Ammonia heterocyclic synthesis

The use of carbonyl function is classic approach in heterocyclic synthesis. In case of fluorinated pyrroles this approach was frequently used. Convenient method for synthesis of pyrroles 221 is based on the reaction of fluorinated 5-keto acid esters or amides 220 with ammonia. In case of methyl and ethyl esters amidolysis was... 

This synthesis came shortly after one by Prelog, Kohlberg, Cerkovnikov, Rezek and Piantanida (1937) based on a series of reactions which, with modifications and extensions. Prelog and his colleagues have applied to the syntheses of bridged heterocyclic nuclei, of which this is an example. 4-Hydroxymethyltetrahydropyran (VI R =. OH) is converted via the bromo-compound (VI R = Br) and the nitrile (VI R = CN) into tetrahydropyran-4-acetic acid of which the ethyl ester (VII) is reduced to 4-()3-hydroxyethyl)-tetrahydropyTan (VIII). This is converted by fuming hydrobromic acid into 3-(2-bromoethyl)-l 5-dibromopentane (IX) which with ammonia in methyl alcohol yields quinuclidine (V). 

The Hantsch pyridine synthesis provides the final step in the preparation of all dihydrop-yridines. This reaction consists in essence in the condensation of an aromatic aldehyde with an excess of an acetoacetate ester and ammonia. Tlie need to produce unsymmetrically subsrituted dihydropyridines led to the development of modifications on the synthesis. (The chirality in unsymmetrical compounds leads to marked enhancement in potency.) Methyl acetoacetate foniis an aldol product (30) with aldehyde 29 conjugate addition of ethyl acetoacetate would complete assembly of the carbon skeleton. Ammonia would provide the heterocyclic atom. Thus, application of this modified reaction affords the mixed diester felodipine 31 [8]. 

Nitroenamines and related compottnds have been used for synthesis of a variety of heterocyclic compottnds. Rajappahassummaiized the chemistry of nltroenamines fseeSecdon4.2. Anga and coworkers have developed the synthesis of heterocycles based on the reacdon of nltropytidones or nltropyrimldmone v/ith nucleophiles. For example, 2-subsdntted 3-nltro-pyridmes are obtained by the reacdon of l-methyl-3,5-dinitro-2-pyridones wiih ketones in the presence of ammonia fEq. 10.82. ... 

A fused heterocyclic compound (146) distantly related to the antiinflammatory agent cintazone (Chapter 12), which itself can be viewed as a cyclized derivative of phenylbutazone, retains the activity of the prototype, in the synthesis of 146, reaction of the nitroaniline 139 with phosgene gives intermediate 140, which is then reacted with ammonia to afford the substituted urea (141). Cyclization of the ortho nitrourea function by means of sodium hydroxide leads to the N-oxide (142) this last reaction represents... 

Our own group is also involved in the development of domino multicomponent reactions for the synthesis of heterocycles of both pharmacologic and synthetic interest [156]. In particular, we recently reported a totally regioselective and metal-free Michael addition-initiated three-component substrate directed route to polysubstituted pyridines from 1,3-dicarbonyls. Thus, the direct condensation of 1,3-diketones, (3-ketoesters, or p-ketoamides with a,p-unsaturated aldehydes or ketones with a synthetic equivalent of ammonia, under heterogeneous catalysis by 4 A molecular sieves, provided the desired heterocycles after in situ oxidation (Scheme 56) [157]. A mechanistic study demonstrated that the first step of the sequence was a molecular sieves-promoted Michael addition between the 1,3-dicarbonyl and the cx,p-unsaturated carbonyl compound. The corresponding 1,5-dicarbonyl adduct then reacts with the ammonia source leading to a DHP derivative, which is spontaneously converted to the aromatized product. 

The reaction of iminium ions with dihydropyridines is a method, suggested from biosynthetic studies, for the formation of carbon-carbon bonds to these six-membered heterocycles. The 1,4-dihydropyridine (8), a presumed intermediate from the reaction of ammonia with glutaraldehyde, reacts with the cyclic iminium ion (159) to give, after oxidation, nicotine (160) (72CC1091). Another example of this reaction has provided a total synthesis of olivacine (163). The 1,2-dihydropyridine ring system in (161), generated from its chromium tricarbonyl complex, was observed to undergo an intramolecular cyclization... 

