Ligand-accelerated Pd-catalyzed ketone γ-arylation via C-C cleavage with aryl chlorides

Article abstract of DOI:10.1021/ol300119u

A highly efficient Pd-catalyzed arylative ring expansion of cyclobutanols via C-C bond cleavage is presented. The method allows the coupling of aryl chlorides at low catalyst loadings with a wide range of functional groups and substitution patterns, thus constituting a straightforward alternative for preparing rather elusive γ-arylated ketones.

Full text of DOI:10.1021/ol300119u

ORGANIC
LETTERS
2012
Vol. 14, No. 5
1266–1269
Ligand-Accelerated Pd-Catalyzed Ketone
γ-Arylation via CÀC Cleavage with Aryl
Chlorides
Asraa Ziadi and Ruben Martin*
Institute of Chemical Research of Catalonia (ICIQ), Av Paısos Catalans 16, 43007,
¨
Tarragona, Spain
rmartinromo@iciq.es
Received January 17, 2012
ABSTRACT
A highly efficient Pd-catalyzed arylative ring expansion of cyclobutanols via CÀC bond cleavage is presented. The method allows the coupling of
aryl chlorides at low catalyst loadings with a wide range of functional groups and substitution patterns, thus constituting a straightforward
alternative for preparing rather elusive γ-arylated ketones.
While the functionalization of carbonyl compounds has
evolved into routine tools in organic synthesis,1 only
recently have extensions of this chemistry to R-arylation
processes become possible.2 In striking contrast, cata-
lytic methods in route to rather elusive but naturally
occurring γ-arylated ketones3 have been much less ex-
plored. Despite formidable advances in the field of
γ-arylation (Scheme 1, path a),4 these methods still have
some limitations with respect to the R- vs γ-regioselec-
tivity: the need for R,β-unsaturated ketones, which
necessarily requires a subsequent reduction step, self-
condensation under basic conditions, and low reactiv-
ity of the resulting enolates. Therefore, a more flexible
and general approach to γ-arylated ketones is still of
critical importance.
Over the past few years, the functionalization of inert
bonds5 has widely been recognizedas a powerful tool in the
arsenal of the synthetic organic chemist, particularly in the
field of CÀH functionalization.6 However, the develop-
ment of catalytic methods for CÀC bond cleavage still
constitutes a tremendous challenge.7 Among the available
strategies for promoting catalytic CÀC bond cleavage,
β-carbon elimination8 has been shown to be particularly
(5) Murai, S. Activation of unreactive bonds and organic synthesis;
Topics in Organometallic Chemistry; Springer-Verlag: Berlin, 1999; Vol. 3.
(6) For selected reviews: (a) Hartwig, J. F. Chem. Soc. Rev. 2011, 40,
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1992. (b) McMurry, L.; OHara, F.; Gaunt, M. Chem. Soc. Rev. 2011, 40,
1885. (c) Lyons, T. W.; Sanford, M. Chem. Rev. 2010, 110, 1147.
(d) Chen, X.; Engle, K. M.; Wang, D. H.; Yu, J.-Q. Angew. Chem.,
Int. Ed. 2009, 48, 5094 and references therein.
(7) For selected reviews: (a) Murakami, M.; Matsuda, T. Chem.
Commun. 2011, 47, 1100. (b) Seiser, T.; Cramer, N. Org. Biomol. Chem.
2009, 7, 2835. (c) Rubin, M.; Rubina, M.; Gevorgyan, V. Chem. Rev.
2007, 107, 3117. (d) Jun, C.-H. Chem. Soc. Rev. 2004, 33, 610.
(e) Nishimura, T.; Uemura, S. Synlett 2004, 201. (f) van der Boom,
M. E.; Milstein, D. Chem. Rev. 2003, 103, 1759 and references therein.
(8) For selected reviews, see: (a) Seiser, T.; Saget, T.; Tran, D. N.;
(1) Bew, S. P. In Comprehensive Organic Functional Groups Trans-
formation II; Katritzky, A. R., Taylor, R. J. K., Eds.; Elsevier: Oxford, 2005.
ꢀ
(2) For recent reviews, see: (a) Novak, P.; Martin, R. Curr. Org.
Chem. 2011, 15, 3233–3262. (b) Bellina, F.; Rossi, R. Chem. Rev. 2010,
110, 1082. (c) Johansson, C. C. C.; Colacot, T. J. Angew. Chem., Int. Ed.
2010, 49, 676. (d) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36,
234 and references therein.
(3) (a) Majetich, G.; Liu, S.; Fang, J.; Siesel, D.; Zhang, Y. J. Org.
Chem. 1997, 62, 6928. (b) Huneck, S.; Akinniyi, J. A.; Cameron, A. F.;
Connolly, J. D.; Mulholland, A. G. Tetrahedron Lett. 1981, 22, 351.
(4) For selected references: (a) Duez, S.; Bernhardt, S.; Heppekausen,
J.; Fleming, F. F.; Knochel, P. Org. Lett. 2011, 13, 1690. (b) Huang, D. S.;
Hartwig, J. F. Angew. Chem., Int. Ed. 2010, 49, 5757. (c) Hyde, A. M.;
Buchwald, S. L. Org. Lett. 2009, 11, 2663. (d) Hyde, A. M.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2008, 47, 177.
Cramer, N. Angew. Chem., Int. Ed. 2011, 50, 7740. (b) Aıssa, C. Synthesis
¨
2011, 3389. (c) Murakami, M.; Makino, M.; Ashida, S.; Matsuda, T.
Bull. Chem. Soc. Jpn. 2006, 79, 1315.
(9) For a selection of catalytic methods: (a) Schweinitz, A.;
Chtchemelinine, A.; Orellana, A. Org. Lett. 2011, 13, 232. (b) Seiser,
T.Cramer, N. J. Am. Chem. Soc. 2010, 132, 5340. (c) Seiser, T.; Roth,
O. A.; Cramer, N. Angew. Chem., Int. Ed. 2009, 48, 6320. (e) Matsuda,
T.; Shigeno, M.; Murakami, M. J. Am. Chem. Soc. 2007, 129, 12086.
(f) Murakami, M.; Ashida, S.; Matsuda, T. J. Am. Chem. Soc. 2006, 128,
2166 and references therein.
r
10.1021/ol300119u
Published on Web 02/14/2012
2012 American Chemical Society

