From Amino Ketones

Other reagents are available for introducing the 2-oxo group. Thus, 2-amino-3-pyridyl phenyl ketone, ethyl carbamate, and zinc chloride, fused for 45 min at 230°C, gave a good yield of 4-phenylpyrido[2,3-d ] pyrimidin-2-one (see 3). In addition, 2-ferf-butylamino-3-pyridylphenylketonimine, phosgene, and triethylamine, stirred in cold benzene for 10 min, produced 

1- tert-butylamino-4-phenylpyrido[2,3-d]pyrimidin-2-one in good yield.103 

2- Amino-5-chlorobenzophenone and methyl isocyanate, refluxed 15 hr in dichloromethane, gave an excellent yield of 6-chloro-3-methyl-4-phenyl-quinazolin-2-one methyl isothiocyanate in ethanol furnished the corresponding 2-thione.104 

Several other reactions of isatin derivatives will now be described. Isatin-2-oxime (93) underwent a Beckmann-like rearrangement to quinazoline-2,4-dione when heated with dilute sodium hydroxide (no yield given).107 

2-Methoxalylamidoacetophenone (95) and ethanolic ammonia (5 hr at 150°C) gave 4-methylquinazoline-2-carboxamide (good yield).110 

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Most syntheses of 1,5-diazocine systems starting from / -amino ketones employ 2-aminobenzo-phenone or its derivatives. Upon heating in an inert solvent with an acid catalyst, a dimerization... 

Heteroatom rings, such as that found in quinoline derivatives, can be generated from amino-ketones with [hydroxy(tosyloxy)iodo]benzene and perchloric acid. Cyclic imines are converted to pyridine derivatives with NCS and then excess sodium methoxide. ... 

The overall process from amino ketone 36 to Efavirenz (1) required four steps with an overall yield of 72% and quite high purity of the isolated 1, as described above. This process supported initial marketing of Efavirenz but there were a few drawbacks. The key asymmetric addition of acetylide required 2equiv of precious cyclopropylacetylene (37). In addition, two steps out of the total four steps were protection with pMB and its deprotection. 

An important preparation of pyrazines 430 is from -amino ketones or their monooximes which spontaneously condense to give 2,5-dihydropyrazines 429 (Scheme 199) . The -amino ketones are often prepared in situ by reduction of appropriate precursors, and the dihydropyrazines are usually oxidized to pyrazines before isolation (cf. Section 3.Z.2.3.3). Catalytic reduction of -azido ketones <1980OPP265> or -nitro ketones leads to -amino ketones, which dimerize spontaneously. 

An example that illustrates the advantages that an enol ether can offer vis-d-vis the parent carbonyl compound in iminium ion cyclization is found in Overman and Goldstein s construction of the allopumi-liotoxin A alkaloid intermediate (32). A variety of Mannich conditions failed to produce (32) from amino ketone (28), but yielded only cyclopentaoxazolidine (29). However, intramolecular Mannich cyclization was accomplished in 52% yield at low temperature by treatment of the bicyclic trimethylsilyl enol ether (30) with 1.1 equiv. of trimethylsilyl trifluoromethanesulfonate (Scheme 15). Remarkably, (32) produced in this manner was racemic, a result ascribed to facile [3,3] sigmatropic rearrangement of intermediate (31). 

The p-substituted amino ketones can be reduced readily to the more stable P-dialkylamino alcohols, many of which are useful local anaesthetics. Thus the local anaesthetic Tutocaine is made from the Mannich base derived from formaldehyde, methyl ethyl ketone and dimethylamine, followed by reduction and conversion into the p-aminobenzoate ... 

In a second attempt to extend the scope of Lewis-acid catalysis of Diels-Alder reactions in water, we have used the Mannich reaction to convert a ketone-activated monodentate dienophile into a potentially chelating p-amino ketone. The Mannich reaction seemed ideally suited for the purpose of introducing a second coordination site on a temporary basis. This reaction adds a strongly Lewis-basic amino functionality on a position p to the ketone. Moreover, the Mannich reaction is usually a reversible process, which should allow removal of the auxiliary after the reaction. Furthermore, the reaction is compatible with the use of an aqueous medium. Some Mannich reactions have even been reported to benefit from the use of water ". Finally, Lewis-acid catalysis of Mannich-type reactions in mixtures of organic solvents and water has been reported ". Hence, if both addition of the auxiliary and the subsequent Diels-Alder reaction benefit from Lewis-acid catalysis, the possibility arises of merging these steps into a one-pot procedure. 

As anticipated from the complexation experiments, reaction of 4.42 with cyclopentadiene in the presence of copper(II)nitrate or ytterbium triflate was extremely slow and comparable to the rate of the reaction in the absence of Lewis-acid catalyst. Apparently, Lewis-acid catalysis of Diels-Alder reactions of p-amino ketone dienophiles is not practicable. 

Apparently, 4.54 is extremely reluctant to undergo a retro Mannicli reaction. Riviere demonstrated that this behaviour is not unusual for (3-amino ketones. From the study of a large number of Mannich adducts. Riviere concludes that the retro Mannich reaction requires an aromatic group next to the carbonyl functionality. Qearly, 4.54 lacks this arrangement. 

