Palladium-catalyzed conjugate reduction of enones into α,β- dideuterioketones with hexamethyldisilane and deuterium oxide

Article abstract of DOI:10.1039/b618107d

Conjugated enones are reduced by readily available Me ₃SiSiMe₃ and D₂O in the presence of a catalytic amount of [PdCl(η³-C₃H₅)] ₂-PPh₃ to give α,β-dideuterioketones. The Royal Society of Chemistry.

Full text of DOI:10.1039/b618107d

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Palladium-catalyzed conjugate reduction of enones into
a,b-dideuterioketones with hexamethyldisilane and deuterium oxide{
Hidehito Otsuka, Eiji Shirakawa* and Tamio Hayashi*
Received (in Cambridge, UK) 12th December 2006, Accepted 16th January 2007
First published as an Advance Article on the web 8th February 2007
DOI: 10.1039/b618107d
Conjugated enones are reduced by readily available
Me3SiSiMe3 and D2O in the presence of a catalytic amount
of [PdCl(g3-C3H5)]2–PPh3 to give a,b-dideuterioketones.
ð1Þ
Deuterated organic compounds are important for biological
research1 and the elucidation of reaction mechanisms.2 Among
the deuterium sources used for chemical transformations to
Table 1 Palladium-catalyzed conjugate reduction of enones to
a,b-dideuterioketonesa
deuterated compounds, deuterium oxide is undoubtedly the most
inexpensive and easy to handle. In this context, we recently
reported the palladium-catalyzed reduction of alkynes to 1,2-
dideuterioalkenes using hexamethyldisilane and deuterium oxide
as a reductant and a deuterium source, respectively.3 Here, we
report that the combination of a palladium catalyst, hexamethyl-
disilane and deuterium oxide is applicable to the conjugate
reduction of enones into a,b-dideuterioketones. There are some
precedents for the a,b-dideuteration of conjugated enones using
deuterium oxide as a deuterium source.4,5 A plausible reaction
mechanism based on the experimental results, including that from
a stoichiometric reaction using an intermediate equivalent, is also
described.
Deuterium ratioc
Entry R1
R2
Yield (%)b a (-d)
b (-d)
1
2
3
4
5
6
Hex
i-Pr
Cl(CH2)3
Ph
4-MeOC6H4 Ph
4-CF3C6H4 Ph
Ph
Ph
Ph
Ph
Pent
Ph
Ph
Ph
Ph
Ph
82
93
85
81
86
85
92
95
69
92
80
81
1.25/2
1.44/2
1.56/2
1.21/2
1.31/2
1.35/2
1.45/2
1.58/2
1.31/2
1.56/2
1.05/2
3.22/4e
1.20/2
1.13/2
1.17/2
1.02/2
1.09/2
0.97/2
1.05/2
0.96/2
1.05/2
0.98/2
1.06/2
2.00/4e
7
4-MeOC6H4
8d
9
4-Me2NC6H4
4-CF3C6H4
Me
Me
(E)-Styryl
10
11
12
a
We first examined the conjugate reduction of 1-phenyl-2-nonen-
1-one (1a) under essentially the same conditions as we used for the
reduction of alkynes, but at a lower temperature.3 Thus, treatment
of 1a with hexamethyldisilane (2: 1.5 equiv.), D2O (10 equiv.),
[PdCl(g3-C3H5)]2 (3: 5 mol% of Pd) and PPh3 (10 mol%) in DMA
at 60 uC for 24 h gave 2,3-dideuterio-1-phenyl-1-nonanone (4a)
(eqn. (1) and Table 1, entry 1). More than one deuterium atom was
incorporated at both a- (125%) and b- (120%) positions. The
overdeuteration of the a-position is probably due to acid-catalyzed
H–D exchange via an enol form of product 4a,6 whereas that of
the b-position is caused by H–D exchange of enone 1a before
reduction. The actual deuterium ratios of recovered 1a at 63%
conversion were 2% (a) and 29% (b).6 How the H–D exchange at
the b-position takes place will be discussed later. The deuteration
was found to be applicable to various conjugated enones having
aliphatic and/or aromatic substituents on the alkene and carbonyl
carbons (Table 1).{ Substitution on the benzene rings of the
chalcon with an electron-donating or -withdrawing group did not
inhibit the reaction, except for a CF3 group on the 1-phenyl
group of the chalcon, which resulted in moderate yields (Table 1
entries 4–9).
