Dimethyl sulfoxide oxidations

zyxwvuts zyxwvut zyxwvu zyxwvu CHEMICAL REVIEWS VOLUME 67, NUMBER3 MAY25, 1967 DIMETHYL SULFOXIDE OXIDATIONS W. W. EPSTEIN AND F. W. SWEAT Department of Chemistry, University of Utah, Salt Lake City, Utah Received July 13, 1966 CONTENTS zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFE . . . . . . . . . . . 247 A. Toxicity. ..... 11. General Considerations.. ................................. A. DMSO. Structure and Reactivity. . . . . . . . . . . . . ......... 247 ................... 248 + 111. DMSO DCC Method. . . A. General.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. The Oxidation of Nucleotides and Nucleosides. . . . . . . . . ........... C. Oxidation of Carbohydrates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. Acetic Anhydride Method. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V. Phosphorus Pentoxide Method. . . .................. VI. Chloroformate Method. . . . . . . VII. Oxidation of Halides and Tosylates VIII. Oxidation of Thiols. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I X . Miscellaneous Oxidations. . . . . ........ A. Diazonium Method.. . . . . B. Oxidation of Sulfides.. ....................... C. Oxidation of Ketenes and Related Compounds. . D. Air Oxidation of Alcohols. E. Oxidation of Inorganic Halides.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F. Oxidation of Quinol Acetates. . . . . G. Oxidative Halogenation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . H. Oxidation of Epoxides. . . . . . . X. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I. INTRODUCTION 256 256 258 258 259 compounds in dimethyl sulfoxide are potentially danger- compounds (17a)* first employed as an oxidizing agent <48), the knowledge concerning the variety of compounds that can be oxidized by dimethyl sulfoxide has grown considerably. Mild conditions, uncomplicated work-ups, and high yields with which most oxidations can be effected have elevated this technique into prominence. Recent publications have considered dimethyl sulfoxide oxidations to some extent (23, 29, 45, 84), but to date no comprehensive review exists. In the following review only reactions in which dimethyl sulfoxide is clearly the oxidizing agent have been included. The literature has been surveyed through May 1966. A. 248 249 249 252 B. PURIFICATION The drying of dimethyl sulfoxide with magnesium perchlorate has resulted in an explosion (19). Although not normally a purification technique, treatment of dimethyl sulfoxide with sodium hydride in large batches has also resulted in explosions (18). Satisfactory purity can be obtained by distillation under reduced pressure from calcium hydride followed by storage over Linde molecular sieves, Type 4A. No account of difficulties resulting from this method of purification and drying has been published. The nomenclature of the compounds listed in the review is according to Chemical Abstracts, even if the author of the paper has preferred a different one. TOXICITY Caution: Although pure dimethyl sulfoxide is not considered toxic, solutions of inorganic salts or organic 247 zyxwvuts 248 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA W. W. EPSTEIN AND F. W. SWEAT The following abbreviations are commonly employed in the literature and will be used consistently throughout the remainder of this review: DMSO, dimethyl sulfoxide; DMS, dimethyl sulfide; DCC, dicyclohexylcarbodiimide. zy zy zyxwvutsrq - 11. GENERAL CONSIDERATIONS A. DMSO. STRUCTURE AND REACTIVITY Pathway B (CHa)zS==O + R-CH-R I --ic k J ’ (CHB)&+O- I11 R I H R base + R I The physical properties of DMSO are well described in the literature (23, 46). Dimethyl sulfoxide is a colorless, odorless, and very hygroscopic liquid (bp 189”, mp 19.5’) with a slightly bitter taste. The structure of DMSO is usually represented by the following resonance hybrid CHa-S-CHs +L I O R electrophilic species, E (the nature of E is considered in the discussions of the individual methods), which is subsequently displaced by the substrate to be oxidized, usually an alcohol, to form 111. The second pathway involves a leaving group X (X = (CHa)kkO (CHa)ZS--O C1, Br, I or sulfonate) being displaced by DMSO actI I1 ing as a nucleophile and resulting directly in the diResonance structure I owes its existence to the ability methylalkoxysulfonium salt 111. Although it has not of the 3d orbitals of sulfur to accommodate an addibeen verified by experiment, it is generally assumed tional electron pair, in this case the p electrons of the that this step proceeds by way of a bimolecular nucleooxygen (20). Although there is still debate over which philic displacement by the oxygen of DMSO (34, 36, hybrid best represents the structure of DMSO, or 42, 68). It is also possible that both bimolecular and sulfoxides in general, it seems certain that the sulfurunimolecular processes are operative depending on the oxygen bond can be justly characterized as being semisubstrate (37), or that a “merged substitution-elimipolar (78). nation reaction’’ of the type that has been proposed for The oxidizing capacity of DMSO is somewhat det-butyl cyclohexane-4-p-toluenesulfonate is occurring pendent on its ability to act as a nucleophile. Its in some cases (102). The question of oxygen os. basicity is slightly greater than that of water (54a), and sulfur displacement of X has been considered (44, 90) its nucleophilicity has been estimated to exceed that of and in most cases the product from oxygen attack, ethanol toward alkyl sulfonate esters (90). zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA 111, is formed by kinetic control with the sulfur displacement product, an alkyldimethylsulfoxonium salt, B. DMSO AS AN OXIDIZING AGENT [R(CH3)2S-0 ]+ X-, becoming important only after long reaction times (90). The considerations of the Although the evidence is not yet conclusive in every individual oxidations which follow are divided into three case, there is a strong indication that most of the DMSO groups: those which proceed through pathway A, oxidations involve the same dimethylalkoxysulfonium those which proceed through pathway B, and miscelsalt intermediate I11 which subsequently reacts with a laneous cases which are not clear as to mechanism. base to give the observed carbonyl product and DMS. The intimate details of this step will be considered in 111. DMSO DCC METHOD the discussions of the various methods of DMSO oxidation along with the pertinent evidence for the mechaA. GENERAL nism. It has been demonstrated that dimethylmethThis method of oxidation is generally referred to as oxysulfonium fluoroborate, [(CH3)2S-OCH3]@BF4e, rethe “Pfitzner-Moff att” technique, after its originators acts in the presence of base to form formaldehyde (39, (75-77). The reaction involves