Ruthenium-catalyzed regioselective α-alkylation of ketones with primary alcohols

Article abstract of DOI:10.1016/S0040-4039(02)01625-8

Ketones are regioselectively alkylated with an array of primary alcohols in dioxane at 80°C in the presence of a catalytic amount of a ruthenium catalyst together with KOH and a hydrogen acceptor.

Full text of DOI:10.1016/S0040-4039(02)01625-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7987–7989
Ruthenium-catalyzed regioselective a-alkylation of ketones with
primary alcohols
Chan Sik Cho,a,* Bok Tae Kim,b Tae-Jeong Kimb and Sang Chul Shimb,*
aResearch Institute of Industrial Technology, Kyungpook National University, Taegu 702-701, South Korea
bDepartment of Industrial Chemistry, Kyungpook National University, Taegu 702-701, South Korea
Received 27 May 2002; revised 15 July 2002; accepted 2 August 2002
Abstract—Ketones are regioselectively alkylated with an array of primary alcohols in dioxane at 80°C in the presence of a catalytic
amount of a ruthenium catalyst together with KOH and a hydrogen acceptor. © 2002 Elsevier Science Ltd. All rights reserved.
a-Alkylation of ketones has been known as a funda-
mental tool for a carbonꢀcarbon s-bond formation in
synthetic organic chemistry.1,2 The alkylation is gener-
ally achieved by the coupling between nucleophilic eno-
lates (enolate equivalents) and electrophilic alkylating
agents and regioselectivity is determined by initial eno-
late formation.3 In connection with this report, during
the course of our ongoing studies on ruthenium cataly-
sis,4–7 we recently found an unusual type of ruthenium-
catalyzed transfer hydrogenation of ketones by primary
alcohols.8,9 The reaction gives mainly an unconven-
tional transfer hydrogenated secondary alcohol accom-
panied by C–C coupling with concomitant formation of
an alkylated ketone (Scheme 1). The preferential forma-
O
OH
O
cat. [Ru]
+
+
HO
R'
R
R
R'
R
R'
Scheme 1.
Table 1. Ruthenium-catalyzed a-alkylation of 1 with 2 under several conditionsa
O
O
OH
+
+
HO
Ph
Ph
Ph
Ph
Ph
Ph
1
2
3
4
Entry
Hydrogen acceptor
Temp. (°C)
Time (h)
Yieldb (%)
3
4
1
2
3
4
5
6d
7
8
9
1-Dodecene
–
1-Dodecene
1-Dodecene
1-Dodecene
–
1-Octyne
Nitrobenzene
1-Hexene
80
80
80
80
50
180
80
80
20
20
10
5
20
20
20
20
20
(82)
(70)
(61)
36
25
(78)
15
(2)
(14)
(6)
–
–
(9)
–
–
c
c
c
c
6
(79)
80
(2)
a Reaction conditions: 1 (1 mmol), 2 (1 mmol), hydrogen acceptor (1 mmol), RuCl2(PPh3)3 (0.02 mmol), KOH (1 mmol), dioxane (3 ml).
b GLC yield. Isolated yield is shown in parentheses.
c Not determined.
d The reaction was carried out with autoclave.
Keywords: alkylation; ketones; primary alcohols; ruthenium catalyst.
* Corresponding authors. Fax: +82-53-959-5586; e-mail: cscho@knu.ac.kr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01625-8

