Direct Allylic C(sp3)-H Thiolation with Disulfides via Visible Light Photoredox Catalysis

Article abstract of DOI:10.1021/acscatal.0c01232

In spite of the wide utility of allyl thioethers, the direct catalytic allylic C(sp3)-H thiolation remains elusive. Herein, we report the direct allylic C(sp3)-H thiolation mediated by visible light photoredox catalysis. The use of in situ-generated thiyl radical from disulfide as a hydrogen atom transfer (HAT) reagent and a coupling partner enabled selective cleavage of the allylic C(sp3)-H bond followed by C(sp3)-S bond formation. The undesired hydrothiolation, a prevalent reaction from facile thiyl radical addition to olefins, was prevented by the immediate deprotonation of thiol under basic conditions. A wide range of diaryl disulfides and olefins participated in the reaction, producing allyl thioethers with high efficiency. Mechanistic investigations revealed the participation of the photocatalyst as a redox mediator, which was crucial for the transformation of the allyl radical into the allyl cation and further ionic coupling process. Based on the proposed mechanism, a limitation in the synthesis of alkyl allyl sulfide was solved with a rationally designed more reducible unsymmetrical disulfide, which makes the desired catalytic cycle operative.

Full text of DOI:10.1021/acscatal.0c01232

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Article
Direct Allylic C(sp3)–H Thiolation with Disulfides
via Visible Light Photoredox Catalysis
Jungwon Kim, Byungjoon Kang, and Soon Hyeok Hong
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c01232 • Publication Date (Web): 29 Apr 2020
Downloaded from pubs.acs.org on April 29, 2020
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Direct Allylic C(sp )–H Thiolation with Disulfides
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via Visible Light Photoredox Catalysis
†,‡
‡
†,
Jungwon Kim , Byungjoon Kang , and Soon Hyeok Hong *
†Department of Chemistry, Korea Advanced Institute of Science and Technology
(
KAIST), Daejeon 34141, Republic of Korea
‡Department of Chemistry, College of Natural Science, Seoul National University, Seoul
08826, Republic of Korea
KEYWORDS: C–H activation, allylic compound, allyl thioether, photocatalysis, C–S
bond formation
3
ABSTRACT: In spite of the wide utility of allyl thioethers, the direct, catalytic allylic C(sp )–
3
H thiolation remains elusive. Here we report the direct allylic C(sp )–H thiolation mediated
by visible light photoredox catalysis. The use of in situ generated thiyl radical from
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disulfide as a hydrogen atom transfer (HAT) reagent and coupling partner enabled
3
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selective cleavage of the allylic C(sp )–H bond followed by C(sp )–S bond formation. The
undesired hydrothiolation, a prevalent reaction from facile thiyl radical addition to olefins,
was prevented by the immediate deprotonation of thiol under basic conditions. A wide
range of diaryl disulfides and olefins participated in the reaction, producing allyl thioethers
in high efficiency. Mechanistic investigations revealed the participation of the
photocatalyst as a redox mediator, which was crucial for the transformation of the allyl
radical into allyl cation and further ionic coupling process. Based on the proposed
mechanism, a limitation in the synthesis of alkyl allyl sulfide was solved with rationally
designed, more reducible unsymmetrical disulfide, which makes the desired catalytic
cycle operative.
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INTRODUCTION
Allyl thioethers not only serve as an open platform for diverse sulfur functionality
1
(
thioester, sulfoxide, sulfone), but also occupy a pivotal position in biological and
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pharmaceutical fields because of their high bioactivity, including potent anti-cancer
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activity. To fulfill such high demand for allyl thioether surrogate, various synthetic
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approaches, such as S-allylation with allyl (pseudo)halide,3 [3,3]-sigmatropic
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rearrangement, and hydrothiolation of allenes or 1,3-dienes have been developed via
transition-metal catalysis (Scheme 1A). However, the direct introduction of a sulfur
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functionality to an allylic position of simple olefins via C(sp )–H bond activation has not
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been demonstrated, although a wide range of allylic C(sp )–H bond functionalizations
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have been developed. This is mainly due to strong interactions between sulfur and
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transition metal complexes, resulting in deactivation of the catalytic cycle or facile
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oxidation of the sulfur atom under oxidative conditions, which drives the need for a
different catalytic system.
