A study of mono-, di- and tri-tosylated amines: An unexpected sulfonamide

2-Aminobenzylaniline was ditosylated and gave an unexpected product N,N-ditosylamino-2-benzylaminobenzene in which the primary amine had ditosylated, and the benzylamine was unreacted. The benzylamine, although more electron rich, is sterically crowded and less nucleophilic than the primary amine in this ditosylated system. Sterically crowded tosylamides were prepared by reacting o-phenylenediamine, p-phenylenediamine and 1,8-diaminonaphthalene with tosyl chloride.

Condensation with ethylglyoxalate in toluene gave compound 5, which was oxidatively cylised into the benzimidazole derivative 6 (Scheme 2). 1 Ditosylate 4 condenses with α,α′-dibromo-o-xylene 7 and K 2 CO 3 to give an unusual eight-membered ring heterocycle 8 and various derivatives, which were investigated for their biological properties (Scheme 3). 6tosylate 4 condenses with 1,2-dibromopropanol 9 with sodium/EtOH to form the six-membered heterocycle 10 and various derivatives (Scheme 4). 7itosylate 4 condenses with SiCl 4 to form a bis-spirocyclic heterocycle 11, which is bonded around the central silicon atom (Scheme 5). 8This utilises the subtending bite angle of the two N atoms and the large silicon size, and orthogonal bonding prevents steric crowding.Metal complex 12 is a typical and obvious application treating ditosylate 4 as a bidentate ligand. 4

Discussion
Compound 4 was of interest for a new method of phenazine synthesis, and its preparation led to this programme of research. 9,10Initial studies focussed on repeating the syntheses of monotosylate 3 and ditosylate 4 by treating o-phenylenediamine 1 with either 1 or 2 equiv. of tosyl chloride 2 in hot pyridine at 100 °C, respectively.This works well, and only the ditosylate 4 forms using 3 equiv.of tosyl chloride 2 in pyridine.The R f values of compounds 3 and 4 are identical with DCM as the eluent.The new compound o-phenylenediamine tritosylate 13 was formed in DCM with Et 3 N as the base.An X-ray single-crystal structure was obtained for compounds 3, 1-3 4 4-5 and 13.The crystal structures of compounds 3 and 4 are in good agreement with previously published results 11,12 (Cambridge Structural Database 13
A more crowded tetratosyl-o-phenylenediamine derivative 14 did not form even when a reaction was performed with 4 equiv. of tosyl chloride 2 and o-phenylenediamine 1 (Scheme 6), presumably because compound 14 is too sterically crowded.
A successful synthesis of N,N-ditosylamino-2benzylaminobenzene 16 was achieved by tosylating 2-aminobenzylaniline 15 14 with 3 equiv.of tosylchloride (Scheme 7).This result was unexpected because the benzylamino group was expected to be more electron-rich and reactive towards tosyl chloride.The structure must be too crowded to form a tritosyl derivative.In the theoretical equilibrium shown in Scheme 8, compound 16 must be more stable than the unknown compound 17.Steric crowding by the benzyl group effectively makes the benzylamino group less nucleophilic in this system, and the primary amine is more nucleophilic.The nuclear magnetic resonance (NMR) data, both proton and carbon, easily distinguished compound 16 from compound 17.
The tosylation of 1,8-diaminonaphthalene 18 gave a mixture of two products, a tritosyl derivative 19 and a ditosyl derivative 20 (Scheme 9).An X-ray single-crystal structure determination was performed on compound 19.
Compound 19 crystallises with one molecule in the asymmetric unit (Figure 3) in the orthorhombic space group Pbca.The dihedral angles between the C1-C10 naphthalene ring mean plane (root-mean-square deviation = 0.005 Å) and the C11-C16, C18-C23 and C25-C30 phenyl rings are 52.08°(3°), 14.40° (5°) and 84.41° (4°), respectively.The synthesis of a tetratosylated derivative of p-phenylenediamine 21 is shown in Scheme 10.Less crowding occurs around each sulfonamide, so the synthesis is as expected.The compound is soluble in DCM.These   molecules may find applications as rotamers as they are big enough to attach to a surface non-covalently and move across it.
Treatment of o-phenylenediamine 1 with 3 equiv.of (1S)-(+)-10-camphorsulfonyl chloride 23 gave the trifunctionalised derivative 24 (Scheme 11).This compound is waxy, and no X-ray single-crystal structure was obtained for it.The aliphatic proton NMR was too complicated to be interpreted with many overlapping signals, but the aromatic region showed two doublets and two triplets as expected.The carbon-13 spectrum was well resolved.The signals appeared in groups of three, which showed that three different camphor groups were present.There were six methyl groups, six aryl carbons and three carbonyl groups (Supplemental Material).This observation suggests that compound 24 is sterically crowded with the two different camphoryl groups attached to the same N atom.Restricted rotation around the Ar-N bond might explain this if it is slow on an NMR timescale.

