Efficient cyclopropanation of aryl/heteroaryl acetates and acetonitriles with vinyl diphenyl sulfonium triflate

Article abstract of DOI:10.1016/j.tetlet.2018.02.080

A convenient method was developed for the cyclopropanation of aryl acetates and aryl acetonitrile using vinyl diphenyl sulfonium triflate salt. The newly developed conditions are simple, mild, and compatible with a wide range of functional groups, without the need to apply an inert atmosphere, or alkali bases.

Full text of DOI:10.1016/j.tetlet.2018.02.080

Accepted Manuscript
Efficient cyclopropanation of aryl / heteroaryl acetates and acetonitriles with
vinyl diphenyl sulfonium triflate
Mingwei Zhou, Yimin Hu, Ke En, Xuefei Tan, Hong C. Shen, Xuhong Qian
PII:
S0040-4039(18)30280-6
https://doi.org/10.1016/j.tetlet.2018.02.080
TETL 49765
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
14 December 2017
17 February 2018
27 February 2018
Please cite this article as: Zhou, M., Hu, Y., En, K., Tan, X., Shen, H.C., Qian, X., Efficient cyclopropanation of
aryl / heteroaryl acetates and acetonitriles with vinyl diphenyl sulfonium triflate, Tetrahedron Letters (2018), doi:
https://doi.org/10.1016/j.tetlet.2018.02.080
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Efficient cyclopropanation of aryl /
heteroaryl acetates and acetonitriles with
vinyl diphenyl sulfonium triflate
Leave this area blank for abstract info.
Mingwei Zhou a,b, Yimin Hu b, Ke En a, Xuefei Tan b, Hong C. Shen b,*, Xuhong Qian a,*
-
OTf
Ph
Ph
Ar
Ar
DBU, DMSO
21 oC, 12 hrs
EWG: CO2R, CN
35 examples
50 - 96% yield

