1.3- 477-Oxazines 2-amino-5,6-dihydro

The substituent R at position 2 proved to determine the type of the product formed in the malonic acid additions of 5,6-dihydro-277-l,3-oxazines 124. For compounds bearing bulky substituents R (Pr , Bn ), /ra j-substituted 1,3-oxazine / -amino acids 125 were formed in diastereoselective additions (Equation 9), while the analogs with less bulky substituents (R = Me, Et) gave C3-symmetrical, nitrogen-bridged, tricyclic 1,3-oxazine derivatives, instead of the corresponding / -amino acids, under the same conditions <1995T139>. 

Functionalized 5,6-dihydro-4// -oxazines are direct precursors of a series of useful products, for example, of proline derivatives (539), unnatural amino acids (540), and some alkaloids (541). 

Substituted amino naphthols were synthesized with reactions of 1-naphthols and the appropriate aldehydes. Some new 2,4-disubstituted-3,4-dihydro-2/f-naphth [i,2-e][i,i]oxazines that are expected to show biological activities were obtained by the ring-closure reactions with these aminonaphthols and various aldehydes. In addition, substituted-1,3-amino-hydroxy compounds, 2, can be used in chiral ligands synthesis. 

Perhydro derivatives of pyrido[l,2-6][l,2]oxazines are frequently applied in the total synthesis of various alkaloids to control the stereochemistry, and 4-(substituted amino)-5-fluoro-7-oxo derivatives of 3,7-dihydro-2//-pyrido[3,2,l-f7][2,l]benzoxazine- and l,2,3,7-tetrahydropyrido[3,2,l-//]cin-noline-8-carboxylic acids are considered as a subfamily of the third generation of antibacterial quinolones. 

The simplest method for the preparation of dihydro-1,3-oxazines is the cyclization of the corresponding stereoisomeric 1,3-amino alcohol with imi-dates, or acylation of the amino alcohols and subsequent cyclization. 

Bei der Behandlung von N-Phenyl-3.6-dihydro-1.2-oxazin mit Phos-phorsaure erfolgt Hydratation unter Ringspaltung und Orton-Umlage-rung bei Zimmertemperatur und mit 20%iger Saure entsteht N-p-Hydroxyphenyl-4-amino-buten-(2)-ol-(l), bei 60° mit 33%iger Saure cyclisiert dieses wahrend der Reaktion zu N-p-Hydroxyphenyl-A -pyr-rolin 28). 

Diese Reaktionsart ist bei den Addukten aus Butadien-carbonsaure-Derivaten mit der Carboxylgmppe in 3-Stellung allein verwirklicht dabei entstehen 3-Amino-a-pyrone [58, 70, 72). So geht das N-p-Chlorphenyl-3-methoxycarbonyl-6-phenyl-3.6-dihydro-1.2-oxazin bei der Chromato-graphie an Aluminiumoxid in 3-p-Chloranilino-6-phenyl-a-pyron uber (55), der Mechanismus ist analog dem der Pyrrolbildung. 

Alkaline hydrolysis of of 5,6-dihydro //-l,3-oxazines is a convenient method via which to obtain the corresponding 1,3-amino alcohols or their A -acyl derivatives <1996CC1629>. The yields are usually excellent, as in the transformation of 2,4,4-trimethyl-5,6-dihydro //-l,3-oxazine 130 to 3-amino-3-methylbutan-l-ol 131 (Equation 11) <2001JLR265>. 

Acidic hydrolysis of 2-trichloromethyl-5,6-dihydro //-oxazine derivatives gave the corresponding amino alcohols in high yields <1996GC355, 1997TL607, 1998CC761>. 

Reduction of cycloalkane-condensed 2-phenyl-5,6-dihydro-4//-l,3-benzoxazines 144 with lithium aluminium hydride (LAH) afforded A -benzyl-substituted 2-(aminomethyl)cycloalkanols 145 in a reductive ring opening via the ring-chain tautomeric tetrahydro-l,3-oxazine intermediates. Catalytic reduction of 1,3-oxazines 144 under mild conditions in the presence of palladium-on-carbon catalyst similarly resulted in formation of the A -benzyl-1,3-amino alcohols 145. When the catalytic reduction was performed at elevated temperature at hydrogen pressure of 7.1 MPa, the N-unsubstituted 2-(aminomethyl)cycloalkanols 146 were formed in good yields (Scheme 22) <1998SC2303>. 

The ring-opening reactions of l,3-oxazin-6-ones with nucleophiles or electrophiles both result in / -amino acid derivatives. Methanolysis of 2-phenyl-4,5-dihydro-l,3-oxazin-6-one 206 under very mild conditions gave methyl 3-(benzoylamino)propionate 207 (Equation 19) <20030L1575>. 

The asymmetric alcoholytic ring opening of 4-substituted-2-phenyl-4,5-dihydro-l,3-oxazin-6-ones proved to be a efficient method for the preparation of enatiomerically pure /3-amino acid derivatives <2005AGE7466>. Treatment of 2,4-diphenyl-4,5-dihydro-l,3-oxazin-6-one 208 in the presence of the bifunctional chiral thiourea catalyst 211 resulted in formation of an enantiomerically enriched mixture of the unchanged oxazinone (iJ)-208 and allyl (4)-3-benzoyl-amino-3-phenylpropanoate 209. The resolved material (iJ)-208 and the product 209 could easily be separated by a selective hydrolytic procedure that converted oxazinone (iJ)-208 quantitatively into the insoluble iV-benzoyl /3-amino acid 210 (Scheme 37). 