addition of an alcohol 40) and in addition will undergo rapid alkoxide exsubstrate to a solution of DCC in DNSO with phoschange, with inversion of configuration a t sulfur (38, phoric acid or pyridinium trifluoroacetate present as a 39, 41) in the presence of sodium ethoxide and sodium proton source which results in reaction conditions near isopropoxide with subsequent formation of acetylaldeneutrality. Dimethyl sulfoxide concentration may hyde and acetone, respectively (39,40). vary from 10 to 100% of the total solvent with an inert There are two routes by which a substrate may be solvent like benzene making up the remainder. Diconverted into the dimethylalkoxysulfonium salt intermethyl sulfoxide and DCC have been successfully mediate 111, and the route is determined by the strucreplaced by tetramethylene sulfoxide and isopropyl ture of the substrate. These two routes are illustrated carbodiimide. The oxidation technique is applicable in general fashion below. The first pathway involves to primary or secondary alcohol groups in an almost reaction of DMSO with an intermediate “activating” zyxwvut + DIMETHYL SULFOXIDE OXIDATIONB 249 zyxwvuts zyxwvutsrq 0 (less than 5%) but real quantity of tritium was d e zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA tected in the N,N'-dicyclohexylurea which could only have resulted from direct abstraction of the proton iCH3 l2 0 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA + zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA from intermediate I11 without intervention of the ylid I S-0 CH3-S+W3 intermediate V. Varying, but usually small quantities of the side product VI, R2-CHO-CH2SCH3, have been reported in CH,-S-CH3 + 6 0 t some instances (43, 77). A thorough discussion of I this product is presented in a later section. P zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA Thiols have not been studied extensively but generFigure 1. ally are not oxidized by this method (77). It is possible that the high nucleophilicity of the thiol allows it to compete successfully with DMSO for DCC which unlimited variety of compounds including alkaloids, would have the effect of removing both substrate and steroids, carbohydrates, and other complex substances. DCC from further reaction. Although this is not in Steric effects are not important except in highly hincomplete agreement with the experimental facts (77) , dered sytems where oxidation of the less hindered alcohol the reaction of thiols with carbodiimides to give stable will predominate. Tosylates, tertiary alcohols, oleproducts has been established (17, 47). Data for this fins, and amines are unaffected by the conditions of the type of oxidation are given in Table I. reaction. The mechanism illustrated in Figure 1 was proposed B. THE OXIDATION OF NUCLEOTIDES AND NUCLEOSIDES (1, 76, 77) and later proved by O18-and deuterium-labeling studies ( 2 5 ) . The first step involves activation of Treatment of nucleotides possessing a free 3'-hythe DMSO by reaction with DCC (this is the E referred droxyl group with DMSO and DCC results in cleavage to earlier) in an acid-catalyzed process to give an interof the glycosidic as well as the 5'-phosphate bond (75, mediate IV. Formation of IV by nucleophilic attack 76). The glycosidic bond of the corresponding nucleoof DMSO is consistent with the chemistry of carbodiside (3'-hydroxyl present) is cleaved in the presence of imides (47). Attack on intermediate IV by an alcohol DMSO, DCC, and anhydrous phosphoric acid (76). substrate results in dimethylalkoxysulfonium salt I11 If the 3'-hydroxyl is absent (3-dehydro) or blocked and N,N'-dicyclohexylurea. The preceeding sequence (3'-0-acetyl), the 5' position of the nucleoside is oxiwas established by using 0 Wabeled DMSO and noting dized to the 5'-aldehyde. In nucleotides with a blocked that all the 0 ' 8 ended up in the N,N'-dicyclohexylurea 3'-hydroxyl, oxidation or cleavage does not take place and not in the carbonyl compound which would be rebut starting material and dinucleotide pyrophosphates quired if the alternate mechanism of the alcohol first are recovered (76). attacking DCC followed by reaction with DMSO were Oxidation of the 5' position is of importance, since the correct route ( 2 5 ) . other oxidative techniques on the carbohydrate moiety Formation of V by reaction of I11 with a base follead exclusively or in part to the 5' acid (64). lowed by an intramolecular hydrogen transfer to give Oxidative cleavage is reported to proceed by oxidathe observed carbonyl product plus DMS was proved tion of the 3'-hydroxyl, followed by spontaneous 0 by means of deuterium-labeling studies. A deuterium elimination of the heterocyclic base and 5'-phosphate, label on the carbon of the substrate bearing the hyif one is present (76) This proposal is based upon droxyl was found in the DMS isolated from the reaclittle experimental evidence, but repeated attempts a t tion-a fact consistent only with the ylid, intramolecuoxidation of 3'-hydroxyl groups in deoxynucleosides lar hydrogen-transfer pathway (25). and deoxynucleotides have led to glycosidic cleavage The proposed mechanism requires not only acid without any detectable carbonyl intermediates being recatalysis but base catalysis as well, which is consistent covered (76). The data are listed separately in Table with the observation that the reaction fails when a I. strong mineral acid (HCI, HzS04, or HClOJ is used in C. OXIDATION OF CARBOHYDRATES place of phosphoric acid or pyridinium trifluoroacetate (76). The above observation is presumably due to the Application of this oxidation technique to carboinability of an ylid intermediate to form in the absence hydrates will result in the oxidation of most free hyof a strong enough base and the rapid depletion of DCC droxyl groups to the corresponding carbonyl compound by an alternate reaction in the presence of a strong acid (5-7, 24). (47). The intermediacy of ylid V has been further The extremely mild conditions and high yields give substantiated by use of a tritium-labeled alcohol subthis method great potential in carbohydrate oxidations. strate rather than a deuterium one and recovery of While sulfonate esters are capable of undergoing oxidaCHrS-CH2T (93). I n these experiments a small tion and elimination in DMSO, these groups remain E zyxwvutsr zyxwvutsr zyxwvut zyxwvut zyxwvutsr zyxwvu W. W. EPSTEIN AND F. W. SWEAT relatively inert under these reaction conditions (7), but may undergo epimerization to a more stable conformation, i.e., from an axial to equatorial position (5). This method has been shown to fail in the attempted oxidation of several carbohydrates which have hydroxyl groups flanked by acetal and/or ether moieties (7). Thus VII, VIII, and IX remain resistant to oxidation by DMSO