Selective synthesis of unsymmetrical peroxides: Transition-metal-catalyzed oxidation of malononitrile and cyanoacetic ester derivatives by tert-butyl hydroperoxide at the α-position

Article abstract of DOI:10.1055/s-0030-1260027

A novel method was developed for the selective oxidation of -monosubstituted malononitrile and cyanoacetic ester derivatives at the -position based on transition-metal-catalyzed reaction (Cu, Fe, Mn, Co) with tert-butyl hydroperoxide giving unsymmetrical

Full text of DOI:10.1055/s-0030-1260027

PAPER
2091
Selective Synthesis of Unsymmetrical Peroxides: Transition-Metal-Catalyzed
Oxidation of Malononitrile and Cyanoacetic Ester Derivatives by tert-Butyl
Hydroperoxide at the a-Position
P
eroxidation of
N
i
l
trile
s
exander O. Terent’ev,*a Dmitry A. Borisov,a Vsevolod V. Semenov,a Vladimir V. Chernyshev,b,c
Valery M. Dembitsky,d Gennady I. Nikishin*a
a
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prosp., 119991 Moscow,
Russian Federation
Fax +7(499)1355328; E-mail: terentev@ioc.ac.ru
Department of Chemistry, Moscow State University, 119992 Moscow, Russian Federation
b
c
A.N. Frumkin Institute of Physical Chemistry and Electrochemistry, 31 Leninsky prosp., 119991 Moscow, Russian Federation
Institute for Drug Research, P.O. Box 12065, Hebrew University, Jerusalem 91120, Israel
d
Received 2 March 2011; revised 9 April 2011
The transition-metal (Cu, Mn, Co)/hydroperoxide system
Abstract: A novel method was developed for the selective oxida-
was used for the first time by Kharasch in the synthesis of
tion of a-monosubstituted malononitrile and cyanoacetic ester de-
peroxides from alkenes, ketones, and tertiary amines more
rivatives at the a-position based on transition-metal-catalyzed
than six decades ago.9 Since that time, investigations and
reaction (Cu, Fe, Mn, Co) with tert-butyl hydroperoxide giving un-
symmetrical peroxides in 63–94% yields. The method is facile, does the use of this peroxidation method have been document-
not require large excesses of reagents, and is amenable to gram-
scale synthesis.
ed in many research studies. The formation of peroxides
has been observed in a variety of reactions of hydroperox-
ides catalyzed by metal salts and their complexes (Cu,10
Key words: peroxides, tert-butyl hydroperoxide, catalysis, oxida-
Co,11 and Fe12), including Gif13 and metalloporphyrin14
tion, transition metals, malononitrile, cyanoacetic ester
catalysis. Peroxides were synthesized in high yields by the
peroxidation of amines, amides, and lactams catalyzed by
Over the last two decades, organic peroxides have re- ruthenium salts.15
ceived considerable attention from researchers in medical
chemistry and pharmaceutics in relation to drug design for
Considerable advances have been made in hydroxylation
reactions of b-dicarbonyl compounds at the a-position
the treatment of important human parasitic diseases, such
with peracids,16 dimethyldioxirane,17 hydrogen perox-
as malaria1,2 and helminthiases.3 Considerable progress
ide,18 or oxygen,19 which are related to the peroxidation
has been made in the design of effective peroxide antima-
reaction.8b In several studies, peroxides were formed by
larial agents. Thus, the natural peroxide artemisinin and
the oxidation of cyclic b-diketones with singlet oxygen19a
its semisynthetic derivatives are widely used in medical
and with the use of the CeCl3/O2 system,19b as well by the
practice. Certain synthetic peroxides exhibit activity equal
reactions of nitrogen-containing heterocyclic compounds
to or higher than that of artemisinin.4 An ozonide with the
bearing the b-dicarbonyl moiety with the Mn(OAc)2/O2
trivial name arterolane is in the third stage of clinical trials
system.19c
for the treatment of malaria. There is an active search for
It seems unusual that, in spite of a large number of studies
on the oxidation of b-dicarbonyl compounds, methods for
C–O bond formation at the a-position were not available
for their heteroanalogues, such as malononitrile and cy-
anoacetic ester derivatives.
peroxides having antitumor5 and growth-regulatory activ-
ities.6
The development of cyclic peroxide based explosives
may be of particular interest. Triacetone triperoxide is one
of the most sensitive explosives known with a destructive
power similar to that of trinitrotoluene.7 Peroxide deriva-
tives of other lower ketones and aldehydes, as well as of
amines, may be of interest as high-energy materials.
In the present study, we developed an efficient method for
the oxidation of a-monosubstituted malononitrile and cy-
anoacetic ester derivatives at the a-position by transition-
metal-catalyzed (Cu, Co, Mn, Fe) peroxidation with tert-
butyl hydroperoxide. The reaction occurs with high selec-
tivity, does not require large excesses of reagents, and can
be easily scaled up. Derivatives of malononitrile 1a–f and
cyanoacetic ester 3a–f substituted at the a-position were
used as the starting reagents for the synthesis of target per-
oxides 2a–f and 4a–f, respectively (Scheme 1).
The present study is a continuation of our research on the
peroxidation of b-dicarbonyl compounds.8 Earlier, we
found that the transition metals Cu, Fe, Mn, and Co cata-
lyze the selective peroxidation of b-dicarbonyl com-
pounds at the a-position by tert-butyl hydroperoxide.8b
In terms of the discussion of the peroxidation reaction
shown in Scheme 1, it should be noted that in the last de-
cade malononitrile and cyanoacetic ester, their a-mono-
SYNTHESIS 2011, No. 13, pp 2091–2100
Advanced online publication: 05.05.2011
DOI: 10.1055/s-0030-1260027; Art ID: N24211SS
x
x.
x
x
.
