Non-reductive decyanation reactions of disubstituted malononitrile derivatives promoted by NaHMDS

Article abstract of DOI:10.1016/j.tetlet.2017.04.012

A new method for achieving the decyanation of disubstituted malononitrile derivatives without using reducing agents has been developed. Treatment of a six-membered malononitrile derivative with NaHMDS followed by methanol afforded the corresponding acetonitrile derivative in high yield. The present method was applicable to the decyanation reactions of a variety of malononitriles including four- and five-membered compounds as well as acyclic ones.

Full text of DOI:10.1016/j.tetlet.2017.04.012

Accepted Manuscript
Non-reductive decyanation reactions of disubstituted malononitrile derivatives
promoted by NaHMDS
Daisuke Domon, Masaru Iwakura, Keiji Tanino
PII:
S0040-4039(17)30436-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.04.012
TETL 48804
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
24 February 2017
29 March 2017
4 April 2017
Please cite this article as: Domon, D., Iwakura, M., Tanino, K., Non-reductive decyanation reactions of disubstituted
malononitrile derivatives promotedby NaHMDS, Tetrahedron Letters (2017), doi:http://dx.doi.org/10.1016/j.tetlet.
2017.04.012
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1
Tetrahedron Letters
journal homepage: www.elsevier.com
Non-reductive decyanation reactions of disubstituted malononitrile derivatives
promoted by NaHMDS
Daisuke Domon,a Masaru Iwakura,a Keiji Tanino b
a Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo 060-0810, Japan
b Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A new method for achieving the decyanation of disubstituted malononitrile derivatives without
using reducing agents has been developed. Treatment of a six-membered malononitrile
derivative with NaHMDS followed by methanol afforded the corresponding acetonitrile
derivative in high yield. The present method was applicable to the decyanation reactions of a
variety of malononitriles including four- and five-membered compounds as well as acyclic ones.
Available online
Keywords:
2017 Elsevier Ltd. All rights reserved.
Malononitrile
Decyanation
Nitrile
Addition reaction
Alkylation
———
 Corresponding author. E-mail address: ktanino@sci.hokudai.ac.jp (K. Tanino).

