Microwave-promoted rhodium-catalyzed arylation of heterocycles through C-H bond activation

Article abstract of DOI:10.1002/anie.200504289

Performance-enhancing ligands: Two new bridged bicyclic phosphines 1a,b based on the "phoban" skeleton (see structures of their naphth-2-ylmethyl bromide salts; P yellow, Br brown, C white) are central to a practical catalytic method for the direct arylation of a variety of nitrogen heterocycles using aryl bromides. Broad functional-group tolerance was observed, and the use of microwave radiation allowed for short reaction times. (Chemical Equation Presented)

Full text of DOI:10.1002/anie.200504289

Angewandte
Chemie
CÀH Activation
catalyzed arylation reactions in particular suffer from hydro-
dehalogenation of the starting aryl iodide and dehydrogen-
ation of the tricyclohexylphosphine used as an added ligand.
[
6]
DOI: 10.1002/anie.200504289
Herein, we report the solution to several of these problems in
the development of a new microwave-promoted hetero-
cycle–aryl bromide direct coupling reaction that employs
rhodium catalysts in the presence of 9-cyclohexylbicyclo-
Microwave-Promoted Rhodium-Catalyzed
[7]
Arylation of Heterocycles through CÀH Bond
Activation**
[
4.2.1]-9-phosphanonane (“cyclohexylphobane”) ligands.
Our efforts to find phosphines that would maintain the
Jared C. Lewis, Jessica Y. Wu, Robert G. Bergman,* and
Jonathan A. Ellman*
unique steric and electronic qualities of PCy while reducing
3
the ability of the phosphine to undergo dehydrogenation led
[
8]
to the exploration of phobanes, such as 1 (Figure 1a), for the
The advantages of directly forming carbon–carbon (CÀC)
bonds from carbon–hydrogen (CÀH) bonds in organic syn-
[
1]
thesis have driven the development and application of an
expanding body of reactions proceeding through catalytic CÀ
[
2]
H activation. One reaction that has recently received
particular attention is the C2-arylation of azoles (Scheme 1),
the products of which are commonly found in a wide array of
[
9]
Figure 1. a) Structure of 1. b) Synthesis of 2a,b. Cy=cyclohexyl.
[
3]
pharmaceuticals and materials.
Rh-catalyzed CÀH activation/olefin coupling of a dihydro-
[
9]
quinazoline. The efficacy of this phosphine for the alkyla-
tion reaction prompted further investigation into its use for
arylation.While the use of 1 as a ligand in the coupling of
benzimidazole and iodobenzene gave only a 27% yield after
heating for 30 min at 2508C in a microwave reactor, this yield
represented an improvement over that obtained using PCy3
(Table 1).The relative success of 1 also prompted our
Scheme 1. General C2-arylation of azoles.
Despite the progress that has been made in direct azole–
[
4]
aryl iodide couplings, only scattered examples of the use of
[
5]
aryl bromides have emerged. In these cases, the scope with
respect to either coupling partner is limited and the reactions
typically require extended reaction times at high temper-
atures in sealed reaction vessels.Our previously reported Rh-
Table 1: Optimization of Rh-catalyzed direct coupling.
Entry
Base (equiv)
PR3
R
Product
Yield [%]
[*] Prof. R. G. Bergman
Department of Chemistry
[a]
1
2
3
4
5
6
7
Et N (4)
PCy3
1
H
H
H
H
H
CF3
OMe
5
5
5
5
5
6
7
20
3
University of California, Berkeley and
Division of Chemical Sciences
Lawrence Berkeley National Laboratory
Berkeley, CA 94720-1460 (USA)
Fax: (+1)510-642-7714
[a]
Et N (4)
27
3
[a]
Et N (4)
2a,b
2a,b
2a,b
2a,b
2a,b
40
3
[a]
iPr iBuN (4)
71
2
[b]
[c]
[c]
iPr iBuN (3)
91 (76)
2
[b]
iPr iBuN (3)
58 (68)
2
E-mail: bergman@cchem.berkeley.edu
[a]
[c]
iPr iBuN (3)
2
10 (99)
J. C. Lewis, J. Y. Wu, Prof. J. A. Ellman
Department of Chemistry
University of California, Berkeley
Berkeley, CA 94720-1460 (USA)
Fax: (+1)510-642-8369
[
a] Yields were determined by GC analysis relative to hexamethylbenzene
as internal standard; reactions were conducted in 1,2-dichlorobenzene
DCB) heated at 2508C for 30 min in a microwave reactor. [b] Isolated
yields of pure products; reactions were conducted in DCB heated at
508C for 40 min in a microwave reactor. [c] Isolated yields of pure
(
2
E-mail: jellman@cchem.berkeley.edu
products; reactions were conducted in THF heated at 1508C for 24 h in a
sealed tube. coe=cyclooctene.
