Direct β-alkylation of secondary alcohols with primary alcohols catalyzed by a Cp*Ir complex

Article abstract of DOI:10.1021/ol051517o

(Chemical Equation Presented) A new catalytic system for β-alkylation of secondary alcohols has been developed. In the presence of [Cp*IrCl ₂]₂ (Cp* = pentamethylcyclopentadienyl) catalyst and base, the reactions of various secondary alcohols with primary alcohols give β-alkylated higher alcohols in good to excellent yields without any hydrogen acceptor or hydrogen donor. This reaction proceeds via successive hydrogen-transfer reactions and aldol condensation.

Full text of DOI:10.1021/ol051517o

ORGANIC
LETTERS
2005
Vol. 7, No. 18
4017-4019
Direct
â-Alkylation of Secondary
Alcohols with Primary Alcohols
Catalyzed by a Cp*Ir Complex
Ken-ichi Fujita,* Chiho Asai, Tetsuhiro Yamaguchi, Fumihiro Hanasaka, and
Ryohei Yamaguchi*
Graduate School of Human and EnVironmental Studies, Kyoto UniVersity,
Sakyo-ku, Kyoto 606-8501, Japan
fujitak@kagaku.mbox.media.kyoto-u.ac.jp; yama@kagaku.mbox.media.kyoto-u.ac.jp
Received June 29, 2005
ABSTRACT
A new catalytic system for
â
-alkylation of secondary alcohols has been developed. In the presence of [Cp*IrCl2]2 (Cp*
) pentamethylcyclo-
pentadienyl) catalyst and base, the reactions of various secondary alcohols with primary alcohols give
â
-alkylated higher alcohols in good to
excellent yields without any hydrogen acceptor or hydrogen donor. This reaction proceeds via successive hydrogen-transfer reactions and
aldol condensation.
Alcohols are one of the most basic and important classes of
organic compounds because they have a wide variety of uses
in industrial and laboratory chemistry. Although a huge
number of methods for the synthesis of alcohols are known,1,2
the synthesis of a variety of alcohols having intricate
structures through alkylation of simple alcohols usually
requires tedious processes using many reagents. For example,
â-alkylation of a secondary alcohol can usually be ac-
complished via three-step transformations (oxidation,3 alky-
lation,4 and reduction2,5) (eq 1).
catalytic process for â-alkylation of a secondary alcohol with
another alcohol to give a higher alcohol along with H2O as
a coproduct would be highly desirable (eq 2). Only one report
on this subject using a Ru catalyst has appeared;6 however,
it is necessary in this system to add both a large amount of
a sacrificial hydrogen acceptor (5 equiv of 1-dodecene) and
a hydrogen donor (dioxane solvent).7 From the viewpoint
of atom economy, it is most preferable to avoid these
additives.
We have recently found an extremely high catalytic
activity of [Cp*IrCl2]2 toward both oxidative and reductive
hydrogen-transfer reactions,8 demonstrating that the elec-
tronic and steric effects of the Cp* ligand are essential in
high performance as a hydrogen transfer catalyst. In this
paper, we report a new and atom economical catalytic system
using [Cp*IrCl2]2 as a catalyst for â-alkylation of secondary
alcohols with primary alcohols without any sacrificial
additiVes.
Taking into account increasing demands for environmen-
tally benign and economical synthetic methods, a direct
(1) Sweeney, J. B. In ComprehensiVe Organic Functional Group
Transformations; Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.;
Pergamon: Oxford, 1995; Vol. 2, p 37.
(2) Larock, R. C. ComprehensiVe Organic Transformations; VCH: New
York, 1989; p 475.
(3) Ley, S. V.; Madin, A. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 7, p 251.
(4) Heathcock, C. H. In ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 2, p 133.
(5) (a) Greeves, N. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 8, p 1. (b) Harada, K.;
Munegumi, T. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, 1991; Vol. 8, p 139.
(6) Cho, C. S.; Kim, B. T.; Kim, H.-S.; Kim, T.-J.; Shim, S. C.
Organometallics 2003, 22, 3608.
(7) In the system reported in ref 6, employment of 2 equiv of primary
alcohols is also required.
10.1021/ol051517o CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/02/2005