The reaction was carried out in DMA (0.50 mL) at 60 uC for 24 h
under a nitrogen atmosphere using enone (0.40 mmol), Me3SiSiMe3
(0.60 mmol) and D2O (4.0 mmol) in the presence of [PdCl(g3-
b
C3H5)]2 (10 mmol) and PPh3 (40 mmol). Isolated yield based on the
enone. D/(D + H) determined by 1H NMR. Reaction time = 48
h. Both of the double bonds are deuterated.
c
d
e
In our report on the palladium-catalyzed silylation of alcohols
with 2,7 it was shown that 3 is transformed into PdH(Cl)(PPh3)2
(5)8 as a catalytically active complex by treatment with 2 and an
alcohol in the presence of PPh3, and that the Si–Si bond of disilane
2 is cleaved with ROH in the presence of hydridopalladium
catalyst 5 to give Me3SiH (6a) and Me3SiOR. In the present
dideuteration system, where D2O is used in place of ROH,
deuteridopalladium PdD(Cl)(PPh3)2 (5-d), Me3SiD (6a-d) and
Me3SiOD should be generated in place of hydridopalladium 5,
hydrosilane 6a and Me3SiOR, respectively. Thus, we are tempted
to consider that 5-d catalyzes the dideuteration of enones 1, with
6a-d as a reductant, with the aid of D2O, as shown in eqn. (2).9
Actually, the combination of 5 (5 mol%) and PhMe2SiD (6b-d:
3.0 equiv.), instead of 5-d and 6a-d, in the presence of D2O
(10 equiv.), worked effectively in the conjugate reduction of 1a at
60 uC for 24 h to give 4a in 76% yield (a: 1.47/2-d, b: 1.05/2-d).
We investigated the reaction mechanism based on eqn. (2).
Deuteriopalladation of enone 1 with D–Pd–Cl 5-d, giving
b-deuterio-a-palladioketone 7, is probably the first step
(Scheme 1). The corresponding hydropalladation of alkenes is a
Department of Chemistry, Graduate School of Science, Kyoto
University, Sakyo, Kyoto 606-8502, Japan.
E-mail: shirakawa@kuchem.kyoto-u.ac.jp; Fax: +81 75 753 3988
{ Electronic supplementary information (ESI) available: Synthesis,
characterisation data and NMR spectra of the deuterated compounds
prepared. See DOI: 10.1039/b618107d
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(2)
Scheme 2
formation of 9a. The reaction of 79 with 6b-d in the presence of
D2O and the absence of 10 gave 11 (58%, along with 10% of 12)
but not 9a. A plausible overall catalytic cycle is shown in Scheme 2.
Deuteriopalladation of 1 gives a-palladioketone 7, which is in
equilibrium with palladium enolate 8. Palladium complex 7 and/or
8 reacts with 6a-d to regenerate 5-d and give silyl enolate 9,15 which
undergoes deuteriolysis under slightly acidic conditions to give
a,b-dideuterioketone 4.
