Cyanomethyl anion transfer reagents for diastereoselective Corey-Chaykovsky cyclopropanation reactions

Article abstract of DOI:10.1039/c8cc05602a

A readily available and bench-stable cyanomethyl sulfonium salt was used in highly diastereoselective Corey-Chaykovsky cyclopropanation reactions of electron-poor olefins. This efficient method provides a rapid route to access densely functionalized cyclopropyl nitriles.

Full text of DOI:10.1039/c8cc05602a

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
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Cyanomethyl Anion Transfer Reagents for Diastereoselective
Corey Chaykovsky Cyclopropanation Reactions
Renè Hommelsheim,a Katharina J. Hock,a Christian Schumacher,a Mohanad A. Hussein,b Thanh V.
Nguyen*b and Rene M. Koenigs*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Figure 1. Applications of cyclopropyl nitriles and cyclopropyl methylamines
A readily available and bench-stable cyanomethyl sulfonium salt
was used in highly diastereoselective Corey-Chaykovsky
cyclopropanation reactions of electron-poor olefins. This efficient
method provides a rapid route to access densely functionalized
cyclopropyl nitriles.
Cyclopropyl nitriles
NC
O
NC
O
N
CF3
NH
N
N
F3
C
NH2
O
N
S
S
N
Cl
1
2
O
Cyclopropanes are a fascinating class of small molecules and
possess unique properties that are reasoned by the
conformational rigidity and distinctive spatial arrangement of
substituents in this smallest-possible carbocycle.1 Cyclopropyl
nitriles are ubiquitous in pharmaceutical research, for example
N
Cathepsin C inhibitor
NMDA receptor modulator
Cyclopropyl methylamines
N
H
N
O
NH2
O
O
NH2
F
O
O
as Cathepsin C inhibitors (
1, Figure 1) or as NMDA receptor
3
4
5
).3 They are also valuable precursors for the
5HT2C agonist
Tasimelteon
Levomilnacipran
modulators (
2
synthesis of cyclopropyl methylamines,2 as the reduction of
the nitrile group readily furnishes cyclopropyl methylamines.
These compounds in turn are privileged scaffolds in many
current applications of nitrile cyclopropanes are almost
exclusively on trans-substituted cyclopropanes.
biologically active compounds (
3
-
5
) and find applications in
).3,4
We therefore became intrigued in exploring alternative
reagents for the introduction of a cyanomethylene group6,8
and envisaged a Michael initiated ring closing reaction using a
cyanomethylene anion transfer reagent (Scheme 1). In
previous studies,9 it was already demonstrated that halogen-
substituted acetonitrile provides an access to nitrile-
cyclopropanes though with strict limitations to substrate
scope, yield and stereoselectivity.
marketed drugs, e.g. Tasimelteon (4) or Levomilnacipran (
5
The latter was approved in 2013 and is used for the treatment
of depressions (Figure 1).
Despite tremendous research in the synthesis of ester or
trifluoromethyl-substituted cyclopropane ring systems,1,5
synthetic methods of nitrile-substituted cyclopropanes are still
scarce.6 Even today, the introduction of a “cyanomethylene”
group remains a challenge to organic synthetic methodology7
Scheme 1. Cyanomethyl anion transfer.
and only normally proceeds either by transfer of
a
cyanomethyl carbene6a or cyanomethyl radical.6b From a
synthetic perspective, traditional approaches are limited with
respect to the use of either expensive catalysts or hazardous
reagents. From a diversity point of view, they only allow the
synthesis of trans-substituted nitrile-cyclopropanes with
moderate diastereoselectivity. It is thus not surprising that
Inspired by these findings, we set out to explore the
cyclopropanation reaction between nitro styrene, as a model
substrate for electron-deficient olefins to prepare
functionalized cyclopropanes, and halo-acetonitrile in the
presence of different organic and inorganic bases (Table 1).
Unfortunately, only the rapid decomposition of the halo-
acetonitrile was observed under these basic reaction
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conditions. We subsequently evaluated different types of carbonate, DCM solvent and a concentration of 0.1 M proved
nucleophilic additives that could potentially form an to be the best conditions for the Corey-Chaykovsky
intermediate onium salt, which is more acidic and should cyclopropanation reaction, which proceeded in excellent yield
require less basic reaction conditions to proceed (Table 1, and diastereoselectivity. The cis stereochemistry of the nitrile
entries 3-9). Of all additives tested, only dimethyl sulfide gave group and the aromatic ring is remarkable and highlights
some positive results and cyclopropane 7a was isolated in 10% differences in reactivity and complementarity of the carbene5a
yield. The screening of different reaction conditions did not and radical reactivity5b versus the Corey-Chaykovsky
lead to an improvement of this transformation.
reactivity8a,10 as now both diastereoisomers can be accessed
with a high degree of stereo control. We also investigated Z-
nitro styrene and obtained a single product, which turned out
to be the same diastereoisomer as for the E-nitro olefin, albeit
in reduced yield.
