Direct oxidative cyanation of tertiary amines promoted by in situ generated hypervalent iodine(III)-CN intermediate

Article abstract of DOI:10.1016/j.tetlet.2015.08.058

An environmentally benign and metal-free cyanation method of tertiary amines oxidated by hypervalent iodine(III) intermediate generated in situ from PIFA (or DIB) and TMSCN has been developed. A variety of substituent groups on amines are tolerated to the oxidation of α-C-H bond to form C-C bond in the absence of metal catalysts with yields of up to 74%.

Full text of DOI:10.1016/j.tetlet.2015.08.058

Accepted Manuscript
Direct oxidative cyanation of tertiary amines promoted by in situ generated hy-
pervalent iodine(III)-CN intermediate
Hang Shen, Xiaohui Zhang, Qing Liu, Jing Pan, Wen Hu, Yan Xiong,
Xiangming Zhu
PII:
S0040-4039(15)30012-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.08.058
TETL 46642
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
10 July 2015
16 August 2015
22 August 2015
Please cite this article as: Shen, H., Zhang, X., Liu, Q., Pan, J., Hu, W., Xiong, Y., Zhu, X., Direct oxidative cyanation
of tertiary amines promoted by in situ generated hypervalent iodine(III)-CN intermediate, Tetrahedron Letters
(2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.08.058
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Direct oxidative cyanation of tertiary amines
promoted by in situ generated hypervalent
iodine(III)-CN intermediate
Leave this area blank for abstract info.
Hang Shena, Xiaohui Zhanga, Qing Liua, Jing Pana, Wen Hua, Yan Xionga,b,∗ and Xiangming Zhuc

1
Tetrahedron Letters
journal homepage: www.els evier.com
Direct oxidative cyanation of tertiary amines promoted by in situ generated
hypervalent iodine(III)-CN intermediate
Hang Shena, Xiaohui Zhanga, Qing Liua, Jing Pana, Wen Hua, Yan Xionga,b,∗ and Xiangming Zhuc
a School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 400030, China
b Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Science, Chongqing 400714, China
c School of Chemistry & Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland
ARTICLE INFO
ABSTRACT
Article history:
Received
An environmentally benign and metal-free cyanation method of tertiary amines oxidated by
hypervalent iodine(III) intermediate generated in situ from PIFA (or DIB) and TMSCN has been
developed. Variety of substituent groups on amines are tolerated to the oxidation of α-C-H bond
to form C-C bond in the absence of metal catalysts with the yields of up to 74%.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
α-Aminonitriles
Cyanation
N,N-dialkylanilines
Hypervalent iodine
TMSCN
———
∗ Corresponding author. Tel: +86-02365111748; fax:+86-02365111748; e-mail: xiong@cqu.edu.cn (Y. Xiong)

