Boron Lewis Acid-Catalyzed Regioselective Hydrothiolation of Conjugated Dienes with Thiols

Article abstract of DOI:10.1021/acscatal.9b04647

A transition-metal-free hydrothiolation of 1,3-dienes for the synthesis of secondary and tertiary allylic sulfides is reported. The boron Lewis acids tris(pentafluorophenyl)borane, B(C₆F₅)₃, and BF₃·Et₂O are shown to catalyze the regioselective hydrothiolation of a wide range of terminal 1-aryl-1,3-dienes. In the case of internal 1,3-dienes, B(C₆F₅)₃ is by far the better catalyst than BF₃·Et₂O. The process features mild reaction conditions, broad scope, and low catalyst loading, and it can be scaled up quickly over a short reaction time. The reactions are rate-limited by the 1-aryl-directed protonation of 1,3-dienes with thiol-boron Lewis acid complexes, followed by sulfide anion transfer to the resultant allyl cations, as revealed by high-level DFT calculations.

Full text of DOI:10.1021/acscatal.9b04647

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Letter
Boron Lewis Acid-Catalyzed Regioselective
Hydrothiolation of Conjugated Dienes with Thiols
Gautam Kumar, Zheng-Wang Qu, Soumen Ghosh, Stefan Grimme, and Indranil Chatterjee
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b04647 • Publication Date (Web): 13 Nov 2019
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ACS Catalysis
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Boron Lewis Acid-Catalyzed Regioselective Hydrothiolation of
Conjugated Dienes with Thiols
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Gautam Kumar†, Zheng-Wang Qu‡*, Soumen Ghosh†, Stefan Grimme‡, and Indranil Chatterjee†*
†
Department of Chemistry, Indian Institute of Technology Ropar, Nangal Road, Rupnagar, Punjab-140001, India
‡
Mulliken Center for Theoretical Chemistry, Institut für Physikalische und Theoretische Chemie, Rheinische Friedrich-
Wilhelms-Universität Bonn, Beringstrasse 4, 53115 Bonn (Germany)
ABSTRACT: A transition-metal-free hydrothiolation of 1,3-dienes for the synthesis of secondary and tertiary allylic sulfides
.
is reported. The boron Lewis acids tris(pentafluorophenyl)borane, B(C6F5)3 and BF3 Et2O are shown to catalyze the
regioselective hydrothiolation of a wide range of terminal 1-aryl-1,3-dienes. In the case of internal 1,3-dienes, B(C6F5)3 is by
.
far the better catalyst than BF3 Et2O. The process features with mild reaction conditions, broad scope, low catalyst loading,
and can be scaled up quickly over short reaction time. The reactions are rate-limited by the 1-aryl-directed protonation of
1,3-dienes with thiol-boron Lewis acid complexes, followed by sulfide anion transfer to the resultant allyl cations, as revealed
by high-level DFT calculations.
KEYWORDS: Boron • Lewis acids • hydrothiolation • 1,3-diene • density functional calculations
Organosulfur compounds, particularly allylic sulfides and
their derivatives, are important building blocks, serving as
key synthons in organic synthesis and omnipresent in
bioactive compounds and pharmaceuticals.[1,2] Recent years
witnessed increasing attention to develop an efficient
approach to forge C–S bond.[3,4] Typically, C–S bond
formation by thiol addition onto olefin represents a
straightforward and atom-economical[5] approach to
construct organosulfur compounds. While the transition-
metal-catalyzed hydrothiolation of olefins has been well-
explored,[6] the transition-metal-free hydrothiolation
remains less-investigated. The group of Duñach reported
In(OTf)3-catalyzed Markovnikov hydrothiolation of olefins
(Scheme 1, top left).[7] Later, Sinha and co-workers
displayed an anti-Markovnikov hydrothiolation of olefins
triggered by neutral ionic-liquid (Scheme 1, top right).[8]
The group of Stephan elegantly developed two consecutive
metal-free Markovnikov hydrothiolations of olefins using
electrophilic phosphonium cations (EPCs)[9] and Lewis
acidic trityl-cation salt as catalyst (Scheme 1, prior work,
bottom).[10] Shortly after, the group of Huo reported auto-
oxidative hydroxysulfenylation of electron-rich olefins.[11]
In this context, such regioselective hydrothiolation of
conjugated olefins with multiple reaction sites remains
rarely explored and hence developing a metal-free strategy
for it will certainly add extra flavor to this metal-free
hydrothiolation protocols.
