Palladium-catalyzed mono-α-arylation of acetone with aryl imidazolylsulfonates

Article abstract of DOI:10.1002/chem.201201394

Set the ace(tone): A palladium catalyst derived from the bidentate XantPhos ligand and Pd(OAc)₂ has enabled broadly applicable mono-α-arylations of acetone to be performed with air- and moisture-stable aryl imidazolylsulfonates as most user-friendly electrophiles (see scheme). Copyright

Full text of DOI:10.1002/chem.201201394

COMMUNICATION
DOI: 10.1002/chem.201201394
Palladium-Catalyzed Mono-a-Arylation of Acetone with Aryl
Imidazolylsulfonates
Lutz Ackermann* and Vaibhav P. Mehta[a]
Table 1. Optimization studies on the mono-a-arylation of acetone (2)
with aryl imidazolylsulfonate 1a.[a]
À
Palladium-catalyzed arylations of a-C H acidic com-
pounds have emerged as reliable tools for the formation of
3
À
C
(sp ) C
(sp2) bonds.[1,2] In particular, pioneering studies by
the groups of Miura,[3] Buchwald,[4] and Hartwig[5] have set
the stage for broadly applicable a-arylations of various car-
bonyl compounds.[1,6,7] Despite this remarkable progress,[6]
generally applicable mono-a-arylations of the simplest
ketone, acetone, have until very recently proven elusive.[8]
This is largely because the monoarylated acetone derivatives
are inherently more reactive than acetone itself, which can
lead to mixtures of oligo- and polyarylated products that are
difficult to separate. Stradiotto and co-workers’ elegantly de-
signed DalPhos P,N ligands[9] were very recently found to be
the key to controlling the chemoselectivity and reactivity of
challenging mono-a-arylations of acetone.[10] In recent years,
the focus on transition-metal-catalyzed arylations has shifted
to the use of phenol-derived, fluorine-free[11] electrophiles as
arylating reagents because these electrophiles are readily ac-
cessible and can be easily utilized as directing groups in ver-
satile arene functionalization strategies.[12] In this context,
air- and moisture-stable aryl imidazolylsulfonates 1 are par-
ticularly attractive because of the self-destructive, and thus
nongenotoxic properties, of the byproduct imidazolylsulfonic
acid.[13] Within our research program on the use of phenol-
Entry
Ligand
Base
T [8C]
Yield [%]
[b]
1
2
3
4
5
PCy3
dppf
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
110
110
110
110
110
110
80
80
60
80
80
80
80
80
80
80
80
–
50
XantPhos
XantPhos
XantPhos
XantPhos
XantPhos
XantPhos
XantPhos
>98 (79)
[b]
–
K3PO4·H2O
NaOtBu
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
35
–
6
7[c]
8[d]
9
>98 (31)
[b]
–
80 (62)
[b]
10
11
12
13
14
15
16
17
A
–
X-Phos
HIMesCl
dppe
15
–
–
–
[b]
[b]
[b]
dppb
rac-BINAP
DPE-Phos
XantPhos
80 (38)
>98 (69)
>98 (84)
[a] Reaction conditions: 1a (0.5 mmol),
2
(0.5 mL), PdACHTUNGTRENNUNG(OAc)2
(5.0 mol%), ligand (10.0 mol%), base (1.0 mmol), 1,4-dioxane (2.0 mL);
conversion was determined by GC; isolated yields are given in parenthe-
ses; Im=imidazolyl, Cy=cyclohexyl, tBu=tert-butyl, X-Phos=2-dicyclo-
hexylphosphino-2’,4’,6’-triisopropylbiphenyl, IMesH=1,3-bis(2,4,6-trime-
[14,15]
À
based electrophiles for metal-catalyzed C H bond
ary-
lations,[16,17] we became interested in employing user-friendly
imidazolylsulfonates for a-arylations of ketones, with a par-
ticular focus on the use of acetone (2), which we wish to
report herein.
thylphenyl)imidazolium,
dppe=1,2-bis(diphenylphosphino)ethane,
dppb=1,4-bis(diphenylphosphino)butane, rac-BINAP=racemic 2,2’-bis-
(diphenylphosphino)-1,1’-binaphthalene, DPE-Phos=bis(2-diphenylphos-
phinophenyl)ether. [b] Only unreacted 1a observed by GC/MS analysis.
