Use of CaH2 as a reductive hydride source: Reduction of ketones and imines with CaH2/ZnX2 in the presence of a Lewis acid

Article abstract of DOI:10.1016/j.tetlet.2005.01.058

A new combination reagent of CaH₂/ZnX₂ effectively reduced a variety of ketones and imines to the corresponding alcohols and amines, respectively, in the presence of a catalytic amount of a Lewis acid such as Ti(O-i-Pr)₄, Al(O-i-Pr)₃, B(O-i-Pr)₃ and ZnF₂. Published by Elsevier Ltd.

Full text of DOI:10.1016/j.tetlet.2005.01.058

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1667–1669
Use of CaH2 as a reductive hydride source: reduction of ketones and
imines with CaH2/ZnX2 in the presence of a Lewis acid
Toshio Aida, Norikatsu Kuboki, Kenji Kato, Wataru Uchikawa,
Chikashi Matsuno and Sentaro Okamoto*
Department of Applied Chemistry, Kanagawa University, 3-27-1 Rokkakubashi, Kanagawa-ku, Yokohama 221-8686, Japan
Received 10 December 2004; revised 11 January 2005; accepted 13 January 2005
Available online 28 January 2005
Abstract—A new combination reagent of CaH2/ZnX2 effectively reduced a variety of ketones and imines to the corresponding alco-
hols and amines, respectively, in the presence of a catalytic amount of a Lewis acid such as Ti(O-i-Pr)4, Al(O-i-Pr)3, B(O-i-Pr)3 and
ZnF2.
Ó 2005 Published by Elsevier Ltd.
Reduction with metal hydride reagents has been widely
utilized as a routine protocol in organic synthesis and
numerous hydride compounds and reagent systems have
been developed and are used. Recently, efforts have been
made to utilize LiH as a hydride source, which is a basi-
cally inert metal hydride, inexpensive, stable to handle
and environmentally benign. Thus, in 1994 Noyori and
co-workers demonstrated that LiH could be used as an
agent for carbonyl reduction in the presence of TMSCl
and a catalytic amount of ZnX2.1 At the same time, Sato
and co-workers showed that reaction of alkynes or con-
jugated dienes with ZnI2/2LiH reagent underwent
hydrometallation in the presence of Cp2TiCl2.2 Genera-
tion of dialkylzinc hydride ate complexes from LiH and
ZnR2 has been also reported.3 These results prompted
us to investigate use of CaH2 as a reductive hydride
source, which is also a basically inert, inexpensive and
stable metal hydride and is usually used as a drying
agent. Herein we report that a reagent combination of
CaH2 and ZnX2 reduces effectively ketones and imines
to the corresponding alcohols and amines in the pres-
ence of a catalytic amount of a Lewis acid.
under various reaction conditions (Table 1).4,5 Thus, a
mixture of CaH2 (powder, 1.3 mmol) and anhydrous
ZnX2 (0.2–1.4 mmol) in THF (3 mL) was stirred at
room temperature or 40 °C for 1.5 h. To this were added
a solution of ketone 1a or the imine 2a (1.0 mmol) in
THF (1mL) and the additive. The resulting mixture
was stirred for 12 h at room temperature or 40 °C.
As revealed from Table 1, it was found that CaH2 could
act as a reductive hydride source: with a 1.3:1.4 mixture
of CaH2 and ZnBr2, a trace amount of 3a was obtained
by the reaction of 1a (entry 1) and imine 2a was effec-
tively reduced to amine 4a (entry 9). However, a
1.3:1.2 mixture of CaH2 and ZnBr2 did not reduce 1a
and 2a at all (entries 2 and 10). CaH2 in the presence
of a catalytic amount of ZnBr2 and a stoichiometric
amount of TMSCl reduced 1a in THF; however, the
reaction did not complete (entry 3). We found that in
the presence of a catalytic amount of Ti(O-i-Pr)4 an
essentially inert 1.3:1.2 mixture of CaH2 and ZnX2 could
reduce 1a and 2a quantitatively to afford 3a and 4a,
respectively (entries 5–7 and 11), where ZnCl2, ZnBr2,
ZnI2 could be used equally. However, the reaction with
ZnF2 did not proceed at all (entry 8).
