Page 257 - Advanced Organic Chemistry Part B - Reactions & Synthesis

O 229
(CH O) PH + i-PrO CN NCO -i-Pr + Ph P (CH O) PNNHCO -i-Pr + Ph P O
2
2
3
3
3
2
2
2
3
SECTION 3.2
-i-Pr
CO 2 Introduction of
Functional Groups by
(CH O) PNNHCO -i-Pr + ROH ROP(OCH ) Nucleophilic Substitution
2
2
3
3 2
at Saturated Carbon
CO -i-Pr
2
Mixed phosphonate acid esters can also be prepared from alkylphosphonate
monoesters, although here the activation is believed occur at the alcohol. 57
O
+ –
ROP Ph 3 + R′PO 2 R′POR + Ph P O
3
OCH 3 OCH 3
3.2.4. Nitrogen Nucleophiles
The alkylation of neutral amines by halides is complicated from a synthetic point
of view by the possibility of multiple alkylation that can proceed to the quaternary
ammonium salt in the presence of excess alkyl halide.
H+
RNH + R′ X RNR′ + X –
2
H
H+ +
RNR′ + RNH 2 RNR′ + RNH 3
H H
+
–
RNR′ + R′ X RNR′ + X
2
H H
+ +
RNR′ 2 + RNH 2 RNR′ 2 + RNH 3
H
+
–
+ R′ X + X
RNR′ 2 RNR′ 3
Even with a limited amount of the alkylating agent, the equilibria between protonated
product and the neutral starting amine are sufficiently fast that a mixture of products may
be obtained. For this reason, when monoalkylation of an amine is desired, the reaction is
usually best carried out by reductive amination, a reaction that is discussed in Chapter 5.
If complete alkylation to the quaternary salt is desired, use of excess alkylating agent and
a base to neutralize the liberated acid normally results in complete reaction.
Amides are weakly nucleophilic and react only slowly with alkyl halides. The
anions of amides are substantially more reactive. The classical Gabriel procedure for
synthesis of amines from phthalimide is illustrative. 58
O O
– +
N K + BrCH CH Br NCH CH Br
2
2
2
2
O O 70 – 80% Ref. 59
57 D. A. Campbell, J. Org. Chem., 57, 6331 (1992); D. A. Campbell and J. C. Bermak, J. Org. Chem.,
59, 658 (1994).
58 M. S. Gibson and R. N. Bradshaw, Angew. Chem. Int. Ed. Engl., 7, 919 (1968).
59
P. L. Salzberg and J. V. Supniewski, Org. Synth., I, 119 (1932).