Regioselectivity switch achieved in the palladium catalyzed α-arylation of enones by employing the modified Kuwajima-Urabe conditions

Article abstract of DOI:10.1021/ol300401c

A new regioselective approach to the synthesis of α-aryl enones is reported. This represents an important application of the Kuwajima-Urabe protocol toward the synthesis of this simple albeit complex functional array. Several α-aryl enones were synthesized by the palladium catalyzed arylation of triethylsilylenol ethers of enones with high regioselectivity and broad scope, utilizing sterically encumbered electron-rich phosphine ligands to drive the reaction.

Full text of DOI:10.1021/ol300401c

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1808–1811
Regioselectivity Switch Achieved in the
Palladium Catalyzed r-Arylation of
Enones by Employing the Modified
KuwajimaÀUrabe Conditions
Ajit Prabhakar Kale, Govind Goroba Pawar, and Manmohan Kapur*
Department of Chemistry, Indian Institute of Science Education and Research Bhopal,
ITI (Gas Rahat) Building, Raisen Road, Bhopal 462023, India
mk@iiserb.ac.in; mk@iiserbhopal.ac.in
Received February 18, 2012
ABSTRACT
A new regioselective approach to the synthesis of R-aryl enones is reported. This represents an important application of the KuwajimaÀUrabe
protocol toward the synthesis of this simple albeit complex functional array. Several R-aryl enones were synthesized by the palladium catalyzed
arylation of triethylsilylenol ethers of enones with high regioselectivity and broad scope, utilizing sterically encumbered electron-rich phosphine
ligands to drive the reaction.
Transition metal catalyzed, and in particular Pd-cata-
lyzed, R-arylation of ketonesand otherenolizablecarbonyl
compounds is a versatile reaction of tremendous synthetic
utility.1 This reaction belongs to a rather rare class of the
few cross-coupling reactions that form an sp2Àsp3 CÀC
bond. Several catalyst systems and variations of this reac-
tion have been reported in the past few decades, and this
class of reaction has been very well reviewed recently.2,3
The reaction is essentially base catalyzed and involves a
transmetalation/nucleophilic substitution step involving
the oxidatively inserted aryl halide or triflate and the
ketone enolate.3,4
In the course of the synthesis of a resorcylic acid lactone,
we were confronted with the synthesis of an R-aryl enone.
The most common methods of syntheses of this functional
array include aldol condensations, cross-metathesis, and
elimination reactions. Given the sensitive nature of other
functional groups in our target molecule, a mild and simple
synthesis for this functional array is needed. An obvious
contemplation was the base-mediated, transition metal
catalyzed R-arylation reaction. However, an apparent
expected outcome was the possibility of a Heck reaction
involving the olefin of the enone, which has been well
documented and reviewed.5 The regioselectivity for aryla-
tion would depend upon which of the two reactions is
more feasible, the transmetalation with the enolate or
the migratory insertion of the enone double bond.6 Re-
search groups of Buchwald7 and Hartwig8 have reported
(1) Schlummer, B.; Scholz, U. In Modern Arylation Methods (Ed.
Ackermann, L.), Wiley-VCH: Weinheim, 2009, pp 69À120.
(2) (a) Miura, M.; Nomura, M. Top. Curr. Chem. 2002, 219, 211–
241. (b) Llyod-Jones, G. C. Angew. Chem., Int. Ed. 2002, 41, 953–
956. (c) Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082–1146.
(d) Johansson, C. C. C.; Colacot, T. J. Angew. Chem., Int. Ed. 2010,
(5) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009–
3066.
ꢀ
49, 676–707. (e) Novak, P.; Martin, R. Curr. Org. Chem. 2011, 15, 3233–
3262.
(6) Huang, D. S.; Hartwig, J. F. Angew. Chem., Int. Ed. 2010, 49,
5757–5761.
(7) (a) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am.
Chem. Soc. 2000, 122, 1360–1370. (b) Ahman, J.; Wolfe, J. P.; Troutman,
M. V.; Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 1918–
1919.
(3) Kulkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234–245.
(4) For seminal work on palladium catalyzed direct R-arylation of
ketones with bromides, see: (a) Satoh, T.; Kawamura, Y.; Miura, M.;
Nomura, M. Angew. Chem., Int. Ed. 1997, 36, 1740–1742. (b) Palucki,
M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108–11109.
(c) Harmann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119,
12382–12383.
˚
(8) Liao, X.; Weng, Z.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130,
195–200.
r
10.1021/ol300401c
Published on Web 03/20/2012
2012 American Chemical Society

