Allylation and Alkylation of Biologically Relevant Nucleophiles by Diallyl Sulfides

Article abstract of DOI:10.1021/acs.joc.6b02517

Allyl sulfides are bioactive phytochemicals found in garlic, onion, and other members of the genus Allium. Here we showed that diallyl disulfide and diallyl trisulfide can transfer allyl side chains to low molecular weight thiols. Diallyl monosulfide is i

Full text of DOI:10.1021/acs.joc.6b02517

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Allylation and alkylation of biologically-
relevant nucleophiles by diallyl sulfides
Kasi Viswanatharaju Ruddraraju, Zachary D. Parsons, Calvin D. Lewis, and Kent S. Gates
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02517 • Publication Date (Web): 05 Dec 2016
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Allylation and alkylation of biologicallyꢀrelevant
nucleophiles by diallyl sulfides
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Kasi Viswanatharaju Ruddraraju,a Zachary D. Parsons,a Calvin D. Lewis,a and Kent S.
Gatesa,b,*
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aUniversity of Missouri
Department of Chemistry
125 Chemistry Building
Columbia, MO 65211
bUniversity of Missouri
Department of Biochemistry
125 Chemistry Building
Columbia, MO 65211
* To whom correspondence should be addressed: email: gatesk@missouri.edu; phone:
(573) 882ꢀ6763; FAX: (573) 882ꢀ2754
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Abstract: Allyl sulfides are bioactive phytochemicals found in garlic, onion, and other
members of the genus Allium. Here we showed that diallyl disulfide and diallyl trisulfide
can transfer allyl side chains to low molecular weight thiols. Diallyl monosulfide is inert
with respect to this allyl transfer reaction. On the other hand, diallyl sulfone, a known
metabolite of diallyl monosulfide, alkylates both amines and thiols under physiologicallyꢀ
relevant conditions via isomerization to an electrophilic vinyl sulfone.
Diallyl sulfide 1, diallyl disulfide 2, and diallyl polysulfides (e.g. 3) are bioactive
phytochemicals found in garlic, onion, chive, and other members of the genus Allium
(Figure 1).1ꢀ3 These compounds display pleiotropic effects in biological systems. For
example, allyl sulfides possess cancerꢀpreventive properties, the ability to kill or arrest
the growth of cancer, fungal, and bacterial cells, induce vasorelaxation, and inhibit ADPꢀ
induced platelet aggregation.2,4ꢀ9 The biological activities of allyl polysulfides are
generally thought to arise from three molecular processes: i. polysulfideꢀthiol exchange
processes that lead to the modification of cysteine residues on critical target proteins, ii.
thiolꢀmediated release of persulfide anion (RSS–) intermediates that produce reactive
oxygen species (ROS) via redoxꢀcycling or, iii. polysulfide exchange reactions that lead
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to the release of H2S, which is a known bioactive species and putative endogenous
signaling agent (Scheme 1).5,10ꢀ15
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Figure 1. Dietary allyl sulfides and
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some oxidized metabolites
Scheme 1
Diallyl sulfides are substantially more bioactive than the corresponding saturated
analogs (e.g. 2 versus 12).5,16 This is striking because the processes illustrated in Scheme
1 do not imply a central role for the carbon side chains. Thus, it is interesting to consider
possible chemical mechanisms by which allyl groups might contribute to the bioactivity
of the allyl polysulfide natural products. Along these lines, it may be significant that
nucleophilic substitution at carbon in allylic systems is facile.17 The persulfide (pKa ~
6)18ꢀ20 and hydrogen sulfide (pKa = 7) groups embedded within the allyl polysulfides
could provide reasonable leaving groups for such reactions.21 The transfer of allyl groups
from 2 to the thiol residue in glutathione was proposed in 2007, but this supposition was
based only upon an apparent release of H2S from the reaction of 2 and glutathione.7,22
More recently, LCꢀMS was used to provide evidence for the generation of Sꢀallyl
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glutathione in this reaction;22 however, to the best of our knowledge, allyl transfer
products arising from the reaction of 2 or 3 with thiols have not been isolated or subjected
to rigorous spectroscopic characterization. Thus, we set out to examine whether allyl
polysulfides can transfer their allyl groups to biologicallyꢀrelevant nucleophiles such as
thiols and amines. In addition, we explored the reactivity of sulfoxide and sulfone
metabolites of diallyl sulfide.
