Synergistic NaBH4Reduction/Cyclization of 2-Aroylcyclopropane-1-carboxylates: Synthesis of 3-Oxabicyclo[3.1.0]hexane Derivatives

Article abstract of DOI:10.1002/ejoc.201601341

An NaBH₄reduction/cyclization reaction of readily available 2-aroyl-1-cyano-3-arylcyclopropane-1-carboxylate compounds was investigated. The process results in the stereoselective synthesis of 3-oxabicyclo[3.1.0]hexane derivatives in high yield

Full text of DOI:10.1002/ejoc.201601341

A Journal of
Accepted Article
Title: Synergistic NaBH4-reduction/cyclization of 2-aroyl-
cyclopropane-1-carboxylates: novel synthesis of 3-
oxabicyclo[3.1.0]hexane derivatives
Authors: Jiaming Liu, Lizhong Wang, Xushun Qing, Feixiang Zhang,
Ting Wang, and Cunde Wang
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601341
Link to VoR: http://dx.doi.org/10.1002/ejoc.201601341
Supported by

10.1002/ejoc.201601341
European Journal of Organic Chemistry
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Synergistic NaBH4-reduction/cyclization of 2-aroyl-cyclopropane-
1-carboxylates: novel synthesis of 3-oxabicyclo[3.1.0]hexane
derivatives
Jiaming Liu,[a] Lizhong Wang,[a,b] Xushun Qing,[a] Feixiang Zhang,[a] Ting Wang,[a] and Cunde Wang*[a]
Dedication ((optional))
Abstract: The NaBH4-reduction/cyclization of readily available 2-
aroyl-1-cyano-3-arylcyclopropane-1-carboxylate compounds was
investigated, which provides access to the stereoselective synthesis
of 3-oxabicyclo[3.1.0]hexane derivatives in high yields.
Leukotriene production inhibitors3
Hepatitis C virus inhibitors6
Introduction
Figure 1. Examples of 3-oxabicyclo[3.1.0]hexane-containing bioactive
molecules.
3-Oxabicyclo[3.1.0]hexane derivatives have attracted the
attention of medicinal chemists for decades owing to their
unique chemical properties. In particular, several 3-
oxabicyclo[3.1.0]hexanes as core structures are found in many
pharmacological compounds because of their interesting
biological activities, they have been used as ERK2 kinase
inhibitor,1 selective PDE10A inhibitors,2 leukotriene production
inhibitors3 for treatment of cardiovascular, inflammatory and
The great pharmaceutical potential of this scaffold prompted us
to search for new and efficient methods that would provide
diversified structures in a minimum number of steps. Due to the
biological importance, a lot of methods for the construction of 3-
oxabicyclo[3.1.0]hexanes
have
been
developed.2
3-
Oxabicyclo[3.1.0]hexanes can be synthesized by various
strategies, such as the Ireland−Claisen rearrangement
procedure,7,8 intramolecular cyclization of aryldiazoacetates,9 Ru-
catalyzed annulations,10-12 Pd-promoted [2 + 1] cycloaddition
between dihydrofuran derivatives with alkynes,13 or Au-catalyzed
cyclopropanation of substituted (allyloxy)sulfonium ylides.14
Another interesting synthetic pathway, reported by Pathak and
co-author, employs the formation of single diastereomeric
substituted 3-oxabicyclo[3.1.0]hexanes from the corresponding
vinyl selenone with nitromethane, malononitrile, and dimethyl
malonate in the presence of tBuOK in THF at room
temperature.15 Despite the advances, the development of novel
and efficient methods for the preparation of 3-
oxabicyclo[3.1.0]hexanes with various structural features and
substitution patterns, especially those containing cyano group,
remains one of the hottest topics in synthetic chemistry. Herein,
we report, to the best of our knowledge, a new and convenient
synthesis of the 3-oxabicyclo[3.1.0]hexane derivatives by the
synergistic NaBH4-reduction/cyclization of readily available 2-
aroyl-3-aryl-1-cyano cyclopropanecarboxylates.
other diseases, antitumor agents4,5 and hepatitis
inhibitors6 as illustrated in Figure 1.
C virus
ERK2 kinase inhibitor1
Selective PDE10A inhibitors2
Antitumor agents4, 5
Results and Discussion
Cyclopropane-1-carboxylate 1a was readily prepared from ethyl
(E)-3-(4-chloro-phenyl)-2-cyanoacrylate and 1-(2-(4-bromo-
phenyl)-2-oxoethyl)pyridin-1-ium iodide according to the
reported method16 (Scheme 1). The structure of 1a was shown
in Scheme 1.17 X-ray crystallographic analysis determined that
product 1a possess the cis relationship of the benzoyl and
contiguous substituent ester group. 1-cyanopropane-1-
carboxylates 1b-s were prepared via the same method from the
corresponding 1-(2-oxo-2-arylethyl) pyridin-1-ium and 2-cyano-
[a]
[b]
Liu, Jiaming; Wang, Lizhong; Qing, Xushun; Zhang, Feixiang;
Wang, Ting; Wang, Cunde
School of Chemistry and Chemical Engineering
Yangzhou University
180 Siwangting Street, Yangzhou 225002, P. R. China
E-mail: wangcd@yzu.edu.cn.
Wang, Lizhong: Taizhou Polytechnic College, Taizhou 225300, P.R.
China
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201601341
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3-arylacrylates.
reaction proved that a cyano group plays an important role
in the synergistic reduction of cyclopropane-1-carboxylate 1a.
On the basis of stereoscopic evidence the comprehensible
mechanism via the neighbouring-group participation and nitrile-
borane complexes19 was shown in Scheme 4 for an explanation
of the synergistic reduction of carbonyl and ester group through
the intermediate δ-butyrolactone to form a glycol.
