METHYL-2-PROPANESULFINYL CHLORIDE 1

Methyl-2-propanesulfinyl Chloride

O

St-Bu Cl

[31562-43-3] C4H9ClOS (MW 140.63)InChI = 1/C4H9ClOS/c1-4(2,3)7(5)6/h1-3H3InChIKey = ZLJKQOWJEZSNBE-UHFFFAOYAI

[Sulfinylating reagent for OH, NH and SH groups. Precursorof tert-butylsulfonyl derivatives with amines and alcohols (Bus

derivatives)].

Physical Data: bp 53–54 ◦C; d 1.135 g cm−3.Refractive Index: n20/D 1.4830.Solubility: ethyl ether, THF, CH3CN, and methylene chloride.Form Supplied in: liquid; commercially available.Handling, Storage, and Precautions: it is flammable, causes

burns, very toxic by inhalation, irritating to the eyes and respi-ratory system, danger of very serious irreversible effects. Thisreagent should be used in a fume hood.

Introduction. Methyl-2-propanesulfinyl chloride or tert-butylsulfinyl chloride is a versatile reagent mainly used as asulfinylating reagent. It yields tert-butylsulfinamides and tert-butylsulfinates by reaction with amines alcohols, respectively.When these reactions are followed by an oxidation step, they allowthe synthesis of the corresponding tert-butylsulfonyl derivatives(widely used as protecting groups). tert-Butylsulfinyl chloride alsoreacts with thiols, affording the corresponding thiosulfinates andwith oximes yielding N-sulfonylimines.

Preparation. Although tert-butylsulfinyl chloride is commer-cially available, it can be easily prepared from di-tert-butyl disul-fide by reaction with SO2Cl2 in the presence of acetic acid (eq 1).1

S S t-But-Bu

O

St-Bu Cl

SO2Cl2

CH3CO2H

(1)

However, the most frequently used methods for synthesizingtert-butylsulfinyl chloride are those involving two steps, i.e., oxi-dation of di-tert-butyl disulfide and subsequent chlorination of theresulting thiosulfinate (eq 2). Netscher and Prinzbach use H2O2

as the oxidant and Cl2 in the second step.2 Sharpless et al. in-troduced some modifications in the method by using tert-butylhydroperoxide and vanadyl acetylacetonate in catalytic amountsfor the oxidation step, and SO2Cl2 as the halogenating agent.3

Finally, other authors have used H2O2 as the oxidant and SO2Cl2as the halogen source.4

S S t-But-Bu

S S t-But-Bu

O

O

St-Bu Cl

chlorination

oxidation

(2)

The reaction of tert-butylmagnesium chloride with SO2

(excess) at 0 ◦C followed by dilution with HCl (5%) yields thetert-butylsulfinic acid. It reacts with thionyl chloride affordingtert-butylsulfinyl chloride (eq 3).5

MgBrt-Bu

O

St-Bu Cl

SOCl2S OHt-Bu

O

(3)

(b) HCl (5%)

(a) SO2 (excess)

NNN-Sulfinylation. tert-Butylsulfinyl chloride reacts with com-pounds containing an aminic N–H bond to afford their corre-sponding N-tert-butylsulfinyl derivatives. Reaction with ammoniaprovides tert-butylsulfinamide, which is easily oxidized into tert-butylsulfonamide. Reactions of tert-butylsulfinyl chloride withamines provide N-substituted tert-butylsulfinamides, used as thenecessary intermediates for the synthesis of tert-butylsulfony-lamines. The t-BuSO2 group (Bus) is one of the most interestingprotecting groups of primary and secondary amines.

tertterttert-Butylsulfinamide and tertterttert-Butylsulfonamide. Reactionsof ammonia with primary and secondary alkylsulfonyl chlorides,as well as with aryl and heteroarylsulfonyl chlorides, afford thecorresponding sulfonamides in good yields. However, the insta-bility of the tertiary alkylsulfonyl chlorides and its different modeof reactivity toward nucleophiles6 render it impractical for mosttertiary alkyl sulfonamides. Therefore, all successful syntheses ofthese compounds involve the formation of the S–N bond with thesulfur in a lower oxidation state, which is followed by transforma-tion into the sulfonyl group. tert-Butylsulfinyl chloride has beenthe intermediate of choice. It reacts with ammonia to obtain tert-butylsulfinamide, which is oxidized with a variety of reagents(eq 4).3

oxidationNH3

O

St-Bu Cl

O

St-Bu NH2

OS

t-Bu NH2

O(4)