2
Tetrahedron
Br
Br
Alkylation reactions of active methylene compounds have
K2CO3
KI
O
O
O
O
CN
CN
found widespread use in organic synthesis, mainly because these
reactions proceed under mild conditions using a weak base. For
example, the reaction of an alkyl bromide and diethyl malonate
under the influence of sodium ethoxide affords an -substituted
malonate which can be converted to the corresponding -
substituted acetic acid through hydrolysis of the ester moiety
followed by decarboxylation. For obtaining an -substituted
acetonitrile, a similar procedure starting from ethyl cyanoacetate
is available. On the other hand, an alkylation reaction of
malononitrile followed by a decyanation reaction provides an
CH2(CN)2
+
+
+
DMF
90 °C
2a
1a 90%
OTs
K2CO3
KI
H
H
H
CN
CN
CH2(CN)2
OTs
DMF
80 °C
H
2b
2c
1b 99%
K2CO3
KI, TBAI
MS4A
1
alternative way to achieve the same purpose. While SmI2 and
lithium naphthalenide2 are reported to induce the reductive
cleavage of a cyano group from substituted malononitrile
derivatives, there are few example of non-reductive decyanation
reactions of them (Scheme 1).
O
O
O
Br
Br
CN
CN
1c 62%
CH2(CN)2
NMP
100 °C
O
Thus, Reeves3 reported a cyanation of aryl Grignard reagent or
lithium reagents by the addition reaction with dimethylmalono-
nitrile. In this reaction, the anionic intermediate undergoes
decomposition into the desired arenecarbonitrile and an α-
carbanion of isobutyronitrile, which shows promise for achieving
a non-reductive decyanation of ,-disubstituted malononitrile
derivatives. We herein report that the reactions of ,-
Scheme 2. Synthesis of cyclic malononitriles 1
With a view to inducing decyanation via a nucleophilic
addition reaction, malononitrile 1a was treated with 2 equiv. of n-
BuLi in THF at –78 °C (Scheme 3). After 30 min, the reaction
was quenched with diluted hydrochloric acid to give the desired
nitrile 3a in 40% isolated yield along with 51% of byproduct 4.
The result suggested that the reaction proceeded through
decomposition of the anionic intermediate A into the α-cyano
anion B even at –78 °C which attacked the remaining substrate
1a to form 4. On the other hand, the yield of nitrile 3a was
increased to 71% upon warming the reaction to room temperature
before quenching. In this case, a small amount (7%) of byproduct
5, which would come from pentanenitrile and malononitrile 1a.
disubstituted malononitrile derivatives with
a
suitable
nucleophile provided the corresponding ,-disubstituted
acetonitriles in high yield.
CH2(CN)2
PhCH2Br
DMF
SmI2
DBU
80 °C
Ph
Ph
Ph
Ph
ref.1
ref.2
NC
H
THF-HMPA
O
CN
Ph
Ph
97%
BuLi
(2.0 eq.)
NC CN
91%
O
1 M HCl
H
O
O
Li+
then MeI
THF
NH
+
THF
–78 °C
30 min
CN
O
CN
3a 40%
O
NC Me
80%
4
51%
1a
NC
BuLi
(2.0 eq.)
1 M HCl
O
Me
Me
Me Me
3a 71%
+
NH2
CN
Ar
NC CN
THF
–78 ° ~ rt
50 min
CN
N
O
ArMgBr
ArCN
ref.3
5
7%
THF
BrMg
0 °C ~ rt
nBu CN
nBu
Scheme 1. Conventional decyanation reactions of malononitriles
Li
O
O
O
N
C
N
Li
O
C
Initially, six-, five-, and four-membered malononitrile
derivatives 1a-1c were synthesized from the corresponding
dibromide or ditosylate 2a-2c and malononitrile (Scheme 2). The
combined use of K2CO3 and KI4 in DMF was effective for the
synthesis of 1a and 1b, while modified reaction conditions5 were
required for constructing the four-membered ring of 1c.
N
A
B
Scheme 3. Decyanation reactions of cyclic malononitrile 1a
After several efforts to solve the problem, it was unexpectedly
found that NaHMDS is a choice of nucleophiles, leading to
nitrile 3a in high yield (Scheme 4). Thus, malononitrile 1a was
reacted with 2 equiv. of NaHMDS6 in THF at room temperature,
and the mixture was treated with methanol before quenching with
water. During the experiment, -trimethylsilyl nitrile 6 was
found to be the initial product of the reaction,7 which enabled us
to understand the reason for the successful decyanation process
using NaHMDS. Thus, anionic intermediate C decomposes into
-cyano anion D and bis(trimethylsilyl)cyanamide8 which readily

