One-pot sequential multicomponent reaction between in situ generated aldimines and succinaldehyde: facile synthesis of substituted pyrrole-3-carbaldehydes and applications towards medicinally important fused heterocycles

An efficient sequential multi-component method for the synthesis of N-arylpyrrole-3-carbaldehydes has been developed. This reaction involved a proline-catalyzed direct Mannich reaction-cyclization sequence between succinaldehyde and in situ generated Ar/HetAr/indolyl-imines, followed by IBX-mediated oxidative aromatization in one-pot operation. The practical utility of this procedure is shown at gram-scale and the synthesis of diverse bioactive fused heterocyclic scaffolds such as pyrroloquinoline, pyrrolo-oxadiazole, dihydro pyrroloquinoline, and pyrrolo-phenanthridine.


Crystal structure determination and refinement
X-ray intensity data consisting of 10516 reflections were collected at 293(2) K and 4546 reflections were found unique.A crystal of dimensions 0.30 x 0.20 x 0.20 mm was used for data collection on X'calibur CCD area-detector diffractometer, equipped with graphite monochromated MoKα radiation =0.71073Å) [6].The intensities were measured by scan mode for θ ranges 3.7 to 26.0°.A total number of 2862 reflections were treated as observed [I >2σ(I)] .Data were corrected for Lorentz-polarization and absorption factors.The structure was solved by direct methods using SHELXS97 [1].All non-hydrogen atoms of the molecule were located in the best E-map.All the hydrogen atoms were geometrically fixed and allowed to ride on the corresponding non-H atoms with C-H= 0.93-0.94Å and U iso = 1.2 U eq (C), except for the methyl groups where U iso (H) = 1.5U eq (C).The refinement cycles converged the structure to a final R-factor of 0.0513 (wR (F 2 ) = 0.1128) for the 2862 observed reflections.Residual electron densities ranges from -0.271 to 0.270 eÅ -3 .Atomic scattering factors were taken from International Tables for X-ray Crystallography (1992, Vol.C, Tables 4.2.6.8 and 6.1.1.4)[7].
An ORTEP [8] view of the compound with atomic labelling scheme is shown in Figure 1.The geometry of the molecule was calculated using the PARST [4] and PLATON [5] software.
Crystal data, along with data collection and structure refinement details are summarized in Table 1.Selected bond lengths, bond angles and torsion angles are given in Table 2.The geometry of intra and inter molecular interactions is given in Table 2.
The compound 1-(4-methoxyphenyl)-2-(4-nitrophenyl)-1H-pyrrole-3-carbaldehyde, C 18 H 14 N 2 O 4 , crystallizes in the orthorhombic space group P2 1 2 1 2 1 with the unit-cell parameters: a= 8.0230(6), b= 10.5211(8), c= 18.4479(16) Å and Z = 4.The crystal structure was solved by direct methods using single-crystal X-ray diffraction data collected at room temperature and refined by full-matrix leastsquares procedures to a final R-value of 0.0511 for 1184 observed reflections.Crystal structure determination and refinementX-ray intensity data of 4243 reflections (of which 1762 unique) were collected on X'calibur CCD area-detector diffractometer equipped with graphite monochromated MoKα radiation (λ = 0.71073 Å).The crystal used for data collection was of dimensions 0.30 x 0.20 x 0.20 mm.The cell dimensions were determined by least-squares fit of angular settings of 1096 reflections in the θ range 3.85 to 25.01 o .The intensities were measured by ώ scan mode for θ ranges 3.84 to 26.00 o .1184 reflections were treated as observed (I > 2σ(I)).Data were corrected for Lorentz, polarisation and absorption factors.The structure was solved by direct methods using SHELXS97 [1].All non-hydrogen atoms of the molecule were located in the best E-map.Fullmatrix least-squares refinement was carried out using SHELXL97 [1].The final refinement cycles converged to an R = 0.0511 and wR (F 2 ) = 0.0913 for the observed data.Residual electron densities ranged from -0.194<∆ρ < 0.143eÅ -3 .Atomic scattering factors were taken from International Tables for X-ray Crystallography (1992, Vol.C, Tables 4.2.6.8 and 6.1.1.4).The crystallographic data are summarized in Table

Figure 1
Figure 1 ORTEP view of the molecule with displacement ellipsoids drawn at 40%.

Figure 2 :
Figure 2: ORTEP view of the molecule with displacement ellipsoids drawn at the 40% probability level.H atoms are shown as small sphere of arbitrary radii.

Figure 3 :
Figure 3: A dimer formed by intermolecular C-H….O hydrogen bonds

Table 1 :
Crystal and experimental data