Exploiting Aryl Mesylates and Tosylates in Catalytic Mono-α-arylation of Aryl- and Heteroarylketones

Article abstract of DOI:10.1021/acs.orglett.6b00643

The first general palladium catalyst for the catalytic mono-α-arylation of aryl- and heteroarylketones with aryl mesylates and tosylates is described. The newly developed indolyl-derived phosphine ligand L7 has been identified to promote this reaction eff

Full text of DOI:10.1021/acs.orglett.6b00643

Letter
pubs.acs.org/OrgLett
Exploiting Aryl Mesylates and Tosylates in Catalytic Mono-α-
arylation of Aryl- and Heteroarylketones
Wai Chung Fu, Chau Ming So, On Ying Yuen, Irene Toi Chuk Lee, and Fuk Yee Kwong*
State Key Laboratory of Chirosciences and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic
University, Hung Hom, Kowloon, Hong Kong
S
* Supporting Information
ABSTRACT: The first general palladium catalyst for the
catalytic mono-α-arylation of aryl- and heteroarylketones with
aryl mesylates and tosylates is described. The newly developed
indolyl-derived phosphine ligand L7 has been identified to
promote this reaction efficiently. The key to success is
attributed to the enhanced steric congestion of the catalyst and
effective oxidative addition of the C(Ar)−OMs bond. In the presence of Pd(OAc)2 (0.25−2.5 mol %) and L7, selective
monoarylations are achieved with ample reaction scope and product yields up to 95%. Importantly, we demonstrated the
applicability of this protocol with the modification of biological phenolic compounds, rendering it amenable for functionalization
of phenolic (pro)drugs.
ketone is, in general, recognized to be difficult due to the
alladium-catalyzed α-arylation of carbonyl compounds has
Pbeen well documented as versatile approaches to construct increased acidity of the remaining α-C−H bonds after the first
C(sp3)−C(sp2) bonds.1 These approaches opened up new
arylation process, rendering facile formation of ketone enloates
and giving undesirable α,α-diarylated products. Moreover, the
reductive elimination process is sensitive to the catalyst
characteristics in terms of electron richness and steric bulkiness;
minor adjustments between these two factors will lead to a
completely different outcome.7
possibilities to access key structures present in numerous
pharmaceutical intermediates and natural products.2 Since the
pioneering works by Buchwald,3 Hartwig,4 and Miura5 on the
direct α-arylation of ketones, tremendous advancements in this
field have been made.6 However, several challenges persist in this
catalysis (Scheme 1). For instance, selective mono-α-arylation of
Despite the fact that aryl halides were commonly employed as
electophiles in the α-arylation of ketones due to its facile
oxidative addition by palladium and copper catalysts, halo-
genated compounds are not common in view of medicinal
chemistry. The halogenation of specific sites in natural products
or pharmacophores would be undesirable due to lengthy
synthetic pathways and functional group manipulations.
However, biologically active compounds with phenolic moieties
are common and a general while effective method for direct
functionalization of these sites would be highly desirable. In this
regard, aryl sulfonates such as aryl mesylate and tosylate are
indeed more attractive alternatives owing to their cost-
effectiveness over other sulfonating agents,8 as well as their
high stability and environmental friendliness.9 There is room for
development of a general and active catalyst system for accessing
these attractive aryl sulfonates, which are useful complements to
aryl halides. However, the highly demanding oxidative addition
by a palladium species accompanied by the inherent chemical
stability of these aryl sulfonates is still problematic, and a suitable
ligand candidate is needed to tackle these concerns. Thus, a very
limited number of phosphine ligands were known to promote
such difficult oxidative additions, including BrettPhos,10 Mor-
dalPhos,11 CM-Phos,12 and a few others.13 Unfortunately, the
Scheme 1. Palladium-Catalyzed Mono-α-arylations
Received: March 7, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00643
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
high electron-richness embedded with these ligands may result in
the inefficacy against electron-deficient arene substrates in
ketone arylation reactions, as reported in literatures.14,15 In
terms of aryl mesylates specifically, only one report by Stradiotto
and co-workers detailed the α-arylation of strictly alkylketones
with aryl mesylates using a [Pd(cinnamyl)Cl]2/Mor-DalPhos
catalyst.6w Taking the aforementioned points into account, the
identification of a general palladium catalyst system for the
monoarylation of arylketones with aryl mesylates is deemed a
challenge. Herein, we describe the first general palladium catalyst
for mono-α-arylation of arylmethylketones with aryl mesylates
and tosylates. Under mildly basic conditions, excellent functional
group tolerance was achieved with a modest catalyst loading
(0.25−2.5 mol %) and no diarylated products were detected.