The cyclocondensation of l,3-amino alcohols with carboxylic acid derivatives is a method often applied for the synthesis of 5,6-dihydro-4/7-l,3-oxazines <1996CHEC-II(6)301 >. Ebsorb-4, a weakly acidic zeolite-type adsorbent with 4 A pore size, proved an efficient catalyst of the cyclization of benzoic acid and 3-aminopropanol <2002TL3985>. In the presence of zinc chloride as a catalyst, the expulsion of ammonia drove the reactions of 3-aminopropanol with nitriles to completion, affording 2-substituted 5,6-dihydro-47f-l,3-oxazines in good yields... 

BKC115>. Amides derived from aromatic carboxylic acids and benzotriazole were reported to form 2-aryl-5,6-dihydro-4//-l,3-oxazines with 3-aminopropanol in excellent yields when subjected to microwave irradiation in the presence of SOCI2 <2004JOC811 >. Imidates have often been applied to cyclize 1,3-amino alcohols directly to 5,6-dihydro-l,3-oxazine derivatives <1996ACS922, 2004JHC69, 2004JHC367>. 

When the unsaturated Y-benzoyl a-amino ester 443 was treated with MCPBA, the oxirane 444 formed first immediately underwent an intramolecular rearrangement with cleavage of the oxirane ring by attack of the amide oxygen to give a 3 1 mixture of two cis- and /ra r-isomers of 5,6-dihydro-47/-l,3-oxazine derivatives 445 and 446, the configurations of which were determined via their 0-3,5-dinitrobenzoyl derivatives (Scheme 85) <2003M69>. 

Amino-l,4-naphthoquinone 492 was reacted as a bidentate nucleophile in condensations with acetals 493 to form m-2,4 disubstituted-l,4-dihydro-27f-naphth[2,3-,7 [l,3]oxazine-5,10-diones 494 stereoselectively by 6-endo-trig-nng closure of the N,C-dialkylated intermediates (Equation 56) <1995T6565>. 

When 2-amino-l,4-naphthoquinone 492 was reacted with aliphatic aldehydes in the presence of a catalytic amount of TEA, the opposite diastereoselectivity of the reaction was reported. Except for the unsubstituted compound (R = H), the product proved to be a mixture of the diastereomers of l,4-dihydro-2//-naphth[2,3-rf [l,3]oxazine-5,10-diones in which the /ra r-isomer 495 was the predominant component (Equation 57). A slight tendency could be observed for increasing bulkiness of the substituent R to favor a higher proportion of the m-isomer 494 in the diastereomeric mixture <2003MI51>. 

When methyl 5-amino-2,4-pentadienoates 496 were heated with an excess of acetaldehyde in a sealed tube, diastereomeric mixtures of 2,3-dihydro-67/-l,3-oxazine derivatives 497 and 498 were obtained instead of the expected [4- -2] cycloaddition products (Equation 58). Each condensation took place in a stereoselective way to give the /ra r-isomer 498 as the major product <1997CPB27>. 

While this chapter was being edited and revised, new data appeared on the chemistry of 1,3-oxazine derivatives. In a recent review on the applications of 1,3-amino alcohols in asymmetric organic syntheses, the use of numerous 1,3-oxazine derivatives for this purpose was discussed <2007CRV767>. A compilation on the progesterone receptor ligands provides a brief summary of the progesterone receptor modulatory effects of 6-aryl-l,4-dihydro-3,l-benzoxazin-2-ones <2007MI374>. 

The alkylation of metalated imines, hydrazones, 4,5-dihydrooxazoles, 4,5-dihydroisoxazoles, 5,6-dihydro-4/7-1,2-oxazines and 2,5-dialkoxy-3,6-dihydropyrazines (i.e., azaenolates) is a commonly used method in asymmetric synthesis of enantiomerically enriched aldehydes, ketones, spiroacetals, amines, /J-oxo esters, carboxylic acids, lactones, 1,3-amino alcohols, /(-hydroxy ketones and amino acids. 

Ready addition of 2-nitrosopyridine to 1,3-dienes gives 3,6-dihydro-1,2-oxazines, e.g. (774) — (773), and condensation with aromatic amines gives azo compounds, e.g. (774) — (775). Nitroso compounds are oxidized by ozone or sodium hypochlorite to the corresponding nitro compounds. 5-Nitrosopyrimidines can be reduced to the 5-amino derivatives or condensed with activated methylene groups. 

Cycloaddition of a-nitroso acrylic esters (749) to alkenes followed by base hydrolysis provides a route to 5,6-dihydro-4//-l,2-oxazine-3-carboxylic acids (750). These heterocycles on heating above 150 °C decarboxylate to furnish y-hydroxynitriles (thus the overall c/s-addition of OH and CH2CN to a double bond), which can be transformed further to y-lactones (751) by treatment with methanolic hydrochloric acid (Scheme 172) (79CC1090). The adducts were also reduced to a-amino esters (752) by the action of aluminum amalgam (Scheme 173) (79CC1089). 

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