Cobalt-catalyzed redox-neutral synthesis of isoquinolines: C–H activation assisted by an oxidizing N–S bond

Article abstract of DOI:10.1016/S1872-2067(16)62491-9

A redox-neutral avenue to access isoquinolines has been realized by a Co(III)-catalyzed C–H activation process. Starting from readily available N-sulfinyl imine substrates and alkynes, the reaction occurred via N–S cleavage with broad substrate scope and functional group compatibility in the presence of cost-effective cobalt catalysts.

Full text of DOI:10.1016/S1872-2067(16)62491-9

Chinese Journal of Catalysis 37 (2016) 1423–1430
a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m
j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / c h n j c
Article
Cobalt‐catalyzed redox‐neutral synthesis of isoquinolines: C–H
activation assisted by an oxidizing N–S bond
Fen Wanga,b, Qiang Wangb, Ming Baoa, Xingwei Li b,*
a School of Chemistry and Chemical Engineering, Dalian University of Technology, Dalian 116024, Liaoning, China
b Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, Liaoning, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A redox‐neutral avenue to access isoquinolines has been realized by a Co(III)‐catalyzed C–H activa‐
tion process. Starting from readily available N‐sulfinyl imine substrates and alkynes, the reaction
occurred via N–S cleavage with broad substrate scope and functional group compatibility in the
presence of cost‐effective cobalt catalysts.
Received 6 June 2016
Accepted 24 June 2016
Published 5 August 2016
© 2016, Dalian Institute of Chemical Physics, Chinese Academy of Sciences.
Published by Elsevier B.V. All rights reserved.
Keywords:
Cobalt(III) catalyst
Carbon–hydrogen activation
N‐sulfinyl imine
Isoquinoline
1. Introduction
occurred under oxidative conditions, as demonstrated by
Fagnou et al. [41] under Rh(III) catalysis. Subsequently, the
Isoquinolines are an important class of heterocycles that
have found wide applications in synthetic organic chemistry
and as core structures of pharmaceuticals and materials. Tradi‐
tional methods to access isoquinolines suffered from employ‐
ment of functionalized starting materials and strong acids
[1–7]. For example, the Larock group [1–5] applied palladium
catalysis to the annulative coupling between ortho‐bromo func‐
tionalized imines and alkynes. To overcome these limitations,
the past decade has witnessed significant progress in heterocy‐
cle synthesis via a C–H activation strategy [8–13], in which
abundant arenes are used as readily available starting materi‐
als. Thus, a number of transition metals such as Rh, Ir, Pd and
Ru have been reported to effectively catalyze the C–H activation
of arenes leading to isoqinoline synthesis [14–40].
groups of Chiba [18,21,23], Li [19], Hua [25], and others [20,29]
have extended the arene substrate to those bearing an oxidiz‐
ing N–O and N–N bond as a directing group, which allowed
annulation under redox‐neutral and mild conditions with high
efficiency and selectivity. Besides rhodium catalysis, the em‐
ployment of Ru(II) catalysts has also allowed efficient isoquino‐
line synthesis [33–37]. Despite the significant progress, these
systems are limited to the employment of relatively costly no‐
ble metals such as rhodium and ruthenium catalysts. Very re‐
cently, the groups of Kanai [42,43], Glorius [44,45], Ackermann
[46,47], Chang [48,49], Ellman [50,51], and others [52–57]
have applied earth‐abundant and cost‐effective cobalt catalysts
to the C–H activation of arenes, which allowed efficient synthe‐
sis of various heterocycles under operational simple conditions.
In some cases, the Co(III) catalysts have explicitly shown com‐
Early examples of isoquinoline synthesis via C–H activation
* Corresponding author. Tel: +86‐411‐84379089; E‐mail: xwli@dicp.ac.cn
This work was supported by the Dalian Institute of Chemical Physics, Chinese Academy of Sciences and the National Natural Science Foundation of
China (21272231).
DOI: 10.1016/S1872‐2067(16)62491‐9 | http://www.sciencedirect.com/science/journal/18722067 | Chin. J. Catal., Vol. 37, No. 8, August 2016

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Fen Wang et al. / Chinese Journal of Catalysis 37 (2016) 1423–1430
benzophenone by‐product and the isoquinolines product acci‐
Previous work ([43,47,56,57])
dentally have the same Rf in chromatography, so NaBH4 was
added to convert benzophenone to the corresponding alcohol.
