Rh(I)-catalyzed arylation of heterocycles via C-H bond activation: Expanded scope through mechanistic insight

Article abstract of DOI:10.1021/ja0748985

A practical, functional group tolerant method for the Rh-catalyzed direct arylation of a variety of pharmaceutically important azoles with aryl bromides is described. Many of the successful azole and aryl bromide coupling partners are not compatible with methods for the direct arylation of heterocycles using Pd(O) or Cu(I) catalysts. The readily prepared, low molecular weight ligand, Z-1-tert-butyl-2,3,6,7-tetrahydrophosphepine, which coordinates to Rh in a bidentate P-olefin fashion to provide a highly active yet thermally stable arylation catalyst, is essential to the success of this method. By using the tetrafluoroborate salt of the corresponding phosphonium, the reactions can be assembled outside of a glovebox without purification of reagents or solvent. The reactions are also conducted in THF or dioxane, which greatly simplifies product isolation relative to most other methods for direct arylation of azoles employing high-boiling amide solvents. The reactions are performed with heating in a microwave reactor to obtain excellent product yields in 2 h.

Full text of DOI:10.1021/ja0748985

Published on Web 02/02/2008
Rh(I)-Catalyzed Arylation of Heterocycles via C-H Bond
Activation: Expanded Scope through Mechanistic Insight
Jared C. Lewis, Ashley M. Berman, Robert G. Bergman,* and Jonathan A. Ellman*
Department of Chemistry, UniVersity of California and DiVision of Chemical Sciences,
Lawrence Berkeley National Laboratory, Berkeley, California, 94720
Received July 18, 2007; E-mail: jellman@berkeley.edu; rbergman@berkeley.edu
Abstract: A practical, functional group tolerant method for the Rh-catalyzed direct arylation of a variety of
pharmaceutically important azoles with aryl bromides is described. Many of the successful azole and aryl
bromide coupling partners are not compatible with methods for the direct arylation of heterocycles using
Pd(0) or Cu(I) catalysts. The readily prepared, low molecular weight ligand, Z-1-tert-butyl-2,3,6,7-
tetrahydrophosphepine, which coordinates to Rh in a bidentate P-olefin fashion to provide a highly active
yet thermally stable arylation catalyst, is essential to the success of this method. By using the
tetrafluoroborate salt of the corresponding phosphonium, the reactions can be assembled outside of a
glovebox without purification of reagents or solvent. The reactions are also conducted in THF or dioxane,
which greatly simplifies product isolation relative to most other methods for direct arylation of azoles
employing high-boiling amide solvents. The reactions are performed with heating in a microwave reactor
to obtain excellent product yields in 2 h.
electron-rich substrates,6 or C-H bond acidity7 to selectively
Introduction
The direct arylation of privileged heteroarenes1 provides a
highly efficient means to synthesize functional biaryl compounds
utilized extensively throughout the pharmaceutical and materials
industries.2 This approach eliminates the need for the organo-
metallic starting materials required in traditional cross-coupling
methods,3 and over the past several years a number of reactions
that exploit directing groups,4 repulsive steric interactions,5
activate and functionalize a specific C-H bond with a transition-
metal catalyst have been developed. When applicable to a
substrate class, these methods reduce reaction byproducts,
increase the number of available substrates, and decrease the
synthetic effort required for formation of the desired C-C bond.
Our group recently described a Rh-catalyzed arylation method
in which mixtures of endo- and exo-9-cyclohexylbicyclo-[4.2.1]-
9-phosphanonane (cyclohexylphobane) served as highly active
ligands for the direct arylation of a variety of heterocycles using
aryl bromides (eq 1).8 Experimental and computational studies
on the heterocycle activation step of this reaction provided
(1) This area has enjoyed explosive growth, so only references from the past
five years are listed. For a nice method utilizing aryl chlorides, see: (a)
Chion, H. A.; Daugulis, O. Org. Lett. 2007, 9, 1449. Direct arylation of
electron-rich heterocycles is described, but unprotected N-H azoles were
not tolerated, and overarylation was observed in some cases. See references
therein for previous scattered examples utilizing aryl chlorides. For examples
using aryl bromides, see: (b) Bellina, F.; Calandri, C.; Cauteruccio, S.;
Rossi, R. Tetrahedron 2007, 63, 1970 (three examples, 2 equiv of CuX
required). (c) Cerna, I.; Pohl, R.; Kepetarova, B.; Hocek, M. Org. Lett.
2006, 8, 5389 (one example). (d) Pariseien, M.; Valette, D.; Fagnou, K. J.
Org. Chem. 2005, 70, 7578 (six examples). (e) Alagille, D.; Baldwin, R.
M.; Tamagnan, G. D. Tetrahedron Lett. 2005, 46, 1349 (electron-rich aryl
bromides were coupled with benzothiazole and benzoxazole). (f) Rieth, R.
D.; Mankad, N. P.; Calimano, E.; Sadighi, J. P. Org. Lett. 2004, 6, 3981
(stoichiometric metalation of pyrrole required). (g) Park, C.-H.; Ryabova,
R.; Seregin, I. V.; Sromek, A. W.; Gevorgyan, V. Org. Lett. 2004, 6, 1159
(only indolizine arylation reported). (h) Mori, A.; Sekiguchi, A.; Masui,
K.; Shimada, T.; Horie, M.; Osakada, K.; Kawamoto, M.; Ikeda, T. J. Am.
