Straightforward synthesis of 1,2-dicyanoalkanes from nitroalkenes and silyl cyanide mediated by tetrabutylammonium fluoride

Article abstract of DOI:10.1002/chem.201404780

A straightforward synthesis of 1,2-dicyanoalkanes by reacting nitroalkenes with trimethylsilyl cyanide in the presence of tetrabutylammonium fluoride is described. The reaction proceeds through a tandem double Michael addition under mild conditions. Employing the hypervalent silicate generated from trimethylsilyl cyanide and tetrabutylammonium fluoride is essential for achieving this transformation. Mechanistic studies suggest that a small amount of water included in the reaction media plays a key role. This protocol is applicable to various types of substrates including electron-rich and electron-deficient aromatic nitroalkenes, and aliphatic nitroalkenes. Moreover, vinyl sulfones were found to be good alternatives, particularly for electron-deficient nitroalkenes. The broad substrate scope and functional group tolerance of the reaction makes this approach a practical method for the synthesis of valuable 1,2-dicyanoalkanes.

Full text of DOI:10.1002/chem.201404780

DOI: 10.1002/chem.201404780
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&
Synthetic Methods
Straightforward Synthesis of 1,2-Dicyanoalkanes from
Nitroalkenes and Silyl Cyanide Mediated by
Tetrabutylammonium Fluoride
Kensuke Kiyokawa, Takaya Nagata, Junpei Hayakawa, and Satoshi Minakata*[a]
Abstract: A straightforward synthesis of 1,2-dicyanoalkanes
by reacting nitroalkenes with trimethylsilyl cyanide in the
presence of tetrabutylammonium fluoride is described. The
reaction proceeds through a tandem double Michael addi-
tion under mild conditions. Employing the hypervalent sili-
cate generated from trimethylsilyl cyanide and tetrabutylam-
monium fluoride is essential for achieving this transforma-
tion. Mechanistic studies suggest that a small amount of
water included in the reaction media plays a key role. This
protocol is applicable to various types of substrates includ-
ing electron-rich and electron-deficient aromatic nitroal-
kenes, and aliphatic nitroalkenes. Moreover, vinyl sulfones
were found to be good alternatives, particularly for electron-
deficient nitroalkenes. The broad substrate scope and func-
tional group tolerance of the reaction makes this approach
a practical method for the synthesis of valuable 1,2-dicya-
noalkanes.
Introduction
knowledge, no straightforward synthesis of 1,2-dicyanoalkanes
has yet been established.
Nitriles are undoubtedly an important class of compounds in
organic synthesis and they have been recognized as versatile
synthetic intermediates for the preparation of other useful
building blocks.[1] Therefore, numerous efforts have been dedi-
cated to the development of methods for introducing cyano
groups into organic molecules.[2] Despite the significant ach-
ievements made in cyanation reactions, there are only a limited
number of examples of dicyanation reactions. Such reactions
can provide 1,2-dicyanoalkanes (succinonitrile derivatives) that
could be transformed into highly valuable compounds such as
1,2-dicarboxylic acids,[3a] 1,2-diamides,[3b] 1,4-diamines,[3c,d] and
various heterocycles (pyrrolidines, succinimides, and pyr-
roles).[3d–i] Bailey and Jackson reported on the synthesis of 1,2-
dicyanoalkanes by the sequential one-pot Michael addition of
lithium cyanide (LiCN) to a vinyl sulfone.[4] However, only one
example of a substrate was described and this gave only mod-
erate yield. Although Arai and Nishida recently reported on the
palladium-catalyzed 1,2-dicyanation of alkynes, and also dem-
onstrated the reduction of the resulting dicyanoalkene to pro-
