C-C bond formation via C-H bond activation under protic conditions: On the role of phosphane ligand and cosolvent

Article abstract of DOI:10.1021/jo902264u

(Chemical Equation Presented) Effective conditions for the hydroarylation of vinylsilanes, allowing functionalization of various aromatic ketones in good yields at low temperature, using isopropanol, a protic solvent, are reported. Moreover, conducting th

Full text of DOI:10.1021/jo902264u

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involving C-H bond activation are highly desirable, not
C-C Bond Formation via C-H Bond Activation
Under Protic Conditions: On the Role of Phosphane
Ligand and Cosolvent
only because they allow the functionalization of more easily
available starting materials (atom economy concept1) but
also because they produce clean reactions (reduced amounts
of salts).2 In the field of C-C bond formation via C-H
activation,2 several catalytic reactions have been recently
developed,3 and hydroarylation reactions, allowing the func-
tionalization of alkenes with a total atom economy, appear
quite promising.2,4
Another point of concern in the development of green
processes is the reaction solvent. Even if solvent-free reac-
tions are highly desirable, the use of less hazardous and less
toxic solvents is also an attractive alternative.5 Hydroaryl-
ation reactions, involving low-valent active transition metal
complexes (except electrophilic Pd(II)) are generally con-
ducted in inert toxic hydrocarbon solvents like toluene or
benzene.2,4
ꢀ
Marc-Olivier Simon, Remi Martinez, Jean-Pierre Genet, and
Sylvain Darses*
Laboratoire Charles Friedel (UMR 7223, CNRS), Ecole
ꢀ
Nationale Superieure de Chimie de Paris, 11 rue Pierre et
Marie Curie, 75231 Paris Cedex 05, France
sylvain-darses@chimie-paristech.fr
Received October 22, 2009
We report here, for the first time, that hydroarylation
reactions involving C(sp2)-H activation can be conducted in
isopropanol, a protic solvent,6 with higher efficiency and at
moderate temperature (Scheme 1).
We recently reported an effective catalytic system, gener-
ated from an easily available ruthenium(II) source, allowing
either the hydroarylation of alkenes (Murai type reaction)7-9
or the formation of functionalized allysilanes via C-H bond
activation.10 The catalytically active ruthenium species was
generated in situ from the reaction of inexpensive [RuCl2-
(p-cym)]2 (p-cym = p-cymene) and sodium formate, in asso-
ciation with a phosphane ligand, but the reaction has to be
Effective conditions for the hydroarylation of vinyl-
silanes, allowing functionalization of various aromatic
ketones in good yields at low temperature, using isopro-
panol, a protic solvent, are reported. Moreover, conduct-
ing this C-C bond-forming reaction under conditions
similar to those used for hydride transfer reduction, the
reduction of the ketone could be suppressed, simply by
using acetone cosolvent as hydride acceptor. This reac-
tion, conducted with an inexpensive and nontoxic sol-
vent, constitutes the first C(sp2)-H activation under
protic conditions with low-valent ruthenium complexes.
(4) For some recent hydroalkylation reactions see: (a) Grutters, M. M. P.;
€
Muller, C.; Vogt, D. J. Am. Chem. Soc. 2006, 128, 7414. (b) Tsai, A. S.;
Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 6316.
(c) Kuninobu, Y.; Kikuchi, K.; Tokunaga, Y.; Nishina, Y.; Takai, K.
Tetrahedron 2008, 64, 5974. (d) McKeown, B. A.; Foley, N. A.; Lee, J. P.;
Gunnoe, T. B. Organometallics 2008, 27, 4031. (e) Harada, H.; Thalji, R. K.;
Bergman, R. G.; Ellman, J. A. J. Org. Chem. 2008, 73, 6772. (f) Kozhushkov,
S. I.; Yufit, D. S.; Ackermann, L. Org. Lett. 2008, 10, 3409. (g) Nakao, Y.;
Kashihara, N.; Kanyiva, K. S.; Hiyama, T. J. Am. Chem. Soc. 2008, 130,
16170. (h) Luedtke, A. T.; Goldberg, K. I. Angew. Chem., Int. Ed. 2008, 47,
7694. (i) Vasylyev, M.; Alper, H. Angew. Chem., Int. Ed. 2009, 48, 1287. (j)
Kubiak, R.; Prochnow, I.; Doye, S. Angew. Chem., Int. Ed. 2009, 48, 1153.
