Ring Opening of Donor-Acceptor Cyclopropanes with Cyanide Ion and Its Surrogates

Article abstract of DOI:10.1021/acs.joc.9b03098

A straightforward method for ring opening of donor-acceptor cyclopropanes with trimethylsilyl cyanide as a surrogate of cyanide ion in the presence of B(C₆F₅)₃ or trifluoromethanesulfonic acid as a catalyst has been developed. The methodology provides a short route to γ-cyanoesters that can be useful synthetic intermediates for the synthesis of diverse bioactive molecules such as glutaric and δ-aminovaleric acid derivatives, 3-arylpiperidines, or other substituted phenethylamines. Oppositely, the attempts to synthesize these γ-cyanoesters by direct reaction of cyclopropanes with sodium cyanide under typical S_N2 conditions led to the formation of 2-arylsuccinonitriles.

Full text of DOI:10.1021/acs.joc.9b03098

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Article
Ring Opening of Donor-Acceptor Cyclopropanes
with Cyanide Ion and Its Surrogates
Maksim Boichenko, Ivan Andreev, Alexey O. Chagarovskiy, Irina I.
Levina, Sergey S. Zhokhov, Igor V. Trushkov, and Olga A. Ivanova
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03098 • Publication Date (Web): 05 Dec 2019
Downloaded from pubs.acs.org on December 6, 2019
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Ring Opening of Donor-Acceptor Cyclopropanes with Cyanide Ion and Its
Surrogates
†
‡,II
‡,II
Maksim A. Boichenko, Ivan A. Andreev, Alexey O. Chagarovskiy, Irina I.
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§
†
‡,II,
†,‡,
Levina, Sergey S. Zhokhov, Igor V. Trushkov, * Olga A. Ivanova *
†
Department of Chemistry, M. V. Lomonosov Moscow State University,
Leninskie gory 1-3, Moscow 119991, Russian Federation; iv@kinet.chem.msu.ru
‡
N. D. Zelinsky Institute of Organic Chemistry Russian Academy of Sciences,
Leninsky pr. 47, Moscow 119991, Russian Federation; trush@ioc.ac.ru
II
Laboratory of Chemical Synthesis, Dmitry Rogachev National Medical
Research Center of Pediatric Hematology, Oncology and Immunology, Samory
Mashela 1, Moscow 117997, Russian Federation
§
N. M. Emanuel Institute of Biochemical Physics, Russian Academy of Sciences,
Kosygina 4, Moscow 119334, Russian Federation
Abstract:
Ar
CO Me
2
CO Me
2
`
TMSCN
Ar
CN CO Me
2
CO Me
2
up to 88% yield
3 examples
B(C F ) or TfOH
6
5
1
HFIP
A straightforward method for ring opening of donor-acceptor cyclopropanes with
trimethylsilyl cyanide as a surrogate of cyanide ion in the presence of B(C F )
6
5 3
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or trifluoromethanesulfonic acid as a catalyst has been developed. The
methodology provides a short route to -cyanoesters that can be useful synthetic
intermediates for the synthesis of diverse bioactive molecules such as glutaric and
0
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-aminovaleric acid derivatives, 3-arylpiperidines or other substituted
phenethylamines. Oppositely, the attempts to synthesize these -cyanoesters by
direct reaction of cyclopropanes with sodium cyanide under typical SN2
conditions led to the formation of 2-arylsuccinonitriles.
Introduction
Even though cyclopropanes with donor and acceptor substituents at the vicinal
1
carbon atoms (DA cyclopropanes) are known more than 125 years, they were
predominantly considered as exotic compounds until seminal works by Wenkert2
3
and Reissig who laid the foundations for the explosive growth of the study of
DA cyclopropanes as building blocks in the synthesis of a broad diversity of
acyclic, alicyclic, and heterocyclic compounds, observed in the last two decades.4
The presence of donor and acceptor substituents at vicinal carbon atoms provides
excellent reactivity of three-membered rings as synthetic equivalents of all-
5
6
carbon 1,3-dipoles in diverse (3+n)-cycloadditions or 1,3-difunctionalizations.
Moreover, DA cyclopropanes usually demonstrate higher reactivity against
nucleophiles in comparison with the corresponding electrophilic cyclopropanes
7
without a donor substituent. Ring openings of DA cyclopropanes with diverse
8
9
10
nucleophiles including anilines, phenols, indoles, other electron-abundant
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1
1
12
(
het)arenes, as well as various anions such as CH-acid-derived enolates, azide-
ion,7a,11a,13 etc. are well studied and employed in total syntheses.4b,g,7a Therefore,
we were surprised that despite multiple investigations of electrophilic
1
1
1
1
1
1
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1
1
1
2
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0
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0
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9
0
1
4
cyclopropanes reactivity towards cyanide ion (Scheme 1, a) there is only one
reported example of DA cyclopropanes opening with this nucleophile (Scheme
1
5
1, b). We decided to bridge this gap and developed the method for the synthesis
of 2-(het)aryl-2-cyanoethyl-substituted malonates (Scheme 1, c), given that they
contain 2-arylacetonitrile moiety which is present in diverse bioactive compounds
including approved drugs such as antiarrhythmic and antihypertensive agent
16
17
verapamil or opioid analgesic piritramide (Figure 1). Moreover, such products
could be intermediates for the synthesis of a broad diversity of valuable
compounds, being, for example, latent 2-arylethylamines and 3-arylpiperidines;
these structural motifs are encountered in many important bioactive products and
pharmaceuticals (anxiolytic phenibut,18  and D receptors antagonist
2
19
preclamol, etc., see Figure 1). Herein, we report the results of our investigations.
Scheme 1. Cyclopropanes Hydrocyanation
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a) Electrophilic cyclopropanes opening
(previous works):
NC
EWG
EWG'
EWG
CN
ref 11
EWG'
EWG, EWG' = CO R, C(O)R, SO R, NO , etc.
2
2
2
b) Single example of DA cyclopropane opening
(
previous work):
0
1
2
3
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5
6
7
8
9
0
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0
1
2
3
4
5
6
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8
9
0
NO2
NaCN
Ph
NO2
Ph
DMF, 60 °C
CN CO Et
CO Et
2
2
ref 12
4
1%
c) DA cyclopropanes opening (this work):
EDG
CO Me
2
CO Me
TMSCN
2
EDG
B(C F ) or TfOH CN CO Me
6
5 3
HFIP
2
CO Me
2
MeO
MeO
CN
H NOC
2
N
N Me
N
MeO
MeO
Ph
Ph
CN
verapamil
piritramide
HO
Ph
NH2
N
CO H
2
phenibut
preclamol
Figure 1. Selected Bioactive Arylacetonitriles and 3-Arylpiperidines
Results and Discussion
We commenced this study with the ring opening of 3,4-dimethoxyphenyl-
substituted cyclopropane 1a as a model substrate with sodium cyanide under
typical S 2 conditions. The reaction conditions optimization was performed
N
under the variation of solvents, reaction temperature and additives. We found that
heating of 1a with NaCN in DMF or DMSO was inefficient (Table 1, entries 1–
3
). One of the possible reasons can be the reversibility of the studied reaction
7
a
similar to that found for the reaction of 1 with azide ion; as a result, side
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reactions, such as oligomers formation, dominated over the target process. In the
7
a
above study, the use of triethylamine hydrochloride allowed to prevent the
reverse cyclization via protonation of the incipient malonate anion; however, this
additive was found to be inefficient for the reaction in question (Table 1, entries
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
, 6). The use of nitromethane as a mild protonating agent allowed us to obtain a
low-molecular-weight product, but we found that 3,4-dimethoxyphenyl-
substituted succinonitrile 2a was obtained instead of the target product 3a (Table
1
, entry 7). A further variation of reaction conditions allowed to increase the yield
of 2a up to 43% (Table 1, entry 9) but was unsuccessful in terms of 3a
preparation.