vide a 1,2-dicyanoalkane, the method requires a two-step pro-
tocol involving a transition-metal-catalyzed reaction.[5] To our
Nitroalkenes, which are easily prepared by nitro-aldol reac-
tions,[6] have been widely used as Michael acceptors in organic
synthesis.[7–9] Conjugate addition of a cyanide anion to a nitroal-
kene derivative is the simplest route to b-nitronitriles,[10] which
are suitable precursors of cyanoalkenes. Corey and Estreicher
reported that the Michael addition of sodium cyanide (NaCN)
to 1-nitrocyclohexene under acidic conditions provided the
corresponding b-nitronitrile, which, after treatment with 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU), gave the corresponding
1-cyanocycloalkene.[11] Although a few examples of the Michael
addition of cyanide anions to nitroalkenes to produce cyanoal-
kenes through the elimination of HNO2 in situ have been re-
ported,[12] the direct use of such cyanoalkenes in further trans-
formations has not been recorded. We have now designed
a new strategy for the straightforward synthesis of 1,2-dicya-
noalkanes from nitroalkenes by a tandem double Michael addi-
tion. The first Michael addition involves the addition of a cya-
nide anion to nitroalkene I (Scheme 1, I to II) and the second
involves the addition of a cyanide anion to cyanoalkene III
formed in situ from the b-nitronitrile II through the elimination
of HNO2 (Scheme 1, III to IV). Thus, we report a novel synthetic
method for the preparation of 1,2-dicyanoalkanes from nitroal-
[a] Dr. K. Kiyokawa, T. Nagata, J. Hayakawa, Prof. Dr. S. Minakata
Department of Applied Chemistry
Graduate School of Engineering
Osaka University, Yamadaoka 2-1
Suita, Osaka 565-0871 (Japan)
Fax: (+81)6-6879-7402
E-mail: minakata@chem.eng.osaka-u.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404780.
Scheme 1. Strategy for the straightforward synthesis of 1,2-dicyanoalkanes
from nitroalkenes.
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kenes by using two equivalents of silyl cyanide mediated by
tetrabutylammonium fluoride (TBAF).
hypervalent silicate generated from TMSCN and TBAF was an
appropriate nucleophile for the dicyanation reaction.[15]
We then investigated the origin of the proton source in the
dicyanation (cf. Scheme 1). The solution of TBAF (1m in THF,
0.2 mL) in acetonitrile (4 mL) contained 4218 ppm of H2O, as
determined by Karl Fischer titration (the average of two experi-
ments), demonstrating that 0.76 mmol of H2O was present in
the reaction mixture under the standard conditions on
a 0.2 mmol scale. Indeed, the reaction of 1a with TMSCN em-
ploying TBAF·3H2O instead of TBAF (1m in THF) gave 2a in
a comparable yield (92%).[16] Thus, deuterium labeling experi-
ments were carried out, in an attempt to gain more insights
into the reaction mechanism under the “moist” conditions.
When the deuterated substrate [D]-1a was used in the reac-
tion, no deuterium incorporation in the product 2a was de-
tected (Scheme 2, Eq. 1). In contrast, the reaction of 1a in ace-
Results and Discussion
We initially chose trimethylsilyl cyanide (TMSCN) as a cyanide
source to examine the 1,2-dicyanation reaction using trans-b-
nitrostyrene (1a) at room temperature, as shown in Table 1.
Table 1. Optimization of reaction conditions.[a]
Entry Cyanide Additive
[equiv]
Time
[h]
Yield
[%][b]
Recovery of 1a
[%][b]
2a
2a’
1
2[c]
TMSCN none
TMSCN TBAF
24
24
0
11
0
92
24 61
(0.2)
TMSCN TBAF
(0.5)
TMSCN TBAF
(1.0)
TMSCN CsF
3[c]
4[c]
5
2
2
2
2
2
2
2
2
52
24 24
95 (93)
29
0
9
0
16
(1.0)
TMSCN KF
6
5
16 63
27 27
22 14
(1.0)
TMSCN KF/[18]crown-6
(1.0)
TMSCN KF/[18]crown-6
(1.0)
[15]crown-5
(2.0)
Bu4NCN none
7
38
8[d]
9
55
NaCN
39
0
0
0
0
Scheme 2. Mechanistic experiments.