1
Tetrahedron Letters
Efficient cyclopropanation of aryl / heteroaryl acetates and acetonitriles with vinyl
diphenyl sulfonium triflate
Mingwei Zhoua,b, Yimin Hub, Ke Ena, Xuefei Tanb, Hong C. Shenb,*, Xuhong Qiana,*
a Shanghai Key Laboratory of Chemical Biology, East China University of Science and Technology, Shanghai 200237, China.
b Roche Innovation Center Shanghai, Roche Pharmaceutical Research and Early Development, Shanghai 201203, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A convenient method was developed for the cyclopropanation of aryl acetates and aryl
acetonitrile using vinyl diphenyl sulfonium triflate salt. The newly developed conditions are
simple, mild, and compatible with a wide range of functional groups, without the need to apply
an inert atmosphere, or alkali bases.
Available online
2017 Elsevier Ltd. All rights reserved.
Keywords:
Cyclopropanation
Vinyl diphenyl sulfonium triflate salt
Building block for medicinal chemistry
Email address: hong.shen.hs1@roche.com
Introduction
Cyclopropyl-containing molecules are widely utilized in
synthetic organic chemistry and highly useful in medicinal
chemistry.1 In medicinal chemistry, the introduction of a
cyclopropyl moiety often enables the modification of molecular
properties such as lipophilicity, aqueous solubility and
conformation, as well as influences biological activity, metabolic
stability and toxicity. As such, the cyclopropyl moiety is
frequently present in preclinical candidates and clinical
compounds.2
In general, the reaction is carried out using either dimethyl
carbonate (DMC), ethylene sulfate or ethylene dihalogens as the
alkylating agent in the presence of a strong base such as sodium
hydride, sodium alkoxide, lithium hexamethyldisilazide
(LHMDS) or aqueous sodium hydroxide, as well as a phase
transfer catalyst (PTC). Despite moderate to good yields, the use
of highly toxic NaCN and KCN in preparing the acetonitrile
precursors, restricts the widespread application of this method.
Another approach starts with the corresponding phenylacetate.5
Similarly, the reaction utilizes DMC, ethylene sulfate and
ethylene dihalogens as the alkylating agent in the presence of a
strong base such as sodium hydride, sodium alkoxide, or
LHMDS. However, the yields are often low.5 In addition, the
reaction can be sensitive to air and moisture due to the reactivity
of the strong alkali base. Furthermore, the presence of a strong
base will most likely deprotonate -OH and –NHR containing
functional groups to generate the corresponding alkylation by-
products.
O
O
F
F
O
OH
H
N
O
O
NH
O
F
F
H
HO
N
N
O
O
F
F
O
N
F
F
O
O
O
F
OH
c, Tezacaftor
HO
HO
b, Lumacaftor
O
a, ABBV-2222
CFTR Channel Correctors
Phase II, Galapagos & AbbVie
CFTR Channel Correctors
Approved, Vertex
CFTR Channel Correctors
Phase III, Vertex
O
N
S
HO
O
O
HN
O
N
O
Cl
Cl
O
N
H
H
O
O
F
HO
d, Itanapraced
Recently, we reported the highly efficient cyclopropanation of
oxindoles with vinyl diphenyl sulfonium triflate.6 Numerous
advantages using the vinyl diphenyl sulfonium as the
cyclopropanation reagent were disclosed, such as high yields,
mild reaction conditions, good reaction selectivity, and the
potential for broad application in late-stage functionalization.
Additionally, vinyl sulfonium salts can be easily prepared using
robust and safe protocols from 2-bromoethanol.7 Herein, we
report the application of this efficient cyclopropanation protocol
to aryl acetates as well as aryl acetonitriles, which significantly
broadens the scope of this cyclopropylation methodology.
e, BMS-986202
LPAR1 Antagonists
Phase II, Bristol-Myers Squibb
f, DN-108
Aldose Reductase Inhibitors
Preclinical, Torii
gamma-Secretase Modulators
Phase II,Nikem Research Chiesi
Scheme 1. Clinical compounds or preclinical candidates containing
phenylcyclopropanecarboxylic acid or its derivatives.
The phenylcyclopropanecarboxylic acid motif is one of the key
scaffolds in clinical or preclinical compounds for the prevention
and treatment of cystic fibrosis and neurodegenerative diseases
(Scheme 1).3 To date, the most common synthetic route to
phenylcyclopropanecarboxylic acid involves initial preparation of
the corresponding acetonitrile precursors (Scheme 2).3,4
*Corresponding author.