Table 1. Initial investigations on the cyanomethyl anion transfer reaction.
Table 2. Optimization of reaction conditions.
a
#
X
base
additives
Yield (7a)
1
2
Br, Cl
Br, Cl
NEt3, DBU, TBAT, TBAF
-
-
No rct.
No rct.
Li2CO3, Na2CO3, K2CO3,
Cs2CO3, CsF, NaOEt, KOH
a
#
base
solvent
concentration
Yield (7a)
3
4
5
6
7
8
9
Br
Br
Br
Br
Br
Br
Br
K2CO3
Na2CO3
CsF
Me2S
Me2S
Me2S
Me2S
PhSMe
Ph2S
10%
traces
No rct.
No rct.
No rct.
No rct.
No rct.
1
2
Li2CO3
Na2CO3
K2CO3
DCM
DCM
0.2 M
0.2 M
0.2 M
0.2 M
0.2 M
0.2 M
0.2 M
0.2 M
0.2 M
0.2 M
0.2 M
0.8 M
0.1 M
0.1 M
traces
76%
63%
60%
64%
73%
43%
53%
55%
72%
62%
60%
93%
43%
NEt3
3
DCM
K2CO3
K2CO3
K2CO3
4
Cs2CO3
NEt3
DCM
5
DCM
DMAP
6
CsF
DCM
aReaction conditions: 6a (0.2 mmol), 2 eq. halo acetontitrile and 1.5 eq. of base
were stirred in 2 mL of DCM for 12 h at rt. Yields refer to isolated products as
single diastereoisomer.
7
TBAT
DCM
8
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
EtOAc
THF
9
10
11
12
13
1,4-dioxane
CHCl3
DCM
We thus decided to exchange the halogen moiety by a neutral
leaving group and turned our attention to the preformed
DCM
sulfonium salt
8
(Table 2) for Corey-Chaykovsky
substitute of bromo
14b
DCM
cyclopropanation reactions as
a
acetonitrile.10 In 1966, Baizer described the synthesis of a
cyanomethyl sulfonium salt for the first time,11a which is being
aReaction conditions: 6a (0.2 mmol), 2 eq. 8 and 1.5 eq. of Na2CO3 were stirred in
2
mL of DCM for 12 h at rt. Yields refer to isolated products as single
diastereoisomer. breaction with Z-nitro styrene.
used today as
a versatile coupling reagent in peptide
synthesis.12 From a synthetic perspective, sulfonium salts are
much less explored, e.g. in carbonyl homologation
reactions11b,d or in the synthesis of pyridine-2H-ones and
isatines.11c,d Jeckel and Gosselck reported the reaction with
malonic acid derivatives in cyclopropanation reactions, though
only two single examples are provided.11e The deprotonation
of a cyanomethyl sulfonium salt provides a sulfur ylide, whose
nucleophilic and kinetic properties were well studied by Mayr
and co-workers.13
In further experiments, we studied different nitro olefins to
evaluate the applicability of this transformation. Different
electron-withdrawing and electron-donating substituents in
ortho-, meta- or para-position were well-tolerated and the
desired cyclopropanes were isolated as
diastereoisomer with good to high yields (Scheme 2, entries
7b 7l). Similarly, heterocycles, such as thiophene (7p), furane
7o) or pyridine 7n) and other carbocycles (7m were
a
single
-
(
(
)
tolerated and the corresponding nitro olefins reacted
smoothly to afford the cyclopropanation products. Notably, an
aliphatic substrate was converted to the desired cyclopropane
We examined different bases and solvents for the
cyclopropanation reaction (Table 2) and in all cases we could
isolate the desired cyclopropane as a single diastereoisomer,
which was identified as the trans-isomer 7a (referring to the
relative stereochemistry of the nitro and nitrile moiety) as
determined by NOE spectroscopy.14 The aryl group is arranged
in cis stereochemistry to the nitrile group. Only in the case of
TBAT (tetrabutylammonium triphenyl difluorosilicate, entry 7)
we could observe a trace amount of a second isomer, which
was identified as the all-cis isomer as shown by NOE
experiments. The concentration had a significant effect on the
yield (entries 2, 12 and 13) and the combination of sodium
(
7q) in good isolated yield. In the case of β-methyl-trans-β-
nitro styrene, the cyclopropane was obtained only in low yield,
albeit as a single diastereoisomer (7r). On the other hand, α-
methyl-trans-β-nitro styrene did not provide the desired
cyclopropanation product; both these results can be attributed
to steric hindrance of the methyl group at the nitro olefin. In a
scale-up of this cyclopropanation reaction we could
demonstrate that the desired cyclopropane 7a can be
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obtained on gram-scale (1.04 g 7a, 82%, 6.7 mmol reaction diastereoisomer, irrespective of solvent and base, which is also
scale).