facile synthesis of starting 1,3-dienes. Key challenges
associated with hydrothiolation of dienes, promoted by
free-radicals[12] or strong Brønsted acid[13] represent
undesired oligomerization and intractable by-product
formation. In recent years, transition-metal-based catalysts
have offered quite good improvement of regioselective
hydrothiolation processes to provide allylic sulfides by He
et al. and Dong et al.[14] In this line, developing a transition-
metal-free hydrothiolation protocol for the synthesis of
allylic sulfides will be highly fascinating, yet regiochemically
challenging.
Recently, the activation of Lewis basic alkynes and
alkenes using the strong Lewis acid B(C6F5)3, has been
emerged as a new alternative metal-free tool for the
formation of C–C and C–heteroatom bonds.[15,16] We
envisioned that the protonation of conjugated dienes by
thiols bound to Lewis acids followed by sulfide anion
transfer could also lead to the formation of a new C–S bond.
The envisaged process consists of specific challenges that
need to be overcome: (1) regioselectivity of hydrothiolation
at diene sites 1 and 2, 3 and 4, or 1 and 4; (2) Markovnikov
versus anti-Markovnikov addition; (3) oligomerization of
1,3-diene substrates under Lewis acidic condition. Herein,
we reveal a highly regioselective 4,3-hydrothiolation of 1,3-
dienes catalyzed by boron Lewis acids (Scheme 1, bottom,
this work).
Hydrofunctionalization of conjugated dienes recently
attracts ample attention owing to the ready availability and
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Scheme 1. Regioselective metal-free hydrothiolation.
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18
19
20
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Table 1: Optimization study and reaction set-up.
Metal-free hydrothiolation of Olefins
(prior works)
R1
SR
catalyst (mol%)
solvent, rt, 2 h
H
[hmim]Br
In(OTf)3
H
1
3
H
R2
SR
R2
R1
Ph
R3, R4 = H
R4 = H
R4
4
R3
PhSH
2
Ph
SPh
Markovnikov
Duñach, 2006
anti-Markovnikov
Sinha, 2015
1a
2a
3
, rr > 20:1
R1
R3
[a]
+
RSH
Entry catalyst (mol%)
Solvent
Yield (%)
3
R2
SR
1
2
B(C6F5)3 (10)
B(C6F5)3 (10)
B(C6F5)3 (10)
B(C6F5)3 (10)
B(C6F5)3 (10)
Dioxane
THF
nr
nr
SR
H
R2
R3, R4 = H
R4 = H
H
R2
R1
R1
R3
3
4
5
6
7
8
EtOH
nr
[Ph3C][B(C6F5)4]
or
[(C6F5)3PF][B(C6F5)4]
MeNO2
DCM
20
61
[(MeOC6H4)CPh2][BF4]
B(C6F5)3 (10)1,2-difluorobenzene 64
Markovnikov
Markovnikov
B(C6F5)3 (10)
B(C6F5)3 (5)
Toluene
Toluene
Toluene
99
99
99
Stephan, 2015
Stephan, 2016
Metal-free hydrothiolation of 1,3-dienes
(this work)
9
B(C6F5)3 (2.5)
B(C6F5)3 (1)
B(C6F5)3 (0.5)
R4 R2
R4 R2
10
11
Toluene >99 (98)[b]
catalytic
boron Lewis acid
R1
R1
2
4
Toluene
66
H
3
88[b]
1
.