This sequence can be performed in only one step by reactionof tert-butylsulfinyl chloride with hydroxylamine.7 However, toavoid the use of free hydroxylamine, which is unstable, unsafe,and difficult to handle, Sharpless et al. prepared tert-butylsulfona-mide by reaction of tert-butylsulfinyl chloride in refluxingacetonitrile containing suspended sodium azide and smallamounts of water (eq 5).3

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2 METHYL-2-PROPANESULFINYL CHLORIDE

H2ONaN3

O

St-Bu Cl

O

St-Bu N3

OS

t-Bu NH2

O(5)

CH3CN(reflux)

tert-Butylsulfinamide and tert-butylsulfonamide are precursorsof N-tert-butylsulfinyl8 and N-tert-butylsulfonylimines,9 respec-tively, which are widely used as activated imines in nucleophilicadditions to C=N bonds. tert-Butylsulfinamide has also been usedas the precursor of the corresponding chloramine salts by reactionwith tert-butyl hypochlorite and NaOH (eq 6). These salts havebeen used as the nitrogen source in catalytic aminohydroxylationof unsaturated amides and aziridination of olefins.3

t-Bu S NCl

O

O

t-Bu S NH2

O

O

t-BuOCl

NaOHt-Bu

SCl

O

(6)

Enantiomerically pure tert-butylsulfinamide has been widelyused in the synthesis of N-tert-butylsulfinylimines, which havefound many applications in asymmetric synthesis.8 However, allthe trials to obtain it by chemical or enzymatic resolution of theracemic compounds were unsuccessful. Therefore optically puretert-butylsulfinamide has been prepared by methods not involv-ing the tert-butylsulfinyl chloride.10 However, sulfinyl chloridesreact with optically pure oxazolidinones providing mixtures oftert-butylsulfinamides (epimers at sulfur) in low de’s. Once sepa-rated, these compounds have been used as excellent chiral sulfinyltransfer agents.11 This procedure has been occasionally appliedto the tert-butylsulfinyl chloride.12

NNN-Organyl tertterttert-Butylsulfonamides (Bus Protecting Group).Sulfonyl groups have a long history in the protection of amines andother nitrogenated functionalities.13 The t-BuSO2 group (Bus),introduced by Weinreb et al. in 1997,5 is one of the most efficientprotecting groups of amines, exhibiting some advantages withrespect to other sulfonyl groups. It combines a higher stability tomany reaction conditions (due to the steric hindrance of the tert-butyl group) with its easy removal (the main drawback of otherN-sulfonyl protecting groups). Thus, it is quite stable under basicand metallation conditions (affecting Boc and Tosyl groups), aswell as under thermal (180 ◦C for 3 h) and mild acidic conditions(such as 0.1N HCl/MeOH at rt, or 0.1N TFA/CH2Cl2, at rt for1 h), but it can be removed with 0.1N triflic acid in dichlo-romethane containing anisole as a cation scavenger.5

As is the case with ammonia, the direct reaction of the amineswith t-BuSO2Cl does not work.6,14 Consequently, the Bus groupmust be incorporated by reaction of amines with t-BuSOCl inthe presence of Et3N, followed by oxidation with m-CPBA5,15

or other oxidizing reagents such as KMnO4,16 RuCl3/NaIO4,5

H2O2/LiOH,17 or dioxirane18 (eq 7).

NHRS

O

t-Bu

O

oxidationEt3N

NHRS

O

t-Bu

RNH2

O

St-Bu Cl

(7)

+

The stability of the N-Bus derivatives obtained from primaryamines is surprisingly higher than that of the secondary ones. Thisdifference in reactivity permits the chemoselective deprotection ofsecondary amines (0.1N TfOH/anisole, 0 ◦C for about 15 min) inthe presence of the primary amines (0.1N TfOH/anisole, rt for 2–3h) by controlling the temperature and the reaction time (eq 8).5

HN

NH2

t-Bu S Cl

O BusN

BusHN

HN

NHBus

(a)

(b) m-CPBA

TfOH/anisole

CH2Cl2, 0 °C(72%)

(86%)

(8)

25 min

OOO-Sulfinylation. Racemic sulfinate esters19 are obtained byreaction of sulfinyl chlorides with alcohols in the presence ofEt3N.20 This method can be successfully applied to the tert-butylsulfinyl chloride for obtaining tert-butylsulfinate esters. Thelack of acidic α-hydrogens in these compounds provides someadvantages with respect to other sulfinates in their reactions withorganometallics, affording sulfoxides (eq 9).