7988
C. S. Cho et al. / Tetrahedron Letters 43 (2002) 7987–7989
tion of alcohol to ketone may be due to the use of the
molar ratio of alcohol/ketone=3. This observation led
us to seek an effective method for the ruthenium-cata-
lyzed a-alkylation of ketones with primary alcohols.
Herein we report on a ruthenium-catalyzed regioselec-
tive a-alkylation of ketones with primary alcohols in
the presence of a hydrogen acceptor.
transfer hydrogenation product, 1-phenylethanol was
detected on GLC analysis of the crude reaction mix-
ture.10 On the other hand, when the reaction was
carried out in the absence of 1-dodecene, the product
3 was produced in 70% yield along with considerable
amount of 4 (14%) (entry 2). These results clearly
indicate that 1-dodecene plays a role for the selectivity
of 3 to 4. The yield of 3 increases with prolonging the
reaction time up to 20 h (entries 1, 3, 4). Lower
reaction temperature resulted in lower yield of 3 (entry
5), but higher reaction temperature under the absence
of 1-dodecene gave no significant change on the
product yield and selectivity (entry 6). Other hydrogen
acceptors such as 1-octyne and nitrobenzene deactivate
the reaction itself (entries 7 and 8), but 1-hexene was
effective as 1-dodecene for the yield and selectivity
(entry 9).
Table 1 shows optimization of the conditions for the
a-alkylation of acetophenone (1) with benzyl alcohol
(2). Treatment of an equimolar amount of 1 and 2 in
dioxane in the presence of RuCl2(PPh3)3 (2 mol%) and
KOH together with 1-dodecene as hydrogen acceptor
at 80°C for 20 h afforded 1,3-diphenylpropan-1-one
(3) in 82% isolated yield with concomitant formation
of further hydrogenated 1,3-diphenylpropan-1-ol (4,
2% yield) (entry 1). Only a trace amount of the direct
Table 2. Ruthenium-catalyzed a-alkylation of ketones with primary alcoholsa
Yieldb (%)
Alcohols
Ketones
Products
O
O
HO
R
Ar
Ar
R
Ar = Ph
Ar = Ph
Ar = Ph
Ar = Ph
Ar = Ph
R = Ph
82
80
78
70
78
R = 1-naphthyl
R = phenethyl
R = Pr
R = pentyl
Ar = Ph
R = i-Bu
R = Ph
R = Ph
R = Ph
80
81
79
78
83
76
68
Ar = 2-MeC6H4
Ar = 3-MeC6H4
Ar = 4-MeC6H4
Ar = 4-MeOC6H4 R = Ph
Ar = 4-FC6H4
Ar = 2-naphthyl
O
R = Ph
R = Ph
O
R = phenethyl
R = Pr
55
50
R
4
4
O
O
R = phenethyl
59
Ph
O
Ph
O
R
57
48
R = phenethyl
R = Ph
R
O
O
R = Ph
R = Ph
R = Ph
76
52
86
Ph
O
O
Ph
O
O
Ph
a Reaction conditions: ketone (1 mmol), primary alcohol (1 mmol),
1-dodecene (1 mmol), RuCl2(PPh3)3 (0.02 mmol), KOH (1 mmol), dioxane
(3 ml), 80 oC, for 20 h.
b Isolated yield.

