Iron-catalysed Markovnikov hydrothiolation of styrenes

Article abstract of DOI:10.1002/adsc.201100731

The bis(triflimide)iron(III) salt catalyzes the hydrothiolation of styrenes in a Markovnikov fashion with good selectivities and high yields. After isolation, different benzylic thioethers are obtained. This iron(III) catalyst is unique in terms of regioselectivity and represents a sustainable and economic alternative to those processes based on stoichiometric reagents. Copyright

Full text of DOI:10.1002/adsc.201100731

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DOI: 10.1002/adsc.201100731
Iron-Catalysed Markovnikov Hydrothiolation of Styrenes
Jose R. Cabrero-Antonino,a Antonio Leyva-Pꢀrez,a,* and Avelino Cormaa,*
a
Instituto de Tecnologꢁa Quꢁmica (UPV-CSIC), Universidad Politꢀcnica de Valencia, Consejo Superior de Investigaciones
Cientꢁficas, Avda. de los Naranjos s/n, 46022 Valencia, Spain
Fax : (+34)-9638-77809; phone: (+34)-9638-77800; e-mail: anleyva@itq.upv.es or acorma@itq.upv.es
Received: September 20, 2011; Revised: November 14, 2011; Published online: February 23, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100731.
Abstract: The bis(triflimide)ironACTHNUTRGNE(NUG III) salt catalyzes alternative to those processes based on stoichiomet-
the hydrothiolation of styrenes in a Markovnikov ric reagents.
fashion with good selectivities and high yields. After
isolation, different benzylic thioethers are obtained. Keywords: benzylic thioethers; bis(triflimide)-
This ironACHTUNGTRENNUNG(III) catalyst is unique in terms of regiose- ironACHTUNGTRENN(UGN III); hydrothiolation; iron catalysis; Markovni-
lectivity and represents a sustainable and economic kov addition; styrenes
Introduction
ceed in two ways: free-radical (pathway A)[5] or elec-
trophilic (pathway B, Scheme 1).
Carbon-sulfur bonds are present in compounds of in-
The addition of thiols to double bonds via a free-
dustrial interest,[1] in many natural products,[2] and in radical mechanism (pathway A) readily occurs under
pharmaceuticals with therapeutic activity such as ci- mild conditions and is fairly well described in the lit-
metidine (antiulcer), 6-mercaptopurine (leukemia), erature.[6–9] This process results exclusively in the for-
and thorazine (antipsychotic).[1] Specifically, thioeth- mation of the anti-Markovnikov product and is gener-
ers play an important role in organosulfur chemistry.[3] ally carried out in the presence of a radical initiator
The synthesis of thioethers historically predates that (AIBN, light, etc.).[6–9] In contrast, the Markovnikov
of ethers and, as the latter, generally involves nucleo- addition occurs when using over-stoichiometric
philic substitution of conveniently functionalized sub- amounts of Brønsted acids such as H2SO4 in
strates (i.e., Williamsonꢂs or Mitsunobuꢂs procedures). AcOH,[10] p-TSA[11] and HClO4
or Lewis acids
[12]
However, in the last years, the search for waste-free, (TiCl4,[13] AlCl3[14]). Very few examples of catalytic
environmentally-sustainable synthetic methods has systems giving Markovnikov addition have been re-
stimulated chemists to explore the direct addition of ported, and those include InACTHNUTRGENNGU ACHTUNGTRNE(NUGN III) (as
(OTf)3,[15] Fe
X H species (X=heteroatom) to unsaturated C C hemim complex[16] or as porphinato complex,[16b] using
bonds (hydroadditions). This strategy is 100% atom- NaBH4 as external reducing agent in over-stoichio-
economical since it allows both reactants to be fully metric amounts in both cases) and, finally, Montmoril-
incorporated in the final product. In fact, the hydra- lonite (K10) clay.[17] In these works, the scope of sub-
tion (H2O), hydroalkoxylation (alcohols), and hydro- strates is limited[15] or the yields are poor.[16] Related
esterification (esters) of alkenes are currently indus- examples with other metal catalysts have been report-
trial processes.[4] Following Markovnikovꢂs rule, the ed.[18]
ꢀ
ꢀ
[19]
ꢀ
oxygen nucleophile adds onto the more positive
Because of its ability to activate C C bonds, sev-
carbon but, in contrast, the addition of thiols can pro- eral iron-catalyzed transformations of alkenes have
appeared in recent years, including arylations,[20,21] 1,4
Scheme 1. Possible reaction pathways for the hydrothiolation of double bounds.
