Carbonyl reduction with CaH2 and R3SiCl catalyzed by ZnCl2

Article abstract of DOI:10.1016/j.tetlet.2007.10.123

Ketones and aldehydes were effectively reduced to the corresponding alcohols (or their silyl ethers) by the reaction with CaH₂ and R₃SiCl in the presence of a catalytic amount of ZnCl₂. In the absence of the carbonyl substrate, the reagent reduced R₃SiCl to the corresponding hydrosilane under mild reaction conditions.

Full text of DOI:10.1016/j.tetlet.2007.10.123

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 9120–9123
Carbonyl reduction with CaH2 and R3SiCl catalyzed by ZnCl2
Akiko Tsuhako, Jing-Qian He, Mariko Mihara, Naoko Saino and Sentaro Okamoto*
Department of Material and Life Chemistry, Kanagawa University, 3-27-1 Rokkakubashi, Kanagawa-ku, Yokohama 221-8686, Japan
Received 8 September 2007; revised 20 October 2007; accepted 25 October 2007
Available online 30 October 2007
Abstract—Ketones and aldehydes were effectively reduced to the corresponding alcohols (or their silyl ethers) by the reaction with
CaH2 and R3SiCl in the presence of a catalytic amount of ZnCl2. In the absence of the carbonyl substrate, the reagent reduced
R3SiCl to the corresponding hydrosilane under mild reaction conditions.
Ó 2007 Elsevier Ltd. All rights reserved.
Reduction of carbonyl compounds with metal hydride
reagents is one of the most basic transformations in
organic synthesis.1 Recently, efforts have been devoted
to utilize basically inert metal hydrides LiH and CaH2
as a reductive hydride source because they are inexpen-
sive, stable, easy to handle, and environmentally benign:
with the use of LiH, reduction (formal hydrosilylation)
of ketones by cat. ZnX2/LiH/Me3SiCl2 and hydrozinca-
tion of dienes and alkynes by cat. (cyclopentadie-
ketones.8 Herein, we report the development of a new
CaH2-based reagent, cat. ZnX2/CaH2/R3SiCl, which
effectively reduced (hydrosilylated) a variety of carbonyl
compounds including aromatic, aliphatic ketones with a
cyclic and acyclic form and aldehydes.
To overcome the aforementioned drawbacks to the
reported LiH- and CaH2-based reduction, we concen-
trated our effort to develop more general reagent system
based on CaH2. Inspired by the LiH-based reducing
agent developed by Noyori et al., initial investigations
were begun by reacting acetophenone (1a),
2-octanone (1b) and 3-phenylpropanal (1c) with a com-
bination reagent cat. ZnX2/CaH2/Me3SiCl. Thus, the
reactions with CaH2 (1.5 equiv) in the presence of Me3-
SiCl (1.3 equiv) and a catalytic amount of ZnX2 were
carried out and the results are summarized in Table 1,
where the yields were given for the corresponding alco-
hol obtained after acidic work-up. The possibility of the
use of other metal salts instead of ZnX2 was also
examined.
3
nyl)2TiCl2/2LiH/ZnI2 have been reported by Noyori
et al. and by Sato et al., respectively, where a zinc
hydride species derived from LiH and ZnX2 was pro-
posed as an active hydride. Generation of dialkylzinc
hydride ate complexes from LiH and ZnR2 has also
been documented.4 Meanwhile, although there had been
no report for the use of CaH2 as a reductive hydride,
except for reactions through the synthesis of boron5
and aluminium6 hydrides and the reductions of sulfates
to sulfides,7 we have recently reported the first example
of a direct use of CaH2 for the reduction of carbonyl
compounds, where a mixture of CaH2 and ZnX2
reduced ketones and imines in the presence of a catalytic
amount of a Lewis acid such as Ti(O-i-Pr)4, B(O-i-Pr)3,
Al(O-i-Pr)3 and ZnF2.8 Carbonyl reduction with these
stable metal hydrides is promising as a practical process
applicable to a large-scale synthesis. However, the reac-
tion of aldehydes having a-hydrogen with the LiH-based
reagent gave a complex mixture including aldol conden-
sation products2,9 and the CaH2-based reagent also
resulted in the formation of a complex mixture from
aldehydes and no reaction with acyclic aliphatic
As revealed from the results of the reaction of acetophe-
none (1a) (entries 1–8), in the absence of metal salt the
reaction did not take place at all (entry 1), whereas, in
the presence of ZnX2 the reaction proceeded to afford
the expected alcohol (entries 2–4). Though the reaction
at room temperature sometimes faced the problem of
reproducibility (entry 2), performing the reaction at
40 °C helped to overcome this matter (entries 3 and 4).
Other metal salts such as MgBr2, CuCl2, Co(acac)3
and FeCl3 did not catalyze the reaction (entries 5–8).
To our delight, acyclic aliphatic ketone 1b and aldehyde
1c having a-hydrogens were reduced to the correspond-
ing alcohols in good yields (entries 9 and 10), although
*
Corresponding author. Tel.: +81 45 481 5661; fax: +81 45 413
9770; e-mail: okamos10@kanagawa-u.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.123