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Recently, visible light photoredox catalysis approach for direct allylic C(sp )–H bond
functionalization has emerged as a powerful tool. After MacMillan and co-workers
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demonstrated an elegant protocol for direct allylic C(sp )–H arylation using a thiol
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organocatalyst, a number of examples of photocatalytic C–C bond formation reactions
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at the allylic position have been reported.7d,7e,11 Inspired by these studies, along with the
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reported photocatalytic activation of disulfides, we envisioned the utilization of visible
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light photoredox catalysis for activation of disulfide and selective allylic C(sp )–H bond
cleavage by hydrogen atom transfer (HAT) with the generated thiyl radical (Scheme 1B,
blue arrow).10,13 In this approach, highly versatile hydrothiolation between olefin and sulfur
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surrogate should be avoided (Scheme 1B, orange arrow). Many examples using visible
light photoredox catalysis for the initiation of the hydrothiolation have been reported.15
Very recently, Glorius and co-workers reported the utilization of a disulfide under
photoredox catalysis for a versatile disulfide-ene reaction.12c To prevent the facile and
reactive addition process, an introduction of basic conditions was proposed, which would
aid the removal of the hydrogen source (mainly thiol); thus, the reversible thiyl radical
addition could be shifted backward in order for the desired allylic thiolation to proceed
(Scheme 1C). This mechanism-based suppression of the well-established hydrothiolation
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enabled us to develop the first direct allylic C(sp )–H thiolation under visible light
irradiation conditions (Scheme 1D). Experimental and computational studies revealed
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that the reaction proceeded predominantly via ionic coupling between allyl cation and
thiolate with the aid of photocatalyst as a redox mediator.
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Scheme 1. Synthesis of Allyl Thioethers
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A. Synthetic routes of allylic thioether
R
R1 R2
Allylic
Overman
rearrangement
S
O
substitution
X
R4
R
R
R4
R3
R3
Functionalized
olefins
R1 R2
Carbamothiate
precursors
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RS
R4
R
R3
R
R
•
R
R1
R2
Elusive
R R
Hydrothiolation
Allylic C–H
activation
R4
R3
R
Allenes
Simple olefins
1,3-Dienes
3
B. Hurdle in allylic C(sp )–H thiolation: hydrothiolation
R1 R2
R1 R2
[cat.]
H
R4
FG
R4
FG = OR, O, NHR, aryl, alkyl, ...
R3
R3
3
No example for FG = SR (allylic C(sp )–H thiolation) reported
R1
R2
3
R1
R2
R1
R2
C(sp )–H
Hydro-
thiolation
H
thiolation
RS
R4
H
R4
R4
RS
R3
Unexplored reactivity
R3
SR
R3
• Well-established
click" reaction
•
"
3
C. Proposed strategy: allylic C(sp )–H bond cleavage by thiyl radical
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Allylic C(sp )–H thiolation (target pathway)
RS
R1 R2
R1 R2
R1 R2
RS
H
R4
R4 or RSSR
RS
R4
R3
R3
R3
RS : removal of hydrogen source
RSH
-
RS
+RS
"
Base"
R1
R2
R1
R2
H
Hydrothiolation
(well-known pathway)
R4
R4
RS
RS
R3
RS
R3
3
D. Visible light photoredox allylic C(sp )–H thiolation (this work)
ArSSAr
R1 R2
Ir photocatalyst
NaOH
R1 R2
or
+
H
R4
RS
R4
Blue LED
BztSSAlk
R3
R3
Bzt = 2-benzothiazolyl
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RESULTS AND DISCUSSION
Initial optimization of reaction conditions was conducted with a reaction between diphenyl
disulfide (1a) and 2,3-dimethyl-2-butene (2a) as the model substrates (Table S1). It was
revealed that the desired allyl thioether 3aa can be synthesized in high yields (91%) under
visible light irradiation (40 W blue LED) with Ir(CF ppy) (2.0 mol%) and NaOH (1.0 equiv)
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(Scheme 2A). However, unfortunately, relatively high equivalence of olefin (20 equiv) was
required to obtain full conversion of 1a and high yields of 3aa. Sensitivity assessment of
the developed reaction showed that the reaction was moderately sensitive to the variation
of the reaction conditions (Scheme 2A and Table S2).16 Notably, the hydrothiolation
product was not observed under the standard reaction conditions. When cyclohexene
(2h), which rapidly undergoes the hydrothiolation reaction, was used as a substrate, a
noticeable base effect was observed (Scheme 2B). The choice of base (NaOH) was
critical to achieve high efficiency and selectivity toward allyl thioether 3ah (Scheme S1).
Under the base-free conditions, a significant amount of the addition product 3ah’ was
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formed (32%), supporting the hypothesis on the role of the base in inhibiting the
hydrothiolation (Scheme 2B).
