Amines amidine synthesis

Since alkoxymethyleneiminium salts with nearly any substitution pattern are easy to prepare, this amidine synthesis has attained widespread application. Thus N-unsubstituted, IV-monosub-stituted and lV,A(-disubstituted alkoxymethyleneiminium salts (138) have been transformed to amidinium salts (137) by treatment with ammonia,primary and secondary amines and amine deri-vatives. ... 

The action of ammonia, primary and secondary amines on alkoxymethyleneiminium salts or alkylmercaptomethyleneiminium salts affords amidinium salts. Provided the educts are chosen in such a manner that the substitution pattern of the resulting amidinium salts does not exceed that of A/jV.AT -trisubstituted salts, the amidines can be released from the salts by addition of bases (see also Section 2.7.2.5.3). Very often the alkoxymethyleneiminium salts were prepared in situ and reacted without further purification with the amino compound to give the desired amidine. This amidine synthesis is of special synthetic interest, since it was stated that formamidines, derived from alicyclic amines, e.g. (306 equation 164), which are simple to obtain by this method, are readily transformed to reactive carbanions. Heterocycles, e.g. (307 equation 165), containing amidine structures, are accessible by reaction of appropriate difunctional compounds with iminium salts. ... 

Amidine synthesis. Alkynes, amines, and suUbnylazides (or phosphoryl azides) are combined to generate amidines. The alkynes and/or the amines can he functionahzed, and their use leads to amidines containing an a-amino group or a phosphoranylalkyl group, when starting from ynamides and imidophosphoranes, respectively. 

The most frequently used synthesis of guanidines involves the displacement by an amine of a suitable group, X, from the amidine-type compound shown. 

A useful method for the synthesis of 5-chloro-l,2,4-thiadiazoles (206) is the reaction of amidines with trichloromethylsulfenyl chloride (see Equation (30)). 3-Halo derivatives (349) (X = Cl, Br, I) (Equation (57)) have been obtained in moderate yields from the corresponding amines (348) via the Sandmeyer-Gatterman reaction <84CHEC-I(6)463>. 3-Chloro-l,2,4-thiadiazolin-5-ones (350) and (351) can be prepared by reacting chlorocarbonylsulfenyl chloride with carbodiimides or cyanamides respectively (Scheme 79) <84CHEC-I(6)463>. 

A -Silylmethyl-amidines and -thioamides (42) (X=NR or S) undergo alkylation at X with, for example methyl triflate, and then fluorodesilylation to give the azomethine ylides 43 (identical with 38 for the thioamides) (25,26). Cycloaddition followed by elimination of an amine or thiol, respectively, again leads to formal nitrile ylide adducts. These species again showed the opposite regioselectivity in reaction with aldehydes to that of true nitrile ylides. The thioamides were generally thought to be better for use in synthesis than the amidines and this route leads to better yields and less substituent dependence than the water-induced desilylation discussed above. 

When solid-phase peptide synthesis was initially being developed, the question of whether or not a separate neutralization step is necessary was considered. Since it was known from the work of others that the chloride ion promotes racemization during the coupling step in classical peptide synthesis, and since we were deprotecting the Boc group with HC1, it seemed advisable to neutralize the hydrochloride by treatment with TEA and to remove chloride by filtration and washing. This short, additional step was simple and convenient and became the standard protocol. Subsequently, we became aware of three other reasons why neutralization was desirable (1) to avoid weak acid catalysis of piperazine-2,5-dione formation, 49 (2) to avoid acid-catalyzed formation of pyroglutamic acid (5-oxopyr-rolidine-2-carboxylic acid), 50 and (3) to avoid amidine formation between DCC and pro-tonated peptide-resin. The latter does not occur with the free amine. 

---