R3 SR
R3
12
BF3 Et2O (1)
Toluene
This work
+
13
14
15
BCl3 (1)[c]
Toluene
Toluene
Toluene
83[b]
75[b]
78[b]
allylic sulfides
RSH
Tf2NH (1)
4,3-hydrothiolation in major cases
Cu(OTf)2 (1)
mild reaction condition, scale up
broad substrate scope; terminal/internal dienes
[a] Reaction condition 1a (1.2 equiv) and 2a (1.0 equiv) stirred
in solvent at rt for 2 h. Yield determined by 1H NMR using
CH2Br2 as internal standard. Reaction scale for 1 mol% catalyst
We commenced our study by reacting (E)-buta-1,3-dien-
1-ylbenzene (1a, 1.2 equiv) as the model substrate with
thiophenol (2a, 1.0 equiv) in a series of solvents (1.5 M) in
the presence of B(C6F5)3 as catalyst at rt for 2 h (Table 1).
While solvents like dioxane, THF and EtOH provided no
conversion, MeNO2 promoted the reaction with 20% 1H
NMR yield (Table 1, entries 1–4). However, the reaction in
dichloromethane (DCM) resulted in a drastic improvement
of the reactivity delivering 3 in 61% yield and complete
regioselectivity for 4,3-hydrothiolation (Table 1, entry 5).
1,2-difluorobenzene also showed similar reactivity like
DCM (Table 1, entry 6). To our delight, using toluene as a
solvent, the desired product 3 was obtained in excellent
isolated yield and regioselectivity (>20:1 rr). The catalyst
loading can be lowered to 1 mol% without affecting the
.
(0.58 mmol) and for 5 or 10 mol% (0.12 mmol); with BF3 Et2O:
for 1 mol% (0.90 mmol) [b] Isolated yield. [c] Used as 1M
solution in DCM. nr = no reaction. rr = regiomeric ratio,
determined by 1H NMR of crude reaction mixture.
The optimized reaction conditions were applied to test
the reactivity of various thiols with 1a, as summarized in
Scheme 2. For each substrate, reactions were performed
.
two times with B(C6F5)3 and BF3 Et2O as the catalyst.
Thiophenol and its derivatives having halogen and methoxy
group as a substituent at the para-position worked well in
the presence of B(C6F5)3 to furnish allylic sulfides 3–5 in
.
high yield and complete regioselectivity. Using BF3 Et2O as a
catalyst similar reactivity was observed except for the
product 5. While naphthalene-2-thiol remained sufficiently
reactive (Scheme 2, entry 6), aliphatic thiols were found to
be less reactive, requiring higher catalyst loading of
B(C6F5)3. Aliphatic thiols having benzyl, heteroarene, and
isobutyl group provided products 7–9 in good yields.
.
yield (Table 1, entries 7–11). Interestingly, BF3 Et2O also
furnished the desired product 3 in high yield (Table 1, entry
12). Other boron Lewis acid, BCl3, provided 3 with 83%
isolated yield (Table 1, entry 13). Tf2NH and transition-
metal based catalyst Cu(OTf)2 were also able to catalyze the
reaction, albeit in lower yield (Table 1, entry 14–15).
.
Moreover, BF3 Et2O exhibited higher reactivity for aliphatic
.
Interestingly, using excess (10 mol%) BF3 Et2O and Tf2NH
thiols (7–10) requiring only 1 mol% catalyst loading. High
yield and regioselectivity were also observed for secondary
thiol (10). Thiol having ester functionality (11) also worked
smoothly in the presence of B(C6F5)3, whereas high catalyst
we obtained a lower yield of 3 owing to the oligomerization
of 1a. Notably, the reactions conducted with the catalysts
.
B(C6F5)3 and BF3 Et2O were much clean and easy to purify.
