Syntheses and crystal structures of the anhydride 4-oxatetracyclo[5.3.2.02,6.08,10]dodec-11-ene-3,5-dione and the related imide 4-(4-bromophenyl)-4-azatetracyclo[5.3.2.02,6.08,10]dodec-11-ene-3,5-dione

The Diels–Alder cycloaddition of cycloheptatriene and maleic anhydride produces the title carboxylic anhydride; reaction of this anhydride with 4-bromophenylaniline forms the corresponding tetracyclic imide. The anhydride features C—H⋯O hydrogen bonds in the solid state, while the imide also features C—H⋯O hydrogen bonds as well as C—H⋯π and lone pair–π interactions.

The syntheses and crystal structures of the two title compounds, C 11 H 10 O 3 (I) and C 17 H 14 BrNO 2 (II), both containing the bicyclo[2.2.2]octene ring system, are reported here [the structure of I has been reported previously: White & Goh (2014). Private Communication (refcode HOKRIK). CCDC, Cambridge, England]. The bond lengths and angles of the bicyclo[2.2.2]octene ring system are similar for both structures. The imide functional group of II features carbonyl C O bond lengths of 1.209 (2) and 1.210 (2) Å , with C-N bond lengths of 1.393 (2) and 1.397 (2) Å . The five-membered imide ring is nearly planar, and it is positioned exo relative to the alkene bridgehead carbon atoms of the bicyclo[2.2.2]octene ring system. Non-covalent interactions present in the crystal structure of II include a number of C-HÁ Á ÁO interactions. The extended structure of II also features C-HÁ Á ÁO hydrogen bonds as well as C-HÁ Á Á and lone pair-interactions, which combine together to create supramolecular sheets.

Chemical context
Cycloheptatriene, a, exhibits valence isomerism with norcaradiene, b, in solution ( Fig. 1). The norcaradiene isomer readily reacts with maleic anhydride, c, to form the unique tricyclic anhydride, I (White & Goh, 2014). This reaction has been known since 1939 (Kohler et al., 1939), but the structure of the major product was not determined until 1953, when it was elucidated that the product contained a cyclopropane ring (Alder & Jacobs, 1953). The combination of a rigid tricyclic structure with alkene, anhydride and cyclopropane functional groups makes this structure interesting as a scaffold for drug ISSN 2056-9890 Figure 1 Valence isomerism of cycloheptatriene a with norcaradiene b, then the Diels-Alder reaction with maleic anhydride c to give the title anhydride I. design because of the ability to specifically place groups in molecular space and thus design molecules to interact selectively with protein active sites.
In a high-throughput screen of 356,000 compounds for activity against vaccinia and cowpox viruses, Bailey et al. (2007) discovered antiviral activity of imide derivatives related to I, including e (tecovirimat, C 19 H 15 F 3 N 2 O 3 ; Fig. 2). SAR studies showed that this derivative was the most active of the entire library, and its mode of action was to inhibit extracellular virus formation. Interestingly, hydrogenation of the alkene had little effect on the activity of the compound. Tecoviramat has been approved as a treatment for smallpox, and the United States has created a stockpile of two million doses stored at the US Strategic National Stockpile (Hughes, 2019).
Substituted anilines, such as p-bromoaniline f, have also been reacted with the anhydride I to form imides that show insecticidal activity (Fig. 2, Brechbuhler & Petitpierre, 1975). A wide range of imides were synthesized, including compound II, and were shown to protect crops by inhibiting the growth of lepidoptera. Finally, we note that all of these imide derivatives will undergo a retro-Diels-Alder cycloaddition to form cycloheptatriene and a substituted maleimide. Structural investigations have shown that there is an increase in the length of the C-C bonds that are involved in the retro-Diels-Alder reaction relative to the other C-C bonds in the molecule (Birney et al., 2002;Pool et al., 2000). Herein we report the syntheses and crystal structures of the anhydride I and imide II. The structure of the anhydride was previously reported as a Private Communication to the CSD (refcode HOKRIK; White & Goh, 2014).

Structural commentary
The structure of the title anhydride I was solved in the monoclinic space group P2 1 /n with two molecules in the asymmetric unit. The atom labeling scheme (starting with C1 and C1a for the two molecules) is shown in Fig. 3. This structure is quite similar with respect to the bond lengths and angles described below for the imide II. The bond lengths of the carbonyl groups of the anhydride are shorter than the imide, as expected, with C1 O1 = 1.1943 (18), C2 O2 = 1.1904 (17), C1-O3 = 1.3868 (17) and C2-O3 = 1.3978 (16) Å . The corresponding data for the C1a molecule are 1.1913 (17), 1.1871 (18), 1.3855 (17) and 1.3905 (18) Å , respectively. The configurations of the stereogenic centres in the arbitrarily chosen asymmetric molecules are: C3 S, C4 R, C5 R, C8 S, C9 S, C10 R and C3a R, C4a S, C5a S, C8a R, C9a R, C10a S: crystal symmetry generates a racemic mixture in the bulk.
The structure of the imide II was solved in the monoclinic space group P2 1 /n, and its atom labeling scheme is shown in Fig. 4 Synthesis of the smallpox antiviral compound Tecovirimat, and the title imide II, which both use anhydride I as the starting material.

Figure 3
The molecular structure of the anhydride I, with the atom-labeling scheme for both crystallographically unique molecules. Displacement ellipsoids are shown at the 40% probability level using standard CPK colors.

Figure 4
The molecular structure of the imide II, with the atom-labeling scheme. Displacement ellipsoids are shown at the 40% probability level using standard CPK colors. bond lengths of 1.209 (2) and 1.210 (2) Å , with C-N bond lengths of 1.393 (2) and 1.397 (2) Å . The O-C-N bond angles of the imide functional group are 123.98 (17) and 123.97 (17) . The aromatic ring, C12-C17, is oriented nearly perpendicular to the plane containing the atoms of the imide functional group with a C1-N1-C12-C17 torsion angle of 65.0 (2) . The five-membered ring that contains the imide functional group (-C1-N1-C2-C4-C3-) is close to planar with a Cremer-Pople value of 2.8 (Cremer & Pople, 1975). When considering the bicyclo[2.2.2]octene ring system (C3-C10), both C11 and the atoms of the imide functional group are oriented exo relative to the bridgehead alkene carbon atoms C6-C7. The length of the C6 C7 double bond is 1.324 (3) Å , and the cyclopropyl ring C9-C11 has C-C-C bond angles ranging from 59.89 (13)-60.14 (14) . The stereogenic centres in the asymmetric molecule of II are C3 R, C4 S, C5 S, C8 R, C9 R and C10 S; again, crystal symmetry generates a racemic mixture.
Cg1 is the centroid of the C12-C17 ring.

Database survey
The structure of the anhydride I has been deposited in the  (Coxon et al., 1986), which bears a very complex fused-ring system in the place of the cyclopropane ring on anhydride I. A search of the CSD for structures containing a bicyclo-[2.2.2]octene ring system fused to a cyclic imide resulted in 125 structures related to imide II. Structure COZMAH (Wu et al., 2014) also bears a p-bromobenzene ring bonded to the imide nitrogen atom, but is derivatized with two esters and an indole ring on the octene portion of the ring system. The structure of tecovirimat (e, Fig. 2) has been deposited as SOKVIY (Bailey et al., 2007). Finally, structure HARNEV bears two cyclic imide groups on either side of the octene ring system (Song et al., 2012).