Primary amines cyclization

The diester (429) has been cyclized with ammonia or primary amines to give the esters (430) (72AP2), whilst the related diester (431) has likewise been converted to (432). Similar reactions starting with TV-substituted o-phenylenediamines have been used as the basis of a synthesis of deazariboflavins (433) (77TL2551). 

Diacylhydrazines (32) on heating with a primary amine undergo cyclization to the 1,2,4-triazole derivative (38). It is assumed that the amidrazone (37) is an intermediate in the reaction. Most practical syntheses of 1,2,4-triazoles now utilize an amidrazone or a derivative of this alicyclic intermediate containing three nitrogen atoms, and these variations are discussed in Chapter 4.12. 

The formation of 3-acylpyridinium compounds (59/) from primary amines and l-methoxybutene-3-one can be regarded as the enamine alkylation of a vinylogous amide followed by cyclization and loss of methanol and water. 

Aniline 77 was converted into its diazonium salt with nitrous acid and this was followed by reduction with stannous chloride to afford the corresponding arylhydrazine 78. Condensation of 78 with 3-cyanopropanal dimethylacetal 79 gave the arylhydrazone 80. Treatment of 80 with PPE resulted in cyclization to indole 81. The nitrile group was then reduced to the primary amine by catalytic hydrogenation. Reaction of the amine with excess formalin and sodium borohydride resulted in Imitrex (82). 

Separately, Paal and Knorr described the initial examples of condensation reactions between 1,4-diketones and primary amines, which became known as the Paal-Knorr pyrrole synthesis. Paal also developed a furan synthesis in related studies. The central theme of these reactions involves cyclizations of 1,4-diketones, either in the presence of a primary amine (Paal-Knorr pyrrole synthesis), in the presence of a sulfur(II) source (Paal thiophene synthesis), or by dehydration of the diketone itself (Paal furan synthesis). 

An interesting extrapolation of this synthesis deals with the preparation of the bispyridinium salt 62 from 1,2-phthalic dicarboxaldehyde and its subsequent reaction with primary amines (92BSB509).Tlie expected diimines 63 readily cyclize so that 2-aryl-l-arylimino-2,3-dihydro-l//-isoindoles 64 can be isolated in excellent yields (90-95%). Contrary to the reactions performed by employing the dialdehyde and amines directly, the syntheses involving the azinium salts do not produce those typical dark-colored complex mixtures of products (77JOC4217 85JHC449) (Scheme 20). 

The reaction of disubstituted diacetylenes with hydrazine hydrate was reported by Darbinyan et al. (70AKZ640). In the first stage the addition of hydrazine to the terminal carbon atom of the diacetylene system is analogous to that of primary amines to diacetylene (69ZC108 69ZC110). With monosubstituted diacetylenes (R = H), hydrazine adds to the terminal triple bond. This leads to the formation of vinylacetylenic hydrazine 22 which cyclizes to dihydropyrazole 23 subjected to further isomerization to the pyrazole 25. It is possible that hydrazine 22 undergoes hydration to the ketone 24 which can easily be cyclized to the pyrazole 25... 

The cyclization of the imine 158 is believed (81UK1252) to involve the addition of the second formamide molecule to C-3 (at least primary amines readily add in a similar manner to such systems). 

Alkylation lo yield a leriiary amine may occur easily if the formation involves cyclization (ii). Catalysts may have a marked influence. In reductive alkylation of ammonia wilh cyclohexanones, more primary amine was formed over Ru and Rh and more secondary amine over Pd and Pt. Reduction of the ketone to an alcohol is an important side reaction over ruthenium. 

A useful route to 2,1,3-benzothiadiazoles is the F -catalyzed cyclization of l-(4-X-C6F4)-3-trimethylsilyl-l, 3-diaza-2-thiallenes [90JFC(50)359]. Fluoride ion catalysis is also used in the formation of heterocycles from pentafluorobenzoyl and -phenoxy compounds (81BCJ3447). Pentafluoro-phenylcarbonimidoyl dichloride with primary amines gave guanidines,... 

Ring-opening products derived from primary amines are attractive precursors for the preparation of (3-lactams [57]. With methylmagnesium bromide as the base, diamino esters 33 cyclized readily in THF and stereospecifically generated anti-3-amino- 3-lactams 34 (Table 12.15). 

Methyl 3-(2-phenylsulfonylethyl)-2-quinoxalinecarboxylate 1,4-dioxide (66) and diethylamine gave only methyl 3-(2-diethylaminoethyl)-2-quinoxalme-carboxylate 1,4-dioxide (67) (Et2NH, MeCN, 20°C, 2 h 40%) ° when ammonia or a primary amine was used similarly, the analogous (unisolated) product (68, R = H or alkyl) underwent spontaneous cyclization to afford, for... 

Other cyclizations at phosphorus have been observed when certain phosphinates were used in the acid-catalyzed Mannich reaction. As observed previously with various phosphonous acid derivatives, reaction of aliphatic phosphinic acids with primary amines favored the formation of 2 1 adducts (73). Thus, glycine and other a-amino acids reacted under the typical conditions with excess formaldehyde and alkyl phosphonous acids to give the bis-phosphinylmethyl adducts 125. 

One of the most common approaches to pyrrole synthesis is the Paal-Knorr reaction, in which 1,4-dicarbonyl compounds are converted to pyrroles by acid-mediated dehydrative cyclization in the presence of a primary amine. The group of Taddei has reported a microwave-assisted variation of the Paal-Knorr procedure, whereby a small array of tetrasubstituted pyrroles was obtained (Scheme 6.181) [342], The pyrroles were effectively synthesized by heating a solution of the appropriate 1,4-dicarbonyl compound in the presence of 5 equivalents of the primary amine in acetic acid at 180 °C for 3 min. The same result was obtained by heating an identical mixture under open-vessel microwave conditions (reflux) for 5 min. Interestingly, the authors were unable to achieve meaningful product yields when attempting to carry out the same transformation by oil-bath heating. 

Alternatively, Ballini devised a new strategy to synthesize tri-alkylated pyrroles from 2,5-dialkylfurans and nitroalkanes <00SL391>. This method involves initial oxidation of 2,5-dimethylfuran with magnesium monoperoxyphthalate to cA-3-hexen-2,5-dione (6). Conjugate addition of the nitronate anion derived from the nitro compound 7 to 6 followed by chemoselective hydrogenation of the C-C double bond of the resulting enones 8 (obtained by elimination of nitrous acid from the Michael adduct) completes the conversion to the alkylated y-diketones 9. Final cyclization to pyrroles 10 featured improved Paal-Knorr reaction conditions involving reaction of the diketones with primary amines in a bed of basic alumina in the absence of solvent. 

A similar but simpler 4-imino-hexahydropyrrolo[l,2-tf]pyrazin-l(277)-one 311 was prepared starting from the product obtained by nucleophilic substitution of a primary amine to the bromoacetamide of the L-prolylnitrile 310 (Scheme 40). The cyclization occurred directly in basic medium by refluxing for 96 h in EtOAc. This compound showed a potent activity as an orally bioavailable dipeptidyl peptidase IV inhibitor with anti-hyperglycemic properties <2003JME2774>. 

Piperidines. Grieco et al. have described a general synthesis of piperidines by reaction of the acid salt of a primary amine with an allylsilane and 2 equiv. of formaldehyde in water. The reaction involves reaction of iminium ion (a), derived from the amine and formaldehyde, with the allylsilane to form a homoallylamine (b), which can form a second iminium ion (c), which cyclizes with capture of water to the piperidine. 

---