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Reaction scale: 0.58 mmol with 1 mol% B(C6F5)3, 0.12 mmol
with 5 or 10 mol% B(C6F5)3; 0.90 mmol with 1 mol% BF3.Et2O,
isolated yields unless otherwise mentioned. The yields in
parentheses are with BF3.Et2O. [a] Reaction scale 8.4 mmol,
1.56 g of 3 was obtained. [b] At 80 oC. [c] Using 10 mol%
BF3.Et2O. dr = diastereoselectivity and rr = regiomeric ratio,
determined by 1H NMR of crude reaction mixture.
loading (10 mol%) of BF3 Et2O was required for a good yield
of 11. Tertiary thiols such as Ph3CSH remained unreactive
probably due to steric effects. The employment of a racemic
thiol led to the formation of allylic sulfide 12 in dr = 1.3:1
1
2
3
4
5
6
7
8
.
and 1.6:1 in the presence of B(C6F5)3 and BF3 Et2O
respectively. Additionally, using propane-1,3-dithiol, an
intermolecular di-hydrothiolation product 13′ was
detected along with the desired hydrothiolation product 13,
which were easily separable.
Next, we investigated the scope of various substituted
1,3-dienes using thiophenol 2a as a model thiol substrate,
as depicted in Scheme 3. Terminal 1-aryl 1,3-dienes with
Me, OMe and Cl substituents (14–16) worked well with high
regioselectivity for the 4,3-hydrothiolation. Both 1-
heteroaryl and 2-naphthalenyl 1,3-dienes were found to be
9
10
11
12
13
14
15
16
17
18
19
20
21
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23
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27
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.
equally reactive (17 and 18). Using BF3 Et2O as a catalyst
instead led to moderate to low yields for the above
substrates. Interestingly, 1-ferrocenyl 1,3-diene delivered a
mixture of both the singly and doubly hydrothiolated
products 19 and 19 in the presence of B(C6F5)3 but in the
Scheme 2. 4,3-Hydrothiolation of 1a with various thiols.
B(C6F5)3 (1-10 mol%)
H
or
1
BF3.Et2O (1 mol%)
RS
3
.
presence of BF3 Et2O mainly the expected 4,3-
+
RSH
Ph
4
hydrothiolation product 19 was obtained. The reactions of
terminal 1-alkyl 1,3-dienes were relatively less
regioselective: aliphatic 1,3-dienes having n-butyl and
cyclohexyl group at site 1 provided both 4,3- and (less
favored) 1,4-hydrothiolation products (20–21 and 20–21,
respectively) as well as with minor homoallylic sulfides
(20–21). Surprisingly, in addition to the 1,4-
hydrothiolation product 22, 1-phenethyl-1,3-diene
furnished the homoallylic sulfide 22 as a main product
instead of the expected 4,3-hydrothiolation product 22. 1,1-
disubstituted dienes also exhibited high efficiency for the
selective hydrothiolations to deliver products 23–25. 1,4-
disubstituted internal dienes having a methyl or butyl
group as a substituent at the 4-position (R5 = Me or n-butyl)
showed moderate to good reactivity (26–27). To our
delight, internal 1,3,4- or 1,2,4-trisubstituted 1,3-dienes
reacted smoothly to produce tertiary allylic sulfides with
moderate to good yields and complete regioselectivity (28–
31). Isoprene (feedstock diene) furnished mainly the 4,1-
2
toluene, rt, 2 h
(1.0 equiv)
(1.2 equiv)
Ph
1a
2a-2k
3-13
, >20:1 rr
Variation of thiol for the 4,3-hydrothiolation
aromatic thiols
Cl
OMe
H
H
H
H
S
S
S
S
Ph
Ph
Ph
Ph
3
4
5
6
98% (1 mol%)[a]
79% (1 mol%)
(77%)
98% (5 mol%)
(21%)
90% (1 mol%)
(99%)
(89%)
aliphatic thiols
Me
Me
H
H
O
H
H
Ph
S
S
S
S
Ph
Ph
along
with
minor
1,4-hydrothiolation
products
Ph
Ph
.
