C O M M U N I C A T I O N S
Table 2. R-Alkylation of Nitriles with Alcohols Using Ru/HTa
Scheme 2
entry
donor
alcohol
product
yield (%)b
1
2
3
4c
5c
6c
7
R1 ) Ph
1a
1b
1c
1d
1e
R2 ) Me
2a
2a
2a
2a
2a
2b
3a
3b
3c
3d
3e
3f
3g
3h
98 (94)
83
99
92
89
86
65
94 (86)
85
91 (77)
85
R1 ) 4-Cl-Ph
R1 ) 4-Me-Ph
R1 ) 4-MeO-Ph
R1 ) 1-naphthyl
afford 2-ethyl-2-phenylglutarodinitrile (6a), a highly useful inter-
mediate of sedative Glutethimide,5b,e in 93% yield. The conventional
method for the synthesis of 6a from 1a using iodoethane, NaNH2,
and Triton B gave less than 39% yield.5b For this single pot
synthesis, the Ru species and base sites on the Ru/HT surface
participate in four sequential reactions: oxidatiVe dehydrogenation,
aldol condensation, hydrogenation, and Michael reaction to finally
produce R,R-dialkylated phenylacetonitriles.
R1 ) 2-thiophenyl 1f
2a
1a
1a
1a
1a
R2 ) H
8
R2 ) n-Pr 2c
R2 ) i-Pr 2d
9c
10d,e
11d,f
3i
3j
R2 ) Ph
2e
2e
PhC(O)CH3
1g
1h
PhC(O)CH2Bn
i-PrC(O)CH2n-Bu 68
12c,d,g i-PrC(O)CH3
2c
In conclusion, the Ru/HT efficiently catalyzed the R-alkylation
of a variety of nitriles with alcohols and was further extended for
the synthesis of R,R-dialkylated phenylacetonitrile through the co-
operative catalysis between the grafted-Ru species and the surface
base sites. Nanostructured heterogeneous catalysts, which possess a
multifunctional surface, will contribute pivotally in the development
of economically and environmentally friendly chemical processes.
a Donor (1 mmol), alcohol (2 mL), Ru/HT (0.15 g, Ru: 0.0075 mmol),
180 °C, 20 h, Ar. b Based on donor. Values in parentheses are isolated yield.
c Ru/HT (0.3 g, Ru: 0.015 mmol). d 2 mL of toluene was used. e 2e (1.5
mmol). f 2e (1.0 mmol). g 2c (2.0 mmol).
Scheme 1
Acknowledgment. We thank Dr. Tomoya Uruga (JASRI) for
the XAFS measurements.
Supporting Information Available: Experimental procedure and
curve fitting analysis. This material is available free of charge via the
2-4). The R-ethylation of a sterically hindered 1-naphthylaceto-
nitrile (1e) proceeded successfully to form 2-(1-naphthyl)-butyro-
nitrile in high yield (3e). The Ru/HT catalyst system was applicable
to a heteroarylacetonitrile including a sulfur atom as a donor (1f).
A diverse set of primary alcohols was usable for this R-alkylation
reaction (entries 1, 7-10); interestingly, the reaction of 1a with
n-butanol (2c) gave 2-phenylhexanonitrile (3h), a precursor of the
systemic fungicide Systhane,5c in 94% yield. The Ru/HT catalyst
could also promote the R-alkylation of carbonyl compounds as a
donor (entries 11 and 12). For example, acetophenone (1g) reacted
with 2e to produce 1,3-diphenyl-1-propanone (3k) in 85% yield.
This is the first report for the R-alkylation of ketones with alcohols
achieved by a heterogeneous catalyst.10 A 20 mmol scale reaction
of 1a with 2a afforded 3a in 82% yield with a high TOF of 14 h-1
and a high TON of 412, which are considerably higher than those
of a previously reported homogeneous Ru catalyst combined with
the stoichiometric amount of Na2CO3 (TOF, 0.77 h-1; TON, 18).6
The hydrogen transfer from benzyl alcohol to (Z)-2-phenylcin-
namonitrile in the presence of the Ru/HT yielded 2,3-diphenylpro-
pionitrile along with benzaldehyde.8,11 In a separate experiment,
the parent HT promoted aldol condensation of 1a with benzaldehyde
to afford (Z)-2-phenylcinnamonitrile.8 From the above results, it is
reasonable that the present R-alkylation consists of the following
three consecutive reactions (Scheme 1): oxidative dehydrogenation
of alcohols to aldehydes (i, ii), base-catalyzed aldol condensation
of nitriles with aldehydes (iii), and hydrogenation of R,â-unsaturated
nitriles with a Ru-H species (iv, v).12 Upon treatment of the
Ru/HT with benzyl alcohol, the IR spectrum showed a signal at
2120 cm-1 assignable to ν(Ru-H).8,13 Vide supra, the reaction of
the Ru-H species with dioxygen might lead to the exclusive
formation of the R,â-unsaturated nitrile (Table 1, entry 2).14
The applicability of the present Ru/HT catalyst is highlighted
by a one-pot synthesis of R,R-dialkylated phenylacetonitriles
(Scheme 2). For example, after completion of the alkylation of 1a
with 2a, acrylonitrile (5a) was added and allowed to further react
at 150 °C for 1 h. The base-catalyzed Michael reaction occurred to
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JA049181L
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J. AM. CHEM. SOC. VOL. 126, NO. 18, 2004 5663