Rhodium(III)-catalyzed cyclization-olefination of N-acetoxyl ketoimine-alkynes

Article abstract of DOI:10.1021/ol301371p

N-Acetoxyl ketoimine-alkynes undergo Rh(III)-catalyzed oxidative olefination to afford (2-acetoxymethyl)isoquinolines bearing an ortho-olefinated aryl group via a sequence that involves (1) Rh(III)-catalyzed alkyne cyclization with intramolecular 1,3-acetoxyl migration and (2) isoquinoline-directed ortho C-H olefination.

Full text of DOI:10.1021/ol301371p

ORGANIC
LETTERS
2012
Vol. 14, No. 13
3400–3403
Rhodium(III)-Catalyzed
CyclizationÀOlefination of N-Acetoxyl
Ketoimine-Alkynes
Peng Zhao, Fen Wang, Keli Han, and Xingwei Li*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023,
P. R. China
xwli@dicp.ac.cn
Received May 17, 2012
ABSTRACT
N-Acetoxyl ketoimine-alkynes undergo Rh(III)-catalyzed oxidative olefination to afford (2-acetoxymethyl)isoquinolines bearing an ortho-olefinated
aryl group via a sequence that involves (1) Rh(III)-catalyzed alkyne cyclization with intramolecular 1,3-acetoxyl migration and (2) isoquinoline-
directed ortho CÀH olefination.
Construction of CÀC, CÀN, and CÀO bonds via metal-
catalyzed CÀH activation has attracted increasing atten-
tion for the past several decades owing to the ubiquity
of CÀH bonds.1 By taking advantage of this strategy, a
large number of synthetic methods have been developed
and they have been effectively applied to the synthesis of
complex structures.2 Oxidative CÀH olefination via a
CÀH activation pathway has been extensively studied
since the 1980s,3 and many systems have been developed
using palladium4 and ruthenium5 catalysts. Recently
Miura and Satoh,6 Glorius,7 Li,8 and others9 have reported
that Rh(III) can catalyze the olefination of a number
of arenes via cyclometalation with high efficiency, high
selectivity, and high functional group tolerance.1a,b In
addition, olefination reactions catalyzed by Rh(III) and
Pd(II) can be complementary in selectivity since dif-
ferent reaction mechanisms may be followed.9b Despite
the success, this strategy usually requires a preinstalled
heteroatom directing group and has little to do with the
(1) For selected reviews, see: (a) Song, G.; Wang, F.; Li, X. Chem.
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2011, 40, 4740. (c) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111,
1215. (d) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147.
(e) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Commun. 2010, 46, 677. (f) Engle,
K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 201210.1021/
ar200185g.
(2) (a) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int.
Ed. 2009, 48, 9792. (b) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q.
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2011, 76, 3024. (b) Ueyama, T.; Mochida, S.; Fukutani, T.; Hirano, K.;
Satoh, T.; Miura, M. Org. Lett. 2011, 13, 706. (c) Mochida, S.; Hirano,
K.; Satoh, T.; Miura, M. Org. Lett. 2010, 12, 5776.
(7) (a) Patureau, F. W.; Nimphius, C.; Glorius, F. Org. Lett. 2011, 13,
6346. (b) Rakshit, S.; Grohmann, C.; Besset, T.; Glorius, F. J. Am.
Chem. Soc. 2011, 133, 2350. (c) Patureau, F. W.; Besset, T.; Glorius, F.
Angew. Chem., Int. Ed. 2011, 50, 1064. (d) Patureau, F. W.; Glorius, F.
J. Am. Chem. Soc. 2010, 132, 9982.
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Lett. 2011, 13, 5808. (b) Wang, F.; Song, G.; Du, Z.; Li, X. J. Org. Chem.
2011, 76, 2926. (c) Wang, F.; Song, G.; Li, X. Org. Lett. 2010, 12, 5430.
(d) Li, X.; Zhao, M. J. Org. Chem. 2011, 76, 8530.
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(b) Gong, T.-J.; Xiao, B.; Liu, Z.-J.; Wan, J.; Xu, J.; Luo, D.-F.; Fu, Y.;
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132, 14137. (e) Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int.
Ed. 2010, 49, 6169. (f) Lu, Y.; Wang, D.-H.; Engle, K. M.; Yu, J-.Q. J.
Am. Chem. Soc. 2010, 132, 5916. (g) Wasa, M.; Engle, K. M.; Yu, J-.Q. J.
Am. Chem. Soc. 2010, 132, 3680. (h) Shi, B.-F.; Zhang, Y.-H.; Lam,
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r
10.1021/ol301371p
Published on Web 06/12/2012
2012 American Chemical Society

