Pyrrolo oxazines

Whereas the previous methods for the synthesis of pyrrolo-oxazines were based on traditional ionic cyclization, the preparation of 7-rncthyltctrahydro-l //-pyrrolo[2,1 -c][l,4]oxazin K3//)-one 176 was reported using a new radical cyclization induced by photoelectronic transfer catalysis. This reaction is proceeding under very mild conditions and in neutral medium (Scheme 26). 

Snyder DS, Tradtrantip L, Yao C, Kurth MJ, Verkman AS (2011) Potent, metaboUcaUy stable benzopyrimido-pyrrolo-oxazine-dione (BPO) CFTR inhibitors for polycystic kidney disease. J Med Chem 54 5468-5477... 

Addition to Tetrahydro-2//-l,3-oxazines, Hexahvdro-1 f/-pyrrolo[l,2-r]imidazoles and... 

Pyrido[2, 3 4,5]pyrrolo[2,l-A][l,3]oxazine <2002TL1205, 2003USP2003105087, 2005BP74> Pyridazino[4,5- ]indolizine <1998USP5756501>... 

The hexahydro-l//-pyrrolo[2,l-f][l,4]oxazin-l-one 82 (obtained by radical cyclization see Section 11.11.7.3) was transformed into the proline derivative 83 by hydrogenation in the presence of the Pearlman s catalyst and a stoichiometric amount of trifluoroacetic acid (TFA) (Scheme 10). This reaction led with high yield to the disub-stituted proline 83 in an enantiomerically pure form <2003SL1058>. In an analogous approach, the chiral (4/ ,7/ ,8aA)-methyl 6,6-dimethyl-l-oxo-4-phenylhexahydro-l//-pyrrolo[2,l-r-][l,4]oxazine-7-carboxylate 84 was hydrogenated on Pd(OH)2 in the presence of TFA to give enantiomerically pure 5,5-dimethylproline derivatives 85 <2001SL1836> (Scheme 10). 

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>,... 

An intermediate 5-hydroxy-5,6-dihydro-2/7-pyrrolo[l,2- ][l,2]oxazin-7(4a//)-one 142 has been described in the total synthesis of (—)-loline, a pyrrolizidine alkaloid extracted from rye grass Lolium cuneatum. The key step of the synthesis was an intramolecular cycloaddition of acylnitrosodienes (obtained by in situ oxidation of the corresponding hydroxamic acids 143). This reaction generated predominantly the rro/o-stereoisomer that was further cleaved at the N-O bond with Na(Hg) and further elaborated in several steps to reach the target compound (Scheme 19) <2001J(P 1)1831 >. 

The 3,5-diphenylmorpholine-2-one 161 was used to prepare bicyclic lactams 162 by reaction with the cesium fluoride/tetramethoxysilane system and different Michael acceptors. The adducts were rapidly obtained as a mixture of diastereoisomers that could be separated by column chromatography just after TFA-mediated cyclization to the 8-substituted-4,8a-diphenyltetrahydro-l//-pyrrolo[2,l-r1[l,4]oxazine-l,6(7//)-diones 62 and 163 <1997SL935>. These compounds were then reduced to give substituted prolines as described in Section 11.11.6.1. 

Crane and Corey prepared 8a-(hydroxymethyl)-3,7,7-trimethyl-3-phenyl-17/-pyrrolo[2,l-f][l,4]oxazine-... 

A series of l/f-pyrrolo[2,l-r][l,4]oxazin-l-ones 196 are also the product of an LJgi multicomponent reaction between proline (and also other a-amino acids that gave the corresponding monocyclic compounds) and several isonitriles in the presence of commercially available glycolaldehyde dimer (Equation 3) <20010L4149>. 

Pyrrolo[l,2- ][l,2]oxazines are a class of compounds with very few references regarding synthesis and reactivity. An interesting preparation has been described by intramolecular cyclization of IV-hydroxy pyrrolidines carrying a methoxyallene substituent at C-2 (242, Scheme 32). These compounds were obtained by addition of a lithiated allene to chiral cyclic nitrones 241. Cyclization occurred spontaneously after some days at relatively high dilution (0.05 M). Compounds 243 (obtained with excellent diastereoselectivity) can be submitted to further elaboration of the double bond or to hydrogenolysis of the N-O bond to form chiral pyrrolidine derivatives (Section 11.11.6.1) <2003EJ01153>. 