At first, we investigated the iridium-catalyzed â-alkylation
of 1-phenylethanol (1a) with 1-butanol (2a) under various
conditions (Table 1). When the reaction of almost equimolar
Table 2. Cp*Ir Complex Catalyzed â-Alkylation of Various
Secondary Alcohols with Primary Alcoholsa
Table 1. â-Alkylation of 1-Phenylethanol (1a) with 1-Butanol
(2a) under Various Conditionsa
yieldb (%)
entry catalyst (% metal)
base
solvent (mL) 3a
4a
1
2
3
4
5c
6
7
[Cp*IrCl2]2 (1.0)
[Cp*IrCl2]2 (0.5)
[Cp*IrCl2]2 (0.5)
[Cp*IrCl2]2 (1.0)
[Cp*IrCl2]2 (0.5)
[Cp*IrCl2]2 (0.5)
[Cp*IrCl2]2 (0.5)
NaOtBu toluene (0.3) 90
NaOtBu toluene (0.3) 82
6
7
4
0
3
20
7
1
2
2
NaOH
toluene (0.3) 77
Na2CO3 toluene (0.3)
0
NaOtBu toluene (0.3) 52
NaOtBu toluene (3.0) 60
NaOtBu none
52
12
8d [Cp*IrCl2]2 (0.5)
9e
[Cp*IrCl2]2 (0.5)
10
11
12
NaOtBu THF (3.0)
NaOtBu dioxane (3.0) 23
Cp*IrCl2(PPh3) (1.0) NaOtBu toluene (0.3) 10
[IrCl(cod)]2 (1.0)
[Cp*RhCl2]2 (1.0)
NaOtBu toluene (0.3) 30
NaOtBu toluene (0.3) 26
5
2
a The reaction was carried out with 1a (3.0 mmol), 2a (3.6 mmol),
catalyst, and base (3.0 mmol) at 110 °C for 17 h. b GC yield based on 1a.
c At 90 °C. d At 65 °C. e At 100 °C.
amounts of 1a (3.0 mmol) and 2a (3.6 mmol) was carried
out in the presence of [Cp*IrCl2]2 (1.0%Ir) catalyst and
NaOtBu (3.0 mmol) at 110 °C for 17 h in toluene (0.3 mL),7
1-phenylhexan-1-ol (3a) was formed in a yield of 90% along
with a small amount of 1-phenylhexan-1-one (4a, 6%) (entry
1). The reaction proceeded in a high yield of 3a (82%) with
a reduced amount of catalyst (0.5%Ir) (entry 2). NaOH was
also effective as a base comparable to NaOtBu (entry 3),
while the use of a weaker base (Na2CO3) gave no product
(entry 4). The reaction at 90 °C resulted in a lower yield
(entry 5). The amount of toluene was important to obtain
the desired product 3a selectively; when the reaction was
carried out in an increased amount of toluene (3.0 mL), the
formation of a considerable amount of 4a (20%) in addition
to 3a (60%) was observed (entry 6). The reaction without
solvent, in THF, or in dioxane resulted in a lower yield
(entries 7-9). Other catalysts such as Cp*IrCl2(PPh3),
[IrCl(cod)]2, or [Cp*RhCl2]2 showed lower activity than
[Cp*IrCl2]2 (entries 10-12).
a The reaction was carried out with secondary alcohol (3.0 mmol),
primary alcohol (3.6 mmol), catalyst, and base (3.0 mmol) in toluene (0.3
mL) at 110 °C for 17 h. b Isolated yield based on secondary alcohol. Values
in parentheses indicate the isolated yield of corresponding ketone. c For-
mation of a small amount of the corresponding ketone which was not
isolated was observed by GC analysis (5-10%). d Mixture of diastereomers
(1:1). e Reaction was carried out in 3.0 mL of toluene. f Mixture of
diastereomers (cis/trans ) 54:46).
â-alkylated products in high yields (entries 1-4). The
reactions of 1a with benzyl alcohols bearing an electron-
donating or an electron-withdrawing substituent also pro-
ceeded efficiently (entries 5-9). In these cases, optimum
results were obtained by the reactions in 3.0 mL of toluene.
The reactions of 1-arylethanols (1b-e) with 2a also gave
the â-alkylated products (entries 12-15). In these reactions
a considerable amount of the corresponding ketone products
were also isolated in addition to the desired alcohol product.
Other secondary alcohols such as 1f-h were also applicable
to the present catalytic system to give moderate to good
yields (entries 16-18). The reaction of 1,2,3,4-tetrahydro-
1-naphthol (1h) with 2a gave a diastereomeric mixture (cis/
trans ) 54:46) of 2-butyl-1,2,3,4-tetrahydronaphthalen-1-ol
(3r, 65%) in addition to 3,4-dihydro-2-butylnaphthalen-
1(2H)-one (4r, 34%) (entry 18).
On the basis of the above results, we next examined the
reactions of various secondary alcohols with primary alcohols
under the optimized conditions (Table 2). The reactions of
1a with aliphatic primary alcohols gave the corresponding
(8) (a) Fujita, K.; Yamaguchi, R. Synlett. 2005, 560. (b) Fujita, K.; Fujii,
T.; Yamaguchi, R. Org. Lett. 2004, 6, 3525. (c) Fujita, K.; Kitatsuji, C.;
Furukawa, S.; Yamaguchi, R. Tetrahedron Lett. 2004, 45, 3215. (d) Fujita,
K.; Li, Z.; Ozeki, N.; Yamaguchi, R. Tetrahedron Lett. 2003, 44, 2687. (e)
Fujita, K.; Yamamoto, K.; Yamaguchi, R. Org. Lett. 2002, 4, 2691. (f)
Fujita, K.; Furukawa, S.; Yamaguchi, R. J. Organomet. Chem. 2002, 649,
289.
To obtain information concerning the reaction mechanism,
the R-alkylation of ketone with a primary alcohol9 and
4018
Org. Lett., Vol. 7, No. 18, 2005

