In Situ Generated Magnesium Cyanide as an Efficient Reagent for Nucleophilic Cyanation of Nitrosoalkenes and Parent Nitronates

Article abstract of DOI:10.1002/ejoc.201801761

In situ generated magnesium cyanide [NaCN/Mg(ClO₄)₂] is suggested as a convenient, readily available, non-volatile and organic-soluble reagent for hydrocyanation reactions. It was successfully used for nucleophilic cyanation of nitrosoalkenes, nitronates, as well as other typical π-electrophiles, such as imines, α,β-unsaturated ketones, alkylidenemalonates and azoalkenes.

Full text of DOI:10.1002/ejoc.201801761

A Journal of
Accepted Article
Title: In Situ Generated Magnesium Cyanide as an Efficient Reagent
for Nucleophilic Cyanation of Nitrosoalkenes and Parent
Nitronates
Authors: Pavel Yu. Ushakov, Andrey A. Tabolin, Sema L. Ioffe, and
Alexey Yurievich Sukhorukov
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801761
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801761
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10.1002/ejoc.201801761
European Journal of Organic Chemistry
COMMUNICATION
In Situ Generated Magnesium Cyanide as an Efficient Reagent for
Nucleophilic Cyanation of Nitrosoalkenes and Parent Nitronates
Pavel Yu. Ushakov,[a],[b] Andrey A. Tabolin,[a] Sema L. Ioffe[a] and Alexey Yu. Sukhorukov[a],[c]*
Abstract: In situ generated magnesium cyanide (NaCN/Mg(ClO4)2)
is suggested as a convenient, readily available, non-volatile and
organic-soluble reagent for hydrocyanation reactions. It was
successfully used for nucleophilic cyanation of nitrosoalkenes,
nitronates, as well as other typical -electrophiles, such as imines,
,-unsaturated ketones, alkylidenemalonates and azoalkenes.
cyanides, such as TMSCN, are easier to handle, yet these
volatile reagents are toxic and easily produce HCN upon
hydrolysis on air. Furthermore, desilylation of final product is
required, which is not always easy.[7] Non-alkali p-metal
cyanides (Et2AlCN, Ca(CN)2) are sometimes used as cyanide
8]
sources,[6,
however, these reagents are not generally
accessible. Transition metal cyanides like CuCN, Zn(CN)2 and
K4[Fe(CN)6] suffer from low solubility in organic solvents.
Introduction
Addition of the cyanide anion to carbon-centered electrophiles is
one of the most fundamental C,C-bond forming reactions in
organic synthesis. Although being known for more than 150
years, nucleophilic cyanation is still an active area of research
mainly focused on the development of enantioselective methods
for 1,2- and 1,4-additions,[1] transition metal-catalyzed cyanation
of aryl halides,[2] and oxidative cyanation of CH[3] and C=C
bonds.[4]
Despite of a significant progress in these areas, there is still a
challenge in developing appropriate and safe reagents for
Scheme 1. Side processes in hydrocyanation of multiple C=X bonds.
nucleophilic
1,2-
and
1,4-hydrocyanation
reactions.[5]
Nucleophilic addition of CN- to multiple bonds is usually
reversible and results in the generation of anionic species A
(Scheme 1), which can react with the initial substrate leading to
side reactions (e.g. oligomerization).[6] To shift the equilibrium
and stabilize the cyanation product, it is needed to trap anion A,
usually, either by protonation (with solvent or acid additive) or
with an external electrophile (for example, a silylating agent).
The nature of cyanation reagent is, thus, a key factor governing
selectivity in the nucleophilic addition of the cyanide anion to -
electrophiles.
Here, we suggest in situ generated magnesium cyanide
(NaCN/Mg(ClO4)2) as a non-volatile, soluble in DMF and cheap
reagent for 1,2- and 1,4-hydrocyanation reactions.[9] It combines
a nucleophilic cyanide anion and a Lewis acid (Mg2+), which
covalently binds to anions A preventing their degradation and
can be easily removed by aqueous work-up. This reagent was
successfully used for nucleophilic - and -cyanation of
nitronates 1, which was not efficient with standard reagents such
as NaCN, Zn(CN)2 and silyl cyanides.
