Furo pyrrole

Internal nitrenes normally react at the adjacent position. Reduction of 2-(2-nitrophenyl)furan by ethyl phosphite yields furoindole derivatives in fair yield (34%) only, whereas much better results attend the pyrolysis of 2-(2-azidophenyl)furan.280 Furopyrazoles are obtained similarly.281 Azidofurans yield nitrenes that insert into adjacent CH links to form furo-pyrroles.282 Quite different results attend either the pyrolysis or the photolysis of azide 107a for the expected insertion into the side chain occurs giving the related indole but it is accompanied by the surprising replacement of furan oxygen by nitrogen producing 107b and similar products.283... 

The differences in aromaticity follow the results of theoretical analyses on the acidity of the NH proton of the pyrrole fragment of furo[ ]pyrroles <2000PJC207> and are nicely reflected in the observed stability of both systems. The total energy difference between methyl 4f/-furo[3,2- ]pyrrole-5-carboxylate 8a and methyl 6f/-furo[2,3- ]pyr-role-5-carboxylate 31a is rather small (—7.2 kj mol ) indicating the higher stability of the former system. However, if the increase of energy of the appropriate anions is compared (relative to the parent molecules), then it indicates that formation of 67/-furo[2,3-7]pyrrole-5-carboxylate anion is much easier (by —22.5 kJ mol ) than formation of 4//-furo[3,2- ]pyrrole-5-carboxylate anion. 

Puterov et al. (2004) have prepared different benzothiazolium compounds by reaction of 5-arylfuran-2-carboxaldehydes and furo[ ]pyrrole type aldehydes with 2-methyl-3-methyl or ethyl benzothiazolium bromide. The new compounds were based on highly conjugated systems that have potential biological activity. Cyanine dye precursors can also be obtained by the reaction of furo[fc]pyrrole type aldehydes with benzothiazolium salts (Puterova et al. 2004). 

Dihydrofuran (376) and 2,5-dihydrofuran (377) react with nitrile oxides to give furo[2,3-6 ]isoxazoles (378) and furo[3,4-rf]isoxazoles (379), respectively, as cycloadducts. The double bonds of furan, pyrrole and thiophene also react when the nitrile oxide is generated in situ. Thus furan and benzonitrile oxide gave (380), and with 2-methyl-2-oxazoline the cycloadduct (381) was obtained (71AG(E)810). These and related cycloadditions are discussed in Chapter 4.36. 

Furo[2,3-amino-synthesis, 4, 986 Furo[3,4-d]pyrimidinedione synthesis, 4, 987 Furopyrimidines, 4, 986 Furo[2,3-d]pyrimidines synthesis, 4, 986 Furo[3,2-d]pyrimidines synthesis, 4, 987 Furo[3,2- 6]pyrone synthesis, 4, 994 Furo[3,2-c]pyrone synthesis, 4, 993 Furo[3,2-6]pyrrole, hexahydro-biological activity, 6, 1024 1 H-Furo[3,4-6]pyrrole-2,3-dione, 4,6a-diphenyl-6-(phenylimino)-6,6a-dihydro-synthesis, 6, 1004 Furopyrroles... 

In a similar way to the above, azidopropenoylfuro[3,2- ]pyrroles such as 27 can be thermolyzed in a mixture of diphenyl ether and tributylamine to give the 8-oxo-7,8-dihydropyrrolo[2, 3 4,5]furo[3,2-r]pyridines 28, again via the intermediate isocyanates. The lactam 28 can be chlorinated and reduced using standard methods (POCI3 then Zn/AcOH) to give the pyrrolo[2, 3 4,5]furo[3,2-r]pyridines 29 <1995M753> (Scheme 8). 

An alternative strategy for the synthesis of these tricyclic compounds involves the reaction of the azidoalkenyl-functionalized furo[3,2-A]pyrrole 30, which reacts with triphenylphosphine to give the corresponding iminophos-phoranes 31 these upon reaction with aryl isocyanates give the pyrrolo[2, 3 4,5]furo[3,2-r-]pyridines 32, via the corresponding carbodiimides which are not isolated < 1994H(37) 1695, 1992M807> (Scheme 9). 