transfer hydrogenation of an R,â-unsaturated ketone10 under
the present catalytic conditions was undertaken. The reaction
of acetophenone with 1-butanol (2a) in the presence of
[Cp*IrCl2]2 (1.0%Ir) and NaOH (1.0 equiv) at 110 °C for
17 h in toluene gave 1-phenylhexan-1-one (4a) in 91% yield
(eq 3).
Scheme 1. Possible Mechanism for Cp*Ir Complex Catalyzed
â-Alkylation of Secondary Alcohols with Primary Alcohols
When the transfer hydrogenation of benzylideneacetophe-
none using 2-propanol (5.0 equiv) as a hydrogen donor was
carried out in the presence of [Cp*IrCl2]2 (1.0%Ir) and
NaOtBu (1.0 equiv) at 110 °C for 17 h in toluene, 1,3-
diphenylpropan-1-ol (3e) was formed in 59% yield (eq 4).11,12
give an R,â-unsaturated ketone. Successive transfer hydro-
genation of CdC and CdO double bonds of the R,â-
unsaturated ketone by the hydrido iridium species would
occur to give the product. It should be noted that, in this
catalytic system, the hydrido iridium species generated at
the stage of the oxidation of alcohols are consumed at the
stage of the reduction of R,â-unsaturated ketone. Thus,
additions of hydrogen donor and acceptor are not required,
making this catalytic system a highly atom economical
process.
In summary, we have shown a new efficient system for
the â-alkylation of secondary alcohols with primary alcohols
catalyzed by a Cp*Ir complex. It should be noted that the
coproduct in these reactions is only H2O. Moreover, the
present system requires an extra addition of neither hydrogen
acceptor nor donor. In addition, almost equimolar amount
of substrates are sufficient to obtain good yields of products.
A possible mechanism for Cp*Ir complex-catalyzed
â-alkylation of secondary alcohols with primary alcohols is
described in Scheme 1. The first step of the reaction would
involve the oxidation of primary and secondary alcohols to
aldehyde and ketone accompanied by the generation of a
hydrido iridium species.8 Then, base-mediated cross-aldol
condensation between aldehyde and ketone would occur to
(9) Transition-metal-catalyzed R-alkylation reactions of ketones with
primary alcohols have been recently reported by Ishii et al. and Cho et al.:
(a) Taguchi, K.; Nakagawa, H.; Hirabayashi, T.; Sakaguchi, S.; Ishii, Y. J.
Am. Chem. Soc. 2004, 126, 72. (b) Cho, C. S.; Kim, B. T.; Kim, T.-J.;
Shim, S. C. Tetrahedron Lett. 2002, 43, 7987. (c) Cho, C. S.; Kim, B. T.;
Kim, T.-J.; Shim, S. C. J. Org. Chem. 2001, 66, 9020.
(10) For example: (a) Albrecht, M.; Miecznikowski, J. R.; Samuel, A.;
Faller, J. W.; Crabtree, R. H. Organometallics 2002, 21, 3596. (b) Hillier,
A. C.; Lee, H. M.; Stevens, E. D.; Nolan, S. P. Organometallics 2001, 20,
4246. (c) Yi, C. S.; He, Z.; Guzei, I. A. Organometallics 2001, 20, 3641.
See also, (d) Sakaguchi, S.; Yamaga, T.; Ishii, Y. J. Org. Chem. 2001, 66,
4710. (e) Brieger, G.; Nestrick, T. J. Chem. ReV. 1974, 74, 567.
(11) 1,3-Diphenylpropan-1-one (4e) was also formed in 14% yield as a
byproduct.
Supporting Information Available: Full experimental
details and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(12) Similar transfer hydrogenation of benzylideneacetophenone using
1.0 equiv of 2-propanol as a hydrogen donor gave 1,3-diphenylpropan-1-
one (4e) in 73% yield.
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