IMDAV reaction between phenylmaleic anhydride and thienyl(furyl)allylamines: synthesis and molecular structure of (3aSR,4RS,4aRS,7aSR)-5-oxothieno- and (3aSR,4SR,4aRS,7aSR)-5-oxofuro[2,3-f]isoindole-4-carboxylic acids

To establish the scope and limitations of the IMDAV reaction by elucidation of its regio- and stereoselectivity, the products of the reaction between phenylmaleic anhydride and thienyl(furyl)allylamines were studied by X-ray diffraction

The title compounds C 24 H 21 NO 3 S, I, and C 24 H 21 NO 4 , II, are the products of the IMDAV reaction between phenylmaleic anhydride and thienyl(furyl)allylamines. Their molecular structures comprise fused tricyclic systems containing thiophene, cyclohexene and pyrrolidine rings (I) or furan, cyclohexene and pyrrolidine rings (II). The central cyclohexene and pyrrolidine rings in both compounds adopt slightly twisted boat and envelope conformations, respectively. The dihedral angles between the basal plane of the pyrrolidine ring and the thiophene (in I) or furan (in II) ring plane are 22.74 (16) and 26.29 (5) , respectively. The nitrogen atom both in I and II has practically planar environment [the sums of the bond angles are 359.8 and 358.9 , respectively]. In the crystal of I, the molecules form hydrogen-bonded zigzag chains along [010] through strong intermolecular O-HÁ Á ÁO hydrogen bonds involving carboxylic and keto groups, whereas in the crystal of II, the molecules are joined into centrosymmetric dimers by strong O-HÁ Á ÁO hydrogen bonds between the carboxylic groups. In II, the atoms involved into these hydrogen bonds (and hence the whole carboxylic group) are disordered over two sets of sites with an occupancy ratio of 0.6:0.4. Compounds I and II crystallize as racemates consisting of enantiomeric pairs of the 3aSR,4RS,4aRS,7aSR and 3aSR,4SR,-4aRS,7aSR diastereomers, respectively.

Chemical context
Cascade transformations including one or more tandem or sequential [4 + 2] cycloaddition reactions are a useful and high-usage tool in organic synthesis (Parvatkar et al., 2014;Sears & Boger, 2016;Borisova et al., 2018). In most cases, conjugated linear or cyclic alkadienes are the starting materials for these transformations. Along with this, it has long been known that furan, thiophene and pyrrole, possessing a conjugated system of double bonds, can also act as a diene moiety. Around 50 years ago, it was found that 2-vinylfurans and 2-vinylthiophenes can play the role of dienes in the intermolecular Diels-Alder reaction, which cleared a short way to benzofuran or benzothiophene derivatives (Paul, 1943;Szmuszkovicz & Modest, 1950;Schmidt, 1953;Scully & Brown, 1953;Davies & Porter, 1957a,b;Kaufmann & Sen Gupta, 1963;Ancerewicz & Vogel, 1993;Drew et al., 2002;Wavrin et al., 2004;Ghobsi et al., 2008). At the end of the last ISSN 2056-9890 century, it was demonstrated that this reaction could be performed in an intramolecular variant when both a heterocyclic diene and a dienophilic moiety are incorporated in the same molecule.
The IMDAV (IntraMolecular Diels-Alder Vinylarenes) reaction ( Fig. 1) has become a powerful tool in organic synthesis because of its simplicity and reliability, which assures good yields of benzofurans and benzothiophenes annulated with other carbo-and heterocycles (Maas et al., 2006;Patre et al., 2007;Kim et al., 2014). Previously, with the example of the interaction between maleic anhydride and 3-thienyl(furyl)allylamines, our group demonstrated the possibility of the domino-sequence involving N-acylation, IMDAV reaction and aromatization steps leading to 4H-furo-or thieno[2,3-f]isoindoles (Horak et al., 2015(Horak et al., , 2017Zubkov et al., 2016). The aim of the present study was elucidation of the regio-and stereoselectivity of the reaction between phenylmaleic anhydride and thienyl(furyl)allylamines in order to establish the scope and the limitations of the IMDAV reaction (Fig. 2).
The reaction proceeds smoothly at room temperature, a simple filtration of the resulting crystalline products from ethyl acetate giving adducts I and II in good yields. The Diels-Alder reaction proceeds regio-and stereoselectively as an exo-[4 + 2] cycloaddition (Fig. 2). The nucleophilic attack of the nitrogen atom is directed at the least sterically hindered carbon atom of the carbonyl group of phenylmaleic anhydride, thus amide A is not formed. The intermediate amide B cannot be isolated, and the spontaneous intramolecular Diels-Alder reaction completes the process, leading to the target compounds I and II. The migration of proton H3a in adducts I, II and the formation of compound C is not observed under these conditions (Horak et al., 2015(Horak et al., , 2017Zubkov et al., 2016).  Synthesis of (3aSR,4RS,4aRS,7aSR)-5-oxothieno[2,3-f]isoindole-4-carboxylic acid (I) and (3aSR,4SR,4aRS,7aSR)-5-oxofuro[2,3-f]isoindole-4carboxylic acid (II).