10
21
[a] Reaction conditions: 1a (0.5 mmol), cyanide (1.0 mmol), additive,
MeCN (10 mL), RT. [b] Determined by 1H NMR spectroscopic analysis of
the crude product using mesityrene or 1,1,2,2-tetrachloroethane as an in-
ternal standard. The value in parenthesis is the isolated yield. [c] TBAF
(1m in THF) was used. [d] H2O (1% v/v MeCN) was added.
tonitrile containing 5% D2O by volume afforded the 1,2-dideu-
terated product [D2]-2a (Scheme 2, Eq. 2). When the nondeu-
terated product 2a was exposed to identical conditions, deute-
rium was incorporated into the a-position, whereas no H/D
exchange was detected at the b-position (Scheme 2, Eq. 3).
Taken together, the proton at the b-position of 2a appears to
be incorporated through protonation by water rather than as
result of a proton transfer from the a-position.[4] Under the
standard conditions, a small amount of water was included in
the reaction media due to the use of TBAF in a THF solution,
and this water appears to serve as a proton source in the reac-
tion.
When the reaction was run without an additive, no product
was obtained, and the starting material 1a was recovered
(entry 1). To enhance the reactivity of TMSCN, the addition of
a catalytic amount of TBAF (1m in THF)[13] was examined,
which resulted in the formation of the corresponding 1,2-di-
cyanoalkane 2a in low yield together with cyanoalkene 2a’,
with no b-nitronitrile product being observed (entry 2). Increas-
ing the amount of TBAF was effective (entry 3), and the use of
one equivalent of TBAF provided 2a in excellent yield
(entry 4).[14] In contrast, low to moderate yields were observed
when CsF or KF were used (with or without added [18]crown-
6) as a fluoride anion instead of TBAF (entries 5–8). Other cya-
nide sources such as sodium cyanide (NaCN) and tetrabutylam-
monium cyanide (Bu4NCN), the cyanide anion of which is
strongly nucleophilic, resulted in low yields, and unidentified
by-products that might have been formed from the polymeri-
zation of 1a (entries 9 and 10). These results suggest that the
Based on the experimental results, a plausible reaction
mechanism is depicted in Scheme 3. First, the silicate V gener-
ated from TMSCN and TBAF reacts with nitroalkene I to pro-
vide intermediate VI, which is then protonated by water to
give b-nitronitrile II. When the resulting hydroxide anion ab-
stracts the a-proton from II, elimination of the nitro group
occurs to provide cyanoalkene III, along with Bu4NNO2, which
is stable under the reaction conditions and would no longer
participate in the reaction.[17] Finally, the second Michael addi-
tion of a cyanide anion to III leads to the formation of dicya-
nated product IV. To establish the precise mechanism of the
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product yields (entries 9–11).[21] Substrates bearing 2,6-dichloro
or 3,4-dioxo functional groups, and a polycyclic aromatic
moiety performed well (entries 12–16). Heteroaromatic moiet-
ies including pyridyl, thienyl, furyl, and indolyl groups were
also compatible with the reaction (entries 17–20). Moreover,
the introduction of four cyano groups in one treatment could
be accomplished when the bis-nitroalkene 1v was used
(entry 21).
In the case of the reaction of a-methyl-b-nitrostyrene (1w),
b-nitronitrile 3 was obtained (Scheme 4, Eq. 1). This is attribut-
Scheme 3. Plausible reaction mechanism.
Scheme 4. Reactions of a- or b-methyl-b-nitrostyrenes. [a] The d.r. value
could not be determined because of the overlap of the signals in the NMR
spectra.
