Synthesis and Reactions of Furo[2,3-b]pyrroles

Methyl 6H-furo[2,3-b]pyrrole-5-carboxylate (2a) was prepared by thermolysis of the corresponding methyl 2-azido-3-(3-furyl)propenoate (1). 6-Methyl (2b) and 6-benzyl (2c) derivatives were obtained using phase-transfer catalysis conditions (PTC). The formylation of 2a-2c gave 2-formylated compounds (3a-3c). Compounds 4b, 4c were prepared by reactions of corresponding esters 2b, 2c with hydrazine in refluxing ethanol. By reaction of 3a-3c with hydroxylammonium chloride in acetic anhydride in the presence of pyridine, methyl 2-cyano-6-R 1-furo[2,3-b]pyrrole-5-carboxylates (5a-5c) were obtained. The reaction of these compounds with sodium azide and ammonium chloride in dimethylformamide led to methyl 2-(5'-tetrazolyl)-6-R 1-furo[2,3-b]pyrrole-5-carboxylates (6a-6c). A series of 5-methoxycarbonyl-6-R 1-furo[2,3-b]pyrrole-2-carbaldehyde N,N-dimethylhydrazones (7a-7c) was prepared from methyl 2-formyl-6-R 1-furo[2,3-b]pyrrole-5-carboxylates (3a-3c) and unsym-dimethylhydrazine. The correlation of the 13 C and 15 N chemical shifts with the data of the calculated (AM1) net atomic charges is discussed.


Introduction
Furo [2,3-b]pyrroles (2a-2c) and their positional isomers furo [3,2-b]pyrroles (8a-8c) belong to A,Bdiheteropentalenes, which possess differing degrees of aromaticity based upon chemical behaviour such as their ability to undergo substitution reactions with electrophilic reagents.A,B-diheteropentalenes rank among the electronrich heterocycles, but a quantitative measurement of their aromaticities is less easily determined [1].The wide range of potential criteria available for this purpose has been surveyed [1,2].

2a-2c 8a-8c
Most of the available criteria point to an order of decreasing aromaticity of 1,4 > 1,6 ring system which is influenced by the heteroatom in the order S>Se≥N>O.Substituents attached to the A,B-heteropentalene structures can strongly influence the aromaticity.Until recently 1,6diheteropentalenes containing S, Se heteroatoms had been studied [1,2] and a few derivatives of the furo [2,3-b]pyrole system had been prepared [3].The parent furo [2,3b]pyrrole has not been reported.In the past we were interested in syntheses and studies of the reactions of furo [3,2-b]pyrroles and their benzo or dibenzo derivatives [4][5][6][7][8][9].
In continuation of our programme aimed at developing efficient syntheses of fused oxygen-nitrogen-containing heterocycles, we report here the study of the synthesis of methyl furo [2,3-b]pyrrole-5-carboxylate (2a) and its utilization in synthesis.Our main interest is a comparison of the behaviour of 1,6-O,N-diheteropentalene system (2) with isomeric 1,4-system (8).