Pyrrolo[l,2-c][l,3]oxazin-l-one 248 has been obtained by reaction of allylsilanes with a pyrrolidine-lV-acyliminium ion 247 (Scheme 32), formed by addition of a Lewis acid on compound 244. The /3-silyl carbocation formed by the reaction with allylsilane 246 reacted with the oxygen of the N-15OC group followed by the loss of 2-methylpropene. The reaction was not very stereoselective when trimethylsilane was used, whereas with larger group on the silicon the selectivity was increased <1997J(P1)2163>. 

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... 

A series of novel pyrroloxazines were prepared by thermal extrusion of sulfur dioxide from pyrrolo[l,2< [l,3]thi-azole 2,2-dioxides. The reaction on the acyl derivatives 369, carried out at 600 °C and 10 3mmHg, generated a transient azafulvenium methide 370 that electrocyclized to oxazines 371 <2001J(P1)1795>. The reaction was compatible with different aromatic and aliphatic groups <2000CC675>. 

Ylide 373 was also the intermediate for the Cu(l)-catalyzed transformation of the diazo malonyl ester of the tetrahydropyridine 372 to the 7-vinylhexahydro-l/7-pyrrolo[2,l-f][l,4]oxazine-8 -carboxylate 374 (Scheme 48) <20050L2075>. 

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>. 

Dioxino[4,5-t)]pyrrole 1,3-Dioxino[5,4-h]pyrrole x = 0 pyrrolo[2,3-d]-1,3-oxazine PyiTOlo[3,4-d]-1,3-thiazine... 

Two further unusual examples involve a different bicyclic system and an acyclic system as precursors. In the first instance, use is made of the reactivity of a pyrrolo[2,3-<7]-l,3-oxazin-4-one 178 (Equation 67). Treatment of this compound with hydrazine hydrate afforded the 3-amino derivative 179a while reaction with 4-methoxyaniline produced 179b <2000IJB764>. 

Preparations of pyridazino[3,4- [l,3]oxazines by ozonolysis of pyrrolo[2,3-b]pyridazine-3-carboxylates and from the reaction of A -(4-ethoxycarbonylpyridazin-3-yl)phosphinimines with acyl halides were described in CHEC-II(1996) <1996CHEC-11(7)737>. A simpler form of the latter approach has now been reported <1994CC2451>, wherein the 1-A -oxide of 3-aminocinnoline-4-carboxylic acid undergoes cyclization with acetic anhydride (Equation 126). The isomeric pyridazino[4,3-, [l,3]oxazines have been prepared in a similar manner (Equation 127) <1997PHA838>. 

A number of oxazine-fused systems, including the pyrrolo[2,3-r/][l,3]oxazine (295 R = PhCH2), have been obtained by reacting dichlorotriphenylphosphorane with a 1,2-aminoester (e.g. (294 R = Et)) (Equation (105)). The r-butyl ester (294 R = Bu ) reacts with methyl pyruvate in the presence of acetic acid and sodium acetate to yield the pyrrolooxazine (295 R = Me) <90MI 707-05). 

The 3-chloro-l,7-dimethylpyridazino[3,4-(7][l,3]oxazine-4,5-dione (149) was prepared in a four-step synthesis starting with (Z)-methyl-3-(3,6-dichloro-l-methyl-4-oxo-l,4-dihydropyridazin-5-yl)-2-methylacrylate (146) which is converted with sodium azide into the 6-azido compound (147). Heating in o-dichlorobenzene at 150°C results in cyclization to methyl 3-chloro-l,6-dimethyl-4-oxo-1,4-dihydro(7//)pyrrolo[2,3-c]pyridazine-5-carboxylate (148) via a nitrene intermediate. Ozonolysis effects ring-enlargement of the pyrrole ring into the 3-chloro-l,7-dimethylpyridazino[3,4-d][l,3]oxazine-4,5-dione (149) (Scheme 26) <79JHC1213>. 

Table2. Hexahydro-lff-pyrrolo[l,2-e][l,3]oxazin-l-ones and Tetrahydro-1 f/,3/f-pyrrolo[l,2-c]oxazol-3-ones by Halocyclization of 2-(l-Alkenyl)-l-pyrrolidine Carboxylates...

In systems described in Sections XIV-XVI, the 1,4-arrangement of heteroatoms is not expected to affect the relative importance of the transconformation shown by indolizidine. In line with this, the perhydro-pyrrolo[2,l-c][l,4]oxazin-3-one has been shown to adopt the trans-conformation (505) (74CC395) (see Section XV). 

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