Cp?CoIII Catalyzed Site-Selective C-H Activation of Unsymmetrical O-Acyl Oximes: Synthesis of Multisubstituted Isoquinolines from Terminal and Internal Alkynes

Article abstract of DOI:10.1002/anie.201507744

The synthesis of isoquinolines by site-selective C-H activation of O-acyl oximes with a Cp?Co^III catalyst is described. In the presence of this catalyst, the C-H activation of various unsymmetrically substituted O-acyl oximes selectively occurred at the sterically less hindered site, and reactions with terminal as well as internal alkynes afforded the corresponding products in up to 98% yield. Whereas the reactions catalyzed by the Cp?Co^III system proceeded with high site selectivity (15:1 to 20:1), use of the corresponding Cp?Rh^III catalysts led to low selectivities and/or yields when unsymmetrical O-acyl oximes and terminal alkynes were used. Deuterium labeling studies indicate a clear difference in the site selectivity of the C-H activation step under Cp?Co^III and Cp?Rh^III catalysis. Isoquinolines are obtained by the C-H activation of O-acyl oximes with a Cp?Co^III catalyst. Whereas the reactions catalyzed by the Cp?Co^III system proceed with high site selectivity favoring C-H activation at the sterically less hindered site, the use of the corresponding Cp?Rh^III catalyst leads to low selectivities and/or yields when unsymmetrical O-acyl oximes and terminal alkynes are used.

Full text of DOI:10.1002/anie.201507744

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Angewandte
Communications
International Edition: DOI: 10.1002/anie.201507744
German Edition: DOI: 10.1002/ange.201507744
À
C H Activation
III
À
Cp*Co Catalyzed Site-Selective C H Activation of Unsymmetrical
O-Acyl Oximes: Synthesis of Multisubstituted Isoquinolines from
Terminal and Internal Alkynes
Bo Sun, Tatsuhiko Yoshino, Motomu Kanai,* and Shigeki Matsunaga*
À
Abstract: The synthesis of isoquinolines by site-selective C H
comparison with Cp*RhIII are still limited.[8] Our group
utilized the high nucleophilicity of alkenyl CoIII species in
a one-pot pyrroloindolone synthesis.[8a] Glorius et al. capital-
ized on the high Lewis acidity of a cationic CoIII catalyst to
activation of O-acyl oximes with a Cp*CoIII catalyst is
À
described. In the presence of this catalyst, the C H activation
of various unsymmetrically substituted O-acyl oximes selec-
tively occurred at the sterically less hindered site, and reactions
with terminal as well as internal alkynes afforded the
corresponding products in up to 98% yield. Whereas the
reactions catalyzed by the Cp*CoIII system proceeded with high
site selectivity (15:1 to 20:1), use of the corresponding Cp*RhIII
catalysts led to low selectivities and/or yields when unsym-
metrical O-acyl oximes and terminal alkynes were used.
produce
6H-pyrido[2,1-a]isoquinolin-6-ones.[8b]
More
recently, we[8c] and the Glorius group[8d] independently
utilized the oxophilic properties of CoIII for the dehydrative
À
C H allylation with free allylic alcohols. Herein, we describe
our efforts to further explore the unique catalytic activity of
Cp*CoIII over Cp*RhIII catalysts. Cp*CoIII catalysts were
À
found to exhibit superior site selectivity in the C H activation
Deuterium labeling studies indicate a clear difference in the
site selectivity of the C H activation step under Cp*Co and
of unsymmetrically substituted O-acyl oximes, which enables
the formation of multisubstituted isoquinolines from terminal
and internal alkynes.
III
À
Cp*RhIII catalysis.