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Iron-Catalysed Markovnikov Hydrothiolation of Styrenes
additions to dienes,[21] hydroaminations,[22] epoxidation
of aromatic olefins and 1,3-dienes,[23] addition of 1,3-
dicarbonyl nucleophiles,[24] dimerisation of styrenes,[25]
as well as transformations of alkynes such as hydroar-
ylation,[26] carbonylation,[27] aminocarbonylation,[28]
and intramolecular alkyne-carbonyl metathesis.[29a]
These highly efficient iron-catalysed processes involve
soft nucleophiles, constituting therefore an attractive
starting point to seek for a possible hydrothiolation of
alkenes. According to the hardness-softness principle,
a metal salt containing a hard cation and a very soft
counteranion, such as the low-coordinating triflate or
triflimide, would be a strong Lewis acid with reduced
hardness. We envisaged that this kind of metal center
could act as a soft, while strong, Lewis catalyst and
could incorporate concomitantly the thiol and the
alkene in its coordination sphere, then activating the
Markovnikov position[29b] and minimising the radical
anti-Markovnikov addition. It will be shown here that
this strategy indeed works and allows the addition of
thiols to styrenes with good conversion and selectivity
and without polymerisation of styrene, contrary to
what occurs with strong protic acids[10–12] or metal
salts in over-stoichiometric amounts.[13,14]
Table 1. Catalyst screening for the hydrothiolation of 4-
chlorostyrene 1 with thiophenol 2.
Entry[a] Cation Anion Conv. [%][b] 3 [%][b] 4 [%][b]
1
2
3
4
none
H+
none
ꢀOTf
89 (65)
80 (84)
1 (0)
5 (1)
24 (0)
1 (0)
48
74 (17) 3 (14)
65
1 (0)
84 (55) 9(5)
81 (60)
70 (79)
57 (86)
2 (3)
ꢀNTf2 83 (91)
Fe3+
ꢀCl
6 (4)
82
85 (41)
77
5
ꢀOTf
28
6[c]
7[c,d]
8[e]
5
9 (18)
6 (4)
9[c]
ꢀNTf2 98 (70)
10[c,d]
11[c,f]
12[c,f,g]
13[c,h]
14[e]
15[c]
16[c]
17[c]
81
94
97
95
63
85
82
88
19 (2)
79
20
61
11
2
6
1
20 (4)
11
58
6
44 (23)
ꢀPF6
ꢀBF4
97
86
ꢀSbF6 94
[a]
Standard
reaction
conditions:
4-chlorostyrene
(0.25 mmol, 30 mL), thiophenol (0.25 mmol, 26 mL), cata-
lyst (0.025 mmol, 10 mol%), anhydrous 1,4-dioxane
(0.5 mL) at 808C for 24 h.
Conversion and yields to 3 and 4 calculated by GC.
Small amounts of the dimer of thiophenol were found,
which completed mass balance.
Catalyst was preformed as [MCln (10 mol%)+nAg (salt)
(30 mol%)] in anhydrous 1,4-dioxane (0.5 mL) for 30 min
at room temperature.
[b]
[c]
Results and Discussion
Catalyst Screening
[d]
[e]
FeCl3 (99.99%) was used.
The reaction of 4-chlorostyrene 1 with thiophenol 2 in
anhydrous 1,4-dioxane was chosen as a test reaction
(Scheme 2).
The reactions were run at 808C after screening
more than twenty metal species as triflate or trifli-
mide salts [MACHTUNGTRENNUNG(OTf)n or MACHTUGNTREN(NGUN NTf2)n, n=1–4], and the
corresponding Brønsted acids HOTf and HNTf2, as
catalysts for the above reaction (Table 1). The corre-
Catalyst was preformed as [MCln (10 mol%)+nLi (salt)
(30 mol%)] in anhydrous 1,4-dioxane (0.5 mL) for 30 min
at room temperature.