The mixture was stirred at room temperature for 30 min. Puri‐
fication was performed by flash column chromatography on
silica gel using EtOAc and petroleum ether to afford the desired
product.
R1
Co(III) cat.
R
N
N
+
R = H or OR
with or without
oxidant
R1
R2
R2
Our previous work
O
S
O
O
Co(III) cat.
N
N
N
N
tBu
O
+
2.3. Spectral data for products
DCE
N
R
R
1
This work
3aa. H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 8.3 Hz, 1H),
R1
O
S
7.82 (d, J = 6.9 Hz, 2H), 7.72 (d, J = 8.4 Hz, 1H), 7.60–7.46 (m,
5H), 7.45–7.27 (m, 7H), 7.21–7.12 (m, 3H). 13C NMR (101 MHz,
CDCl3) δ 159.8, 149.6, 140.9, 139.8, 137.5, 136.9, 131.3, 130.4,
130.2, 129.9, 129.7, 128.5, 128.29, 128.28, 127.51, 127.47,
127.3, 127.0, 126.6, 126.0, 125.4.
Co(III) cat.
tBu
+
N
HOAc, DCE
R1
R2
R2
Scheme 1. C–H activation of imines for heterocycle synthesis.
1
3ba. H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 8.3 Hz, 1H),
7.86–7.77 (m, 2H), 7.71 (d, J = 8.4 Hz, 1H), 7.58–7.43 (m, 5H),
7.35 (d, J = 8.1 Hz, 2H), 7.24–7.15 (m, 4H), 6.99 (d, J = 8.0 Hz,
2H), 2.40 (s, 3H), 2.26 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
159.5, 149.5, 139.9, 138.1, 137.2, 136.8, 136.5, 134.6, 131.1,
130.3, 130.2, 129.7, 129.4, 129.1, 128.4, 128.3, 128.2, 127.4,
126.3, 126.03, 125.3, 21.3, 21.2.
plementary activity to the rhodium congeners [58,59]. In par‐
ticular, Sun et al. [43], Kornhaaß et al. [47], and Sen et al. [57]
recently independently reported the redox‐neutral annulative
coupling between oxime and alkynes for efficient synthesis of
isoquinolines (Scheme 1). On the other hand, although oxidiz‐
ing N–O, N–N, and even C–N bonds have been utilized as an
internal oxidant for redox‐neutral couplings [19,41,43,47,57,6
0,61], oxidizing N–S bonds has been rarely applied for this
purpose although a N–S linkage can be readily installed to an
arene [62]. We recently reported the applications of N‐sulfinyl
imines as an arene source for the coupling with olefins and
dioxazolones [58]. With the cleavage of the N–S bond, isoindole
and quinazoline rings have been efficiently constructed. We
now report redox‐neutral isoquinoline synthesis via annulative
coupling between N‐sulfinyl imine and alkynes.
3ca. 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 8.3 Hz, 1H), 7.81
(d, J = 7.0 Hz, 2H), 7.73 (d, J = 8.4 Hz, 1H), 7.60–7.42 (m, 5H),
7.39 (d, J = 8.7 Hz, 2H), 7.25–7.16 (m, 2H), 6.94 (d, J = 8.5 Hz,
2H), 6.73 (d, J = 8.7 Hz, 2H), 3.84 (s, 3H), 3.74 (s, 3H). 13C NMR
(101 MHz, CDCl3) δ 159.5, 158.8, 158.7, 149.4, 140.0, 137.5,
133.7, 132.4, 131.8, 130.3, 130.0, 129.8, 128.9, 128.5, 128.3,
127.5, 126.3, 126.0, 125.3, 114.0, 113.1, 55.3, 55.2.
1
3da. H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 8.3 Hz, 1H),
7.81 (d, J = 6.9 Hz, 2H), 7.77 (d, J = 8.4 Hz, 1H), 7.60–7.44 (m,
5H), 7.39 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.26–7.14
(m, 4H), 1.37 (s, 9H), 1.24 (s, 9H). 13C NMR (101 MHz, CDCl3) δ
159.5, 150.2, 149.7 (two overlapping signal), 140.1, 138.1,
137.2, 134.6, 131.0, 130.3, 130.1, 129.7, 129.6, 128.4, 128.3,
127.4, 126.4, 126.2, 125.3, 125.2, 124.4, 34.64, 34.4, 31.5, 31.3.