the trans-isomer as shown by NOE spectroscopy.14 The
To further expand the scope and applicability of this substitution pattern on the aromatic rings of other analogous
cyclopropanation reaction, we examined different unsaturated substrates (Scheme 2, entry 10b 10f) had little influence on
-
carbonyl compounds. Interestingly, typical Michael acceptors, the cyclopropanation reaction. Similarly, sulfur-containing
such as cinnamic aldehyde, nitrile or ethyl ester did not heterocycles (10i), carbocycles (10g) and aliphatic substrates
provide the desired reaction products. Only in the case of
benzylidene malodinitrile the cyclopropanation product (
could be isolated, though with poor yield. We next turned our significantly diminished yields
(
10j) reacted smoothly under the present conditions. β-
substituted unsaturated ketones or benzyl acrylate gave
10k ), which might be
9)
(
-m
attention to terminal α,β-unsaturated ketones. In our model attributed to steric hindrance due to the substituent in the β-
reaction, we were delighted to observe that the desired position. In all cases the trans configured product was
single obtained exclusively as a single diastereoisomer.14
cyclopropane 10a could be isolated as
a
Scheme 2 Substrate scope of nitro olefins and unsaturated carbonyl compounds.
EWG
metal-free
readily available, bench
stable sulfonium salts
electron-poor olefins
single diastereoisomer
EWG
S
CN
R
R
CN
Michael Acceptor
Cyclopropane
Sulfonium Salt
Reaction with Nitro Olefins
NO2
NO2
NO2
NO2
NO2
NO2
CN
CN
7e, 80%
CN
CN
CN
7b, 78%
NO2
CN
F3C
MeO
F
Cl
7c, 78%
7d, 71%
7f, 82%
7a, 93%
gram scale: 82% (1.04 g)a
NO2
NO2
NO2
NO2
NO2
OMe
NO2
F
Cl
CN
CN
CN
CN
CN
CN
CN
Cl
7g, 89%
OMe
7h, 82%
7j ,76%
NO2
7k, 79%
7i, 67%
NO2
7l, 65%
NO2
NO2
NO2
O2N
CN
N
CN
CN
7o, 65%
CN
7p, 88%
CN
O
S
7m, 65%
7n, 61%
7q, 67%
7r, 30%
Reaction with unsaturated carbonyl compounds
Cl
MeO
Ph
NC
NC
CN
CN
CN MeO
CN
CN
CN
CN
O
O
O
10c, 85%
O
O
O
10f, 87%
9, 31%
10a, 90%
10b, 85%
10d, 85%
10e, 76%
R
O
O
S
Ph
O
BnO
MeO
CN
CN
CN
CN
CN
CN
CN
O
O
O
O
O
O
10g, 91%
10h, 85%
10i, 87%
10j, 71%
R = Me, 10k, 28%
R = Ph, 10l, 25%
10m, 42%b
11, 93%b
6 : 1 d.r.
gram scale: 89% (1.11 g)c
Reaction conditions: Michael acceptor (0.2 mmol), 2 eq. 8 and 1.5 eq. of Na2CO3 were stirred in 2 mL of DCM for 12 h at rt. Yields refer to isolated products as single
diastereoisomer; a6.7 mmol scale; busing 1.75 eq. Cs2CO3 in 2 mL 1,4-dioxane; c6.2 mmol scale.
Finally, we decided to study applications of this protocol in the reaction scale). The stereochemistry of the major product was
synthesis of a key precursor of Levomilnacipran (5
). For this confirmed to be trans by comparison with literature data.15
purpose, we investigated the reaction of 2-phenyl acrylic acid The stereochemistry of this cyclopropanation reaction is
ester with our sulfonium salt. To our delight, this ester reacted consistent with previous observations8a in Corey Chaykovsky
smoothly to form the desired cyclopropane 11 in excellent cyclopropanation reactions and can be rationalized by the
yield, albeit in moderate diastereoselectivity. Unfortunately, mechanism depicted in Scheme 3a. We believe the
even after extensive screening of solvents and bases the cyclopropanation of Z-nitro styrene involved a re-orientation
diastereoselectivity of this transformation could only be process when the nitro group on the carbanion intermediate
improved to a 6:1 ratio.14 This can be rationalized by the lack rotated to avoid steric clash with the cyano group (see step 2
of steric discrimination between the ester and phenyl groups. of mechanism depicted in Scheme 3b) to prepare for the SN2
In a gram-scale experiment we were able to demonstrate the cyclopropanation, hence forming the same product as the E-
scalability of this transformation (1.11 g 11, 89%, 6.2 mmol isomer.
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for the highly diastereoselective synthesis of nitrile-substituted
cyclopropanes. We could demonstrate applications of
a
(cyanomethyl) dimethyl sulfonium salt in cyclopropanation
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of Levomilnacipran.
9
Conflicts of interest
There are no conflicts to declare.
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