Hydroxamates cyclization

Earlier reported syntheses have been shown to give isoxazolin-5-ones. Other isoxazolin-3-ones have been prepared by the reaction of methylacetoacetic esters and hydroxylamine. An additional synthesis was reported by the action at 0°C of hydroxylamine on ethyl -benzoylpropionate to produce an insoluble hydroxamic acid which cyclized on acid treatment. The hydroxamic acid acetal was similarly transformed into the isoxazolin-3-one (Scheme 149) (71BSF3664, 70BSF1978). 

Krogsgaard-Larsen and co-workers have protected the P-keto functionality as a ketal as a modification to the traditional conditions so attack of hydroxylamine is directed towards the ester. They prepared hydroxamic acid 10 from ester 9 then cyclized with sulfuric acid to isoxazole 11, in route to 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), a selective GABAa receptor agonist studied clinically for insomnia. 

In 2000, an efficient three-step procedure for the synthesis of 5-substituted 3-isoxazolols (without formation of undesired 5-isoxazolone byproduct) was published. The method uses an activated carboxylic acid derivative to acylate Meldrum s acid, which is treated with A,0-bis(ten-butoxycarbonyl)hydroxylamine to provide the N,0-di-Boc-protected P-keto hydroxamic acids 14. Cyclization to the corresponding 5-substituted 3-isoxazolols 15 occurs upon treatment with hydrochloric acid in 76-99% yield. 

A variety of condensation processes can lead to cyclic hydroxamic acids. These involve either the condensation of two molecules or the intramolecular cyclization of a single compound. In some cases, a primary hydroxamic acid function is already present and formation of a cyclic compound can arise by suitable reaction on nitrogen. These processes will be dealt with first. 

Shaw and McDowellhave prepared imidazolone derivatives by cyclization of a-acylamino amides. In a variation of this reaction the azlactone (30) was gradually converted to the hydroxamic acid (31) by methanolic hydroxylamine. Sodium methoxide and hydroxylamine readily gave the acyclic hydroxamic acid (32) which could be cyclized to 31 by dilute acid. Benzyloxyurea has been used in the sjrnthesis of pyrimidine hydroxamic acids (33) by reaction with /S-diketones followed by catalytic hydrogenation of the benzyl group. Protection... 

In general, a hydroxamic acid function results from the condensation of a hydroxylamine group with a carboxylic acid derivative. If these two groups are positioned suitably in the same molecule, spontaneous cyclization can occur. The most usual technique involves... 

Other zinc reductions have been used extensively. Zinc dust in aqueous ammonium chloride is a standard reagent for the reductive cyclization of nitro esters to hydroxamic acids. These reactions are usually carried out at low temperatures (0°-10°) to avoid further reduction. Despite the fact that good yields can often be obtained, these reductions are highly capricious, depending on the quality of the zinc (impurities seem to improve the reaction) and other unknown factors. 

Perhaps the most reliable method for the reductive cyclization of a nitro ester to a hydroxamic acid is that which involves treatment with sodium horohydride in the presence of palladium on charcoal. Although under these conditions aromatic nitro compounds are reduced to amines, o-nitro esters such as 53, in which the ester group is suitably oriented with respect to the nitro group, give good yields of cyclic hydroxamic acids (54). Coutts and his co-... 

N-Acylnitroso compounds 4 are generated in situ by periodate oxidation of hydroxamic acids 3 and react with 1,3-dienes (e.g. butadiene) to give 1,2-oxazines 5 (Scheme 6.3). The periodate oxidation of 4-O-protected homo-chiral hydroxamic acid 6 occurs in water in heterogeneous phase at 0°C, and the N-acylnitroso compound 7 that is generated immediately cyclizes to cis and tranx-l,2-oxazinolactams (Scheme 6.4) [17a, b]. When the cycloaddition is carried out in CHCI3 solution, the reaction is poorly diastereo-selective. In water, a considerable enhancement in favor of the trans adduct is observed. 

An alternative procedure for the synthesis of aliphatic 2-substituted oxazoline hydroxamates was described by Pirrung and colleagues in the context of preparing inhibitors of E. coli LpxC zinc amidase [378], As shown in Scheme 6.210 a, the protocol involved the cyclization of suitable amides, formed in situ by acylation of a serine-derived 0-2,4-dimethoxybenzyl (DMB)-protected hydroxamate. The cyclization... 

Bromolactamization (11, 76). This reaction can be used for stereoselective preparation of 3,4-disubstituted 3-lactams.1 Thus the P,-y-unsaturated hydroxamic acid 1, prepared in several steps from tiglic acid, on reaction with bromine and K2C03 in aqueous CH,CN cyclizes mainly to a rrans-p-lactam (2). In contrast, the protected a-amino-p,y-unsaturated hydroxamic acid 3, prepared in several steps from L-methionine, cyclizes on reaction with bromine mainly to a ris-p-lactam (4). 

Intramolecular addition of hydroxylamines and hydroxamic acids to the non-activated double bonds is possible through oxidative cyclization. Reaction of O-Acyl fi,y-unsaturated hydroxamates (e.g. 56, equation 38) with bromine provides 3,4-substituted iV-hydroxy -lactams such as 57 with high diastereoselectivity. Analogous reaction of O-benzyl hydroxylamine 58 (equation 39) with iodine results in five-membered cyclization with 2 1 ratio of diastereomers. ... 