To investigate the possibility of the use of CaH2 as a
reductive hydride source, we carried out the reactions
of acetophenone (1a) and an imine 2a derived from
benzaldehyde and benzyl amine with CaH2 and ZnX2
With these results, we studied the stoichiometry of CaH2
and ZnX2 in the reaction. As can be seen from Eq. 1, it
was found that the reduction was stoichiometric on both
CaH2 and ZnX2: thus, a 2:1and 1:1mixture of CaH
2
and ZnBr2 reduced 1a in a stoichiometric fashion to
the amount of ZnBr2. However, a 1:2 mixture of CaH2
and ZnBr2 was nearly inert.
Keywords: Calcium hydride; Reduction.
*
Corresponding author. Tel.: +8145 481566;1 fax: +8145 431
9770; e-mail: okamos10@kanagawa-u.ac.jp
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.01.058

1668
T. Aida et al. / Tetrahedron Letters 46 (2005) 1667–1669
a
Table 1.
CaH2 (1.3 equiv)
ZnX2 (0.2~1.4 equiv)
H
R
X
X
additive
Ph
Ph
R
THF, r.t~40 oC
3a: X = O, R = Me
4a: X = N-Bn, R = H
1a: X = O, R = Me
2a: X = N-Bn, R = H
12 h
Entry
Substrate
ZnX2 (equiv)
Additive (mol%)
Product
Recovered 1 or 2b, %
Yieldb, %
1
1a
1a
1a
1a
1a
1a
1a
1a
2a
2a
2a
ZnBr2 (1.4)
ZnBr2 (1.2)
ZnBr2 (0.2)
ZnBr2 (0.2)
ZnBr2 (1.2)
ZnCl2 (1.2)
ZnI2 (1.2)
—
—
3a
3a
3a
3a
3a
3a
3a
3a
4a
4a
4a
<5
0
ꢀ90%
2
Quant
60c
3
TMSCl (150)
TMSCl (150)
Ti(O-i-Pr)4 (5)
Ti(O-i-Pr)4 (5)
Ti(O-i-Pr)4 (5)
Ti(O-i-Pr)4 (5)
—
40c
4d
5
0c
Quantc
Quant
Quant
Quant
0
0
6
0
7
0
Quant
8
ZnF2 (1.2)
ZnBr2 (1.4)
ZnBr2 (1.2)
ZnBr2 (1.2)
9
Quant
0
Quant
0
10
11
—
Ti(O-i-Pr)4 (5)
Quant
0
a The reactions were performed at 40 °C except for entries 3 and 4 (room temperature).
b Yields were determined by 1H NMR analysis of the crude residue using an internal standard.
c Elongation of the reaction time (48 h) did not improved the yield.
d The reaction was carried out in toluene.
CaH2/ZnBr2
Table 2.
OH
Me
O
Ti(O-i-Pr)4 (5 mol%)
THF, 40 oC 12 h
CaH2 (1.3 equiv)
ZnBr2 (1.2 equiv)
additive (5 mol%)
THF, 40 oC 12 h
H
X
Ph
Ph
Me
X
3a
1a
R
Ph
Ph
R
ð1Þ
equiv.
