An efficient method for one-pot reductive cleavage of acetals to primary alcohols using a bimetal redox couple CoCl2.6H2O-Zn

Article abstract of DOI:10.2174/157017809789869456

Acyclic or cyclic O, O-acetals and O, S-acetals underwent reductive cleavage to give primary alcohols efficiently on treatment with Zn-CoCl ₂.6H₂O-bimetal redox system in dry tetrahydrofuran at ambient temperature to give good to excellent yields.

Full text of DOI:10.2174/157017809789869456

568
Letters in Organic Chemistry, 2009, 6, 568-572
An Efficient Method for One-Pot Reductive Cleavage of Acetals to
Primary Alcohols Using a Bimetal Redox Couple CoCl2.6H2O-Zn
Kuladip Sarma and Amrit Goswami*
Synthetic Organic Chemistry Division, North East Institute of Science and Technology, (a constituent establishment of
CSIR, Govt. of India), Jorhat-785006, India
Received March 09, 2009: Revised August 08, 2009: Accepted August 11, 2009
Abstract: Acyclic or cyclic O,O-acetals and O,S-acetals underwent reductive cleavage to give primary alcohols
efficiently on treatment with Zn-CoCl2.6H2O-bimetal redox system in dry tetrahydrofuran at ambient temperature to give
good to excellent yields.
Keywords: Alcohols, acetals, bimetal redox system, deprotection, hydroxy ether, reductive cleavage.
INTRODUCTION
acetal to prepare 2S,3S-epoxybutan-1-ol which is used as
intermediate in the synthesis of erythromycin antibiotic. To
our knowledge, there are no reports for direct preparation of
primary alcohols of the corresponding aldehydes from their
acetals, but to the hydroxy ethers only. The positive role of
Lewis acid in activating different hydrides in the reductive
cleavage of acetals tempted us to explore the reactivity of a
Lewis acid in combination with a more electropositive metal
which can form a bimetal redox couple in a suitable dry
solvent to avoid expensive and explosive hydride reagents.
Acetals and thioacetals are extremely important
intermediates in various synthetic routes. They are prepared
as protecting groups of aldehydes [1] especially in the total
synthesis of complex natural products, pharmaceuticals,
phytopharmaceuticals, fragrances and also in lacquer
industries as intermediates or as end products [2-8].
Although 1,2-diacetals have been known since 1938 [9],
considerable interests in the application of these compounds
have been received only in the recent years [10]. These are
generally stable under acidic conditions. However, it may be
noted here that benzylidene acetals have a special appealing
feature of readiness to undergo reductive cleavage to
regioselectively protected alcohols on manipulation of
reaction condition [11]. Thus, it was revealed in subsequent
studies that activation of different conventional reducing
agents by Lewis acids favours chemo, stereo and
regioselectivity in reductive cleavage of acyclic as well as
cyclic acetals [12]. Facilitation by Lewis acids in such
methodologies turned out to be especially fruitful in
carbohydrate chemistry where reductive opening of acetals
favours protective group manipulation.
RESULTS AND DISCUSSION
Bimetallic systems [21] are very attractive reagents for
various syntheses of organic compounds. In our earlier
studies [22] on selective reduction of aldehydes to primary
alcohols, a bimetal redox couple Zn-CoCl2.6H2O was
developed. Although acetalization of aldehydes using
anhydrous cobalt chloride is reported [23], regeneration of
aldehydes or other carbonyls from their respective acetals
using such reagents or to their corresponding reduced
alcoholic form has not yet so far been reported.
When this system was applied consisting of Zn-
CoCl2.6H2O in 3:1 molar ratio [22] to trans-2-butenal diethyl
acetal ‘1a’, it straightway gave trans-2-buten-1-ol (1b, Table
1) in very good yield (81%) without affecting the C=C bond.
Accordingly a series of open chain O,O-acetals were treated
with this redox couple under similar condition in dry THF.
All these acetals were found to give primary alcohols in
excellent yields (81-92%) (1b-7b, Table 1) in 4-6 hours.
After successful syntheses of primary alcohols directly from
open chain acetals using Zn-CoCl2.6H2O bimetal redox
couple, the system was applied to a second series of cyclic
acetals under similar condition. The system was also found
to be effective in case of these cyclic O,O-diacetals to give
their corresponding primary alcohols in 78-93% yields (1b-
8b, Table 2) at room temperature in 4-6 hours.
Hydroxy ethers are important compounds as perfume
chemicals or as raw materials for perfumes [13]. In order to
have such specific compounds of commercial value and also
for synthetic purposes, acetals or ketals are transformed into
them through regioselective reductive cleavage using
activated
hydrides
[14],
BF3.Et2O/Me3SiH
[11a],
Li/C10H8/THF [15], activated zinc in methanol [16], silane-
Rh-PPh3 [17], CF3COOH/triethyl silane [18], Co(CO)8 under
synthesis gas [19] etc. These reagents however are not
effective to cleave the acyclic or cyclic O,O-acetals or O,S-
acetals directly to the primary alcohols of the corresponding
aldehydes. In our continued effort on chiral epoxidation of
olefins [20], we were looking for an efficient system to have
trans-2-buten-1-ol directly from trans-2-butenal diethyl
Finally the system was examined with a few cyclic O,S-
diacetals in a similar manner, but at 60 °C and ended up with
encouraging yields (77-91%) of primary alcohols in 3-6
hours (1b-8b, Table 3) without any accompanying products
*Address correspondence to this author at the Synthetic Organic Chemistry
Division, North East Institute of Science and Technology, (a constituent
establishment of CSIR, Govt. of India), Jorhat-785006, India; Tel: +91-376-
2372948; Fax: +91-376-2370011; E-mail: amritg_2007@rediffmail.com
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

