Direct C-arylation of free (NH)-indoles and pyrroles catalyzed by Ar-Rh(III) complexes assembled in situ

Article abstract of DOI:10.1021/ja050279p

Ar-Rh(III) pivalate complexes assembled in situ from the reaction of [RhCl(coe)₂]₂ (coe = cis-cyclooctene), [p-(CF₃)C₆H₄]₃P, and CsOPiv effectively catalyzed the direct C-arylation of free (NH)-indoles and (NH)-pyrroles in good yields and with high regioselectivity. The reaction displayed excellent functional group compatibility and low moisture sensitivity. Kinetics studies support a mechanism involving phosphine displacement by indole in complex 2 (resting state of the catalyst), followed by a rate-limiting C-H bond metalation. Copyright

Full text of DOI:10.1021/ja050279p

Published on Web 03/16/2005
Direct C-Arylation of Free (NH)-Indoles and Pyrroles Catalyzed by Ar-Rh(III)
Complexes Assembled In Situ
Xiang Wang, Benjamin S. Lane, and Dalibor Sames*
Department of Chemistry, Columbia UniVersity, 3000 Broadway, New York, New York 10027
Received January 15, 2005; E-mail: Sames@chem.columbia.edu
Scheme 1. A New Approach to C-Arylation of (NH)-Azoles (route
B)
The direct C-arylation of free (NH)-azoles holds significant
synthetic potential as it eliminates the need for introducing
protecting groups and reactive functionalities prior to C-C forma-
tion, thereby enabling direct access to valuable heteroaromatic
compounds. Such methods require selective targeting of C-H bonds
in the presence of a reactive N-H functionality.1 Faced with this
challenge, we have recently employed azolylmagnesium or zinc
salts as “protected” and “activated” substrates in a palladium (or
cobalt)-catalyzed coupling with haloarenes (Scheme 1, route A).2,3
However, due to the presence of the N-M moiety (M ) Mg, Zn),
this approach suffered from considerable moisture sensitivity and
limited functional group scope.4 Herein, we report an entirely
different solution to this problem, which rests on the high reactivity
and selectivity of aryl-rhodium(III) complexes, formed in situ, and
allows direct arylation of free (NH)-indoles and pyrroles in the
presence of a mild base (route B).
Table 1. Substrate and Functional Group Scopea
This project was initiated by uncovering an exciting lead;
selective C-2 arylation of free indole was detected in the presence
of [Rh(coe)2Cl]2 (coe ) cis-cyclooctene), triphenylphosphine, and
a weak base. On the basis of the assumption that this process
proceeded via electrophilic metalation, we examined electron-
deficient phosphines, which in turn led to the identification of
[p-(CF3)C6H4]3P as the best performing ligand. Subsequent opti-
mization of other reaction parameters, notably, the base (see below)
and the solvent, led to an efficient and selective catalytic system
(Table 1, entry 1). Thus, the cross-coupling of indole and iodo-
benzene was achieved in the presence of [Rh(coe)2Cl2]2 (1),
[p-(CF3)C6H4]3P, and CsOPiv, furnishing 2-phenyl indole in 82%
isolated yield with excellent regioselectivity (>50:1).
Next, we examined the functional group compatibility and
substrate scope of this new system. Of particular interest were the
protic functional groups, such as carbamate, carboxamide, and
sulfonamide, which were problematic for the previous methods
employing azolylmagnesium salts. This was due to the greater
acidity of these groups in comparison to that of the indole amine
(e.g., pKa of sulfonamide ∼ 13, azole amine ∼ 21). Remarkably,
these functionalities were well tolerated under the new catalytic
conditions, affording the corresponding 2-phenyl derivatives as the
principal products in good yield (Table 1, entries 3-5). This
represents an important advance in the scope of the arylation
methodology as the new system targets C-H bonds exclusiVely in
the presence of two acidic N-H bonds!
a For complete list of substrates (15 examples), see Supporting Informa-
tion. Reaction conditions: 1 equiv of azole, ArI (1.2 equiv), CsOPiv (1.4
equiv), 1 (2.5 mol %), L (15 mol %). Dioxane/120 °C/18-36 h. b Indole
(1.17 g), 1 (1 mol %), L (6 mol %), all reagents weighed in air, 120 °C/56
h. L) [p-(CF3)-C6H4]3 P.
dling, and gram scale experiments employing only 1 mol % of
complex 1 (Table 1, entries 1 and 2).