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Table 1. Allyl Transfer from Compound 2.
Reactants Equiv Solvent
Rxn
Time
14 h
14 h
2 h
14 h
24 h
36 h
2 h
14 h
24 h
14 h
24 h
24 h
24 h
24 h
24 h
Product Yield
RSH
2 + 6
2 + 6
2 + 6
2 + 6
2 + 6
2 + 6
2 + 6
2 + 6
2 + 6
2 + 10
2 + 10
2 + 10
1 + 6
3 + 6
12 + 6
1
3
5
5
5
5
10
10
10
5
5
5
10
10
10
MeOH, TEA, 40˚C
MeOH, TEA, 40˚C
MeOH, TEA, 40˚C
MeOH, TEA, 40˚C
MeOH, TEA, 40˚C
MeOH, TEA, 40˚C
MeOH, TEA, 40˚C
MeOH, TEA, 40˚C
MeOH, TEA, 40˚C
MeOH, TEA, 40˚C
MeOH, TEA, 40˚C
H2O, pH 7.5, 40˚C
MeOH, TEA, 40˚C
MeOH, TEA, 40˚C
MeOH, TEA, 40˚C
7, Trace
7, 14%
7, Trace
7, 23%
7, 56%
7, 58%
7, Trace
7, 24%
7, 68%
11, 29%
11, 61%
11, 13%
7, 0%
7, 29%
13, 0%
The reaction of 2 (0.11 M) with 4ꢀtꢀbutylthiophenol 6 (1 equiv) in dry methanol
containing triethylamine (1 equiv) at 40 ˚C for 14 h did not produce isolable amounts of
1
the allyl transfer product 7. Instead, HꢀNMR and mass spectrometric analysis of the
crude reaction mixture revealed the expected disulfide exchange and oxidation products 8
(75%) and 9 (20%) alongside just a trace of 7 (Supporting Information S2). However,
when 2 was allowed to react with 3 equiv of 6 in methanol containing triethylamine (3
equiv) at 40 ˚C for 14 h a 14% isolated yield of 7 was obtained (Scheme 2, Table 1). The
spectral data for 7 isolated from this reaction matched that of authentic material prepared
by the reaction of allyl bromide with 2 (Supporting Information S3). The reaction of 2
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with 5 equiv of 6 in methanol containing triethylamine (5 equiv) at 40 ˚C gave a 23%
yield of 7 at 14 h and 56% at 24 h (Table 1). The reaction of 2 with 10 equiv of 6 in
methanol containing triethylamine (10 equiv) at 40 ˚C gave a 24% yield of 7 at 14 h and
68% at 24 h. Interestingly, the reaction of 2 with 6 (3 equiv) in tetrahydrofuran (THF)
produced 8 (29%) and 9 (71%), but not 7. Benzylamine and phenol did not react with 2
under these reaction conditions.
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Importantly, the allyl transfer reaction also operates in neutral aqueous solution.
Specifically, reaction of the water soluble thiol, 4ꢀcarboxythiophenol 10 (5 equiv), with 2
in HEPES buffer (20 mM, pH 7.5, containing 5 mM diethylenetriamine pentaacetic acid
to inhibit background autoxidation of the thiol23) for 24 h at 40 ˚C gave the allylated thiol
11 in 13% isolated yield (Scheme 3).
Scheme 2
Scheme 3
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We investigated the analogous reaction of 6 (10 equiv) with other allyl and alkyl
sulfides (~0.1 M) in methanol containing triethylamine (10 equiv) at 40 ˚C for 24 h.
Stirring 6 with the allyl monosulfide 1 did not produce detectable yields of 7 (for
comparison, diallyl disulfide 2 gave a 68% yield of 7 under these conditions). Diallyl
trisulfide 3 produced a 29% yield of 7. Stirring dipropyl disulfide 12 with 6 (10 equiv)
under these reaction conditions did not generate any of the alkyl transfer product, 4ꢀ
(propylthio)ꢀtꢀbutylbenzene 13.