effective for rapidly constructing carbonyl compounds.9 In
1999, Uemura described a ring expansion of tert-cyclo-
butanols10 with aryl bromides via β-carbon elimination.11
Unfortunately, however, no examples with functionalized
or particularly hindered backbones were reported. Simi-
larly, 3,3-unsubstituted tert-cyclobutanols (Scheme 1, R2 =
R3 = H) were not described, likely due to the proclivity of
the σ-bound palladium intermediate to β-hydride elimina-
tion. Importantly, the method was restricted to aryl bro-
mides; thus, aryl chlorides, which from the standpoint of
cost and availability are more attractive coupling coun-
terparts,12 remained unreactive.13 Consequently, a new
catalytic system capable of operating at low catalyst load-
ings employing the more readily available aryl chlorides13
as substrates would be an extremely valuable tool for the
synthetic community. Herein, we present a general ketone
γ-arylation via CÀC bond cleavage that not only allows
the coupling of aryl chlorides at low catalyst loadings but
also tolerates a wide range of functional groups and sub-
stitution patterns (Scheme 1, bottom), including hindered
substrate combinations and the use of elusive 3,3-unsubsti-
tuted tert-cyclobutanols (Scheme 1, R2 = R3 = H) in which
no β-hydride elimination was observed.
success as many elementary steps within the catalytic cycle
can dramatically be accelerated. Among the ligands ex-
amined, L7 was found to be particularly effective when
using 2.5 mol % Pd(OAc)2, and NatBuO in toluene at
110 °C (entry 7). Prompted by these results, we wondered
whether the method could operate at lower catalyst load-
ings. As shown in entries 8À13, this was indeed the case.
After some optimization, we found that the use of L9
allowed the preparation of 2a in a quantitative yield at
0.50 mol % Pd loadings in a Pd/L ratio of 1:2 (entry 13). At
present, we believe that the bulky and electron-donating
character of L9 is crucial for stabilizing monoligated L1Pd-
(0) species, which are believed to be the key propagating
species in many cross-coupling reactions,16 thus allowing
the oxidative addition to proceed at a faster rate.
Scheme 2. Optimization of Reaction Conditionsa
Scheme 1. Ketone γ-Arylation via CÀC Cleavage
We began our study with chlorobenzene and 1a14 as the
model substrate (Scheme 2). As expected, the previously
reported procedure for aryl bromides resulted in very low
conversion to 2a (entry 1).10,11 Therefore, a variety of
experimental variables, such as the Pd precatalysts, li-
gands, bases, and solvents were systematically examined.
On the basis of our own findings when activating inert
molecular bonds,15 we hypothesized that the use of bulky
and electron-rich ligands would be critical for achieving
a Reaction conditions: 1a (0.50 mmol), PhCl (1.30 equiv), Pd(OAc)2
(x mol %), L (y mol %), NatBuO (1.10 equiv), PhMe (2 mL) at 110 °C for
12 h. bGC yields using dodecane as internal standard. cL1 was used following
conditions reported in ref 10: Pd2dba3 (0.5 mol %), L1 (2.0 mol %), K2CO3
(1.10 equiv) in dioxane (0.20 M). dDiglyme (2 mL) was used as the solvent.
eKOH (1.10 equiv) was used as the base.
Having established the optimized reaction conditions,
we set out toexplore the scope of this reaction. As shown in
Scheme 3, a host of aryl chlorides with electron-withdraw-
ing (2e) or electron-donating substituents (2c, 2d, and 2f)
reacted equally well with 1a in good to excellent yields. Our
protocol was found to be tolerant of a number of func-
tional groups such as thioethers (2d), amines (2f), ketones
(2g), alkenes (2h), acetals (2i), and heterocycles (2m and
2o).17 Interestingly, we could effect monofunctionalization
when employing 1,3-dichlorobenzene, affording 2j in 82%
yield. Particularly noteworthy is the preparation of 2g as it
has been shown that classical R-arylation of carbonyl
(10) Nishimura, T.; Uemura, S. J. Am. Chem. Soc. 1999, 121, 11010.
(11) (a) Nishimura, T.; Matsumura, S.; Maeda, Y.; Uemura, S.
Chem. Commun. 2002, 50. (b) Maysumura, S.; Maeda, Y.; Nishimura,
T.; Uemura, S. J. Am. Chem. Soc. 2003, 125, 8862.
(12) According to Aldrich Chemical Co., PhCl is about three times
cheaper than PhBr (approximately 0.027h/mL vs 0.078h/mL).
(13) (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
(b) Grushin, V. V.; Alper, H. Chem. Rev. 1994, 94, 1047.
(14) Multigram quantities of tert-cyclobutanols can be easily pre-
pared from readily available compounds: Johnston, B. D.; Czyzewska,
E.; Oehlschlager, A. C. J. Org. Chem. 1987, 52, 3693.
ꢀ
(15) (a) Novak, P.; Correa, A.; Gallardo-Donaire, J.; Martin, R.
(16) Christmann, U.; Vilar, R. Angew. Chem., Int. Ed. 2005, 44, 366.
(17) It is worth mentioning that, while good yields were achieved for
2m and 2o, the use of other heteroaromatics such as 2-chloropyridine,
3-chloropyridine, or 3-chlorothiophene gave no conversion to products.
See Supporting Information for details.
Angew. Chem. 2011, 123, 12444. (b) Flores-Gaspar, A.; Martin, R. Adv.
ꢀ
Synth. Catal. 2011, 353, 1223. (c) Alvarez-Bercedo, P.; Flores-Gaspar,
ꢀ
A.; Correa, A.; Martin, R. J. Am. Chem. Soc. 2010, 132, 466. (d) Alvarez-
Bercedo, P.; Martin, R. J. Am. Chem. Soc. 2010, 132, 17352. (e) Correa,
A.; Martin, R. J. Am. Chem. Soc. 2009, 131, 15974.
Org. Lett., Vol. 14, No. 5, 2012
1267

