Perhydro-1,3-benzoxazines

Radical cyclization of perhydro-l,3-benzoxazines 64, promoted by Bu4SuH in the presence of AIBN gave a mixture of perhydropyrido[2,l-6][1,3]benzoxazin-9-ones 65 and 66 and seven membered tricyclic derivatives 67 and 68, formed in a 6-exo and 7-endo cyclization process, respectively (99TL2421). Cyclization of parent acrylamide 64 (R = R = H) occured with moderate regioselectivity (6-exo/7-endo ratio 65 35) and poor stereoselectivity (65/66 ratio 42 43). The presence of a /3-methyl group in... 

Diastereoseleetive 6-exo-trig radieal eyelization of (-)-perhydro-l,3-benzoxazines 69, 71, 74 with Bu3SnH and AIBN gave a diastereomerie mixture of perhydropyrido[2,l-Z)][l,3]-benzoxazines 39, 70, and 72, 73, and 40, 75, respeetively (00TA2809). 

Radical cyclization of perhydro-l,3-benzoxazines 518, promoted by Bu vSnI I in the presence of 2,2 -azobis(2-methylpro-pionitrile) (AIBN) gave a mixture of perhydropyrido[2,T ][l,3]benzoxazin-9-ones 519 and 520 and the seven-membered tricyclic derivatives 521 and 522, formed by a 6-exo- and a 7-rwr/o-cyclization process, respectively (Scheme 54) < 1999TL2421 >. Cyclization of parent acrylamide 518 (R = R1 = H) occurred with moderate regioselectivity (()-exo/7-endo ratio = 65 35) and poor stereoselectivity (519/520 ratio = 42 43). The presence of a [1-methyl group in crotylamide 518 (R = Me, R1 = H) disfavored the 7-/w/ -cyclization process, but did not influence the stereoselectivity of the cyclization (519/520 ratio = 66 34). The presence of an a-methyl group in methylacrylamide 518 (R=H, R1 Me) caused a retardation of the 6-oeo-attack, favoring the 7-/w/ -cyclization with a higher stereoselectivity (521/522 ratio = 75 12). 

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. 

Both single and double cyclizations of the Schiff bases 65A and 66A occur in the multicomponent tautomeric mixtures derived from as- and /ra t-cyclohexane aminodiols 69 and 70, to give monocyclized ring forms of C-2-epimeric perhydro-l,3-benzoxazines (B and G) and oxazolidines (D and E), besides 7,ll-dioxa-9-azatricyclo[7.2.1.0 °]-dodecane diastereomers 67 and 68 (Scheme 10). The tautomeric ratios are found to satisfy by Equation (1) (Table 1) and are influenced by the cis- or rra t-geometry of the cyclohexane substituents in the Schiff base (A). For the equilibria... 

Studies on the stereostructures of cis- and /ra r-perhydro-l,3- and 3,1-benzoxazines 86-89 revealed that/ra r-fused derivatives 87 and 89 attain a biased chair-chair conformation, while their -counterparts 86 and 88 can be characterized by conformational equilibria of the O-in/N-in (a) and O-out/N-out (b) isomers, which, for 3,1-benzox-azines 88, are strongly influenced by the bulkiness of the substituent R attached to the nitrogen <1996CHEC-11(6)301, 1998AHC(69)349>. 

In the reactions of the perhydro-l,3-benzoxazine derivatives 236 with benzeneselenyl chloride in dichloromethane-methanol, methoxyselenylation of the double hond in the C-2 side chain occurred in a highly regio- and diastereo-selective way (Scheme 43). Reductive deselenylation of 237 with triphenyltrn hydride in the presence of a catalytic amount of azobisisobutytonitrile (AIBN) resulted in formation of the methoxy derivatives 238 <2006JOC2424>. 

Whereas the Hofmann rearrangement of the amidoalcohols 452 with the usual NaOCl did not occur, reaction of the oxygen-bridged 452 (X = 0) with bis(acetoxy)iodobenzene under mild conditions led to a 9 1 mixture of the corresponding cyclic and acyclic carbamate derivatives 197 and 453 (X = 0) (Equation 50). In the similar reaction of the methylene-bridged analog 452 (X = CH2), the product of perhydro-3,l-benzoxazin-2-one type 197 (X = CH2) was obtained exclusively <20030PP429>. 

However, Aae can still be used in suitable cases as an indication of conformation, particularly for polycyclic compounds. Thus Aae measurements on TV-CH2X protons may be used to establish the cis or trans nature of the ring fusion in 1,3-heterocyclic systems. For example, the trans-fused perhydro-pyrido[3,2,l-iJ][3,l]benzoxazine (21) shows Aae 0.84 ppm, indicative of the anti-coplanar CH-nitrogen lone-pair geometry, whereas the cis-fused isomer (22), in which the nitrogen lone pair bisects the CH2 group, shows Aae 0.12 ppm.45... 

The first representative 57 of pyrido[2,l-/]-3,l-benzoxazine ring system was synthesized by the ring-closing methathesis of perhydro-3,l-benzox-azine 113 in the presence of the second generation of Grubb s catalyst (06TL3815). 

NMR Data of trans and O-inside cis Conformations of Perhydropyrido[1,2-c][1,3]oxazine(20, X = O) in CD2CI2-CFCI3 at 203 (92MRC129) AND Its Hydrochloride Salt in CDCI3 at Room Temperature (88MRC748), and Those of Stereochemically Locked Perhydro[3,2,1-i ][1,3]benzoxazines (25-28) in CDCI3 at Room Temperature (92MRC129) (ppm)... 

Dihydro-1,3-oxazines and derivatives. 5.3.2 5,6-Dihydro-2H-l, 3-oxazines. 5.3.3 Perhydro-1,3-oxazines Addition Reactions. 5.4.1 4H-3,l-Benzoxazines. 5.4.2 Dihydro-1,3-oxazines... 

In the case of cw-4a,5,6,7,8,8a-hexahydro-4/f-l,3-benzoxazines, the heterocycle is flattened out compared to the perhydro-l,3-benzoxazines, and there can be no 1,3-synaxial interaction of a hydrogen atom at C-2 with the carbocycle. The axial preference is insensitive to the configuration... 

Perhydro-3,l-benzoxazine-2-thiones (83) cis and trans) react with methyl iodide and potassium hydroxide to afford 2-methylthio derivatives (84), but in the absence of potassium hydroxide ring opening occurs to produce iodomethyl thiocarbamates (85) (Scheme 18). In the latter case it is assumed that hydrogen iodide released in the first S-methylation step is responsible for initiating... 

Perhydro derivatives (497), (498), and (514) were synthesized from [4 + 2] atom fragments by reacting the morpholine derivative (513) with bifunctional electrophiles (Scheme 41), for example, ethyl chloroacetate and diethyl oxalate <64AP(297)632>. The [l,4]oxazino[4,3,2-de]-l,4-benzoxazine derivative (515) was prepared in the reaction between chloropentafluorobenzene and diethanolamine <88MI 825-03). 

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