Imidates. reaction with hydrazine

Dihydro-1,2,4-benzotriazines (485) are obtained from the reaction of A -(2-chlorophenyl)-imidates (484) with hydrazines. They can be oxidized to l-alkyl-l,2,4-benzotriazinium salts (486) (67MI21900). 

The cyclization of formamidincs (24) has been extended to similar reactions of amidrazones (29), which give 1,5-diaminoimidazoles when treated with bases (Scheme 2.2.10). Again, depending on the basic strength, the 4-substituent is cyano or cyanoformimidoyl. The amidrazones are available in almost quantitative yield by treatment of the imidate (27) with hydrazine hydrate at room temperature [35]. 

The product of this reaction is an imide, a diacyl derivative of an amine. Either aqueous acid or aqueous base can be used to hydrolyze its two amide bonds and liberate the desired primary amine. A more effective method of cleaving the two amide bonds is by reaction with hydrazine ... 

An ingenious synthesis of 1-arylisoindolcs has been developed by Vebor and Lwowski, based upon the reaction of an o-phthalimido-methylbenzophenone (41, R = aryl) with hydrazine (Table IV). The benzophenone is prepared by a Friedel-Crafts reaction with o-phthalimidomethylbenzoyl chloride (40). The mechanism of isoindole formation can be represented sehematically by a sequence involving attack by hydrazine at the imide to give the ring-opened hj drazide (42), followed by cyclization to phthalazine-l,4-dione (44) with displacement of the o-aminomethylbenzophenone (43). Intramolecular condensation of the latter can lead, via the isoindolenine... 

The hydrolytic cleavage is usually slow, and requires drastic reaction conditions. A more elegant method is presented by the Ing-Manske procedure, where the A-alkylated imide is treated with hydrazine under milder conditions. In addition to the desired amine 5, the cyclic phthalic hydrazide 6 is then formed ... 

As in 10-55 hydrazides and hydroxamic acids can be prepared from carboxylic esters, with hydrazine and hydroxylamine, respectively. Both hydrazine and hydroxylamine react more rapidly than ammonia or primary amines (the alpha effect, p. 445). Imidates, RC(=NH)OR, give amidines, RC(=NH)NH2. Lactones, when treated with ammonia or primary amines, give lactams. Lactams are also produced from y- and 5-amino esters in an internal example of this reaction. 

The Diels-Alder adduct, anhydride 63, on treatment with hydrazine hydrate in acetic acid for 20 min yielded 252 which on keeping in acetic acid for further 8 h gave the imide derivative 253. This adduct, imide 253, underwent retro-Diels-Alder reaction to eliminate furan giving amino maleimide derivative 254 (Scheme 45) <2005J OC4553>. 

The synthesis of a series of 2-pyridyl-substituted 1,2,4-triazoles was achieved from methyl 4-cyanobenzimidate 88 by reaction with the appropriate acid chloride and hydrazine via the unstable iV-aroyliruidatc intermediate. For example, reaction of 88 with 4-methoxybenzoyl chloride gave the imidate 89, subsequent reaction of which with pyridylhy-drazines 90a and 90b gave 1,2,4-triazoles 91a and 91b (Equation 33) <2004BMC2013>. 

Simple amides are satisfactory protective groups only if the rest of the molecule can resist the vigorous acidic or alkaline hydrolysis necessary for their removal. For this reason, only amides that can be removed under mild conditions have been found useful as amino-protecting groups. Phthalimides are used to protect primary amino groups. The phthalimides can be cleaved by treatment with hydrazine. This reaction proceeds by initial nucleophilic addition at an imide carbonyl, followed by an intramolecular acyl transfer. 

The enantioselective complexation technique can also be applied as one step in the reaction sequence, providing chiral substrates for the next step. We will now discuss the example of Gabriel synthesis between potassium phthalimide 41 and alkyl bromide 42, which leads to optically active amines (Scheme 1) [51], Instead of the complicated preparation of chiral alkyl bromides (halides), imides (43), which are reaction intermediates, have been resolved. Upon treatment with hydrazine and KOH, these gave optically active amines. The chiral host (S,S)-(-)-6 or the chiral biaryl host (,S>(-j-40 was used for the effective resolution of the intermediates 43. Racemic mixtures 43a-d were resolved by complex formation with the host (S,S)-(-)-6 in a mixture of diethyl ether and light petroleum. 