During the initial investigations, we surveyed an array of state-
of-the-art ligand candidates which are effective in aryl sulfonate
cross-couplings or ketone arylations (Scheme 2). Preliminary
screening employing Buchwald’s biaryl10,13a,b or Stradiotto’s
P,N-type phosphine ligands11 resulted in modest product yields
(6−37% yield), but they demonstrated the importance of the
steric bulkiness of ligands with an increasing trend of yields (from
L1 to L5). With our previous experience in aryl mesylate cross-
couplings,12 we then chose the CM-Phos-type ligands (L6 and
L7) in our ligand library for evaluation in this model reaction. We
found that these ligands were able to give the monoarylated
product in excellent yields while the new L7 was even more
promising (95% yield). We attribute the superior performance of
L7 over L6 to the enhanced steric congestion provided by the
indolyl scaffold. These results complied with previous findings
regarding the importance of steric bulkiness in reductive
elimination of ketone arylation reactions.6v,q,w Other mono-/
bidentate phosphine and N-heterocyclic carbene ligands were
shown to be ineffective (L8 to L13).16
To improve the effectiveness of the Pd/L7 catalyst system, we
further investigated the reaction conditions with various Pd
sources, bases, and solvents (Table S1, Supporting Information).
We found that using neat t-BuOH as solvent led to an unstirrable
reaction mixture, rendering unstable results (Table S1, entry 1).
Various solvents were used in an attempt to dilute the mixture,
and THF was found to be the best counterpart in a 1:1 ratio with
t-BuOH (Table S1, entries 2−5 vs 6). Yet, the use of neat THF
provided an inferior result (Table S1, entry 6 vs 7). Lowering the
ketone equivalents to 4 equiv was found to preserve the catalytic
performance of the system (Table S1, entry 9 vs 8 and 10−11). It
is worth noting that 5−10 equiv of ketones were required for the
cross-coupling with aryl mesylates in a previous report (Scheme
1, B) .6w The best metal-to-ligand ratio was found to be 1:3
(Table S1, entry 9 vs 12). The effect of water equivalents in
K3PO4·H2O was minimal (Table S1, entry 13 vs 14). Replacing
K3PO4 with either Na3PO4 or Cs2CO3 resulted in a significant
drop in product yields (Table S1, entry 13 vs 15−16). The source
of palladium has a minimal effect on the reaction; Pd(OAc)2 was
shown to have comparable performance to [Pd(cinnamyl)Cl]2
(Table S1, entry 17 vs 13 and 18−20). This relatively more cost-
effective Pd(OAc)2 was then chosen for further study.
a
Scheme 2. Ancillary Ligand Screen
Having identified the best reaction conditions, we next
investigated the functional group tolerance of our system by
examining a wide range of aryl mesylates and tosylates. In
general, 1.0 to 2.0 mol % of Pd completed the cross-couplings of
acetophenone enolate with no diarylated product formation
(Table 1). Electron-neutral and -rich arenes were converted to
the corresponding products in good-to-excellent yields (Table 1,
entries 1−6). Sterically hindered substrates were also applicable
in our system (Table 1, entries 7−8). Notably, electron-deficient
arenes, which proved to be difficult substrates in ketone
arylations,15 gave moderate-to-good product yields (Table 1,
entries 9−10). An enolizable amide group was well-tolerated and
gave chemoselective ketone α-arylation products (Table 1,
entries 11−12). An ester and a variety of heterocyclics such as
benzodioxole, pyrrolylarene, quinoline, and benzothiazole were
compatible (Table 1, entries 13−20).
To demonstrate the applicability of our system in a wider
scope, we synthesized a diverse library of mono-α-arylated
arylketones. Electron-neutral (Scheme 3, 1a−1d, 1h), -rich
(Scheme 3, 1e−1g), and -poor (Scheme 3, 1j) arylmethylketones
were suitable counterparts and afforded the corresponding
products in good-to-excellent yields (65−94% yield). While
achieving mono-α-arylations with arylketones, our system is
capable of handling highly sterically hindered α-substituted
arylketones such as α-tetralone and deoxybenzoin with good
a
Reaction conditions: Pd(OAc)2 (0.5 mol %), ligand (1.5 mol %), 2-
naphthyl mesylate (0.5 mmol), acetophenone (2.0 mmol), K3PO4 (1.0
mmol), t-BuOH/THF (1:1, 4.0 mL) at 90 °C under N2 for 18 h,
calibrated GC-FID yields were reported.