CH2Cl2

Et3NO

St-Bu Cl R OH

O

St-Bu OR+ (9)

tert-Butylsulfinates resulting from the reactions of propargylicalcohols with tert-butylsulfinyl chloride afford tert-butylallenyl-sulfones by refluxing in chlorobenzene (eq 10).21

CH2Cl2

Et3N ∆O

S

t-Bu

O

OHO

St-Bu Cl

H•

SO2t-Bu

H H (10)

+

Allylic tert-butylsulfinates can be transformed into allylictert-butylsulfones. This 1,3-allylic O,S-rearrangement is cat-alyzed by Pd0 and it is highly enantioselective (>93% ee) in thepresence of bisphosphane (BPA) as the chiral ligand (eq 11).22

A list of General Abbreviations appears on the front Endpapers

METHYL-2-PROPANESULFINYL CHLORIDE 3

O

St-Bu Cl

Et3N

CH2Cl2

R

R′

OH

R

R′

t-BuOSO

R

SO2t-Bu

BPA, CH2Cl2

(11)

+Pd2(dba)3, rt

R′

The tert-butylsulfinate obtained by reaction of the N-methylephedrine (benzylic alcohol) and tert-butylsulfinyl chlorideis transformed into N,N-dimethyl 3-tert-butylsulfinyl-3-phenyl-2-propylamine during its chromatographic purification on silicagel (eq 12).23

O

St-Bu Cl

OH

H

Ph

Me2NMe

H

Et2O

SO2t-Bu

H

Ph

Me2N Me

H

+–70 °C rt

82% de

(12)

silica gel

(a)

(b)

Similarly interesting is the use of tert-butylsulfinates as theprecursors of tert-butylsulfonates,2 which are more efficient alky-lating agents than other sulfonates (mesylates, tosylates, or tri-flates) because attack of the nucleophiles on the sulfur, inducingsulfur–oxygen cleavage as a competitive process to the alkylation,is precluded by the bulky tert-butyl group. tert-Butylsulfonates,which cannot be obtained by reaction of alcohols with tert-butyl-sulfonyl chloride, are easily prepared by CF3–CO3H oxidation oftert-butylsulfinates (eq 13).

R OH

O

St-Bu OR

CF3CO3HO

St-Bu OR

O

CH2Cl2

Et3NO

St-Bu Cl

+

(13)

Synthesis of Optically Pure Sulfinates. Chiral sulfinateesters have been extensively used as the primary source for chi-ral sulfur compounds such as sulfoxides24 and sulfinamides,8,25

because they are configurationally stable species, easily ob-tained from sulfinyl chlorides. In this context, tert-butylsulfinateesters play a relevant role because they allow the prepara-tion of bulky tert-butyl sulfoxides which often exhibit someadvantages with respect to p-tolyl sulfoxides in asymmetricprocesses.24

Conventional methods for obtaining chiral sulfinates by usingthe reaction of sulfinyl chlorides with enantiomerically purealcohols, yield mixtures of epimers with low de’s. Such mix-tures have to be separated by crystallization. The main limita-

tion of these procedures derives from the fact that many sulfi-nates are not crystalline solids. Different alcohols are requiredto obtain sulfinates bearing different groups joined to the sulfuratom.24

There are several diastereoselective methods providing opti-cally pure tert-butylsulfinates, the most efficient one being thatusing diacetone-D-glucose (DAG) as a unique inducer of chirality(eq 14).26 This method allows the stereodivergent synthesis of thesulfinate esters by changing the base used in the process. Thus,pyridine favors the formation of (RS)-tert-butylsulfinate (84% de)whereas the (SS) isomer is predominant in the presence of Et3N(72% de). Both epimers can be purified by column chromatogra-phy and then treated with various Grignard reagents to give thecorresponding alkyl- and aryl tert-butyl sulfoxides with very highee’s (eq 14).

