Green synthesis of vicinal dithioethers and alkenyl thioethers from the reaction of alkynes and thiols in water

Article abstract of DOI:10.1002/ejoc.200901101

The reaction of a wide range of alkynes with thiols to give vicinal dithioethers in water, under mild conditions, is reported. In addition, non-terminal propargyl alcohols react with aryl thiols in water to produce a highly regio-and stereoselective monohydrothiolation product, (E)-alkenyl thioether. Reaction mechanism and computational studies on the selectivity of the product are presented.

Full text of DOI:10.1002/ejoc.200901101

FULL PAPER
DOI: 10.1002/ejoc.200901101
Green Synthesis of Vicinal Dithioethers and Alkenyl Thioethers from the
Reaction of Alkynes and Thiols in Water
Zhuang Jin,[a] Bo Xu,[a] and Gerald B. Hammond*[a]
Keywords: Radicals / Green chemistry / Alkynes / Thiols / Hydrothiolation
The reaction of a wide range of alkynes with thiols to give
stereoselective monohydrothiolation product, (E)-alkenyl
vicinal dithioethers in water, under mild conditions, is re- thioether. Reaction mechanism and computational studies on
ported. In addition, non-terminal propargyl alcohols react
with aryl thiols in water to produce a highly regio- and
the selectivity of the product are presented.
in the synthesis of dendrimers (so called “thiol-ene click”
chemistry).[12] The spectrum of application of these dendri-
mers, ranging from medicine to nanoengineering[13] should
spur the development of novel and efficient synthesis of
macromolecules.[14] Herein, we wish to report an atom-eco-
nomical and “green” synthesis of vicinal dithioethers from
the reaction of alkyne and thiol without the use of metal
catalysts or radical initiators, and using water as the sole
solvent. Furthermore, this method can also be used for re-
gio- and stereoselective monohydrothiolation of propargyl
alcohols, which leads to an effective synthesis of alkenyl
thioethers with exclusive (E)-selectivity.
Introduction
Organosulfur compounds have become increasingly im-
portant as the role of sulfur is probed deeper in biological
processes, new materials, and chemical synthesis.[1] As a re-
sult, the synthesis of organosulfur compounds has attracted
much attention.[2] Specifically, vicinal dithioethers and alk-
enyl thioethers have been widely used as target or interme-
diates.[3–6] For example, vicinal dithioethers have been used
as ligands for zirconium or titanium complexes for alkene
polymerization[3–5] and hydroamination.[7]
Vicinal dithioethers can be made by nucleophilic substi-
tutions,[3,4] or nucleophilic ring-opening reaction of thi-
olate.[5] Vicinal dithioethers can also be prepared from an
alkene and a disulfide under acid or metal catalysis.[8]
Hydroelementation is a versatile and atom-efficient method
for installing heteroelements to unsaturated carbon–carbon
bonds.[9] Therefore, one of the most straightforward meth-
ods to make vicinal dithioethers is the dihydrothiolation of
an alkyne (Scheme 1). Under controlled conditions,
monohydrothiolation of alkynes could yield alkenyl thi-
oethers. There are reports on the preparation of vicinal di-
thioethers from alkynes and thiols in organic solvents[10]
using various radical initiators, and/or heating or UV light.
The use of water as solvent has also been reported by Osh-
ima and co-workers, who isolated the vicinal dithioether as
a side product, during their investigation of thiolyne radical
reactions in water assisted by a water-soluble radical initia-
tor.[11] In all these literature syntheses, there are detracting
experimental limitations, including the use of metal cata-
lysts, high temperatures or radical initiators, and organic
solvent. The addition of thiols to alkenes has been used
Scheme 1. Synthesis of vicinal dithioethers and alkenyl thioethers
from alkynes and thiols.
Results and Discussion
Effects of Solvents on Dihydrothiolation
We used the reaction of 1-hexyne and 4-methylbenz-
enethiol as our model reaction (Table 1). While THF,
MeOH, H2O, individually or as a mixture, or non-solvent
conditions gave good results, traditional organic solvents,
such as CH3CN, CH2Cl2 and toluene, were not satisfactory.
Considering both, chemical yields and the increasing en-
vironmental consciousness of the scientific community, we
chose water as the ideal reaction media. It is surprising that
water was found to be the best solvent for the reaction con-
[a] Department of Chemistry, University of Louisville,
Louisville, Kentucky 40292, USA
E-mail: gb.hammond@louisville.edu
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901101.
