Stereochemical aspects of the Pummerer reaction. Regioselectivity as a criterion for the differentiation of ylide and E2 pathways in the product-determining step of the reactions of

benzyl methyl halo- and oxysulfonium cations

Received December 1 I , 1978

SAUL WOLFE and PETER MICHAEL KAZMAIER. Can. J. Chem. 57,2388 (1979). +

The conversion of p-Y-C6H4CHZS(X)CH3 (X = C1, OCH,, OCOCH,, OCOCHCI,, OCOCF,) to a regioisomeric mixture of p-Y-C6H4CHXSCH3 and p-Y-C6H4CH,SCH2X has been studied as a function of X, Y, and deuteration in the benzyl and methyl positions. The conclusion is reached that, when X is acyloxy, the transformation of the sulfoniurn cation to an a-thiocarbonium ion and thence to the products proceeds via an E2 pathway. Trifluoroacetic anhydride is a much more reactive reagent than acetic anhydride for Purnmerer reactions of benzyl methyl sulfoxides. However, with other sulfoxides, this reagent is not as effective as acetic anhydride. Acetyl trifluoroacetate is not effective as a Purnrnerer reagent.

SAUL WOLFE et PETER MICHAEL KAZMAIER. Can. J. Chern. 57,2388 (1979). On a Ctudie I'influence de X et Y ainsi que de la deuttration des positions benzyle et methyle

1

sur la conversion de p-Y-C,H,CH,S(X)CH, (X = C1, OCH,, OCOCH,, OCOCHC12, OCOCF,) des mtlanges regio-isorneres de p-Y-C6H4CHXSCH3 et p-Y-C6H4CH2SCH2X. On arrive a la conclusion que si X est un acyloxy, la transformation du cation sulfonium en un ion a-thiocarbonium, et donc en produit, s'effectue par une rtaction E2. L'anhydride tri- fluoroacetique est beaucoup plus rtactif que I'anhydride acttique pour les reactions de Pummerer des sulfoxydes de methyle benzyle. Toutefois avec d'autres sulfoxydes ce rtactif n'est pas aussi efficace que I'anhydride acetique. Le trifluoroacetate d'acttyle n'est pas efficace comme reactif de Pummerer.

[Traduit par le journal]

The Pummerer reaction, e.g., 1 -, 2 (I), is an internal redox process, in which tetravalent sulfur (1, X = halogen, alkoxy, acyloxy) is reduced, and the adjacent carbon atom is oxidized. A vinylogous Pummerer reaction is also known (2). The sulfonium cation substrates 1 are prepared by halogenation of sulfides, or by alkylation or acylation of sulfoxides. In the Pummerer reactions of alkoxysulfonium salts (3), alkylation and redox can be performed in separate steps; however, when X is halogen (4) or acyloxy (9, the intermediate sulfonium cation is not isolable, and its intervention has to be inferred by indirect means.

There is extensive evidence (1) that the conversion of 1 to 2 proceeds via the cc-thiocarbonium ion 3, and that intermolecular capture of this carbonium ion by X- occurs, except in a few special cases (6,7). One of these (6) is the transformation of benzyl-2- carboxyphenyl sulfoxide (4) to 2-benzyl-1,3-benz- oxathian-6-one (5), which occurs (6a) with partial

asymmetric induction in the formation of the C-0 bond of the product. This interesting result has a number of practical and mechanistic implications, which have prompted the investigations reported in this and the following three papers.

0 II

R,-CHAR.

0 3 4 5

Ab initio SCF-MO calculations (8) suggest that there is significant n-overlap between carbon and sulfur in an cc-thiocarbonium ion, leading to a rather high barrier to rotation about the C-S bond. There- fore, if it is assumed that the cc-thiocarbonium ion 6 is an intermediate in the conversion of 4 to 5, the observed transfer of chirality from sulfur to carbon can be understood in terms of a preferential removal of one of the diastereotopic methylene protons of 4 (or a sulfonium cation derived from 4), followed by C-0 bond formation prior to rotation about the C-S bond of 6. However, the direction and mag- nitude of such selectivity will depend upon the manner in which the elements of HX are eliminated

0008-4042I791182388-09$01 .OO/O @I979 National Research Council of CanadalConseil national de recherches du Canada

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

120.

117.

138.

77 o

n 11

/09/

14Fo

r pe

rson

al u

se o

nly.

WOLFE A N D KAZMAIER 2389

from the sulfonium cation to form the cr-thiocar- bonium ion.

If C-H bond-breaking precedes S-X bond- breaking, the reaction will proceed via a sulfonium ylide (1). On the other hand, when S-X bond- breaking precedes C-H bond-breaking, the reaction will proceed via a dication (9). Between these two extremes, an E2 process is operative. Each of these pathways has different stereochemical consequences.

In the case of a sulfonium cation such as 7, the Pummerer reaction can lead to two regioisomers, viz., 8 and 9, the regiochemistry being determined during the conversion of 7 to the mixture of cr-thio- carbonium ions 10 and 11. Interconversion of 10 and 11 prior to capture by X- seems unlikely, since rearrangement of the cr-thiocarbonium ion has not been observed even in the case of the substrate 12, which affords 13 as the sole Pummerer product (10).

The proportions of 10 and 11 and, therefore, of 8 and 9, that will be formed from an ylide precursor will depend upon the acidities of the benzyl and methyl protons. On the basis of the work of Johnson (3) and Wilson (4) and their collaborators, the relevant acidity here is the kinetic acidity. For example, no significant deuterium incorporation is observed when an alkoxysulfonium cation is re- arranged to an a-alkoxysulfide in deuteriomethanol. In addition, conversion of the methoxyvinylsulfon- ium cation 14 to the sulfide 15 proceeds with only 8.3% incorporation of deuterium. Since it is well established (11) that the kinetic acidities of benzyl protons adjacent to sulfur are much higher than those of methyl protons adjacent to sulfur, it can be expected that, when the Pummerer reaction of 7 proceeds via an ylide intermediate, the benzyl- substituted regioisomer 8 will predominate.

