Arylation of Heterocycles via Rhodium-Catalyzed C-H Bond Functionalization

Article abstract of DOI:10.1021/ol035985e

(Equation presented) A new method for the rhodium-catalyzed arylation of a variety of heterocycles has been developed. The reaction provided moderate to good yields of the arylated products. A preliminary mechanistic investigation of this reaction revealed the intermediacy of an isolable N-heterocyclic carbene complex.

Full text of DOI:10.1021/ol035985e

ORGANIC
LETTERS
2004
Vol. 6, No. 1
35-38
Arylation of Heterocycles via
Rhodium-Catalyzed C−H Bond
Functionalization
Jared C. Lewis,† Sean H. Wiedemann,†,‡ Robert G. Bergman,*,†,‡ and
,†
Jonathan A. Ellman*
Center for New Directions in Organic Synthesis, Department of Chemistry, and
DiVision of Chemical Sciences, Lawrence Berkeley National Laboratory,
UniVersity of California, Berkeley, California 94720
bergman@cchem.berkeley.edu; jellman@uclink.berkeley.edu
Received October 12, 2003
ABSTRACT
A new method for the rhodium-catalyzed arylation of a variety of heterocycles has been developed. The reaction provided moderate to good
yields of the arylated products. A preliminary mechanistic investigation of this reaction revealed the intermediacy of an isolable N-heterocyclic
carbene complex.
Metal-mediated cross-coupling reactions of organometallic
reagents and halides constitute an essential class of carbon-
carbon bond forming reactions1 and provide access to a wide
array of natural products, pharmaceuticals, ligands, and other
materials. However, the organometallic starting materials
required for these reactions frequently either are not com-
mercially available or are expensive and result in undesired
metal byproducts. Much greater starting material availability
and elimination of stoichiometric metal byproducts could
theoretically be achieved by the direct cross-coupling of
organic compounds through functionalization at a C-H bond.
Relatively few examples of this type of intermolecular
coupling have been reported.2 In general, such methods
involve ortho arylation of benzene derivatives bearing a
pendant directing group.3 A notable exception was reported
by Miura et al. in which a number of heterocycles were
arylated using a palladium catalyst,4 and a number of related
methods have since emerged.5 Sames and co-workers have
also very recently developed a cobalt catalyst for the arylation
of a number of azoles.6
Previous work in our laboratories has shown that the
C2-H bond of various azoles can be activated by a rhodium-
(2) For reviews, see: (a) Dyker, G. Chem. Ber. 1997, 130, 1567-1578.
(b) Dyker, G. Angew. Chem., Int. Ed. 1999, 38, 1698-1712. (c) Miura,
M.; Nomura, M. Top. Curr. Chem. 2002, 219, 212-237.
† Center for New Directions in Organic Synthesis, Department of
Chemistry.
(3) (a) Satoh, T.; Inoh, J.; Kawamura, Y.; Kawamura, Y.; Miura, M.;
Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71, 2239-2246. (b) Oi, S.; Fukita,
S.; Inoue, Y. Chem. Commun. 1998, 2439-2440. (c) Kametani, Y.; Satoh,
T.; Miura, M.; Nomura, M. Tetrahedron Lett. 2000, 41, 2655-2658. (d)
Oi, S.; Fukita, S.; Hirata, N.; Watanuki, N.; Miyano, S.; Inoue, Y. Org.
Lett. 2001, 3 (16), 2579-2581. (e) Oi, S.; Ogino, Y.; Fukita, S.; Inoue, Y.
Org. Lett. 2002, 4, 1783-1785. (f) Kakiuchi, F.; Murai, S. Acc. Chem.
Res. 2002, 35, 826-834. (g) Bedford, R. B.; Coles, S. J.; Hursthouse, M.
B.; Limmert, M. E. Angew. Chem., Int. Ed. 2003, 42, 112-114.
(4) (a) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M.
Bull. Chem. Soc. Jpn. 1998, 71, 467-473.
