2-Pyridinesulfonyl Chloride

[66715-65-9]  · C5H4ClNO2S  · 2-Pyridinesulfonyl Chloride  · (MW 177.62)

(heteroarylsulfonyl chloride for the formation of 2-pyridinesulfonate esters which are excellent metal-assisted leaving groups in SN2 displacement reactions with magnesium halides,2 as well as in elimination reactions;2 alkyl 2-pyridinesulfonate esters are transformed into 2-alkylpyridines upon treatment with organometallic reagents3)

Physical Data: colorless crystalline solid.

Solubility: sol chlorinated hydrocarbons and in dipolar aprotic solvents; insol cold water (gradual hydrolysis).

Preparative Method: prepared essentially according to the published procedure.1 Chlorine gas is bubbled into a solution of 2-Pyridinethiol (4 g, 36 mmol) in concd. Hydrochloric Acid (32 mL) at 0 °C for 90 min. The solution is poured into ice-water (100 mL), and the precipitate is rapidly filtered and washed with ice-cold water (50 mL). The colorless crystalline product is dried at 0 °C (pump), then stored at 0 °C for use; yield 3.6 g (55%).

Handling, Storage, and Precautions: the crystalline reagent is stable when stored at 0 °C under argon for several months. Use in a fume hood.

Preparation of 2-Pyridinesulfonates.2

The reagent (3.0 g, 3.5 mmol) is added in portions to a solution of the alcohol (3.00 mmol) in dry pyridine (5 mL) at 0 °C. After stirring for a few hours (cholestanol, 3 h; t-butylmethyl alcohol, 18 h), the solution is poured into ice-water and the 2-pyridinesulfonate is isolated by filtration in some cases. Otherwise, the aqueous solution is extracted with dichloromethane, which is then washed with dil. HCl and water and processed in the usual way. The 2-pyridinesulfonate is isolated by crystallization or by flash chromatography. For example, 2-pyridinesulfonates are prepared from cholestanol (quant.), mp 127-128 °C; 1,2:3,4-di-O-isopropylidene-D-galactose (97%), mp 89-90 °C; L-borneol (93%), mp 99-100 °C; t-butylmethanol (90%), mp 47 °C; 1-octanol (94%), 2-octanol (85%), and ethyl lactate (93%), isolated as oils.

Preparation of Alkyl Halides from 2-Pyridinesulfonates.

The conceptual basis in designing novel nucleofugal esters such as 2-pyridinesulfonates was predicated upon the anticipation of an accelerated, metal-assisted SN2 displacement reaction especially with divalent ions. Indeed, upon treatment of primary and secondary 2-pyridinesulfonates with Magnesium Bromide etherate (1.3 equiv) in dichloromethane at 0 °C, the corresponding bromides are obtained within seconds or minutes (eq 1).2 With carbohydrate derivatives, the displacements are slower (several hours) presumably because of the presence of ether-type oxygen atoms which can also coordinate with the reagent. Comparisons of the reaction of various norbornyl sulfonates demonstrates the extremely efficient transformations using 2-pyridinesulfonates (1.3 equiv MgBr2.Et2O, 5 mL CH2Cl2): 8-quinolinesulfonate (120 min); tosylate (70 min); p-nitrobenzenesulfonate (40 min); 2-pyridinesulfonate (30 s, 70% of isolated bromide). Replacement of MgBr2.Et2O with other sources of bromide ion (Lithium Bromide, Tetra-n-butylammonium Bromide in DMF or CH2Cl2), requires heating and longer reaction times, while the addition of an external source of bromide does not accelerate the reaction.

Typical products are 1-octyl bromide (0 °C, 5 min; 88%); 2-octyl bromide, [a]D25 +33.4° (c, 4.23), (0 °C, 30 s, 74%); 2-benzyloxy-1-bromoethane (0 °C, 30 min, 94%); (R)-ethyl 2-bromopropionate, [a]D25 +32.4° (c, 3.93), (0 °C, 10 min, 81%); exo-2-bromobicyclo[2,2,1] heptane, (0 °C, 30 s, 70%); and 3a-cholestanyl bromide, mp 102 °C, [a]D25 +30° (c, 1.0), (0 °C, 5 min, 82%). Nucleophilic displacement reactions based on the remote activation of the nucleofugal component have also been demonstrated with alkyl imidazolylsulfonates,4 and in the synthesis of O-, C-, and related glycosides.5,6 Related heteroatom and metal-assisted SN2 displacement reactions of tosylates have been recently reported.7

Miscellaneous Reactions of 2-Pyridinesulfonates.

Other reactions well known for arenesulfonates are also possible with 2-pyridinesulfonates. For example, treatment of 3b-cholestanyl 2-pyridinesulfonate with Sodium Borohydride (DMF, 80 °C), Lithium Iodide (1,2-dichloroethane, 25 °C, 3 h), and LiN3 (DMF, 80 °C, 4 h), gives cholestane (78%), 3a-iodocholestane (76%), and 3a-azidocholestane (63%), respectively.8 Treatment of 3b-cholestanyl 2-pyridinesulfonate with Palladium(II) Chloride (2 equiv) in DMF (80 °C, 30 min), gives 2-cholestene (80%).9

2-Substituted Pyridines.

Although there are examples of the synthesis of 2-alkylpyridines10 by direct and indirect methods, the yields in some cases are low and the conditions harsh. Treatment of alkyl 2-pyridinesulfonates (methyl, propyl, t-butylmethyl) with n-Butyllithium, n-butylmagnesium bromide, Allylmagnesium Bromide, and Phenyllithium at -78 °C (lithium reagents) or at 0 °C (Grignard reagents), gives the corresponding 2-substituted pyridines in 68-80% yields (eq 2). In principle, any alkyl 2-pyridinesulfonate can be used. However, for convenience of handling, the crystalline t-butylmethyl 2-pyridinesulfonate can be used.

Related Reagents.

Benzenesulfonyl Chloride; 4-Bromobenzenesulfonyl Chloride; Mesitylenesulfonyl Chloride; p-Toluenesulfonyl Chloride.

1. Falik, Z.; Plazek, E. Acta Pol. Pharm. 1955, 12, 5 (CA 1957, 51, 17 911c); see also Caldwell, W. T.; Kornfeld, E. C. JACS 1942, 64, 1695 for the preparation of 5-acetamido-2-pyridinesulfonyl chloride.
2. Hanessian, S.; Kagotani, M.; Komaglo, K. H 1989, 28, 1115.
3. Hanessian, S.; Kagotani, M. S 1987, 409.
4. Hanessian, S.; Vatèle, J.-M. T 1981, 22, 3579.
5. Hanessian, S.; Bacquet, C.; LeHong, P. Carbohydr. Res. 1980, 80, C17.
6. Stewart, A. O.; Williams, R. M. JACS 1985, 107, 4289.
7. Hanessian, S.; Thavonekham, B.; Dehoff, B. JOC 1989, 54, 5831.
8. For a discussion of reactions occurring via prior coordination, see, Beak, P.; Meyers, A. I. ACR 1986, 19, 356.
9. Place, P.; Roumestant, M.-L.; Goré, J. BSF(2) 1975, 169.
10. Scriven, E. F. V. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R.; Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 2, p 262.

Stephen Hanessian

University of Montreal, Quebec, Canada

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