and DCC mixtures (7). TABLEI DIMETHYL SULFOXIDEOXIDATION OF ALCOHOW Yield, Substrate 1-Butanol 1-Hexanol 1-Octanol Isobutyl alcohol 1,4-Butanediol Neopentyl alcohol 2-Butanol ( - )-Menthol Citronellol Cinnamyl alcohol 3-Phenyl-1-propanol Product(s) Butyraldehyde Hexanal 0ctanal Isobutyraldehyde 1,4-Butanedione Pivaldehyde 2-Butanone Menthone Citronellal Cinnamaldehyde 3-Phenyl-1-propanal 1-Phenyl-2-propanone 1-Phenyl-1-propene Benzaldehyde o-Nitrobenzaldehyde m-Nitrobenzaldehyde p-Nitro benzaldehyde p-Nitrobenzaldehyde p-Nitrobenzyl acetate p-Nitro benzaldehyde o-Chlorobenzaldehyde p-Chlorobenzaldehyde p-C hlorobenzaldehyde p-Methoxybenzaldehyde p,p'-Dimethoxybibenzyl p-Methylbenzaldehyde 3-Cholestanone 3-Cholestanone As-3-Cholestenone 24-C holanal A4-Androstene-3,17-dione A4-Androstene-3,17-&one 11-Oxoprogesterone 11-Oxoprogesterone 11-Oxoprogesterone Cortisone acetate A6-Androstene-3,17-dione 3~-Acetoxy-17-oxo-A5-androsten19-a1 3, 17-0xo-A4-androsten-19-al Yohimbinone Methyl ketoreserpate Aj malidine Aspidospermone 3-Dehydro~pegazzinidnedimethyl ether Hydroxyketoepiibogamine 1,2-O-Isopropylidene-Dglucohexodialdose 3'-O-Acetylthymidine-5'-aldehyde 2 ',3'-O-Isopropylideneuridine-5'aldehyde 2',3'-O-Isopropylideneadenosine5'-aldehyde Thymine Thymihe Thymine Method Chloroformate Chloroformate DCC Chloroformate Chloroformate Chloroformate Chloroformate Chloroformate Chloroformate % Ref (collidine) (collidine) 65 9 68 9 100 77 (collidme) 70 9 (collidme) 80 9 (collidine) 57 9 (collidine) 78 9 (collidine) 26 9 (collidine) 46 9 60 95 0 2 26 95 0 2 25 95 0 2 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPO 36 80 0 2 95 27 95 0 2 63 95 0 2 77 95 0 2 AciO 75 1 25 92 DCC 77 78 95 0 2 86 95 0 2 DCC 100 77 8.8 95 0 2 85 95 0 2 85 95 0 2 Chloroformate (collidine) 20 9 DCC 80 77 DCC 66 77 DCC 94 77 DCC 92 77 Act0 1 34 AciO 13 1 DCC 99 77 DCC 0 77 ACZO 1 53 DCC 90 77 DCC 53 77 zyxwvutsrqpo 1-Phenyl-2-propanol Benzyl alcohol o-Nitrobenzyl alcohol m-Nitrobenzyl alcohol p-Nitrobenzyl alcohol p-Nitrobenzyl alcohol p-Nitrobenzyl alcohol o-Chlorobenzyl alcohol p-Chlorobenzyl alcohol p-Chlorobenzyl alcohol p-Methoxybenzyl alcohol p-Methylbenzyl alcohol Cholestanol Cholestanol Cholesterol 24-Hydroxycholane Testosterone Testosterone 11a-Hydroxyprogesterone 1la-Hydroxyprogesterone 11pHydroxyprogesterone 11~-Hydroxy-21-acetoxyhydrocortisone 3p-Hydroxy-A5-androsten-17-one 19-Hydroxy-3~-acetoxy-As-androsten17-one 19-Hydroxy-A4-androstene-3,17-dione (a or D)-Yohimbine Methyl reserpate Ajmaline Aspidospermine Spegazzinidine dimethyl ether DCC AczO AQO Ac20 DCC DCC 82 80-85 33 DCC BFs 50 15 32 DCC DCC 90 75 75 77 112 1 1 zyxwvutsrq ( i~)-Dihydroxyepiibogadne 1,2-O-Isopropylidene-5,6-anhydroD-glucose 3 '-0-Acetylthymidine 2',3'-O-Isopropylideneuridine 2 ',3 '-0-Isopropylideneadenosine Thymidine 5'-phosphate 5'-O-Acetylthymidme pl,p*-Dithymidine pyrophosphate ... ... 83 14 77 DCC 75 DCC DCC DCC 75 75 75 zyxwvu 251 zyxwvutsrqp DIMETHYL SULFOXIDE OXIDATIONS zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQP T a m I (Continued) Yield, zyxwvutsrqponmlkjihgf Product(#) Substrate Method % Ref 25 72 COOCH3 CH,OAc I p4010 MeOH Ad{; 0.4c CHzOAc DCC o y - 65 72 60 91 74 7 24 DCC 80 7 DCC zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQ DCC DCC 86 96 5 5 z 252 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA W. W. EPSTEIN AND F. W. SWEAT zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPON %& OH M MI v1I OH VI1 is oxidized in good yield by DMSO-Ac20 or DMSO-P4010 (72, 91), perhaps because of less steric requirements of the oxidation intermediate in the latter methods. The carbohydrates which have been oxidized by this method are listed in Table I. IV. ACETICANHYDRIDE METHOD This method, which is similar to the Pfitzner-Moffatt technique, utilizes DMSO and acetic anhydride mixtures to oxidize primary and secondary alcohols to the corresponding carbonyl compound (1, 2). Acetic anhydride is the “E” of pathway A which activates the DMSO for reaction with the alcohol to form the dimethylalkoxysulfonium salt intermediate 111. Acetic anhydride can be replaced by benzoic anhydride (presumably other anhydrides would work as well) and tetramethylene sulfoxide can replace DMSO. The reaction of DMSO and organic acid anhydrides has been well studied (33, 40,70, 74a, ‘79) and intermediate X (FigureZ),which results from nucleophilic attack of DMSO at one carbonyl of the acetic anhydride, is generally accepted as the product of the first step of the reaction. Intermediate X may undergo one of two reactions (1). One sequence involves attack by the alcohol substrate to form dimethylakoxysulfonium salt I11 and give a carbonyl product via an intramolecular hydrogen transfer (93). A second pathway requires elimination of acetate to give a sulfonium ylid XI which can also react with the alcohol substrate to yield the side product V I (1). The major route to the carbonyl product proceeds through ylid intermediate V which has been established by labeling studies similar to those described in the previous section (93). It appears that this method of oxidation will be of limited utility for oxidation of many unhindered primary and secondary alcohols, in light of the higher yields obtained with the Pfitzner-Moffatt technique. Formation of acetates (1, 93) as well as increased amounts of methylthiomethyl ether VI as side products are also distinct disadvantages. This method appears to be superior to the DMSO-DCC method in hindered systems. More hindered axial alcohol groups of steroids are oxidized in higher yields than the corresponding equatorial epimers (1) contrary to the PfitznerMoff a t t technique. It may be that the difference in the selectivity of the two methods is due to the difference in size between the DMSO-DCC intermediate and X. The data for this method are given in Table I. V. PHOSPHORUS PENTOXIDE METHOD Phosphorus pentoxide and DMSO have been used for a limited number of carbohydrate oxidations (72). No mechanistic details have been elaborated, but in light of previous mechanisms phosphorus pentoxide ( P ~ ~ I which o ) , is an anhydride, probably acts as an E group to activate the DRISO resulting in oxidation via pathway A. This oxidation method like DMSO-Ac20, will probably be capable of oxidizing some carbohydrates which remain inert to the Pfitzner-Moff a t t technique (7, 72). The formation of methylthiomethyl ether IV as a side product has been reported in this oxidation (73), which is consistent with oxidation via pathway A. Since there is a limited amount of data available (Table I), it is difficult to assess the utility of this method. zyxwvutsr VI. CHLOROFORMATE METHOD Another approach to the oxidation of alcohols involves conversion of the alcohol to the chloroformate XI1 which will react