Scheme 1
In conclusion, we have disclosed a new dideuteration method
for conjugated enones using readily available deuterium oxide as
the deuterium source, a palladium complex as the catalyst and
hexamethyldisilane as the reductant.
well known process,10 but it is difficult to observe a-palladioketone
7 because of the facile reverse reaction, b-hydride elimination.11
The H–D exchange at the b-position of enone 1 prior to the
reduction (vide supra) is possibly ascribed to a series of reactions
initiated by deuteriopalladation (Scheme 1). Thus, (aS*,bR*)-7,
generated by the deuteriopalladation, undergoes a 1,3-Pd shift,
giving palladium enolate 8. The reverse 1,3-Pd shift to the opposite
side, followed by b-hydride elimination, gives b-deuterioenone 1-b-
d via (aR*,bR*)-7.12
Notes and references
{ General procedure for the dideuteration of enones: To a solution of
[PdCl(g3-C3H5)]2 (3: 3.7 mg, 0.010 mmol) and PPh3 (10.5 mg, 0.0400 mmol)
in DMA (0.50 mL) were added, successively, the enone (1: 0.40 mmol),
hexamethyldisilane (2: 87.9 mg, 0.600 mmol) and D2O (72 mL, 4.0 mmol).
After stirring at 60 uC for 24 h, the resulting mixture was diluted with
diethyl ether (20 mL), washed with water (10 mL 6 5) and brine (10 mL),
and dried over anhydrous magnesium sulfate. Filtration and evaporation
of the solvent followed by PTLC on SiO2 (hexane–ethyl acetate), column
chromatography on SiO2 (hexane–ethyl acetate) or bulb-to-bulb distillation
gave the corresponding a,b-dideuterioketone 4. Deuterium ratios were
determined by 1H NMR. The results are summarized in Table 1.
Next, we examined which of the remaining substrates, 6a-d and
D2O, reacts with a-palladioketone 7. We used a less volatile
deuteriosilane, PhMe2SiD (6b-d), and a more stable a-palladioke-
tone, Pd(CH2COPh)Cl(PPh3)2 (79), 13 which is free from b-hydride
elimination. a-Palladioketone 79 was intact upon treatment with
D2O (rt, 1 h), whereas 6b-d readily reacted with 79 in the presence
of 1,8-bis(dimethylamino)naphthalene (10: 3.0 equiv.)14 to give
silyl enolate 9a in 63% yield (eqn. (3)).
1 For examples, see: (a) K. Liu, J. Williams, H. Lee, M. M. Fitzgerald,
G. M. Jensen, D. B. Goodin and A. E. McDermott, J. Am. Chem. Soc.,
1998, 120, 10199–10202; (b) I. Sack, Y. S. Balazs, S. Rahimipour and
S. Vega, J. Am. Chem. Soc., 2000, 122, 12263–12269.
2 For examples, see: (a) D. Sellmann, J. Ka¨ppler and M. Moll, J. Am.
Chem. Soc., 1993, 115, 1830–1835; (b) M.-Y. Chou, A. B. Mandal and
M.-K. Leung, J. Org. Chem., 2002, 67, 1501–1505.
3 E. Shirakawa, H. Otsuka and T. Hayashi, Chem. Commun., 2005,
5885–5886.
ð3Þ
4 a,b-Dideuteration of a,b-unsaturated carbonyl compounds has been
accomplished using D2O as the deuterium source in combination with a
reductant. (a) Metal reductants: N. Kambe, K. Kondo, S. Morita,
S. Murai and N. Sonoda, Angew. Chem., Int. Ed. Engl., 1980, 19,
1009–1010; (b) J. M. Concello´n and H. Rodr´ıguez-Solla, Chem. Eur. J.,
2002, 8, 4493–4497; (c) J. M. Concello´n, H. Rodr´ıguez-Solla and
C. Concello´n, Tetrahedron Lett., 2004, 45, 2129–2131; (d) Zinc as a
reductant, with the aid of a rhodium catalyst: T. Sato, S. Watanabe,
H. Kiuchi, S. Oi and Y. Inoue, Tetrahedron Lett., 2006, 47, 7703–7705;
(e) Biocatalysts: A. R. Battersby, A. L. Gutman and C. J. R. Fookes,
a-Deuterioacetophenone (11), a major by-product, was probably
produced by the reaction of 9a with 5-d, generated during the
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J. Chem. Soc., Chem. Commun., 1981, 645–647; (f) G. Fronza,
C. Fuganti, P. Grasselli, A. Mele, A. Sarra, G. Allegrone and
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M. Lorenz, W. Boland, H. Simon and K. Dettner, Tetrahedron, 1994,
50, 6859–6874; (h) R. Eck and H. Simon, Tetrahedron, 1994, 50,
13631–13640.