Table 1. Attempts toward Base Catalyzed R-Arylation of
Scheme 1. KuwajimaÀUrabe Protocol for R-Arylation of
Enonesa
Methyl Ketones
they utilized trialkyltin fluoride for the in situ generation of
R-stannyl ketones via silylÀstannyl exchange (Scheme 1).14
Consequently, many reports utilizing silyl enol ethers in
Pd-catalyzed arylation have appeared.15À18 An important
outcomeofHartwig’s study was the synergistic effectof the
use of two fluorides, tributyltin fluoride and cesium
fluoride.17 This method has an advantage over base-
mediated R-arylation in that the functional group toler-
ance is much higher and regiochemistry can be very well
controlled. This variant of the R-arylation has been used
on ketones and tothe best of our knowledgehas never been
tried with enone systems. We attempted to apply this
strategy to enone systems (Scheme 2).
dioxane
ligand
S-Phos
THF
(ratio of 3:4)
toluene
DMF
60:40 (50)
79:21 (58)
NR
23:77 (40)
51:49(55)
1:99 (70)
9:91 (65)
Messy
21:79(50)
55:45 (60)
1:99 (45)
8:92 (50)
Messy
1:99 (80)
3:97 (70)
1:89 (75)
1:99 (70)
1:99 (75)
1:99 (95)
X-Phos
XantPhos
BINAP
NR
tBu-XPhos
DTBPF
NR
30:70 (30)
4:96 (30)
5:95 (30)
a Ratios determined by GCMS; NR = Less than 10% conversion
after 14 h; numbers in parentheses denote conversions after 14 h.
enantioselective R-arylation of exocyclic cycloalkenones
using aryl bromides and triflates, respectively. Several
groups have also reported γ-arylations and related
reactions.9À12
Scheme 2. Ligands Scanned for This Transformation
On careful search of the literature it was realized that the
R-arylation of enones was not general, and very few
instances of the same have been reported and are substrate
specific.13 Here we report our results on studies related to
the regioselective R-arylation of enones using a broad
spectrum of aryl bromides and triflates. This protocol
resulted in moderate to good yields of the R-arylated
products. A variety of enones were scanned, and the
reaction was found to be fairly general. Our studies began
by examining the feasibility of the base mediated, Pd-
catalyzed R-arylation reaction with simple acyclic enones.
In most of the cases we ended up with a mixture of
products arising out of a combination of base mediated
R-arylation and the Heck reaction (Table 1). The loss of
stereocontrol in the Heck reaction was probably a result of
steric crowding at the β-position of the enone. When the
enone was substituted with an alkyl chain instead of the
phenyl ring at the β-position, a complex mixture of pro-
ducts was obtained which could not be analyzed accu-
rately. Use of stronger bases such as NaHMDS led mostly
to polymeric products. Other palladium sources led to
mostly similar results.
Several catalyst systems were initially scanned, and since
the outcome with simple phosphine ligands was quite
disappointing, we turned to scanning bulky, electron-rich
phosphine ligands. It has been well documented by
several research groups that the use of bulky, electron-rich
phosphines promotes the stabilization of the metal center
by decreasing the energy of the low coordinate Pd(0)
species.19 It is also postulated that the increase in the
electron density at the metal enhances the rate of oxidative
Having failed in getting any single catalyst system to
result in the regioselective R-arylated product, we came up
with the idea of utilizing Kuwajima and Urabe’s method
for Pd-catalyzed R-arylation of simple ketones wherein
(14) (a) Kuwajima, I.; Urabe, H. J. Am. Chem. Soc. 1982, 104, 6831–
6833. (b) Kuwajima, I.; Nakamura, E. Acc. Chem. Res. 1985, 18, 181–
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Satoh, T.; Miura, M.; Nomura, M. Tetrahedron 2001, 57, 5967–5974.
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Takizawa, O.; Nagase, H.; Honda, T. Tetrahedron Lett. 2008, 49, 3983–
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7, 1716–1722. (e) Guo, Y.; Tao, G.-H.; Blumenfeld, A.; Shreeve, J. M.
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Org. Lett., Vol. 14, No. 7, 2012
1809

