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Nickel(II)-Catalyzed Addition of Aryl and Heteroaryl Boroxines to the Sulfinylamine Reagent TrNSO: The Catalytic Synthesis of Sulfinamides, Sulfonimidamides, and Primary Sulfonamides

Pui Kin Tony Lo and Michael C. Willis*

*Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, United Kingdom, Email:

P. K. T. Lo, M. C. Willis, J. Am. Chem. Soc., 2021, 143, 15576-15581.

DOI: 10.1021/jacs.1c08052

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A redox-neutral Ni(II)-catalyzed addition of (hetero)aryl boroxines to N-sulfinyltritylamine (TrNSO). The initially formed sulfinamides undergo oxidative chlorination with trichloroisocyanuric acid to produce sulfonimidoyl chlorides as key intermediates. Whereas in situ reaction with amines delivers sulfonimidamides, hydrolysis provides primary sulfonamides.

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Preparation of arylboroxines

A 25 mL RBF charged with aryl boronic acid (~ 100 200 mg) was heated to the indicated temperature (120 or 160C) and time (1 - 16 h) under high vacuum (< 1 mbar). After cooling to rt, the flask was filled with N2. The arylboroxine was used without further purification.

1. 1H NMR analysis was used to check the ratio of boroxine:boronic acid (BRX:BA) with CDCl3 as the NMR solvent. The ratio of BRX:BA was generally greater than 90:10 after heating under vacuum.

2. Some boroxines (and boronic acids) did not dissolve sufficiently in CDCl3, so instead an ampoule of d6-DMSO was frequently used as the NMR solvent. As DMSO absorbs water from moist air quickly
and boroxines are moisture sensitive, this could lower the ratio observed in 1H NMR spectra for BRX:BA to ~80:20 or lower. Generally, we assumed the samples were all boroxines.

Four-step synthesis of sulfonimidamides

Cs2CO3 (65.2 mg, 0.200 mmol, 1.00 equiv.) was added to an oven-dried 10 mL reaction tube. The tube was then sealed with a rubber septum and heated at 160 C under vacuum for at least 2 h or overnight to dry the Cs2CO3. After cooling the tube to rt and filling with N2, pre-weighted arylboroxine (0.067 mmol, 0.33 equiv.), NiCl2(glyme) (4.4 mg, 0.020 mmol, 10 mol%), dNbpy (8.2 mg, 0.020 mmol, 10 mol%) and TrNSO (61.1 mg, 0.200 mmol, 1.00 equiv.) were quickly added. The tube was re-sealed, evacuated and filled with N2 ( 4). Dioxane (1.2 mL, 0.17 M) was added and the reaction mixture was heated at 80 C for 16 h. After cooling to rt, trichloroisocyanuric acid (23.2 mg, 0.100 mmol, 0.50 equiv.) was added and the mixture was stirred at rt for 20 min. Et3N (56 μL, 0.400 mmol, 2.00 equiv.) and amine (2.00 equiv.) were added and the mixture was stirred at rt for 1 h. MsOH (0.2 mL, 1.00 M) was added dropwise (caution: gas formation) and the mixture was stirred at rt for 30 min. The mixture was diluted with CH2Cl2 (10 mL) and transferred to a 50 mL separating funnel, before neutralizing with sat. aq NaHCO3 (10 mL) (caution: gas formation). After collecting the organic phase, the aqueous phase was extracted with CH2Cl2 (2 10 mL). The combined organic phases were dried (Na2SO4), filtered and concentrated at ≤25 C. Purification by flash column chromatography afforded the product.

Note: 1. Hydroylsis of TrNSO can be an issue. Hence, the exclusion of H2O from step 1 is important for the success of these reactions. Arylboroxines and especially Cs2CO3 were the major sources of H2O. Arylboroxines were freshly prepared before use by heating the corresponding arylboronic acids under vacuum at the indicated temperature and time (See general procedure A). Cs2CO3 tended to absorb H2O while being weighed out, thus limiting its contact with air as minimum as possible was very important. Cs2CO3 (~ 2 - 3 g) was added to a 25 mL RBF and dried by heating to 160 C, under vacuum (< 5 mbar), overnight. It was further dried before use as indicated in the General Procedure B. The other solid reagents (boroxine, NiCl2(glyme), dNbpy, TrNSO) were weighed out first and quickly added into the reaction tube to minimize the contact of Cs2CO3 with air.

2. NiCl2(glyme) was purchased from Sigma-Aldrich. dNbpy was purchased from Sigma-Aldrich or Alfa Aesar. TrNSO was prepared using the literature method, stored under N2 at −20 C and checked for its purity by 13C NMR analysis. Cs2CO3 was purchased from Fluorochem and dried as indicated in note 1. Anhydrous 1,4-dioxane was purchased from Sigma-Aldrich or Acros Organic. Trichloroisocyanuric acid (TCCA) and MsOH were purchased from Alfa Aesar. Anhydrous Et3N was purchased from Sigma-Aldrich.

3. The reaction was evacuated (< 5 mbar) and back filled with N2 ( 4). The first evacuation lasted for at least 5 min. The remaining three times lasted for at least 1 min.

4. Stirring speed in step 1 was set to be 1400 rpm. This high stirring speed seemed to be important, probably for better stirring of Cs2CO3.

5. Each step was easily monitored by HPLC analysis for the conversion of starting materials to intermediates and products.

6. Using EtOAc as an extraction solvent in aqueous workup would cause significant retritylation in this NH sulfonimidamide synthesis. Using CH2Cl2 instead would only form a negligible amount of the retritylation product. Keeping the rotary evaporator water bath below 25 C would reduce the chance of retritylation.

7. The crude product was dry-loaded with silica gel or loaded as a CH2Cl2 solution onto a pre-packed silica gel column.

8. Ninhydrin is an excellent TLC stain for most compounds with NH bonds in this study, including sulfonimidamides, primary sulfonamides and primary sulfinamide.

9. The NH sulfonimidamides may sometimes decomposed in CDCl3, maybe due to the trace amount of acidic substrates in this solvent and hence DMSO-d6 was used in some cases. Basifying CDCl3 with K2CO3 may help suppress the decomposition.

Harnessing Sulfinyl Nitrenes: A Unified One-Pot Synthesis of Sulfoximines and Sulfonimidamides

T. Q. Davis, M. J. Tilby, J. Ren, N. A. Parker, D. Skolc, A. Hall, F. Duarte, M. C. Willis, J. Am. Chem. Soc., 2020, 142, 15445-15453.

Key Words

sulfonimidamides, TCCA

ID: J48-Y2021