2
Tetrahedron Letters
1. Introduction
2. Results and Discussion
Since α-aminonitriles are widely used in the construction of
The optimization studies for C-H functionalization were
initiated by using N,N-dimethylaniline as tertiary amine and
TMSCN as cyanide source along with hypervalent iodine
reagents as oxidants in DCE. As depicted in Table 1, the
efficiencies of different additives and hypervalent iodine reagents
were examined. bis(trifluoracetoxy)iodobenzene (PIFA) that was
premixed with TMSCN for preactivation of 40 min before adding
N,N-dimethylaniline was proved to be most effective and
(diacetoxyiodo)benzene (DIB) afforded a comparable result,
biologically active compounds and functional materials,1 such as
α-amino acids, α-amino aldehydes, α-amino alcohols and 1,2-
diamines etc., a variety of methods for the synthesis of α-
aminonitriles have been developed, in which Strecker reaction2
involving the one pot condensation of a carbonyl compound, an
amine and cyanide is a traditional method (i, Scheme 1). On the
other hand, organic oxidation, especially for sp3 C-H bond
oxidation to form C-C bond, is of great importance in organic
synthesis owing to avoiding prefunctionalization of substrates
and generally shorter synthetic procedures.3 Therefore, numerous
protocols have been employed to achieve α-aminonitriles by
direct C-H oxidation in recent years,4-13 which often go through
the oxidation of tertiary amines into iminium ions catalyzed by
metal-based catalysts, such as Ru,4 V,5 Au,6 Mo,7 Fe,8 Cu,9 Ir,10
Ti,11 Co12 and Re13 in the presence of oxidants, followed by the
nucleophilic attack of the cyanide ions (ii, Scheme 1). However,
expensive or moisture sensitive metal catalysts and high toxic
cyanide reagents such as NaCN or HCN are inevitable in most of
these protocols, and the sparse availability and expensive nature
of metal catalysts limit their wide applications in organic
synthesis.
while
using
iodosobenzene
(PhIO)
and
[Hydroxy(tosyloxy)iodo]benzene (HTIB) did not furnish the
desired product (entries 1-4). With PIFA, increasing the time of
preactivation and shorten the reaction time led to the same yield
(entry 5 vs entry 2). In order to alleviate the side reaction resulted
from high temperature under strongly oxidative conditions, the
temperature was lowered, which as a result, delivered the same
level of reactivity (entries 6-7). It is also observed that during the
reaction, unreacted substrate was not detected by TLC due to the
interaction with CF3COOH released from PIFA. In consideration
of this phenomenon, we tried to screen different bases and
various inorganic salts to affect the interaction and consequently,
better results were obtained except for Cs2CO3 (entries 8-13, for
details see supporting information), in which Na2SO4 was found
to be the best one with the yield of 52%.
Table 1: Evaluation of additives and oxidants in the cyanation of
tertiary aminesa
Scheme 1. Methods of preparation of α-aminonitriles.
Entry
Oxidant
T (°C)
t (h)
Additive
Yield (%)b
1
2
1a
1b
1c
80
80
80
80
80
r.t.
0
8
8
8
8
1
1
1
1
1
-
30
32
0
Scheme 2. Our proposal on preparation of α-aminonitriles using
I(III)-CN intermediate.
-
3
-
In recent years, metal-free methods to prepare α-aminonitriles
by direct C-H oxidation have attracted much attentions.14 In view
of our research interest on hypervalent iodine reagents which
have been extensively used in C-H oxidation for their low
4
1d
1b
1b
1b
1b
1b
1b
1b
1b
1b
-
-
0
5
32
32
35
52
37
46
38
48
0
6
-
toxicity,
commercial
availability
and
environmental
friendliness.15 Zhdankin’s group have reported cyanation of N,N-
dimethylanilines to synthesize the α-aminonitriles using
cyanobenziodoxole as cyanide source.14a In our previous work,
we attempted to prepare β-ketonitriles through cyanation of silyl
enol ethers by means of cyanobenziodoxole,16 however, our
endeavours have proved to be unsuccessful. So we turned to
synthesis of cyanide intermediate (I(III)-CN) in situ generated
from PhIO/BF3.OEt2/TMSCN (trimethylsilyl cyanide), and
eventually umpolong stratgy for cyanation of silyl enol ethers to
furnish β-ketonitriles was achieved. Herein, we would like to
report the cyanation of tertiary amines through the combination
of hypervalent iodide and TMSCN where a C-H oxidation by
active hypervalent iodine(III)-CN intermediate takes place to
form an iminium ion and nucleophilic attack of the cyanide ions
is followed to provide cyantion product (Scheme 2).
7
-
8
0
Na2SO4
NaOH
K2CO3
t-BuOK
CsF
9
0
0
10
11
12
13
1
1
0
0
0
1
1
Cs2CO3
a
Conditions: N,N-dimethylaniline (0.5 mmol), Oxidant (0.75 mmol),
TMSCN (1.0 mmol) and additives (2.0 mmol) in DCE (3.0 mL).
b Isolated yields.
DCE = 1,2-dichloroethane.