Results and Discussion
Reaction of 3-furancarbaldehyde with methyl azidoacetate in the presence of sodium methoxide proceeded smoothly to give the azide 1, thermolysis of which was carried out in boiling toluene leading to the compound 2a.Phase transfer catalysis was found to be successful for methylation and benzylation of 2a giving the derivatives 2b and 2c (Scheme 1).The compounds 2a-2c gave under Vilsmeier conditions 2-formylated products 3a-3c.By refluxing the compounds 2b and 2c with hydrazine in ethanol the corresponding hydrazides 4b and 4c were formed.Our experiments to synthesize 6H-furo [2,3b]pyrrole-5-carboxyhydrazide (4a) under conditions which were used for preparation of 4b and 4c were unsuccessful.The reaction of 3a-3c with hydroxylammonium chloride in acetic anhydride in the presence of pyridine at 90°C gave the corresponding cyano-substituted compounds 5a-5c.The reaction of the compounds 5a-5c with sodium azide and ammonium chloride in dimethylformamide led to the tetrazoles 6a-6c.N,N-Dimethylhydrazones 7a-7c were prepared from the aldehydes (3a-3c) and unsym-dimethylhydrazine in refluxing toluene, using a catalytic amount of 4methylbenzenesulfonic acid.
During the synthesis and reaction studies of both systems we found out that the 1,4 system ( 8) is more stable than its 1,6 positional isomer (2).This empirical conclusion is in agreement with the results of AM1 semiempirical MO calculations that we have carried out for the parent furopyrroles and the ester derivatives 2a and 8a. Figure 1 shows the calculated properties for the methyl esters 2a and 8a including their heats of formation (∆H f ).The 1,4 system (8a) is calculated to be thermodynamically more stable than the 1,6-isomer (2a).The 1,4-system (8a) is also calculated to have a significantly larger dipole moment (µ) (Figure 1), which may result in greater solvent stabilisation.Comparable results were obtained for the unsubstituted heterocycles (Figure 2).Calculated net atomic charges and molecular geometries are given in Tables 4-7.The calculated ionisation potentials (using Koopmaan' theorem) (Figure 1) are consistent with the classification of these heterocycles as electron-rich.
The 13 C chemical shifts of 2a-2c and 8a-8c are reported in Table 1, 1H and 13 C NMR data of other compounds are in the experimental part.The different 13 C chemical shift values of the corresponding carbon positions for compounds 2a and 8a relative to the carbons of furan [13] and methyl 2-pyrrolecarboxylate [14] (Table 2) show, that in the 1,4-isomer 8a the differences are greater than in 2a.In 8a carbon C-2 shows a downfield shift ∆δ = 5.09 ppm, C-3 an upfield shift ∆δ = -11.51ppm as well as for C-6 ∆δ = -18.17ppm.This demonstrates that the electron density of both compared systems changes due to the annelated ring interaction, but the effect of the annelated ring is greater in the case of the 1,4 system.An analogous upfield shift was observed in 1H,4H-pyrrolo[3,2-b]pyrrole [15].In order to make a direct comparison of both types of furopyrroles we carried out the correlation of the 13 C and 15 N chemical shifts (Tables 1 and 3) with net atomic charges, calculated using the AM1 method (Tables 4 and  6).In compounds 2a-2c signals C-2 and C-5 appear at higher magnetic field and C-3 and C-4 at lower field in comparison with corresponding carbons in 8a-8c (Table 1).The relative values of the calculated net atomic charges for the parent systems (Table 4) and the esters 2a and 8a (Table 6) are in good agreement with these experimental data.The comparison of 13 C chemical shifts of substituted furo [2,3-b]pyrroles shows that the greatest effect of substituents in the 2-position was observed at C-2 and C-3, analogous to the 2-substituted furans [13] and the 1,4-O,Nsystem [16].were obtained directly from the spectra.Selective excitation was applied to prove that the 3 J( 15 N,H) coupling constants are due to the proton on the pyrrole ring; 60 and 100 ms evolution times were used for other compounds and spectral patterns measured were compared with simulated ones using the SIMEPT programme [17].It was assumed, taking the data for compounds 2a and 8a into account, that the greater coupling constants were due to interaction with the proton on the pyrrole ring.The slightly larger negative values of the 15 N chemical shifts in 2a-2c compared to 8a-8c agree with the relative values of the calculated (AM1) negative charges on nitrogen (Tables 4  and 6).
The configurational assignment of the substituents on the double bond of the hydrazone 7a has been determined by 15 N NMR spectra using the stereospecific coupling constants 2 J( 15 N,H-7).The orientation of the lone-pair of the nitrogen and the corresponding proton has a marked effect on the value of the respective coupling constant.The comparison of the coupling constants 2 J( 15 N,H-7) = 6.5 Hz with those of model compounds in ref. [18,19] confirms the E-isomer of 7a.The same configuration was determined for some hydrazones in our previous paper [20].C chemical shifts were referred to internal TMS (δ = 0.00). 15N NMR spectra were measured using non-refocused INEPT [21].The evolution time used was 2.6 ms for compounds 2a and 8a and 60 and 100 ms for other compounds. 15N chemical shifts were referred to external nitromethane (δ = 0.0) placed in a coaxial capillary.
Negative values of chemical shifts denote upfield shifts with respect to standards.Melting points were determined on a Kofler hot plate apparatus and are uncorrected.UV spectra were measured on a M-40 (Carl Zeiss, Jena) spectrophotometer in methanol [λ max (log ε); λ max in nm, ε in m 2 mol -1 ].The IR spectra were taken on a FTIR PU 9802/25 (Philips) spectrophotometer using KBr technique (0.5 mg in 300 mg KBr, ν in cm -1 ).
Molecular orbital calculations were carried out using the AM1 semiempirical method [22].The geometry of each molecule studied was found by minimising the energy with respect to all geometrical variables.

Table 2 .
Difference Positive sign denotes a downfield shift from furan and methyl 2-pyrrolecarboxylate, respectively.