A. Tsuhako et al. / Tetrahedron Letters 48 (2007) 9120–9123
Table 1. Reaction of carbonyl compounds with CaH2/Me3SiCl/MXn
9121
a
Entry
R1
R2
MXn
—
h
Yieldb (%)
1
1a: Ph
1a: Ph
1a: Ph
1a: Ph
1a: Ph
1a: Ph
1a: Ph
1a: Ph
1b: n-C6H13
Me
24
1
0.5 96
1.5 93
24
24
ꢀ0
2c
3
Me ZnCl2
Me ZnCl2
Me ZnBr2
Me MgBr2
Me CuCl2
Me Co(acac)3 24
Me FeCl3
Me ZnCl2
40–98
4
5
6
7
8
9
10
ꢀ0
ꢀ0
ꢀ0
ꢀ0
24
0.3 87
24
74e
d
1c:
Ph(CH2)2
H
ZnCl2
a Commercial anhydrous was used.
b Isolated yield.
c Performed at room temperature.
d 0.2 equiv of ZnCl2 was used.
e 26% of 1c was recovered.
the reduction of aldehyde needed longer reaction time
even with the use of 0.2 equiv of ZnCl2. Thus, the pres-
ent method overcame the aforementioned limitation of
the reported LiH- and CaH2-based carbonyl
reduction.2,8
Figure 1. Reduction of carbonyl compounds with a CaH2/R3SiCl/
ZnCl2 catalyst system.12 aFor work-up, H2O was used instead of 1 M
HCl. bFor work-up, n-Bu4NF in THF was used instead of 1 M HCl.
Since the reaction with cat. ZnX2/CaH2/Me3SiCl system
provided a mixture of the reduced alcohol and its silyl
ether after neutral aqueous work-up or on TLC analysis
of the reaction mixture, the reaction initially formed the
corresponding Me3Si ethers but they often were unstable
to isolate. Therefore, an acidic aqueous work-up (or
treatment with ammonium fluoride) was performed to
isolate the products as the corresponding alcohol in
the above-mentioned reactions. While the reaction used
more bulky silyl chloride such as PhMe2SiCl rather than
Me3SiCl, the work-up under neutral conditions gave the
corresponding silyl ether 3a as an isolated product in
good yield (Scheme 1).
e
c1.8 equiv of R3SiCl was used. d0.2 equiv of ZnCl2 was used. 26 % of
f
the substrate was recovered. 0.2, 6 and 2.6 equiv of ZnCl2, CaH2 and
Me3SiCl, respectively, were used.
ethers 3d, 4f, 3h and 3j were obtained after a neutral
work-up. In addition, imine 5 was also reduced effec-
tively to give the corresponding amine 6.
The results in Table 2 indicate a functional group com-
patibility of the present reaction. Thus, 4-substituted
acetophenones 1m–p were reduced to the corresponding
aryl alcohols in good yields where cyano, iodo and nitro
groups present in the substrates survived (entries 1–3).
As shown in entries 4 and 5, acetophenone (1a) was
reduced with the reagent in the presence of 1 equiv of
substituted benzene (Ar-FG, 7). The reduction of 1a to
2a proceeded with complete recovering of esters 7a
and 7b having a propargyl ether with a terminal alkyne.
It was noteworthy that the reaction in the presence of
Ph–CO2Et was somewhat slow and gave 2a in 63%
along with 35% of recovered 1a (entry 2). Lewis basicity
of an ester moiety may affect reaction, probably due to
the coordination to the metal center of an active species.
Figure 1 shows the reduction (or hydrosilylation) of
other representative carbonyl compounds 1 with a
CaH2/R3SiCl/ZnX2 (1.5/1.3/0.1 or 0.2 equiv) reagent,
where the structure of the product alcohol 2 (with the
use of Me3SiCl) and silyl ether 3 or 4, the reaction time
and the yield are given. The reagent effectively reduced a
variety of carbonyl compounds including aromatic, ali-
phatic, alkenyl ketones and aldehydes to alcohol 2 by
using a CaH2/Me3SiCl/ZnX2 reagent after an acidic
work-up. 1,2-Dione 1k was converted to 1,2-diol 2k in
a meso-selective fashion. The reactions with PhMe2SiCl
or Et3SiCl instead of Me3SiCl, the corresponding silyl
Scheme 2 demonstrates the steric nature of the present
reagent system and the reported systems for LiH- and
CaH2-based reduction. Thus, 4-t-butylcyclohexanone
was subjected to the reduction with these reagents, pro-
viding a mixture of two diastereoisomers, that is, ax-2q
and eq-2q. CaH2-based reagents, cat. Ti(O-i-Pr)4/
ZnCl2/CaH2 and cat. ZnCl2/CaH2/Me3SiCl systems,
exhibited the similar stereoselectivity and gave equato-
rial alcohol predominantly. The results suggest that
Scheme 1. Reaction with PhMe2SiCl.

