Pd-catalyzed intramolecular acylation of aryl bromides via C-H functionalization: A highly efficient synthesis of benzocyclobutenones

Article abstract of DOI:10.1021/ja909811t

(Chemical Equation Presented) A new catalyst system for the intramolecular acylation of aldehydes with aryl bromides via C-H functionalization is described. The transformation is distinguished by a remarkable functional group tolerance and hence allows fo

Full text of DOI:10.1021/ja909811t

Published on Web 12/28/2009
Pd-Catalyzed Intramolecular Acylation of Aryl Bromides via C-H
Functionalization: A Highly Efficient Synthesis of Benzocyclobutenones
Paula Álvarez-Bercedo, Areli Flores-Gaspar, Arkaitz Correa, and Ruben Martin*
Institute of Chemical Research of Catalonia (ICIQ), AV. Pa¨ısos Catalans 16, 43007 Tarragona, Spain
Received November 19, 2009; E-mail: rmartinromo@iciq.es
Table 1. Optimization of Reaction Conditions
Benzocyclobutenones (BCBs) are an intriguing class of four-
membered-ring ketones.1 Their large ring strain and the great
electrophilicity of their carbonyl unit make them highly susceptible
to further manipulation. As a result, they have been successfully
used as powerful intermediates in a wide variety of remarkable
synthetic transformations,1a,2 even in the context of the total
synthesis of complex molecules.3 Surprisingly, however, a limited
number of methods have been developed for the selective formation
of BCBs. Indeed, their synthesis is usually accomplished by
intramolecular cyclization of stochiometric organolithium reagents
(route a, Scheme 1)4 or [2 + 2] cycloadditions (route b, Scheme
1).1a,5 In the latter, the regioselectivity can be nicely controlled by
the elegant approach of Suzuki using either proximal ring strain5a
or R-alkoxybenzynes.5b,c However, the need for such ortho-directing
groups as well as the use of highly reactive organolithium species
might become important issues when preparing backbones with
sensitive functional groups. Therefore, more general and direct
routes to BCBs, particularly the design of regioselective strategies
with the metal source being catalytic, would be highly desirable.
behavior. Importantly, L8 and L9 gave low conversions to either
2a or 3a, thus indicating that the nature of the diarylphosphine
backbone is crucial to the reactivity of the catalyst system. It is
worth mentioning that at the same time we conducted our work,
Larock reported the synthesis of styrene derivatives 3a in modest
yields;18 interestingly, 2a was not formed under their reaction
conditions.
Scheme 1
Having established the optimized reaction conditions, we set out
to explore the scope of this reaction. As shown in Table 2, a host
of aryl bromides with ortho, meta, or para electron-donating or
electron-withdrawing substituents reacted with good to excellent
Table 2. Pd-Catalyzed Synthesis of Benzocyclobutenonesa,b
In recent years, metal-catalyzed acylation of π systems such as
alkenes and alkynes have become powerful tools in organic
synthesis.6 Despite the advances realized,7-9 particularly the Heck-
type process recently reported by Xiao,10,11 direct acylation of
aldehydes with aryl halides via metal-catalyzed C-H bond func-
tionalization remains less explored.12,13 As part of our investigations
into Pd chemistry,14 we present herein a versatile intramolecular
acylation of aryl bromides via a C-H bond-functionalization event
for the synthesis of BCBs (route c, Scheme 1).15,16 The protocol is
distinguished by its wide scope, thus opening access to function-
alized BCB cores with a diverse set of substitution patterns that
are beyond reach otherwise.
We began our study using readily available 1a as the model
substrate (Table 1).17 A variety of experimental variables, such as
the Pd precatalyst, ligand, base, and solvent, were systematically
examined. After several rounds of optimization, we found that the
best results were accomplished using Pd(OAc)2, Cs2CO3, and a
bidentate diarylphosphine in dioxane at 110 °C. Under these reaction
conditions, we obtained variable amounts of 2a and 3a. While low
conversions to 2a were found for commonly employed L1-L5,
the use of the binaphthyl-type ligands L6 and L7 exclusiVely
afforded 2a with not eVen a trace of 3a detected in the crude
reaction mixtures. At present, we have no explanation for this
a Conditions: ArBr (0.5 mmol), Pd(OAc)2 (2 mol %), L6 (3 mol %),
Cs2CO3 (0.6 mmol), dioxane (2 mL), 110 °C. b Isolated yields, average
of two runs. c From ArCl. d Pd(OAc)2 (4 mol %). e Using L7. f Cs2CO3
(2.40 equiv).
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10.1021/ja909811t  2010 American Chemical Society

