Dehydrogenative silylation process of organic compounds having active hydrogen

A dehydrogenative silylation process of organic compounds having active hydrogen which comprises reacting an organic compound having active hydrogen with t-butyldimethylsilane in the presence of a catalyst which is a metal of Group VIII of the periodic table or its compound. The reaction may be carried out in a solvent. When the organic compound is a strongly acidic compound, the reaction may be carried out without use of any catalyst.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
This invention relates to a novel dehydrogenative silylation process 
wherein a tert-butyldimethylsilyl is introduced into organic compounds. 
2. Description of the Prior Art 
In recent trends for the preparation of .beta.-lactam antibiotics or 
prostaglandins, an --NH group and/or --OH group are usually protected with 
a t-butyldimethylsilyl group. This is because the protective group is 
resistant to the Grignard reaction, the Wittig reaction, diisobutyl 
aluminum hydride reduction and the Jones oxidation but can be very readily 
eliminated by the attack of F ions (see T. N. Saltzman et al., J. Am. 
Chem. Soc. 102, 6161 (1980)). 
Silylating agents conventionally used to protect active hydrogen with a 
t-butyldimethylsilyl group are a chlorosilane of the formula, 
(CH.sub.3).sub.3 CSi(CH.sub.3).sub.2 -Cl, without exception. The reason 
why this chlorosilane is utilized for this purpose is believed due to the 
fact that studies in this field have been made mainly by the Corey 
procedure (E. J. Corey et al, J. Am. Chem. Soc., 94, 6190 (1972)). 
The use of the tert-butyldimethylchlorosilane has the following drawbacks: 
solid quaternary ammonium salts secondarily produced during the silylation 
reaction have to be removed; since the chlorosilane causes reactor 
materials, particularly iron, to be corroded, a glass-lined reactor must 
be used; and the t-butyldimethylchlorosilane is solid at room temperature 
and is rather difficult to handle. 
SUMMARY OF THE INVENTION 
It is accordingly an object of the invention to provide a novel 
dehydrogenative silylation process which overcomes the drawbacks of the 
prior art processes by the use of t-butyldimethylsilane which is liquid at 
normal temperatures, is corrosion-free and is easy in handling. 
It is another object of the invention to provide a novel dehydrogenative 
silylation process whereby side products except for hydrogen are not 
formed and any specific removal procedure is not necessary as in the prior 
art processes. 
It is a further object of the invention to provide a silylation process for 
protecting organic compounds having active hydrogen in a high efficiency. 
The above objects can be achieved, according to the invention, by a 
dehydrogenative silylation process which comprises reacting 
tert-butyldimethylsilane of the formula, (CH.sub.3).sub.3 
CSiH(CH.sub.3).sub.2, and an organic compound having active hydrogen 
reactive with the t-butyldimethylsilane at a temperature of from 
20.degree. C. to 200.degree. C. The above reaction should preferably be 
carried out in the presence of a catalyst for the silylation.

DETAILED DESCRIPTION AND EMBODIMENTS OF THE INVENTION 
In the silylation process of the invention, it is essential to use 
tert-butyldimethylsilane. The t-butyldimethylsilane is a compound which 
has a boiling point of 82.degree. C. and is liquid at normal temperatures. 
This compound is prepared in large amounts without use of expensive 
tert-butyl lithium according to the following reaction sequence 
##STR1## 
In the above formula, t-Bu represents a tertiary-butyl group. 
The organic compounds which are reacted with the t-butyldimethylsilane 
should have active hydrogen in the molecule. Such active hydrogen means a 
hydroxyl group, an amino group, a carboxyl group or the like. These groups 
may be silylated according to the process of the invention in the 
following manner. 