Run with 4-tert-butylcatechol (0.25 mmol, 41.6 mg) as
radical inhibitor.
[f]
[g]
[h]
Catalyst 5 mol%.
Under an N2 atmosphere.
sponding chloride salts gave no Markovnikov product combined high yield and good Markovnikov selectivi-
in any case. The results for reactions carried out at ty (3) was obtained when iron(III)-based salts were
used as catalysts (entries 6, 7, 9, 10–13). For instance,
(NTf2)3 (preformed from reaction of FeCl3 +
AHCTUNGTRENNUNG
508C are shown in parentheses.
When no catalyst is added, only the anti-Markovni- FeACHTUNGTRENNUNG
kov addition occurs (entry 1). When the Brønsted 3AgNTf2) gave an 84% yield of 3 (entry 9), and Fe-
acids HOTf and HNTf2 are added in catalytic (OTf)3 (preformed from FeCl3 +3AgOTf) gave 74%
AHCTUNGTRENNUNG
amounts (10 mol%), the results show very low selec- (entry 6). The possible catalytic activity of metal im-
tivity for the Markovnikov product (entries 2 and 3). purities in the iron salt is negligible since ultrapure
This indicates that protons do not activate efficiently ironACTHNUTRGNEUNG
(III) gives similar results (entries 7 and 10),[30] and
the benzylic position of the styrene. In contrast, a FeCl3 does not give any product (entry 4). These re-
Scheme 2. Hydrothiolation of 4-chlorostyrene 1 with thiophenol 2 using 10 mol% of catalyst.
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sults reflect the high impact on the catalytic activity species tested here. When the reaction is carried out
when low-coordinating counteranions are used in under anaerobic conditions, the Markovnikov selec-
combination with FeACTHNUTRGNE(UNG III). The better yield obtained tivity increases slightly (+4%) since oxygen removal
with the bis(triflimide) (ꢀNTf2) group compared to from the reaction medium allows a further minimisa-
the triflate (ꢀOTf) group is related to the stronger tion of the radical process (entry 13). The same effect
Lewis acidity that the former confers to FeACTHNUTRGNEUNG
(III).[31]
When other low-coordinating anions (AgPF6, AgBF4
and AgSbF6) were employed (entries 15, 16 and 17)
the selectivity to the Markovnikov regioisomer could
not be improved, although a nearly comparable selec-
tivity to that of ꢀNTf2 was obtained with the anion
ꢀPF6 (79%). Some changes in selectivity depending
ꢀ
ꢀ
ꢀ
on the compensating anion (ꢀNTf2, OTf, PF6, BF4
or ꢀSbF6) can be observed. The catalytic activity for
18 more metals in different oxidation states was
tested (Supporting Information, Table S1). The effect
of the anion is also observed in the case of other
metals such as Mn2+ (entries 9 and 25), Cu+ (en-
tries 10 and 26), Rh3+ (entries 16 and 31), Ni2+ (en-
tries 18 and 33), Pd2+ (entries 19 and 34) and Hgꢀ+ (en-
tries 20 and 35). In all cases, the metal salt with NTf2
ꢀ
shows better selectivity than that in the case of OTf.
Bi3+, Cu+, Cu2+, Au3+, Rh3+, Ru3+ and Hg+ metal salts
show some Markovnikov selectivity (42–69%; en-
tries 8, 11, 14, 17, 26, 27, 29, 31, 32, 35, respectively),
albeit in any case below those obtained with
bis(triflimide)iron
ACHTUNGTRENNUNG
for bis(triflimide)ironAHCTNUGTRENNNUG
Figure 2. Plot-time yield for the reaction of 1 with 2 cata-
lysed by 10 mol% of FeCl3 +3AgNTf2 at 808C in anhydrous
1,4-dioxane. A) Yield to 3 without 4-tert-butylcatechol; B)
yield to 3 with (1 equiv.) of 4-tert-butylcatechol; C) yield to
4 without 4-tert-butylcatechol; D) yield to 4 with (1 equiv.)
of 4-tert-Butylcatechol.
