Pyrrolo oxazoles

The H and 13C NMR descriptions of a great number of perhydro-pyrrolo-oxazoles have appeared since the important contribution in the field by Meyers et al. They are mainly used for structural determination and to prove the stereochemistry of the substitution of these compounds. Some NOESY experiments were performed for the structural elucidation of diethyl (3R,5A,7aA)-5-methyl-3-phenylhexahydropyrrolo[2,l- ]-[l,3]oxazol-5-yl-phosphonate 181 <2004TL5175>. 

H,3H- Pyrrolo[l, 2-c]oxazole-l, 3-dione, 5,6,7,8-tetrahydro-IR spectra, 6, 978 [2.2](2,5)Pyrrolophane, N-aryl-rearrangements, 4, 209 Pyrrolophanes natural products, 7, 764 synthesis, 7, 771 Pyrrolophanes, N-aryl-synthesis, 7, 774 (2,4)Pyrrolophanes synthesis, 7, 771 Pyrrolo[3,4-c]pyran-4-ones synthesis, 4, 288 Pyrrolopyrans synthesis, 4, 525, 526 Pyrrolopyrazines synthesis, 4, 526 Pyrrolo[l, 2-a]pyrazines synthesis, 4, 516 Pyrrolo[2,3-6]pyrazines Mannich reaction, 4, 504 Vilsmeier reaction, 4, 505 Pyrrolo[3,4-c]pyrazole, 1,3a,6,6a-tetrahydro-structure, 6, 976 synthesis, 6, 1019 Pyrrolopyrazoles synthesis, 5, 164 Pyrrolo[l,2-6]pyrazoles synthesis, 6, 1002, 1006 Pyrrolo[3,4-c]pyrazoles reactions, 6, 1034 synthesis, 6, 989, 1043 Pyrrolo[3,4-c]pyrazolones synthesis, 6, 989 Pyrfolopyridazines synthesis, 4, 517 Pyrrolo[l, 2-6]pyridazines synthesis, 4, 297 6/7-Pyrrolo[2,3-d]pyridazines synthesis, 4, 291 2/f-Pyrrolo[3,4-d]pyridazines synthesis, 4, 291 6/7-Pyrrolo[3,4-d]pyridazines synthesis, 4, 291... 

Furthermore, oxazoles of type 9-82 bearing a secondary amino functionality can be converted into pyrrolo[3,4-b]pyridines 9-86 by reaction with appropriate acid chlorides 9-83 in a triple domino process consisting of amide formation/hetero Diels-Alder reaction and retro-Michael cycloreversion via 9-84 and 9-85 (Scheme 9.17). The pyrrolo[3,4-fc]pyridines can be obtained in even higher yields when the whole sequence is carried out as a four-component synthesis in toluene. Here, 1.5 equiv. NH4C1 must be added for the formation of the now intermediate oxazoles [56b]. 

The Michael type reaction of (3R)-5-t-butyldimethysiloxy-3-phenyl-17/-pyrrolo[ 1,2-c]oxazole with nitroethylene proceeds in the presence of Lewis acid to give the alkylated product in good chemical yield and diastereoselectivity. In the case of nitroethylene, the Diels-Alder type transition state is favored to give the yy/i-adduct selectively (Eq. 4.72).91... 

Pyrrolo[l,2-r]oxazole (F). This parent structure must be partially saturated. There are three possible isomeric systems H,3H-( ) 15, 3H,SH-( ) 16, 3H,lH-( ) 17. 

The studies of the reactivity of saturated pyrrolo[2,l- )oxazoles are in general associated with the reactivity of Meyers chiral bicyclic lactams and their applications in asymmetric synthesis. 

Cleavage of 5-(3-phenyl-hexahydro-pyrrolo[2,l- ]oxazol-5-yl)-pent-3-en-2-one 195, when conducted in methanol with HC1 gas, produced compounds 196 and 197 in an 80/20 ratio, or after treatment with sulfuric acid in methanol at 60 °C afforded 198 as a single isomer (Scheme 26). Compound 198 was used for the total synthesis of the potent neurotoxic (-F)-ferruginine <1997JOC6704>. 

Aromatic pyrrolo[2,l- ]oxazoles are unknown compounds. Dihydro derivatives 228 and 229 have been obtained from the thermal rearrangement of dihydrooxazole 226 through intermediate 227 (Scheme 32) <2003EJ01438>. 

Aromatic pyrrolo[l,2-r(]oxazoles cannot be drawn, and the only structure that one can find in the literature is the l //,3/7-derivativcs. The derivatives 377,5/7 and 3 //.7// are unknown. All compounds described are dihydro and mainly oxo perhydro derivatives. 

