Cobalt-catalyzed hydrocyanation and hydroarylation of enamines

Article abstract of DOI:10.1016/j.tetlet.2019.151314

A mild, general and efficient hydrocyanation and hydroarylation of enamines catalyzed by Co(salen) complexes are described. Both reactions include regioselective C[sbnd]H bond formation of enamines, and the corresponding products are obtained in high yield. Hydroarylation critically discriminates the benzyl and benzoyl aromatic rings on nitrogen in cyclization step, and the corresponding isoindolinones including quaternary carbons are exclusively given.

Full text of DOI:10.1016/j.tetlet.2019.151314

Tetrahedron Letters xxx (xxxx) xxx
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Tetrahedron Letters
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Cobalt-catalyzed hydrocyanation and hydroarylation of enamines
a
a
a,b
Shigeru Arai a,b, , Yuichi Sato , Natsuki Ito , Atsushi Nishida
⇑
a Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, 260-8675 Chiba, Japan
b Molecular Chirality Research Center, Chiba University, 1-33 Yayoi-cho, 263-8522 Chiba, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild, general and efficient hydrocyanation and hydroarylation of enamines catalyzed by Co(salen) com-
plexes are described. Both reactions include regioselective CAH bond formation of enamines, and the cor-
responding products are obtained in high yield. Hydroarylation critically discriminates the benzyl and
benzoyl aromatic rings on nitrogen in cyclization step, and the corresponding isoindolinones including
quaternary carbons are exclusively given.
Received 12 September 2019
Revised 18 October 2019
Accepted 23 October 2019
Available online xxxx
Ó 2019 Elsevier Ltd. All rights reserved.
Keywords:
Hydrocyanation
Hydroarylation
Cobalt
Enamine
Cobalt-catalyzed hydrogen atom transfer [1–3] has been one of
the most practical synthetic tools due to the use of less-toxic rad-
ical initiators, less-expensive metal species, mild reaction condi-
tion, and functional group tolerance. Particularly, Co(salen)
complexes with silanes have been potentially useful to install CN
[4,5], oxime [6], aromatic [7,8], nitrogen [9–13], oxygen [14,15],
sulfur [16], and halogen [17,18] functionalities into simple and
unactivated olefins with highly regioselective manner. Further
applications to prepare complex molecules have been demon-
strated to prove their power as a synthetic methodology [3,19].
On the other hand, enamines have been typically used as nucle-
ophiles however, their utilization in radical chemistry has been
still limited [20–23]. Herein we report the synthetic transforma-
tions focused on hydrocyanation and hydroarylation that are trig-
gered by cobalt-mediated regioselective hydrogen atom transfer
processes (Scheme 1).
First of all, we examined hydrocyanation using 1a (Scheme 2).
The reaction completed under Carreira’s condition [3–5] using Co
(salen) (cat. A, 2 mol%) with TsCN and PhSiH3) in EtOH at room
temperature within 20 min, and 2a was obtained in 87% yield
without any regioisomer (3a) nor hydrosilylation products such
as 3b [24]. According to the report by Nemoto and co-workers,
Ni-catalyzed hydrocyanation of 1a gives a mixture of 2a and 3a
with the ratio of 1:3.4 [25]. Above exclusive formation of 2a under
cobalt catalysis proves its potential synthetic utility using enami-
nes and further investigations were continued.
First, we estimated the relative reactivity of enamine using 3a
and 3c (1:1 M ratio). Both were reactive however the former was
much more reactive to give 2a in 82% yield whereas 3d was
resulted in 46% yield within 20 min (Scheme 3) [4]. This result sug-
gests that the effect of nitrogen functionality on C@C bond gives a
positive influence in rate enhancement.
The substrate scope was next investigated (Table 1). When
other substituted N-acyl enamines were examined, their reactivity
was highly dependent on the nature of substituents. For example, a
methyl group (1b) was suitable to give 2b in 73%, exclusively how-
ever, both phenyl and CO2Me groups (1c,d) completely prevented
the reaction even after 25 h (entries 1–3). The N-formyl enamides
which have N-Boc and -alloc groups were smoothly transformed to
the corresponding carbonitriles (2e,f) in respective yields of 68%
and 25% (entries 4, 5). In the case of N-benzoyl substituents, 2g-i
were given in the range of 67–88% yields, suggesting that the elec-
tronic property of benzene rings does not influence seriously in the
reaction efficiency (entries 6–8). The regioselectivity observed in
2a-i would be dependent on the predominant formation of nitro-
gen-stabilized carboradical intermediate (4), which smoothly
reacts with TsCN to form a C-CN bond. N-mono-acyl group such
as pyrrolidone derivatives were also suitable for this reaction and
2i,k were obtained in respective yields of 28% and 75% (entries 9,
10). In case of cyclic and NH free enamines containing a benzoyl
group gave the corresponding adducts of 2l,m in 80% and 66%
yield, respectively (entries 11, 12). N-phenyl and -benzyl oxazoli-
done derivatives were both applicable to be transformed to 2n,o
in moderate yield within 30 min (entries 13, 14).
⇑
Corresponding author at: Graduate School of Pharmaceutical Sciences, Chiba
University, 1-8-1 Inohana, Chuo-ku, 260-8675 Chiba, Japan.
During the above studies, we observed that the plausible radical
intermediate such as 4 was reactive enough to promote cyclization
E-mail address: araisgr@chiba-u.jp (S. Arai).
https://doi.org/10.1016/j.tetlet.2019.151314
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: S. Arai, Y. Sato, N. Ito et al., Cobalt-catalyzed hydrocyanation and hydroarylation of enamines, Tetrahedron Letters, https://doi.
org/10.1016/j.tetlet.2019.151314