(5) (a) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice;
Oxford University Press: New York, 1998. (b) Sherman, J.; Chin, B.; Huibers,
P. D. T.; Garcia-Valls, R.; Hatton, T. A. Environ. Health Perspect. 1998, 106
To develop environmentally friendly processes for C-C
bond formation, much attention has been paid to green and
sustainable reactions. Among them, catalytic reactions
(1) (a) Trost, B. M. Science 1991, 254, 1471. (b) Trost, B. M. Angew.
Chem., Int. Ed. 1995, 34, 259. (c) Trost, B. M. Acc. Chem. Res. 2002, 35, 695.
(2) Reviews: (a) Dyker, G. Angew. Chem., Int. Ed. 1999, 38, 1698.
(b) Guari, Y.; Sabo-Etienne, S.; Chaudret, B. Eur. J. Inorg. Chem. 1999,
1047. (c) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633.
(d) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. Rev. 2002, 102, 1731.
(e) Kakiuchi, F.; Chatani, N. Adv. Synth. Catal. 2003, 345, 1077.
(f) Campeau, L.-C.; Stuart, D. R.; Fagnou, K. Aldrichim. Acta 2007, 40, 35.
(g) Park, Y. J.; Park, J.-W.; Jun, C.-H. Acc. Chem. Res. 2008, 41, 222.
(h) Kakiuchi, F. Top. Organomet. Chem. 2007, 24, 1. (i) Mori, A.; Sugie, A. Bull.
Chem. Soc. Jpn. 2008, 81, 548. (j) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013.
(3) For some recent examples of coupling reactions involving C-H bond
activation, see: (a) Kakiuchi, F.; Matsuura, Y.; Kan, S.; Chatani, N. J. Am.
Chem. Soc. 2005, 127, 5936. (b) Stuart, D. R.; Fagnou, K. Science 2007, 316,
1172. (c) Yang, S.-D.; Sun, C.-L.; Fang, Z.; Li, B.-J.; Li, Y.-Z.; Shi, Z.-J.
Angew. Chem., Int. Ed. 2008, 47, 1473. (d) Wang, D.-H.; Wasa, M.; Giri, R.;
Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 7190. (e) Zhao, X.; Yu, Z. J. Am.
Chem. Soc. 2008, 130, 8136. (f) Shi, B.-F.; Maugel, N.; Zhang, Y.-H.; Yu,
J.-Q. Angew. Chem., Int. Ed. 2008, 47, 4882. (g) Deng, G.; Zhao, L.; Li, C.-J.
Angew. Chem., Int. Ed. 2008, 47, 6278. (h) Cho, S. H.; Hwang, S. J.; Chang, S.
J. Am. Chem. Soc. 2008, 130, 9254. (i) Ban, I.; Sudo, T.; Taniguchi, T.;
ꢀ
(Suppl 1), 253. (c) Horvath, I. T. Green Chem. 2008, 10, 1024. (d) Alfonsi, K.;
Colberg, J.; Dunn, P. J.; Fevig, T.; Jennings, S.; Johnson, T. A.; Kleine, H. P.;
Knight, C.; Nagy, M. A.; Perry, D. A.; Stefaniak, M. Green Chem. 2008, 10, 31.
(6) For a review of C-H bond activation in water, see: (a) Herrerıas, C. I.;
Yao, X.; Li, Z.; Li, C.-J. Chem. Rev. 2007, 107, 2546. For recent examples of
palladium-catalyzed C-H bond activation under protic conditions, see:
(b) Wang, D.-H.; Mei, T.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130,
17676. (c) Giri, R.; Maugel, N.; Li, J.-J.; Wang, D.-H.; Breazzano, S. P.;
Saunders, L. B.; Yu, J.-Q. J. Am. Chem. Soc. 2007, 129, 3510.
(7) (a) Martinez, R.; Chevalier, R.; Darses, S.; Genet, J.-P. Angew. Chem.,
Int. Ed. 2006, 45, 8232. (b) Martinez, R.; Simon, M.-O.; Chevalier, R.;
Pautigny, C.; Genet, J.-P.; Darses, S. J. Am. Chem. Soc. 2009, 131, 7887.
(8) For ruthenium-catalyzed hydroarylation processes (Murai reaction)
see: (a) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.;
Sonoda, M.; Chatani, N. Nature 1993, 366, 529. (b) Kakiuchi, F.; Sekine, S.;
Tanaka, Y.; Kamatani, A.; Sonoda, M.; Chatani, N.; Murai, S. Bull. Chem.
Soc. Jpn. 1995, 68, 62. (c) Sonoda, M.; Kakiuchi, F.; Chatani, N.; Murai, S.
Bull. Chem. Soc. Jpn. 1997, 70, 3117. (d) Kakiuchi, F.; Murai, S. Acc. Chem.
Res. 2002, 35, 826.
€
Itami, K. Org. Lett. 2008, 10, 3607. ( j) Ozdemir, I.; Demir, S.; C-etinkaya,
B.; Gourlaouen, C.; Maseras, F.; Bruneau, C.; Dixneuf, P. H. J. Am. Chem.
Soc. 2008, 130, 1156. (k) Chaumontet, M.; Piccardi, R.; Baudoin, O. Angew.
Chem., Int. Ed. 2009, 48, 179.
(9) Martinez, R.; Genet, J.-P.; Darses, S. Chem. Commun. 2008, 3855.
(10) Simon, M.-O.; Martinez, R.; Genet, J.-P.; Darses, S. Adv. Synth.
Catal. 2009, 351, 153.
208 J. Org. Chem. 2010, 75, 208–210
Published on Web 12/03/2009
DOI: 10.1021/jo902264u
r
2009 American Chemical Society

Simon et al.
JOCNote
SCHEME 1. Ruthenium-Catalyzed C-C Bond Formation
under Protic Conditions
TABLE 1. Ruthenium-Catalyzed Ortho-Alkylation of Aromatic
Ketones under Protic Conditionsa
entry
product
conditions Ab,d
93 (98:2)
conditions Bc,d
1
2
3
4
5
3a
3b
3c
3d
3e
3f
91 (89:11)
98 (84:16)
84 (83:17)
89
83 (72:28)
81 (41:59)
70 (50:50)
77 (66:34)
49
95
6
83e (40:60)
70e (63:37)
96e (55:45)
46
7
8
9
3g
3h
3i
10
11
12
13
14
3j
3k
3l
3m
3n
70 (94:6)
89e (87:13)
89 (8:92)
81 (100:0)
90 (90:10)
84 (0:100)
82
70
aReaction conducted with 1 mmol of 1 and 2 mmol of 2 at 80 °C for 4
to 20 h. bConditions A: [Ru(OCOH)2PPh3(p-cym)] (5 mol %) and PPh3
(10 mol %) in isopropanol. Conditions B: [RuCl2(p-cym)]2 (5 mol %
Ru), (4-CF3C6H4)3P (15 mol %), and NaOCOH (30 mol %) in iso-
propanol/acetone (1:1). dYields of mono- and disubstituted adducts.
The proportion of mono-/disubstituted adducts for 4-substituted sub-
strates and selectivity for 6- and 2-substituted products for 3-substituted
substrates are given in parentheses. eWith 3 equiv of 2.
