Crystal structure of N-[(1S,2S)-2-aminocyclohexyl]-2,4,6-trimethylbenzenesulfonamide

In the crystal structure of the title compound, the sulfonamide N—H group forms an intermolecular hydrogen bond to the amine N atom.


Chemical context
Many sulfonamides have been reported as anticancer, antiinflammatory, and antiviral agents (Navia, 2000;Yan et al., 2006;Palakurthy & Mandal, 2011). The use of sulfonamides as catalysts in asymmetric synthesis has also been reported (Lao et al., 2009;Feng et al., 2010;Jin et al., 2010). Through explicit hydrogen-bonding interactions with specific functional groups, the electrophilicity and stereoselectivity of a given substrate is enhanced.
Conjugate addition reactions of aldehydes and ketones to nitroalkenes, catalyzed by chiral primary amines, have been reported (Huang & Jacobsen, 2006;Rabalakos & Wulff, 2008;Lao et al., 2009;Sun et al., 2012;Zhou et al., 2014;Ruiz-Olalla et al., 2015;Yang et al., 2015). The catalytic activity of chiral primary amine organocatalysts with particular emphasis on the role of the N-H acidity and hydrogen bonding has also been investigated (Lao et al., 2009). Although the N-H acidity and hydrogen-bonding modes could have an effect on the catalytic activity of the organocatalysts, the nature of the substrate and reaction conditions could be more important. Asymmetric conjugate addition reactions of aldehydes to nitroalkenes have also been reported as a convenient synthesis of -amino acids (Horne & Gellman, 2008;Wiesner et al., 2008;Chi et al., 2008).
In line with our research interest in the synthesis of heterogeneous foldamers (Hayen et al., 2004), we synthesized the title compound as a chiral organocatalyst for conjugate addition. This conjugate addition was then applied for the ISSN 2056-9890 synthesis of -amino acids, which have been shown to be interesting foldamer building blocks (Horne & Gellman, 2008). Therefore, as the title compound is of interest in our ongoing effort on foldamer design and synthesis, we report here on the synthesis and crystal structure of this chiral sulfonamide.

Structural commentary
The asymmetric part of the unit cell is shown in Fig. 1 along with the atom-numbering scheme. The absolute stereochemistry of this chiral sulfonamide was confirmed by a Flack parameter of 0.00 (2) (Parsons et al., 2013). The cyclohexyl (C1-C6) and benzene (C7-C12) substituents are oriented gauche around the sulfonamide S-N bond, with a C1-N1-S1-C7 torsion angle of 70.4 (2) . A weak intramolecular interaction is present between the amine H2A atom and the sp 2 -hybridized sulfonamide N1 atom (Table 1).
As described in the Database survey section below, the structure of a racemic crystal of this compound has been reported (FAVHEP; Balsells, et al., 1998). In this crystal, there are two crystallographically unique molecules of the sulfonamide compound in the asymmetric unit. Here, the cyclohexyl and benzene substituents are oriented gauche around the S-N bond with torsion angles of 86.8 (8) and 69.1 (7) . While we expected that there would be an intramolecular hydrogen bond in this crystal, in the model deposited in the CSD there are no intramolecular hydrogen bonds present between the amine N-H group and the sulfonamide N atom.

Supramolecular features
Molecules of the title compound are held together in the solid state by intermolecular hydrogen-bonding interactions between the donor sulfonamide N1-H1 and the acceptor amine N2 atoms (Table 1 and Fig. 2). These hydrogen bonds arrange molecules into supramolecular chains that are oriented along the [100] axis (Fig. 2). Weaker N2-H2BÁ Á ÁO1(1 + x, y, z) interactions with an H2BÁ Á ÁO1(1 + x, y, z) distance of 2.72 Å between the donor amine N2-H2B and the acceptor sulfonamide O1 atoms can also be noticed within this chain.
As for the racemic crystal FAVHEP, in the model deposited in the CSD there is one intermolecular hydrogen bond present between a donor sulfonamide N1-H1 and a nearby amine The asymmetric part of the unit cell along with the atom-numbering scheme and displacement ellipsoids drawn at the 50% probability level. An intramolecular N-HÁ Á ÁN interaction is shown with a blue dashed line. Only N-H hydrogens are shown for clarity. Table 1 Hydrogen-bond geometry (Å , ).

Figure 2
Intra-and intermolecular hydrogen-bonding interactions present in the crystal.

Database survey
The Cambridge Structural Database (CSD, Version 5.36, May 2015; Groom & Allen, 2014) contains 35 sulfonamides bearing a mesitylene group on the S atom. Of these, there are four structures where the substituent bonded to the sulfonamide N atom is an aliphatic six-membered ring. In structures RAWMAF (Hou et al., 2012) and ZIQPAS (Wu et al., 2014), the aminocyclohexane substituent is part of a larger fused-ring system. Interestingly, there are two structures with 1,2-diaminocyclohexane rings as the amide substituent. In structure OTOPAP (Schwarz et al., 2010), both amines of the trans-1,2diaminocyclohexane ring are bonded to a mesitylsulfonamide group. Structure FAVHEP (Balsells et al., 1998) is the same as the title compound, but is present as a racemic mixture that crystallized in the space group P1.

Synthesis and crystallization
To a stirred solution of (1S,2S)-(+)-1,2-diaminocyclohexane (0.77 g, 6.74 mmol) in 5 ml of CH 2 Cl 2 at 273 K was added a solution of 2,4,6-trimethylbenzene-1-sulfonyl chloride (0.44 g, 2.01 mmol) in 5 ml CH 2 Cl 2 . After the addition was complete (20 min), the mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was washed with H 2 O (3 Â 25 ml) and the aqueous layer was backextracted with CH 2 Cl 2 (20 ml). The combined organic extracts were dried over Na 2 SO 4 and the solvent was removed under reduced pressure. The residue was purified by column chromatography over silica gel (CH 2 Cl 2 /EtOAc 1:1 v/v) to afford a pale-yellow-white solid (yield: 0.46 g, 78%). Part of the purified product was redissolved in CH 2 Cl 2 and after slow evaporation for several days, white large chunky crystals (stained yellow) were formed that were suitable for analysis by X-ray diffraction (m.p. 406-407 K).

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. The positions of all non-polar H atoms were calculated geometrically and refined to ride on their parent atoms, with U iso (H) = 1.2U eq (C) for methine, methylene and aryl groups, and U iso (H) = 1.5U eq (C) for methyl groups. H atoms bonded directly to N atoms (H1, H2A and H2B) were located in difference-Fourier maps and refined isotropically.  program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015); molecular graphics: OLEX2 (Dolomanov et al., 2009;Bourhis et al., 2015); software used to prepare material for publication: CrystalMaker (Palmer, 2007).