Chem. Soc. 2003, 125, 1700 (one example). (i) Yokooji, A.; Okazawa, T.;
Satoh, T.; Miura, M.; Nomura, M. Tetrahedron 2003, 59, 5685 (thiazole
arylation). (j) Li, W.; Nelson, D. P.; Jensen, M. S.; Hoerrner, R. S.; Javadi,
G. J.; Cai, D.; Larsen, R. D. Org. Lett. 2003, 5, 4835 (imidazo[1,2-a]-
pyridine arylation). (k) Glover, B.; Harvey, K. A.; Liu, B.; Sharp, M. J.;
Tymoschenko, M. F. Org. Lett. 2003, 5, 310 (furan and thiophene arylation).
(l) Okazawa, T.; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem. Soc.
2002, 124, 5286 (thiazole multiple arylation). (m) McClure, S. M.; Glover,
B.; McSorley, E.; Millar, A.; Osterhout, M. H.; Roschangar, F. Org. Lett.
2001, 3, 1677 (two examples of furan arylation). For a significant recent
example utilizing aryl iodides and Cu catalysis see: (n) Do, H.-Q.; Daugulis,
O. J. Am. Chem. Soc. 2007, 129, 12404.
(3) The importance of modern cross-coupling methods, particularly the Suzuki
reaction, for the formation of aryl-aryl bonds cannot be overstated. For
recent developments, see: (a) Billingsley, K.; Buchwald, S. L. J. Am. Chem.
Soc. 2007, 129, 3358. (b) Barder, T. E.; Walker, S. D.; Martinelli, J. R.;
Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685. (c) Littke, A. F.; Dai,
C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020.
(4) (a) Daugulis, O.; Zaitsev, V. G. Angew. Chem., Int. Ed. 2005, 44, 4046.
(b) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem.
Soc. 2005, 127, 7330. (c) Thalji, R. K.; Ahrendt, K. A.; Bergman, R. G.;
Ellman, J. A. J. Org. Chem. 2005, 70, 6775. (d) Kakiuchi, F.; Murai, S.
Acc. Chem. Res. 2002, 35, 826.
(5) (a) Chen, H.; Schlecht, S.; Semple, T. C.; Hartwig, J. F. Science 2000,
287, 1995. (b) Cho, J.-Y.; Iverson, C. N.; Smith, M. R. J. Am. Chem. Soc.
2000, 122, 12868. (c) Ishiyama, T.; Takagi, J.; Kousaku, I.; Miyaura, N.;
Anastasi, N. R.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 124, 390.
(6) The vast majority of methods for heterocycle arylation falls into this
category.1 In addition, see: (a) Tunge, J. A.; Foresee, L. N. Organometallics
2006, 24, 6440. (b) Yanagisawa, S.; Sudo, T.; Noyori, R.; Itami, K. J. Am.
Chem. Soc. 2006, 128, 11748. (c) Ferreira, E. M.; Stoltz, B. M. J. Am.
Chem. Soc. 2003, 125, 9578. (d) Jia, C. G.; Piao, D. G.; Oyamada, J. Z.;
Lu, W. J.; Kitamura, T.; Fujiwara, Y. Science 2000, 287, 1992.
(7) (a) Garcia-Cuadrado, D.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M.
J. Am. Chem. Soc. 2006, 128, 1066. (b) Lafrance, M.; Fagnou, K. J. Am.
Chem. Soc. 2006, 128, 16496. (c) Lafrance, M.; Shore, D.; Fagnou, K.
Org. Lett. 2006, 8, 5097. (d) Lafrance, M.; Rowley, C. N.; Woo, T. K.;
Fagnou, K. J. Am. Chem. Soc. 2006, 128, 8754. (e) Stuart, D. R.; Fagnou,
K. Science 2007, 316, 1172.
(2) (a) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol.
Chem. 2006, 4, 2337. (b) Hashimoto, H.; Maeda, K.; Ozawa, K.; Haruta,
J.; Wakitani, K. Bioorg. Med. Chem. Lett. 2002, 12, 65. (c) Sisko, J.;
Kassick, A. J.; Mellinger, M.; Filan, J. J.; Allen, A.; Olsen, M. A. J. Org.
Chem. 2000, 65, 1516 and references therein. (d) Roncali, J. Chem. ReV.
1997, 97, 173.
(8) Lewis, J. C.; Wu, J. Y.; Bergman, R. G.; Ellman, J. A. Angew. Chem., Int.
Ed. 2006, 118, 1619.
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J. AM. CHEM. SOC. 2008, 130, 2493-2500
2493

A R T I C L E S
Lewis et al.
evidence that coordination of the heterocycle to the catalytically
active Rh-phosphine fragment precedes an intramolecular C-H
activation step, which provides a Rh-H intermediate that
ultimately tautomerizes to an N-heterocyclic carbene complex.9
This mechanism of C-H bond activation leads to unique
selectivity and has enabled the arylation of a wide variety of
heterocycles using Rh catalysis,10 many of which are incompat-
ible with electrophilic Pd-catalyzed methods or Cu-catalyzed
methods1n that require strong bases and presumably proceed via
heterocycle deprotonation. In particular, unprotected N-H
azoles and nonaromatic heterocycles were viable arylation
substrates, and a wide array of functionalized aryl bromides was
compatible with the arylation conditions. However, a number
of important problems regarding substrate scope, functional
group tolerance, and practicality still remained.
Figure 1. (a) ORTEP diagram of 3. (b) Line illustration of 3.
commenced by heating d8-THF solutions of 1a and [RhCl-
1
(coe)2]2 and monitoring the H and 31P NMR spectra of this
mixture in situ (eq 2).14 Conversion to a complex assigned as
bisphosphine 2 based on 31P chemical shifts was initially
observed when 4 equiv of 1a were utilized with respect to
[RhCl(coe)2]2. Subsequently, complete conversion of 2 to
complex 3 was observed. Importantly, complex 3 was also
present in the crude arylation reaction mixtures utilizing 1a/b
under optimized arylation conditions.