The same result is anticipated in the case of a dication mechanism. In this case, the regiochemistry of the deprotonation step is governed by the relative stabilities of a-thiobenzyl and cr-thiomethyl carbo- nium ions.

The specific objectives of the present paper are to examine the regiochemistry of Pummerer reactions of 7 as a function of the electrophile X, the presence of deuterium in the methyl and benzyl positions, and the presence ofpara-substituents in the benzene ring. As one result of this work, the relationship between the ratio 819 and the mechanism of HX loss from 7 would appear to have the form shown in Fig. 1. I t has also become clear that acyloxysulfonium cations having the general structure 7 undergo the Pummerer reaction via an E2 pathway.

Y l i d e E 2 E l i m i n a t i o n Continuum I l i c a t i a n Mechanism Mechanism

FIG. 1. Schematic representation of the ratio of regioisomers produced in the reaction 7 + 8 + 9, as a function of C-H and S-X bond-breaking in the product-determining transition state. The 'statistical distribution' of 0.4 is the ratio of the number of benzylic hydrogens to the total number of hydrogens adjacent to sulfur.

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

120.

117.

138.

77 o

n 11

/09/

14Fo

r pe

rson

al u

se o

nly.

2390 CAN. J . CHEM. VOL. 57. 1979

TABLE 1. Reactions of benzyl methyl sulfide, benzyl methyl sulfoxide, and benzyl methyl methoxysulfonium fluoroborate with various electrophiles

Pummerer Yield Temp. Entry Substrate reagent (%) ("C) Solvent Product ratio Ref.

I 1 PhCH2SCH3 BF,- CH30Na4*b

I 67' 25 MeOH PhCHSCH, PhCH2SCH20CH3 3

+ 0 0 0

(1 00)

I I 3 PhCH2SCH3

I I I l I CH,COCCH,"sb 39' 130 Ac20 PhCHSCH, PhCH2SCH20Ac

(45) (55)

0

(53) (47)

OTFA

8 PhCHZSCH, S02C12'.b 86' 40 CH2C12 PhCHSCH, PhCH2SCH2CI 13 I

(100) (0) 'Present work. bProduct ratio was determined by 'Hrnr. <Isolated yields.

Results and Discussion substitution at the more substituted carbon atom

Table 1 summarizes the regioselectivity observed (cf eq. [I]). This result is incompatible with an in the reactions of benzyl sulfide, benzyl ylide pathway, in which the relative proportions of

methyl sulfoxide, and benzyl methoxysulfo- the regioisomers are controlled by the

nium fluoroborate under various Pummerer con- acidities of methyl and isopr0pyl (I5).

ditions. With the exception of entries 1 and 8, no regioselectivity is evident in these reactions. We believe that the benzyl regioselectivity observed in entry 1 constitutes evidence for an ylide pathway, especially in view of the alkaline reaction conditions employed in this case. However, in the case of the benzyl regioselectivity observed in entry 8, either an ylide or a dication pathway is possible. For example, Tuleen and Stephens (14) have found that the chlorination of unsymmetrical sulfides with sulfuryl chloride or N-chlorosuccinimide (NCS) leads to

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

120.

117.

138.

77 o

n 11

/09/

14Fo

r pe

rson

al u

se o

nly.

WOLFE A N D KAZMAIER

On the other hand, Kruse et al. (16) have reported that an ylide, assigned structure 16, can be charac- terized spectroscopically as an intermediate in the chlorination of 1,3-dithiane with sulfuryl chloride in chloroform solvent, and that this ylide rearranges to 2-chloro-1,3-dithiane (17) a t room temperature.

The assignment of structure 16 to this inter- mediate was based upon the appearance of a sharp singlet a t 6 6.90 in the 'Hmr spectrum, assigned to the C2 proton. However, if this assignment is correct, then the C2 proton of 16 is alnzost 5 p p m further downjield than the C2 proton of the 1,3- bissulfonium ylide 18, which appears a t 2.02 ppm (17). Chemical shifts near 2 ppm have also been observed for the C2 protons of a number of acyclic 1,3-bissulfonium fluoroborates (18) and tetraphenyl- borates (19).

The dithienium cation 19 (X = BF,-) has been described by Corey and Walinsky (20). Its 'Hmr spectrum (in CD,N02) shows the C2 proton at 11.10 ppm. This chemical shift is close to that (10.65) of the C2 proton of 17 in sulfur dioxide solvent at -50°C (21). According to Arai and Oki (21, 22), the nmr spectra of 17 and other a-chloro- sulfides are very dependent upon the temperature and the solvent, because of the occurrence of the ioniza- tion process 17 $ 19 (X = C1-). Since the C2 proton of 17 is found at 6.2 and 6.21 ppm in deu- teriochloroform and carbon disulfide, respectively, a permissive reinterpretation of the observations of Kruse et al. is that the chlorosulfonium cation 20 is converted, by loss of HCI, to 19 (X = C1-), and that the 6.90 chemical shift of the C2 proton reflects the position of the 17 $ 19 equilibrium in the presence of the small amounts of sulfur dioxide produced from the sulfuryl chloride reagent. A dication pathway would not be ruled out by this interpreta- tion. Likewise, a dication pathway is not ruled out by the observation (4) that the product isotope effects (kH/kD) for the chlorination and bromination of 2,2-d2-thiophane (21) are 5.1 and 3.6, respectively. Indeed, although their discussion differs somewhat from that given here, Wilson and Albert (4) consider that their bromination results are consistent with 'the El extreme transition state.'