yield , %
3a: X = O, R = Me
4a: X = N-Bn, R = H
1a: X = O, R = Me
2a: X = N-Bn, R = H
CaH2 ZnBr2
57
8
1.3
0.6
0.6
0.6
1.2
0.6
Entry
Substrate
Additive
Product
a
Yield, %
Quant (92)b
61
1Ketone
1a
Ti(O-i-Pr)4
Al(O-i-Pr)3
B(O-i-Pr)3
ZnF2
3a
3a
3a
3a
4a
4a
4a
4a
2
3
4
5
6
7
8
1a
1a
1a
Quant
Quant
Quant
Quant (86)b
Quant
78c
The results shown in Table 1 and Eq. 1 may be
explained by the following assumptions: (i) CaH2 and
ZnX2 except for ZnF2 can make a complex(es) in a 1:1
ratio when one or more equivalent of CaH2 was mixed
with ZnX2. A 1:2 mixture of CaH2 and ZnX2 may make
a different species. (ii) A 1:1 complex(es) of CaH2 and
ZnX2 thus generated is essentially inert for reduction
of ketones and imines. Ti(O-i-Pr)4 may act as a Lewis
acid activating the substrates in a catalytic manner to
undergo the reduction with a CaH2/ZnX2 (1:1) reagent.6
Imine 2a
Ti(O-i-Pr)4
Al(O-i-Pr)3
B(O-i-Pr)3
ZnF2
2a
2a
2a
Quant
a Unless otherwise indicated, yields were determined by 1H NMR
analysis of the crude residue using an internal standard.
b Isolated yield.
c 22% of 2a was recovered.
Based on these hypotheses we carried out the reaction
with other Lewis acid catalysts (Table 2). As expected,
in addition to Ti(O-i-Pr)4 other metal alkoxides
(5 mol%) such as Al(O-i-Pr)3 and B(O-i-Pr)3 could effec-
tively catalyze the reduction of 1a and 2a with CaH2/
ZnBr2 (1.3:1.2). Similarly, ZnF2 catalyzed the reduction
of ketone and imine (entries 4 and 8).6
As revealed from Table 3, diaryl and aryl alkyl ketones
and cyclic ketones could be effectively reduced. Alde-
hydes and acyclic aliphatic ketones, however, were not
good substrates. As shown in entries 1and 5, ZnCl as
2
well as ZnBr2 could be equally used for the reduction.
CaH2(2.6 eq)
ZnBr2 (2.4 eq)
Ti(O-i-Pr)4 (0.05 eq)
With these results in hand, we chose a reagent system
CaH2/ZnBr2/Ti(O-i-Pr)4 (1.3:1.2:0.05) and carried out
the reduction of other ketones and imines.7 The results
of the reactions with the representative carbonyl com-
pounds and imines are summarized in Tables 3 and 4,
respectively.
OH
O
Ph
Ph
Ph
ð2Þ
Ph
THF, 40 oC 12 h
OH
91% yield
only meso
O

T. Aida et al. / Tetrahedron Letters 46 (2005) 1667–1669
1669
Table 3.
In summary, herein we have reported that CaH2 could
be used as a reductive hydride source together with
ZnX2 and a catalytic amount of a Lewis acid, the re-
agent system of which could perform the reduction of
ketones and imines to the corresponding alcohols and
amines in good yield. To our knowledge, this is the first
example of a CaH2-based reduction of organic mole-
cules except for those through boron hydride formation
and reduction of sulfate to sulfide.8,9
CaH2/ZnBr2/Ti(O-i-Pr)4
(1.3:1.2:0.05)
OH
R2
O
R1
R1
THF, 40 oC, 12 h
R2
3
1
Entry
R1
R2
Yield of 3a, %
1Ph
2
n-Bu
Ph
86 (85)b
Ph
p-BrC6H4
p-MeOC6H4
90
92
90
3
CH3
CH3
4
b
5
–(CH2)7–
–(CH2)5–
CH3(CH2)6
Ph
91(91)
38c,d
Tracec
Acknowledgments
6
7
CH3
H
We thank the Ministry of Education, Culture, Sports,
Science and Technology (Japan) for financial support.
8
Complex mixturec
a Isolated yield unless otherwise indicated.
b ZnCl2 was used instead of ZnBr2.
c Determined by 1H NMR analysis of the crude residue using an
internal standard.
References and notes
d 62% of 1 was recovered.
1. Ohkuma, T.; Hashiguchi, S.; Noyori, R. J. Org. Chem.
1994, 59, 217.
2. 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.
3. Uchiyama, M.; Furumoto, S.; Saito, M.; Kondo, Y.;
Sakamoto, T. J. Am. Chem. Soc. 1997, 119, 11425.