2
0
1
1
© Georg Thieme Verlag Stuttgart · New York

2092
A. O. Terent’ev et al.
PAPER
t-BuOOH, Mn+
catalytic amounts of transition-metal salts (Cu, Fe, Co) as
oxidizing agents. In no case was the formation of perox-
ides of b-dicarbonyl compounds observed due to the high
selectivity of these reactions.
NC
R
CN
NC
CN
solvent
OOt-Bu
R
1a–f
2a–f
Data on the oxidation of malononitrile, cyanoacetic ester,
and their a-monosubstituted derivatives at the a-position
to form the C–O bond are lacking in the literature. Hence,
the discovered peroxidation with tert-butyl hydroperox-
ide, which acts simultaneously as the oxidizing agent and
the second component of the reaction, was quite unex-
pected.
a: R = Bn; b: R = 4-ClC6H4CH2; c: R = 4-MeOC6H4CH2;
d: R = i-Pr; e: R = c-Pent; f: R = CH(Me)CH2COOEt
O
O
t-BuOOH, Mn+
solvent
CN
CN
EtO
EtO
R
OOt-Bu
R
The present study involved several steps. Initially, we
evaluated the possibility of peroxidation by examining a-
benzyl-substituted malononitrile 1a and cyanoacetic ester
3a and optimized the reaction conditions (the ratio of the
reagents, the type of the catalyst, and the solvent). Then
we synthesized a series of unsymmetrical peroxides 2 and
4 with the aim of determining the scope of the reaction and
the applicability of this method to the preparative synthe-
sis of previously unavailable compounds.
3a–f
4a–f
a: R = Bn; b: R = 4-ClC6H4CH2; c: R = 4-MeOC6H4CH2;
d: R = CH2CH=CH2; e: R = CH2COMe; f: R = CH2CH2COOEt
Scheme 1 Synthesis of a-tert-butylperoxy malononitrile 2a–f and
cyanoacetic ester derivatives 4a–f
substituted derivatives,20,21a and, to a greater extent,
related b-dicarbonyl compounds were used in the oxida-
tive coupling with alkanes, alkenes, amines, esters, and
compounds containing the benzyl group.21 In several stud-
ies, the coupling with b-dicarbonyl compounds was car-
ried out using tert-butyl hydroperoxide,21b–d di-tert-butyl
peroxide,21d and tert-butyl benzoate21d,e combined with
We chose 2-benzylmalonitrile (1a) containing two active
reaction centers, CH and CH2, as one of the reagents for
the optimization of the peroxidation conditions (Table 1).
The reaction of dinitrile 1a with tert-butyl hydroperoxide
afforded 2-benzyl-2-(tert-butylperoxy)malononitrile (2a).
Table 1 Synthesis of 2-Benzyl-2-(tert-butylperoxy)malononitrile (2a) by Peroxidation of 2-Benzylmalononitrile (1a) with tert-Butyl Hydro-
peroxide Catalyzed by Transition-Metal Saltsa
CN
Ph
CN
catalyst
solvent
Ph
OO
HOO
+
CN
1a
CN
2a
Entry
1
t-BuOOH (equiv) Catalyst
Cat. (equiv)
0.05
Time (h) Solvent
Conv. (%)
73
Yield (%)
53
3
3
3
5
2
3
3
3
3
3
3
3
3
3
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
0.5
1
MeCN
MeCN
MeCN
MeCN
MeCN
AcOH
EtOH
2
0.1
100
100
100
67
94
3
0.1
0.5
0.5
0.5
0.5
0.5
0.5
1
94
4
0.1
92
5
0.1
60
6
0.1
98
trace
17
7
0.1
98
8
0.1
benzene
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
77
35
9
Cu(ClO4)2·6H2O (o-phenanthroline)
Cu(ClO4)2·6H2O (pyridine)
Cu(ClO4)2·6H2O (Et3N)
Cu(ClO4)2·6H2O (proline)
Cu(BF4)2·6H2O
0.1 (0.3)b
0.1 (0.6)b
0.1 (0.6)b
0.1 (0.6)b
0.1
100
100
100
27
81
10
11
12
13
14
1
32
1
6
1
17
1
100
98
90
Cu(OAc)2·H2O
0.1
1
trace
Synthesis 2011, No. 13, 2091–2100 © Thieme Stuttgart · New York

PAPER
Peroxidation of Nitriles
2093
Table 1 Synthesis of 2-Benzyl-2-(tert-butylperoxy)malononitrile (2a) by Peroxidation of 2-Benzylmalononitrile (1a) with tert-Butyl Hydro-
peroxide Catalyzed by Transition-Metal Saltsa (continued)
CN
Ph
CN
catalyst
solvent
Ph
OO
HOO
+
CN
1a
CN
2a
Entry
15
16
17
18
19
20
21
22
23
24
25
26
27
t-BuOOH (equiv) Catalyst
Cat. (equiv)
0.1
Time (h) Solvent
Conv. (%)
Yield (%)
3
3
3
3
3
3
3
3
3
3
3
3
3
CuCl2
1
1
1
1
1
1
1
1
1
1
1
1
1
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
90
98
22
21
13
50
20
4
trace
trace
21
11
4
Cu(acac)2
CoCl2·6H2O
0.1
0.1
Co(ClO4)2·6H2O
FeCl3
0.1
0.1
Mn(OAc)2·4H2O
Ni(BF4)2·6H2O
CeCl3·6H2O
PdCl2
0.1
26
0
0.1
0.1
0
0.1
15
13
43
15
5
0
ZrOCl2·8H2O
RuCl3·nH2O
Mg(ClO4)2
KClO4
0.1
0
0.1
0
0.1
0
0.1
0
a Reaction conditions: catalyst (0.05–0.1 equiv) and 70% aq t-BuOOH (2–5 equiv) were added to a soln of dinitrile 1a (0.3 g, 1.92 mmol) in
solvent (5 mL). The mixture was refluxed for 0.5–1 h (79–119 °C).
b General reaction conditions: catalyst Cu(ClO4)2·6H2O (71 mg, 0.19 mmol, 0.1 equiv), amine (0.3, 0.6 equiv), and 70% aq t-BuOOH (0.74 g,
5.76 mmol, 3 equiv) were added to a soln of dinitrile 1a (0.3 g, 1.92 mmol) in MeCN (5 mL). The mixture was refluxed for 1 h.