C. S. Cho et al. / Tetrahedron Letters 43 (2002) 7987–7989
7989
Given the controlled conditions, with various ketones
References
and primary alcohols the alkylation products were
formed in the range of 48–86% yields with the minimal
formation of coupled secondary alcohols (Table 2).
From the reactions between 1 and several straight and
branched primary alcohols, the corresponding alkylated
ketones were produced in good yields. The alkylation
was not significantly affected by the position and elec-
tronic nature of the substituent on the aromatic ring of
ketones. In the case of dialkyl ketones, although the
product yield was lower than that of the case of alkyl
aryl ketones, the alkylation took place exclusively at
less-hindered position over a-methylene and methine.
Similar regioselectivity was observed by our recent
reports6 and others.11 Benzo-fused cyclic ketones 1-
indanone and 1-tetralone having only the methylene
reaction site were readily alkylated with benzyl alcohol
to give the corresponding products, whereas the reac-
tion of cyclohexanone with primary alcohol afforded a
complicated mixture on GLC analysis.
1. Caine, D. In Comprehensive Organic Synthesis; Trost, B.
M.; Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3,
pp. 1–63.
2. Transition metal-catalyzed direct a-alkylation of ketones:
(a) Inoue, Y.; Toyofuku, M.; Taguchi, M.; Okada, S.;
Hashimoto, H. Bull. Chem. Soc. Jpn. 1986, 59, 885; (b)
Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.;
Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168; (c)
Camacho, D. H.; Nakamura, I.; Oh, B. H.; Saito, S.;
Yamamoto, Y. Tetrahedron Lett. 2002, 43, 2903.
3. d’Angelo, J. Tetrahedron 1976, 32, 2979.
4. (a) Cho, C. S.; Lim, H. K.; Shim, S. C.; Kim, T. J.; Choi,
H.-J. Chem. Commun. 1998, 995; (b) Cho, C. S.; Kim, J.
H.; Shim, S. C. Tetrahedron Lett. 2000, 41, 1811; (c) Cho,
C. S.; Kim, J. H.; Kim, T.-J.; Shim, S. C. Tetrahedron
2001, 57, 3321.
5. (a) Cho, C. S.; Oh, B. H.; Shim, S. C. Tetrahedron Lett.
1999, 40, 1499; (b) Cho, C. S.; Oh, B. H.; Shim, S. C. J.
Heterocycl. Chem. 1999, 36, 1175; (c) Cho, C. S.; Kim, J.
S.; Oh, B. H.; Kim, T.-J.; Shim, S. C. Tetrahedron 2000,
56, 7747; (d) Cho, C. S.; Oh, B. H.; Kim, J. S.; Kim,
T.-J.; Shim, S. C. Chem. Commun. 2000, 1885; (e) Cho, C.
S.; Kim, T. K.; Kim, B. T.; Kim, T.-J.; Shim, S. C. J.
Organomet. Chem. 2002, 650, 65.
As the reaction pathway based on our recent report,8
this involves a sequence such as oxidation of primary
alcohol to aldehyde by a ruthenium, cross aldol reac-
tion between the starting ketone and the aldehyde to
produce a,b-unsaturated ketone, and selective reduction
of the olefinic double bond of the unsaturated ketone.
Although the role of 1-dodecene for the selectivity is
not clear, it seems to both suppress further reduction of
3 to 4 by hydrogen transfer from solvent dioxane to
1-dodecene and reoxidize 4 back to 3 by transfer hydro-
genation between 4 and 1-dodecene.12,13 It is known
that dioxane is used as a hydrogen donor in ruthenium-
and rhodium-catalyzed transfer hydrogenation of
olefins, aldehydes and ketones.14
6. Cho, C. S.; Kim, B. T.; Lee, M. J.; Kim, T.-J.; Shim, S.
C. Angew. Chem., Int. Ed. 2001, 40, 958.
7. Cho, C. S.; Park, J. H.; Kim, T.-J.; Shim, S. C. Bull.
Korean Chem. Soc. 2002, 23, 23.
8. Cho, C. S.; Kim, B. T.; Kim, T.-J.; Shim, S. C. J. Org.
Chem. 2001, 66, 9020.
9. This methodology could also be successfully applied to
modified Friedlaender quinoline synthesis by the ruthe-
nium-catalyzed oxidative cyclization of 2-aminobenzyl
alcohol with ketones: Cho, C. S.; Kim, B. T.; Kim, T.-J.;
Shim, S. C. Chem. Commun. 2001, 2576.
10. For recent reviews, see: (a) Noyori, R.; Hashiguchi, S.
Acc. Chem. Res. 1997, 30, 97; (b) Naota, T.; Takaya, H.;
Murahashi, S.-I. Chem. Rev. 1998, 98, 2599; (c) Palmer,
M.; Wills, M. Tetrahedron: Asymmetry 1999, 10, 2045.
11. Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997,
119, 11108.
12. Though not yet clear, the fate of 1-dodecene may be
dodecane, however, GLC analysis attempt to detect
dodecane from crude mixture met with failure since 1-
dodecene and dodecane peaks are exactly eclipsed.
13. A reviewer suggested that 1-dodecene is possible to work
as a ligand and thus needs a catalytic amount. However,
a separate experiment using a catalytic amount of 1-
dodecene (10 mol%) gave similar results (3, 67%; 4, 16%)
as that when the reaction was carried out in the absence
of 1-dodecene.
General experimental procedure: a mixture of ketone (1
mmol), primary alcohol (1 mmol), 1-dodecene (1
mmol), RuCl2(PPh3)3 (0.02 mmol) and KOH (1 mmol)
in dioxane (3 ml) was placed in a 5 ml screw-capped
vial and allowed to react at 80°C for 20 h. The reaction
mixture was filtered through a short silica gel column
(ethyl acetate) to eliminate inorganic salts. Removal of
the solvent left a crude mixture, which was separated by
thin layer chromatography (silica gel, ethyl acetate–hex-
ane mixture) to give alkylated ketones.
In summary, we have shown that ketones can be
regioselectively a-alkylated with various primary alco-
hols in the presence of a ruthenium catalyst and a
hydrogen acceptor under a base. The present reaction
will serve as an alternative a-alkylation route of
ketones.
14. (a) Nishiguchi, T.; Tachi, K.; Fukuzumi, K. J. Am.
Chem. Soc. 1972, 94, 8916; (b) Nishiguchi, T.; Fukuzumi,
K. J. Am. Chem. Soc. 1974, 96, 1893; (c) Imai, H.;
Nishiguchi, T.; Fukuzumi, K. J. Org. Chem. 1976, 41,
665.
Acknowledgements
C.S.C. gratefully acknowledges a MOE-KRF Research
Professor Program (2001-050-D00015).