The condensed isobenzofuran derivative l,3-dimethyl-2,5,7-triphenyl-2/f-furo[3,4-/]isoindoloquinone (64), has been prepared in four steps from a pyrrole derivative143 (Scheme 79) a thiophene analog of64 has been obtained in a similar manner.144 Key intermediates in both types of reactions are condensed rhodacyclopentadienes (cf. 63) which are obtained from appropriate diynes. 

Furo[3,4-c]pyrrolediones are important intermediates in the synthesis of diketo-pyrrolopyrrole (DPP) pigments. Smith and coworkers have described the preparation of several different 3,6-diaryl-substituted furo[3,4-c]pyrrole-l,4-diones by microwave-assisted cyclization of readily available 4-aroyl-4,5-dihydro-5-oxo-2-arylpyrrole-3-carboxylates (Scheme 6.192) [353]. While conventional heating in Dowtherm A at 230-240 °C for 64 h provided only moderate product yields, microwave irradiation of the neat starting material at 250 °C for 10 min provided significantly increased yields. 

Ultraviolet (UV) spectra of some selected furo[3,2-3]- and furo[2,3 ]pyrroles were published and their apparent ionization constants determined by spectrometric titration (Table 5), and correlated with their structures <2001CCC1615>. 

Phase-transfer catalysis was found <1996CHEC-II(7)1> to be successful for N-substitution of the furo[3,2-/ ]pyrrole system. The reaction of 81a with methyl iodide or benzyl chloride gave 81b and 81c derivatives. Methyl 4-acetyl-2-[3-(trifluoromethyl)phenyl]furo[3,2-3]pyrrole-5-carboxylate 82 was obtained by reacting 81a in boiling acetic anhydride (Scheme 6) <2005CEC311>. 

Acetyl-2-[3-(trifluoromethyl)phenyl]furo[3,2- ]pyrrole 84 was obtained during heating in boiling acetic anhydride of 2-[3-(trifluoromethyl)phenyl]-42/-furo[3,2- ]pyrrole-5-carboxylic acid 83, and it was used for preparing parent compound 85a and the N-substituted compounds 8Sb and 85c (Scheme 7) <2005CEC311>. 

Benzo[4,5]furo[3,2- ]pyrrole 86 and benzo[4,5]thieno[3,2- ]pyrrole 87 were used for the synthesis of new constrained aryl-substituted 4,4-difluoro-4-bora-3a,4a-diaza-r-indacene (BODIPY) dyes 86 and 89 <2000JOC2900>. Their fluorescence characteristics were investigated and compared with the unconstrained systems published by Burghart and co-workers (Scheme 8) <199881276, 1999JOC7813>. 

The furo[3,4- ]pyrroles 132, 133 <2002TL6983>, thieno[2,3-f]furan 134, <1996JOC6166>, and furo[2,3-f]pyrrole 135 <1995T193>, which are mostly less stable than the benzo-fused analogues, were trapped by Diels-Alder reactions with dienophiles followed by elimination of water to give the corresponding indoles 136-139, 140, 141, and benzothiephenes 142, 143, and 144 with good to excellent yields (Scheme 13). 

The Diels-Alder reaction of furo[2,3-f]pyrrole 135 with either 1 or 2 equiv of DM AD in benzene gave a stable 1 2 cycloadduct 145 in 88% yield <1995T193>. 

The formylation of methyl furo[2,3-/)]pyrrole-5-carboxylate 31a and its variously iV-substituted derivatives 31b, 31c, and 153 has been studied and 31d-f, and 154 were obtained (Equation 2) <1997MOL69, 1999CCC1135>. 

An attempt to introduce a bulky triphenylmethyl substituent at N-(y of methyl 677-furo[2,3-7]pyrrole-5-carboxylate 31a led to C-2 triphenylmethyl substitution giving the product 157, which with ethyl propynoate in acetonitrile gave the Michael addition product 158 <2000PJC207> (Scheme 16). 

By the hydrolysis of esters 81a-c, the corresponding acids 83a-c were formed. The 2-[3-(trifluoromethyl)phenyl]-4//-furo[3,2-7]pyrrole-5-carboxylic acid 83a was decarboxylated in acetic anhydride to 4-acetyl-2-[3-(trifluoromethyl)-phenyl]furo[3,2-7]pyrrole 84 (see 10.01.05.1.2, Scheme 7). 

