4/7-Furo pyrrole-2-carboxylate

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. 

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. 

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>. 

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 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 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>. 

Substituted hydrazones 85 and 86 were synthesized by the reaction of the corresponding furo[3,2-h]pyrrole-5-carbohydrazides 83 with 6-substituted-4-oxo-chromene-3 -carbaldehydes 84 andmethyl 2-formylfuro[3,2- ]pyrrole-5-carboxylates 80 under microwave irradiation as well as by the classical method. The beneficial effect of microwave irradiation on these reactions was a shortening of the reaction time and an increase in the yields (Scheme 13) [23],... 

Fig. 13 6-Methyl-2-[( )-(oxo-2-phenyl-l,3-oxazol-5(47/-ylidene)methyl]furo[2,3-fc] pyrrole-5-carboxylate 233b, 6-methoxymethyl-2-[( )-(oxo-2-phenyl-l,3-oxazol-5(4//-ylidene) methyl] furo[2,3-fc]pyrrole-5-carboxylate 233d [22] 3-benzyl-2-[( )-2-[5-(methoxycarbonyl)-6-methoxymethylfuro[2,3-fe]pyrrol-2-yl]vinyl -l,3-benzotiazolium bromide 234 [23]...

In ethyl 4//-furo[3,2-Z>]pyrrole-5-carboxylate (8a) the furan and pyrrole rings are nearly coplanar, with a dihedral angle between the rings of 1.0(2)°. The molecules are linked by N—H- -O hydrogen bonds <88AX(C)2032>. 

In compounds (94) and (95), where C-2 and C-5 are substituted, formylation afforded the N-formylated products (96) and (97). Prolonged reaction times led to the C-6 formylated products (98) and (99). In the case of ethyl l//-benzo[6]furo[3,2-6]pyrrole-2-carboxylate (100) <82CCC3288> the C-3 formylated product (101) was formed <90CCC597>. 

The Mannich reaction occurred at C-6 of ethyl 2-phenyl-4//-furo[3,2-6]pyrrole-5-carboxylate (94) giving the amine (106). 2-Aryl-4//-furo[3,2-6]pyrroles <83CCC772> easily undergo reaction with benzenediazonium chloride at C-5 forming the azo compounds (107) and (108). 

The 1,3-dipolar cycloadditions of ethyl 4//-furo[3,2-/>]pyrrole-5-carboxylate (8a) or its 4-methyl derivative (8f) (Equation (2)) with C-benzoyl-A-phenylnitrone and ACV-diphenylnitrone proceeded regiospecifically at positions 2 and 3 of the furan ring. During these reactions, exclusively endo cycloadducts were formed, because their transition states are stabilized by secondary orbital interactions <81CCC2421>. 

The reactions of the methyl furo[2,3-6]pyrrole-5-carboxylate (153) or its 6-methyl derivative (154) with DMAD proceed via [4 -I- 2] cycloaddition at the a,a -positions of the furan ring, giving cycloadducts which by subsequent 1,5-sigmatropic rearrangement give trimethyl 5-hydroxyindole-2,6,7-tricarboxylate (155) or its 1-methyl derivative (156) <94UP 70i-0i>. 

Oxiranylmethyl)furo[3,2-/)]pyrrole-5-carboxylate (272) with morpholine undergoes oxirane ring opening to form the. -substituted derivative of methyl 4-(3-amino-2-hydroxypropyl)furo[3,2-/>]pyrrole-5-carboxylate (273). Using pyrrolidine as nucleophile the fused aza-lactone (274) is formed (Scheme 18) <95UP 701-01). 

Thermolysis of azidoacrylate (519) obtained by condensation of the appropriate benzo[Z>]furan-2-carbaldehyde (518) with ethyl azidoacetate afforded the corresponding alkyl benzo[Z ]furo[3,2-Z ]pyrrole-2-carboxylates (520) with 61% overall yield (Scheme 42) <82CCC3288>. 

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