Chemistry Reference
In-Depth Information
3.2.4.5
Thioimidate
Activation of thioamides to thioimidates with alkylation is also applied to the synthesis of
amidines. Dijkink et al. [28] applied this method to the synthesis of chiral bicyclic amidines
from (S)-malic acid as a key step. However, the amidine was found to be unstable due to
isomerization of the imine double bond followed by elimination of the silyloxy group
(Scheme 3.15).
g
-Lactam, which is derived from pyroglutamic acid by reduction, protection of the
hydroxy group and conjugate addition to acrylonitrile, is subjected to a similar synthetic
route to afford a desired amidine [15] (Scheme 3.16). Intermolecular hydrogen bonding
between hydrogen on the hydroxy group and imino nitrogen was observed by X-ray
crystallographic analysis.
3.2.5 Multi-Component Reaction
Multi-component reaction for the preparation of a variety of compounds in a single step is a
powerful tool in combinatorial chemistry and drug discovery. Reaction of cyclohexyliso-
nitrile and isobutyraldehyde inmethanol in the presence of dimethylamine hydrochloride as
a weak acid catalyst produces N-cyclohexyl-
a
-dimethylaminoisovaleramide and the
corresponding
-Aminoamidine is obtained
as a sole product when dimethylamine is added as a nucleophile. Keung et al. [30] optimized
the reaction conditions using various metal catalysts. Scandium (III) triflatewas found to be
the best catalyst and tolerant to a wide variety of amine and aldehyde units.
N-Sulfonylamidines can be prepared by three-component coupling [31] of alkynes
(R
1
a
-hydroxy compound [29] (Scheme 3.17).
a
[32] The use of alkyl azides in place of sulfonyl azidewithout a copper catalyst results in the
formation of 1,2,3-triazoles (Scheme 3.18). This reaction shows substrate tolerance to each
component. Reaction with an optically active amino ester is performed without racemiza-
tion. N-Boc-ynamide (R
1
¼
alkyl, aryl or silyl), sulfonyl azide and amine, which is known as
click chemistry.
¼
NPhBoc) can act as the alkyne component in the synthesis of N-
Boc-aminoamidines [33].
A step-wise procedure for the preparation of N-sulfonylamidines via N-sulfonylimidates
has also been reported [34]. Similar multi-component reaction using alcohols gives N-
sulfonylimidates, which are converted to N-sulfonylamidines by treatment with primary
and secondary amines in the presence of catalytic amount of sodium cyanide (NaCN) [24a]
(Scheme 3.19). This indirect process sometimes shows a better yield than the above direct
method: for example, the one-pot reaction of phenylacetylene (R
1
¼
Ph), p-toluenesulfonyl
azide (R
2
¼
Ts) and morpholine (2R
3
¼
CH
2
CH
2
OCH
2
CH
2
) provides amidines in 19%
yield, whereas product is obtained in 72% yield in the step-wise procedure via imidate
(R
4
¼
Me).
-Alkynylamines can be used as a combined component of alkyne and amine, in which
two kinds of cyclic amidines are formed dependent upon the conditions used [35]
(Table 3.2). When 5-amino-1-pentyne is reacted in the presence of copper catalyst, a
five-membered amidine is obtained as a major product with the loss of one carbon (run 1).
On the other hand, reaction using 6-amino-1-hexyne in the presence of rhodium [Ru(III)]
catalyst affords a six-membered amidine as a major product (run 2).
This selectivity could be rationalized as follows: a stable exo-methylene pyrrolidine
from alkynylamines (n
o
1) reacts with TsN
3
to give spirotriazoline 9, which liberates
diazomethane (CH
2
N
2
) to furnish a five-membered amidine, whereas a bicyclic triazoline
¼
