Microwave-assisted C-H bond activation: A rapid entry into functionalized heterocycles

Article abstract of DOI:10.1021/ol030050j

(Matrix presented) Microwave irradiation strongly accelerates the rhodium-catalyzed intramolecular coupling of a benzimidazole C-H bond to pendant alkenes. The cyclic products were formed in moderate to excellent yields with reaction times less than 20 min. Additionally, the use of microwave irradiation allowed the reactions to be performed without any solvent purification and with minimal precautions to exclude air.

Full text of DOI:10.1021/ol030050j

ORGANIC
LETTERS
2003
Vol. 5, No. 12
2131-2134
Microwave-Assisted C−H Bond
Activation: A Rapid Entry into
Functionalized Heterocycles
,†,‡
Kian L. Tan,† Anil Vasudevan,§ Robert G. Bergman,*
,†
,|
Jonathan A. Ellman,* and Andrew J. Souers*
Center for New Directions in Organic Synthesis, Department of Chemistry,
UniVersity of California-Berkeley, Berkeley, California 94720,
DiVision of Chemical Sciences, Lawrence Berkeley National Laboratory,
Berkeley, California 94720, and Medicinal Chemistry Enabling Technologies and
Metabolic Disease Research, Abbott Laboratories, 100 Abbott Park Road,
Abbott Park, Illinois 60064
andrew.souers@abbott.com
Received April 1, 2003
ABSTRACT
Microwave irradiation strongly accelerates the rhodium-catalyzed intramolecular coupling of a benzimidazole C−H bond to pendant alkenes.
The cyclic products were formed in moderate to excellent yields with reaction times less than 20 min. Additionally, the use of microwave
irradiation allowed the reactions to be performed without any solvent purification and with minimal precautions to exclude air.
Microwave-assisted organic synthesis has emerged as a
powerful tool in organic chemistry. The ability to rapidly
heat and thermally quench reactions has resulted in dramatic
increases in the rates and yields of a variety of chemical
transformations.1 Because of the safe and reproducible
heating of sealed vessels in a microwave reactor, both the
academic and industrial communities have utilized this
technology. Furthermore, automation now enables its use in
high-throughput reaction optimization and in rapid analogue
synthesis, particularly for drug discovery efforts. The utility
of microwave-assisted synthesis is exemplified by its recent
successful application to transition metal-mediated reactions
such as transfer hydrogenation, allylic alkylation, hydro-
acylation,2 Heck-type couplings, and Suzuki, Stille, and
Sonogashira couplings.1
Recently, we developed both the inter-3 and intramolecu-
lar4 alkylation of heterocycles by C-H bond activation
(Scheme 1).5 This methodology allows for the rapid func-
(2) (a) Jun, C. H.; Chung, J. H.; Lee, D. Y.; Loupy, A.; Chatti, S.
Tetrahedron Lett. 2001, 42, 4803-4805. (b) Loupy, A.; Chatti, S.; Delamare,
S.; Lee, D. Y.; Chung, J. H.; Jun, C. H. J. Chem. Soc., Perkin Trans. 1
2002, 1280-1285.
(3) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2002,
124, 13964-13965.
(4) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2001,
123, 2685-2686.
(5) For reviews of C-H activation, see: (a) Dyker, G. Angew. Chem.,
Int. Ed. 1999, 38, 1699-1712. (b) Jia, C. G.; Kitamura, T.; Fujiwara, Y.
Acc. Chem. Res. 2001, 34, 844-844. (c) Kakiuchi, F.; Murai, S. Acc. Chem.
Res. 2002, 35, 826-834. (d) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV.
2002, 102, 1731-1769.
† University of California-Berkeley.
‡ Lawrence Berkeley National Laboratory.
§ Medicinal Chemistry Enabling Technologies, Abbott Laboratories.
| Metabolic Disease Research, Abbott Laboratories.
(1) For reviews of microwave applications in organic chemistry, see:
(a) Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem. Res. 2002, 35, 717-
727. (b) Wathey, B.; Tierney, J.; Lidstrom, P.; Westman, J. Drug DiscoVery
Today 2002, 7, 373-380. (c) Lew, A.; Krutzik, P. O.; Hart, M. E.;
Chamberlin, A. R. J. Comb. Chem. 2002, 4, 95-105. (d) Lidstrom, P.;
Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225-
9283.
10.1021/ol030050j CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/16/2003

