Highly stereoselective synthesis of 1-cyanocyclopropane-carboxamides from 3-substituted-2-cyanoacrylamides with N-tosylhydrazones under metal-free conditions

Article abstract of DOI:10.1016/j.tetlet.2017.05.070

A metal-free cyclopropanation of electron-deficient olefins 3-substituted-2-cyanoacrylamides with N-tosylhydrazones has been successfully developed. This strategy provide a simple route to the synthesis of very valuable 1-cyanocyclopropanecarboxamides wit

Full text of DOI:10.1016/j.tetlet.2017.05.070

Accepted Manuscript
Highly stereoselective synthesis of 1-cyanocyclopropane-carboxamides from 3-
substituted-2-cyanoacrylamides with N-tosylhydrazones under metal-free con-
ditions
Xufeng Nie, Yachuan Wang, Lijun Yang, Zaijun Yang, Tairan Kang
PII:
S0040-4039(17)30663-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.05.070
TETL 48963
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
6 April 2017
16 May 2017
19 May 2017
Please cite this article as: Nie, X., Wang, Y., Yang, L., Yang, Z., Kang, T., Highly stereoselective synthesis of 1-
cyanocyclopropane-carboxamides from 3-substituted-2-cyanoacrylamides with N-tosylhydrazones under metal-
free conditions, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.05.070
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2
Graphical Abstract
A metal-free cyclopropanation of electron-deficient
olefins 3-substituted-2-cyanoacrylamides with N-
tosylhydrazones has been successfully developed. This
strategy provide a simple route to the synthesis of very
valuable 1-cyanocyclopropanecarboxamides with a
quaternary stereogenic center in good yields and with
high diastereoselectivities (up to 90% yield with 19:1 dr).
The reaction could be performed in one-pot fashion and
in a gram-scale from aryl aldehydes.
Highly stereoselective synthesis of 1-
cyanocyclopropane-carboxamides from 3-
substituted-2-cyanoacrylamides with N-
tosylhydrazones under metal-free conditions
Xufeng Niea, Yachuan Wanga, Lijun Yanga, Zaijun Yanga,
and Tairan Kanga,b∗

1
Tetrahedron Letters
journal homepage: www.els evier.com
Highly stereoselective synthesis of 1-cyanocyclopropane-carboxamides from 3-
substituted-2-cyanoacrylamides with N-tosylhydrazones under metal-free conditions
Xufeng Niea, Yachuan Wang a, Lijun Yang a, Zaijun Yanga, and Tairan Kanga,b∗
a Chemical Synthesis and Pollution Control Key Laboratory/Collaborative Innovation Center of Tissue Repair Material of Sichuan Province, 1 Shida Road,
Nanchong 637000, China
b State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, Cancer Center, West China Hospital, 3 people's south road, Chengdu
610000, China
ARTICLE INFO
ABSTRACT
Article history:
Received
A metal-free cyclopropanation of electron-deficient olefins 3-substituted-2-cyanoacrylamides
with N-tosylhydrazones has been successfully developed. This strategy provide a simple route to
the synthesis of very valuable 1-cyanocyclopropanecarboxamides with a quaternary stereogenic
center in good yields and with high diastereoselectivities (up to 90% yield with 19:1 dr). The
reaction could be performed in one-pot fashion and in a gram-scale from aryl aldehydes.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
N-Tosylhydrazones
1-cyanocyclopropane carboxamides
electron-deficient olefins
Transition-Metal-Free
diazomethane