Regardless of the precise interpretation to be given to the benzyl regioselectivity observed in entry 8 of Table 1, the lack of regioselectivity seen in entries

2-7 must be interpreted in terms of a mechanism in which neither an ylide nor a dication is an inter- mediate. I t seems reasonable to suppose that an E2 process is operative in these cases, especially since the stereochemical course of the alpha-halogenation of sulfoxides has already been found to be best inter- preted in terms of E2 elimination of HX from a halo- oxosulfonium cation (23) (eq. [2]).

I H I

q s ' O X

Table 2 shows the regioselectivities obtained in the Pummerer reactions of a series of deuterated benzyl methyl sulfoxides with trifluoroacetic anhydride (TFAA) in chloroform at 25°C. These results demonstrate that there is a significant hydrogen isotope effect in the product-determining step of the reaction. The magnitude of this effect (kH/kD) is calculated to be 4.0; this value is obtained by division of the 819 ratio of entry 5 by the 819 ratio of entry 1.

This result is consistent with the suggestion that the mechanistic change signalled by the lack of regioselectivity in the Pummerer reactions of the acyloxysulfonium and chloro- and bromosulfoxo- nium cations is a change to an E2 pathway. Such a conclusion is also supported by the observation that carbon-hydrogen bond-breaking occurs in the product-determining step of the reaction, and by the results of an examination of the effects of para-sub- stituents upon the regioselectivity of the reaction. These results are presented in Table 3, and were obtained under the same conditions as those of Table 2. The Hammett o-p plot for the effects of the para-substituents upon the regioselectivity of the reaction is shown in Fig. 2. This gives a p-value of 1.0.

For E2 reactions of the type shown in eq. [3], p values range from +2.07 to +3.77 as the leaving group Y is varied from iodide to trimethylammonium (25). The increase in p for the poorer leaving group

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

120.

117.

138.

77 o

n 11

/09/

14Fo

r pe

rson

al u

se o

nly.

CAN. J. CHEM. VOL. 57. 1979

TABLE 2. Effect of deuterium substitution upon the products of the reaction of trifluoroacetic anhydride with benzyl methyl s u l f o ~ i d e ~ ~ ~

% trifluoro- % trifluoro- acetoxybenzyl acetoxymethyl

Entry Substratec regioisomerd regioisomere 8 9

1 ~ i '

P~+S-CH] 5 3 47 H

6 P~+S-CD] 4' - 50' - 50f

D

'All experiments were performed in CDC13 at 25°C with 1 equiv. of trifluoroacetic anhydride and a sulfoxide concentration of 0.32 M.

bThe product deuterium isotope effect was estimated by dividing the 819 ratio of entry 5 by the 819 ratio of entry 1 to obtain a value of 4.0.

=See the Experimental for the syntheses of these compounds. *Determined by integration of the proton nmr spectrum; 'Hmr (CDC13) 6: 7.03 (IH, s, PhCHS), 2.13

(3H, s, SCH,). 'Determined by integration of the proton nmr spectrum; 'Hmr (CDC13) 6: 5.23 (ZH, s, S-CH,-0),

3.87 (2H, s, PhCH,S). JEstimated from the relative integrals of the phenyl peaks of the two regioisomers; 'Hmr (CDCI,) 6:

7.40 (5H, s, PICHS), 7.30 (5H, s, PhCH2S).

TABLE 3. Substituent effects upon the regioselectivity of the Pummerer reaction of aryl methyl sulfoxides with trifluoro-

acetic anhydride"

o Relative Relative Substituent valueb % of 8" % of 9" Log (819)

p-NO2 0.778 87 13 0.82 p-NOz 0.778 88 12 0.87 p-C1 0.227 61 39 0.19 p-CI 0.227 63 37 0.23 P-H 0.00 53 47 0.052 P-H 0.00 57 43 0.049 p-CH3 -0.170 34 66 -0.29

QReactions were performed at 2S°C in deuteriochloroform with 1 equiv. of trifluoroacetic anhydride, and a concentration of 0.32 M.

bThe u values were obtained from ref. 24. =Determined by integration of the IHmr spectra.

can be interpreted in terms of increased carbanionic character in the transition state. The application of these and other analogies to the elimination of tri- fluoroacetic acid from 7 (X = OTFA) leads to the expectation of a large positive p for an ylide mech- anism, a small positive or negative p for an E2 mechanism (depending upon the degree of C-H and S-X bond-breaking in the transition state), a

zero p for a cyclic cis-elimination mechanism (26), and a large negative p for a dication mechanism (27). The value 1.0 obtained in the present work appears to be consistent only with an E2 mechanism, with some carbanionic character in the transition state, and a very good leaving group.

Thus the interpretation of the results of Table 1 in terms of Fig. 1, the isotope effect studies of Table 2, and the para-substituent studies of Table 3, lead in each case to the conclusion that the Pummerer reactions of acyloxysulfonium cations proceed via an E2 pathway. The assumption that this E2 elimina- tion process takes an anti stereochemical course has interesting consequences, as will be seen in the following two papers.

The use of trifluoroacetic anhydride (TFAA) as a reagent for Pummerer reactions is a relatively recent development (28). As seen in Table 1, this permits the reaction to be ~erformed at much lower tem- peratures than is the case with acetic anhydride and, in the case of benzyl methyl sulfoxide as the sub- strate, the product is obtained in significantly higher yield. In a comparative study based upon the dis-

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

120.

