphate (0.75 mmol) and IIe (1 mol %) was added
to the solution of aryl halides (0.25 mmol) and cyclopropylboronic
7.57 (t, J¼7.38 Hz, 1H), 7.47 (d, J¼7.57 Hz, 2H), 7.14 (d, J¼8.2 Hz,
2H), 1.97 (m, 1H), 1.08 (m, 2H), 0.80 (m, 2H). GCeMS, (EI): [Mþ]:
222.6.
acid (0.5 mmol) in toluene (2.0 mL) and water (100
mL). The
mixture was heated to 100 ꢀC for a proper time under nitrogen
atmosphere and cooled to room temperature. Water (10 mL) was
added and the mixture was extracted with EtOAc (3ꢁ15 mL),
evaporated and purified by chromatography on silica gel.
4.3.4. 4-Cyclopropylbenzoic acid methyl ester (3d)12
(CDCl3, 400 MHz, ppm):
.
1H NMR
d
7.91 (d, J¼8.2 Hz, 2H), 7.09 (d, J¼8.2 Hz,

904
M. Zhang et al. / Tetrahedron 68 (2012) 900e905
Table 4
Palladium-catalyzed coupling reactions of cyclopropylboronic acid with aryl chloridesa
IIe, K3PO4·7H2O
Cl
B(OH)2
toluene/H2O, 100 oC, Time
R
R
3
2
4
Entry
1
Aryl chloride
Product
Time (h)
Yieldb (%)
H3COC
H3COC
8
72
Cl
4a
3a
Cl
H3COC
NC
H3COC
2
3
4
4
4
8
81
63
78
4b
3b
Cl
Cl
NC
4c
3e
O2N
O2N
4d
3g
NO2
NO2
Cl
5
6
8
45
68
3h
4e
Cl
5.5
Cl
CHO
4f
CHO
3t
N
N
7
4
87
N
Cl
N
4g
3u
a
Conditions: aryl chloride: 0.25 mmol, 1 mol % IIe, cyclopropylboronic acid: 0.5 mmol, K3PO4$7H2O: 0.75 mmol, toluene/H2O¼2 mL/100
m
L, 100 ꢀC, nitrogen.
b
Isolated yield.
2H), 3.89 (s, 3H), 1.93 (m, 1H), 1.05 (m, 2H), 0.76 (m, 2H). GCeMS,
7.15 (d, J¼7.84 Hz, 1H), 2.39 (m, 1H), 1.05 (m, 2H), 0.71 (m, 2H).
GCeMS, (EI): [Mþ]: 163.0.
(EI): [Mþ]: 176.6.
4.3.5. 4-Cyclopropylbenzonitrile (3e)13 1H NMR (CDCl3, 400 MHz,
.
4.3.9. 4-Cyclopropyl-1-fluoro-2-nitrobenzene (3i)17
400 MHz, ppm): 7.71 (s, 1H), 7.32 (m, 1H), 7.15 (t, 1H), 1.94 (m, 1H),
1.05 (m, 2H), 0.71 (m, 2H). GCeMS, (EI): [Mþ]: 181.0.
.
1H NMR (CDCl3,
ppm):
d
7.52 (d, J¼7.72 Hz, 2H), 7.11 (d, J¼7.72 Hz, 2H), 1.92 (m, 1H),
d
1.08 (m, 2H), 0.76 (m, 2H). GCeMS, (EI): [Mþ]: 143.0.
4.3.6. 2-Cyclopropylbenzonitrile (3f)14 1H NMR (CDCl3, 400 MHz,
.
4.3.10. 1-Cyclopropylnaphthalene (3j)18
ppm):
.
1H NMR (CDCl3, 400 MHz,
8.45 (d, J¼8.44 Hz, 1H), 7.89 (d, J¼8.30 Hz, 1H), 7.74 (d,
ppm):
d
7.58 (d, J¼8.46 Hz, 1H), 7.46 (m, 1H), 7.22 (m, 1H), 6.94 (d,
d
J¼7.98 Hz,1H),2.28(m,1H),1.14(m, 2H),0.79(m, 2H).13CNMR(CDCl3,
J¼8.10 Hz,1H), 7.58 (m,1H), 7.54 (m,1H), 7.42 (m,1H), 7.31 (d, J¼7.01 Hz,
1H), 2.38 (m, 1H), 1.10 (m, 2H), 0.81 (m, 2H). GCeMS, (EI): [Mþ]: 168.0.
100 MHz):
d 147.7, 132.7, 132.5, 125.7, 125.4, 118.3, 112.9, 14.0, 9.5.
HRMS (ESI) calcd for C10H9N ([MþH]þ): 143.0735, found: 144.0812.
4.3.11. 1-Cyclopropyl-3-methoxybenzene (3k)19
.
