Phenylthiocyclopropane1a,1c

[14633-54-6]  · C9H10S  · Phenylthiocyclopropane  · (MW 150.26)

(a particularly valuable building block able to transfer a three-carbon unit to various organic molecules, allowing the synthesis of cyclobutanones from aldehydes or ketones)

Alternate Name: cyclopropyl phenyl sulfide.

Physical Data: bp 51-52 °C/0.1 mmHg or 62-63 °C/1 mmHg.2

Preparative Methods: easily prepared from 1-phenylthio-3-chloropropane (itself obtained on reaction of 1-bromo-3-chloropropane and phenylthiolates) and Potassium Amide in liquid ammonia (eq 1).3

1,3-Bis(phenylthio)propane reacts with n-Butyllithium in THF to produce the title reagent (1) on reaction with only 1 equiv n-Buli, or 1-lithio-1-phenylthiocyclopropane (2) if 2 equiv are used (eq 2).4,5

(1) has also been synthesized from 3-tributylstannylpropanal (available from tributylstannyllithium and Acrolein) and trimethylsilyl phenyl sulfide in the presence of Titanium(IV) Chloride as acid catalyst (eq 3),6 and on substitution of (i) Cyclopropyllithium with Diphenyl Disulfide (eq 4), (ii) cyclopropyl bromide with potassium benzenethiolate (eq 5)7 or (iii) 1,1-dibromocyclopropane,8 also with benzenethiolates, and by reduction of a-bromocyclopropyl phenyl sulfide with sodium methanethiolate (eq 6).9 In addition, cyclopropyl phenyl sulfoxide can be reduced to (1) in more than 70% yield with Chlorotrimethylstannane-benzenethiol (eq 7).10

Handling, Storage, and Precautions: use in a fume hood.

Reactions of Phenylthiocyclopropane.

The reactions of (1) are those typical of sulfides. Oxidation or alkylation can occur at the sulfur, whereas halogenation or metalation can occur on the cyclopropane ring at the carbon bearing the phenylthio group. The latter reaction, which produces phenylthiocyclopropyllithium, is the one most frequently used in organic synthesis. (1) also reacts with Hydrogen Chloride and Hydrogen Bromide to produce thiophenol,11 and higher homologs provide ethyl ketones in reasonably good yields (eq 8).12

Oxidation and Alkylation of Phenylthiocyclopropane.

Oxidation of (1) to the corresponding sulfoxide, sulfone, and sulfoximine is easily achieved. However, the best synthetic route to the sulfone involves the cyclization of 3-halopropyl phenyl sulfone on reaction with bases.3 Oxidation to the sulfoxide has been typically carried out with peroxy acids or Sodium Periodate (eq 9, route a).13-15 Asymmetric oxidation of (1) has been efficiently carried out by Holland14 using the fungus Mortierella isabellina ((R)-cyclopropyl phenyl sulfoxide, 58% yield, ee 66%) or better by Kagan16 using the modified Sharpless method (Titanium Tetraisopropoxide (+)-diethyl tartrate, H2O, t-Butyl Hydroperoxide, CH2Cl2, -20 °C, 24 h, (R)-cyclopropyl phenyl sulfoxide, 73% yield, ee 95%) or by Davis17,18 using (-)-a,a-dichlorocamphorsulfonyloxaziridine (CCl4, 20 °C, 18 h, (S)-cyclopropyl phenyl sulfoxide, 90% yield, ee 92%).

Acid-catalyzed addition of (1) to 1,4-Benzoquinone, followed by methylation of the resulting dihydroxysulfonium salt with Diazomethane affords the corresponding diarylcyclopropylsulfonium salt in reasonably good yield (eq 10).19 Otherwise the synthesis of Cyclopropyldiphenylsulfonium Tetrafluoroborate, a valuable precursor of the corresponding cyclopropylide, is best achieved by cyclization in basic media of 3-chloro-1-propyldiphenylsulfonium tetrafluoroborate.20 The synthesis of the related (dimethylamino)cyclopropylsulfonium tetrafluoroborate has been carried out from cyclopropyl phenyl sulfoxide by a sequence which involves reaction with Hydrazoic Acid (eq 11).13