168
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Green Synthesis of Vicinal Dithioethers and Alkenyl Thioethers
Table 1. Effect of solvents on dihydrothiolation of alkyne 1.[a]
Table 2. Dihydrothiolation of alkyne 1.[a]
[a] 1 mmol alkyne, 2.4 mmol 4-methylbenzenthiol and 0.5 mL sol-
vent, reacted for 24 h at room temp. [b] Determined by NMR,
0.4 mmol benzyl bromide as internal standard.
sidering that both starting material and product are vir-
tually insoluble in water. According to Sharpless and co-
workers,[15] reaction rates can be accelerated when insoluble
reactants were stirred in aqueous suspension, denoted as
“on water” conditions. Thus, this reaction could be consid-
ered as an “on water” reaction.
Scope of Aqueous Dihydrothiolation
With optimized conditions in hand, we examined the
scope of this dihydrothiolation reaction; the results are
summarized in Table 2. 1-Hexyne and aryl thiols reacted
smoothly (Table 2, Entries 1, 2 and 3) and in good yields.
The reaction of functionalized terminal alkynes, such as
methyl propargyl ether and 4-pentyn-1-ol, with an aryl thiol
also gave good to excellent yields (Entries 4 and 5). How-
ever, propargyl alcohol and 2-hexyne reacted with 4-chloro-
thiophenol to produce moderate yields of 3 (Entries 6 and
7). The low yield in Entry 8 is probably due to the volatility
of the substrate, as higher molecular weight alkynes reacted
[a] 1 mmol alkyne, 2.4 mmol thiol and 0.5 mL water, reacted at
indicated temperature for 24 h. [b] Isolated yields.
Our mechanistic studies hinted that the reaction proba-
effectively with aliphatic thiols under mild heating (Entries bly proceeded through a radical mechanism, because no re-
9 and 10). action occurred in the presence of galvinoxyl free radical
Unfortunately, under our conditions, phenylacetylene (1.1 equiv. to thiol).[17] The possibility of a nucleophilic ad-
and other internal alkynes reacted with thiols to give only dition could be ruled out since nucleophilic dihydrothiol-
the monohydrothiolation product.[16] Upon further investi- ation of alkynes normally gives thioacetals.[18] Furthermore,
gation, we found that aryl thiols are more reactive than ali- small amounts of disulfide (less than 5% yield based on
phatic thiols; aryl chloride accelerates the dihydrothiol- thiol), formed from the homocoupling of thiolate radical,
ation, and weak electron-donating groups slow the reaction. were observed in the course of this study, which is consis-
The observed reaction rates follow this order: 4-chloro- tent with the proposed radical mechanism. Furthermore, no
thiophenol Ͼ thiophenol Ͼ 4-methylbenzenthiol. Strong hydration product was found in the reaction mixture. The
electron-withdrawing groups, such as nitro, methyl ester radical initiator could be dioxygen in the air. The specific
and carboxylic acid, on the para position of thiophenol hin- role of the solvent is not clear at this time, it seems water
der the reaction. This may be related to their ease of emulsi- has some ability to stabilize the radical intermediate and
fication, as 4-nitrothiophenol, 4-mercaptobenzoic acid and therefore facilitates the radical-mediated reaction. A litera-
methyl 4-mercaptobenzoate do not form an emulsion with ture report[19] speculated that a hydrogen bond between
alkynes, whereas the thiol in Table 2 readily formed an thiol and water could enable a nucleophilic addition to the
emulsion with alkyne in water upon stirring.
alkene.