St-Bu ODAG

O

St-Bu ODAG

OO

St-Bu Cl

O

O

OHO

O

O

O

St-Bu Cl

DAGEt3N, toluene

Py, THF

:

:

(14)

The above indicated diastereoselective resolution of tert-butyl-sulfinyl chloride with (l)-N-methylephedrine (eq 12) is less effi-cient. It produces diastereomerically enriched sulfinates (de’s upto 82%) in moderate yields (50%) in 3 days at rt.23

Efficient enantioselective methods for synthesizing tert-butylsulfinate esters have been recently reported. The first examplewas due to Ellman’s group and involved the dynamic resolution ofracemic tert-butanesulfinyl chloride with an N-methylimidazole-containing octapeptide (0.5%) acting as a chiral acyl-transfercatalyst.27 The method provides tert-butylsulfinate esters with ee’sup to 81% (eq 15).

ROH

ORS

t-Bu

O

catalystO

St-Bu Cl

ORS

t-Bu

O

+

:

protonsponge

(15)

:

or

The main drawback of this method is the multistep sequencerequired for synthesizing the octapeptide used as the catalyst.It was solved and the stereochemical results improved with theincorporation of the cinchona alkaloids as the chiral bases ofthese reactions. They were first applied by the Toru’s group inthe synthesis of the arylsulfinate esters by using stoichiometricamounts of quinidine (or quinine) acetate/arylsulfinyl chloridecombinations as enantioselective sulfinylating agents.28 Severalmonths later almost simultaneously Ellman and Toru reportedthe catalytic version of this reaction. The former author usescommercially available quinidine,29 which provides very goodyields (≥90%) and higher ee’s (>90%) than those he had pre-viously obtained with the octapeptide. Toru’s group reported the

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4 METHYL-2-PROPANESULFINYL CHLORIDE

use of catalytic amounts (0.1 equiv) of quinidine and quinine1-naphthoates, which allowed the synthesis of the tert-butyl-sulfinate esters in both configurations with up to 95% ee’s.30

OOO-Sulfinylation Leading to NNN-Sulfinylation. N-Sulfony-limines are among the most reactive imine derivatives towardnucleophiles.9 In this field N-tert-butylsulfonylimines have theadvantage of affording the easily cleavable N-tert-butylsulfonylamines (N-Bus, see above). One of the methods for preparingN-tert-butylsulfinylimines involves the reaction of oximes withtert-butylsulfinyl chloride (eq 16).31 The resulting O-tert-butyl-sulfinyl oximes suffer the rearrangement known as Hudson’sreaction.32 It consists in the homolytic cleavage of the N–O bondfollowed by the coupling of the resulting radicals through thesulfur atom, resulting in the formation of N-tert-butylsulfony-loximes.

S

O

Clt-Bu

HO

R′

N R

SOt-Bu

ON

R′

R ∆

N

R′

R

SO2

t-Bu

+

(16)

The O-tert-butylsulfinyl oximes can be used as precursors ofradicals that can be trapped by a variety of reagents. Thus, whenaldoximes or ketoximes supporting pendant alkenes react withtert-butylsulfinyl chloride at −50 ◦C, the iminyl radical resultingfrom the homolytic cleavage of the N–O bond intramolecularlyreacts with the double bond affording a new radical that can betrapped by (PhSe)2 (eq 17).33 The use of 2,6-dimethylbenzene-sulfinyl chloride instead of tert-butylsulfinyl chloride providesbetter results in these reactions.

N SePh

Ph2Se2

NOSOt-Bu

NOH

∆

O

St-Bu Cl

(17)

Hydroxylamines also react with tert-butylsulfinyl chloridein ether affording the N-Bus derivatives of the correspondingamines.7,34 The O-tert-butylsulfinyl hydroxylamine intermediateundergoes Hudson’s reaction, yielding the N-tert-butylsulfonylderivative (eq 18).

