Rhodium(III)-catalyzed isoquinolone synthesis: The N-O bond as a handle for C-N bond formation and catalyst turnover

Article abstract of DOI:10.1021/ja102571b

An external-oxidant-free process to access the isoquinolone motif via cross-coupling/cyclization of benzhydroxamic acid with alkynes is described. The reaction features a regioselective cleavage of a C-H bond on the benzhydroxamic acid coupling partner as well as a regioselective alkyne insertion. Mechanistic studies point out the important involvement of a N-O bond as a tool for C-N bond formation and catalyst turnover.

Full text of DOI:10.1021/ja102571b

Published on Web 04/30/2010
Rhodium(III)-Catalyzed Isoquinolone Synthesis: The N-O Bond as a Handle
for C-N Bond Formation and Catalyst Turnover
Nicolas Guimond,* Christina Gouliaras, and Keith Fagnou
Centre for Catalysis Research and InnoVation, Department of Chemistry, UniVersity of Ottawa, 10 Marie Curie,
Ottawa, Ontario K1N 6N5, Canada
Received March 26, 2010; E-mail: nguim025@uottawa.ca
Table 1. Selected Observations during Reaction Developmenta
The abundance of nitrogen-containing heterocycles in biologi-
cally active molecules has occasioned many efforts for their
synthesis and functionalization.1 As a result, direct approaches
toward their construction have become competitive with more
traditional protocols based on substrate preactivation. Indeed,
methods involving C-H bond cleavage and subsequent C-N bond
formation are emerging as attractive alternatives (Scheme 1).2
However, such strategies generally require an external oxidant to
account for the change in oxidation state of the C-H bond and to
enable catalyst turnover. In a recent elegant report,3 Hartwig
addressed this issue using a N-O bond contained in the substrate
as a built-in oxidant.4 This indole formation was the first example
of a non-nitrene-based5 redox neutral intramolecular amination
achieved from C-H and N-X coupling partners. In this com-
munication, we wish to disclose an intermolecular and mechanisti-
cally distinct process that affords the isoquinolone motif via Rh(III)-
catalyzed annulation of benzhydroxamic acids with alkynes. This
external-oxidant-free process strategically utilizes a N-O bond as
an instrument for C-N bond formation and catalyst release.
1H NMR yield
3a + 4a
1H NMR ratio
3a:4a
Entry
Solvent
additive (equiv)
1
2
3
4
DMF
DMF
MeOH
MeOH
Cu(OAc)2 ·H2O (2)
CsOAc (2)
CsOAc (2)
89
1:1.1
1:20
1:20
1:20
38
97 (92)b
97 (90)b
CsOAc (0.3)
a 1a (1 equiv), 2a (1.1 equiv), [Cp*RhCl2]2 (2.5 mol %), additive (x
equiv), solvent (0.2 M), 60 °C, 16 h. b Isolated yield.
With this set of conditions in hand, the scope of isoquinolone
formation was demonstrated with a variety of substituted benzhydrox-
amic acids. As shown in Table 2, the reaction provides the desired
isoquinolones regardless of the electron-donating or -withdrawing
character of the benzhydroxamic acid substituents. Additionally, when
meta-substituted benzohydroxamic acids are used, the arene rhodation
occurs at the less hindered site, providing exclusively the C-7
substituted regioisomer (4e, 4f). Also, both symmetrical and unsym-
metrical alkynes are tolerated as coupling partners.7 Moreover, the
insertion of an aryl-alkyl disubstituted alkyne occurs regioselectively
with the sp2 center being installed at the 3-position. Of note, these
mild and copper-free conditions allow an alkyne bearing a pyridyl
group to undergo the isoquinolone formation (4i).
Scheme 1. Heterocycles via C-H Cleavage/C-N Formation
Table 2. Reaction Scopea
Pursuing our interest in heterocycle formation, we sought to use
an oxidative coupling approach analogous to those employed by
Satoh and Miura2a,b as well as our group2c,d to gain entry to different
nitrogen-containing heterocycles. We postulated that the isoqui-
nolone motif could be accessed using a benzamide-derived starting
material.6 Inspired by Yu’s work in direct amination,2n we reasoned
that benzhydroxamic acids could serve as a directing group for C-H
functionalization as well as predisposing the substrate toward C-N
reductive elimination. However, initial attempts toward the forma-
tion of isoquinolone 3a resulted in product mixtures (Table 1, entry
1). Interestingly, the major product (4a) of the reaction had
undergone N-O bond cleavage. Considering that an additional
synthetic step is usually required to achieve this reduction,2n we
decided to further explore this direct reaction pathway to obtain
4a in one step. To our delight, replacing Cu(OAc)2 ·H2O by a
catalytic amount of base and using methanol as solvent revealed
that 4a could be obtained in high yield (Table 1, entry 2-4).
a Isolated yields. b Reaction conducted in a sealed tube at 100 °C for
40 h. c Isolated as a 20:1 mixture of regioisomers. d 2 equiv of CsOAc
used.
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6908 J. AM. CHEM. SOC. 2010, 132, 6908–6909
10.1021/ja102571b  2010 American Chemical Society