Scheme 1. Preparation of the starting material 1a
Scheme 4. Tentative reaction mechanism of the synergistic reduction of
carbonyl and ester
Our investigation began with the reaction of ethyl 2-(4-
bromobenzoyl)-1-cyano-3-(4-chlorophenyl)cycloprop- ane-1-
carboxylate (1a) with NaBH4 at room temperature for 3 h
(Scheme 2). As expected, the reaction proceeded smoothly to
afford the desired alcoholic product 2ao in a conversion of 100%
based on TLC. After simple workup, the crude product was used
directly to the following cyclization without further purification.
Partial sample was purified by flash chromatography for the
confirmation of the structure. The molecular structure of 2ao was
elucidated from its spectroscopic analyses as described herein
for 2ao. The mass spectrum of 2ao displayed the molecular ion
peak at m/z = 391.95 (M+1), which is in good agreement with
Our further investigations of the cyclization reaction focused on
optimizing the reaction conditions of the intermediate glycol in
the presence of different acid anhydride, bases and solvents.
Without any base the cyclization reaction the intermediate glycol
2ao in the presence of Tf2O using DCM as a solvent did not
occur (Table 1, entry 1). To our delight, the reaction proceeded
to give the desired product 2a in 15 % yield when it was
conducted in DCM with an equivalent NaOH (Table 1, entry 2).
Thus, we screened a series of bases, including K2CO3, DBU,
DABCO, Et3N and DMAP (Table 1, entries 3−7), and the base
DMAP was shown to be the most effective for this reaction.
1
the proposed structure. The H NMR spectrum of 2ao exhibited
three signals at 5.77 ppm, 5.44 ppm, 4.59 ppm for ArCHOH and
CH2OH, respectively. Characteristic 1H chemical shift of
ArCHOH and CH2OH unequivocally indicated the the carbonyl
and ester group all were reduced. (see: Supporting Information).
Table 1. Optimization of reaction conditions in the synthesis of 2ª
Entry
Base (equiv)
Anhydride
(equiv)
Solvent
t (h)
Yield
(%)a
0
1
2
3
4
5
6
7
8
-
Tf2O(2.0)
Tf2O(2.0)
Tf2O(2.0)
Tf2O(2.0)
Tf2O(2.0)
Tf2O(2.0)
Tf2O(2.0)
Tf2O(2.0)
Tf2O(2.0)
Tf2O(2.0)
Tf2O(2.0)
Tf2O(1.0)
Tf2O(2.0)
Tf2O(2.0)
Ac2O(2.0)
Tf2O(2.0)
DCM
DCM
DCM
DCM
DCM
DCM
DCM
C6H5CH3
1,4-dioxane
DMF
EtOAc
DCM
DCM
DCM
DCM
DCM
8
5
5
5
6
6
5
5
7
5
5
8
5
5
5
9
NaOH(1.0)
K2CO3(1.0)
DBU(1.0)
DABCO(1.0)
Et3N(1.0)
DMAP(1.0)
DMAP(1.0)
DMAP(1.0)
DMAP(1.0)
DMAP(1.0)
DMAP(1.0)
DMAP(0.75)
DMAP(1.5)
DMAP(1.0)
DMAP(1.0)
15
12
42
25
13
95
10
32
0
Scheme 2. The synergistic reduction of cyclopropane-1-carboxylate 1a
9
10
11
12
13
14
15
16b
0
82
89
93
0
95
a Isolated yields. The reaction was carried out at room temperature unless
otherwise mention. b at 0oC
Scheme 3. The reduction of cyclopropane-1,1-dicarboxylate 3
Somewhat surprisingly, cyclopropane-1,1-dicarboxylate 318 was
reduced using the same reduction system to give the product 4
which only carbonyl of ketone was reduced (Scheme 3). The
Based on this encouraging result, we then studied the effect of
solvent on reaction, the reaction was carried out with different
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10.1002/ejoc.201601341
European Journal of Organic Chemistry
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solvents such as toluene, 1,4-dioxane, DMF and EtOAc, the
solvents toluene and 1,4-dioxane gave the desired product 2a in
low yields (Table 1, entries 8, 9), however, DMF and EtOAc as
solvents did not work (Table 1, entries 10, 11) and the
intermediate glycol 2ao was yielded, screening of the solvents
revealed that DCM was a good candidate. Further study on the
effect of the amount of Tf2O led to the observation that the
reaction using 1.0 equiv Tf2O afforded the yield of product 2a in
82 % (entry 12). When the reaction was carried out using 0.75
equiv DMAP (Table 1, entry 13) or 1.5 equiv DMAP (Table 1,
entry 14), the yield of product 2a was slightly decreased. The
replacement of Tf2O with Ac2O did not give the desired product
2a (Table 1, entry 15), the intermediate glycol 2ao was
recovered. Additionally, the reaction of the cyclopropane-1-
carboxylate 1a in the presence of Ac2O and DMAP in DCM
under refluxing gave the diester of glycol 2ao (see: Supporting
Information). Reducing the temperature of the title reaction from
oxabicyclo[3.1.0]hexane-1-carbonitrile bicycle protons. Products
3-oxabicyclo[3.1.0]hexane-1-carbonitriles 2b and 2p were
further characterized by single X-ray crystallography (Figure 3).16
2b
2p
Figure 3. Molecular structure of 3-oxabicyclo[3.1.0]hexane-1-carbonitriles 2b
and 2p
Table 2 Substrate scope of 1-cyanocyclopropane carboxylates.a
o
room temperature to 0 C afforded the same best result, as it
should be needed the longer reaction time (Table 1, entry 16).