117.

138.

77 o

n 11

/09/

14Fo

r pe

rson

al u

se o

nly.

WOLFE A N D KAZMAIER

a value

FIG. 2. Hammett plot showing the substituent effect upon the regioselectivity of the reaction of benzyl methyl sulfoxide with trifluoroacetic anhydride in chloroform at 25°C.

appearance of the sulfoxide, the reaction in acetic anhydride solvent was complete in 2 h at 130°C, while the reactions with dichloroacetic anhydride (1.4 equiv.) and TFAA (1.0 equiv.) were complete in 70 min and 5 min at 25OC, respectively. It was, therefore, of interest to examine the reactions of TFAA with other sulfoxides. These results and others taken from the literature are collected in Table 4.

Although the data are not extensive, the failures in the cases of thiophane sulfoxide and the phthali- midopenicillin sulfoxide are noteworthy. Since it is known that thiophane sulfoxides do react success- fully with acetic anhydride (30), we suggest that TFAA may succeed as a Pummerer reagent when relatively acidic ti-hydrogens are present, and when the a-thiocarbonium ion is sufficiently reactive for capture by the poorly nucleophilic trifluoroacetate anion. The rearrangement of the thiazolidine sulf-

u

oxide is reminiscent of the Morin rearrangement (31) of a penicillin sulfoxide to a A3-cephem; however, the Morin rearrangement itself fails when TFAA is substituted for acetic anhydride because of rapid cleavage of the p-lactam by the trifluoroacetic acid product.

The mixed anhydride acetyl trifluoroacetate (ATFA) was also examined as a reagent for the

OAc I

Ph-C-H

ATFA 22

Pummerer reaction. However, the reaction of this compound with benzyl methyl sulfoxide led only to the mixed acylal 22, identified by comparison with an authentic specimen prepared by the reaction of ATFA with benzaldehyde (32).

Experimental Genernl

Melting points were determined on Kofler hot-stage or Meltemp equipment, and are uncorrected. Refractive indices were measured on a Bausch and Lomb refractometer. The 'Hmr spectra were obtained on Varian T60, Varian EM360, Varian HA100, o r Bruker HXI6 spectrometers; 10% solutions were employed. The 13Cmr spectra were obtained on a Bruker HXl6 spectrometer, equipped with a BSV 3PM pulse unit and a BNC-12 computer. Tetramethylsilane (TMS) or sodium 2,2-dimethyl-2-silapentane-5-sulfonate (DSS) were employed as internal standards, as required. Mass spectra were obtained on JEOL JMS-OISC, Hitachi Perkin Elmer RMU-6E o r Dupont 21-491B mass spectrometers under electron impact conditions at 70 eV. Infrared spectra were recorded on either Perkin Elmer 180 or Acculab 6 instruments. Ultraviolet spectra were obtained on a Unicam SP800 spectrometer. Analyses are by Galbraith Laboratories, Knoxville, TN.

The 13Cmr spectra were assigned by correlations within series of compounds. In some instances, 'H-13C coupling was used to confirm these assignments. Column chromatography was performed with 60 mesh silica gel (Merck). Thin layer chromatography was performed on silica gel plates containing a fluorescent indicator. Spots were observed under ultraviolet light, or were visualized with ninhydrin, 10% phosphomolybdic acid in ethanol, ceric sulfate in ethanol, or iodine vapour. Solvents were routinely distilled before use and dried as required by standard procedures. Materials were of reagent grade purity obtained from commercial sources.

The substrates benzyl methyl sulfoxide, RSISR-benzyl-a-d methyl sulfoxide, RRISS-benzyl-a-d methyl sulfoxide, benzyl- a,a-dz methyl sulfoxide. p-nitrobenzyl methyl sulfoxide, p- methoxybenzyl methyl sulfoxide, p-methylbenzyl methyl sulfoxide benzyl phenyl sulfoxide, and thiophane-S-oxide were synthesized by standard procedures (33-36). Only the synthesis of p-methylbenzyl methyl sulfoxide, a new com- pound, is reported here. The penicillin sulfoxide was obtained from Mr. R. J. Bowers, whom we thank.

p-Mefhylbenzyl Mefhyl Sulfoxide Sodium mefn-periodate (6.52 g, 33.7 mmol) was suspended

in waterlmethanol (40 mL/10 mL). The solution was cooled to 0°C in a salt-ice bath and p-methylbenzyl methyl sulfide (5.12 g, 33.7 mmol) was added in one portion. After stirring at 0°C overnight, the reaction mixture was extracted with chloroform (5 x 20 mL) and the organic phase was dried (magnesium sulfate). After removal of the solvent, the syrupy product was chromatographed on silica gel (etherlmethylene chloride, then methanol) to yield a crystalline product (5.21 g, 92%), mp 66°C; 'Hmr (CDCI,) 6: 7.13 (4H, s), 4.10, 3.87 (2H, AB, 12), 2.40 (3H, s), 2.33 (3H, s); 13Cmr (CDCI,) 6: 138.0, 136.7, 129.9, 129.6 (phenyl), 59.9 (PhCHzSO), 37.2 (SOCH,), 21.1 (CH3); ir (KBr): 1025 (s, sulfoxide) cm-'; uv (water, 25°C) h,,, (log E): 231 (3.49).

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

120.

117.

138.

77 o

n 11

/09/

14Fo

r pe

rson

al u

se o

nly.

CAN. J. CHEM. VOL. 57. 1979

TABLE 4. The reaction of trifluoroacetic anhydride with various sulfoxides

Sulfoxide Temp. Yield

Solvent ("C) (%) Product(s) Ref.