Figure 1. Plot-time yield for the reaction of 1 with 2 at 808C
catalysed by 10 mol%: A) FeCl3 +3AgNTf2; B) RuCl3 +
3AgNTf2; C) Bi
3AgNTf2.
G
Figure 3. Plot-time yield for hydrothiolation of 4-chlorostyr-
ene 1 with thiophenol 2 without catalyst at 808C.
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Iron-Catalysed Markovnikov Hydrothiolation of Styrenes
is observed when the reaction is carried out by adding from FeCl3 +3AgNTf2, is the most active and selec-
4-tert-butylcatechol (1 equiv.) as radical inhibitor (en- tive catalyst for the hydrothiolation of styrenes.
tries 11 and 12). Nevertheless, for experimental con-
venience, experiments have been carried out under catalyst in the presence or absence of a radical inhibi-
ambient conditions unless otherwise indicated. tor are shown (Figure 2). In the presence of 4-tert-bu-
Kinetic studies for the more active metal species tylcatechol the progressive formation of the Markov-
Kinetic experiments performed with FeACTHUGNTERN(NUG NTf2)3 as
were performed and also showed that iron
most active catalyst (Figure 1).
ACHTUNGTRENNUNG
It can be seen that the activity of the group VIII inhibited (curve D). Both initial rates diminished
transition metals Fe(III) and Ru(III) are one order of when 4-tert-butylcatechol is used as the radical inhibi-
magnitude higher than those of the group XI metals tor but the differences between both adducts are
Cu(II) and Au(III), and also than Bi(III) (for initial more pronounced (curves C and D). These results
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
rates at three different temperatures see Supporting confirm that the Markovnikov product is obtained
Information, Figure S2–S6). The latter shows a partic- through a non-radical mechanism. As expected, when
ular kinetic behaviour, since, although it is the less no catalyst is used, the anti-Markovnikov product is
active, it deactivates more slowly under the reactions produced from a radical process (Figure 3).
conditions. In view of the results in Figure 1 and
Table 1, we can say that FeACHTNUGRTNEUNG(NTf2)3, generated in situ
Table 2. Markovnikov hydrothiolation of styrenes with different thiols catalyzed by FeACHTNUTRGNEUNG(NTf2)3.
Entry[a]
1
Alkene
Thiol
Main product
Yield [%][b]
88 [83]
2[c,d]
80 [69]
89 [81]
97 [90]
3
4
5[c]
68 [49]
53 [47]
6
7[c]
82 [71]
86 [75]
8[c,d]
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Table 2. (Continued)
Entry[a]
Alkene
Thiol
Main product
Yield [%][b]
87 [80]
9
10
87 [83]
90 [82]
83 [75]
11
12[c]
13[e]
91 [86]
14
15
92 [84]
83 [76]
16[e]
87 [79]
86 [83]
17
18
85 [79]
76 [58]
79 [70]
19[f]
20[c]
[a]
Standard reaction conditions: styrene (0.25 mmol), thiophenol (0.25 mmol), FeCl3 (0.025 mmol, 4 mg), AgNTf2
(0.075 mmol, 30 mg), anhydrous 1,4-dioxane (0.5 mL) at 808C for 24 h.
GC yield; between brackets isolated yields.
50 h reaction time.
With 4-tert-butylcatechol (1 equiv.).
Styrene (0.5 mmol), thiol (0.25 mmol).
Catalyst 20 mol%.
[b]
[c]
[d]
[e]
[f]
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Iron-Catalysed Markovnikov Hydrothiolation of Styrenes
Table 3. Additional scope for the hydrothiolation of 4-chlorostyrene 1 with various thiophenols.
Entry[a]
1
Alkene
Thiol
Main product
Yield [%][b]
97 [90]
2
3
89 [81]
81
4
71
5
67
6
64
7[c,d]
80[69]
68[49]
8[c]
9[c]
19
10
n.r.
