Rh-Catalyzed Domino Addition-Enolate Arylation: Generation of 3-Substituted Oxindoles via a Rh(lll) Intermediate

Article abstract of DOI:10.1021/acs.orglett.5b01737

A Rh-catalyzed domino conjugate addition-arylation sequence via a Rh(III) intermediate is reported. This process involving a proposed intramolecular oxidative addition of a rhodium enolate was utilized to achieve the synthesis of 3-substituted oxindole derivatives in moderate to excellent yields.

Full text of DOI:10.1021/acs.orglett.5b01737

Letter
pubs.acs.org/OrgLett
Rh-Catalyzed Domino Addition−Enolate Arylation: Generation of
3‑Substituted Oxindoles via a Rh(lll) Intermediate
Young Jin Jang, Hyung Yoon, and Mark Lautens*
Davenport Research Laboratories, Department of Chemistry, University of Toronto, Toronto M5S 3H6, Canada
S
* Supporting Information
ABSTRACT: A Rh-catalyzed domino conjugate addition−arylation
sequence via a Rh(III) intermediate is reported. This process involving a
proposed intramolecular oxidative addition of a rhodium enolate was
utilized to achieve the synthesis of 3-substituted oxindole derivatives in
moderate to excellent yields.
and catalytic access to diverse oxindole derivatives that exhibit
ransition metal catalyzed α-arylation has attracted
Tconsiderable attention due to its versatility and utility in numerous biological activities.6
Although oxidative addition of Rh(I) is well documented,7
the synthesis of many medicinal targets.1 A myriad of catalytic
variants have been developed since Semmelhack’s seminal
report in 1973.2 Transition metal catalysts including palladium,
copper, and nickel are most widely used, and of these,
only a limited number of examples involve oxidative addition
into a carbon−halogen bond under mild conditions. In recent
years, Chatani8 and Cramer9 have demonstrated the utility of
Rh-catalyzed cascade processes involving oxidative addition of
Rh(I) species to access diverse building blocks.
palladium catalysts have been most thoroughly studied.3
A
major drawback of current methods resides in the use of strong
bases in the generation of enolate nucleophiles and, combined
with the use of transition metals that are prone to facile
oxidative addition, can limit functional group tolerance. In
addition, current methods often suffer from poor selectivity
toward monoarylation, leading to decreased yields.4 To
circumvent these problems, we sought to develop an alternative
α-arylation strategy with a broader scope and applicability.
In 2006, Hayashi reported a Rh-catalyzed cascade conjugate
addition−α-arylation sequence to ynamides using aryl-zinc
species (Scheme 1).5 Therein, a novel intramolecular oxidative
addition of a Rh(I) allenolate was proposed, generating
rhodacycle A en route to methylene oxindoles (Scheme 1a).
We hypothesized that through the use of more readily available
boronic acids and o-bromoaniline derived acrylamides, we
could access Rh(I) enolate species. This would allow efficient
Furthermore, the use of boron reagents provides a simple
way to incorporate diverse carbon-based functional groups. In
addition, organoboron reagents, in comparison to organozinc
reagents, are more compatible with protic solvents and are
more easily accessible.
To test this approach, 1a was treated with [Rh(COD)Cl]2
(2.5 mol %), PhB(OH)2 (1.5 equiv), and KOH (3 equiv) in a
dioxane/water (10:1) solution at 50 °C. After 3 h, 2a was
isolated in 21% yield from a mixture with 3 and 4, resulting
from β-hydride elimination via the Rh(I)-catalyzed Heck-type
process.10 Attempts to suppress these byproducts using
substrates such as 3 led to complex mixtures.
A series of optimization reactions were carried out in order to
improve the yield of 2a. The [Rh(COD)Cl]2 catalyst was found
to be superior compared to other dimeric rhodium species
(Table 1, entry 2). Increasing the temperature to 110 °C
provided a moderate increase in yield (entry 3). The use of
bidentate phosphine ligands such as ( )-BINAP significantly
increased the yield of 2a to 64% (entry 4). Switching to
Cs2CO3 further promoted the reaction and eliminated the need
for a phosphine ligand (entry 5). Switching to the
trifluoroborate salt showed a further increase in yield (entry
7). Finally, our optimized conditions were achieved by elevating
the temperature to 120 °C and decreasing the catalyst loading
to 1.25 mol %, providing an isolated yield of 84% (entry 9).
With the optimized conditions in hand, we examined the
scope of the reaction (Scheme 2). To probe the oxidative
Scheme 1. Oxindole Synthesis via Rh-Catalyzed Domino
Conjugate Addition−Arylation
Received: June 15, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01737
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Rh-Catalyzed Domino Conjugate Addition−Arylation: Optimization of Reaction Parameters
bd
,
entry
RhI dimer
[Rh(COD)Cl]2
Ar[B] source
base
temp (°C)
ligand
yield 1b (%)
c
1
2
3
4
5
6
7
8
9
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhBF3K
KOH
50
50
−
−
−
35
[Rh(COD)OH]2
KOH
21
[Rh(COD)Cl]2
KOH
110
110
110
110
110
110
120
40
[Rh(COD)Cl]2
KOH
BINAP
64
[Rh(COD)Cl]2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
−
−
74
[Rh(COD)Cl]2
78
[Rh(COD)Cl]2
PhBF3K
BINAP
74
[Rh(COD)Cl]2 (1.25 mol %)
[Rh(COD)Cl]2 (1.25 mol %)
PhBF3K
−
−
84
PhBF3K
89 (84)
a
b
See the Supporting Information for reaction details. Yields were determined by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as internal