OTFA TFAO

0 100" I I

PhCHSCH3b + PhCHzSCHz C

OTF A

0 100" I

PhCHSPhb C

.Yields were determined by 'Hrnr integration of crude reaction mixtures because the products were moisture-sensitive. These compounds were characterized on the basis of their spectral characteristics and by hydrolysis to benzaldehyde. CPresent work. dlsolated as a by-product in an arninosulfurane synthesis. <Isolated yields. JA complex mixture of products resulted in this case. T h e reaction led to loss of the p-lactam ring.

At~al. calcd. for CgHl20S: C 64.24, H 7.19; found: C 64.69, H 7.51.

Renction of Benzyl Metl~yl Methoxysrrlforziurr~ Fluor.oborate with Sodilrln Methoxide

In a dry box, carefully dried benzyl methyl sulfoxide (1.76 g, 11.4 mmol) in methylene chloride (5 mL) was added over a 5 min period to trimethyloxonium fluoroborate (2.35 g, 11.4 mmol). The reaction mixture was stirred for 1 h. Addition of ether afforded an oil, which crystallized upon standing in the refrigerator. After trituration of the crystals with ether, sodium methoxide in methanol (15.0 mL of 0.834 N) was added over a period of 5 min at 25°C. The reaction mixture was immediately evaporated to dryness, giving a milky oil. This was poured into brine (pH 7), to which a small portion of sodium carbonate had been added to raise the p H to 8.0. The mixture was extracted with ether (4 x 10 mL) and the com- bined extracts were dried over anhydrous sodium sulfate con- taining a small amount of sodium carbonate. Evaporation

Attempts to separate the two components by chromatography on Florisil were abandoned after some isomerization to a,a-dimethyl thiotoluene and UP-dimethoxytoluene was detected.

Renction of Benzyl Metlgvl Srrlfoxide with Acetic Atzlgvdride Benzyl methyl sulfoxide (0.0969 g, 0.629 mmol) was dis-

solved in acetic anhydride (10 mL) and the solution was heated to 130°C for 2 h. After cooling, the reaction mixture was poured into saturated potassium bicarbonate. The aqueous solution was extracted with chloroform (4 x 20mL). After drying (magnesium sulfate), and evaporation of the solvent, the product was isolated as a colourless syrup (48 mg, 39%). 'Hmr indicated formation of the two isomers (a-acetoxybenzyl methyl sulfide/a-acetoxymethyl benzyl sulfide) in the ratio 45/55. a-Acetoxybenzyl methyl sulfide: 'Hmr (CDC13) 6: 7.35 (5H, s), 6.95 ( IH, s), 2.10 (3H, s), 2.15 (3H, s).a-Acetoxymethyl benzyl sulfide: 'Hmr (CDCI,) 6 : 7.30 (5H, s), 5.05 (2H, s), 3.85 (2H, s), 2.03 (3H, s).

yielded a syrup (557 mg, 31%) consisting of a 2: 1 mixture of Reaction of Benzyl Metlzyl Sulfide lvith Suljirryl Ct~lor.ide a-methoxybenzyl methyl sulfide and benzyl methyl sulfide. Sulfuryl chloride (8.1 mL, 13.5 g, 0.1 mol) was added drop-

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

120.

117.

138.

77 o

n 11

/09/

14Fo

r pe

rson

al u

se o

nly.

WOLFE AND

wise (36 min) to a solution of benzyl methyl sulfide in meth- ylene chloride (20 mL). After the addition was complete, the solution was refluxed (1 h). Evaporation of the solvent and distillation (bp 102-106"C/12 Torr (lit. (13) bp 1 18-12l0C/14 Torr) yielded a colourless oil which rapidly turned orange (12.8 g, 86%); 'Hmr (CDCI,) 6 : 7.40 (5H, m), 6.07 ( lH, s), 2.32 (3H, s).

Reaction of Benzyl Metlryl Sulfoxide wit11 Diclrloroacetic Anlrydride

To benzyl methyl sulfoxide (90 mg, 0.6 mmol) in chloroform (0.5 mL) was added dichloroacetic anhydride (278 mg, 0.86 mmol). The reaction was followed by 'Hmr at room tempera- ture, and was complete in 70 min. There were two products, viz., cc-dichloroacetoxybenzyl methyl sulfide and benzyl a- dichloroacetoxymethyl sulfide in the ratio 53/47. cc-Dichloro- acetoxybenzyl methyl sulfide: 'Hmr (CDCI,) 6 : 7.45 (5H, s), 7.05 (1 H, s), 6.05 (IH, s), 2.18 (3H,s). Benzyl cc-dichloroacetoxy- methyl sulfide: 'Hmr (CDCI3) 6: 7.38 (5H,s), 5.95 ( lH , s), 5.23 (2H, s), 3.92 (2H, s).

Reaction of Betrzyl Metlryl Sirlfoxide ~vitlr Trifiioroacetic Atrlrydrirle

Benzyl methyl sulfoxide (25 mg, 0.16 mmol) was dissolved in carbon tetrachloride (0.5 mL) containing trifluoroacetic anhydride (0.16 mmol). After 5 min, a 'Hmr spectrum of the reaction mixture indicated that the starting material had disappeared and that a mixture of the two regioisomeric tri- fluoroacetoxybenzyl methyl sulfides had been produced. The ratio of the two regioisomers (methyl a-trifluoroacetoxybenzyl sulfide/benzyl cc-trifluoroacetoxymethyl sulfide) was 53/47. Methyl cc-trifluoroacetoxybenzyl sulfide: 'Hmr (CDCI,) 6 : 7.40 (5H, s), 7.03 ( lH , s), 2.13 (3H, s). Benzyl cc-trifluoro- acetoxymethyl sulfide: 'Hmr (CDCI-,) 6 : 7.30 (5H, s), 5.23 (2H, s), 3.87 (2H, s).

