· (MW 149.00)
(synthesis of chloromethanesulfonates and chloromethanesulfonamides, used for conversion of alcohols into the inverted acetates,2 azides and nitriles,1 and rearrangement of carbon-carbon1 and carbon-oxygen bonds3 under mild conditions, and in electrophilic and radical reactions4)
Physical Data: bp 80-81 °C/25 mmHg; d 1.67 g cm-3; nD26 1.4840-1.4850.
Solubility: insoluble in H2O; soluble in dichloromethane, pyridine, and most organic solvents.
Form Supplied in: colorless liquid; purchased from TCI, E-Merck and Alfa.
Preparative Methods: reaction of s-trithiane with chlorine in acetic acid-H2O (20-32%);5,6 reaction of sodium chloromethanesulfonate with phosphorus pentachloride (79%).7
Handling, Storage, and Precautions: moisture-sensitive, corrosive lachrymator, severe skin and eye irritant, LD50 (rat, oral) 372 mg/kg. Store under nitrogen atmosphere and refrigerator.
Chloromethanesulfonates (monochlates) of alcohols can be readily prepared by treatment of an alcohol with chloromethanesulfonyl chloride in pyridine or in the presence of lutidine in methylene chloride under the same procedure for the preparation of methanesulfonates (mesylates) and p-toluenesulfonates (tosylates).1-3 Chloromethanesulfonates can be purified by SiO2 column chromatography. They generally react much faster than the corresponding mesylates and tosylates, and are more stable than the corresponding trifluoromethanesulfonates (triflates), as described below. Aryl and pyridazinyl chloromethanesulfonates are prepared from the sodium or potassium salts.8,9
Chloromethanesulfonamides can also be prepared by treatment of an amine with chloromethanesulfonyl chloride in the presence of a base (usually pyridine,7 triethylamine,10 or diisopropylethylamine11,12 using the same procedure for the preparation of chloromethanesulfonates. Benzene,7 THF10 or methylene chloride11,12 can be used as solvent.
Addition to Alkenes and Alkynes
Chloromethanesulfonyl chloride reacts with hept-1-ene in the presence of benzoyl peroxide to give 1,3-dichlorooctane via free radical addition evolving sulfur dioxide (1).13 Chloromethanesulfonyl chloride, in the presence of excess of oct-1-ene and 1 mol % of copper(II) chloride, is largely decomposed into methylene chloride and sulfur dioxide. With styrene, on the other hand, an adduct with undecomposed sulfonyl chloride is formed (2).14
Chloromethanesulfonyl chloride adds to appropriately activated alkenes such as ketene diethylacetal15 and enamines16 in the presence of triethylamine to afford the thietane dioxide derivatives via the cycloaddition of chlorosulfene (eqs 3 and 4). Chloromethanesulfonyl chloride also reacts with diazomethane in the presence of triethylamine to give 2-chlorothiirane 1,1-dioxide via a chlorosulfene intermediate (5).6
A series of homologous a-sulfonamidyl radicals are generated by reaction of a-halomethanesulfonamides with tributyltin hydride under AIBN catalysis to afford the intramolecular cyclization products. Where possible, five-membered sultams are formed by 5-exo transition states (6).11 Paquette and co-workers also report direct synthesis of sultams by intramolecular cyclization of a-sulfonimide radicals (eqs 7 and 8).12 In these reactions, 5-exo ring closure is more kinetically favorable than in the 6-endo pathway (7) and 7-endo cyclization is kinetically dominant (8). The 7-endo-chloromethanesulfonamide product was heated with tributyltin hydride and AIBN to afford the bridgehead disulfonimide (8).