2
corresponding cyclopropanation products. It should be noted
Previous work:
that substrates containing functional groups such as NH2,
NHBoc, and boronic acid (Table 2, 4q, 4r, and 4s, respectively)
also led to the desired cyclopropyl containing products without
N- or O-alkylation, demonstrating a wide range of functional
group compatibility. However, this cyclopropanation reaction
cannot take place for alkyl acetates due to the significant lower
acidity of the alpha proton.
z
O
O
X
X
or
X
R
Ar
R
N
Ar
Ar
N
Base
Z = CO, SO2
X, Y = Cl, Br
z
2
4
H+ / OH-
1
O
O
or
X
OR'
OR'
R
Ar
R
O
O
Base
3
This work:
-
S+
OR'
OTf
Ph
Table 2. Reaction scope and isolated yields for the cyclopropylation of aryl
acetates.a,b
OR'
Ph
Ar
R
Ar
R
O
O
DBU
4
3
Scheme 2. Synthetic routes towards phenylcyclopropanecarboxylic acid
derivatives.
+ OTf -
O
S
O
R'
Ph
Ph
R'
R
A
Ar
Ar
R
O
O
4b-s
Base, Solvent
3b-s
Results and Discussion
O
O
O
O
O
O
Br
Initially, the cyclopropanation of methyl 2-phenylacetate 3a
with vinyl diphenyl sulfonium salt was examined using CH2Cl2
as the reaction solvent. After screening a variety of bases, DBU
was found to give the desired cyclopropylated product 4a in 20%
yield, which was more efficient than the reactions using triethyl
amine (TEA), diisopropylethylamine (DIPEA), and cesium
carbonate (Table 1, entry 3 vs. entries 1 and 2). Through solvent
screening (Table 1, entries 3, 5-7) and adjustment of base
equivalents (Table 1, entries 7 and 8), it was found that polar
aprotic solvents such as DMF and DMSO were superior to
CH2Cl2 and MeCN leading to higher yields, and that the yields
were correlated to the solvent polarity. Specifically, the
optimized reaction conditions were identified as those in entry 8
of Table 1. Conducting the reaction at a lower temperature (0 oC)
or under an inert atmosphere did not significantly affect the
reaction yield (Table 1, entries 9 and 10).
O
O
O
F
Br
4c, 85%
4d, 84%
4b, 73%
O
O
Cl
Cl
F
O
O
O
O2N
Br
4e, 86%
4g, 92%
4f, 90%
F
O
O
O
O
O
F
O
O
O
4j,76%
4h, 54%
4i, 68%
O
N
O
O
O
O
4k, 68%
4m, 95%
4l, 70%
Br
O
O
O
O
O
S
N
O
O
N
S
O
N
4o, 84%
4n, 95%
4p, 96%
O
O
O
HO
O
N
O
Table 1. Optimization of the reaction conditions.a
B
O
N
H
H2N
4r, 65%
OH
4s, 58%
4q, 50%
OTf -
a
S+
Reagents and conditions: 3 (1 mmol), A (1.2 mmol), DBU (3 mmol), DMSO
O
O
A
Ph
(5 mL), 21 oC, 12 h;bIsolated yield.
Ph
Base, Solvent
O
O
4a
3a
Entry
Base (equiv.)
Solvent
Yield 4a
Table 3. Reaction scope and isolated yields for the cyclopropylation of aryl
and heteroaryl acetonitriles.a,b
(%)d
0
1
2
3
4
5
TEA (2.0)
DIPEA (2.0)
DBU (2.0)
Cs2CO3 (2.0)
DBU (2.0)
DBU (2.0)
DBU (2.0)
DBU (3.0)
DBU (3.0)
DBU (3.0)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
DMF
DMSO
DMSO
DMSO
DMSO
0
20
0
46
65
70
73
74
74
+ OTf -
S
Ph
Ph
A
R
Ar
N
R
Ar
N
Base, Solvent
F
6
7
1a-p
2a-p
Br
8
9b
N
N
N
N
N
10c
F
F
2c, 90%
2f, 95%
2i, 96%
2b, 93%
CF3
2a, 95%
2d, 92%
aReagents and conditions unless otherwise specified: 3a (0.2 mmol), A (0.24
mmol), base, solvent (1 mL), 21 oC, without a N2 atmosphere, 12 h; bReaction
conducted at 0 oC; cReaction conducted with a N2 atmosphere; dIsolated yield.
F
N
N
CF3
Br
2e, 94%
O
With the optimized conditions in hand, we then examined the
scope of aryl acetate substrates for cyclopropanation. As shown
in Table 2, substrates containing both electron donating groups
(e.g. methyl, methoxy), and weak or strong electron withdrawing
substituents (e.g. halogen, nitro), generated the corresponding
cyclopropanation products in moderate to excellent yields (Table
F
O
O
N
N
F
HO2C
2h, 85%
2g, 70%
2j, 92%
N
N
N
N
N
O
2k, 85%
2n, 96%
2l, 83%
2, 4b-j).
In particular, 1-(2,2-difluoro-1,3-benzodioxol-5-
yl)cyclopropanecarboxylic acid ester (4j), as the key intermediate
for the clinic candidates Lumacaftor, Tezacaftor, and ABBV-
2222, was obtained with 76% yield (Table 2, 4j). The literature
preparations of such compounds proceed through complicated
routes with lower yields for the cyclopropanation product.8 In
addition, heteroaryl acetates bearing a pyridine (Table 2, 4m, 4n),
thiophene (Table 2, 4o), imidazo[1,2-a]pyridine (Table 2, 4p), or
thiazole (Table 2, 4q) reacted smoothly to afford the
S
N
N
N
N
2o, 90%
2m, 93%
F
O
O
HN
N
N
Cl
2p, 76%