Thus, we defined that the reaction of the cyclopropane-1-
carboxylate 1a was carried out with 2.0 equiv NaBH4 firstly in
THF at room temperature, then with 2.0 equiv Tf2O and 1.0
equiv DMAP in DCM at room temperature for 5 h as the
standard conditions (Table 1, entry 7). The structure of 2a was
shown in Figure 2.17 X-ray crystallographic analysis determined
that product 2a possess cis two aryls and cyano at C(4), C(6)
and C(1) of 3-oxabicyclo[3.1.0]hexane. On the basis of
spectroscopic evidence the structure of compound 2a was
identified as cis-4-(4-bromophenyl)-6-(4-chlorophenyl)-3-oxabi-
cyclo[3.1.0]hexane-1-carbonitrile (2a).
Entry
1
2
3
4
5
6
7
8
R1
p-Cl
p-Br
p-Br
R2
p-Br
p-Cl
p-CH3O
p-Br
p- Br
H
Product
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
Yield (%)b
95
96
94
92
92
94
96
96
94
96
95
95
96
94
92
92
o-Br
m-Cl
m-Cl
m-CH3
m-CH3
o-Br
m-Cl
p-Cl
p-Cl
p-PhO
m-Cl
m-Br
p-O2N
p-(3-FC6H4O)
p-Cl
H
p-CH3O
p-CH3O
p-CH3O
p-CH3O
p-Cl
p-Cl
p-Cl
H
9
10
11
12
13
14
15
16
17
18
19
p-CH3O
H
H
95
94
95
o-Cl
p-Br
2s
a Reaction conditions: (1)1-cyanocyclopropane-1-carboxylates 1a-s (2 mmol),
NaBH4 (0.3026 g, 4mmol) and THF (15 mL), room temperature, 3-5 h; (2) 4-
dimethylaminopyridine (0.2443 g, 2 mmol), trifluoromethanesulfonic anhydride
(0.33 ml, 2 mmol), dried CH2Cl2 (10 mL), room temperature, 5 h.
Figure 2. Molecular structure of 3-oxabicyclo[3.1.0]hexane-1-carbonitrile 2a
b Isolated yields.
The scope of this two-step transformation was then investigated
under the standard conditions using different cyclopropane-1-
carboxylates. The results are summarized in Table 2. A variety
of cyclopropane-1-carboxylates 1a–s underwent the formal
cyclization with NaBH4 and Tf2O-DMAP system smoothly to
deliver the targeted products. Variation of R1 and R2 substituents
showed that the benzene rings with an electron-donating group
(-OMe or -OAr) or an electron-withdrawing group (-Br, -Cl, -NO2)
as well as o-halo were well tolerated, producing the desired 3-
oxabicyclo[3.1.0]hexane-1-carbonitriles in 92–96% yield.
On the basis of the above experimental results together with
related reports, the reaction mechanism of the cyclization of the
glycol shown in Scheme
tetrahydrofuran formations,
5
was proposed. In terms of
the selective
trifluoromethylsulfonation of the glycol with Tf2O in the presence
of DMAP gave firstly the intermediate δ-hydroxylbutyl
trifluoromethylsulfonate [A],20 then intramolecularly nucleophilic
substitution afforded tetrahydrofuran.
All corresponding substituted 3-oxabicyclo[3.1.0]hexane-1-
carbonitriles were analyzed by their 1H NMR, 13C NMR and
HRMS.
Characteristic
1H
chemical
shifts
of
3-
oxabicyclo[3.1.0]hexane-1-carbonitriles at δ ca 5.08(1H), 4.16
(1H), 4.06 (1H), 2.76 (1H), and 2.56 (1H), unequivocally
indicated the exclusive chemical environment of 3-
Scheme 5. Tentative reaction mechanism of the cyclization of the glycol
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10.1002/ejoc.201601341
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o
Conclusions
White solid, yield 95%; m.p. 170.2-171.0 C (EA/PE); IR (KBr, cm-1): ν =
3056, 2927, 2877, 2236, 1741, 1490, 1418, 1076, 1008, 917, 819, 783;
1H NMR (400 MHz, CDCl3) δ (ppm): 7.50 (d, J = 8.3 Hz, 2H), 7.29 (d, J =
8.4 Hz, 2H), 7.18 (d, J = 9.8 Hz, 4H), 5.08 (s, 1H), 4.16 (d, J = 8.7 Hz,
1H), 4.06 (d, J = 8.7 Hz, 1H), 2.76 (d, J = 5.3 Hz, 1H), 2.56 (d, J = 5.2 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ (ppm): 136.8, 132.8, 131.1, 130.9,
127.9, 127.9, 126.7, 121.5, 115.6, 79.8, 67.9, 35.9, 29.8, 23.9; HRMS
(ESI) calcd. for C18H13BrClNO [(M+Na)+]: 395.9767; Found: 395.9766.
(±) cis-6-(4-bromophenyl)-4-(4-chlorophenyl)-3-oxabicyclo[3.1.0]hexane-
1-carbo nitrile (2b)
In summary, we have presented the synergistic-NaBH4-
reduction/cyclization of readily available 2-aroyl-1-cyano-3-
arylcyclopropane-1-carboxylate compounds, providing access to
the selective synthesis of 3-oxabicyclo[3.1.0]hexane-1-
carbonitrile derivatives. Due to the described pharmacological
usefulness
of
3-oxabicyclo[3.1.0]hexane-1-carbonitrile
derivatives such simple reaction conditions and functional group
tolerance is offering a new attractive method to access such
structures. Therefore, from these results, it can be envisioned
that this method will find many applications in medicinal
chemistry.
o
White solid, yield 96%; m.p. 170.3-171.0 C (EA/PE); IR (KBr, cm-1): ν =
3055, 1985, 2875, 2298, 2231, 1904, 1794, 1571, 1487, 1408, 1303,
1
1256, 1188, 1066, 1005, 957, 858, 815, 716; H NMR (400 MHz, CDCl3)
δ (ppm): 7.50 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.23 (d, J =
8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 5.13 (s, 1H), 4.21 (d, J = 8.7 Hz,
1H), 4.11 (d, J = 8.7 Hz, 1H), 2.74 (d, J = 5.2 Hz, 1H), 2.54 (d, J = 5.3 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ (ppm): 136.4, 133.5, 131.6, 130.9,
128.3, 128.2, 126.5, 121.0, 115.6, 79.9, 68.0, 36.0, 30.0, 24.0; HRMS
(ESI) calcd. for C18H13BrClNO [(M+Na)+]: 395.9767; Found: 395.9738.
