Crystal structure of tert-butyl 4-[4-(4-fluorophenyl)-2-methylbut-3-yn-2-yl]piperazine-1-carboxylate

A sterically congested piperazine derivative, tert-butyl 4-[4-(4-fluorophenyl)-2-methylbut-3-yn-2-yl]piperazine-1-carboxylate, was prepared using a modified Bruylants approach. Its novel chemistry with a synthetically useful second nitrogen atom on the N-tert-butyl piperazine substructure generates a pharmacologically useful core.

The title sterically congested piperazine derivative, C 20 H 27 FN 2 O 2 , was prepared using a modified Bruylants approach. A search of the Cambridge Structural Database identified 51 compounds possessing an N-tert-butyl piperazine substructure. Of these only 14 were asymmetrically substituted on the piperazine ring and none with a synthetically useful second nitrogen. Given the novel chemistry generating a pharmacologically useful core, determination of the crystal structure for this compound was necessary. The piperazine ring is present in a chair conformation with di-equatorial substitution. Of the two N atoms, one is sp 3 hybridized while the other is sp 2 hybridized. Intermolecular interactions resulting from the crystal packing patterns were investigated using Hirshfeld surface analysis and fingerprint analysis. Directional weak hydrogenbond-like interactions (C-HÁ Á ÁO) and C-HÁ Á Á interactions with the dispersion interactions as the major source of attraction are present in the crystal packing.

Structural commentary
The title compound, prepared from achiral reagents as a racemic mixture, crystallizes in the chiral monoclinic space group P2 1 with one molecule in the asymmetric unit as shown in the Scheme and Fig. 2. No heavy atoms are present in the structure and data were collected using Mo K radiation. Thus, the absolute structure of the randomly chosen crystals could not be determined reliably (Parsons et al., 2013;Zhou et al., 2015). In the molecule, the NC( O)O group of the carbamate exists in resonance. The bond lengths between carbon and other atoms (  (4) Å ] is the shortest among all the bond lengths in the phenyl group, possibly due to the inductive effect of fluorine. The spatial distance between the extreme atoms of propargylamine groups (C7Á Á ÁN1) was observed to be 3.508 (3) Å , which is slightly longer than for the other reported propargylamines (3.372-3.478 Å ; Marvelli et al., 2004;Sidorov et al., 1999Sidorov et al., , 2000, and possibly due to the open L-shaped structure of the molecule. Also, the piperazine ring is shown in its most stable chair form conformation in Fig. 3, as evidenced by the bond angles (Table 1) Table 1 Selected geometric parameters (Å , ).
contact distances. These data also suggested the absence ofstacking as CÁ Á ÁC contacts contribute 0% of the Hirshfeld surfaces (Fig. 6d).

Database survey
A search in the Cambridge Structural Database (Version 5.41 update of March 2020; (Groom et al., 2016)) for compounds possessing an N-tert-butyl piperazine substructure identified 51 compounds. These compounds were several variations of BuckyBall adducts, diketopiperazine derivatives, and ligands. There were only 14 compounds viz. DIYWAK (McDermott et al., 2008), HEHZOL (Legnani et al., 2012), HICYID, HICYOJ (Sinha et al., 2013b), JIFHEO (Zhong et al., 2018), OFUDAW (Korotaev et al., 2012), PUYNUS (Jin & Liebscher, 2002), RIPWUJ (Bobeck et al., 2007), TILJIJ (Sinha et al., 2013a), UPIBIF, UPIBOL (Wiedner & Vedejs, 2010), UYIHOB (Chen & Cao, 2017), WANTAJ (Golubev & Krasavin, 2017), and WINMAH (Brouant & Giorgi, 1995) that were asymmetrically substituted on the piperazine ring, and none with a synthetically useful second nitrogen. All were effectively 'nonintermediate' compounds that could not reasonably serve for additional substitution at the second nitrogen and none had alkyne substitutions. The quaternary carbon piperazines were explored by Sinha et al. (2013a,b) using an Ugi reaction; however, the present structure is the only compound containing an ,-dimethyl carbon attached to an alkyne and an amine. This new methodology required the X-ray studies to confirm the generated structure. In summary, to the best of the authors' knowledge, there is no published crystal structure like the title compound, for a molecule containing asymmetrical substitutions on the piperazine ring, having a synthetically useful second nitrogen, and an ,-dimethyl carbon attached to an alkyne and an amine.
Note: the aqueous extracts (pH > 10) were collected and the residual cyanide was oxidized to cyanate with sodium hypochlorite (Gerritsen & Margerum, 1990) and absence of a cyanide ion was confirmed with an MQuant 2 Koening Cyanide test indicator from EM sciences.
tert-Butyl 4-[4-(4-fluorophenyl)-2-methylbut-3-yn-2-yl]piperazine-1-carboxylate (1): A 250 mL flame-dried, round-bottom flask was cooled under argon and then charged with 1-ethynyl-4-fluorobenzene 4 (1.98 g, 16.5mmol) in 50 mL of anhydrous THF. This solution was cooled with an external ice-bath. A commercial solution of methyl magnesium bromide (5.25 mL, 16.5 mmol) (Acros, $3.2 M in THF, assayed against anhydrous diphenyl acetic acid with 2 mg 1,10-phenanthroline as an indicator) was added with slow dropwise addition over 10 minutes.  Computer programs: SMART and SAINT (Bruker, 1998), SHELXS97 (Sheldrick, 2008), SHELXL2018/3 (Sheldrick, 2015) and CrystalMaker (Palmer, 2014). was stirred at ice-bath temperature for an additional 20 minutes, which resulted in a pale-yellow solution. A solution of tert-butyl 4-(2-cyanopropan-2-yl)piperazine-1-carboxylate 3 (Firth et al., 2016) (2.33 g, 9.2 mmol) in 25 mL THF was added dropwise to this mixture over 10 minutes; the internal temperature was maintained between 274-275.3 K. This deepyellow solution was permitted to stir with the external ice-bath slowly melting and rising to room temperature, while progress was monitored by TLC (R f of product at 0.6 1:1 H:EA, SiO 2 plates, SWUV and I 2 visualization). Following stirring for 12 h at 296 K, the crude reaction mixture was cooled to ice-bath temperature and the reaction was quenched with the addition of 10 mL of ice-cold water at a rate of addition that maintained the internal temperature below 278 K. After quenching the organo-base, an additional 50 mL of water were added. Small aliquots of brine and ethanol were used, as required, to break the emulsion in the following extraction. This mixture was extracted with 3 Â 20 mL of ethyl acetate, washed (3 Â 10 mL H 2 O, 3 Â 10 mL brine) dried (Na 2 SO 4 ), decanted, and the solvent removed under reduced pressure to afford 30.6 g of a yellow solid. This was separated on 50 g of SiO 2 with hexane/ethyl acetate (1/1) as the eluent to yield tert-butyl 4-[4-(4-fluorophenyl)-2-methylbut-3-yn-

Refinement
Crystal data, data collection, and structure refinement details are summarized in Table 3. H atoms were localized in a difference-Fourier map. C-bound H atoms were treated as riding, with C-H = 0.93, 0.96 or 0.97 Å , and with U iso (H) = 1.2U eq (C) for aromatic and 1.5U eq (C) for methyl groups. where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.12 e Å −3 Δρ min = −0.11 e Å −3 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.

Crystal data
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )