Iodine-catalyzed allylic alkylation of thiols with allylic alcohols

Article abstract of DOI:10.1055/s-2008-1078254

An efficient iodine-catalyzed allylic alkylation of a wide variety of aryl and alkyl thiols with allylic alcohols is reported herein. The reaction is operationally straightforward, tolerant to air and moisture, and proceeds under very mild conditions at room temperature in good to excellent yields (50-92%). Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078254

2204
LETTER
Iodine-Catalyzed Allylic Alkylation of Thiols with Allylic Alcohols
A
llylic Alkylation
i
of Thio
a
ls oxiang Zhang, Weidong Rao, Philip Wai Hong Chan*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
Fax +65 63166984; E-mail: waihong@ntu.edu.sg
Received 2 July 2008
SR1
OH
R3
I2 (10 mol%)
Abstract: An efficient iodine-catalyzed allylic alkylation of a wide
variety of aryl and alkyl thiols with allylic alcohols is reported here-
in. The reaction is operationally straightforward, tolerant to air and
moisture, and proceeds under very mild conditions at room temper-
ature in good to excellent yields (50–92%).
R1SH
+
R2
R3
R2
1,4-dioxane
air, r.t., 1.5 h
3
1
2
R1, R2, R3 = H, alkyl, aryl
Key words, allylic alcohols, allylic thioethers, alkyl and aryl thiols,
carbon–sulfur bond formation, molecular-iodine catalysis
Scheme 1 Iodine-catalyzed allylic alkylation of thiols with allylic
alcohols
(Scheme 1). The reactions proceed in good to excellent
yields (up to 92%), at room temperature, and without the
need for inert and moisture-free reaction conditions.
There has been a recent resurgence of interest in Lewis
acid catalyzed allylic alkylation reactions that make use of
allylic alcohols as the allylating reagent.1–5 The reactions
were reported to be highly atom economical,6 forming
H2O as the only byproduct, and versatile due to the wide
availability of the alcohol substrate or carbonyl precursor.
However, in contrast to the increasing number of studies
on C–X (X = C, N, O) bond formations using allylic alco-
hols as the pre-electrophile, a similar approach for the
preparation of allylic thioethers has remained sparse.7 To
our knowledge, there are currently only two known exam-
ples on C–S bond formation that make use of such starting
materials. The first was by Firouzabadi and co-workers
who showed the allylic alkylation of thiols with allylic al-
cohols could be accomplished employing silica-supported
ZrCl4 as the catalyst.2 At about the same time, Sanz and
co-workers also described the installing of the allylic thiol
moiety through the use of polymer-supported PTSA.3 We
envisaged a different strategy that also relies on the use of
allylic alcohols but in combination with molecular iodine
catalysis as the basis for developing a metal-catalyst-free
and operationally simple version of this useful carbon–
sulfur bond-forming reaction that can be accomplished
under mild conditions. An inexpensive, commercially
available reagent that has a high tolerance to air and mois-
ture, molecular iodine has been shown to be versatile in
mediating a wide variety of organic transformations in ex-
cellent yields and with high selectivity.5,8 We recently also
demonstrated molecular iodine to be an efficient catalyst
for the allylic alkylations of 1,3-dicarbonyl compounds,
sulfonamides, and carbamates with allylic alcohols.5 As
part of an ongoing program on carbon–heteroatom bond
formations in our group,5a,9 we report herein the allylic
alkylation of a wide variety of aryl and alkyl thiols with
allylic alcohols catalyzed by molecular iodine
At the outset of this study, we chose the substrates 4-
methylbenzenethiol (1a) and (E)-1,3-di-p-tolylprop-2-en-
1-ol (2a) as the model compounds to establish the reaction
conditions (Table 1). This revealed that treatment of a so-
lution of 1,4-dioxane containing four equivalents of 1a
and one equivalent of 2a in an open round-bottom flask
with 10 mol% of iodine at room temperature for 1.5 hours
gave the best result, furnishing (E)-(1,3-di-p-tolylallyl)(p-
tolyl)sulfane (3a) in 84% yield (Table 1, entry 1). The re-
tention of trans stereochemistry in the allylated product
1
was confirmed by comparison with H NMR literature
data of closely related compounds.10 In addition, no
byproducts that could be attributed to oxidation of 1a
1
could be detected by TLC or H NMR analysis of the
crude mixtures.
Under similar conditions, an examination of solvent ef-
fects revealed slightly lower product yields of 71–80%
were obtained for reactions in CH2Cl2, toluene, THF, and
H2O (Table 1, entries 4 and 6–8). The only instance when
a markedly lower product yield was afforded was with
MeNO2 as solvent (Table 1, entry 9). Further inspection
of entries 3–5 in Table 1 reveals reaction time and loading
of the thiol nucleophile to also have an effect on the out-
come of reactions in CH2Cl2 as solvent. As previously
noted, a product yield of 79% was obtained under these
latter conditions (Table 1, entry 3). A product yield of
86% that was comparable to that afforded for the analo-
gous reaction conducted in 1,4-dioxane was only achieved
by increasing the reaction time from 1.5 to 14 h (Table 1,
entry 4). In contrast, when the reaction was repeated but
with a decrease in the loading of 1a from four to two
equivalents, a mixture of side products was afforded that
1
could not be determined by H NMR analysis (Table 1,
entry 5). As anticipated, no reaction was observed in the
absence of the iodine catalyst and both starting materials
were recovered in quantitative yields (Table 1, entry 2).
SYNLETT 2008, No. 14, pp 2204–2208
Advanced online publication: 13.08.2008
DOI: 10.1055/s-2008-1078254; Art ID: D24708ST
© Georg Thieme Verlag Stuttgart · New York
2
2
.0
8
.2
0
0
8