Experimental Section
All melting points were determined in a Yanaco melting point apparatus
and are uncorrected. IR spectra were recorded in a Nicolet FT-IR 5DX
1
spectrometer. The H NMR (400 or 600 MHz) and 13C NMR (100 or 150
(±)
cis-6-(4-bromophenyl)-4-(4-methoxyphenyl)-3-oxabicyclo[3.1.0]
MHz) spectra were recorded in a Bruker AV-400 spectrometer with TMS
as internal reference in CDCl3 solutions. The J values are given in hertz.
Only discrete or characteristic signals for the 1H NMR are reported. High-
resolution ESI mass spectra were obtained on a UHR-TOF maXis (ESI)
mass spectrometer. X-ray crystallographic analysis was performed with a
SMART APEX-II diffractometer. Flash chromatography was performed
on silica gel (230-400 mesh) eluting with ethyl acetate-hexanes mixture.
All reactions were monitored by thin layer chromatography (TLC). All
reagents and solvents were purchased from commercial sources and
purified commonly before used.
hexane-1-carbo nitrile (2c)
White solid, yield 94%; m.p. 160.4-161.0 C (EA/PE); IR (KBr, cm-1): ν =
2964, 2355, 2228, 1747, 1580, 1505, 1351, 1298, 1242, 1180, 1066,
960, 828, 747. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.44 (d, J = 8.4 Hz,
2H), 7.22 (d, J = 8.5 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.6 Hz,
2H), 5.06 (s, 1H), 4.10 (d, J = 8.7 Hz, 1H), 4.04 (d, J = 8.7 Hz, 1H), 3.77
(s, 3H), 2.75 (d, J = 5.2 Hz, 1H), 2.53 (d, J = 5.2 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ (ppm): 158.8, 131.9, 130.9, 130.0, 128.3, 126.7, 120.8,
115.9, 113.3, 80.2, 67.5, 54.3, 35.9, 29.9, 24.0; HRMS (ESI) calcd. for
C19H16BrNO2 [(M+Na)+]: 392.0262; Found: 392.0285.
o
General procedure for synthesis of 3-oxabicyclo[3.1.0]hexane-1-
carbonitrile derivatives
(±) cis-6-(2-bromophenyl)-4-(4-bromophenyl)-3-oxabicyclo[3.1.0]hexane-
1-carbo nitrile (2d)
o
White solid, yield 92%; m.p. 128.5-129.1 C (EA/PE); IR (KBr, cm-1): ν =
To a solution of 2-aroyl-3-aryl-1-cyanocyclopropane-1-carboxylates 1a-s
(2 mmol) in THF (15 mL), NaBH4 (0.3026 g, 4mmol) was added, the
mixture was stirred at room temperature for 5 hrs, and the completion of
reaction was confirmed by TLC (Hexanes/EtOAc, 8/1). Subsequently, the
reaction was quenched by adding water (5mL), the solvent THF was
removed by reduce pressure, the residues were extracted with
dichloromethane (10 mL X 2). The organic phase was washed with water
(10 mL) and brine (5 mL), and dried over anhydrate sodium sulfate. After
removal of dichloromethane, the crude product was not purified further
for the next step directly.
3077, 2970, 2927, 2874, 2351, 2241, 1700, 1473, 1435, 1413, 1348,
1302, 1257, 1183, 1123, 1060, 1026, 961, 917, 886, 858, 816, 795, 774,
749, 731, 712, 671; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.62-7.59 (m,
1H), 7.53-7.50 (m, 2H), 7.29-7.24 (m, 1H), 7.21 (s, 1H), 7.19 (s, 2H),
7.18-7.13 (m, 1H), 5.11 (s, 1H), 4.26 (d, J = 8.6 Hz, 1H), 4.08 (d, J = 8.6
Hz, 1H), 2.84 (d, J = 5.5 Hz, 1H), 2.72 (d, J = 5.5 Hz, 1H); 13C NMR (101
MHz, CDCl3) δ (ppm): 137.1, 132.4, 132.1, 131.1, 128.6, 128.0, 126.8,
126.6, 125.4, 121.6, 115.6, 79.9, 67.9, 35.8, 31.4, 23.9; HRMS (ESI)
calcd. for C18H13Br2NO [(M+Na)+]: 441.9241; Found: 441.9232.
(±) cis-4-(4-bromophenyl)-6-(3-chlorophenyl)-3-oxabicyclo[3.1.0]hexane-
1-carbo nitrile (2e)
To the mixture of last crude product and 4-dimethylaminopyridine (0.2443
g, 2 mmol) in dried dichloromethane (10 mL) was added dropwise
o
White solid, yield 92%; m.p. 175.8-176.3 C (EA/PE); IR (KBr, cm-1): ν =
trifluoromethanesulfonic anhydride (0.33 ml,
2
mmol) at room
temperature, the resultant mixture was stirred for 5 hrs, and the
completion of reaction was confirmed by TLC (Hexanes/EtOAc, 8/1).