a
Scheme 1. Intra- and Intermolecular Coupling Reactions
Table 1. Substrate Generality with RhCl(PPh3)3
tionalization of a variety of heterocycles, which have proven
to be important scaffolds in drug discovery.6 Furthermore,
the use of C-H activation overcomes several limitations of
traditional cross-coupling reactions. The coupling of a C-H
bond and an alkene obviates the need to prefunctionalize
the starting materials, and consequently, fewer byproducts
are formed. Because of the simplicity of the starting
materials, the pool of commercially available compounds is
both vast and inexpensive. However, the air-sensitive nature
of the catalyst, as well the high temperatures and long
reaction times required, make this methodology difficult to
apply to industrial drug discovery applications. Herein, we
report a facile microwave-assisted intramolecular C-H bond
activation-cyclization that circumvents the limitations de-
scribed above. This was achieved through the optimization
of the catalytic conditions and solvent selection.
We had previously reported that Wilkinson’s catalyst could
be used to effect the cyclization of alkene 1 (cf. Table 1) in
modest yield when heated to 160 °C in toluene for several
hours in a sealed vessel. This commercially available and
air-stable catalyst represented a good starting point for the
optimization of the microwave conditions. However, the poor
microwave absorption characteristics of toluene and THF7
afforded little to no conversion of compound 1 to 2 when
heated at elevated temperatures for 20 min in the microwave
reactor.8 Previous studies with conventional heating dem-
onstrated that commonly used microwave solvents such as
water, DMSO, and DMF were poor media for the C-H/
alkene coupling reaction. After investigating different sol-
vents and solvent combinations with varying dielectric
constants and heating profiles, we found that heating 1 at
250 °C for 20 min in o-dichlorobenzene (DCB) afforded
efficient conversion to 2.
a Conditions: 3:1 DCB/acetone, 20 min, 250 °C, 10 mol % RhCl(PPh3)3.
1
b Yield determined by H NMR.
solvent polarity and coordination ability. It was also antici-
pated that the solubility of most heterocycles in DCB would
be limited. We therefore tested the compatibility of cosol-
vents in the reaction by using mixtures of DCB with varying
amounts of THF, CH3CN, and acetone. The solvent screen
was conveniently performed by use of a liquid handler and
programmable robotic interface, which allowed for rapid
evaluation of solvent mixtures. This effort led to the
discovery that both CH3CN and THF had a negative impact
on the reaction rate. However, acetone proved to have a
beneficial effect, which not only resulted in a modest
improvement in reaction yield but also helped to solubilize
the catalyst and starting materials.
The solvent system was further optimized by performing
a survey of different ratios of acetone and o-dichlorobenzene.
The addition of 10-25% of acetone in o-dichlorobenzene
gave optimal results. The origin of this effect is not easily
discerned. Because of the facility with which the target
temperature is achieved using the acetone/DCB mixture
(relative to neat DCB), combined with the improved solubil-
ity of reaction components, a simple thermal effect cannot
be ruled out. Interestingly, the addition of as much as 20%
water in DCB was also an effective solvent system for the
conversion of alkene 1 to product 2. Because of the high
pressures that resulted from the biphasic mixture of water
and DCB, the reactions were often interrupted due to built-
in safety features in the microwave reactor.
Encouraged by this result, we turned our attention toward
increasing the reactivity of the system by adjusting the
(6) (a) Roth, T.; Morningstar, M. L.; Boyer, P. L.; Hughes, S. H.;
Buckheit, R. W.; Michejda, C. J. J. Med. Chem. 1997, 40, 4199. (b) Wienen,
W.; Hauel, N.; Van Meel, J. C. A.; Narr, B.; Ries, U.; Entzeroth, M. Brit.
J. Pharmacol. 1993, 110, 245.
(7) Both toluene and THF have low values of tan ꢀ, making them poor
microwave solvents. Hayes, B. L. MicrowaVe Synthesis: Chemistry at the
Speed of Light; CEM Publishing: Matthews, NC, 2002; pp 29-62.
(8) Reactions with THF and toluene solutions were aborted above
temperatures of 180 °C due to pressure maxima.
With conditions that were optimal for reactivity and
solubility, we next examined the substrate generality by
2132
Org. Lett., Vol. 5, No. 12, 2003