2. Experimental
2.1. General
1
3ea. H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.3 Hz, 1H),
All cobalt‐catalyzed reactions were carried out in a nitro‐
gen‐filled dry box. 1H and 13C NMR spectra were recorded using
CDCl3 as a solvent on a 400 MHz spectrometer at 298 K. The
chemical shift is given in dimensionless δ values and is fre‐
7.85–7.78 (m, 2H), 7.70–7.61 (m, 2H), 7.60–7.50 (m, 6H),
7.37–7.29 (m, 4H), 7.18 (d, J = 8.3 Hz, 2H). 13C NMR (101 MHz,
CDCl3) δ 160.3, 148.4, 139.5, 139.4, 136.7, 136.2, 132.9, 132.0,
131.8, 130.9, 130.3, 130.1, 128.7, 128.5, 128.4, 127.7, 127.0,
125.6, 125.5, 121.8, 121.7.
1
quency referenced relative to SiMe4 in H and 13C NMR spec‐
troscopy. High‐resolution mass spectra were obtained on an
Agilent Q‐TOF 6540 spectrometer. Dichloroethane was distilled
from CaH2 and was stored in a dry box. All other solvents were
obtained from commercial sources and were used as received.
1
3fa. H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 8.3 Hz, 1H),
7.83–7.76 (m, 2H), 7.68 (d, J = 8.4 Hz, 1H), 7.65–7.58 (m, 1H),
7.56–7.50 (m, 4H), 7.42–7.33 (m, 2H), 7.29–7.21 (m, 2H),
7.12–7.08 (m, 2H), 6.94–6.84 (m, 2H). 13C NMR (101 MHz,
CDCl3) δ 162.1 (d, JC‐F = 245.6 Hz), 162.0 (d, JC‐F = 245.4 Hz),
2.2. General procedure for the synthesis of compounds 3
160.1, 148.8, 139.6, 136.9, 136.8 (d, JC‐F = 3.2 Hz), 133.3 (d, JC‐F
=
3.5 Hz), 132.9 (d, JC‐F = 7.9 Hz), 132.1(d, JC‐F = 8.1 Hz), 130.2,
130.1, 128.7, 128.6, 128.3, 127.6, 126.8, 125.7, 125.4, 115.7 (d,
N‐Sulfinyl imine (1a, 57.1 mg, 0.2 mmol), CoCp*(CO)I2 (9.5
mg, 10 mol%), AgNTf2 (15.5 mg, 20 mol%), HOAc (12 mg, 1.0
equiv.), and diphenylacetylene (2a, 42.8 mg, 1.2 equiv.) were
weighed into a pressure tube, to which was added 1,2‐dichlo‐
roethane (3 mL) under N2. The reaction mixture was stirred for
18 h at 120 °C. After removal of 1,2‐dichloroethane under re‐
duced pressure, methanol (3 mL) was added, followed by addi‐
tion of sodium borohydride (22.8 mg, 3 equiv.). The hydrolyzed
J
C‐F = 21.3 Hz) , 114.6 (d, JC‐F = 21.2 Hz).
3ga. H NMR (400 MHz, CD2Cl2) δ 8.19 (d, J = 8.4 Hz, 1H),
1
7.79 (d, J = 6.4 Hz, 2H), 7.70–7.65 (m, 3H), 7.63–7.53 (m, 5H),
7.51 (s, 1H), 7.38–7.25 (m, 4H), 7.09 (t, J = 7.9 Hz, 1H). 13C NMR
(101 MHz, CD2Cl2) δ 160.9, 148.5, 143.3, 140.0, 139.9, 137.2,
134.6, 133.9, 131.3, 131.0, 130.8, 130.69, 130.68, 130.65,

Fen Wang et al. / Chinese Journal of Catalysis 37 (2016) 1423–1430
1425
129.63, 129.62, 129.3, 129.2, 128.9, 128.1, 127.8, 126.2, 126.1,
123.0, 122.3.
18H). 13C NMR (101 MHz, CDCl3) δ 159.0, 155.7, 140.6, 135.1,
130.2, 129.3, 128.1, 128.0, 127.6, 127.14, 127.09, 127.0, 125.6,
18.8, 11.1.