Subsequently, the reaction was quenched by adding ice-water (5 mL),
the mixture was separated, the aqueous phases were extracted with
dichloromethane (10 mL X 2). The combined organic phase was washed
with water (10 mL) and brine (5 mL), and dried over anhydrate sodium
sulfate. After removal of dichloromethane, the crude product was purified
by flash chromatography (silica gel, EtOAc/hexanes, 1/30) to give the
desirable products 2a-s.
3063, 2969, 2928, 2873, 2232, 1758, 1574, 1481, 1398, 1315, 1254,
1191, 1067, 1005, 957, 904, 871, 786, 698; 1H NMR (400 MHz, CDCl3) δ
(ppm): 7.56-7.54 (m, 2H), 7.26-7.24 (m, 1H), 7.23 (s, 1H), 7.22-7.16 (m,
3H), 7.12-7.06 (m, 1H), 5.07 (s, 1H), 4.15 (d, J = 8.7 Hz, 1H), 4.05 (d, J =
8.7 Hz, 1H), 2.77 (d, J = 5.2 Hz, 1H), 2.55 (d, J = 5.3 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ (ppm): 136.9, 134.6, 133.6, 131.1, 129.0, 127.1,
127.1, 126.8, 124.7, 121.6, 115.4, 79.9, 68.0, 35.8, 30.0, 24.0; HRMS
(ESI) calcd. for C18H13BrClNO [(M+Na)+]: 395.9767; Found: 395.9752.
(±)
carbonitrile (2f)
White solid, yield 94%; m.p. 125.6-126.1 C (EA/PE); IR (KBr, cm-1): ν =
cis-6-(3-chlorophenyl)-4-phenyl-3-oxabicyclo[3.1.0]hexane-1-
(±) cis-4-(4-bromophenyl)-6-(4-chlorophenyl)-3-oxabicyclo[3.1.0]hexane-
1-carbo nitrile (2a)
o
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10.1002/ejoc.201601341
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3066, 2970, 2925, 2860, 2351, 2234, 1701, 1600, 1483, 1450, 1348,
(±) cis-6-(2-chlorophenyl)-4-(4-methoxyphenyl)-3-oxabicyclo[3.1.0]hex-
ane-1- carbonitrile (2k)
1
1214, 1059, 1039, 967, 929, 917, 889, 848, 808, 784, 775, 732, 703; H
NMR (400 MHz) δ (ppm): 7.37 (dd, J = 7.6 and 7.2 Hz, 2H), 7.31 (dd, J =
7.6 and 7.2 Hz, 3H), 7.24 (d, J = 6.1 Hz, 3H), 7.12-7.08 (m, 1H), 5.11 (s,
1H), 4.15 (d, J = 8.7 Hz, 1H), 4.10 (d, J = 8.7 Hz, 1H), 2.82 (d, J = 5.3 Hz,
1H), 2.56 (d, J = 5.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm): 158.8,
131.9, 130.9, 130.0, 128.3, 126.7, 120.8, 115.9, 113.3, 80.2, 67.5, 54.3,
35.9, 29.9, 24.0; HRMS (ESI) calcd. for C18H14ClNO [(M+Na)+]:
318.0662; Found: 318.0655.
White solid, yield: 95%; m.p. 142.8-143.3 oC (EA/PE); IR (KBr, cm-1): ν =
2967, 2919, 2230, 1611, 1583, 1514, 1498, 1463, 1440, 1352, 1308,
1061, 1029, 966, 878, 827, 775, 756,733, 705; 1H NMR (600 MHz,
CDCl3) δ (ppm): 7.28 (d, J = 8.3 Hz, 2H), 7.22 (d, J = 8.5 Hz, 2H), 7.15
(d, J = 8.3 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 5.05 (s, 1H), 4.09 (d, J = 8.7
Hz, 1H), 4.04 (d, J = 8.7 Hz, 1H), 3.76 (s, 3H), 2.75 (d, J = 5.2 Hz, 1H),
2.54 (d, J = 5.2 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ (ppm): 159.8,
133.7, 132.4, 131.0, 129.0, 128.9, 127.7, 116.9, 114.3, 81.2, 68.4, 55.3,
36.9, 30.8, 25.0; HR-MS (ESI) calcd. for C19H16ClNO2 [(M+Na)+]:
348.0767, Found: 348.0757.
(±) cis-4-phenyl-6-(m-tolyl)-3-oxabicyclo[3.1.0]hexane-1-carbonitrile (2g)
White solid, yield 96%; m.p. 118.9-119.4 oC (EA/PE); IR (KBr, cm-1): ν =
3033, 2921, 1854, 2315, 2233, 1704, 1600, 1492, 1454, 1347, 1265,
1056, 1009, 967, 930, 843, 781, 699; 1H NMR (400 MHz, CDCl3) δ
(ppm): 7.39-7.34 (m, 2H), 7.30 (dd, J = 7.4 and 7.1 Hz, 3H), 7.19 (d, J =
4.8 Hz, 1H), 7.06 (d, J = 7.7 Hz, 1H), 7.02 (d, J = 8.4 Hz, 2H), 5.10 (s,
1H), 4.15 (d, J = 8.6 Hz, 1H), 4.11 (d, J = 8.6 Hz, 1H), 2.82 (d, J = 5.3 Hz,
1H), 2.56 (d, J = 5.3 Hz, 1H), 2.30 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
(ppm): 138.2, 137.4, 132.6, 127.9, 127.6, 127.5, 127.4, 125.2, 123.6,
116.1, 80.7, 68.1, 36.1, 30.6, 24.0, 20.4; HRMS (ESI) calcd. for
C19H17NO [(M+Na)+]: 298.1208; Found: 298.1207.