(32:32=5:1) in the presence of B(C6F5)3. Using BF3 Et2O
instead we obtained exclusively 32 albeit in low yield. The
commercially available 1,3-diene, myrcene, was also
provided the 4,1-hydrothiolation product 33 with high
regioselectivity. To our delight, cyclic-1,3-diene readily
furnished 4,3-hydrothiolation product 34 with excellent
yield. As such, highly regioselective 4,3-hydrothiolation (rr
>20:1) was achieved for 1-aryl-substituted 1,3-dienes while
1,4-hydrothiolation was additionally obtained for 1-alkyl
substituted 1,3-dienes in the presence of B(C6F5)3 as
7
8
9
10
68% (10 mol%)
(98%)
48% (5 mol%)
(50%)
88% (10 mol%) 89% (10 mol%)
(98%)
(99%)
Ph
HS
Ph
S
Ph
H
O
O
Me
H
S
13
, 59% (1 mol%) (56%)
H
S
+
H
Ph
Ph
S
S
.
Ph
catalyst. BF3 Et2O remained a less effective catalyst for
H
11
12
Ph
, 19% (1 mol%) (30%)
internal 1,3-dienes as well as terminal 1-alkyl 1,3-dienes.
94% (5 mol%)[b]
(76%)[c]
85%, 1.3:1 dr (1 mol%)
(80%, 1.6:1 dr)
13'
Scheme 3. Hydrothiolation of various 1,3-dienes.
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R2 R4
R2
R4 SPh
R2 R4
B(C6F5)3 (1-10 mol%)
or
3
1
R5
H
1
2
3
4
5
6
7
8
R1
SPh
PhS
R1
R1
+
PhSH
+
2
4
H
R3
R3 R5
.
BF3 Et2O (1 mol%)
R3 R5
(1.0 equiv)
(1.2 equiv)
1b-1v
toluene, rt, 2 h
2a
14-34
1-substituted
H
H
PhS
H
PhS
Fc
PhS
H
H
PhS
H
PhS
Fc =
Fe
H
+
+
>20:1 rr
PhS
Fc
9
H
14
,
R = Me,
78% (44%)
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
15
R = OMe, , 78% (20%)
>20:1 rr
>20:1 rr
R
>20:1 rr
Fc
SPh
70%[a] (14%)
16
,
R = Cl,
17
18
, 88% (58%)
, 98% (nr)
19
, 44% (62%)
19'
, 28% (5%)
1-aliphatic substituted
1,1-disubstituted
1,4-disubstituted
PhS
R2
H
H
SPh
SPh
H
PhS
H
H
SPh
+
R1
+
R1
R1
23
R5
>20:1 rr
R1
20''-22''
20-22
20'-22'
R1 = Ph, R2 = Me,
[4:1],
R1 = n-butyl,
[12:1]
[1.3:1] = 7:3:1 rr, 80%[b] (nr)
:20''
[2:1]
20
:20'
98%[a] (66%)
>20:1 rr
52%[b] (nr)
R1 = R2 = Ph, , 99% (76%)
R1 = cyclohexyl,
R1 = CH2CH2Ph,
[13:1]
[2.2:1]
[1.3:1] = 4.6:3.3:1 rr, 55%[b] (nr)
[1.8:1] = 0.05:1.2:1 rr, 54%[b] (nr)
24
21
:21'
:21''
R5 = Me,
,
26
R1-R2 = Cyclohexyl, , 96% (13%)
25
22
:22'
[nd]
:22''
[5.5:1]
R5 = n-butyl, , 66%[b] (nr)
27
1,3,4-trisubstituted or 1,2,4-trisubstituted
SPh
2-substituted
SPh
Cyclic 1,3-diene
PhS
H
Me
H
R4
SPh
H
Me
>20:1 rr
R5
33
[4:1], >20:1 rr, 85%
R4 = Me, R5 = H ,
R4 = Me, R5 = Me ,
R4 = Me, R5 = n-butyl,
R4 = Me, R5 = Ph,
, 88% (nr)
+
28
H
from
H
Me
PhS
Me
Me
29
30
31
, 82% (nr)
, 51% (nr)
>20:1 rr
32'
, (30%)
32
[10:1], (0%)
Me
34
, 91% (nr)
R3 = Me,
= 5:1 rr, 80%
[c]
, 39% (nr)
myrcene
32:32'
.