Alkali metal cyanides in water or alcohols are classical reagents
for hydrocyanation reactions. However, they produce new
nucleophilic species (hydroxide or alkoxide anions), which can
compete with addition of CN-.[6] Systems containing hydrogen
cyanide or its surrogates (KCN/protic acid, acetone cyanohydrin)
are dangerous to work with because of high toxicity. Trialkyl silyl
Results and Discussion
Nitronates 1 for a long time have been considered as synthetic
equivalents of parent nitro compounds, which are classical -C-
nucleophiles.[10] We have demonstrated that under certain
activation conditions (treatment with strong silicon-centered
Lewis acids) nitronates 1 can serve as - and -electrophilic
[a]
Mr. P. Yu. Ushakov, Dr. A. A. Tabolin, Prof. Dr. S. L. Ioffe, Dr. habil.
A. Yu. Sukhorukov, Laboratory of Functional Organic Compounds
N. D. Zelinsky Institute of Organic Chemistry
119991, Leninsky prospect, 47, Moscow, Russia
sukhorukov@ioc.ac.ru, https://twitter.com/SukhorukovAlex
Mr. P. Yu. Ushakov,
Department of Chemistry, M. V. Lomonosov Moscow State
University
119991, Russian Federation, Moscow, Leninskie gory, 1, str. 3.
Plekhanov Russian University of Economics
Stremyanny per. 36, Moscow, Russia 117997
11]
reagents.[10a,
In particular, recently we reported a TBSOTf-
promoted addition of TBSCN to cyclic O-alkyl nitronates Alk-1
affording corresponding -cyano-substituted nitroso acetals 2
(Scheme 2).[12] Also, we developed -cyanation of O-silyl
nitronates Si-1 through their transformation to N,N-
[b]
[c]
bis(silyloxy)enamines
4 and addition of TMSCN via the
intermediacy of nitrosoalkenes NSA (Scheme 2).[13] Upon
deprotection, cyanooxime derivatives 5 cyclized into valuable 5-
aminoisoxazoles 6.[14] However, these silicon-mediated
processes have drawbacks associated with the lack of efficiency
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201801761
European Journal of Organic Chemistry
COMMUNICATION
and the need of desilylation, which is not selective in the case of
of acetate 9a was also obtained (Scheme 3). Both products are
most likely formed by a competitive 1,4-addition of HCN and
AcOH to nitrosoalkene moiety of B.
nitrosoacetals 2.[12, 15] We, therefore, attempted to perform the
aforementioned
transformations
avoiding
silicon-based
cyanation reagents.
We reasoned that the use of an oxophilic Lewis acid may
prevent anionic intermediates of type B from cyclization thus
enabling the intermolecular nucleophilic attack of CN- on the
nitrosoalkene unit. After testing some readily available metal
cyanides (CuCN and Zn(CN)2) and NaCN/Lewis acid systems
(Lewis acid  BF3Et2O, AgOTf, Mg(OTf)2, Mg(ClO4)2) we found
that the use of NaCN/Mg(ClO4)2 in DMF led to a smooth
transformation of model enamine 7a into the desired 5-
aminoisoxazole 6a (yield 79 %).[17] Unlike d-metal cyanides,
which are poorly soluble in organic solvents, in situ generated
magnesium cyanide gives a clear viscous solution in DMF.
Reaction could be also performed in EtOH/H2O (1 : 1) mixture,
however, lower yield of product 6a was observed (54 %).
This cyanation system was successfully used to prepare 5-
aminoisoxazoles 6a-m bearing various substituents and
functionalized alkyl chains at C-3 atom. Importantly, this
procedure tolerated 5- and 6-membered cyclic N,N-
bis(oxy)enamines 7 as well as acyclic N,N-bis(silyloxy)enamines
4 as can be seen from examples shown in Scheme 4.