3
undergo an inter-molecular transfer of a silyl group. Therefore,
the reactive anion D is immediately captured by a silyl group to
give 6, and the resulting anion E is sufficiently stable to avoid
side reactions. The silyl group of 6 is then removed in one-pot
simply by adding methanol to the reaction mixture. The protocol
was also effective for the decyanation reactions of malononitriles
1b and 1c, giving rise to the corresponding nitriles 3b and 3c in
85% and 70% yields, respectively.
NaHMDS
(2.0 eq.)
O
O
SiMe3
CN
MeOH
3a 89%
1a
THF
–78 °C ~ rt
1 h
6
Me3Si
Me3Si
Na+
N CN
SiMe3
Me3Si
–
N
Me3Si N CN
Na+
Na+
–
–
N
E
6
+
C
N
C
N
C
D
H
H
H
NaHMDS
(2.0 eq.)
CN
CN
MeOH
MeOH
CN
THF
–78 °C ~ rt
50 min
H
3b 85%
(dr=58:42)
1b
NaHMDS
(2.0 eq.)
O
O
O
CN
CN
CN
O
THF
–78 ° ~ rt
4 h
1c
3c 70%
Scheme 4. Decyanation reaction of malononitriles mediated by NaHMDS
We then turned our attention to the decyanation of acyclic
substrates. Various ,-disubstituted malononitriles 7 were
easily synthesized from (3-phenylpropyl)malononitrile (8) and
the corresponding alkylating agents in a similar fashion with the
preparation of 1a (Table 1). Upon treatment with NaHMDS in
THF followed by methanol, malononitriles 7 possessing a methyl
group or a (2-benzyloxy)ethyl group at the -position underwent
smooth decyanation reactions to afford nitriles 9 in good yields
(entries 1 and 2). Surprisingly, the substrate having an allyl group
failed to give the desired product, resulting in formation of a
complex mixture (entry 3). We found that the use of less polar
solvents dramatically changes the result. Thus, the desired nitrile
9 was obtained in 85% yield by the reaction in a mixture of ether
and toluene (entry 4), and an analogue having a prenyl group was
also synthesized in a similar manner (entry 5).
Since nitriles 9 would also be obtainable directly from 5-
phenylpentanenitrile through the alkylation reactions with R'-X,9
the present two-step synthesis of
9 via decyanation of
malononitriles 7 may show little advancement. On the other
hand, it has been recognized that malononitrile can serve as an
effective nucleophile in Michael addition to ,-unsaturated
ketones,10 which contrasts with that a simple alkanenitrile
generally prefers 1,2-addition rather than 1,4-addition.

4
Tetrahedron
Table 1. Two-step synthesis of acyclic nitriles a
A regioisomeric mixture of malononitriles 11 and 11' was also
R'-X
synthesized from the corresponding diketone 12 which was
prepared from malononitrile and methyl vinyl ketone by the
double Michael reaction mediated by a silica nano-particle.12
Upon treatment with NaHMDS in THF followed by methanol,
malononitriles 10 and 11 (containing 11') were cleanly
transformed into the desired nitriles 13 and 14 (containing 14'),
respectively.
NaHMDS
(2.0 eq.)
K2CO3
additive
CN
CN
CN
R'
CN
R'
MeOH
R
CN
R
H
R
DMF
rt ~ 100 °C
conditions
8
7
9
R = Ph(CH2)3
Yield of
7
Yield of
Entry
R'-X
MeI
Additive
Conditions
9
We next turned our attention to the Michael addition reactions
of 1,1-dicyanoalkene with nucleophiles, which showed promise
for preparing malononitriles with a bulky substituent (Scheme 6).
The condensation reaction of cyclohexanone with malononitrile
afforded dicyano compound 15 in high yield.13, 14 The reaction of
15 with a Grignard reagent in the presence of copper(I) chloride15
proceeded in good yield to afford malononitrile 16 which was
subjected to the alkylation reaction with MeI. Although
NaHMDS failed to induce the decyanation reaction of the
sterically demanding malononitrile 17 even under refluxing
condition, the use of KHMDS led to formation of the desired
nitrile 18 in 81% yield.
1
2
3
4
5
-
NaI
-
90%
83%
98%
98%
96%
(i)
(i)
96%
95%
-
BnOCH2CH2OMs
CH2=CHCH2I
(i)
CH2=CHCH2I
-
(ii)
(ii)
85%
96%
Me2C=CHCH2Br
NaI
a
Reaction condition (i): To a THF solution of 7 was added a 1.1 M THF
solution of NaHMDS at –78 °C, and the solution was warmed up to room
temperature. After 2.5 h, the reaction was quenched with methanol at room
temperature. Reaction condition (ii): To an ethereal solution of 7 was added a
0.6 M toluene solution of NaHMDS at –78 °C, and the solution was warmed
up to room temperature. After 3 h, the reaction was quenched with methanol
at room temperature.
CN
Indeed, the advancement of the indirect method for obtaining
nitriles was shown in Scheme 5. Thus, under the influence of
sodium hydride and TIPSOTf, methylmalononitrile reacted with
2-cyclohexen-1-one to afford enol silyl ether 10 in excellent
yield.11
MgBr
MeI
K2CO3
CN
CN
Me
CN
CN
CuCl
THF
–78 °C
DMF
35 °C
CN
16 89%
15
17 93%
KHMDS
(2.0 eq.)
CN
H
Me
MeOH
OTIPS
O
TIPSOTf
NaH
NaHMDS
(2.0 eq.)
THF
reflux
CN
CN
OTIPS
+
18 81%
CN
CN
Me
THF
0 °C
THF
rt
Me
10
CN
CN
CN
MeLi
MeI
NaHMDS
(2.0 eq.)
MeOH
–
CN
H
Me
Me
Me
15
THF
rt
ether
rt
F
19 79%
13 75% (2 steps)
(dr=52:48)
CN CN
CN CN
CN
Me
CN
MeOH
O
O
Me
Me
Me
O
TIPSOTf
Et3N
+
silica NP
CH2(CN)2
+
20
20'
21
21'
EtOH
rt, 1.5 h
CH2Cl2
rt, 4 h
NC CN
12 88%
(2.0 eq.)
67% (91: 9)
CN
9% (59:41)
CN
OTIPS
OTIPS
+
OTIPS
OTIPS
20, 20'
–
CN
Me
NaHMDS
(2.0 eq.)
Me
MeOH
F
19
THF
rt, 3 h
NC CN
NC CN
CN
CN CN
Me
CN CN
11
11'
base
–
–
Me
Me
81% (ca. 80:20)
OTIPS
OTIPS
G
F
22
OTIPS
OTIPS
Scheme 6. Conversion of 1,1-dicyanoalkene 15 to nitriles through
+
decyanation reactions
NC
H
NC
14'
H
14
Interestingly, the reaction of β, γ-unsaturated malononitrile 19,
which was prepared by the methylation of 1516, mainly afforded
dinitrile 20 along with the desired nitrile 21 in 9% yield. The
unusual result can be explained by the transcyanation of the
anionic intermediate F with the remaining substrate 19 at the -
96% (ca. 80:20)
Scheme 5. Synthesis of nitriles through conjugate addition reactions

