RuHCl(CO)(PPh3)3-catalyzed R-alkylation of ketones with primary alcohols

Article abstract of DOI:10.1021/ol302145a

The α-alkylation reaction of ketones with primary alcohols to give α-alkylated ketones was achieved using RuHCl(CO)(PPh₃) ₃ as a catalyst in the presence of Cs₂CO₃ as a base. This reaction proceeds via an aldol condensation of ketones with aldehydes, formed via transfer dehydrogenation of alcohols, to give α,β-unsaturated ketones, which then undergo transfer hydrogenation with primary alcohols to give R-alkylated ketones and aldehydes, the latter of which participate in the next catalytic cycle. While the reaction of aliphatic primary alcohols was sluggish compared with that of benzylic alcohols, a catalytic amount of 1,10-phenanthroline was found to promote the alkylation dramatically.

Full text of DOI:10.1021/ol302145a

ORGANIC
LETTERS
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Vol. XX, No. XX
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RuHCl(CO)(PPh3)3‑Catalyzed r‑Alkylation
of Ketones with Primary Alcohols
Takashi Kuwahara, Takahide Fukuyama, and Ilhyong Ryu*
Department of Chemistry, Graduate School of Science, Osaka Prefecture University,
Sakai, Osaka 599-8531, Japan
ryu@c.s.osakafu-u.ac.jp
Received August 4, 2012
ABSTRACT
The R-alkylation reaction of ketones with primary alcohols to give R-alkylated ketones was achieved using RuHCl(CO)(PPh3)3 as a catalyst in the
presence of Cs2CO3 as a base. This reaction proceeds via an aldol condensation of ketones with aldehydes, formed via transfer dehydrogenation
of alcohols, to give R,β-unsaturated ketones, which then undergo transfer hydrogenation with primary alcohols to give R-alkylated ketones and
aldehydes, the latter of which participate in the next catalytic cycle. While the reaction of aliphatic primary alcohols was sluggish compared with
that of benzylic alcohols, a catalytic amount of 1,10-phenanthroline was found to promote the alkylation dramatically.
R-Alkylation of ketones is one of the most fundamental
reactions in organic synthesis. In the most common pro-
tocols, ketones are transferred to metal enolates1 or
enamines,2 which are ready to react with carbon electro-
philes to give R-alkylated ketones. In recent years,
alternative approaches based on the transition-metal-
catalyzed R-alkylation of ketones have been developed,3ꢀ8
in which alcohols are employed as latent aldehydes by
catalytic transfer dehydrogenation. In 2002, Shim and co-
workers reported that RuCl2(PPh3)3 can catalyze R-alky-
lation of ketones with primary alcohols. In this Ru-cata-
lyzed reaction, to avoid the reduction of product ketones a
stoichiometric amount of a terminal alkene, such as 1-do-
decene, is used as a hydrogen trap.4 The Pd/C system can
also be used as a catalyst in combination with 1-decene as a
hydrogen trap.5 In a similar transformation but without
the need for the addition of alkenes, Ishii and co-workers
found that [IrCl(cod)]2 is an excellent catalyst for the
R-alkylation of ketones with primary alcohols.6 Yus and
co-workers also reported that [Ru(dmso)4]Cl2 catalyzed
the R-alkylation of ketones with benzylic alcohols.7 Recycla-
ble catalyst systems such as Pd/AlO(OH)8a and viologen
polymers8b,c and a heterogeneous system using Ag/Mo
oxides8d are also actively being pursued. In these studies,
the metal-catalyzed transfer hydrogenation reaction is
combined with a classical aldol condensation using a
strong base, which is typically KOH, and the overall
transformation is highly atom-economical, since the only
byproduct is water (Scheme 1).
(1) For recent reviews, see: (a) Casiraghi, G.; Battistini, L.; Curti, C.;
Rassu, G.; Zanardi, F. Chem. Rev. 2011, 111, 3076. (b) Palomo, C.;
Oiarbide, M.; Garcıa, J. M. Chem. Soc. Rev. 2004, 33, 65. (c) Arya, P.;
Qin, H. Tetrahedron 2000, 56, 917.
(2) For recent reviews, see: (a) Mlynarski, J.; Gut, B. Chem. Soc. Rev.
€
2012, 41, 587. (b) Cheong, P. H.-Y.; Legault, C. Y.; Um, J. M.; C-elebi-O
€
lc-um, N.; Houk, K. N. Chem. Rev. 2011, 111, 5042.
(3) For recent reviews, see: (a) Nixon, T. D.; Whittlesey, M. K.;
Williams, J. M. J. Dalton Trans. 2009, 753. (b) Hamid, M. H. S. A.;
Slatford, P. A.; Williams, J. M. J. Adv. Synth. Catal. 2007, 349, 1555. (c)
ꢀ
Guillena, G.; Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2007, 46,
2358. (d) Shibahara, F.; Krische, M. J. Chem. Lett. 2008, 37, 1102.
(4) (a) Cho, C. S.; Kim, B. T.; Kim, T. ꢀJ.; Shim, S. C. Tetrahedron
Lett. 2002, 43, 7987. Reaction with a stoichiometric amount of Ni
nanoparticles: (b) Alonso, F.; Riente, P.; Yus, M. Eur. J. Org. Chem.
2008, 4908.
(5) Cho, C. S. J. Mol. Catal. A ; Chem. 2005, 240, 55.
(6) (a) Taguchi, K.; Nakagawa, H.; Hirabayashi, T.; Sakaguchi, S.;
Ishii, Y. J. Am. Chem. Soc. 2004, 126, 72. (b) Maede, K.; Obora, Y.;
Sakaguchi, S.; Ishii, Y. Bull. Chem. Soc. Jpn. 2008, 81, 689. (c) Morita,
M.; Obora, Y.; Ishii, Y. Chem. Commun. 2007, 2850. (d) Iuchi, Y.;
Obora, Y.; Ishii, Y. J. Am. Chem. Soc. 2010, 132, 2536.
ꢀ
(7) (a) Martınez, R.; Brand, G. J. ; R.; Ramon, D. J.; Yus, M.
ꢀ
Tetrahedron 2005, 46, 3683. (b) Martınez, R.; Ramon, D. J.; Yus, M.
Tetrahedron 2006, 62, 8988.
We have been interested in the potential of RuHCl(CO)-
(PPh3)3 as a multitask catalyst9 for atom-economical
cross-addition reactions and previously reported that the
reaction of R,β-unsaturated aldehydes with primary
(8) (a) Kwon, M. S.; Kim, N.; Seo, S. H.; Park, I. S.; Cheedrala, R. K.;
Park, J. Angew. Chem., Int. Ed. 2005, 44, 6913. (b) Yamada, Y. M. A.;
Uozumi, Y. Org. Lett. 2006, 8, 1375. (c) Yamada, Y. M. A.; Uozumi, Y.
Tetrahedron 2007, 63, 8492. (d) Cui, X.; Zhang, Y.; Shi, F.; Deng, Y.
Chem.;Eur. J. 2011, 17, 1021.
r
10.1021/ol302145a
XXXX American Chemical Society