To explore additional pathways by which allyl sulfides might covalently modify
biological nucleophiles, we examined the reactivity of two known4,24 metabolites of 1,
diallyl sulfoxide (4) and diallylsulfone (5). Compound 4 was prepared in 85% yield by
treatment of 1 with oxone (1.1. equiv) in THF/water (1:1) for 1 h (0 ˚C→24 ˚C) and 5
was prepared in 92% yield using a larger excess of oxone (5 equiv) under the same
reaction conditions. When the sulfoxide metabolite 4 (0.26 M) was stirred with
benzylamine (5 equiv) or the thiophenol derivative 6 (5 equiv) in methanol containing
triethylamine (5.5 equiv) at 40 ˚C for 24 h, no new products were observed. On the other
hand, when the sulfone metabolite 5 (0.23 M) was stirred with benzylamine (5 equiv)
under these reaction conditions, the alkylation product 15 was generated in 40% yield,
with significant amounts of starting material remaining at the end of the reaction (Scheme
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4). Similarly, the reaction of the arylmercaptan 6 with 5 generated a mixture of 16 and
17 under these reaction conditions (Scheme 5). The products 15ꢀ17 likely arise via baseꢀ
catalyzed isomerization of the double bond in 5 to yield the electrophilic vinyl sulfone
14.25,26 Indeed, we found that stirring of 5 in methanol containing triethylamine (5 equiv)
in the absence of benzylamine or the thiophenol 6 gave substantial amounts of the vinyl
sulfone derivative 14, that was detected by diagnostic resonances in the proton NMR at
3.67 and 1.92 ppm (Supporting Information, S12). The yield of the vinyl sulfone
observed in our experiment is generally consistent with the reported 56:44 product ratio
of allylsulfone:vinylsulfone resulting from the reflux of methylvinylsulfone in neat
triethylamine for 18 h.26 Finally, we showed that these reactions occur under
physiologicallyꢀrelevant conditions. The reaction of 5 with benzylamine in pH 7.5
HEPES buffer produced a 26% yield of 15, and the reaction of 5 with the aromatic thiol 6
under these conditions provided 16 and 17 in 34% and 8% yields respectively.
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Scheme 4
Scheme 5
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In summary, we characterized several reactions by which the side chains of allyl
sulfide natural products might contribute to their bioactivity. We found that 2 and 3 can
transfer allyl groups to nucleophilic thiol groups. The aryl thiols used here, with aqueous
pKa values near 7, may be reasonable models for reactive cysteine residues in proteins.27
The observed allyl transfer reactions involving 2 and 3 required the presence of excess of
the thiol. The nucleophilic attack of thiols on the sulfur centers in SꢀS linkages is fast28,29
and reactions containing only 1 equiv of thiol rapidly reached a “deadꢀend” in the
disulfide exchange and oxidation products 8 and 9. On the other hand, when a
stoichiometric excess of thiol was present, rapid and reversible sulfurꢀsulfur exchange
equilibria were followed by slower reactions involving nucleophilic attack of aryl thiol on
allyl side chains to generate substantial amounts of the allylated product 7. Our findings
with regard to thiol stoichiometry are in line with the recent results of Liang et al.22 Allyl
sulfide 1 is inert with respect to the allyl transfer process. The failure of allyl sulfide 1 to
generate 7 in reactions with 6 suggests that thiolate (RS–) is not an effective leaving
group in the allyl transfer process, whereas the persulfide (RSS–) or hydrogen sulfide
(HS–) leaving groups available in diallyl disulfide and diallyl trisulfide enable
nucleophilic substitutions on the allyl side chain. Eqns 1ꢀ5 depict reasonable reactions
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leading to the transfer of allyl groups from 2 to a thiol residue. Dipropyl disulfide failed
to alkylate the aryl thiol 6, consistent with the higher reactivity of allyl systems compared
to propyl systems toward nucleophilic substitution processes.17 Overall, our results
support the possibility that allylation of protein thiol groups could contribute to the
bioactivities of allyl disulfides and polysulfides.