3
The effects of different amounts of PIFA, TMSCN, additives
and solvents on the reaction were further studied (Table 2, for
details see supporting information). The results showed that 0.5
equivalent of Na2SO4 proved to be the most suitable by
comparing different amounts of Na2SO4 in the presence of 1.5
equivalents of PIFA and 2.0 equivalents of TMSCN (entries 1),
while varying the amounts of TMSCN is unfavorable and further
increasing the loading of PIFA to 2.0 equivalents were observed
to be optimal for this reaction (entry 2). Different solvents such
as DCE, CH3CN, CHCl3, CH2Cl2 and CH3OH were screened and
the highest yield was obtained in DCE (entries 3–6). The reaction
was found to be sensitive to the premixed time of PIFA with
TMSCN (entries 7–9). It is worthy to note that only trace of
desired product was yielded without preactivation of TMSCN
and PIFA. According to the procedures reported, the attempt to
improve the yields through elevating reaction temperature,
prolonging reaction time and adding metal catalysts such as
Pd(OAc)2, FeCl2, and CuBr failed (entries 10-14).
corresponding α-aminonitriles 3b-i in yields of 17 to 74%.
ortho-Substituent was found to be more favorable than m-
substituent (3e vs 3f) and the ability of withdrawing electron of
groups have less influence on the reactions (3f vs 3g).
Additionally, disubstituted derivates even having big steric
hindrance like 2l provided cyanation products 3j-l in moderate to
good yields (37-60%). Furthermore, the system can also be
efficiently applied to cyclic amine affording 3m and 3n in 20%
and 25% yield, respectively.
Table 3: Substrate scope in the oxidative cyanations of tertiary
aminesa
Me
N
Table 2: Optimization of reaction conditionsa
CN
CH2
3a, 56%b
3b, 32%c
3c,71%d
Br
Me
N
CH2CN
PIFA
(x eq.)
Entry
Solvent
Yield (%)b
3d,74%d
3e, 17%d
3f, 46%e
I
Me
N
MeOOC
O2N
1
1.5
DCE
54
Me
Me
CH2CN
N
N
2
2
DCE
56
CN
CH2
CH2CN
3
2
CH3CN
36
3g, 41%c
3h, 53%c
3i, 40%e
4
5
2
2
2
2
2
2
2
2
2
2
2
CHCl3
CH2Cl2
CH3OH
DCE
37
50
6
0
3j, 45%c
3k, 37%e
3n, 25%d
3l, 60%e
7
tracec
26d
40e
50f
52g
55h
40i
20j
N
8
DCE
NC
3m, 20%d
9
DCE
a
Conditions: PIFA (1.0 mmol), TMSCN (1.0 mmol), DCE (3.0 mL),
premixed at r.t. for 40 min, Na2SO4 (0.25 mmol) and tertiary amine (0.5 mmol)
reacted at 0 °C for 1 h; isolated yields.
10
11
12
13
14
DCE
DCE
b Reaction at 0 oC for 1 h.
c Reaction at 0 oC for 5 h.
DCE
d 1.25 mmol DIB and 1.25 mmol TMSCN, reflux in seal tube for overnight.
e Reaction at r.t. for overnight.
DCE
DCE
Interestingly, in the absence of TMSCN, N,N-dimethylaniline
was oxidated by HTIB and DIB, and benzidine was generated
with the yield of 14% and 9%, respectively (Scheme 3), which
deliveries metal-free strategy for self-coupling of aniline as
Ichikawa’s work.17 With the addition of TEMPO (2,2,6,6-
Tetramethylpiperidin-1-oxyl), the pathway of self-coupling was
blocked, which suggested a free radical coupling process.18
a
Conditions: Oxidant (specified), TMSCN (1 mmol), Solvent (3.0 mL),
Na2SO4 (0.25 mmol), N,N-dimethylaniline (0.5 mmol), 0 °C, 1 h.
b Isolated yields.
c Preactivation for 0 min.
d Preactivation for 10 min.
e Preactivation for 70 min.
f Reaction time was 2 h.
g At r.t.
h 10 mmol% Pd(OAc)2 was added.
i
10 mmol% FeCl2 was added.
10 mmol% CuBr was added.
j
With the optimal conditions for the oxidative cyanation of
tertiary amines in hand, the scope of the reaction was investigated
by using TMSCN as the cyanide source, PIFA as the oxidant and
Na2SO4 as the additive. As described in Table 3, the reactions of
substituted N,N-dimethylanilines, containing electron-donating
groups such as methyl, i-Pr, t-Bu and electron-withdrawing
groups such as ester, bromo, iodo, nitro effectively afforded the
Scheme 3. Synthesis of benzidine using hypervalent iodine
reagents.
To gain insight into the mechanism, 2 equivalents of radical
scavenger TEMPO were added to the reaction mixture under
optimal conditions and resulted in the nearly same yield of 52%,