[c] [{(cinnamyl)PdCl}2] (2.5 mol%). [d] [Pd2dba3] (2.5 mol%); dba=di-
benzylideneacetone.
Our optimization studies were initiated by probing a set
of ligands for the difficult mono-a-arylation of acetone (2)
with aryl imidazolylsulfonate 1a in 1,4-dioxane as the sol-
vent (Table 1 and Table S1 in the Supporting Information).
Interestingly, although monodentate phosphine ligands only
provided unsatisfactory results, chemoselective and efficient
catalysis was accomplished with bisphosphines 1,1’-bis(di-
phenylphosphino)ferrocene (dppf)[18] and 4,5-bis(diphenyl-
phosphino)-9,9-dimethylxanthene (XantPhos)[19] (Table 1,
entries 1–3). Among a variety of bases, Cs2CO3 proved to be
optimal, whereas NaOtBu led to an undesired decomposi-
tion of the organic electrophile 1a (Table 1, entry 6). Reac-
tions proceeded most satisfactorily in 1,4-dioxane as the sol-
vent, with transformations performed in THF, toluene, or
MeCN being less successful. Different palladium(II) com-
pounds served as viable precatalysts; the most efficient cat-
[a] Prof. Dr. L. Ackermann, Dr. V. P. Mehta
Institut fꢀr Organische und Biomolekulare Chemie
Georg-August-Universitꢁt, Tammannstrasse 2
37077 Gçttingen (Germany)
alysis was achieved by employing inexpensive PdACHTUNGTRENNUNG(OAc)2
which ensured high catalytic efficacy even at a significantly
lower reaction temperature (Table 1, entries 7–17).[20] It is
worth noting that in a previous study the inexpensive pre-
Fax : (+49)551-39-6777
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Homepage: http://www.org.chemie.uniso-goettingen.de/ackermann/
cursor Pd
ACHTUNGRTENN(UNG OAc)2 led to a low conversion of acetone (2) (<
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201394.
5%).[10a]
Chem. Eur. J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
1
&
ÞÞ
These are not the final page numbers!

Scheme 2. Mono-a-arylation of alkyl methyl ketones
4 (nPent=n-
pentyl).
Scheme 1. Palladium-catalyzed mono-a-arylation of acetone (2).
We tested the scope of the optimized catalytic system
using the mono-a-arylation of acetone (2) (Scheme 1). A va-
riety of aryl imidazolylsulfonates 1, with para, meta or ortho
substituents, furnished the desired products 3b–3s with ex-
cellent chemoselectivities. The catalytic system proved to be
broadly applicable and was found to be tolerant of valuable
electrophilic functional groups such as fluoro, chloro or
ester substituents as well as heterocyclic moieties. Further-
more, sterically shielded di-ortho-substituted electrophiles
1t and 1u were converted with high catalytic efficacy to the
desired mono-arylated products 3t and 3u, respectively. Im-
portantly, acetophenone derivative 1v delivered the mono-
a-arylation product 3v of acetone 2 as the only product of
a competition experiment, which is a strong testament for
the excellent chemoselectivity of the palladium catalyst (see
below).
The optimized catalytic system was not restricted to the
a-arylation of acetone (2), but also enabled the efficient
functionalization of alkyl methyl ketones 4 with aryl imida-
zolylsulfonates 1, including a cyclopropane derivative, to
give monoarylated products 5 (Scheme 2). Notably, the pal-
ladium-catalyzed functionalization occurred with excellent
site- and monoselectivity at the sterically less congested
methyl substituent of ketones 4.
Scheme 3. Chemoselective mono-a-arylation of aryl methyl ketones 6.
However, the protocol for a-arylations with imidazolylsul-
fonates 1 was not limited to methyl ketones. Indeed, the op-
timized catalytic system allowed for effective a-arylations of
diversely substituted alkyl ketones 8, including cyclic sub-
strates (Scheme 4).
Given the remarkable chemoselectivity exerted by the op-
timized palladium catalyst in mono-a-arylations with imida-
zolylsulfonates 1, we became interested in probing its mode
of action. Intermolecular competition experiments revealed
that aryl imidazolylsulfonates 1 are significantly more reac-
tive than aryl tosylates 10 or mesylates 11, even when they
are electronically deactivated (Scheme 5).