SCHEME 2. Catalyst System Evaluation for the C-H Bond
c
Activation in Isopropanola
for such reduction reactions.12 Moreover, the reduction
product was minimized to 4% by using our recently de-
scribed ruthenium complex [Ru(OCOH)2PPh3(p-cym)],7b
and consumption of 1e was quantitative (Scheme 2). As
judged by the results obtained for several aromatic ketones
(Table 1, conditions A), these new conditions proved to be
quite general and compared favorably to those previously
reported, all the more so since a reaction temperature as low
as 80 °C allowed the C-C bond formation, compared to the
140 °C used for the reaction conducted in toluene.7
Despite the efficiency of the catalytic system employed, it
was not satisfactory since it necessitated the preparation and
isolation of [Ru(OCOH)2PPh3(p-cym)]. The use of an in situ
generated catalyst would be more desirable but, as noticed
previously, under these conditions, byproduct issued from
the reduction of ketone, of either starting material or pro-
duct, under hydride-transfer conditions was obtained.12 To
suppress the reduction of the keto functional group, we
envisaged to introduce a sacrificial hydride acceptor in the
reaction medium. We were pleased to find that the simple use
of acetone as cosolvent suppressed, to a large extent, the
reduction of acetophenone.13 Indeed, reaction of 1e with 2,
catalyzed by in situ-generated ruthenium catalyst from
[RuCl2(p-cym)]2 with sodium formate and triphenylpho-
sphane, afforded the expected product 3e with 93% conver-
sion, along with only 5% of reduction product (Scheme 2).
Evaluation of several phosphane ligands revealed that the
use of (4-CF3C6H4)3P as ligand for ruthenium, afforded the
fastest reactions and completely suppressed the reduction of
the substrates (Figure 1). Moreover, it appeared that the
most effective ligands in that reaction were generally elec-
tron-deficient ones. Indeed, reaction of 1e with 2 in a 1:1
aReagents and conditions: [Ru] cat.: (a) [RuCl2(p-cym)]2 (2.5 mol %),
NaOCOH (30 mol %), PPh3 (15 mol %); (b) [Ru(OCOH)2PPh3(p-cym)]
(5 mol %), PPh3 (10 mol %); and (c) same as (a), using acetone as co-
solvent.
conducted at high temperature with toluene as solvent. We
have also shown that the active ruthenium species was more
efficiently generated in isopropanol compared to toluene, the
reaction solvent used for the reaction.7b We wondered if this
protic solvent would be more suited to conduct the hydro-
arylation reaction.
We were pleased to find that, using our previously de-
scribed ruthenium catalytic system generated in situ from the
reaction of [RuCl2(p-cym)]2 with sodium formate and a
phosphane ligand, the reaction of 4-methylacetophenone
(1e) with vinyltriethoxysilane (2) afforded the expected
hydroarylation product 3e with 76% conversion, conducting
the reaction in isopropanol at only 80 °C (Scheme 2).
However, the reaction product was contaminated with by-
product, arising from the reduction of acetophenone (4e,
12%) and from intramolecular trans-alkoxylation of the
silane moiety.11 We reasoned that the reduction of aceto-
phenone originated from ruthenium-catalyzed reduction via
hydride transfer, because the reaction was conducted with a
slight excess of the basic sodium formate, classical condition
(11) Formation of 3,3-diethoxy-1,7-dimethyl-1,3,4,5-tetrahydrobenzo-
[e][1,2]oxasilepine:
(13) For the use of acetone as hydride acceptor in other reactions, see: (a)
Pucheault, M.; Darses, S.; Genet, J.-P. J. Am. Chem. Soc. 2004, 126, 15356.
(b) Mora, G.; Darses, S.; Genet, J.-P. Adv. Synth. Catal. 2007, 349, 1180. (c)
Chuzel, O.; Roesch, A.; Genet, J.-P.; Darses, S. J. Org. Chem. 2008, 72, 7800.
(14) The second substitution of the starting material is occurring con-
comitantly to the first one, that is before complete consumption of the
starting material for several substrates, preventing the isolation of only
monosubstituted adduct.
(12) Reviews: (a) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30,
97. (b) Gladiali, S.; Alberico, E. Chem. Soc. Rev. 2006, 35, 226. (c) Ikariya, T.;
Blacker, A. J. Acc. Chem. Res. 2007, 40, 1300.
J. Org. Chem. Vol. 75, No. 1, 2010 209

Simon et al.
JOCNote
We have thus described improved conditions for the hydro-
arylation of vinylsilanes, allowing functionalization of various
aromatic ketones in good yields, using isopropanol, a protic
solvent. Moreover, even conducting this C-C bond forming
reaction under conditions similar to those used for hydride
transfer reduction, the reduction of the keto functional group
could be suppressed, simply by using acetone cosolvent as
hydride acceptor. This reaction, conducted with an inexpen-
sive and nontoxic solvent, constitutes the first C(sp2)-H
(a quite inert bond) activation under protic conditions with
low-valent ruthenium complexes.