S

O

Clt-BuRR′NOH S

O

Ot-Bu NRR′∆

SNHRt-Bu

OO (18)

SSS-Sulfinylation. Thiosulfinate esters are interesting substratesin sulfur chemistry. They have been the subject of mechanisticstudies concerning the different reactivity of the sulfur atomsin reactions with nucleophiles.35 They have also been investi-gated as precursors of α-disulfoxides36 and thioaldehydes.37 Inmany cases, tert-butyl thiosulfinate esters are interesting due tothe restrictions imposed by the size of the tert-butyl group. Asthe synthesis of these compounds by oxidation of disulfides takesplace with moderate regioselectivity, a more satisfactory methodfor preparing unsymmetrical dialkyl thiosulfinates, uncontami-nated by their isomers, involves the coupling of tert-butylsulfinylchloride with mercaptans in the presence of pyridine (eq 19),38

which is the adaptation of a general method used with other acylchlorides.39 The reaction of tert-butylsulfinyl chloride with organ-otin thiolates40 also yields tert-butylthiosulfinates (eq 20). Bothmethods require very mild conditions to avoid the ready dispropor-tionation of the thiosulfinates into thiosulfonates and disulfides.

S

O

Clt-BuS

O

St-BuR′+ R′SH

pyridine, Et2O

0 °C(19)

S

O

Clt-BuSn S

R

R

R R′

S

O

St-BuR′

+ CHCl3, 10 min

–10 °C to rt

R3SnCl

+

(20)

Related Reagents. tert-Butyl Sulfinates; tert-Butyl Sulfina-mides; tert-Butyl Thiosulfinates.

1. Youn, J. H.; Herrmann, R., Tetrahedron Lett. 1986, 27, 1493.

2. Netscher, T.; Prinzbach, H., Synthesis 1987, 683.

3. Gontcharov, A. V.; Liu, H.; Sharpless, B., Org. Lett. 1999, 1, 783.

4. Schleusner, M.; Koep, S.; Guenter, M.; Tiwari, S. K.; Gais, H.-J.,Synthesis 2004, 967.

5. Sun, P.; Weinreb, S. M.; Shang, M., J. Org. Chem. 1997, 62, 8604.

6. Stetter, H.; Krause, M.; Last, W.-D., Chem. Ber. 1969, 102, 3357.

7. Hovius, K.; Engberts, J. B. F. N., Tetrahedron Lett. 1972, 13, 181.

8. Ellman, J. A.; Owens, T. D.; Tang, T. P., Acc. Chem. Res. 2002, 35,984.

9. For a comprehensive review of N-sulfonylimines see: Weinreb, S. M.,Top. Curr. Chem. 1997, 190, 131.

10. Cogan, D. A.; Liu, G.; Kin, K.; Backes, B.; Ellman, J. A., J. Am. Chem.Soc. 1998, 120, 8011.

11. Evans, D. A.; Faul, M. M.; Colombo, L.; Bisaha, J. J.; Clardy, J.; Cherry,D., J. Am. Chem. Soc. 1992, 114, 5977.

12. Fawcett, J.; House, S.; Jenkins, P. R.; Lawrence, N. J.; Russell, D. R., J.Chem. Soc. Perkin Trans. 1, 1993, 1, 67.

13. Greene, T. W.; Wuts, P. G. M., Protecting Groups in Organic SynthesisWiley: New York; 3rd Ed.; 1999, p 615.

14. King, J. F.; Lam, J. Y. L.; Dave, V., J. Org. Chem. 1995, 60, 2831 andreferences cited therein.

15. Kells, K.; Chong, J. M., J. Am. Chem. Soc. 2004, 126, 15666.

16. (a) Polonski, T., Tetrahedron 1985, 41, 603. (b) Richey, H. G., Jr.; Farkas,J., J. Org. Chem. 1987, 52, 479. (c) Oppolzer, W.; Wills, M.; Starkemann,C.; Bernardinelli, G., Tetrahedron Lett. 1990, 31, 4117.

17. Martinez-Merino, V.; Gil, M. J.; Zabalza, J. M.; Gonzalez, A.,Heterocycles 1995, 41, 2737.

A list of General Abbreviations appears on the front Endpapers

METHYL-2-PROPANESULFINYL CHLORIDE 5

18. (a) Hodgson, D. M.; Miles, T. J.; Witherington, J., Synlett 2002, 310.(b) Hodgson, D. M.; Miles, T. J.; Witherington, J., Tetrahedron 2003,59, 9729. (c) Hodgson, D. M.; Maxwell, C. R.; Miles, T. J.; Paruch,E.; Mattherws, I. R.; Witherington, J., Tetrahedron 2004, 60, 3611.(d) Hodgson, D. M.; Stefane, B.; Miles, T. J.; Witherington, J., Chem.Commun. 2004, 19, 2234.

