Allium chemistry: Synthesis and sigmatropic rearrangements of alk(en)yl 1-propenyl disulfide S-oxides from cut onion and garlic

Full text of DOI:10.1021/ja953444h

J. Am. Chem. Soc. 1996, 118, 2799-2810
2799
Allium Chemistry: Synthesis and Sigmatropic Rearrangements
of Alk(en)yl 1-Propenyl Disulfide S-Oxides from Cut Onion
and Garlic1
Eric Block,* Thomas Bayer, Sriram Naganathan, and Shu-Hai Zhao
Contribution from the Department of Chemistry, State UniVersity of New York at Albany,
Albany, New York 12222
ReceiVed October 12, 1995X
Abstract: Reduction (LiAlH4) of propyl 1-propynyl sulfide (8) to (E)-1-propenyl propyl sulfide ((E)-10), C-S cleavage
(Li/NH3) to lithium (E)-1-propenethiolate (Li (E)-11), and reaction with MeSO2Cl gives (E,E)-bis(1-propenyl) disulfide
((E,E)-2); i-Bu2AlH reduction of 8 to (Z)-10 and reaction with Li/NH3 and then MeSO2Cl gives (Z,Z)-2 via Li
(Z)-11. Reaction of MeSO2SR (R ) Me (12a), n-Pr (12b), CH2CHdCH2 (12c), CHdCHMe (12d)) with K (E)-11
gives (E,Z)-2 from (Z)-12d; Li (E,Z)-11 gives alkyl (E)- and (Z)-1-propenyl disulfides (MeCHdCHSSR, R ) Me
(3a), n-Pr (3b), CH2dCHCH2 (3c)) from 12a-c, respectively. Oxidation at -60 °C of (E,E)-, (Z,Z)-, and (E,Z)-2
gives (E)-1-propenesulfinothioic acid S-(E)-1-propenyl ester ((E,E)-13, (E,E)-MeCHdCHS(O)SCHdCHMe) from
(E,E)-2, (Z,Z)-13 from (Z,Z)-2, and ca. 2:1 (E,Z)-13)/(Z,E)-13 from (E,Z)-2. Warming (Z,Z)-13 gives (()-
(1R,2R,3â,4R,5â)-2,3-dimethyl-5,6-dithiabicyclo[2.1.1]hexane 5-oxide (1a), endo-5-methyl-exo-6-methyl-2-oxa-3,7-
dithiabicyclo[2.2.1]heptane (14a), and exo-5-methyl-endo-6-methyl-2-oxa-3,7-dithiabicyclo[2.2.1]heptane (14b).
Warming (E,E)-13 gives 14a and 14b; (E,Z)-13/(Z,E)-13 gives (1R,2R,3R,4R,5â)-2,3-dimethyl-5,6-dithiabicyclo-
[2.1.1]hexane 5-oxide (1b), exo-5-methyl-exo-6-methyl-2-oxa-3,7-dithiabicyclo[2.2.1]heptane (14c), and endo-5-
methyl-endo-6-methyl-2-oxa-3,7-dithiabicyclo[2.2.1]heptane (14d). Oxidation of 3a-c gives MeCHdCHSS(O)R
(4) and MeCHdCHS(O)SR (5). At -60 °C, m-CPBA (2 equiv) converts (E,E)-2 into (Z,Z)-d,l-2,3-dimethyl-1,4-
butanedithial 1,4-dioxide (26) while (Z,Z)-2 gives meso- and d,l-26. With NaIO4, 4/5 (R ) Me) gives (E)- or (Z)-
12a and MeCHdCHSO2SMe (6a); with m-CPBA (Z)-MeS(O)CHMeCHdS+sO- (25a) forms. At 85 °C 2 gives
1:1 cis- and trans-2-mercapto-3,4-dimethyl-2,3-dihydrothiophene (29).
Introduction
oxidation of bis(1-propenyl) disulfide, (MeCHdCHS)2 (2; eq
1).3 In order to better understand the origin of 1 and other
Zwiebelanes1,2 (1a,b)2 are sulfur-containing flavorants
from freshly cut onion (Allium cepa), easily synthesized by
X Abstract published in AdVance ACS Abstracts, March 1, 1996.
(1) Preliminary communications: (a) Bayer, T.; Wagner, H.; Block, E.;
Grisoni, S.; Zhao, S. H.; Neszmelyi, A. J. Am. Chem. Soc. 1989, 111, 3085.
(b) Block, E.; Bayer, T. J. Am. Chem. Soc. 1990, 112, 4584. (c) Block, E.;
Zhao, S. H. Tetrahedron Lett. 1990, 31, 4999. (d) Block, E.; Zhao, S. H. J.
Org. Chem. 1992, 57, 5815.
unusual compounds from cut onion,4 we have examined the low-
temperature oxidation with 1 or 2 equiv of oxidant of stereospe-
cifically synthesized geometric isomers of 2, as well as the
related alkyl 1-propenyl disulfides (E)- and (Z)-MeCHdCHSSR
(3). Compounds 2 and 35a-e and S-oxides 4,2,6a,b,e,i 5,2,6a,b,e 6,2,6c
and 72,6h are found in extracts and distillates of Allium spp. They
are thought to account for the insecticidal (as well as insect
attracting6f,g), larvicidal, nematicidal, antimicrobial, antiasth-
matic, or other medicinal properties of these plants, and may
make important flavor contributions.5f,6c,d,h Structural assign-
ments for 4-6 are based primarily on spectroscopic analysis,
which in a few cases is open to question. None of these
compounds have been previously synthesized. Evidence is
presented for facile [3,3]-sigmatropic rearrangement of 2, its
(2) Chemical Abstracts names of compounds not otherwise named in
the text: 1a, (1R,2R,3R,4R,5â)-2,3-dimethyl-5,6-dithiabicyclo[2.1.1]hexane
5-oxide; 1b, (()-(1R,2R,3â,4R,5â)-2,3-dimethyl-5,6-dithiabicyclo[2.1.1]-
hexane 5-oxide; 4, alkanesulfinothioic acid S-(E,Z)-1-propenyl ester isomers;
(E,Z)-4a, methanesulfinothioic acid S-(E)-1-propenyl ester; (E,Z)-4b, 1-pro-
panesulfinothioic acid S-(E,Z)-1-propenyl ester; (E,Z)-4c, 2-propene-1-
sulfinothioic acid S-(E or Z)-1-propenyl ester; 5, (E)-1-propenesulfinothioic
acid S-alk(en)yl ester isomers; (E)-5a, (E)-1-propenesulfinothioic acid
S-methyl ester; (E,Z)-5b, (E,Z)-1-propenesulfinothioic acid S-n-propyl ester;
(E,Z)-5c, (E,Z)-1-propenesulfinothioic acid S-2-propenyl ester; 6, (E)-1-
propenesulfonothioic acid S-methyl ester; 7, 1-propenethiosulfate; K (E)-
11, potassium (E)-1-propenethiolate; 12a, methanesulfonothioic acid S-(E,Z)-
1-propenyl ester; 12b, n-propanesulfonothioic acid S-(E,Z)-1-propenyl ester;
(E,E)-13, 1-(E)-propenesulfinothioic acid S-1-(E)-propenyl ester; (Z,Z)-13,
1-(Z)-propenesulfinothioic acid S-1-(Z)-propenyl ester; (E,Z)-13, 1-(E)-
propenesulfinothioic acid S-1-(Z)-propenyl ester; (Z,E)-13, 1-(Z)-propene-
sulfinothioic acid S-1-(E)-propenyl ester; 14a, endo-5-methyl-exo-6-methyl-
2-oxa-3,7-dithiabicyclo[2.2.1]heptane; 14b, exo-5-methyl-endo-6-methyl-
2-oxa-3,7-dithiabicyclo[2.2.1]heptane; 14c, exo-5-methyl-exo-6-methyl-2-
oxa-3,7-dithiabicyclo[2.2.1]heptane; 14d, endo-5-methyl-endo-6-methyl-2-
oxa-3,7-dithiabicyclo[2.2.1]heptane; 15, exo-4-ethyl-2-oxa-3-thiabicyclo-
[3.3.0]oct-7-ene; 15a, cis-2-[1′-tert-butyldithio)propyl]-4-cyclopentenol; 16,
2,5-bis-endo-dichloro-7-thiabicyclo[2.2.1]heptane; 17a-d, 3,4-dimethyl-2-
hydroxy-5-(phenyldithio)thiolanes; 21a, (2R,3S/2S,3R)-2,3-dimethyl-1,4-
butanedithial S-oxide; 21b, 2R,3R/2S,3S)-2,3-dimethyl-1,4-butanedithial
S-oxide; 25a, 2-(methylsulfinyl)propanethial S-oxides; 25b, 2-(n-propyl-
sulfinyl)propanethial S-oxides; 25c, 2-(2-propylsulfinyl)propanethial S-
oxides; 26, 2,3-dimethyl-1,4-butanedithial 1,4-dioxide; 29a,b, cis- and trans-
2-mercapto-3,4-dimethyl-2,3-dihydrothiophene; 31a,b, cis- and trans-2-
(methylthio)-3,4-dimethyl-2,3-dihydrothiophene.
(3) (a) Block, E.; Thiruvazhi, M.; Toscano, P. J.; Bayer, T.; Grisoni, S.;
Zhao, S.-H. J. Am. Chem. Soc. 1996, 118, 0000 (accompanying paper). (b)
While 1a and related compounds in this paper are racemates, for convenience
we have chosen to display these structures in one enantiomeric form.
(4) For leading references, see refs 1 and 3 in the accompanying paper.3a
(5) (a) Talyzin, V. V.; Anisimova, V. Ya.; Yakovleva, O. I.; Golovnya,
R. V.; Misharina, T. A.; Vitt, S. V. Zh. Anal. Khim. (Engl. Transl.) 1988,
718. (b) Yu, T.-H.; Wu, C.-M.; Liou, Y.-C. J. Agric. Food Chem. 1989,
37, 725. (c) Schreyer, L.; Dirinck, P.; van Wassenhove, F.; Schamp, N. J.
Agric. Food Chem. 1976, 24, 336, 1147. (d) Kuo, M.-C.; Chien, M.; Ho,
C.-T. J. Agric. Food Chem. 1990, 38, 1378. (e) Nishimura, H.; Wijaya, C.
H.; Mizutani, J. J. Agric. Food Chem. 1988, 36, 563.
0002-7863/96/1518-2799$12.00/0 © 1996 American Chemical Society

2800 J. Am. Chem. Soc., Vol. 118, No. 12, 1996
Block et al.
Scheme 1a,b
S-oxide, and its S,S′-dioxide, as well as for related processes
involving 4 and the corresponding dioxides of 3. These studies
on the chemistry of 2 and 3 and their S-oxides complement our
earlier work on the chemistry of 2-propenyl disulfides,
CH2dCHCH2SSR, characteristic of garlic.7 The work in this
and the accompanying paper3a more fully defines the extraor-
dinary organosulfur chemistry of plants of the genus Allium.4
Results and Discussion
A. Stereospecific Synthesis of Isomers of 2 and 3. In order
to obtain detailed information on the processes occurring during
oxidation of 2 and 3, individual disulfide isomers were ste-
reospecifically synthesized (Scheme 1) and the course of
oxidation was followed using low-temperature NMR. Propyl
1-propynyl sulfide (8), available from base-catalyzed isomer-
ization8 of propyl 2-propynyl sulfide (9), was reduced to either
(E)- or (Z)-propenyl propyl sulfide ((E)- or (Z)-10) by known
methods.8c,9a Cleavage of sulfides 10 (Li/NH3) with retention
of stereochemistry gives lithium thiolates 11 which afford
disulfides 3 with the appropriate thiosulfonate 12. Reaction of
Li (E)- or (Z)-11 with MsCl gives (E,E)- or (Z,Z)-2. These
reaction conditions were chosen to minimize E/Z isomerization
of the disulfides 2, a problem encountered with I2 oxidation of
11. Reaction of (E)-MeCHdCHSK (K (E)-11)9b with (Z)-
MeCHdCHSSO2Me ((Z)-12d)1d,2 at -78 °C gives (E,Z)-2.