compounds usually requires strong bases;2 in our hands,
however, R-arylation was completely suppressed and ex-
clusive formation of the γ-arylated ketone 2g was obser-
ved. Similarly, the reaction of 4-chloroaniline also showed
complete selectivity for the R-arylated ketone 2f; no
N-arylation at the free aniline was observed by NMR
spectroscopy of the crude reaction mixture. Notably, un-
like previous β-carbon elimination procedures utilizing
aryl bromides,10,11 our method allows, for the first time,
the use of bis-ortho substituted electrophiles in essentially
quantitative yields (2l). We believe that the excellent acti-
vity and functional group compatibility in Scheme 3 illus-
trates the robustness and the application profile of our
method based upon L9.
use of completely unsubstituted tert-cyclobutanols 3a
(Scheme 3, R2À4 = H) in intermolecular reactions via β-
carbon elimination pathways. This is likely due to the high
reactivity of the initially generated alkylmetal species to-
ward syn-β-hydride elimination, thus preventing the cou-
pling process. An illustrative example is shown in Scheme 4.
While L9 exclusively afforded the desired γ-arylation
product (4a) via reductive elimination from I, the use of
structurally related bidentate ligands such as L12, among
others, showed the exclusive formation of the β-hydrogen
elimination product (5a). The use of L10 or L11 resulted
in 4a:5a mixtures in which competitive β-hydride elimina-
tion could not be avoided. We believe the experiments
in Scheme 4 illustrate the unique reactivity of our new
catalytic γ-arylationprotocol baseduponL9. We currently
propose that L9 retards β-hydride elimination18 and en-
hances the subsequent reductive elimination step within
the catalytic cycle.19
Scheme 3. Reaction Scope with Different ArCla
Scheme 4. Ligand Effect in Unsubstituted tert-Cyclobutanols
Scheme 5. Reaction Scope with 3,3-Unsubstituted Backbonesa
a Reaction conditions same as those for Scheme 2 (entry 13); isolated
yields, average of at least two independent runs. bPd(OAc)2 (1.0 mol %).
cK2CO3 (1.10 equiv) and L7 were used. dPd(OAc)2 (2.5 mol %).
Next, we turned our attention to study the substitution
pattern on the cyclobutanol backbone. As becomes appar-
ent from the results in Scheme 3, a diverse set of substitu-
tion patterns including aliphatic or aromatic groups gave
the corresponding γ-arylated ketones in good to excellent
yields (2pÀ2t). Remarkably, no side products were ob-
tained for 2s and 2t, thus indicating that the presence of
acidic R-protons in alkyl-substituted ketones does not
interfere with productive formation of the corresponding
coupling products.
a Reaction conditions same as those for Scheme 3; isolated yields,
average of at least 2 independent runs. bPd(OAc)2 (2.0 mol %), K2CO3
(1.10 equiv), and L7 were used.
(18) (a) Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem. Soc.
1996, 118, 7215. (b) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1996,
118, 7217.
While some progress has been achieved when employ-
ing 3-monosubstituted tert-cyclobutanols (Scheme 3, 2p
and 2r),10,11 there are no catalytic methods dealing with the
(19) Hartwig, J. F. Inorg. Chem. 2007, 46, 1936.
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Org. Lett., Vol. 14, No. 5, 2012