Get~eralProcerlu,e for. rlre Reaction of Derrteraterl Betrzyl Metlryl Sulfoxides wit11 Trifl~roroncetic Atrlryrlride

Trifluoroacetic anhydride (0.16 mmol) was added to benzyl methyl sulfoxide (0.16 mmol) in deuteriochloroform (0.5 mL) at ambient temperature. The 'Hmr spectrum was run immedi- ately and the proportions of the regioisomers were estimated from the peak integrals of undeuterated portions of the substrate. For benzyl methyl sulfoxide-d5, the relative propor- tions of the two regioisomers were estimated from the integrals of the two phenyl peaks.

Getreml Procerlrrre for tlre Reriction of p-Srrbstituterl Benzyl Merlryl Srrlfosides with Trifliroroacetic Anrlydride

Trifluoroacetic anhydride (0.16 mmol) was added to a solution of the sulfoxide (0.16 mmol) in deuteriochloroform (0.5 mL) and the 'Hmr spectrum was run. The proportions of the two regioisomers were estimated from the integrals of the methine proton (6 ca. 7.0) of the benzyl substituted regioisomer and the SCH,O methylene hydrogens (6 ca. 5.0) of the methyl substituted regioisomer.

Reaction of Berrzyl Plrerryl Srilfoxide )vitlr Trif~roroacetic Atrlrydride

Trifluoroacetic anhydride (0.3 mL, 2 mmol) was added to benzyl phenyl sulfoxide (40 mg, 0.19 mmol) in deuteriochloro- form (0.5 mL) and the 'Hmr spectrum was recorded immedi- ately. This indicated a quantitative yield of cc-trifluoroacetoxy- benzyl phenyl sulfide; 'Hmr (CDCI,) 6: 7.0-7.5 ( l l H , m). This product proved very hygroscopic and, on exposure to moist air, the odour of benzaldehyde was apparent. Addition of 2,4-dinitrophenylhydrazine produced benzaldehyde-2,4-dini- trophenylhydrazone. Recrystallization from ethyl acetate yielded red crystals (202 mg, 31%), mp 234-239°C (lit. (37) mp 237°C).

Reaction of Tl~iolarre-S-Oside ~vitlr Trif~ioronceric Anlryrl,.ide Thiolane-S-oxide (1.0 g, 9.6 mmol) was dissolved in carbon

tetrachloride (9.6 mL). The mixture was cooled to 4°C and trifluoroacetic anhydride (1.4 mL, 9.6 mmol) was added in one portion. Within seconds, the reaction mixture had separated into two layers, the upper layer consisting of a deep red oil. The product was not investigated further.

Reaction of N-Benzoyl-2,2-rlit~1etI1yI-4R-ttretlroxycarborryl-I,3- tlriazoliditre-S-oxide ~ ~ i t l r Trifluoroacetic Anl~ydride at 25°C arrd -30°C

Trifluoroacetic anhydride (0.3 mL, 2 mmol) was added to N-benzoyl-2,2-dimethyl-4R-methoxycarbonyl-l,3-thiazolidi11e- S-oxide (38) (24 mg, 0.081 mmol) in deuteriochloroform (0.5 mL). There was an immediate change in the 'Hmr spectrum and the sole product detectable by nmr was identified as N-benzoyl-2,3-dehydro-5-methoxycarbonyl-3-metl1yl-l,3-thia- zine by con~parison with an authentic sample (39); 'Hmr (CDCI-,) 6: 7.52-7.57 (SH, s), 5.97 ( lH, t, 3), 5.62 ( lH , s), 3.82 (3H, s), 3.50 (2H, d, 3), 1.67 (3H, s). Repetition of the reaction at -30°C gave identical results.

Renctiotr of Metl~yl N-Pl~tl~nlitnidopetricillit~ote-R-o& lvirh Trifluoroncetic Anhydride

Trifluoroacetic anhydride (0.10 mL, 0.71 mmol) was added in one portion to a solution of methyl N-phthalimidopenicil- linate-R-oxide (15.1 mg, 0.04 mmol) in deuteriochloroform (0.5 mL). After 1 min, the 'Hmr spectrum showed the absence of the p-lactam protons (6 4.0-6.0) and the reaction was not investigated further.

Acetyl Trifrroroocetate (40,41) Acetic anhydride (3.35 mL, 0.0355 mol) and trifluoroacetic

anhydride (5.00 mL, 0.0355 mol) were dissolved in carbon tetrachloride (10 mL). The reaction was stirred at ambient temperature for 48 h, and the infrared spectrum was monitored periodically. During this period, the 1760 cm-'/I820 cm-' peaks of acetic anhydride and the 1800 cm-'/1860cm-' peaks of trifluoroacetic anhydride were replaced by the 1780 cm-'/I850 cm-' peaks of acetyl trifluoroacetate. The yield was quantitative.