Isomers of 2 can also be separated by preparative HPLC. While
(E,E)-2 and (Z,Z)-2 were relatively stable at room temperature,
(E,Z)-2 on standing underwent disproportionation to a mixture
a
(i) NaOMe (85%). (ii) LiAlH4 (81%). (iii) Li/NH3. (iv) DIBAL
(75%) or Cu2Br2, LiAlH(OMe)3 (73%). (v) RSSO2Me (12a-c; 53-
63%). (vi) m-CPBA, -60 °C (73-82%). (vii) MeSO2Cl (61-82%).
(viii) (Z)-MeCHdCHSSO2Me (12d; 60%). b R ) Me (3-5a), n-Pr (3-
5b), or CH2dCHCH2 (3-5c).
B. Monooxidation of 3. Oxidation (m-CPBA/-60 °C) of
(E)-MeCHdCHSSMe ((E)-3a) gives 2:1 (E)-MeCHdCHSS-
(O)Me ((E)-4a2)/(E)-MeCHdCHS(O)SMe ((E)-5a2) while (Z)-
3a gives the corresponding (Z)-isomers in a 6:1 (Z)-4a/(Z)-5a
ratio; isomers are separable by preparative TLC or HPLC.
Oxidation at sulfur is more difficult next to a (Z)- than an (E)-
1-propenyl group. Similarly, oxidation of (E)- or (Z)-
MeCHdCHSS-n-Pr ((E)- or (Z)-3b) gives (E)- or (Z)-4b2 and
(E)- or (Z)-5b,2 (Scheme 1, R ) n-Pr) while (E)- or (Z)-
MeCHdCHSSAll ((E)- or (Z)-3c) gives (E)- or (Z)-4c2 and (E)-
or (Z)-5c2 (Scheme 1, R ) All). Preparative TLC of samples
containing either (E)- or (Z)-4a leads to the same mixture
containing 1.7:1 (E)-4a/(Z)-4a. A similar (E)-4a/(Z)-4a ratio
arises when oxidized solutions of either pure (E)-3a or (Z)-3a
are stored overnight at 25 °C. Individual isomers of (E)- and
(Z)-5a are configurationally stable under all conditions exam-
ined. The mechanistic significance of these observations will
be discussed below.
1
of all three isomers of 2. Table 1 gives the H and 13C NMR
methyl group chemical shifts for isomers of 2 and 3a-c. While
isomers of 2 have been previously prepared,10 our syntheses
give better stereoselectivity and overall yields than earlier
methods.
(6) (a) Bayer, T.; Breu, W.; Seligmann, O.; Wray, Y.; Wagner, H.
Phytochemistry 1989, 28, 2373. Wagner, H.; Dorsch, W.; Bayer, T.; Breu,
W.; Willer, F. Prostaglandins, Leukotrienes Essent. Fatty Acids 1990, 39,
59. (b) Lawson, L. D.; Wood, S. G.; Hughes, B. G. Planta Med. 1991, 57,
263. (c) Tada, M.; Hiroe, Y.; Kiyohara, S.; Suzuki, S. Agric. Biol. Chem.
1988, 52, 2383. (d) Brodnitz, M. H., Pascale, J. V., Vock, M. H. Ger. Offen.
2,166,074, Oct 19, 1972; Chem. Abstr. 1973, 78, 15515f. (e) Freeman, G.
G.; Whenham, R. J. Phytochemistry 1976 15, 521. (f) Pierce, H. D., Jr.;
Vernon, R. S.; Borden, J. H.; Oehlschlager, A. C. J. Chem. Ecol. 1978, 4,
65. Vernon, R. S.; Judd, G. J. R.; Borden, J. H.; Pierce, H. D., Jr.;
Oehlschlager, A. C. Can. J. Zool. 1981, 59, 872. (g) Auger, J.; Lecomte,
C.; Thibout, E. J. Chem. Ecol. 1989, 15, 1847; Auger, J.; Lalau-Keraly, F.
X.; Belinsky, C. Chemosphere 1990, 21, 837. (h) Yamato, O.; Yoshihara,
T.; Ichihara, A.; Maede, Y. Biosci. Biotech. Biochem. 1994, 58, 221. (i)
Bayer, T. Ph.D. Thesis, University of Munich, 1988.
(7) (a) Block, E.; Ahmad, S.; Catalfamo, J.; Jain, M. K.; Apitz-Castro,
R. J. Am. Chem. Soc. 1986, 108, 7045. (b) Block, E.; Iyer, R.; Grisoni, S.;
Saha, C.; Belman, S.; Lossing, F. P. J. Am. Chem. Soc. 1988, 110, 7813.
(8) (a) Brandsma, L.; Wijers, H. E.; Arens, J. F. Recl. TraV. Chim. Pays-
Bas 1963, 82, 1040. (b) Brandsma, L. PreparatiVe Acetylene Chemistry,
2nd ed.; Elsevier: Amsterdam, 1988. (c) Parry, R. J.; Sood, G. R. J. Am.
Chem. Soc. 1989, 111, 4514.
1-Propenyl thiosulfinates 4a-c/5a-c have been fully char-
acterized spectroscopically. Data for (E)- and (Z)-4a and -4b
are in excellent agreement with those published for compounds
isolated from cut onion6a but differ significantly from some of
the data published for isomers of 4 and 5 in crushed garlic.11
IR spectroscopy confirms the presence of a S(O)S function
(1090 cm-1 band) while CI-mass spectra (CI-MS) confirm the
(10) (a) Hiramitsu, T. Jpn. Kokai Tokkyo Koho JP 01,117,856 [89,117,-
856] (Cl. C07C149/00), May 10, 1989; Chem. Abstr. 1989, 111, 194106t.
See also: Hiramitsu, T; Sakamoto, K. U.S. 5,011,975, April 30, 1991. (b)
Brandsma, L.; Schuijl, P. J. W. Recl. TraV. Chim. Pays-Bas 1969, 88, 513.
(9) (a) Vermeer, P.; Meijer, J. Eylander, C.; Brandsma, L. Recl. TraV.
Chim. Pays-Bas 1976, 95, 25. (b) For stereospecific synthesis of K (E)-11
under mild conditions, see the Experimental Section.

Synthesis of Alk(en)yl 1-Propenyl Disulfide S-Oxides
J. Am. Chem. Soc., Vol. 118, No. 12, 1996 2801
Table 1. 1H (13C) Methyl Group NMR Chemical Shifts in RS(O)nSR′ a
R
R′
compd no.
C-3
C-1
n
C-1′
C-3′
(E)-1-propenyl
(Z)-1-propenyl
(E)-1-propenyl
(Z)-1-propenyl
(E)-1-propenyl
(E)-1-propenyl
(E)-1-propenyl
(Z)-1-propenyl
Me
Me
Me
3a
3a
3b
3b
3c
2
1.79 (17.9)
1.76 (14.3)
1.77 (18.1)
1.75 (14.2)
1.78 (18.0)
1.78 (18.1)
1.79 (18.1)
1.77 (14.4)
0
0
0
0
0
0
0
0
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2.39 (22.0)
2.43 (23.0)
n-Pr
n-Pr
allyl
(E)-1-propenyl
(Z)-1-propenyl
(Z)-1-propenyl
Me
1.78 (18.1)
1.77 (14.4)
1.77 (14.4)
2
2
2.99 (42.7)
2.67 (14.5)
2.60 (17.3)
2.69
(E)-1-propenyl
(Z)-1-propenyl
Me
Me
Me
5a
5a
4a
4a
5b
4b
4b
5c
4c
4c
13
13
13
13
1.98 (13.8)
1.96
(E)-1-propenyl
(Z)-1-propenyl
n-Pr
(E)-1-propenyl
(Z)-1-propenyl
All
(E)-1-propenyl
(Z)-1-propenyl
(E)-1-propenyl
(Z)-1-propenyl
(E)-1-propenyl
(Z)-1-propenyl
Me
2.98 (42.1)
3.04 (42.7)
1.92 (18.9)
1.86 (15.1)
Me
(E)-1-propenyl
n-Pr
n-Pr
(E)-1-propenyl
All
All
(E)-1-propenyl
(E)-1-propenyl
(Z)-1-propenyl
(Z)-1-propenyl
Me
(E)-1-propenyl
Me
1.94 (17.4)
1.97 (17.5)
1.90 (15.1)
1.84 (18.9)
1.89 (19.0)
1.84 (15.1)
1.91 (17.9)
1.84 (15.4)
1.84 (17.9)
1.86
1.99 (19.5)
2.10 (19.5)
1.97 (15.8)
1.96
3.29 (48.8)
2.68 (18.3)
2.57 (29.8)
Me
6a
12a
12a
2.00 (17.0)
(E)-1-propenyl
(Z)-1-propenyl
3.26 (47.9)
3.23 (48.6)
1.94 (19.0)
1.87 (15.1)
Me
a Structure: C3-C2-C1-S(O)n-S-C1′-C2′-C3′.
Scheme 2a
molecular formulas and EI-MS allow regioisomers to be readily
distinguished. The base peak for MeCHdCHSS(O)Me (4a) at
m/z 73 corresponds to MeCHdCHS+ while that for Me-
CHdCHS(O)SMe (5a) at m/z 88 corresponds to
CH2dCHCHdSdO•+; there are only very small peaks at m/z
88 and 73 in 4a and 5a, respectively. LC-atmospheric pressure
chemical ionization-MS/MS studies (LC-APCI-MS/MS) con-
firm the identity of synthetic 4a-c and 5a-c with constituents
of onion and garlic homogenates.12 The 1H NMR data in Table
1 indicate that compounds with MeS(O)S- groups show singlets
at δ 2.99-3.04 while those with MeSS(O)- groups show
singlets at δ 2.60-2.67. The methyls of the (E)- and (Z)-
MeCHdCHSS(O)- groups appear as doublets at δ 1.91-1.93
and 1.86-1.87, respectively, while those of (E)-MeCHdCHS-
(O)S- appear as doublets at δ 1.93-1.99. The regiochemistry
of unsymmetrical thiosulfinates also follows from 13C NMR shift
data given in Table 1. Thus, MeS(O)S- groups appear at δC
42-43 while MeSS(O)- groups appear at δC 13-15 ppm.
C. Monooxidation of 2. Oxidation of a pure sample of
(Z,Z)-2 with NaIO4 in methanol-water at room temperature for
5 h gave trans-zwiebelane 1a in 26% isolated yield, along with
minor amounts (1.2%) of cis-zwiebelane 1b; the latter compound
may arise by [2,3]-sigmatropic E-Z isomerization of (Z,Z)-
MeCHdCHS(O)SCHdCHMe (13)2 prior to cyclization (see
below). When (E,E)-2 was oxidized under identical conditions,
1a and 1b could not be detected.
a
(i) m-CPBA, Na2CO3, CDCl3, -60 °C.
with retention of double bond stereochemistry (Scheme 2).
Unsymmetrical disulfide (E,Z)-2 gives a 2:1 mixture of (E,Z)-
13 and (Z,E)-13. Relative rates of oxidation are (E,E)-2 >
(E,Z)-2 > (Z,Z)-2. Structural assignments for (E,Z)-13 and
(Z,E)-13 are based on comparison of the NMR data in Table 1
for thiosulfinates 4a, 5a, and 13 as well as the (above)
observation that oxidation at sulfur is more difficult next to a
(Z)- than an (E)-1-propenyl group.
D. Low-Temperature Rearrangement of Thiosulfinates
13. Solutions of isomers of 13 in NMR tubes containing
dioxane as internal standard were kept at -40 °C for 3 h
whereby (Z,Z)-13 gives trans-zwiebelane 1a along with bicyclic
sultenes 14a2 (major) and 14b2 (minor), (E,E)-13 gives only
14a2 (major) and 14b2 (minor), and (E,Z)-13/(Z,E)-13 gives cis-
zwiebelane 1b along with bicyclic sultenes 14c2 (major) and
14d2 (minor) (Schemes 3-6). Thus, the initial products of
rearrangement after 3 h at -40 °C are, for (Z,Z)-13, 25:3.3:1
Isomers of 2 at -60 °C were treated with chilled solutions
of m-CPBA in the presence of dry Na2CO3. After 5 min the
reaction mixture was analyzed by NMR methods at -60 °C.
