N-heterocyclic carbene dichotomy in Pd-catalyzed acylation of aryl chlorides via C-H bond functionalization

Article abstract of DOI:10.1021/ol3023819

The first Pd-catalyzed intramolecular acylation of aryl chlorides via C-H bond functionalization is presented. The method allows for the synthesis of a variety of elusive benzocyclobutenones with a wide range of functional groups and substitution patterns. We demonstrate that a change in the ligand backbone dictates the selectivity pattern.

Full text of DOI:10.1021/ol3023819

ORGANIC
LETTERS
2012
Vol. 14, No. 20
5234–5237
N‑Heterocyclic Carbene Dichotomy in
Pd-Catalyzed Acylation of Aryl Chlorides
via CÀH Bond Functionalization
ꢀ
ꢀ
Areli Flores-Gaspar, Alvaro Gutierrez-Bonet, and Ruben Martin*
Institute of Chemical Research of Catalonia (ICIQ), Av. Paısos Catalans, 16, 43007,
¨
Tarragona, Spain
rmartinromo@iciq.es
Received August 28, 2012
ABSTRACT
The first Pd-catalyzed intramolecular acylation of aryl chlorides via CÀH bond functionalization is presented. The method allows for the synthesis
of a variety of elusive benzocyclobutenones with a wide range of functional groups and substitution patterns. We demonstrate that a change in the
ligand backbone dictates the selectivity pattern.
Metal-catalyzed CÀH arylation protocols are now widely
recognized as powerful synthetic tools in organic synthesis.1
Despite the utility of aldehydes, perhaps the most versatile
synthon in organic synthesis, an arylation event via CÀH
functionalization of the aldehyde motif, is underrepresented
in the CÀH arylation arena.2 A close survey of the existing
methodologies shows that directing groups are generally
required and that the control of selectivity still represents a
major concern;2,3 however, the cleavage of directing groups
is notoriously difficult under mild reaction conditions, thus
limiting the application profile of these methodologies and
enforcing a change in strategy. In this regard, the use of aryl
halides constitutes an excellent alternative for increasing
molecular complexity while lowering the overall cost for
producing fine chemicals.4
In order to demonstrate the potential of the intramolec-
ular acylation techniques via CÀH functionalization, we
envisioned the synthesis of benzocyclobutenones (BCBs),
unique scaffolds with great significance due to their versa-
tility as synthetic intermediates.5 Such logic unravels read-
ily accessible R-aryl aldehydes6 as the key building blocks
(Scheme 1). This transformation is quite remarkable, as
one CÀC bond must be formed while generating a rather
strained ring. Recently, we reported the preparation of
BCBs via CÀH functionalization with aryl bromides
as coupling counterparts.7 Unfortunately, this protocol
was not yet satisfactory, since (a) the less reactive and
more accessible aryl chlorides were totally inert;4 (b) the
method showed low selectivity with multiple reaction sites,
and (c) the reaction was restricted to R,R-disubstituted
benzocyclobutenones. Although one might anticipate that
(1) For selected reviews: (a) Yeung, C. S.; Dong, M. V. Chem. Rev.
2011, 111, 1215. (b) Hartwig, J. F. Chem. Soc. Rev. 2011, 40, 1992.
(c) McMurray, L.; O’Hara, F. O.; Gaunt, M. Chem. Soc. Rev. 2011, 40,
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Zhou, M.; Wei, W.; Deng, G.; Yin, D.; Li, J.-H. J. Am. Chem. Soc. 2010,
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Catal. 2010, 352, 1145. (d) Sangwon, K.; Byungman, K.; Chang, S.
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(4) Metal-catalyzed Cross-Coupling Reactions; Diederich, F., Stang,
P. J., Eds.; Wiley-VCH: New York, 1998.
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r
10.1021/ol3023819
Published on Web 10/03/2012
2012 American Chemical Society