with DRISO at room temperature or below in the presence of a base like triethylamine, to give the corresponding aldehyde or ketone (9). The chloroformate XI1 has two purposes in the reaction. It first acts as the E group to activate the DMSO giving salt XIII, and second as the source of the alcohol sub0 x: RICHOH + C1- e -C1 + n 8 -C1 zyxwvutsrqponmlkjihg XI1 0 zyxwvutsrqponmlkjihgfedcbaZ RSCH4- R ~ c H -I11 -o~(cH~), III Figure 2. (CzHd:N __t R-C-R+CH$CHI 1 I t) DIMETHYL SULFOX~DE OXIDATIOXS 253 zyxwvutsrq strate which by necessity is in near proximity to the activated DMSO. Intermediate XI11 collapses giving carbon dioxide and the dimethylalkoxysulfonium salt intermediate I11 which, in the presence of the base triethylamine, is converted, likely via ylid V, into the observed products. Addition of DMSO and triethylamine together to the chloroformate results in no carbonyl compound being formed, indicating an intermediate such as XIII. Data for this method are given in Table I. VII. OXIDATION OF HALIDES AND TOSYLATES I n the previous sections, DMSO oxidations involving pathway A were considered. The following discussion will consider oxidations proceeding by pathway B, i.e., formation of the dimethylalkoxysulfonium salt 111 by direct nucleophilic displacement of a leaving group by DMSO. Applications of this technique to a-halo esters (Br, C1, I) or acids (34), phenacyl halides (48, 59), benzyl halides (49, 68), primary sulfonates (49, 60, 68), primary iodides (37), and a limited number of secondary halides (35,67,92) and secondary tosylates (36,42, 83) have been successful in a preparative sense. Oxidation never proceeds past the carbonyl, and other functional groups remain generally inert. In contrast to nalkyl iodides and tosylates, chlorides and bromides are not oxidized in yields large enough to be of preparative significance, but these compounds may be converted in situ to the corresponding tosylate and oxidized without prior purification (49). In the oxidation of secondary sulfonates (36,42) and halides (36, 67) elimination becomes a competing (35, 36, 42, 67) and often the major reaction (65, 66), particularly when the reaction is carried out in the absence of a suitable base, e.g., collidine (42). I n cases where elimination is structurally prohibited, as with diphenylmethyl chloride, oxidation will occur in good yield (68). Factors affecting oxidation and elimination will be considered later. The oxidations are facilitated by adding halide or tosylate to an excess of DMSO with an acid acceptor present, usually sodium bicarbonate or collidine. The nonalkaline hydrogen bromide scavenger 1,2-epoxy-3phenoxypropane has also been employed (34). I n the absence of base many activated halides are capable of being oxidized but in lower yields (42) while secondary tosylates react in DMSO, in the absence of base, to form mainly olefins (65, 66). The reactions of DMSO with halides and tosylates are similar to those of tertiary amine oxides with alkyl halides since the salts formed are also capable of forming aldehydes and ketones in basic media (34). The role of the base is probably twofold. In reacting with HX formed during a halide oxidation the base decreases the possible side reactions shown in the following equations (34). CIlaSCH3 + BrCHzCR /I - 0 CHsSCHa + [(CH3)&CH2CR]Br- ii [(CH&CH2CR]Br- - (CH&S +Br- II 0 + CHaSCH2C-R II zyxwvutsrqponm 0 The second role of base is that of promoting proton abstraction in the actual oxidation step. It has been established that secondary alkyl tosylates are primarily oxidized via dimethylalkoxysulfonium salt intermediates like I11 and ylid V to the carbonyl compound in the same manner as was discussed in earlier sections (93). I n light of the above, and the fact that pathway A oxidations proceed from ylid V by means of an intramolecular hydrogen-transfer step to the final products, it is attractive to suggest the same route for halide oxidations. A direct proton abstraction pathway rather than ylid formation must be considered for situations where acid strengthening groups are CY to the halide, for example, a-halo ketones and esters. I n these cases it may be that both mechanisms are operative. The notable absence in the literature of any reports of the formation of the side product methylthiomethyl ether VI in pathway B oxidations (34-37, 42, 67) and their common occurrence in pathway A oxidations (1, 73, 77) have an important bearing on the mechanism of formation of VI. Two suggestions have been made to account for VI. One proposal involves rearrangement of dimethylalkoxysulfonium salt I11 to give VI directly (77). This proposal is inconsistent with the fact that VI has never been reported in pathway B oxidations. These pathway B, or displacement, oxidations have been shown to involve the same dimethylalkoxysulfonium intermediate I11 as the pathway A oxidations (93). Therefore the absence of methylthiomethyl ether VI in the pathway B oxidations can be taken as evidence against its formation proceeding from the common intermediate. The other proposal suggests the formation of sulfonium ylid XI, CH?S+CHa (1, 76), which can react nTith an alcohol substrate but not with a tosylate or halide to give VI, which is consistent with the observed data. A survey of the yields and temperatures necessary to effect oxidation of the analogous substrates from the data in Tables I1 and I11 indicates that in most cases the reactivity toward oxidation follows the order TsO- > I- > Br- > C1- which is in support of an initial S N process. ~ Considerable evidence favoring a S N DMSO ~ attack based upon steric considerations of reactivity toward steroid sulfonate esters has also been presented (42). Some substrates, for example, (CsH&CH-X (X = C1, OTs), certainly react by an initial SNI process (37). zyxwv zyxwvu zyxwvu (CHI),S=O zyxwvutsrqp + 2HX -P CHsSCH, + X1 + H20 zyxwvuts zyxwv 254 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA W. W. EPSTEIN AND F. W. SWEAT TABLE I1 DIMETHYL SULFOXIDE OXIDATION OF HALIDES Substrate Product(8) Method Yield, % Ref Methyl iodide Heptyl chloridea Heptyl bromide" Heptyl iodide0 Octyl iodide Dodecyl iodide 2-Iodooctane 1-Iodo-7-octene 1-Iodo-7-octyne p-Bromobenzyl bromide" p-Methylbenzyl bromides p-Methylbenzyl bromide p-Xitrobenzyl bromidea p-Nitrobenzyl bromide Benzyl chloride Diphenylchloromethane 6-Iodohexan-1-01 8-Iodo-2-octanone Phenacyl bromide p-Bromophenacyl bromide p-Chlorophenacyl bromide p-Phenylphenacyl bromide a-Bromobenzylphenone Chloroacetic acid Ethyl bromoacetate Trimethylsulfoxonium iodide Heptanal HeptanaI Heptanal Octanal Dodecaldehyde 2-Octanone 7-Octenal 7-Octynal p-Bromobenzaldehyde p-Methylbenzaldehyde p-Me thylbenzaldehyde p-Nitrobenzaldehyde p-Xtrobenzaldehyde Benzaldehyde Benzophenone 6-H