Reaction scale: 0.58 mmol with 1 mol% B(C6F5)3, 0.12 mmol with 5 or 10 mol% B(C6F5)3, 0.90 mmol with 1 mol% BF3 Et2O, isolated
yields unless otherwise mentioned. rr = regioisomeric ratio determined by H NMR analysis of crude reaction mixture. The yields
1
.
with BF3 Et2O are shown in parentheses. E/Z ratios are indicated in brackets. [a] 10 mol% B(C6F5)3. [b] 5 mol% B(C6F5)3. [c] Reaction
conducted at 10 oC. nr = no reaction. rr = regiomeric ratio, determined by 1H NMR of crude reaction mixture. nd = not determined.
Additionally, the synthetic potential of this methodology
was demonstrated by converting allylsulfides to
corresponding sulfones 35 and 36 (see ESI for details) in
high yields by the treatment with meta-chloroperbenzoic
acid (mCPBA) (Scheme 4, right). 1,3-diene was formally
mono-hydrogenated using a one-pot hydrothiolation and
hydrodesulfurization protocol to obtain a mixture of
alkenes 37 and 37′ (Scheme 4, left).
formation was detected when thioanisole was used instead
of thiophenol under the optimized reaction condition
(Scheme 5a). A deuterium-experiment was also performed
confirming the regioselective deuterium transfer from S–D
group of PhSD to the 1,3-diene 1a (Scheme 5b).
Scheme 5. Control experiment and Deuterium-
labelling.
a) Control experiment
SMe
Scheme 4. Synthetic application of the developed
B(C6F5)3 (1 mol%)
methodology.
+
no reaction
Ph
toluene, rt, 2 h
1) B(C6F5)3
(5 mol%)
1) B(C6F5)3
(1 mol%)
R2
R2
R2
(1.2 equiv)
(1.0 equiv)
b) Deuterium-labelling experiment
toluene, rt
2 h
toluene, rt
2 h
R1
R1
Me
37
R1
R2 SO2Ph
H
SPh
B(C6F5)3 (1 mol%)
PhSD
+
+
+
Ph
R1
D
2) Et3SiH
2) mCPBA
CH2Cl2
PhSH
Ph
37'
Me
toluene, rt, 2 h
(76% D)
3-d
, 91%
(1.2 equiv)
(1.0 equiv)
R1 = Ph, R2 = H
37/37'
R1 = Ph, R2 = H,
73%
(75% D)
35,
R1 = Ph, R2 = Ph, , 72%
36
,
(1.6:1) 98%
To gain deeper mechanistic insight, the 1,3-diene 1a and
thiophenol 2a were chosen as model substrate in our DFT
studies at the PW6B95-D3/def2-QZVP
RS(toluene)// TPSS-D3/def2-TZVP + COSMO(toluene) level
of theory.[17] The lowest-lying reaction free energy paths (at
298 K and 1mol/L reference state) are shown in Figure 1. It
is shown that thiophenol 2a and B(C6F5)3 may reversely
form a weak B···S adduct A that is 2.1 kcal/mol higher in
free energy at room temperature but should be observable
Monitoring the hydrothiolation process of the model
reaction by 1H NMR spectroscopy revealed that the
B(C6F5)3-catalyzed reaction is finished within two hours.