(±) cis-4,6-bis(4-chlorophenyl)-3-oxabicyclo[3.1.0]hexane-1-carbonitrile
(2l)
White solid, yield: 95%; m.p. 164.5-165.2 oC (EA/PE); IR (KBr, cm-1): ν =
3056, 2927, 2877, 2236, 1490, 1418, 1341,1260, 1076, 1008, 959, 917,
844, 819, 783, 721; 1H NMR (600 MHz, CDCl3) δ (ppm): 7.34 (d, J = 8.2
Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 8.2
Hz, 2H), 5.08 (s, 1H), 4.14 (d, J = 8.7 Hz, 1H), 4.05 (d, J = 8.7 Hz, 1H),
2.75 (d, J = 5.2 Hz, 1H), 2.55 (d, J = 5.2 Hz, 1H); 13C NMR (150 MHz,
CDCl3) δ (ppm): 136.4, 133.5, 132.9, 131.1, 128.2, 128.03, 128.02,
126.5, 115.6, 79.9, 68.0, 36.0, 29.9, 24.0; HRMS (ESI) calcd. for
C18H13Cl2NO [(M+Na)+]: 352.0272, Found: 352.0263.
(±)
cis-4-(4-methoxyphenyl)-6-(m-tolyl)-3-oxabicyclo[3.1.0]hexane-1-
carbonitrile (2h)
White solid, yield 96%; m.p. 132.9-133.3 oC (EA/PE); IR (KBr, cm-1): ν =
3055, 2973, 2866, 2835, 2351, 2232, 1715, 1611, 1585, 1514, 1460,
1309, 1253, 1185, 1060, 1042, 1009, 962, 906, 863, 809, 787, 707; 1H
NMR (400 MHz, CDCl3) δ (ppm): 7.23 (d, J = 8.6 Hz, 2H), 7.24 (d, J = 7.5
Hz, 1H), 7.09 (dd, J = 7.8 and 7.8 Hz, 2H), 7.08 (s, 1H), 6.89 (d, J = 8.6
Hz, 2H), 5.05 (s, 1H), 4.10 (d, J = 8.6 Hz, 1H), 4.05 (d, J = 8.6 Hz, 1H),
3.77 (s, 3H), 2.78 (d, J = 5.3 Hz, 1H), 2.54 (d, J = 5.3 Hz, 1H), 2.30 (s,
3H); 13C NMR (150 MHz, CDCl3) δ (ppm): 158.8, 137.4, 132.7, 130.3,
127.6, 127.6, 127.4, 126.8, 123.6, 116.3, 113.3, 80.3, 67.6, 54.3, 35.9,
30.5, 24.0, 20.4; HRMS (ESI) calcd. for C20H19NO [(M+Na)+]: 328.1313;
Found: 328.1311.
(±)
cis-4-(4-chlorophenyl)-6-(4-phenoxyphenyl)-3-oxabicyclo[3.1.0]
hexane-1-carbonitrile (2m)
White solid, yield: 96%; m.p. 102.6-103.1oC (EA/PE); IR (KBr, cm-1): ν =
3067, 2870, 2235, 1609, 1582, 1224, 1162, 1076, 1015, 965, 861, 807,
1
759; H NMR (600 MHz, CDCl3) δ (ppm): 7.33 (d, J = 8.0 Hz, 2H), 7.27
(dd, J = 7.2 and 7.5 Hz, 3H), 7.22 (d, J = 8.0 Hz, 2H), 7.05 (dd, J = 7.2
and 7.4 Hz, 1H), 6.95 (dd, J = 7.8 and 8.0 Hz, 3H), 6.89 (d, J = 8.7 Hz,
1H), 6.87 (s, 1H), 5.06 (s, 1H), 4.13 (d, J = 8.7 Hz, 1H), 4.04 (d, J = 8.7
Hz, 1H), 2.74 (d, J = 5.2 Hz, 1H), 2.55 (d, J = 5.2 Hz, 1H); 13C NMR (150
MHz, CDCl3) δ (ppm): 156.6, 155.7, 136.5, 134.5, 133.4, 129.1, 128.8,
128.1, 126.5, 122.5, 121.3, 118.0, 117.3, 117.2, 115.7, 79.9, 68.0, 35.9,
30.4, 24.1; HR-MS (ESI) calcd. for C24H18ClNO2 [(M+Na)+] : 410.0924,
Found:410.0915.
(±)
cis-6-(2-bromophenyl)-4-(4-methoxyphenyl)-3-oxabicyclo[3.1.0]
hexane-1-carbonitrile (2i)
White solid, yield 96%; m.p. 130.6-131.0 oC (EA/PE); IR (KBr, cm-1): ν =
3099, 2971, 2657, 2455, 2340, 2245, 2175, 2056, 1908, 1696, 1517,
1274, 1184, 1069, 962, 827, 709; 1H NMR (400 MHz, CDCl3) δ (ppm):
7.24 (d, J = 8.1 Hz, 3H), 7.18 (t, J = 9.2 Hz, 2H), 7.13 (d, J = 7.1 Hz, 1H),
6.89 (d, J = 7.7 Hz, 2H), 5.09 (s, 1H), 4.21 (d, J = 8.7 Hz, 1H), 4.06 (d, J
= 8.5 Hz, 1H), 3.77 (s, 3H), 2.85 (d, J = 4.6 Hz, 1H), 2.71 (d, J = 4.5 Hz,
1H); 13C NMR (101 MHz, CDCl3) δ (ppm): 158.8, 132.7, 132.1, 130.2,
128.5, 128.0, 126.8, 126.6, 125.4, 116.0, 113.3, 80.2, 67.3, 54.3, 35.7,
31.3, 24.0; HRMS (ESI) calcd. for C19H16BrNO2 [(M+Na)+] : 392.0262;
Found: 392.0239.