3
aReagents and conditions: 3 (1 mmol), A (1.2 mmol), DBU (3 mmol), DMSO
(5 mL), 21 oC, 12 h;bIsolated yield.
mild reaction conditions, no requirement for an inert
atmosphere or alkali bases, and the remarkable compatibility
with a broad range of functional groups, demonstrate the
potential of this reaction as a versatile method to generate aryl or
heteroaryl acetates or acetonitriles containing a cyclopropyl
moiety at the alpha position. As such, this method appears
suitable for wide-spread application in medicinal chemistry.
Subsequently aryl acetonitrile substrates were explored as
shown in Table 3. The reactions proceeded smoothly for aryl
substrates in which the aryl groups is substituted with either
electron donating groups (e.g. methyl, methoxy), or electron
withdrawing groups (e.g. trifluoromethyl, halogen), affording the
corresponding cyclopropanation products in good to excellent
yields (Table 3, 2a-l). In addition, substrates containing a
heteroaryl (e.g. pyridinyl, thiophene, carbolines) also provided
the desired products (Table 3, entries 2m-p). Similar to the
previous observation that functional groups containing acidic
protons did not interfere the desired cyclopropanation (Table 2,
4q-s), an unprotected carboxylic acid andcarbolines also led
to the corresponding cyclopropanation product in excellent yield
(Table 3, 2j and 2p).
Acknowledgments
We thank Liqin Chen for the HRMS support, and Professor
Yufang Xu for helpful discussions.
Supplementary data
Supplementary data associated with this article can be found, in
the online version.
Furthermore, 1,3-dicarbonyl substrates were explored as
shown in Table 4. The reactions proceeded efficiently for both
aryl- (Table 4, 5a) and alkyl-containing substrates (Table 4, 5b),
as well as diethyl malonate (Table 4, 5c).
References and notes
1
Gopal PR, Prabakar AC, Chandrashekar ERR, Bhaskar BV, Somaiah
PV. J Chin Chem. Soc. 2013; 60: 639-644. (b) Ghosh NH, Sheldrake
M, Searcey M., Pors K. Curr Top Med Chem. 2009; 9: 1494-1524.
(c) Zechmeister K, Brandl F, Hoppe W, Hecker E, Opferkuch HJ,
Adolf W. Tetrahedron Lett. 1970; 11: 4075-4078. (d) Nani RR.,
Reisman SE. J Am Chem Soc. 2013; 135: 7304-7311. (e) Seebach
MV, Kozhushkov SI, Boese R, Benet-Buchholz J, Yufit DS, Howard,
JAK, Meijere AD. Angew Chem Int Ed. 2000; 39: 2495-2498. (f)
Mao Z, Qu H, Zhao Y, Lin X. Chem Commun. 2012; 48: 9927-9929.
Talele TT. J Med Chem. 2016; 59: 8712-8756.
(a) McPhail G, Clancy JP. Drugs of the Future 2012; 37: 717-723. (b)
Hadida Rua S, Hamilton M, Miller M, Grootenhuis, PDJ, McCarthy
B, Bear J, Zhou J. Patent WO 2007056341, 2007. (c) Tanoury GJ,
Harrison C, Littler BJ, Rose PJ, Hughes RM, et al., Patent WO,
2011133751, 2011. (d) Kym PR, Wang X, Searle XB, Liu B, Yeung
MC, Altenbach RJ, Voight E, Bogdan A, Koenig JR. Patent WO,
2016069757, 2016. (e) Hutchinson JH, Seiders TJ, Swaney JS. Patent
WO, 2011159632, 2011. (f) Peretto PI, Radaelli S, Parini C,
Imbimbo, BP. et al., J Med Chem. 2005; 48: 5705-5720. (g) Taira S,