Table 2. RuHCl(CO)(PPh3)3-Catalyzed R-Alkylation Reac-
Scheme 1. Concept of the Metal-Catalyzed R-Alkylation of
Ketones
tions of Ketones with Nonbenzylic Alcoholsa
alcohols gave good yields of R-hydroxymethyl ketones
(eq 1).9b Since this reaction involves an effective transfer
dehydrogenation of primary alcohols togive aldehydes, we
believed that this Ru-H catalyst would also be useful even
for the R-alkylation of ketones. Herein we report the
results.
Using RuHCl(CO)(PPh3)3 as a catalyst and acetophe-
none (1a) and 4-methylbenzyl alcohol (2a) as test sub-
strates, we examined the R-alkylation of ketones under
several conditions (Table 1). When 1a was reacted with 2a
in the presence of 5 mol % of RuHCl(CO)(PPh3)3 and
1.5 equiv of potassium carbonate at 140 °C (bath temp) for
20 h, the desired R-alkylated ketone 3a was formed in 7%
yield (entry 1). After survey of several bases, we found that
Cs2CO3 gave good yield of 3a (entry 4). Catalyst loading as
low as 1 mol % gave 3a in 86% yield (entry 5). Even a
Table 1. Optimization of the Reaction Conditionsa
entry
cat. (mol %)
base (mol %)
yieldb (%)
1
5
5
5
5
1
1
1
1
1
K2CO3 (150)
Na2CO3 (150)
NEt3 (150)
7c
2
ndd
ndd
73
3
4
Cs2CO3 (150)
Cs2CO3 (150)
Cs2CO3 (30)
Cs2CO3 (150)
Cs2CO3 (150)
Cs2CO3 (150)
5
86
6
74
7e
8f
9f,g
14c
69
a Reaction conditions: ketone 1 (1.3 mmol), alcohol 2 (1.0 mmol),
RuHCl(CO)(PPh3)3 (1 mol %), Cs2CO3 (1.5 mmol), toluene (3 mL),
140 °C (bath temp), 20 h. b Isolated yields. c KOH (1.5 mmol) was used
instead of Cs2CO3. d 1,10-phenanthroline (Phen; 3 mol %) was used as an
additive. e RuHCl(CO)(PPh3)3 (3 mol %) and Phen (6 mol %) were used.
79
a Reaction conditions: 1a (1.3 mmol), 2a (1.0 mmol), RuHCl(CO)-
(PPh3)3, base, toluene (3 mL), 140 °C (bath temp). b Isolated yield.
c NMR yield. d Not detected. e 110 °C (bath temp). f 5 h. g 1,10-phenan-
throline (3 mol %) was used.
reduced amount of Cs2CO3 (30 mol %) sufficed for the
reaction (entry 6). A lower temperature (110 °C) resulted in
B
Org. Lett., Vol. XX, No. XX, XXXX