Herein, we report the solution to many of these problems
through the synthesis and evaluation of a set of 2,3,6,7-tetra-
hydrophosphepine P-olefin ligands previously unexplored in
transition-metal catalysis. The development of these ligands was
based on an investigation into the reaction of [RhCl(coe)2]2 with
1a that revealed dehydrogenation of 1a to form a P-olefin Rh
complex (vide infra). The method developed using these new
ligands significantly expands the scope of heterocycle and aryl
bromide coupling partners that may be used over that observed
for 1a/b. Moreover, the method was further modified to allow
assembly of the reactions without the need for a glovebox or
reagent purification.
Complex 3 was prepared in good yield by heating a THF
solution of 1a and [RhCl(coe)2]2 at 125 °C for 2 h, concentrating
the mixture, and then washing the resulting yellow solid with
pentane. This material was crystallized from pentane/THF, and
the structure of 3 was determined using single-crystal X-ray
analysis (Figure 1). The structure clearly showed that one of
the phoban ligands had been selectively dehydrogenated to
generate a P-olefin binding motif with Rh1-P1 and Rh1-P2
bond distances of 2.2816(18) and 2.379(2) Å, respectively, and
Rh1-C16 and Rh1-C17 bond distances of 2.123(9) and
2.123(7) Å, respectively.15 The second phoban ligand was not
dehydrogenated as evidenced by the sp3 hybridization of the
carbon atoms in the four-carbon bridge of the ligand. The
stability of this complex even under extended heating at 125
°C indicated tighter chelation of the rhodium center relative to
the analogous complex formed in situ from Rh/PCy3, which
we assume underwent multiple rounds of cyclometalation/â-
hydride elimination due to the observed pseudo-catalytic hy-
drodehalogenation of PhI and complete decomposition of the
Rh species.12
Investigation of Rh-Phosphine Complexes
Aryl halide hydrodehalogenation11 was identified as a key
side reaction in early studies on Rh-catalyzed arylation employ-
ing PCy3 as a ligand.12 While greatly reduced through the use
of 1a/b and aryl bromides, this deleterious side reaction was
still observed to a significant extent in sluggish arylations
between poorly reactive coupling partners. Dehydrogenation of
1a/b, in a manner similar to that previously observed for PCy3,
was suspected as the “H2” source for aryl bromide hydrode-
halogenation, though the site(s) of dehydrogenation in 1a/b was
not known.13 Eliminating this reaction was thus deemed essential
to further optimization efforts. Our work toward this goal
(9) (a) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2002,
124, 3202. (b) Wiedemann, S. H.; Lewis, J. C.; Bergman, R. G.; Ellman,
J. A. J. Am. Chem. Soc. 2006, 128, 2452.
(10) The corresponding heterocycle alkylation reactions were developed and
extensively studied in our group before our work on heterocycle arylation.
(a) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2001,
123, 2685. (b) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem.
Soc. 2002, 124, 13964. (c) Tan, K. L.; Park, S.; Ellman, J. A.; Bergman,
R. G. J. Org. Chem. 2004, 69, 7329. (d) Wiedemann, S. H.; Bergman, R.
G.; Ellman, J. A. Org. Lett. 2004, 6, 1685. (e) Wiedemann, S. H.; Ellman,
J. A.; Bergman, R. G. J. Org. Chem. 2006, 71, 1969.
(11) For an extensive review on hydrodehalogenation, see: Alonso, F.;
Beletskaya, I. P.; Yus, M. Chem. ReV. 2002, 102, 4009.
(12) (a) Lewis, J. C.; Wiedemann, S. H.; Bergman, R. G.; Ellman, J. A. Org.
Lett. 2004, 6, 35. See also: (b) Christ, M. L.; Sabo-Etienne, S.; Chaudret,
B. Organometallics 1995, 14, 1082 and references therein.
(13) For other recent studies on phoban-based catalyst systems, see: (a) Klingler,
R. J.; Chen, M. J.; Rathke, J. W.; Kramarz, K. W. Organometallics 2007,
26, 352. (b) Dwyer, C. L.; Kirk, M. M.; Meyer, W. H.; Janse van Rensburg,
W.; Forman, G. S. Organometallics 2006, 25, 3806. (c) Konya, D.; Almeida
Lenero, K. Q.; Drent, E. Organometallics 2006, 25, 3166.
(14) We previously demonstrated that 1b is converted to 1a upon heating, and
therefore 1a was utilized in our stoichiometric studies to simplify analysis
of reaction mixtures (see ref 8).
(15) This transformation is analogous to that described by Frost and coworkers
for the dehydrogenation of tricyclopentyl phosphine: Douglas, T. M.; Le
Noˆtre, J.; Brayshaw, S. K.; Frost, C. G.; Weller, A. S. Chem. Commun.
2006, 3408.
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Arylation of Heterocycles via C−H Bond Activation
A R T I C L E S
Scheme 1. Synthesis of (Z)-1-Substituted
2,3,6,7-Tetrahydrophosphepine Ligands
a Starting from PhP(O)Cl2; no oxidation conducted.
in the use of other P-olefin ligands for a variety of transforma-
tions.17 Recently, Lammertsma and co-workers published the
synthesis of (Z)-1-phenyl-2,3,6,7-tetrahydrophosphepine but
used the material in situ to generate a variety of interesting
Mo-phosphepine complexes and did not isolate the free
ligand.18 We utilized a modified version of the Lammertsma
procedure to prepare a small set of phosphepine ligands (Scheme
1).19 Specifically, a three-step procedure, involving addition of
2 equiv of 3-butenylmagnesium bromide to the appropriate
phosphine chloride followed by an alcohol quench, peroxide
oxidation, aqueous workup, and olefin metathesis, was devel-
oped to construct the substituted 2,3,6,7-tetrahydrophosphepine
ring with only a single purification after the final step. The
desired phosphines were then obtained by heating toluene
solutions of the phosphine oxides and phenylsilane to reflux,
concentrating the reaction mixture in vacuo, and purifying the
products by Ku¨gelrohr distillation.