In the course of our investigation, the key importance of the
base was noted as only cesium carboxylates gave appreciable yields
(carbonates and phosphates of alkali metals as well as amines were
ineffective); CsOPiv clearly stood out as the base of choice (CsOAc
versus CsOPiv, 45 versus 82% yield). These observations led us
to examine the mechanism, including the role of pivalate, in more
detail. The 31P NMR of the catalytic reaction mixture revealed a
single observable Rh-phosphine species (δ 25.2 ppm, d, JRh-P
)
113 Hz), which was later isolated and characterized as Rh(OPiv)2-
(Ph)L2 {2, L ) [p-(CF3)C6H4]3P}. Complex 2 was also synthesized
independently on a preparative scale in 89% yield from [Rh-
(coe)2Cl2]2, the phosphine ligand, iodobenzene, and CsOPiv (Figure
1A). Thus, ligation of rhodium(I) by the phosphine, oxidative
addition of iodobenzene, and displacement of the halides by pivalate
at the Rh(III) center describes the likely course of events. Owing
to unfavorable solubility properties of 2, its tolyl analogue, Rh-
(OPiv)2(4-tolyl)L2 (3), was prepared in a similar manner (55%
Other common groups including halide, ketone, and ester were
also compatible (see Supporting Information). A notable exception
was 7-azaindole, which was completely inert under the reaction
conditions (Table 1, entry 7). The inactivation by the basic sp2
nitrogen represents a significant limitation of the present method
and will be addressed in the future.5 Otherwise, this protocol
displayed low moisture sensitivity and allowed the direct use of
commercial chemicals without further purification, benchtop han-
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10.1021/ja050279p CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Proposed Catalytic Cyclea
Figure 1. (A) Synthesis of 2 and 3. (B) X-ray structure of 3 (ORTEP).
Scheme 2. Reactivity of Complex 2a
a L ) [p-(CF3)C6H4]3P.
of functional groups, including those with acidic NH bonds. We
propose that this remarkable selectivity stems from a greater
electrophilicity of the Ar-Rh(III) fragment [as compared to Ar-
Pd(II)], further augmented by the “electron-deficient” phosphine
and the pivalate ligand, which translates to higher reactivity of this
intermediate and, consequently, milder reaction conditions. In stark
contrast to N-metalation and activation of the azole substrate by
magnesium or zinc bases, CsOPiv activates the rhodium catalyst
by providing the required pivalate ligand, which in turn plays an
important role in the key C-H metalation step.
a L ) [p-(CF3)C6H4]3P, 4-Tol ) p-(CH3)C6H4. Conditions: 2 (25 mM),
dioxane, L (1 equiv), 120 °C, 120 min.
yield), and this complex yielded to crystallographic analysis.
Complex 3, in the solid state, is a five-coordinate rhodium species,
containing two monodentate pivalate ligands (Figure 1). The
ORTEP diagram revealed a surprising square pyramidal structure
with five atoms (P1, P2, O1, O3, and Rh) forming the base plane.
Rhodium complex 2 proved to be a competent catalyst, identical
to the [Rh(COE)2Cl]/[p-(CF3)C6H4]3P system in terms of rate and
chemical yield. In stoichiometric experiments (in the absence of
PhI and CsOPiv), complex 2 reacted with indole at 120 °C to furnish
2-phenyl indole in 65% yield (Scheme 2). This reaction displayed
well-behaved initial rate kinetics (Supporting Information) and was
determined to be first order in complex 2 and indole, inVerse first
order in L, and zero order in PhI. Although the yield of this reaction
could be improved by the addition of CsOPiv and 4-Tol-I, the initial
rate was not affected by these reagents. Thus, it seems that both
CsOPiv and 4-Tol-I serve as trapping reagents,6 preventing
decomposition of the Rh(I) fragment formed in the reaction, instead
of directly participating in the C-H bond functionalization.