The isoquinoline framework is an important structural
motif found in a series of biologically active natural products
and pharmaceuticals.[9] Cyclization reactions of oxime deriv-
À
T
he transition-metal-catalyzed functionalization of C H
bonds is an atom-[1] and step-economic[2] organic transforma-
tion that has emerged over the last two decades.[3] A directing-
group-assisted C H bond activation process to form metal-
lacyclic intermediates is frequently used to realize regio- and
atives and alkynes by C H activation to give isoquinolines
À
without any external oxidants[10,11] have been developed using
various transition-metal catalysts.[12–14] For example, Chiba
and co-workers reported a Cp*RhIII catalyzed annulation
reaction of O-acyl oximes with internal alkynes (Sche-
me 1a).[13a] Zhao, Jia, Li, and co-workers also reported
À
À
chemoselective transformations of selected C H bonds.
Among the numerous catalysts explored in this field, Cp*RhIII
(Cp* = pentamethylcyclopentadienyl) complexes are often
employed for the directing-group-assisted functionalization
À
of aromatic C H bonds owing to their high reactivity,
generality, and functional-group compatibility.[4] The high
cost of Cp*RhIII complexes, however, can be an obstacle to
future large-scale applications for producing valuable materi-
als and biologically active compounds. In 2013, we thus began
to investigate Cp*CoIII catalysis as an inexpensive alternative
to Cp*RhIII catalysis.[5,6] Since then, we and other groups have
shown that several Cp*CoIII complexes indeed catalyze
[7]
À
various C H bond functionalization reactions that have
already been established with Cp*RhIII catalysts. On the other
hand, reports on the unique catalytic activity of Cp*CoIII in
[*] B. Sun, Prof. Dr. M. Kanai
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
E-mail: kanai@mol.f.u-tokyo.ac.jp
Scheme 1. Cp*RhIII and Cp*CoIII catalyzed isoquinoline syntheses; site
selectivity with unsymmetrical oxime derivatives and alkynes.
Dr. T. Yoshino, Prof. Dr. S. Matsunaga
Faculty of Pharmaceutical Sciences
Hokkaido University
Kita-ku, Sapporo 060-0812 (Japan)
E-mail: smatsuna@pharm.hokudai.ac.jp
a similar reaction of oximes under Cp*RhIII catalysis.[13b]
However, in both cases, the substrate scope was limited to
internal alkynes.[13,15] Moreover, the site selectivity in the
Dr. T. Yoshino, Prof. Dr. S. Matsunaga
ACT-C (Japan) Science and Technology Agency (Japan)
À
C H activation step leading to a metallacycle was also
problematic when unsymmetrical meta-substituted oxime
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201507744.
derivatives were used. Only very few substrates bearing
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Chemie
À
methyl or alkoxy groups reacted with sufficient site selectivity
in previously reported transition-metal-catalyzed isoquino-
line syntheses from oxime derivatives.[13,14] We hypothesized
that steric repulsion between the Cp* ligand and the substrate
would be larger with the Cp*CoIII than with the Cp*RhIII
catalyst as the ionic radius of cobalt is smaller than that of
rhodium. Thereby, Cp*CoIII would efficiently differentiate
between the two ortho positions in unsymmetrical meta-
substituted oxime derivatives.
C H activation proceeded with poor site selectivity in all
cases (entries 13–16).
The scope of unsymmetrically substituted O-acyl oximes
1 is summarized in Scheme 2. O-Acyl oximes bearing halogen
substituents at the meta position generally reacted with high
À
site selectivity, and the less hindered C H bond was
functionalized (3aa–3ib). A second substituent in the para
position (Y in 1) did not affect the selectivity or reactivity
(3ca, 3 db, 3eb, 3 fa). Various substituents at the meta
position, such as ester, methyl, and CF3 groups, were
compatible with the reaction, and high site selectivity was
observed with terminal aryl alkyne 2b. When the reaction
conditions were slightly modified
We optimized the reaction conditions using meta-chloro-
substituted O-acyl oxime 1a and terminal alkyne 2a as the
model substrates (Table 1). A cationic benzene complex,
and CsOAc was used as the base,
the terminal alkyl alkynes 2d–2g
Table 1: Optimization studies and control experiments.[a]
also afforded the corresponding
products with high site selectivity
(> 20:1) and in good to moderate
yields (3hd, 3kd, 3md–3mg). We
also evaluated the reactivity of the
Entry
Catalyst (mol%)
Ag salt (mol%)
Base (mol%)
T [8C]
Yield [%][b]
3/4
Cp*RhIII catalyst with several ter-
minal alkynes and unsymmetrical
O-acyl oximes, but the yields and/or
site selectivities were much less
satisfactory (3 db/4 db: 38%, 1:1.7;
3eb/4eb: 62%, 1:1.2; 3hb/4hb:
18%, 1.1:1; 3kb/4kb: 9%, > 20:1;
3lb/4lb: 30%, > 20/:1; 3mb/4mb:
trace, n.d.; 3md/4md: 6%, > 20:1).
