Stereoselective Construction of Nitrile-Substituted Cyclopropanes from 2-Substituted Ethenesulfonyl Fluorides via Carbon-Sulfur Bond Cleavage

Article abstract of DOI:10.1002/adsc.201900635

The intermolecular cyclopropanation of 2-aryl and 2-styryl substituted ethenesulfonyl fluorides with active cyano-containing methylene compounds was described. This reaction proceeds via carbon-sulfur bond cleavage under metal-free conditions in up to 99% yield, affording a variety of nitrile-substituted cyclopropanes with high diastereoselectivity. (Figure presented.).

Full text of DOI:10.1002/adsc.201900635

Title: Stereoselective Construction of Nitrile-Substituted Cyclopropanes
from 2-Substituted Ethenesulfonyl Fluorides via Carbon-Sulfur
Bond Cleavage
Authors: Hao Liu, Balakrishna Moku, Fei Li, Jiabing Ran, Jinsong Han,
Njud Alharbi, Sihui Long, Gao-Feng Zha, and Huali Qin
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900635
Link to VoR: http://dx.doi.org/10.1002/adsc.201900635

Advanced Synthesis & Catalysis
10.1002/adsc.201900635
UPDATE
DOI: 10.1002/adsc.201
Stereoselective
Construction
of
Nitrile-Substituted
Cyclopropanes from 2-Substituted Ethenesulfonyl Fluorides via
Carbon-Sulfur Bond Cleavage
a
b
c
d
c
a,
Hao Liu, Balakrishna Moku, Fei Li, Jiabing Ran, Jinsong Han, Sihui Long, * Gao-
a,b
b
Feng Zha * and Hua-Li Qin
aKey Laboratory for Green Chemical Process of Ministry of Education; Hubei Key Laboratory of Novel Reactor and
Green Chemical Technology; Hubei Engineering Research Center for Advanced Fine Chemicals; School of Chemical
st
Engineering and Pharmacy, Wuhan Institute of Technology, 206 1 Rd Optics Valley, East Lake New Technology
Development District, Wuhan, 430205, China; Fax: +86 27 87194465; Email: sihuilong@wit.edu.cn (S. Long);
zgflmx@whut.edu.cn (G.-F. Zha)
bSchool of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, 205 Luoshi Road,
Wuhan, 430070, China.
cSchool of Engineering, China Pharmaceutical University, Nanjing, 210009, China
dKey Laboratory of Analytical Chemistry for Biology and Medicine, Ministry of Education, College of Chemistry and
Molecular Sciences, Wuhan University, Wuhan, 430072, China
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract The intermolecular cyclopropanation of 2-aryl metastasis.[4]
and 2-styryl substituted ethenesulfonyl fluorides with active
cyano-containing methylene compounds was described.
This reaction proceeds via carbon-sulfur bond cleavage
under metal-free conditions in up to 99% yield, affording a
variety of nitrile-substituted cyclopropanes with high
diastereoselectivity.
Keywords: Cyclopropanation; Ethenesulfonyl fluorides;
Diastereoselectivity; Nitrile-substituted;
Scheme 1. Structures of natural and bioactive synthetic
cyclopropanes
Cyclopropyl group, the smallest cyclic alky
group, is an indispensable building block of a lot of
natural products and bioactive synthetic compounds
However, in spite of the excellent properties of
cyano-substituted cyclopropanes, the construction of
(
Scheme 1) for its special
benefits including
its derivatives under mild conditions is quite
challenging. Currently, three major strategies have
been reported: cyclopropanation of alkyene and
malononitrile analogs with catalytic amount of
enhancing potency, reducing off-target effect,
increasing metabolic stability, and increasing brain
permeability, etc.[1] Cyano group, which possesses
special biological activities and can be easily
converted into a variety of functional groups, has
been extensively introduced into certain molecules to
[5]
molecular iodine and a stoichiometric oxidant
(
Scheme 2a); cyclopropanation of olefins by Ru-
[
6]
[7]
[8]
[2,3]
porphyrins,
myoglobin
iron,
catalysed decomposition of diazo
acetonitrile (Scheme 2b); Michael-initiated ring-
Rh
2
(S-PTAD)
4
,
engineered
endow them with unique properties.