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Scheme 2. Optimized Reaction Conditions and the Effect of the Base
A. Optimized reaction conditions
Ir(CF ppy)3 (2.0 mol%)
3
NaOH (1.0 equiv)
PhSSPh
+
PhS
DMA (0.25 M), rt, 24 h
0 W Blue LED
4
1a
2a
3aa
(20 equiv)
91%
(isolated)
B. Effect of base in switching reactivity
Ir(CF ppy)3 (1.0 mol%)
3
NaOH (1.0 equiv)
PhSSPh
+
+
DMA (0.25 M), rt, 24 h
PhS
3ah
PhS
3ah'
40 W Blue LED
1a
2h
(10 equiv)
with NaOH
without NaOH
89%
29%
N. D.
32%
With the optimal conditions in hand, we investigated the scope of the reaction (Table
). Initially, a variety of diaryl disulfides were tested. Diaryl disulfides bearing electron-
1
withdrawing (1b, 1c, 1d, 1e, 1f, 1i, 1l) or electron-donating substituents (1g, 1h, 1j, 1k,
1m, 1n) provided the desired allyl thioethers in moderate to good yields. Trifluoromethyl-
(1e) and trifluoromethoxy-(1f) groups were well tolerable, producing the desired allyl
thioethers in excellent yields. Meta-(1i-1l) or ortho-substituted (1m & 1n) diaryl disulfides
could also be used in this reaction. Notably, the reactions with bis(2-benzothiazolyl)
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disulfides (1o & 1p) smoothly proceeded to functionalize the allylic position. A scaled-up
reaction (5 mmol (1.1 g) of 1a) with more light sources (4 × 40 W Blue LEDs) produced
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3aa in a synthetically useful yield (69%). Unfortunately, dialkyl disulfides, such as dibenzyl
disulfide (1q), were not reactive under the reaction conditions, and only the corresponding
thiols were obtained.
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Next, different olefins bearing allylic C(sp )–H bonds were applied in the reaction. In
addition to 2,3-dimethyl-2-butene (2a), other tetra-/tri-substituted linear (2b, 2c) or cyclic
(2f, 2g) olefins were successfully functionalized with disulfide 1a. In those cases, a
regioselectivity preference (secondary>primary>>tertiary) was observed, presumably
due to the combinatorial effect of HAT efficiency and steric effect. To our delight, (+)-α-
pinene (2g) was also reactive, providing the corresponding allyl thioether (3ag) as a single
stereoisomer. The reaction of 2g demonstrated that the developed reaction can serve as
a complementary method to a conventional two-step approach—allylic bromination,
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which gives a mixture of regioisomers, and nucleophilic substitution with thiolate. Not
only multi-substituted olefins but also di-substituted olefins, which are more susceptible
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to the competitive hydrothiolation reaction, selectively generated allyl thioethers in
moderate to good yields. Cyclic olefins with different ring sizes (2h-2l), substituted
cyclohexene (2m), a heteroatom-bearing cyclic olefin (2n), and even simple linear internal
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olefins (2d & 2e) were selectively functionalized at the allylic C(sp )–H position without
the generation of any hydrothiolation byproducts. In some olefin substrates, migration of
the double bond in the product was observed. When 3-methylcyclohexene (2o) or trans-
4-methyl-2-pentene (2p) was used in the reaction, allyl thioethers bearing migrated
double bonds (3af & 3ap, respectively) were observed exclusively, showing a preference
toward the secondary allylic position in the coupling step.
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9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 1. Substrate Scopea
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R2
R1
R2
Ir(CF3ppy)3 (2.0 mol%)
NaOH (1.0 equiv)
R
R1
R4
R
S
S
R4
+
S
R
R3
DMA, rt, 24 h
R3
3
40 W Blue LED
1
2
(
20 equiv)
Variation of disulfide
F
Cl
Br
F3C
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
S
S
S
S
S
3aa
91% (69%)b
3ba
55%
3ca
56%
3da
53%
3ea
>99%
F3CO
Me
S
S
S
F
S
Me
R
S
3fa
3ga
40%
3ha
74%
3ia
74%
3ja
55%
>
99%
Cl
N
S
S
S
MeO
S
Cl
S
S
Me
3
6
ka
5%
3la
65%
3ma
3na
44%
R = H (3oa); 65%
R = Cl (3pa); 46%
68%
Variation of olefin
Ph
S
S
Ph
S
Ph
Standard
conditions
Standard