1
3ha. H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 8.3 Hz, 1H),
7.82 (d, J = 6.8 Hz, 2H), 7.72–7.70 (m, 2H), 7.57–7.51 (m, 4H),
7.40 (dd, J = 14.0, 7.8 Hz, 1H), 7.25–7.00 (m, 6H), 6.95–6.86 (m,
1H). 13C NMR (101 MHz, CDCl3) δ 162.8 (d, JC‐F = 245.8 Hz),
162.4 (d, JC‐F = 245.8 Hz), 160.4, 148.2 (d, JC‐F = 2.4 Hz), 142.8 (d,
3ab. 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 8.6 Hz, 1H),
7.76 (d, J = 8.0 Hz, 2H), 7.51 (s, 1H), 7.49–7.30 (m, 10H),
7.25–7.16 (m, 3H), 2.50 (s, 3H), 2.46 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 159.5, 149.7, 141.1, 140.1, 138.2, 137.8, 137.2, 137.1,
131.4, 130.4, 130.1, 129.0, 128.9, 128.7, 128.2, 127.4, 127.4,
127.1, 126.8, 124.8, 123.8, 22.1, 21.3.
JC‐F = 7.6 Hz), 139.5 (d, JC‐F =3.0 Hz) , 139.4, 136.6, 130.4, 130.1,
130.0, 129.0 (d, JC‐F = 8.0 Hz) , 128.74, 128.70, 128.4, 127.7,
127.1 (d, JC‐F = 3.0 Hz), 127.0, 126.0 (d, JC‐F = 3.0 Hz), 125.7,
125.6, 118.2 (d, JC‐F = 21.3 Hz) , 117.2 (d, JC‐F = 22.4 Hz), 114.6
(d, JC‐F = 20.9 Hz), 114.2 (d, JC‐F = 21.0 Hz).
3ia. 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 8.4 Hz, 1H),
7.83–7.80 (m, 2H), 7.69–7.62 (m, 2H), 7.61–7.48 (m, 4H),
7.46–7.41 (m, 1H), 7.38–7.31 (m, 1H), 7.25–7.19 (m, 2H),
7.13–7.05 (m, 3H), 6.91 (t, J = 9.1 Hz, 1H). 13C NMR (101 MHz,
CDCl3) δ 160.4 (d, JC‐F = 245.4 Hz), 160.7, 159.7 (d, JC‐F = 245.8
1
3ac. H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 9.2 Hz, 1H),
7.83–7.72 (m, 2H), 7.48–7.34 (m, 5H), 7.33–7.30 (m, 2H),
7.24–7.13 (m, 4H), 7.12–7.05 (m, 2H), 6.98 (d, J = 2.5 Hz, 1H),
3.91 (s, 3H), 3.74 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.5,
160.0, 158.8, 150.2, 141.2, 139.1, 137.9, 132.5, 131.5, 131.2,
130.4, 129.5, 128.6, 128.4, 127.4, 127.2, 126.9, 121.2, 118.7,
113.7, 104.2, 55.4, 55.2.
3ad. 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 8.8 Hz, 1H),
8.07 (s, 1H), 7.95–7.83 (m, 4H), 7.72–7.70 (m, 1H), 7.44–7.40
(m, 5H), 7.30–7.28 (m, 2H), 7.24–7.18 (m, 3H). 13C NMR (101
MHz, CDCl3) δ 158.3, 151.3, 142.6, 140.0, 136.4, 136.2, 133.9,
131.4 (q, JC‐F = 32.4 Hz), 131.1, 131.0, 130.6, 130.3, 128.7, 128.2,
128.0, 127.74, 127.70, 127.6, 126.0, 125.5 (q, JC‐F = 3.7 Hz),
125.0, 124.0 (q, JC‐F = 4.5 Hz), 122.8, 122.6 (q, JC‐F = 3.1 Hz),
122.3.