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A. Tsuhako et al. / Tetrahedron Letters 48 (2007) 9120–9123
Table 2. Functional group compatibility
Scheme 3. Reduction of PhMe2SiCl with cat. ZnCl2/CaH2.
ZnCl2 (0.1 equiv) and Me3SiCl (1.3 equiv) reduced 1a
in 15% yield after 2 h at 40 °C but the precipitate was
essentially inert even after the addition of Me3SiCl
(1.3 equiv) and ZnCl2 (0.1 equiv). These suggest that a
certain species soluble in THF was generated and it
could reduce 1a.
Entry
1
Substrate (s)
Isolated yield (%)
2m: 94%
2
3
2n: 98%
2p: 75%
On the basis of the results, we thought about the possi-
bility of the generation of a hydrosilane(s) from CaH2
and silyl chloride. Thus, we carried out the reaction of
PhMe2SiCl (1.0 equiv) and CaH2 (1.5 equiv) in the pres-
ence or the absence of ZnCl2 (0.10 equiv) in THF (for
2 h at 40 °C) (Scheme 3).
2a: 62% (1a: 35%
recovered)
4
5
1a + Ph–CO2Et (7a, 1.0 equiv)
7a: quantitatively
recovered
Though the reaction without the zinc salt did not pro-
vide the corresponding hydrosilane at all, 83% yield of
PhMe2SiH was obtained by the reaction in the presence
of ZnCl2 after aqueous work-up. It has been reported
that the reaction of CaH2 and Me3SiCl provided
2a: 80%
10
Me3SiH in the presence of a catalytic amount of AlCl3
1a + (7b, 1.0 equiv)
7b: quantitatively
recovered
but it needed a high reaction temperature (270 °C).
Accordingly, it should be noted that the present hydros-
ilane formation proceeded under much milder
conditions.
The results may suggest that the present carbonyl reduc-
tion would proceed via hydrosilylation by in situ gener-
ated R3SiH.11 However, 1a did not react with Et3SiH or
PhMe2SiH (1.3 equiv) in the presence of a catalytic
amount of ZnCl2 (10 mol %) in THF at 40 °C (12 h).
Possible mechanism of the present reduction (or hydro-
silylation) is illustrated in Scheme 4, which involves
hydrozincation of carbonyl compounds with a zinc
hydride species generated from CaH2 and ZnX2, where
R3SiCl may act as a Lewis acid to activate carbonyl
compounds and as a silylation agent of the resulting
zinc-alkoxides to give the corresponding silyl ether and
zinc-chloride species. However, a hydrosilylation path-
way (shown with gray arrows in Scheme 4) by in situ
generated R3SiH cannot be neglected even when the
results in Scheme 3 could be considered because in the
Scheme 2. Reduction of 4-t-butylcyclohexanone with LiH- and CaH2-
based reagents.
the reaction may involve a small hydride source allowing
an attack from the axial position and/or the reactions
may proceed through the product-developing control
process.9 Meanwhile, interestingly, it has been reported
that the reduction of 1q with cat. Zn(OSO2Me)2/LiH/
Me3SiCl system gave the axial alcohol predominantly.2
The reduction with cat. ZnX2/CaH2/Me3SiCl was heter-
ogeneous throughout the reaction. After mixing the
reagents, solid and liquid phases of the resulting hetero-
geneous mixture were separated by filtration and the
reactivity of these phases was investigated. It was found
that the filtrate from a mixture of CaH2 (1.5 equiv),
Scheme 4. Possible reaction mechanism.