ydroxyhexanal 2-Octanon-8-a1 Phenylglyoxal p-Bromophenylglyoxal p-C hlorophenylglyoxal p-P henylphenylglyoxal Benzyl Glyoxylic acid Ethyl glyoxylate Iodoacetic acid hlethyl chloroacetate Ethyl chloroacetate Ethyl a-bromopropionate Diethyl bromomalonate 2a-Bromo-5a-cholestan-3-one Trichlorophosphine BCla Glyoxylic acid 34 Methyl glyoxylate 34 Ethyl glyoxylate 34 Ethyl pyruvate 34 Diethyl mesoxalate 34 60 2-0xo-3-hydroxy-5a-cholest-3-ene NaHC03 67 12 3-Oxo-5a-cholest-1-ene 2cu-Hydroxy-5a-cholestan-3-one 15 3-0xo-2-bromo-5a-cholest-l-ene NaHCOn 50 67 3p-Acetoxy-7-oxo-cholest-5-ene NaHCOa 73 35 Cholesta-3,5-dien-7-one 12 5a-Cholestan-3-one Collidine 55 42 5a-Cholest-2-ene 27 Methyl 3,4-dioxo-5p-cholanate 25 35 NaHCOs Methyl 3-ketochol-4-enate 28 3~-Acetoxy-6-hydroxycholest-5-en-7-one NaHCOa, Nz 55 35 dZ-l,2-Dibromo-l,2-bk(3-methyl-211 1,2-E~~y-363 quinoxaly1)ethane phenoxypropane dl-1,2-Diiodo-l,2-bis(3-methyl-220 63 1,2-Epo~y-3quinoxaly1)ethane phenoxypropane Benzoyl chloride 49 3,82 11 Benzoic acid 49 Berizenesulfonic acid 48 69 Benzenesulfonyl chloride 49 Triphenylphosphine oxide 82 Diphenylphosphonic acid 94 3,82 75 Phenylphosphoric acid 3,82 Diphenylphosphoric acid 48 3 Trimetaphosphimate 82 84 Cyanuric acid 3, 81, 82 Sulfur dioxide, 11 -92 Chloromethyl methyl sulfide Phosphoric acid 96 3 97 CHa--S--CH&l zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA 53 Sic14 ClB4 S102,chloromethyl methyl sulfide 2,2-Dibromo-5cu-cholestan-3-one 3p-Acetoxy-6p-bromo-5a-cholestan-7-one 3fl-Bromo-5cu-cholestane Methyl 4fl-bromo-3-keto-5,9-cholanate 7cu-Bromo-3~-acetoxy-5~-cholestan-6-one 2,3-Bk (bromomethy1)quinoxaline 2,3-Bis(iodomethyl)quinoxaline Benzoyl chloride Benzenesulfonyl chloride Triphenylphosphine Diphenylcholorophosphine Phenyldichlorophosphine Diphenylphosphorus oxychloride Hexachlorocylotriphosphazatriene Cyanuric chloride Thionyl chloride NaHCO: NaHCO: NaHCO, NazCOa Glyme MgO NaHCOa NaHCOa NaHCOg NaHCOa NaHC03 NaHCOa NaHCOa NaHCOa NaHCOs NaHCOa NaHCO3 71 74 70 74 44 32 83 70 76 65 63 76 48 58 44 62 25 71 84 69 85 95 1,2-Epoxy-3-phenoxypropane 70 51 49 49 49 37 37 37 37 37 49 49 68 49 zyx 45 68 66 37 37 48 48 48 48 48 34 34 I 100 53 zyxwvu zyxwvutsr zyxwvuts DIMETHYL SULFOXIDE OXIDATIONS zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPO 255 TABLE I1 (Continued) Product(a) Substrate NbCls Method Yield, % Ref NbOClr * PDMSO, Chloromethyl methyl sulfide NbOBra. SDMSO, Chloromethyl methyl sulfide TaOCla .2DMSO Chloromethyl methyl sulfide TaOBrs. 2DMSO Chloromethyl methyl sulfide MOOCla * 2DMSO Mo02C12.2DMSO VOClz * 3DMSO NbBrs TaC15 TaBr6 MOC& VCl, 22 22 22 22 33a 33a 33b Converted to tosylate with AgOTs. TABLE I11 DIMETHYL SULFOXIDE OXIDATION OF SULFONATES Produot(s) Substrate n-Propyl tosylate %-Pentyl tosylate n-Hexyl tosylate Octyl tosylate Neopentyl tosylate Oleyl tosylate Elaidyl tosylate 1,3-Diphenoxy-2-propyltosylate p-Methylbenzyl tosylate p-Bromobenzyl tosylate p-Nitrobenzyl tosylate 5a-Cholestan-3p-yl-tosylate 5-a-Cholestan-38-yl tosylate Cholesterol-38-yl tosylate Sa-Cholestan-76-yl tosylate 5a-Cholestan-3-p-yl met'hanesulfonate 5a-Cholestan-7p-yl met.hanesulfonate Methyl reserpate p-bromobenzenesulfonate Yohimbine-o-tosylate p-Yohimbine-o-tosylate Propionaldehyde Valeraldehyde Capraldehyde Octanal Starting material Oleyaldehyde Elaidaldehyde 1,3-Diphenoxy-2-propanone p-Methylbenzaldehyde p-Bromobenzaldehyde p-X'itrobenzaldehyde Sa-Cholestan-3-one A2-Cholestene 5a-C holest an-3 a-01 5a-Cholestan-3-one A2-Cholestene 5a-Cholestane-38-yl tosylate 5a-Cholestan-6-one Cholest-4-en-3-one A3p5-Cholestadienecholesterol Cholesterol 5a-Cholestan-7-one 5a-Cholestan-7-ene 5a-Cholestan-3-one 5a-Cholestan-2-ene 5~~Cholestan-7-one 5a-Cholestan-7-ene Methyl ketoreserpate Yohimbino ne Yohimbinone As was noted earlier, in the oxidation of secondary halides and tosylates, elimination usually predominates. There are a limited number of cases known where the oxidation could be of synthetic utility and these compounds are listed in Table 111. Several attempts have been made to differentiate the mechanisms leading to oxidation and elimination (35, 36, 42, 67). The proposal that a common intermediate (ie., the dimethylalkoxysulfonium salt) proceeds to ketone and olefin has been made (36); however, this is not completely consistent with other experimental results. It has been demonstrated that axial Method NaHCOp NaHCOs NaHCOs NaHCOn NaHC03 NaHCOs NaHCOl NaHCOs NaHC03 NaHCOa NaHCOa Collidine NaOAc NaOAc Collidine Collidine Collidine Triethylamine Tri-n-propylamine Tri-n-propylamine Yield, % 20 78 100 64 72 90 74 65 84 64 26 10 20 32 48 51 12 7 9 76 23 42 10 64 10 60 38 25 Ref 68 68 68 49 49 60 60 4 49 49 49 42 36 36 zy 42 42 42 83 2 2 halides or tosylates will give more elimination than the corresponding equatorial isomers (35, 42, 67). If S N ~ attack is assumed to be correct, an axial halide or tosylate would be displaced by DMSO and result in the formation of an equatorial dimethylalkoxysulfonium salt, which should undergo elimination less readily than the axial intermediate formed by S N reaction ~ of DRilSO with an equatorial halide or tosylate (35). It appears that elimination and oxidation does not involve the common dimethylalkoxysulfonium intermediate. It should also be noted that tosylate eliminations carried out in DRilSO do not appear to proceed by zyxwvut zyxwvut W. W. EPSTEIN AND F. W. SWEAT 256 a trans-diaxial mechanism (35). The data for halides are given in Table I1 and for sulfonates in Table 111. VIII. OXIDATION OF THIOLS Thiols (RSH, ArCH2SH, ArSH) can be oxidized to disulfides (R-S-S-R, etc.) by DMSO (96-99, 101) (see Table IV). Oxidation of 1,4-butane- and 1,3propanedithiol resulted in the formation of 1,3-dithianes (98). Success of the oxidation of dithiols depends on slow addition to an excess of DMSO to avoid polymerization. Despite this method an attempt to oxidize 1,Zethanedithiol resulted in polymer formation (98). Other sulfoxides have been used but DMSO and tetramethylene sulfoxide remain the most satisfactory in this oxidation (98). Reactivity depends upon the acidity of the thiol (ArSH > ArCHzSH > RCHzSH) (98). Aromatic thiols are oxidized spontaneously a t room temperatures (97), whereas higher temperatures are required for oxidation of aliphatic thiols (101). The mechanism proposed for this reaction (99) is analogous to that of the reaction of sulfoxides with hydrogen iodide (50, 52). Intermediate XIV is formed by nucleophilic attack a t the sulfur of the protonated sulfoxide. Attempts to isolate or detect the presence of this intermediate by nmr failed (99). Formation of intermediate XIV has been suggested as the ratelimiting step. Reaction of intermediate XIV with another molecule of thiol leads to the formation of disulfide XV. The last step (XIV --c XV) conceivably involves attack of thiol anion on intermediate XIV, in a manner similar to that predicted for the reaction of Iin the sulfoxide oxidation of hydrogen iodide (52). The previous mechanistic proposals have analogy in the reaction of trimethylsulfoxonium iodide XVI with thiols to form the corresponding methyl aryl sulfides XVII (100). + ArSH + HI zyxwvu (CHa)k3=0 [(CH3)aS--O]+IXVI [( CHa)aS-O] +%Ar ArSCHa XVII + (CHa)B=O A. DIAZONIUM METHOD Benzaldehydes have been obtained by diazotization of benzylamines in DMSO (86). Intermediate formation of a carbonium ion XVIII is a reasonable prediction (86). Reaction of this carbonium ion with DMSO would result in the formation of aldehyde presumably via the dimethylalkoxysulfonium salt XIX. HNOa p-R-CaHaCHz-NHz p-R-CsH4CHz’ XVIII zyxwvutsr zyxwvutsr zyxwvutsr + R-SH e R S - XVIII + (CHa)zS=O (CHa)zS-S-R XIV G R-SS-R xv + DMS + HzO + ~ - R - C ~ H ~ - C H Z - - O S (CHa)i XIX + XIX +(CH3)2bHs I + R-SH + [(CHa)sS-O]+&Ar IX. MISCELLANEOUS OXIDATIONS + p-R-CeHa-CHO + CHaSCHa B. OXIDATION OF SULFIDES OH XIV + The aliphatic sulfides, di-n-propyl and di-n-butyl sulfides, have been shown to undergo oxygen exchange with DMSO forming di-n-propyl and di-n-butyl sulfoxides in yields of 59 and 55%, respectively (87). Al- TABLE IV DIMETHYL SULFOXIDE OXIDATION OF THIOLS Substrate Product (a) Yield, % ’ Ref 1-Butanethiol 1-Dodecanethiol 1-Hexadecanethiol 1-Octadecanethiol 1,3-Propanedithiol 1,4-Butanedithiol 2-Mercaptoacetic acid 3-Mercaptopropionic acid 2-Diethylaminoethanethiol hydrochloride a-Toluenethiol p-Chloro-a-toluenethiol p-Bromo-a-toluenethiol Beneenethiol p-Chlorobenzenethiol o- Aminobenzenethiol p-Methylbenzenethiol o-Methylbenzenethiol Pentachlorobenzenethiol ZNaphthalenethiol Di-n-butyl disulfide Di-n-do de cane disulfide Di-n-hexadecane disulfide Di-n-octadecane disulfide l12-Dithiacyclopentane 1 2-Dithiacy clohexane Dithiodiglycolic acid 3,3’-Dithiodipropionic acid 2,2’-Diethylamine diethyl disuliide hydrochloride Dibenzyl disulfide Di-p-chlorobenzyl disulfide Di-p-bromobenzyl disulfide Diphenyl disulfide Di-p-chlorophenyl disulfide Di-o-aminophenyl disulfide Di-p-methylphenyl disulfide Di-o-methylphenyl disulfide Dipentachlorophenyl disulfide Di-2-naphtha1 disulfide 86 72 84 72 70 89 92 93.8 91.4 96 97,98,101 97,98 98 98 98 96 96 96 96.5 96.8 95 94.5 96.5 80 70 96-98,101 96 96 96,97 96-98 96 96 99 96 98 zyxwvutsrq 80 98 DIMETHYL SULFOXIDE OXIDATIOKS zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONM 257 TABLE V MISCELLANEOUS OXIDATIONS WITH DIMETHYL SULFOXIDE Substrate Yield, % zyxw zyxwvutsr zyxwvutsrqpo Product(s) Method Benzylamine p-Methylbenz ylamine p-Methoxybenzylamine Di-t-butyl sulfide Di-n-propyl sulfide Di-n-butyl sulfide Diphenylketene-N-p-tolylimine Diphenylketene-N-p-tolylimine Benzaldehyde p-Methylbenzaldehyde p-Methoxybenzaldehyde Di-t-butyl sulfoxide Di-n-propyl sulfoxide Di-n-butyl sulfoxide N-(p-Tolyl)-a-hydroxydiphenylacetamide N-(p-Tolyl)-a-methoxydiphenylacetamide Diphenylketene-N-p-tolylimine Diphenylketene 1,l-Diphenylsila-2-cyclohexanol 2,5-Dimethyl-o-quinol acetate 2,3,5-Trimethyl-o-quinol acetate 2,3,5,6-Tetramethyl-o-quinolacetate Methyl 9,1O-epoxy-(cis or trans)octadecanoate Cyclohexene oxide Cyclohexene oxide 2p, 3p-Epoxy-5a-cholestane N-(p-Tolyl)-diphenylacetamide Benzilic acid l,l-Diphenylsila-2-cyclohexanone 3-Hydroxy-4-methylbenzaldehyde 2-Hydroxy-3,4-dimethylbenzaldehyde 3-Hydroxy-2,4,5-trimethylbenzaldehyde Methyl 9-hydroxy-10-keto octadecanoate, or -10-hydroxy-9-keto2-Hydroxy cy clohexanone 2-hydroxy cyclohexanone 3p-Hydroxy-5a-cholestan-3-one 5a-Cholestane-2,3-dione 5a-Cholestane-2p,3a-diol 3p-Hydroxy-5a-cholestan-2-one 5a-Cholestane-2,3-dione 5a-Cholestane-2p,3au-diol Phenacyl alcohol Phenacyl alcohol 1-Hydroxy-2-octanone Methyldiphenylsilanol Bis(methyldipheny1)siloxane Bz03 Na2O KzO Styrene oxide Styrene oxide 1,2-Epoxyoctane Methyldiphen ylsilane Diborane Sodium Potassium though this method circumvents the formation of sulfones in the preparation of sulfoxides from sulfides, a more recent technique utilizing Gbutyl hypochlorite will surpass this method for laboratory preparation of sulfoxides (88). C. OXIDATIOX O F KETENES AND RELATED COMPOUNDS Nitrous acid Nitrous acid Nitrous acid Aqueous acid Methanol Aqueous acid Anhydrous acid Aqueous acid DCC NaHCOa KaHCOa NaHC03 BFa BF3, dioxane BF3 0 2 0 2 82 60 65 59 55 91.5 70 66 88 io 58 48 45 65 76 65 55 11 10 45 19 19 57 92 72 Ref 86 86 86 87 87 87 57 57 57 57 12 56 56 56 13 21 95a 21 21 21 95a 95a 74 61 71 71 between these reactions and the initial acid-catalyzed reaction of DMSO with DCC. D. AIR OXIDATION O F ALCOHOLS A variety of benzyl alcohols have been successfully oxidized by refluxing in DMSO while passing a stream of air through the reaction mixture (95). In the absence of air the reaction failed. Dimethyl sulfide was obtained in 60-65% yield along with the aldehyde, establishing DMSO as the oxidant. A free-radical mechanism is indicated from the fact that oxidation proceeds, though in lower yield, in the presence of tbutyl peroxide (0.001 M ) under oxygen-free conditions. Benzylic and tertiary alcohols undergo elimination by refluxing in DMSO under a nitrogen atmosphere (94). Some evidence indicates that these dehydrations involve intermediate formation of a carbonium ion. Although the oxidation mechanism remains obscure, a carbonium ion intermediate is possible. This is congruent with the general increased yields observed with p-nitro- and p-chloro-substituted benzylic alcohols (95). zy zyxwvutsrqpo Oxidation of keteneimine (XXb) and a ketene (XXa) by DMSO has been demonstrated (57) to occur as indicated, but the generality of this reaction is not yet known. Acid catalysis is required. The following mechanism has been proposed to account for the observed products (57). There is an obvious similarity H' + (CeH&C&=X ( C ~ H ~ ) Z C = C = ~ H(CHa)zS=O XXa, X = 0 ( C~HE,)&=C-XH XXb, X = N-CeH4-p-CHa I O-S(CHa)z (CaHs)zC=C-XH d-$( + ROH + CH3)2 zyxwvuts (CeHs)zC-c-XH Rd 8 + H + + CHsSCH3 zy zyxwvutsr zyxwvutsrqpo 258 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA W. W. EPSTEIN AND F. W. SWEAT E. dehydes by DMSO and a base, e.g., NaHC03 (55,56). The reaction appears to be general for these compounds and is selective for oxidation of alkyl groups in the three position with respect to the phenol hydroxyl group. Other alkyl substituents remain inert. Quinol acetates XXVIII are readily prepared from the proper substituted phenol by reaction with lead tetraacetate. The proposed mechanism for these oxidations is (56) OXIDATION OF INORGANIC HALIDES While most inorganic halides form coordination compounds with DMSO (23), several halides have been shown to undergo oxidation (3,22,53,54,80,82). Other sulfoxides also form