construction of a new framework prior to olefination
(Figure 1).1a,b
Ag2CO3 was selected as an oxidant, and a maximum yield
of 3ad (68%) was obtained when this reaction was con-
t
ducted in AmOH (entry 9). Interestingly, reactions per-
formed at a higher or lower temperature all resulted in a
lower isolated yield of 3ad. NMR analysis of product 3ad
showed that the olefination occurred at the ortho position
of the phenyl group, instead of at the 4-position of the
isoquinoline ring, which we would expect if the rhodium
aryl intermediate generated is directly functionalized by an
olefin. Here the rhodium aryl intermediate generated via
a cyclizationÀacetoxyl shift process preferentially under-
goes a relatively fast protonolysis to give isoquinoline 4a,
which constitutes an intermediate for further olefination
via cyclometalation (vide infra).
Figure 1. Different strategies in Rh(III)-catalyzed oxidative
olefination.
With the optimized mono-olefination reaction in hand,
we set out to explore the scope and limitations of this
reaction (Scheme 1). Imine 1a readily coupled with a series
of acrylates in good yield (65À86%), together with the
simple cyclization product 4a. Styrenes are also viable
coupling partners, and coupling with the simple and para-
substituted styrenes afforded products 3agÀ3al in yields
ranging from 57% to 68%. The coupling of 1a is less efficient
when acrylonitrile was used (27% yield), where 4a is the
major product. Different alkyne-imine substrates were
explored in the coupling with n-butyl acrylate, and this cou-
pling reaction proceeded well when para- andortho-halogen,
OMe, and Me groups were introduced into the phenyl ring
of the imine substrate, and the desired products (3bcÀ3fc)
were isolated in high yields. However, the olefination effi-
ciency is decreased when a para-bromo group was intro-
duced, and product 3gc was isolated in 40% yield, although
no Heck coupling product was detected. Under the same
conditions, imine substrates bearing an alkyl alkyne unit
only afforded the cyclizationÀacetoxyl migration product.
As a continuation of our efforts in Rh(III)-catalyzed
oxidative olefination of arenes,8 we aim to deliver molec-
ular complexity by executing a series of tandem reactions.
Our objective is to construct a framework and generate a
directing group for subsequent CÀH olefination under the
same conditions (Figure 1). This should broaden the scope
and applications of Rh(III) catalysis in the construction of
complex structures. We now report Rh(III)-catalyzed
oxidative coupling between olefins and alkynes bearing
an N-acetoxyl ketoimine functionality, leading to CÀN
and CÀC bond formation.
We initiated our studies with the coupling between
N-acetoxyl imine 1a and tert-butyl acrylate (2d) (Table 1).
Recent work indicated when catalyzed by Pd and Rh, the
NÀOR (R = H, OMe, Ac, and Piv) bond in imine and
amide substrates can act as an internal oxidant in the
external oxidant-free coupling with alkenes and alkynes.10
Although the NÀO bond in 1a might serve this purpose,
after extensive screenings of the external oxidant-free
coupling with 2d using palladium(II) and rhodium(III)
catalysts, no desired olefinated isoquinoline could be
detected. Interestingly, when PdCl2 was applied as a
catalyst (Table 1, entry 1), only a cyclization product (4a)
was isolated(32% yield), which was generatedasa resultof
a redox-neutral process that involves metal-catalyzed
cyclization with a formal 1,3-acetoxyl migration. The ob-
servation of 4a indicates that Rh-promoted cyclization did
occur but the rhodium(III) aryl species was not functiona-
lized by the olefin. SincetheOAc group isretainedin4a, we
reasoned that a stoichiometric amount of oxidant is neces-
sary for a subsequent olefination reaction. However, this
was not achieved when various Cu(II) and Ag(I) oxidants
were introduced under palladium catalysis. By switching to
[RhCp*(MeCN)3](SbF6)2 (A) as a catalyst (5 mol %) using
Ag(I) oxidants, the cyclizationÀolefination product (3ad)
started to be obtained (entries 3À8). Further improve-
ment of the efficiency of this coupling was achieved when
Table 1. Screening of the Reaction Conditionsa
yield of
yield of
entry
cat.
oxidant
solvent
3ad (%)
4a (%)
1b
2b
3
PdCl2
À
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
THF
0
32
Pd(OAc)2
À
trace
trace
35
trace
18
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Cu(OAc)2
Ag2CO3
AgOAc
Ag2O
4
28
5
30
21
6
49
17
7
Ag2CO3
Ag2CO3
Ag2CO3
37
15
8
PhCl
tAmOH
35
21
9
68
12
a Reaction conditions: 1a (0.20 mmol), 2a (0.22 mmol), catalyst
(5À10 mol %), oxidant (0.40 mmol for Cu(OAc)2 or AgOAc and 0.30
mmol for Ag2CO3), solvent (2 mL), sealed tube under nitrogen, 90 °C,
12 h, isolated yield. b 10 mol % of the catalyst was used. c A =
[RhCp*(MeCN)3](SbF6)2, 5 mol %.
(10) (a) Guimond, N.; Gouliaras, C.; Fagnou, K. J. Am. Chem. Soc.
2010, 132, 6908. (b) Rakshit, S.; Grohmann, C.; Besset, T.; Glorius, F.
J. Am. Chem. Soc. 2011, 133, 2350. (c) Too, P.-C.; Wang, Y.-F.; Chiba,
S. Org. Lett. 2010, 12, 5688. (d) Zhang, X.; Chen, D.; Zhao, M.; Zhao, J.;
Jia, A.; Li, X. Adv. Synth. Catal. 2011, 353, 719. (e) Wu, J.; Cui, X.; Chen,
L.; Jiang, G.; Wu, Y. J. Am. Chem. Soc. 2009, 131, 13888.
Org. Lett., Vol. 14, No. 13, 2012
3401