c
d
standard. 3 equiv of base were used. Yield in parentheses represents isolated yields.
produced the desired oxindoles in excellent yields. Hetero-
Scheme 2. Rh-Catalyzed Domino Conjugate Addition−
a
aromatic (2m) and aliphatic (2n) boronic acids also gave
moderate yields. Different protecting groups on the nitrogen
can be used (2o, 2p), except for the −Boc group and the free
N−H amide which failed to undergo the desired trans-
formation. Lastly, the presence of a methyl group next to the
bromide impedes the reaction, and replacing the bromide with
an iodide (1r) or a chloride (1s) lowers the yield.
Arylation: Reaction Scope
To gain a better understanding of the reaction mechanism, a
number of control experiments were conducted (Scheme 3).
a
Scheme 3. Control Experiments
a
b
See the Supporting Information for reaction details. Isolated yield.
The first control experiment with a substrate lacking the
ortho bromo group (Scheme 3a) demonstrates that the halide
is necessary to achieve the ring formation. Additionally,
subjecting the product from conjugate addition-protonation
(6) under the optimized conditions does not generate the
enolate, illustrating that both the conjugate addition and the
oxidative addition process have to occur sequentially without
hydrolysis of the rhodium enolate (B). Based on these
observations we propose the following catalytic cycle (Scheme
4).
We speculate the Rh(I) species undergoes transmetalation
with the boronic acid to produce Rh−Ar species that
subsequently carborhodation onto 1a to produce intermediate
B. Intermediate B can undergo either oxidative addition to
produce intermediate C or β-hydride eliminate to produce
intermediate 3. Intermediate C will reductively eliminate to
furnish the desired oxindole and regenerate the active catalyst.
a
b
See the Supporting Information for reaction details. NMR yield;
yields were determined by 1H NMR spectroscopy using 1,3,5-
trimethoxybenzene as internal standard. Inseparable from byproducts;
see Scheme 5 for details.
c
addition process of the Rh-enolate, the electronics of the aryl
ring were varied. Electron-rich as well as electron-deficient
substrates gave moderate yields (2a−2e). Dihalogenated
acrylamides (2f, 2g) are tolerated with high fidelity to produce
halogenated oxindoles with no formation of Rh-catalyzed
Suzuki coupled products.11
A diverse array of boronic acids can be incorporated (2i−2l).
Electron-rich as well as electron-deficient boronic acids
B
DOI: 10.1021/acs.orglett.5b01737
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Notes
Scheme 4. Proposed Catalytic Cycle
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We would like to thank Dr. L. Zhang (Stanford University) and
D. Petrone (University of Toronto) for fruitful discussions and
guidance throughout the project. We would also like to thank
X. Hou (University of Toronto) for proofreading the
manuscript.
REFERENCES
■
(1) For selected examples of application of α-arylation in total
syntheses, see: (a) Carril, M.; SanMartin, R.; Churruca, F.; Tellitu, I.;
Dominguez, E. Org. Lett. 2005, 7, 4787. (b) Honda, T.; Namiki, H.;
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(2) Semmelhack, M. F.; Stauffer, R. D.; Rogerson, T. D. Tetrahedron
Lett. 1973, 14, 4519.
On the other hand, production of intermediate 3 will produce
the Rh−H species which may undergo hydrolysis to regenerate
the active catalyst, Rh−OH, or it may consume either of the
two substrates 1a or 3 leading to 4 or 2a, respectively. Trace
amounts of compounds 3 and 4 are observed in the reaction
mixture in a combined yield of <5%.
Further product derivatization experiments were performed
to demonstrate the synthetic utility of the oxindoles (Scheme
5). A Suzuki reaction of the aryl bromide 2g was accomplished
(3) (a) Hamann, B.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119,
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Kagawa, N.; Kakiuchi, K.; Harada, Y.; Fukumoto, Y.; Chatani, N.;
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a
Scheme 5. Derivatization of Oxindole Products
(8) Harada, Y.; Nakanishi, J.; Fujihara, H.; Tobisu, M.; Fukumoto, Y.;
Chatani, N. J. Am. Chem. Soc. 2007, 129, 5766.
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a
b
See the Supporting Information for reaction details. Isolated yield.
(10) Lautens, M.; Mancuso, J.; Grover, H. Synthesis 2004, 12, 2006.
(11) Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2005, 7, 2229.
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to produce the phenylated oxindole 7 in 88% yield. −MOM
protected acrylamide (1s) underwent a stepwise cyclization and
allylation to form oxindole 8 in 67% yield over two steps.
In conclusion, we developed an alternative method for the
rhodium-catalyzed domino conjugate addition−arylation se-
quence to furnish various 3-substituted oxindole derivatives.
Further studies will be carried out to expand the scope and
versatility of these types of cascade reactions.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and full compound characterization
data. The Supporting Information is available free of charge on
the ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01737.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: mlautens@chem.utoronto.ca.
C
DOI: 10.1021/acs.orglett.5b01737
Org. Lett. XXXX, XXX, XXX−XXX