complexes which are generally more stable than those of DMSO. Stability of the DMSO metal complex is somewhat dependent on the polarizability of the metal halogen bond and in the case where the bond is highly polarizable, a 1,3 shift of a halogen is predicted (3, 53). (CH3)254 + M(X)n O=hl(X),z XXII + [(CHa)2S-O-R~(X),-~ItXXXI + [(CHa)zSf - X]XXXIII CHZSCHX XXIV + xxw + HX Oxidation is proposed to proceed by S N attack ~ by oxygen of DMSO a t the electron-deficient metal, resulting in formation of intermediate XXI (53). XXI can decompose by a l,&halide shift forming the reaction products X X I I and XXIV. The 1,3 shift QH QH leading to formation of intermediate XXIII is supported by the fact that when X = Br- the more stable [(CH&SBr]+Br- is isolatable (22). An ylid intermediate and intramolecular halide shift would also exIf the carbon attached to the aromatic ring is secondary plain the formation of the chloromethyl methyl sulfide XXIX, a ketone is formed, XXX, although in lower XXIV (3). The oxidation of sulfuryl chloride to sulyield. A tertiary carbon substituted at the 3 position fur dioxide by a sulfoxide seems to support such a (XXXI) will be oxidized to an alcohol. postulate, and a mechanism to account for the observed reaction products has been proposed (11). zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA 0 /I p-CHaOCsHd3-CHa + SOC12 zyxwvuts e- CH3 0 XXM XXX zyxwvutsrqponmlkjihgfed [p-CH~OCsH4~~~-CI]ClXXV c1 XXV + [p-CH30CsH4-+CH3]+C1- - HC1 + SO2-+ c1 XXXI G. XXVI Chloromethyl p-methoxyphenyl sulfide (XXVII) is recovered, and no sulfide is found with chloro substitution on the activated aromatic ring. This product could result from the ylid intermediate XXVI (3). These oxidations are not limited to the replacement of one halogen as is evident from the list of reactions. The great utility of these reactions is not in the resultant metal, but in the synthesis of monohalogenat,ed sulfides. F. OXIDATION O F QUINOL ACETATES Quinol acetates XXVIII have been shown to be selectively oxidized to substituted m-hydroxybenzal- OXIDATIVE HALOGENATION Sulfoxides in general will oxidize hydrogen bromide and hydrogen iodide via an acid-catalyzed reaction to give Br2 and Iz,respectively (46,52). (CHs)zS=O + HX + CHaS-CH3 + Xa + HZ0 Therefore DMSO in the presence of hydrogen halides is capable of effecting halogenations (31). This technique afforded a superior method for bromination of 2-aminofluorenone (-11) to 2-amino-3-bromofluorenone (XXXIII) (27). I n the presence of ethyl bromide and DMSO, phenol reacted to give a mixture of brominated phenols, ethyl ether, ethyl phenyl ether, and unreacted phenol (S9). When a primary or secondary alkyl or benzyl halide, instead of hydrogen halide, is used as a bromine source, both bromination zyxwvut zyxwvutsrq = wBr zyx zy zyxwvuts zyxwvutsrqp DIMETHYL SULFOXIDE OXIDATIONS 259 not consumed during the reaction and DMS is formed and N-alkylation take place in the presence of an amine (26, 2 8 ) . Use of t-butyl bromide results in amine broestablishing DMSO as the oxidant (95a). The reacmination only. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA tion does not occur when air is absent but if t-butyl hydroperoxide is present the reaction proceeds but in lower yield indicating the likelihood of a free radical rather than ionic mechanism (8). 0 NH, 0 ‘NH, X. REFERENCES xxxm XXXII The bromination of 4a-methyl-l,3,9-triphenyl-4aHfluorene (XXXIV) was carried out with DMSO and ethyl bromide ( 6 2 ) . Chlorinations of this same compound (XXXIV) were effected with thionyl chloride or phosphorus oxychloride with the oxidant DMSO in yields of ca. 90% ( 6 2 ) . XXXIV zyxwvutsrqpo zyxwv X- C1, Br Previous proposals of intermediates in the reaction of DMSO with phosphorus oxychloride, thionyl chloride, 12, and Br2 (11, 30, 62) implicates XXXV as the reactive intermediate effecting these halogenations. + [( CHa)&-XlX - XXXV, X = C1-, Br-, I- There does not appear to be any greater degree of selectivity in this method of halogenation than that observed in direct halide addition. It should be mentioned, however, that the use of DMSO and alkyl bromides, and presumably iodides, results in a near-neutral media for halogenations. H. (1) Albright, J. D., and Goldman, L., J. Am. Chem. SOC.,87, 4214 (1965). (2) Albright, J. D., and Goldman, L., J. Org. Chem., 30, 1107 (1965). ( 3 ) Amonoo-Neiaer, E. H., Ray, S. K., Shaw, R. A., and Smith, B. C., J. Chem. SOC.,6250 (1965). (4) Baker, R.I. M., J . Org. Chem., 25, 670 (1960). (5) Baker, B. R., and Buss, D. H., J. Org. Chem., 30, 2308 (1965). (6) Baker, B. R., and Buss, D. €I., J. Org. Chem., 31, 217 (1966). (7) Baker, B. R., and Buss, D. H., J. Org. Chem., 30, 2304 (1965). ( 8 ) Barnard, D., Bateman, L., Cole, E. R., and Cunneen, J. I., Chem. Znd. (London), 918 (1958). (9) Barton, D. H. R., Gardner, B. J., and Wightman, R. H., J. Chem. SOC.,1855 (1964). (10) Block, L. H., Drug Cosmetic Znd., 95, 342 (1964). (11) Bordwell, F. G., and Pitt, B. M., J. Am. Chem. SOC.,77, 572 (1955). (12) Brook, A. G., and Pierce, J. B., J . Org. Chem., 30, 2566 (1965). (13) Brousse, E., and Lefort, AI. I).,Compt. Rend., 261, 1990 (1965). (14) Brown, K. S., and Iljerassi, C., J. Am. Chem. SOC.,86, 2453 (1964). (15) Buchi, G., Coffen, D. L., Kocsis, K., Sonnet, P. E., and Ziegler, F. E., J . Am. Chem. SOL, 87, 2073 (1965). (16) Buckley, A,, J. Chem. Educ., 42, 674 (1965). (17) Busch, &Blume, I., G., and Pungs, E., J. Prakt. Chem., 79, 513 (1.309); Chem. Abstr., 4, 898 (1910). (17a) Chem. Eng. News, 35, 87 (March 4, 1957). (18) Chem. Eng. News, 43, 62 (Sept 13, 1965). (19) Chem. Eng. News, 44, 48 (April 11, 1966). (20) Cilento, G., Chem. Rev., 60, 147 (1960). (21) Cohen, T., and Tsuji, T., J . Org. Chem., 26, 1681 (1961). (22) Copley, D. B., Fairbrother, F., Grundy, K. H., and Thompson, A., J . Less-Co?izmonJlelals, 6 , 407 (1964). (23) “DMSO: Reaction Medium and Reactant,” CrownZellerbach Corp., Camus, Wash., June 1962. (24) Dyer, J. R., McGonigal, W. E., and Rice, I<. C., J . Am. Chem. SOC.,87, 654 (1965). (25) Fenslau, A. H., and Moflatt, J. G., J. Am. Chem. SOC.,88, 1762 (1966). (26) Fletcher, T. L., and Pan, I L L . , J. Am. Chem. Soc., 78, 4812 (1956). (27) Fletcher, T. L., Namkung, hl. J., and Pan, H.-L., Chem. Ind. (London), 660 (1987). (28) Fletcher, T. L., and Pan, H.