[
**] This work was supported by the NIH (grant no. GM069559, to
J.A.E.) and by the Director, Office of Energy Research, Office of Basic
Energy Sciences, Chemical Sciences Division, US Department of
Energy (contract no. DE-AC03-76SF00098, to R.G.B.). J.Y.W. is
funded by the Jean Dreyfus Boissevain Award. We gratefully
acknowledge Dr. Fredrick J. Hollander and Dr. Allen G. Oliver at the
UCB X-ray diffraction facility (CHEXRAY) for solving the structures
of 4a and 4b, and Jeffrey McMahon for many helpful discussions.
Dr. Wolfgang Meyer of Sasol Corp. is acknowledged for helpful
advice on phobane alkylation.
investigation of its isomer 2a.However, while protocols
exist for the synthesis of 1/2a mixtures and pure 1, neither 2a
nor 2b have been prepared in isomerically pure form to our
[
10]
knowledge. We were able to obtain a mixture of 2a,b (ca.
:1) from the alkylation of the corresponding secondary
2
bicyclic phosphine in analogy to 1 (Figure 1b).
The phosphine mixture was then used for the Rh-
catalyzed arylation of benzimidazole with PhI (Table 1).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Communications
Gratifyingly, use of 2a,b improved the yield of 2-phenyl-
ture to 2508C for 40 minutes in a microwave reactor led to
complete conversion of the mixture into 2a according to
P{ H} NMR spectroscopy.Possibly as a result of this isomer-
benzimidazole to 40% and little to no hydrodehalogenation
of PhI occurred over the course of a conventionally heated
3
1
1
1
reaction, as monitored by in situ H NMR spectroscopy
ization, no significant differences in yield were observed when
either isomerically pure 2a or 2b was used in the arylation of
benzimidazole with iodobenzene.Therefore, the mixture 2a,b
was used exclusively in coupling experiments.The applic-
ability of this mixture is of practical importance as it can be
obtained by Kugelrohr distillation of the crude alkylation
reaction mixture obtained in two steps from commercial
materials, with no chromatography needed (Figure 1b).
Compared to [RhCl(coe) ] /PCy , 2a,b-derived CÀH
(
Table 1, entry 3).The use of a more hindered amine base,
diisopropylisobutylamine, in combination with 2a,b provided
the desired product in 71% yield (Table 1, entry 4).Further
optimization of the reaction time and stoichiometry allowed
isolation of 2-phenylbenzimidazole in 95% yield.Both
electron-rich and electron-poor aryl iodides were observed
[
11]
to couple (Table 1, entries 6 and 7). The desired products
could also be obtained in good yields by conventionally
heating the reaction mixtures in sealed tubes.Most impor-
tantly, bromobenzene was observed to couple in 80% isolated
yield under the optimized reaction conditions.
2
2
3
arylation catalysts uniquely promote the direct coupling of
benzimidazole to aryl bromides without significant interfer-
ence from hydrodehalogenation.This reaction also exhibits
considerable functional group tolerance. para-Substituted 2-
arylbenzimidazoles incorporating a wide variety of functional
groups, including nitrile, chloride, alkoxy, ketone, and amide
substituents, were isolated in good to high yields under
standard microwave reaction conditions (Table 2).While the
reaction of aryl bromides that lack a sensitive functionality
could be conducted at concentrations of 0.3m, more-
reactive functional groups required more-dilute condi-
tions (0.05 or 0.1m) to obtain high yields of the desired
products. meta-Substitution had little effect on the out-
come of the reaction, but o-CH or o-CF substitution
To determine if there are any differences in reactivity
between 2a and 2b and to confirm the previously unreported
structure of 2b, a protocol to isolate pure 2a and pure 2b was
developed.Following protection of the mixture as the
corresponding borane adducts 3a,b, chromatography was
successfully used to resolve the two isomers (Scheme 2).Acid
3
3
completely suppressed the desired reaction, consistent
with known difficulties for sterically hindered cross-
[
14]
coupling reactions. Highly electron-rich aryl bromides
led to decreased yields (Table 2, entries 9 and 12), but the
use of aryl iodides circumvents this problem (Table 1,
entry 7).
Scheme 2. Separation and characterization of 2a and 2b.
Besides tolerating various substituted aryl bromides,
the optimized reaction conditions were compatible with a
number of different heterocycles (Table 3).As previously
observed for the conventionally heated coupling of aryl
[
12]
deprotection provided the pure phosphines 2a and 2b,
which were alkylated with naphth-2-ylmethyl bromide to
provide crystalline phosphonium salts 4a and 4b.
Single-crystal X-ray analysis revealed that 4a and 4b are
indeed isomers differing in the orientation of the cyclohexyl
Table 2: Functional group tolerance under optimized arylation condi-
tions.
[
13]
substituent (4a exo, 4b endo; Figure 2).