Hz), 146.7, 139.4, 136.3, 132.7 (d, JC‐F = 3.5 Hz), 131.8 (d, JC‐F
=
3.3 Hz), 130.4, 130.2, 129.9 (d, JC‐F = 8.0 Hz), 129.5, 129.49 (d,
JC‐F = 8.0 Hz), 128.9, 128.7, 128.6, 128.3, 127.8, 127.1, 126.0,
125.7, 125.5, 124.4, 124.3, 123.8 (d, JC‐F = 3.5 Hz), 123.6 (d, JC‐F
=
3.4 Hz), 115.4 (d, JC‐F =21.9 Hz), 115.2 (d, JC‐F = 22.0 Hz).
3ja. 1H NMR (400 MHz, CDCl3) δ 8.09–8.07 (m, 1H),
7.77–7.75 (m, 2H), 7.58–7.47 (m, 7H), 7.46–7.42 (m, 2H),
7.37–7.35 (m, 2H), 2.81–2.70 (m, 2H), 1.84–1.70 (m, 2H), 0.87
(t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 159.6, 152.1,
140.0, 137.9, 136.8, 130.4, 130.1, 129.8, 129.6, 128.42, 128.40,
128.3, 127.4, 127.3, 125.7, 125.6, 124.7, 37.7, 23.5, 14.1.
3ka. 1H NMR (400 MHz, CDCl3) δ 8.17–8.10 (m, 2H),
7.79–7.70 (m, 3H), 7.62–7.57 (m, 2H), 7.57–7.43 (m, 6H),
7.43–7.37 (m, 1H), 3.13–2.98 (m, 2H), 1.88–1.69 (m, 2H), 0.99
(t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 158.2, 151.4,
141.8, 139.9, 136.2, 130.2, 129.8, 129.5, 128.24, 128.20 (two
overlapping signal), 128.1, 128.0, 127.4, 126.2, 125.9, 124.0,
30.9, 24.6, 14.5.
1
3ae. H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 9.0 Hz, 1H),
7.80–7.74 (m, 2H), 7.73 (d, J = 2.0 Hz, 1H), 7.58–7.52 (m, 2H),
7.48 (dd, J = 9.0, 2.0 Hz, 1H), 7.46–7.37 (m, 5H), 7.32–7.27 (m,
2H), 7.25–7.18 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 158.4,
150.8, 140.3, 138.0, 137.7, 136.6, 136.6, 135.0, 131.5, 131.1,
130.3, 129.2, 128.9, 128.7, 128.6, 127.7, 127.68, 127.6, 127.3,
125.0, 123.5.
3af. 1H NMR (400 MHz, CDCl3) δ 8.05 (dd, J = 9.2, 5.7 Hz, 1H),
7.73–7.65 (m, 2H), 7.34–7.25 (m, 5H), 7.23 (dd, J = 10.8, 2.5 Hz,
1H), 7.20–7.05 (m, 8H). 13C NMR (101 MHz, CDCl3) δ 164.4 (JC‐F
= 2.1 Hz), 161.9 (JC‐F = 5.7 Hz), 158.5, 150.6, 140.4, 139.0 (JC‐F
=
1
3la. H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.5 Hz, 2H),
9.7 Hz), 137.0, 135.6 (JC‐F = 3.3 Hz), 131.9 (JC‐F = 8.2 Hz), 131.1,
130.4 (JC‐F = 5.3 Hz), 130.3, 129.5 (JC‐F = 5.4 Hz), 128.5, 127.6,
7.72–7.63 (m, 3H), 7.57–7.40 (m, 4H), 3.15–2.99 (m, 4H),
1.97–1.83 (m, 2H), 1.82–1.72 (m, 2H), 1.16 (t, J = 7.3 Hz, 3H),
1.08 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 158.1,
152.2, 140.1, 136.1, 130.0, 129.4, 128.2, 128.1, 128.0, 127.1,
125.3, 125.2, 123.3, 37.4, 29.9, 24.1, 23.6, 14.7, 14.3.
3ma+3ma’. 1H NMR (400 MHz, CDCl3) δ 8.18–8.07 (m,
2.7H), 7.79–7.48 (m, 4.5H), 7.68 (d, J = 7.3 Hz, 2H), 7.62–7.46
127.3, 122.6, 117.0 (JC‐F = 25.1 Hz), 115.5, 115.3, 109.8 (JC‐F
=
22.2 Hz),.
3ag. 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.66–7.54 (m,
3H), 7.44–7.26 (m, 10H), 7.21–7.11 (m, 3H), 2.48 (s, 3H), 2.47
(s, 3H). 13C NMR (101 MHz, CDCl3) δ 159.4, 148.9, 141.1, 140.0,
138.1, 137.8, 136.5, 135.2, 132.2, 131.4, 130.8, 130.5, 129.6,
129.2, 128.3, 128.1, 127.5, 127.3, 127.2, 126.9, 126.3, 125.9,
125.7, 21.9, 21.6.