Heck-type processes could also be utilized for similar
purposes,8 the inherent rigidity of the four-membered ring
makes such a scenario highly unlikely.9 Despite the simple
structure of BCBs, the drawbacks imparted by classical
methods in terms of functional group tolerance and sub-
stitution patterns10 contribute to the perception that our
approach in Scheme 1 represents a straightforward alter-
native to these compounds. Herein, we describe the first
successful intramolecular acylation of aryl chlorides via
CÀH functionalization as a means to access BCBs that are
beyond reach otherwise. In addition to the preparative
aspects, our results reveal exquisite selectivity control
depending on the chosen ligand.
Scheme 2. Striking NHC Effects on Selectivitya
Scheme 1. Synthetic Approach to BCBs Using Aryl Chlorides
a GC yields using dodecane as internal standard. b Using 5 (2 mol %).
The observed selectivity switch by catalyst tuning allows
ustodistinguish betweendifferent mechanistic scenarios.16
At present, we suggest that the higher buried volume of
L3 is critical for achieving selectivity.17,18 Subsequently,
the effects of palladium precatalysts, solvents, bases, and
temperatures were systematically examined (Table 1).
While typically employed Pd(OAc)2 resulted in lower yields
(entry 1), the use of allyl chloride palladium dimers 5À6
gave better results (entries 3À4), with a catalyst based upon
5 being the most active (entry 5). At this stage, we hypothe-
sized that the presence of additives could accelerate the
CÀH functionalization event; as shown in entries 8À12, this
was indeed the case. After some optimization, we found that
the synergistic use of L3 and allyl ether (9) allowed for the
preparation of 2a in 80% yield (entry 10). We currently
support the notion that allyl ether might be crucial for
stabilizing monoligated L3ÀPd(0) species.19,20
We began our study with 1a as the model substrate
(Scheme 2). On the basis of our own findings,11 we
anticipated that the supporting ligand would play an
important, if not crucial, role in the route to 2a. Among
all the ligands examined, N-heterocyclic carbenes (NHCs),
showed superior activity as compared to phosphine
ligands.12 It is noteworthy that, unlike other aldehyde
CÀH functionalization reactions,2 competitive decarbo-
nylation of 1a was not observed in the crude reaction
mixtures. Intriguingly, while L1 afforded 3a exclusively,13
the presence of a bulky adamantyl group in L2 had a
deleterious impact on selectivity, with 2a in a 1:2 ratio
(2a:3a). Gratifyingly, we found that L3, readily avail-
able on large scale from cheap commercial sources,14
produced 2a as the only product, albeit in lower yields.
Other related NHCs such as L4ÀL6 afforded mixtures of
both 2a and 3a, thus showing the subtleties of the catalytic
system.15
Next, we set out to explore the preparative scope of this
reaction. As shown in Scheme 3, the functional group
tolerance is nicely illustrated by the fact that differently
substituted silyl ethers (2d and 2e), alkenes (2g), esters (2l),
aldehydes (2m and 2q), ketones (2n), nitriles (2p), amines
(2o and 2r), fluorides (2t), or heterocycles (2s) are perfectly
(8) For Heck-type acylation approaches using aryl halides not involv-
ing CÀH bond-activation protocols, see: (a) Colbon, P.; Ruan, J.; Purdie,
M.; Xiao, J. Org. Lett. 2010, 12, 3670. (b) Ruan, J.; Saidi, O.; Iggo, J. A.;
Xiao, J. J. Am. Chem. Soc. 2009, 130, 10510.
(9) The double bond in the enamine intermediate is not flexible
enough to bend in the proper conformation for the Heck coupling:
Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009.
(10) For selected references: (a) Hamura, T.; Ibusuki, Y.; Sato, K.;
Matsumoto, T.; Osamura, Y.; Suzuki, K. Org. Lett. 2003, 5, 3551.
(b) Hosoya, T.; Hasegawa, T.; Kuriyama, Y.; Matsumoto, T.; Suzuki,
K. Synlett 1995, 177. (c) Aidhen, I. S.; Ahuja, J. R. Tetrahedron Lett.
1992, 33, 5431.
(16) For recent examples of this concept: (a) Shareet, A.-R.; Sherman,
D. H.; Montgomery, J. Chem. Sci. 2012, 3, 892. (b) Kwak, J.; Kim, M.;
Chang, S. J. Am. Chem. Soc. 2011, 133, 3780. (c) Urban, S.; Ortega, N;
Glorius, F. Angew. Chem., Int. Ed. 2011, 50, 3803. (d) Malik, H. A.;
Sormunen, G. J.; Montgomery, J. J. Am. Chem. Soc. 2010, 132, 6304.
(17) (a) Hillier, A. C.; Sommer, W. J.; Yong, B. S.; Petersen, J. L.;
Cavallo, L.; Nolan, S. P. Organometallics 2003, 22, 4322. (b) Dorta, R.;
Stevens, E. D.; Scott, N. M.; Costabile, C.; Cavallo, L.; Hoff, C. D.;
Nolan, S. P. J. Am. Chem. Soc. 2005, 127, 2485. (c) Clavier, H.; Nolan,
S. P. Chem. Commun. 2010, 46, 841.
(11) (a) Ziadi, A.; Martin, R. Org. Lett. 2012, 14, 1266. (b) Barbero,
ꢀ
N.; Martin, R. Org. Lett. 2012, 14, 796. (c) Novak, P.; Correa, A.;
Gallardo-Donaire, J.; Martin, R. Angew. Chem. 2011, 123, 12444.
(d) Correa, A.; Martin, R. J. Am. Chem. Soc. 2009, 131, 15974.
€
(12) For recent reviews, see: (a) Droge, T.; Glorius, F. Angew. Chem.,
(18) According to ref 12, the calculated buried volumes in Ni(CO)3L
are the following: %Vbur(IMes) = 26, %Vbur(IPr) = 29, %Vbur(ICy) =
23, and %Vbur(IAd) = 37.
Int. Ed. 2010, 49, 6940. (b) Kantchev, E. A. B.; O’Brien, C. J.; Organ,
M. G. Angew. Chem., Int. Ed. 2007, 46, 2768.
(13) For a related transformation using aryl bromides as substrates:
Flores-Gaspar, A.; Martin, R. Adv. Synth. Catal. 2011, 353, 1222.
€
(14) Richter, H.; Schwertfeger, H.; Schreiner, P. R.; Frohlich, R.;
(19) (a) Selvakumar, K.; Zapf, A.; Spannenberg, A.; Beller, M.
Chem.;Eur. J. 2002, 8, 3901. (b) Jackstell, R.; Andreu, M. G.; Frisch,
€
A. C.; Selvakumar, K.; Zapf, A.; Klein, H.; Spannenberg, A.; Rottger,
Glorius, F. Synlett 2009, 193.
(15) For the use of other NHC ligands, see Supporting Information.
D.; Briel, O.; Karch, R.; Beller, M. Angew. Chem., Int. Ed. 2002, 41, 986.
(20) Christmann, U.; Vilar, R. Angew. Chem., Int. Ed. 2005, 44, 366.
Org. Lett., Vol. 14, No. 20, 2012
5235