19. Zoller, U. In The Chemistry of Sulphinic Acids, Esters, and theirDerivatives; Patai, S., Ed.; Wiley: New York, 1990, p 217.

20. Tillett, J. G. In The Chemistry of Sulphinic Acids, Esters, and theirDerivatives; Patai, S., Ed.; Wiley: New York, 1990, p 602.

21. (a) Pourcelot, G.; Cadiot, P.; Willemart, A., C. R. Acad. Sci. 1961, 252,1630. (b) Veniard, L.; Benaim, J.; Pourcelot, G., Comp. Rend. Ser. C1968, 266, 1092. (c) Gais, H.-J.; Gumpel, M.; Schleusner, M.; Raabe,G.; Runsink, J.; Vermeeren, C., Eur. J. Org. Chem. 2001, 22, 4275.

22. Jagusch, T.; Gais, H.-J.; Bondarev, O., J. Org. Chem 2004, 69,2731.

23. Drabowicz, J.; Bujnicky, B.; Biscarini, P.; Mikolajczyk, M., Tetrahedron:Asymmetry 1999, 1, 3177.

24. For leading reference see: Fernández, I.; Khiar, N., Chem. Rev. 2003,103, 3651.

25. Zhou, P.; Chen, B.-C.; Davis, F. A., Tetrahedron 2004, 50, 8003.

26. (a) Khiar, N.; Fernández, I.; Alcudia, F., Tetrahedron Lett. 1994, 35, 5719.(b) Khiar, N.; Fernández, I.; Llera, J. M.; Alcudia, F., J. Org. Chem. 1992,57, 6789.

27. Evans, J. W.; Fierman, M. B.; Millet, S. J.; Ellman, J. A., J. Am. Chem.Soc. 2004, 126, 8134.

28. Shibata, N.; Matsunaga, M.; Nakagawa, M.; Fukuzumi, T.; Nakamura,S.; Toru, T., J. Am. Chem. Soc. 2005, 127, 1374.

29. Peltier, H. M.; Evans, J. W.; Ellman, J. A., Org. Lett. 2005, 7, 1733.

30. Shibata, N.; Matsunaga, M.; Fukuzumi, T.; Nakamura, S.; Toru, T.,Synlett 2005, 1699.

31. Artman, G. D.; Bartolozzi, A.; Franck, R. W.; Weinreb, S. M., Synlett2001, 232.

32. Brown, C.; Hudson, R. F.; Record, K. A. F., J. Chem. Soc., Perkin Trans.2, 1978, 8, 822.

33. Lin, X.; Stien, D.; Weinreb, S. M., Org. Lett. 1999, 1, 637.

34. (a) Bouma, W. J.; Engberts, J. B. F. N., J. Org. Chem. 1976, 41, 143.(b) Bleeker, I. P.; Engberts, J. B. F. N., J. Org. Chem. 1981, 46, 1012.

35. (a) Oae, S.; Toshikazu, T.; Hae, K. Y., Tetrahedron Lett. 1977, 18, 4219.(b) Kice, J. L.; Liu, C.-C. K., J. Org. Chem. 1979, 44, 1918.

36. Oae, S.; Takata, T.; Kim, Y. H., Bull. Chem. Soc. Jpn. 1982, 55, 2484and references cited therein.

37. Baldwin, J. E.; Gerald Lopez, R. C., Tetrahedron 1983, 39, 1487.

38. Block, E.; O’Connor, J., J. Am. Chem. Soc. 1974, 96, 3921.

39. Baker, H. J.; Kloosterziel, H., Recl. Trav. Chim. Pays-Bas 1954, 73,129.

40. Harpp, D. N.; Aida, T.; Chan, T. H., Tetrahedron Lett. 1983, 24, 5173.

José Luis García Ruano & José AlemánUniversidad Autónoma de Madrid, Madrid, Spain

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