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We found that the sulfone metabolite4 of allyl sulfide 1 readily alkylates amine
and thiol nucleophiles. These reactions likely proceed via baseꢀcatalyzed generation of
the vinyl sulfone 14. Reactions of this type could be biologically relevant. For example,
vinyl sulfones are electrophilic30 and have been described as enzyme inactivators.25,26,31ꢀ35
It is possible that one pathway for mechanismꢀbased inactivation of cytochrome P450
2E1 by 1 involves oxidation to 5, followed by conversion to the vinyl sulfone 14 as the
ultimate enzyme inactivator.4,24
EXPERIMENTAL SECTION
Materials and Methods. Unless otherwise noted, all reagents were purchased from
commercial suppliers and used without further purification. Tetrahydrofuran was
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distilled under a nitrogen atmosphere over sodium metal with benzophenone ketyl
indicator and distilled freshly. Organic solvents were evaporated using either rotary
evaporator or by blowing with a stream of nitrogen gas. Column chromatography was
performed using 230ꢀ400 mesh silica gel as stationary phase. 1HꢀNMR spectra were
recorded on either a 500 MHz or a 600 MHz spectrometer with chemical shifts reported
in δ ppm. 13CꢀNMR spectra were obtained on the same instruments at 125 and 150 MHz,
respectively. 1HꢀNMR chemical shifts (δ) are reported in ppm relative to TMS as
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internal reference. The CꢀNMR spectra employed CDCl3 as an internal reference. FTꢀ
IR spectra were obtained on NaCl plates. Melting points were recorded on a Unitemp
capillary melting point apparatus.
General procedure for allyl transfer reactions in methanol: To a stirred solution of
thiol 6 or 10 (1, 3, 5 or 10 equiv) and triethylamine (1, 3, 5 or 10 equiv) in methanol (3
mL) was added polysulfides 1, 2, 3 or 12 (1 equiv) and the mixture heated at 40 ˚C for 14
or 24 h. Solvent was completely removed in vacuo and products purified by column
chromatography on silica eluted with mixtures of ethyl acetateꢀhexanes or methanolꢀ
dichloromethane.
General procedure for allyl transfer reactions in pH 7.5 buffer: To a stirred solution
of thiol 6 or 10 (1, 3, 5 or 10 equiv) in N2ꢀpurged buffer (20 mM HEPES, 5mM DTPA or
50 mM HEPES, pH 7.5, 100 mM NaCl, 1 mM EDTA, 3 mL) was added polysulfides 1,
2, 3 or 12 (1 equiv) and the mixture heated at 40 ˚C for 14 or 24 h. Solvent was
completely removed in vacuo and products purified by column chromatography on silica
gel eluted with mixture of acetateꢀhexanes or methanolꢀdichloromethane.
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Synthesis of authentic allyl(4-(tert-butyl)phenyl)sulfane (7). To a cooled solution of
thiol (100 mg, 0.6 mmol) and triethylamine (210 µL, 1.5 mmol) in dry THF (5 mL) was
added allyl bromide (123 µL, 1.5 mmol) and the reaction stirred for 30 min at room
temperature. Solvent was completely removed in vacuo and column chromatography on
silica gel eluted with 10% methanolꢀdichloromethane gave 7 (110 mg, 89% yield) as a
colorless oil, Rf = 0.57 (hexanes); 1H NMR (600 MHz, CDCl3) δ 7.32ꢀ7.28 (m, 4H), 5.93ꢀ
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5.86 (m, 1H), 5.16ꢀ5.06 (m, 2H), 3.53 (d, J = 7.2, 1.2 Hz, 2H), 1.31 (s, 9H); C NMR
(150 MHz, CDCl3) δ 149.5, 133.8, 132.3, 129.9, 125.8, 117.5, 37.5, 34.4, 31.2; FTꢀIR
(cmꢀ1) 3074, 2962, 2900, 2861, 1492, 1356, 1121, 916, 824; HRMS (EIꢀTOF, [M]+) m/z
calcd for C13H18S: 206.1129, found 206.1135.