The reactions of substituted furo[3,2- ]pyrrole-5-carbohydrazides with 5-arylfuran-2-carbaldehydes, 4,5-disubsti-tuted furan-2-carbaldehydes, and thiophene-2-carbaldehyde have been studied <2005CEC622>. The advantage of microwave (MW) irradiation on some of these reactions was reflected in the reduced reaction time and increased yields (Table 8). The series of substituted hydrazones 241-246 was obtained from these... 

Substituted hydrazones 254 and 255 were synthesized by the reaction of the corresponding furo[3,2- ]pyrrole-5-carbohydrazides with 6-substituted 4-oxochromene-3-carbaldehydes 252 and methyl 2-formylfuro[3,2- ]pyrrole-5-car-boxylates 253 under MW irradiation as well as by the classical method(C). The beneficial effect of the MW irradiation on these reactions was a shortening of the reaction time and an increase in the yields <2005CCC2101> (Scheme 25). 

The condensation of furo[3,2- ]pyrrole-type aldehydes 8g and 265-267 with hippuric acid was carried out in dry acetic anhydride catalyzed by potassium acetate as is shown in Scheme 26. The product methyl and ethyl 2-[( )-(5-oxo-2-phenyl-l,3-oxazol-5(4//)-ylidene)methyl]furo[3,2- ]pyrrol-5-carboxylates 268a-d were obtained. The course of the reaction was compared with the reaction of 5-arylated furan-2-carbaldehydes with hippuric acid. It was found that the carbonyl group attached at G-2 of the fused system 8 is less reactive than the carbonyl group in 5-arylated furan-2-carbaldehydes in this reaction <2004MOL11>. The configuration of the carbon-carbon double bond was determined using two-dimensional (2-D) NMR spectroscopic measurements and confirmed the (E) configuration of the products. 

The condensation reaction of some selected furo[3,2-b]pyrrole aldehydes (8g, 266,267) with benzothiazolium salts was carried out in refluxing methanol with pyridine as catalyst giving 269a-d <2004MOL241>. 

The reactions of methyl 2-formyl-677 or 6-substituted furo[2,3-. ]pyrrole-5-carboxylates 31d-f or 154 <1997MOL69, 1999CCC1135> with malononitrile, methyl cyanoacetate, and 2-furylacetonitrile, respectively, afforded the corresponding methyl 2-(2,2-dicyanovinyl)-677- or 6-substituted furo[2,3-. ]pyrrole-5-carboxylates 294a-d, methyl 2-[2-cyano-2-(methoxycarbonyl)vinyl]-677- or 6-substituted furo[2,3-. ]pyrrole 5-carboxylates 295a-d, and methyl... 

Milkiewicz et al. <2003TL4257> prepared a series of novel tetrasubstituted furo[3,2-/ ]pyrroles from the methyl or ethyl 3-bromo-2-phenylfuro[3,2-3]pyrrole-5-carboxylate 336. The compounds 336 were subjected to a Suzuki coupling with 4-chlorophenylboronic acid to form 337, which was treated with a variety of alkylating agents to afford the corresponding esters 338. The esters were then saponified to acids 339 (Scheme 34). 

Methyl 2-[3-(trifluoromethyl)phenyl]-4/7-furo[3,2-4]pyrrole-5-carboxylate 81a was made by thermolysis of the corresponding methyl 2-azido-3- 5-[3-(trifluoromethyl)phenyl]-2-furyl propenoate 378, which was formed by condensation of 5-[3-(trifluoromethyl)phenyl]furan-2-carbaldehyde 377 with methyl azidoacetate under sodium meth-oxide catalysis (Scheme 40) <2006KGS825>. 

Knoevenagel condensation of the corresponding 3-methylfuran-2-carbaldehyde 379 and 3-methybenzo[4]furan-2-carbaldehyde 382 with diethyl malonate followed by bromination with iV-bromosuccinimide (NBS) in the presence of dibenzoyl peroxide afforded bromides 380 and 383, respectively. Treatment of 380 and 383 with benzylamine, isopropylamine, /-butylamine 3-hydroxypropylamine, aniline and -toluidine in ethanol yielded furo[2,3-c]pyrroles 381 and benzo[4,5]furo[2,3-c]pyrroles 384, respectively (Scheme 41). The yields of furopyrroles 381 are only moderate (16-46%), because these compounds are highly sensitive to acid, and partially polymerized upon silica... 

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