has been drawn to the potential chemical reactivity of readily
available aryl ketoxime derivatives.6 Herein, we wish to
report the preliminary result of an efficient C-C and C-N
bond formation sequence7 to prepare highly substituted
isoquinolines utilizing aryl ketone O-acetyloximes and
3-phenylisoxazol-5-ones with internal alkynes under the
catalytic redox-neutral8,9 [Cp*RhCl2]2-NaOAc system, where
the N-O bond of oxime derivatives could work as an internal
oxidant to maintain the catalytic cycle.
for this transformation (entries 4 and 5). The reaction of
O-methyloxime 1a′ was sluggish, affording isoquinoline 1aa
in 13% yield with 64% recovery of oxime 1a′ even after
19 h (entry 6). This indicates that the leaving group reactivity
(as -OR1) is essential for this isoquinoline formation.
By utilizing the [Cp*RhCl2]2-NaOAc catalytic system
(Table 1, entry 2), the scope of the isoquinoline formation
was investigated (Table 2).12 The present process showed
wide substrate tolerance with internal alkynes (entries 1-5).
Insertion of an unsymmetrical alkyne, 1-phenyl-1-propyne
(2b), occurred regioselectively to provide 4-methyl-3-phe-
nylisoquinoline 3ab as a sole product (entry 1). Similarly,
3-phenyl-2-propyn-1-ol (2c) afforded isoquinoline 3ac with
high regioselectivity albeit in moderate yield that was
improved by protection of a hydroxy group with TBS (entries
2 and 3). The reactions with dialkyl-substituted alkynes also
proceeded smoothly (entries 4 and 5). As substituents on
the benzene ring of acetophenone O-acetyloxime 1, both
electron-donating and -withdrawing groups could be intro-
duced. This process could keep a C-Br bond intact (entries
8, 11, and 12). In the case of meta-substituted substrates,
regioisomeric mixtures were obtained where the sterically
less hindered C-H bond was preferentially cleaved (marked
in blue) (entries 12 and 13). This method allowed construc-
tion of a thieno[2,3-c]pyridine structure (entry 14). At the
C(1) position of isoquinolines 3, phenyl and alkenyl groups
as well as a methoxycarbonyl moiety could be installed
(entries 15-17). R-Tetralone O-acetyloxime (1n) was suc-
cessfully applied for preparing tricyclic isoquinoline 3na
(entry 18).
To obtain detailed mechanistic information of the present
catalytic process, several reactions were performed as shown
in Scheme 1. When O-acetyloxime 1a was treated in MeOD
in the absence of alkynes, deuteration of the ortho-positions
was observed with deacetylation (Scheme 1a). On the
contrary, the reaction in MeOD in the presence of alkyne
2a afforded isoquinoline 3aa-d without deuterium incorpora-
tion at the C(8) position (Scheme 1b). These results could
suggest that the C-H rhodation initiates the catalytic cycle
and is most likely the rate-determining step. It was rather
interesting that deuterium was incorporated into the methyl
group of isoquinoline 3aa-d (Scheme 1b), whereas it was
confirmed that treatment of isoquinoline 3aa under the
present catalytic conditions in MeOD did not result in
deuteration of the methyl group. These observations indicated
that deuterium incorporation into the methyl group of
isoquinoline 3aa might have occurred during the catalytic
ring formation process.13
Table 1. Optimization of Reaction Conditions
entry oximes additive solvent conditions yield of 3aab
1
2
3
4
5
6
1a
1a
1a
1a
1a
1a′
none
NaOAc MeOH
CsOAc MeOH
CsOAc t-BuOH 80 °C, 7 h
CsOAc DMF
MeOH
60 °C, 7 h
60 °C, 6 h
60 °C, 4 h
0c
82
80
14c
4c
80 °C, 23 h
60 °C, 19 h
NaOAc MeOH
13 (64)d
a Reactions were carried out on the scale of 0.3 mmol of 1a and 2a in
MeOH (0.2 M) under a N2 atmosphere. b Isolated yields. c NMR yields
from the crude mixture. d Recovery yield of 1a′.