second Michael addition, we investigated the effect of an addi-
tive on the reaction of cyanoalkene, 2-methylene-4-phenylbu-
tanenitrile (5a’), with TMSCN.[18] Interestingly, the results
showed that the cyanation reaction was promoted in the pres-
ence of a catalytic amount of fluoride anion, but not nitrite or
hydroxide ions. Therefore, we propose a reaction mechanism
that involves silicate V, which reacts with cyanoalkene III to
afford the product IV through protonation of intermediate VII
by water. However, the dicyanation proceeded smoothly in the
presence of TMSCN and a half equivalent of TBAF. According
to the reaction profile of 4a, one equivalent of silicate V gener-
ated at the start of the reaction would be rapidly consumed in
the first Michael addition,[18] indicating that the resulting trime-
thylsilyl fluoride (TMSF) and Bu4NOH would participate in the
equilibrium to regenerate TBAF, which then triggers the cata-
lytic second Michael addition.[19] Based on the mechanism,
most of the added TBAF is converted into inert Bu4NNO2 via
Bu4NOH during the reaction. Therefore, an appropriate amount
of TBAF is required to complete the dicyanation (Table 1, en-
tries 2–4). Moreover, it is noteworthy that the “moist” condi-
tions are a key factor for suppressing the polymerization by
rapid protonation of anion intermediates (VI and VII), and re-
generation of fluoride anion by the hydrolysis of TMSF.[20] As
mentioned above, in this dicyanation, the hypervalent silicate
V is a suitable nucleophile, but not Bu4NCN, which may form
from V.
ed to the absence of a hydrogen atom at the a-position,
which is required for the production of the cyanoalkene inter-
mediate. In contrast, b-methyl-b-nitrostyrene (1x) was smooth-
ly converted into 1,2-dicyanoalkane 2x as a mixture of diaste-
reomers (Scheme 4, Eq. 2); unfortunately, the diastereomeric
ratio (d.r.) could not be determined because of overlap of the
signals in the NMR spectra.
The successful transformation of aromatic nitroalkenes into
1,2-dicyanoalkanes prompted us to investigate the reactions of
aliphatic nitroalkenes. When the simple aliphatic nitroalkene
4a was reacted under the standard conditions for 2 h, 1,2-di-
cyanated product 5a was obtained in low yield (22% yield),
along with the corresponding cyanoalkene 5a’ and b-nitroni-
trile 5a’’.[18] Gratifyingly, these intermediates were nearly com-
pletely consumed when the reaction was conducted for 40 h,
providing 5a in 80% yield (Table 3, entry 1). Sterically bulkier
secondary benzyl, isopropyl, and tert-butyl substituted nitroal-
kenes were converted into the corresponding products in
good yields (entries 2–4). Various types of functional groups,
With optimized conditions in hand, we next explored the
scope of the reactions with respect to aromatic trans-b-nitroal-
kenes 1 (Table 2). Substrates bearing electron-donating groups
provided the corresponding products 2 in excellent yields (en-
tries 1–6). The reaction of 4-fluoro-trans-b-nitrostyrene (1h)
proceeded efficiently, whereas 4-Cl analogue 1i resulted in
a lower yield (entries 7 and 8). Although reactions with highly
electron-deficient substrates containing trifluoromethyl, cyano,
and ester groups resulted in low yields due to the polymeri-
zation of the nitroalkenes, the addition of 1% water by volume
was found to suppress the side reactions and improve the
Scheme 5. Representative transformations of dicyanoalkane 5i.
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reomers, a change in the ratio was observed during
purification by flash column chromatography on
silica gel, affording one stereoisomer predominantly.
In addition, we found that the obtained dicyano
compound 5i could be further transformed into
imide, dicarboxylic acid, and amidine derivatives
(Scheme 5). Thus the developed method provides ef-
ficient access to valuable compounds from readily
available nitro alkenes.
Table 2. Scope of the reaction with respect to aromatic nitroalkenes.[a]
Entry
1
2
Yield
[%][b]
In addition to nitroalkenes, vinyl sulfones 6 were
also suitable substrates for the dicyanation reaction
(Table 4).[4] The reaction of vinyl sulfone 6a with
TMSCN in the presence of TBAF furnished 2a in high
yield (entry 1). The simplest terminal vinyl sulfone 6b
afforded succinonitrile (7b; entry 2). Although reac-
tions using electron-deficient nitroalkenes such as b-
nitroacrylates and b-nitroacrylamides failed due to
polymerization, use of the corresponding vinyl sul-
fones 6c and 6d led to the formation of 1,2-dicyano
products 7c and 7d, respectively (entries 3 and 4).
