Page 266 - Advanced Organic Chemistry Part B - Reactions & Synthesis

238 and its precursors, as well as the explosion hazard of diazomethane, requires that
all recommended safety precautions be taken. Entries 19 to 21 involve formation of
CHAPTER 3
esters by alkylation of carboxylate salts. The reaction in Entry 19 was done in the
Functional Group presence of 5 mol % 18-crown-6. A number of carboxylic acids, including pivalic acid
Interconversion
by Substitution, as shown in the example, were alkylated in high yield under these conditions. Entry 20
Including Protection and shows the alkylation of the rather hindered mesitoic acid by a secondary iodide. These
Deprotection
conditions also gave high yields for unhindered acids and iodides. Entry 21 involves
formation of a methyl ester using CH I and KF as the base in DMF. Entry 22 involves
3
formation of a sulfonate ester under Mitsunobu conditions with clean inversion of
configuration. The conditions reported represent the optimization of the reaction as
part of the synthesis of an antihypertensive drug, fosinopril.
Sections I and J of Scheme 3.2 show reactions with sulfur and phosphorus
nucleophiles. The reaction in Entry 25 is a useful method for introducing thiol groups.
The solid thiourea is a convenient source of sulfur. A thiouronium ion is formed and
this avoids competition from formation of a dialkyl sulfide. The intermediate is readily
hydrolyzed by base.

+
N H 2 NaOH
RCH Br + S C(NH ) RCH S RCH 2 SH
2
2 2
2
NH 2 H 2 O

3.3. Cleavage of Carbon-Oxygen Bonds in Ethers and Esters

The cleavage of carbon-oxygen bonds in ethers or esters by nucleophilic substi-
tution is frequently a useful synthetic transformation.

–
R O CH 3 + Nu – RO + CH 3 Nu
O
–
RC O CH 3 + Nu – RCO + CH 3 Nu
2
The alkoxide group is a poor leaving group and carboxy is only slightly better. As
a result, these reactions usually require assistance from a protic or Lewis acid. The
classical ether cleavage conditions involving concentrated hydrogen halides are much
too strenuous for most polyfunctional molecules, so several milder reagents have been
developed, 86 including boron tribromide, 87 dimethylboron bromide, 88 trimethylsilyl
iodide, 89 and boron trifluoride in the presence of thiols. 90 The mechanism for ether
cleavage with boron tribromide involves attack of bromide ion on an adduct formed

86 M. V. Bhatt and S. U. Kulkarni, Synthesis, 249 (1983).
87 J. F. W. McOmie, M. L. Watts, and D. E. West, Tetrahedron, 24, 2289 (1968).
88
Y. Guindon, M. Therien, Y. Girard, and C. Yoakim, J. Org. Chem., 52, 1680 (1987).
89 M. E. Jung and M. A. Lyster, J. Org. Chem., 42, 3761 (1977).
90
(a) M. Node, H. Hori, and E. Fujita, J. Chem. Soc., Perkin Trans. 1, 2237 (1976); (b) K. Fuji, K. Ichikawa,
M. Node, and E. Fujita, J. Org. Chem., 44, 1661 (1979).