Amidine formation

The lactam moiety in benzodiazepines is active toward nucleophiles and numerous analogues have been made by exploiting this fact. For example, heating demoxepam (3) with N-cyclopropylmethylamine leads to amidine formation, the minor tranquilizer cyprazepam... 

From A(-substituted carboxamides, the 3-unsubstituted derivatives were formed, with loss of the corresponding amine. This reaction is to be expected from the mechanism of the ring closure amidine formation and subsequent nucleophilic attack of the amidine nitrogen on the carbonyl group. 

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. 

The amino and bromo substituents in the 3//-azepine (111 X = Br) are susceptible to nucleophilic displacement and are hydrolyzed surprisingly easily by aqueous methanol or DMF to the azepine-2,7-dione. Sodium thiocyanate in DMF yields the aminothiocyanate (111 R = SCN) (67JOC2367). It has been noted that amidine formation with the lactim thioether (112) is much slower than with isomer (113) (77JHC933). 

Platinum-catalyzed hydrolytic amidation of unactivated nitriles was reported by Cobley and coauthors. The platinum(ii) complex, [(Me2PO- H- PMe2)PtH (PMe2OH)], efficiently catalyzes the direct conversion of unactivated nitriles into N-substituted amides with both primary and secondary amines. Possible mechanisms for this reaction are discussed and evidence for initial amidine formation is reported. Isolated yields vary from 51 to 89% [25]. 

SCHEME 19.5 Conjugation of carbohydrates by amidine formation with Lys side chains. 

The amidine formation can take place when polymers with a degree of hydrolysis in the order of 20-80% are used. Furthermore acidic surface groups can also induce the amidinium ion formation. 

The reactivity of coordinated nitriles towards nucleophiles, and electrophiles when deprotonated, has been of major interest. Addition of OH- to the nitrile carbon occurs readily in alkaline solution, kobs = oh[OH-]) and the rate is increased some 106—107 times by coordination (equation 24).176177 k0H has values of 1-50mol-1 dm3 s 1 for R = alkyl177 [e.g. 3.4 (Me) 35 (CH=CH,)j and varies over a wider range for substituted benzonitriles following a Hammett relationship.For 2-cyanoben-zonitrile addition of one equivalent of OH is followed by intramolecular amidine formation on treatment with further alkali (29), or by rearrangement in acid and hydrolysis to the diamide (31), or cyclization to the alternative amidine isomer (32 Scheme 17).179 The alkaline hydrolysis of the... 

The readiness of amidine formation in reactions of lactim ethers with amines has been used in the synthesis of 8,9-poly methylene-purines.97 Attempts to condense 2 (R = Me) with uramil and l,3-dimethyl-4,5-diaminouracil failed.97 Lactim ethers were also found not to react with derivatives of 5-aminouracil, probably due to the low basicity of the latter.97... 

Nucleophilic attack of ammonia or of a primary or secondary amine on an O-alkyl thiocarboxylate (2) provides a formally straightforward approach to thioamides and a number of examples have been reported (equation l). - However, some limitations should be noted. Thus, there is a tendency of esters (2) to rearrange to their 5-alkyl isomers on heating (cf. Volume 6, Chapter 2.5) and these yield amides with amines rather than thioamides. Besides, excess primary amine will lead to amidine formation, or the tetrahedral intermediate of the substitution reaction may break down to an imidate rather than a thioamide (cf. Volume 6, Chapter 2.7). These unwanted side reactions are favoured in polar, protic solvents such as ethanol. In contrast, THF has proven to be particularly useful in the synthesis of tertiary thioamides according to equation (1). For improved reactivity in the preparation of V-aryl derivatives and milder reaction conditions, it is advantageous to employ the amine in the form of its Mg salt. ... 

Scheme 3.7 Amidine formation from p,fi-diethoxypropionate and N-methyl- and N-butylethylenediamine...

On the development of copper-catalysed olefin aziridination, Evans et al. [36] reported oxidative amidine formation. Treatment of cyclohexene, a less reactive substrate towards... 

Fradet and co-workers reported on the thermal ROP of y-carboxyethyl- s-caprolactam and y-aminoethyl- s-caprolac-tam (compare Scheme 7). Both monomers were polymerized in bulk at 250 °C. In both cases, the authors observed that monomer conversion was limited and did not exceed a plateau value of 0.53 (after a reaction time of 3 h) or 0.57 (after 30 min) for y-carboxyethyl- s-caprolactam and y-aminoethyl- s-caprolactam, respectively. The limiting monomer conversion was ascribed to ring-chain equilibria in both cases. The polymerizations could be accelerated by the addition of polyamidation catalysts, such as phosphorous and hypo-phosphoric acids, but no change of the maximum monomer conversion was observed. In a control experiment, 4-aminoethyl-1,7-heptanedioic acid was polymerized via thermal polymerization however, this only resulted in a low molecular mass compound. This was attributed to the much faster rate of the intra- versus the intermolecular amidation reaction. Cross-linked material was obtained, when both monomers were heated for a prolonged time, and loss of NH3 was observed, which was ascribed to amidine formation and deamination. 

Forsberg et al. (41) discovered that trivalent lanthanide salts (i.e. La (CIO.) are powerful catalysts for the formation of pyrimidines ( >50% yield) fA>m acetonitrile and cyclic secondary amines. The lanthanide ion seems to be catalyze the amidine formation from acetonitrile and amine and may be also be involved in further steps of the reactions (eq. 28j). 

Frutos prepared 2-fluoromethylimidazoles via the cyclization of the amidines formed by the Cu(I)-piomoted addition of a-amino acetals to fluoroacetonitrile (Scheme 19) [29]. The reactions were performed either stepwise or in a one-pot fashion (depending upon the removal of Cu salts before or after the cycUzation) in which the amidine formation was carried out in the absence of any solvent followed by the cyclization using TFA or HQ-MeOH. Thus, the addition of (methylamino) acetaldehyde dimethyl acetal and (benzylamino)acetaldehyde diethyl acetal with fluoroacetonitrile followed by cyclization afforded the corresponding 2-(fluoro-methyl)imidazoles in 96 % and 53 % yields, respectively. 

In addition, irrespective of the fact that polymerization has started under anhydrous conditions, water is always generated during amidine formation. Water may give rise to hydrolytic reactions, in particular with acyl lactams and acylamidine stmc-tures, yielding carboxylic end groups (Scheme 10), which take part in the polymerization process as well. 

As compared to the addolytic, aminolytic, and hydrolytic routes, entailing the same reactions involved for unsuhstituted lactams (excluding amidine formation), the polymerization initiated by protic acids, such as HCl, differs for the most part. The most relevant aspeas characterizing the cationic polymerization of N-substituted lactams are, as said already, the absence of the detrimental formation of amidines and a much simpler mechanism compared to that pertaining to N-unsubstituted lactams. 

However, the process is not so simple, implying several types of reactions. The aminolytic CL polymerization exhibits an induction period and its initial rate is proportional to the amine concentration, while the maximum rate of polymerization is proportional to the square root of the amine concentration. The decomposition of the tetrahedral intermediate in this case as well as in the cationic and hydrolytic polymerization, affords amidine and water. The presence of the induction period has been assumed to be associated with slow amidine formation, while the progressive increase of the polymerization rate has been related to the further contribution of the formed carboxylic groups. ... 

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