Table 1. Optimization of the Reaction Conditionsa
CO Me
2
MeO
NaCN
CO Me
2
conditions
MeO
MeO
MeO
1
a
MeO
MeO
CO Me
2
CN
CN CO Me
CN
2a
2
3
a, not obtained
entry additive
Solvent
T, C t, h Yield, %
1
2
3
4
DMSO
DMSO
DMF
80
3
3
3
5
3
3
-b
-b
-b
-
140
100
[BMIM]PF6c 100
5
6
Et N·HCl
DMF
100
100
-b
-b
3
Et N·HCl
DMSO
3
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5
5
5
5
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9
CH NO
DMSO
DMSO
DMSO
DMSO
NMP
100
100
120
8
31
41
43
37
39
31
3
2
2
CH NO
3d
1d
3
CH NO
3
2
1
0
1
2
CH NO
140 0.25
3
2
0
1
2
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9
0
1
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3
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5
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9
0
1
2
3
4
5
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8
9
0
1
2
3
4
5
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9
0
1
2
3
4
5
6
7
8
9
0
1
1
CH NO
100
120
3
1
3
2
HFIPe
DMSO
a
Concentration of 1a was 0.1 M. b Oligomers of starting cyclopropane and product of
c
hydrolysis were detected in the reaction mixture.
1-Butyl-3-methylimidazolium
d
e
hexafluorophosphate. Under microwave irradiation. 1,1,1,3,3,3-Hexafluoroisopropanol.
Under the same conditions, cyclopropanes 1b-d were transformed into 2-
arylsuccinonitriles 2b-d, but products were obtained in low yields in comparison
2
0
with those in reported methods making this approach inappropriate for further
development.
The possible mechanism of products 2 formation is shown in Scheme 2.
The attack of cyanide ion on DA cyclopropane affords the desired product 3,
which decomposes to dimethyl malonate and -cyanostyrene 4. The Michael
addition of the second cyanide ion to this acceptor alkene accomplishes the
2
1
formation of succinonitrile 2. The intermediacy of styrene 4 and, therefore, the
disclosed chemoselectivity can result from the conjugation of the formed C=C
bond with both nitrile group and aromatic moiety. The last conjugation seems to
be crucial as cyclopropanes without an aromatic group afforded “normal”
products of cyanide ion addition.14
Scheme 2. 2-Arylsuccinonitriles Obtained and Possible Mechanism of Their
Formationa
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Ar
NC
NaCN
CO Me
2
Ar
CO Me
DMSO, W
20 °C, 1 h
CN
2a-d
2
1
1
a-d
NaCN
NaCN
CO Me
2
Ar
–
CH (CO Me)
2
2
2
NC
OMe
Ar
NC
H O
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
4
MeO
Me
Cl
NC
CN
NC
2c
26%
CN
NC
CN
2
b
30%
2d
33%
a
For reaction conditions, see Table 1, entry 9.
Our attempts to use sodium cyanide in combination with Lewis acids as
well as acetone cyanohydrin as a surrogate of cyanide ion were unsuccessful, and
thus we switched our attention to trimethylsilyl cyanide. This reagent was
previously used for the formal addition of hydrogen cyanide to Michael
acceptors.20b,22 Moreover, DA cyclopropane opening with TMSN in the presence
3
of TfOH (10 mol %) in HFIP at room temperature was recently demonstrated to
be a good alternative to the direct reaction with sodium azide.11b
Indeed, under disclosed conditions, TMSCN afforded the desired
cyanoethyl-substituted malonate 3a in 25% yield (Table 2, entry 1). The variation
of reaction temperature, catalyst loading, etc. did not increase the target product
yield. We studied other catalysts and found that under similar conditions B(C F )
6
5 3
induced the formation of 3a in comparable yield; products of cyclopropane 1a
23
24
24,25
dimerizations (5a, 6a ) and isomerization (7a)
were also formed (Table 2,
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
entry 2). Under microwave irradiation, the yield of 3a did not change, but only
one side product (dimer 5a) was formed (entry 3). When the reaction was
performed in the presence of Sc(OTf) , product 3a was not obtained at all; the
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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9
0
1
2
3
4
5
6
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9
0
product of cyclopropane 1a opening with HFIP (compound 8a) was
predominantly formed (Table 2, entry 4). It is the first example of DA
2
6
cyclopropane ring opening with this low-nucleophilic alcohol. The increase of
temperature, reaction time and TMSCN loading did not increase the yield of 3a
(entries 5-9). Oppositely, the highest yield was obtained under stirring at 0 C
(entry 10). This temperature dependence comports with the decomposition of
cyanomalonates 3, yielding succinonitriles 2 under heating with NaCN at 100 C
and higher temperatures.
Table 2. Optimization of Conditions for the Reaction between DA
Cyclopropane 1a and TMSCNa
CO Me
TMSCN
(2 equiv)
2
MeO
MeO
MeO
MeO
CO Me
2
CO Me
catalyst
(10 mol%)
HFIP
2
CN CO Me
2
1a
3a
CO2Me
CO Me
2
MeO C
MeO2C
MeO
MeO
2
CO Me
2
MeO
OMe
CO Me
2
MeO
OMe
CO Me
OMe
OMe
2
CO Me
2
5a
6a
MeO
MeO
CO Me
MeO
MeO
2
CO Me
2
CO Me
2
(
CF ) CHO
CO Me
2
3
2
7a
8a
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entry catalyst T, C t, h Yield, %b
1
2
3
4
5
6
7
8
9
TfOH
20
3
17
2
(25)
40c
B(C F )
20
6
5 3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
20d
41e
-g
B(C F )
6
5 3
20f
B(C F )
3
6
5 3
58h
25i
B(C F )
4
6
5 3
B(C F ) 60d,h 14
30
6
5 3
B(C F )
80d
7
58 (50)
6
5 3
B(C F ) 80d,h 24
36j
6
5 3
B(C F )
0k
1
60 (55)i
6
5 3
a
b
Concentration of 1a was 2 M. NMR yields (hexamethyldisiloxane was used as internal
c
standard); in parentheses – yields after chromatography. 5a (10%), 6a (15%), 7a (5%) were
d
e
f
also formed. Under microwave irradiation. 5a (25%) was also obtained. Concentration of
g
1a was 0.06 M; in the presence of Sc(OTf) (10 mol %). 7a (15%) and 8a (55%) were formed.
3
h
i
j
k
3
equiv of TMSCN. 5a (15%) was also formed. 5a (17%) was also formed. Concentration
of 1a was 1.3 M.
Next, we studied the scope of the disclosed reaction employing a series of
DA cyclopropanes wherein a donor substituent is either a phenyl group
containing diverse substituents or five-membered heterocycles. Three procedures
were applied: B(C F ) -induced reaction under microwave irradiation at 80 C
6
5 3
(
method A), reaction in a sealed vial in the presence of the same Lewis acid at
0 C, rt or moderate heating (method B), as well as TfOH-catalyzed process at
room temperature (method C) (Scheme 3).
The obtained results demonstrated that yields of products 3 were
consistently higher when method B was used; for compounds 3i,k bearing
electron-rich aromatic groups high yields were achieved even with method A.