The reactions were carried out with the use of the copper The use of Cu(BF4)2·6H2O (entry 13) also gave good re-
salts Cu(ClO4)2·6H2O, Cu(BF4)2·6H2O, Cu(OAc)2·H2O, sults (the yield of 2a was 90%); Cu(OAc)2·H2O, CuCl2,
CuCl2, and Cu(acac)2 (entries 1–16), the cobalt salts and Cu(acac)2 (entries 14–16) proved to be inefficient in
CoCl2·6H2O and Co(ClO4)2·6H2O (entries 17 and 18), the this reaction.
iron salt FeCl3 (entry 19), and the manganese salt
The transition-metal salts CoCl2·6H2O, Co(ClO4)2·6H2O,
Mn(OAc)2·4H2O (entry 20). In all the examples given in
FeCl3, and Mn(OAc)2·4H2O (entries 17–20) have a lower
Table 1, the peroxidation occurred selectively at the CH
catalytic
activity
than
Cu(ClO4)2·6H2O
and
fragment, whereas the benzyl CH2 moiety remained in-
tact.
Cu(BF4)2·6H2O.
The
transition-metal
salts
Ni(BF4)2·6H2O, CeCl3·6H2O, PdCl2, ZrOCl2·8H2O, and
According to entries 1–5 and 9–20, acetonitrile proved to RuCl3·nH2O (entries 21–25) do not exhibit catalytic activ-
be the most efficient solvent for the peroxidation; acetic ity at all; the formation of peroxide 2a was not observed
acid (entry 6), ethanol (entry 7), and benzene (entry 8) are also in the reactions with the use of main group metal per-
unsuitable for use as solvents.
chlorates MgClO4 and KClO4 (entries 26 and 27).
In entries 1–5, the influence of the amount of the catalyst Under the conditions of entry 2, reactions using other hy-
Cu(ClO4)2·6H2O (0.05–0.1 equiv) and tert-butyl hydro- droperoxides, such as hydrogen peroxide, cumyl hydro-
peroxide (2–5 equiv) and the effect of the reaction time peroxide, or 1-adamantyl hydroperoxide, did not afford
(0.5–1 h) on the conversion and the yield of target perox- the target peroxides.
ide 2a were examined. The best results were obtained in
entries 2 and 3; the conversion of 1a was 100% and the
yield of 2a was 94%.
To optimize the peroxidation with tert-butyl hydroperox-
ide, we also chose ethyl 2-cyano-3-phenylpropanoate
(3a), from which ethyl 2-(tert-butylperoxy)-2-cyano-3-
The addition of amines (o-phenanthroline, pyridine, tri- phenylpropanoate (4a) was generated (Table 2).
ethylamine, and proline), which can form complexes with
copper ions, to the reaction mixture (entries 9–12) did not
lead to an increase in the yield of peroxide 2a.
The complete conversion of cyano ester 3a in the reaction
with the use Cu(ClO4)2·6H2O was achieved in the pres-
ence of a 5–10-fold molar excess of tert-butyl hydroper-
Synthesis 2011, No. 13, 2091–2100 © Thieme Stuttgart · New York

2094
A. O. Terent’ev et al.
PAPER
Table 2 Synthesis of Ethyl 2-(tert-Butylperoxy)-2-cyano-3-phenylpropanoate (4a) by Peroxidation of Ethyl 2-Cyano-3-phenylpropanoate
(3a) with tert-Butyl Hydroperoxide Catalyzed by Transition-Metal Salts
O
O
OEt
Ph
catalyst
MeCN
Ph
OEt
OO
HOO
+
CN
CN
3a
4a
Run
1
t-BuOOH (equiv) Catalyst
Cat. (equiv)
0.4
Conditionsa
Time (h)
1
Conv. (%) of 3a Yield (%) of 4a
5
Cu(ClO4)2·6H2O
A
A
B
C
A
C
C
C
C
77
83
90
100
100
98
7
60
2
5
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Cu(BF4)2·6H2O
CoCl2·6H2O
0.6
1
63
3
2 × 3
2 × 5
10
0.6
2 × 0.5
2 × 0.5
1
63
4
2 × 0.4
0.8
81
5
66
6
2 × 5
2 × 5
2 × 5
2 × 5
2 × 0.4
2 × 0.4
2 × 0.4
2 × 0.4
2 × 0.5
2 × 0.5
2 × 0.5
2 × 0.5
83
7
traces
traces
traces
8
FeCl3
33
9
9
Mn(OAc)2·4H2O
a Reaction conditions: A: Cu(ClO4)2·6H2O (0.4–0.8 equiv) and 70% aq t-BuOOH (5–10 equiv) were added to a soln of 3a (0.3 g, 1.48 mmol)
in MeCN (5 mL) and the mixture was refluxed for 1 h (79–81 °C); B: Cu(ClO4)2·6H2O (0.33 g, 0.89 mmol, 0.6 equiv) and 70% aq t-BuOOH
(0.57 g, 4.44 mmol, 3 equiv) were added to a soln of 3a (0.3 g, 1.48 mmol) in MeCN (5 mL) and the mixture was refluxed for 0.5 h (79–81 °C);
additional 70% aq t-BuOOH (0.57 g, 4.44 mmol, 3 equiv) was added, and the mixture was refluxed for 0.5 h (79–81 °C); C: catalyst (0.4 equiv)
and 70% aq t-BuOOH (3–5 equiv) were added to a soln of 3a (0.3 g, 1.48 mmol) in MeCN (5 mL). The mixture was refluxed for 0.5 h (79–
81 °C); additional catalyst (0.4 equiv) and 70% aq t-BuOOH (3–5 equiv) were added, and the mixture was refluxed for 0.5 h (79–81 °C).