2
Introduction
although the metal-catalyzed cyclopropanation of various
alkenes with stable diazo reagents have been reported,9a-i the
metal-free reaction of trisubstituted alkenes bearing one or two
electron withdrawing groups with unstable diazo reagents
generated from N-tosylhydrazones to form the cyclopropane
product has been largely undeveloped so far.10,12,13
Amide- or nitrile-substituted cyclopropanes present unique
biological activities,1-5 which include bradykinin β1 antagonists,1
hepatitis C virus (HCV) NS3 protease inhibitor,2 nicotinamide
phosphori-bosyl transferase (NAMPT) inhibitor3 and ketol-acid
reducto-isomerase inhibitor4 (Figure 1). Especially those bearing
a cyano group attached to a stereogenic carbon of the
cyclopropanecarboxamides not only exist in some bioactive
compounds but also serve as valuable tools for medicinal
chemistry.4-7 For example, nitriles can be easily transformed to
carboxylic acids, amines, ketones, amides, and aldehydes.
Therefore, the synthesis of 1-cyanocyclo-propanecarboxamides
motif which can be easily further transformed into densely
Cl
MeO
MeO2C
F3C
HN
N
O
O
O
O
O
H
H
N
S
N
N
H
H
N
N
O
O
F
O
O
Bradykinin β1 receptor
O
O
HCV NS3 protease inhibitor
functionalized
cyclopropane
molecules,
has attracted
N
S
O
O
considerable attention during the past years from synthetic
chemists.6,7 For example, in 2010, Fan and coworkers reported
O
N
H
N
H
CN
that
a tandem reaction of 2-cyanoacetamides with α,β-
Ketol-acid reductoisomerase inhibitor
NAMPT inhibitor
unsaturated malonates, provided 1-cyanocyclopropanecarbox-
amides in good yields and with excellent diastereoselectivities.6a
In 2014, Liang and Dong’s group reported that one-pot synthesis
Figure 1. Bioactive cyclopropanecarboxamide containing
compounds.
of
1-cyanocyclo-propanecarboxamides
derivatives
were
developed from 2-cyanoacrylamides and dimethyl malonate in
the presence of N-bromosuccinimide and triethylamine.6b
Takemoto also reported that an organocatalyzed asymmetric
cyclopropanation
cyanoacrylamides providing optically active 1-cyanocyclopropa-
of
bromonitromethane
with
2-
ne-carboxamides in excellent enantioselectivities.6c Charette
developed an enantio- and diastereoselective Rh(II)-catalyzed
cyclopropanation of α-cyano diazoacetamides with styrene in the
synthesis of chiral 1-cyanocyclopropane-carboxamides in 2009.6d
In addition, the other examples for synthesis of 1-
cyanocyclopropane-1-carboxy derivatives have also been
reported.7 For example, Zhang reported that a Co(II)-catalyzed
cyclopropanation of the olefins containing electron-withdrawing
groups with diazoacetates affording 2-cyanocyclopropane
carboxylates.7a In the past three decades, the metal-catalyzed
(such as copper, rhodium, and ruthenium) cyclopropanation
between styrene or some electron-rich olefins and diazo reagents
have been fully developed.8,9a-f However, the metal-catalyzed
cyclopropanation of electron-deficient olefins containing two
electron-withdrawing groups such as α,β-unsaturated carbonyl
compounds and nitriles with diazoacetates has proven to be a
challenging problem.6a,7a,8,9
The metal-free-catalyzed cyclopropanation of olefins with
diazo reagents will also be of importance. N-tosylhydrazones are
very useful reagents and can be utilized as precursors for the
generation of unstable α-aryl or alkyl diazomethanes.10 Indeed,
the metal- or metal-free-catalyzed reaction using the unstable
diazo reagents generated from N-tosylhydrazones in situ as
substrates have appeared in literatures.11 The metal-free-
catalyzed reaction of various substituted alkenes with N-
tosylhydrazones have also been developed in recent years.10,12
For instance, metal-free-catalyzed cyclopropanation of terminal
alkenes with N-tosylhydrazones delivering cyclopropane were
reported by Jiang’s and other groups (Scheme 1a).12 However,
the reactions of the trisubstituted alkenes bearing one electron
withdrawing groups (such as cyano, nitro and ester groups) with
N-tosylhydrazones, were described only to afford the sole
pyrazole products, in which the expected cyclopropanes were
not obtained (Scheme 1b).13 In 1989, Hirata found that the
reaction between 1-phenyldiazoethane and the trisubstituted
alkenes 3-substituted-2-cyano-3-phenylacrylates, which bear two
electron withdrawing groups, provided to form the mixture of
cyclopropane, olefin and pyrazoline products.14 Therefore,
Scheme 1. Reactions of alkenes with N-tosylhydrazones.
More recently, our group reported that a metal-free ring-
expansion reaction of six-membered N-sulfonylimine with N-
tosylhydrazone, provided an approach toward seven-membered
enesulfonamide.15f As a part of our ongoing research on organic
synthesis,15 herein, we report that a metal-free cyclopropanation
of the 3-substituted-2-cyano-3-phenyl-acrylamide (2a) with N-
tosylhydrazones under metal free conditions, which provides the
very valuable 1-cyanocyclo-propanecarboxamides with
a
quaternary carbon center (Scheme 1c). To the best of our
knowledge, there has been few systematic study on this type
reaction so far.12,13
Results and Discussionthe
At the outset of our studies, the reaction conditions were
optimized starting from N-tosylhydrazone (1a) and (E)-N-benzyl-
o
2-cyano-3-phenylacrylamide (2a) in 1,4-dioxane at 70 C in the
presence of a variety of bases, such as DBU, KOtBu, K2CO3 and