2
S. Arai et al. / Tetrahedron Letters xxx (xxxx) xxx
Table 1
The substrate scope of hydrocyanation using 1b-o.
Scheme 1. Hydrocyanation and hydroarylation of enamines.
Scheme 2. Hydrocyanation of 1a under cobalt catalysis.
1Five mol% cat. A was used.
Scheme 3. Competitive experiment using 1a and 3c.
with aromatic ring on nitrogen. For example, the reaction using 5a
with cat. A (2 mol%) and PhSiH3 (1.2 eq) at room temperature pro-
moted hydroarylation [7,8] to give 6a in 58% together with 8a in
15% yield, respectively (Scheme 4). The benzylic aromatic ring
was less reactive, and the corresponding adduct such as 7a was
not obtained at all. The structure of a former product (6a) is isoin-
dolinone with a quaternary carbon and is a structural motif of
cyclopramides and speradines [26,27]. This hydroarylative cycliza-
tion is a highly potential synthetic method to enable facile control
of regiochemistry and discrimination of two inequivalent (red and
blue) aromatic rings in 5a [28].
Scheme 4. Hydroarylative cyclization of 5a under cobalt catalysis.
Above preliminary result prompted us to optimize the condi-
tions (Table 2). A use of a larger amount of silane was not effective
to increase the yield of 6a (entry 1). The use of iPrOH slightly
increased the formation of 8a and t-BuOH decreased the reaction
rate to give similar conversion (entry 2, 3). Next, we turned to
examine Co(salen) B-D, that are used for hydroarylation of olefins
[7,8]. They exhibited the similar catalytic activity to give 6a in high
yields (entries 4–6), and sequential solvent effect revealed that
ethanol is the best solvent of choice in both conversion to 6a and
preventing hydrolysis of 5a (entries 6–10). Reducing amount of
silane (0.1 eq) was enough to proceed the reaction and 6a was
given in 90% yield after 2 h (entry 11). Finally, the reaction using
0.2 eq. of silane completed within 30 min in 86% yield of 5a (entry
12). A use of toluene instead was less effective in conversion even
after 4 h (entry 13).
Please cite this article as: S. Arai, Y. Sato, N. Ito et al., Cobalt-catalyzed hydrocyanation and hydroarylation of enamines, Tetrahedron Letters, https://doi.
org/10.1016/j.tetlet.2019.151314