(1) reacts with N-Chlorosuccinimide (1.2 equiv NCS, pyridine, benzene, 20 °C, 12 h) to produce 1-chloro(phenylthio)cyclopropane in quantitative yield (eq 9, route b).15,21 Similar results are obtained from cyclopropyl phenyl sulfoxide and Thionyl Chloride (1.2 equiv SOCl2, CH2Cl2, 20 °C, 2 h) or Sulfuryl Chloride in the presence of pyridine (eq 9, route a).15,21 It is remarkable that ring-opened products are not found in these reactions, since solvolysis of 1-chloro(phenylthio)cyclopropane affords some allylic derivatives. These chlorinations may proceed via the initial formation of chlorosulfonium salts, which then decompose affording the a-chloro sulfides through an ylide-ylidene ion-pair intermediate as in the Pummerer reaction, rather than involving a free carbonium ion.15,21

The synthesis of 1-iodo(phenylthio)cyclopropane has been achieved by metalation of (1) with n-Butyllithium and subsequent reaction with iodine (eq 12).22 This compound is a valuable precursor of 1-methoxy(phenylthio)cyclopropane and of 1-lithio-1-methoxycyclopropane.22,23 1-Methoxy(phenylthio)cyclopropane has also been synthesized from cyclopropyl phenyl sulfoxide via a sequence of reactions which involve the intermediate formation of the corresponding methoxysulfonium salt and its rearrangement (of Pummerer type) on reaction with sodium methoxide in methanol (eq 13).24

Reactions involving 1-Lithio-1-phenylthiocyclopropane (2).

This compound is easily synthesized according to the Trost procedure by metalation of (1) with n-butyllithium (1 equiv, THF, 0 °C, 2 h, 20 °C, 2 h, >90% yield) (eq 12).1a,25-28 (2) is the only a-thio carbanion bearing two alkyl substituents to be generated by hydrogen-metal exchange.29 It has been alternatively generated4,5 from 1,3-bis(phenylthio)propane and 2 equiv n-butyllithium in THF (-78 to 0 °C, >85% yield, eq 2), or by reductive lithiation of 1,1,3-tris(phenylthio)propane30 and of 1,1-bis(phenylthio)cyclopropane31 using Methyllithium-N,N,N,N-Tetramethylethylenediamine or 1-(dimethylamino)naphthalenide, respectively.

(2) is a useful reagent in the preparation of:

  • 1)cyclobutanones,1a,26-28,32-35 including cyclobutanone itself (eq 14),26 the a-vinyl1a,27,28,32,35-39 and a-aryl40 analogs, a-(1-phenylthiocyclopropyl)cyclobutanones,41 g-ketocyclobutanones,42 2-alkyl(or aryl)-1,1-bis(phenylthio)cyclobutanes (eq 15),43 1-phenylthiocyclobutenes (eq 15),28,32,44 3-alkyl(or aryl)-2-(phenylthio)-1,3-butadienes (eq 15),43 cyclobutanes,32,44 annulated cyclopentanones45 cyclohexen-3-ols,38 g,d-cyclooctenones,36
  • 2)alkylidenecyclopropanes (eq 16),46 allylidenecyclopropanes (eq 17),47 g-keto sulfides (eq 8),12 ethyl ketones (eq 8),12 g-methoxycarbonyl-1,1-bis(phenylthio)acetals,35 vinyl sulfides (eq 18),48 1-methoxy-1-(phenylthio)cyclopropane (eq 13),22 and 1-trimethylsilyl-1-(phenylthio)cyclopropane,31,49 as well as 1-lithio-1-methoxycyclopropane (eq 12) and 1-lithio-1-trimethylsilylcyclopropane.49

    1-Lithio-1-phenylthiocyclopropane reacts with many electrophiles. In reactions where lithium phenylthiolate is formed (from cyclopropanone thioacetal or from 1,3-bis(phenylthio)propane), Copper(I) Iodide is used to scavenge the thiolate to improve yields of alkylated or hydroxyalkylated derivatives.5,31

    Very high yields of b-hydroxyalkyl sulfides are obtained from saturated aldehydes and ketones,1a,4,5,25-28,32,34,40,43,44,50 including Formaldehyde (80% yield)26 and hindered or quite enolizable ketones such as tetramethylcyclohexanone (92% yield)25,27 or trispiro[3.1.3.1.3.1]pentadecane-1,5,10-trione (54% yield) (eq 19).44 The reaction occurs regioselectively on the carbonyl group of a,b-unsaturated aldehydes and ketones,1a,25,27,32,37-39,45,51 including 2-hydroxymethylene ketones,42 and proceeds stereoselectively with 4-t-butylcyclohexanone to produce almost exclusively the alcohol resulting from an equatorial attack (THF, 0 °C, 98% yield, 99:1 ratio of stereoisomers, eq 14).28 With a-selenoaldehydes, (2) leads predominantly to the stereoisomer of b-hydoxyalkyl selenide predicted on the basis of Cram's rules.41,52