C O M M U N I C A T I O N S
The absence of added oxidant and the loss of the N-methoxy
substituent in the isoquinolone product prompted us to probe the
mechanism of this redox neutral process. The role of the N-methoxy
group was initially evaluated by carrying out two experiments in
deuterated methanol, the first with 1a and the second with
benzamide. In both cases, deuterium was incorporated exclusively
ortho to the directing group (eqs 1 and 2). In addition, no cleavage
of the N-O bond was observed with 1a. These results suggest that
the first step of the mechanism is a reversible cyclometalation.8
Also, the integrity of the N-methoxy group is inconsistent with a
mechanism involving N-O bond oxidative addition as has previ-
ously been demonstrated in Hartwig’s system.3 Next, a reaction
starting from benzamide was run in the presence of 2a and 20 mol
% of Rh(III) (eq 3). From this experiment, 71% of the starting
material was recovered, along with 6% of the benzannulation
product 5.9 No formation of isoquinolone 4a was observed,
signifying that the N-methoxy group is a prerequisite for C-N bond
formation. Lastly, to determine whether the N-O bond simply acts
as an oxidant for Rh(I) after C-N bond reductive elimination, 1a
and 2b were reacted in the presence of 3a. No formation of 4a
from 3a was observed (eq 4), indicating that N-O bond cleavage
happens intramolecularly with the substrate on which C-N bond
formation occurs.
In conclusion, we have developed a conceptually new approach
to C-N bond formation from benzhydroxamic acid precursors. This
redox neutral isoquinolone synthesis operates under mild conditions,
is not sensitive to air or moisture, and does not require an external
oxidant. This interesting reactivity should find a broader use in the
formation and functionalization of other heterocycles.
Acknowledgment. We thank NSERC, the University of Ottawa,
Eli Lilly, Amgen, AstraZeneca, and the Sloan Foundation (fellow-
ship, K.F.). N.G. thanks NSERC for a graduate student scholarship.
C.G. thanks OGS for a graduate student scholarship. Dr. David R.
Stuart is acknowledged for numerous fruitful discussions. We also
thank Prof. A. Beauchemin and the Fagnou group for their help
throughout the preparation of this manuscript. Prof. Keith Fagnou
passed away unexpectedly on November 11, 2009.
Supporting Information Available: Detailed experimental proce-
dures and characterization data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
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The postulated mechanism is presented in Scheme 2.10 The
mechanistic information revealed above is consistent with the first
step being a reversible arene rhodation providing 6. The alkyne
can then undergo an insertion into the Rh-C bond, forming
intermediate 7. At this point, a concerted or stepwise C-N bond
forming/N-O bond cleaving event can occur, affording the desired
isoquinolone and releasing the catalyst. Computational and experi-
mental studies are underway to further establish the nature of this
last catalytic step.
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in alkyne dimerization.
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Scheme 2. Postulated Mechanism
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