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1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Oppositely, for substrates 1 with electron-neutral aryl substituents all methods
furnished the desired products 3p,q in trace amounts only. Other cyclopropanes
with electron-abundant (hetero)aromatic groups afforded 3 with yields varying
from 37 to 86%. In reactions with moderate yields of products, dimerization
and/or oligomerization of starting cyclopropanes were predominant side
processes. It is worth noting that a three-membered ring opening with TMSCN
proceeds exclusively via attack of the carbon atom of cyanide moiety on the
benzylic atom of cyclopropane, providing no isomeric products.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 3. Scope of DA Cyclopropanes Ring Opening with TMSCNa
CO Me
2
TMSCN (2 equiv)
Ar
CO Me
2
catalyst (10 mol %)
HFIP, 20 or 80 °C, W
CO Me
CN CO2Me
2
Ar
1
3
MeO
O
MeO
O
MeO
O
O
3a
3b
3c
3d
A: 50%; B: 55%
A: 48%
A: 18%; B: 42%
C: 28%
A: 52%
OMe
OMe
MeO
MeO
OMe
MeO
MeO
OMe
OMe
3
e
3f
B: 70%
3g
A: 20%; B: 52%b
B: 86%; C: 37%c,d
O
N
MeS
Me N
2
N
3
h
3i
A: 72%
3j
B: 78%
3k
A: 88%
R
C: 51%c
R
R
S
O
3
l, R = H
traces
3n, R = H
traces
3p, R = H
traces
3m, R = Me
B: 60%
3o, R = Me
A: 38%; B: 62%
3q, R = Me
traces
a
Reaction conditions: 2 M solution of 1 in HFIP, TMSCN (2 equiv). Method A: microwave
irradiation, B(C F ) (10 mol %), 80 C, 7 h; Method B: closed vial, B(C F ) (10 mol %),
6
5 3
6 5 3
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b
c
0
d
C, rt or 50 C; Method C: closed vial, TfOH (10 mol %), rt. At 70 C. 20 mol % TfOH.
Cyclopropane 1i dimer 9 with tetralin framework was also obtained in 33% yield; see
Experimental part.
A series of further transformations of nitriles 3 was performed to
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
demonstrate the synthetic utility of these compounds (Scheme 4). In particular,
we converted nitrile moieties in 3 into the corresponding ester 10, amide 11 and
Boc-protected amines 12a,b. Moreover, we synthesized arylpiperidone 13 by
HCl-induced cyclization of 12a, demonstrating that the developed method can be
19
27
used as a short route to 3-arylpiperidines (preclamol, OSU-6162, etc.) which
have important bioactivities.
Scheme 4. Post-modifications of Compounds 3
MeO
CO Me
2
MeO C
CO Me
2
2
O
O
10
81%
CO Me
2
TMSCl
MeOH
CO Me

TMSCl
H O
2
2
H N
O
1
2

1
Ar
78%
CO Me
2
NiCl2
NaBH4
CN CO Me
2
Ar
3
CO Me
Boc O
2
2
1
) NiCl2
MeOH
CO Me
2
NaBH4
Boc O
MeOH
2) HCl
EtOAc
BocHN
2
12a: Ar = 3,4-(MeO) C H
2 6 3
4
7%
2b: Ar = 2,4,5-(MeO) C H
6 2
MeO
MeO
CO Me
2
1
3
68%
O
NH
OMe
13
65%, dr 55:45
Encouraged by the obtained results, we investigated the efficiency of the
TMS-Nu/catalyst/HFIP combination for the ring opening of DA cyclopropanes 1
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1
1
1
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1
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1
2
2
2
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2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
6
with other N-containing nucleophiles. Indeed, under catalysis with triflic acid, the
reaction of phenyl-substituted cyclopropane 1r with trimethylsilyl isocyanate
produced carbamate 14 via a three-membered ring opening followed by the
interception of the intermediate isocyanate with HFIP (Scheme 5). It is worth
noting that the secondary reaction with alcohol allowed to suppress side-
processes and isolate the ring opening product in reasonable yield even for
cyclopropane, which was inefficient in the reaction with TMSCN.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Moreover, N-silylated morpholine and pyrrolidine reacted with DA
cyclopropanes 1 affording the corresponding amines 15 and 16. After a short
screening of the reaction conditions, we found that the best yields were obtained
under heating of HFIP solution of 1 with N-trimethylsilylamine (2 equiv) and
TfOH (10 mol %) at 80 C under microwave irradiation for 10 h (Scheme 5).
Again, a reverse reaction was impossible for three-membered ring opening with
amines that allowed moderately active substrates to react efficiently.
Scheme 5. DA Cyclopropanes Ring Opening with Various TMSNu Reagents
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TMSNCO
(2 equiv)
Ph
CO Me
2
(
F C) HCO
NH CO Me
3
2
2
TfOH (20 mol%)
HFIP, 20 °C
O
1
4
61%
Ar
CO Me
2
CO Me
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
TMS N
O
N
CO Me
2
CO Me
2
TfOH (10 mol%)
HFIP, 80 °C, W
O
Ar
1
5a, Ar = 4-FC H4
6
1
8
1%
15b, Ar = 2-MeC H4
6
8
3%
Br
TMS N
CO Me
2
TfOH (10 mol%)
HFIP, 80 °C, W
N
CO Me
2
1
6
64%
Conclusions
In conclusion, we have developed a method for the ring opening of DA
cyclopropanes with trimethylsilyl cyanide, providing direct access to the
synthetically important -cyanoesters, which are valuable building blocks toward
a variety of bioactive molecules. On the contrary, heating of DA cyclopropanes
with sodium cyanide in dipolar solvents produced 2-arylsuccinonitriles. The
developed approach was successfully applied for DA cyclopropanes ring opening
with trimethylsilyl isocyanate and N-silylated secondary amines (morpholine,
pyrrolidine) providing -aminobutyric acid derivatives. Moreover, post-
modifications of the obtained -cyanoesters allowed to synthesize 2-arylglutaric
acid and 5-amino-4-arylvaleric acid derivatives, including 5-arylpiperidin-2-
ones, scaffolds presenting in various bioactive compounds.
Experimental Section
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5
5
6
General Information
NMR spectra were recorded on Agilent-400MR (400 MHz for H and 100 MHz
1
1
3
1
13
for C), Bruker Avance 500 (500 MHz for H and 125 MHz for C), and Bruker
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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8
9
0
1
2
3
4
5
6
7
8
9
0
1
13
Avance 600 (600 MHz for H and 150 MHz for C) spectrometers at room
temperature if not specified other; the chemical shifts δ were measured in ppm
1
13
with respect to solvent (CDCl : Н: δ = 7.26 ppm, C: δ = 77.0 ppm; DMSO-d :
3
6
1
13
19
Н: δ = 2.50 ppm, C: δ = 39.5 ppm). F NMR spectra were recorded at 470
MHz with fluorobenzene as an internal reference (δ = –112.96 ppm in CDCl3).
Splitting patterns are designated as s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; dd, doublet of doublets and br (broad). Coupling constants (J) are given
in Hz. The structures of synthesized compounds were elucidated with the aid of
1
13
19
1
1
1
13
1D NMR ( H, C, F) and 2D NMR (COSY H- H, HSQC and HMBC H- C,
1
15
1
1
HMBC H- N, NOESY H- H) spectroscopies. IR spectra were recorded on
Thermo Nicolet IR 200 FT-IR spectrometer. Registration of spectra was carried
-1
out at a resolution of 4 cm , the number of scans 20. Samples were placed on the
working surface of the internal reflection (ATR) element from ZnSe with the
angle of incidence of 45°. High resolution mass spectra were recorded on a
Bruker microTOF-QTM spectrometer with electrospray ionization (ESI).
Analytical thin-layer chromatography (TLC) was carried out using precoated
aluminum sheets of silica gel 60 (F254). The visualization of the TLC plates was
done by UV lamp (365 nm). Column chromatography was performed on silica
gel 60 (230-400 mesh). Melting points (mp) were determined using
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Electrothermal 9100 and SMP-20 capillary melting point apparatus. Column
chromatography was performed on silica gel 60 (230-400 mesh). All the reactions
were carried out using freshly distilled and dry solvents from solvent stills.
Experiments under microwave irradiation were performed in sealed tubes using
Anton Paar Monowave 200 equipment with an external surface sensor.