To verify the structure of the Rh catalysts generated from
these ligands, we next prepared a d8-THF solution of 5c and
[RhCl(coe)2]2 and monitored the mixture using 1H NMR
spectroscopy. Again, we initially observed formation of a
bisphosphine species, followed by complete conversion to
P-olefin complex 7 (eq 4). The structure of this material was
confirmed by single-crystal X-ray analysis (Figure 4a). The
ligand is coordinated to Rh in a bidentate P-olefin fashion with
a Rh1-P1 bond distance of 2.190(1) Å, and Rh1-C4 and
Rh1-C5 bond distances of 2.130(6) and 2.105(5) Å, respec-
tively. The Rh-binding motifs found in 3 and 7 exhibited a great
deal of similarity, indicating that removing the two-carbon
bridge from 1a did not significantly alter the desired coordina-
tion geometry (Figure 4c).
Figure 2. Plot of conversion versus time for arylation of benzimidazole
using PhBr in the presence of various Rh catalysts.
Figure 3. Conceptual evolution of ligands used for heterocycle arylation
leading to the (Z)-2,3,6,7-tetrahydrophosphepine skeleton.
The activity of 3 as a catalyst for the arylation of benzimi-
dazole using PhBr was next explored to determine the effects
of the introduced unsaturation (eq 3, Figure 2). As shown in
Figure 2, complex 3 catalyzed the arylation of benzimidazole
to provide a final yield of product similar to that obtained with
the use of [RhCl(coe)2]2/1a/b. Fairly similar kinetic behavior
between the different catalysts was observed, with the apparent
zero-order kinetic behavior being a notable feature of the
reactions. In general, these data indicate that complex 3 formed
under the reaction conditions employing phosphines 1a/b and
exhibits surprising stability, presumably due to bidentate P-olefin
Rh chelation. This, in turn, suggests that conversion of [RhCl-
(coe)2]2/1a/b to the stable complex 3, rather than solely ligand
sterics and electronics, is largely responsible for the superior
activity of arylation catalysts derived from phosphines 1a/b.
Although complex 3 was an active arylation catalyst with
interesting kinetic behavior and attractively low levels of aryl
bromide hydrodehalogenation, it was also a step back in terms
of catalyst simplicity and ligand modularity. We therefore sought
to simplify the phosphine ligand while maintaining the P-olefin
binding motif that conferred the unique activity of 3 and
correspondingly [RhCl(coe)2]2/1a/b, which undergoes in situ
ligand dehydrogenation to 3. Specifically, it was envisioned that
a ligand lacking the two-carbon bridge present in the phoban
skeleton, such as a (Z)-2,3,6,7-tetrahydrophosphepine, might
fulfill these design specifications (Figure 3).
Having established the Rh coordination chemistry of 5c, we
next investigated the activity of ligands 5a-e in the arylation
of benzimidazole with PhBr under reaction conditions utilizing
conventional heating (eq 5, Figure 5). Although all of the ligands
provided active arylation catalysts when mixed with [RhCl-
(coe)2]2 in an optimized ratio of 1.5:1 (P/Rh), phosphepine 5b
with a tert-butyl substituent was by far the most effective and
resulted in quantitative reaction conversion. Phosphepine 5a with
a phenyl substituent was also interesting because of the rapid
Synthesis and Evaluation of
(Z)-2,3,6,7-Tetrahydrophosphepines
Substituted (Z)-2,3,6,7-tetrahydrophosphepines have been
reported in the literature16 but were completely unexplored as
ligands for transition-metal catalysis, despite recent advances
(16) (a) Van Reijendam, J. W.; Baardman, F. Tetrahedron Lett. 1972, 51, 5181.
(b) Shima, T.; Bauer, E. B.; Hampel, F.; Gladysz, J. A. J. Chem. Soc.,
Dalton Trans. 2004, 7, 1012.
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A R T I C L E S
Lewis et al.
Figure 4. (a) X-ray structure of 7. (b) Line illustration of 7. (c) Overlay of common Rh-binding motifs of 3 and 7. (d) Diagram deconstructing overlay
shown in Figure 4c.
Figure 5. Plot of conversion versus time for arylation using 5a-e.
initial reaction rate but gave only moderate conversion because
of catalyst inactivation. A number of aryl phosphepine deriva-
tives were prepared and evaluated, including 2,6-disubstituted
phenyl phosphepines designed to prevent orthometalation, but
improvements in catalyst stability were not observed (data not
shown).
(17) (a) Park, Y.; Meek, D. W. Bull. Korean Chem. Soc. 1995, 16, 524. (b)
Thomaier, J.; Boulmaaz, S.; Scho¨nberg, H.; Ru¨egger, H.; Currao, A.;
Gru¨tzmacher, H.; Hillebrecht, H.; Pritzkow, H. New J. Chem. 1998, 947.
(c) Deblon, S.; Liesum, L.; Harmer, J.; Scho¨nberg, H.; Gru¨tzmacher, H.
Chem.-Eur. J. 2004, 10, 4198. (d) Maire, P.; Deblon, S.; Breher, F.; Geier,
J.; Bo¨hler, C.; Ru¨egger, H.; Scho¨nberg, H.; Gru¨tzmacher, H. Chem.-Eur.
J. 2004, 10, 4198. (e) Shintani, R.; Duan, W.-L.; Nagano, T.; Okamoto,
A.; Hayashi, T. Angew. Chem., Int. Ed. 2005, 44, 4611. (f) Shintani, R.;
Duan, W.-L.; Okamoto, K.; Hayashi, T. Tetrahedron: Asymmetry 2005,
16, 3400. (g) Thoumazet, C.; Richard, L.; Gru¨tzmacher, H.; Le Floch, P.
