1.3- Oxazines tetrahydro-, reactions

H-1,2-Oxazine, 3,6-dihydro-6-(2-pyridyl)-mass spectra, 2, 529 2H-1,2-Oxazine, tetrahydro-synthesis, 2, 92 4H-l,2-Oxazine, 5,6-dihydro-pyrolysis, 3, 999 synthesis, 3, 1017 tautomerism, 3, 999 4H-1,2-Oxazine, 5,6-dihydro-3-methyl-metallation, 1, 484 4H-l,2-Oxazine, 5,6-dihydro-3-nitro-reactions, 3, 1000 6H-l,2-Oxazine, 3,5-diphenyl-stability, 3, 997 synthesis, 3, 1014... 

It was recently shown that the formation of a Schiff s base is the first step of the reaction between 3-aminopropan-l-ol and an aldehyde. The action of acid chlorides, such as tosyl chloride, on the SchifTs base forms the W-acyl derivative of tetrahydro-1,3-oxazine. 

A similar reaction of y-bromopropyl derivatives under the influence of silver nitrate was described by Kohn as early as 1904. The 3-hydroxyketone formed from chloral and acetophenone can react with a chlorocarbamate to yield a pseudourethane which is probably a 4-hydroxy-2-0X0 tetrahydro-l,3-oxazine. ... 

A number of simple reactions are now known which form 2-oxo-tetrahydro-1,3-oxazine (18). Here, also, 3-aminopropanol and some of its derivatives are frequently used, Cyclizing reagents are carbonic acid esters in strongly basic medium, " ethyl chloropropionate, trichloracetic esters, or phenyl isocyanate. An example of the first of these methods is ... 

The simple ring opening of tetrahydro-1,3-oxazine derivatives is not the only possible reaction of these heterocyclic compounds catalyzed by mineral acids. An interesting rearrangement of 6-aryl-6-alkyltetrahydro-l,3-oxazines when warmed with concentrated hydrochloric acid was found by Schmiedle and Mansfield ... 

Reaction of tetrahydropyridin-4-one 119 and l,r-carbonyldiimidazole furnished l,3,4,4n,5,6-hexahydropyrido[l,2-c][l,3]oxazine-l,6-dione 120 (99JA2651). Similarly, pyrido[l,2-c][l,3]oxazine-l-one 121 and [1,3] oxazino[4,3-n]isoquinoline-4-one 122 were prepared from the respective 2-(2-hydroxypropyl)piperidine and l-(2-hydroxypropyl)-1,2,3,4-tetrahy-droisoquinoline (99JOC3790). Reaction of a 2 1 diastereomeric mixture of l-(l,2-dihydroxyethyl)-6,7-dihydroxy-l,2,3,4-dihydroisoquinolines 123 and 124 with l,l -carbonyldiimidazole gave a 2.7 1 mixture of 1,9,10-trihy-droxy-l,6,7,ll/)-tetrahydro-2//,4//-[l,3]oxazino[4,3-n]isoquinoline-4-ones 125 and 126, which were separated on preparative TLC plate (99BMC2525). 

Treatment of tert-butyl (2/. )-2-(2-propcny lidene (piperidine-1-carboxylate with McjSil and PhOH yielded 3-substituted-3,4,7,8-tetrahydro-l//,6//-pyrido[l,2-c][l,3]oxazin-l-ones <2005T1595>. Reaction of l-(benzoxycarbonyl)2-styrylpiperidin-4-one with I2 resulted in the formation of r-3,4a-//-/ra r-4-//-4-iodo-3-phenylperhydropyrido[l,2-d-[l,3]oxazine-l,6-dione <2002JOC1972>. A diastereomeric mixture of 3-iodomethylperhydropyrido[ 1,2 z [ 1,3]oxazin-l-ones (e.g., 178) was obtained by intramolecular iodocarbamation of l-(alkoxycarbonyl)-2-allylpiperidines (e.g., 177) with I2 (Equation 34) <1999JOC8402, 2002OL3459>. 

The tetrahydro-[l,3]oxazino[3,4-b][l,2]oxazin-8-one 389 was prepared by cycloaddition reaction of the C-nitroso derivative 408 (Scheme 65) <1999TL4391>. 