A. Tsuhako et al. / Tetrahedron Letters 48 (2007) 9120–9123
9123
5. Gerhard, H.; Horst, J. Chem. Ber. 1959, 92, 2022;
Mikheeva, V. I.; Fedneva, E. M.; Alpatova, V. I. Dokl.
Akad. Nauk. SSSR 1959, 131, 318; Koester, R.; Huber, H.
Inorg. Synth. 1977, 17, 17.
6. Schwarz, M.; Haidue, A.; Stil, H.; Paulus, P.; Greerlings,
H. J. Alloys Compd. 2005, 404-406, 762.
reaction mixture zinc salts may be no longer ZnCl2.
Further study to clarify the mechanism is underway.
In summary, we have demonstrated that CaH2/silyl
chloride reduced carbonyl compounds in the presence
of a catalytic amount of zinc salt.12 The cat. ZnX2/
CaH2/R3SiCl system developed here is more general
for carbonyl reduction than the previously developed
CaH2- or LiH-based reagents. Although reaction mech-
anism is unclear at this time, the method may be useful
because of its inexpensiveness and high functional group
compatibility. In addition, it was found that hydrosil-
anes from chlorosilanes could be obtained under the
mild reaction conditions by treatment with CaH2 in
the presence of a ZnX2 catalyst.
7. Caldwell, W. E.; Krauskopf, F. C. J. Am. Chem. Soc.
1929, 51, 2936.
8. Aida, T.; Kuboki, N.; Kato, K.; Uchikawa, W.; Matsuno,
C.; Okamoto, S. Tetrahedron Lett. 2005, 46, 1667.
9. It has been reported that Me2ZnHLi reagent reduces
aldehydes having a a-hydrogen effectively. See Ref. 4.
10. Calas, R.; Bourgeois, P. Bull. Soc. Chim. Fr. 1971, 3263.
11. ZnCl2-Catalyzed hydrosilylation has been reported: Lap-
kin, I. I.; Dvinskikh, V. V. Zh. Obshch. Khim. 1978, 48,
2509; Asymmetric reduction of ketones with polymethyl-
hydrosiloxane in the presence of a chiral zinc catalyst has
been reported: Mimoun, H.; de Saint Laumer, J. Y.;
Giannini, L.; Scopelliti, R.; Floriani, C. J. Am. Chem. Soc.
1999, 121, 6158.
Acknowledgement
12. General procedure for the reduction (or hydrosilylation) of
carbonyl compounds: A mixture of CaH2 (3.0 mmol) and
ZnX2 (10–20 mol %) in THF (10 mL) was stirred for 1 h at
40 °C. To this were added the substrate 1 (2.0 mmol) and
R3SiCl (2.6 mmol) and the mixture was stirred at 40 °C.
After checking the completion of the reaction by TLC
analysis, the mixture was filtered through a pad of Celite
with ether and the filtrate was washed with aqueous 1 M
HCl (for isolation of the alcohol) or saturated aqueous
NH4Cl (for isolation of the silyl ether) and extracted with
ether. The combined organic layers were washed with
saturated aqueous NaHCO3. The following usual work-up
gave the corresponding alcohol 2 or its silyl ether. For
work-up, other appropriate solvents such as hexane and
pentane than ether can be used for filtration and extrac-
tion. After filtration, the resulting cake containing the
remaining CaH2 should be quenched by treatment with 2-
propanol for safe. CaH2 (powder), anhydrous ZnCl2 and
ZnBr2 were purchased from Wako Pure Chemical Indus-
tries, Ltd.
This study was partially supported by the Scientific
Frontier Research Project from the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan.
References and notes
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Borohydrides in Organic Synthesis; VHC, 1991.
2. Ohkuma, T.; Hashiguchi, S.; Noyori, R. J. Org. Chem.
1994, 59, 217.
3. Gao, Y.; Urabe, H.; Sato, F. J. Org. Chem. 1994, 59, 5521;
Gao, Y.; Harada, K.; Hata, T.; Urabe, H.; Sato, F. J. Org.
Chem. 1995, 60, 290.
4. Uchiyama, M.; Furumoto, S.; Saito, M.; Kondo, Y.;
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