Cobalt-Catalyzed oxidative α-cyanation of tertiary aromatic amines with trimethylsilyl cyanide and tert -butyl hydroperoxide

Article abstract of DOI:10.1055/s-0033-1338937

In this Letter is described that a cobalt(II)-tert-butyl hydroperoxide oxidizing system was used to catalyze the α-cyanation of aromatic tertiary amines in the presence of trimethylsilyl cyanide to produce the corresponding α-aminonitriles in good yields. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1338937

LETTER
▌1283
lCettoerbalt-Catalyzed Oxidative α-Cyanation of Tertiary Aromatic Amines with
Trimethylsilyl Cyanide and tert-Butyl Hydroperoxide
Oxidative α-Cyanation of Tertiary Aromatic Amines
Norio Sakai,* Akihiro Mutsuro, Reiko Ikeda, Takeo Konakahara
Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science (RIKADAI), Noda, Chiba
278-8510, Japan
Fax +81(4)71239890; E-mail: sakachem@rs.noda.tus.ac.jp
Received: 06.03.2013; Accepted after revision: 16.04.2013
example of the α-cyanation of tertiary amines using the
Abstract: In this Letter is described that a cobalt(II)–tert-butyl hy-
combination of a cobalt chloride catalyst and TBHP, with
droperoxide oxidizing system was used to catalyze the α-cyanation
the noted exception of one report10 wherein Murahashi et
of aromatic tertiary amines in the presence of trimethylsilyl cyanide
al. described the possibility of the cyanation of tertiary
amines with CoCl2 and molecular O2, but an actual inves-
tigation has not been demonstrated.11
to produce the corresponding α-aminonitriles in good yields.
Key words: cobalt, oxidation, cyanation, aminonitriles, tertiary
amines
Table 1 Examinations of Reaction Conditions
Me
N
Me
N
α-Aminonitriles have been used to constitute the basic
skeleton, or a useful precursor, of natural products, bio-
logically active substances, and functional materials.1
Thus, the development of a facile and effective method for
the preparation of nitriles has attracted considerable atten-
tion in the field of applied chemistry. Thus far, the de-
mand has been satisfied by substituting amines that have
a leaving group with a cyano source2 or by using Strecker-
type reaction with an imine intermediate, which can be
generated from an amine and an aldehyde.3 During the
past two decades, direct C–H functionalization at the α-
position of tertiary amines with an appropriate cyano
source, such as sodium cyanide or trimethylsilyl cyanide
(TMSCN), in the presence of a transition metal has been
developed as a straightforward and clean approach. For
example, Murahashi and co-workers initially developed
the ruthenium-catalyzed oxidative α-cyanation of tertiary
amines with molecular oxygen (O2) or hydrogen peroxide
(H2O2) in the presence of sodium cyanide.4 Also Sain and
Jain et al. reported that a vanadium or an iron catalyst
would catalyze the cyanation of tertiary amines with O2 or
H2O2 in the presence of sodium cyanide to produce ami-
nonitriles.5 Ofial and Zhu disclosed the iron- or gold-com-
plex-catalyzed oxidative α-cyanation of tertiary amines
with TBHP in the presence of TMSCN.6 Recently, Prabhu
found that a molybdenum catalyst had a similar catalytic
effect for the α-cyanation of amines with O2 in the pres-
ence of TMSCN.7 In recent interesting examples, several
groups reported that either a visible-light photoredox sys-
tem,8 or some promoters, such as a tropylium ion and an
iodine molecule, have been used to mediate the α-cyana-
tion of tertiary amines.9
CoCl2 (cat.)
TBHP
Me
+
TMSCN
60 °C, 3 h
CN
Me
Me
1
Entry
CoCl2
(mol%)
TBHP
(equiv)
TMSCN Solvent
(equiv)
Yield
(%)a
1
2
3
4
5
6
7
5
5
5
5
5
2
1
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2
CHCl3
MeCN
THF
25
27
9
2
2
2
MeOH
MeOH
MeOH
MeOH
75
80
83
(80)
2.5
2.5
2.5
a GC (isolated) yield.