(1) Silylation of alcohols 
##STR2## 
wherein R represents a linear or branched alkyl group having from 1 to 10 
carbon atoms, an aryl group such as phenyl, tolyl, xylyl or the like, an 
aralkyl group such as benzyl, phenylethyl, methylphenyl or the like. These 
groups may be unsubstituted or substituted with a halogen atom, an ether 
group or the like. The halogen atom includes, chlorine bromine, iodine or 
fluorine. 
(2) Silylation of primary and secondary amines 
##STR3## 
wherein R.sup.1 and R.sup.2 have, respectively, the same meaning as 
defined with respect to R provided that R.sup.2 is hydrogen when primary 
amines are used for silylation. 
(3) Silylation of organic acids 
EQU R.sup.3 -COOH+t-BuSiH(CH.sub.3).sub.2 .fwdarw.R.sup.3 
COO-Si(CH.sub.3).sub.2 t-Bu 
wherein R.sup.3 has the same meaning as defined with respect to R. 
Specific examples of the organic compounds which are particularly suitable 
and useful for industrial purposes include alcohols such as 
3-phenyl-1-propanol, benzyl alcohol, .alpha.-methylbenzyl alcohol, 
cyclohexanol and the like; amines such as morpholine, benzylamine, 
.alpha.-methylbenzylamine, 4-hydroxymethyl-2-azetidinone and the like; and 
organic acids such as 3-phenylpropionic acid, 2-methylbutanoic acid and 
the like. Of these, 4-hydroxymethyl-2-azetidinone is preferred although 
the above-specified compounds are all useful. 
The reaction between t-butyldimethylsilane and organic compounds having 
active hydrogen proceeds at a temperature of from 20.degree. C. to 
200.degree. C., preferably from 40.degree. to 150.degree. C. 
This reaction should preferably be carried out in the presence of a 
catalyst which is a metal of Group VIII of the periodic table or a 
compound of the metal. Examples of the catalyst include Ru, Rh, Pd, 
Ru-carbon, Rh-carbon, Pd-carbon, PdCl.sub.2, [Pd(.pi..sup.3 -C.sub.3 
H.sub.5)Cl].sub.2, 
##STR4## 
and the like. Of these, Pd(II) complexes are preferred. This is because 
these complexes are reduced with t-butyldimethylsilane during the reaction 
to precipitate metallic Pd, which has very high catalytic activity for the 
silylation. In addition, Pt and platinum compounds such as H.sub.2 
PtCl.sub.6 may also be used, but they are not favorable when compounds to 
be silylated have unsaturated bonds such as double or triple bonds in the 
molecule. This is because such unsaturated bonds react with 
t-butyldimethylsilane thereby causing hydrosilation. The amount of the 
catalyst is generally in the range of from 0.12 mole % to 20 mole %, 
preferably from 1 to 10 mole %, based on the organic compound to be 
silylated. 
The silylation reaction proceeds smoothly without use of any catalyst when 
an acid having high acidity such as, for example, CF.sub.3 SO.sub.2 -OH is 
used. However, the reaction rarely proceeds in the absence of the catalyst 
when moderately or weakly acidic compounds such as acetic acid, alcohols, 
organic amines and the like are used. Thus, the use of catalyst depends on 
the type of starting organic compound having active hydrogen. 
In order to carry out the process of the invention, an organic compound 
having active hydrogen and tert-butyldimethylsilane are mixed together and 
reacted at a temperature defined before in the presence or absence of a 
catalyst as set out before. The reaction time may vary depending upon the 
type of organic compound and the presence or absence of catalyst and the 
reaction temperature and is generally in the range of from 1 to 10 hours. 
By the reaction, a t-butyldimethylsilylated product is obtained along with 
hydrogen generated as a side product. The product is separated and 
purified by any known techniques such as distillation or column 
chromatography. t-Butyldimethylsilane should preferably be used in amounts 
equimolar to or larger than that of compound to be silylated. However, too 
large an amount is not economical and it is general to use the silane in 
an amount of 1 to 3 times by mol, preferably 1.05 to 1.5 times by mol, 
that of compound to be silylated. 