(±) cis-6-(3-chlorophenyl)-4-(4-chlorophenyl)-3-oxabicyclo[3.1.0]hexane-
1- carbonitrile (2n)
White solid, yield: 94%, m.p. 180.7-181.3oC (EA/PE); IR (KBr, cm-1): ν =
3069, 2982, 2876, 2237, 1617, 1599, 1569, 1492, 1433, 1359, 1324,
1256, 1218, 1196, 1093, 1062, 1034, 1012, 958, 933, 908, 884, 865,
824, 796, 783, 766, 726, 701; 1H NMR (600 MHz, CDCl3) δ (ppm): 7.34
(d, J = 8.2 Hz, 2H), 7.27–7.23 (m, 3H), 7.22 (s, 2H), 7.09 (d, J = 6.0 Hz,
1H), 5.08 (s, 1H), 4.14 (d, J = 8.8 Hz, 1H), 4.05 (d, J = 8.7 Hz, 1H), 2.77
(d, J = 5.2 Hz, 1H), 2.55 (d, J = 5.2 Hz, 1H); 13C NMR (150 MHz, CDCl3)
δ (ppm): 136.3, 134.6, 133.7, 133.5, 129.0, 128.2, 127.2, 127.1, 126.5,
124.7, 115.5, 79.9, 68.0, 35.8, 30.0, 24.0; HR-MS (ESI) calcd. for
C18H13Cl2NO [(M+Na)+]: 352.0272, Found: 352.0259.
(±) cis--6-(3-chlorophenyl)-4-(4-methoxyphenyl)-3-oxabicyclo[3.1.0]hex-
ane-1- carbonitrile (2j)
White solid, yield: 96%; m.p. 148.9-149.2 oC (EA/PE); IR (KBr, cm-1): ν =
3071, 2963, 2332, 2232, 1753, 1581, 1509, 1459, 1308, 1257, 1181,
(±) cis-6-(3-bromophenyl)-4-phenyl-3-oxabicyclo[3.1.0]hexane-1-carbo-
nitrile (2o)
1
1060, 877, 805, 702; H NMR (600 MHz, CDCl3) δ (ppm): 7.25-7.21 (m,
5H), 7.10 (d, J = 6.5 Hz, 1H), 6.88 (d, J = 8.5 Hz, 2H), 5.05 (s, 1H), 4.10
(d, J = 8.7 Hz, 1H), 4.04 (d, J = 8.7 Hz, 1H), 3.76 (s, 3H), 2.77 (d, J = 5.2
Hz, 1H), 2.54 (d, J = 5.2 Hz, 1H); 13C NMR (150MHz, CDCl3) δ (ppm):
158.8, 134.9 133.6, 129.9, 129.0, 127.1, 127.0, 126.8, 124.7, 115.8,
113.3, 80.2, 67.5, 54.3, 35.8, 29.9, 24.1; HR-MS (ESI) calcd. for
C19H16ClNO2 [(M+Na)+] : 348.0767; Found: 348.0757.
White solid, yield: 92%; m.p. 133.7-134.5oC (EA/PE); IR (KBr, cm-1): ν =
3064, 2969, 2859, 2234, 1597, 1564, 1480, 1449, 1347, 1310, 1262,
1213, 1191, 1098, 1074, 1004, 967, 928, 915, 886, 849, 782, 773, 731,
1
696; H NMR (400 MHz, CDCl3) δ (ppm): 7.38 (d, J = 6.8 Hz, 3H), 7.35
(s, 1H), 7.31 (t, J = 7.2 Hz, 3H), 7.20-7.13 (m, 2H), 5.11 (s, 1H), 4.15 (d,
J = 8.8 Hz, 1H), 4.10 (d, J = 8.7 Hz, 1H), 2.81 (d, J = 5.2 Hz, 1H), 2.56 (d,
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10.1002/ejoc.201601341
European Journal of Organic Chemistry
FULL PAPER
J = 5.1 Hz, 1H); 13C NMR (151 MHz, CDCl3) δ (ppm): 137.9, 135.1,
130.1, 130.0, 129.3, 128.0, 127.6, 125.2, 121.8, 115.7, 80.6, 68.0, 36.0,
29.9, 24.2; HR-MS (ESI) calcd. for C18H14BrNO [(M+Na)+]: 362.0156,
Found: 362.0146.
Acknowledgements ((optional))
Financial support of this research by the National Natural
Science Foundation of China (NNSFC 21173181) is gratefully
acknowledged by authors. A project was funded by the Priority
Academic Program Development of Jiangsu Higher Education
Institutions. The senior visiting scholar project was funded by
Jiangsu province.
(±) cis-4-(4-methoxyphenyl)-6-(4-nitrophenyl)-3-oxabicyclo[3.1.0]hexane-
1- carbonitrile (2p)
White solid, yield: 92%; m.p. 105.6-106.2oC (EA/PE); IR (KBr, cm-1): ν =
3076, 2980, 2877, 2236, 1612, 1598, 1151, 1347, 1245, 1178, 1069,
959, 858, 816, 745, 698; 1H NMR (400 MHz, CDCl3) δ (ppm): 8.19 (d, J =
8.7 Hz, 2H), 7.40 (d, J = 8.7 Hz, 2H), 7.23 (d, J = 8.6 Hz, 2H), 6.91 (d, J =
8.6 Hz, 2H), 5.11 (s, 1H), 4.15 (d, J = 8.8 Hz, 1H), 4.08 (d, J = 8.8 Hz,
1H), 3.78 (s, 3H), 2.87 (d, J = 5.2 Hz, 1H), 2.67 (d, J = 5.2 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ (ppm): 137.15, 132.45, 132.16, 131.15,
128.67, 128.01, 126.88, 126.67, 125.41, 121.61, 115.68, 79.99, 67.93,
35.84, 31.46, 23.99; HR-MS (ESI) calcd. for C19H16N2O4 [(M+Na)+]:
359.1008, Found: 359.1000.