Furthermore, acetophenones 6 provided the desired mon-
oarylated products 7 with high yields of isolated products,
again through
methyl group of ketones 6 (Scheme 3).
a
chemoselective transformation of the
In summary, we have reported the first a-arylations of
carbonyl compounds with user-friendly aryl imidazolylsulfo-
&
2
&
www.chemeurj.org
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Palladium-Catalyzed Mono-a-arylation of Acetone
COMMUNICATION
Acknowledgements
Support by the Alexander von Humboldt foundation (fellowship to
V.P.M.) is gratefully acknowledged.
À
À
Keywords: arylation · C H activation · C O activation ·
imidazolylsulfonate · palladium · phosphane ligands
[1] For selected reviews, see: a) F. Bellina, R. Rossi, Chem. Rev. 2010,
110, 1082–1146; b) C. C. C. Johansson, T. J. Colacot, Angew. Chem.
2010, 122, 686–718; Angew. Chem. Int. Ed. 2010, 49, 676–707; c) P.
Novꢃk, R. Martin, Curr. Org. Chem. 2011, 15, 3233–3262; for an ac-
count, see: d) D. A. Culkin, J. F. Hartwig, Acc. Chem. Res. 2003, 36,
234–245.
[2] B. Schlummer, U. Scholz in Modern Arylation Methods (Ed.: L. Ac-
kermann), Wiley-VCH, Weinheim, 2009, pp. 69–120.
[3] T. Satoh, Y. Kawamura, M. Miura, M. Nomura, Angew. Chem. 1997,
109, 1820–1822; Angew. Chem. Int. Ed. Engl. 1997, 36, 1740–1742.
[4] M. Palucki, S. L. Buchwald, J. Am. Chem. Soc. 1997, 119, 11108–
11109.
[5] B. C. Hamann, J. F. Hartwig, J. Am. Chem. Soc. 1997, 119, 12382–
12383.
Scheme 4. a-Arylation of alkyl ketones 8 with imidazolylsulfonates 1.
[6] For selected examples of palladium-catalyzed a-arylations, see: a) L.
Wu, L. Falivene, E. Drinkel, S. Grant, A. Linden, L. Cavallo, R.
Dorta, Angew. Chem. 2012, 124, 2924–2927; Angew. Chem. Int. Ed.
2012, 51, 2870–2873; b) C. Richter, K. V. S. Ranganath, F. Glorius,
Adv. Synth. Catal. 2012, 354, 377–382; c) P. F. Li, S. L. Buchwald,
Angew. Chem. 2011, 123, 6520–6524; Angew. Chem. Int. Ed. 2011,
50, 6396–6400; d) S. Duez, S. Bernhardt, J. Heppekausen, F. F.
Fleming, P. Knochel, Org. Lett. 2011, 13, 1690–1693; e) X. Liao,
L. M. Stanley, J. F. Hartwig, J. Am. Chem. Soc. 2011, 133, 2088–
2091; f) A. M. Taylor, R. A. Altman, S. L. Buchwald, J. Am. Chem.
Soc. 2009, 131, 9900–9901; g) J. Garcꢄa-Fortanet, S. L. Buchwald,
Angew. Chem. 2008, 120, 8228–8231; Angew. Chem. Int. Ed. 2008,
47, 8108–8111; h) G. D. Vo, J. F. Hartwig, Angew. Chem. 2008, 120,
2157–2160; Angew. Chem. Int. Ed. 2008, 47, 2127–2130; i) W. Su, S.
Raders, J. G. Verkade, X. Liao, J. F. Hartwig, Angew. Chem. 2006,
118, 5984–5987; Angew. Chem. Int. Ed. 2006, 45, 5852–5855; j) A.
Ehrentraut, A. Zapf, M. Beller, Adv. Synth. Catal. 2002, 344, 209–
217, and references therein.
[7] For previous examples of palladium-catalyzed a-arylations from our
laboratories, see: a) L. Ackermann, R. Vicente, N. Hofmann, Org.
Lett. 2009, 11, 4274–4276; b) L. Ackermann, J. H. Spatz, C. J.
Gschrei, R. Born, A. Althammer, Angew. Chem. 2006, 118, 7789–
7792; Angew. Chem. Int. Ed. 2006, 45, 7627–7630.
[8] a) D. A. Culkin, J. F. Hartwig, Organometallics 2004, 23, 3398–3416;
b) D. A. Culkin, J. F. Hartwig, J. Am. Chem. Soc. 2001, 123, 5816–
5817.