Table 1. Optimization of Reaction Conditionsa
Scheme 3. Reaction Scope
a 1a (0.50 mmol), Pd (5 mol %), L3 (7.5 mol %), Cs2CO3 (1.30 equiv),
dioxane (0.25 M); GC yield using dodecane as internal standard.
b 50 mol %. c THF as solvent. d Cyclpentylmethyl ether as solvent.
e Pd/L3 = 1:2. f K2CO3 (1.30 equiv). g NaOtBuO (1.30 equiv).
accommodated, thus providing an additional handle for
further manipulation. The successful preparation of 2s
indicates that the Pd catalytic species are not deactivated
by the presence of strong nitrogen donors. Likewise, even
unprotected alcohols (2v) could be coupled in good yields
as well. As shown for 2t and 2u, ortho-substitution did not
hinder the reaction at all. Even more important is the fact
that this method allows, for the first time, the preparation
of a monosubstituted BCB (2f) when using R-silylated aryl
aldehydes as precursors. This is particularly noteworthy
in view of the inability of aryl bromides to promote an
otherwise identical reaction.7,21 In striking contrast to the
previous use of aryl bromides,7 the method could also be
extended to the preparation of five-membered rings (2w).
Notably, no competing intermolecular acylation events
were detected by spectroscopy of the crude reaction mix-
tures, thus selectively obtaining 2m and 2q. Overall, we
believe these results not only show the exceptional activity
and functional group compatibility but also the robustness
of CÀH functionalization catalysts based on L3.22 En-
couraged by the selectivity switch in Scheme 2 when
utilizing L1, a further extension of the scope of styrene
derivatives was envisaged. As shown in Scheme 4 (bottom),
the protocol based on L1 allows for the preparation of
trisubstituted olefins 3b, 3c, 3d, and 3e with total regiocon-
trol and diastereoselectivities up to 8.4:1, even in the pre-
sence of free alcohols (3c).
a As for Table 1 (entry 10); isolated yields, average of two independent
runs. The 2-(trimethylsilyl)pentanal derivative was used followed by
b
TBAF treatment. c Due to its volatility, the product was isolated as the
benzocyclobutanol by treatment with NaBH4 in MeOH. d 5 (5.0 mol %)
was used. e Cs2CO3 (2.60 equiv) was used. f 5 (3.0 mol %), L3 (12 mol %),
allyl ether (60 mol %). g 5 (2 mol %) and L1 (6.0 mol %); isolated yields.
h E/Z = 8.4:1. i E/Z = 1:1.6. j 140 °C.
possessing multiple CÀH or CÀCl reactive sites could
be equally employed, affording 2x and 2y exclusively
(Scheme 4); importantly, not even traces of 10 via intramo-
lecular CÀH arylation24 or 11 were observed by NMR
spectroscopy of the crude material.25 These findings chal-
lenge the general perception that the preparation of smaller
and more strained rings are lower yielding than standard
routes to thermodynamically more stable medium-sized
rings.
The proven flexibility of this method suggested that our
intramolecular CÀH acylation event should be applic-
able to site-selectivity approaches.23 Gratifyingly, substrates
The exceptional reactivity and versatility of BCBs is
illustrated in Scheme 5. Exposure of 2b to NaBH4 followed
(21) No monosubstituted benzocyclobutenones were obtained under
the reaction conditions reported in ref 7.
(22) The protocol based upon L3 could also be utilized with similar
yields when utilizing aryl bromides as substrates (ref 7).
(23) For a review on site selectivity in CÀH bond functionalization:
Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936.
(24) For selected examples of CÀH intramolecular arylation with
aryl chlorides, see: (a) Lafrance, M.; Lapointe, D.; Fagnou, K. Tetra-
hedron 2008, 64, 6015. (b) Campeau, L.-C.; Parisien, M.; Jean, A.;
Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581.
(25) Trace amounts of dechlorinated 2y were observed in the crude
reaction mixture by GC-MS.
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Org. Lett., Vol. 14, No. 20, 2012