B
DOI: 10.1021/acs.orglett.6b00643
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Pd-Catalyzed Selective Mono-α-arylation of
Acetophenone Enolate with Aryl Mesylates and Tosylates
Scheme 3. A Library of Mono-α-arylated Arylketones
Synthesized Using Pd(OAc)2/L7 Catalyst
a
a
a
Reaction conditions: Pd(OAc)2/L7 = 1:3 (mol % as indicated),
ArOMs or ArOTs (0.3 mmol), acetophenone (1.2 mmol), K3PO4 (0.6
mmol), t-BuOH/THF (1:1, 2.4 mL) at 110 °C under N2 for 21 h.
Reaction time was not optimized for each substrate. Isolated yields
were reported.
reactivity (Scheme 3, 1k−1l). Previously, there were very few
successful attempts with the mono-α-arylations of heteroar-
ylketones, even with the use of aryl halides.17 With our system,
various acetyl furans, thiophene, and pyrrole-embedded
arylketone were successfully monoarylated (Scheme 3, 1m−
1r). Additionally, our protocol allowed for modification of a
human sex hormone 17β-estradiol. The mesyated 17β-estradiol
was coupled smoothly with arylmethylketones to furnish 1s and
1t (Scheme 3). The aliphatic mesylate on the ketone products
remained intact during the course of the reaction, thus allowing
for further functionalization with other common organic
syntheses. We anticipate our system will be useful in the
modification of various phenolic (pro)drugs.18
In summary, we have developed a general and efficient Pd
catalyst for the mono-α-arylation of arylmethylketones with aryl
mesylates and tosylates. The new L7−Pd system exhibited good
compatibility to a wide range of functional groups and
heterocyclics within the aryl mesylates and tosylates. Excellent
chemo- and monoselectivity at a modest catalyst loading (0.25−
2.5 mol %) were attained. Heteroarylketones were smoothly
monoarylated, and heteroaromatic substituents were well-
tolerated. Furthermore, this protocol provided a straightforward
modification of biologically active phenolic compounds. We
believe this newly developed palladium catalyst would be useful
a
Reaction conditions: Pd(OAc)2/L7 = 1:3, ArOMs or ArOTs (0.30
mmol), arylketone (1.2 mmol), K3PO4 (0.6 mmol), t-BuOH/THF
(1:1, 2.4 mL) at 110 °C under N2 for 21 h. Catalyst loading and
reaction time were not optimized for each substrate. Isolated yields
were reported.
in the synthesis of a drug library for lead optimizations and fine-
tuning the biological properties of phenolic drugs. Further
investigations in the exceptional reactivity of phosphine ligand
C
DOI: 10.1021/acs.orglett.6b00643
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Alsabeh, P. G.; Stradiotto, M. Eur. J. Org. Chem. 2012, 2012, 6042.
(p) Ackermann, L.; Mehta, V. P. Chem. - Eur. J. 2012, 18, 10230.
(q) Hesp, K. D.; Lundgren, R. J.; Stradiotto, M. J. Am. Chem. Soc. 2011,
L7 for aryl mesylate cross-couplings are underway in our
laboratory.
133, 5194. (r) Li, P.; Lu, B.; Fu, C.; Ma, S. Adv. Synth. Catal. 2013, 355,
̈
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00643.
■
1255. (s) Gabler, C.; Korb, M.; Schaarschmidt, D.; Hildebrandt, A.;
̈
S
Lang, H. Adv. Synth. Catal. 2014, 356, 2979. (t) MacQueen, P. M.;
Chisholm, A. J.; Hargreaves, B. K.; Stradiotto, M. Chem. - Eur. J. 2015,
21, 11006. (u) Rotta-Loria, N. L.; Borzenko, A.; Alsabeh, P. G.; Lavery,
C. B.; Stradiotto, M. Adv. Synth. Catal. 2015, 357, 100. (v) Fu, W. C.; So,
C. M.; Chow, W. K.; Yuen, O. Y.; Kwong, F. Y. Org. Lett. 2015, 17, 4612.
(w) Alsabeh, P. G.; Stradiotto, M. Angew. Chem., Int. Ed. 2013, 52, 7242.
(x) Xu, Y.; Su, T.; Huang, Z.; Dong, G. Angew. Chem., Int. Ed. 2016, 55, 1.