In this regard,
[
9]
it was hypothesized that the synergistic effect of
combining a cyano and a cyclopropyl group into one
entity may grant some target pharmacologically active
molecules fascinating properties. For instance,
Odanacatib, a FDA-approved drug derived from
[10]
closure reaction (Scheme 2c). Besides, as the
potential approaches to build cyano-substituted
cyclopropanes, vinyl selenones /vinyl sulfonium
salts -mediated cyclopropanation reactions were
also reported. Each of them has shown some unique
[11]
[12]
cyano-substituted
cyclopropanes,
has
been
extensively utilized for osteoporosis and bone
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201900635
advantages but also inevitably has some non- Table 1. Screening of Reaction Conditions of
Cyclopropanation
Fluoridesa
of
2-Substituted
Ethenesulfonyl
negligible defects.
DBU
Reaction
Additive
Yield
Yield
Entry Solvent Loading Temperature
(Y eq.)
(3a, %) (4a, %)
(
X mol%)
(oC)
1
2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DCM
DMF
5
50
5
10-15
10-15
10-15
10-15
10-15
30
/
/
76 (75) trace
28
0
65
50
3
NaHCO
3
(2.0)
4
5
Na PO
3
4
(2.0)
(2.0)
(2.0)
(2.0)
(2.0)
(2.0)
0
26
5
5
K
K
K
K
K
2
2
2
2
2
HPO
HPO
HPO
HPO
HPO
4
4
4
4
4
0
68
Scheme 2. Previous work and proposed construction of nitrile-
substituted cyclopropane through a 1,3-elimination of SO F
2
6
5
0
86
7
5
50
0
94
8
5
70
0
80
In this work, we proposed a novel strategy based
on Sulfur (VI) Fluoride Exchange (SuFEx), which
showed some advantages over the aforementioned
conventional methods at certain aspects and might
9
5
50
0
trace
10b
5
50
K
2
HPO
(1.2)
0
95 (94)
4
aReaction conditions: (E)-2-([1,1'-biphenyl]-4-yl) ethene-1-
inspire future research work on the synthesis of sulfonyl fluoride (1a, 26 mg, 0.1 mmol), Malononitrile (2a, 0.3
mmol), solvent (1.0 mL), additive and DBU were added to a
reaction tube (20 mL) and reacted for 12 h. The yields were
derivatives of cyano-substituted cyclopropanes.
Arylethenesulfonyl fluoride, an emerging synthon in
determined by HPLC using 1a, 3a，4a as the external standard
1a = 6.223 min, λmax = 308 nm; t3a = 3.348 min, λmax = 332 nm;
4a = 4.08 min, λmax = 258 nm, CH CN / water = 70 : 30 (v / v)).
SuFEx Chemistry[ and a unique bis-electrophile,
could be inimitably attacked by two chemoselective
nucleophiles.[ On the basis of the pioneering work
of Sharpless, Arvidsson, and our group, β-substituted
vinyl sulfonyl fluorides can be easily prepared from
abundant and cheap reagents (e.g., organic iodides,
13]
(
t
t
3
14a]
Isolated yields on a 0.5 mmol scale are reported in parentheses.
b
Malononitrile (2a, 0.12 mmol, 1.2 eq.) was used.