Based on conventional methods, the cyanation of N,N-di-
methyl-p-toluidine with trimethylsilyl cyanide in the pres-
ence of a cobalt catalyst and an oxidizing agent, tert-butyl
hydroperoxide (TBHP) was examined as the initial model
(Table 1).12 When the reaction was conducted with 5
mol% of CoCl2 and 1.5 equivalents of TBHP in chloro-
form at 60 °C, the expected cyanation proceeded to pro-
duce the desired α-aminonitrile (1) in a 25% yield (Table
1, entry 1). This result showed that the oxidizing system,
which consisted of CoCl2 and TBHP readily activated the
α-C(sp3)–H bond adjacent to a nitrogen atom in a tertiary
aromatic amine to generate an iminium intermediate.
Thus, to improve the yield, a solvent effect was investigat-
ed using several solvents. A typical coordinative solvent,
such as acetonitrile and tetrahydrofuran, was ineffective
for this cyanation (Table 1, entries 2 and 3). However,
gratifyingly, when a similar reaction was carried out in
methanol, the yield was remarkably improved to a 75%
yield (Table 1, entry 4). Finally, the loading of only
We report herein the α-cyanation of the C(sp3)–H bond of
tertiary amines catalyzed by a novel cobalt–TBHP oxidiz-
ing system. As far as we know, there has been no reported
SYNLETT 2013, 24, 1283–1285
Advanced online publication: 08.05.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1338937; Art ID: ST-2013-U0209-L
© Georg Thieme Verlag Stuttgart · New York

1284
N. Sakai et al.
LETTER
1 mol% of CoCl2 and 1.5 equivalents of TBHP promoted
sufficient cyanation to produce the expected aminonitrile
in a good yield (Table 1, entries 5–7).
CoCl2 (1 mol%)
TBHP (1.5 equiv)
+
TMSCN
(2.5 equiv)
N
N
MeOH, 60 °C, 5 h
Ph
Ph
CN
11: 66%
With the optimal conditions shown in Table 1, the scope
of this oxidation was examined with a variety of tertiary
aromatic amines (Scheme 1). When substrates bearing an
electron-donating group, such as a methyl or methoxy
group, were treated with TMSCN under these conditions,
the corresponding α-aminonitriles 3–5 were obtained in
good yields. Also for substrates having a relatively weak
electron-withdrawing group, such as halogens, oxidative
cyanation proceeded cleanly, producing the desired
aminonitriles 6 and 7.
Scheme 2 α-Cyanation onto a tetrahydroisoquinoline skeleton
3). When the reaction was carried out with radical scaven-
gers, 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) and
2,6-di(tert-butyl)-p-cresol (BHT), a decrease in the yield
of 2 was observed in both cases. Thus, it was implied that
the reaction rate of the α-cyanation with a CoCl2–TBHP
system was mainly controlled by a single electron transfer
(SET) rather than by an ionic path.
n
n
CoCl2 (1 mol%)
TBHP (1.5 equiv)
N
N
CoCl2 (5 mol%)
TBHP (1 equiv)
inhibitor (1 equiv)
+
TMSCN
Me
N
Me
N
R
R
MeOH, 60 °C
(2.5 equiv)
CN
CN
Me
(n = 0, 1)
TMSCN
(2 equiv)
+
2–10
MeOH, 60 °C, 3 h
Me
N
Me
N
Me
2
N
TEMPO
BHT
36% (GC)
47% (GC)
CN
CN
CN
Me
2: 70% (4 h)
4: 70% (4 h)
Me
3: 77% (3 h)
Scheme 3 Control experiments with a radical inhibitor
Me
N
Me
N
Me
N
A plausible mechanism is shown in Scheme 4. The cobalt
catalyst initially reacted with TBHP to produce a tert-
butylperoxy radical, which undertook the SET reaction of
a tertiary aromatic amine to form a radical cation interme-
diate.11,13,14 The radical cation intermediate was converted
into an iminium intermediate through both proton transfer
(PT) and SET in the presence of the cobalt catalyst. Final-
ly, the trimethylsilyl cyanide attacked the iminium inter-
mediate to produce the final α-aminonitrile derivative.