Sugimoto A. Patent WO, 1997032863, 1997.
Table 4. Reaction scope for the cyclopropylation of 1,3-dicarbonyls.a,b
+ OTf -
O
O
S
O
O
Ph
Ph
R'
A
R
O
O
R'
R
O
DBU, DMSO
5a-c
6a-c
2
3
O
O
O
O
O
O
O
O
O
6a, 96%
6b, 91%
6c, 97%
aReagents and conditions: 3 (1 mmol), A (1.2 mmol), DBU (3 mmol), DMSO
(5 mL), 21 oC, 12 h;bIsolated yield.
Based on the above results and literature reports,9 a mechanism
was proposed for the cyclopropanation of an aryl acetate
(Scheme 3). Presumably, the substrate first undergoes
deprotonation in the presence of DBU, followed by conjugate
addition to the vinyl sulfonium salt. The subsequent 1,3-proton
shift and intramolecular SN2 reaction to expel phenyl sulphide
from the zwitterionic intermediate affords the cyclopropanation
product.
4
(a) Arava VR, Siripallia UBR, Dubey PK. Tetrahedron Lett. 2005;
46: 7247-7248. (b) Massimo V, Livius C. et al., Patent WO,
2014206897, 2014.
5
6
Zhang D, Zheng H, Wang X, Tetrahedron 2016; 72: 1941-1953.
Zhou M, En K, Hu Y, Xu Y, Shen HC, Qian X. RSC Adv. 2017; 7:
3741-3745.
7
(a) Gosselck J, B´eress L, Schenk H. Angew Chem Int Ed. 1966; 5:
596-597. (b) Wang Y, Zhang W, Colandrea VJ, Jimenez LS,
Tetrahedron 1999; 55: 10659-10672. (c) Unthank MG, Hussain N,
Aggarwal VK. Angew Chem Int Ed. 2006; 42: 7224-7227; (c)
Unthank B, Tavassoli B, Aggarwal VK. Org Lett. 2008; 10: 1501-
1504.
S+
S+
H
H
Base
- H+
-
-
Ar
EWG
Ar
EWG
Ar
EWG
8
9
(a) Siesel D, Patent WO, 2009076142, 2009. (b) Ye T, Lu X, Yu G,
He S. Patent CN, 105153105.
(a)Yar M, McGarrigle EM, Aggarwal VK. Angew Chem Int Ed. 2006;
42: 7224-7227. (b) Unthank MG, Hussain N, Aggarwal VK. Angew
Chem Int Ed. 2006; 45: 7066-7069.
S+
- Ph2S
Ar
EWG
-
Ar
EWG
Scheme 3. The proposed mechanism for cyclopropanation of an aryl acetate
using vinyl sulfonium salt.
Summary
In conclusion, a highly efficient cyclopropanation reaction
was developed for the cyclopropanation of aryl or heteroaryl
acetates, acetonitriles, and 1,3-dicarbonyl compounds using
commercially available vinyl diphenyl sulfonium triflate. The
reactions proceed under ambient conditions to provide the
desired cyclopropanation products in high yields. The simple and

4
 Highly efficient cyclopropanation of aryl
and heteroaryl acetates and acetonitriles, as
well as dicarbonyl compounds
 Convenient reaction protocol devoid of the
use of strong base
 Reaction compatible with various functional
groups such as carboxylic acid, boronic
acid, amine, and carbamate
 Potential wide application in medicinal
chemistry

5
Graphical Abstract
To create your abstract, type over the instructions in the
template box below.
Fonts or abstract dimensions should not be changed or altered.
Efficient cyclopropanation of aryl /
heteroaryl acetates and acetonitriles with
vinyl diphenyl sulfonium triflate
Leave this area blank for abstract info.
Mingwei Zhou a,b, Yimin Hu b, Ke En a, Xuefei Tan b, Hong C. Shen b,*, Xuhong Qian a,*
-
OTf
Ph
Ph
Ar
Ar
DBU, DMSO
21 oC, 12 hrs
EWG: CO2R, CN
35 examples
50 - 96% yield