A copper-mediated oxidative N-cyanation reaction

Article abstract of DOI:10.1039/c4cc03439b

Copper-promoted N-cyanation of aliphatic sec-amine by CuCN is achieved via oxidative coupling. This procedure employs O₂ as a clean oxidant. Notably, sulfoximines and 1,1,3,3-tetramethylguanidine also worked well in this procedure. Thus, it represents a key progress in the C-N bond formation reaction as well as in the cyanation reaction. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc03439b

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A copper-mediated oxidative N-cyanation
reaction†
Cite this: Chem. Commun., 2014,
50, 8412
Fan Teng,a Jin-Tao Yu,a Yan Jiang,a Haitao Yanga and Jiang Cheng*ab
Received 7th May 2014,
Accepted 4th June 2014
DOI: 10.1039/c4cc03439b
www.rsc.org/chemcomm
Copper-promoted N-cyanation of aliphatic sec-amine by CuCN is
In this respect, the oxidative coupling of alkynes with
achieved via oxidative coupling. This procedure employs O2 as a clean N-containing compounds was developed by Stahl and Bolm,
oxidant. Notably, sulfoximines and 1,1,3,3-tetramethylguanidine also respectively (Scheme 1).5 To the best of our knowledge, such a
worked well in this procedure. Thus, it represents a key progress in the strategy has never been applied in the coupling of cyanides with
C–N bond formation reaction as well as in the cyanation reaction.
amines, which affords cyanamides. Importantly, the cyanamide core
is an important pharmacophoric substructure and is widely found in
Amine and its derivatives serve as nucleophiles owing to their several bioactive molecules.6 Moreover, cyanamides serve as cyanide
inherent properties in the transition-metal-catalyzed C–N bond for- sources,7 ligands8 and versatile building blocks in the synthesis of
mation reaction.1 The Csp2–N bond coupling includes the reaction amidines, guanidines,9 and heterocycles10 via cycloaddition.
2
between a nitrogen nucleophile and a Csp –X unit as an electrophile,
However, sharply in contrast with the well-developed transition-
typified by the Hartwig–Buchwald reaction (Scheme 1),2 as well as the metal-catalyzed C–CN bond formation reaction,11 to date, the
oxidative coupling of nitrogen nucleophile with another aromatic efficient method for the construction of N–CN bond is limited
nucleophile, such as the Chan–Lam reaction (Scheme 1).3 However, to the nucleophilic cyanation of amines by XCN (X = halo).12 For
less attention has been paid to the construction of the Csp–N bond. tertiary amines, it was known as the von Braun reaction13 BrCN
Among the sp-hybridized carbon reaction partners, terminal alkynes is highly toxic and sensitive to moisture. Herein, we report
and cyanides are likely the most abundant chemicals. Therefore, the an efficient N-cyanation of aliphatic sec-amine, sulfoximine
oxidative coupling is probably the most straightforward strategy and 1,1,3,3-tetramethylguanidine using CuCN as the cyanation
leading to the Csp–N bond formation.4
source under mild conditions.
Initially, Bn2NH (1a) was selected as the model substrate to
optimize the reaction conditions. Initial success was achieved by
using 0.05 mmol of Cu2O and 0.6 mmol of N,N,N,N-tetramethyl
ethylene diamine (TMEDA) under O2 in CH3CN at 50 1C, producing
the N-cyanation product in 35% yield (Table 1, entry 1). Following
this promising result, other copper(I) and (II) sources, such as CuO,
CuBr2, CuCl2, Cu(OAc)2 and CuI were tested in the procedure and
found to promote the cyanation reaction to some extent (Table 1,
entries 2–6). To our delight, CuBr2 and CuCl2 gave the N-cyanation
product in 55% and 54% yields, respectively (Table 1, entries 3 and 4).
At 100 1C, no cyanation product was isolated (Table 1, entry 3).
In DCM, the yield decreased to 29% and no reaction took place in
toluene (Table 1, entries 7 and 8). Intriguingly, in the presence of
Na2SO4, the reaction was further increased to 78% (Table 1, entry 9).
The possibility of Na2SO4 acting as the drying reagent was ruled out,
as adding 10 equivalents of water did not inhibit the reaction.
Replacing TMEDA with bipy and DABCO resulted in no reaction or
low yield, indicating that TMEDA may not solely act as the ligand
(Table 1, entry 9). The employment of CsF, NaOH decreased the
yield (Table 1, entries 10 and 11). No cyanation reaction took
Scheme 1 The C–N bond formation reaction.
a Changzhou University, School of Petrochemical Engineering, Jiangsu Province Key
Laboratory of Fine Petrochemical Engineering, Changzhou 213164, P. R. China.
E-mail: shchengjiang@163.com
b Changzhou University, Chemistry Department, 1 Gehu Rd., Changzhou, China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc03439b
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Table 1 Optimization of reaction conditionsa
It turned out that the cyclic sec-amine ran smoothly under the
standard conditions to provide the N-cyanation products in
good to excellent yields (e.g. 3b, 3e–3j and 3m). Meanwhile, the
acyclic analogues also worked well in this reaction (e.g. 3c, 3d,
3k, 3l, and 3n–3p). For example, dibutyl amine provided the