conditions
Ph
S
+
3ab + 3ab'
+
2
b
d
2c
2e
3ac + 3ac'
47%, 4.9:1 rr
5
0%, 2.3:1 rr
Ph
Ph
Ph
S
S
S
+
Standard
conditions
Standard
conditions
2
3ad + 3ad'
6%, 1.1:1 rr
3ae
36%
5
n = 1 (3ah); 86%
n
n = 0 (3ai); 72%
n = 2 (3aj); 41%
n = 3 (3ak); 37%
n = 7 (3al); 29% (5:1 E/Z)
Standard
conditions
Standard
conditions
n
Ph
Ph
S
S
2
f
3af
8%
2h - 2l
6
O
O
H
S
Standard
conditions
Standard
Ph
Ph
conditions
S
2m
3am
9%, 1.4:1 dr
2n
3an
72%
5
radical
Standard
conditions
H
+
Br
Ph
Br
bromination
S
(ref. 17)
Allyl bromides
2g
((+)--pinene)
3ag
55%
(
2.3:1 rr)
Migration of double bond
Ir(CF3ppy)3 (2.0 mol%)
NaOH (1.0 equiv)
Ph
S
+
+
S
Ph
Ph
Ph
DMA, rt, 24 h
0 W Blue LED
S
S
4
1
a
2o
3af
79%
(20 equiv)
Ir(CF3ppy)3 (2.0 mol%)
NaOH (1.0 equiv)
Ph
S
S
Ph
DMA, rt, 24 h
0 W Blue LED
4
1
a
2p
3ap
47%
(
20 equiv)
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1
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a
Reaction conditions: 1 (0.25 mmol), 2 (5.0 mmol), Ir(CF ppy) (0.0050 mmol), NaOH
3
3
(0.25 mmol), and DMA (1 mL) in a 4 mL reaction vial irradiated with a 40 W Blue LED
b
under fan cooling. Reaction conditions: 1 (5.0 mmol), 2 (100 mmol), Ir(CF ppy) (0.10
3
3
mmol), NaOH (5.0 mmol), and DMA (20 mL) in a 100 mL quartz round-bottom flask
irradiated with 4 × 40 W Blue LED under fan cooling. All yields are isolated yields.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 3. Utilization of Allyl Thioethers
SPh
+
N
Ph
Me
S+
O-
Interrupted Pummerer
[3,3]-rearrangement
(c)
N
Me
4
3
ahsulfoxide
76%
52%
from
[O] (a)
3ah
R1 R2
from 3aa, + Me3Si
N2
R
Me3Si
PhS
S
R4
Doyle-Kirmse reaction
R3
(d)
from
3
5
63%
2
oa
x [O] (b)
+
Ph
Modified Julia olefination Ph
e)
O
S
O
N
S
(
O
3oasulfone
6
66%
83%
(a) 3ah (0.50 mmol, 1.0 equiv), H O (1.5 mmol, 3.0 equiv), acetic acid (3 mL), rt, 24 h.
2
2
(b) 3oa (0.34 mmol, 1.0 equiv), (NH ) Mo O ·4H O (0.085 mmol, 25 mol%), H O (3.4
4
6
7
24
2
2
2
mmol, 10 equiv), MeOH (4 mL), rt, 1 h (c) 3ahsulfoxide (0.15 mmol, 1.0 equiv), N-
methylindole (0.15 mmol, 1.0 equiv), trifluoroacetic anhydride (0.165 mmol, 1.1 equiv),
NaHCO (0.33 mmol, 2.2 equiv), CH Cl (1.5 mL), -78 °C to rt, 3 h. (d) 3aa (0.20 mmol,
3
2
2
1.0 equiv), (trimethylsilyl)diazomethane (0.40 mmol, 2.0 equiv), FeBr (0.020 mmol, 10
2
mol%), DPPE (0.020 mmol, 10 mol%), 1,2-dichloroethane (2 mL), reflux, 12 h. (e)
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3
oasulfone (0.25 mmol, 1.0 equiv), 3-phenylpropionaldehyde (0.275 mmol, 1.1 equiv),
potassium bis(trimethylsilyl)amide (0.325 mmol, 1.3 equiv), THF (2.5 mL), -78 °C to rt, 7
h.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The synthesized allyl thioethers could be further functionalized (Scheme 3). Synthesis
of sulfoxide or sulfone was performed under appropriate oxidation conditions, giving
18
3ahsulfoxide and 3oasulfone from 3ah and 3oa, respectively. It is noteworthy that selective
oxidations to sulfoxide or sulfone could be accomplished while the olefin functional group
remained intact. The synthesized 3ahsulfoxide was further utilized in interrupted Pummerer
coupling/[3,3]-sigmatropic rearrangement with N-methylindole to produce 2,3-
19
disubstituted indole 4. In the case of 3oasulfone, modified Julia olefination was applied
with hydrocinnamaldehyde to produce 1,3-diene 6.20 The result suggested that our
reaction can serve as a useful synthetic tool for various conjugated dienes from simple
olefins. The utility of allyl thioether itself was also demonstrated by a Doyle-Kirmse
reaction with carbenoid, generating functionalized hydrocarbon skeleton 5 in good
efficiency.21
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1
1
1
1
1
1
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
When the reaction was designed, it was hypothesized that Ir photocatalyst can aid the
3
generation of thiyl radical, and further allylic C(sp )–H bond cleavage and coupling
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
reaction were expected to proceed via radical pathway without any involvement of the
photocatalyst (Scheme 1C). However, only trace amount of desired transformation was
observed under photocatalyst-free conditions (Scheme 4A, entry 2), although a homolytic