1
2
3
4
5
6
7
8
X=4-NMe2
X=4-OMe
X=2-OMe
X=3-OMe
X=4-OH
X=4-Me
X=4-F
X=4-Cl
X=4-CF3
X=4-CN
1b
1c
1d
1e
1 f
1g
1h
1i
2b
2c
2d
2e
2 f
2g
2h
2i
98
92
99
98
96
91
91
71
81
59
79
94
9[c]
10[c,d]
11[c]
12
1j
1k
1l
2j
2k
2l
X=4-CO2Me
X=2,6-Cl2
1m
2m
13
14
15
1n
1o
1p
2n
2o
2p
93
99
96
Conclusion
The straightforward synthesis of 1,2-dicyanoalkanes
by the reaction of nitroalkenes with TMSCN in the
presence of “moist” TBAF under mild conditions has
been developed. A wide range of substrates, includ-
ing electron-rich and electron-deficient aromatic ni-
troalkenes, and aliphatic nitroalkenes, are tolerated in
the reaction. Moreover, vinyl sulfones were found to
be good alternatives, particularly for electron-defi-
cient nitroalkenes. The reaction system is very useful
and practical from the point of view of the availabili-
ty of starting materials. In addition, detailed mecha-
nistic studies suggest a unique mechanism for the di-
cyanation under “moist” conditions.
16
1q
1r
2q
2r
97
53
17[c]
18
19
1s
1t
2s
2t
98
85
Experimental Section
20
1u
1v
2u
2v
76
42
General procedure for dicyanation
TBAF (1m in THF, 0.2 mmol) was added to a mixture of
nitroalkene (0.2 mmol) and TMSCN (0.4 mmol) in MeCN
(4 mL), under an atmosphere of N2. The mixture was
stirred for 2 h at RT, then the reaction was quenched by
elution through a short column of silica gel with ethyl
acetate. The solution was concentrated to give the crude
product, which was purified by flash column chromatog-
raphy (silica gel) to give the product.
21[e]
[a] Reaction conditions: nitroalkene (0.2 mmol), TMSCN (0.4 mmol), TBAF (1m in THF,
0.2 mL), MeCN (4 mL), RT, 2 h. [b] Isolated yield. [c] H2O (1% v/v MeCN) was added.
[d] TMSCN (3 equiv) was used. [e] TMSCN (4 equiv) and TBAF (2 equiv) were used.
including cyclopropane, olefin, epoxide, and alcohol moieties,
were all well tolerated (entries 5–8). Fortunately, cyclic nitroal-
kene 4i was also smoothly converted into the corresponding
Acknowledgements
This work was supported by Grants-in-Aid for Scien-
product under heating conditions (entry 9); performing this re-
action at room temperature provided only the cyanoalkene. Al-
though the latter reaction afforded 5i as a mixture of diaste-
tific Research (No. 25288047 and No. 26105735) from the Min-
istry of Education, Culture, Sports, Science, and Technology
(MEXT), Japan.
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Table 3. Scope of the reaction with respect to aliphatic nitroalkenes.[a]
Entry
4
5
Yield
[%][b]
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1[c]
2[c]
4a
4b
5a
5b
80
74[d]
3
4
4c
5c
70
67
4d
5d
5
4e
4 f
5e
5 f
77
6
65
7
4g
4h
5g
5h
70[e]
83[e]
[6] Useful direct syntheses of nitroalkenes by nitration of ole-
fins have also been reported, see: a) S. Maity, S. Manna, S.
Rana, T. Naveen, A. Mallick, D. Maiti, J. Am. Chem. Soc. 2013,
135, 3355; b) T. Naveen, S. Maity, U. Sharma, D. Maiti, J. Org.
Chem. 2013, 78, 5949; c) S. Maity, T. Naveen, U. Sharma, D.
Maiti, Org. Lett. 2013, 15, 3384.
