Gold-complexes catalyzed oxidative α-cyanation of tertiary amines

Article abstract of DOI:10.1039/c0cc03844j

Oxidative α-cyanation of tertiary amines is catalyzed by gold complexes with trimethylsilyl cyanide to afford the corresponding α-aminonitriles in the presence of tert-butyl hydroperoxide in good to excellent yields under acid-free conditions at room temp

Full text of DOI:10.1039/c0cc03844j

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Gold-complexes catalyzed oxidative a-cyanation of tertiary aminesw
Yan Zhang,a Hao Peng,a Ming Zhang,a Yixiang Chenga and Chengjian Zhu*ab
Received 14th September 2010, Accepted 17th November 2010
DOI: 10.1039/c0cc03844j
Oxidative a-cyanation of tertiary amines is catalyzed by gold
complexes with trimethylsilyl cyanide to afford the corresponding
a-aminonitriles in the presence of tert-butyl hydroperoxide in
good to excellent yields under acid-free conditions at room
temperature.
Transition metal catalyzed activation of C–H bonds, especially
sp3 C–H bonds, and subsequent carbon–carbon bond formation
Scheme 1
which avoids the use of prefunctionalized starting material is
therefore a valuable and straightforward synthetic strategy.1
Although many excellent results have been achieved, catalytic
functionalization of sp3 C–H bonds is still a challenge.2 Direct
cyanation of tertiary amines has attracted much interest since
a-aminonitriles are extremely useful synthetic intermediates,
which have widely been used in the construction of a variety of
synthetically, as well as biologically important compounds
such as alkaloids.3 In order to activate sp3 C–H bonds at the
Fig. 1 Gold complexes 1, 2 and 3.
a-position of tertiary amines, two strategies can be used: (i)
catalytic efficiency of various gold catalysts (Fig. 1), different
treatment with oxometal (MQO) species such as cytochrome
P-450 enzyme4 and (ii) using low-valence metal catalysts such
cyanide source and solvents. The results are listed in Table 1.
as Ru,5 V,6and Fe.7
Among the gold catalysts tested, 1 was found to be the most
effective catalyst for the reaction. No reaction was observed
without using any catalyst. AuClPPh3 showed no catalytic
activity to the reaction. Although other gold-complexes show
moderate catalytic activity, the reactions need a relatively
longer time to reach reasonable yields (entries 1–6). TMSCN
was the best cyanide source compared to K3[Fe(CN)6] and
Bu4NCN (entries 7–10). The reaction also provided an
excellent yield when the amount of 1 was reduced to 3 mol%
(entries 11 and 12). Methanol is the most effective solvent,
although ethanol, ethyl acetate, and acetonitrile can also be
used (entries 13–15). Other oxidants, such as H2O2, O2, were
also examined. However, no product was detected. After the
optimization process, the following oxidative cyanation was
performed under the standard conditions: 10 mol% of 1 as the
catalyst, 1.2 equiv. of TBHP as the oxidant relative to amines,
2 equiv. of TMSCN as the cyanide source and methanol as the
solvent. The reaction temperature was maintained at room
temperature without exclusion of air.
Organic transformations catalyzed by both gold(I)
and gold(III) complexes have been a focus of attention in
recent years.8 New transformations, such as direct arene
functionalizations9 and carbene insertions to benzene, O–H,
and N–H bonds,10 have been developed. Gold species also
showed unique activities in mediating reactions involving
alkynes and alkenes.11 In contrast, the gold-catalyzed oxida-
tion chemistry has been less developed,12 which should have
potential applications in synthetic oxidation chemistry.
Herein we report an activation of sp3 C–H bonds at the
a-position (with respect to the nitrogen atom) of tertiary
amines catalyzed by gold–bipy complexes with tert-butyl
hydroperoxide (TBHP) under mild and acid-free conditions
which gives the corresponding a-aminonitriles with high efficiency
(Scheme 1). To the best of our knowledge, this is the first
example of direct oxidative cyanation of tertiary amines
catalyzed by gold catalyst.
Initially, the oxidative cyanation of N,N-dimethylaniline
using TBHP as the oxidant was selected as the model reaction
for the optimization of reaction conditions. We studied the
