1782
CLINGMAN AND RICHTMYER
VOL.29
bromide in acetic acid according to the conditions of Lloyd and 3.20 g. (867,), m.p. 186-186.5'. A second recrystallization Stacey3for a compound described as I, gave V in almost quantita~ i 0.5' ( c 1, gave small prisms, m.p. 186.0-186.5", [ a ] +1.5 tive yield, with physical constants in agreement with those chloroform); 3.10 (NH), 5.73 (OAc), 6.02, and 6.50 p reported8; n.m.r. dataz8: r 8.15 (6-OAc), 7.93 (4-0.4c), 7.89 (3(NHAc); 1i.m.r. data? 7 8.09 (6-OAc), 7.97 (3,4-OAc), T.93 OAc), 3.40 (doublet, H-1, Jl,2= 3.5 c.p.5.). (2-NAc), 7.89 (1-OAc), 4.27 (doublet, H-1, Jl.2 8.5 C.P.S.); 2-Acetamido-l,3,4,6-tetra-0-acety~-2-deoxy-Ct-~-g~ucopyranose X-ray powder diffraction dataz8: 9.31 in, 7.08 s, [ 2 , 2 ) , 6.66 (III).-This compound12*'3was prepared in 56Y0 yield by direct w , 6.24 m , 5.19 w, 4.85 vs ( I ) , 4.60 w, 4.21 m, 3.79 s ( 2 , 2 ) , acetylation of 2-amino-2-deoxy-~-glucose hydrochloride by the 3.55 s ( 3 ) , 3.26 w. The product was only moderrztely acetic anhydridesodium acetate procedure.'* It could also be soluble in chloroform, almost insoluble in water, and readilv obtained by acetylation of I1 with acetic anhydride in an excess soluble in methanol. The above route provides a synthesis of of pyridine." The pure material had m.p. 139.5140.5", [ a ] D TX from 2-amino-2-deoxy-~-g~ucosehydrochloride, in 67yo +93" (c 1.0, chloroform); X:I 2.92 (XH), 5.74 (OAc), 6.00, over-all yield, by way of 2-acet:~inido-2-deoxy-o-glucose and \-I .'s8 6.57 (NHAc), and 11.82 p (equatorial H at C-1); n.m.r. dataz8: A sample of VI11 (347 mg.), as used in t'he conversion to \'IT, r 8.09 (6-OAc), 7.98 (3,4-OAc), 7.93 (2-NAc), T.81 (1-OAc), was acetylated with acetic anhydride in excess pyridine solution, 3.82 (doublet, H-1, JI,Z= 3.5 c.p.5.); X-ray powder diffraction and after conventional processing crystalline IX was obtained in dataz8: 12.28 m, 9.31 vs ( l ) , 7.03 w, 6.28 w, 5.99 vw, 5.44 ti, 290". (75%) yield, m.p. lStr~186". A repeat preparation 5.13 m, 4.80 m, 4.58 vw, 4.37 m, 4.17 s (2), 4.00 m, 3.63 s (3), with the hydrochloride salt of VI11 (383 mg.) also gave I X iri 3.52 m, 3.35 m, 3.13 m. 310-mg. (8070)yield. Similnr results were obtained when TITI2-Acetamido-l,3,4,6-tetra-0-acety~-2-deoxy-p-~-g~ucopyranoseHC1 was acetylated by the acetic anhydride-sodium acetate proce(IX).-The following procedure provided a facile route t o this dure.'5 In all cases the product was identical with t.hat prepared 2-Acetamido-3,4,6-tri-0-acetyl-%-deoxy-ol-n-gluco- by the first procedure. compound. pyranosyl chloride (VI)8 (3.47 g.) wm dissolved in acetic acid (30 ml.), mercuric acetate (3.18 9 . ) was added, and the mixture Acknowledgment.-The author is indebted to Mr. was stirred for 2 hr. a t room temperature. Chloroform (150 ml.) T. Page (Battelle Memorial Inst'itute, Columbus) and was added to the clear solution followed by water (10 ml.), the Mr. B. Bossenbroek for measurement' of n.m.r. spectra, mixture was shaken, and the organic layer was separated and and to Mr. L. D. Sannes for the column chromaBodried over magnesium sulfate. After evaporation of the chlorographic separation. form, the product was crystallized from methanol-ether yielding
Aryl Thioglycopyranosides, Aryl Glycopyranosyl Sulfones, and the Novel Oxidation-Acetylation of Aryl 1-Thio-p-D-glucopyranosidesto 6-O-Acetyl-p-~-glucopyranosyl Aryl Sulfones' A . LIONELCLING MAN^
AND
YEISONK. RICHTMYER
National Institute of Arthritis and Metabolic Diseases, National Institutes of Health, Public Health Service, U.S . Department of Health, Education, and Welfare, Bethesda, Maryland 2001.4 Received December 6. 1963 When p-tolyl 1-thio-p-D-ghcopyranoside in a mixture of glacial acetic acid and 307, hydrogen peroxide is allowed to stand for several days a t room temperature, the product, obtained in nearly quantitative yield, is not the expected p-n-glucopyranosyl p-tolyl sulfone but the 6-0-acetyl derivative of the sulfone. Experiments indicate that this novel acetylation reaction may occur a t the intermediate sulfoxide stage. A number of other aryl thioglycosides and aryl glycosyl sulfones are described, and some of their reactions and their infrared and nuclear magnetic resonance spectra are discussed.