From the 1H/13C NMR methyl group chemical shift data (Table
1), we conclude that oxidation of individual isomers of 2 gives
isomers of thiosulfinates MeCHdCHS(O)SCHdCHMe (13)2
(11) (a) After we pointed out the discrepencies between our NMR data
and his, L. Lawson agreed that some of his chemical shift data were in
error.11b (b) Lawson, L. D. In Garlic: The Science and Therapeutic
Applications of Allium satiVum L. and Related Species; Koch, H. P., Lawson,
L. D., Eds.; Williams and Wilkins: Baltimore, MD, 1996; p 56.
(12) Calvey, E.; Block, E.; Matusik, J.; White, K. D.; DeOrazio, R.; Sha,
D. Manuscript in preparation

2802 J. Am. Chem. Soc., Vol. 118, No. 12, 1996
Block et al.
1b/14a/14b, for (E,E)-13, 4:1 14a/14b, and for (E,Z)-13/(Z,E)-
13, 10:12:1 1a/14c/14d. Compounds 14a-d, which showed
neither sulfinyl nor sulfonyl bands in their IR spectra, defied
all efforts at chromatographic purification. Structures of 14a-d
could be assigned on the basis of their 1H and 13C NMR spectra.
(EtCHdS+sO-, 20) might be thought to preclude formation
of MeCHdCHS(O)SCHdCHMe (13), sulfenic acid 19 and
related compounds have been trapped with alkynes.14a-c The
occurrence of thiosulfinates 4 and 5 (MeCHdCHSS(O)R and
MeCHdCHS(O)SR) in onion extracts also suggests that 19 can
be trapped before it rearranges. Since we have shown that pairs
of thiosulfinates RS(O)SR′/R′S(O)SR rapidly scramble, afford-
ing mixtures with RS(O)SR/R′S(O)SR′,14a formation of 13/RS-
(O)SR from 4/5 is reasonable. Finally, ab initio (HF/6-31G*)
calculations indicate that a 33 kcal/mol activation energy barrier
separates the lower homolog of 19, ethenesulfenic acid
(CH2dCHSOH), from the more stable (by 2.9 kcal/mol) LF
(20) lower homolog, (Z)-ethanethial S-oxide ((Z)-CH3-
CHdS+sO-).14d We therefore suggest that isomers of 13 are
indeed formed along with the LF 20 when an onion is cut but
immediately undergo an unusually facile [3,3]-sigmatropic
rearrangement to isomers of 2,3-dimethylbutanedithial S-oxide
(21) (Schemes 3-6). More highly substituted homologs of 13,
where rearrangement is retarded, are known to be stable.15
Solutions of thiosulfinates (E,E)-13, (Z,Z)-13, and (E,Z)-13/
(Z,E)-13 in NMR tubes containing dioxane as internal standard
were warmed to -15 °C. The disappearance of peaks associated
with 13 was followed with time. The so-determined first-order
rate constants for disappearance of 13 at -15 °C are 8 × 10-4
s-1 for (E,E)-13, 4 × 10-4 s-1 for (E,Z)-13/(Z,E)-13, and 3 ×
10-4 s-1 for (Z,Z)-13. If the ratio of these rate constants, 2.7:
1.3:1, is compared to the analogous ratio for Claisen rearrange-
ment of isomeric 1-propenyl 2-butenyl ethers,16a it is apparent
that the rate ratio for the rearrangement of thiosulfinates is
contracted, suggesting a more adVanced transition state than
for the Claisen rearrangement. Activation parameters for
rearrangement of (Z,Z)-13 at 273 K are Ea ) 16 kcal/mol, ∆Hq
) 15.5 kcal/mol, ∆Sq ) -15.3 cal/mol K, and ∆Gq ) 19.5
kcal/mol (see below).
1
In particular, H and 13C NMR bands at δ 5.90 (s, 1 H) and
4.84 (d, J ) 3 Hz, 1 H) and at δ 100.6 and 82.4, respectively,
for 14a, and at δ 5.88 (s, 1 H) and 4.56 (s, 1 H) and at δ 99.8
and 82.9, respectively, for 14c, suggest the presence of
O-CH1-S (δ 5.90) and S-CH4-S (δ 4.84) groups (see
structure of 14a below for numbering). Sultenes 15a-c2 have
been previously reported.13a-c Sultene 15a13a shows NMR
absorptions at δC 95.0 (C-1) and 64.8 (C-4) and δH 5.3 (H1)
and 3.3 (H4), respectively, while 15b13b shows δC 113.0 (C-1)
and 86.4 (C-5). In 16,2 bridgehead protons H1,4 appear at δ
3.64, coupled to the vicinal exo-protons H2,3x,5,6x with J ) 3.4;
J ) 0 for the corresponding bridgehead proton-vicinal endo-
proton coupling H1-H6n/H4-H3n.13d In 14a protons H1 (δ 5.90)
and H4 (δ 4.84) have adjacent endo (H6) and exo (H5) protons,
as indicated by the respective values of J ) 0 and 3.4 Hz.
Protons H5 and H6 in 14c must both be endo to account for the
absence of coupling with the bridgehead protons. Just as sultene
15a reacts rapidly with 2-methyl-2-propanethiol to give 4-cy-
clopentenol 15d,2 14a,b react with thiophenol, giving a mixture
of isomeric 2-hydroxythiolanes 17a-d.2,13e
We propose that following oxidation of (E,E)-2 with 1 equiv
of peracid, in the chairlike transition state for the [3,3]-
sigmatropic rearrangement, the thiosulfinate oxygen assumes a
pseudoaxial orientation analogous to that favored in 1,2-dithiane
1-oxides16b and sultines16c and in the sulfoxide thio-Claisen
rearrangement.17 Rearrangement from this transition state gives
dithial S-oxide ((Z)-21a),2 which can assume an appropriate
conformation to undergo a very facile intramolecular 1,3-dipolar
cycloaddition reaction18a-c involving the thial S-oxide group as
(14) (a) Block, E.; O’Connor, J. J. Am. Chem. Soc. 1974, 96, 3929. (b)
Shelton, J. R.; Davis, K. E. J. Am. Chem. Soc. 1967, 89, 718. (c) Block, E.;
Penn, R. E.; Revelle, L. K. J. Am. Chem. Soc. 1979, 101, 2200. (d) Turecek,
F.; McLafferty, F. W.; Smith, B. J.; Radom, L. Int. J. Mass Spectrom. Ion
Processes 1990, 101, 283. (e) For early interest in the formation of 13, see
Whitaker, J. R. In AdVances in Food Research; Chichester, C. O., Mrak,
E. M., Stewart, G. F., Eds.; Academic Press: New York, 1976; Vol. 22, p
73 ff.
(15) (a) Highly substituted compounds of type R2CdCRS(O)SCRdCR2
are isolable at room temperature.15b-d (b) Bonini, B. F.; Foresti, E.; Leardini,
R.; Maccagnani, G.; Mazzanti, G. Tetrahedron Lett. 1984, 25, 445. (c) van
der Linden, J. B.; Timmermans, J. L.; Zwanenburg, B. Recl. TraV. Chim.
Pays-Bas 1995, 114, 91. (d) Oxidation of Me2CdCHS(O)nSCHdCMe2, i,
n ) 0, affords i, n ) 1 and 2, which are moderately stable at 25 °C. We
assume that the rate of [3,3]-sigmatropic rearrangement of i (n )1) is
retarded relative to the rate for 13 by the gem-methyl groups.
(16) (a) Vittorelli, P.; Hansen, H.-J.; Schmid, H. HelV. Chim. Acta 1975,
58, 1293. (b) Juaristi, E.; Cruz-Sanchez, J. S.; Petsom, A.; Glass, R. S.
Tetrahedron 1988, 44, 5653. (c) Breau, L.; Sharma, N. K.; Butler, I. R.;
Durst, T. Can. J. Chem. 1991, 69, 185.
(17) (a) Block, E.; Ahmad, S. J. Am. Chem. Soc. 1985, 107, 6731. (b)
Hwu, J. R.; Anderson, D. A. Tetrahedron Lett. 1986, 27, 4965. (c) Malherbe,
R.; Rist, G.; Bellus, D. J. Org. Chem. 1983, 48, 860 and references therein.
(18) (a) Block, E.; Bazzi, A. A.; Revelle, L. K. J. Am. Chem. Soc. 1980,
102, 2490. (b) For analogous intramolecular heterobicyclo[2.2.1]heptane-
forming processes involving nitrones, see: Lumma, W. C., Jr. J. Am. Chem.
Soc. 1969, 91, 2820. (c) Hwu, J. R.; Robl, J. A. J. Chem. Soc., Chem.
Commun. 1986, 704.
E. Mechanistic Considerations. While facile rearrange-
ment of (E)-1-propenesulfenic acid ((E)-MeCHdCHSOH, (E)-
19; from enzymatic cleavage of (E)-(+)-S-(1-propenyl)-L-
cysteine S-oxide ((E)-18); see Scheme 1, accompanying paper3a)
to onion lachrymatory factor (LF) (Z)-propanethial S-oxide
(13) (a) Block, E.; Wall, A. J. Org. Chem. 1987, 52, 809. (b) Ishii, A.;
Jin, Y.-N.; Hoshino, M.; Nakayama, J. Heteroatom Chem. 1995, 6, 181.
(c) Huisgen, R.; Mioston, G. Unpublished results. (d) Corey, E. J.; Block,
E. J. Org. Chem. 1966, 31, 1663. (e) The stereochemistry is not shown.
The stereochemistry at the hydroxy carbon is probably lost since a 4:1 14a/
14b mixture gives a 1:1 mixture (by NMR) of isomers 17a,b on reaction
with thiophenol. Similarly, a 12:1 14c/14d mixture gives a 2.5:1 mixture
of isomers 17c,d, different from those obtained with 14a/14b. Isomer 17a
shows an OH stretch in the IR spectrum, a D2O exchangeable peak at 1.67
ppm (1 H) coupled to a peak at δ 5.29 (1 H, O-CH-S), and other peaks
at δ 7.2-7.6 (m), 4.61 (d, 1 H), 2.46 (m, 1 H), 2.08 (m, 1 H), 1.97 (m, 1
H), 1.25 (d, J ) 7 Hz, 3 H), 1.17 (d, J ) 7 Hz, 3 H). Isomers 17b-d show
similar spectra. Mechanistic and full experimental details concerning 17a-d
are given elsewhere.13f (f) Naganathan, S. Ph.D. Thesis, SUNYsAlbany,
1992.

Synthesis of Alk(en)yl 1-Propenyl Disulfide S-Oxides
J. Am. Chem. Soc., Vol. 118, No. 12, 1996 2803
Scheme 3
Scheme 5
Scheme 4
Scheme 6
a 1,3-dipole4 and the thial group as a 1,3-dipolarophile,19a-c
affording 14a,b2 (Scheme 3). Intermolecular cycloadducts of
thiones and thione S-oxides are known.13c Upon analogous
oxidation of (Z,Z)-2, steric effects associated with the Z double
bonds lead the intermediate to adopt a transition state geometry
in which the thiosulfinate oxygen is pseudoequatorial, resulting
in the formation of (E)-(2R,3S/2S,3R)-2,3-dimethyl-1,4-butane-
dithial S-oxide ((E)-21a), where the geometry of the (E)-
CdS+sO- group favors the intramolecular head-to-tail [2 +
2] process,20a yielding 1b over the sterically now more difficult
1,3-dipolar cycloaddition (Scheme 4). The formation of 14a,b
from (Z)-21a but not from (E)-21a is analogous to the
observation that syn-carbonyl oxide 22a cyclizes to give
1-phenyl-2,3,7-oxabicyclo[2.2.1]heptane (23; eq 2) (bridghead
CH, δ 6.22 ppm) whereas anti-carbonyl oxide 22b, because it
cannot achieve a suitable conformation for intramolecular
cyclization, gives mainly oligomeric material (eq 3).20b
(19) (a) Huisgen, R.; Rapp, J. J. Am. Chem. Soc. 1987, 109, 902. (b)
Huisgen, R.; Fisera, L.; Giera, H.; Sustmann, R. J. Am. Chem. Soc. 1995,
117, 9671. (c) Sustmann, R.; Sicking, W.; Huisgen, R. J. Am. Chem. Soc.
1995, 117, 9679.
(20) (a) For related examples, see Ishii, A.; Ding, M.-X.; Maeda, K.;
Nakayama, J.; Hoshino, M. Bull. Chem. Soc. Jpn. 1992, 65, 3343. Ishii,
A.; Nakayama, J.; Ding, M.; Kotaka, N.; Hoshino, M. J. Org. Chem. 1990,
55, 2421. (b) Brunnelle, W. H.; Lee, S.-g. Tetrahedron Lett. 1994, 35, 8141.