It will be noted that the reaction may be carried out in the absence of any 
solvent but a solvent may be used. Suitable solvents include, for example, 
hydrocarbons such as n-hexane, cyclohexane and the like, halogenated 
hydrocarbons such as dichloromethane, chloroform, dichloroethane and the 
like, ethers such as diethyl ether, dibutyl ether, tetrahydrofuran and the 
like, nitriles such as acetonitrile, and aromatic hydrocarbons such as 
benzene, toluene, xylene and the like. The reaction temperature and time 
may depend on the type of solvent, if used. 
The present invention is more particularly described by way of examples. 
EXAMPLE 1 
Preparation of the t-butyldimethylsilyl derivative of 3-phenyl-1-propanol 
##STR5## 
A small-size, two-necked flask was filled with an argon gas, into which 
53.2 mg (0.05 mmols) of 10% Pd on carbon was placed. Thereafter, 136.2 mg 
(1.00 mmol) of 3-phenyl-1-propanol dissolved in 1.5 ml of dry n-hexane was 
charged into the flask, followed by further charge of 174.4 mg (1.5 mmols) 
of t-butyldimethylsilane and 2.0 ml of dry n-hexane. The solution was 
agitated at 25.degree. C. After 2 hours, the resultant reaction product 
was sampled and subjected to gas chromatography, revealing that the 
conversion of the propanol into the silyl derivative was 96%. At this 
stage, the reaction was stopped. The Pd/C catalyst was removed by 
filtration, followed by removal of the solvent and unreacted 
t-butyldimethylsilane under reduced pressure. 
As a result, a colorless, oily silylated product of the following formula 
was obtained at a yield of 89%. 
##STR6## 
The product was subjected to NMR and IR spectrum analyses with the 
following results. 
NMR analysis: .sup.1 H-NMR (CDCl.sub.3, 90MHz), .delta.0.05 (s, 6H), 0.1 
(s, 9H), 1.7-2.0(m, 2H), 3.63(t, 2H), 7.2-7.3(m, 5H) 
IR analysis: IR (neat) cm.sup.-1 1490, 1460, 1385, 1250, 1100, 960, 830, 
770, 735, 690 
EXAMPLE 2-8 
The general procedure of Example 1 was repeated except that the type of 
catalyst, reaction temperature and reaction time were changed, thereby 
obtaining the following results 
______________________________________ 
Catalyst Temperature 
Time Conversion 
Example (5 mol %) (.degree.C.) 
(hrs.) 
(%) 
______________________________________ 
2 (RhCN).sub.2 PdCl.sub.2 
60 5 48 
3 PdCl.sub.2 55 5 25 
4 10% Pd/C 25 2 96 
5 10% Pd/C 70 2 100 
6 10% Rh/C 70 1 99 
7 10% Ru/C 70 4 96 
8 nil 70 10 0 
______________________________________ 
EXAMPLES 9-13 
Preparation of the t-butyldimethylsilyl derivative of cyclohexanol 
##STR7## 
The general procedure of Example 1 was repeated except that cyclohexanol 
was used as the starting compound and the reaction temperature and time 
were changed along with the type of solvent indicated below. The product 
obtained by the respective procedures was isolated by gas chromatography 
and subjected to NMR and IR analyses. The results of the analyses and the 
conversion are summarized below. 
NMR analysis: .sup.1 H-NMR (CDCl.sub.3, 90MHz), .delta.0.05 (s, 6H), 
0.89(s, 9H), 1.1-1.9(m, 10H), 3.4-3.8 (m, 1H) 
IR analysis: IR (neat) cm.sup.-1 1470, 1460, 1445, 1370, 1360, 1250, 1135, 
1095, 1050, 1015, 1005, 995, 885, 870, 835, 770, 660 
______________________________________ 
Temperature 
Time Conversion 
Example Solvent (.degree.C.) 