oxide and 40–80 mol% of the catalyst (entries 1–5); in radical t-BuOO (or its complex with metal),10b,11b,24 which
entry 4 compound 4a was obtained in the highest yield is consumed in step B. The process E is another pathway
(81%). The salt Cu(BF4)2·6H2O was also proved to be the for the generation of the radical t-BuOO. In this case,
efficient catalyst for peroxidation (entry 6); the yield of Cu(II) in the form of a salt or complex II with dinitrile ox-
the target peroxide was 83%.
idizes t-BuOOH to the radical t-BuOO (which is con-
sumed in step B) to form monovalent copper.10a,g,14
With the aim of determining the scope of the peroxidation
reaction as applied to other a-monosubstituted malononi-
trile and cyanoacetic ester derivatives and preparing
previously unavailable compounds, we synthesized per-
oxides 2a–f and 4a–f under the optimized reaction condi-
tions (Table 3).
Table 3 Peroxides 2a–f and 4a–f from Malononitrile 1a–f and Cy-
anoacetic Ester 3a–f Derivatives
Entry
Conditionsa Peroxide 2 or 4
Yield (%)
t-BuOO
t-BuOO
CN
CN
Based on the results of the synthesis of structurally differ-
ent peroxides in 63–94% yields, it can be suggested that
this peroxidation method is applicable also to other a-sub-
stituted malononitrile and cyanoacetic ester derivatives.
1
A
A
2a
2b
94
Taking into account the results of the previous studies8b,22
and the data on the complexation of transition metals with
mono- and dinitriles,23 it can be suggested that the perox-
idation of malononitrile and cyanoacetic ester derivatives
proceeds according to Scheme 2 [with an example of sub-
stituted malononitrile I and Cu(II) as the catalyst]. In step
A, dinitrile I and Cu(II) form complex II (probably the
structure of complex II is more complicated), which re-
acts with the radical t-BuOO (step B) to give the target
peroxide III and Cu(I). In step C, monovalent copper is
oxidized by tert-butyl hydroperoxide to form Cu(II) and
the radical t-BuO. This radical abstracts a hydrogen from
the tert-butyl hydroperoxide molecule (step D) to give the
CN
CN
2
3
89
68
Cl
t-BuOO
CN
CN
A
2c
OMe
Synthesis 2011, No. 13, 2091–2100 © Thieme Stuttgart · New York

PAPER
Peroxidation of Nitriles
2095
Table 3 Peroxides 2a–f and 4a–f from Malononitrile 1a–f and Cy-
anoacetic Ester 3a–f Derivatives (continued)
Apparently, the efficiency of Cu(ClO4)2 as the catalyst for
peroxidation [like that of Cu(BF4)2] is determined mainly
by a combination of three factors: (1) Copper(II) perchlo-
rate can form complexes with nitriles. As a result, the re-
action system contains, in addition to the starting nitrile I
and Cu(ClO4)2, complex II. (2) In acetonitrile Cu(ClO4)2
is a strong oxidant,25 it is stronger, for example, than
Cu(NO3)2 and CuCl2.26 Due to this property, Cu(ClO4)2
rapidly oxidizes tert-butyl hydroperoxide to the radical
t-BuOO. (3) The efficiency of Cu(ClO4)2 as the catalyst is
manifested in the monovalent copper generated in step B
(apparently, in the form of CuClO4) which readily forms
the complex CuClO4·4MeCN with acetonitrile.27 In this
complex, monovalent copper is relatively easily oxidized
by tert-butyl hydroperoxide to divalent copper (step C),
i.e., the regeneration of the catalyst occurs.
Entry
4
Conditionsa Peroxide 2 or 4
Yield (%)
78
t-BuOO
t-BuOO
CN
CN
A
A
2d
2e
CN
CN
5
6
69
73
t-BuOO
CN
CN
A
B
2f
O
OEt
O
As an additional comment to the reaction mechanism of
peroxidation, it should be noted that reactions of unsubsti-
tuted malononitrile and cyanoacetic ester afford complex
mixtures of products, the conversion of the starting re-
agents being complete. Apparently, compound III
(R = H) can form complex II (R = t-BuOO) containing
the unstable vinyl peroxide moiety. It also becomes possi-
ble that a second t-BuOO group is included in the complex
and diperoxides which are unstable under the reaction
conditions are formed.
t-BuOO
OEt
7
8
4a
81
71
CN
O
t-BuOO
OEt
CN
B
4b
Peroxides 2c–f, 4a, and 4c–f are liquids; 2a, 2b, and 4b
are solids with melting points lying in the range 54–55 °C
(2b) to 71–72 °C (2a). The structures of these compounds
Cl
O
1
were established by H and 13C NMR spectroscopy, and
t-BuOO
elemental analysis. The 13C NMR spectra show informa-
tive signals of the carbon atoms of the CN group at d =
112.4–116.2 ppm (which is evidence that this group is rel-
atively inert to tert-butyl hydroperoxide in the course of
the reaction), signals of the quaternary carbon atom of the
tert-butylperoxy group at d = 82.7–84.6 ppm, and signals
of the quaternary carbon atom at the a-position with re-
OEt
CN
9
B
4c
63
OMe
EtO
1
10
11
B
B
4d
4e
64
83
O
spect to the CN group (d = 71.9–82.7 ppm). In the H
NMR spectra, the disappearance of the signal for the pro-
ton of the a-CH group (d = 3.54–4.29 ppm) and the ap-
pearance of the signal of the C(CH3)3 group (d = 1.23–
1.32 ppm) are most informative.
t-BuOO
CN
O
t-BuOO
OEt
CN
Since reliable proof of the structures of organic peroxides,
even in spite of the NMR spectroscopic and elemental
analysis data, is generally a difficult problem, we deter-
mined the structure of compound 2a by X-ray diffraction,
which unequivocally confirmed the structures of the per-
oxides (Figure 1).