‡ Division of Chemical Sciences, Lawrence Berkeley National Labora-
tory.
(1) (a) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang,
P. J., Eds.; Wiley-VCH: New York, 1998. (b) Yamamoto, Y., Negishi, E.,
Eds. J. Organomet. Chem. 1999, 576, 1-317 (special edition). (c) Stille, J.
K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508-524. (d) Miyaura, N.;
Suzuki, A. Chem. ReV. 1995, 95, 2457-2484. (e) Suzuki, A. J. Organomet.
Chem. 1999, 576, 147-168. (f) Denmark, S. E.; Sweis, R. F. Acc. Chem.
Res. 2002, 35, 835-846.
10.1021/ol035985e CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/09/2003

Table 1. Identification of Suitable Coupling Partnera
Table 2. Effects of Added Bases on Conversion
entry
X
equiv
time (h)
conversion (%)b
entry
base
time (h)
conversion (%)a
1
B(OH)2
B(OH)2
SnMe3
OTf
Cl
Br
I
5
5
15
13
15
6
18
18
18
20
10
0
0
0
0
10
15
16
1
2
3
4
5
6
7
8
Li2CO3
MgO
6
6
6
20
18
0
0
13
9
2c
3
4
5
6
7
8e
1.5
2
1.5
1.5
1.5
1.5
NaOH
KOtBu
DMPb
PMPc
iPr2EtN
Et3N
6
20
20
6
33
32
I
6
a coe ) cyclooctene. b Conversion to 1 was monitored by GC-MS
relative to hexamethyl-benzene internal standard. c 5 equiv of K2CO3 used.
d Reaction performed at 105 °C. e Free phosphine (PCy3) used.
a Conversion to 1 was monitored by GC-MS relative to hexamethyl-
benzene internal standard. b 2,6-dimethylpyridine. c 1,2,2,6,6,-pentameth-
ylpiperidine.
(I) catalyst and subsequently coupled to an alkene, yielding
the alkylated azole.7 Investigation into the mechanism of this
reaction revealed that the catalysis proceeds via an N-
heterocyclic carbene (NHC) intermediate.8 It was hypoth-
esized that such an intermediate might be capable of
undergoing other coupling processes, such as arylation.9
Initial efforts toward this goal focused on the identification
of a suitable coupling partner to accomplish the desired cross-
coupling reaction with benzimidazole using optimized condi-
tions from the alkylation reaction (Table 1). Entry 1 shows
that phenylboronic acid does indeed provide the desired
product, but addition of a Brønsted base (entry 2), in analogy
with conventional Suzuki couplings,1a,e gave no conversion.
Neither trimethyl(phenyl)tin nor phenyl triflate gave encour-
aging results (entries 3 and 4). The best results in this initial
screen were obtained using aryl halides as coupling partners
(entries 5-8). The order of reactivity was found to be ArCl
< ArBr < ArI. In the case of aryl iodides, product was
observed even at the reduced temperature of 105 °C, and
the free phosphine was found to be comparable to PCy3‚
HCl (entry 8), which had proven advantageous in the
alkylation reaction.7c
catalyst decomposition or other deleterious side reactions.
Thus, a thorough investigation of the effect of added base
on the coupling reaction was undertaken (Table 2). A number
of inorganic bases were initially screened (entries 1-4).
Lithium carbonate provided a moderate increase in the
observed conversion, but other oxygen bases, such as metal
oxides, hydroxides, and alkoxides, failed to give further
increases in conversion. Nitrogen bases were next screened
(entries 5-8), and a positive influence of hindered, tertiary
alkylamines was observed. Triethylamine served as an
efficient and convenient base, providing the product in 32%
conversion in 6 h.
A diverse array of phosphines, having variable steric and
electronic properties, were also screened (Table 3). Triaryl
phosphines, chelating phosphines, phosphites, and phos-
phoramidites gave no conversion. A number of hindered
trialkylphosphines provided yields comparable to that using
tricyclohexylphosphine (entries 2 and 4), but none could
provide conversion higher than that originally obtained for
tricyclohexylphosphine. Interestingly, conversion was ob-
Because HI is the sole byproduct of the coupling reaction,
it was thought that this strong acid might be responsible for
Table 3. Effects of Phosphine on Conversion
(5) (a) Okazawa, T.; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem.