(c) Block, E.; O’Connor, J. J. Am. Chem. Soc. 1974, 96, 3921.
Pseudoaxial and pseudoequatorial thiosulfinate oxygen transi-
tion state geometries should be favored with (E,Z)-13 and (Z,E)-
13, respectively. Thus, oxidation of (E,Z)-2 could afford
comparable amounts of the heterobicyclo[2.1.1]hexane and

2804 J. Am. Chem. Soc., Vol. 118, No. 12, 1996
Block et al.
Scheme 7a
Table 2. Comparative Activation Parameters for [3,3]-Sigmatropic
Rearrangements
Ea
compda (kcal/mol) (kcal/mol) (cal/(mol K)) (kcal/mol)
∆Hq
∆Sq
∆Gq
ref
(Z,Z)-13
(Z,Z)-2
A
16
19
15.5
18.3
19.3
25.4
-15.3
-24.8
-4.3
19.5
27.5
this work
this work
17a
B
-15.9
15
a Compound A ) allyl vinyl sulfoxide, CH2dCHCH2S(O)CHdCH2;
compound B ) 2-butenyl 1-propenyl ether, MeCHdCHCH2OCHdCH-
Me.
heterobicyclo[2.2.1]heptane systems (1a and 14c,d, respectively)
(Schemes 5 and 6). While there is variation in the type of ring
system formed on monooxidation of (E,E)-, (E,Z)-, and (Z,Z)-
2, there is high stereoselectivity in carbon-carbon bond
formation.3 The low temperature (-15 °C) at which rearrange-
ment of (Z,Z)-13 occurs, compared to that for the corresponding
2-butenyl 1-propenyl ether and allyl vinyl sulfoxide (see Table
2), reflects the weakness of the S-S bond (estimated bond
a
R ) Me, n-Pr, CH2dCHCH2.
facile isomerization of isomers of 4, but not 5 nor precursor
disulfides 3, can be explained by a [2,3]-sigmatropic rearrange-
ment (Scheme 7) analogous to reactions of allylic sulfoxides
or thiosulfinates.22 This process is retarded by hydrogen
bonding to the sulfinyl oxygen,22b as we observe. Efforts to
intercept the thial intermediate with 2,3-dimethyl-1,3-butadiene
were unsuccessful. This isomerization explains the surprising
observation, noted above in part B, that although only (+)-S-
(E)-1-propenyl-L-cysteine S-oxide ((E)-18) occurs naturally,
presumably affording only (E)-MeCHdCHSOH ((E)-19), both
(E)- and (Z)-4, but only (E)-5, are found in Allium extracts and
distillates. Compound 5 is, of course, incapable of isomerization
by the mechanism of Scheme 7.
energy 46 kcal mol-1 20c
as well as the rate-enhancing effect
)
of the zwitterionic sulfinyl group.17b
F. Mechanisms Associated with Natural Occurrence of
Zwiebelanes. An enigma arises connecting the mechanism of
processes taking place following monooxidation of stereoiso-
mers of 2 to reactions that occur when an onion is cut. We
have shown that trans-zwiebelane 1a originates from (Z,Z)-13
but not from (E,E)-13. Formation of (Z,Z)-13 in onion
homogenates is unlikely in that it would require condensation
of two molecules of (Z)-1-propenesulfenic acid ((Z)-19).
However, since (Z)-(+)-S-(1-propenyl)-L-cysteine S-oxide ((Z)-
18) is not found in onion, and since the barrier to interconversion
of (E)- to (Z)-1-propenesulfenic acid (19) is anticipated to be
substantial (see part E above),14d it is improbable that sufficient
quantities of (Z)-19 would be present so that self-condensation
would be likely. Furthermore, the detection in Allium spp.
extracts of substantial amounts of (E)-MeCHdCHS(O)SR ((E)-
5) but no Z-isomers also argues against the formation of
significant amounts of (Z)-19 and therefore (Z,Z)-13. In onion
extracts, formation of 1a,b might be enzymatically catalyzed
with likely altered transition state stereochemistry. Since use
of a chiral GC column, which resolves the enantiomers of 1a,
shows 1a present in extracts of cut onion to be completely
racemic, this proposal is unlikely. It is possible that 14a,b
undergo isomerization to 1a in an aqueous medium at low pH,
similar to sultene 15b,13b,21b although addition of 14a,b to an
onion homogenate led to no increase in the concentration of
1a,b. Identification of the alliinase-induced cleavage products
from synthetic (E)- and (Z)-(+)-S-(1-propenyl)-L-cysteine S-
oxide (18) under controlled conditions might help resolve this
enigma.
H. Oxidation of Mono-r,â-Unsaturated Thiosulfinates.
We examined the oxidation of thiosulfinates MeCHdCHSS-
(O)R (4) and RSS(O)CHdCHMe (5) as a route to the corre-
sponding thiosulfonates MeCHdCHSSO2R (12)2 and RSSO2-
CHdCHMe (6),2 of interest as natural products themselves (e.g.,
(E)-MeCHdCHSO2SMe ((E)-6a)2 has been isolated from Allium
grayi)6c as well as synthetic reagents for preparation of R,â-
unsaturated disulfides. “Nucleophilic” oxidation23 of (E)-4/(E)-5
or (Z)-4/(Z)-5 (MeCHdCHSS(O)R/MeCHdCHS(O)SR) at the
sulfinyl sulfur using NaIO4/HOAc gave, respectively, (E)-12/
(E)-6 or (Z)-12/(Z)-6 (MeCHdCHSSO2R/ MeCHdCHSO2SR)
with no stereoisomerization (Scheme 8). Unlike (E)- and (Z)-
4, stereoisomers of 12 were configurationally stable, showing
no tendency to undergo E/Z isomerization. “Electrophilic”
oxidation23 of either (E)-4/(E)-5 or (Z)-4/(Z)-5 at the sulfenyl
sulfur with m-CPBA gave identical 1:1 mixtures of compounds
characterized as (Z)-2-(alkylsulfinyl)propanethial S-oxide (Z)-
25 (Scheme 9) (see the Experimental Section for proof of the
structure). We presume that initial oxidation of 4/5 gives
R-disulfoxide 24 (MeCHdCHS(O)S(O)R). While 24 could
undergo pseudopericyclic24a rearrangement to 25, the stereo-
chemistry would be expected to be conserved, which is not the
case. Therefore, (1) stereochemistry in 24 is lost through [2,3]-
sigmatropic rearrangement (Scheme 8) which is more rapid than
pseudopericyclic processes, (2) two diastereomers of 24 are
G. E,Z-Isomerization of Mono-r,â-Unsaturated Thiosul-
finates. All attempts to isolate pure samples of (E)- or (Z)-4
(MeCHdCHSS(O)R) from mixtures with 5 (MeCHdCHS(O)-
SR) always led to mixtures of (E,Z)-4. Furthermore, stereo-
chemically pure samples of (E)-5/(E)-4 or (Z)-5/(Z)-4 were
converted during the course of 1 h at 25 °C into (E)-5/(E,Z)-4
or (Z)-5/(E,Z)-4, respectively.6i An equilibrium ratio of 1.6:1
(E)-4/(Z)-4 was reached after 24 h at 25 °C in CDCl3; the
equilibration process was considerably slower in CD3OD. The
(22) (a) Baldwin, J. E.; Ho¨fle, G.; Choi, S. J. Am. Chem. Soc. 1971, 93,
2810. (b) Braverman, S. In The Chemistry of Sulfenic Acids and their
DeriVatiVes; Patai, S., Ed.; Wiley: New York, 1990; Chapter 8 and
references therein.
(23) Kim, Y. H.; Takata, T.; Oae, S. Tetrahedron Lett. 1978, 26, 2305.
(24) (a) Ross, J. A.; Seiders, R. P.; Lemal, D. M. J. Am. Chem. Soc.
1976, 98, 4325. (b) Detection of (Z,Z)-d,l-26 and RSO2SR during electro-
philic oxidation of 4/5 supports the third possibility ((Z,Z)-d,l-26 and RSO2-
SR could arise from dimerization of MeCHdCHSO• and RSO•, respectively,
according to Scheme 11). Scrambling of thiosulfinates 4/5 prior to or during
oxidation could give 13 and RS(O)SR, which on oxidation would also give
(Z,Z)-d,l-26 and RSO2SR.
(21) (a) Okuyama, T.; Miyake, K.; Fueno, T.; Yoshimura, T.; Soga, S.;
Tsukurimichi, E. Heteroatom Chem. 1992, 3, 577. (b) On the basis of
arguments made in part E, (E,Z)-13 (but not (Z,E)-13) should result from
scrambling14a of thiosulfinates (Z)-4 and (E)-5. Conversion of (E,Z)-13 to
14c,d (Scheme 6) could then be followed by isomerization to 1b in the
aqueous medium, explaining formation of the predominant naturally
occurring zwiebelane.

Synthesis of Alk(en)yl 1-Propenyl Disulfide S-Oxides
J. Am. Chem. Soc., Vol. 118, No. 12, 1996 2805
Scheme 8a,b
Scheme 10
(d,l-27) (eq 4) and different from authentic meso-27,26 establish-
a
R ) Me, n-Pr, CH2dCHCH2. b (i) m-CPBA. (ii) NaIO4, HOAc,
ing 26 as (Z,Z)-d,l-2,3-dimethyl-1,4-butanedithial 1,4-dioxide
(d,l-26) (Scheme 10). Dioxidation of (Z,Z)-2 and (E,Z)-2 affords
two different bissulfines, separable by HPLC. On the basis of
1H and 13C NMR analysis of the mixture, (Z,Z)-meso-2,3-
dimethyl-1,4-butanedithial 1,4-dioxide (meso-26) appears to be
formed along with d,l-26.
H2O.
Scheme 9a,b
J. Natural Occurrence of 26. Extraction of onion homo-
genates followed by column chromatography led to isolation
of (Z,Z)-d,l-26 with NMR spectra identical to those of synthetic
(Z,Z)-d,l-26. Furthermore, either normal or reversed phase
HPLC of onion homogenate extracts showed a strongly UV
absorbing peak with retention time identical to that of synthetic
(Z,Z)-d,l-26 and different from that of (Z,Z)-meso-26. Finally,
LC-APCI-MS analysis showed the MS fragmentation of
synthetic and natural (Z,Z)-d,l-26 to be superimposable.12
Bissulfine (Z,Z)-d,l-26 was also found in homogenates of shallot
and leek.27
K. Mechanistic Considerations Associated with Forma-
tion of 26. Compound (Z,Z)-d,l-26, noteworthy as the first bis-
(thial S-oxide),28 bears a close relationship to the 2,3-dimethyl-
1,4-butanedithial 1-oxides (21) postulated as intermediates in
the rearrangement of 13. We therefore propose that following
oxidation of (E,E)-2 with 2 equiv of peracid, in the chairlike
transition state for [3,3]-sigmatropic rearrangement, the vicinal
sulfinyl oxygens of (E,E)-bis(1-propenyl) Vic-disulfoxide (28)
can assume an anti geometry, suggested by theoretical calcula-
tions on an acyclic system to be favorable,29,30 leading directly
to (Z,Z)-d,l-26 (Scheme 10). Compound 28 should undergo a
particularly facile [3,3]-sigmatropic (double sulfoxide-acceler-
ated dithio-Claisen) rearrangement due to the weakness of the
S-S bond (ca. 36 kcal)29 and the rate-enhancing effect of the
two zwitterionic sulfinyl functions.17b The exclusive formation
of d,l-26 from dioxidation of (E,E)-2 is consistent with concerted
[3,3]-sigmatropic rearrangement of 28 and with the above
a
R ) Me, n-Pr, CH2dCHCH2. b (i) m-CPBA. (ii) Concerted 1,3-
shift.
formed initially, or (3) conversion of 24 to 25 involves a free
radical mechanism (Scheme 9).24b
I. Dioxidation of Bis(1-propenyl) Disulfides. Formation
of 2,3-Dimethyl-1,4-butanedithial 1,4-Dioxides. In view of
the unusual chemistry found on monooxidation of (MeCHdCHS)2
(2) to MeCHdCHS(O)SCHdCHMe (13) followed by rear-
rangement of the latter compound, we were interested in
examining the reaction of 2 with 2 equiv of oxidant. We find
that addition of a chilled CH2Cl2 solution of 2.2 equiv of
m-CPBA to (E,E)-2 in CH2Cl2 at -60 °C followed by workup
gives 26 in 34% yield. Compound 26 is a colorless unstable
solid of formula C6H10S2O2, showing a single, sharp, strongly
UV absorbing peak on HPLC on either normal or C-18 silica
gel. Extracts of onion show a strong HPLC peak at the identical
retention time (see below). The 1H and 13C NMR spectra (see
the Experimental Section) for 26 in CDCl3 and C6D6 are similar
to those for 2025 and 25, suggesting that 26 is a (Z,Z)-bissulfine
(e.g., -OsS+dCHCHMeCHMeCHdS+sO-). Sequential treat-
ment of synthetic 26 with O3 (-50 °C), H2O2/HCO2H, and
MeOH/H2SO4 gave in 88% yield a compound identical by GC-
MS and NMR with authentic d,l-dimethyl 2,3-dimethylsuccinate
(26) From methylation of d,l- and meso-2,3-dimethylsuccinic acids
(Aldrich Chemical Co.).
