Page 268 - Advanced Organic Chemistry Part B - Reactions & Synthesis

240 Allylic ethers are cleaved in a matter of a few minutes by TMSI under in situ conditions.

CHAPTER 3 CH 3 CH
(CH ) SiCl 3
CH 3 3
Functional Group Ph 2
Interconversion O NaI, CH CN Ph OH
by Substitution, 3 min 3 90%
Including Protection and Ref. 94
Deprotection
Diiodosilane, SiH I , is an especially effective reagent for cleaving secondary alkyl
2 2
ethers. 95
TMSI also effects rapid cleavage of esters. The cleavage step involves iodide
attack on the O-silylated ester. The first products formed are trimethylsilyl esters, but
these are hydrolyzed rapidly on exposure to water. 96

O + OSi(CH 3 ) 3 O
RCO R′ + (CH ) SiI RCO R′ + I – RCOSi(CH ) + R′I
3 3
3 3
O
RCOSi(CH ) + H O RCO 2 H + (CH ) SiOH
3 3
2
3 3
Benzyl, methyl, and t-butyl esters are rapidly cleaved, but secondary esters react
more slowly. In the case of t-butyl esters, the initial silylation is followed by a rapid
ionization to the t-butyl cation.
Ether cleavage can also be effected by reaction with acetic anhydride and Lewis
acids such as BF , FeCl , and MgBr . 97 Mechanistic investigations point to acylium
3
2
3
ions generated from the anhydride and Lewis acid as the reactive electrophile.
+
(RCO) O + MX n RC O + [MX O CR] –
2
n
2
+ +
RC O + R′ O R′ R′ O R′
R C O
+
R′ O R′ + X – R′ X + RCO R′
2
R C O
Scheme 3.3 gives some specific examples of ether and ester cleavage reactions.
Entries 1 and 2 illustrate the use of boron tribromide for ether cleavage. The reactions
are conducted at dry ice-acetone temperature and the exposure to water on workup
hydrolyzes residual O−B bonds. In the case of Entry 2, the primary hydroxy group
that is deprotected lactonizes spontaneously. The reaction in Entry 3 uses HBr in
acetic acid to cleave a methyl aryl ether. This reaction was part of a scale-up of
the synthesis of a drug candidate molecule. Entries 4 to 6 are examples of the
cleavage of ethers and esters using TMSI. The selectivity exhibited in Entry 6 for

94
A. Kamal, E. Laxman, and N. V. Rao, Tetrahedron Lett., 40, 371 (1999).
95
E. Keinan and D. Perez, J. Org. Chem., 52, 4846 (1987).
96 T. L. Ho and G. A. Olah, Angew. Chem. Int. Ed. Engl., 15, 774 (1976); M. E. Jung and M. A. Lyster,
J. Am. Chem. Soc., 99, 968 (1977).
97
C. R. Narayanan and K. N. Iyer, J. Org. Chem., 30, 1734 (1965); B. Ganem and V. R. Small, Jr.,
J. Org. Chem., 39, 3728 (1974); D. J. Goldsmith, E. Kennedy, and R. G. Campbell, J. Org. Chem., 40,
3571 (1975).