An Efficient Method for One-Pot Reductive Cleavage of Acetals
Letters in Organic Chemistry, 2009, Vol. 6, No. 7
569
Table 1. In-Situ Formation of Alcohols by the Reductive Cleavage of Open Chain O,O-Acetals Using Cobalt Chloride Hexahydrate
with Zinc Dust in Tetrahydrofuran at Room Temperaturea
OR
CoCl2.6H2O, Zn
OR
1a-7a
R1CH2OH
THF, RT
R1
1b-7b
Productsb
1b-7b
Time
(hours)
Entry
Yieldc (%)
Reference
Substrates
1a-7a
1
OEt
4
81
[26a]
CH2OH
OEt
C4H9
CH2OH
CH2OH
CH2OH
2
3
4
OMe
OMe
6
6
4
83
82
90
[26b]
[26c]
[26d]
C4H9
OMe
OMe
C10H21
C10H21
OMe
OMe
5
CH2OH
4
91
[26e]
OMe
OMe
MeO
MeO
6
7
4
4
92
81
[26f]
[26g]
OMe
OMe
CH2OH
OMe
OMe
CH2OH
aThe reactions were run with the open chain O,O-acetals (8-10 mmol), cobalt chloride hexahydrate (2.37 g, 10 mmol), zinc dust (1.96 g, 30 mmol) at room temperature for 4-6 hours.
bThe products were characterized from their respective IR, NMR and mass spectroscopic data and comparison with literature records.
cIsolated yields of products.
Table 2. In-Situ Formation of Alcohols by the Reductive Cleavage of Cyclic O,O-Acetals Using Cobalt Chloride Hexahydrate with
Zinc Dust in Tetrahydrofuran at Room Temperaturea
O
CoCl2.6H2O, Zn
RCH2OH
O
THF, RT
R
8a-15a
1b-8b
Productsb
1b-8b
Entry
Time (hours)
Yieldc (%)
Reference
Substrates
8a-15a
1
4
78
[26a]
CH2OH
O
O
C4H9
CH2OH
2
5
83
[26b]
O
O
C5H11

570 Letters in Organic Chemistry, 2009, Vol. 6, No. 7
Sarma and Goswami
(Table 2). Contd…..
Productsb
1b-8b
Entry
Time (hours)
Yieldc (%)
Reference
Substrates
8a-15a
3
C10H21
CH2OH
4
84
93
[26c]
O
O
C11H23
4
5
4
4
[26d]
[26e]
CH2OH
O
O
CH2OH
92
O
O
MeO
MeO
6
7
4
4
88
81
[26f]
[26g]
O
CH2OH
O
CH2OH
O
O
8
6
80
[26h]
CH2OH
O
O
aThe reactions were run with the cyclic O,O-acetals (8-10 mmol), cobalt chloride hexahydrate (2.37 g, 10 mmol), zinc dust (1.96 g, 30 mmol) at room temperature for 4-6 hours.
bThe products were characterized from their respective IR, NMR and mass spectroscopic data and comparison with literature records.
cIsolated yields of products.
Table 3. In-Situ Formation of Alcohols by the Reductive Cleavage of Cyclic O,S-Acetals Using Cobalt Chloride Hexahydrate with
Zinc Dust in Tetrahydrofuran at 60 °Ca
S
CoCl2.6H2O, Zn
RCH2OH
O
THF, 60 0C
R
16a-23a
1b-8b
Productsb
1b-8b
Entry
Time (hours)
Yieldc (%)
Reference
Substrates
16a-23a
1
5
77
[26a]
CH2OH
S
O
C4H9
CH2OH
2
3
5
5
83
84
[26b]
[26c]
S
O
C5H11
C10H21
CH2OH
S
O
C11H23