Scheme 2. Umpolung - and -cyanations of nitronates with TMSCN
2 equiv. NaCN
Mg(ClO4)2
DMF/CH2Cl2
R
R
R
O
NH2
NH2
R1
or
N
N
R1
N
In our initial experiments aimed at preparing 5-aminoisoxazoles
6 from cyclic N,N-bis(oxy)enamines 7, we reacted model
enamine 7a with NaCN in DMF (Scheme 3). Surprisingly, this
did not result in the addition of the cyanide anion. Instead,
pyranone oxime 8a was formed as the major product, which
arises from the nucleophilic attack on silicon atom and
subsequent recyclization via anionic intermediate B.[16]
O
O
rt, 2 h
HO
OTMS
7 R1 = Alk, cyclic
4 R1 = TMS, acyclic
6k-m
6a-j
(from
(from 4)
7
)
Examples
OMe
OH
R
OH Ph
OH
( )n
NH2
H
NH2
N
O
N
O
H
NH2
6e, 64 %
N
6a, R = Ph, 79 %
O
6b, R = 4-Cl-C6H4, 92 %
6c, R = Me, 39 %
6d, R = OBz, 49 %
6f, 85 % (n = 0)
6g, 80 % (n = 1)
OMe
Ph
Ph
OH
EtO2C
HO
NH2
NH2
NH2
HO
N
N
N
O
O
O
6j, 60 %
6i, 58 %
6h, 80 %
MeO2C
Ph
Ph
NH2
NH2
NH2
N
N
N
O
O
O
6l, 95 %
6k, 90 %
(with TMSCN:[13] 72 %)
6m, 47 %
Scheme 3. Reaction of model enamine 7a with NaCN.
Scheme 4. Synthesis of 5-aminoisoxazoles 6 using NaCN/Mg(ClO4)2 system.
When NaCN/AcOH system was used, the desired
With this new reagent in hand, we attempted to achieve
aminoisoxazole 6a did form, however, an almost equal amount
nucleophilic addition of the cyanide anion to the -carbon atom
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10.1002/ejoc.201801761
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COMMUNICATION
of nitronates Alk-1. Indeed treatment of Alk-1 with
NaCN/Mg(ClO4)2 system in DMF afforded corresponding
cyanooxime derivatives 3 in good to high yields as mixtures of
E/Z-isomers (Scheme 5). Products 3 are likely formed through
the nucleophilic addition/ring opening mechanism.[11]
Previously reported cyanation of nitronates 1 with TBSCN used
strong Lewis acids (such as silyl triflates) to activate the C=N
bond through coordination with the N-oxide moiety.[12] Results
shown in Schemes 5,6 demonstrate that the cyanide anion is
nucleophilic enough to react with nitronates 1 without the need
of prior activation of the nitronate moiety.
Unfortunately, we failed to achieve hydrocyanation of O-silyl
nitronates Si-1, which transformed into nitroalkanes upon
treatment with NaCN/Mg(ClO4)2 as exemplified in Scheme 7.
2 equiv. NaCN
Mg(ClO4)2
DMF/CH2Cl2
R
R
CN
CN
R
H
O
N
N
N
rt, 2 h
O
O
HO
OH
O
Mg(II)
3
1
Alk-
Examples
OMe
OMe
Scheme 7. Attempted -cyanation of silyl nitronate Si-1a.
HO
OH
HO
CN
CN
CN
H
H
N
N
OH
N
Finally, we tested NaCN/Mg(ClO4)2 system for nucleophilic
cyanation of other typical electrophilic substrates (Scheme 8).
OH
OH
3b, 77 %
Z/E = 2 : 1
3c, 74 %
3a
, 82 %
Z/E = 6 : 1
Z/E = 2 : 1
OMe
OMe
NaCN, Mg(ClO4)2
HN
N
DMF/CH2Cl2
OH
HO
CN
(1)
OH
CN
CN
rt, 4 h
CN
Cl
H
Cl
N
N
12, 80 %
OH
11
MeO2C
OH
N
OH
3f, 63 %
Z/E = 7 : 1
3d, 81 %
Z/E = 5 : 1
3e, 80 %
Z/E = 1.3 : 1
NaCN, Mg(ClO4)2
MeO2C
CO2Me
CO2Me
DMF/CH2Cl2
(2)
(3)
CN
rt, 2 h
Scheme 5. Synthesis of cyanooxime derivatives 3 by -cyanation of nitronates
Alk-1 using NaCN/Mg(ClO4)2 system.
MeO
MeO
13
14, 92 %
CN
O
NaCN, Mg(ClO4)2
O
Reaction of nitronate Alk-1a with NaCN in the absence of
Mg(ClO4)2 resulted in only 39 % yield of cyanooxime 3a
(Scheme 6). The second product was enoxime 10a, which likely
arises from the fragmentation of oxy-anion D. The latter is
formed upon deprotonation of the initial nitronate Alk-1a with
highly basic oximate anion C originating from the nucleophilic
addition of CN- to Alk-1a.[11, 18] This experiment demonstrates the
importance of a Lewis acid (Mg(II) salt) for trapping reactive oxy-
anions (such as C) in nucleophilic cyanation reactions.