In a previous report, the use of the
Cp*RhIII catalyst had also resulted
in low site selectivity when meta-
bromo-substituted O-acyl oxime 1b
and internal alkyne 2h were
1
2
3
4
5
6
7
8
9
[Cp*Co(C6H6)][PF6]2 (10)
[Cp*Co(CO)I2] (10)
[Cp*Co(CO)I2] (10)
[Cp*Co(CO)I2] (10)
[Cp*Co(CO)I2] (10)
[Cp*Co(CO)I2] (10)
[Cp*Co(CO)I2] (10)
[Cp*Co(CO)I2] (10)
[Cp*Co(CO)I2] (10)
[{Cp*RhCl2}2] (2.5)
[{Cp*RhCl2}2] (2.5)
[[{Cp*RhCl2}2] (5)
[{Cp*RhCl2}2] (5)
–
KOAc (20)
KOAc (20)
KOAc (20)
KOAc (20)
KOAc (20)
K2CO3 (20)
CsOAc (20)
CsOPiv (20)
–
NaOAc (30)
CsOAc (30)
KOAc (20)
KOAc (20)
K2CO3 (20)
CsOAc (20)
CsOPiv (20)
120
120
120
120
120
120
120
120
120
60
80
80
120
120
120
120
46
73
65
14:1
17:1
19:1
16:1
17:1
13:1
19:1
17:1
17:1
n.d.
n.d.
n.d.
1:1.3
1:1.6
1:1.3
1:1.3
AgPF6 (20)
AgBF4 (20)
AgNTf2 (20)
AgSbF6 (20)
AgSbF6 (20)
AgSbF6 (20)
AgSbF6 (20)
AgSbF6 (20)
–
70
82[c]
71
63
64
55
trace
trace
trace
11
9
28
10[d]
11[d]
12
13
14
15
16
–
AgSbF6 (20)
AgSbF6 (20)
AgSbF6 (20)
AgSbF6 (20)
AgSbF6 (20)
[{Cp*RhCl2}2] (5)
[{Cp*RhCl2}2] (5)
[{Cp*RhCl2}2] (5)
employed
(3bh/4bh = 2.7:1).[13a]
13
The Cp*CoIII catalyst exhibited
much superior site selectivity with
both aryl and alkyl internal alkynes
(2h and 2i), and a broad range of
unsymmetrically substituted O-acyl
oximes were converted into the
desired products 3ah–3ki with
[a] Reactions were run using 1a (0.15 mmol) and 2a (0.18 mmol) in ClCH2CH2Cl unless otherwise
noted. [b] Combined yield of 3aa and 4aa determined by 1H NMR analysis with 1,1,2,2-tetrachloro-
ethane as the internal standard. [c] Yield of isolated product after column chromatography on silica gel.
[d] The reaction was run in MeOH (reaction conditions reported in Ref. [13a,b]).
[Cp*Co(C6H6)][PF6]2 combined with KOAc at 1208C
afforded the desired annulated product 3aa and its isomer
4aa in 46% yield and good selectivity (3aa/4aa = 14:1;
> 20:1 site selectivity and in 45–97% yield.