I n an attempt to find new antimalarials, Montgomery, Richtmyer, and Hudson3 prepared a series of substituted phenyl 1-thio-b-D-glucopyranosides. In 1947, one of these compounds, the p-tolyl 1-thio-0-Dglucopyranoside (IV), was dissolved in glacial acetic acid and oxidized with an excess of 30% hydrogen peroxide for several days a t room temperature. The product, obtained in nearly quantitative yield, was expected to be the b-D-glucopyranosyl p-tolyl sulfone (111),4 but carbon and hydrogen analyses corresponded almost exactly t o the values required for a 1 : l double compound between the sulfone and the ~ulfoxide.~ This seemed quite plausible in view of a paper en(1) Presented in part before the Division of Carbohydrate Chemistry a t the 145th National Meeting of the American Chemical Society, New York, N. Y . . Sept.. 1963. ( 2 ) Associate in the Visiting Program of the National Institutes of Health, Oct., 1961, t o Sept., 1963. (3) E . M . Montgomery, N. K. Richtmyer, and C . S. Hudson, J . O w . Chem., 11, 301 (1946). (4) I t was thus listed, under Survey No. 15418* and N.I.H. No. 2873 b y G . R. Coatney, W. C. Cooper, N. B. Eddy, and J. Greenberg in "Survey of Antimalarial Agents." Public Health Monograph No. 9, U. S. Government Printing Office, 1953, p. 214. (5) Anal. Calcd. for CisHaeOiaS?: C, 50.31; H. 5.85. Found: C , 50.30; H , 5.80.
titled "Mixed Crystals of Sulfoxides and Sulfones'' that had been published shortly before.e Ten years later, however, when an infrared spectrum of our compound revealed what appeared to be strong carbonyl absorption a t 1695 cm.-I, the problem seemed t o warrant further study. A survey of the literature showed that the oxidation products of thioglycosides included both sulfones and sulfoxides. Wrede and Zimmermann' prepared the first sulfones; these were mainly of the bis(P-D-glycopyranosyl) sulfone type and were made by oxidation of the acetylated bis(b-D-glycopyranosy1) sulfides with potassium permanganate in acetic acid and then deacetylating the crystalline products. Micheel and Schmitz8 described the first sulfoxide, ethyl a-D-glUcopyranosyl sulfoxide; this was obtained by the oxidation of ethyl l-thio-a-~-glucopyranosidewith dilute aqueous hydrogen peroxide. Bonner and Driskog oxidized five acetylated thioglycosides to their respective sulfones by heating either with aqueous potassium (6) (7) (8) (9)
H Rheinboldt and E . Giesbrecht, J . A m . Chem. S a c . , 68, 973 (1946). F. Wrede and W. Zimmermann, Z . physzol. Chem., 148, G5 (1925). F. Micheel and H. Schmlts, Ber., 72, 992 (1939). W . A . Bonner and R. W. Drisko, J . A m . Chem. Soc., 70, 2435 (1948).