S. Arai et al. / Tetrahedron Letters xxx (xxxx) xxx
3
Table 2
Optimization of hydroarylative cyclization of 5a.
Entry
Catalyst1
PhSiH3 (eq)
Conditions
6a (%)
8a (%)
5a (%)
Yield %
0
Yield %
72
Yield %
72
1
2
3
4
5
6
7
8
A
A
A
B
2
EtOH, 1 h
45
61
64
84
85
85
93
68
90
88
90
86
71
12
24
12
3
0
0
5
10
0
9
2
0
0
0
0
0
0
0
0
0
0
0
0
18
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
0.1
0.2
0.2
iPrOH, 1 h
t-BuOH, 12 h
EtOH, 2 h
EtOH, 2 h
EtOH, 2 h
Toluene, 2 h
CH2Cl2, 5 h
CH3CN, 6 h
THF, 3 h
EtOH, 2 h
EtOH, 0.5 h
Toluene, 4 h
89
88
95
89
88
95
89
88
95
C
D
D
D
D
D
D
D
D
9
10
11
12
13
3
5
1Racemic complexes of B-D were used as a catalyst.
Table 3
The substrate scope of hydroarylative cyclization using 5b-k.
O
O
FG
O
FG
FG
cat. D (2 mol%)
R1
PhSiH3 (0.2 eq)
N
NHR1
N
R1
H
+
EtOH, rt
R2
R2
6b-k
5b-k
8
entry
substrates
time (h)
products
O
O
FG
FG
2
1
2
3
4
0.5
0.5
0.5
0.5
5b: FG = 4-CF3
6b: 83%
6c: 73%1)
6d: 93%
6e: 94%
8b: 6%
Bn
Bn
3
5c: FG = 2-Br
N
N
Bn
H
5d: FG = 3,5-Me2
5e: FG = 3,5-F2
4
Me
O
5
Me
O
5
6
2
5
5f: R2 = (CH2)2Ph
5g: R2 = CO2Me
8f: 8%
8h: 2%
6f: 68%2)
6g: 74%
N
Bn
H
N
N
R2
O
R2
O
R1
O
7
8
0.5
4
6h: 90%
5h: R1 = (CH2)2Ph
5i: R1 = allyl
N
R2
H
6i: 41%2,3)
Me
3
Me
O
O
Me
Bn
N
Me
N
Me
Bn
H
N
Bn
H
8j: 5%
9
0.5
0.5
Me
Me
Me
5j
6j-1: 64%
6j-2: 25%
Me
H
Bn
O
O
N
Bn
N
N
Bn
O
10
Me
H
Me
6k-1: 36%
5k
6k-2: 39%
CCDC: 1942426
1PhSiH3 (0.4 eq) was used.
2PhSiH3 (3 eq) was used.
3Catalyst loading: 7 mol%.
Please cite this article as: S. Arai, Y. Sato, N. Ito et al., Cobalt-catalyzed hydrocyanation and hydroarylation of enamines, Tetrahedron Letters, https://doi.
org/10.1016/j.tetlet.2019.151314

4
S. Arai et al. / Tetrahedron Letters xxx (xxxx) xxx
resulting residue was purified by column chromatography (hex-
ane:AcOEt = 15:1) to give 6d (60.9 mg, 0.242 mmol, 93%) as brown
solid.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgment
This work was supported by the Grant-in-Aid from the Japan
Society for the Promotion of Science (JSPS) (Grant No. 17K08205).
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.151314.
Scheme 5. Plausible reaction pathway.
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To a solution of 5d (64.3 mg, 0.26 mmol) and Co complex D
(3.1 mg, 0.0052 mmol) in EtOH (1.3 mL, 0.2 M) was added PhSiH3
lL, 0.052 mmol) at room temperature. After being stirred for
(6
30 min, the solvent was removed under reduced pressure. The
Please cite this article as: S. Arai, Y. Sato, N. Ito et al., Cobalt-catalyzed hydrocyanation and hydroarylation of enamines, Tetrahedron Letters, https://doi.
org/10.1016/j.tetlet.2019.151314