Our DFT calculations suggest that the S–H group of the thiol
is responsible for the protonation. In fact, no conversion
was observed when H2O (1.0 equiv) was added under the
optimized reaction condition suggesting that 1a cannot be
protonated. Furthermore, no hydrothiolation product
+
COSMO-
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at low temperatures. 11B NMR of B(C6F5)3 alone in toluene-
1
2
3
d8 at room temperature (δ = 58.51 ppm) and B(C6F5)3 + 2a
in toluene-d8 (δ = 21.73 ppm at room temperature and δ =
o
1.51 ppm at – 30 C) also indicate the formation of B···S
adduct A (see ESI). In contrast, the formation of an adduct
of 1,3-diene 1a and B(C6F5)3 is 13.2 kcal/mol endergonic
and thus much less favorable (see ESI). Proton transfer from
the SH bond of 2a via adduct A is highly selective (by 11.4
kcal/mol) to the carbon site 4 rather than the Ph-
substituted site 1 of 1a, which is 11.8 kcal/mol endergonic
over a moderate barrier of 18.2 kcal/mol via the transition
structure TSAB, forming two separated ionic species of B+
and C in solution.[18] The high regioselectivity is mainly due
to conjugation effects of the site-1 phenyl to stabilize the
allyl cation intermediate. Further addition of anion C to the
carbon 3 of cation B+ is almost barrier less to form the
adduct D with a new CS bond, followed by rapid B(C6F5)3
elimination to form the main product 3. Similar addition of
C to the carbon 1 of B+ is thermodynamically 4.0 kcal/mol
less favorable to form the adduct 3', which should be rapidly
converted into more stable 3 over a barrier of 12.0 kcal/mol
(via ionic B+ and C) when catalyzed by B(C6F5)3 (see ESI).
At high substrate concentration, trapping of B+ with 1,3-
diene 1a may also occur selectively (by 3.0 kcal/mol) at the
respective carbon sites 3 and 4 of B+ and 1a, which is 0.5
kcal/mol exergonic over a barrier of 6.6 kcal/mol (Figure 1,
reaction channel denoted in red) to form the allyl cation E+,
followed by either sulfide anion transfer from C or further
oligomerization of 1,3-dienes. Catalyzed by Lewis acid
B(C6F5)3, the reaction is thus directed by the stabilizing 1-
aryl -conjugation for the initial 1,3-diene protonation and
the thermodynamic control of subsequent sulfide anion
transfer, leading to selective 4,3-hydrothiolation.
4
5
6
7
8
9
10
11
12
13
14
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21
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41
42
43
44
45
46
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48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. DFT computed Gibbs free energy reaction profiles (in
kcal/mol at 298 K and 1 mol/L reference state) for B(C6F5)3
catalyzed hydrothiolation of 1,3-diene PhCH=CHCH=CH2 (1a)
with thiol PhSH (2a).
We disclose here a transition-metal-free regioselective
hydrothiolation of 1,3-dienes to construct secondary and
tertiary allylic sulfides. This approach benefits from mild
conditions, easy scalability and broad scope with good
functional group compatibility. The efficient conversion to
allyl sulfones and formal mono-hydrogenation of 1,3-diene
via thiolation/hydrodesulfurization provide additional
opportunity to this overall transition-metal-free technique.
The combined experimental and theoretical studies portray
a clear mechanistic scenario, where the reaction is initiated
by protonation of the 1,3-diene and finalized by C–S bond
formation relying on a Lewis adduct formation between the
acidic borane and thiol.