Addition to Unsaturated Linkages
1-Metalated 1-halosulfonic acid derivatives offer unique synthetic potential. The reaction of a-lithio-chloromethanesulfonylmorpholide, prepared from chloromethanesulfonyl chloride, with aldehydes affords a mixture of diastereomeric alcohols in THF at -60 °C (9).10 By contrast, the reaction of the lithium compound with Michael acceptors gives the ring-closed cyclopropanes in THF at -60 °C (10).10 An imine affords a sulfonyl-substituted enamine as product (11).10
The asymmetric phase transfer-catalyzed Darzens condensation of aldehydes and ketones with the chiral reagent L-menthyl chloromethanesulfonate using triethylbenzylammonium chloride as the phase transfer catalyst gives a,b-epoxysulfonates [R1 = R2 = Me; R1 = Ph, 2-naphthyl, Me2CH, Me, 2,4,6-Me3C6H2, p-MeC6H4, R2 = H; R1R2 = (CH2)4, (CH2)5] with 9-17% chiral induction (12).17
Neopentyl and phenyl chloromethanesulfonates react with a variety of nitrobenzenes in the presence of powdered sodium hydroxide in dimethyl sulfoxide to give mixtures of the ortho and para isomers of the corresponding neopentyl or phenyl nitrophenylmethanesulfonates via the vicarious nucleophilic substitution of hydrogen faster than nucleophilic substitution of halogen (13).9 Nitro derivatives of thiophene, furan, and pyrrole also react with the carbanions giving products of replacement of hydrogen.18
Inversion of Secondary Alcohols
Inversion of a variety of secondary alcohols using the chloromethanesulfonate as a favorable leaving group with cesium acetate in the presence of 18-crown-6 under mild conditions has been performed to give the inverted acetates in high yields (eqs 14 and 15).2 The chloromethanesulfonates (monochlates) react with cesium acetate in each reaction much faster than the corresponding mesylates and tosylates, and are more stable than the corresponding triflates. The use of the chloromethanesulfonates is especially effective for sterically hindered alcohols where mesylates are minimally reactive and triflates are unstable (eqs 15 and 16).2,19
The chloromethanesulfonate is also an effective leaving group for conversion of a wide range of alcohols, especially sterically hindered alcohols, into the inverted azides and nitrile with NaN3 or LiN3 and NaCN, respectively (eqs 17, 18 and 19).1,19 Phenylselenylation of the chloromethanesulfonate proceeds smoothly via SN2 reaction to afford the selenide in the construction of the A,B,C-ring system of complex natural product, ciguatoxin (20).20
An efficient method for rearrangement of the C-C bond of a variety of structurally diverse alcohols has been reported by reaction of the corresponding chloromethanesulfonates (monochlates) with Zn(OAc)2 in dioxane at 90 °C, in which the methyl group antiperiplanar to the OH group preferentially migrates to give the alkenes (21).1 The chloromethanesulfonate prepared from 11 a-hydroxyprogesterone reacts with Zn(OAc)2 in AcOH-H2O at 90 °C to afford the ring-enlarged compound in high yield through migration of the C8-C9 bond antiperiplanar to the OH group (22).1 Ring-expansion of the chloromethanesulfonate of a diol with Zn(OAc)2 in AcOH-H2O at 85 °C smoothly proceeds to give 5,7,8,9-tetrahydrobenzocyclohepten-6-one in 95% yield via the novel pinacol rearrangement (23).1 Although the sterically hindered hydroxyl group was generally eliminated in the pinacol rearrangement, the primary hydroxyl group of the diol was removed in the presence of the tertiary hydroxyl group to afford the ketone. Reaction of isoborneol, a structurally rigid alcohol, with chloromethanesulfonyl chloride in pyridine at 0 °C directly affords camphene in 95% yield via migration of the C1-C6 bond antiperiplanar to the OH group (24).1