[9] R. J. Lundgren, K. D. Hesp, M. Stradiotto, Synlett 2011, 2443–2458.
[10] a) K. D. Hesp, R. J. Lundgren, M. Stradiotto, J. Am. Chem. Soc.
2011, 133, 5194–5197; for elegant mono-a-arylations of acetate
esters and aryl methyl ketones by using aryl chlorides, see: b) M. R.
Biscoe, S. L. Buchwald, Org. Lett. 2009, 11, 1773–1775.
Scheme 5. Competition experiments with different electrophiles.
[11] For an illustrative example of palladium-catalyzed a-arylations with
aryl triflates, see: a) M. S. Viciu, R. F. Germaneau, S. P. Nolan, Org.
Lett. 2002, 4, 4053–4056; for the use of aryl tosylates, see ref. [10a]
and: b) H. N. Nguyen, X. Huang, S. L. Buchwald, J. Am. Chem. Soc.
2003, 125, 11818–11819.
nates as electrophiles. A catalytic system derived from bi-
dentate phosphine XantPhos and inexpensive PdACTHNUTRGNEUNG(OAc)2
proved widely applicable, and allowed for the challenging
mono-a-arylation of acetone with ample scope.
À
[12] For recent reviews on challenging arylations through C O bond
cleavages, see: a) M. Tobisu, N. Chatani, ChemCatChem 2011, 3,
1410–1411; b) B.-J. Li, D.-G. Yu, C.-L. Sun, Z.-J. Shi, Chem. Eur. J.
2011, 17, 1728–1759; c) B. M. Rosen, K. W. Quasdorf, D. A. Wilson,
N. Zhang, A.-M. Resmerita, N. K. Garg, V. Percec, Chem. Rev. 2011,
111, 1346–1416; d) D.-G. Yu, B.-J. Li, Z.-J. Shi, Acc. Chem. Res.
2010, 43, 1486–1495.
Chem. Eur. J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
3
&
ÞÞ
These are not the final page numbers!

L. Ackermann and V. P. Mehta
3
À
[13] For aryl imidazolylsulfonates 1 in metal-catalyzed arylations, see:
a) L. Ackermann, R. Sandmann, W. Song, Org. Lett. 2011, 13, 1784–
1786; b) L. Ackermann, S. Barfꢀßer, J. Pospech, Org. Lett. 2010, 12,
724–726; c) Y. Luo, J. Wu, Organometallics 2009, 28, 6823–6826;
d) J. Albaneze-Walker, R. Raju, J. A. Vance, A. J. Goodman, M. R.
Reeder, J. Liao, M. T. Maust, P. A. Irish, P. Espino, D. R. Andrews,
Org. Lett. 2009, 11, 1463–1466. For the recent use of sulfamates,
see: e) K. W. Quasdorf, A. Antoft-Finch, P. Liu, A. L. Silberstein, A.
Komaromi, T. Blackburn, S. D. Ramgren, K. N. Houk, V. Snieckus,
N. K. Garg, J. Am. Chem. Soc. 2011, 133, 6352–6363; f) S. D. Ramg-
ren, A. L. Silberstein, Y. Yang, N. K. Garg, Angew. Chem. 2011, 123,
2219–2221; Angew. Chem. Int. Ed. 2011, 50, 2171–2173; g) T. Shi-
masaki, M. Tobisu, N. Chatani, Angew. Chem. 2010, 122, 2991–
2994; Angew. Chem. Int. Ed. 2010, 49, 2929–2932; h) S. J. Shirbin,
B. A. Boughton, S. C. Zammit, S. D. Zanatta, S. M. Marcuccio, C. A.
Hutton, S. J. Williams, Tetrahedron Lett. 2010, 51, 2971–2974;
i) T. K. Macklin, V. Snieckus, Org. Lett. 2005, 7, 2519–2522; j) P. M.
Wehn, J. Du Bois, Org. Lett. 2005, 7, 4685–4688, and references
therein; for the synthesis of aryl imidazolylsulfonates 1, see re-
fs. [13a,b,d] and: k) S. Barfꢀßer, PhD Thesis, Georg-August-Univer-
sitꢁt Gçttingen (Germany), 2011.
