Atom-efficient arylation of N-tosylimines mediated by cooperative ZnAr2/Zn(C6F5)2 combinations

By combining the Lewis acid Zn(C6F5)2 with nucleophilic diarylzinc (ZnAr2) reagents, we report the atom-efficient arylation of N-tosylimines under mild conditions. Mechanistic studies through the isolation of key intermediates reveal how the two zinc species act cooperatively to activate the imine substrate and regenerate the ZnAr2 reagent, enabling a limiting 50 mol% to be employed.


Experimental General Considerations
All manipulations were carried out under an inert atmosphere of argon using standard Schlenk line 1,2 or glove-box techniques (MBraun UNILab Pro ECO, <0.5 ppm H2O and O2). THF was dried and distilled from Na/benzophenone and stored over 4 Å molecular sieves. Hexane, Et2O, toluene and benzene were dried using a MBraun MBSPS 5 and stored over 4 Å molecular sieves. THF-d8, toluene-d8 and C6D6 were dried and distilled over NaK2.8 and stored over 4 Å molecular sieves in a glove-box prior to use. Zn(C6F5)2 was purchased from Sigma Aldrich or ChemCruz and used as received unless other specified. TMEDA was dried and distilled over CaH2 and stored over 4 Å molecular sieves. All diarylzinc reagents were prepared according to established literature procedures 3,4 and sublimed or thoroughly dried in vacuo prior to use to remove residual Et2O. All other reagents were used as supplied unless otherwise stated.
NMR spectra were recorded on a Bruker Avance III HD 300 MHz spectrometer at 300 K unless otherwise specified. 1 H NMR spectra were referenced internally to the corresponding residual protio solvent peaks.
CHN elemental microanalyses were performed on a Flash 2000 Organic Elemental Analyser (Thermo Scientific). High resolution mass spectra were recorded on a Thermo Scientific LTQ Orbitrap XL spectrometer (HRMS ESI, nano-electrospray) in positive ionisation mode (samples were diffused in a stream of MeCN).

Synthesis of N-tosylimines (1a-p)
N-tosylimines (1a-p) were prepared following the general unoptimised procedure. 5 To a 0.2 M solution of the corresponding aldehyde (1.05 equivalents) in anhydrous benzene containing activated 4 Å molecular sieves, p-toluenesulfonamide (1 equivalents) and BF3·OEt2 (1 equivalents) was added at room temperature. The reaction was heated at 80 °C overnight (14-18 hours) then cooled to room temperature and filtered through celite. All volatiles were removed in vacuo affording the corresponding imines, often without the need for further purification. Imine 1p was prepared using catalytic piperidine (20 mol%) in DCM according to literature procedures. 6

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Analytical data in accordance with the literature. 7

Reaction Optimisation
N-(4-Fluorobenzylidene)-4-methylbenzenesulfonamide 1k (0.25 mmol) and the corresponding phenyl-zinc reagent were combined in 2.5 mL of anhydrous solvent (toluene or THF) and stirred at room temperature for 2 hours. The reaction was quenched by the addition of MeOH (1 mL) and hexamethylbenzene (0.042, 0.16 equivalents) was added as an internal standard. An aliquot of the reaction mixture was evaporated to dryness and then redissolved in CDCl3 for 1 H and 19 F NMR spectroscopic analysis, with yields determined by comparison of integrals with the internal standard. Table S1 summarises the reaction optimisation with various solvents, phenyl-zinc reagents and stoichiometries.

Comparison of Conditions
Whilst comparable yields of addition product were observed when using 1 equivalent of ZnPh2 (Table S1, entry 2) or 0.5 equivalents each of ZnPh2 and Zn(C6F5)2 (Table S1, entry 4), this was not necessarily true for all diarylzinc reagents tested. Scheme S1 summaries the yields obtained for each diarylzinc reagent under these two different reaction conditions. In general, the yields obtained when using 0.5 equivalents each of ZnAr2 and Zn(C6F5)2 were higher than when simply using 1 equivalent of ZnAr2 in the absence of Zn(C6F5)2, particularly for less nucleophilic ZnAr2 compounds.