CN
CN
CN
OMe
5: 68% (2 h)
Cl
Br
6: 79% (4 h)
7: 74% (4 h)
Me
N
N
N
CN
9: 72% (3 h)
CN
CN
10: 70% (4 h)
O2N
8: 24% (24 h)
Scheme 1 CoCl2-catalyzed α-cyanation of various tertiary aromatic
t-BuOOH
amines; isolated yields are given
CoCl2
t-BuOO•
CH3
t-BuOO–
t-BuOO–
In contrast, this oxidative system was affected by a nitro
group, which led to a decrease in the yield and to the re-
covery of the starting material. Moreover, this cyanation
could be extended to the α-cyanation of cyclic tertiary
amines. For example, when the oxidative cyanation was
performed using a tertiary amine with pyrrolidine and pi-
peridine rings, the corresponding products 9 and 10 were
obtained in good yields. In contrast, although there is no
clear explanation except a steric repulsion around the re-
action site, use of N,N-diethylaniline as a substrate did not
produce the corresponding α-aminonitrile at all.
•
+
N
CH3
•
CH2
••
••
N
N
Ar
Ar
Ar
t-BuOOH
CoCl2
t-BuOO• t-BuOO–
TMSCN TMSOOt-Bu
H2
C
CH2
+
N
••
CN
N
Ar
Ar
Scheme 4 Plausible reaction path for cobalt-catalyzed α-cyanation
of tertiary aromatic amines with TBHP
In addition, as application, the substrate embedded in a
tetrahydroisoquinoline skeleton could also be converted
into the expected aminonitrile derivative 11 in a 66%
yield, in which the α-cyanation at the benzyl position pref-
erentially occurred (Scheme 2).
In conclusion, we demonstrated the cobalt-catalyzed oxi-
dative cyanation of aromatic tertiary amines in the pres-
ence of TBHP leading to the preparation of aminonitriles.
Further investigation into the mechanism of this reaction
is now in progress.
To better understand the reaction pathway for the cyana-
tion series, control experiments were conducted (Scheme
Synlett 2013, 24, 1283–1285
© Georg Thieme Verlag Stuttgart · New York

LETTER
Oxidative α-Cyanation of Tertiary Aromatic Amines
1285
solution (6.0 μL, 0.0060 mmol), aromatic tertiary amine
(0.60 mmol), TMSCN (188 μL, 2.50 mmol), and 5.5 M
TBHP in decane solution (164 μL, 0.900 mmol) under an
ambient atmosphere. The resultant mixture was stirred at
60 °C (bath temperature), and consumption of the starting
amine was monitored by GC analysis. After the reaction the
resultant mixture was quenched with a aqueous solution of
Na2CO3. The aqueous layer was extracted with CH2Cl2, then
the organic phases were dried over anhyd Na2SO4, filtered,
and evaporated under a reduced pressure. The crude product
was purified by silica chromatography (hexane–EtOAc, 4:1)
to give the corresponding α-aminonitrile.
Acknowledgment
This work was partially supported by a grant from the Japan Private
School Promotion Foundation of MEXT.
References and Notes
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(3) Selected reviews for asymmetric Strecker-type reaction, see:
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(b) Das, B.; Damodar, K.; Shashikanth, B.; Srinivas, Y.;
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J. Am. Chem. Soc. 2008, 130, 11005. (c) Murahashi, S.-I.;
Komiya, N.; Terai, H. Angew. Chem. Int. Ed. 2005, 44, 6931.
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Selected Data for the Prepared Aminonitriles
N-Methyl-N-(4-methylphenyl)aminoacetonitrile (1)
1H NMR (500 MHz, CDCl3): δ = 2.28 (s, 3 H), 2.95 (s, 3 H),
4.12 (s, 2 H), 6.78 (d, 2 H, J = 9.0 Hz), 7.11 (d, 2 H, J = 9.0
Hz). 13C NMR (125 MHz, CDCl3): δ = 20.3, 39.4, 42.8,
115.3, 115.4, 129.8, 129.9, 145.6. MS (EI): m/z (%) = 160
(100) [M+].
