Cleavage of a p-cyanobenzyl group from protected alcohols, amines, and thiols using triethylgermyl sodium

Article abstract of DOI:10.1246/cl.2002.1032

Alcohols, amines, and thiols protected with a p-cyanobenzyl group can be easily and quantitatively deprotected using triethylgermyl sodium under mild conditions.

Full text of DOI:10.1246/cl.2002.1032

1032
Chemistry Letters 2002
Cleavage of a p-Cyanobenzyl Group from Protected Alcohols, Amines, and Thiols
Using Triethylgermyl Sodium
Yasuo Yokoyama,ꢀ Shuichi Takizawa,y Masato Nanjo,y and Kunio Mochidaꢀy
Department of Chemistry, Faculty of Science and Technology, Sophia University, 7-1 Kioicho, Chiyoda-ku, Tokyo 102-8554
yDepartment of Chemistry, Faculty of Science, Gakushuin University, 1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588
(Received June 10, 2002;CL-020489)
Table 1. Reactions of p-cyanobenzyl ether (1a) with R3GeM in
HMPA/solvent
Alcohols, amines, and thiols protected with a p-cyanobenzyl
group can be easily and quantitatively deprotected using
triethylgermyl sodium under mild conditions.
Run
R3GeM
Solvent
Product (Yield/%)a
1
2
3
4
5
6
7
8
9
Et3GeNa
00
Hexane
Benzene
Ether
THF
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
75
76
84
91
99
60
55
88
94
82
64
00
Benzyl groups have found extensive use in organic chemistry
for protection of alcohols. The benzyl group from protected
alcohols can be removed by Pd-catalyzed hydrogenation,1
trimethylsilyl iodide (Me3SiI),2 Birch reduction,3 Lewis acids,4
cathodic cleavage,5 and so forth. However, for benzyl ethers
several difficulties in terms of yields, reaction conditions,
reagents, and others associated with their removal depending
upon the alcohols have still remained. These results prompted us
to investigate a p-cyanobenzyl group for the protection of
alcohols instead of the benzyl group. The only cathodic cleavage
of the p-cyanobenzyl group from protected alcohols reported is
not easy for laboratory manipulation.6
On the other hand, organogermyl alkali metal compounds are
both representative nucleophiles and electron transfer reagents.
Their extraordinary nucleophilicity makes them valuable
reagents for introducing triorganogermyl groups into
molecules.7{9 During the course of our study of organogermyl
alkali metals, we found that alcohols protected with a p-
cynaobenzyl group can easily and quantitatively be deprotected
using triethylgermyl sodium under mild conditions.
00
00
Et3GeLi
Et3GeK
Me3GeNa
Bu3GeNa
iPr3GeNa
PhEt2GeNa
10
11
aIsolated yields.
the benzyl group on the yields of 2a under similar conditions was
in the order: p-CN ð99%Þ > o-CN ¼ H (81%) > m-CN (78%).
The reactions of 1a with other reductants under similar conditions
were also examined. The use of Et3SiNa and Et3SnNa resulted in
low yields (51–60%), and conventional reductants such as lithium
naphthalenide (LiNp) and lithium di-tert-butylbiphenyl (LDBB)
proved to give moderate yields (82–84%). These results of
reductants are summarized in Table 2.
Table 2. Reactions of p-cyanobenzyl ether (1a) with reductants
Product (Yield/%)a
First, we examined the reactions of p-cyanobenzyloxy-3-
phenylpropane (1a) as a model compound with triethylgermyl
sodium (Et3GeNa),10 which was prepared by hexaethyldiger-
mane (Et3GeGeEt3) and sodium metal in HMPA/solvent, under
various conditions.
Run
R3GeM
1
2
3
4
5
Et3SiNa
Et3GeNa
Et3SnNa
LiNp
51
99
60
84
82
LDBB
aIsolated yields.
Et3GeNa
(2.4 mol amt.)
Ph(CH2)3OH
Ph(CH2)3O-CH2
CN
50 oC, 5 h
Next, the optimized conditions were applied to various p-
cyanobenzyl ether (1b–i), and the results are summarized in
Table 3.
2a
1a
The p-cyanobenzyl ether (1a) was treated with 2.4 mol
amounts of Et3GeNa in HMPA/1,4-dioxane at 50 ꢁC for 5 h to
give 3-phenylpropanol (2a) in 99% yield. The amount of
Et3GeNa exactly required was 2.4 mol amounts against that of
1a. Lowering the reaction temperature from 50 to 40 ꢁC resulted
in longer reaction times (10 h). At somewhat higher temperature
(60 ꢁC) the reaction completed in only 1 h, but afforded unknown
products besides 2a (84%). Employing a less polar solvent
decreased the yields of 2a: hexane (75%), benzene (76%), ether
(84%), THF (91%). The effect of alkali metal cations (Mþ) of
Et3GeM on the yields of 2a was in the order:
M ¼ Na (91%) > Li (60%) > K (55%). The substituent on the
germanium largely did not influence the yields of 2a. These
results are summarized in Table 1. The effect of the substituent on
Et3GeNa
(2.4 mol amt.)
RO-CH2-
CN
ROH
HMPA/1,4-Dioxane
50 oC
2b-i
1b-i
As shown in Table 3, the substituted p-cyanobenzyl ethers as
protected primary-, secondary-, and olefinic-alcohols when
treated with 2.4 mol amounts of Et3GeNa under similar condi-
tions afforded the corresponding alcohols in very high yields. The
methoxylmethyl-, ethoxylmethyl-, and benzyl ethers-substituted
p-benzyl ether proved to be very effective toward Et3GeNa. The
p-cyanobenzyl group in deprotected diols was also cleaved with
Et3GeNa at room temperature to give the alcohols in good yields.
In all cases, the p-cyanobenzyl ethers shown in Table 3 can be
Copyright Ó 2002 The Chemical Society of Japan