cleavage of diaryl disulfide under irradiation of blue LED has been utilized in various
22
radical cyclization processes. Even the use of Ir photocatalyst having larger triplet-state
energy (entry 3)23 or the use of 370 nm LED light source (entry 4), which can further
facilitate homolytic cleavage of diaryl disulfide, gave a trace amount of the coupled
product 3aa (<2%).24 Hypothetically, the generated thiyl radical could induce the HAT
3
from the allylic C(sp )–H bond. Then, further coupling reaction between the allylic radical
and the disulfide would be able to form the C–S bond with the regeneration of thiyl radical
without the aid of photocatalyst (radical pathway in Scheme 4B). However, based on the
observed necessity of the appropriate Ir photocatalyst for high efficiency, an additional
redox process mediated by the photocatalyst was proposed involving allyl cation as the
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other intermediate to perform ionic coupling between the allyl cation and aryl thiolate
ionic pathway in Scheme 4B).25
(
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 4. The Possible Role of a Photocatalyst
A. Effect of Ir photocatalyst
(Ir catalyst (2.0 mol%))
NaOH (1.0 equiv)
PhSSPh
+
PhS
DMA, rt, 24 h
40 W Blue LED
1a
2a
3aa
(20 equiv)
Entry
Variation
Yield 3aa
91%
<2%
<2%
<1%
1
2
3
4
with Ir(CF ppy) (E = 56.4 kcal/mol)
3 3 T
without Ir catalyst
with [Ir(dFCF ppy) (dtbbpy)](PF ) (E = 60.4 kcal/mol)
3
2
6
T
without Ir catalyst, 370 nm LED
B. Proposed reaction mechanism - possible role of Ir photocatalyst
ionic pathway
Ir(III)* Ir(III)
[
O]
ArS
ArS + ArS
ArS + ArS
R
R H
ArSH
HAT
or hv
ArSSAr
R
R SAr
-
ArS or ArSSAr
radical pathway
Ir(II) Ir(III)
To determine whether the allyl cation is involved in the reaction, reactions with single-
electron oxidants under photocatalyst-free conditions were conducted using olefin 2a or
2h as a substrate (Table 2). Interestingly, various types of single-electron oxidants, such
as Ce4+ (entry 2), tris(4-bromophenyl)ammoniumyl (TBPA ) (entry 3), and (2,2,6,6-
tetramethylpiperidin-1-yl)oxyl (TEMPO) (entry 4), can promote the coupling reactions in
+
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
the absence of a photocatalyst, proving that the separated approaches (HAT by thiyl
radical from light irradiation and further generation of allyl cation by single-electron
oxidant) can promote the same reaction. In addition, no desired product was observed
when the oxidant has an oxidizing power below a certain threshold. For example,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
ferrocenium (Fc ) (entry 6) cannot participate in the thiolation reaction with olefins 2a or
2h, and 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) (entry 5) produces very little
allyl thioether (3aa) or almost no product (3ah). These trends suggest that an oxidant with
a certain level of oxidizing power (0.51 – 0.65 V) is required to induce oxidation of the allyl
+
radical. In addition, the reaction with TBPA under dark conditions did not produce the
desired thioether (entry 7), further demonstrating that the thiyl radical is necessary for the
reaction.
Table 2. Reaction without Photocatalyst: Effect of Single-Electron Oxidanta
Oxidant (1.0 equiv)
NaOH (1.0 equiv)
PhSSPh
+
or
PhS
or
DMA, rt, 24 h
0 W Blue LED
PhS
4
1a
2a
2h
3aa
3ah
(20 equiv)
(20 equiv)
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entry oxidant
Eob
yield
3aac
yield
3ahc
1
2
None
-
<2%
17%
N. D.
19%e
Ce(NH
4
)
2
(NO
3
)
1.06 Vd
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
1.05 Vf
3
4
5
6
7j
(TBPA)(SbCl
TEMPO
DDQ
6
)
36%
13%
3%
6%
0.65 Vg
23%
<1%
N. D.
N. D.
0.51 Vh
0.4 Vi
(Fc)(BF
4
)
N. D.
N. D.
(TBPA)(SbCl
6
)
1.05 Vf
aReaction conditions: 1a (0.25 mmol), 2a or 2h (5.0 mmol), oxidant (0.25 mmol), NaOH
0.25 mmol), and DMA (1 mL) in 4 mL reaction vial irradiated with a 40 W Blue LED under
(
b
c
fan cooling. vs SCE in MeCN Yields determined by GC using dodecane as the internal
d
e
f
g
h
i
j
standard. ref.26. Ce(SO ) was used as an oxidant. ref.27. ref.28. ref.29. ref.30. Dark
4
2
conditions. N. D. = not detected.