[a]
Standard reaction conditions: styrene (0.25 mmol), thiophenol (0.25 mmol), FeCl3 (0.025 mmol, 4 mg), AgNTf2
(0.075 mmol, 30 mg), anhydrous 1,4-dioxane (0.5 mL) at 808C for 24 h; n.r.=no reaction.
GC yield; between brackets isolated yields.
50 h reaction time.
With 4-tert-butylcatechol (1 equiv.).
[b]
[c]
[d]
Scope of the Reaction
(entries 1–9), alkylic thiols (entries 10–14), and a thio-
acid (entry 15) can be added to 4-chlorostyrene 1 in
The hydrothiolation of different styrenes and alkynes high yields and selectivities. There is a thiol comple-
is shown in Table 2. A wide array of sulfur derivatives mentarily, i.e., a variety of styrene derivatives includ-
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ing para- (entry 17), ortho- (entry 18), a- (entry 19), Other substituents such as methyl and halogens F, Cl,
and b-substituted (entry 20) substrates can engage and Br give also good yields (Table 3, entries 3–7).
with thiophenol.[32]
However, groups having labile hydrogens such as al-
Results of a further study on the influence of elec- cohol, carboxylic acid and amine give lower yields
tron-poor and electron-rich substituents on the aryl (entries 8–10). For substituted styrenes, methyl,
ring of various thiophenols and styrenes are shown in fluoro, and alkynyl substituents give good yields
Table 3 and Table 4. For substituted thiophenols, both (Table 4, entries 1–4), regardless of the position on
electron-rich (methoxy, Table 3, entry 1) and electron- the ring (Table 4, entry 3). However, the presence of
poor (nitro, Table 3, entry 2) groups are compatible both electron-poor and electron-rich substituents,
and give excellent yields of isolated product (90%).
Table 4. Additiional scope for the hydrothiolation of various styrenes with thiophenol 2.
Entry[a]
1
Alkene
Thiol
Main product
Yield [%][b]
85 [79]
2
86 [83]
3
4
69
73
5
49
40
6[c]
7[d,e]
36
29
8
[a]
Standard reaction conditions: styrene (0.25 mmol), thiophenol (0.25 mmol), FeCl3 (0.025 mmol, 4 mg), AgNTf2
(0.075 mmol, 30 mg), anhydrous 1,4-dioxane (0.5 mL) at 808C for 24 h.
GC yield; between brackets isolated yields.
Catalyst 20 mol%.
50 h reaction time.
With 4-tert-butylcatechol (1 equiv.).
[b]
[c]
[d]
[e]
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Iron-Catalysed Markovnikov Hydrothiolation of Styrenes
having or not having labile hydrogens, lowered the Reaction Mechanism Studies
yield to <50% (Table 4, entries 5–8).
A possible mechanism for the FeACTHUNTGRNEUNG(III)-catalysed Mar-
kovnikov hydrothiolation of styrenes is depicted in
Scheme 3. This mechanistic proposal is based on the
well-known capability of ironACTHNUGTRNEUNG(III) to activate concom-
itantly the benzylic position of double bonds[20] and
soft nucleophiles toward additions.[33a] The first step
would consist in the formation of an iron-olefin com-
plex (intermediate A). In the second step, the thiol
adds onto the benzylic position. At this point, the
mechanism of the thiol addition is uncertain. Al-
though an outer-sphere attack is feasible, thiol coordi-
nation and nucleophilic attack can also occurs (inter-
mediate B). We presume that the thiol is coordinated
to the iron Lewis acid since it becomes more nucleo-
philic if coordinated to the metal.[15] The interaction
between thiol and the ironACTHNUTRGENUGN(III) site is inferred from
the fact that styrene does not dimerise at all[25] and, in
contrast, dimers of the thiol are systematically ob-
served during the reaction.
Since the dimers of the thiol are observed in the re-
action medium (Supporting Information, Scheme S1),
we have studied the influence of the pair[33b] thiol-
dimer on the reaction, by performing two different
experiments. When the dimer was used as starting re-
actant, the hydrothiolation proceeds (Scheme 4, see
also Supporting Information, Table S2 and Table S3).