As the Cp*RhIII complex exhibited only modest to poor
reactivity with terminal alkynes,[15,16] we further examined the
synthetic utility of the Cp*CoIII catalyst with various terminal
alkynes and symmetrical O-acyl oximes. Aryl, alkyl, hetero-
aryl, and ferrocenyl terminal alkynes reacted smoothly with
O-acyl oxime 1n, giving the products 3na–3nr in 52–92%
yield (Scheme 3). The reaction could also be run on gram
scale without difficulty, and 3nb was then obtained in 88%
yield. Regarding the scope of symmetrical O-acyl oximes, 1o–
1u gave 3oa–3ub in 72–81% yield. The ortho-substituted
bicyclic O-acyl oxime 1v gave 3vb in 73% yield, and the
benzophenone-derived O-acyl oxime 1w also afforded the
corresponding product in excellent yield (3wb, 98%). With
1w and 2b, we attempted to reduce the catalyst loading. The
reaction proceeded smoothly with 5.0 mol% of the cobalt
catalyst, and 3wb was obtained in 97% yield. Decreasing the
À
entry 1). The less hindered C H bond was thus selectively
functionalized under Cp*CoIII catalysis. In situ generation of
an active catalyst using [Cp*Co(CO)I2] and cationic Ag salts
led to higher reactivity (entries 2–5), and AgSbF6 afforded the
best result (82% yield, 17:1 selectivity; entry 5). Other bases
were less effective (entries 6–8). In the absence of KOAc, the
yield of 3aa decreased (55% yield; entry 9). We also
evaluated the catalytic activity of Cp*RhIII complexes under
several conditions to investigate the difference between CoIII
and RhIII. Under the reaction conditions reported for internal
alkynes (acetate bases in MeOH,[13a,b] 60–808C), no reaction
occurred (entries 10 and 11). When AgSbF6 and carboxylate/
carbonate bases were used in 1,2-dichloroethane at 1208C, the
annulated products were obtained in 9–28% yield, but the
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Scheme 3. Variation of terminal alkynes 2. Reaction conditions:
1 (0.15 mmol), 2 (0.18 mmol), [Cp*Co(CO)I2] (10 mol%), AgSbF6
(20 mol%), and KOAc (20 mol%) in ClCH2CH2Cl at 1208C for 24 h
unless otherwise noted. Yields of isolated 3 after purification by
column chromatography on silica gel are given. [a] The yield in
parentheses was obtained using 1n (5.0 mmol, 1.06 g) and 2b
(6.0 mmol). [b] CsOAc (20 mol%) instead of KOAc. 1 (0.10 mmol) and
2 (0.15 mmol) were used.
Scheme 2. Variation of unsymmetrical O-acyl oximes 1. Reaction
conditions: 1 (0.15 mmol), 2 (0.18 mmol), [Cp*Co(CO)I2] (10 mol%),
AgSbF6 (20 mol%), and KOAc (20 mol%) in ClCH2CH2Cl at 1208C for
24 h unless otherwise noted. Combined yields of isolated 3 and its
regioisomer 4 are given. The numbers in parentheses correspond to
the ratios of 3/4 determined by 1H NMR analysis of the crude mixture.
[a] CsOAc (20 mol%) instead of KOAc. 1 (0.10 mmol) and 2
(0.15 mmol) were used. [b] 808C. [c] 1008C. Cy =cyclohexyl.
Scheme 4. H/D exchange experiments under a) Cp*CoIII catalysis and
b) Cp*RhIII catalysis.
ysis was confirmed by deuterium exchange experiments
(Scheme 4). When O-acyl oxime 1a was subjected to the
optimized reaction conditions using Cp*CoIII in the presence
of CD3CO2D, selective deuterium incorporation was
observed at the less hindered position (37%D vs. 3%D;
catalyst loading to 2.5 mol% resulted in diminished reactivity,
but an acceptable yield (82%) was still achieved.
