A convenient biphasic process for the monosilylation of symmetrical 1,n- primary diols

Article abstract of DOI:10.1016/S0040-4039(00)00626-2

A simple and mild biphasic process was developed for the selective protection of one of two chemically equivalent primary hydroxyl groups in 1,n-diols using t-butyldiphenyl silyl chloride in diisopropyl ethyl amine and dimethyl formamide. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00626-2

Tetrahedron Letters 41 (2000) 4281±4285
A convenient biphasic process for the monosilylation of
symmetrical 1,n-primary diols
Chengzhi Yu, Bin Liu and Longqin Hu*
Department of Pharmaceutical Chemistry, College of Pharmacy, Rutgers, the State University of New Jersey,
160 Frelinghuysen Road, Piscataway, NJ 08854-8020, USA
Received 11 February 2000; accepted 14 April 2000
Abstract
A simple and mild biphasic process was developed for the selective protection of one of two chemically
equivalent primary hydroxyl groups in 1,n-diols using t-butyldiphenyl silyl chloride in diisopropyl ethyl
amine and dimethyl formamide. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: selective protection; 1,n-diol; silylation; biphasic.
Selective derivatization/protection of one of two hydroxyl groups in the same molecule is a
very important issue in organic synthesis.1 Chemically non-equivalent hydroxyl groups such as
primary, secondary, and tertiary hydroxy can be readily di€erentiated from each other by
employing common protection and deprotection strategies. However, two chemically equivalent
hydroxyl groups such as those in 1,n-primary diols are often dicult to di€erentiate. Derivatization
of these diols with a stoichiometric amount of a reagent usually generates a mixture of the
unreacted, the monoderivatized and the diderivatized diol in a statistical distribution of 1:2:1.2
Selective protection of only one hydroxyl group in a 1,n-diol is dicult to achieve. It requires
careful control of experimental conditions;3 the cleavage of cyclic intermediates;4 or the use of
catalysts such as strongly acidic ion-exchange resins,1a inorganic polymer supports,1b and
hydrolytic enzymes.5 All of these conditions resort to costly and time-consuming recycling
procedures. One method of selective protection of 1,n-diols employs NaH/t-butyldimethyl silyl
chloride (TBDMSCl) in THF.6 This method gives good yields for the primary diols tested, but
the formation of sodium alkoxides in the presence of stoichiometric amounts of NaH requires
careful manipulation. Besides, this condition is too strong to be compatible with diols containing
base-sensitive functional groups. Therefore, there is still a need to develop a mild and convenient
method for the selective protection of 1,n-diols.
* Corresponding author. Tel: (732) 445-5291; fax: (732) 445-6312; e-mail: longhu@rci.rutgers.edu
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00626-2

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In our endeavor to synthesize potential protein kinase inhibitors, we needed to protect one of
the two chemically equivalent primary hydroxyl groups in 1 (Scheme 1). t-Butyldiphenyl silyl ether
(TBDPS) was chosen over TBDMS as the protecting group because TBDPS group is considerably
more stable (100 times) than TBDMS group towards acidic hydrolysis, and is more stable to
many other reagents where TBDMS is labile.7
Scheme 1.
We tried various conditions to introduce TBDPS on one of the primary hydroxyl groups in 1
but failed to obtain the desired monosilylated product 2. With the exception of excess TBDPSCl
plus imidazole in DMF, none of the conditions gave any silylated products, and most of the
starting material was recovered.8 Excess TBDPSCl (3 equiv.) and imidazole (10 equiv.) in DMF,
however, a€orded only the diprotected compound 3 in 89% yield while no monosilylated product
2 was isolated. We thought that the low reactivity of 1 might be due to the strong intramolecular
hydrogen bonding interaction that inhibited the reaction of the hydroxyl groups with the bases
added.9 If this is true, use of a polar aprotic solvent should decrease such intramolecular hydrogen
bonding interaction and facilitate the protection reaction. Indeed, our subsequent experiments
showed that selective protection could be achieved in a mixed solvent of CH2Cl2 and THF (1:1) in
the presence of DIEA. Under this condition, the desired product 2 was obtained in 66% yield and
none of the diprotected product 3 was isolated. When we changed the solvent to DMF and used
excess DIEA as the base, the reaction proceeded very well to give 2 in an even higher yield (87%).
More interesting and to our surprise, we found that DIEA had limited solubility in DMF and
that excess DIEA formed a light phase on top of the DMF phase. Based on this phenomenon, we
believe that the unique selectivity under this biphasic condition could be in part due to the constant
concentration (16%) of base (DIEA) maintained in the reaction phase (DMF) during silylation.10
However, the exact source of selectivity is not understood.
The following general procedure was then developed to prepare the monosilylated symmetrical
1,n-primary diols: A solution of 1,n-diol (1 mmol) in anhydrous DMF (3 mL) was charged with
redistilled DIEA (10 equiv., 1.7 mL) forming a biphasic mixture at room temperature. TBDPSCl
(1.05 equiv.) was added dropwise into the biphasic mixture with stirring under argon. The reaction
mixture was stirred at room temperature and the reaction progress was monitored by TLC. Upon
completion, the reaction was quenched with cold water (20 mL), extracted with t-butyl methyl
ether (3Â50 mL), and washed with 2N HCl (2Â20 mL), saturated NaHCO3 (aq., 20 mL), and
then brine (20 mL). The organic phase was dried over MgSO4, ®ltered through a cotton pad, and
concentrated in vacuo. The residue was puri®ed by ¯ash column chromatography on silica gel
with acetone11 and hexane as the eluent.
To explore the synthetic generality of this biphasic protection reaction, we investigated several
primary diols. As shown in Table 1, reasonable yields and selectivity were observed for all 1,n-diols
examined, ranging from 1,2-ethanediol (4) to 1,9-nonanediol (11).12 The 1:2:1 statistical distribution