To verify the involvement of allyl cation in the reaction, DFT calculations of redox
potentials for allyl radicals were conducted following Liu and Guo’s protocol (Scheme 5).31
o
First, allyl radical (2a-rad) derived from olefin 1a showed E (calc., 2a-cat/2a-rad) = 0.54
V (vs SCE in MeCN), which matched the experimentally observed oxidation potential
threshold (~0.51 V) (Scheme 5A). Next, in the case of olefin 2h, both allyl radical (2h-rad)
and thiyl radical adduct (3ah-rad) were considered (Scheme 5B). Because phenyl thiyl
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1
1
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
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5
5
5
5
5
5
5
6
radical (1a-rad) is known to readily attack 1,2-disubstituted olefin systems, we wonder
whether this thiol-ene type mechanism can be a part of the reaction pathway via
sequential single-electron oxidation by the Ir photocatalyst and deprotonation of a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
32
sulfonium intermediate (3ah-cat). The results clearly suggest that the redox potential of
2
h-rad (E1o (calc., 2h-cat/2h-rad) = 0.61 V vs SCE in MeCN) is well-matched with the
experimentally determined oxidation threshold (0.51 V – 0.65 V), whereas 3ah-rad is
o
much more easily oxidizable (E (calc., 3ah-cat/3ah-rad) = 0.04 V vs SCE in MeCN) and
2
does not match the observed threshold in Table 2. In addition, the observed
3
chemoselectivity in the reactions with olefin 2f or 2n further supports the allylic C(sp )–H
cleavage pathway (Scheme 5C).14d,15a Based on these analyses, we concluded that a
mechanism involving HAT by the thiyl radical operates in the developed reactions,
together with the oxidation of the allyl radical to the allyl cation prior to the coupling
process as a major pathway.
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1
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 5. Involvement of Allyl Cation Intermediate
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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A. Reaction pathway between diphenyl disulfide (1a) and 2,3-dimethyl-2-butene (2a)
PhS-
H
PhS
PhS
a-rad
HAT
[O]
1
2a
2a-rad
2a-cat
3aa
E° (calc., 2a-cat / 2a-rad) = 0.54 V (vs SCE in MeCN)
B. Reaction pathway between diphenyl disulfide (1a) and cyclohexene (2h)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
Allylic C(sp )–H pathway
E ° (calc., 2h-cat / 2h-rad) = 0.61 V (vs SCE in MeCN)
1

Matched with experimentally observed threshold
[O]
PhS-
E °
1
2h-rad
2h-cat
PhS
H
PhS
PhS
PhS
a-rad
2h
3ah
[O]
1
- H+
E °
2
3ah-rad
3ah-cat
Thiol-ene type pathway
E ° (calc., 3ah-cat / 3ah-rad) = 0.04 V (vs SCE in MeCN)
2
C. Changed chemoselectivity via different reaction pathway
BnS
3
Thiol-ene
Allylic C(sp )–H
ref. 15a
standard conditions
PhS
PhS
2f
3af
SPh
O
3
Thiol-ene
Allylic C(sp )–H
O
O
ref. 14d
standard conditions
2n
3an
To further check the viability of the proposed reaction strategy, two possible reaction
pathways (hydrothiolation & allylic thiolation) were analyzed via DFT calculation (Figure
3
1). In the reaction pathway, olefin 2h can be involved in both allylic C(sp )–H bond
‡
cleavage via HAT by phenyl thiyl radical (ΔG =18.1 kcal/mol) and thiol-ene addition
‡
33
(ΔG =12.1 kcal/mol). In the case of thiol-ene pathway, hydrogen transfer by thiophenol
(
PhSH) exhibited an energy barrier of 18.8 kcal/mol, which is very similar to the energy
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barrier of the HAT process. This clearly indicates that control of reaction pathways relying
on the innate reactivity of thiyl radical and olefin is highly challenging, which is consistent
with the result of the reaction between disulfide 1a and olefin 2h under base-free
conditions (Scheme 2B). However, under basic conditions, appropriate hydrogen source
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
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4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(PhSH) was removed, so that the completion of a hydrothiolation was prohibited. Besides,
3
the basic conditions prevent the reverse HAT of thiol to 2h-rad, making the allylic C(sp )–H
bond cleavage pathway irreversible. This clearly suggests that the application of basic
3
conditions is crucial to derive the desired allylic C(sp )–H thiolation while preventing the
facile hydrothiolation.