Chemistry Letters 2002
1033
Table 3. Reactions of p-cyanobenzyl ethers (1b–i) with Et3GeNa
(2.4 mol amt.) in HMPA/dioxane at 50 ꢁC
We propose an electron-transfer reaction mechanism for the
debenzylation of p-cyanobenzyl ether with Et3GeNa as depicted
in Scheme 1. Initially, p-cyanobenzyl ether with high electron
affinity is readily reduced by Et3GeNa11 to give a radical anion of
p-cyanobenzyl ether. Et3GeNa is oxidized to give Et3Geꢂ.Then,
subsequent cleavage of the radical anion of p-cyanobenzyl ether
occurs to give an alkoxyl anion and a p-cyanobenzyl radical. The
alkoxyl anion reacts with proton to give the corresponding
alcohol. On the other hand, the p-cyanobenzyl radical easily
abstracts hydrogen to afford p-cyanotoluene. The Et3Geꢂ couples
to give digermane. Actually, the formation of (Et3Ge)2 and p-
cyanotoluene was detected by GC in 90% yield.
Run
RO
Time/h Product, Yield/%
1
2
CH3(CH2)9O (1b)
Ph(CH2)3O (1c)
7.5
5
2b, 87
2c, 99
3
(1d)
(1e)
15
2d, 97
O
16
28
2e, 99
2f, 98
4
5
O
RE-CH2-
RE-CH2-
RE
Ge
+ Et3Ge
CN
RE-CH2-
CN + Et3
CN
CN
tBu
(1f)
O
+
RE
CH2
CH3
6a) CH3OCH2O(CH2)4O (1g)
70
50
2g, 86
2h, 81
H2O
7a) CH3O(CH2)2OCH2O(CH2)4O
REH
solvent
(1h)
CN
CH2
8a)
O(CH ) O(1i)
(CH2)2
CN
45
2g, 50
2 4
2 Et3Ge
Et3Ge-GeEt3
a) r.t.
Scheme 1.
easily and quantitatively converted into the corresponding
alcohols.
A typical procedure is as follows: A mixture of 0.60 mol/l
Et3GeNa (0.4 ml),10 prepared from Et6Ge2 and Na in HMPA, was
added to a solution of p-cyanobenzyloxy-3-phenylpropane 1a
(0.10 mmol) in dioxane (0.5 ml) at 50 ꢁC. After being stirred for
5 h, silica gel (Wako gel C 200) and hexane were added to the
solution. The mixture was filtered with silica gel and the filtrate
was evaporated. The residue was chromatographed (Merck silica
gel 60) with 4 : 1 benzene-ethyl acetate to give phenylpropanol
(0.10 mmol, 99%).
A combination of a p-cyanobenzyl substituent as the
protecting group with Et3GeNa was applied to amines and thiols.
The p-cyanobenzyl group from protected amines and thiols was
removed with Et3GeNa to give the corresponding amines and
thiols. Cleavage of their p-cyanobenzyl groups with Et3GeNa at
50 ꢁC required a long time compared with that of benzyl ethers.
These results of amines are summarized in Table 4.
Et3GeNa
R2
N CH2
(2.0 mol amt.)
R1
R1R2NH
CN
References
HMPA/THF
60 oC
1
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shown in Table 4.
2
3
4
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Table 4. Reactions of p-cyanobenzyl amines with Et3GeNa at 50 ꢁC
Run
R1, R2
Time/h
Product, Yield/%a
1
2
3
4
5
R1=Ph, R2=Bu
R1=1-Np, R2=Et
R1, R2=Ph
4
43
68
48
92
99
97
98
80
39
5
6
7
R1=1-Np, R2=Ph
R1=C18H37, R2=Me
8
9
For exampoles see a) D. A. Armitage, in ‘‘Comprehensive Organome-
tallic Chemsitry,’’ ed. by G. Wilkinson, F. G. A. Stone, and E. W. Abel,
Pregamon, New York (1982), Vol. 2, Chap. 9, pp 99–104. b) H.
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‘‘Organic Compounds of Germanium,’’ Interscience, New York (1971).
c) K. Mochida, Yuki Gosei Kagaku Kyokaishi, 49, 288 (1991).
aIsolated yields.
p-Cyanobenzyl substituent as a protecting group and the
Et3GeNa system are also applied to thiols, even for a long time,
depending on the substrates.
Et3GeNa
(2.4 mol amt.)
RS-CH2-
CN
RSH
HMPA/1,4-Dioxane
50 oC
R = CH3(CH2)9
Ph(CH2)3
91% (for 5 h)
95% (for 30 h)
10 E. J. Bulten and J. G. Noltes, J. Organomet. Chem., 29, 409 (1971).
11 K. Mochida and T. Kugita, Main Group Met. Chem., 1988, 215.