Chem. Commun. 2005, 1592. (h) See ref 15. (i) Piras, E.; La¨ng, F.; Ru¨egger,
H.; Stein, D.; Wo¨rle, M.; Gru¨tzmacher, H. Chem.-Eur. J. 2006, 12, 5849.
(j) Mora, G.; van Zuphen, S.; Thoumazet, C.; Le Goff, X. F.; Ricard, L.;
Gru¨tzmacher, H. Organometallics 2006, 25, 5528. (k) Kasa´k, P.; Arion,
V. B.; Widhalm, M. Tetrahedron: Asymmetry 2006, 17, 3084.
(18) van Assema, S. G. A.; Ehlers, A. W.; de Kanter, F. J. J.; Schakel, M.;
Spek, A. L.; Lutz, M.; Lammertsma, K. Chem.-Eur. J. 2006, 12,
4333.
(19) We also explored a borane protection route as described by Gouverneur
and coworkers: (a) Schuman, M.; Trevitt, M.; Redd, A.; Gouverneur, V.
Angew. Chem., Int. Ed. 2000, 39, 2491. (b) Slinn, C. A.; Redgrave, A. J.;
Hind, S. L.; Edlin, C.; Nolan, S. P.; Gouverneur, V. Org. Biomol. Chem.
2003, 1, 3820. This ultimately failed, perhaps because of olefin hydrobo-
ration as described in: (c) Scheideman, M.; Shapland, P.; Vedejs, E. J.
Am. Chem. Soc. 2003, 125, 10502 and references therein.
Having observed quantitative product formation and essen-
tially no hydrodehalogenation of PhBr during the course of the
arylation reaction with tert-butyl-substituted phosphepine 5b,
we next re-evaluated this ligand using microwave heating to
shorten the reaction time. Conditions previously optimized using
ligands 1a/b were first investigated for the arylation of benz-
imidazole with PhBr (eq 6). A 74% yield of the desired 2-phen-
ylbenzimidazole was observed under these conditions (Table
1, entry 1), but functionalized aryl bromides were poorly toler-
ated. These results utilizing microwave heating differed greatly
from those observed in d8-THF at 150 °C under conventional
heating, under which broad functional group tolerance was
1
observed by H NMR spectroscopy over long reaction times
(data not shown). Product decomposition was suspected as a
cause for the low yields obtained in some of these cases;
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Arylation of Heterocycles via C−H Bond Activation
A R T I C L E S
Table 2. Scope of Aryl Bromides Compatible with Arylation
Reaction
Table 1. Optimization of Reaction Conditions Using Microwave
Heating
entry
solvent
time (min)
temp (
°
C)
yield (%)a
1
2
3
4
5
DCB
40
40
120
240
120
250
250
200
200
200
74
77
88
84
83
DCB/THF (1:1)
DCB/THF (1:1)
DCB/THF (1:1)
THF
a Determined by 1H NMR spectroscopy relative to 2,6-dimethoxytoluene
internal standard.
however, catalyst decomposition, indicated by the presence of
significant Rh black precipitate in the reaction vessels, was also
cause for concern.
Both of these difficulties most probably arose from either
the high temperature or the solvent, 1,2-dichlorobenzene (DCB),
employed in our previously published conditions.8 Investigation
of reaction solvent, time, and temperature for reactions conduct-
ed in a microwave reactor revealed that the reaction temperature
could be reduced to 200 °C from 250 °C by extending the
reaction time to 2 h from 40 min in a DCB/THF solvent mixture
(Table 1, entries 1-4). Furthermore, at this reduced temperature,
THF could be used without a high-boiling cosolvent to provide
the desired product in good yield and with no Rh black
precipitation (entry 5).20 The elimination of DCB, a halogenated
and toxic solvent, has significant practical implications for
reaction workup, waste disposal, and product purification.
a Isolated yield of pure product.
Substrate Scope
The optimized reaction conditions were then utilized to arylate
benzimidazole with a variety of aryl bromides in good to
excellent yield (eq 7, Table 2). Very high functional group
tolerance was observed, and many substrates not compatible
with our previously published methods, and not demonstrated
using Pd catalysis, are now viable. In particular, sulfinyl, chloro,
acetamide, free hydroxy, and free amine groups were all
tolerated (entries 1-12). However, while para and meta sub-
stitution were tolerated, ortho substitution was not. Electron-
rich heteroaryl bromides, including 5-bromo-1-methylindole,
5-bromobenzoxazole, 5-bromobenzothiazole, and 3-bromothio-
phene, also coupled in excellent yields (entries 13-16). These
results are particularly notable given that these electron-rich
heterocycles undergo electrophilic metalation by Pd catalysts,
which complicates their use in palladium-mediated direct
arylation chemistry.1a
Table 3. Scope of Heterocycles Compatible with Arylation
Reaction
A variety of additional heterocycles were also compatible with
the Rh-catalyzed arylation conditions, and conveniently, optimal
yields with these substrates were obtained at an increased
a Isolated yield of pure product. b Six-hour reaction time.
(20) The reaction pressures obtained under these conditions can reach the limits
of commercial microwave reactors, so care must be taken to leave enough
head space in the reaction vessel to avoid overpressure errors and vial bursts
(3 mL of THF can be heated to 200 °C in a 5-mL Biotage microwave vial
without incident).
reaction concentration of 0.3 M (eq 8, Table 3). N-Methylben-
zimidazole and benzoxazole coupled in good yield (entries 1
and 2, respectively), and for the first time using Rh catalysis,
9
J. AM. CHEM. SOC. VOL. 130, NO. 8, 2008 2497

A R T I C L E S
Lewis et al.
formation was readily accomplished by briefly stirring 5b with
excess aqueous HBF4, extracting the salt with CH2Cl2, and
concentrating the organic extracts to yield [5bH]BF4 as an air-
stable white solid. Importantly, this material provided results
identical to those obtained using the free phosphine (5b) in the
coupling of benzimidazole and PhBr (eq 9, Table 4, entries 1
and 2).