ASSOCIATED CONTENT
Previously, the interaction between Lewis acids with either
Supporting Information The Supporting Information is
available free of charge on the ACS Publications website
Experimental procedures, spectral data for the
synthesized products (PDF)
[7]
thiols (Lewis acids such as In(OTf)3 and trityl-cations[10]
)
or olefins (such as EPCs[9]) was proposed to initialize the
Markovnikov hydrothiolation of olefins. Since weaker
interaction between Lewis acids with olefins than with
conjugated 1,3-dienes can be expected, our DFT
calculations support the initial interaction between Lewis
acids and thiols for the hydrothiolation of simple olefins as
well. The reduced 4,3-hydrothiolation selectivity observed
for 1-alkyl 1,3-dienes is due to relatively weaker
hyperconjugation (instead of -conjugation) by 1-alkyl
groups for initial 1,3-diene protonation. This is supported
by our DFT calculations showing that the protonation of 1-
methyl 1,3-diene by adduct A is kinetically only 1.9
kcal/mol more favorable at site 4 than at site 1 (see ESI).
The dominant 4,1-hydrothiolation observed for 2-alkyl 1,3-
dienes is likely due to steric effects during sulfide anion
transfer from C, while the unusual formation of homoallylic
sulfide 22 instead of the expected 4,3-hydrothiolation in
the case of 1-phenethyl-1,3-diene is likely directed by the
flexible 1-phenethyl that may favor intramolecular phenyl-
carbocation -adducts.
Corresponding Author
* E-mail: indranil.chatterjee@iitrpr.ac.in (I. Chatterjee)
* E-mail: qu@thch.uni-bonn.de (Z.-W. Qu)
ORCID
Gautam Kumar : 0000-0001-6332-9143
Zheng-Wang Qu : 0000-0001-6631-3681
Soumen Ghosh : 0000-0002-0551-177X
Stefan Grimme : 0000-0002-5844-4371
Indranil Chatterjee : 0000-0001-8957-5182
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
ACKNOWLEDGMENT
I. Chatterjee wishes to acknowledge financial support from
Indian Institute of Technology, Ropar and SERB, DST, India
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Page 6 of 8
Markovnikov Selective Hydrothiolation of Unactivated
Alkenes. Org. Lett. 2016, 18, 2114-2117. (e) Yi, H.; Song, C.; Li,
Y.; Pao, C.-W.; Lee, J.-F.; Lei, A. Single-Electron Transfer
Between CuX2 and Thiols Determined by Extended X-Ray
Absorption Fine Structure Analysis: Application in
Markovnikov-Type Hydrothiolation of Styrenes. Chem. - Eur. J.
2016, 22, 18331-18334. (f) Kristensen, S. K.; Laursen, S. L. R.;
Taarning, E.; Skrydstrup, T. Ex Situ Formation of Methanethiol:
Application in the Gold(I)-Promoted Anti-Markovnikov
Hydrothiolation of Olefins. Angew. Chem., Int. Ed. 2018, 57,
13887−13891.
(ECR/2018/000098). G. Kumar and S. Ghosh thank IIT Ropar
1
2
3
4
5
6
7
8
and UGC, New Delhi, respectively, for their research
fellowships. Z.-W. Qu and S. Grimme thank the Deutsche
Forschungsgemeinschaft (Leibniz Prize to S. Grimme) for
funding.
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Catalyzed Hydroarylation of 1,3- Dienes with Phenols. Angew.
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Eichkorn, K.; Weigend, F.; Treutler, O.; Ahlrichs, R. Auxiliary
Basis Sets for Main Row Atoms and Metals and Their Use to
Approximate Coulomb Potentials. Theor. Chem. Acc. 1997, 97,
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transition-metal-free
regioselectivity >20:1
mild conditions
R2
R4 SR
H
R1
broad scope
R3 R5
R5
B(C6F5)3
(1-10 mol%)
4,3-hydrothiolation
4
(C6F5)3B
R
for R1 = aryl/alkyl
R3
2
or
H
3 R4
R1 1 R2
.
BF3 Et2O
(1 mol%)
S
R1
SR/H
10
11
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H/SR
DFT calculations
>30 examples
upto 99% yield
R3
1,4-/4,1-hydrothiolation
for R1/R3= alkyl
superiority of B(C6F5)3
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