(m, 12.5H), 7.45–7.36 (m, 3.3H), 2.72 (s, 3H), 2.57 (s, 2.3H). 13
C
NMR (101 MHz, CDCl3) δ 159.5, 158.2, 151.0, 148.2, 141.5,
139.9, 139.8, 138.0, 137.0, 136.7, 130.2, 130.1, 130.0, 129.9,
129.7, 128.6, 128.3, 128.2, 128.01, 128.0, 127.5, 127.4, 127.36,
126.3, 125.7, 125.34, 125.3, 124.8, 123.9, 123.1, 23.3, 15.7.
3na. 1H NMR (400 MHz, CDCl3) δ 8.28–8.22 (m, 2H), 8.15 (d,
J = 8.5 Hz, 1H), 8.09 (s, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.88–7.80
(m, 2H), 7.70–7.67 (m, 1H), 7.60–7.49 (m, 6H), 7.44–7.41 (m,
1H). 13C NMR (101 MHz, CDCl3) δ 160.4, 150.2, 139.9, 139.6,
137.9, 130.3, 130.1, 128.7, 128.6, 128.5, 128.3, 127.6, 127.5,
127.1, 126.9, 125.8, 115.7,
1
3ah+3ah’. H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 8.8 Hz,
1.04H), 8.04 (s, 1H), 8.00 (d, J = 8.6 Hz, 0.27H), 7.95 (d, J = 8.0
Hz, 0.49H), 7.82 (d, J = 8.1 Hz, 0.51H), 7.73 (d, J = 7.8 Hz, 2.03H),
7.68 (d, J = 8.8, 1.3 Hz, 1.04H), 7.51 (s, 0.3H), 7.45–7.38 (m,
8.76H), 7.31–7.29 (m, 2.57H), 7.21–7.18 (m, 3.82H), 2.49 (s,
3H), 2.46 (s, 0.75H). 13C NMR (101 MHz, CDCl3) δ 159.9, 151.1,
140.7 (JC‐F = 14.1 Hz), 140.4, 139.0, , 136.6, 136.4 (JC‐F = 3.6 Hz),
131.6, 131.3, 131.26, 130.5 (JC‐F = 19.3 Hz), 130.46, 130.2,
130.1, 129.2, 129.0, 128.6, 128.4, 127.8, 127.6, 127.4, 127.1,
1
3oa. H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 8.5 Hz, 1H),
126.8, 126.3, 125.33, 125.30, 125.2, 125.09, 124.8 123.7 (JC‐F
=
7.90–7.83 (m, 2H), 7.78 (d, J = 7.2 Hz, 2H), 7.67 (t, J = 7.5 Hz,
1H), 7.56–7.47 (m, 4H), 1.66–1.55 (m, 3H), 1.20 (d, J = 7.5 Hz,
4.9 Hz), 122.5, 122.1 (JC‐F = 3.0 Hz), 22.2, 21.4.
3ai. 1H NMR (400 MHz, CDCl3) δ 8.23–8.16 (m, 1H),

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Fen Wang et al. / Chinese Journal of Catalysis 37 (2016) 1423–1430
7.67–7.64 (m, 1H), 7.59–7.55 (m, 2H), 7.39–7.30 (m, 5H),
7.38–7.28 (m, 5H), 3.07 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
157.7, 149.4, 141.0, 137.6, 136.0, 131.4, 130.2, 129.9, 129.1,
128.2, 127.6, 127.1, 126.9, 126.5, 126.2, 126.1, 125.5 22.7.
3aj. 1H NMR (400 MHz, CDCl3) δ 8.30–8.28 (m, 1H),
7.68–7.65 (m, 1H), 7.61–7.51 (m, 2H), 7.58–7.52 (m, 2H),
7.46–7.44 (m, 2H), 7.39–7.34 (m, 3H), 7.26–7.23 (m, 2H),
7.20–7.16 (m, 3H), 4.03 (dt, J = 13.5, 6.8 Hz, 1H), 1.53 (d, J = 6.8
Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 164.9, 148.5, 141.3, 138.1,
136.5, 131.4, 130.6, 129.3, 128.4, 128.3, 127.4, 127.1, 126.8,
126.5, 126.2, 124.8, 124.5, 31.3, 22.3.