These results indicate that the disulfide can act as nu-
Scheme 3. Plausible mechanism for the Markovnikov hydro-
thiolation of 4-chlorostyrene 1 with thiophenol 2 by using
FeACHTUNGTRENNUNG(NTf2)3 as catalyst.
cleophile under ironACTHNUGRTENUNG(III)-catalysed conditions, al-
though less efficiently than the corresponding thiol. In
fact, some dithiolation can be observed (Supporting
Information, Table S2). However, protodemetalation
preferentially occurs and thus thioether 3 is the main
product formed. Reduction of diphenyl disulfide 67 to
thiophenol 2 does not occur directly if any alkene is
not present in the reaction medium (Supporting Infor-
mation, Table S3). However, a possible redox reaction
between the thiol and the iron center (2RSH+
2Fe3+ ! RSSR+2H+ +2Fe2+) should not be discard-
ed. A second experiment was conducted by adding p-
methoxythiophenol 9 (1 equiv.) along with 4-chloros-
Scheme 4. Hydrothiolation of 4-chlorostyrene 1 with diphen-
yl disulfide 67 in different reaction conditions. GC yields are
given in parentheses.
tyrene
1 and diphenyl disulfide 67 (0.5 equiv.;
Scheme 5. Hydrothiolation of 4-chlorostyrene 1 with p-methoxythiophenol 9 (1 equiv.) and diphenyl disulfide 67 (0.5 equiv.)
using Fe(NTf2)3 as catalyst. GC yields are given in parentheses.
ACHTUNGTRENNUNG
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Jose R. Cabrero-Antonino et al.
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ꢀ
ꢀ
(m, C H), 2864 (m, C H), 2000–1600 (l, overtones), 1490
ꢀ
ꢀ
ꢀ
(vi, arC C), 1479 (m, arC C), 1439 (l, CH3), 1093 (vi,
ꢀ1
+·
ꢀ
ꢀ
arC Cl), 828 (vi), 791 (m), 690 cm (m, C S); GC-MS (M
248, major peaks given): m/z=248 (46%), 233 (2%), 197
(4%), 141 (100%), 103 (100%), 77 (46%); 1H NMR: d=
7.31–7.29 (9H, mult), 4.33 (1H, q, J=7.1 Hz), 1.64 (3H, d,
J=7.1 Hz). 13C NMR: d=141.8 (C), 132.7 (2ꢄC), 128.7 (4ꢄ
CH), 128.6 (3ꢄCH), 128.5 (CH), 127.4 (CH), 47.4 (CH),
22.2 (CH3).
Scheme 6. Hydrothiolation of 4-chlorostyrene 1 with thio-
phenol 2 using FeACHTUNGTRENNUNG(NTf2)3 as catalyst in the presence of 2,6-
di-tert-butylpyridine (30 mol%). GC yields are given in pa-
Supporting Information
Supporting information for this article, including additional
schemes, figure and tables, reaction procedures, compound
characterization, and NMR spectra, is available.
rentheses.
Scheme 5) and it was found that thiol exchange
indeed occurs, even in the absence of ironACTHNUTRGNEUG(N III) or
alkene (Supporting Information, Scheme S2). Finally,
the reaction was performed in the presence of a hin-
dered base such as 2,6-di-tert-butylpyridine (30 mol%)
and formation of the Markovnikov product was
almost completely inhibited (Scheme 6). This result
accounts for the important role of H+ in the reaction.
Acknowledgements
The work have been supported by Consolider-Ingenio 2010
(proyecto MULTICAT), and PROMETEO from Generalitat
Valenciana. J.R.C.-A. thanks MCIINN for the provision of a
doctoral grant. A.L.-P. thanks ITQ for financial support. We
thank Dr. M. Domine for the HR-MS measurements.
Conclusions
References
It can be said that the iron-catalysed Markovnikov
hydrothiolation of styrene derivatives has been ac-
complished. The metal salt FeACTHNUTRGNEUNG(NTf2)3 is a superior
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is formed, the use of a chiral anion[34] might allow
enantioselective induction. Studies in this sense are
currently underway.
[3] a) Organic Sulfur Chemistry: Structure and Mechanism,
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3073 (m, arC H), 3058 (m, arC H), 2968 (m, C H), 2924
686
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