In order to explore the scope of substrates of the oxidative
cyanations in the 1/TMSCN/TBHP system, a series of tertiary
anilines were investigated in methanol at room temperature.
As shown in Table 2, all the substrates were selectively and
efficiently converted to the corresponding a-aminonitriles in high
to excellent yields. Substituted N,N-dimethylanilines bearing
both electron-donating and electron-withdrawing substituents
gave the corresponding cyanated products (entries 1–3).
The reaction can also be applied efficiently to cyclic amines:
piperidine, pyrrolidine, and tetrahydroisoquinoline derivatives
can be converted into the corresponding a-cyanoamines
(entries 6, 7, and 9). Thus the protocol developed represents
a State Key Laboratory of Coordination Chemistry,
School of Chemistry and Chemical Engineering,
Nanjing University, Nanjing 210093, China.
E-mail: cjzhu@nju.edu.cn; Fax: +86 25-83317761;
Tel: +86 25-83594886
b State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
w Electronic supplementary information (ESI) available: Synthetic
procedures and characterizations of products and catalysts. See
DOI: 10.1039/c0cc03844j
c
2354 Chem. Commun., 2011, 47, 2354–2356
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Table 1 Optimization of reaction conditionsa
Entry
Catalyst (mol%)
Cyanide source (equiv.)
Equiv. TBHP
t/h
Yieldc (%)
1
2
3
4
5
6
7
8
None
TMSCN (1.2)
TMSCN (1.2)
TMSCN (1.2)
TMSCN (1.2)
TMSCN (1.2)
TMSCN (1.2)
K3[Fe(CN)6] (1.2)
Bu4NCN (1.2)
TMSCN (2.0)
TMSCN (2.0)
TMSCN (2.0)
TMSCN (2.0)
TMSCN (2.0)
TMSCN (2.0)
TMSCN (2.0)
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.5
1.2
1.2
1.2
1.2
1.2
1.2
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
0
0
AuClPPh3 (10)
Bu4NAuCl4 (10)
1b (10)
2b (10)
3b (10)
1 (10)
1 (10)
1 (10)
1 (10)
1 (8)
80
90
70
62
20
10
93
98
92
83
85
74
76
9
10
11
12
13d
14e
15f
1 (3)
1 (10)
1 (10)
1 (10)
a
t
b
Reaction conditions: 0.5 mmol N,N-dimethylaniline, BuOOH (5–6 M in decane), 1 ml MeOH, rt. Gold complexes: Fig. 1. Yield of the
c
d
isolated product after column chromatography on silica gel. Ethanol as solvent. Ethyl acetate as solvent. Acetonitrile as solvent.
e
f
an efficient methodology for the oxidative cyanation of tertiary
amines, which are extremely useful synthetic intermediates,
and have widely been used in the construction of a variety of
synthetically, as well as biologically important compounds.
The exact mechanism for the product formation is not
clear at the present stage. Plausible reaction mechanism
Table 2 Gold-catalyzed oxidative cyanations of tertiary aminesa
Entry
Substrate
t/h
5
Product
Yieldb (%)
1
2
3
98
95
96
Scheme 2 The proposed reaction mechanism for the gold-catalyzed
oxidative cyanation of tertiary amines with TBHP.
5
is showed in Scheme 2. The gold complex [dpyCl2AuIII]Cl
undergoes reaction with TBHP to give the oxo-gold13 species
[dpyCl2AuVQO]Cl which produces an iminium ion inter-
mediate by electron transfer and subsequent hydrogen transfer.
Nucleophilic attack by TMSCN on the iminium ion inter-
mediate provides the corresponding a-cyanated products,
TMSOH and [dpyCl2AuIII]Cl to complete the catalytic cycle.
In conclusion, we have demonstrated the novel gold-catalyzed
activation of sp3 C–H bonds of tertiary amines in the presence
of tert-butyl hydroperoxide in good to excellent yields under
acid-free conditions at room temperature. The reaction proceeds
with high efficiency to give the corresponding a-cyanated
amines which are extremely useful synthetic intermediates
in the construction of biologically important compounds.
Research is currently underway to elucidate the mechanism
and to apply the principle to other catalytic systems.
5
4
5
6
5
5
5
98
95
93
7
8
5
95
5
5
92
98
9
We gratefully acknowledge the National Natural Science
Foundation of China (20832001, 20972065, 21074054) and the
National Basic Research Program of China ((2007CB925103,
2010CB92330) for their financial support. The Major Scientific
and Technological Special Project (2009ZX09103-081) is also
acknowledged.
a
Reaction conditions: 0.5 mmol amine, 1.0 mmol TMSCN, 0.1 ml of
tBuOOH (5–6 M in decane), 10 mol% gold complex 1, 1 ml MeOH,
b
rt. Yield of the isolated product after column chromatography on
silica gel.
c
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