Cyclopropanes 1 were prepared by Knoevenagel/Corey-Chaykovsky reactions
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
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2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
8
sequence from the corresponding aldehydes. Compounds 6a, 7a were described
previously.24
Dimethyl 2-(2,4,5-trimethoxyphenyl)cyclopropane-1,1-dicarboxylate (1i). To a
stirred suspension of NaH (60% suspension in oil, 329 mg, 8.2 mmol) in dry DMF
(14 mL) trimethylsulfoxonium iodide (1.81 g, 8.2 mmol) was added in a single
portion under argon atmosphere at room temperature. Vigorous evolution of
hydrogen lasted ca. 10 min, after which the reaction mixture was stirred for
additional 30 min. Dimethyl 2-(2,4,5-trimethoxybenzylidene)malonate (2.22 g,
6.9 mmol) in dry DMF (2 mL) was added in portions. The resulted mixture was
stirred for 2 h, poured into ice-cooled aq. solution NH Cl (25 mL) and extracted
4
with ethyl acetate (510 mL). The combined organic fractions were washed with
water (510 mL), dried with Na SO and concentrated in vacuo. The resulting
2
4
residue was purified by recrystallization from Et O yielding cyclopropane 1i.
2
1
Yield 1.38 g (60%); colorless solid; mp 109–110 ºC. H NMR (CDCl , 400 MHz):
3
2
3
2
3

= 1.71 (dd, J = 5.2 Hz, J = 9.4 Hz, 1H, CH ), 2.13 (dd, J = 5.2 Hz, J = 8.4
2
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1
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
4
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5
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5
5
6
3
3
Hz, 1H, CH ), 3.26 (dd, J = 9.4 Hz, J = 8.4 Hz, 1H, CH), 3.37 (s, 3H, CH O),
2
3
3
.76 (s, 3H, CH O), 3.77 (s, 6H, 2×CH O), 3.84 (s, 3H, CH O), 6.45 (s, 1H, Ar),
3
3
3
1
3
1
6.50 (s, 1H, Ar). С{ H} NMR (CDCl , 100 MHz):  = 19.0 (CH ), 28.3 (CH),
3
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
9
6.2 (C), 52.0 (CH O), 52.5 (CH O), 55.8 (CH O), 56.40 (CH O), 56.44 (CH O),
3
3
3
3
3
7.1 (CH, Ar), 111.9 (CH, Ar), 114.1 (C, Ar), 142.2 (C, Ar), 148.8 (C, Ar), 153.5
(
C, Ar), 167.2 (CO Me), 170.3 (CO Me). IR (KBr):  = 2926, 2950, 2841, 1721,
2
2
-1
1515, 1471, 1440, 1431, 1401, 1318, 1294, 1276, 1211, 1123, 1030 сm . HRMS
+
ESI-TOF m/z: [M+Na] Calcd for C H NaO 347.1101; Found 347.1098. Anal.
1
6
20
7
Calcd for C H O : C, 59.25; H, 6.22. Found: С, 59.16; H, 6.05.
1
6
20
7
Dimethyl 2-[4-(methylsulfanyl)phenyl]cyclopropane-1,1-dicarboxylate (1j). To a
stirred suspension of NaH (60% suspension in oil, 271 mg, 6.8 mmol) in dry DMF
(
30 mL) trimethylsulfoxonium iodide (1.49 g, 6.8 mmol) was added in a single
portion under argon atmosphere at room temperature. Vigorous evolution of
hydrogen lasted ca. 10 min, after which the reaction mixture was stirred for
additional 30 min. Then dimethyl 2-[4-(methylsulfanyl)benzylidene]malonate
(
1.5 g, 5.6 mmol) in dry DMF (2 mL) was added in a single portion. The resulted
mixture was stirred for 3 h, poured into ice-cooled aq. solution of NH Cl (25 mL)
4
and extracted with ethyl acetate (510 mL). The combined organic fractions were
washed with water (510 mL), dried with Na SO and concentrated in vacuo. The
2
4
resulting residue was purified by column chromatography on silica gel yielding
cyclopropane 1j. Yield 1.12 g (71%); colorless solid; R = 0.70 (petroleum ether
f
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1
2
:
ethyl acetate; 4:1); mp 58–59 ºC. H NMR (CDCl , 400 MHz):  = 1.69 (dd, J
3
3
2
3
=
5.2 Hz, J = 9.2 Hz, 1H, CH ), 2.12 (dd, J = 5.2 Hz, J = 8.1 Hz, 1H, CH ),
2
2
3
3
2.41 (s, 3H, CH S), 3.15 (dd, J = 9.2 Hz, J = 8.1 Hz, 1H, CH), 3.36 (s, 3H,
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
CH O), 3.74 (s, 3H, CH O), 7.06–7.12 (m, 4H, Ar). С{ H} NMR (CDCl , 100
3
3
3
MHz):  = 15.6 (CH S), 19.1 (CH ), 32.1 (CH), 37.1 (C), 52.2 (CH O), 52.7
3
2
3
(
CH O), 126.0 (2×CH, Ar), 128.8 (2×CH, Ar), 131.2 (C, Ar), 137.6 (C), 166.9
3
(CO Me), 170.1 (CO Me). IR (KBr):  = 3022, 2944, 2951, 2921, 2846, 1729,
2
2
-1
1
599, 1497, 1436, 1332, 1284, 1217, 1131, 1092, 1017, 967 сm . HRMS ESI-
+
TOF m/z: [M+H] Calcd for C H O S 281.0842; Found 281.0835. Anal. Calcd
1
4
17
4
for C H O S: C, 59.98; H, 5.75. Found: С, 60.29; H, 5.78.
1
4
16
4
Synthesis of 2-arylsuccinonitriles 2а-d (General procedure). A dry reaction
microwave tube was charged with 0.5 M solution of cyclopropane 1 (1 equiv) in
DMSO under Ar atmosphere, MeNO (5 equiv) and NaCN (4 equiv) were added.
2
The reaction mixture was heated in a microwave reactor at 120 °C for 1 h,
quenched with conc. aqueous NaHCO and extracted with ethyl acetate (3×10
3
mL). The combined organic extracts were washed with NaHCO and brine, dried
3
with anhydrous Na SO and concentrated in vacuo. The residue was purified by
2
4
column chromatography on a silica gel to afford the desired product.
-(3,4-Dimethoxyphenyl)succinonitrile (2a) was obtained according to the
2
2
3b
General procedure from cyclopropane 1a (300 mg, 1.01 mmol), NaCN (200
mg, 4.08 mmol), MeNO (310 mg, 5.09 mmol) in DMSO (2.0 mL). Yield 90 mg
2
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6
(
41%); beige solid; R = 0.58 (petroleum ether : ethyl acetate; 1:1). Spectral data
f
are consistent with previously reported ones.29
2-(4-Methoxyphenyl)succinonitrile (2b) was obtained according to the General
0
1
2
3
4
5
6
7
8
9
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1
2
3
4
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6
7
8
9
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7
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7
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6
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8
9
0
2
3b
procedure from cyclopropane 1b (270 mg, 1.02 mmol), NaCN (200 mg, 4.08
mmol), MeNO (310 mg, 5.09 mmol) in DMSO (2.0 mL). Yield 58 mg (30%);
2
pale-yellow oil; R = 0.80 (petroleum ether : ethyl acetate; 1:1). Spectral data are
f
consistent with previously reported ones.30
2
-(4-Methylphenyl)succinonitrile (2c) was obtained according to the General
3
1
procedure from cyclopropane 1c (255 mg, 1.03 mmol), NaCN (200 mg, 4.08
mmol), MeNO (305 mg, 5.00 mmol) in DMSO (2.0 mL). Yield 56 mg (33%);
2
yellow oil; R = 0.73 (petroleum ether : ethyl acetate; 2:1). Spectral data are
f
consistent with previously reported ones.30
2
-(4-Chlorophenyl)succinonitrile (2d) was obtained according to the General
12c
procedure from cyclopropane 1d (300 mg, 1.12 mmol), NaCN (220 mg, 4.50
mmol), MeNO (340 mg, 5.60 mmol) in DMSO (2.3 mL). Yield 70 mg (33%);
2
yellow oil; R = 0.69 (petroleum ether : ethyl acetate; 1:1). Spectral data are
f
consistent with previously reported ones.30
Synthesis of dimethyl 2-cyano-2-(het)arylethylmalonates 3. Method A. A dry
reaction microwave tube was charged with 2 M solution of cyclopropane 1 in
HFIP, TMSCN (2 equiv) and B(C F ) (10 mol %) were added under N
6
5 3
2
atmosphere. The reaction mixture was heated in a microwave reactor at 80 °C for
7
h, quenched with conc. aqueous NaHCO and extracted with ethyl acetate (3×10
3
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mL). The combined organic extracts were washed with NaHCO and brine, dried
3
with anhydrous Na SO and concentrated in vacuo. The residue was purified by
2
4
column chromatography on a silica gel to afford the desired product.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
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2
3
4
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2
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9
0
Method B. A dry reaction vial was charged with 2 M solution of cyclopropane 1
in HFIP, TMSCN (2 equiv) and B(C F ) (10 mol %) were added under N
6
5 3
2
atmosphere. The reaction mixture was stirred at the specified temperature for the
specified time, quenched with conc. aqueous NaHCO and extracted with ethyl
3
acetate (3×10 mL). The combined organic extracts were washed with NaHCO3
and brine, dried with anhydrous Na SO and concentrated in vacuo. The residue
2
4
was purified by column chromatography on a silica gel to afford the desired
product.