3
2
4-FC6H4
4-ClC6H4
4-Br 6H4
3b
3c
3d
3e
3f
85
83
84
86
86
90
79
80
77
80
78
85
79
77
73
76
83
80
-
14:1
19:1
17:1
19:1
14:1
19:1
14:1
18:1
19:1
19:1
19:1
19:1
18:1
19:1
19:1
19:1
14:1
19:1
-
Cs2CO3 (Table 1, entries 1-4). Among these bases, Cs2CO3 was
the best choice, and the expected cyclopropane product 3a was
obtained in 90% yield with >19:1 diastereomeric ratio (dr). The
reaction was sensitive to solvent. The other solvents like toluene,
DCE, CH3CN, DMF, DMSO and THF were not suitable (Table
1, entries 5-10). In all these reactions, the cyclopropane 3a was
afforded with 19:1 dr. (see Supporting Information for details)
3
4
5
4-NO2C6H4
4-CF3C6H4
4-CNC6H4
4-MeC6H4
4-MeOC6H4
4-NMe2C6H4
3-ClC6H4
3-BrC6H4
3-NO2C6H4
3-MeC6H4
3-MeOC6H4
2-BrC6H4
2-naphthyl
2-thienyl
6
7
3g
3h
3i
Table 1. Optimization of reaction conditions.a
8
9
10
11
12
13
14
15
16
17
18
19
20
3j
3k
3l
Entry
Base
Solvent
Dioxane
Dioxane
Dioxane
Dioxane
Toluene
DCE
Yield [%]b
Dr.c
1
2
DBU
58
82
75
90
44
32
37
60
69
80
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
3m
3n
3o
3p
3q
3r
3s
-
KOtBu
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
3
4
5
6
7
CH3CN
DMF
2-furyl
8
n-Bu
9
DMSO
THF
a Reaction conditions: N-Tosylhydrazones 1 (0.11 mmol), 2a (0.1 mmol),
base (0.075 mmol) in 0.5 mL of solvent at 70 oC for 5-7 h under N2
atmosphere.
10
a Reaction conditions: N-Tosylhydrazones 1 (0.11 mmol), 2a (0.1 mmol),
base (0.075 mmol) in 0.5 mL of solvent at 70 oC for 5-7 h under N2
atmosphere.
b Isolated yield.
c Diastereomeric ratio (dr) were determined by NMR.
b Isolated yield.
c Diastereomeric ratio (dr) were determined by NMR.
influence on the reaction. The halogen-substituted (-F, -Cl, -Br)
and the electron-donating groups (-CH3, -OCH3) at the 4-position
of the aryl ring could react smoothly to afford the desired
products 4a-4e in good yield (79-85%) with >14:1 dr (Table 3,
entries 1-5). Notably, when meta-Cl, -OCH3 and ortho-Br on the
aromatic ring of the α-cyanoacrylamides were used as the
substrates, a moderate to good yields (77-80%) and excellent
steroselectivity (>14:1 dr) were afforded (entries 6-8). The
reaction also worked with heterocyclic aromatic 2-thienyl
substrates, providing product 4i in 82% yield with 19:1 dr (entry
9). Interestingly, the alkyl group (cyclohexyl ring) attached on
the β-position of α- cyanoacrylamide successfully participated in