Later, ICrook and Miller found that /3-mesylates of benzyl hydroxamate of a-acylserine (149c X = OMs R = = H R = CHiPh) can be directly cyclized under... 

An alternative procedure that generates stable, storable nitrone intermediates 175 from 170, mediated by dry m-CPBA as oxidating reagent, is shown in Scheme 77 ". Conversion of the nitrone 175 to the hydroxylamine by an exchange reaction with hydroxylamine hydrochloride was followed by EDC/HOAt-mediated cyclization to hydroxamic acid 174 (HOAt l-hydroxy-7-azabenzotriazole). 

While the silver and zinc salts were effective Lewis acids for these cyclizations, Kikugawa and coworkers reported that the alkoxynitrenium ions could be generated directly from hydroxamic esters (4) using hypervalent iodine oxidants such as hydroxy(tosyloxy) iodobenzene (HUB) and phenyliodine(lll)bis(trifluoroacetate) (PIFA) . Presumably, with such reagents the reactions proceed through A-(oxoiodobenzene) intermediates (54), which can themselves be regarded as anomeric hydroxamic esters and sources of alkoxynitrenium ions (55) (Scheme 11). 

The formation of numerous ring-substituted spirolactams (53b) employed this methodology, which to date has also found application in a number of natural product syntheses. For example, the critical spirane junction-forming step in the synthesis of the muscarinic Mj receptor antagonist (—)-TAN1251A (58) from L-tyrosine involves PIFA-induced cyclization of the hydroxamic ester 56 to 57 according to Scheme 12 °. 

Romero and coworkers employed FIFA, in the synthesis of PNU-95666E, a selective high-aflinity agonist at the dopamine D2 receptor, by successive nitrenium ion cycliza-tions (Scheme 14). Nitrenium ion cyclizations converted 62 to the lactam 63 which, after reductive demethoxylation to 64, protection as 65 and Af-functionaUzation, afforded the hydroxamic ester (66). A second cyclization with FIFA afforded the benzimidazolinone (67), which was readily reduced to the product 68 in overall yield of 26%. ... 

The cyclizations of hydroxamic acids (204) (Y = O or S), with various reagents capable of undergoing nucleophilic attack twice at the same carbon atom, are very important routes for the synthesis of the ring systems in this chapter (Scheme 39). 

As it has been shown, there are many ways to assemble the 1,4-(oxa/thia)-2-azole ring. Most of them are performed by inter- or intramolecular cyclization of suitable acyclic precursors. Some of them are found to be suitable for the synthesis of various ring systems, by using readily available, and properly modified reactants. Of particular importance are the following (a) the cyclizations of sulfenamides leading to (oxa/thia)azolium salts (Scheme 33) (b) the cyclization of hydroxamic acids (Scheme 39) (c) the dipolar cycloaddition methodology (Scheme 40) (d) the cyclizations of chlorosulfenyl chlorides (Scheme 46) and (e) the cyclizations of chloromethane sulfonamides (Schemes 47 and 48). Other cyclizations reported are preparative ways used mainly for the synthesis of specific compounds and the scope of these reactions has not been widely studied. 

Intramolecular Cyclization of 0-, W-Alkylhydroxylamines and Hydroxamates. 9.4 Cycloaddition of Nitrones to Unsaturated Compounds. 9.5 Hetero-Diels-Alder [4+2]-Reactions... 

A previous review has highlighted the following methods of ring synthesis intramolecular cyclization of oximes, nitro alkenes, and nitrones, and [4+2] cycloaddition reactions <1996CHEC-II(6)279>. In addition to that, this review includes the intramolecular cyclization of hydroxylamines, hydroxamates, hetero-Diels-Alder [4+2], 1,3-dipolar cycloaddition of nitrile oxides to alkenes, and [3+3] cycloaddition reactions. This review does not cover cycloaddition reactions of the [4+2] [3+2] and [4+2] [3+2] [3+2] types which primarily led to heterocycle-fused oxazine ring systems. 

Cyclization of the hydroxamic derivative 127 with ethyl orthoformate gives the pyrazolo[3,4-d] pyrimidines 128 (74GEP2356690). 

The literature contains several references to reductive cyclizations producing cyclic hydroxamic acids like those described above, though not in solid-phase chemistry.43-47 We showed that this reaction competes well with lactam formation. The relative extent of these two reaction pathways is highly dependent on the presence and the nature of other heteroatoms and substituents around the ring system as well as on the conditions used to effect the reduction. 

P,y-Diamino analogues 49 of statine are prepared stereoselectively starting from the O-methyl hydroxamate derivative of N-protected statine. The reaction sequence involves the formation of a p-lactam intermediate obtained by internal cyclization under Mitsunobu conditions.184 Alternatively, direct amination of either a p-oxo ester 31 followed by reduction of the resulting enamine 50, 85 or by reduction of the corresponding ,p-unsaturated ester, 88 gives an enantiomeric mixture of the corresponding unprotected p-amine, which is protected by a carbamate prior to chromatographic separation (Scheme 20). 

Rearrangement is also observed in the irradiation of Formula 450 which gives the hydroxamic acid (Formula 451) (203). This interesting rearrangement probably involves ring opening in the alkoxy radical (Formula 452) followed by recombination with nitrous oxide and cyclization (203). Oxidative fission of alkoxy radicals produced in nitrite... 

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