Reaction of Benzyl Metlryl Slrlfoxide ~vitlr Acetyl Trif~roro- acetate

Benzyl methyl sulfoxide (300 mg, 1.95 mmol) was dissolved in deuteriochloroform (2 mL). T o this was added, dropwise, acetyl trifluoroacetate (0.25 mL, 2 mmol), and the progress of the reaction was monitored by 'Hmr. The product of the reaction was a-acetoxy-cc-trifluoroacetoxytoluene; 'Hmr (CDCI,) 6: 7.73 (IH, s), 7.42 (5H, s), 2.15 (3H, s); ir: 1785 cm-'. Evaporation of the solvent below 20°C yielded a syrup (280 mg). 2,4-Dinitrophenylhydrazine (Brady's reagent) gave a positive aldehyde and ketone test, and the addition of semicarbazide hydrochloride and methanol (1 mL) followed by 10 drops of pyridine yielded the semicarbazone of benzal- dehyde (45 mg, 15%), mp 211-213°C (lit. (37) mp 217°C).

cc,cc-Diacetoxytolrrerre Benzaldehyde (14.3 g, 0.135 mol) and acetic anhydride

(28.6 g. 0.277 mol) were mixed under nitrogen and cooled in an ice bath. Concentrated sulfuric acid (0.2 mL) was then added dropwise. A deep purple colour developed after the addition of the first drop. After 25 min, 'Hmr indicated that all of the benzaldehyde had been consumed. The reaction mixture was poured into ice-cold saturated sodium bicarbonate solution, and stirred until gas evolution ceased (15 min). Extraction with methylene chloride (3 x 70 mL), drying over anhydrous sodium sulfate, and evaporation yielded a syrup, which crystallized upon cooling at - 10°C (28.0 g, 9973. Re- crystallization from ethanol yielded white needles (23.7 g,

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

120.

117.

138.

77 o

n 11

/09/

14Fo

r pe

rson

al u

se o

nly.

2396 CAN. J . CHEM. VOL. 57. 1979

84%); mp 39-44°C (lit. (32) mp 4445°C); ir (Nujol): 1750 (s, acetate) cm-' ; 'Hmr (CDCI,) 6: 7.67 ( lH , s), 7.43 (SH, s), 2.13 (6H, s); 13Crnr (CDCI,) 6 : 168.6 (carbonyl), 135.6, 129.7, 128.6, 126.6 (phenyl), 89.7 (CH), 20.7 (CH,).

a-Acetoxy-a-tr~~uoroocetoxyfolue,~e Benzaldehyde (14.3 g, 0.135 mol) and acetyl trifluoroacetate

(32 mL, 0.280 mol) were mixed at 4"C, and concentrated sulfuric acid (0.2 mL) was added. The solution turned purple immediately. 'Hmr showed that the reaction was complete within 5 min. The product was flash distilled to yield a colour- less, water-white liquid (14.1 g, 40%), 1 1 , ~ ~ 1.4376; 'Hmr (CDCI,) 6 : 7.77 ( lH, s), 7.48 (SH, s), 2.17 (3H, s); ir (film): 1785 (s, carbonyl) cm-'.

a,a-Tr$~toroacetoxytol~ie~~e Benzaldehyde (14.3 g, 0.135 mol) and trifluoroacetic anhy-

dride (40 mL, 0.280 mol) were mixed at 4' C. Concentrated sulfuric acid (ca 0.2 mL) was added and the solution turned dark purple. The progress of the reaction was followed by 'Hmr. The reaction was complete after ca. 8 h. The product was flash distilled to yield a water-white liquid (33.7 g, 7973, nuz4 1.3988; 'Hmr (CDCI,) 6: 7.82 ( lH , s), 7.55 (SH, s); 13Cmr (CDCI,) 6 : 156 (q, 44, carbonyI), 132.2, 129.8, 127.6 (phenyl), 115.1 (q, 285, CF,), 94.6 (CH); ir (film): 1795 (s, OCOCF,) cm- I .

Acknowledgements

13. F. G. BORDWELL and B. M. PITT. J. Am. Chem. Soc. 77. 572 (1955).

14. D. L. TULEEN and T . B. STEPHENS. J . Org. Chem. 34.31 (1969).

15. S. Bony. R. LET.^. B. MOREAU. and A. MARQUET. Tet- rahedron Lett. 4921 (1972).

16. C. G. KRUSE, N. L. J . M. BROEKHOF, A. WIJSMAN, and A. V A N D E R GEN. Tetrahedron Lett. 885 (1977).

17. I. STAHL and J . GOSSELCK. Tetrahedron, 29.2323 (1973); I . STAHL. Personal communication.

18. S. WOLFE. P. CHAMBERLAIN, and T. F. GARRARD. Can. J . Chem. 54,2847 (1976).

19. C. P. LILLYA and P. MILLER. J. Am. Chem. Soc. 88. 1560 (1966). E. J . COREY and S. W. WALINSKY. J. Am. Chem. Soc. 94. 8932 (1972). K. ARAI and M. OKI . Bull. Chem. Soc. Jpn. 49,553 (1976). M. OKI and K. ARAI. Abstract W7. International Sym- posium on Stereochemistry. Kingston, Ont.. Canada. 1976. S . BORY. R. LETT. B. MOREAU. and A. MARQUET. C. R. Acad. Sci. Ser. C, 276, 1323 (1973); S. IRIUCHIJIMA and G. TSUCHIHASHI. Bull. Chem. Soc. Jpn. 46.921 (1973);46,929 (1973); T. DURS-r. K.-C. T I N , and M. J. V. MARCH. Can. J . Chem. 51, 1704 (1973); P. CALZAVARA. M. CINQUINI . S. COLONNA, R. FORNASIER, and F. MONTANARI. J . Am. Chem. Soc. 95. 7431 (1973); J. KLEIN. Chem. Lett. 359 ( 1979).

we thank the ~ ~ ~ i ~ ~ ~ i ~~~~~~~h council of 24. J . H;NE. ~ h ~ s i c a l o r g a n i c c h e m i s t r ~ . 2nd ed. McCraw-Hill. Toronto. 1962. p. 87. Canada for support Of this work, and for 25. W. H. SAUNDERS. JR. 111 The chemistry of alkenes. Edited

the Award of a 1967 Science Scholarship. hv S. Patai. Interscience, London. 1964. D. 155.