LETTER
Allylic Alkylation of Thiols
2205
Table 1 Optimization of the Reaction Conditionsa
to the reactions of 1a with 2h, which bears both an aryl
and alkyl group, also gave 3q as a single regioisomer (Ta-
ble 2, entry 16). Similarly, reactions of 1a with the 2° and
3° terminal allylic alcohols 2i and 2j afforded 3s as a sin-
gle regioisomer and 3r as an inseparable mixture of regio-
isomers in a 10:1 ratio (Table 2, entries 17 and 18).
Interestingly, while the reason for the differences in reac-
tivity is currently not clear, the analogous reactions of
these latter allylic alcohols in 1,4-dioxane were found to
afford a wide variety of side products that could not be
separated by flash column chromatography or identified
by 1H NMR analysis of the respective crude mixtures.
SR1
R3
OH
R3
I2 (10 mol%)
solvent, r.t.
R1SH
+
R2
R2
3a
1a
2a
R1, R2, R3 = Tol
Entry
Solvent
Yield (%)b
84
1
1,4-dioxane
1,4-dioxane
CH2Cl2
CH2Cl2
CH2Cl2
toluene
THF
2c
3
–
d
79
86
We tentatively propose that the mechanism of the present
procedure proceeds in a manner similar to that for the al-
lylic alkylation of 1,3-dicarbonyl compounds, sulfon-
amides, and carbamates with allylic alcohols.5 This
involves formation of a putative allylic carbocation spe-
cies from reaction of the allylic alcohol 2 with HI gener-
ated in situ. The regioselectivities obtained in these
reactions could be due to subsequent attack at the sterical-
ly less hindered carbon of this presumed allylic carboca-
tion intermediate by 1 to give the allylated product 3.
Alternatively, the allylic carbocation species could be at-
tacked by another molecule of 2 to produce a reactive
dimer 4 of the type shown in Scheme 2, which reacts fur-
ther in the presence of 1 to give 3. To support the possible
involvement of such intermediates, we undertook the fol-
lowing experiments. The dimer 4, obtained following the
literature procedure,5 could be converted into 3a in 85%
yield on treatment with four equivalents of 1a and 10
mol% of iodine catalyst in 1,4-dioxane for 1.5 hours at
room temperature (Scheme 2). In addition, 3a was fur-
nished in a slightly lower yield of 76% for the analogous
reaction of 1a with 2a under the same conditions as those
described in Table 1 (entry 1) but with NaI (10 mol%) and
trifluoroacetic acid (10 mol%) in place of iodine as cata-
lyst.
4e
5f
6
g
–
80
73
71
48
7
8
H2O
9
MeNO2
a All reactions were performed at r.t. for 1.5 h with an I2/1a/2a ratio
of 1:40:10.
b Isolated yield.
c Reaction conducted in the absence of the iodine catalyst.
d No reaction after 18 h based on TLC analysis.
e Reaction conducted for 14 h.
f Reaction conducted with 2 equiv of 1a.
g Unknown mixture of byproducts obtained based on TLC and 1H
NMR analysis.
To define the scope of the iodine-catalyzed allylic alkyla-
tion reactions, we applied this process to a series of sub-
stituted aryl and alkyl thiols 1a–i and allylic alcohols 2a–j.
As shown in Figure 1 and Table 2, allylic alkylation of a
variety of substituted aryl thiols with allylic alcohols bear-
ing electron-withdrawing and electron-donating groups
proceeded in good-to-excellent yields. Notably, this in-
cluded the allylic alkylations of sterically encumbered
aryl thiols 1f and 1g with 2a, which gave the correspond-
ing allylic thioethers 3f and 3g in good yields (Table 2, en-
tries 5 and 6). The present procedure was also shown to
work well for the allylic alkylations of alkyl thiols with 2a
and 2c, which gave the corresponding adducts 3h–j in
good yields (Table 2, entries 7–9). However, an inspec-
tion of entries 12–14 (Table 2) reveals the allylic alkyla-
tions of 1a with either 2d, 2e, or 2f, which contain two
slightly different substituted aryl groups, to proceed with
poor regioselectivity. In these reactions, the correspond-
ing allylated adducts 3m, 3n, and 3o were furnished as a
1:1 mixture of inseparable regioisomers. On the other
hand, under the slightly modified conditions of CH2Cl2 in-
stead of 1,4-dioxane as solvent, reaction of 1a with the
conformationally restricted allylic alcohol 2g was found
to be regioselective, giving 3p as the sole product in good
yield (Table 2, entry 15). Applying these latter conditions
Me
Me
I2 (10 mol%)
1a (4 equiv)
O
1,4-dioxane
r.t., 1.5 h
Me
Me
4
Me
S
Me
Me
3a
85%
Scheme 2 Iodine-catalyzed conversion of the dimer 4 into the allyl-
ated aryl thiol 3a
Synlett 2008, No. 14, 2204–2208 © Thieme Stuttgart · New York