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Scheme S1: Comparison of yields obtained when using 0.5 equivalents each of ZnAr2 and Zn(C6F5)2 versus 1 equivalent of ZnAr2. a Reaction heated to 80 °C for 2 hours. b Reaction heated to 80 °C for 20 hours.

Spectroscopic Studies
A series of spectroscopic studies were carried out to provide further insights into the reaction mechanism, and to specifically assess the dissociation of "PhZn(C6F5)" from intermediate 5a. Compound 5a is insoluble in toluene-d8 but dissolution in THF-d8 gives three major species by 19 F NMR spectroscopy attributed to  Figures S1-3). The proposed species 6a can be rationally prepared by the zincation of 2a with Zn(C6F5)2the formation of C6F5H confirms the clean deprotonation of 2a. The formation of 6a by dissolution of 5a confirms that "PhZn(C6F5)" dissociates (to some degree) and S19 redistributes to its homoleptic components, ZnPh2 and Zn(C6F5)2. Given that the quantity of Zn(C6F5)2 is significantly larger in the green and blue traces (Figures S1-3), it is possible that 6a further redistributes into homoleptic species, Zn(C6F5)2 and the corresponding bis-amido-zinc.

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Monitoring these reactions by 1 H NMR spectroscopy support that ZnPh2 is liberated from 5a upon dissolution in THF-d8 (Figures S4-5). The 1 H NMR spectra of 5a and in situ generated 6a both give two signals for in the CH and CH3 region (Figure S4 insets) which are tentatively attributed to 6a and the corresponding homoleptic bis-amido-zinc species.

X-ray Crystallography
The crystal structures have been deposited into the Cambridge Crystallographic Data Centre (CCDC) and have been assigned the following numbers: 3a -2251615; 3a.TMEDA -2251616; 4a -2251617; 5a -2251618. Selected crystallographic and refinement parameters are presented below (Tables S2-3). In all cases, crystals immersed in an inert oil were mounted at ambient conditions and transferred into the nitrogen stream (100 or 173 K).
All measurements were made on a RIGAKU Synergy S area-detector diffractometer using mirror optics monochromated Cu Kα radiation ( = 1.54184 Å). Data reduction was performed using the CrysAlisPro program. 14 The intensities were corrected for Lorentz and polarization effects, and an absorption correction based on the Gaussian method using SCALE3 ABSPACK in CrysAlisPro was applied. The structure was solved by direct methods or intrinsic phasing using SHELXT, 15 which revealed the positions of all nonhydrogen atoms of the compounds. All non-hydrogen atoms were refined anisotropically. H-atoms were assigned in geometrically calculated positions and refined using a riding model where each H-atom was assigned a fixed isotropic displacement parameter with a value equal to 1.2Ueq of its parent atom (1.5Ueq for methyl groups). Refinement of the structure was carried out on F 2 using full-matrix least-squares procedures, which minimized the function Σw(Fo 2 -Fc 2 ) 2 . The weighting scheme was based on counting statistics and included a factor to downweight the intense reflections. All calculations were performed using the SHELXL-2014/7 16 program in OLEX2. 17 For compound 3a, areas containing disordered solvents were found where a satisfactory solvent model could not be achieved, therefore, a solvent mask was used to include the contribution of electron density S23 found in void areas into the calculated structure factor. The total number of electrons found in the void areas was 89 electronsthis corresponds to a disordered toluene molecule.
For compound 3a.TMEDA, areas containing disordered solvents were found where a satisfactory solvent model could not be achieved, therefore, a solvent mask was used to include the contribution of electron density found in void areas into the calculated structure factor. The total number of electrons found in the void areas was 202 electronsthis corresponds to a disordered toluene or hexane molecule.   Table S3: Crystal data and structure refinement details for 4a and 5a.