We embarked on the investigation with reactions of
acetophenone O-acetyloxime (1a) and diphenylacetylene
(2a), and Table 1 lists representative data using [Cp*RhCl2]2
as a catalyst.10 Although no reaction was observed with only
[Cp*RhCl2]2 in MeOH (entry 1), addition of a metal acetate
as a cocatalyst (30 mol %) resulted in the formation of
isoquinoline 3aa in good yields at 60 °C (entries 2 and 3).11
Other solvents such as t-BuOH and DMF were not viable
(6) For recent reports on ortho-metallation of aryloxime derivatives, see:
(a) Sun, C.-L.; Liu, N.; Li, B.-J.; Yu, D.-G.; Wang, Y.; Shi, Z.-J. Org. Lett.
2010, 12, 184. (b) Thirunavukkarasu, V. S.; Parthasarathy, K.; Cheng, C.-
H. Angew. Chem., Int. Ed. 2008, 47, 9462. (c) Yu, W.-Y.; Sit, W. N.; Lai,
K.-M.; Zhou, Z.; Chan, A. S. C. J. Am. Chem. Soc. 2008, 130, 3304. (d)
Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am. Chem. Soc. 2006, 126, 9048.
(e) Desai, L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126,
9542.
(7) ForreportsonRh(III)-catalyzedoxidativeC-Hbondfunctionalization-C-N
bond formation sequence triggered by amido and indole N-H bonds, see:
(a) Hyster, T. K.; Rovis, T. J. Am. Chem. Soc. 2010, 132, 10565. (b) Rakshit,
S.; Patureau, F. W.; Glorius, F. J. Am. Chem. Soc. 2010, 132, 9585. (c)
Morimoto, K.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2010, 12, 2068.
(d) Mochida, S.; Umeda, N.; Hirano, K.; Satoh, T.; Miura, M. Chem. Lett.
2010, 39, 744. (e) Stuart, D. R.; Bertrand-Laperle, M.; Burgess, K. M. N.;
Fagnou, K. J. Am. Chem. Soc. 2008, 130, 16474.
Based on these results, a potential mechanistic possibility
was outlined in Scheme 2. It commences with ortho-C-H
activation of aryl ketone O-acetyloximes 1 with the aid of
the oxime sp2 nitrogen to give arylrhodium intermediate A,
(8) For a report on Rh(III)-catalyzed redox-neutral synthesis of isoqui-
nolones from benzhydroxamic acid derivatives and alkynes, see: Guimond,
N.; Gouliaras, C.; Fagnou, K. J. Am. Chem. Soc. 2010, 132, 6908
.
(9) For reports on Pd-catalyzed redox-neutral intramolecular aromatic
C-H amination processes of O-acyloximes for the synthesis of indoles,
see: (a) Tan, Y.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 3676. (b)
(12) All O-acetyloximes 1 in Table 2 were prepared from the corre-
sponding ketones by treatment with hydroxylamine followed by acetylation
of the resulting oximes. These processes could provide the desired anti
stereochemistry as a sole/major isomer (see Supporting Information).
(13) 6π-Electrocyclization was most likely ruled out from the possible
reaction pathways by the reactions of ortho-alkenyloxime; see Supporting
Information.
Chiba, S.; Zhang, L.; Sanjaya, S.; Ang, G. Y. Tetrahedron 2010, 66, 5692
(10) Rh(I) catalysts such as RhCl(PPh3)3 did not work at all for the
present process.
.
(11) (a) Li, L.; Brennessel, W. W.; Jones, W. D. Organometallics 2009,
28, 3492. (b) Davies, D. L.; Al-Duaij, O.; Fawcett, J.; Giardiello, M.; Hilton,
S. T.; Russell, D. R. Dalton Trans. 2003, 4132.
Org. Lett., Vol. 12, No. 24, 2010
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