O
O
EtO
12
B
4f
64
EtO
O
t-BuOO
CN
a General conditions: A (synthesis of 2): Cu(ClO4)2·6H2O (0.1 equiv)
and 70% aq t-BuOOH (3 equiv) were added to a soln of 1 (0.3g, 1.57–
2.78 mmol) in MeCN (5 mL) and the mixture was refluxed for 1 h
(79–81 °C); B (synthesis of 4): the catalyst (0.4 equiv) and 70% aq
t-BuOOH (5 equiv) were added to a soln of 3 (0.3 g, 1.27–1.96 mmol)
in MeCN (5 mL) and the mixture was refluxed for 0.5 h (79–81 °C).
Then additional portions of the catalyst (0.4 equiv) and 70% aq
t-BuOOH (5 equiv) were added, and the mixture was refluxed for 0.5
h (79–81 °C).
It was found that transition-metal salts (Cu, Fe, Mn, Co)
catalyze the peroxidation of a-monosubstituted malononi-
trile and cyanoacetic ester derivatives at the a-position
with tert-butyl hydroperoxide. A new method was devel-
oped for the selective oxidation of a-monosubstituted ma-
lononitrile and cyanoacetic ester derivatives at the a-
position to form unsymmetrical a-(tert-butylperoxy) de-
rivatives. The synthesis can be easily scaled up without a
decrease in the yield of the target peroxides, which can be
Synthesis 2011, No. 13, 2091–2100 © Thieme Stuttgart · New York

2096
A. O. Terent’ev et al.
PAPER
.
t-BuOO
CuII
B
N
N
C
C
R
II
.
t-BuOO
A
– H+
NC
CN
OOt-Bu
D
R
CuI
t-BuOOH
III
t-BuOOH
NC
CN
.
t-BuO
R
I
C
CuII
E
E
t-BuOOH
Scheme 2 Proposed reaction mechanism of peroxidation of b-dinitriles using copper salts as the catalyst
1H, 75.48 MHz for 13C) in CDCl3. TLC analysis was carried out on
standard silica gel chromatography plates. Melting points were
determined on a Kofler hot-stage apparatus. Chromatography was
performed on silica gel (63–200 mesh). Malononitrile, ethyl cy-
anoacetate, Cu(OAc)2·H2O, Cu(ClO4)2·6H2O, Cu(BF4)2·6H2O,
Cu(acac)2, CuCl2, Mn(OAc)2·4H2O, FeCl3, Co(ClO4)2·6H2O,
Co(acac)2, CoCl2·6H2O, RuCl3·nH2O, PdCl2, ZrOCl2·8H2O,
CeCl3·6H2O, Ni(BF4)2·6H2O, MgClO4, KClO4, CH2Cl2, petroleum
ether (PE, bp 40–60 °C), hexane, EtOAc, EtOH, MeCN, AcOH,
benzene, 70% aq t-BuOOH soln, arylaldehydes, ketones, allyl bro-
mide, chloroacetone, ethyl acrylate, proline, 1,10-phenanthroline,
pyridine, and Et3N were purchased from commercial suppliers.
b-Dinitriles 1a–f and b-cyano esters 3a–f were prepared in accor-
dance with known methods: 1a–f,28 3a–c,29 3d,30 3e,31 3f.32
2-Benzyl-2-(tert-butylperoxy)malononitrile (2a); General Pro-
cedure for Table 1
A 70% aq t-BuOOH soln (0.49–1.23 g, 3.84–9.6 mmol, 2–5 equiv)
was added to a soln of 1a (0.3 g, 1.92 mmol) and the catalyst (0.05–
0.1 equiv) in solvent (5 mL). The mixture was refluxed (79–119 °C)
for 0.5–1 h, cooled to 20–25 °C, poured into H2O (40 mL), stirred,
and extracted with CH2Cl2 (3 × 10 mL). The combined extracts
were washed with H2O (3 × 10 mL), dried (Na2SO4), and filtered.
The filtrate was evaporated and the residue was chromatographed
(0–20% EtOAc–PE) to give 2a as white crystals; mp 71–72 °C;
Rf = 0.82 (hexane–EtOAc, 10:1).
1H NMR (300.13 MHz, CDCl3): d = 1.29 (s, 9 H, CH3), 3.42 (s, 2
H, CH2), 7.29–7.46 (m, 5 H, CaromH).
13C NMR (75.48 MHz, CDCl3): d = 26.2 (CH3), 42.7 (CH2), 72.2
(CCN), 84.4 (CCH3), 112.8 (CN), 128.8, 129.0, 129.5, 130.6
(Carom).
Figure 1 The molecular structure of 2a, showing the atomic num-
bering and 50% probability displacement ellipsoids; H atoms are
omitted for clarity (CCDC no. 808516)
prepared in gram quantities. The reactions proceed in ac-
etonitrile in the presence of 10–40% mol of the catalyst
[Cu(ClO4)2 is the catalyst of choice] in an aqueous solu-
tion of tert-butyl hydroperoxide (3–10 equiv, relative to
the amount of the compound subjected to peroxidation).
The reaction can be applied to structurally different a-
monosubstituted malononitrile and cyanoacetic ester de-
rivatives; the yields of the target products synthesized by
the reactions with the use of these two types of the re-
agents are up to 94 and 83%, respectively.
Anal. Calcd for C14H16N2O2: C, 68.83; H, 6.60; N, 11.47. Found: C,
68.94; H, 6.42; N, 11.31.