3ak. 1H NMR (400 MHz, CDCl3) δ 8.29–8.27 (m, 1H),
7.66–7.64 (m, 1H), 7.56–7.50 (m, 2H), 7.45–7.42 (m, 2H),
7.37–7.32 (m, 3H), 7.25–7.22 (m, 2H), 7.20–7.15 (m, 3H),
3.67–3.60 (m, 1H), 2.09–1.93 (m, 6H), 1.82 (d, J = 12.5 Hz, 1H),
1.58–1.51 (m, 2H), 1.45–1.34 (m, 1H). 13C NMR (101 MHz,
CDCl3) δ 164.4, 148.6, 141.3, 138.1, 136.5, 131.4, 130.6, 129.3,
128.3 (two overlapping signal), 127.4, 127.1, 126.8, 126.5,
126.2, 124.8, 124.5, 41.8, 32.5, 26.9, 26.3.
imine by addition of 4A molecular sieves also failed, and no
reaction was observed (Table 1, entry 6). It has been reported
that carboxylic acid can facilitate C–H activation and subse‐
quent cyclization in transition metal catalysis. Indeed, switch‐
ing the KOAc to HOAc under otherwise the same conditions
improved the yield, and a maximum yield of 73% was secured
when one equivalent of HOAc was used (Table 1, entry 10).
With the optimized conditions in hand, we next examined
the scope and generality of this coupling system (Table 2). The
scope of the alkyne substrate was first explored in the coupling
with 1a. It was found that symetrically substituted
diarylalkynes
bearing
both
electron‐donating
and
‐withdrawing groups at ortho, meta, and para positions all
coupled with good to high efficiency (3aa–3ia). The installed
halogen groups in these coupled product should readily allow
further chemical functionalizations. The symetric alkyne
substrate has been extended to a dialkyl‐substituted alkyne
such as 4‐octyne albeit in moderate yield (3la). Extension of the
alkyne to unsymetrical ones proved successful. Thus,
1‐phenyl‐1‐propyne coupled to afford product 3ma (major)
and 3ma’ (mnior) as a mixture of inseperable regioisomers in
1.3:1 ratio (only the major was shown). Similarly, 1‐phenyl‐
1‐pentyne coupled to give two regioisomers (3ja and 3ka) in a
toal yield of 69% that are chromatograpohycally seperated.
Terminal akynes also proved viable as a coupling partner. The
reaction of phenylacetylene afforded the corresponding
isoquoniline in 40% yield (3na), and a higher isolated yield
(63%) was obtained when tri(iso‐propyl)acetylene was used
(3oa).
We next examined the scope with respect to the imine sub‐
strate in the coupling with diphenylacetylene. Symmetrically
substituted benzophenone imines all coupled smoothly, where
both electron‐donating, ‐withdrawing, and halogen groups
were tolerated (3ac–3af). The reaction occurred at the less
hindered ortho site for the N‐sulfinyl imine of
di(m‐tolyl)methanone (3ag). The coupling of an electronically
biased imine afforded two isomeric products (3ah and 3ah’) in
4:1 ratio, where C–H activation at the more electron‐poor ring
took preference. The imine substrate was not limited to that of
benzophenone, and several acetophenone‐derived imines all
coupled smoothly to deliver the products in good to high yields
(3ai–3ak).
3. Results and discussion
We commenced our studied with the optimization of reac‐
tion conditions of the coupling between N‐sulfinyl imine 1a and
diphenylacetylene with Cp*Co(CO)I2/AgNTf2 as a catalyst (Ta‐
ble 1). The coupling at 120 °C in DCE afforded the desired iso‐
quinoline product 3aa in 54% isolated yield together with a
small amount of benzophenone (Table 1, entry 1). Introduction
of KOAc as an additive further improved the yield to 64% (Ta‐
ble 1, entry 2). In contrast, a diminished yield was isolated
when NaOAc was used (Table 1, entry 8). Screening of the sol‐
vent revealed that reactions performed in other common sol‐
vents such as HFIP, TFE, and acetone all gave inferior results
(Table 1, entries 3–5). Attempts to inhibit hydrolysis of the
Table 1
Optimization studies.