Method C. A flame dried flask, equipped with a reflux condenser, was charged
with cyclopropane 1 (1 equiv), TMSCN (2 equiv) and molecular sieves (4 Å)
under N atmosphere, then TfOH (10 mol %) in HFIP (2 M) was added. The
2
reaction mixture was stirred at room temperature for 3 h, quenched with conc.
aqueous NaHCO and extracted with ethyl acetate (3×10 mL). The combined
3
organic extracts were washed with brine, dried with anhydrous Na SO and
2
4
concentrated in vacuo. The residue was purified by column chromatography on a
silica gel to afford the desired product.
Dimethyl 2-[2-cyano-2-(3,4-dimethoxyphenyl)ethyl]malonate (3a) was obtained
2
3b
according to the Method A from cyclopropane 1a (200 mg, 0.68 mmol) and
TMSCN (135 mg, 0.17 mL, 1.36 mmol) using B(C F ) (36 mg, 0.07 mmol) in
6
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
HFIP (0.35 mL). Yield 109 mg (50%); yellow oil; R = 0.57 (petroleum ether :
f
ethyl acetate; 4:1).
The compound 3a was also obtained according to the Method B at 0 ºC for
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
h from cyclopropane 1a (200 mg, 0.68 mmol), TMSCN (135 mg, 0.17 mL, 1.36
mmol) using B(C F ) (36 mg, 0.07 mmol) in HFIP (0.35 mL). Yield 120 mg
6
5 3
1
3
(55%). H NMR (CDCl , 500 MHz):  = 2.44–2.54 (m, 2H, CH ), 3.55 (dd, J =
3
2
3
7
3
.9 Hz, J = 6.9 Hz, 1H, CH), 3.76 (s, 3H, CH O), 3.79 (s, 3H, CH O), 3.89 (s,
3
3
3
3
H, CH O), 3.85 (dd, J = 8.1 Hz, J = 7.4 Hz, 1H, CH), 3.92 (s, 3H, CH O), 6.84
3
3
4
3
3
4
(
d, J = 2.0 Hz, 1H, Ar), 6.87 (d, J = 8.3 Hz, 1H, Ar), 6.89 (dd, J = 8.3 Hz, J =
1
3
1
2.0 Hz, 1H, Ar). С{ H} NMR (CDCl , 125 MHz):  = 34.7 (CH ), 34.9 (CH),
3
2
4
9.1 (CH), 53.08 (CH O), 53.10 (CH O), 56.17 (CH O), 56.20 (CH O), 110.5
3
3
3
3
(
CH, Ar), 111.8 (CH, Ar), 120.0 (CH, Ar), 120.1 (CN), 126.9 (С, Ar), 149.4 (С,
Ar), 149.8 (С, Ar), 168.7 (CO Me), 168.8 (CO Me). IR (KBr):  = 3095, 2956,
2
2
-1
2841, 2241, 1751, 1736, 1595, 1518, 1440, 1344, 1259, 1242, 1146, 1026 сm .
+
HRMS ESI-TOF m/z: [M+H] Calcd for C H NO 322.1285; Found 322.1284.
1
6
20
6
Anal. Calcd for C H NO : C, 59.81; H, 5.96; N, 4.36. Found: С, 60.08; H, 5.86;
1
6
19
6
N, 4.32.
Dimethyl 2-[2-cyano-2-(2,3-dihydro[1,4]benzodioxin-6-yl)ethyl}malonate (3b)
23b
was obtained according to the Method A from cyclopropane 1e (200 mg, 0.68
mmol) and TMSCN (136 mg, 0.17 mL, 1.37 mmol) using B(C F ) (40 mg, 0.078
6
5 3
mmol) in HFIP (0.35 mL). Yield 105 mg (48%); yellow oil; R = 0.73 (petroleum
f
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1
ether : ethyl acetate; 2:1). H NMR (CDCl , 400 MHz):  = 2.33–2.45 (m, 2H,
3
3
3
3
3
CH ), 3.47 ( J = 7.7 Hz, J = 6.7 Hz, 1H, CH), 3.80 (d, J = 7.7 Hz, J = 6.7 Hz,
2
1H, CH), 3.70 (s, 3H, CH O), 3.71 (s, 3H, CH O), 4.20 (s, 4H, CH O), 6.73 (dd,
3
3
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
4
4
J = 8.1 Hz, J = 2.2 Hz, 1H, CH, Ar), 6.79 (br. d, J = 2.2 Hz, 1H, CH, Ar), 6.80
3
13
1
(
br. d, J = 8.1 Hz, 1H, CH, Ar). С{ H} NMR (CDCl , 100 MHz):  = 34.4
3
(
CH), 34.5 (CH ), 48.9 (CH), 52.98 (CH O), 53.00 (CH O), 64.37 (CH O), 64.38
2
3
3
2
(CH O), 116.4 (CH, Ar), 118.0 (CH, Ar), 120.0 (CN), 120.4 (CH), 127.4 (C, Ar),
2
1
3
1
43.8 (С, Ar), 144.1 (С, Ar), 168.6 (CO Me), 168.7 (CO Me). IR (KBr):  =
2
2
465, 2983, 2955, 2881, 2242, 1750, 1736, 1592, 1510, 1437, 1334, 1289, 1252,
-1
+
200, 1157, 1067, 1049, 921, 889 сm . HRMS ESI-TOF m/z: [M+Na] Calcd for
C H NNaO 342.0948; Found 342.0953. Anal. Calcd for C H NO : C, 60.18;
1
6
17
6
16 17
6
H, 5.37; N, 4.39. Found: С, 60.00; H, 5.03; N, 4.40.
Dimethyl 2-[2-([1,3]benzodioxol-5-yl)-2-cyanoethyl]malonate (3c) was obtained
O
3
2
according to the Method A from cyclopropane 1f (150
CO Me
2
1'
2'
O
2
CN CO Me
2
mg, 0.54 mmol) and TMSCN (107 mg, 0.13 mL, 1.08
mmol) using B(C F ) (28 mg, 0.055 mmol) in HFIP (0.27 mL). Yield 30 mg
6
5 3
(18%).
The compound 3c was obtained according to the Method B at room
temperature for 26 h from cyclopropane 1f (150 mg, 0.54 mmol) and TMSCN
(107 mg, 0.13 mL, 1.08 mmol) using B(C F ) (28 mg, 0.05 mmol) in HFIP (0.27
6
5 3
mL). Yield 69 mg (42%).