Caution: Although we have encountered no difficulties in working
with peroxides, precautions, such as the use of shields and fume
hoods, and the avoidance of heating or shaking the transition-metal
salts, should be taken whenever possible.
2-Benzyl-2-(tert-butylperoxy)malononitrile (2a) (Table 1, Entry
2)
A 70% aq t-BuOOH soln (0.74 g, 5.76 mmol, 3 equiv) was added to
a soln of 1a (0.3 g, 1.92 mmol) and Cu(ClO4)2·6H2O (71 mg, 0.19
mmol, 0.1 equiv) in MeCN (5 mL). The mixture was refluxed (79–
81 °C) for 1 h, cooled to 20–25 °C, poured into H2O (40 mL),
stirred, and extracted with CH2Cl2 (3 × 10 mL). The combined ex-
Filtrates were evaporated using a water-jet vacuum pump. NMR
spectra were recorded on a Bruker spectrometer (300.13 MHz for
Synthesis 2011, No. 13, 2091–2100 © Thieme Stuttgart · New York

PAPER
Peroxidation of Nitriles
2097
tracts were washed with H2O (3 × 10 mL), dried (Na2SO4), and fil-
tered. The filtrate was concentrated and the residue was
chromatographed (10–40% EtOAc–PE); yield: 0.44 g (1.8 mmol,
94%).
was refluxed (79–81 °C) for 1 h, cooled to 20–25 °C, poured into
H2O (40 mL), stirred, and extracted with CH2Cl2 (3 × 10 mL). The
combined extracts were washed with H2O (3 × 10 mL), dried
(Na2SO4), and filtered. The filtrate was evaporated and the residue
was chromatographed (0–20% EtOAc–PE).
2-Benzyl-2-(tert-butylperoxy)malononitrile (2a); Large-Scale
Synthesis
2-(tert-Butylperoxy)-2-(4-chlorobenzyl)malononitrile (2b)
White crystals; mp 54–55 °C; Rf = 0.75 (hexane–EtOAc, 10:1).
1H NMR (300.13 MHz, CDCl3): d = 1.28 (s, 9 H, CH3), 3.40 (s, 2
H, CH2), 7.28 (d, J = 8.1 Hz, 2 H, CaromH), 7.37 (d, J = 8.8 Hz, 2 H,
A 70% aq t-BuOOH soln (9.87 g, 76.8 mmol, 3 equiv) was added to
a soln of 1a (4 g, 25.6 mmol) and Cu(ClO4)2·6H2O (0.95 g, 2.56
mmol, 0.1 equiv) in MeCN (65mL). The mixture was refluxed (79–
81 °C) for 1 h, cooled to 20–25 °C, poured into H2O (250 mL),
stirred, and extracted with CH2Cl2 (3 × 80 mL). The combined ex-
tracts were washed with H2O (3 × 80 mL), dried (Na2SO4), and fil-
tered. The filtrate was evaporated and the residue was
chromatographed (0–20% EtOAc–PE); yield: 5.68 g (23.3 mmol,
91%).
CaromH).
13C NMR (75.48 MHz, CDCl3): d = 26.2 (CH3), 42.0 (CH2), 71.9
(CCN), 84.6 (CCH3), 112.6 (CN), 128.0, 129.1, 132.0, 135.3
(Carom).
Anal. Calcd for C14H15ClN2O2: C, 60.33; H, 5.42; Cl, 12.72; N,
10.05. Found: C, 60.51; H, 5.63; Cl, 12.75; N, 9.85.
Ethyl 2-(tert-Butylperoxy)-2-cyano-3-phenylpropanoate (4a);
Typical Procedures for Table 2
Entries 1, 2, 5: Cu(ClO4)2·6H2O (0.4–0.8 equiv) and 70% aq
t-BuOOH (5–10 equiv) were added to a soln of 3a (0.3 g, 1.48
mmol) in MeCN (5 mL). The mixture was refluxed for 1 h (79–81 °C).
2-(tert-Butylperoxy)-2-(4-methoxybenzyl)malononitrile (2c)
Oil; Rf = 0.61 (hexane–EtOAc, 10:1).
1H NMR (300.13 MHz, CDCl3): d = 1.30 (s, 9 H, CH3), 3.38 (s, 2
H, CH2), 3.83 (s, 3 H, CH3), 6.84 (d, J = 8.8 Hz, 2 H, CaromH), 7.20
(d, J = 8.1 Hz, 2 H, CaromH).
13C NMR (75.48 MHz, CDCl3): d = 26.2 (CH3), 42.0 (CH2), 55.3
(OCH3), 72.5 (CCN), 84.3 (CCH3), 112.9 (CN), 114.3, 121.3,
131.9, 160.1 (Carom).
Entry 3: Cu(ClO4)2·6H2O (0.33 g, 0.89 mmol, 0.6 equiv) and 70%
aq t-BuOOH (0.57 g, 4.44 mmol, 3 equiv) were added to a soln of
3a (0.3 g, 1.48 mmol) in MeCN (5 mL). The mixture was refluxed
for 0.5 h (79–81 °C). Then additional 70% aq t-BuOOH (0.57 g,
4.44 mmol, 3 equiv) was added, and the mixture was refluxed for
0.5 h (79–81 °C).
Anal. Calcd for C15H18N2O3: C, 65.68; H, 6.61; N, 10.21. Found: C,
65.84; H, 6.53; N, 10.07.
Entries 4, 6–9: The catalyst (0.4 equiv) and 70% aq t-BuOOH (3–5
equiv) were added to a soln of 3a (0.3 g, 1.48 mmol) in MeCN (5
mL). The mixture was refluxed for 0.5 h (79–81 °C). Then addition-
al catalyst (0.4 equiv) and 70% aq t-BuOOH (3–5 equiv) were add-
ed, and the mixture was refluxed for 0.5 h (79–81 °C).
2-(tert-Butylperoxy)-2-isopropylmalononitrile (2d)
Oil; Rf = 0.75 (hexane–EtOAc, 20:1).