(y) Fu, W. C.; Zhou, Z.; Kwong, F. Y. Organometallics 2016, in press,
doi:10.1021/acs.organomet.6b00154.
Detailed experimental procedures; H, 13C, 31P NMR
spectra; and characterization data of all new compounds
(PDF)
1
AUTHOR INFORMATION
Corresponding Author
■
(7) Our previous work demostrated the introduction of one or two
methoxy groups in the lower aryl ring will greatly increase the product
yield; see ref 6v. See also ref 6k for a detailed investigation into these
factors by Hartwig and co-workers.
*E-mail: fuk-yee.kwong@polyu.edu.hk.
Notes
(8) According to Aldrich catalog 2014: mesyl chloride ($168/1 L),
tosyl chloride ($91.1/1 kg), and triflic anhydride ($1690/1 kg).
(9) (a) Kozhushkov, S. I.; Potukuchi, H. K.; Ackermann, L. Catal. Sci.
Technol. 2013, 3, 562. (b) Wilkinson, M. C. Org. Lett. 2011, 13, 2232.
(10) For the use of BrettPhos in Pd-catalyzed cross-couplings of aryl
mesylates, see: Fors, B. P.; Watson, D. A.; Biscoe, M. R.; Buchwald, S. L.
J. Am. Chem. Soc. 2008, 130, 13552.
(11) For the use of Mor-Dal Phos in cross-coupling reactions of aryl
mesylates, see: Reference 6w and (a) Lundgren, R. J.; Stradiotto, M.
Angew. Chem., Int. Ed. 2010, 49, 8686.
(12) (a) So, C. M.; Kwong, F. Y. Chem. Soc. Rev. 2011, 40, 4963. (b) So,
C. M.; Lau, C. P.; Kwong, F. Y. Chem. - Eur. J. 2011, 17, 761. (c) Fu, W.
C.; So, C. M.; Kwong, F. Y. Org. Lett. 2015, 17, 5906. (d) Yeung, P. Y.;
So, C. M.; Lau, C. P.; Kwong, F. Y. Angew. Chem., Int. Ed. 2010, 49, 8918.
(e) Choy, P. Y.; Chow, W. K.; So, C. M.; Lau, C. P.; Kwong, F. Y. Chem. -
Eur. J. 2010, 16, 9982. (f) So, C. M.; Lau, C. P.; Kwong, F. Y. Angew.
Chem., Int. Ed. 2008, 47, 8059.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Research Grants Council of Hong Kong (CRF:
C5023-14G), General Research Fund (PolyU 153008/14P), and
State Key Laboratory of Chirosciences for financial support.
REFERENCES
■
(1) For selected reviews on Pd-catalyzed α-arylation of carbonyl
compounds, see: (a) Sivanandan, S. T.; Shaji, A.; Ibnusaud, I.; Seechurn,
C. C. C. J.; Colacot, T. J. Eur. J. Org. Chem. 2015, 2015, 38.
(b) Johansson, C. C. C.; Colacot, T. J. Angew. Chem., Int. Ed. 2010, 49,
676. (c) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234.
(d) Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082. (e) Novak, P.;
Martin, R. Curr. Org. Chem. 2011, 15, 3233.
(2) (a) Li, H. Q.; Luo, Y.; Song, R.; Li, Z. L.; Yan, T.; Zhu, H. L.
ChemMedChem 2010, 5, 1117. (b) Venkatesan, H.; Davis, M. C.; Altas,
Y.; Snyder, J. P.; Liotta, D. C. J. Org. Chem. 2001, 66, 3653.
(c) Vontzalidou, A.; Zoidis, G.; Chaita, E.; Makropoulou, M.;
Aligiannis, N.; Lambrinidis, G.; Mikros, E.; Skaltsounis, A.-L. Bioorg.
Med. Chem. Lett. 2012, 22, 5523. (d) Kim, Y. W.; Hackett, J. C.;
Brueggemeier, R. W. J. Med. Chem. 2004, 47, 4032. (e) Kanagalakshmi,
K.; Premanathan, M.; Priyanka, R.; Hemalatha, B.; Vanangamudi, A. Eur.
J. Med. Chem. 2010, 45, 2447.
(3) (a) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108.
(b) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc.
2000, 122, 1360.
(4) (a) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119,
12382. (b) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121,
1473.