Table 4. Comparison of Reaction Conditions
entry
phosphine
[Rh]
base
setup
yield (%)a
Significantly, [RhCl(coe)2]2, an expensive and air-sensitive
catalyst, could be replaced with [RhCl(cod)]2 (cod ) cyclo-
octadiene), a much cheaper and air-stable catalyst, with essen-
tially no change in product yield (Table 4, entry 3). Previous
attempts to use this Rh source in both the arylation and alkyla-
tion reactions developed in our group had resulted in decreased
product yields, presumably due to the greater difficulty of
displacing a bidentate olefin ligand with the monodentate,
sterically hindered phosphines employed in those methods. In
contrast, the bidentate P-olefin ligand 5b readily displaces the
cod ligand to provide the active arylation catalyst. Most
importantly, the aforementioned phosphine and Rh substitutions
enabled easy assembly of the arylation reactions outside a
glovebox, without purification of any reagents, using only a N2
line to provide an inert atmosphere in the microwave vessel
(entry 4). A small set of arylation reactions were repeated under
the modified conditions to establish the generality of this
protocol (eq 10, Table 5). Good to high yields of the desired
1
2
3
4
5b
[RhCl(coe)2]2 i-Pr2i-BuN glovebox
98
98
100
90
[5bH]BF4 [RhCl(coe)2]2 i-Pr2i-BuN glovebox
5b
[5bH]BF4 [RhCl(cod)]2
[RhCl(cod)]2
i-Pr2i-BuN glovebox
i-Pr2i-BuN N2 line
a Isolated yield of pure product.
benzothiazole was a viable substrate (entry 3). Pharmaceutically
important bisarylimidazoles were also excellent arylation sub-
strates, and both indolyl and pyridyl substitution, common to a
number of known drug candidates, could be present on the
imidazole ring (entries 4-7), although pyridine substitution did
result in reduced yield (entry 7).21 Finally, arylation of 4,5-
dimethylthiazole and the nonaromatic 4,4-dimethyloxazoline
provided moderate yields of the corresponding arylated products
(entries 8 and 9).
Direct Arylation Using [5bH]BF4 under Convenient
Conditions without Use of a Glovebox
The success observed for the arylation of heterocycles using
5b next led us to pursue strategies designed to simplify the
experimental procedure by avoiding the use of a glovebox and
purified reagents. We therefore sought to protect the air-sensitive
ligand 5b as its corresponding HBF4 salt, as previously described
by Netherton and Fu for the protection of PtBu3.22 The excess
base present under our reaction conditions could then be
exploited to generate the active phosphine in situ. HBF4 salt
products were obtained for a range of aryl bromides and
heterocycles. Only modest decreases in product yield were
Table 5. Arylation of Azoles Using [5bH]BF4
a Concentration of heterocycle. b Isolated yield of pure product.
9
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Arylation of Heterocycles via C−H Bond Activation
A R T I C L E S
Table 6. Determination of Catalyst Loading
entry
solvent
concna
temp (
°
C)
time (h)
yield (%)b
1
2
3
4
5
THF
0.1
0.1
0.3
0.3
0.3
165
165
165
165
175
120
120
72
48
24
62
82
100
90c
90c
dioxane
dioxane
dioxane
dioxane
a Concentration of benzimidazole. b Yield determined by GC with
dodecane as an internal standard unless otherwise noted. c Isolated yield of
pure product.
observed relative to the original protocol, and thus it is
anticipated that these conditions will be appropriate for most
applications. Because of the higher boiling point of dioxane
relative to that of THF, a subset of reactions was also performed
with dioxane at a reduced 2.5% precatalyst loading, and good
yields were also observed under these reaction conditions
(entries 2, 4, 6, and 8).
Figure 6. Proposed mechanism for heterocycle arylation employing
Rh/5b.
The high product yields and long catalyst lifetimes observed
in heterocycle arylation reactions using ligand 5b in combination
with [RhCl(L)2]2 (L ) coe or cod) precatalysts are believed to
result from stabilization of the Rh center by hemilabile olefin
coordination. On the other hand, a variety of bidentate phos-
phines and P-N ligands were also screened as ligands for the
Rh-catalyzed arylation of benzimidazole with bromobenzene,
but little or no product was observed in each case. The (Z)-
2,3,6,7-tetrahydrophosphepine scaffold must therefore provide
a unique coordination environment well suited for our hetero-
cycle arylation chemistry and may prove useful in other
transition-metal-catalyzed reactions.
Catalyst Loading
Preliminary investigation of catalyst loading, which becomes
increasingly important for large-scale reactions, was also
performed (eq 11, Table 6). For this study, conventional heating
was used because microwave heating is not typically performed
with large-scale reactions. At 1% loading of the [RhCl(coe)2]2
precatalyst, high conversion with high isolated yields could be
achieved by performing the reaction in dioxane with benzimi-
dazole at 0.3 M (entries 3-5). By performing the reaction at
175 °C, a high yield of arylation product was obtained within
24 h (entry 5). Lower conversions and/or extended reaction times
were required when the reactions were performed in THF (entry
1) or at a lower benzimidazole concentration (entry 2).
Conclusions
In summary, we have developed a practical, functional group
tolerant method for the Rh-catalyzed direct arylation of a variety
of pharmaceutically important heterocycles with aryl bromides.