I. R. PUMMERER. Ber. 43, 1401 (1910); L. HORNER and P. KAISER. Justus Liebigs Ann. Chem. 631, 198 (1960); G. A. RUSSELL and G. J. MIKOL. 111 Mechanisms of molecular migrations. Vol. I. Edited by B. S. Thyagarajan. Intersci- ence, London. 1968. p. 157; T . DURST. Adv. Org. Chem. 6, 285 (1969); S. OAE and T. NUMATA. IN Isotopes in organic chemistry. Vol. 5. Editetl by E. Buncel and C. C. Lee. Elsevier, Amsterdam. 1979. In press.

2. H. KOSUGI. H. UDA, and S. YAMAGIWA. J. Chem. Soc. Chem. Commun. 192 (1975); H. KOSUGI, H. UDA, and S . YAMAGIWA. J . Chem. Soc. Chem. Commun. 71 (1976); G. A. KOPPEL and L. J. MCSHANE. J. Am. Chem. Soc. 100. 288 (1978).

3. C. R. JOHNSON and W. G. PHILLIPS. J . Org. Chern. 32, 1926 (1967); C. R. JOHNSON and W. G. PHILLIPS. J . Am. Chem. Soc. 91,682 (1969).

4. G. E. WILSON. JR. and M. G. HUANG. J. Org. Chem. 35, 3002 (1970); G. E. WILSON, JR. and R. ALBERT. J. Org. Chem. 38.2 160 (1973).

5. S. IWANAMI. S. ARITA, and K. TAKAHASHI. Yuki Gosei Kagaku Kyokai Shi. 26.375 (1968).

6. ( ( I ) B. STRIDSBERG and S . ALLENMARK. Acta Chem. Scand. Ser. B. 28, 591 (1974); (17) B. STRIDSBERG and S . ALLEN- MARK. Acta Chem. Scand. Ser. B, 30. 219 (1976); ( c ) S. OAE and T . NUMATA. Tetrahedron, 30,2641 (1974).

7. T. NUMATA and S . OAE. Tetrahedron Lett. 1337 (1977); T . NUMATA, 0. ITOH. and S. OAE. Chem. Lett. 909 (1977).

8. F. BERNARDI, I. G. CSIZMADIA. H. B. SCHLEGEL, and S . WOLFE. Can. J . Chem. 53, 1144 (1975).

9. S . OAE. Q. Rept. Sulfur Chem. 5-53 (1970). 10. W. E. PARHAM and L.D. EDWARDS. J. Org. Chem. 33,4150

(1968); see also T. P. AHERN, D. G. KAY, and R. F . LANG- L E R . Can J. Chem. 56,2422 (1978).

I I. A. RAUK, E. BUNCEL, R, Y. MOIR, and S. WOLFE. J. Am. Chern. Soc. 87,5498 (1965).

12. M. CINQUINI and S. COLONNA. J. Chem. Soc. Perkin Trans. I , 1883 (1972).

6. G. SMITH, F. D. B A G L E Y , ~ ~ ~ R. TAYLOR. J. Am. Chem. SOC. 83,3647 (1961). P. R. WELLS. Linear free energy relationships. Academic Press, London. 1968. A. K. SHARMA and D. SWERN. Tetrahedron Lett. 1503 (1974); A. K. SHARMA. T. Ku , A. D. DAWSON, and D. SWERN. J. Org. Chem. 40,2758 (1975). Y. OIKAWA and 0 . YONEMITSU. Tetrahedron. 30. 2653 (1974). S. GLUE, I. T. KAY, and M. R. KIPPS, J. Chem. Soc. Chem. Commun. 1158 (1970); J. E. MCCORMICK and R. S. MCELHINNEY. J. Chem. Soc. Perkin Trans. I, 2533 (1976). R. B. MORIN, B. G. JACKSON, R. A. MUELLER, E, R. LAVAGNINO. W. B. SCANLON. and S. L . ANDREWS. J . Am. Chem. Soc. 91, 1401 (1969); R. B. MORIN. D. 0 . SPRY, and R. A. MUELLER. Tetrahedron Lett. 848 (1969). M. J. GREGORY. J. Chem. Soc. B, 1201 (1970). A. RAuK. Ph.D. Thesis. Queen's University. Kingston. Ont., 1968. P. M. KAZMAIER. Ph.D. Thesis, Queen's University, Kingston, Ont., 1978. I. D. ENTWHISTLE. R. A. W. JOHNSTONE, and B. J. MIL- LARD. J . Chem, Soc. C, 302 (1967). BEILSTEIN. Handbuch der Organischen Chemie. Erstes Erganzungswerk. Vol. 6. Springer Verlag. 1931. p. 225. H. T . OPENSHAW. A laboratory manual of qualitative or- ganic analysis. 3rd ed. Cambridge University Press, Cam- bridge. England. 1955. p. 49. A. W. A. JEFFREY. MSC Thesis, Queen's University. Kingston, Ont.. 1975; S. WOL.FE and A. W. A. JEFFREY. Unpublished results. M. IWAKAWA, B. M. PINTO, and W. A. SZAREK. Can. J. Chem. 56,326 (1978). T. G. B O N N E R ~ ~ ~ E. G. GABB. J . Am. Chem. Soc. 85,3291 (1963). E. J . BOURNE. M. STACEY, J . C. TATLOW, and R. WOR- RALL. J . Chem. Soc. 2006(1954).

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

120.

117.

138.

77 o

n 11

/09/

14Fo

r pe

rson

al u

se o

nly.