4. CaH2 (powder), anhydrous ZnCl2, ZnBr2, ZnI2 and ZnF2
were purchased from Wako Pure Chemical Industries, Ltd.
5. Under similar conditions the reaction of CaH2 with MgBr2
in the presence or absence of Ti(O-i-Pr)4 did not reduce 1a
at all.
6. Although formation of metal hydrides derived from Ti(O-i-
Pr)4, B(O-i-Pr)3 or Al(O-i-Pr)3 cannot be ruled out, the fact
that ZnF2, which was inert in the presence of Ti(O-i-Pr)4,
was an effective catalyst as well as Ti(O-i-Pr)4 and activated
the reaction with CaH2/ZnBr2 (1.3:1.2) may suggest a role
of these metal alkoxide as a Lewis acid. In addition, the
reaction of 1a and CaH2 (1.3 equiv) with 1.3 equiv of
Ti(O-i-Pr)4, B(O-i-Pr)3 or Al(O-i-Pr)3 in the absence of
ZnX2 did not proceed at all.
Table 4.
CaH2/ZnBr2/Ti(O-i-Pr)4
(1.3:1.2:0.05)
R2
R3
R2
R3
HN
R1
N
THF, 40 oC
R1
4
2
Entry R1
R2
R3
Yield of 4a, %
b
1Ph
Bn
H
86 (85)
2
3
4
5
6
7
8
Ph
Ph
n-Pr
Ph
H
H
H
H
H
H
83
92 (90)b
91
85
p-BrC6H4
2-Furyl
Bn
Bn
(E)-PhCH@CH CH2CH@CH2
81
84
n-C5H11
Ph
Bn
Bn
CH3 91
a Isolated yield.
b ZnCl2 was used instead of ZnBr2.
7. General procedure: a suspension of CaH2 (1.3 mmol) and
ZnX2 (1.2 mmol) in THF (3 mL) was stirred for 1.5 h at
40 °C. To this were added a solution of ketone or imine
(1.0 mmol) in THF (1 mL) and Lewis acid (0.05 mmol).
The resulting mixture was stirred for 12 h at 40 °C. After
being cooled to room temperature, the mixture was slowly
poured into aqueous saturated NH4Cl. The mixture was
extracted with ether or AcOEt, dried over MgSO4 and
concentrated.
The reduction of benzil by the present method provided
meso-hydrobenzoin exclusively (Eq. 2). The stereoselec-
tivity can be explained by considering the chelation con-
trol mechanism similar to that proposed for the
reduction with other metal hydrides.
As listed in Table 4,
a
CaH2/ZnX2/Ti(O-i-Pr)4
8. It has been reported that CaH2 and B(OMe)3 gave a
complex at 215 °C, which reduced carbonyl compounds:
Hesse, Gerhard; Jager; Horst Chem. Ber. 1959, 92, 2022;
Formation of B2H6 by the reaction of CaH2 and BF3 at
120 °C has been reported: Mikheeva, V. I.; Fedneva, E. M.;
Alpatova, V. I. Dok. Akad. Nauk SSSR 1959, 131, 318;
Formation of Ca(BH4)2 from CaH2 and Et3NBH3 has
been reported: Koester, R; Huber, H. Inorg. Synth. 1977,
17, 1 7.
(1.3:1.2:0.05) reagent could reduce a variety of imines
in excellent yields. Thus, imines derived from aromatic
and aliphatic aldehydes were cleanly converted to the
corresponding amines. Imines having a benzyl, alkyl,
or aromatic group as an N-substituent were good sub-
strates. Functional groups such as bromo and alkenyl
moieties present in the substrate were tolerant as shown
in entries 4 and 6. Ketimine was also reduced in excellent
yield (entry 8). ZnCl2 was again found to be equally
effective as ZnBr2 (entries 1and 3).
9. Caldwell, W. E.; Krauskopf, F. C. J. Am. Chem. Soc. 1929,
51, 2936.