Scheme 4. Site Selectivity with Multiple Reaction Sites
Scheme 6. Mechanistic Studies
observation given the known literature data for related
processes.3b,7 Quite illustrative, the deuterium label in
1a-D1 was totally transferred to the aromatic motif in
3a-D1 using L1 as the ligand. At present, we support a
mechanistic scenario in which the initial oxidative addition
species undergoes a CÀH functionalization via a concerted
metalation deprotonation pathway (CMD)26 and, in the
presence of L3, final reductive elimination to afford the
desired BCB 2while recovering the active species.7,27 We pro-
pose that the less-sterically encumbered L1 facilitates an
intramolecular proton transfer followed by CO extrusion
and β-hydride elimination, thus affording the olefin 3.13
In summary, the first intramolecular acylation of aryl
chlorides via CÀH bond functionalization en route to
benzocyclobutenones has been developed. The protocol
is characterized by its broad scope and exceptional site
selectivity in which the ligand backbone dictates the selec-
tivity pattern. We believe such a transformation will bring
new knowledge in catalyst design. In further studies, we
aim to explore the asymmetric reaction and the potential
of this and related transformations.
by PPh3/I2 treatment cleanly afforded synthetically attrac-
tive 12 in high overall yield. Likewise, indanone 13 posses-
sing two contiguous quaternary centers or phthalide 14
could easily be obtained via ring expansion promoted
by ICl5c or regioselective BaeyerÀVilliger oxidation with
magnesium monoperphthalate.5e
Scheme 5. Synthetic Applicability
Acknowledgment. We thank the ICIQ Foundation,
MICINN (CTQ2009-13840), and European Research Coun-
cil (ERC-277883) for financial support. Johnson Matthey,
Umicore, and Nippon Chemical Industrial are acknowledged
for a gift of metal and ligand sources. A. Ziadi at ICIQ is
also acknowledged for performing initial screening experi-
ments. A.F.-G. and R.M. thank MICINN for FPU&RyC
fellowships.
In order to gain more insight into the mechanism, we
decided to gather indirect evidence via isotope labeling
(Scheme 6). We observed kH/kD = 0.93 when comparing
the initial rates of 1b and 1b-D1. This experiment suggests
that CÀH cleavage is not rate determining, an intriguing
(26) (a) Rousseaux, S.; Davi, M.; Sofack-Kreutzer, J.; Pierre, C.;
Kefalidis, C. E.; Clot, E.; Fagnou, K.; Baudoin, O. J. Am. Chem. Soc.
2010, 132, 10706. (b) Chaumontet, M.; Piccardi, R.; Audic, N.; Hitce, J.;
Peglion, J.-L.; Clot, E.; Baudoin, O. J. Am. Chem. Soc. 2008, 130, 15157.
(c) Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Am. Chem. Soc. 2008,
130, 10848.
Supporting Information Available. General procedures
and spectral data for all new compounds (2aÀ2y, 3aÀ3f,
and 12À14). This material is available free of charge via
the Internet at http://pubs.acs.org.
(27) We cannot rule out a mechanism consisting of an addition of the
C;Pd bond across the CdO bond. For selected insertions of Pd
ꢀ
oxidative addition complexes across the CdO bond, see: (a) Sole, D.;
ꢀ
ꢀ
Fernandez, I.; Sierra, M. A. Chem.;Eur. J. 2012, 18, 6950. (b) Fernandez,
ꢀ
I.; Sole, D.; Sierra, M. A. J. Org. Chem. 2011, 76, 1592. (c) Quan, L. G.;
The authors declare no competing financial interest.
Lamrani, M.; Yamamoto, Y. J. Am. Chem. Soc. 2000, 122, 4827.
Org. Lett., Vol. 14, No. 20, 2012
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