[15] For representative reviews on C
G
a) H. Li, B.-J. Li, Z.-J. Shi, Catal. Sci. Technol. 2011, 1, 191–206;
b) O. Baudoin, Chem. Soc. Rev. 2011, 40, 4902–4911; c) R. Jazzar, J.
Hitce, A. Renaudat, J. Sofack-Kreutzer, O. Baudoin, Chem. Eur. J.
2010, 16, 2654–2672; d) M. Tobisu, N. Chatani, Angew. Chem. 2006,
118, 1713–1715; Angew. Chem. Int. Ed. 2006, 45, 1683–1684, and
references therein.
À
[16] For metal-catalyzed direct C H bond arylations through challenging
À
C O bond cleavages with fluorine-free electrophiles, see: a) K.
Muto, J. Yamaguchi, K. Itami, J. Am. Chem. Soc. 2012, 134, 169–
172; b) C. M. So, C. P. Lau, F. Y. Kwong, Chem. Eur. J. 2011, 17,
761–765; c) L. Ackermann, S. Fenner, Chem. Commun. 2011, 47,
430–432; d) L. Ackermann, A. Althammer, S. Fenner, Angew.
Chem. 2009, 121, 207–210; Angew. Chem. Int. Ed. 2009, 48, 201–
204; e) L. Ackermann, M. Mulzer, Org. Lett. 2008, 10, 5043–5045;
f) L. Ackermann, R. Vicente, A. Althammer, Org. Lett. 2008, 10,
2299–2302; g) L. Ackermann, A. Althammer, R. Born, Angew.
Chem. 2006, 118, 2681–2685; Angew. Chem. Int. Ed. 2006, 45, 2619–
2622.
[17] For recent reviews, see: a) L. Ackermann, Pure Appl. Chem. 2010,
82, 1403–1413; b) L. Ackermann, R. Vicente, Top. Curr. Chem.
2010, 292, 211–229.
[18] For abbreviations and acronyms of the ligands, see the Supporting
Information.
[19] a) P. C. J. Kamer, P. W. N. M. van Leeuwen, J. N. H. Reek, Acc.
Chem. Res. 2001, 34, 895–904; for palladium-catalyzed a-arylations
with XantPhos as the ligand, see: b) L. V. Desai, D. T. Ren, T.
Rosner, Org. Lett. 2010, 12, 1032–1035.
[20] The use of 2.5 mol% of the palladium catalyst resulted in an unsat-
isfactorily low yield of the desired product 3a (see Table S1 in the
Supporting Information).
À
[14] For selected recent reviews on C H bond functionalizations, see:
a) C. S. Yeung, V. M. Dong, Chem. Rev. 2011, 111, 1215–1292; b) L.
Ackermann, Chem. Rev. 2011, 111, 1315–1345; c) O. Daugulis, Top.
Curr. Chem. 2010, 292, 57–84; d) L. Ackermann, H. K. Potukuchi,
Org. Biomol. Chem. 2010, 8, 4503–4513; e) D. A. Colby, R. G. Berg-
man, J. A. Ellman, Chem. Rev. 2010, 110, 624–655; f) J. Bouffard, K.
Itami, Top. Curr. Chem. 2010, 292, 231–280; g) K. Fagnou, Top.
Curr. Chem. 2010, 292, 35–56; h) R. Giri, B.-F. Shi, K. M. Engle, N.
Maugel, J.-Q. Yu, Chem. Soc. Rev. 2009, 38, 3242–3272; i) P. Than-
sandote, M. Lautens, Chem. Eur. J. 2009, 15, 5874–5883; j) T. Satoh,
M. Miura, Chem. Lett. 2007, 36, 200–205, and references therein.
Published online: && &&, 0000
&
4
&
www.chemeurj.org
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Palladium-Catalyzed Mono-a-arylation of Acetone
COMMUNICATION
À
C O Activation
L. Ackermann,* V. P. Mehta &&&& — &&&&
Set the ace
derived from the bidentate XantPhos
ligand and Pd(OAc)2 has enabled
broadly applicable mono-a-arylations
G
of acetone to be performed with air-
and moisture-stable aryl imidazolylsul-
fonates as most user-friendly electro-
philes (see scheme).
Palladium-Catalyzed Mono-a-Aryla-
tion of Acetone with Aryl Imidazolyl-
sulfonates
Chem. Eur. J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
5
&
ÞÞ
These are not the final page numbers!