It should be noted that specially purified individual stereoisomers of six-membered cyclic nitronates were used in coupling with silyl ketene acetal. Hence, the mechanistic model of the C,C-coupling reaction can be discussed on the basis of the configurations of the stereocenters of the starting nitronates of intermediate cations (357) (see Section 3.5.2.1), and the resulting tetrahydro-oxazines (358) (for more details, see below). It should be noted that most of C,C-coupling reactions of six-membered cyclic nitronates with silyl ketene acetal are characterized by a very high diastereoselectivity. 

In an attempt to improve the enantioselectivity, following the precedent from Ponsford and Southgate,188 Hashimoto demonstrated that the tetrahydro-l,3-oxazine system gave great selectivity in the C-H activation reaction. Indeed, highly selective formation of the / -lactam 60 was accomplished in up to 94% yield and 96% ee using Rh2(V-PTA)4 (Equation (51)).189 This strategy was applied in a novel approach to a key intermediate 61 in the synthesis of trinem 62 (Equation (52)).190,191... 

To increase the yields of the ring closure reactions, a new method was developed that was successfully applied for the synthesis of alicyclic fused systems of both the parent oxazolidine-2-thione and tetrahydro-1,3-oxazine-2-thione (85S1149). As an example, the synthesis of 2-thioxoperhydro-l,3-benzoxazine 103 is described. The dithiocarbamate 101, prepared from the amino alcohol 100, carbon disulfide and triethylamine, was treated with ethyl chloroformate in the presence of triethylamine, to give the thioxo derivative 103 via the transition state 102 (85S1149). In this way, the fused-skeleton thioxooxazines (91, X = S, 92) can be prepared with considerably higher yields (50-70%) than by the earlier methods (85S1149). 

The ring-chain tautomerism of tetrahydro-l,3-oxazines is very sensitive to the stability differences, the substituents and the ring-fusion effect (Section IV,A). It also reveals a considerable stability difference in favor of the cis isomers. In the reactions of the cis- and trans-2-amino-l-cyclohexanols, as compared with the hydrindane analog systems, where the heteroatoms form an oxazolidine ring cis- or tra 5-fused with cyclohexane, the corresponding stability differences were again found to be in favor of the cis isomer (93JOC1967). 

Hydrolytic reactions can also be applied in the synthesis of aldehydes or ketones via the corresponding 1,3-oxazine derivatives. The anion formed from 3-methyl-2-(4-pyridyl)tetrahydro-l,3-oxazine 155 on treatment with BuLi proved to react with various electrophiles (alkyl halides, carboxylic esters, acid chlorides, or aldehydes) exclusively at position 2 of the 1,3-oxazine ring and not at the pyridine nitrogen atom. The readily formed 2,2-disubstituted-l,3-oxazine... 

Because of their ring-chain tautomeric character, tetrahydro-l,3-oxazines can be used as aldehyde sources in acid-catalyzed condensation reactions involving the carbon transfer via the open forms. This approach is especially advantageous in those cases where the aldehydes required for the condensations are unstable or difficult to access <2003EJ03025>. 

By the addition of 2-sulfanylacetic acid to the open tautomeric form of tetrahydro-l,3-oxazines, 3-(3-hydroxypro-pyl)thiazolidin-4-ones were obtained in moderate to good yields. The process proved to be slower than the analogous reactions of oxazolidines <2006RJ01101>. 

When heated at 230 °C, tetrahydro-l,3-oxazines 173, bearing an a,/3-unsaturated ester substituent at position 2, underwent a retro-ene reaction and yielded 5,6-dihydro-477-l,3-oxazines 174 together with methyl 4-methyl-3-pentenoate 175 (Equation 16). For the methyl-substituted oxazine 173 (R = Me), the yields of both products were somewhat higher than those in the reaction of the unsubstituted analog 173 (R = H) <1997JHC501>. 

The A -acyl derivatives of 4-substituted-3,4,5,6-tetrahydro-27/-l,3-oxazin-2-ones proved to behave as effective chiral auxiliaries in asymmetric enolate alkylations and aldol reactions, the stereoselectivities of which were found to be higher for 4-isopropyl than for 4-phenyl derivatives <2006OBC2753>. The transformations of 4-isopropyl-6,6-dimethyl-3-propa-noyl-3,4,5,6-tetrahydro-2/7-l,3-oxazin-2-one 251 to 252 or 253 proceeded with excellent diastereoselectivities (Scheme 47). 6,6-Dimethyl substitution within the oxazine ring facilitated exclusive exocyclic cleavage upon hydrolysis of the C-alkylated and the aldol products 252 and 253, to furnish a-substituted carboxylic acids 254 or a-methyl-/ -hydroxycarboxylic acids 256. 

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