cyanation product 3o in 82% yield. Particularly, diallylamine
worked under the procedure, delivering the target product 3p in
52% yield. However, this procedure did not tolerate the aromatic
amine very well. For example, N-methyl aniline provided the desired
product in low yield because of the significant homocoupling side
reaction leading to N–N bond formation.14 Similarly, diphenyl amine
did not work under the standard procedure. Disappointingly,
primary aliphatic amines, such as benzylamine and butylamine
failed to take part in the cyanation reaction.
Entry
Catalyst
Solvent
Additive
Yield (%)
1
2
3
4
5
6
7
8
Cu2O
CuO
CuBr2
CuCl2
Cu(OAc)2
CuI
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
—
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
Toluene
DCM
MeCN
MeCN
MeCN
MeCN
—
—
—
—
—
—
—
—
Na2SO4
CsF
NaOH
Na2SO4
35
40
55(o1)b
54
40
31
o1
29
9
78(o5)c(o1)d,e
10
11
12
73
50
65
The substrate scope was not only limited to sec-amine and
sulfoximine could also run smoothly under the standard procedure
leading to N-cyano sulfoximines as potential insecticides (Fig. 2).15
This procedure is applicable for both aryl alkyl sulfoximine and
the diaryl analogues. For example, (S-methylsulfonimidoyl)benzene
derivative provided the N-cyanation product 4a in 76% yield.
Particularly, sulfonimidoyldibenzene produced the cyanation
product 4d in 91% yield. Indeed, this method provided a funda-
mentally different pathway to access N-cyano sulfoximines.16
Notably, 1,1,3,3-tetramethylguanidine also took part in the
N-cyanation reaction in 78% yield (4f).
To increase the practicality, a 20 mmol scale reaction was
conducted and 3d was isolated in a comparable 77% yield.
More experiments were conducted to gain some insight
into the reaction. Firstly, UV spectrum was tested (see ESI†),
indicating TMEDA acted as the ligand in the catalytic cycle.17
However, heating the combination of TMEDA (0.05 mmol),
CuBr2 (0.05 mmol), amine (0.3 mmol) and CuCN (0.6 mmol)
under 50 1C provided trace of the desired product. The cyana-
tion reaction took place well only by adding an additional 2.0
equivalents of TMEDA to the reaction mixture. This result
indicated that TMEDA also played other roles in the reaction,
most probably as a base. Lei reported the dual role of TMEDA in
a
Reaction conditions: 1a (0.3 mmol), CuCN (0.6 mmol), Cu catalyst
(0.05 mmol), TMEDA (0.6 mmol), additive (0.6 mmol), and 3 mL of
b
c
indicated solvent, O2, 50 1C, 12 h. 100 1C. Bipy, no TMEDA.
d
e
DABCO, no TMEDA. No TMEDA.
place in the absence of CuCN, indicating CH3CN did not serve
as the cyanation source. In the absence of CuBr2, the cyanation
product was isolated in 65% yield, indicating the CuCN could
promote the cyanation reaction (Table 1, entry 12).
With the optimized reaction conditions in hand, the sub-
strate scope of sec-amine was also studied, as shown in Fig. 1.
a
Fig. 2 The oxidative cyanation of sulfoximine and guanidine by CuCN. a All
reactions were run with 1 (0.3 mmol), CuCN (0.6 mmol), Na2SO4 (0.6 mmol),
CuBr2 (0.05 mmol), TMEDA (0.6 mmol), and 3 mL of CH3CN, O2, 50 1C, 12 h.
Fig. 1 The oxidative cyanation of sec-amine by CuCN. All reactions
were run with 1 (0.3 mmol), CuCN (0.6 mmol), Na2SO4 (0.6 mmol), CuBr2
(0.05 mmol), TMEDA (0.6 mmol), and 3 mL of CH3CN, O2, 50 1C, 12 h.
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Secondly, the ratio of the consumed O2 and the N-cyanation
product was tested and found to be nearly 1 : 2 (see ESI†).
Finally, the XPS study confirmed that the valence of copper
was (II) after the reaction.19
Based on the above experiments and earlier reported litera-
ture, the proposed mechanism was outlined in Scheme 2.
Initially, the ligand exchange between the Cu(II) catalyst coordi-
nated by TMEDA and Bn2NH forms a copper(II) species 6. Then, the
reaction between 6 and CuCN produces another Cu(II) species 7 via
the second ligand exchange. Then the intermediate 7 is oxidized to a
Cu(III) species 7 by O2. Finally, the reductive elimination of 8 delivers
the final N-cyanation product, along with a Cu(I) species. The Cu(I)
species is oxidized by O2 to regenerate the Cu(II) catalyst. However,
the role of Na2SO4 is not clear in the current stage.
In conclusion, we have developed a copper-mediated oxidative
N-cyanation of sec-amine, sulfoximine and 1,1,3,3-tetramethyl-
guanidine by CuCN. This procedure employed O2 as a clean
terminal oxidant. Thus, it provided a practical approach to
access cyanamides and N-cyano sulfoximines.
We thank the National Natural Science Foundation of China
(no. 21272028 and 21202013), ‘‘Innovation & Entrepreneurship
Talents’’ Introduction Plan of Jiangsu Province, the Natural Science
Foundation of Zhejiang Province (no. R4110294), State Key Labora-
tory of Coordination Chemistry of Nanjing University, Jiangsu Key
Laboratory of Advanced Catalytic Materials & Technology, Jiangsu
Province Key Laboratory of Fine Petrochemical Engineering, and
the Priority Academic Program Development of Jiangsu Higher
Education Institutions for financial support.
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