DMF/CH2Cl2
rt, 24 h
15
16, 70 %
O
O
NaCN, Mg(ClO4)2
H
CN
H
DMF/CH2Cl2
(4)
H
H
rt, 48 h
H
H
AcO
AcO
RSM: 49 %
18, 40 % (no 1,2-addition)
17
Previous methods: TMSCN/ZnI2 34 % (+ 52% of 1,2-addition)[22]
NaCN/MeOH 76 % with deacylation[23]
Ph
NaCN, Mg(ClO4)2
Ph
Ph
DMF/CH2Cl2
NH2
Cl
(5)
N
N
N
N
N
rt, 2 h
Boc
NHBoc
Boc
20, 47 %
19
AZA
Scheme 8. Nucleophilic cyanation of various -electrophiles with
NaCN/Mg(ClO4)2 system.
Scheme 6. Reaction of nitronate Alk-1a with NaCN in the absence of
Mg(ClO)4. An - 4-MeOC6H4-.
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We were able to perform hydrocyanation of model imine 11 as
well as simple Michael acceptors such as arylidenemalonate 13
and benzylidene acetone 15 (Scheme 8, eqs. (1)-(3)). The yields
of corresponding nitriles 12,[19] 14[20] and 16[21] were comparable
with those previously obtained employing other hydrocyanation
reagents.
quenching of this reaction. Appropriate safety precautions and
procedures should be employed if the reaction is performed on
large scale.
Acknowledgements
Hydrocyanation of a complex steroidal ,-unsaturated ketone
17 (3-acetoxypregna-5,16-dien-20-one) afforded exclusively
1,4-addition product 18 as a single diastereomer (82 % based
on converted 17, Scheme 8, eq. (4)). It is noteworthy, that
TMSCN/ZnI2 system afforded a mixture of 1,4- and 1,2-addition
products with the latter being predominant.[22] Previously
reported reaction of steroid 17 with NaCN in MeOH resulted in
selective 1,4-cyanide addition, however the product underwent
deacetylation under these conditions.[23]
Since NaCN/Mg(ClO4)2 system performed well in Michael
addition to unstable nitrosoalkenes NSA, we attempted involve
azoalkenes AZA in the same reaction (Scheme 8, eq. (5)). To
the best of our knowledge, nucleophilic cyanation of AZA has
not been reported so far.[24] As expected, reaction of chloro-
substituted hydrazone 18 (the precursor of AZA) with
NaCN/Mg(ClO4)2 delivered the desired 5-aminopyrazole, albeit
in moderate yield.
This work was supported by Russian Foundation for Basic
Research (grant 17-03-01079).
Keywords: cyanides • nucleophilic addition • nitronates •
magnesium • isoxazoles
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generated magnesium cyanide. A mixture of sodium cyanide
(98 mg, 2 mmol) and magnesium perchlorate (233 mg, 1 mmol)
was dissolved in DMF (4 ml) under inert atmosphere. After
stirring for 1 h at r.t., a solution of electrophile (1 mmol) in 2 ml of
CH2Cl2 was added and the mixture was stirred for additional 2 h
(if not stated otherwise). Then, the mixture was diluted with
water or 0.25 M solution of sodium bisulfate (50 ml) and
extracted with MTBE or diethyl ether (50 ml). The organic layer
was washed with water (50 ml) and brine (50 ml). Aqueous layer
was saturated with NaCl and washed with MTBE or diethyl ether
(50 ml). Combined organic extracts were dried over anhydrous
Na2SO4 and concentrated under reduced pressure to give crude
product, which was purified by flash column chromatography.
Caution: Hydrogen cyanide (HCN) can be produced in the
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COMMUNICATION
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COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
In situ generated magnesium
Pavel Yu. Ushakov, Andrey A. Tabolin,
Sema L. Ioffe, Alexey Yu. Sukhorukov*
cyanide is
a convenient, readily
available, non-volatile and organic-
soluble reagent for hydrocyanation
Page No. – Page No.
reactions.
cyanation of -electrophiles such as
nitronates, conjugated nitrosoalkenes,
imines,
Efficient
nucleophilic
In Situ Generated Magnesium
Cyanide as an Efficient Reagent for
Nucleophilic Cyanation of
,-unsaturated
ketones,
Nitrosoalkenes and Parent Nitronates
methylenemalonates and azoalkenes
was demonstrated.
Key topic – Hydrocyanation reactions
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