To establish the intermediacy of the cyclization product
4a in the olefination of 1a, an isolated sample of 4a was
allowed to react with 2c under the standard conditions.
The expected product 3ac was isolated in 91% yield (eq 1).
This result confirmed that 4a is an intermediate that leads
to olefination. A related Rh(III)-catalyzed olefination of
2-phenylpyridines has been reported by Miura and Satoh,
where selective mono- and diolefination has been achieved
by careful control of the stoichiometry of the olefin and of
other reaction conditions.11
but no corresponding simple cyclization product was
detected.
Scheme 1. Mono-olefination of Imine-Alkynesa
Formation of product 4a suggests that [RhCp*-
(MeCN)3] (SbF6)2 (A) is intrinsically electrophilic and
can activate the alkyne toward nucleophilic attack. Indeed,
when no olefin or oxidant is present, the Rh(III)-catalyzed
cyclization of 1a afforded 4a in 65% isolated yield (110 °C,
tAmOH). Under these conditions various alkyne sub-
strates are efficiently converted to the isoquinoline pro-
ducts in 44À76% yield (Scheme 2), and both alkyl and aryl
alkyne units in the substrate can be tolerated. Zhang and
co-workers have reported that silver-catalyzed cyclization
of N-acetoxyl aldimine-alkyne afforded an isoquinolone.12
While in their report acetoxyl shift is also involved, it is
followed by elimination of an acetaldehyde to afford
an NH isoquinolone product. In addition, the Au(I)-cata-
lyzed cyclization of related alkyne-oximes afforded isoqui-
noline N-oxides without any cleavage of the NÀO bond.13
Scheme 2. Cyclization of Imine-Alkynea,b
a Conditions: alkyne (0.2 mmol), olefin (1.05 equiv), Ag2CO3 (1.5 equiv),
tAmOH (3 mL), 90 °C, 12 h, under Ar. bIsolated yield.
a Conditions: alkyne (0.20 mmol), tAmOH (2 mL), [RhCp*(MeCN)3]-
(SbF6)2 (5 mol %), 110 °C, 16 h. bIsolated yield.
In addition to mono-olefination, selective diolefina-
tion can also be achieved when imine-alkyne substrates
bearing a simple or a para substituted phenyl group were
allowed to react with an excess of both n-butyl acrylate and
Ag2CO3. Thus products 5acÀ5fc were isolated in good
yields (eq 2). In addition to the diolefination product, the
mono-olefination product was isolated as a side product,
To probe the mechanism of the acetoxyl migration,
crossover experiments were performed under the standard
cyclization conditions for 1b and 1k. HPLC analysis of the
reaction mixture reveals that only 4b and 4k were gener-
ated with no crossover (eq 3). These results confirmed that
the formal 1,3-migration of the acetoxyl group is intra-
molecular. We noted that intramolecular migration of
(12) Gao, H.; Zhang, J. Adv. Synth. Catal. 2009, 351, 85.
(13) Yeom, H. S.; Lee, Y.; Lee, J. E.; Shin, S. Org. Biomol. Chem.
2009, 7, 4744.
(11) Umeda, N.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem.
2009, 74, 7094.
3402
Org. Lett., Vol. 14, No. 13, 2012