Keywords: 3-oxabicyclo[3.1.0]hexane • synergistic NaBH4-
reduction • cyclization • 2-aroyl-1-cyano-3-arylcyclopropane-1-
carboxylate • trifluoromethanesulfonate
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(±) cis-6-(4-(3-fluorophenoxy)phenyl)-4-phenyl-3-oxabicyclo[3.1.0]hexane
-1- carbonitrile (2q)
White solid, yield: 95%; m.p. 134.6-135.4oC(EA/PE); IR (KBr, cm-1): ν =
3065, 2859, 2232, 1610,1584, 1510, 1355, 1276, 1208, 1064, 966, 894,
825, 753, 697. 1H NMR (600 MHz, CDCl3) δ (ppm): 7.35 (t, J = 7.4 Hz,
2H), 7.30 (d, J = 7.1 Hz, 1H), 7.27 (t, J = 6.3 Hz, 4H), 7.12 (t, J = 9.3 Hz,
1H), 7.03 (t, J = 7.4 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.93 (t, J = 8.9 Hz,
3H), 5.07 (s, 1H), 4.11 (d, J = 8.7 Hz, 1H), 4.06 (d, J = 8.7 Hz, 1H), 2.72
(d, J = 5.1 Hz, 1H), 2.52 (d, J = 5.2 Hz, 1H); 13C NMR (150 MHz, CDCl3)
δ (ppm): 155.9, 152.8 (d, J = 248.6 Hz), 143.0 (d, J = 11.9 Hz), 137.9,
129.7 (d, J = 3.9 Hz), 128.8, 128.0, 127.5, 125.1, 122.8 (d, J = 7.1 Hz),
122.4, 120.2, 116.3 (d, J = 80.2 Hz), 98.9, 80.6, 67.8, 36.0, 29.8, 24.1;
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HRMS (ESI) calcd. for C24H18FNO2 [(M+Na)+]
: 394.1219, Found:
394.1211.
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carbonitriles 2a, 2b, 2p have been deposited with the Cambridge
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(±)
cis-6-(4-chlorophenyl)-4-phenyl-3-oxabicyclo[3.1.0]hexane-1-
carbonitrile (2r)
White solid, yield: 94%; m.p. 148.4-149.1oC (EA/PE); IR (KBr, cm-1): ν =
3038, 2958, 2880, 2232, 1895, 1757, 1552, 1493, 1351, 1303, 1190,
1067, 1005, 959, 877, 832, 766, 704; 1H NMR (400 MHz, CDCl3) δ
(ppm): 7.38-7.34 (m, 2H), 7.32-7.30 (m, 2H), 7.29-7.27 (m, 2H), 7.18-
7.16 (m, 2H), 7.16-7.14 (m, 1H), 5.12 (s, 1H), 4.15 (d, J = 8.7 Hz, 1H),
4.10 (d, J = 8.6 Hz, 1H), 2.79 (d, J = 5.3 Hz, 1H), 2.57 (d, J = 5.3 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ (ppm): 137.9, 132.8, 131.3, 128.0, 127.9,
127.5, 125.1, 115.8, 80.6, 67.9, 36.2, 29.9, 24.1; HR-MS (ESI) calcd. for
C18H14ClNO [(M+Na)+]: 318.0662, Found: 318.0648.
(±) cis-4-(4-bromophenyl)-6-(2-chlorophenyl)-3-oxabicyclo[3.1.0]hexane-
1- carbonitrile (2s)
White solid, yield: 95%; m.p. 110.8-111.7 oC (EA/PE); IR (KBr, cm-1):
2981, 2879, 2240, 1617, 1566, 1482, 1414, 1342, 1257, 1189, 1138,
1064, 959, 873, 812, 746; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.49 (d, J
= 8.4 Hz, 2H), 7.44-7.37 (m, 1H), 7.26-7.18 (m, 4H), 7.18 (s, 1H), 5.09 (s,
1H), 4.22 (d, J = 8.6 Hz, 1H), 4.06 (d, J = 8.6 Hz, 1H), 2.83 (d, J = 5.5 Hz,
1H), 2.75 (d, J = 5.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm): 137.1,
134.8, 131.1, 130.7, 128.8, 128.4, 127.7, 126.8, 126.0, 121.6, 115.7,
79.9, 67.8, 35.4, 28.9, 23.7; HR-MS (ESI) calcd. for C18H13BrClNO
[(M+Na)+] : 395.9767, Found: 395.9757.
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3-Oxabicyclo[3.1.0]hexane derivatives
were synthesized via the synergistic
NaBH4-reduction/cyclization from
readily available 2-aroyl-1-cyano-3-
arylcyclopropane-1-carboxylates.
oxabicyclo[3.1.0]hexane
Jiaming Liu,[a] Lizhong Wang,[a,b] Xushun
Qing,[a] Feixiang Zhang,[a] Ting Wang,[a]
and Cunde Wang*[a]
Page No. – Page No.
Synergistic NaBH4-reduction/
cyclization of 2-aroyl-cyclopropane-1-
carboxylates: novel synthesis of 3-
oxabicyclo[3.1.0]hexane derivatives
*one or two words that highlight the emphasis of the paper or the field of the study
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Author(s), Corresponding Author(s)*
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*one or two words that highlight the emphasis of the paper or the field of the study
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