As shown in Scheme 5, our arylative ring-opening
reaction employing unsubstituted tert-cyclobutanol 3a
cross-coupled, with high yields, a representative set of
aryl chlorides possessing thioethers (4b), alkenes (4c),
or even with di-ortho-substitution as well (4d). As for
2s and 2t (Scheme 3), the reaction of alkyl substituted
tert-cyclobutanol 3b possessing acidic R-protons af-
forded 4e. On the basis of these results, we anticipated
that high levels of regioselectivity could be obtained
when using unsymmetrically substituted backbones.
As expected, this was indeed the case and cis-fused 4f,
4g, and 4h were obtained as single regioisomers in
which the CÀC bond cleavage occurs at the less steri-
cally hindered position.
and high chemoselectivity profile makes this method a
straightforward alternative to the existing methods for the
synthesis of γ-arylated ketones. In further studies, we aim
to explore the enantioselective variant of this reaction,
unravel the mechanism,20 and fully explore the potential of
this and related transformations.
Acknowledgment. We thank the ICIQ Foundation,
Consolider Ingenio 2010 (CSD2006-0003), European Re-
search Council (ERC-277883) and MICINN (CTQ2009-
13840) for financial support. Johnson Matthey, Umi-
core, and Nippon Chemical Industrial are acknowledged
for a gift of metal and ligand sources. Dr. X. Cambeiro at
ICIQ is acknowledged for insightful discussions. R.M.
thanks MICINN for a RyC fellowship.
In summary, a highly active Pd-catalyzed ketone
γ-arylation via CÀC cleavage with aryl chlorides at low
catalyst loadings has been developed. The broad scope
Supporting Information Available. Experimental proce-
dures and spectral data for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(20) Deuterium labeling on the tert-cyclobutanol backbone showed a
constant kH/kD = 0.60. Whether this kinetic isotope effect might be
attributed to a steric isotope effect is a matter of current mechanistic
investigations in our laboratories, and it will be reported in due course.
The authors declare no competing financial interest.
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