(27) Compound 26 shows moderate in vitro inhibition of 5-lipoxygenase
in porcine leucocytes: Wagner, H.; Breu, W. Unpublished results.
(28) Several examples of bis(thione S-oxides) are known: (a) Nakayama,
J.; Mizumura, A.; Yokomori, Y.; Krebs, A.; Schu¨tz, K. Tetrahedron Lett.
1995, 36, 8583. (b) Zwanenburg, B.; Wagenaar, A.; Thijs, L.; Strating, J.
J. Chem. Soc., Perkins Trans. 1 1973, 73.
(29) Freeman, F.; Angeletakis, C. N.; Pietro, W. J.; Hehre, W. J. J. Am.
Chem. Soc. 1982, 104, 1161.
(30) (a) Note that parallel R-disulfoxides30b-d are formed upon oxidation
of various bicyclic thiosulfinates, although they appear to be less stable
than the corresponding antiparallel R-disulfoxides: Folkins, P. L.; Harpp,
D. N. J. Am. Chem. Soc. 1993, 115, 3066. (b) Folkins, P. L.; Harpp, D. N.
J. Am. Chem. Soc. 1991, 113, 8998. (c) Freeman, F.; Lee, C. J. Org. Chem.
1988, 53, 1263. (d) Freeman, F. Chem. ReV. 1984, 84, 117.
(25) Block, E.; Revelle, L. K.; Bazzi, A. A. Tetrahedron Lett. 1980, 21,
1277.

2806 J. Am. Chem. Soc., Vol. 118, No. 12, 1996
Block et al.
Scheme 11
Scheme 13
L. Pyrolysis of Bis(1-propenyl) Disulfide (2). To comple-
ment our study of the [3,3]-sigmatropic rearrangements of
MeCHdCHS(O)SCHdCHMe (13) and MeCHdCHS(O)S(O)-
CHdCHMe (28), as well as earlier studies of pyrolysis of bis-
(2-propenyl) disulfide,7 we examined the pyrolysis of isomers
of bis(1-propenyl) disulfide (2). When a 1% solution of isomers
of 2 in benzene is kept at 85 °C for 3 h, GC-MS analysis
reveals the formation in over 85% yield of equal amounts of
two new compounds, 29a,b (Scheme 13), isomeric with the
starting material, as well as ca. 20% of 3,4-dimethylthiophene
(30), previously observed as the predominant product formed
when 2 is heated to 150-200 °C in the presence of KHSO4.33a
Prolonged heating at higher temperatures results in the conver-
sion of 29a,b to 30.33b Attempts to separate 29a,b by TLC or
HPLC were unsuccessful; extensive decomposition occurred
under all conditions tried. Compounds 29a and 29b could be
identified, respectively, as cis- and trans-2-mercapto-3,4-di-
methyl-2,3-dihydrothiophene primarily on the basis of their 1H
and 13C NMR and mass spectra. Methylation of 29a,b affords
1:4 cis- and trans-2-(methylthio)-3,4-dimethyl-2,3-dihydrothio-
phene (31a/31b) (Scheme 13). Compounds 31a,b were stable
to storage and could be separated by HPLC on a C-18 column.
The basis for assignment of cis and trans stereochemistry to
31a and 31b, respectively, appears in the supporting information.
Individual isomers of 2 were heated in benzene. HPLC
analysis during the reaction showed that all three isomers gave
the same mixture of 29a/29b and that no isomerization from
one isomer of 2 to another occurred under the pyrolysis
conditions. The relative rates of reaction of the three isomers
of 2 were found to be E,Z > E,E > Z,Z. For (Z,Z)-2, activation
parameters at 373 K are Ea ) 19 kcal/mol, ∆Hq ) 18.3 kcal/
mol, ∆Sq ) -24.8 cal/mol K, and ∆Gq ) 27.5 kcal/mol. On
the basis of the above studies, we suggest that 29a,b are formed
via a concerted dithio-Claisen [3,3]-sigmatropic rearrange-
ment34,35 from 2 (estimated S-S bond energy 60 kcal/mol)
followed by thioenolization and intramolecular addition of SH
to CHdS (Scheme 13) similar to known cyclizations involving
1,4-diketones.36 The absence of interconversion of isomers of
2 under the reaction conditions precludes a homolytic route to
Scheme 12
observations on the stereospecificity of products from monooxi-
dation of isomers of 2. On the other hand in the case of (Z,Z)-
2, steric considerations suggest that, for the sulfinyl oxygens to
be antiperiplanar, the bis(1-propenyl) Vic-disulfoxide would have
to assume an open conformation, unsuitable for a [3,3]-
sigmatropic rearrangement. In this case, a homolytic process
could occur, giving mixtures of (Z,Z)-d,l-26 and (Z,Z)-meso-
26, as is observed (Scheme 11).31 Similar, if not more complex,
stereochemical possibilities could occur on dioxidation of (E,Z)-
2. Nonantiperiplanar arrangement of the vicinal sulfinyl oxy-
gens might also be possible (e.g., see (Z,Z)-28b, Scheme 11),
leading to formation of E,Z-isomers of d,l-26 or meso-26, as is
apparently observed in the cases of dioxidation of (Z,Z)- and
(E,Z)-2.
A possible mechanism for formation of bissulfine 26 in onion
extracts is shown in Scheme 12. Acid-catalyzed activation of
(E)-MeCHdCHS(O)SR ((E)-5) by alkylsulfenyl transfer from
a second molecule of thiosulfinate32 is followed by nucleophilic
attack of (E)-MeCHdCHSOH ((E)-19) at the sulfinyl sulfur of
the sulfonium ion intermediate, giving (E,E)-28 which then
rearranges to (Z,Z)-d,l-26. Whatever mechanism is actually
involved in formation of (Z,Z)-d,l-26 in onion homogenates, it
is highly probable that R-disulfoxide (E,E)-28 is the immediate
precursor.
(33) (a) Boelens, H.; Brandsma, L. Recl. TraV. Chim. Pays-Bas 1972,
91, 141. (b) Pyrolysis of 2 at 100-110 °C affords 30 as the major product.
(34) Campbell, M. M.; Evgenios, D. M. J. Chem. Soc., Perkin Trans. 1
1973, 2866.
(35) Larsson, F. C. V.; Brandsma, L.; Lawesson, S.-O. Recl. TraV. Chim.
Pays-Bas 1974, 93, 258.
(31) If the second oxygen is also introduced into an equatorial position
and the [3,3]-sigmatropic rearrangement then occurs, the product would be
(E,E)-d,l-26. While this could isomerize to (Z,Z)-d,l-26, the carbon
framework would be unaffected; thus, formation of (Z,Z)-meso-26 cannot
be explained by this mechanism.
(36) March, J. AdVanced Organic Chemistry, 3rd ed.; John Wiley &
Sons: New York, 1985; p 791.
(32) Kice, J. L. AdV. Phys. Org. Chem. 1980, 17, 65.

Synthesis of Alk(en)yl 1-Propenyl Disulfide S-Oxides
J. Am. Chem. Soc., Vol. 118, No. 12, 1996 2807
yellow solution was warmed to -30 °C, and NH3 was evaporated under
reduced pressure. The milky white residue was diluted with THF (50
mL), and a solution of the corresponding thiosulfonate (0.2 mol) in
THF (50 mL) was added rapidly. After the addition was complete the
mixture was allowed to warm slowly to 25 °C. The mixture was poured
into cold saturated aqueous NH4Cl and hexanes, and the aqueous layer
was separated and extracted with hexanes. Organic layers were
combined, dried, and concentrated, yielding the crude disulfide which
was purified by distillation under reduced pressure or by preparative
reversed phase HPLC.
29a,b. Pyrolysis of bis(2-methyl-1-propenyl) disulfide, which
is unable to undergo thioenolization after dithio-Claisen rear-
rangement, led to a complex mixture with no major product.
Attempted intramolecular addition of the SH group of 29a,b to
the double bond under either free radical-catalyzed (UV
irradiation; thermolysis in the presence of AIBN) or acid-
catalyzed conditions were unsuccessful, leading instead to
formation of thiophene 30. We believe that thiophene 30, one
of the significant contributors to the aroma of garlic, leek,37a
and cooked or fried onions,37 is formed in these plants from
29a,b by loss of H2S. These previously unknown compounds
may play an important role in the characteristic odor and flavor
of onions and other alliaceous plants. We have used compounds
29a,b as starting materials for the synthesis of 2-(alkyldithio)-
3,4-dimethylthiophenes,38a postulated to occur in distilled oils
of scallions (Allium fistulosum L. var. Caespitosum) and Welsh
onions (Allium fistulosum L. var. Maichuon).38b,c
Methyl (E)-1-Propenyl Disulfide ((E)-3a).39 The above procedure
was followed using MeSO2SMe (12a; 25.2 g, 0.2 mol). Bulb-to-bulb
distillation at 55 °C, 17 mmHg, yielded 7.57 g (63%) of pure
disulfide: 1H NMR δ 6.10-5.90 (m, 2 H), 2.39 (s, 3 H), 1.79 (d, J )
6.6 Hz, 3 H); 13C NMR δ 130.05, 124.30, 21.98, 17.94; IR (νmax) 3011
(m), 2912 (s), 2849 (m), 1431 (s), 1376 (m), 1306 (m), 1232 (m), 935
(s) cm-1; EI-MS m/z (rel intens) 122 (M+ + 2, 5), 120 (M+, 41), 87
(4), 80 (12), 75 (16), 73 (12), 72 (24), 71 (13), 47 (23), 45 (100).
Methyl (Z)-1-Propenyl Disulfide ((Z)-3a).39 The above procedure
was followed except that after the blue color faded solid NH4Cl (8 g,
0.15 mol) was added followed by MeSO2SMe (12a; 7 g, 55.6 mmol),
with half the indicated amounts of the other reagents. Distillation gave
Experimental Section
(E)-1-Propenyl Propyl Sulfide ((E)-10).10b Propyl 1-propynyl
sulfide (8; 57 g, 0.5 mol), prepared by refluxing propyl 2-propynyl
sulfide (9) in NaOMe/MeOH for 36 h, was added all at once to a stirred
suspension of LiAlH4 (19 g, 0.5 mol) in THF (500 mL) at 0 °C. The
gray suspension was heated at reflux for 18 h, cooled to 25 °C, and
quenched by slow addition to a vigorously stirred mixture of 2 N NaOH
(500 mL) and pentane (1 L) at 0 °C. The aqueous layer was extracted
with pentane (4 × 250 mL), and the combined extracts were dried,
concentrated, and distilled to yield 47 g (81%) of (E)-10: bp 58 °C,
1
3.2 g (53%) of a pale yellow oil: bp 69-70 °C, 30 mmHg; H NMR
δ 6.13 (dq, J ) 8, 2 Hz, 1 H), 5.77 (dq, J ) 8, 7 Hz, 1 H), 2.43 (s, 3
H), 1.76 (dd, J ) 7, 2 Hz, 3 H); 13C NMR δ 128.87, 128.00, 23.03,
14.33; IR (νmax) 2973 (m), 2913 (s), 2850 (m), 1611 (m), 1430 (m),
1378 (m), 1326 (s), 1306 (m), 1140 (m), 1068 (m), 953 (m), 931 (m),
754 (m) cm-1; EI-MS m/z (rel intens) 122 (M+ + 2, 10), 120 (M+,
100), 105 (5), 87 (10), 80 (25), 75 (37), 74 (21), 73 (27), 72 (56).