Conclusion
o-Phenylenediamine 1 was mono-, di-and tri-tosylated with tosyl chloride in either hot pyridine at 100 °C or DCM to give mono-, di-or tri-tosyl-o-phenylenediamines 3, 4 or 13, respectively.1,8-Diaminonaphthalene 18 was di-and tritosylated to give the corresponding di-tri-tosylated-1,8-aminonaphthalenes, respectively.2-Aminobenzylaniline 15 was ditosylated and gave an unexpected product N,Nditosylamino-2-benzylaminobenzene 16 in which the primary amine had ditosylated, and the benzylamine was unreacted.The benzylamine, although more electron-rich, is sterically crowded and less nucleophilic than the primary amine in this ditosylated system.The two possible ditosylated products 16 and 17 were easily distinguished by proton and 13 NMR.X-ray single-crystal structure determinations were performed on compounds 3, 4, 13 and 19.
In no case did we observe tetratosylated derivatives from o-phenylenediamine 1 which are too sterically crowded to form.6][17] Compound 24 has three different camphoryl groups in it (see Supplemental Material).

Experiment
Infrared (IR) spectra were recorded on a diamond attenuated total reflection Fourier-transform IR spectrometer.Ultraviolet (UV) spectra were recorded using a PerkinElmer Lambda 25 UV-Vis spectrometer with EtOH as the solvent.The term 'sh' means shoulder. 1H and 13 C NMR spectra were recorded at 400 and 100.5 MHz, respectively, using a Varian 400 spectrometer.Chemical shifts, δ, are given in ppm and measured by comparison with the residual solvent.Coupling constants, J, are given in Hz.The term 'br' stands for broad.High-resolution mass spectra were obtained at the University of Wales, Swansea, using an Atmospheric Solids Analysis Probe (ASAP) (positive mode) Instrument: Xevo G2-S ASAP.Melting points were determined on a Kofler hot-stage microscope.

Crystal structures
The crystal structures of 3 (colourless needle, 0.61 × 0.03 × 0.03 mm, recrystallised dichloromethane:light petroleum ether), 4 (colourless needle 0.29 × 0.04 × 0.03 mm, recrystallised from dichloromethane:light petroleum ether), 13 (colourless lath, 0.30 × 0.04 × 0.01 mm, recrystallised from dichloromethane:light petroleum ether) and 19 (colourless prism, 0.22 × 0.20 × 0.06 mm, recrystallised from dichloromethane:light petroleum ether) were established using intensity data collected at 100 K on a Rigaku CCD diffractometer using Cu Kα radiation (λ = 1.54178Å).The structures were routinely solved by dual-space methods using SHELXT, 18 and the structural models were completed and optimised by refinement against |F| 2 with SHELXL-2019. 19The N-bound hydrogen atoms were located in difference maps: For compound 3, they were refined as riding atoms in their as-found relative positions, and for compounds 4 and 13, their positions were freely refined.The carbon-bound hydrogen atoms were placed in idealised locations (C-H = 0.95-0.98Å) and refined as riding atoms.The constraint U iso (H) = 1.2U eq (carrier) or 1.5U eq (methyl carrier) was applied in all cases.The methyl groups were allowed to rotate, but not to tip, to best fit the electron density.Full details of the structures and refinements are available in the deposited crystallographic information files.

Figure 3 .
Figure 3.The molecular structure of compound 19 showing 50% displacement ellipsoids with hydrogen bonds indicated by double-dashed lines.