4283
Table 1
Monosilyation of primary diols under the biphasic conditiona
found in most conditions was not a problem under this biphasic condition. It should be noted
that excess TBDPSCl does not adversely a€ect the selective protection of one of the two hydroxyl
groups as shown for compounds 6 and 8 in Table 1.
For direct comparison of our method with the commonly used condition of TBDPSCl/DIEA/
CH2Cl2, both 1,3-propanediol (5) and 2-methyl-2-amino propanediol (7) were also treated with
TBDPSCl (1 equiv.) at ambient temperature in a mixture of DIEA and CH2Cl2 (1:1). Using our
biphasic condition, both 5 and 7 gave the monosilylated products in isolated yields of 80 and
81%, respectively, with little or no bissilylated product isolated (as shown in Table 1). However,
TBDPSCl treatment of 5 in DIEA/CH2Cl2 gave only the bissilylated product in 75% after isola-
tion while TBDPSCl treatment of 7 in DIEA/CH2Cl2 failed to give any silylated product as
monitored by TLC. These results clearly demonstrate the superiority of our biphasic condition
for the formation of monosilylated derivatives of 1,n-diols.
In conclusion, a biphasic silylating process was developed to prepare in high yield mono-
silylated derivatives of symmetrical 1,n-primary diols, which are important building blocks in
organic synthesis.13 This method is mild and convenient. In addition, only stoichiometric silylat-
ing reagent is needed. The same condition could be adapted to the synthesis of monoacylated
derivatives of symmetrical diols, which are also important bifunctional building blocks.1a

4284
Acknowledgements
We gratefully acknowledge the ®nancial support of grant DAMD 17-98-1-8544 from the US
Army Department of Defense Prostate Cancer Research Program and grant GM61242 from the
National Institutes of Health.
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8. The conditions we tried but failed to give any silylated products include: (a) TBDPSCl (1.05 equiv.), DIEA (10
equiv.), CH2Cl2, rt, 36 h; (b) TBDPSCl (1.05 equiv.), Et3N (10 equiv.), CH2Cl2, rt, 24 h; (c) TBDPSCl (1.05
equiv.), Et3N (10 equiv.)/DMAP (0.05 equiv), CH2Cl2, rt, 24 h; (d) TBDPSCl (1.05 equiv.), DMAP (10 equiv.),
CH2Cl2, rt, 24 h; (e) TBDPSCl (1.05 equiv.), pyridine, rt, 24 h; (f) TBDPSCl (1.05 equiv.), imidazole (5 equiv.),
DMF, rt, 24 h; (g) TBDPSCl (1.05 equiv.), NaH (1 equiv.), THF, 0ꢀC±rt, 3 h.
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10. In a typical procedure, DIEA (10 mmol, 1.7 mL) and DMF (3 mL) form two immiscible solution phases at room
temperature. Using NMR, we found that the top DIEA phase contained about 18% DMF (mol) and the bottom
DMF phase contained about 16% DIEA. TLC analysis indicated that reactants used in our experiments were
mainly in the bottom DMF phase. We also found that using saturated DIEA solution in DMF as the reaction
media decreased both the reaction yield and the selectivity of silylation.
11. Acetone±hexane was found to be a better eluting solvent system than the commonly used ethyl acetate/hexane for
the puri®cation and structure assignment of the monosilylated 1,n-primary diols, since ethyl acetate can be
strongly retained in compounds containing hydroxyl groups and it is hard to remove completely in vacuo.
12. Selected 1H NMR (200 MHz, CDCl3) data: ꢀ ppm compound 1: 7.60 (dd, 2H, J=7.5, 1.3 Hz), 7.41±7.26 (m, 3H),
4.13±3.89 (m, 6H), 3.08 (t, 2H, J=6.6 Hz), 1.98 (br s, 2H, OH), 1.18 (t, 3H, J=7.1 Hz); compound 2: 7.76±7.20
(m, 15H), 4.24±4.12 (m, 2H), 4.03±3.90 (m, 4H), 2.55 (dd, 1H, J=5.7, 4.0 Hz, OH), 1.08 (t, 3H, J=7.8 Hz), 1.06
(s, 9H); compound 3: 7.76±7.67 (m, 10H), 7.44±7.26 (m, 15H), 4.36 (Abq, 2H, Áꢁ=14.0 Hz, J=9.5 Hz), 3.65 (q,
2H, J=6.8Hz), 1.05 (s, 18H), 0.82 (t, 3H, J=7.1 Hz); mono-TBDPS-4: 7.78±7.73 (m, 4H), 7.49±7.43 (m, 6H),
3.85±3.80 (m, 2H), 3.74 (br s, 2H), 2.45 (br s, 1H, OH), 1.15 (s, 9H); mono-TBDPS-5: 7.75±7.70 (m, 4H), 7.45±7.42
(m, 6H), 3.88 (t, 2H, J=5.6 Hz), 3.87 (t, 2H, J=5.8 Hz), 2.54 (br s, 1H, OH), 1.80 (q, 2H, J=5.7 Hz), 1.10 (s, 9H);
mono-TBDPS-6: 7.82±7.68 (m, 4H), 7.52±7.38 (m, 6H), 3.60 (d, 2H, J=5.5 Hz), 3.56 (s, 2H), 2.68 (t, 1H, J=5.5
Hz, OH), 1.42±0.75 [m, 23H, including 1.12 (s, 9H), 0.92 (t, 3H, J=6.1 Hz), 0.81 (t, 3H, J=6.5 Hz)]; mono-
TBDPS-7: 7.70±7.65 (m, 4H), 7.45±7.39 (m, 6H), 3.53±3.33 (m, 4H), 1.85 (br s, 2H, NH2), 1.09 (s, 9H), 1.04 (s,
3H); mono-TBDPS-8: 7.83±7.79 (m, 4H), 7.50±7.45 (m, 4H), 7.33 (br s, 3H), 4.89 (s, 2H), 4.73 (s, 2H), 3.20 (br s,
1H, OH), 1.17 (s, 9H); mono-TBDPS-9: 7.76±7.71 (m, 4H), 7.45±7.41 (m, 6H), 3.73 (t, 2H, J=6.2 Hz), 3.64 (t, 2H,

4285
J=5.5 Hz), 2.05 (br s, 1H, OH), 1.68±133 (m, 6H), 1.12 (s, 9H); mono-TBDPS-10: 7.75±7.70 (m, 4H), 7.44±7.41
(m, 6H), 3.71 (t, 2H, J=6.3 Hz), 3.66 (Abq, 2H, Áꢁ=12.2 Hz, J=6.6 Hz), 1.75 (br s, 1H, OH), 1.61±1.55 (m, 4H),
1.44±1.31 (m, 6H), 1.10 (s, 9H); mono-TBDPS-11: 7.73±7.68 (m, 4H), 7.43±7.39 (m, 6H), 3.69 (t, 2H, J=6.5 Hz),
3.65 (t, 2H, J=6.4 Hz), 1.65±1.50 (m, 4H), 1.48±1.25 (m, 10H), 1.08 (s, 9H).
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