Initially, (E)-2-([1,1'-biphenyl]-4-yl) ethene-1-
sulfonyl fluoride 1a and malononitrile 2a were
selected as model substrates to optimize the direct
cyclopropanation reaction (Table 1 and supporting
information). When 5% DBU was added as the sole
base for this reaction, only Michal adduct product 3a
was obtained with 76% yield (entry 1, Table 1). After
screening of DBU loading (see supporting
information for details), we observed the
dicyanocyclopropanation product 4a in 65% yield but
with a certain amount of 3a by using 50% DBU as the
base. Extensive screening of additive (entry 3-5),
reaction temperature (entry 6-8), solvent (entry 9),
[14]
aryl-boronic acids and aryl-diazonium salts). In our
previous work[ , the Michael adduct generated from
p-nitrophenylethenesulfonyl fluoride and diethyl
15]
malonate ( DBU and NaHCO in DCM serving as
3
catalysis and additive, respectively) can be driven to
eliminate sulfonyl fluoride, and formed an enedione
when DBU approaches one equivalent, with SO
serving as the leaving group (Scheme 2d). Therefore,
we envisioned possible construction of
cyclopropane through a 1,3-elimination of SO
Scheme 2): after Michael addition and deprotonation
2
F
a
2
F
(
using a suitable base, the adduct generated in situ
would be converted into the corresponding reactive
methine carbon. Afterwards, the as-prepared activated
methine carbon attacked the neighbouring carbon of
reaction ratio of 1a and 2a (entry 10) revealed that
o
K
2
HPO
4
(1.2 eq.) and 5 mol% DBU in DMF at 50 C
for 12 h were required to afford the optimized isolated
yield of 94% of 4a (entry 10).
SO
2
F and resulted in the SO F leaving. As a result,
2
the corresponding cyclopropanation product was
obtained.
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201900635
Table 2. DBU-Catalyzed Cyclopropanation of 2-
Substituted Ethenesulfonyl Fluorides (1) and Malononitrile
(
2a)a
Scheme 3. Cyclopropanation of 1,3-dienylsulfonyl
fluorides and malononitrile 2a
Then, with ethyl cyanoacetate (2b) as the
nucleophile, the optimized reaction conditions are
proven to be suitable for its cyclopropanation reaction
with different arylethenesulfonyl fluorides to afford
the
corresponding
ethyl-1-cyano-2-
phenylcyclopropane-1-carboxylate 5 in good to
excellent yields (Table 3). The exclusively trans
configuration was confirmed by the X-ray crystal
structure of 5i with a slightly reduced torsion angle
between the phenyl and cyclopropane planes (from
o
o [16]
6
7.477 to 61.301 ) , owing to the larger steric
hindrance from the ester group compared to the cyano
group. Remarkably, the efficiency of
cyclopropanation reaction did not deteriorate when
the reaction was performed on a 8 mmol (1a, 2.1 g)
scale, furnishing the corresponding product 5a in 91%
isolated yield and excellent diastereoselectivity.
aReaction conditions: 2-substituted ethenesulfonyl fluorides (1,
.5 mmol), malononitrile (2a, 0.6 mmol), DMF (1.0 mL),
HPO (1.2 eq.) and DBU (5 mol%) were added to a reaction
tube (20 mL) and the mixture was stirred at 50 C for 12 h.
Isolated yields were shown.
0
K
2
4
o
Table 3. DBU-Catalyzed Cyclopropanations of 2-
Substituted Ethenesulfonyl Fluorides (1) and Ethyl
Next, we set out to evaluate functional group
tolerance and scope of the reaction of substituted
cyanoacetate (2b)a
(
hetero)arylethenesulfonyl
fluorides
1
and
malononitrile 2a with the optimized reaction
conditions. As shown in Table 2, a broad scope of
(
hetero)arylethenesulfonyl fluorides substrates were
examined for the cyclopropanation process. The
substrates functionalized with both electron-
withdrawing groups(e.g., Nitro (1h), acyl (2i and 2k),
trifluoromethyl (2j) and halogens (2e-2g)) and
electron-donating groups (e.g., alkyl (2i and 2j), aryl
(
2a), and ethers (2b)) were well tolerated under the
reaction conditions in good to quantitative yields
from 57 to 96%). The X-ray crystal structure of 4a
demonstrated that the phenyl connected to the
(
aReaction conditions: 2-substituted ethenesulfonyl fluorides (1,
0
.5 mmol), ethyl cyanoacetate (2b, 0.6 mmol), DMF (1.0 mL),
cyclopropane was approximately perpendicular to the K HPO (1.2 eq.) and DBU (5 mol%) were added to a reaction
2
4
o
o
cyclopropane ring (with the torsion angle of 67.477
tube (20 mL) and the mixture was stirred at 50 C for 12 h.