Pyrrolo[ 1,2-c]oxazolc itself was used for further elaboration of more complex molecules. The main members of this family that are used as intermediates in organic synthesis are the 3-oxo and 5-oxo perhydro derivatives. One can find also a number of 1,3-dioxo, 3,5-dioxo, 3,7-dioxo, and 5,7-dioxo perhydropyrrolo[l,2-r ]oxazoles that were prepared and/ or converted into another valuable compounds. 

When the pyrrolo[l,2-c]oxazole 269 was treated with trimethyl orthoformate in the presence of BF3 Et20, in dichloromethane at — 78 °C, a mixture of compounds was obtained from which the expected 5-dimethoxymethyl derivative, 270, was isolated in poor yield (12%) with another dimethoxylated compound 271 (23%). The formation of 271 could be explained by the addition of the formyl cation equivalent at C-7, followed by the protonation at C-6 of the resulting enamide 272 leading to the electrophilic iV-acyliminium ion 273 (Scheme 40). The regioselectivity of this electrophilic addition of trimethylorthoformate to the silyloxypyrrole 269 at C-7, in a non-vinylogous manner, is unusual <1999TL2525>. 

Interestingly, deprotonation of the 3-oxo-pyrrolo[l,2-f]oxazole 277 with r-BuLi at —78°C took place at the C-5 position. Addition of an electrophile provided the substituted products 278 in good yields. Stannyl and silyl chlorides, dimethyl sulfate, ketones, and benzaldehyde were successfully used as electrophiles. A significant feature of this lithiation-substitution reaction is the generally high Ar-diastereoselectivity only single diastereomers of products were isolated (Scheme 41) <2001JA315>. 

A hydroxy group can be introduced on this bicyclic system as a nucleophile. The pyrrolo[l,2-c]oxazole system can be hydroxylated at the 7a-position to produce in good yield the corresponding 7a-hydroxypyrrolo[l,2-c]oxazole. The diastereoselectivity of this nucleophilic addition is total, with attack at the iminium ion on the face hindered by the phenyl group at C-3. <2002TL463, 2004JOC7558, 2006TA53>. 

The unsubstituted pyrrolo[l,2-f]oxazol-3-one 295 underwent a dihydroxylation with catalytic osmium tetroxide to exclusively give diol 296. This diol resulted from attack of the oxidizing agent from the concave face of the molecule due to the pseudoaxial protons that sterically hinder the /3-face to be attacked by the osmium reagent (Equation 51) <2004AJC669>. 

In some cases, the pyrrolo[l,2-f]oxazoles were epoxidized with hydrogen peroxide in dichloromethane affording the epoxide with control of stereoselectivity (Equation 52) <1997TA2421, 2000T2437, 2004TA1239>. 

The silyloxypyrrole 309 was prepared in 91% yield from the ,/3-unsaturated lactam 308 with TBDMSOTf and 2,6-lutidine (Equation 54) <1999TL2525>. Alternatively, the pyrrolo[l,2-f]oxazoles derivatives 311 were prepared by reaction between the stable bcnzotriazol-1 -yl(l //-pyrrol-2-yl)methanone 310 and various ketones (Equation 55) <2004JOC9313>. These two examples are the rare representatives of the pyrrolo[l,2-r ]oxazole ring system described in the literature to date. 

The Michael addition reaction of the serine-derived oxazolidine 326 with ethyl acrylate gave two products. The major product of the reaction was found to be the bicyclic compound 327, which was formed in 27% yield, accompanied by the unsaturated ester 328. The Dess-Martin oxidation of 327 resulted only in formation of the elimination product, the 7,7a-dihydro-177, 377-pyrrolo[l,2-r ]oxazole 328 (Scheme 46) <2001JOC7555>. 

The rhodium acetate complex catalyzed the intramolecular C-H insertion of (/ )-diazo-fR)-(phenylsulfonyl)acet-amides 359 derived from (f )-amino acids to afford in high yield the 6-benzenesulfonyl-3,3-dimethyl-7-phenyl-tetrahydro-pyrrolo[l,2-c]oxazol-5-one 360 (Equation 63) <2002JOC6582, 2005TL143>. 

Finally, 5(4Ff)-oxazolones react as masked 1,3-dipoles with nitrileimines, l-nitroso-2-naphthol and [60]fullerene to give 1,2,4-triazoles, naphth[l,2-ci oxazoles and 5 -phenyl-2 7/-pyrrolo[3, 4 l,2][60]fullerene, respectively. 

Cvclohexeriyl)-tetrahyflro-.3-phenYl-l//,5//-pyrrolo l,2-c]oxazol-5-one (4, R = 2-cyclohexenyl) Typical Procedure11 ... 

R,6S,7S,7aS)-6-benzyl-7- bis(methox carbonyr)methyH-tetrahydro-3-phenyl-t i,5li-pyrrolo[t, 2-c -oxazol-5-one... 

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