ARYLTHIOGLYCOPYRANOSIDES
JULY,1964
1783
SCHEME I
R I
R 1
HaCOAc
R I
HzCOH
HzOz AcOH
O-+S+O
NaOCHs
Ac OAc
OH
I NaOCH,
HaCOH
KOH
R I S
o t s -I b o
HzCOAC
\
P
He?-
VI
permanganate in acetic acid or with 30% hydrogen peroxide in acetic acid. They attempted to oxidize phenyl tetra-o-acetyl-l-thio-/3-D-ghcopyranoside with one molecular equivalent of permanganate and thus obtain the sulfoxide, but isolated instead only a mixture of sulfone and starting thioglucoside. Wagner and Kuhmstedt, lo however, were able to prepare sulfoxides by the action of one and sulfones by the action of two or more molecular equivalents of 30% hydrogen peroxide in glacial acetic acid upon the completely acetylated derivatives of p-hydroxyphenyl l-thio-P-D-glucopyranoside and p-P-D-glucopyranosyloxyphenyl l-thioP-D-glucopyranoside. In this investigation we have prepared three new aryl 1-thio-0-D-gluco- and galactopyranosides (X, XVII, and XX) and their tetraacetates (VIII, XIV, and XVIII) by well-known procedures; five new aryl P-D-gluco- and P-D-galactopyranosyl sulfone tetraacetates (11, IX, XI, XV, and XIX) by the action of 30% hydrogen peroxide in glacial acetic acid upon the corresponding thioglycoside tetraacetates"; and, by deacetylation, three new aryl P-D-gluco- and b-D-galactopyranosyl sulfones (111, XII, and XVI). Although sulfoxides have been isolated in the sugar series,8,10we, like Bonner and D r i ~ k o ,were ~ unsuccessful with ptolyl 1-thio-P-D-glucopyranoside tetraacetate (I) and limited amounts of hydrogen peroxide or sodium metaperiodate, l 2 and with iodosobenzene. l 3 When one molecular equivalent of potassium permanganate in glacial acetic acid was used and the product deacetylated, a paper chromatogram dipped in silver nitrate reagents revealed mainly the thioglucoside with some sulfone; a paper chromatogram sprayed with a new specific reagent sensitive to sulfoxide^'^ indicated the H.
(IO) G . Wagner and KUhmstedt, Nahrwissenschaften, 46, 425 (1959); Arch. Pharm., 394, 147 (1961). (11) Bonner and Drisko (ref. 9) reported t h a t partial deacetylation occurred when their reaction mixture was refluxed for 2 hr.: we have observed no deacetylation when the reaction is carried o u t a t room temperature. (12) N. J. Leonard and C . R. Johnson, J. Ore. Chem., 87, 282 (1962). (13) A. H. Ford-Moore, J. Chem. Soc.. 2126 (1949). (14) J. F. Thompson, W. N. Arnold, and C. .J. Morris, Nature, 197, 380 (1963).
/
I11
J VI1
probable presence of only a very small amount of sulfoxide. In an example outside the sugar series an interesting possibility of disproportionation reactions between two sulfoxide molecules has been suggestedx5to explain the failure of repeated efforts to isolate the desired sulfoxide. The degradation of P-D-glucopyranosyl p-tolyl sulfone (111) with hot aqueous potassium hydroxide, like that of the unoxidized phenyl and p-dimethylaminophenyl 1-thio-P-D-glucopyranosides reported earlier,16 yielded lJ6-anhydro-~-~-glucopyranose (levoglucosan, VI). The reductive desulfurization with Raney nickel of tetra-0-acetyl-P-D-glucopyranosyl sulfone (11), followed by deacetylation, yielded 1,5-anhydro-D-glucitol (polygalitol, VII) just as the desulfurization of the unoxidized p-phenyl and p-tolyl 1-thio-P-D-glucopyranosides had. l7 These degradation and desulfurization reactions confirm the pyranoside ring structures of the sulfones as determined by periodate oxidation methods. The attempted reduction of the sulfone tetraacetate (11) with lithium aluminum hydride also yielded levoglucosan (VI), and the sulfone thus appears to be sensitive to the basicity of that solutio11 even a t room temperature. Acetolysis and bromine in chloroform18 seemed to cause no reaction with the sulfone tetraacetate (11). (See Scheme I.) As noted earlier in this paper, the action of 30% hydrogen peroxide in glacial acetic acid upon the free ptolyl 1-thio-P-D-glucopyranoside (IV) led not to the expected sulfone (111) but to a compound that showed carbonyl absorption in its infrared spectrum. Subse(15) H. H . Szmant and L. Alfonso, unpublished work cited by H. H . Szmant, "Organic Sulfur Compounds," Val. I , N. Kharasch, E d . , Pergamon Press, Inc., New York, N. Y., 1961, p. 1131. (16) E. M. Montgomery, N. K. Richtmyer, and C. S. Hudson, .I. Ore. Chem., 10, 194 (194.5). (17) H. 0.Fletcher. J r . , and N. I