insertion and also serves to increase turnover numbers by
suppressing side reactions such as phosphine cleavage.
Our attempts with electron-rich phosphines succeeded
in giving a regioselective reaction in the form of the
R-arylated product. Although the reaction worked fairly
well with Pd2(dba)3/BINAP or PdCl2(DTBPF)19i systems,
the cleanest conversions were obtained with Pd(OAc)2/
DTBPF. The substrate scope with bromides was found to
be quite general and is shown in Table 2. The use of cesium
fluoride was found to be necessary for this reaction; the
reaction was very sluggish in the absence of it. Other
sources of fluorides that were scanned were not as effective
as CsF. At this point, the exact role of CsF is not under-
stood. The best yields were obtained in nonpolar solvents.
In particular, toluene was found to be the solvent of
choice.20 The reaction with the DTBPF system was very
fast at 85 °C and required at most 2À3 h to complete. The
reaction worked well with neutral alkyl substituted aro-
matic bromides, and the yields with ortho substituted
bromides were notably good. In particular, the mesityl
bromide (Table 2, entry 4) resulted in the highest
yield among all the substrates scanned. The yields with
electron-richaromatic bromides were expectedly moderate
(Table 2, entries 5, 6). The reaction condition was tolerated
by a wide variety of functional groups such as esters
(Table 2, entry 7) and nitriles (Table 2, entry 12). Entries
8 and 9 (Table 2) expectedly resulted in isocoumarin
formation.18b The formation of the isocoumarin could
not be circumvented. The reaction with 2-bromobenzoni-
trile (Table 2, entry 18) resultedin low yield presumably for
the same reason. In all cases, the regioselectivity was
excellent (>90:10), and the reaction worked well with all
the enone systems that we tried, although the reactions
with the cyclohex-2-enone system were slightly sluggish as
compared to the acyclic versions. The yields with triflates
were rather low with this catalyst system. Thankfully
Table 2. Substrate Scope with Aryl Bromides
(19) (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998, 37,
3387–3388. (b) Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron
Lett. 1998, 33, 617–620. (c) Kawatsura, M.; Hartwig, J. F. J. Am. Chem.
Soc. 1999, 121, 1473–1478. (d) Fox, J. M.; Huang, X.; Chieffi, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 1360–1370. (e) Moradi,
W. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7996–8002.
(f) Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 5816–
5817. (g) Rataboul, F.; Zapf, A.; Jackstell, Harkal, S.; Riermeier, T.;
Monsees, A.; Dingerdissen, U.; Beller, M. Chem.;Eur. J. 2004, 10,
2983–2990. (h) Culkin, D. A.; Hartwig, J. F. Organometallics 2004, 23,
3398–3416. (i) Grasa, G. A.; Colacot, T. J. Org. Lett. 2007, 9, 5489–5492.
(j) Fu, G. C. Acc. Chem. Res. 2008, 41, 1555–1564. (k) Martin, R.;
Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461–1473. (l) Hartwig, J. F.
Acc. Chem. Res. 2008, 41, 1534–1544. (m) Barrios-Landeros, F.;
Carrow, B. P.; Hartwig, J. F. J. Am. Chem. Soc. 2009, 131, 8141–8154.
(n) Hill, L. L.; Crowell, J. L.; Tutwiler, S. L.; Massie, N. L.; Hines, C. C.;
Griffin, S. T.; Rogers, R. D.; Shaughnessy, K. H.; Grasa, G. A.;
Johansson Seechurn, C. C. C.; Li, H.; Colacot, T. J.; Chou, J.;
Woltermann, C. J. J. Org. Chem. 2010, 75, 6477–6488. (o) Johansson
Seechurn, C. C. C.; Parisel, S. L.; Colacot, T. J. J. Org. Chem. 2011, 76,
7918–7932. (p) Liu, L.; Ishida, N.; Ashida, S.; Murakami, M. Org. Lett.
2011, 13, 1666–1669. (q) Cao, C.; Wang, L.; Cai, Z.; Zhang, L.; Guo, J.;
Pang, G.; Shi, Y. Eur. J. Org. Chem. 2011, 1570–1574. (r) Hesp, K. D.;
Lundgren, R. J.; Stradiotto, M. J. Am. Chem. Soc. 2011, 133, 5194–5197.
(20) The reaction works best with freshly prepared TES-enol ethers,
which were prepared by methods reported in the literature. TMS-enol
ethers were not very stable upon prolonged storage, and therefore the
reaction was performed with TES-enol ethers. See ref 18e. The arylation
reaction was performed without a glovebox or dry box, in a sealed tube.
See Supporting Information for all experimental details.
a All yields are isolated yields.
for us, the Pd(OAc)2/tBuXPhos system worked well for
triflates. The substrate scope for triflates is depicted in
Table 3. The reaction with triflates required ∼12 h to
complete and worked well for most triflates and enones
that were attempted.21 Only a couple of exceptions were
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Org. Lett., Vol. 14, No. 7, 2012