    Alkylation of 1-phenylthiocyclopropyllithium takes place in good yield with primary alkyl bromides and iodides but not with secondary alkyl halides (eq 8).12,31,46 With Benzyl Bromide, however, halogen-metal exchange occurs, leading to bibenzyl and 1-bromocyclopropyl phenyl sulfide.12 Allylation works successfully if copper(I) iodide (0.5 equiv) is present and the reaction is carried out at low temperature (eq 15).47,53 (2) adds to epoxides to form 1-(b-hydroxy)cyclopropyl phenyl sulfides (eq 8).12 Excellent regioselectivity of attack occurs at the less hindered primary carbon of 1,2-epoxybutane, and even with cyclohexene oxide a high yield of adduct is obtained.12 Reaction with Chlorotrimethylsilane, Iodine, esters, or DMF and carbonic anhydride leads to 1-trimethylsilyl(phenylthio)cyclopropane (Me3SiCl, 88% yield),31,49 1-iodo(phenylthio)cyclopropane (eq 12),22 1-alkoyl-1-(phenylthio)cyclopropanes (80% yield),38,41 and 1-(phenylthio)cyclopropanecarboxylic acid (55% yield),41 respectively.

    Thus 1-phenylthiocyclopropylcarbinols are valuable precursors of cyclobutanones.1a,26-28,32-40,42 The rearrangement takes place in the presence of an acid catalyst. The more general and vigorous conditions involve the use of Tin(IV) Chloride in methylene chloride (eq 14).32 Protic acids with a nonnucleophilic anion, such as 48% aqueous Tetrafluoroboric Acid, work nicely with b-hydroxy sulfides derived from sterically unhindered ketones, but increasing steric hindrance led to no reaction.32 The reaction has also been performed with p-Toluenesulfonic Acid in wet benzene32 or tetralin.26 These conditions require heating and are particularly useful for the adducts derived from saturated aldehydes.32 They have been used for the synthesis of the parent cyclobutanone26 (70-120 °C in the presence of Mercury(II) Chloride as a thiol trap). The rearrangement is stereoselective.28,32,33 For example, the b-hydroxyalkyl sulfide derived from 4-t-butylcyclohexanone shown in eq 14 leads selectively to the cyclobutanone arising from axial migration1a,28,32 and allows the introduction of the substituted carbon-carbonyl bond on the sterically less crowded face. The stereochemical outcome of this process is complementary to the one which involves cyclopropylidenediphenylsulfurane20 and introduces instead the carbon-carbonyl bond on the more sterically hindered face.32

    1-Phenylthiocyclopropylcarbinols produce cyclobutanone enol thioethers on reaction with anhydrous p-toluenesulfonic acid in refluxing benzene (eq 19) or more efficiently with the Burgess reagent ((carboxysulfamoyl)triethylammonium hydroxide inner salt methyl ester).32 Alternatively, reaction of 1-phenylthiocyclopropylcarbinols derived from aldehydes with excess of thiophenol (5 equiv) in the presence of 48% hydrobromic acid-zinc bromide affords cyclobutanone phenylthio acetals (eq 15).43 Their further reaction with copper triflate and Hünig's base produces very good yields of cyclobutanone enol thioethers43 precursors of 2-(phenylthio)-1,3-butadienes (eq 15).32,43

    1-Alkyl- and 1-allylcyclopropyl phenyl sulfides are efficiently converted to alkylidenecyclopropanes46 and allylidenecyclopropanes (eqs 16 and 17),47 respectively on methylation to the corresponding sulfonium salt followed by reaction with a base. The reaction is expected to occur via the intermediate formation of a sulfur ylide of the type described in eq 12.46 Otherwise 1-alkylcyclopropyl phenyl sulfides afford12 ethyl ketones on reaction with hydrobromic acid-acetic acid, and b-keto sulfides on reaction with mercury(II) chloride (see eq 8).

    Related Reagents.

    Cyclopropyldiphenylsulfonium Tetrafluoroborate; Cyclopropyllithium; 1-Lithio-1-methoxycyclopropane.


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    Alain Krief

    Facultés Universitaires Notre-Dame de la Paix, Namur, Belgium



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