An Efficient Method for One-Pot Reductive Cleavage of Acetals
Letters in Organic Chemistry, 2009, Vol. 6, No. 7
571
(Table 3). Contd…..
Productsb
1b-8b
Entry
Time (hours)
Yieldc (%)
Reference
Substrates
16a-23a
4
4
91
[26d]
CH2OH
S
O
5
CH2OH
4
90
[26e]
S
O
MeO
MeO
6
7
4
3
88
81
[26f]
[26g]
O
CH2OH
S
CH2OH
S
O
8
6
81
[26h]
CH2OH
S
O
aThe reactions were run with the cyclic O,S-acetals (8-10 mmol), cobalt chloride hexahydrate (2.37 g, 10 mmol), zinc dust (1.96 g, 30 mmol) at 60 °C for 3-6 hours.
bThe products were characterized from their respective IR, NMR and mass spectroscopic data and by comparison with literature data.
cIsolated yields of products.
of hydroxy ethers. As observed earlier, the C=C double bond
(1a, Table 1) and the ether linkage (5a, Table 1) were found
to be resistant towards the system at room temperature. The
hydrogen source for this reduction is believed to be from the
water of crystallization [24] of CoCl2.6H2O.
1,1-dimethyl acetal ‘6a’ (1.66 g, 10 mmol) in dry
tetrahydrofuran solvent (10 mL). The mixture was then
stirred at room temperature for 4 hours. The progress of the
reaction was monitored from time to time on TLC. At the
end, the reaction mixture was filtered and washed the residue
with THF (3 x10 mL). The filtrate containing the organic
layer was concentrated in rotavapor and 20 mL of ethyl
acetate was added to it. The organic layer was then
sufficiently washed with NaHCO3 solution (5%, 10 mL X 3)
and the two layers were separated. The extract was dried
over anhydrous Na2SO4 and then solvent was removed under
reduced pressure. The pure alcohol 2-phenyl ethanol ‘6b’
(1.1 g, 90% yield) was purified from the crude reaction
mixture as colourless liquid by column chromatography
using 5% ethyl acetate: hexane, 1H NMR (300 MHz,
CDCl3): ꢀH 1.99 (b, 1H, CH2OH), 2.82 (t, 2H, J = 6.63 Hz,
PhCH2CH2), 3.79 (t, 2H, J = 6.63 Hz, CH2CH2OH), 7.19-
7.32 (m, 5H, Ar-H, Ph); 13C NMR (75 MHz, CDCl3): ꢀC
38.86 (PhCH2CH2), 63.35 (CH2CH2OH), 126.18, 128.29,
128.42, 128.78, 129.05, 138.27 (6 X C, Ph). ꢁmax (neat/cm-1):
3340, 3079, 3010, 2936, 2916. Anal. calcd. for C8H10O: C,
78.69; H, 8.19. Found C, 78.62; H, 8.21. MS (EI) m/z = 122
[M+]. Applying the same procedure, all other acetals 1a-23a
were converted to their respective primary alcohols 1b-8b at
25-60 °C in 3-6 hours and then characterized from their
respective NMR, IR, CHN, GC and mass spectroscopic data.
To support this path, cobalt chloride hexahydrate was
made anhydrous following standard procedure [25].
Anhydrous CoCl2 with metallic zinc in dry THF, however,
did not give any primary alcohol even after 30 hours from
the corresponding aldehyde. This has clearly indicated the
involvement of water of crystallization of cobalt chloride
hexahydrate as the hydrogen source. The reaction proceeds
initially via intermediacy of aldehyde (isolated in trace
amount) from the acetal. The aldehyde formed was
subsequently reduced to the corresponding primary alcohol
by single electron transfer [22] from Co(0) generated in situ
from Co(II) by Zn(0).
In conclusion, we have established a very mild, safe and
efficient method for one pot reductive cleavage of open
chain O,O-acetals as well as cyclic O,O and O,S-acetals
directly to primary alcohols with very good yields. The
method is believed to be an alternative of expensive and
explosives hydride reagents.
TYPICAL EXPERIMENTAL PROCEDURE
ACKNOWLEDGMENTS
In a 50 mL round bottomed flask, CoCl2.6H2O (2.37 g,
10 mmol) and zinc powder (1.96 g, 30 mmol) were mixed
together with subsequent addition of phenyl acetaldehyde-
We gratefully acknowledge the Department of Science &
Technology, New Delhi for financial support and Dr. P. G.

572 Letters in Organic Chemistry, 2009, Vol. 6, No. 7
Sarma and Goswami
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