-L., J . Org. Chem., 24, 141 (1959). (29) Hsu, F. P., Hua Hsueh Tung Pao, 654 (1965); Chem. Abstr., 62, 7626h (1965). (30) Gilman, H., “Organic Chemistry,” Vol. I, John Wiley and Sons, Inc., New York, N. Y., 1943, p 872. (31) Gilman, H., and Eisch, J., J. Am. Chem. SOC.,77, 3862 (1955). (32) Henseke, G., and Hanisch, G., Sngew. Chem. Intern. Ed. Engl., 2, 324 (1963). OXIDATION O F E P O X I D E S Epoxides can be oxidized by DMSO in two different fashions. I n the presence of boron trifluoride etherate and DAIS0 epoxides are converted into a-hydroxy ketones (13, 21). Results of a limited number of studies indicate that a mixture of two possible products will be obtained and the predominant compound will depend upon the relative steric hindrance to attack by DMSO. In spite of the fact that boron trifluoride will react with epoxides in the absence of DJISO, it seems likely that the DMSO is activated by the boron trifluoride, acting as an E group. Boron trifluoride is known to form a 1 : l complex with DMSO (54, 58). If the above is true, the reaction would fit into a pathway A classification. The second method of oxidation required a stream of air to be bubbled through a solution of the epoxide in DMSO (95a). I n a limited number of cases good yields have been obtained by this means. Oxygen is zyxwvutsrq zyxw 260 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA W. W. EPSTEIN AND F. W. SWEAT (33) Horner, L., and Kaiser, P., Ann., 626, 19 (1959). (33a) Horner, S. M., and Tyree, S. Y., Znorg. Chem., 1, 122 (1962). (33b) Horner, S. M., Tyree, S. Y., and Veneaky, D. L., Znorg. Chem., 1, 844 (1962). (34) Hunsberger, I. M., and Tien, J. M., Chem. Znd. (London), 88 (1959). (35) Iacona, R. N., Rowland, A. T., and Nace, H. R., J . Org. Chem., 29, 3495 (1964). (36) Jarreau, F. X., Tchoubar, hl. B., and Goutarel, R., Bull. SOC.Chim. France, 887 (1962). (37) Johnson, A. P., and Pelter, A., J . Chem. Soc., 520 (1964). (38) Johnson, C. R., J . Am. Chem. SOC.,85, 1020 (1963). (39) Johnson, C. R., and Phillips, W. G., Abstracts, 149th National Meeting of the American Chemical Society, Detroit, Mich., April 1965, p 46P. (40) Johnson, C. R., and Phillips, W. G., Tetrahedron Letters, No. 25, 2101 (1965). (41) Johnson, C. R., and Sapp. J. B., Abstracts, 145th Sational Meeting of the American Chemical Society, New York, N. Y., Sept 1963, p 23Q. (42) Jones, D. N., and Saeed, M.A., J . Chem. Soc., 4657 (1963). (43) Jones, J. B., and Wigfield, D. C., Tetrahedron Letters, No. 46,4103 (1965). (44) Kenney, W. J., Walsh, J. A., and Davenport, D. A., J . Am. Chem. SOC.,83, 4019 (1961). (45) Kharasch, N., and Thyagarajan, B. S., Quart. Rev. Sulfur Chem., 1, 16 (1966). (46) Kharasch, N., Ed., “Organic Sulfur Compounds,” Pergamon Press, New York, N. Y., 1961, p 170. (47) Khorana, H. G., Chem. Rev., 53, 145 (1953). (48) Kornblum, N., Powers, J. W., Anderson, G. J., Jones, W. J., Larson, H. O., Levand, O., and Wearer, W. M., J. Am. Chem. SOC.,79, 6562 (1957). (49) Kornblum, N., Jones, W.J., and Anderson, G. J., J . Am. Chem. SOC.,81, 4113 (1939). (50) Krueger, J. H., Znorg. Chem 5 , 132 (1966). (51) Kuhn, R., and Trischmann, €I., Ann., 611, 117 (1958). (52) Landini, D., and Montannri, F., Tetrahedron Letters, No. 38, 2691 (1964). (53) Lappert, M. F., and Smith, J. K., J. Chem. SOC.,3224 (1961). (54) Lappert, M. F., and Smith, J. K., J . Chem. Soc., 7102 (1965). (54a) Leake, C. D., Nature, 152, 1646 (1966). (55) Leitich, J., and Wessely, F., Monatsh, 93, 566 (1962). (56) Leitich, J., and Wessely, F., Monatsh, 95, 129 (1964). (57) Lillien, I., J. Org. Chem., 29, 1631 (1964). (58) Lindquist, I., “Inorganic Adduct Molecules of 0x0Compounds,” Academic Press Inc., New York, N. Y., 1963, p 72. (59) Major, R. T., and Hess, H. J., J. Org. Chem., 23, 1563 (1958). (60) Mahadevan, T’., J. Am. Oil Chemists’ SOC.,41 (7), 520 (1964). (61) RIcAchran, G. E., and Shore, S. G., Znorg. Chem., 4 125 (1965). (62) Moore, H. W., and Snyder, H. R., J . Org. Chem., 29, 97 (1964). (63) Rloriconi, E. J., and Fritsch, A. J., J . Org. Chem., 30, 1542 (1965). (64) Moss, G. P., Reese, C. B., Schofield, K., Shapiro, R., and Todd, L., J. Chem. SOC.,1149 (1963). (65) Nace, H. R., Chem. Znd. (London), 1629 (1958). (66) Nace, H. R., J. Am. Chem. SOC.,81, 5428 (1959). (67) Nace, H. R., and Iacona, R. N., J . Org. Chem., 29, 3498 (1964). (68) Nace, H. R., and Monagle, J. J., J . Org. Chem., 24, 1792 (1959); U. S. Patent, 2,888,488 (1959). (69) Leonard, N. J., and Johnson, C. R., J . Am. Chem. SOC., 84, 3701 (1962). (70) Oae, S., Kitao, T., Kawamura, S., and Kitaoka, Y., Tetrahedron, 19, 817 (1963). (71) O’Connor, D. E., and Lyness, W. I., J . Org. Chem., 30, 1620 (1965). (72) Onodera, K., Hirano, S., and Kashimura, N., J. Am. Chem. SOC.,87, 4651 (1965). (73) Onodera, K., Hirano, S., Kashimura, N., Masuda, F., Yajima, T., and Miyazaki, N., J. Org. Chem., 31, 1291 (1966). (74) Ouellette, R. J., and Marks, D. L., Tetrahedron Letters, No. 46,3449 (1964). (74a) Parham, W. E., and Groen, S. H., J . Org. Chem., 30, 728 (1965). (75) Pfitzner, K. E., and Moffatt, J. G., J . Am. Chem. SOC.,85, 3027 (1963). (76) Pfitzner, K. E., and Moffatt, J. G., J . Am. Chem. SOC.,87, 5661 (1965). (77) Pfitzner, K. E., and Moffatt, J. G., J . Am. Chem. SOC.,87, 5670 (1965). (78) Price, C. C., Chem. Eng. News, 42, 58 (Nov 30, 1964). (79) Pummer, R., Ber., 43, 1401 (1910). (80) Ratz, R., and Sweeting, 0. J., J . Org. Chem., 28, 1612 (1963). (81) Ratz, R., and Sweeting, 0. J., Tetrahedron Letters, NO.8, 529 (1963). (82) Ray, S. K., Shaw, R. A,, and Smith, B. C., Nature, 196, 372 (1962). (83) Robinson, M. hl., Pierson, W. G., Lucas, R. A., Hsu, I., and Dziemian, R. L., J . Org. Chem., 28, 768 (1963). (84) Ryohei, O., Kagaku, 20 (2), 122 (1965). (85) Saizew, A., Ann. Physik, 139, 354 (1866). (86) Scheit, K. €I., and Kampe, W., Angew. Chem. Intern. Ed. Engl., 4, No. 9, 787 (1965). (87) Searles, S., andHays, H. R., J . Org. Chem., 23,2028(1958). ( 8 8 ) Skell, P. S., and Epstein, M.F., Abstracts, 147th National Meeting of the American Chemical Society, Philadelphia, Pa., April 1964, p 26N. (89) Smith, X, Moffatt, J. G., and Khorana, H. G., J . Am. Chem. SOC.,80, 6204 (1958). (90) Smith, S. G., and Winstein, S., Tetrahedron, 3, 317 (1958). (91) Sowa, W., and Thomas, G. H. S., Can. J . Chem., 44, 836 (1966). (92) Srivastava, H. C., Chem. Znd. (London), 159 (1959). (93) Sweat, F. W., and Epstein, W. W., unpublished observations. (94) Traynelis, V. J., Hergenrother, W. L., and in part with Hanson, H. T., and Valicenti, J. A., J . Org. Chem., 29, 123 (1964). (95) Traynelis, V. J., and Hergenrother, W. L., J . Am. Chem. zyxwvutsrq Soc., 86, 298 (1964). (95a) Tsuji, T., Tetrahedron Letters, 2413 (1966). (96) Yiannois, C. N., and Karabinos, J. V., J . Org. Chem., 28, 3246 (1963). (97) Wallace, T. J., Chem. Znd. (London), 501 (1964). (98) Wallace, T. J., J. Am. Chem. SOC.,86, 2018 (1964). (99) Wallace, T. J., and Mahon, J. J., J . Am. Chem. SOC.,86, 4099 (1964). (100) Wallace, T. J., and Mahon, J. J., Chem. Ind. (London), 765 (1965). (101) Wallace, T. J., and Mahon, J. J., J . Org. Chem., 30, 1502 (1965). (102) Winstein, S., Darwish, D., and Holness, N. J., J . Am. Chem. SOC.,78, 2915 (1956). zyxwvuts zyxwvuts zyxwvu ~ zyxwvuts zyxwvuts