1.3- Oxazines, tetrahydro- from

The ring opening of tetrahydro-l,3-oxazines to aldehydes has recently found wide application through the work of Meyers.2-3 2-Alkylidene-tetrahydro-l,3-oxazines, prepared from the readily available 5,6-dihydro-4//-1,3-oxazines, possess strong nucleophilic properties and can react with alkyl halides and carbonyl compounds. The derivatives so obtained can be reduced to tetrahydro-l,3-oxazines, and through ring opening the latter can furnish acyclic, alicyclic, and a,jS-unsaturated aldehydes and their C-l deuterated derivatives.221-223 228... 

The conformations of the 2-oxo-tetrahydro-l,3-oxazines obtained from phosgene and the isomeric 3-amino-2,3-diphenylpropanols were used by Fodor et al. as an ingenious criterion for the configurational determination of the aminopropanols.13,14 The erythro form yielded an oxazinone that showed optical activity 4-8 times stronger than that from the threo form. 

Maier, R., Woitun, E., Wetzel, B., and Lechner, U. (1988). Synthesis, structure, and biological activity of tetrahydro-l,3-oxazines derived from 9(S)-erythromycylamine and substituted acetaldehydes. Presented at 28th Intersci. Conf. Antimicrob. Agents Chemother (Oct. 23-26, Los Angeles). Abstr. No. 917. 

Tetrahydro-l,2-oxazine ring from ethylene derivs. and a-diloronitrones... 

The synthesis of functionalized tetrahydro-1,2-oxazines 76 from nitroolefins 75 and nitrosoarenes has been studied by Zhong and coworkers. This enantio and diastereoselective organocatalytic process takes place via a domino sequence comprising an initial proline-catalyzed enantioselective aminoxylation of the starting material taking place by addition of the enamine onto the 0=N nitroso bond, followed by a final aza-Michael addition (Scheme 3.20) [57]. The same group has reported a very similar reaction starting from 2-alkylidene derivatives of malonic ester [58]. 

The tetrahydro-l,3-oxazine (132) from cyclohexanone and aminopro-panol was converted to the diazo-intermediate (133) and cyclised using rhodium acetate to the tra i-P-lactam (134). Non-selective reduction of the ketone gave both hydroxy epimers. Progression through the sequence as outlined provided the thiol-ester phosphorane (138) possessing the required ( )-acetamidoethenyl substituent. Cyclisation in boiling toluene gave the two epimers of (139) which were separated, and deprotected to afford (+)-MM 22383 (140) and ( )-iV-acetyldehydrothienamycin (141). 

One of the most extensively investigated groups of 1,3-oxazine derivatives is the 5-nitro derivatives of tetrahydro-l,3-oxazine. They were first prepared from 1-nitropropane, aqueous formaldehyde, and ammonia by Hirst et and independently by Senkus from other primary nitroparaffins, formaldehyde, and primary amines. Numerous compounds of the general formula (6) were later prepared from primary nitroparaffins. " ... 

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. ... 

Another line of approach to the practical application of 1,3-oxazine derivatives was the suggested use of tetrahydro-1,3-oxazine derivatives as detergents for textile industry, as anticorrosion chemicals, and polymers from 2-oxo derivatives as additives to improve the properties of paper and textiles. ... 

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). 

Alkoxy-3-(4-biphenyl)perhydropyrido[], 2-c][], 4]oxazines were obtained from 3-hydroxy derivative with PrOH and Br(CH2)30H in a boiling acidified medium (00JMC609, 00MIP13). Spontaneous dehydration of b-hydroxy-1,3,4,6,7,1 lZ -hexahydro[l,4]oxazino[3,4-n]isoquinolin-4-one 258 in CHCI3 gave 3,4,6,7-tetrahydro derivative 259 (97JOC2080). 

Tetrahydropyrido[2,1 -HI 1,4 oxazinc-7,9-dicarboxylate 278 was obtained from the 1,8-dihydro derivative 277 by hydrogenation over a Pd/C catalyst (Equation 51) <1997CAP2188071 >. Catalytic hydrogenation of an epimeric mixture of (4.S, 9a.S )-l -trimcthylsilyloxy-4-phenyl-3,4,6,7-tetrahydro-l//-pyrido[2,1 -HIl,4]oxazine over Raney-Ni afforded perhydro derivatives <2000SC2565>. 

The stereodynamics of /V-siloxy-ene- nitroso acetals related to 3-alkylen-substituted 4//-tetrahydro-1,2-oxazines (e.g., see (416 d)) differs from that of BENA in that free rotation about the C,N bond in oxazines cannot occur, but the ring inversion should take place (process Ir) (see Scheme 3.228). 

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... 

Enantiomerically pure tetrahydro-l//-pyrrolo[2, l -acrylamides derived from proline (see Section 11.11.7.4), are versatile intermediates for the synthesis of natural products or drugs. Compound 86a was submitted to debromination with Bu3SnH followed by ring opening in KOH and further reduction with BHj to give diol 89 that was then easily transformed into (A)-4-(2,2,4-trimethyl-l,3-dioxolan-4-yl)-lT>utanol 90, a key intermediate for )-frontalin, <2002TA155>,... 

A series of enantiomerically pure tetrahydro-l//-pyrrolo[2,l-c][l,4]oxazine-l,4(3//)-diones 86a-d have been prepared by bromolactonization of acrylamides derived from proline mediated by NBS (Equation 5). These compounds... 