5
position of the cyano group to afford intermediate 22. which is
converted to 20 via anionic intermediate G.
In conclusion, a new method for achieving the decyanation of
disubstituted malononitrile derivatives without using reducing
agents has been developed. Treatment of a six-membered
malononitrile derivative with NaHMDS followed by methanol
afforded the corresponding acetonitrile derivative in high yield.
The present method was applicable to the decyanation reactions
of a variety of malononitriles including four- and five-membered
compounds as well as acyclic ones. The mild non-reductive
reaction condition tolerates functional groups such as benzyl
ether (Table 1, entry 2), which shows promise for use in natural
product synthesis.
Acknowledgments
This work was supported by JSPS KAKENHI Grant Numbers
JP15H05842 in Middle Molecular Strategy and JP15H03806.
References and notes
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Marsini, M. A.; Sader, C. A.; Fandrick, K. R.; Busacca, C. A.;
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CN 103232340, August, 7, 2013.
6. The use of 1.1 equiv. of NaHMDS led to a decrease in the yield of
nitrile 3a (54%) due to the recovery of malononitrile 1a (33%),
while the reason of the incomplete transformation is not clear.
7. In case that the reaction mixture was treated with a THF solution
of acetic acid (5 eq.) at –78 °C before quenching with water, -
silyl nitrile 6 was isolated in 80% yield along with 7% of nitrile 3a.
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Non-reductive decyanation reactions of
disubstituted malononitrile derivatives
promoted by NaHMDS
Leave this area blank for abstract info.
Daisuke Domon, Masaru Iwakura, Keiji Tanino
CN
R'
CN
R'
MeOH
NaHMDS
THF
R
CN
R
H
OTIPS
Me
OTIPS
H
OTIPS
O
O
CN
CN
H
CN
H
CN
H
H
O
O
CN

A new synthetic method of aliphatic and alicyclic mononitriles is described.
Treatment of substituted malononitriles with NaHMDS followed by MeOH gave nitriles.
The clean transformation is attributable to formation of -silylated intermediates.