(hrs.) (%) 
______________________________________ 
9 n-C.sub.6 H.sub.14 
70 7 92 
10 CH.sub.2 Cl.sub.2 
40 5 22 
11 THF 70 19 19 
12 CH.sub.3 CN 
40 5 11 
13 C.sub.6 H.sub.6 
70 19 9 
______________________________________ 
EXAMPLE 14 
Preparation of the t-butyldimethylsilyl derivative of morpholine 
##STR8## 
The general procedure of Example 1 was repeated exept that morpholine was 
used as the starting material and benzene was used as the solvent. The 
conversion into the derivative was 93%. 
The formation of the silyl derivative was confirmed through NMR analysis. 
NMR analysis: .sup.1 -NMR (CDCl.sub.3, 90MHz), .delta.0.03 (s, 6H), 0.86(s, 
9H), 2.8-3.0(m, 4H), 3.4-3.6 (m, 4H) 
EXAMPLES 15-18 
The general procedure of Example 14 was repeated except that the solvent, 
reaction temperature and time were changed, with the following results. 
______________________________________ 
Temperature 
Time Conversion 
Example Solvent (.degree.C.) 
(hrs.) (%) 
______________________________________ 
15 n-C.sub.6 H.sub.14 
70 4 59 
16 CH.sub.2 Cl.sub.2 
40 4 41 
17 THF 70 4 70 
18 CH.sub.3 CN 
80 4 84 
______________________________________ 
EXAMPLE 19 
Preparation of the t-butyldimethylsilyl derivative of 3-phenylpropionic 
acid: 
##STR9## 
The general procedure of Example 1 was repeated except that phenylpropionic 
acid was used and the reaction temperature and time were changed as 
indicated below. The results are shown below. 
______________________________________ 
Temperature (.degree.C.) 
Time (hours) 
Conversion (%) 
______________________________________ 
50 5 89 
______________________________________ 
The formation of the silyl derivative was confirmed through NMR and IR 
analyses. 
NMR analysis: .sup.1 H-NMR (CDCl.sub.3, 90MHz), .delta.0.26 (s, 6H), 
0.93(s, 9H), 2.5-2.8 (m, 2H), 2.8-3.1 (m, 2H), 7.25 (s, 5H) 
IR analysis: IR (neat) cm.sup.-1 1720, 1605, 1495, 1460, 1410, 1365, 1290, 
1255, 1190, 1075, 945, 870, 840, 820, 805, 790, 740, 695 
EXAMPLE 20 
Preparation of the t-butyldimethylsilyl derivative of 
4-hydroxymethyl-2-azetidinone 
##STR10## 
All of the reaction systems used an atmosphere of argon. A two-necked flask 
was provided, into which 10.6 mg (0.01 mmol) of 10% Pd on carbon (10% 
Pd/C) and 33.8 g (0.33 mmols) of 4-hydroxymethyl-2-azetidinone were 
charged. Thereafter, 116.24 mg (1.00 mmol) of t-butyldimethylsilane 
dissolved in 1.5 ml of dry n-C.sub.6 H.sub.14 was added to the mixture. In 
this state, dissolution was not complete, and 1.5 ml of dry CH.sub.2 
Cl.sub.2 was further added to the mixture. The resultant solution was 
agitated at 25.degree. C. for 2 hours, after which the Pd/C catalyst was 
removed by filtration. The solvent and excess t-butyldimethylsilane were 
distilled off from the filtrate to obtain an N,O-di-silylated product of 
the 4-hydroxymethyl-2-azetidinone was obtained as a colorless transparent 
oily substance. The yield was 80%. The product was confirmed through NMR. 
NMR analysis: .sup.1 H-NMR (CDCl.sub.3, 90MHz), .delta.0.06 (s, 6H), 0.22 
(s, 3H), 0.24 (s, 3H), 0.90 (s, 9H), 0.96(s, 9H), 2.5-3.2 (m, 2H), 3.4-3.8 
(m, 3H)