(13) For the use of DCPP, SPhos, and XPhos in Pd-catalyzed cross-
couplings of aryl mesylates, see: (a) Choy, P. Y.; Luk, K. C.; Wu, Y.; So,
C. M.; Wang, L.-l.; Kwong, F. Y. J. Org. Chem. 2015, 80, 1457.
(b) Ackermann, L.; Fenner, S. Chem. Commun. 2011, 47, 430.
(c) Munday, R. H.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc.
2008, 130, 2754.
(14) For the effect of electon-rich phosphine ligands on electron-
deficient substrates in ketone arylation reactions, see: Reference 1c, 6q,
and w.
(15) We have recently designed an indolylphosphine ligand which is
capable of handling electron-deficient arenes in acetone arylation; see ref
6v.
(16) For the use of L8 and L9 in Pd-catalyzed α-arylation of ketones,
see ref 6d, m. For the use of L10−L12 in a cross-coupling reaction of aryl
sulfonates and other challenging catalysis, see: (a) Zhang, J.; Bellomo,
A.; Creamer, A. D.; Dreher, S. D.; Walsh, P. J. J. Am. Chem. Soc. 2012,
134, 13765. (b) Sha, S.-C.; Zhang, J.; Carroll, P. J.; Walsh, P. J. J. Am.
Chem. Soc. 2013, 135, 17602. For a recent review on the use of N-
heterocyclic carbene ligands in Pd catalysis, see: (c) Valente, C.;
Çalimsiz, S.; Hoi, K. H.; Mallik, D.; Sayah, M.; Organ, M. G. Angew.
Chem., Int. Ed. 2012, 51, 3314.
(17) For a few successful attempts in mono-α-arylation of heteroaryl
ketone, see: References 4a, 6m−o, and t.
(18) For selected examples of modifying phenolic sites to improve
pharmacological properties, see: (a) Hoffman, W. F.; Woltersdorf, O.
W.; Novello, F. C.; Cragoe, E. J.; Springer, J. P.; Watson, L. S.; Fanelli, G.
M. J. Med. Chem. 1981, 24, 865. (b) Lee, J.; Lee, J.; Kang, M.-S.; Kim, K.-
P.; Chung, S.-J.; Blumberg, P. M.; Yi, J.-B.; Park, Y. H. Bioorg. Med. Chem.
2002, 10, 1171. (c) Thomas, J. D.; Majumdar, S.; Sloan, K. B. Molecules
2009, 14, 4231. (d) Latham, K. R. WO2013010102 A2, 2013.
(5) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew. Chem., Int.
Ed. Engl. 1997, 36, 1740.
(6) For recent reviews on Pd-catalyzed α-arylation of carbonyl
compounds, see: Reference 1. For notable examples of Pd-catalyzed α-
arylation of ketones, see: (a) Lundgren, R. J.; Stradiotto, M. Chem. - Eur.
J. 2012, 18, 9758. (b) Gildner, P. G.; Colacot, T. J. Organometallics 2015,
34, 5497. (c) Viciu, M. S.; Germaneau, R. F.; Nolan, S. P. Org. Lett. 2002,
4, 4053. (d) Grasa, G. A.; Colacot, T. J. Org. Lett. 2007, 9, 5489.
(e) Grasa, G. A.; Colacot, T. J. Org. Process Res. Dev. 2008, 12, 522.
(f) Hamada, T.; Chieffi, A.; Åhman, J.; Buchwald, S. L. J. Am. Chem. Soc.
2002, 124, 1261. (g) Rutherford, J. L.; Rainka, M. P.; Buchwald, S. L. J.
Am. Chem. Soc. 2002, 124, 15168. (h) Nguyen, H. N.; Huang, X.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 11818. (i) Liao, X.; Weng,
Z.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 195. (j) Adjabeng, G.;
Brenstrum, T.; Frampton, C. S.; Robertson, A. J.; Hillhouse, J.; McNulty,
J.; Capretta, A. J. Org. Chem. 2004, 69, 5082. (k) Culkin, D. A.; Hartwig,
J. F. Organometallics 2004, 23, 3398. (l) Ehrentraut, A.; Zapf, A.; Beller,
M. Adv. Synth. Catal. 2002, 344, 209. (m) Marelli, E.; Corpet, M.;
Davies, S. R.; Nolan, S. P. Chem. - Eur. J. 2014, 20, 17272. (n) Biscoe, M.
R.; Buchwald, S. L. Org. Lett. 2009, 11, 1773. (o) Crawford, S. M.;
D
DOI: 10.1021/acs.orglett.6b00643
Org. Lett. XXXX, XXX, XXX−XXX