Soc. 2002, 124, 5286-5287. (b) Gallagher, W. P.; Maleczka, R. E. J. Org.
Chem. 2003, 68, 6775-6779. (c) Mori, A.; Sekiguchi, A.; Masui, K.;
Shimada, T.; Horie, M.; Osakada, K.; Kawamoto, M.; Ikeda, T. J. Am.
Chem. Soc. 2003, 125, 1700-1701. (d) Sezen, B.; Sames, D. J. Am. Chem.
Soc. 2003, 125, 5274-5275.
(6) Sezen, B.; Sames, D. Org. Lett. 2003, 5, 3607-3610.
(7) (a) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc.
2001, 123, 2685-2686. (b) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J.
Am. Chem. Soc. 2002, 124, 13964-13965. (c) Tan, K. L.; Vasudevan, A.;
Bergman, R. G.; Ellman, J. A.; Souers, A. J. Org. Lett. 2003, 5, 2131-
2134.
entry
phosphine
PPh3
conversion (%)a
1
2
3
4
5
6
7b
0
26
2
30
4
P(i-Pr)3
P(t-Bu)3
P(t-Bu)2Me
Cy2P(CH2)3PCy2
PCy3
(8) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2002,
124, 3202-3203.
31
50
(9) McGuiness et al. have shown that NHC complexes can undergo
stoichiometric oxidative addition and reductive elimination at a metal
center: (a) McGuinness, D. S.; Cavell, K. J.; Skelton, B. W.; White, A. H.
Organometallics 1999, 18, 1596-1605. (b) McGuinness, D. S.; Cavell, K.
J.; Yates, B. F.; Skelton, B. W.; White, A. H. J. Am. Chem. Soc. 2001,
123, 8317-8328.
PCy3
a Conversion to 1 was monitored by GC-MS relative to hexamethyl-
benzene internal standard. b 0.4 equiv PCy3, 4 equiv Et3N, 13 h.
36
Org. Lett., Vol. 6, No. 1, 2004

Table 4. Substrate Generality
Figure 1. ORTEP drawing of 9. A molecule of solvent and disorder
in two of the cyclohexyl groups (alternate conformers) were omitted
for clarity.
To aid in the optimization of the reaction, a preliminary
mechanistic study was undertaken. In situ NMR studies of
the catalytic reaction of N-methylbenzimidazole with iodo-
benzene revealed the rapid appearance and gradual depletion
1
of H and 31P resonances consistent with signals observed
for the NHC intermediate proposed in the analogous alkene
coupling.12 Indeed, complex 9 was obtained in 71% yield
from the stoichiometric reaction of N-methylbenzimidazole
with [RhCl(coe)2]2 and PCy3.13 Recrystallization provided
X-ray quality crystals for structural characterization (Figure
1).
a 150 °C, 6 h. b 135 °C, 18 h. c 105 °C, 18 h.
Complex 9 (0.1 equiv) was shown to be kinetically
equivalent to the standard [RhCl(coe)2]2/PCy3 system in
catalyzing the coupling of N-methylbenzimidazole with
iodobenzene under the optimized reaction conditions, sug-
gesting its intermediacy in this reaction. Qualitative rate
studies of the stoichiometric reaction of 9 with iodobenzene
also revealed that this process is inhibited by added phos-
phine, suggesting that phosphine dissociation occurs prior
to oxidative addition of iodobenzene. Additional resonances
observed in the in situ H NMR spectrum of the stoichio-
metric reaction indicated the presence of an additional
transient carbenoid species.14
These preliminary observations suggest the mechanism
shown in Scheme 1 for the reaction under investigation.15
served to increase with increasing phosphine concentration
up to nearly 8 equiv relative to rhodium. Beyond this
stoichiometry, a decrease in conversion was observed. Final
optimization of reactant stoichiometry provided additional
increases in conversion (Table 3, entry 7). Of solvents
investigated, only THF and o-dichlorobenzene provided good
yields of the desired products.