Scheme 3. Suggestive Pathway for the Reaction with Enones
Scheme 4. Fluoride Mediated Arylation of the Monoaryl
Enone
the slower migratory insertion of the olefin of the R,β-
unstaturated system (Scheme 3).
The absence of a strong base to mediate the β-H
elimination for the competing Heck reaction could also
be a contributing factor to the regioselectivity.
Table 3. Substrate Scope with Aryl Triflates
Another interesting observation was that of the diaryla-
tion product in the reaction mixture17 and the yield of this
product was substrate dependent. This product was not
expected, given the proposed reaction mechanism in which
the diarylation product would be expected only in a base-
mediated reaction. In this case it seemed that the fluoride
anion in the anhydrous solvent was acting as a base.22 To
test this hypothesis, the arylation reaction was attempted
with the parent enone with the Pd(OAc)2/DTBPF catalyst
system in the presence of the added fluoride additives
(Scheme 4). Almost no reaction was observed even after
24 h. Monoaryl product 3, when subjected to the same condi-
tions, resulted in the diarylation product 49 in about 30%
yield after about 14 h at 85 °C. This more or less confirmed
the fact that the fluoride anion was basic enough to promote
the arylation of the monoarylated product due to the sub-
strate’s enhanced acidity as compared to the parent enone.
In summary, we have developed a new method for the
regioselective synthesis of R-aryl enones by employing
sterically encumbered, electron-rich phosphine ligands in
a modified KuwajimaÀUrabe protocol of arylation of
silylenol ethers with a wide range of aryl bromides and
triflates. The reaction is of general scope and is expected to
have excellent synthetic utility. The application of this
protocol in the synthesis of macrocyclic natural products
is currently in progress.
Acknowledgment. We wish to thank DST-INDIA for
a research grant for this project (SR/S1/OC-60/2010).
We are indebted to UGC and CSIR for grant of research
fellowships to APK and GGP respectively. We would also
like to thank Director, IISER Bhopal, for start-up funding
and research facilities.
a All yields are isolated yields. b Product obtained could not be
completely purified.
observed (Table 3, entries 9À11). The regioselectivity of
the reaction was probably governed by the faster in situ
silylÀstannyl exchange and consequent transmetalation vs
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(21) LiCl as an additive was necessary in case of the triflates; see
(a) Echavarren, A. M.; Stille, J. K. J. Am. Chem. Soc. 1987, 109, 5478–
5486. (b) Farina, V.; Krishnan, B.; Marshall, D. R.; Roth, G. P. J. Org.
Chem. 1993, 58, 5434–5444.
(22) Clark, J. H. Chem. Rev. 1980, 80, 429–452.
The authors declare no competing financial interest.
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