(E,E)-Bis(1-propenyl) Disulfide ((E,E)-2). A solution of (E)-10
(4.64 g, 40 mmol) in 30 mL of ether was added slowly to a blue solution
of Li (0.56 g, 80 mmol) in 40 mL of NH3 at -78 °C under Ar. A
white suspension was obtained. Excess NH3 was removed below -60
°C under a 0.2 mmHg vacuum using a liquid N2 trap. More ether (40
mL) was added at -78 °C, MsCl (9.1 g, 80 mmol, 2 equiv) in ether
(40 mL) was added at -78 °C, and the mixture was stirred at 5 °C
during 1 h and then quenched with water and extracted with pentane.
The organic layer was washed with NaHCO3, dried, and concentrated
to give (E,E)-2 (2.4 g, 82%): 1H NMR δ 5.85-6.10 (AB d, J ) 15.5,
6.6 Hz, 4 H), 1.78 (dd, J ) 6.7, 1.2 Hz, 6 H); 13C NMR δ 130.49,
124.47, 18.06; GC-MS (EI) m/z 148 (M+ + 2, 1), 146 (M+, 14), 113
(7), 73 (18), 71 (15), 45 (100). Spectroscopic data for (E,E)-2 agree
well with published values.10,39
1
18 mmHg (lit.10b bp 34.5 °C, 15 mmHg); H NMR δ 5.91 (dq, J )
15.5, 2 Hz, 1H), 5.64 (dq, J ) 15.5, 7 Hz, 1 H), 2.60 (t, J ) 8 Hz, 2
H), 1.73 (dd, J ) 7, 2 Hz, 3 H), 1.66 (sextet, J ) 8 Hz, 2 H), 0.98 (t,
J ) 8 Hz, 3 H); 13C NMR δ 125.59, 123.72, 34.89, 22.88, 18.49, 13.34;
IR (νmax) 3015 (m), 2962 (s), 2873 (s), 1623 (m), 1448 (m), 1377 (m),
1335 (m), 1290 (m), 1235 (m), 936 (s), 783 (m) cm-1; EI-MS m/z (rel
intens) 116 (M+, 39), 87 (22), 74 (100), 73 (25), 71 (13), 59 (20). The
E/Z ratio was 49:1 as determined by GC.
(Z)-1-Propenyl Propyl Sulfide ((Z)-10).10b To a solution of 8 (22.8
g, 0.2 mol) in pentane (200 mL) at -4 °C under argon was slowly
added DIBAL (1 M in 350 mL of CH2Cl2, 0.35 mol) via cannula during
1 h. The solution was stirred at 25 °C for 22 h when GC analysis
indicated completion of the reaction. The mixture was then added
slowly to ice cold NaOH (1 L, 3 M) with vigorous stirring. After
extraction with ether, drying, and concentration, (Z)-10 (17.5 g, 75%,
cis:trans > 99:1), a clear colorless oil, was obtained by distillation (bp
55 °C at 18 mmHg): 1H NMR δ 5.89 (dq, J ) 9, 2 Hz, 1 H), 5.70 (dq,
J ) 9, 7 Hz, 1 H), 2.62 (t, J ) 7 Hz, 2 H), 1.68 (dd, J ) 7, 2 Hz, 3
H), 1.62 (sextet, J ) 7 Hz, 2 H), 0.97 (t, J ) 7 Hz); 13C NMR δ
125.94, 123.44, 35.71, 23.57, 14.41, 13.10; IR (νmax) 3020 (m), 2962
(s), 2932 (m), 2873 (m), 1613 (m), 1456 (m), 1379 (m), 1334 (s), 1292
(m), 1240 (m), 935 (m), 755 (m), 662 (s) cm-1; EI-MS m/z (rel intens)
118 (M+ + 2, 2), 116 (M+, 45), 87 (25), 75 (8), 74 (100), 73 (28), 72
(8), 71 (12), 59 (20). GC analysis of the freshly prepared sample shows
no E-isomer. At 0 °C (Z)-10 undergoes slow isomerization and
becomes a 1:1 E/Z mixture in about 6 weeks.
(Z,Z)-Bis(1-propenyl) Disulfide ((Z,Z)-2).39 As in the synthesis of
(E,E)-2, (Z)-10 (4.87 g, 0.042 mol) in dry Et2O (30 mL) was added to
Li (0.58 g, 0.084 mol) dissolved in liquid NH3. After the addition,
NH3 was removed at 0.025 mmHg (at -70 °C) from the now white
suspension. Ether (40 mL) was added followed by a solution of MsCl
(7.0 mL, 10.4 g, 0.091 mol) in ether (30 mL). The mixture was stirred
for 10 min at the same temperature. After quenching with water (10
mL), the mixture was rapidly warmed to 25 °C and diluted with pentane
(100 mL). Layers were separated, and the aqueous layer was extracted
with pentane (100 mL). Combined organic layers were dried (MgSO4),
filtered, and concentrated, and the residue was immediately purified
by flash column chromatography (silica gel, hexanes) to yield 1.88 g
(61%) of a yellow oil: 1H NMR δ 6.12 (qd, J ) 9.3, 1.6 Hz, 2 H),
5.76 (qd, J ) 9.6, 6.8 Hz, 2 H), 1.77 (dd, J ) 6.8, 1.6 Hz, 6 H); 13C
δ 128.72, 128.06, 14.35; GC-MS (EI) same as that for (E,E)-3.
(E)-1-Propenyl Thiobenzoate. (E)-1-Bromopropene40 (10 mmol,
1.2 g, 856 µL) in the Trapp mixture (42 mL of THF/ether/pentane,
4:1:1) was treated with 2 equiv of t-BuLi (1.7 M in pentane) at -110
°C for 1 h. Styrene sulfide41 (2.04 g, 15 mmol) in THF (10 mL) was
added at -78 °C, and the mixture was stirred at that temperature for
2.5 h. Benzoyl chloride (15 mmol) was added by a syringe, and the
mixture was stirred for 1 h at -78 °C. After extraction with ether and
washing with aqueous NaHCO3, the title compound (1.24 g, 70% yield)
General Procedure for the Synthesis of Alkyl 1-Propenyl Di-
sulfides (3). In a 1 L 3-necked round-bottom flask at -78 °C, NH3
(200 mL) was condensed. Small pieces of Li metal (1.4 g, 0.2 mol)
were added. After all the Li had dissolved, THF (50 mL) was added
to the blue solution followed by dropwise addition of a solution of 10
in THF (11.6 g, 0.1 mol in 50 mL). When the addition was complete,
more 10 was added dropwise to discharge the blue color. The pale
(37) (a) Tokarska, B.; Karwowska, K. Nahrung 1983, 27, 443. (b)
Boelens, M.; de Valois, P. J.; Wobben, H. J.; van der Gen, A. J. Agric.
Food Chem. 1971, 19, 984. (c) Brodnitz, M. H.; Pollock, C. L.; Vallon, P.
P. J. Agric. Food Chem. 1969, 17, 760.
(38) (a) Block, E.; Thiruvazhi, M. J. Agric. Food Chem. 1993, 41, 2235.
(b) Kuo, M.-C.; Chien, M.; Ho, C.-T. J. Agric. Food Chem. 1990, 38, 1378;
Kuo, M.-C.; Ho, C.-T. J. Agric. Food Chem. 1992, 40, 111, 1906. (c)
Alternative synthesis of 32: Bertram, H.-J.; Gu¨ntert, M.; Hopp, R.; Sommer,
H.; Werkhoff, P. Nat. Prod. Lett. 1993, 3, 219.
(39) Wijers, H. E.; Boelens, H.; Van der Gen, A.; Brandsma, L. Recl.
TraV. Chim. Pays-Bas 1969, 88, 519.
(40) Hayashi, T.; Konishi, M.; Okamoto, Y., Kabeta, K.; Kumada, M.
J. Org. Chem. 1986, 51, 3772.
(41) Guss, C. O.; Chamberlain, D. L., Jr. J. Am. Chem. Soc. 1952, 74,
1342.

2808 J. Am. Chem. Soc., Vol. 118, No. 12, 1996
Block et al.
was isolated by chromatography on silica gel (CH2Cl2/hexane, 1:9) as
a colorless, low melting solid: 1H NMR δ 7.95 (m, 2 H), 7.57 (m, 1
H), 7.46 (m, 2 H), 6.62 (dq, J ) 15.6, 2 Hz, 1 H), 6.03 (dq, J ) 15.6,
6.6 Hz, 1 H), 1.91 (dd, J ) 6.6, 2 Hz, 3 H); 13C NMR δ 189.90, 136.66,
133.44, 132.03, 128.59, 127.11, 116.70, 18.88; GC-MS (EI) m/z 178
(M+, 4.1), 105 (100), 77 (69.4), 51 (34.2). Hydrolysis conditions to
prepare (E)-MeCHdCHSK are as follows: (E)-1-propenyl thiobenzoate
(160 mg, 0.9 mmol) was added at -60 °C to a suspension of K2CO3
(350 mg, 2.5 mmol) in 15 mL of dry MeOH, prepared by stirring at
20 °C for 4 h. The mixture was warmed to 0 °C during 2 h.
(E)-1-Propenyl (Z)-1-Propenyl Disulfide ((E,Z)-2). A solution of
K2CO3 (350 mg, 2.5 mmol) in dry MeOH (15 mL) was stirred at 25
°C for 0.5 h. (E)-1-Propenyl thiobenzoate (160 mg, 0.9 mmol) was
added to the resultant suspension at -60 °C. The mixture was allowed
to warm to 0 °C during 2 h. Analysis by TLC showed complete
disappearance of starting material (5% EtOAc in hexanes). The reaction
was cooled to -78 °C, and (Z)-1-propenyl methanesulfonothioate ((Z)-
5; 155 mg, 1.02 mmol) in THF (2 mL) was added via syringe. The
reaction mixture was warmed to -50 °C during 30 min and quenched
with aqueous NH4Cl. Extraction with pentane afforded the crude
product which was purified by column chromatography (silica gel,
hexanes) to give (E,Z)-2 as a pale yellow liquid (79 mg, 60%; purity
>90% by GC): 1H NMR (CDCl3) δ 5.95-6.15 (m, 3 H), 5.77 (m, 1
H), 1.71 (dd, J ) 6.4, 1.1 Hz, 3 H), 1.70 (dd, J ) 6.9, 1.5 Hz, 3 H);
13C NMR (CDCl3) δ 130.7, 128.5, 124.8, 127.9, 18.1, 14.4; GC-MS
(EI) same as that for (Z,Z)-3.
mmol) in CH2Cl2 (5 mL). The reaction was warmed to room
temperature during 2 h. Solid anhydrous K2CO3 was added, and the
reaction mixture was filtered through Celite and rapidly concentrated
1
in vacuo without warming. Analysis of the crude concentrate by H
NMR showed a 6:1 (Z)-4a/(Z)-5a mixture as indicated by δ 6.32-
6.47 (m, 2H), 3.04 (s, 3H), 1.86 (dd, J ) 6, 1.5 Hz, 3H) ((Z)-4a, major)
and δ 6.52-6.20 (m), 2.69 (s), 1.97 (dd). Concentration and purifica-
tion by PCTLC using 1:9 EtOAc/hexanes as eluent yielded 256 mg
(63%) of (E)- and (Z)-4a3a (1.6:1 E/Z) with spectroscopic properties
identical to those of the mixture obtained from oxidation of (E)-3a.
Compound (Z)-5a, estimated by NMR to be originally present in ca.
10% yield, could not be isolated following chromatography in this
reaction or in repetitions of this reaction on twice the scale.
Low-Temperature Monooxidation of Isomers of 2 (NMR Study).