On the basis of our previous related mechanistic studies
[58], this system likely follows a C–H activation mechanism
because substrate 1a can readily undergo H/D exchange with
CD3COOD when catalyzed by Co(III) catalysts. To further probe
the C–H activation process, kinetic isotope effect (KIE) has been
measured by using intramolecular competition (Eq. (1)):
O
Entry
1
2
3
4
5
6 b
7
8
9
Additive (equiv.)
—
Solvent
DCE
DCE
HFIP
TFE
Acetone
DCE
DCE
DCE
DCE
DCE
Yield a (%)
54
KOAc (0.2)
KOAc (0.2)
KOAc (0.2)
KOAc (0.2)
KOAc (0.2)
KOAc (0.4)
NaOAc (0.2)
HOAc (2)
64
62
<5
30
Trace
50
43
66
73
Ph
Cp*Co(CO)I2 (10 mol%)
AgNTf2 (20 mol%)
S
N
(eq 1)
KIE = 2.8
HOAc (1.0 equiv)
DCE, 120 oC, 10 min
10
11
HOAc (1)
HOAc (0.5)
Ph
DCE
68
d5
Reaction conditions: imine 1a (0.2 mmol), 2a (0.24 mmol), Cp*Co(CO)I2
(10 mol%), AgNTf2 (20 mol%), solvent (3 mL), 120 °C, 18 h, sealed tube
under nitrogen.
The coupling of 1a‐d5 with diphenylacetylene afforded a
mixture of isotologues, H NMR analysis of which revealed a
KIE = 2.8. Although no solid conclusion can be drawn for the
turnover‐limiting step using a intramolecular experiment, this
1
a Yields of isolated products.
b 4A molecular seives (200 mg) were added.

Fen Wang et al. / Chinese Journal of Catalysis 37 (2016) 1423–1430
1427
Table 2
Scope of Co‐catalyzed synthesis of isoquinolines.
Yield *
(%)
Yield *
(%)
Yield *
(%)
Yield *
(%)
Entry
1
Product
Entry
8
Product
Entry
14
Product
Entry
20
Product
F
N
N
N
73
64
66
26
43
87
54
N
F
H
3na
F
F
3aa
3ha
F
3af
N
N
2
3
75
68
9
15
16
21
22
N
TIPS
F
3oa
H
3ia
3ba
Me
N
N
N
N
10
26
44
80
F3C
OMe
3ja
3ab
3ca
OMe
3ah+3ah'
(major:minor = 4:1)
OMe
N
N
N
N
4
5
26
43
11
12
13
43
44
76
17
18
19
76
26
71
23
24
25
54
66
78
tBu
MeO
3ai
3ka
tBu
3ac
3da
CF3
N
N
N
F3C
Br
3la
3ea
3ad
Br
N
6
7
44
50
3ak
Reaction conditions: imine 1a (0.2 mmol), 2 (0.24 mmol), Cp*Co(CO)I2 (10 mol%), AgNTf2 (20 mol%), HOAc (1 equiv.), DCE (3 mL), 120 °C, 18 h,
sealed tube under nitrogen. * Yields of the isolated products.
result suggests that a C–H activation mechanism should be
involved.
mechanism of this coupling system has been proposed (Scheme
2). C–H activation of 1a give a metalacycle A. Insertion of al‐
kyne to the Co‐aryl bond generates a seven‐membered meta‐
On the basis of literature precedents [56,58], a plausible

1428
Fen Wang et al. / Chinese Journal of Catalysis 37 (2016) 1423–1430
12051.
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Graphical Abstract
Chin. J. Catal., 2016, 37: 1423–1430 doi: 10.1016/S1872‐2067(16)62491‐9
Cobalt‐catalyzed redox‐neutral synthesis of isoquinolines: C–H activation assisted by an oxidizing N–S bond
Fen Wang, Qiang Wang, Ming Bao, Xingwei Li *
Dalian University of Technology; Dalian Institute of Chemical Physics, Chinese Academy of Sciences
A redox‐neutral avenue to access isoquinolines has been realized by a Co(III)‐catalyzed C–H activation process. Starting from readily
available N‐sulfinyl imine substrates and alkynes, the reaction occurred via N–S cleavage with broad substrate scope and functional group
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