N-Methyl-N-(4-bromophenyl)aminoacetonitrile (7)
1H NMR (500 MHz, CDCl3): δ = 2.99 (s, 3 H), 4.15 (s, 2 H),
6.72 (d, 2 H, J = 9.0 Hz), 7.38 (d, 2 H, J = 9.0 Hz). 13C NMR
(125 MHz, CDCl3): δ = 39.3, 42.1, 112.5, 115.1, 116.4,
132.2, 146.7. MS (EI): m/z (%) = 224 (100) [M+]. The
characterization of other α-aminonitriles was confirmed by
1H NMR and 13C NMR spectroscopic analysis.
(13) (a) Li, Z.; Bohle, D. S.; Li, C.-J. Proc. Natl. Acad. Sci. U.S.A.
2006, 103, 8928. (b) Boess, E.; Schmitz, C.; Klussmann, M.
J. Am. Chem. Soc. 2012, 134, 5317.
(14) One reviewer pointed out that a reaction of CoCl2 with
TBHP initially generated Co(III)Cl2(OH) and a tert-
butyloxy radical (t-BuO•, Equation 1, a). Those species are
acceptable. However, both species would be promptly
oxidized by an excess amount of TBHP to finally produce a
tert-butylperoxy radical (t-BuOO•) through the following
plausible oxidation steps (Equation 1, b and c).
(5) (a) Singhal, S.; Jain, S. L.; Sain, B. Adv. Synth. Catal. 2010,
352, 1338. (b) Singhal, S.; Jain, S. L.; Sain, B. Chem.
Commun. 2009, 2371.
(6) (a) Zhang, Y.; Peng, H.; Zhang, M.; Cheng, Y.; Zhu, C.
Chem. Commun. 2011, 47, 2354. (b) Han, W.; Ofial, A. R.
Chem. Commun. 2009, 5024.
Also, several groups reported that ruthenium-, rhodium-, or
copper-catalyzed oxidative substitution of amines with
TBHP, producing not the N,O-aminal derivative, but the
amino peroxide derivative.4f,13b,15 Moreover, Doyle et al.
showed that Co(OAc)2 converted TBHP into the tert-
butylperoxy radical.11 Therefore, we proposed the initial
formation of the tert-butylperoxy radical by CoCl2 as the
plausible reaction path.
(7) Alagiri, K.; Prabhu, K. R. Org. Biomol. Chem. 2012, 10,
835.
(8) Rueping, M.; Zhu, S.; Koenigs, R. M. Chem. Commun.
2011, 47, 12709; and references cited therein.
(9) For selected metal-free oxidative α-cyanation, see: (a) Allen,
J. M.; Lambert, T. H. J. Am. Chem. Soc. 2011, 133, 1260.
(b) Liu, L.; Wang, Z.; Fu, X.; Yan, C.-H. Org. Lett. 2012, 14,
5692.
(10) Murahashi, S.-i.; Komiya, N. EP 1174419A1, 2002; Chem.
Abstr. 2002, 136, 118063.
(a)
(b)
(c)
Co(III)Cl2(OH) + t-BuO•
CoCl2 + H2O + t-BuOO•
t-BuOH + t-BuOO•
CoCl2 + t-BuOOH
Co(III)Cl2(OH) + t-BuOOH
t-BuO• + t-BuOOH
(11) During this study, Doyle and co-workers reported that a
Co(OAc)2-TBHP oxidizing system undertook an oxidative
Mannich-type reaction through a single electron transfer,
see: Ratnikov, M. O.; Doyle, M. P. J. Am. Chem. Soc. 2013,
135, 1549.
Equation 1
(15) Catino, A. J.; Nichols, J. M.; Nettles, B. J.; Doyle, M. P.
(12) General Procedure
J. Am. Chem. Soc. 2006, 128, 5648.
To a 5 mL screw vial containing freshly distilled MeOH (0.6
mL) were successively added 1.0 M CoCl2 in a MeOH
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1283–1285