A solution of 2 in CDCl3 (1 mL) cooled to -60 °C containing
anhydrous Na2CO3 (1 equiv) was treated with a solution of m-CPBA
in CDCl3 (1 equiv in 0.5 mL), also cooled to -60 °C. After 5 min the
reaction mixture was transferred to an NMR tube cooled to -60 °C
using a cold pipet. The NMR probe was cooled to the required
temperature, and then the sample was introduced for analysis. Spectra
were recorded at -30 to -40 °C; the progress of each oxidation was
followed with time. Oxidation of (E,E)-2 gives a product with 1H NMR
δ 6.65-6.30 (m, 4 H), 1.99 (d, J ) 6.3 Hz, 3 H), 1.91 (d, J ) 5 Hz,
3 H) and 13C NMR δ 145.37, 136.37, 130.67, 115.61, 19.45, 17.91.
1
Oxidation of (Z,Z)-2 gives a product with H NMR δ 6.6-6.0 (m, 4
H), 1.96 (d, J ) 6.3 Hz, 3 H), 1.86 (d, J ) 6.3 Hz, 3 H). Oxidation
of (E,Z)-2 gives a mixture of two products (minor product indicated
by asterisk) with 1H NMR δ 6.65-6.20 (m, 4 H), 2.10 (d, J ) 5 Hz),
1.97* (d, J ) 7 Hz), 1.92* (d, J ) 5 Hz), 1.84 (d, J ) 7 Hz) and 13C
NMR δ 145.65, 137.52*, 136.44*, 134.96, 131.16, 117.01, 115.42*,
19.48, 17.90*, 15.75*, 15.42. The relative rate of oxidation is (E,E)-2
> (E,Z)-2 > (Z,Z)-2. The above data are consistent with products being
(E,E)-13 from (E,E)-2, (Z,Z)-13 from (Z,Z)-2, and a 3:1 (E,Z)-13/(Z,E)-
13 mixture from (E,Z)-2 (see Scheme 2 for structures; composition
based on integration of the methyl doublets).
Oxidation of Alkyl 1-Propenyl Disulfides 3 and Thiosulfinates
4/5. NMR Experiments. Crude disulfide was purified by preparative
HPLC (C-18, 4:1 MeOH/water). To a solution of the disulfide (or
thiosulfinate) containing 5 µL of an internal standard, usually dioxane
(0.0586 mmol) or anisole (0.0461 mmol), in CDCl3 at -60 °C was
added a solution of m-CPBA also at -60 °C. After stirring for 5 min,
a portion of the reaction mixture was transferred into an NMR tube at
-60 °C using a cooled pipet. The tube was introduced into the probe
at -52 °C. Analysis at various temperatures was obtained by gradually
warming the probe.
Room Temperature Oxidation of (Z,Z)-2. (()-(1r,2r,3â,4r,5â)-
and (1r,2r,3r,4r,5â)-2,3-Dimethyl-5,6-dithiabicyclo[2.1.1]hexane
5-Oxide (1a and 1b). A solution of (Z,Z)-2 (1.2 g, 8.2 mmol) in MeOH
(13 mL) was added to a MeOH/water (2:1; 216 mL) solution of NaIO4
(6.4 g, 30 mmol) at 25 °C. After 5 h, the yellow reaction mixture was
filtered through Celite which was then washed well with MeOH. The
yellow filtrate was concentrated on a rotary evaporator (bath temperature
36 °C). The remaining aqueous layer was extracted with CH2Cl2 (3 ×
50 mL). The combined organic layers were dried (MgSO4), filtered,
and concentrated until about 1 mL of solution remained. This was
immediately purified by flash column chromatography (20% EtOAc/
hexanes), yielding 1a3 as a colorless oil (350 mg, 26%) which solidifies
when cooled. Fractions containing 1b3 were also obtained (1.2%, NMR
yield).
Monooxidation of Methyl (E)-1-Propenyl Disulfide ((E)-3a).
Methanesulfinothioic Acid (E,Z)-S-1-Propenyl Ester (4a) and (E)-
1-Propenesulfinothioic Acid S-Methyl Ester (5a). A solution of
disulfide (E)-3a (330 mg, 2.75 mmol) in CH2Cl2 (20 mL) containing
anisole (0.184 mmol) as internal NMR standard was cooled to -78 °C
and treated with a cold solution of m-CPBA (475 mg, 2.75 mmol) in
CH2Cl2 (5 mL). The reaction was stirred at -78 °C for 30 min and
then warmed to -10 °C during 1 h. Solid anhydrous K2CO3 was added,
and the reaction mixture was filtered. NMR analysis at temperatures
e0 °C indicated a 3:1 (E)-4a/(E)-5a mixture and an 82% combined
yield of thiosulfinates. Concentration and purification by PCTLC using
1:4 ethyl acetate/hexanes as eluent yielded 98 mg (26%) of (E)-5a and
201 mg (54%) of (E)- and (Z)-4a3a (1.6:1 E/Z) with the following
spectral data: (E)-4a3a (major): 1H NMR δ 6.32-6.47 (m, 2 H), 2.98
(s, 3 H), 1.92 (dd, J ) 6, 1 Hz, 3 H); 13C NMR δ 137.30 (SCHd),
116.84 (MeCHd), 42.14 (CH3S(O)), 15.16 (CH3CHd); UV (hexanes)
λ (log ꢀmax) 220 (4.12), 264 (3.69). (E)-5a (minor): 1H NMR δ 6.30-
6.62 (m, 2 H), 2.60 (s, 3 H), 1.98 (dd, J ) 6, 1 Hz, 3 H); 13C NMR
135.78, 132.94, 17.32, 13.76; IR (neat, νmax) 2970 (m), 2920 (m), 1627
(m), 1438 (m), 1329 (m), 1309 (m), 1290 (m), 1129 (m), 1095 (s),
1074 (s), 949 (m) cm-1; UV (hexanes) λ (log ꢀmax) 208 (4.10), 266
(3.67); CI-MS (CH4) m/z (rel intens) 139 (M+H + 2, 18), 137 (M+H,
100), 120 (53), 113 (21), 105 (27), 88 (50). (Z)-4a3a (minor): 1H NMR
Rearrangement of Thiosulfinates 13. Upon warming to -15 °C
in the NMR probe, (E,E)-13, (E,Z)-13/(Z,E)-13, and (Z,Z)-13 rearranged
with half-lifes of ca. 15, 30, and 40 min, respectively. Rate constants
for disappearance of (Z,Z)-13, monitored by integrating the methyl
1
group H NMR signals, were determined at -25, -15, -9, and 0 °C
as 0.4 × 10-4, 3.0 × 10-4, 4.3 × 10-4, and 12.2 × 10-4 s-1
,
respectively. A plot of ln k vs 1/T gave activation parameters at 273
K: Ea ) 16 kcal/mol, ∆Hq ) 15.5 kcal/mol, ∆Sq ) -15.3 cal/mol K,
and ∆Gq ) 19.5 kcal/mol.
For analytical purposes, a solution of mixed isomers of 2 in CH2Cl2
was treated at -40 °C with dry Na2CO3 (1 equiv) and peracetic acid
(35% in HOAc, 1 equiv) and the solution was warmed to room
temperature during 2.5 h and rapidly worked up as above. Analysis
by 1H NMR spectroscopy showed peaks in the δ 4.0-5.0 ppm region
at 4.12 (s), 4.21/4.25 (dd), 4.56 (s), 4.58 (s), 4.83 (d), and 4.90 (d). If
it is assumed that the 4.12 and 4.21/4.25 peaks correspond to two
protons each and the remaining peaks in this region to a single proton,
from the integrated areas the relative amounts of the C6H10S2O isomers
is as follows: 1a, 10; 1b, 6; 14a, 10; 14b, 2; 14c, 11; 14d, 1.
For preparative purposes, solutions of individual isomers of 2 (75
mg, 0.5 mmol) in CH2Cl2 (2 mL) were treated with stirring at -40 °C
with anhydrous Na2CO3 (1 equiv) followed by peracetic acid (35% in
HOAc, 1 equiv) for 3 h and then warmed to 0 °C. The product was
δ 6.32-6.47 (m, 2 H), 3.04 (s, 3 H), 1.86 (dd, J ) 6, 1.5 Hz, 3 H); 13
C
NMR δ 144.08 (SCHd), 115.71 (MeCHd), 42.66 (CH3S(O)), 18.91
(CH3CHd); UV (hexanes) λ (log ꢀmax) 216 (4.17), 266 (3.68). 4a: IR
(neat, νmax) 3003 (m), 2912 (m), 1440 (m), 1416 (m), 1332 (m), 1087
(s), 944 (m), 673 (m) cm-1; EI-MS m/z (rel intens) 138 (M+ + 2, 2),
136 (M+, 15), 73 (100), 45 (95); CI-MS (CH4) m/z (rel intens) 139
(M+H + 2, 15), 137 (M+H, 100), 120 (22), 113 (25), 105 (7); HRMS
calcd for C4H8OS2, 136.0017, found 136.0047.
Monooxidation of Methyl (Z)-1-Propenyl Disulfide ((Z)-3a).
Methanesulfinothioic Acid (E,Z)-S-1-Propenyl Ester (4a) and (Z)-
1-Propenesulfinothioic Acid S-Methyl Ester (5a). A stirred solution
of disulfide (Z)-3a (360 mg, 3 mmol) in CH2Cl2 (10 mL) was cooled
to -60 °C and treated with a cold solution of m-CPBA (570 mg, 3.3

Synthesis of Alk(en)yl 1-Propenyl Disulfide S-Oxides
J. Am. Chem. Soc., Vol. 118, No. 12, 1996 2809
poured into cold, saturated NaHCO3 solution, and the organic layer
was separated and extracted with an equal volume of CH2Cl2. The
combined organic layers were dried and concentrated in vacuo and
dissolved in CDCl3 for analysis by NMR. The major product from
oxidation of (E,E)-2, 14a, showed the following: 1H NMR δ 5.90 (s,
1 H), 4.84 (d, J ) 3 Hz, 1 H), 2.01 (m, 1 H), 1.75 (m, 1 H), 1.24 (d,
J ) 7 Hz, 3 H), 1.01 (d, J ) 7 Hz) and small peaks at δ 4.60 (s) and
0.97 (d), attributed to isomer 14b; 13C NMR δ 100.64, 82.43, 47.59,
42.96, 18.97, 15.09; IR (neat, νmax) 2960 (m), 2917 (m), 1146 (m),
917 (m) cm-1. The 14a/14b ratio was 4:1 from NMR analysis; an
identical 14a/14b ratio was obtained by substituting m-CPBA for
peracetic acid. Oxidation of (Z,Z)-2 under the above conditions gave
a mixture of 1a (major product), as indicated by the 4.21/4.25 doublet
of doublets, among other characteristic peaks,3 along with the above
peaks for 14a (lesser product) and 14b (trace) in a 1a/14a/14b ratio of
25:3.3:1. Oxidation of (E,Z)-2 under the above conditions gave a
mixture of 1b, as indicated by the δ 4.12 singlet among other
characteristic peaks,3 along with a compound identified as 14c: 1H
NMR δ 5.88 (s, 1 H), 4.56 (d, 1 H), 2.24 (m, 2 H), 2.08 (m, 2 H), 1.10
(d, J ) 7 Hz, 3 H), 0.89 (d, J ) 7 Hz) and a small peak at 4.91 (d)
attributed to 14d; 13C NMR δ 99.81, 82.94, 43.34, 31.32, 14.60, 13.73.
The 1b/14c/14d ratio was 10:12:1 from NMR analysis. Compounds
14a-d defied all efforts at chromatographic purification (silica gel,
C-18 silica gel, alumina, Florisil, polyacrylamide gel).
saturated aqueous NaHCO3 followed by 10% aqueous sodium thio-
sulfate solution, dried, concentrated, and purified by PCTLC, giving
(E)-6a (49 mg, 57%), a yellow oil: 1H NMR δ 6.87 (dq, J ) 15, 7 Hz,
1 H), 6.47 (dq, J ) 15, 1.5 Hz, 1 H), 2.57 (s, 3 H), 2.00 (dd, J ) 7,
1.5 Hz, 1 H); 13C NMR 142.9, 133.4, 29.8, 17.0; IR (νmax) 2925 (m),
1634 (m), 1438 (m), 1329 (s), 1290 (m), 1127 (s), 945 (m) cm-1; CI-
MS m/z (rel intens) 155 (M+ + H + 2, 3), 153 (M+ + H, 13), 105
(25), 89 (40), 73 (100). Spectroscopic data for synthetic and natural6c
(E)-16a are in good agreement.