lower conversion (entry 7). Although the reaction was not
complete in 5 h (entry 8), acceleration of the reaction was
observed with the addition of 1,10-phenanthroline as an
additive (entry 9).
For example, when the alkylation of 1a using 1-hexanol
(2k) was carried out in the presence of 3 mol % of
RuHCl(CO)(PPh3)3, the desired ketone 3o was obtained
in only 22% yield (entry 15). However, we were delighted
to find that the addition of 1,10-phenanthroline (Phen)
dramatically accelerated the reaction, thus delivering 3o in
88% yield (entry 16). OtheradditivessuchasDPPB(40%),
2,20-bipyridine (24%), and PCy3 (43%) did not work as
effectively as 1,10-phenanthroline. In a similar manner,
branched alcohol 2l and 2m also particpated in the alkyla-
tion of 1a, giving good yields of the corresponding ketones
3p and 3q, respectively (entries 17 and 18). The reaction of
cyclohexanemethanol 2n with 1a gave the corresponding
ketone 3r in 72% yield (entry 19).
In summary, we have found that the R-alkylation reac-
tion of ketones with primary alcohols can be effectively
catalyzed by RuHCl(CO)(PPh3)3 in the presence of
Cs2CO3 as a base. We also found that a catalytic amount
of 1,10-phenanthroline dramatically promoted R-alkyla-
tion using nonbenzylic aliphatic alcohols. A detailed
mechanistic study involving the precise role of 1,10-phe-
nanthroline in the promotion of alkylation using aliphatic
alcohols as well as synthetic applications of the present
reactions is currently underway in this laboratory.
Having the optimized conditions in hand (Table 1, entry 5),
we then examined the generality of the present R-alkyla-
tion of ketones, and the results are summarized in Table 2.
R-Alkylation of acetophenone (1a) with a variety of
substituted benzyl alcohols 2bꢀg proceeded well to give
the corresponding R-substituted ketones 3bꢀg in good
yields (entries 2ꢀ7). The reaction of p-methoxyacetophe-
none (1b) with 2a gave 3h in 55% yield due to a low
conversion under the employed conditions (entry 8). In
contrast, p-bromoacetophenone (1c) was alkylated in
excellent yield (entry 9). Several hydroxymethyl hetero-
aryls such as 3-pyridinemethanol (2h) and 2-thiophene-
methanol (2i) also reacted with acetophenone to give 3j
and 3k in good yields, respectively (entries 10 and 11).
Furfuryl alcohol (2j) gave the corresponding ketone 3l in
65% yield (entry 12). Although the alkylation of pinaco-
lone (1d) was sluggish under the standard conditions, the
use of KOH in place of Cs2CO3 significantly promoted
the reaction to deliver the corresponding ketone 3m in
85% yield (entry 13). R-Tetralone (1e) was alkylated by 2a
to give 3n in 64% yield (entry 14).
Acknowledgment. This work was supported by a
Grant-in-Aid for Scientific Research on Innovative Areas
(No. 2105) from the MEXT. T.F. acknowledges a Grant-
in-Aid for Scientific Research (C) from JSPS for financial
support.
We also examined the alkylation of ketones using non-
benzylic primary alcohols; however, the results were poor.
(9) For our recent work on RuHCl(CO)(PPh3)3-catalyzed transfor-
mation, see: (a) Fukuyama, T.; Okamoto, H.; Ryu, I. Chem. Lett. 2011,
40, 1453. (b) Denichoux, A.; Fukuyama, T.; Doi, T.; Horiguchi, J.; Ryu,
I. Org. Lett. 2010, 12, 1. (c) Omura, S.; Fukuyama, T.; Murakami, Y.;
Okamoto, H.; Ryu, I. Chem. Commun. 2009, 6741. (d) Omura, S.;
Fukuyama, T.; Horiguchi, J.; Murakami, Y.; Ryu, I. J. Am. Chem.
Soc. 2008, 130, 14094. (e) Fukuyama, T.; Doi, T.; Minamino, S.; Omura,
S.; Ryu, I. Angew. Chem., Int. Ed. 2007, 46, 5559. (f) Doi, T.; Fukuyama,
T.; Minamino, S.; Ryu, I. Synlett 2006, 3013. (g) Doi, T.; Fukuyama, T.;
Horiguchi, J.; Okamura, T.; Ryu, I. Synlett 2006, 721. (h) Doi, T.;
Fukuyama, T.; Minamino, S.; Husson, G.; Ryu, I. Chem. Commun.
2006, 1875.
Supporting Information Available. Experimental pro-
cedure and compound characterization. This material is
available free of charge via the Internet at http://pubs.acs.
org.
The authors declare no competing financial interest.
Org. Lett., Vol. XX, No. XX, XXXX
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