Figure 3
Molecular structure of I. Displacement ellipsoids are shown at the 50% probability level. H atoms are presented as small spheres of arbitrary radius.

Figure 4
Molecular structure of II. Displacement ellipsoids are shown at the 50% probability level. H atoms are presented as small spheres of arbitrary radius. The minor occupancy position of the -COOH group is depicted with dashed lines.

Figure 1
Intra-and intermolecular Diels-Alder reaction in vinylfurans and vinylthiophenes in the synthesis of benzofurans and benzothiophenes.
Compound I crystallizes in the monoclinic space group P2 1 /n, while compound II crystallizes in the triclinic space group P1.
The molecules of I and II comprise fused tricyclic systems containing thiophene, cyclohexene and pyrrolidine rings in I (Fig. 3) and furan, cyclohexene and pyrrolidine rings in II (Fig. 4). The central cyclohexene and pyrrolidine rings in both compounds adopt slightly distorted boat and envelope conformations, respectively. The dihedral angles between the basal plane of the pyrrolidine ring (N5/N6/C4A/C7) and the thiophene (in I) or furan (in II) ring planes are 22.74 (16) and 26.29 (5) , respectively. The N6 nitrogen atom both in I and II has practically planar environment (the sums of the bond angles are 359.8 and 358.9 , respectively).
In the molecule of II, the carboxylic group is disordered over two orientations with interchanging hydrogen atom positions (Fig. 4), the occupancy ratio being 0.6:0.4.
The molecules of I and II possess four asymmetric centers at the C3A, C4, C4A and C7A carbon atoms and potentially can have numerous diastereomers. The crystals of I and II are racemic and consist of enantiomeric pairs with the following relative configuration of the centers: 3aSR,4RS,4aRS,7aSR and 3aSR,4SR,4aRS,7aSR, respectively, thus I and II differ in the configuration at the C4 atom.

Supramolecular features
In the crystal of I, molecules form hydrogen-bonded zigzag chains propagating along [010] through strong O-HÁ Á ÁO hydrogen bonds involving the carboxylic and keto groups (Table 1, Fig. 5).
Contrary to I, in the crystal of II, molecules form hydrogenbonded centrosymmetric dimers through pairs of strong O-HÁ Á ÁO hydrogen bonds between two carboxylic groups (Table 2, Fig. 6). The dimers are stacked along the a-axis direction.

Figure 5
The hydrogen-bonded zigzag chains along the b-axis direction in I.

Figure 6
The hydrogen-bonded centrosymmetric dimers of II. Dashed lines indicate the intermolecular O-HÁ Á ÁO hydrogen bonds. The minor occupancy -COOH groups are omitted for clarity.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. X-ray diffraction studies were carried out on the 'Belok' beamline of the National Research Center 'Kurchatov Institute' (Moscow, Russian Federation) using a Rayonix SX165 CCD detector. A total of 720 images for each compounds were collected using an oscillation range of 1.0 (' scan mode, two different crystal orientations) and corrected for absorption using the SCALA program (Evans, 2006). The data were indexed, integrated and scaled using the utility iMOSFLM in the CCP4 program (Battye et al., 2011).
The COOH-group in II is disordered over two orientations. The refinement of their occupancy factors was unstable, thus the occupancies were constrained to a 0.6:0.4 ratio. The two positions of this group were refined at fixed C O and C-O distances of 1.210 (3) and 1.320 (3)    the anisotropic displacement parameters for the oxygen atoms of the C O and C-O groups were restrained to be equal. The hydrogen atoms of the OH groups were localized in difference-Fourier maps and refined isotropically with fixed displacement parameters [U iso (H) = 1.5U eq (O)]. The other hydrogen atoms were placed in calculated positions with C-H = 0.95-1.00 Å and refined using the riding model with fixed isotropic displacement parameters [U iso (H) = 1.5U eq (C) for the CH 3 groups and 1.2U eq (C) for all others].
A relatively large number of reflections (a few dozen) were omitted for the following reasons: (1) In order to achieve better I/ statistics for high-angle reflections we selected a larger exposure time, which resulted in some intensity overloads in the low-angle part of the area. These corrupted intensities were excluded from the final steps of the refinement.

Special details
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Special details
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.