5 Transition metal-catalyzed conjugate reduction of a,b-unsaturated
carbonyl compounds with deuteriosilanes gives b-deuterated carbonyl
compounds: (a) I. Ojima and T. Kogure, Organometallics, 1982, 1,
1390–1399; (b) E. Keinan and N. Greenspoon, J. Am. Chem. Soc., 1986,
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T. Hiyama, Tetrahedron, 1999, 55, 4573–4582. a-Deuterated ketones
are obtained by the use of hydrosilanes in the presence of D2O. See
ref. 5b–e.
6 We examined the deuteration of 1a for short (3.5 h) and prolonged
(72 h) reaction times to obtain a time profile for the deuteration ratios
of the a- and b-positions of 4a. The resulting profile for a/b was
1.01/1.16 (3.5 h), 1.25/1.20 (24 h: Table 1, entry 1) and 1.82/1.25
(72 h), where the conversions 1a/yields 4a were 63%/45% (3.5 h), .99%/
82% (24 h) and .99%/88% (72 h). The time profile clearly shows that
H–D exchange at the a-position takes place at least mainly after the
reduction.
9 PdD(Cl)(PPh3)2 (5-d) is also considered to be a catalyst in the
dideuteration of alkynes. See ref. 3.
10 For reviews, see: (a) V. V. Grushin, Chem. Rev., 1996, 96, 2011–2033; (b)
E.-i. Negishi, in Handbook of Organopalladium Chemistry for Organic
Synthesis, ed. E.-i. Negishi, Wiley, New York, 2002, pp. 135–139; (c)
The hydropalladation of acrylonitrile, a similar alkene to enones, is
reported to proceed to give Pd[CH(CN)CH3](S2CNMe2)(PEt3):
D. L. Reger and D. G. Garza, Organometallics, 1993, 12, 554–558.
11 a-Palladio carbonyl compounds are known to be typical but rarely
observable intermediates leading to b-substituted enones in the
Mizoroki–Heck reaction. For a review of the Mizoroki–Heck reaction,
see: I. P. Beletskaya and A. V. Cheprakov, Chem. Rev., 2000, 100,
3009–3066.
12 Similar p–s–p rearrangements are widely known in allylpalladium
chemistry. For a review, see: L. Acemoglu and J. M. J. Williams, in
Handbook of Organopalladium Chemistry for Organic Synthesis, ed. E.-i.
Negishi, Wiley, New York, 2002, pp. 1689–1705.
13 P. Veya, C. Floriani, A. Chiesi-Villa and C. Rizzoli, Organometallics,
1993, 12, 4899–4907.
14 We added 10 to avoid the acid-induced decomposition of silyl enolate
9a. The reaction in the absence of 10 gave 9a, 11 and 12 in 35, 32 and
8% yields, respectively.
15 In the platinum-catalyzed dehydrogenative silylation of ketones with
hydrosilanes, giving silyl enolates, a mechanism involving the reaction of
a platinum enolate with a hydrosilane is proposed: (a) F. Ozawa,
S. Yamamoto, S. Kawagishi, M. Hiraoka, S. Ikeda, T. Minami, S. Ito
and M. Yoshifuji, Chem. Lett., 2001, 972–973; (b) F. Ozawa and
M. Yoshifuji, C. R. Chim., 2004, 7, 747–754.
7 E. Shirakawa, K. Hironaka, H. Otsuka and T. Hayashi, Chem.
Commun., 2006, 3927–3929.
8 K. Kudo, M. Hidai, T. Murayama and Y. Uchida, J. Chem. Soc.,
Chem. Commun., 1970, 1701–1702.
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