Isolated yields shown. Isolated yields referred to the trans product
after column chromatography; the dr was determined from the
between the two planes)[
16]
.
1
b
When 1,3-dienylsulfonyl fluorides 1v and 1w crude reaction mixture by H-NMR. The reaction was conducted
on a 8 mmol scale (1a, 2.1 g).
were chosen as the substrates, the corresponding
alkenylcyclopropanes 4v and 4w were afforded
readily with good yields (Scheme 3). The addition
Besides, 2-cyano-N, N-dimethylacetamide (2c)
[15a]
position is consistent with our previous work.
As was a suitable substrate for the reaction, affording the
expected, the cyclopropanation reaction failed when corresponding 1-cyano-N, N-dimethylcyclopropane-
2-alky substituted ethenesulfonyl fluoride (1x) was 1-carboxamide (6) in 54% yield with excellent
[17]
selected as the electrophile
.
diastereoselectivity (entry1, table 4). However, when
the nitrile group of malononitrile was replaced with a
non-electron withdrawing phenyl group, only an
addition product (7) was obtained in 75% yield (entry
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201900635
2, table 4). When it was replaced with an enolizable
carbonyl compound, δ-Sulton products were obtained
by direct annulative SuFEx Click reaction under this
reaction condition (entry 3-5, table 4). Interestingly,
with bis-sulfonyl nucleophile (2h) being utilized as
reaction partner, the corresponding cyclopropanation
product 11 was afforded with good yield and
excellent diastereoselectivity (entry 6, table 4). Thus,
these cyclopropanation reactions need methylene
compounds with relatively strong bis-electron
withdrawing groups which can’t be enolized under
basic conditions. If single substituted or enolized
methylene compounds were employed under these
reaction conditions, the corresponding Michael
addition products or δ-sulton products were afforded
respectively.
Scheme 4. “Two-step” cyclopropanation reaction
To gain some insight into the reaction
mechanism, two-step cyclopropanation reactions were
designed (Scheme 4). Michael adduct product 3a was
first synthesized in 75% isolated yield without the
additvie (K
2
HPO ). Then the cyclopropanation
4
reaction was also conducted smoothly with excellent
yield. When ethyl cyanoacetate (2b) was employed
for this “ two-step” reaction, the Michael adduct
product 5aa was observed as diastereomeric mixture
(dr = 3 : 2), which was transformed into the
corresponding cyclopropanation product (5a) with
excellent diastereoselectivity (dr > 20 : 1). The
control experiments is consistent with our initial
conception. Based on our mechanism study and recent
Table 4. DBU-Catalyzed Cyclopropanations of (E)-2-
(
[1,1'-Biphenyl]-4-yl) ethene-1-sulfonyl fluoride (1a) and
a
Active Methylene Compounds (2)
[18]
research , a plausible mechanism is illustrated in
Scheme 5. Initially, the intermediate 12 was afforded
after Michael addition. The hydrolysis of sulfonyl
fluoride under DBU catalysis generated the sulfonic
-
acid intermediates 13 and 14. Fluoride ion (F )
generated from this step was obviously observed from
1
9
the reaction F-NMR spectra (see the mechanism
study in supporting information). With an
intramolecular attack by the activated methine carbon
-
and leaving of sulfite (HSO
3
), intermediate 14 is
favored over intermediate 13 due to steric effects,
affording the trans diastereomer 5. However, the
details still remain unclear.
aReaction conditions: (E)-2-([1,1'-biphenyl]-4-yl) ethene-1-
sulfonyl fluoride 1a (1a, 0.5 mmol), active methylene
compounds (2, 0.6 mmol), DMF (1.0 mL), K
2 4
HPO (1.2
eq.) and DBU (5 mol%) were added to a reaction tube (20
o
mL) and the mixture was stirred at 50 C for 12 h. Isolated Scheme 5. A plausible mechanism for the stereoselective
b
yields. Isolated yields referred to the trans product after
construction of nitrile-substituted arylcyclopropanes
column chromatography; the dr was determined from the
1
crude reaction mixture by H-NMR.