The wide variety of ketomethylene and amino ketone monomers that could be synthesized, and the abiUty of the quinoline-forming reaction to generate high molar mass polymers under relatively mild conditions, allow the synthesis of a series of polyquinolines with a wide stmctural variety. Thus polyquinolines with a range of chain stiffness from a semirigid chain to rod-like macromolecules have been synthesized. Polyquinolines are most often prepared by solution polymerization of bis(i9-amino aryl ketone) and bis (ketomethylene) monomers, where R = H or C H, in y -cresol with di-y -cresyl phosphate at 135—140°C for a period of 24—48 h (92). 

The exploration of the chemistry of azirines has led to the discovery of several pyrrole syntheses. From a mechanistic viewpoint the simplest is based upon their ability to behave as a-amino ketone equivalents in reactions analogous to the Knorr pyrrole synthesis cf. Section 3.03.3.2.2), as illustrated in Schemes 91a and 91b for reactions with carbanions. Parallel reactions with enamines or a-keto phosphorus ylides can be effected with electron-deficient 2//-azirines (Scheme 91c). Conversely, electron-rich azirines react with electron deficient alkynes (Scheme 91d). 

Azirines react with alcohols in the presence of alkoxides to give alkoxyaziridines (67JA4456). Further treatment with alcohol and alkoxide results in the formation of amino ketone acetals. Alkoxyaziridines are not isolated in general from the acid-catalyzed addition of methanol to azirines. Azirines are also known to react with amines (66JOC1423). Frequently the initially produced adducts undergo subsequent transformations. 

Rearrangement of N.N-dimethyttiydrazone or tosylate derivatives of oxime to azirines and from there to a-amino ketones. 

Tnflrc anhydride is a useful reagent for the preparation of covalent triflate esters from alcohols, ketones, and other organic substrates [66] In many cases, very reactive triflates can be generated m situ and subjected to subsequent transformation without isolation [94, 95, 96, 97] Typical examples are cyclization of amides into dihydroisoqumolines (equation 45) and synthesis of Al-hydroxy-a-amino acid denvatives (equation 46) via the intermediate covalent triflates... 

Preparation of Heterocyclic Enamines from y- and h-Amino Ketones... 

The salts of some enamines crystallize as hydrates. In such cases it is possible that they are derived from either the tautomeric carbinolamine or the amino ketone forms. Amino ketone salts (93) ( = 5, 11) can serve as examples. The proton resonance spectra of 93 show that these salts exist in the open-chain forms in trifluoroacetic acid solution, rather than in the ring-closed forms (94, n = 5, 11). The spectrum of the 6-methylamino-l-phenylhexanone cation shows a multiplet at about 2.15 ppm for phenyl, a triplet for the N-methyl centered at 7.0 ppm and overlapped by signals for the methylene protons at about 8.2 ppm. The spectrum of 93 ( = 11) was similar. These assignments were confirmed by determination of the spectrum in deuterium oxide. Here the N-methyl group of 93 showed a sharp singlet at about 7.4 ppm since the splitting in —NDjMe was much reduced from that of the undeuterated compound. 

The importance of chemical syntheses of a-amino acids on industrial scale is limited by the fact that the standard procedure always yields the racemic mixture (except for the achiral glycine H2N-CH2-COOH and the corresponding amino acid from symmetrical ketones R-CO-R). A subsequent separation of the enantiomers then is a major cost factor. Various methods for the asymmetric synthesis of a-amino acids on laboratory scale have been developed, and among these are asymmetric Strecker syntheses as well. ... 

The presence of unsaturation in the side chain is also compatible with antihistaminic activity. Mannich condensation of p-chloroacetophenone with formaldehyde and pyrollidine affords the amino ketone, 109. Reaction with an organometallic reagent from 2-bromopyridine gives 110. Dehydration leads to triproli-dine (111). ... 

A solution of a 2-aminobenzophenone (0.1 mol) and an z-amino acid ethyl ester hydrochloride (0.15 mol) in pyridine (200 mL) was refluxed. During the first 4h, 20-50 mL of liquid was allowed to distill and was replaced by fresh pyridine. Heating was continued for a further 11 h, the mixture was evaporated under reduced pressure and H20 and Et20 were added. In most cases some of the reaction product remained undissolved and was filtered off. The aqueous layer was separated, made alkaline and extracted with Et20. The comhined F.t20 phases were washed with H20. dried and evaporated and the reaction product was separated from unchanged amino ketone by crystallization. 

S)- and (+ )-(7 )-l-Amino-2-(methoxymethyl)pyrrolidine- (SAMP and RAMP)-hydrazones derived from methyl ketones and chiral hydrazines are metalated regioselectively at the methyl... 

Addition of ( )-enamines 3, derived from aldehydes and ketones, to various benzylideneimini-um salts 2 has been investigated. The reaction exclusively gives the Mannich bases anti-4 in good to excellent yield (72-94%). Therefore, this method provides an efficient and highly stereoselective route to /i-amino ketones and aldehydes1415. 

A similar microwave-assisted cyclization in the presence of ammonium acetate of an a-ketoamide, obtained by acylation of an a-aminoketone, was recently described for the synthesis of the antifungal agent Nortopsedin D [46]. The problem of the instabiUty of the a-amino ketones was successfully resolved by in situ acylation of the amine derived from Staudinger reaction of the azide 50 with a phosphine (Scheme 16). This ketoamide was... 

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