4
Tetrahedron Letters
which indicated that the reaction did not proceed through a
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radical pathway. As mentioned above, only trace of cyanation
product yielded without preactivation, which suggested that
conversion of N,N-dimethylanilines into iminium ion and
successively nucleophilic attack of cyanide anion was not
promoted by PIFA. Kita’s group19 have reported active
hypervalent iodine(III)-CN intermediate were generated from
PIFA and TMSCN in the presence of BF3•Et2O. Attempts in
isolation and spectroscopic detection of the hypervalent iodine(III)
intermediate that were precipitated during the period of
preactivation were made but failed due to their instability. So a
similar hypervalent iodine intermediate is speculated to be
formed in our reaction, an oxidation of 2a is followed to give 5
and then H-absorption of trifluoroacetyl anion affords the
iminium ion intermediate 6 which is attacked by cyanide ion to
furnish 3a.
3.
4.
(a) Murahashi, S.; Komiya, N.; Terai, H.; Nakae, T. J. Am. Chem. Soc.
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CH3
PIFA + TMSCN
Ph
N
3a
5.
6.
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CH2CN
in situ
X
NC
Ph
Ph
7.
8.
Alagiri, K.; Prabhu, K. R. Org. Biomol. Chem. 2012, 10, 835–842.
(a) Han, W.; Ofial, A. R. Chem. Commun. 2009, 33, 5024–5026; (b)
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S.; Lingaiah, N. ChemCatChem 2012, 4, 1173–1178.
I
I
Ph
CH3
N
NC
Ph
CH3
CH2
H3C
N
N
Ph
CH2
H
CH3
CF3COO
CN
2a
X = OCOCF3 or CN
5
6
9.
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5317−5325.
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Scheme 4. The proposed reaction mechanism for the cyanation
of tertiary amines.
In conclusion, we have developed an oxidative cyanation to
accomplish α-aminonitriles, which directly oxidates sp3 C-H
bond using a hypervalent iodine reagent combined with TMSCN
in the absence of metal catalysts to form C-C bond and provides
a useful tool for the synthesis of various nitrogen-containing
compounds. Further studies about synthetic utility of this
versatile oxidative system and more mechanistic details are
presently pursued in our laboratories.
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7286–7290.
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Acknowledgments
−
−1197
; (e)
We gratefully acknowledge funding from the National Natural
Science Foundation of China (No. 21372265), the Natural
7365 7368; (d) Zhdankin, V. V. J. Org. Chem. 2011, 76, 1185
Moteki, S.; Usui, A.; Zhang, T.; Solorio A., Cesar R.; Maruoka, K.
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ChemCatChem 2014, 6, 76–78.
Science
Foundation
Project
of
CQ
CSTC
(No.
cstc2013jcyjA0217), the Fundamental Research Funds for the
Central Universities (No. CQDXWL-2013-Z012 and No.
CDJZR14225502), and the Chongqing University Postgraduatesʼ
Innovation Project.
16. (a) Shen, H.; Li, J.; Liu, Q.; Pan, J.; Huang, R.; Xiong, Y. J. Org. Chem.
2015, doi: 10.1021/acs.joc.5b01102. Also see selected reports on
conversion of cyano group: (b) Kahne, D.; Collum, D. B. Tetrahedron
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Supplementary data (detailed experimental description and
condition optimization; characterization data of NMR for all
1
compounds; details of copies of the H NMR and 13C NMR)
associated with this article can be found in the online version.