Synthesis of 1,2-bis(4-(tert-butyl)phenyl)disulfane (9). To a solution of hydrogen
peroxide (50 µL of 30% hydrogen peroxide) in a 1:1 mixture of diethyl ether and water
(4 mL), was added sodium carbonate (38 mg, 0.36 mmol) followed by 6 (50 mg, 0.30
mmol). The resulting mixture was stirred at room temperature for 1 h. The ether layer
was separated, washed with DI water, and dried over anhydrous Na2SO4. The solvent
o
was evaporated to yield 9 as a white solid (48 mg, 96%): mp = 70ꢀ72 C; Rf = 0.64
1
(hexanes); H NMR (600 MHz, CDCl3) δ 7.48 (d, J = 8.4 Hz, 4H), 7.36 (d, J = 8.4 Hz,
4H), 1.33 (s, 18H); 13C NMR (150 MHz, CDCl3) δ 150.4, 134.0, 127.7, 126.1, 34.5, 31.3;
FTꢀIR (cmꢀ1) 2963, 1493. 1474, 1462, 1387, 1362, 1260, 1120, 1014, 830; HRMS (ESIꢀ
TOF, [M]+) m/z calcd for C20H26S2: 330.1476, found 330.1466. Spectral data matched
published.36
Synthesis of authentic 4-(allylthio)benzoic acid (11). To a cooled solution of thiol 10
(100 mg, 0.65 mmol) and triethylamine (228 µL, 1.62 mmol) in dry THF (5 mL) was
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added allyl bromide (107 µL, 1.3 mmol) and the mixture stirred for 30 min at room
temperature. Solvent was completely removed in vacuo and column chromatography on
silica gel eluted with 10% methanolꢀdichloromethane gave 11 (102 mg, 81% yield). As a
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white solid, Rf = 0.41 (10% methanol/dichloromethane); H NMR (500 MHz, CDCl3) δ
7.99 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 8.5 Hz, 2H), 5.94ꢀ5.86 (m, 1H), 5.29 (dd, J = 17.0,
13
1.5 Hz, 1H), 5.17 (dd, J = 10.0, 1.0 Hz, 1H), 3.65 (d, J = 6.5 Hz, 2H); C NMR (125
MHz, CDCl3) δ 172.1, 144.7, 132.5, 130.4, 126.8, 118.5, 35.2; FTꢀIR (cmꢀ1) 3015, 2981,
2553, 1688, 1596, 1418, 1291, 1213, 1082, 905, 754; HRMS (ESIꢀTOF, [M + H]+) m/z
calcd for C10H11O2S: 195.0480, found 195.0486. Spectral data was consistent with
published. 37
Synthesis of (4-(tert-butyl)phenyl)(propyl)sulfane (13): To a solution of thiol 6 (50
mg, 0.30 mmol) and triethylamine (84 µL, 0.60 mmol) in dry THF (10 mL) at 0ꢀ5 ˚C,
was added 1ꢀiodopropane (44 µL, 0.45 mmol) dropwise under an atmosphere of N2. The
resulting mixture was stirred at room temperature for 2 h. The solvent was completely
removed in vacuo, the residue dissolved in ethyl acetate (10 mL), washed with HC (1 M,
2 × 15 mL) and DI water (1 × 15 mL). The ethyl acetate layer was dried over anhydrous
Na2SO4 and evaporated under reduced pressure to yield 13 as yellow oil (61 mg, 97%
1
yield). Rf = 0.42 (Hexanes); H NMR (600 MHz, CDCl3) δ 7.31 (q, J = 16.2, 8.4 Hz,
4H), 2.89 (t, J = 7.2 Hz, 2H), 1.66ꢀ1.72 (m, 2H), 1.33 (s, 9H), 1.04 (t, J = 7.2 Hz, 3H);
13C NMR (150 MHz, CDCl3) δ 149.0, 133.3, 129.3, 125.9, 36.1, 34.4, 31.3, 22.7, 13.5; IR
(cmꢀ1) 2954, 2927, 2863, 1496, 1116, 906, 819, 728; HRMS (EIꢀTOF, [M]+) m/z calcd
for C13H20S: 208.1286, found 208.1291.