Starting from
isolated 3a,b, each step in sequence provided a single
3
1
1
phosphorus-containing species as judged by P{ H} NMR
spectroscopy, suggesting that the configuration at phosphorus
remained constant throughout.Heating a solution of 2a,b to
1
508C for several hours led to no change of the mixture by in
[a]
[b]
Entry
R
Conc. [m]
Product
Yield [%]
3
1
1
situ P{ H} NMR spectroscopy.However, heating the mix-
1
2
3
4
5
6
7
8
9
p-CF3
p-CN
p-Cl
p-COEt
p-CONH2
p-Ph
p-H
p-Me
p-OMe
m-CO Et
0.3
0.1
0.1
0.05
0.1
0.3
0.3
0.3
0.1
0.05
0.1
6
8
9
10
11
12
5
13
7
77 (60)
90
67
77 (59)
60
81
80 (28)
91
54 (24)
70
79
46
10
11
12
14
15
16
2
m-Me
m-OEt
0.05
[a] Reaction concentration relative to azole starting material. [b] Isolated
yields of pure products. Yields in parentheses were obtained from in situ
Figure 2. ORTEP diagrams of a) 4a and b) 4b. Thermal ellipsoids are
NMR spectroscopic analysis of reactions that were conducted in [D ]THF
8
shown at the 50% probability level.
and conventionally heated at 1508C for 24 h in a sealed tube.
1
590
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Angewandte
Chemie
Table 3: Heterocycle scope for Rh-catalyzed arylation.
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[
a]
[b]
Entry
Heterocycle
Conc. [m]
Product
17
Yield [%]
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2
0.1
55
63
0.1
18
[
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4] a) Nomura and co-workers found Pd(OAc) /PPh to be a viable
2
3
3
4
0.05
0.05
19
20
45
75
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mides were coupled with benzothiazole and benzoxazole in: D.
5
6
0.1
0.1
21
22
86
50
Alagille, R.M. Baldwin, G.D. Tamagnan,
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2
[
6] J.C.Lewis, S.H.Wiedemann, R.G.Bergman, J.A.Ellman,
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[
a] Reaction concentration relative to azole starting material. [b] Isolated
yields of pure products.
[
717 – 727; b) B.A.Roberts, C.R.Strauss, Acc. Chem. Res. 2005,
3
8, 653 – 661.
iodides, both N-methylbenzimidazole and benzoxazole
couple in moderate yields, but benzothiazole was incompat-
ible with the reaction conditions.Dihydroquinazoline, which
contains a non-aromatic heterocycle, provided 2-phenylquin-
[
8] “Phoban” is commerically available as a technical mixture of
3.3.1] and [4.2.1] isomers and has received limited but continual
[
attention since its original patent in 1968: a) R.G.Mason, J.L.
van Winkle (Shell Oil Co.), US Patent 3400163, 1968; b) For
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[
6]
azoline as observed previously. Bis(aryl) imidazoles, a
[
15]
highly important class of bioactive compounds, were also
highly effective arylation substrates.The observed substrate
scope is fully consistent with our mechanistic understanding
based on N-heterocyclic carbene/rhodium complexes as
1
995, 14, 759 – 766; d) G.S. Forman, A.E. McConnell, M.J.
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lics, 2004, 23, 4824 – 4827.
[
16]
intermediates in CÀC bond formation.
Organometal-
J. Org. Chem.,
In conclusion, a highly general method for the direct
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shown to provide rapid access to medicinally relevant
compounds.The bulky trialkylphosphines 2a and 2b were
synthesized and characterized and proved to be superior to
PCy3 under our arylation conditions, presumably because
their rigid bicyclic structure prohibits dehydrogenation, a
[9] S.H.Wiedemann, R.G.Bergman, J.A.Ellman,
in press.
10] a) see ref.[8d]; b) C.L.Dwyer, M.M.Kirk, W.H.Meyer, W.J.
van Rensburg, G.S.Forman, unpublished results.
11] Significant amounts of demethylation were observed for the
microwave-mediated arylation using iodoanisole, presumably
due to nucleophilic displacement by iodide anion at high
temperatures.
[
[
liability of PCy .The use of microwave radiation as a heat
3
source for the arylation reactions allowed a convenient access
to the temperatures needed to allow complete reaction in only
[12] Z.Chen, Q.Jiang, G.Zhu, D.Xiao, P.Cao, C.Guo, X.Zhang,
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Org. Chem. 1997, 62, 4521 – 4523.
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996, 35, 5805 – 5812; b) S.J.Coles, P.G.Edwards, M.B.Hurst-
4
0 minutes and eliminated the safety concerns associated with
sealed-tube conditions used for other arylation methods.
Thus, information provided by mechanistic studies was used
to guide relatively conservative modifications to our existing
catalytic system and led to dramatic improvements in
generality and practicality.
1
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[
[
Received: December 2, 2005
Published online: January 30, 2006
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J. Am. Chem. Soc.
2
Keywords: arylation · CÀH activation · heterocycles ·
.
phosphane ligands · rhodium
Angew. Chem. Int. Ed. 2006, 45, 1589 –1591
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
1591