The well-known application of 2,4,6-tris(ethoxycarbonyl)-l,3,5-triazine as a diene in inverse electron demand Diels-Alder cyclizations was adapted for the synthesis of purines <1999JA5833>. The unstable, electron-rich dienophile 5-amino-l-benzylimidazole was generated in situ by decarboxylation of 5-amino-l-benzyl-4-imidazolecarboxylic acid under mildly acidic conditions (Scheme 54). Collapse of the Diels-Alder adduct by retro-Diels-Alder reaction and elimination of ethyl cyanoformate, followed by aromatization by loss of ammonia, led to the purine products. The reactions proceeded at room temperature if left for sufficient periods (e.g., 25 °C, 7 days, 50% yield) but were generally more efficient at higher temperatures (80-100 °C, 2-24 h). The inverse electron demand Diels-Alder cyclization of unsubstituted 1,3,5-triazine was also successful. This synthesis had the advantage of constructing the simple purine heterocycle directly in the presence of both protected and unprotected furanose substituents (also see Volume 8). 

Paal-Knorr synthesis It is a useful and straightforward method for the synthesis of five-membered heterocyclic compounds, e.g. pyrrole, furan and thiophene. However, necessary precursors, e.g. dicarbonyl compounds, are not readily available. Ammonia, primary amines, hydroxylamines or hydrazines are used as the nitrogen component for the synthesis of pyrrole. 

FORMAMIDE. Form amide (meibanamide), HCONHi. is the lirsi member of the primary amide series and is the only one liquid at room temperature. II is hygroscopic and has a faint odor of ammonia. Formamide is a colorless to pale yellowish liquid, freely miscible with water, lower alcohols and glycols, and lower esters and acetone. It is virtually immiscible in almost all aliphatic and aromatic hydrocarbons, chlorinated hydrocarbons, and ethers. By virtue of its high dielectric constant, close to that of water and unusual for an organic compound, formamide has a high solvent capacity lor many heavy-metal salts and for salts of alkali and alkalinc-carth metals. It is an important solvent, in particular for resins and plasticizers. As a chemical intermediate, formamide is especially useful in the synthesis of heterocyclic compounds, pharmaceuticals, crop protection agents, pesticides, and for the manufacture of hydrocyanic acid. 

Similar enamine cyclization processes occur in several other successful heterocycle syntheses, e.g. in the Fischer indole synthesis. In this case, however, a labile N—N bond of a l-aryl-2-vinylhydrazine is cleaved in a [3,3]-sigmatropic rearrangement, followed by cyclization and elimination of ammonia to yield the indole (B. Robinson, 1963, 1969 R. J. Sundberg, 1970). Regioselectivity is only observed if R2 contains no enolizable hydrogen, otherwise two structurally isomeric indoles are obtained. Other related cyclization reactions are found in the Pechmann synthesis of triazoles (T.L. Gilchrist, 1974) and in G. Bredereck s (1939) imidazole synthesis (M.R. Grimmett, 1970). 

Treatment of meso-ionic l,2,3,4-oxatriazole-5-thiones (286) (Section VII, I, 3) with boiling ethanolic ammonia yields the isomers 297.200 These belong to a new class of meso-ionic heterocycle, which by O-alkylation with triethyloxonium tetrafluoroborate yield the salts 298.200 These are useful intermediates for the synthesis of a number of novel types of meso-ionic 1,2,3,4-thiatriazoles (299,207 300,200 and 301).212... 

Asinger-type condensations allow the synthesis of a wide range of 5-, 6- and 7-membered heterocyclic compounds, such as 2,5-dihydro-l,3-oxazolines718 and 5,6-dihydro-2//-l,3-oxazines719. In the latter, a /J-hydroxyaldehyde is treated with a ketone (or aldehyde) and ammonia, giving up to 50% yields of the useful heterocyclic product (equation 203). 

As a result of interaction of 843 and pyridine, the adduct 845 is formed [53], The structures of coordination compounds 844 and 845 were proved by x-ray diffraction. As shown above (Sec. 3.4.3.2), the direct ammonia synthesis [55,56] with participation of various ligands (especially aliphatic, aromatic, and heterocyclic amines, aminoalcohols), elemental metals (or their oxides), and NH4SCN in mostly non-aqueous media, opens definite possibilities for obtaining thiocyanate complexes. In this respect, transformation (4.9) should be mentioned [57] ... 

N,N -diarylglyoxaldihydrazonoyl dihalides (91), versatile intermediates for the synthesis of heterocyclic systems, reacted with KSeCN in ethanol at reflux to yield 2,2 -bi(4-aryl-4,5-dihydro-5-imino-l,3,4-selenadiazoles) (92) directly in good yield. Similarly, the reaction of the dihalides with selenourea and acylselenourea gave the biselenadiazoles in one step by elimination of ammonia or aniline. [94PS129]... 

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