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Synthesis of diallyl sulfoxide (4). To a cooled suspension of Oxone® (5.92 g, 19 mmol)
in THF/H2O (1:1) was added diallyl sulfide (2.0 g, 17 mmol) at 0 ˚C slowly and stirred at
room temperature for 1 h. The reaction mixture was filtered and THF evaporated in
vacuo. The resulting residue was extracted with dichloromethane (2 × 20 mL), the
organic layer dried over Na2SO4, and concentrated to afford crude product. The crude
product was purified by column chromatography on silica gel eluted with 40% ethyl
acetate/hexanes to give 4 as a colorless oil (1.90 g, 83%). Rf = 0.22 (40% ethyl
acetate/hexanes); 1H NMR (500 MHz, CDCl3) δ 5.87−5.79 (m, 2H), 5.39 (d, J = 10.0 Hz,
2H), 5.33 (d, J = 17.0 Hz, 2H), 3.48 (d, J = 7.5 Hz, 1H), 3.45 (d, J = 7.0 Hz, 1H), 3.35 (d,
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J = 7.5 Hz, 1H), 3.33 (d, J = 7.5 Hz, 1H); C NMR (125 MHz, CDCl3) δ 125.5, 123.5,
53.9; HRMS (ESIꢀTOF, [M + Na]+) m/z calcd for C6H10OSNa: 153.0350, found
153.0346. Spectral data was consistent with published.38
Synthesis of diallyl sulfone (5). To a cooled suspension of Oxone® (26.9 g, 87 mmol)
in THF/H2O (1:1) was added diallyl sulfide (2.0 g, 17 mmol) at 0 ˚C slowly and the
resulting mixture stirred at room temperature for 1 h. The reaction mixture was filtered
and THF was evaporated in vacuo. The resulting residue was extracted with
dichloromethane (2 × 20 mL), the organic layer dried over Na2SO4, and concentrated to
afford the sulfone 5 as a colorless oil (2.3 g, 92% yield). Rf = 0.58 (40% ethyl
acetate/hexanes); 1H NMR (500 MHz, CDCl3) δ 5.93−5.85 (m, 2H), 5.48 (d, J = 10.0 Hz,
2H), 5.41 (d, J = 17.5 Hz, 2H), 3.68 (d, J = 7.5 Hz, 4H); 13C NMR (125 MHz, CDCl3) δ
124.9, 124.8, 55.9; IR (cmꢀ1) 3090, 3027, 2979, 2919, 1640, 1426, 1318, 1290, 1132, 937,
869; HRMS (EIꢀTOF, [M]+) m/z calcd for C6H10O2S: 146.0402, found 146.0406.
Spectral data was consistent with published.38
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Synthesis of 1-(allylsulfonyl)-N-benzylpropan-2-amine (15) in methanol. To a stirred
solution of diallyl sulfone 5 (100 mg, 0.68 mmol) and triethylamine (520 µL, 3.76 mmol)
in methanol (3 mL) was added benzylamine (373 µL, 3.42 mmol) and the reaction heated
at 40 ˚C for 14 h. The solvent completely removed by blowing with a stream of nitrogen
gas and column chromatography on silica gel eluted with 70% ethyl acetateꢀhexanes gave
15 as a colorless oil (69 mg, 40% yield). Spectral data provided below.
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Synthesis of 1-(allylsulfonyl)-N-benzylpropan-2-amine (15) in pH 7.5 buffer. To a
stirred solution of diallyl sulfone 5 (50 mg, 0.34 mmol) in buffer (50 mM HEPES, pH
7.5, 100 mM NaCl, 1 mM EDTA, 2 mL) was added benzylamine (186 µL, 1.71 mmol)
and the mixture heated at 40 ˚C for 24 h. The solvent was completely removed by
blowing stream of nitrogen gas on the mixture. The residue was dissolved in ethyl
acetate and washed with H2O and brine. The organic layer evaporated in vacuo and
column chromatography on silica gel eluted with 70% ethyl acetateꢀhexanes gave 15 as a
1
colorless oil (23 mg, 26% yield). Rf = 0.19 (50% ethyl acetate/hexanes); H NMR (500
MHz, CDCl3) δ 7.37−7.33 (m, 4H), 7.31−7.26 (m, 1H), 5.96−5.88 (m, 1H), 5.47 (d, J =
10.0 Hz, 1H), 5.38 (d, J = 17.5 Hz, 1H), 3.91−3.83 (m, 2H), 3.78−3.71 (m, 2H),
3.46−3.33 (m, 1H), 3.15 (dd, J = 14.5, 8.0 Hz, 1H), 2.94 (dd, J = 14.5, 4.0 Hz, 1H), 1.29
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(d, J = 6.5 Hz, 3H); C NMR (125 MHz, CDCl3) δ 139.7, 128.5, 128.1, 127.1, 125.1,
124.6, 58.9, 57.2, 51.0, 47.9, 20.6; FTꢀIR (cmꢀ1) 3620, 2965, 2923, 1485, 1389, 1305,
1110, 835; HRMS (ESIꢀTOF, [M + H]+) m/z calcd for C13H19NO2S: 254.1215, found
254.1219.
Synthesis of (4-(tert-butyl)phenyl)(1-(vinylsulfonyl)propan-2-yl)sulfane (16) and
(sulfonylbis(propane-1,2-diyl))bis((4-(tert-butyl)phenyl)sulfane) (17) in methanol.