Next, three different pathways for the formation of allyl thioether (3ah) from allyl radical
(2h-rad) were considered. Coupling between two radical species would not be favorable,
due to the low effective concentration of 1a-rad in consumption through HAT process and
reversible thiol-ene addition between 1a-rad and 2h. The reaction between 1a and 2h-rad
is also possible (21.7 kcal/mol activation barrier), but only as the minor pathway,
considering the experimental supports of the observed primary KIE (k /k = 3.99 with 2h,
H
D
Figure S10), low quantum yield (Φ = 0.029), and the control experiment under the Ir-free
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
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3
4
4
4
4
4
4
4
4
4
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6
conditions (Scheme 4A). Therefore, after the conversion of 2h-rad into 2h-cat via
oxidation by Ir(III)*, relatively long-lived and less-reactive intermediates (2h-cat and PhS-)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
can undergo the ionic coupling to produce the desired product. In summary, removal of
free thiol from the reaction conditions and introduction of redox-active Ir photocatalyst are
3
keys to achieving the allylic C(sp )–H thiolation selectively.
3

G (kcal/mol)
<Thiol-ene pathway>
<Allylic C(sp )–H pathway>
TS-C
21.7
TS-D
8.8
S
TS-A
PhSSPh
PhS
Ph
1
18.1
TS-B
2.1
SET
Ir(II)
3ah-rad
.9
PhS
PhSH
1
PhS
PhSH
PhS
PhS
0.0
7
Ir(III)*
3
.5
-0.7
-1.9
SPh
PhS
-7.2
Prevention of hydrothiolation
via removal of PhSH
Irreversible
HAT
PhS
SPh
2h
(rls)
2h-rad
2h-cat
3ah
3ah'
Ph
S
Ph
S
S
-38.5
H
S
S
SPh
Ph
Ph
-43.7
SPh
S
H
Ph
Ph
3ah
TS-D
TS-B
TS-A
TS-C
3ah
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Figure 1. Computed energy profile for reaction pathway. Free energies in solution (DMA)
at the (U)M06-2X(PCM)/SDD/6-311+G**//(U)B3LYP/LANL2DZ/6-31G** level are
displayed.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
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3
3
3
3
3
4
4
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4
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4
4
4
5
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5
5
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5
5
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5
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Based on the experimental and theoretical studies, a plausible reaction mechanism was
proposed (Figure 2). At first, the S–S bond can be homolytically cleaved by irradiation of
blue LED, and this step can be accelerated by the energy transfer process by the
photoexcited Ir photocatalyst (Ir(III)*)12c or the complexation between disulfide and
34
olefin . The generated thiyl radical can participate in either HAT from the allylic position
to produce ally radical (Int-1) or addition to olefin (R–H) to form thiol-ene radical adduct
(Int-2). The resulting thiophenol is immediately deprotonated by hydroxide, which
prevents further hydrogen transfer to Int-2, driving the irreversible HAT process. Int-1
o
undergoes single-electron oxidation (E (calc., 2a-cat/2a-rad) = 0.54 V vs SCE in MeCN)
o
23
by photoexcited Ir photocatalyst (Ir(III)*, E (Ir(III)*/Ir(II) = 0.63 V vs SCE in MeCN) to
allyl cation (Int-3), which can further react with the thiolate. The reduced photocatalyst
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
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o
23
red
(
Ir(II), E (Ir(III)/Ir(II) = –2.13 V vs SCE in MeCN) is re-oxidized by diaryl disulfide (E
p
35
(
PhSSPh) = –1.65 V vs SCE in DMF), producing Ir(III) species, thiyl radical, and thiolate
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
at the same time. Meanwhile, Int-1 can directly react with disulfide in the minor pathway,
producing the desired product and thiyl radical. Throughout the reaction, quenching of
o
∙
-
36
Ir(III)* by thiolate (E (PhS /PhS ) = 0.40 V vs SCE in MeCN) is also possible (Figure
S6), and this process could facilitate the HAT from olefin via the production of reactive
thiyl radical.
HAT (rate-limiting step)
hv
(
k /k = 3.99 with 2h)
H
D
Ir(III)*
Ir(III)
Deprotonation
OH
H2O
ArSSAr
ArS
ArSH
R2
ArS
hv
ArS
R1
R2
Initiation
R-H
R2
R4
SET
R3
R1
R4
R1
R4
H
R2
R3
R3
Int-3
Ir(III)*
hv
Ir(II)
R1
R4
Int-1
ArSSAr
R3
ArS +ArS
Ir(III)
R-H
(minor pathway)
R2
ArSSAr ArS
R2
ArS
R3
ArS
R1
R4
R1
R4
R3
ArSH
ArS
Int-2
Figure 2. Proposed mechanism.