8[f]
9[g]
4i
5i
89[e]
[7] Y. Takemoto, M. Stadler, in Comprehensive Chirality Vol. 6
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[a] Reaction conditions: nitroalkene (0.2 mmol), TMSCN (0.6 mmol), TBAF (1m in THF,
0.2 mL), MeCN (4 mL), RT, 40 h. [b] Isolated yield. [c] TMSCN (2 equiv) was used. [d] A
d.r. of 1:1 was determined by 1H NMR spectroscopic analysis. [e] The d.r. value could
not be determined because of the overlap of signals in the NMR spectra. [f] Reaction
performed on 0.05 mmol scale. [g] Reaction was carried out at 808C for 20 h.
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Table 4. Scope of the reaction with respect to vinyl sulfones.[a]
Entry
6
Time
[h]
Product
Yield
[%][b]
1[c]
2[c]
6a
6b
20
20
2a
7b
80
98
[11] E. J. Corey, H. Estreicher, J. Am. Chem. Soc. 1978, 100, 6294.
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4624.
3
4
6c
2
6
7c
83
85
6d
7d
[a] Reaction conditions: vinyl sulfone (0.2 mmol), TMSCN (0.4 mmol), TBAF (1m in THF,
0.2 mL), MeCN (4 mL), RT. [b] Isolated yield. [c] TMSCN (3 equiv) and TBAF (2 equiv)
were used.
[13] TBAF (1m in THF; ca. 10 wt% of water) was purchased from
Nacalai Tesque Inc., Japan.
[14] Screening of solvents revealed that acetonitrile was optimal. See the
Supporting Information for details.
Keywords: cyanides · fluoride · Michael addition · reaction
mechanism · synthetic methods
[15] a) T. Hiyama, Y. Hatanaka, Pure Appl. Chem. 1994, 66, 1471; b) H. Konno,
E. Toshiro, N. Hinoda, Synthesis 2003, 2161; c) E. D. Soli, A. S. Manso,
M. C. Patterson, P. DeShong, D. A. Favor, R. Hirschmann, A. B. Smith III, J.
Org. Chem. 1999, 64, 3171; d) J. Gawronski, N. Wascinska, J. Gajewy,
Chem. Rev. 2008, 108, 5227.
[1] a) R. C. Larock, Comprehensive Organic Transformation: A Guide to Func-
tional Group Preparation, 2ednd edWiley, New York, 1999; b) F. F. Flem-
ing, Q. Wang, Chem. Rev. 2003, 103, 2035.
[16] TBAF·3H2O was purchased from Nacalai Tesque Inc., Japan.
Chem. Eur. J. 2014, 20, 1 – 7
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[17] The ammonium nitrite, Bu4NNO2, was isolated quantitatively by silica
gel column chromatography after the reaction. See the Supporting In-
formation for details.
[20] Although it is unlikely that TMSF can function as a Lewis acid in the re-
action system, the possibility cannot be ruled out at this stage.
[21] Without the addition of water, 1j, 1k, and 1l were obtained in 61, 45,
and 27%, respectively. See the Supporting Information for details.
[18] See the Supporting Information for details.
[19] The use of Bu4NOH as a catalyst in combination with PhMe2SiF promot-
ed the reaction of 2-methylene-4-phenylbutanenitrile (5a’) with
TMSCN. See the Supporting Information for details. The hydrolysis of
TMSF under basic conditions has been reported, see: J. A. Gibson, A. F.
Janzen, Can. J. Chem. 1972, 50, 3087.
Received: August 8, 2014
Published online on && &&, 0000
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FULL PAPER
Direct cyanation: A straightforward
synthesis of 1,2-dicyanoalkanes by the
reaction of nitroalkenes with trimethyl-
silyl cyanide in the presence of tetrabu-
tylammonium fluoride (TBAF) is report-
ed (see scheme). The method has wide
substrate scope and tolerates a wide va-
riety of functional groups. Mechanistic
studies suggest that a small amount of
water present in the reaction media
plays a key role in the reaction.
&
Synthetic Methods
K. Kiyokawa, T. Nagata, J. Hayakawa,
S. Minakata*
&& – &&
Straightforward Synthesis of 1,2-
Dicyanoalkanes from Nitroalkenes and
Silyl Cyanide Mediated by
Tetrabutylammonium Fluoride
Chem. Eur. J. 2014, 20, 1 – 7
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