varying the alkene substitution (Table 1). We found that
utilization of 10 mol % Wilkinson’s catalyst allowed for a
wide range of cyclic products to be formed in less than 20
min when the reaction mixture was microwave-heated to 250
°C. The solvents employed for the microwave reactions were
used without drying or degassing, and minimal precautions
were taken to exclude air from the reaction vessels. The
cyclization of alkene 3 afforded product 4 in 55% isolated
yield with a regioselectivity of 4:1 (five- vs six-membered
ring). Use of the more sterically hindered compound 5
resulted in the exclusive formation of tricycle 6. Comparable
yields were observed under the previously optimized thermal
conditions,4 but a dramatic reduction in reaction time was
observed under the microwave conditions. Aryl-substituted
alkene 7 could also be cyclized efficiently. Geminally
substituted compound 9 favored formation of the terminal
six-membered product 10, probably due to steric factors.
Finally, the use of N-allyl benzimidazole afforded the product
12 in 59% yield.
Table 2. Results with [RhCl(coe)2]2 and HClPCy3
Pleased with the initial results using RhCl(PPh3)3, we next
sought to improve the yield and reduce the catalyst loading
and reaction time. Previous studies3 of the intermolecular
reaction had demonstrated that addition of Lewis or Brφnsted
acids to [RhCl(coe)2]2 (coe ) cyclooctene) and PCy3
increased the rate and yield of the C-H/alkene coupling.
We therefore examined the application of this catalyst system
to the intramolecular coupling with one variation. Instead
of using lutidinium chloride or MgBr2 as an additive, the
HCl salt of PCy3 was employed. By combining the Brφnsted
acid with the optimal phosphine, the number of required
reagents was reduced, enhancing the operational simplicity.
Furthermore, the HCl salt also renders the phosphine air
stable9 and soluble in a variety of organic solvents. This
allows solutions of catalyst to be prepared for use in high-
throughput optimization of reactions with no rigorous glove-
box or Schlenk flask manipulations.
Application of the optimal microwave conditions with
[RhCl(coe)2]2 and HClPCy3 as the catalyst system provided
the cyclized products with substantial increases in yield.
Additionally, lower temperatures, reaction times, and catalyst
loadings were implemented (Table 2). As before, the solvents
were not degassed or dried before use. The only precaution
taken to exclude air was the purging of the reaction vessels
with nitrogen after the addition of reagents and before
capping the container.10 The cyclization of 1 proceeded at
225 °C in less than 6 min in excellent yield. The coupling
of 3 again led to a mixture of the terminal five- and six-
membered ring products with an improved regioselectivity
of 8.8:111 in favor of 4. When 11 was cyclized to 12, the
yield of the reaction was 50%, with the isomerized enamine
being the major byproduct. Vinylsilane 13, which contains
a functional group handle for further manipulation, cyclized
quantitatively in less than 12 min. The major product was
a Conditions: 225 °C, 6-12 min, 3:1 DCB/acetone, 2.5 mol %
[RhCl(coe)2]2, 5 mol % HClPCy3. b Conditions: 250 °C, 12 min, 4:1 DCB/
acetone, 2.5 mol % [RhCl(coe)2]2, 5 mol % HClPCy3. c Conditions: 250
°C, 12 min, 85:15 DCB/acetone, 5 mol % [RhCl(coe)2]2, 10 mol %
HClPCy3.
the desired heterocycle 14, but the remainder of the material
appeared to be 12 resulting from protodesilyation of the
product 14. The use of Wilkinson’s catalyst with this
substrate afforded the protodesilylated 12 almost exclusively.
Having successfully demonstrated the cyclization of a
variety of substrates using microwave irradiation, we at-
tempted to extend the scope to the intermolecular coupling
of an untethered alkene to benzimidazole. Initial attempts
to couple neohexene to benzimidazole with Wilkinson’s
catalyst afforded the alkylated product 16 in low yields.
Gratifyingly, implementation of the [RhCl(coe)2]2 and
HClPCy3 catalyst system afforded the desired compound in
58% yield in 12 min (Scheme 2). We are currently optimizing
the conditions of the reaction and extending this methodology
to other heterocycles and alkene substrates.
Scheme 2. Intermolecular Coupling
(9) Though the phosphine hydrochloride is stable to air oxidation, the
salt is hydroscopic and should be handled accordingly.
(10) Reactions could be performed in air in many cases. However, for
more challenging substrates, modest increases in yield were observed when
the vessel was purged with N2.
1
(11) Ratio determined by H NMR of the crude reaction mixture.
Org. Lett., Vol. 5, No. 12, 2003
2133

In conclusion, we have developed an efficient and
operationally simple cyclization method utilizing C-H bond
activation to rapidly access heterocyclic products that are
currently difficult to obtain with alternative methods. The
procedure is amenable to high-speed compound synthesis
and to rapid reaction optimization for individual substrates.
Additionally, we have demonstrated the successful inter-
molecular coupling of an alkene to benzimidazole. Further
studies will be reported in due course.
under Contract No. DE-AC03-76SF00098 (to R.G.B.). R.G.B
and J.A.E. acknowledge Personal Chemistry for supplying
the microwave instrument. 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 gratefully acknowledge David Whittern (Abbott
Laboratories) for NMR studies and useful discussion. This
manuscript is dedicated to the memory of Carrie Jane Smith.
Supporting Information Available: Experimental de-
tails, including analytical data for all compounds described
in the article. This material is available free of charge via
the Internet at http://pubs.acs.org.
Acknowledgment. This work was supported by a fel-
lowship (to K.L.T.) from the American Chemical Society,
by the NIH grant GM50353 (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,
OL030050J
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