The optimal parameters obtained were applied toward the
arylation of a number of different heterocycles with a variety
of aryl iodides (Table 4). Of the aromatic heterocycles
investigated (entries 1-5), benzoxazole provided the highest
yield of arylated product. A trend favoring electron-rich aryl
iodides was observed in the coupling to benzoxazole (entries
3-5). Nonaromatic heterocycles also provided good conver-
sion to cross-coupled products.10 As shown in entry 6,
dihydroquinazoline reacted efficiently, providing 2-phe-
nylquinazoline, presumably via cross-coupling followed by
dehydrogenation of an initially formed 2-phenyldihydro-
quinazoline intermediate. Quinazoline provided no conver-
sion to the cross-coupled product after 24 h at 150 °C (entry
7). The oxazoline in entry 8 also gave good conversion to
the desired product at the reduced temperature of 105 °C.
This result is notable because aryl oxazolines serve as
versatile intermediates for the preparation of a range of
compounds.11
1
(11) (a) Michael, R.; Meyers, A. I. Tetrahedron 1985, 41, 837-860. (b)
Ie, Y.; Chatani, N.; Ogo, T.; Marshall, D. R.; Fukuyama, T.; Kakiuchi, F.;
Murai, S. J. Org. Chem. 2000, 65, 1475-1488.
(12) Singlets at 10.19 and 4.16 ppm in the 1H NMR spectrum,
corresponding to the N-H and N-CH3 protons, respectively, and a doublet
at 30 ppm in the 31P NMR spectrum were observed.
(13) For reviews of NHCs and their metal complexes, see: (a) Lappert,
M. F. J. Organomet. Chem. 1988, 358, 185-214. (b) Herrmann, W. A.;
Ko¨cher, C. Angew. Chem., Int. Ed. Engl. 1997, 36, 2162-2187. (c)
Weskamp, T.; Bo¨hm, V. P. W.; Herrmann, W. A. J. Organomet. Chem.
2000, 600, 12-22.
(14) Additional singlets at 10.28 and 4.19 ppm corresponding to the N-H
and N-CH3 protons, respectively, were observed during the reaction. This
complex has not yet been characterized.
(15) Complex 8 is also in equilibrium with its dimer. For relevant studies
on RhCl(PCy3)2, see: (a) Van Gaal, H. L. M.; Van Den Bekerom, F. L. A.
J. Organomet. Chem. 1977, 134, 237-248. (b) Itagaki, H.; Murayama, H.;
Saito, Y. Bull. Chem. Soc. Jpn. 1994, 67, 1254-1257. (c) Wang, K.; Rosini,
G. P.; Nolan, S. P.; Goldman, A. S. J. Am. Chem. Soc. 1995, 117, 5082-
5088.
(10) Our group has been investigating the use of nonaromatic substrates
in the alkene coupling based on the hypothesized compatibility of these
substrates with the proposed carbenoid mechanism (unpublished, ongoing
work).
Org. Lett., Vol. 6, No. 1, 2004
37

Scheme 1. Proposed Mechanism for the Rhodium-Catalyzed
Arylation of N-Methylbenzimidazole
Scheme 2. Proposed Mechanism for Hydrodehalogenation of
PhI
To test this hypothesis, the reactivity of Rh(Cl)(H)2(PCy3)2
11 was studied. Heating 0.1 equiv of 11 with iodobenzene
and triethylamine in d8-THF gave rise to a solution exhibiting
a
31P NMR spectrum containing peaks identical to those
observed in the spectrum obtained from heating a solution
of 0.1 equiv of 8, iodobenzene, and Et3N in d8-THF,
indicating a common product mixture for the two reactions.