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To a stirred solution of diallyl sulfone 5 (100 mg, 0.68 mmol) and triethylamine (520 µL,
3.76 mmol) in methanol (3 mL) was added thiol 6 (589 µL, 3.42 mmol) and the mixture
heated at 40 ˚C for 14 h. The solvent was completely removed by blowing a stream of
nitrogen gas on the mixture and the products 16 and 17 were isolated by column
chromatography on silica gel eluted with 20% ethyl acetateꢀhexanes) as colorless oils, in
43% yield (92 mg) and 19% yield (62 mg), respectively. Spectral data below.
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Synthesis of (4-(tert-butyl)phenyl)(1-(vinylsulfonyl)propan-2-yl)sulfane (16) and
(sulfonylbis(propane-1,2-diyl))bis((4-(tert-butyl)phenyl)sulfane) (17) in pH 7.5
buffer. To a solution of diallyl sulfone 5 (50 mg, 0.34 mmol) in buffer (50 mM HEPES,
pH 7.5, 100 mM NaCl, 1 mM EDTA, 2 mL) was added thiol 6 (294 µL, 1.71 mmol) and
the mixture heated at 40 ˚C for 24 h. The solvent was completely removed by blowing on
the mixture with a stream of nitrogen gas. The residue was mixed with ethyl acetate (3
mL) and the resulting cloudy mixture washed with H2O (2 × 1.5 mL) and brine to remove
buffer salts. The organic layer was evaporated in vacuo and products 16 and 17 isolated
by column chromatography on silica gel eluted with 20% ethyl acetateꢀhexanes as
colorless oils in 34% yield (36 mg) and 8% yield (13 mg), respectively. (16) Rf = 0.15
1
(10% ethyl acetate/hexanes); Colorless oil; H NMR (500 MHz, CDCl3) δ 7.38−7.34 (m,
4H), 5.82−5.74 (m, 1H), 5.37 (dd, J = 10.5, 1.0 Hz, 1H), 5.28 (dd, J = 17.0, 1.0 Hz, 1H),
3.71−3.61 (m, 3H), 3.32 (dd, J = 10.5, 1.0 Hz, 1H), 2.97 (dd, J = 15.0, 10.0 Hz, 1H), 1.53
(d, J = 6.5 Hz, 3H), 1.31 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 151.6, 133.1, 129.0,
126.3, 124.8, 124.7, 59.0, 56.8, 37.4, 34.61, 31.2, 20.7; FTꢀIR (cmꢀ1) 2962, 2923, 2865,
1491, 1391, 1310, 1129, 827; HRMS (ESIꢀTOF, [M + Na]+) m/z calcd for
C16H24O2S2Na: 335.1115, found 335.1109.
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(17) Rf = 0.29 (10% ethyl acetate/hexanes); Colorless oil; H NMR (500 MHz, CDCl3) δ
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7.36−7.31 (m, 8H), 3.66−3.61 (m, 2H), 3.28 (td, J = 13.5, 3.5 Hz, 2H), 3.04 (dd, J = 14.0,
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9.5 Hz, 1H), 2.94 (dd, J = 14.0, 9.5 Hz, 1H), 1.46 (d, J = 5.0 Hz, 6H), 1.31 (s, 18H); C
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NMR (125 MHz, CDCl3) δ 151.6, 151.5, 133.1, 132.9, 128.8, 128.7, 126.3, 60.2, 59.9,
37.2, 37.1, 34.6, 34.5, 31.1, 20.6, 20.5; FTꢀIR (cmꢀ1) 2961, 2926, 2860, 1490, 1456, 1394,
1264, 1128, 828; HRMS (ESIꢀTOF, [M + Na]+) m/z calcd for C26H38O2S3Na: 501.1932,
found 501.1929.
ASSOCIATED CONTENT
Supporting Information. The Supporting Information is available free of charge on the
ACS Publications website at DOI:10.1021/acs.joc.
1Hꢀ and 13CꢀNMR spectra.
AUTHOR INFORMATION
Corresponding Author
*E-mail: gatesk@missouri.edu
ACKNOWLEDGEMENTS
This was made possible in part by Grant Number P50AT006273 from the National
Center for Complementary and Alternative Medicines (NCCAM), the Office of Dietary
Supplements (ODS), and the National Cancer Institute (NCI). Its contents are solely the
responsibility of the authors and do not necessarily represent the official views of the
NCCAM, ODS, NCI, or the National Institutes of Health.
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