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169

Z. Jin, B. Xu, G. B. Hammond
FULL PAPER
Regio- and Stereo-Selective Monohydrothiolation of Non-
Terminal Propargyl Alcohols
lective manner. The thiol only attacked the carbon next to
the alcohol and only the (E)-isomer was isolated. The reac-
tion scope is shown in Table 3. But-2-yn-1-ol and 4-chloro-
thiophenol gave a moderate yield of product with high ster-
eoselectivity (Entry 1). Similarly, 1h reacted with three dif-
ferent thiophenols in moderate to high yields with high (E)-
selectivity (Entries 2–4). Entry 5 also showed satisfactory
yield and stereoselectivity. Reaction of secondary alcohols
(1j and 1k) with thiophenols gave satisfactory yields and
excellent stereoselectivity (Entries 6–9), while tertiary pro-
pargyl alcohol 1l gave very high stereoselectivity (100% E),
albeit in low yield (Entry 10). Reaction of 1m and 4-chloro-
thiophenol 2c was also highly stereoselective (Entry 11). In
Entries 12 and 13, we investigated substrates having a
phenyl group; both of them, without exception, reacted
with aryl thiols to give products with very high stereoselec-
tivity. During this study, we also found that alkyl thiols are
not effective under these conditions, and terminal alkynes,
such as propargyl alcohol, overreacted with thiophenol to
give dihydrothiolation products (Table 2). Regio- and ster-
eoselective monohydrothiolation was observed only with
non-terminal propargyl alcohols, even with excess thiol in
water. While the monohydrothiolation of non-terminal pro-
pargyl alcohol with thiol has been studied before,[20–22] our
mild reaction conditions showed distinctive regio- and
stereoselectivity for a wider range of substrates. A case in
point is the base mediated nucleophilic addition of thiol to
propargyl alcohol (Scheme 2, top) that yields the trans ad-
duct product, Z-alkenyl thioether[20] or a mixture of (Z)-
and (E)-alkenyl thioethers.[21] And, addition of a thiol,
using a radical initiator, usually affords a mixture of (Z)-
(predominant) and (E)-alkenyl thioethers (Scheme 2, bot-
tom).[22]
While investigating dihydrothiolation conditions for non-
terminal propargyl alcohols (e.g. 1g), we found, to our sur-
prise, that only the monohydrothiolation product was ob-
tained, and this reaction proceeded in a regio- and stereose-
Table 3. Regio and stereoselective monohydrothiolation of propar-
gyl alcohols.[a]
Scheme 2. Nucleophilic and radical additions of thiol to propargyl
alcohols.
The reason for the high regio- and stereoselectivity of 4
can be explained by the relative stability of vinyl radical
intermediates (Scheme 3, top). The vinyl radical intermedi-
ates C and D are higher in energy than A and B [Gaussian
03, UB3LYP/6-311+G(d)]. This can explain why the thiol
always attacks the carbon next to hydroxymethyl group.
The stereoselectivity outcome of 4 can be explained by ste-
ric effects and the isomerization of vinyl radical A to B. It
is widely accepted that a hydrogen donor can approach
from the less hindered side of the vinyl radical.[23] The
bulkiness of hydroxymethyl group in radical A may hinder
[a] 1 mmol alkyne, 1.2 mmmol thiol and 0.25 mL water reacted for
12 h at room temp. [b] Isolated yield, E and Z were determined by
NOESY studies.
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Green Synthesis of Vicinal Dithioethers and Alkenyl Thioethers
Scheme 3. Regioselectivity and stereoselectivity considerations.
the approach of the hydrogen donor (thiol) to form a (Z)- catalyzed cross-coupling reactions with Grignard rea-
isomer (Scheme 3, bottom). However, the thiol can easily gents[25] or organozinc reagents[26] to give functionalized al-
approach the less hindered side of the vinyl radical B to lylic alcohols, which are important intermediates in total
produce the (E)-isomer. As a result, radical A may slowly synthesis[27] and methodology.[28]
isomerize to radical B. This is consistent with the fact that
the bulkier the hydroxyalkyl, the higher the stereoselectivity
observed (Table 3). And, the mild conditions (room tem-
perature/water as solvent) minimized the isomerization of
Conclusions
We have found that a wide range of alkynes react with
excess thiols to give vicinal dithioethers under mild condi-
tion using only water as solvent, without radical initiator
or UV light sources. Alternatively, non-terminal propargyl
alcohols reacted with phenyl thiols in water to produce (E)-
alkenyl thioethers in highly regio- and stereoselective fash-
ion. Considering the mild conditions of our reaction, it
could have great potential in the preparation of highly
branched dendrimers, and as linkers incorporating fluores-
cence tags in biological applications.
the final product. This is in contrast with literature reports
in which isomerization may occur at high temperature
(Scheme 2, bottom).[22]
Alkenyl thioesters have already demonstrated their util-
ity.[24] Compound 4 can be used in further transformations;
for example, the free hydroxy group in 4 can be protected
to give 5, and 4 can be easily oxidized to sulfone 6 with
mCPBA (Scheme 4). Both 5 and 6 have been used in nickel-
Experimental Section
General: Substrates 1m and 1o were prepared using a literature
method.[29] Other substrates and reagents were commercially ob-
tained from Alfa or Adrich, and were used without further purifi-
cation. Structures were identified by NMR spectra, assisted by ele-
1
mental analysis or/and IR spectra. H and 13C NMR spectra were
recorded at 500 and 125 MHz, respectively, using CDCl3 as solvent.