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5
6
The compound 3c was also obtained according to the Method C from
cyclopropane 1f (150 mg, 0.54 mmol) and TMSCN (108 mg, 0.13 mL, 1.09
mmol) using TfOH (4.8 µL, 0.05 mmol) in HFIP (0.27 mL). Yield 45 mg (28%);
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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9
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9
0
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9
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1
colorless oil; R = 0.52 (petroleum ether : ethyl acetate; 4:1). H NMR (CDCl ,
f
3
3
3
4
00 MHz):  = 2.41–2.51 (m, 2H, C(1')H ), 3.52 (dd, J = 8.1 Hz, J = 6.9 Hz,
2
3
3
1H, C(2)H), 3.77 (s, 3H, CH O), 3.79 (s, 3H, CH O), 3.89 (dd, J = 8.5 Hz, J =
3
3
3
4
7
.2 Hz, 1H, C(2')H), 6.00 (s, 2H, OCH O), 6.80 (dd, J = 8.2 Hz, J = 1.2 Hz, 1H,
2
3
4
13
1
Ar), 6.82 (br. d, J = 8.2 Hz, 1H, Ar), 6.83 (br. d, J = 1.2 Hz, 1H, Ar). С{ H}
NMR (CDCl , 100 MHz):  = 34.8 (C(1')H ), 34.9 (C(2')H), 49.0 (C(2)H), 53.08
3
2
(CH O), 53.11 (CH O), 101.7 (OCH O), 107.9 (CH, Ar), 109.0 (CH, Ar), 120.0
3
3
2
(CN), 121.2 (CH, Ar), 128.2 (C, Ar), 148.1 (С, Ar), 148.7 (С, Ar), 168.68
(
CO Me), 168.75 (CO Me). IR (KBr):  = 2956, 2917, 2849, 2242, 1736, 1611,
2
2
505, 1510, 1437, 1334, 1289, 1252, 1200, 1157, 1067, 1049, 921, 889 сm-1.
1
+
HRMS ESI-TOF m/z: [M+Na] Calcd for C H NNaO 328.0792; Found
1
5
15
6
3
5
28.0790. Anal. Calcd for C H NO : C, 59.02; H, 4.95; N, 4.59. Found: С,
1
5
15
6
9.13; H, 4.95; N, 4.34.
Dimethyl 2-[2-cyano-2-(4-methoxyphenyl)ethyl]malonate (3d) was obtained
according to the Method A from cyclopropane 1b23b (200 mg, 0.83 mol) and
TMSCN (165 mg, 0.21 mL, 1.67 mmol) using B(C F ) (39 mg, 0.076 mmol) in
6
5 3
HFIP (0.38 mL). Yield 114 mg (52%); yellow oil; R = 0.85 (petroleum ether :
f
1
ethyl acetate; 4:1). H NMR (CDCl , 400 MHz):  = 2.37–2.50 (m, 2H, CH ),
3
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.50 (dd, J = 8.1 Hz, J = 6.9 Hz, 1H, CH), 3.71 (s, 3H, CH O), 3.74 (s, 3H,
3
3
3
CH O), 3.78 (s, 3H, CH O), 3.89 (dd, J = 8.1 Hz, J = 7.4 Hz, 1H, CH), 6.87 (br.
3
3
3
3
13
1
d, J = 8.5 Hz, 2H, Ar), 7.23 (br. d, J = 8.5 Hz, 2H, Ar). С{ H} NMR (CDCl ,
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
00 MHz):  = 34.3 (CH), 34.6 (CH ), 48.9 (CH), 53.0 (2×CH O), 55.4 (CH O),
2
3
3
1
14.7 (2×CH), 120.1 (CN), 126.2 (C, Ar), 128.6 (2×CH, Ar), 159.7 (С, Ar), 168.6
(
CO Me), 168.7 (CO Me). IR (ZnSe):  = 3005, 2954, 2840, 2241, 1751, 1736,
2
2
-1
1612, 1514, 1437, 1306, 1254, 1180, 1157, 1032 сm . HRMS ESI-TOF m/z:
+
[
M+Na] Calcd for C H NNaO 309.1445; Found 309.1445. Anal. Calcd for
1
5
17
5
C H NO : C, 61.85; H, 5.88; N, 4.81. Found: С, 61.86; H, 6.01; N, 4.78.
1
5
17
5
Dimethyl 2-[2-cyano-2-(3,4,5-trimethoxyphenyl)ethyl]malonate (3e) was
obtained according to the Method A from cyclopropane 1g23b (200 mg, 0.62
mmol) and TMSCN (122 mg, 0.15 mL, 1.23 mmol) using B(C F ) (32 mg, 0.06
6
5 3
mmol) in HFIP (0.31 mL). Yield 43 mg (20%); yellow oil; R = 0.48 (petroleum
f
ether : ethyl acetate; 2:1).
The compound 3e was also obtained according to the Method B at 70 C
for 26 h from cyclopropane 1g (200 mg, 0.62 mmol) and TMSCN (122 mg, 0.15
mL, 1.23 mmol) using B(C F ) (32 mg, 0.06 mmol) in HFIP (0.31 mL). Yield
6
5 3
1
1
13 mg (52%). Н NMR (CDCl , 400 MHz):  = 2.45–2.49 (m, 2Н, CH ), 3.56
3
2
3
(
t, J = 7.4 Hz, 1H, CH), 3.75 (s, 3H, CH O), 3.78 (s, 3H, CH O), 3.83 (s, 3H,
3
3
3
CH O), 3.87 (s, 6H, 2×CH O), 3.90 (t, J = 7.8 Hz, 1Н, CH), 6.52 (s, 2H, Ar).
3
3
1
3
1
С{ H} NMR (CDCl , 100 MHz):  = 34.7 (CH ), 35.5 (CH), 49.1 (CH), 53.1
3
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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5
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6
(
CH O), 56.4 (3×CH O), 61.0 (CH O), 104.5 (2×CH, Ar), 119.9 (CN), 130.0 (С,
3
3
3
Ar), 138.1 (С, Ar), 153.9 (2×С, Ar), 168.7 (CO Me), 168.8 (CO Me). IR (KBr):
2
2
 = 3002, 2953, 2842, 2241, 1752, 1738, 1593, 1510, 1463, 1435, 1426, 1336,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1
+
1
242, 1153, 1128, 1052, 1006 сm . HRMS ESI-TOF m/z: [M+Na] Calcd for
C H NNaO 374.1210; Found 374.1203. Anal. Calcd for C H NO : C, 58.11;
1
7
21
7
17 21
7
H, 6.02; N, 3.99. Found: С, 58.10; H, 6.13; N, 3.64.
Dimethyl 2-[2-cyano-2-(2,4,6-trimethoxyphenyl)ethyl]malonate (3f) was
obtained according to the Method B at room temperature for 17 h from
2
5
cyclopropane 1h (200 mg, 0.62 mol) and TMSCN (122 mg, 154 µL, 1.23 mmol)
using B(C F ) (32 mg, 0.06 mmol) in HFIP (0.31 mL). Yield 152 mg (70%);
6
5 3
1
yellow oil; R = 0.52 (petroleum ether : ethyl acetate; 2:1). H NMR (CDCl , 500
f
3
2
3
3
MHz):  = 2.34 (ddd, J = 13.8 Hz, J = 9.3 Hz, J = 6.8 Hz, 1H, C(1')H ), 2.47
2
2
3
3
3
(ddd, J = 13.8 Hz, J = 8.1 Hz, J = 6.5 Hz, 1H, C(1')H ), 3.18 (dd, J = 8.1 Hz,
2
3
J = 6.8 Hz, 1H, C(2)H), 3.54 (s, 3H, CH O), 3.63 (s, 3H, CH O), 3.69 (s, 3H,
3
3
3
3
CH O), 3.70 (s, 6H, 2×CH O), 4.31 (dd, J = 9.3 Hz, J = 6.5 Hz, 1H, C(2')H),
3
3
1
3
1
6
.01 (s, 2H, Ar). С{ H} NMR (CDCl , 125 MHz):  = 23.2 (C(2')H), 30.3
3
(C(1')H ), 49.1 (CH), 52.6 (CH O), 53.0 (CH O), 56.3 (CH O), 56.6 (2×CH O),
2
3
3
3
3
9
0.8 (2×CH), 101.9 (C, Ar), 120.3 (CN), 158.6 (2×C, Ar), 161.7 (С, Ar), 168.8
(CO Me), 169.0 (CO Me). IR (KBr):  = 3002, 2954, 2839, 2240, 1752, 1736,
2
2
-1
1
612, 1515, 1439, 1401, 1347, 1318, 1279, 1210, 1156, 1118, 1032 сm . HRMS
+
ESI-TOF m/z: [M+Na] Calcd for C H NNaO 374.1210; Found 374.1202.