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In the substrate scope evaluation, relatively more electron-rich dialkyl disulfides were
not active under the developed conditions (Table 1). In all attempts, the corresponding
thiol was isolated, indicating that S–S bond cleavage and HAT are still operative under
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
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3
3
3
3
3
4
4
4
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4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
the reaction conditions. However, reoxidation of Ir(II) intermediate (E (Ir(III)/Ir(II) = –2.13
23
red
V vs SCE in MeCN) would be problematic with dialkyl disulfide (E
(MeSSMe) = –2.43
p
35
V vs SCE in DMF) , due to its higher reduction barrier compared to that of diaryl disulfide
(
Epred (PhSSPh) = –1.65 V vs SCE in DMF).35 The higher reduction barrier makes the
catalytic cycle not viable (Scheme 6A) so that the ionic coupling between allyl cation and
thiolate cannot be performed. To overcome this innate limitation on the utilization of dialkyl
disulfide, we envisaged designing unsymmetrical disulfides to realize the direct synthesis
of alkyl allyl sulfides (Scheme 6B). By introducing an electron-deficient aromatic motif in
disulfides, the reduction barrier of disulfide can be lowered for the disulfides to interact
with the Ir(II) intermediate. Then, the selective coupling of the resulting alkyl thiolate with
allyl cation is expected to occur, due to higher nucleophilicity of alkyl thiolate than aryl
thiolate.
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1
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1
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2
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2
2
2
2
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2
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3
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3
4
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4
4
4
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5
5
5
5
6
Scheme 6. Problems and a Proposed Strategy for the Synthesis of Alkyl Allyl Sulfides
A. Problem in utilization of dialkyl disulfide - catalyst turnover
Ir(II)
R
R
E°(Ir(III)/Ir(II)) = -2.13V
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(vs SCE in MeCN)
R
R
PhSSPh
Epred = -1.65 V
Ir(II)
catalytic
Ir(II)
Ir(III)*
Ir(III)*
non
ArSSAr
AlkSSAlk
catalytic
(
vs SCE in DMF)
MeSSMe
Epred = -2.43 V
hv
hv
Ir(III)
Ir(III)
ArS +ArS
AlkS + AlkS
(vs SCE in DMF)
B. Proposed strategy: utilization of unsymmetrical disulfide
Ir(III)* Ir(II)
Ir(II) Ir(III) R-H
R
R
S
Alk
Alk
Ar
S
S
R SAlk
unsymmetrical
disulfide
+
Ar
OH- H2O
S
With the hypothesis, unsymmetrical disulfides bearing aryl moiety were prepared and
evaluated in the reaction with olefin 2a (Table 3). To our delight, desired allyl thioether
3qa began to appear when individually prepared unsymmetrical disulfides, which exhibit
lower reduction barriers, were subjected to the reaction conditions (entries 2-4).
Especially, disulfide bearing 2-benzothiazole moiety (1q ) gave the highest yields of 3qa
Bzt
among tested. Alkyl 2-benzothiazolyl disulfides can be easily prepared by a substitution
reaction between disulfide 1o and alkyl mercaptan, which could allow the unsymmetrical
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disulfide as a practical and versatile reagent.37 Further optimization of the reaction
conditions was conducted. Interestingly, the addition of a catalytic amount of diphenyl
disulfide 1a significantly boosts the yield of 3qa (entry 5), presumably due to the
acceleration of initial HAT by phenyl thiyl radical through the facile S–S bond cleavage
under irradiation. However, increased amount of 1a (10 mol%) rather decreased the
overall reactivity (entry 6). Additional elaboration of catalyst loading and concentration
gave a good yield of 3qa (70%, entry 8).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 3. Survey of Unsymmetrical Disulfidesa
Ir(CF3ppy)3 (2.0 mol%)
NaOH (1.0 equiv)
R
S
Ph
Ph
S
S
+
DMA (0.25 M), rt, 24 h
40 W Blue LED
3qa
1
2a
(20 equiv)
Cl
N
N
R = Ph
O2N
S
1qBzt
S
1q
1qClBzt
1qNO2Ph
Epred
< -2 Vb
-1.63 Vb
-1.61 Vb
-1.97 Vb
entry disulfid changes
in
yield 3qac
e
conditions
1
2
3
1q
None
N. D.
26%
23%
1qBzt
1qClBzt
None
None
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