Other groups that react with chloromethyleneiminium salts include hydroxylamines, hydrazines, oximes, imines, azines, anhydrides, imides and ketene O-alkyl-O -silyl acetal derivatives however, reactions with these compounds have been relatively infrequent. 

Reaction of A -(2-chlorophenyl)imidates with hydrazines affords 1-substituted 1,2-dihydro-1,2,4-benzotriazines 3 which are oxidized on standing to 1-substituted 1,2,4-benzotriazinium salts 4.328... 

In most cases these C,N2 fragments are prepared by reaction of activated carboxylic acid derivatives (C, fragment), such as dithiocarboxylates 2, thioesters 3. nitriles 5, imidates 6, amidines 7, thioamides 8, selenoamides 9, selenoesters 11, orthocarboxylates 14, with hydrazine (N2 fragment) and are transformed to l,4-dihydro-l,2,4,5-tetrazines 17 without isolation. Therefore, these syntheses are treated as a (2 + 1 +2+1) fragment method. 

Dihydrotetrazines (340), which can easily be oxidized to 1,2,4,5-tetrazines, can be formed by dimerization of thiohydrazides (337) or amidrazones (338). The ring closure of hydrazidines (339) in a [5 + 1] fashion proceeds well with activated carboxylic acid derivatives such as imidates (341), orthocarboxylates (342) or dithiocarboxylates (343). The [4 + 2] procedure is found in the transformation of 1,3,4-oxadiazoles (346) or 1,4-dichloroazines (345) with hydrazine. Finally diazoalkanes (344) can be dimerized in a [3 - - 3] manner under the influence of a base the dimerization of diazoacetic ester is an early example, leading to 3,6-tetrazinedicarboxylate (48), which is frequently used in (4 -I- 2) cycloaddition reactions with inverse electron demand. Nitrile imines, reactive intermediates which are formed from many precursors, can dimerize in a [3 -I- 3] fashion to form 1,3,4,6-tetrasubstituted 1,4-dihydrotetrazines. These reactions are summarized in Scheme 57. 

Treatment of the N-cyano-imidates (257) with o-hydrazinobenzoic acid gives triazolo[l,5-a]quinazolines (258). The hydrazine attacks the imidate carbon initially, rather than the nitrile group this contrasts with the preferential reaction at the nitrile function of the similar A -cyano-amidines (221) by amines (see p. 253) (Scheme 103). ... 

Several reactions of the triazepine (7) have been examined. Heating (7) at 80°C in benzene results in isomerization to form quantitatively benzo[c]dnnoline iV-imide (8), which is also obtained directly from the diaminobiphenyl (5) by aprotic diazotization without isolation of the triazepine intermediate (7). The triazepine (7) reacts as a masked diazonium compound with hydrazine, hydriodic acid, hydrobromic acid and copper, or diethyl malonate to give the corresponding products (9)-(12), respectively (Scheme 2). 

Recently Hay and co-workers developed a method for preparing PNI that involves the use of a monomer containing imide rings [67]. The reaction of hydrazine with DNTA proceeds in a similar fashion to that in Scheme 1.4 and yields bis(aminoimide) that reacts with 2,2-bis([4-(3,4-dicarboxyphenoxy)phenyl]propane (dianhydride A) in an m-cresoho-dichlorobenzene mixture under the conditions of the single-stage polycondensation to produce poly(ether naphthalenecarboximide) (PENI) (Scheme 1.14) ... 

If 44 reacts with benzyl bromide, the product is AT-benzylphthalimide (45) via a straightforward Sn2 displacement. To generate the amine, the imide can be hydrolyzed by acid-base reactions (1. aqueous base 2. aqueous acid) to give the amine (46) and phthalic acid (47). The reaction of 45 with aqueous hydroxide is an example of an acyl substitution reaction that will be introduced in Chapter 16 (Section 16.8). For several reasons, it will not be discussed at this time. A better procedure has been developed that treats 45 with hydrazine (NH2NH2) to generate amine 46 and a molecule known as a hydrazide, 48. Hydrazide 48 is easily separated from amine 46. A hydrazide is one of those specialized chemicals encountered from time to time, but not discussed in detail. 

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