1
7
22
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Anal. Calcd for C H NO : C, 58.11; H, 6.02; N, 3.99. Found: С, 57.95; H, 6.08;
1
7
21
7
N, 3.85.
Dimethyl 2-[2-cyano-2-(2,4,5-trimethoxyphenyl)ethyl]malonate (3g) was
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
OMe
5
''
obtained according to the Method C from cyclopropane
1i (0.40 g, 1.2 mmol) and TMSCN (0.46 mL, 0.37 g, 2.4
MeO 4''
6''
1''
1'
2'
2 CO Me
2
3''
2''
OMe CN CO Me
2
mmol) using TfOH (0.02 mL, 0.23 mmol) in HFIP (0.5 mL). Yield 160 mg
37%); yellowish oil; R = 0.58 (petroleum ether : ethyl acetate; 1:1). Additionally,
(
f
the dimeric product 9 was isolated in 33% yield (130 mg).
Compound 3g was also obtained according to the Method B at room
temperature for 17 h from cyclopropane 1i (0.20 g, 0.62 mmol) and TMSCN (0.15
mL, 122 mg, 1.24 mmol) using B(C F ) (32 mg, 0.062 mmol) in HFIP (0.31
6
5 3
1
mL). Yield 187 mg (86%). Н NMR (CDCl , 500 MHz):  = 2.39–2.45 (m, 1Н,
3
3
CH ), 2.53–2.59 (m, 1Н, CH ), 3.48 (t, J = 7.4 Hz, 1H, C(2)H), 3.75 (s, 3H,
2
2
CH O), 3.76 (s, 3H, CH O), 3.84 (s, 3H, CH O), 3.88 (s, 3H, CH O), 3.92 (s, 3H,
3
3
3
3
3
CH O), 4.28 (t, J = 7.7 Hz, 1Н, C(2')H), 6.53 (s, 1H, C(3'')H, Ar), 6.89 (s, 1H,
3
1
3
1
C(6'')H, Ar). С{ H} NMR (CDCl , 125 MHz):  = 29.2 (C(2')H), 32.7 (C(1')H ),
3
2
4
9.2 (C(2)H), 52.94 (CH O), 53.01 (CH O), 56.40 (CH O), 56.41 (CH O), 56.9
3
3
3
3
(
CH O), 97.6 (C(3'')H, Ar), 112.4 (C(6'')H, Ar), 113.4 (С(1''), Ar), 120.3 (CN),
3
1
43.6 (С(5''), Ar), 150.3 (С(2''), Ar), 150.9 (С(4''), Ar), 168.8 (CO Me), 168.9
2
(CO Me). IR (KBr):  = 3003, 2954, 2848, 2241, 1752, 1737, 1612, 1514, 1440,
2
-1
+
1
401, 1347, 1317, 1210, 1156, 1118, 1033 сm . HRMS ESI-TOF m/z: [M+Na]
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Calcd for C H NNaO 374.1210; Found 374.1208. Anal. Calcd for C H NO :
1
7
21
7
17 21
7
C, 58.11; H, 6.02; N, 3.99. Found: С, 58.12; H, 6.03; N, 3.91.
Dimethyl 2-{2-cyano-2-[4-(methylsulfanyl)phenyl]ethyl}malonate (3h) was
prepared according to the Method С at 50 C from cyclopropane 1j (160 mg,
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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7
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9
0
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0
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9
0
0
.57 mmol) and TMSCN (131 mg, 0.16 mL, 1.32 mmol) using TfOH (10 µL,
0.115 mmol) in HFIP (0.28 mL). Yield 89 mg (51%); colorless oil; R = 0.64
f
1
(petroleum ether : ethyl acetate; 4:1). H NMR (CDCl , 400 MHz):  = 2.40–2.48
3
3
3
(
m, 2H, CH ), 2.46 (s, 3H, CH S), 3.52 (dd, J = 7.8 Hz, J = 7.2 Hz, 1H, CH),
2
3
3
3
3
.72 (s, 3H, CH O), 3.75 (s, 3H, CH O), 3.91 (dd, J = 8.2 Hz, J = 7.6 Hz, 1H,
3
3
1
3
1
CH), 7.23 (br. s, 4H, Ar). С{ H} NMR (CDCl , 100 MHz):  = 15.5 (CH S),
3
3
34.4 (CH), 34.6 (CH ), 48.8 (CH), 52.9 (2×CH O), 119.6 (CN), 126.9 (2×CH,
2
3
Ar), 127.8 (2×CH, Ar), 130.8 (C, Ar), 139.5 (С, Ar), 168.45 (CO Me), 168.53
2
(
CO Me). IR (ZnSe):  = 3002, 2954, 2924, 2850, 2242, 1752, 1737, 1600, 1496,
2
-1
1437, 1409, 1354, 1302, 1275, 1253, 1232, 1201, 1157, 1096, 1045, 1016 сm .
+
HRMS ESI-TOF m/z: [M+NH ] Calcd for C H N O S 325.1217; Found
4
15 21
2
4
3
25.1213.
Dimethyl 2-{2-cyano-2-[4-(dimethylamino)phenyl]ethyl}malonate (3i) was
obtained according to the Method A from cyclopropane 1k23b (100 mg, 0.36
mmol) and TMSCN (0.1 mL, 0.8 mmol) using B(C F ) (18 mg, 0.035 mmol) in
6
5 3
HFIP (0.18 mL). Yield 79 mg (72%); yellow oil; R = 0.44 (petroleum ether :
f
1
ethyl acetate; 3:1). H NMR (CDCl , 500 MHz):  = 2.41–2.52 (m, 2H, C(1')H ),
3
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.97 (s, 6H, N(CH ) ), 3.50 (dd, J = 7.5 Hz, J = 6.7 Hz, 1H, C(2)H), 3.76 (s, 3H,
3
2
3
3
CH O), 3.77 (s, 3H, CH O), 3.86 (dd, J = 8.6 Hz, J = 7.3 Hz, 1H, C(2')H), 6.72
3
3
3
3
13
1
(br. d, J = 8.7 Hz, 2H, Ar), 7.18 (br. d, J = 8.7 Hz, 2H, Ar). С{ H} NMR
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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(
CDCl , 125 MHz):  = 34.3 (C(2')H), 34.7 (C(1')H ), 49.1 (C(2)H), 40.5
3
2
(
N(CH ) ), 53.0 (2×CH O), 112.9 (C(3'')H, C(5'')H), 120.5 (CN), 121.5 (C(1''),
3
2
3
Ar), 128.3 (C(2'')H, C(6'')H, Ar), 150.6 (С(4''), Ar), 168.8 (CO Me), 168.9
2
(CO Me). IR (KBr):  = 2993, 2954, 2924, 2894, 2850, 2807, 2240, 1752, 1738,
2
1
1
615, 1602, 1567, 1525, 1483, 1437, 1356, 1289, 1256, 1230, 1207, 1164, 1092,
-1
+
046 сm . HRMS ESI-TOF m/z: [M+H] Calcd for C H N O 305.1496; Found
1
6
21
2
4
305.1491. Anal. Calcd for C H N O : C, 63.14; H, 6.62; N, 9.20. Found: С,
1
6
20
2
4
6
3.04; H, 6.62; N, 9.17.