High conversion of iodobenzene to benzene was observed
in each case. Notably, comparison of these spectra to that
obtained in situ during the catalytic arylation of benzimida-
zole under optimized reaction conditions revealed the pres-
ence of these same peaks. It therefore seems likely that a
rhodium hydride of structure similar to that of 10 is
responsible for competitive depletion of iodobenzene. Con-
version of 8 to a catalytically inactive species would be
responsible for the moderate yields obtained.
In conclusion, a new method for the arylation of hetero-
cycles has been developed. The arylation is believed to
proceed via a NHC intermediate, which defines the substrate
scope of the reaction. Additionally, a competitive hydrode-
halogenation reaction was identified. This insight may allow
further optimization of yield though use of appropriate
phosphine ligands. Continued efforts toward elucidation of
the mechanism of this transformation and use of arylboronic
acids as coupling partners are also underway.
In addition to the desired product, a large amount of
benzene, comprising the mass balance of iodobenzene,
formed during the course of the cross-coupling reaction.
Addition of neither dihydroanthracene nor 2,6-di-tert-butyl-
p-cresol (BHT, 0.5 equiv) to the reaction mixture increased
conversion to either benzene or the desired product, indicat-
ing that radical pathways are probably not responsible for
the deleterious side reaction.
The 1H NMR spectrum of a solution generated in situ from
heating 1 equiv of 8 in d8-THF contained resonances16
consistent with those of a bisphosphinochlororhodium(III)
hydride17 and led to the hypothesis that iodobenzene was
undergoing competitive hydrodehalogenation.18 It is therefore
proposed that the rhodium center could undergo either
cyclometalation19 or intermolecular C-H activation with one
of the cyclohexyl groups of a phosphine ligand.20 â-Hydride
elimination from the metalated species would then give
dihydride complex 10. This species would account for the
observed NMR spectroscopic data (Scheme 2). Elimination
of HCl followed by addition of PhI and subsequent elimina-
tion of the observed PhH would give a bisphosphinorhod-
ium(I) iodide.
Acknowledgment. This work was supported by the NIH
grant GM069559 (to J.A.E.) and by the Director, Office of
Energy Research, Office of Basic Energy Sciences, Chemical
Sciences Division, U.S. Department of Energy, under
Contract DE-AC03-76SF00098 (to R.G.B.). The Center for
New Directions in Organic Synthesis is supported by Bristol-
Meyers-Squibb as a sponsoring member and Novartis as a
supporting member. We thank Kian L. Tan and Dr. Jennifer
R. Krumper for many helpful ideas and discussions. We also
thank Dr. Frederick J. Hollander and Dr. Allen G. Oliver of
the Berkeley CHEXray facility for solving the X-ray crystal
structure.
(16) Initially, a doublet of triplets at -23 ppm and a singlet at 5.6 ppm
in the 1H NMR spectrum and a doublet at 50.5 ppm in the 31P NMR
spectrum were observed. Continued heating of this solution led to formation
of two additional doublets at 50.5 and 48.5 ppm in the 31P NMR spectrum.
These peaks are consistent with exchange of phosphine on 14 to give a
mixture of tricyclohexyl and cyclohexylcyclohexenyl phosphines.
(17) Van Gaal, H. L. M.; Ver Laak, J. M. J.; Posno, T. Inorg. Chim.
Acta 1977, 23, 43-51.
(18) For an extensive review on hydrodehalogenation, see: Alonso, F.;
Beletskaya, I. P.; Yus, M. Chem. ReV. 2002, 102, 4009-4091.
(19) Similar reactivity was observed for RuH2(H2)2(PCy3)2 upon reaction
of this complex with ethylene: Christ, M. L.; Sabo-Etienne, S.; Chaudret,
B. Organometallics 1995, 14, 1082-1084 and references therein.
Supporting Information Available: Crystallographic
data, full experimental details, and characterization for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL035985E
(20) Itagaki et al. reported formation of 14 (vide infra) from 10 in
cyclohexane solution in ref 12b.
38
Org. Lett., Vol. 6, No. 1, 2004