Essential to the success of this method was the use of Z-1-tert-
butyl-2,3,6,7-tetrahydrophosphepine, 5b, as a ligand that coor-
dinates to Rh in a bidentate P-olefin fashion to provide a highly
active yet thermally stable catalyst. Furthermore, the initial
reaction mixtures could be assembled without the use of a
glovebox or purified reagents when the tetrafluoroborate salt
of the phosphine was employed. The arylation reaction likely
occurs via a novel C-H bond activation pathway involving a
substrate-based NHC intermediate, which provides substrate
scope orthogonal to that reported for Pd-catalyzed reactions. In
particular, unprotected N-H azoles and a wide array of
functionalized aryl bromides and electron-rich heteroaryl bro-
mides are compatible with the Rh-phosphepine catalyst. The
reactions can be conducted in THF, which greatly simplifies
product isolation relative to the procedure required under our
previously published conditions, which require 1,2-dichloroben-
zene as solvent, and Pd-based heterocycle arylation methods
carried out with high-boiling amide solvents. By heating the
reaction solutions in a microwave reactor, excellent product
yields were achieved with 2-h reaction times.
Proposed Mechanism
A possible mechanism that accounts for heterocycle arylation
utilizing these new ligands is presented in Figure 6. Combination
of 5b and [RhCl(coe)2]2 provides the dimer complex 7 (vide
supra). Dissociation of this complex and coordination of the
heterocycle would provide the heterocycle complex 36, which
is very similar to that observed in the very well characterized,
related reactions of N-methylbenzimidazole, 3,4-dihydroquinazo-
line, and other heterocycles with RhCl(PCy3)2.9 The formation
of carbene complex 37 is presumed to occur via a C-H
activation/tautomerization process that was also previously
documented in the study of carbene-rhodium complex forma-
tion with 3,4-dihydroquinoline.9 This low-valent, electron-rich
Rh complex is ideally suited for oxidative addition of aryl
halides to generate the (aryl)(carbene)rhodium complex 38.
Elimination of HBr from this complex in either an intramo-
lecular fashion or assisted by the added amine base would then
lead to complex 39. Finally, reductive elimination of the desired
arylated product would regenerate the Rh catalyst.
(21) (a) Chang, L. L.; Sidler, K. L.; Cascieri, M. A.; de Laszlo, S.; Koch, G.;
Li, B.; MacCoss, M.; Mantlo, N.; O’Keefe, S.; Pang, M.; Rolando, A.;
Hagmann, W. K. Bioorg. Med. Chem. Lett. 2001, 11, 2549. (b) de Laszlo,
S.; Hacker, C.; Li, B.; Kim, D.; MacCoss, M.; Mantlo, N.; Pivnichny, J.
V.; Colwell, L.; Koch, G. E.; Cascieri, M. A.; Hagmann, W. K. Bioorg.
Med. Chem. Lett. 1999, 9, 641. See also refs 2a-c.
Experimental Section
(Z)-1-tert-Butyl-2,3,6,7-tetrahydro-1H-phosphepine (5b). To an
oven-dried round-bottom flask under N2 were added tert-butyldichlo-
rophosphine (2.1 g, 13.2 mmol) and THF (45 mL). The solution was
(22) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295.
9
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A R T I C L E S
Lewis et al.
cooled to 0 °C, and a solution of 3-butenylmagnesium bromide (0.76
M, 37.5 mL, 27.7 mmol) was added dropwise via syringe. The reaction
mixture was allowed to warm to room temperature overnight (ca. 12
h) and quenched by slow addition of i-PrOH (10 mL) and water (10
mL). Aqueous hydrogen peroxide (3 mL, 30% wt/wt) was then added
slowly via syringe (caution, exothermic reaction), and the reaction
mixture was stirred at room temperature for 4 h. The reaction mixture
was further diluted with water (100 mL), and the volatile materials
were removed by rotary evaporation. The reaction mixture was then
extracted with CH2Cl2 (3 × 100 mL), and the combined CH2Cl2 extracts
were dried, filtered, and concentrated to give the crude product (dibut-
3-enyl(tert-butyl)phosphine oxide, 3.6 g) as a viscous oil in good purity
as judged by 31P NMR spectroscopy. This residue was degassed using
three cycles of evacuation and N2 purging, dissolved in CH2Cl2, and
added to a round-bottom flask fitted with a condenser and septum under
N2. A CH2Cl2 solution of Grubbs’ first-generation metathesis catalyst
(0.50 g, 0.046 mmol) was added through the condenser, and the
resulting solution (275 mL total volume) was heated at reflux for 24 h
to affect nearly complete conversion to the desire phosphepine oxide
as judged by 31P NMR spectroscopic analysis of an aliquot taken from
the reaction mixture. The solution was concentrated, loaded onto a
Biotage samplet using a minimal amount of CH2Cl2 (ca. 1-3 mL),
and purified using a MeOH/CH2Cl2 gradient (Rf ) 0.3 in 4% MeOH/
CH2Cl2) to provide 2.33 g (95%) of 4b as a brown oil that partially
was vigorously stirred for 15 min. The mixture was extracted with 3
× 25 mL of CH2Cl2, and the combined organic extracts were dried
with MgSO4, filtered, and concentrated to provide 0.0992 g (65%) of
[5bH]BF4 as a white solid. 1H NMR (400 MHz, CDCl3): δ 6.39 (dm,
J ) 488.7 Hz, 1H), 5.94 (m, 2H), 2.72 (m, 6H), 1.94 (m, 2H), 1.41 (d,
J ) 17.2 Hz, 9H). 13C NMR (100 MHz, CDCl3): δ 131.0 (s), 28.6 (d,
J ) 43.3 Hz), 24.9 (s), 19.9 (d, J ) 6.6 Hz), 12.7 (d, J ) 43.3 Hz). 31
P
NMR (162 MHz, C6D6): δ 34.4 ppm. IR (ZnSe, thin film) νmax (cm-1):
2954 (br, w), 1472 (w), 1409 (w), 1378 (w), 1199 (w), 1093 (m),
1045 (s). HRMS-FAB (m/z): [M]+ calcd for C10H20P, 171.130264;
found, 171.130860.