The simplest and most commonly used method for the synthesis of tetrahydro-l,3-oxazines is the ring closure of the corresponding 1,3-amino alcohols with oxo compounds [80H(14)1333]. The parent ring system is known merely in the case of 3,1-perhydrobenzoxazines 18 cis or trans R = H, Ph) it was prepared from cis- and rrans-2-hydroxymethyl-l-cyclohex-... 

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). 

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... 

Flash vacuum pyrolysis (FVP) of the tetrahydro-l,3-oxazine derivative 171, derived from the condensation of spiro-oxazine 170 and methoxymethylene-substituted Meldmm acid, resulted in formation of pyrrolo[l,2-r ][l,3]oxazine 172, which in (CD3)2CO at —20°C proved to be a 47 53 mixture of the keto (A) and enol (B) tautomers (Scheme 28) <2002J(P1)548>. 

A convenient, one-pot procedure devised for the preparation of 2-phenyl-5,6-dihydro-4//-l,3-oxazine 373 was based on the A -bromosuccinimide oxidation of tetrahydro-l,3-oxazine 372, formed in situ from 3-aminopropanol 371 and benzaldehyde (Scheme 69) <2006S2996>. 

The acetic anhydride-induced cyclodehydration of the symmetrical diamide 411, derived from the tetrahydro-benzothiophene / -amino ester 410 and diethyl malonate, afforded the thieno[2,3-r7 [h3]oxazine derivative 413 rather than the expected bis-oxazine 412 (Scheme 78). The reaction probably takes place through sequential cyclizations, in which the pyridine ring of 413 is produced by condensation of the exocyclic double bond of the enamine tautomeric form of the 1,3-oxazine moiety and the mixed anhydride formed by the carboxylic group and acetic anhydride <2003PS245>. 

Maytansine 588 is a macrocyclic tetrahydro-l,3-oxazin-2-one derivative isolated from higher plants, mosses, and an actinomycete, kctinosynnema pretiosum. Despite the extraordinary antitumor activity found for many maytansine derivatives, the Phase II clinical trials with maytansine turned out to be disappointing. The chemistry and biology of maytansinoids have recently been reviewed <2004CPB1>. 

Two naturally occurring 1,3-oxazine derivatives with a unique, 2-chlorinated tetrahydro-l,3-oxazine structure were reported as metabolites isolated from extracts of the endophytic fungus Geotrichum sp. AL4 <2007MI1520>. Halogenated 3-(4-alkylphenyl)-l,3-benzoxazine-2,4(3//)-diones were found to exhibit antimycobacterial activity <2007AP264>. 

Azomethine ylides derived from (55,6/ )-2,3,5,6-tetrahydro-5,6-diphenyl-1,4-oxazin-2-one (53) and various aldehydes have been prepared by Williams and co-workers (87,88) (Scheme 12.19). In a recent communication they reported the application of the azomethine ylide 54 in the asymmetric total synthesis of spirotryprostatin B 56 (88). The azomethine ylide 54 is preferentially formed with ( )-geometry due to the buLkiness of the aldehyde substituent. The in situ formed azomethine ylide 54 reacted with ethyl oxindolylidene acetate to give the 1,3-dipolar cycloaddition adduct 55 in 82% yield as the sole isomer. This reaction, which sets four contiguous stereogenic centers, constmcts the entire prenylated tryprophyl moiety of spirotryprostatin B (56), in a single step. 

Similarly, very useful yields and diastereoselectivities were observed on alkylation of (5R)-2,3,5,6,-tetrahydro-5-phenyl-A-(ter/-butoxycarbonyl)-4/f-l,4-oxazin-2-one (7)92, The latter is available from (A)-phenylglycinol and phenyl 2-bromoacetate with subsequent protection of the amino group. The influence of the base, the counterion and the solvent was studied for this example. Sodium hexamethyldisilazanide in tetrahydrofuran/dimethoxyethane turned out to be by far the best conditions for deprotonation. Also, it seems to be essential that the base is added to the chilled solution of 7 and not vice versa. 

However, in many other series results have been obtained that are compatible with those from other methods and that gave the dipole-moment method an appearance of general reliability now known to be unjustified. Such compatible results include spiropiperidines (Section III,A,4), tropanes (Section III,B,4), 2-alkyltetrahydro-l,2-oxazines (Section III,C,2), perhydro-pyrido[l,2-c][l,3]oxazines (Section III,D,IX perhydropyrido[l,2-c][l,3]thi-azines (Section III,D,2), dialkylhexahydropyrimidines and perhydropyrido-[l,2-c]pyrimidines (Section III,D,3), 5-alkyldihydro-l,3,5-dithiazines (Section III,G,3), 3,5-dialkyltetrahydro-l,3,5-thiadiazines (Section III,G,4) and, in part, l,2,4,5-tetraalkylhexahydro-l,2,4,5-tetrazines (Section III,H,4) as well as piperidines, tetrahydro-l,3-oxazines, and tetrahydro-l,3-thiazines containing an N-H group. 

The low temperature H-NMR spectra of 2-methyl-3,6-dihydro-2H-1,2-oxazine (239) gives a AG° favoring the /V-Meeq of 0.9 kcal mol", which is significantly less than that for the tetrahydro-l,2-oxazine (>1.9 kcal mol"1).246 This is similar to the decrease in conformational free energy of a methyl substituent on going from methylcyclohexane (1.7 kcal mol"1) to 4-methylcyclohexene (1.0 kcal mol 1),247 and the equilibrium 240 241 may represent a balance between lone-pair-Ti-bond repulsion in 240 and lone-pair-lone-pair repulsions in 241.246... 

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