the reaction, giving the product 4j in 85% yield with 19:1 dr
(entry 10).
With the optimized conditions in hand, varieties of N-
tosylhydrazones were examined. The results were summarized in
Table 2. In general, the electronic effect on the aromatic ring
attached on the α-position of N-tosylhydrazone had no apparent
effects on the reaction. Aromatic groups bearing electron-
withdrawing and electron-donating substituents were tolerated,
and the corresponding cyclopropane products 3b-3j were
obtained in 77-90% yield with >14:1 dr (Table 2, entries 2-10).
Steric hindrance had slight effect on this transformation, both
ortho- and meta-substituted phenyl N-tosylhydrazones led to the
formation of 3k-3p in 73-85% yields with excellent dr (Table 2,
entries 11-16). Notably, 1-naphthyl N-tosylhydrazone also
participated in the reaction to give the corresponding product 3q
in 76% yield with >14:1 dr. The heteroaromatic 2-furanyl and 2-
thiophenyl N-tosylhydrazone could provide the desired products
3r, 3s in 83% and 80% yields, with >14:1 dr respectively (Table
2, entries 18-19). However, the N-tosylhydrazone derived from
aliphatic aldehyde (such as butyraldehyde) as substrate failed to
give the expected product. (Table 2, entry 20). This might be due
to the instability of α-alkyl diazomethane at 70 oC.
N-tosylhydrazones can be easily prepared from
tosylhydrazide and aldehydes or ketones. Therefore, we
investigated that the olefin cyclopropanation reactions were
carried out in a one-pot fashion (Table 4). The desired products
3a-3d, 3i, 3l and 3p were obtained in similar yields and with
diastereomeric ratio by heating the corresponding carbonyl
compound 5 with tosylhydrazide prior to the addition of the (E)-
N-benzyl-2-cyano-3-phenylacrylamide 2a, without the need to
isolate the N-tosylhydrazones (see the Supporting Information
for details, selected examples are shown in Table 4). It was
Next, we explored the scope of α-cyanoacrylamides (Table 3).
It was observed that the electronic effect on the aromatic ring
attached on the β-position of α-cyanoacrylamides had little
Table 3. Reactions of N-Tosylhydrazone 1a with various α-
Table 2. Reactions of various N-Tosylhydrazones 1 with (E)-
N-benzyl-2-cyano-3-phenyl-acrylamide 2a.a
cyanoacrylamides 2.a
R2
4
Yield [%]b
81
Dr.c
Entry
Entry
1
R1
3
Yield [%]b
90
Dr.c
1
4-FC6H4
4a
14:1
C6H5
3a
>19:1