Treatment of tetrahydrofuran with Zn(OAc)2, having chloromethanesulfonate as an efficient leaving group on the side chain, effects a stereoselective rearrangement in AcOH-H2O at 50 °C to give the ring-expanded ethers, 2,3-trans-tetrahydropyrans (R = H, Ac) in 85% combined yield (25),3 while the reaction of the corresponding mesylate under the same conditions gives the pyran in only 13% yield, although under reflux conditions the mesylate affords 75% yield of the pyran (R = Ac).21 The best result was obtained in dioxane-H2O at 50 °C (R = H: 97%).3 The rearrangement of the chloromethanesulfonate prepared from 2,2,6,6-tetrasubstituted tetrahydropyran occurs easily with Zn(OAc)2 in AcOH-H2O, even at room temperature, to afford the oxepane in 92% yield (26).3 The rearrangement reaction using the chloromethanesulfonate with Zn(OAc)2 in AcOH-H2O was successfully applied to the synthesis of CD-ring system by double ring expansion in total synthesis of hemibrevetoxin (27).22
The synthesis of the 2,6-disubstituted 2,3-trans-3-hydroxytetrahydropyran part of mucocin, a potent anti-tumor agent, was accomplished based on the Zn(OAc)2-induced ring expansion reaction of a tetrahydrofuran having a chloromethanesulfonate on the C2-side chain (28).23,24
In the above-mentioned rearrangement reactions, each nucleophile is HO- or AcO- and is derived from the solvent or Zn(OAc)2. The next three examples are intramolecular reactions. A unique method for the construction of 6,7-dihydroxy-2,8-dioxabicyclo [3.2.1]octane, a core component of zaragogic acids, was developed based on Zn(OAc)2-mediated rearrangement reaction of a 2,5-dialkyltetrahydrofuran derivative having a C1´-chloromethanesulfonate on the C2-side chain, in which 1,2-hydride shift from the C2- to the C1´-position occurs (29).25 Treatment of an isoxazolidine with chloromethanesulfonyl chloride gave the bicyclic compound, which was subjected to catalytic hydrogenolysis to give the piperidinol in 77% yield (30).26 The ring-expansion reaction of cis-4,5-epoxy compound containing a chloromethanesulfonate on C1-position proceeded in 1,2-dichloroethane at 83 °C to give an oxane derivative (endo-type product) preferentially (31), while the corresponding iodide afforded only exo-product on treatment with AgOTf in aqueous THF.27
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- 3. Hori, N.; Nagasawa, K.; Shimizu, T.; Nakata, T., Tetrahedron Lett. 1999, 40, 2145.
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- 6. Paquette, L. A.; Wittenbrook, L. S., Org. Synth. Coll. Vol. 5 1973, 231.
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- 9. Makosza, M.; Golinski, J., Synthesis 1983, 1023.
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- 11. Leit, S. M.; Paquette, L. A., J. Org. Chem. 1999, 64, 9225.
- 12. Paquette, L. A.; Ra, C. S.; Schloss, J. D.; Leit, S. M.; Gallucci, J. C., J. Org. Chem. 2001, 66, 3564.
- 13. Goldwhite, H.; Gibson, M. S.; Harris, C., Tetrahedron 1964, 20, 1613.
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- 15. Truce, W. E.; Norell, J. R., J. Am. Chem. Soc. 1963, 85, 3231.
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- 18. Makosza, M.; Kwast, E., Tetrahedron 1995, 51, 8339.
- 19. (a) Hiranuma, S.; Shimizu, T.; Nakata, T.; Kajimoto, T.; Wong, C.-H., Tetrahedron Lett 1995, 36, 8247. (b) Takebayashi, M.; Hiranuma, S.; Kanie, Y.; Kajimoto, T.; Kanie, O.; Wong, C.-H., J. Org. Chem. 1999, 64, 5280.
- 20. (a) Oka, T.; Fujisawa, K.; Murai, A., Tetrahedron Lett. 1997, 38, 8053. (b) Oka, T.; Fujisawa, K.; Murai, A., Tetrahedron 1998, 54, 21.
- 21. Nakata, T.; Nomura, S.; Matsukura, H., Tetrahedron Lett. 1996, 37, 213.
- 22. Morimoto, M.; Matsukura, H.; Nakata, T., Tetrahedron Lett. 1996, 37, 6365.
- 23. Takahashi, S.; Fujisawa, K.; Sakairi, N.; Nakata, T., Heterocycles 2000, 53, 1361.
- 24. Nagasawa, K.; Hori, N.; Koshino, H.; Nakata, T., Heterocycles 1999, 50, 919.
- 25. Takahashi, S.; Hirota, S.; Nakata, T., Heterocycles 2000, 53, 1361.
- 26. Kiguchi, T.; Shirakawa, M.; Honda, R.; Ninomiya, I.; Naito, T., Tetrahedron 1998, 54, 15589.
- 27. Hayashi, N.; Noguchi, H.; Tsuboi, S., Tetrahedron 2000, 56, 7123.
Takeshi Shimizu & Tadashi Nakata
RIKEN (The Institute of Physical and Chemical Research), Japan
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