1H NMR (300.13 MHz, CDCl3): d = 1.24 (d, J = 7.3 Hz, 6 H,
CH3CHCH3), 1.32 (s, 9 H, CH3), 2.33–2.49 (m, 1 H, CH).
13C NMR (75.48 MHz, CDCl3): d = 17.0 (CH3CHCH3), 26.2
(CH3C), 36.4 (CH), 76.8 (CCN), 84.2 (CCH3), 112.7 (CN).
Isolation (all entries): The mixture was poured into H2O (40 mL),
stirred, and extracted with CH2Cl2 (3 × 10 mL). The combined ex-
tracts were washed with H2O (3 × 10 mL), dried (Na2SO4), and fil-
tered. The filtrate was evaporated and the residue was
chromatographed (0–20% EtOAc–PE) to give an oil; Rf = 0.72
(hexane–EtOAc, 10:1).
Anal. Calcd for C10H16N2O2: C, 61.20; H, 8.22; N, 14.27. Found: C,
61.04; H, 8.30; N, 14.37.
1H NMR (300.13 MHz, CDCl3): d = 1.16–1.29 (m, 12 H, CH3), 3.25
(dd, J = 13.6, 24.6 Hz, 2 H, CH2), 4.23 (q, J = 7.1 Hz, 2 H, CH2O),
7.24–7.37 (m, 5 H, CaromH).
13C NMR (75.48 MHz, CDCl3): d = 13.8 (CH3), 26.3 (CH3C), 41.2
(CH2), 63.0 (CH2O), 82.4, 82.8 (C), 116.0 (CN), 128.2, 128.5,
130.4, 131.3 (Car), 165.1 (CO).
2-(tert-Butylperoxy)-2-cyclopentylmalononitrile (2e)
Oil; Rf = 0.77 (hexane–EtOAc, 20:1).
1H NMR (300.13 MHz, CDCl3): d = 1.31 (s, 9 H, CH3), 1.56–2.11
(m, 8 H, CH2), 2.52–2.68 (m, 1 H, CH).
13C NMR (75.48 MHz, CDCl3): d = 25.4 (CH2), 26.2 (CH3C), 28.2
(CH2), 45.7 (CH), 75.7 (CCN), 84.1 (CCH3), 113.1 (CN).
Anal. Calcd for C16H21NO4: C, 65.96; H, 7.27; N, 4.81. Found: C,
65.81; H, 7.42; N, 4.89.
Anal. Calcd for C12H18N2O2: C, 64.84; H, 8.16; N, 12.60. Found: C,
65.01; H, 8.08; N, 12.73.
Ethyl 2-(tert-Butylperoxy)-2-cyano-3-phenylpropanoate (4a)
(Table 2, Entry 4)
Ethyl 4-(tert-Butylperoxy)-4,4-dicyano-3-methylbutanoate (2f)
Oil; Rf = 0.54 (hexane–EtOAc, 20:1).
A 70% aq soln of t-BuOOH (0.95 g, 7.4 mmol, 5 equiv) was added
to a soln of 3a (0.3 g, 1.48 mmol) and Cu(ClO4)2·6H2O (0.22 g, 0.59
mmol, 0.4 equiv) in MeCN (5 mL). The mixture was refluxed (79–
81 °C) for 30 min and cooled to 20–25 °C. Then Cu(ClO4)2·6H2O
(0.22 g, 0.59 mmol, 0.4 equiv) and 70% aq t-BuOOH (0.95 g, 7.4
mmol, 5 equiv) were added. The mixture was again refluxed (79–81
°C) for 30 min, cooled to 20–25 °C, poured into H2O (40 mL),
stirred, and extracted with CH2Cl2 (3 × 10 mL). The isolation was
carried out as described in Table 1, entry 2; yield: 0.35 g (1.2 mmol,
81%).
1H NMR (300.13 MHz, CDCl3): d = 1.20–1.35 (m, 15 H, CH3),
2.27–2.41 (m, 1 H, CH2), 2.66–2.77 (m, 1 H, CH2), 2.78–2.92 (m, 1
H, CH), 4.14 (q, J = 7.3 Hz, 2 H, CH2O).
13C NMR (75.48 MHz, CDCl3): d = 14.0 (CH3CH2), 15.1 (CH3CH),
26.0 (CH3C), 35.9 (CH), 37.7 (CH2), 61.1 (CH2O), 75.5 (CCN),
84.5 (CCH3), 112.0 (CN), 112.4 (CN), 169.8 (CO).
Anal. Calcd for C13H20N2O4: C, 58.19; H, 7.51; N, 10.44. Found: C,
58.08; H, 7.62; N, 10.42.
Ethyl 2-(tert-Butylperoxy)-2-cyanoalkanoates 4a–f (Table 3);
General Procedure
A 70% aq t-BuOOH soln (5 equiv) was added to a soln of 3a–f (0.3
g) and catalyst Cu(ClO4)2·6H2O (0.4 equiv) in MeCN (5 mL). The
mixture was refluxed (79–81 °C) for 30 min, cooled to 20–25 °C.
2-(tert-Butylperoxy)malononitriles 2a–f (Table 3); General Pro-
cedure
A 70% aq t-BuOOH soln (3 equiv) was added to a soln of 1a–f (0.3
g) and Cu(ClO4)2·6H2O (0.1 equiv) in MeCN (5 mL). The mixture
Synthesis 2011, No. 13, 2091–2100 © Thieme Stuttgart · New York

2098
A. O. Terent’ev et al.
PAPER
Then further 70% aq t-BuOOH (5 equiv) and catalyst
Cu(ClO4)2·6H2O (0.4 equiv) was added. The mixture was refluxed
(79–81 °C) for 30 min, cooled to 20–25 °C, poured into H2O (40
mL), stirred, and extracted with CH2Cl2 (3 × 10 mL). The combined
extracts were washed with H2O (3 × 10 mL), dried (Na2SO4), and
filtered. The filtrate was evaporated and the residue was chromato-
graphed (0–20% EtOAc–PE).