Experimental Section
General Procedure for the Hydroarylation Reaction
(Conditions B): Preparation of Cyclohexyl-{2-[(2-triethoxysilyl)-
ethyl]phenyl}methanone (3b) (Table 1, entry 2). A septum-
capped vial was charged with [RuCl2(p-cym)]2 (15.3 mg,
25 μmol, 2.5 mol %), triphenylphosphane (39.3 mg, 150 μmol,
15 mol %), and sodium formate (20.4 mg, 300 μmol, 30 mol %).
The vial was placed under vacuum for 15 min then under argon.
Degassed 2-propanol (0.5 mL) and acetone (0.5 mL) were
added, and then cyclohexylphenylketone (1 mmol, 188 mg)
and triethoxyvinylsilane (423 μL, 2 mmol, 2 equiv) were added.
The vial was placed in a preheated oil bath at 80 °C and the
mixture was stirred until completion of the reaction (followed by
GC analysis). After concentration under reduced pressure, the
crude mixture was purified by silica gel chromatography afford-
ing 3b, as a light yellow oil (270 mg). Rf 0.79 (cyclohexane/ethyl
acetate 4:1). GC (DB-1701, program B): tR = 8.3 min. 1H NMR
(300 MHz, CDCl3): δ 7.40 (1H, d, J = 7.5 Hz), 7.27-7.34 (2H,
m), 7.18-7.22 (H, m), 3.84 (6H, q, J = 7.0 Hz), 2.95-3.01 (1H,
m), 2.75-2.81 (2H, m), 1.29-1.89 (10H, m), 1.24 (9H, t, J = 7.0
Hz), 0.95-1.01 (2H, m). 13C NMR (75 MHz, CDCl3): δ 209.0,
143.7, 138.9, 130.4, 130.0, 127.0, 125.4, 58.4, 49.4, 28.9, 26.8,
25.9, 25.8, 18.2, 13.3. MS (EI, m/z): 378 (Mþ•, 0.3%), 332 (81%),
163 (73%), 135 (100%). HRMS: calcd for C21H35O4Si (M þ H)
379.2305, found 379.2311.
FIGURE 1. Effect of the ligand, P(XC6H4)3, in the ruthenium-
catalyzed arylation of 1e with 2 in isopropanol/acetone mixture as
solvent (conditions B).
mixture of acetone/isopropanol at 80 °C, catalyzed by in
situ generated ruthenium catalyst from [RuCl2(p-cym)]2
(5 mol %) with sodium formate and (4-CF3C6H4)3P
(15 mol %) (conditions B), afforded the alkylation adduct
3e in 83% yield (Table 1, entry 5). These conditions proved to
be general and various acetophenones were functionalized
with high yield (Table 1).
In most of the examined reactions with para-substituted
acetophenones, disubstituted adducts were also formed,
leading to mixtures of mono- and disubstituted products.14
The proportion of these products varies according to the
substitution of acetophenones and the reaction times: the
disubstituted product being favored by electron releasing
substituents and prolonged reaction time. In the case of
meta-substituted acetophenones, the two ortho positions of
the acetyl group are not equivalent and two isomers may be
obtained depending on the regioselectivity of the activation.
Indeed, the activation process occurs at the less hindered
position except in the presence of potential complexing
substituent (entries 10-12). A similar regioselectivity was
observed with RuH2(CO)(PPh3)3 complex8 and in the anti-
Markovnikov hydroarylation of styrenes,9 suggesting that a
second complexation on the meta oxygen to ruthenium could
direct the activation to the most congested side.
ꢁ
Acknowledgment. M.-O.S. thanks the Ministere de l’Edu-
cation et de la Recherche for a grant.
Supporting Information Available: Experimental proce-
dures and compound descriptions. This material is available
free of charge via the Internet at http://pubs.acs.org.
210 J. Org. Chem. Vol. 75, No. 1, 2010