1H NMR (CDCl3,
4.3.7. 1-Cyclopropyl-4-nitrobenzene
400 MHz, ppm):
8.10 (d, J¼8.72 Hz, 2H), 7.16 (d, J¼8.72 Hz, 2H),
2.01 (m, 1H), 1.04 (m, 2H), 0.82 (m, 2H). GCeMS, (EI): [Mþ]: 163.1.
(3g)15 1H NMR (CDCl3,
.
400 MHz, ppm): 7.04 (s, 1H), 7.02 (s, 1H), 6.83 (s, 1H), 6.81 (s, 1H),
d
d
3.79 (s, 1H), 1.86 (m, 1H), 0.91 (m, 2H), 0.63 (m, 2H). GCeMS, (EI):
[Mþ]: 148.0.
.
4.3.12. 3-Cyclopropylpyridine (3l)20 1H NMR (CDCl3, 400 MHz,
4.3.8. 1-Cyclopropyl-2-nitrobenzene (3h)16 1H NMR (CDCl3,
.
ppm):
d
8.42 (s, 1H), 8.39 (d, J¼3.68 Hz, 1H), 7.28 (m, 1H), 7.16 (m,
400 MHz, ppm): 7.80 (d, J¼7.52 Hz, 1H), 7.47 (m, 1H), 7.28 (m, 1H),
d

M. Zhang et al. / Tetrahedron 68 (2012) 900e905
905
1H), 1.88 (m, 1H), 1.04 (m, 2H), 0.72 (m, 2H). GCeMS, (EI): [Mþ]:
119.0.
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d
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2784e2793; (f) Ren, G. R.; Cui, X. L.; Wu, Y. J. Eur. J. Org. Chem. 2010,
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8. Wallace, D. J.; Chen, C. Y. Tetrahedron Lett. 2002, 43, 6987e6990.
9. Mochalov, S. S.; Pogodin, S. S.; Gazzaeva, R. A.; Shabarov, Y. S.; Zefirov, N. S.
Khim. Fiz. 2001, 42, 381e386.
10. Gagnon, A.; Duplessis, M.; Alsabeh, P.; Barabe, F. J. Org. Chem. 2008, 73,
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11. Molander, G. A.; Gormisky, P. E. J. Org. Chem. 2008, 73, 7481e7485.
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13. Shu, C.; Sidhu, K.; Zhang, L.; Wang, X. L.; Krishnamurthy, D.; Senanayake, C. H. J.
4.3.14. 5-Cyclopropyl-N,N-dimethylpyridin-2-amine (3n)22
(CDCl3, 400 MHz, ppm):
8.02 (s, 1H), 7.17 (d, J¼8.59 Hz, 1H), 6.45
(d, J¼8.72 Hz, 1H), 3.05 (s, 6H), 1.78 (m, 1H), 0.86 (m, 2H), 0.57 (m,
.
1H NMR
d
2H). 13C NMR (CDCl3, 100 MHz):
d 158.0, 146.0, 135.1, 126.1, 105.6,
38.3, 29.6, 12.0, 7.3. HRMS (ESI) calcd for C10H14N2 ([MþH]þ):
162.1157, found: 163.1235.
4.3.15. 5-Cyclopropylpyridin-2-amine (3o)23
400 MHz, ppm):
7.60 (s, 1H), 7.14 (d, J¼7.94 Hz, 1H), 6.59 (d,
J¼8.72 Hz, 1H), 5.56 (s, 2H), 1.66 (m, 1H), 0.81 (m, 2H), 0.47 (m, 2H).
.
1H NMR (CDCl3,
d
13C NMR (CDCl3,100 MHz):
d 155.1,140.1,138.3,128.5,110.6,11.9, 7.4.
HRMS (ESI) calcd for C8H10N2 ([MþH]þ): 134.0844, found: 135.0921.
4.3.16. 5-Cyclopropyl-2-phenylpyridine (3p)24
400 MHz, ppm):
(dd, J¼8.2 Hz, 1H), 7.37e7.34 (dd, J¼11.3 Hz, 2H), 7.29 (dd,
J¼6.87 Hz, 1H), 7.23 (dd, J¼8.24 Hz, 1H), 1.82 (m, 1H), 0.94 (m, 2H),
0.65 (m, 2H). GCeMS, (EI): [Mþ]: 195.1.
.
1H NMR (CDCl3,
8.41 (s, 1H), 7.87e7.85 (dd, J¼7.85 Hz, 2H), 7.50
d
4.3.17. 5-Cyclopropylthiophene-3-carbonitrile
(CDCl3, 400 MHz, ppm): 7.65 (s, 1H), 6.92 (s, 1H), 2.07 (m, 1H), 1.07
(m, 2H), 0.76 (m, 2H). GCeMS, (EI): [Mþ]: 149.0.