These results are consistent with the following overall structure
of the catalytic cycle. Complex 2 is assembled in situ and represents
the resting state of the catalyst. Subsequently, displacement of the
phosphine ligand by indole takes place in a pre-equilibrium to form
complex 4, which is followed by the slow C-H bond metalation
step (Scheme 3). The resulting intermediate 5 then undergoes
reductive elimination, furnishing the desired coupling product. The
rhodium(I) complex formed in this step is rapidly converted back
to the resting state via oxidative addition of iodobenzene and
halide-pivalate exchange. Thus, in brief, the oxidative addition of
haloarene precedes the slow C-H transformation step.7,8
Acknowledgment. This work is supported by Bristol-Myers
Squibb (the Unrestricted Grants in Synthetic Organic Chemistry
Award), Pfizer (Pfizer Award for Creativity in Organic Chemistry),
Merck Research Laboratories, and GlaxoSmithKline. We thank
Guang Zhu and Prof. Ged Parkin (X-ray crystallography), Dr. J.
B. Schwarz (editorial assistance), and Vitas Votier Chmelar
(intellectual support).
Supporting Information Available: Experimental procedures,
spectral data, crystallographic data for 3 (CIF), kinetics of stoichiometric
and catalytic experiments. This material is available free of charge via
the Internet at http://pubs.acs.org.
References
(1) N-arylation is well established. For lead references, see: (a) Hartwig, J.
F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.; Alcazar-Roman, L.
M. J. Org. Chem. 1999, 64, 5575. (b) Klapars, A.; Antilla, J. C.; Huang,
X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727.
(2) (a) Sezen, B.; Sames, D. J. Am. Chem. Soc. 2003, 125, 5274. (b) Sezen,
B.; Sames, D. Org. Lett. 2003, 5, 3607.
(3) For work of others, see: Rieth, R. D.; Mankad, N. P.; Calimano, E.;
Sadighi, J. P. Org. Lett. 2004, 6, 3981.
(4) These methods require rigorously anhydrous conditions (solvent, glass-
ware) and very pure azole substrates.
(5) For the same reason, imidazole and pyrazole were inert. For a complete
list of substrates, see Supporting Information.
(6) Baranano, D.; Hartwig, J. F. J. Am. Chem. Soc. 1995, 117, 2937.
(7) It should be noted that this mechanism differs significantly from that
proposed for the rhodium-catalyzed arylation of benzimidazole and
benzoxazole at the 2-position (electron-deficient position), wherein C-H
bond activation takes place first, generating a Rh(I)-carbene complex,
followed by the oxidative addition of iodobenzene. Lewis, J. C.;
Wiedemann, S. H.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2004, 6, 35.
(8) No mechanistic data have been generated for Rh-catalyzed directed ortho-
arylation: (a) Sezen, B.; Sames, D. J. Am. Chem. Soc. 2003, 125, 10580.
(b) Bedford, R. B.; Limmert, M. E. J. Org. Chem. 2003, 68, 8669.
(9) The importance of carboxylate ligands in the context of palladium-
mediated C-H bond activation has been discussed, however, no direct
evidence has been provided. Sokolov, V. I.; Troitskaya, L. L.; Reutov,
O. A. J. Organomet. Chem. 1979, 182, 537.
This model is further supported by the large kinetic isotope effect
(kH/kD ) 3.0) at the 2-position of indole. Although the intimate
mechanistic details of the C-H metalation step are unclear, we
propose that the pivalate ligand assists the C-H bond dissociation
as an internal base. This is consistent with the fact that the initial
rates of the reaction between indole and complex 2 were not affected
by the addition of CsOPiv.9,10
(10) Involvement of ArPd-OR species (R ) Ac, Alk, H) in other cross-
coupling reactions has been proposed: (a) Miyaura, N.; Yamada, K.;
Suginome, H.; Suzuki, A. J. Am. Chem. Soc. 1985, 107, 972. (b) Mann,
G.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 13109.
In summary, we describe a novel system for direct C-arylation
of free (NH)-indoles and pyrroles, with tolerance for a wide range
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