13C NMR (75.48 MHz, CDCl3): d = 13.9, 14.0 (CH3), 26.2 (CH3C),
28.5, 30.4 (CH2), 60.9, 63.2 (CH2O), 80.8, 82.8 (C), 115.8 (CN),
165.0, 171.0 (CO).
Anal. Calcd for C15H23NO6: C, 55.80; H, 7.69; N, 4.65. Found: C,
56.00; H, 7.77; N, 4.82.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Ethyl 2-(tert-Butylperoxy)-3-(4-chlorophenyl)-2-cyanopro-
panoate (4b)
White crystals; mp 62–63 °C; Rf = 0.66 (hexane–EtOAc, 10:1).
Acknowledgment
1H NMR (300.13 MHz, CDCl3): d = 1.19–1.31 (m, 12 H, CH3), 3.25
(dd, J = 13.9, 24.9 Hz, 2 H, CH2), 4.27 (q, J = 7.1 Hz, 2 H, CH2O),
7.28 (dd, J = 8.1, 23.5 Hz, 4 H, CaromH).
13C NMR (75.48 MHz, CDCl3): d = 13.9 (CH3), 26.3 (CH3C), 40.5
(CH2), 63.2 (CH2O), 82.1, 83.0 (C), 115.8 (CN), 128.8, 129.9,
131.7, 134.3 (Carom), 165.0 (CO).
This work is supported by the Program for Support of Leading Sci-
entific Schools of the Russian Federation (Grant NSh 4945.2010.3)
and the Grant of the Russian Foundation for Basic Research (Grant
11-03-00857-a).
Anal. Calcd for C16H20ClNO4: C, 58.99; H, 6.19; Cl, 10.88; N, 4.30.
Found: C, 58.77; H, 6.11; Cl, 10.80; N, 4.41.
References
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Ethyl 2-(tert-Butylperoxy)-2-cyano-3-(4-methoxyphenyl)pro-
panoate (4c)
Oil; Rf = 0.61 (hexane–EtOAc, 5:1).
1H NMR (300.13 MHz, CDCl3): d = 1.17–1.33 (m, 12 H, CH3), 3.19
(dd, J = 13.9, 22.0 Hz, 2 H, CH2), 3.78 (s, 3 H, CH3O), 4.23 (q,
J = 7.1 Hz, 2 H, CH2O), 7.02 (dd, J = 8.8, 107.1 Hz, 4 H, CaromH).
13C NMR (75.48 MHz, CDCl3): d = 13.9 (CH3), 26.3 (CH3C), 40.5
(CH2), 55.2 (CH3O), 63.0 (CH2O), 82.70, 82.74 (C), 116.2 (CN),
114.0, 123.2, 131.5 (CAr), 159.5 (CArO), 165.2 (CO).
Anal. Calcd for C17H23NO5: C, 63.54; H, 7.21; N, 4.36. Found: C,
63.69; H, 7.09; N, 4.40.
Ethyl 2-(tert-Butylperoxy)-2-cyanopent-4-enoate (4d)
Oil; Rf = 0.80 (hexane–EtOAc, 10:1).
1H NMR (300.13 MHz, CDCl3): d = 1.26 (s, 9 H, CH3), 1.31 (t,
J = 7.0 Hz, 3 H, CH3), 2.71 (d, J = 5.9 Hz, 2 H, CH2), 4.30 (q,
J = 7.1 Hz, 2 H, CH2O), 5.20–5.32 (m, 2 H, CH2), 5.67–5.84 (m, 1
H, CH).
13C NMR (75.48 MHz, CDCl3): d = 14.0 (CH3), 26.2 (CH3C), 39.5
(CH2), 63.0 (CH2O), 81.5, 82.7 (C), 116.0 (CN), 122.0 (CH2), 127.8
(CH), 165.0 (CO).
Anal. Calcd for C12H19NO4: C, 59.73; H, 7.94; N, 5.81. Found: C,
59.57; H, 8.19; N, 6.02.
Ethyl 2-(tert-Butylperoxy)-2-cyano-4-oxopentanoate (4e)
Oil; Rf = 0.28 (hexane–EtOAc, 20:1).
1H NMR (300.13 MHz, CDCl3): d = 1.23 (s, 9 H, CH3), 1.33 (t,
J = 7.0 Hz, 3 H, CH3), 2.19 (s, 3 H, CH3), 3.25 (dd, J = 16.9, 33.0
Hz, 2 H, CH2), 4.32 (q, J = 7.1 Hz, 2 H, CH2O).
13C NMR (75.48 MHz, CDCl3): d = 13.8 (CH3), 26.1 (CH3C), 29.9
(CH3CO), 47.8 (CH2CO), 63.4 (CH2O), 77.9, 82.7 (C), 115.8 (CN),
164.4 (COOCH2), 201.1 (COCH3).
(l) McCullough, K. J.; Wood, J. K.; Bhattacharjee, A. K.;
Dong, Y.; Kyle, D. E.; Milhous, W. K.; Vennerstrom, J. L.
J. Med. Chem. 2000, 43, 1246.
Anal. Calcd for C12H19NO5: C, 56.02; H, 7.44; N, 5.44. Found: C,
56.18; H, 7.35; N, 5.51.
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Diethyl 2-(tert-Butylperoxy)-2-cyanopentanedioate (4f)
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2.25–2.40 (m, 2 H, CH2), 2.45–2.63 (m, 2 H, CH2), 4.11 (q, J = 7.1
Hz, 2 H, CH2O), 4.29 (q, J = 7.1 Hz, 2 H, CH2O).
Synthesis 2011, No. 13, 2091–2100 © Thieme Stuttgart · New York

PAPER
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