À
The high site selectivity of the C H bond activation step
under Cp*CoIII catalysis in comparison with Cp*RhIII catal-
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Scheme 4a). On the other hand, the Cp*RhIII catalyst
promoted non-selective H/D exchange under the same
conditions (34%D vs. 36%D; Scheme 4b). These results
clearly indicate that the Cp*CoIII catalyst differentiates more
efficiently between the substituents in unsymmetrical meta-
substituted O-acyl oximes than Cp*RhIII. We assume that the
steric repulsion between the Cp* ligand and the substrate is
larger with the Cp*CoIII catalyst than with the Cp*RhIII
catalyst as the ionic radius of cobalt is smaller than that of
rhodium.[17] However, further mechanistic studies are
required to clarify the precise origin of the high site
selectivity.
The Cp*CoIII catalyst exhibited much higher site selectivity
for unsymmetrical O-acyl oximes and higher reactivity
towards terminal alkynes than the Cp*RhIII catalyst. An
À
oxidizing directing group bearing an N O bond was success-
fully utilized as an internal oxidant in this process. Further
mechanistic studies as well as investigations to apply the
unique catalytic activity of Cp*CoIII to other processes are
actively ongoing in our laboratory.[20]
Acknowledgements
Possible reaction pathways to form isoquinolines 3 are
shown in Figure 1. Coordination of O-acyl oxime 1a to the
This work was supported in part by the ACT-C program from
JST, a Grant-in-Aid for Scientific Research on Innovative
Areas, The Asahi Glass Foundation, and the Naito Founda-
tion (S.M.).
À
Keywords: C H activation · cobalt · isoquinolines ·
transition-metal catalysis
How to cite: Angew. Chem. Int. Ed. 2015, 54, 12968–12972
Angew. Chem. 2015, 127, 13160–13164
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À
À
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À
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À
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À
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À
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[11] For selected examples of Cp*RhIII catalyzed redox-neutral C H
[15] 1,3-Dienes were used as alternative substrates to overcome the
difficulty associated with using terminal alkyl alkynes in
combination with Cp*RhIII catalysis: see Ref. [13f].
À
bond activation/annulation reactions that employ directing
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[16] A few terminal alkynes were successfully used as substrates in
the reaction of benzophenone-derived oximes under RuII
catalysis; see Ref. [14d]. When we used a less reactive meta-
substituted oxime and terminal alkyne 2a, however, the RuII
catalyst [{RuCl2(p-cymene)}2] gave the corresponding isoquino-
lines in less than 5% yield and poor 3aa/4aa ratios (1.2:1).
[17] The steric properties of substituted cyclopentadienyl ligands
affect the site, regio-, and diastereoselectivity of RhIII catalyzed
À
C H activation reactions. For systematic studies of these effects
in dihydroisoquinolone synthesis and cyclopropanation, see:
a) T. K. Hyster, D. M. Dalton, T. Rovis, Chem. Sci. 2015, 6, 254;
b) T. Piou, T. Rovis, J. Am. Chem. Soc. 2014, 136, 11292.
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[19] The 6p electrocyclization mechanism was proposed for RhI
catalysis; see: a) D. A. Colby, R. G. Bergman, J. A. Ellman, J.
Am. Chem. Soc. 2008, 130, 3645; see also Ref. [14b].
[20] Editorial Note (15.9.2015): Two very closely related papers were
submitted almost simultaneously to this one; see: H. Wang, J.
Koeller, W. Liu, L. Ackermann, Chem. Eur. J. 2015, 21, DOI:
10.1002/chem.201503624 and M. Sen, D. Kalsi, B. Sundararaju,
Chem. Eur. J. 2015, 21, DOI: 10.1002/chem.201503643.
À
[12] For examples of isoquinoline synthesis by C H activation with
stoichiometric amounts of external oxidants, see a review: a) R.
He, Z.-T. Huang, Q.-Y. Zheng, C. Wang, Tetrahedron Lett. 2014,
55, 5705; for pioneering reports, see also: b) T. Fukutani, N.
Umeda, K. Hirano, T. Satoh, M. Miura, Chem. Commun. 2009,
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12050.
Received: August 19, 2015
Published online: September 28, 2015
12972 www.angewandte.org
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Angew. Chem. Int. Ed. 2015, 54, 12968 –12972