2206
X. Zhang et al.
LETTER
R1
Me
OH
R1
SH
R
SH
SH
SH
R2
R2
R1
R2
1f R1 = H, R2 = Me
1g R1 = R2 = Me
1h R1 = Et, R2 = H
1i R1 = R2 = Me
2a R1 = R2 = Me
2b R1 = R2 = H
2c R1 = R2 = Br
1e
1a R = Me
1b R = H
1c R = OMe
1d R = Cl
2d R1 = Br, R2 = OEt
2e R1 = Cl, R2 = Me
OH
OH
Ph
OH
Me
OH
O
HO
Ph
Ph
Ph
O
Me
2f
2g
2h
2i
2j
Figure 1
Table 2 Iodine-Catalyzed Allylic Alkylation of Thiols 1a–i with Allylic Alcohols 2a–ja
Entry Substrates
Product
Yield (%)b
R
S
1
2
3
1b + 2a
1c + 2a
1d + 2a
3b, R = H
3c, R = OMe
3d, R = Cl
78
80c
66
Me
Me
Me
S
4
1e + 2a
3e
82
Me
Me
R1
R2
5
6
1f + 2a
1g + 2a
3f, R1 = H, R2 = Me
3g, R1 = R2 = Me
80
70
S
Me
Me
R3
7
8
9
1h + 2a
1i + 2a
1i + 2c
3h, R1 = Me, R2 = H, R3 = Et 64
R2
S
3i, R1 = R2 = R3 = Me
68
3j, R1 = Br, R2 = R3 = Me
66
R1
R1
10
11
12
1a + 2b
1a + 2c
1a + 2d
3k, R1 = R2 = H
77
Me
3l, R1 = R2 = Br
90
3m, R1 = Br, R2 = OEt
3m¢, R1 = OEt, R2 = Br
3n, R1 = Cl, R2 = Me
3n¢, R1 = Me, R2 = Cl
85d
S
13
1a + 2e
86d
R1
R2
Me
Me
65d
S
S
14
1a + 2f
3o
O
O
O
O
Synlett 2008, No. 14, 2204–2208 © Thieme Stuttgart · New York