The chemical shifts were reported in δ (ppm) value relative to
CDCl3 (δ =7.26 ppm for 1HNMR and 77.0 for 13C NMR), and
multiplicities are indicated by s (for singlet), d (doublet), dd (double
Scheme 4. Synthetic transformations of 4.
Eur. J. Org. Chem. 2010, 168–173
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171

Z. Jin, B. Xu, G. B. Hammond
FULL PAPER
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doublet), m (multiplet), and br (broad). Coupling constant, J, was
reported in Hz.
[3]
[4]
[5]
General Procedure for Dihydrothiolation of Alkynes: Alkyne
(1 mmol), thiol (2.4 mmol), and water (0.5 mL) were added to a
reaction flask containing a stir bar, and the resulting mixture was
sealed and stirred for 24 h at the indicated temperature. Then the
mixture was extracted by CH2Cl2 (10 mLϫ3), dried with Na2SO4,
filtered, and concentrated in vacuo to finish crude residue, which
was subjected to silica gel column chromatography using gradient
elution from pure hexane to a mixture of hexane/ethyl acetate
(10:1) to get final pure product 3.
1,2-Bis(p-tolylsulfanyl)hexane (3a): 241 mg, 73%, Colorless oil.
C20H26S2 (330.2): calcd. C 72.67, H 7.93; found C 72.80, H 8.25.
1
IR (neat): ν = 2955, 2925, 1491 and 804 cm–1. H NMR (500 Hz.
˜
CDCl3): δ = 0.93 (t, 3J = 7.0 Hz, 3 H, CH3), 1.29–1.39 (m, 2 H,
CH2CH2CH3), 1.43–1.46 (m, 1 H, SCHCHHCH2), 1.53–1.59 (m,
2 H, CH2CH2CH2), 1.95–1.98 (m, 1 H, SCHCHHCH2), 2.34 (s, 3
H, CH3), 2.36 (s, 3 H, CH3), 2.86 (dd, J = 10, 2J = 13.25 Hz, 1
3
[6]
[7]
[8]
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H, SCHCHHS), 3.05–3.10 (m, 1 H, SCHCH2S), 3.23 (dd, 3J = 4.0,
2J = 13.75 Hz, 1 H, SCHCHHS), 7.04 (d, J = 8.0 Hz, 2 H, PhH),
3
3
3
7.09 (d, J = 7.5 Hz, 2 H, PhH), 7.13 (d, J = 7.5 Hz, 2 H, PhH),
7.25 (d, J = 8.0 Hz, 2 H, PhH) ppm. 13C NMR (CDCl3, 125 Hz):
3
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δ = 14.29, 21.31, 21.41, 22.79, 29.22, 32.44, 40.11, 48.80, 129.92,
129.94, 130.52, 130.68, 132.45, 133.39, 136.51, 137.60 ppm.
General Procedure for Monohydrothiolation of Non-Terminal Pro-
pargyl Alcohols: Alkyne (1 mmol), thiol (1.2 mmol), and 0.25 mL
water were added to a reaction flask containing a stir bar, and the
resulting mixture was sealed and stirred for 12 h at room temp.
Final product 4 is purified from the mixture by silica gel column
chromatography using gradient elution from pure hexane to mix-
ture of hexane/ ethyl acetate (10:1).
[9]
(E)-2-(4-Chlorophenylsulfanyl)but-2-en-1-ol (4a): 113 mg, 53%, Col-
orless oil. C10H11ClOS (214.0): calcd. C 56.00, H 5.12; found C
55.94, H 5.16. IR (neat): ν = 3355, 2912, 2854, 1474, 1388, 1079,
˜
[10]
1
3
1011 and 816 cm–1. H NMR (CDCl3, 500 Hz): δ = 1.94 (d, J =
3
7.0 Hz, 3 H, CH3), 4.10 (s, 2 H, CH2OH), 6.38 (q, J = 6.5 Hz, 1
H, HC=CS), 7.20–7.27 (m, 4 H, PhH) ppm. 13C NMR (CDCl3,
125 Hz): δ = 15.31, 65.99, 129.11, 130.04, 132.09, 132.96, 134.02,
135.91 ppm.
Acknowledgments
We are grateful to the US National Science Foundation (NSF) for
financial support (CHE-0809683).
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Green Synthesis of Vicinal Dithioethers and Alkenyl Thioethers
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Received: September 25, 2009
Published Online: November 17, 2009
Eur. J. Org. Chem. 2010, 168–173
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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