Dimethyl 2-{2-cyano-2-[4-(pyrrolidin-1-yl)phenyl]ethyl}malonate (3j) was
3
3
obtained according to the Method B from cyclopropane 1l (195 mg, 0.64 mmol)
and TMSCN (0.16 mL, 1.28 mmol) using B(C F ) (33 mg, 0.06 mmol) in HFIP
6
5 3
(
0.32 mL) at room temperature for 4 h. Yield 166 mg (78%); yellow oil; R = 0.36
f
1
(
petroleum ether : ethyl acetate; 1:1). H NMR (CDCl , 600 MHz):  = 1.98–2.02
3
2
3
3
(m, 4H, 2CH ), 2.42 (ddd, J = 14.0 Hz, J = 7.6 Hz, J = 7.0 Hz, 1H, C(1')H ),
2
2
2
3
3
2
2
.48 (ddd, J = 14.0 Hz, J = 8.6 Hz, J = 7.0 Hz, 1H, C(1')H ), 3.25–3.28 (m, 4Н,
2
3
3
CH N), 3.51 (dd, J = 7.6 Hz, J = 7.0 Hz, 1H, C(2)H), 3.74 (s, 3H, CH O),
2
3
3
3
3
.75 (s, 3H, CH O), 3.83 (dd, J = 8.6 Hz, J = 7.0 Hz, 1H, C(2')H), 6.53 (br. d,
3
3
3
J = 8.6 Hz, 2H, C(3'')H, C(5'')H), Ar), 7.14 (br. d, J = 8.6 Hz, 2H, C(2'')H,
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C(6'')H, Ar). С{ H} NMR (CDCl , 150 MHz):  = 25.3 (2×CH ), 34.1 (C(2')H),
3
2
3
4.5 (C(1')H ), 47.5 (2×CH ), 48.8 (C(2)H), 52.7 (2×CH O), 119.2 (C(2'')H,
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C(6'')H, Ar), 120.1 (C(1''), Ar), 120.4 (CN), 128.1 (C(2'')H, C(6'')H, Ar), 147.27
0
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(
С(4''), Ar), 168.6 (CO Me), 168.7 (CO Me). IR (ZnSe):  = 2956, 2925, 2853,
2
2
2
242, 1749, 1733, 1683, 1600, 1516, 1436, 1393, 1305, 1287, 1260, 1228, 1161
-1
+
сm . HRMS ESI-TOF m/z: [M+H] Calcd for C H N O 347.1652; Found
1
8
23
2
4
331.1645. Anal. Calcd for C H N O : C, 65.44; H, 6.71; N, 8.48. Found: С,
1
8
22
2
4
6
5.10; H, 6.69; N, 8.09.
Dimethyl 2-[2-cyano-2-(4-morpholinophenyl)ethyl]malonate (3k) was obtained
3
3
according to the Method A from cyclopropane 1m (200 mg, 0.63 mmol) and
TMSCN (124 mg, 0.16 mL, 1.25 mmol) using B(C F ) (32 mg, 0.063 mmol) in
6
5 3
HFIP (0.32 mL). Yield 190 mg (88%); yellow solid; mp = 75–76 ºC; R = 0.53
f
1
(
petroleum ether : ethyl acetate; 1:1). H NMR (CDCl , 500 MHz):  = 2.49–2.90
3
3
3
(m, 2H, C(1')H ), 3.14–3.16 (m, 4H, 2×CH ), 3.51 (dd, J = 7.9 Hz, J = 6.8 Hz,
2
2
1
3
H, C(2)H), 3.73 (s, 3H, CH O), 3.75 (s, 3H, CH O), 3.83–3.84 (4H, 2×CH ),
3
3
2
3
3
3
.88 (dd, J = 7.9 Hz, J = 7.1 Hz, 1H, C(2')H), 6.89 (br. d, J = 8.6 Hz, 2H,
3
13
1
C(3'')H, C(5'')H, Ar), 7.21 (br. d, J = 8.6 Hz, 2H, C(2'')H, C(6'')H, Ar). С{ H}
NMR (CDCl , 125 MHz):  = 34.0 (C(1')H ), 34.3 (C(2')H), 48.67 (2×CH ),
3
2
2
4
8.74 (C(2)H), 52.7 (2×CH O), 66.6 (2×CH ), 115.7 (2×CH, C(3'')H, C(5'')H,
3
2
Ar), 119.9 (CN, Ar), 124.9 (C(1''), Ar), 128.1 (C(2'')H, C(6'')H, Ar), 151.1 (С(4''),
Ar), 168.4 (CO Me), 168.5 (CO Me). IR (KBr):  = 2956, 2923, 2896, 2855,
2
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241, 1751, 1736, 1612, 1518, 1450, 1437, 1345, 1306, 1265, 1237, 1158, 1122,
-1
+
050, 927 сm . HRMS ESI-TOF m/z: [M+H] Calcd for C H N O 347.1601;
1
8
23
2
5
Found 347.1609. Anal. Calcd for C H N O : C, 62.42; H, 6.40; N, 8.09. Found:
1
8
22
2
5
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
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4
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0
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7
8
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3
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9
0
С, 62.56; H, 6.46; N, 7.93.
Dimethyl 2-[2-cyano-2-(5-methylthiophen-2-yl)ethyl]malonate (3m) was
obtained according to the Method B at room temperature for 26 h from
3
4
cyclopropane 1o (0.20 g, 0.79 mmol) and TMSCN (0.20 mL, 156 mg, 1.57
mmol) using B(C F ) (40 mg, 0.079 mmol) in HFIP (0.39 mL). Yield 135 mg
6
5 3
1
(60%); yellowish oil; R = 0.58 (petroleum ether : ethyl acetate; 4:1). Н NMR
f
4
(CDCl , 500 MHz):  = 2.47 (d, J = 1.0 Hz, 3H, CH ), 2.49–2.60 (m, 2Н, CH ),
3
3
2
3
3
3
.58 dd, J = 7.9 Hz, J = 7.2 Hz, 1H, CH), 3.77 (s, 3H, CH O), 3.78 (s, 3H,
3
3
3
3
4
CH O), 4.07 (dd, J = 8.3 Hz, J = 7.2 Hz, 1Н, CH), 6.63 (dq, J = 3.5 Hz, J =
3
3
13
1
1.0 Hz, 1H, Ar), 6.20 (d, J = 3.5 Hz, 1H, Ar). С{ H} NMR (CDCl , 125 MHz):
3

= 15.4 (CH ), 30.5 (CH), 34.5 (CH ), 48.8 (CH), 53.07 (CH O), 53.10 (CH O),
3
2
3
3
1
19.1 (СN), 125.3 (CH, Ar), 126.9 (CH, Ar), 133.6 (С, Ar), 141.1 (С, Ar), 168.55
(CO Me), 168.63 (CO Me). IR (ZnSe):  = 2955, 2922, 2851, 2244, 1751, 1738,
2
2
-1
+
1437, 1351, 1308, 1267, 1237, 1159, 1043 сm . HRMS ESI-TOF m/z: [M+Na]
Calcd for C H NNaO S 304.0614; Found 304.0609. Anal. Calcd for
1
3
15
4
C H NO S: C, 55.50; H, 5.37; N, 4.98. Found: С, 55.88; H, 5.33; N, 4.63.
1
3
15
4
Dimethyl 2-[2-cyano-2-(5-methylfuran-2-yl)ethyl]malonate (3o) was obtained
according to the Method B at room temperature for 2.5 h from cyclopropane 1q35
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