Typical Procedure for Cross-Coupling Azoles and Aryl Bromides
(Microwave Protocol), 2-Phenyl-1H-benzo[d]imidazole (17). In an
inert atmosphere box, a stir bar, the appropriate heterocycle (e.g.,
benzimidazole, 0.0481 g, 0.4 mmol), and 1 mL of THF were added to
a 5-mL glass microwave vial. Into a separate vial were weighed 5b
(0.102 g, 0.06 mmol) and [RhCl(coe)2]2 (0.0143 g, 0.02 mmol), and
the catalyst was transferred to the microwave vial using 2 mL of THF.
The appropriate aryl bromide (e.g., bromobenzene, 0.1261 g, 0.8 mmol)
was transferred to the microwave vial using 1 mL of THF, and i-Pr2i-
BuN (0.245 mL, 1.2 mmol) was added directly to the vial via syringe.
The vial was sealed, removed from the inert atmosphere box, and heated
for 2 h at 200 °C. The reaction mixture was then cooled, quenched
with excess Et3N (0.5 mL), and concentrated under reduced pressure.
The residue was dissolved in a minimal amount of methanol/methyelene
chloride (ca. 1-2 mL), loaded onto a silica gel samplet (Biotage No.
SAM-1107-16016), and purified using flash chromatography. A
suitable gradient was calculated by the Biotage SP (10-80% ethyl
acetate/hexanes) given a product Rf of 0.32 in 40% ethyl acetate/
hexanes. The desired product was obtained as 0.0775 g (98% yield,
Table 2, entry 7) of a white solid. For other heterocycles, the
concentration of the reactants was increased to 0.3 M. The amount of
heterocycle (mmol) and the concentration (M) of the reaction are
therefore provided for each entry. Mp 284-285 °C (lit. 285-286 °C).23
1H NMR (400 MHz, CD3OD): δ 8.10 (m, 2H), 7.61 (br s, 2H), 7.54
(m, 2H), 7.27 (m, 2H).
1
solidified on standing. H NMR (400 MHz, CDCl3): δ 5.80 (m, 2H),
2.63 (m, 2H), 2.17 (m, 2H), 1.79 (m, 2H), 1.42 (t, J ) 13.6 Hz, 2H),
1.04 (d, J ) 13.9 Hz, 9H). 13C NMR (100 MHz, CDCl3): δ 132.2 (s),
31.3 (d, J ) 67.5 Hz), 24.1 (s), 22.7 (d, J ) 59.4 Hz), 18.5 (d, J ) 5.1
Hz). 31P NMR (162 MHz, CDCl3): δ 58.0. IR (ZnSe, thin film) νmax
(cm-1): 3020, 2947, 2907, 2862, 1647, 1463, 1394, 1365, 1190, 1151
(PdO). HRMS-EI (m/z): [M]+ calcd for C10H19OP, 186.117354; found,
186.116842.
A vial containing phosphepine oxide 4b (2.33 g, 12.5 mmol) was
fitted with a septum and degassed using three cycles of evacuation
and N2 purging. This material was dissolved in toluene (10 mL) and
added to a round-bottom flask fitted with a reflux condenser and a
septum under N2. Phenylsilane (6.0 mL, 50 mmol) was added, and the
reaction mixture was heated at reflux until complete conversion of the
starting material had occurred (16 h). The volatile materials were
removed under high vacuum, and the residue was distilled under
reduced pressure (0.15 mmHg, 50 °C) using a Ku¨gelrohr apparatus to
provide 1.187 g (56%) of 5b as a colorless liquid. 1H NMR (400 MHz,
C6D6): δ 5.72 (m, 2H), 2.31 (m, 4H), 1.50 (m, 2H), 1.24 (m, 2H),
0.95 (d, J ) 10.9 Hz, 9H). 13C NMR (100 MHz, C6D6): δ 131.6 (s),
27.3 (d, J ) 11.7 Hz), 26.9 (d, J ) 13.2 Hz), 24.3 (d, J ) 13.2 Hz),
20.0 (d, J ) 19.0 Hz). 31P NMR (162 MHz, C6D6): δ 7.0. HRMS-EI
(m/z): [M]+ calcd for C10H19P, 170.122439; found, 170.122376.
(Z)-1-tert-Butyl-2,3,6,7-tetrahydro-1H-phosphonium Tetrafluo-
roborate ([5bH]BF4). In an inert atmosphere box, 5b (0.101 g, 0.587
mmol) and a stir bar were added to a vial. The vial was sealed with a
septum and removed from the box. CH2Cl2 (6 mL) and HBF4 (0.50
mL, 2.94 mmol, 48 wt % aqueous solution) were added, and the mixture
Acknowledgment. This work was supported by the NIH
GM069559 to J.A.E. and by the Director and 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. NIH postdoctoral fellowship support to
A.M.B. is also gratefully acknowledged.
Supporting Information Available: Experimental procedures,
analytical and spectral characterization data for all new com-
pounds, and crystallographic information files (CIF) for com-
pounds 3 and 7. This material is available free of charge via
the Internet at http://pubs.acs.org.
JA0748985
(23) Perry, R. J.; Wilson, B. D. J. Org. Chem. 1993, 58, 7016.
9
2500 J. AM. CHEM. SOC. VOL. 130, NO. 8, 2008