C O M M U N I C A T I O N S
yields. Unlike other [2 + 2] cycloaddition approaches, the regio-
selectivity is totally controlled for unsymmetrical substrates, thus
avoiding the need for directing-group methodologies.5 Particularly
significant is the chemoselectivity profile of this new protocol, as
alkenes (2e, 2f), esters (2r), nitriles (2q), aldehydes (2j, 2k), ketones
(2g), free hydroxy (2t), silyl groups (2h), alkyl halides (2i), and
nitro groups (2l) all were perfectly accommodated. These results
are noteworthy, as classical methods are not suitable for highly
functionalized substrates.1 As clearly shown by the formation of
2s, this protocol could be extended to naphthyl derivatives as well.
Furthermore, aryl chlorides were found to be inert (2m), thus
providing a convenient functional handle for further functionaliza-
tion. Although o-methoxy substituents did not hinder the reaction
(2p), it was necessary to use the more bulky and electron-rich ligand
L7. Gratifyingly, the acidic R-protons in 1g and 1r did not interfere
with productive formation of 2g and 2r, respectively.19 Finally,
although the overall NMR data unambiguously identified the BCB
core, we independently confirmed it by X-ray analysis of 2t.17
Next, we turned our attention to the synthetic applicability of
the resulting BCBs obtained using our method. As shown in Scheme
2, lactone 4 and benzodiazepine 5 could be easily obtained in one
step by Baeyer-Villiger oxidation2g and diazomethylene insertion2b
from 2d in 70 and 43% yield, respectively.
In summary, we have developed a new protocol for the
intramolecular acylation of aryl bromides via C-H functionaliza-
tion. The practicality of the method, as well as the vast array of
functionalized substrates with diverse substitution patterns that can
be accessed, renders this method a powerful alternative to other
approaches for the synthesis of BCBs. Further investigations of
related processes are ongoing in our laboratories.
Acknowledgment. We thank the ICIQ Foundation and Con-
solider Ingenio 2010 (CSD2006-0003) for financial support. Johnson
Matthey and Umicore are acknowledged for a gift of metal sources.
We thank Dr. Benet-Buchholz and Dr. Bozoglian for obtaining the
X-ray structure of 2t and kinetic data. R.M. and A.F.-G. thank
MICINN for a RyC and predoctoral fellowship (FPU).
Supporting Information Available: Experimental procedures,
spectral data for all compounds, and crystallographic data for 2t (CIF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
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Scheme 2. Synthetic Applicability of Benzocyclobutenones
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Scheme 3. Proposed Catalytic Cycles
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In principle, two mechanisms are conceivable for the results
highlighted in Table 2 (Scheme 3): (1) 4-exo-trig-type insertion
across the CdO bond from the oxidative addition complex I20
followed by ꢀ-hydride elimination (mechanism A) or (2) C-H
functionalization, loss of HBr from Pd(IV) intermediate III,21 and
a challenging reductiVe elimination from the five-membered
metallacycle IV (mechanism B). As the available data do not allow
us to distinguish between these two mechanisms, we reasoned that
we could gather indirect evidence by studying the cyclization of
1u. While 1u would be expected to react faster via a 5-exo-trig-
type cyclization in mechanism A,22 a mechanism of type B would
deal with a less favorable six-membered palladacycle. We found
that 1u did not cyclize under our optimized protocol; although this
is not conclusive, we believe this experiment supports mechanism
B. More interestingly, a kinetic isotope effect (kH/kD ) 2.8) was
observed when comparing the reaction rates of 1d and the
monodeuterated substrate 1d-D (Scheme 3). This result implies that
C-H bond cleavage is rate-limiting, thus providing further
experimental evidence for mechanism B.23
(17) See the Supporting Information for details.
(18) Kesharwani, T.; Verma, A. K.; Emrich, D.; Ward, J. A.; Larock, R. C.
Org. Lett. 2009, 11, 2591.
(19) The reaction of aldehydes with R-hydrogens led to decomposition. Similar
behavior was found in other related processes (see ref 16).
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(23) At present, we cannot rule out the intermediacy of acyl palladium
intermediates via 1,4-palladium migration (see ref 18).
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