Page 249 - Advanced Organic Chemistry Part B - Reactions & Synthesis

with clean inversion of stereochemistry. 25 The key intermediate is again an 221
alkoxyphosphonium ion.
SECTION 3.1
+ – Conversion of Alcohols
Ph P + ROH + C H O CN NCO C H Ph POR + C H O CNNHCO C H to Alkylating Agents
2
2 5
2 2 5
2 2 5
2 5
3
3
2
–
C 2 H 5 O 2 CNNHCO 2 C 2 H 5 + CH 3 I C H 5 O 2 CNNHCO 2 C 2 H 5 +I –
2
CH 3
+
Ph P OR + I – RI + Ph P O
3
3
The role of the DEAD is to activate the triphenylphosphine toward nucleophilic attack
by the alcohol. In the course of the reaction the N=N double bond is reduced. As
is discussed later, this method is applicable for activation of alcohols to substitution
by other nucleophiles in addition to halide ions. The activation of alcohols to nucle-
ophilic attack by the triphenylphosphine-DEAD combination is called the Mitsunobu
reaction. 26
A very mild method that is useful for compounds that are prone to allylic
rearrangement involves prior conversion of the alcohol to a sulfonate, followed by
nucleophilic displacement with halide ion.
CH CH CH
CH 3 CH 2 CH 2 3 2 2
1) CH SO Cl
3
2
C CHCH 2 OH C CHCH 2 Cl
2) LiCl, DMF CH CH
CH 3 CH CH 2 CH 3 2 2
2
83% Ref. 27
Another very mild procedure involves reaction of the alcohol with the heterocyclic
2-chloro-3-ethylbenzoxazolium cation. 28 The alcohol adds to the electrophilic hetero-
cyclic ring, displacing chloride. The alkoxy group is thereby activated toward a
nucleophilic substitution that forms a stable product, 3-ethylbenzoxazolinone.
H
C H C 2 5 C 2 5
H
2 5
+ +
N N N
Cl + ROH OR + Cl – O + RCl
O O O
The reaction can be used for making either chlorides or bromides by using the appro-
priate tetraalkylammonium salt as a halide source.
Scheme 3.1 gives some examples of the various alcohol to halide conversions that
have been discussed. Entries 1 and 2 are examples of synthesis of primary bromides
using PBr . Entry 3 is an example of synthesis of a chloride using Ph P–Cl . The
3
2
3
reactant, neopentyl alcohol, is often resistant to nucleophilic substitution and prone
to rearrangement, but reacts well under these conditions. Entries 4 and 5 illustrate
the use of halogenated solvents as chlorine sources in Ph P-mediated reactions. The
3
reactions in Entries 6 and 7 involve synthesis of bromides by nucleophilic substitution
on tosylates. The reactant in Entry 7 is prone to rearrangement via ring expansion,
25
H. Loibner and E. Zbiral, Helv. Chim. Acta, 59, 2100 (1976).
26
D. L. Hughes, Org. React., 42, 335 (1992).
27 E. W. Collington and A. I. Meyers, J. Org. Chem., 36, 3044 (1971).
28
T. Mukaiyama, S. Shoda, and Y. Watanabe, Chem. Lett., 383 (1977); T. Mukaiyama, Angew. Chem.
Int. Ed. Engl., 18, 707 (1979).