4
2
3
Figure 2. X-ray structure of 3e; thermal ellipsoids shown at
4-ClC6H4
4-BrC6H4
4-MeC6H4
4-MeOC6H4
3-ClC6H4
4b
4c
4d
4e
4f
80
85
80
79
77
75
80
82
85
14:1
14:1
18:1
19:1
19:1
19:1
14:1
19:1
19:1
30% probability.
4
5
6
7
3-MeOC6H4
2-BrC6H4
2-thienyl
4g
4h
4i
8
9
10
cyclohexyl
4j
a Reaction conditions: N-Tosylhydrazones 1 (0.11 mmol), 2a (0.1 mmol),
base (0.075 mmol) in 0.5 mL of solvent at 70 oC for 5-7 h under N2
atmosphere.
Scheme 2. Proposed mechanism for this cyclopropanation
reaction.
b Isolated yield.
c Diastereomeric ratio (dr) were determined by NMR.
N2 extrusion. b) The carbene D, which is generated from diazo
compound B in situ react with 2a, giving the product 3a.
Table 4. One-pot reaction between aryl aldehydes 5,
tosylhydrazide and (E)-N-benzyl-2-cyano-3-phenylacryl-
amide 2a.a
Synthetic transformations were performed to demonstrate the
utility of the valuable cyano group of the cyclopropanes (Scheme
3). Reduction of the cyano group of 3a by using LiAlH4 gave the
corresponding primary amine product
6 in 96% yield.
Additionally, the cyano group of 3a also be easily transformed to
the primary amidine 7 in 77% yield by using hydroxylamine
hydrochloride and triethylamine in refluxing ethanol.
R3
3
Yield [%]b
Dr.c
19:1
14:1
19:1
19:1
19:1
19:1
19:1
Entry
1
2
3
4
5
6
7
C6H5
3a
3b
3c
3d
3i
85
82
80
78
77
75
70
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeOC6H4
3-BrC6H4
2-BrC6H4
3l
Scheme 3. Synthetic transformations.
3p
8d
C6H5
(10 mmol)
3a
(2.817g)
Conclusion
84
19:1
a Reaction conditions: 1) N-Tosylhydrazide (0.11 mmol), aryl aldehydes (0.11
In conclusion, we developed a metal-free cyclopropanation
reaction of trisubstituted olefins bearing two electron-
withdrawing groups at the same carbon with N-tosylhydrazones.
This reaction represents an extremely simple way to afford very
o
mmol), in 0.5 mL of MeOH, at 60 C for 1-2 h; 2) 2a (0.1 mmol), Cs2CO3
(0.075 mmol) in 0.5 mL 1,4-dioxane, at 70 oC for 5-7 h.
b Isolated yield.
c Diastereomeric ratio (dr) were determined by NMR.
d
10 mmol scale, reaction conditions: see the Supporting Information for
details.
valuable 1-cyanocyclopropanecarboxamides containing
a
quaternary carbon center in good to excellent yield and with
excellent diastereomeric ratio. Moreover, the reaction can be
performed in one-pot fashion and in a gram-scale from aryl
aldehydes and tosylhydrazide. We believe that this reaction
producing the 1-cyanocyclopropanecarboxamides motifs would
be used in medicinal chemistry.
pleasingly found that the one-pot reactions could be carried out
on a multigame scale, the product 3a (2.817 g) was afforded in
80% yield (Table 4, entry 8, see the Supporting Information for
details).
The structure of 3e was confirmed by X-ray crystal structure
analysis (Figure 2).16 Based on the mechanistic study that
reported by Barluenga’s11a group, the formation of 3a is
rationalized as outlined in Scheme 2. The diazo compound B is
generated in situ by decomposition of N-tosylhydrazone salt A.
From B, there are two possible pathways: a) the pyrazoline C or
intermediate D is formed via an addition reaction of B with 2a,
and then, 3a is generated from pyrazoline C or intermediate D by
Acknowledgments
We thank the Education Department of Sichuan Province
(NO. 15CZ0016), Science & Technology Department of Sichuan
Province (2017TD0008, 2016TD0020) and the National Natural
Science Foundation of China (NO. 21672172) for its financial
support of the project.
A. Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/...

5
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Chem. Soc. 2001, 123, 4119.
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6
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16. CCDC 1506352 (3e) contains the supplementary crystallographic data for
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Crystallographic Data Centre via www.ccdc.cam.ac.uk /data request/cif.

7
A metal-free cyclopropanation of olefins with diazomethanes has been developed.
Trisubstituted olefins bear two electron-withdrawing groups at the same carbon.
The products contain a quaternary carbon centers.
This reaction can be performed from aldehydes without isolating the tosylhydrazones.
The products were afforded in excellent yields and diastereoselectivities.