In conclusion, a mild and practical method for
construction of nitrile-substituted cyclopropanes from
2-aryl and 2-styryl substituted ethenesulfonyl
fluorides via Carbon-Sulfur bond cleavage was
developed. The reaction proceeded without any metal
catalysts, exhibiting excellent compatibility to a large
4
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Advanced Synthesis & Catalysis
10.1002/adsc.201900635
variety of functional groups (over 34 examples),
resulting in good to quantitative yields and excellent
diastereoselectivity.
A. Wallweber, B. M. Liederer, G. Deshmukh, E. Plise,
S. Tay, P. Reynen, J. Herrington, A. Gustafson, Y. Liu,
A. Dirksen, M. G. A. Dietz, Y. Liu, T.-M. Wang, J. E.
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Experimental Section
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Nagasawa, E. Yamaguchi, N. Tada, A. Itoh, Org. Lett.
General Procedures for Cyclopropanation
An oven-dried reaction tube (20 mL) was charged with
arylethenesulfonyl fluoride (1, 0.5 mmol), active methylene
compounds (2, 0.6 mmol, 1.2 eq.), DBU (5 mol%) and
2 4
K HPO (0.6 mmol, 1.2 eq.). The resulting mixture was
o
stirred at 50 C for 12 h. When the arylethenesulfonyl
fluoride had been consumed (monitored by TLC), the
reaction mixture was poured into water (30 mL), extracted
2
016, 18, 8-11.
with ethyl acetate (3 × 25 mL). The combined organic [6] Y. Ferrand, P. Le Maux, G. Simonneaux, Tetrahedron:
layers were then washed with water (3 ×25 mL) and dried
over anhydrous sodium sulfate. The crude products were
purified by column chromatography on silica gel to give
the title compounds.
Asymmetry 2005, 16, 3829-3836.
[
[
7] K. J. Hock, R. Spitzner, R. M. Koenigs, Green Chem.
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Financial support was provided by National Natural Science
Foundation of China (Grant No. 21801197). We are grateful to
Prof. Long Wang (Huazhong University of Science and
[
2
Technology) for helpful discussion. We thank Dr. Njud S. Alharbi [10] a) L. S. Aitken, L. E. Hammond, R. Sundaram, K.
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Advanced Synthesis & Catalysis
10.1002/adsc.201900635
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9
16] CCDC 1916604 and CCDC 1916605 contain the data
of compounds 4a and 5i, respectively. These data can
be obtained free of charge from The Cambridge
Crystallographic
Data
Centre
via
www.ccdc.can.ac.uk/data_request/cif.
17] 4-phenylbut-1-ene-1-sulfonyl fluoride (1x, 0.2 mmol)
malononitrile (2a, 0.24 mmol), DMF (0.5 mL),
K
2
HPO
4
(1.2 eq.) and DBU (5 mol%) were added to a
reaction tube (20 mL) and the mixture was stirred at
o
5
0 C for 12 h. No new spots were detected (TLC).
[
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6
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Advanced Synthesis & Catalysis
10.1002/adsc.201900635
UPDATE
Stereoselective Construction of Nitrile-Substituted
Cyclopropanes from 2-Substituted Ethenesulfonyl
Fluorides via Carbon-Sulfur Bond Cleavage
Adv. Synth. Catal. Year, Volume, Page – Page
Hao Liu, Balakrishna Moku, Fei Li, Jiabing Ran,
Jinsong Han, Sihui Long,* Gao-Feng Zha* and
Hua-Li Qin
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