LETTER
Allylic Alkylation of Thiols
2207
Table 2 Iodine-Catalyzed Allylic Alkylation of Thiols 1a–i with Allylic Alcohols 2a–ja (continued)
Entry Substrates
Product
Yield (%)b
Me
15
1a + 2g
1a + 2h
3p
3q
51
92
S
Me
Me
16e
S
Ph
Me
Me
Me
17e
18e
1a + 2i
1a + 2j
3r
3s
50f
56
S
S
Me
Ph
S
Ph
a All reactions were performed at r.t. for 1.5 h with an I2/1a/2a ratio of 1:40:10.
b Isolated yield.
c 1H NMR yield.
d Isolated as an inseparable mixture of regioisomers in the ratio of 1:1.
e Reaction conducted with CH2Cl2 as solvent.
f Isolated as an inseparable mixture of regioisomers in the ratio of 10:1.
In summary, we have demonstrated a practical and opera-
tionally simplistic method for the allylic alkylation of aryl
and alkyl thiols with allylic alcohols under atmospheric
conditions at room temperature that proceeds in good to
excellent yields. The present protocol is applicable to a
variety of aryl and alkyl thiols, and allylic alcohols con-
taining electron-withdrawing, electron-donating, and ster-
ically encumbered substrate combinations. Efforts are
currently under way to examine the scope and mechanism
of this carbon–sulfur bond-formation strategy and will be
reported in due course.
Acknowledgment
This work was supported by a College of Science Start-Up Grant
from Nanyang Technological University.
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General Procedure
To a solution of 1,4-dioxane (2 mL) containing 1 (4 equiv) and 2 (1
equiv) in a round-bottom flask at r.t. was added molecular iodine
(10 mol%). The reaction was stirred for 1.5 h, quenched with aq
Na2S2O3 and extracted with EtOAc (10 mL). The organic layer was
washed with brine, dried over anhyd MgSO4, concentrated, and pu-
rified by silica gel column chromatography (n-hexane–EtOAc,
400:1) to give the product 3.
Representative Data for 3a
Yellow solid; mp 90–91 °C. 1H NMR (400 MHz, CDCl3): d = 7.02–
7.30 (m, 12 H), 6.39 (dd, 1 H, J = 15.6, 8.5 Hz), 6.21 (d, 1 H,
J = 15.6 Hz), 4.82 (d, 1 H, J = 8.4 Hz), 2.32 (s, 3 H), 2.30 (s, 3 H),
2.28 (s, 3 H). 13C NMR (100 MHz, CDCl3): d = 137.6, 137.5, 137.3,
137.1, 134.1, 133.6, 131.4, 131.1, 129.5, 129.3, 129.2, 128.6, 127.8,
126.4, 56.9, 21.2, 21.2. IR (neat): n = 3020, 2920, 1643, 1510, 1491,
1018, 961, 800 cm–1. GC-MS (EI): m/z = 344 [M+]. HRMS (EI):
m/z calcd for C24H24S: 344.1593; found: 344.1453.
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Synlett 2008, No. 14, 2204–2208 © Thieme Stuttgart · New York

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LETTER
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