Chemistry Reference
In-Depth Information
4.7.1
N-Dealkylation of Tertiary Amines
Direct transformation of N-benzyl-protected tertiary amines 1759 into carbamoyl
chlorides 170, which are versatile intermediates for the direct preparation of
amides, ureas, carbamates, and heterocyclic derivatives, is an attractive alternative
to save deprotection and activation steps involving the free amine as an intermedi-
ate [135, 735].
R
2
N
Y
Y = O, S, N
R
1
R
3
R
2
N
R
2
N
O
1760
Ph
Cl
R
1
R
1
R
2
N
O
1759
170
R
1
H
1761
In a well-established protocol, the above reaction is very useful for the preparation
of the free secondary amines. Several available chloroformates are traditional re-
agents for the N-dealkylation of tertiary amines by cleavage of the intermediate
carbamates [134].
The reaction between phosgene itself and triethylamine has been reported to
give diethylcarbamoyl chloride [133], but, surprisingly enough, when tribenzyl-
amine was used, no C
N bond-breaking was observed, and no carbamoyl chloride
was formed. Instead, tribenzylamine 1762 reacts smoothly with one-third of an
equivalent of triphosgene in dichloromethane to give, very selectively, the expected
carbamoyl chloride 1763 (71% conversion) [135].
a
O
N
Cl
(CCl
3
O)
2
CO
N
1763
1762
The reaction most probably proceeds according to the mechanism described for
chloroformates 1764. Indeed, an equimolar amount of benzyl chloride along with
the carbamoyl chloride 170 has been isolated in all reported reactions.
The results in Table 4.49 also show that the method is compatible with various
functional groups (ketone, ester, amide, unsaturation). However, the presence of a
phenyl group on the nitrogen atom seems to prevent the reaction from occurring
since, in this particular case, the starting material is entirely recovered. Interest-