carboxyl and allyl groups has been reported in metal-
catalyzed cyclization reactions.14
Scheme 3. Proposed Mechanism of the Cyclization of Imine-
Alkynes
On the basis of these results, a plausible mechanism was
proposed (Scheme 3). Activation of the alkyne by coordi-
nation to a Rh(III) species is followed by intramolecular
imine attack to give a metal-stabilized Zwitterionic species (B).
Being adjacent to the isoquinolinium nitrogen, the me-
thyl group is somewhat acidic15 and undergoes depro-
tonation by a catalytic amount of an adventitious base.
The resulting active methyleneisoquinolinene intermediate
(C) is proposed to undergo a 3,3-sigmatropic rearrange-
ment, resulting in concomitant NÀO cleavage and CÀO
formation. This Rh(III) aryl species (D) is protonolyzed to
regenerate the Rh(III) catalyst while furnishing the iso-
quinoline product. Under rhodium-catalyzed oxidative
olefination conditions, the failure to observe any olefina-
tion at the C(4) position in the isoquinoline ring suggests
that protonolysis of the RhÀC bond generated from
Rh-promoted cyclization is irreversible and faster than
olefin insertion into the RhÀC bond.
an N-OAc imine functionality. This reaction produced
isoquinolines bearing an ortho-olefinated 3-aryl group as
a result of CÀN and CÀC coupling. An acetoxymethyl-
isoquinoline has been established as an intermediate via a
cyclizationÀ1,3-acetoxyl migration process. This protocol
allows the synthesis of functionalized isoquinolines under
simple conditions and provides building blocks that may
find applications in the synthesis of complex structures.
Acknowledgment. We thank the Dalian Institute of
Chemical Physics, Chinese Academy of Sciences for finan-
cial support.
In summary, we have achieved rhodium(III)-catalyzed
oxidative coupling between olefins and aryl alkynes bearing
Supporting Information Available. Detailed synthetic
procedures and characterization data of all new products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) (a) Komeyama, K.; Takahashi, K.; Takaki, K. Org. Lett. 2008,
10, 5119. (b) Ueda, M.; Sato, A.; Ikeda, Y.; Miyoshi, T.; Naito, T.;
Miyata, O. Org. Lett. 2010, 12, 2594.
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2009, 15, 5535.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 13, 2012
3403