(3q)25
.
1H
NMR
d
Org. Chem. 2010, 75, 6677e6680.
14. Coleridge, B. M.; Bello, C. S.; Leitner, A. Tetrahedron Lett. 2009, 50,
4475e4477.
15. Bondarenko, O. B.; Gavrilova, A. Y.; Kazantseva, M. A.; Tikhanushkina, V. N.;
Nifant’ev, E. E.; Saginova, L. G.; Zyk, N. V. Russ. J. Org. Chem. 2007, 43,
564e570.
4.3.18. 1-Acetyl-4-methylbenzene (3r)26 1H NMR (CDCl3, 400 MHz,
.
ppm): 7.85 (d, J¼8.00 Hz, 2H), 7.25 (d, J¼8.00 Hz, 2H), 2.57 (s, 3H), 2.41
d
(s, 3H).
16. Wang, Y. H.; Tanko, J. M. J. Chem. Soc., Perkin Trans.
2705e2711.
2 1998,
4.3.19. 1-Acetyl-4-allylbenzene (3s)27. H NMR (CDCl3, 400 MHz,
ppm):
17. Mochalov, S. S.; Pogodin, S. S.; Gazzaeva, R. A.; Shabarov, Y. S.; Zefirov, N. S.
Vestn. Mosk. Univ., Ser. 2: Khim. 2001, 42, 381e386.
18. Yutaka, N.; Hana, T.; Tsuyoshi, T. Tetrahedron Lett. 2007, 48,
6405e6407.
d
7.81 (d, J¼8.00 Hz, 2H), 7.60 (J¼8.00 Hz, 2H), 5.96 (m, 1H),
5.10 (d, 2H), 3.44 (d, 2H), 2.58 (s, 3H).
19. Zyk, N. V.; Gavrilova, A. Y.; Bondarenko, O. B.; Mukhina, O. A.; Tikhanushkina,
V. N. Russ. J. Org. Chem. 2011, 47, 340e354.
4.3.20. 2,4-Dicyclopropylbenzaldehyde (3t)28 1H NMR (CDCl3,
.
20. Suzuki, K. H.; Takada, M.; Iihama, T.; Sano, S.; Shimoda, S. PCT Int. Appl. WO
9711943, 1997.
21. Jian, C.; Yang, X. F.; Hua, X. L.; Deng, Y.; Lai, G. Q. Org. Lett. 2011, 13,
478e481.
22. Czuba, W.; Wodzinska, J. Pol. J. Chem. 1994, 68, 1343e1346.
23. Gardan, S.; Mayer, S.; Schann, S. Eur. Pat. Appl. EP 2210891, 2010.
24. Michael, D.; Frank, S.; Frank, F.; Ehmke, P.; Regine, H. I.; Armin, D. M. Chem. Ber.
1993, 126, 2535e2541.
25. Suzuki, T.; Hasegawa, K.; Furukawa, S.; Nishio, K. Jpn. Kokai Tokkyo Koho, JP
62226567, 1987.
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3641e3650.
27. Louaisil, N.; Pham, P. D.; Boeda, F.; Faye, D.; Castanet, A. S.; Legoupy, S. Eur. J. Org.
Chem. 2011, 1, 143e149.
400 MHz, ppm):
d
10.51 (s,1H), 7.7 (d, J¼8.0 Hz,1H), 6.92 (d, J¼7.96 Hz,
1H), 6.81 (s, 1H), 2.60 (m, 1H), 1.88 (m, 1H), 1.04 (m, 4H), 0.76 (m, 4H).
13C NMR (CDCl3, 100 MHz):
d 191.9, 151.2, 145.9, 131.3, 126.5, 123.7,
122.5,15.8,10.9, 8.4. HRMS (Positive ESI) [MþH]þ: 187.1124 (186.1045).
4.3.21. 2-Cyclopropyl-6-phenylpyrazine (3u)29
400 MHz, ppm):
.
1H NMR (CDCl3,
8.66 (s, 1H), 8.31 (s, 1H), 7.91 (d, J¼1.64 Hz, 1H),
d
7.90 (d, J¼3.58 Hz, 1H), 7.40e7.34 (m, 3H), 2.01 (m, 1H), 1.09 (m,
2H), 0.98 (m, 2H). GCeMS, (EI): [Mþ]: 196.1.
Acknowledgements
28. Tobisu, M.; Nakai, H.; Chatani, N. J. Org. Chem. 2009, 74, 5471e5475.
29. Bilodeau, T. E. J. F.; Beauchemin, A. M. Angew. Chem., Int. Ed. 2009, 48,
8325e8327.
We are grateful to the NSF of China (20972139, 21102133) and
the NSF of Henan (082300423201) for the financial support of this
research.