(Z)-2-(Methylsulfinyl)propanethial S-Oxides (25a). To a stirred
solution of (E,Z)-4a in CH2Cl2 (77 mg, 0.57 mmol, 3 mL) at -50 °C
was added a solution of m-CPBA (108 mg, 0.63 mmol) in CH2Cl2 (3
mL) also cooled to -50 °C. The reaction mixture was allowed to warm
to -20 °C over 2 h, filtered through anhydrous K2CO3, and concen-
trated. Rapid chromatography through silica gel using 1:20 acetone/
CH2Cl2 as eluent yielded 27 mg (31%) of a 1:1 mixture of the two
diastereoisomers, which could be further separated by TLC (ethyl
acetate/hexanes). The yield of sulfinylsulfines as determined by NMR
is 63%. Isomer A: 1H NMR δ 8.27 (d, J ) 8 Hz, 1 H), 5.87 (m, 1 H),
2.68 (s, 3 H), 1.60 (d, J ) 7 Hz, 3 H); 1H NMR (C6D6) δ 7.19 (d, J )
7.8 Hz, 1 H), 5.63 (m, 1 H), 1.98 (s, 3 H), 1.07 (d, J ) 6.2 Hz, 3 H);
13C NMR δ 174.92, 67.80, 44.55, 20.98. Isomer B: 1H NMR δ 8.44
(d, J ) 8 Hz, 1 H), 5.87 (m, 1 H), 2.69 (s, 3 H), 1.57 (d, J ) 7 Hz, 3
1
H); H NMR (C6D6) δ 7.62 (d, J ) 7.8 Hz, 1 H), 5.63 (m, 1 H), 1.94
(s, 3 H), 1.03 (d, J ) 6.2 Hz, 3 H); 13C NMR δ 175.92, 68.51, 44.62,
20.65. Both isomers, IR (νmax) 1135 (s) cm-1; CI-MS (CH4) m/z (rel
intens) 154 (M+ + 2), 152 (M+). Analysis by 1H NMR spectroscopy
of a sample of 25a in CDCl3 containing D2O showed no evidence of
deuterium incorporation. In an experiment in which an excess of
Methanesulfonothioic Acid (Z)-S-1-Propenyl Ester ((Z)-12a). In
a 250 mL three-necked round-bottomed flask with a dry ice condenser
and argon bubbler, NH3 (50 mL) was condensed at -78 °C. Lithium
(0.14 g, 20 mmol) was added in small portions, giving a blue solution.
After 10 min, (Z)-10 (1.14g, 10 mmol) in 30 mL of freshly distilled
THF was added slowly via an addition funnel. The blue color
disappeared immediately, and NH3 was removed at -40 °C under
vacuum (1 mmHg) using a liquid N2 trap during 2 h. More THF (100
mL) was added via syringe. The reaction mixture was transferred into
a dry ice cooled jacketed addition funnel, and added dropwise, during
a period of 30 min, to a solution of MsCl (23 g, 0.2 mol) in THF (50
mL) with vigorous stirring. After completion of addition, the solution
was stirred for 5 min at -78 °C, then quenched with water (100 mL),
warmed to 0 °C, extracted with ether, and washed with NaHCO3 (3 ×
100 mL) and water and the organic layer dried and concentrated.
Excess 2 and MsCl were removed under vacuum using a Vigreaux
column (30 °C, 0.2mmHg), and the residue was chromatographed on
silica gel (CH2Cl2/hexanes, 2:3) to give (Z)-15a (510 mg, 34%): 1H
NMR δ 6.33 (m, 2 H), 3.23 (s, 3 H), 1.87 (d, J ) 5.1 Hz, 3 H); 13C
1
m-CPBA was used, a product was formed having H NMR δ 8.39 (d,
J ) 8.5 Hz, 1 H), 6.19 (dq, J ) 6.2, 8.5 Hz, 1 H), 3.09 (s, 3 H), 1.65
(d, J ) 6.2 Hz, 3 H). This product, thought to be (Z)-25a, decomposed
on attempted chromatography.
Similar oxidation of (E)-5a gave the identical 1:1 25a mixture in
52% yield. Compound 25a could also be prepared by m-CPBA
oxidation of 3a in CH2Cl2 (or less effectively, CHCl3) at -20 °C for
1.5 h. In addition to the major product 25a, traces of (E,Z)-12a and
MeSO2SMe were detected. When the oxidation of 3a was run in CH2-
Cl2 at 20 °C, the major products were (E,Z)-12a and MeSO2SMe, with
minor amounts of 25a and 26. When the oxidation of 3a was run in
ether at -20 °C for 75 min, the major product was (E,Z)-12a, with
only trace amounts of 25a.
Bisoxidation of (E,E)-Bis(1-propenyl) Disulfide (2) to (Z,Z)-d,l-
26. Disulfide 2 (75 mg, 0.5 mmol) was dissolved in CH2Cl2 (2 mL)
and cooled to -60 °C, and m-CPBA (200 mg, 1.16 mmol) in CH2Cl2
(2 mL), also cooled to -60 °C, was added dropwise. The reaction
mixture was warmed to 0 °C over 2 h, and poured into cold saturated
aqueous Na2CO3. The aqueous layer was extracted with CH2Cl2 (2 ×
10 mL), and the organic layers were combined, dried (anhydrous K2-
CO3), concentrated, and analyzed by NMR. The resulting 26, purified
by rapid chromatography (silica gel, 1:20 acetone/CH2Cl2), was a
colorless solid (decomposition point 48 °C); 1H NMR (CDCl3) δ 8.09
NMR δ 139.36 (CH), 116.87 (CH), 48.57 (CH3), 15.14 (CH3); IR (νmax
)
2968 (m), 1314 (s), 1131 (s) cm-1; UV (hexanes) λmax 258, 210 nm;
GC-MS (EI) m/z (rel intens) 152 (M+, 6), 73 (24), 72 (26), 45 (100).
Methanesulfonothioic Acid (E)-S-1-Propenyl Ester ((E)-12a).
Using (E)-10 as in the procedure for the synthesis of (Z)-12a, (E)-12a
was obtained in 22% yield: 1H NMR δ 6.38 (m, 2 H), 3.26 (s, 3 H),
1.94 (d, J ) 4.8 Hz, 3 H); 13C NMR δ 145.09, 116.59, 47.87, 19.02;
CI-MS (EI) m/z same as that for the Z-isomer; HRMS calcd for
C4H8O2S2 151.9966, found 151.9958.
1
(d, J ) 9.6 Hz, 2 H), 3.73 (m, 2 H), 1.24 (d, J ) 6.5 Hz, 6 H); H
Methanesulfonothioic Acid (E,Z)-S-1-Propenyl Ester ((E,Z)-12a).
To a solution of (E,Z)-4a (443 mg, 3.26 mmol) in 7:4 HOAc/water
(11 mL) and THF (3 mL) was added NaIO4 (1.05 g, 4.9 mmol). The
mixture was stirred at 25 °C for 12 h whereupon the brown solution
was poured into a 1:1 water/CH2Cl2 mixture (100 mL). Solid Na2CO3
was added to the stirred mixture until the evolution of CO2 ceased.
The pink organic layer was separated, and the aqueous layer was
extracted once with CH2Cl2 (25 mL). The combined organic layers
were washed with saturated aqueous NaHCO3 followed by 10% aqueous
sodium thiosulfate solution, dried, concentrated, and purified by PCTLC
to yield (E,Z)-12a as a yellow oil (332 mg, 67%).
(E)-1-Propenesulfonothioic Acid S-Methyl Ester ((E)-6a, “Ally-
grin”). To a solution of (E)-4a (77 mg, 0.57 mmol) in a minimum
amount of THF were added 5 mL of acetic acid and 3 mL of water
followed by sodium periodate (320 g, 1.5 mmol), and the reaction
mixture was stirred for 12h. The brownish solution was poured into
50 mL of a 1:1 water/CH2Cl2 mixture, and solid Na2CO3 was added to
the stirred mixture until the evolution of CO2 ceased. The pink organic
layer was separated, and the aqueous layer was extracted once with 25
mL of CH2Cl2. The combined organic layers were washed with
NMR (C6D6) δ 7.06 (d, J ) 9.6 Hz, 2 H), 3.3 (m, 2 H), 0.60 (d, J )
6.3 Hz, 6 H); 13C NMR δ 179.56, 36.11, 17.34; IR (neat) 1120 (s),
1103 (s), cm-1; FD-MS indicated the parent ion at m/z 178; HRMS
calcd for C6H10S2O2 178.0122, found 178.0121. Under LC-APCI-
MS conditions (C-18 column, MeCN/water) synthetic d,l-26 showed
m/z 179 (MH+, 100%); under daughter ion analysis conditions fragment
ions were seen at m/z 160, 112, 96, 80, 68, and 41, along with a m/z
178 parent ion.
(Z,Z)-d,l-2,3-Dimethyl-1,4-butanedithial 1,4-Dioxide (d,l-26) from
Onion. Onion bulbs were peeled, homogenized at 25 °C, chilled to 4
°C, and at this temperature rapidly filtered through cheesecloth,
extracted with CH2Cl2, centrifuged, dried (MgSO4), and concentrated
in vacuo. The concentrate was subjected to column chromatography
(silica gel, 100:1 CH2Cl2/acetone), affording a mixture of 26 and 1a.
Although 26 is not readily separated from 1a, from its NMR spectra,
26 can be characterized as an isomer of 2,3-dimethyl-1,4-butanedithial
1,4-dioxide.
cis- and trans-2-Mercapto-3,4-dimethyl-2,3-dihydrothiophene
(29a,b). A solution of mixed isomers of 2 in benzene (1% solution)

2810 J. Am. Chem. Soc., Vol. 118, No. 12, 1996
Block et al.
was kept at 85 °C for 1 h. Analysis of the reaction mixture by GC
and GC-MS indicated disappearance of starting material and formation
of two compounds isomeric with 2 (85%) along with ca. 20% of 3,4-
dimethylthiophene (30; identified by its mass spectrum). Benzene was
removed in vacuo, and CDCl3 was added for NMR analysis. 29a: 1H
NMR δ 5.77 (s, 1 H), 4.87 (dd, 1 H), 2.89 (dq, 1 H), 1.99 (d, J ) 8.24
Hz, 1 H), 1.76 (s, 3 H), 1.17 (d, J ) 6.67 Hz, 3 H); 13C NMR δ 135.6,
117.5, 57.9, 49.6, 15.95, 12.25; GC-MS (EI) (retention time 11.1 min)
m/z 148 (M + 2, 2%), 146 (M+, 25%), 113 (100%), 111 (95%), 97
(78%), 79 (41%), 45 (96%). 29b: 1H NMR δ 5.65 (s, 1 H), 4.28 (dd,
1 H), 2.70 (dq, 1 H), 2.37 (d, J ) 7.27 Hz, 1 H), 1.75 (s, 3 H), 1.10
(d, J ) 6.78, 3 H); 13C NMR δ 135.2, 115.4, 54.4, 53.8, 15.9, 12.3;
GC-MS (retention time 9.5 min) m/z 148 (M + 2, 3%), 146 (M+,
25%), 113 (100%), 111 (80%), 97 (66%), 79 (40%), 45 (93%).
Pyrolysis of pure samples of (E,E)-2, (E,Z)-2, and (Z,Z)-2 led to identical
mixtures of 29a and 29b, with the order of reaction being (E,Z)-2 >
(E,E)-2 > (Z,Z)-2. Pyrolysis of 2 at 100-110 °C affords 30 as the
major product.
Competitive Grants Program/USDA (Award No. 92-375008086),
and McCormick & Co. We thank Dr. E. Calvey for APCI mass
spectral determinations, Dr. David Putman for experimental
assistance and, Professors F. Hauser, R. W. Murray, R. Parry,
and R. E. K. Winter for helpful suggestions.
Supporting Information Available: Text describing the
general experimental conditions, HPLC isolation of isomers of
2, synthesis of (E)- and (Z)-3b, (E)-3c, (E,Z)-4b,c, (E)-5b,c,
10, 11, (Z)-12b, (Z)-25b,c, and 31a,b, bisoxidation of (Z,Z)-
and (E,Z)-2, natural occurrence of 1a,b and d,l-26, and
ozonolysis of d,l-26 (8 pages). This material is contained in
many libraries on microfiche, immediately following this article
in the microfilm version of the journal, can be ordered from
the ACS, and can be downloaded from the Internet; see any
current masthead page for ordering instructions and Internet
access instructions.
Acknowledgment. We gratefully acknowledge support of
this work by the National Science Foundation, the NRI
JA953444H