Copper-Catalyzed Intermolecular Difunctionalization of Styrenes with Thiosulfonates and Arylboronic Acids via a Radical Relay Pathway

Article abstract of DOI:10.1021/acscatal.9b04887

A general and practical copper-catalyzed intermolecular difunctionalization strategy of styrenes with methyl thiosulfonates and arylboronic acids has been developed. This method provides an efficient and straightforward avenue to a broad range of 2,2-diar

Full text of DOI:10.1021/acscatal.9b04887

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Article
Copper-Catalyzed Intermolecular Difunctionalization of Styrenes with
Thiosulfonates and Arylboronic Acids via a Radical Relay Pathway
qingjin liang, Patrick J Walsh, and Tiezheng Jia
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b04887 • Publication Date (Web): 10 Dec 2019
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ACS Catalysis
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Copper-Catalyzed Intermolecular Difunctionalization of Styrenes with
Thiosulfonates and Arylboronic Acids via a Radical Relay Pathway
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§
‡
Qingjin Liang,†,‡ Patrick J. Walsh and Tiezheng Jia
*,
†School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin 150001, P. R. China
‡Department of Chemistry, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, P. R. China
§Roy and Diana Vagelos Laboratories, Penn/Merck Laboratory for High-Throughput Experimentation, Department of
Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States
ABSTRACT: A general and practical copper-catalyzed intermolecular difunctionalization strategy of styrenes with methyl
thiosulfonates and arylboronic acids has been developed. This method provides an efficient and straightforward avenue to a
broad range of 2,2-diarylethylsulfone derivatives from readily available methyl thiosulfonates and commercially available
styrene and arylboronic acid derivatives. The diverse substrate scope attests to the high functional group tolerance of this
reaction. The mild nature of this protocol make it suitable for late-stage functionalization of bioactive natural products.
Mechanistic investigations support the role of sulfonyl radicals and corroborate a copper-catalyzed radical relay pathway.
KEYWORDS: copper catalysis• radical relay • sulfones • alkenes• difunctionalization
Sulfones are prevalent scaffolds in natural products,1
synthetic bioactive molecules,2 and marketed therapeutics
(such as SB-3CT for the treatment of migraine headaches3 and
anti-androgen receptor Casodex 34). In fact, a study of drug
likeness analysis found that alkyl aryl sulfones are among the
top five drug skeletal fragments.5 Sulfones also find
widespread applications in material science6 and agricultural
industries.7 They serve as important intermediates in organic
synthesis,8 as exemplified by the well-known Julia−Lythgoe
olefination.9 Therefore, methods for the construction of
sulfones have attracted significant attention.
Scheme 1. Previous Synthetic Approaches to 2,2-
Diarylethylsulfones
Despite the importance of sulfones in the applications
outlined above, 2,2-diarylethylsulfones have received little
In recent years, copper-catalyzed coupling reactions
between in situ formed radicals and arylboronic acids have
drawn much attention due to copper’s low cost, bio-
compatibility, and complimentary reactivity to heavier d-
block metals.16 Copper-catalyzed difunctionalization of
alkenes represents one of the most powerful and
straightforward approaches to rapidly increase molecular
complexity, as two chemical bonds are generated in one
step.17 We envisioned that the 2,2-diarylethylsulfones
outlined above could be accessed via a three-component
process involving the arylsulfonylation of styrenes (Figure 1).
attention, probably due to
a
lack of efficient and
straightforward synthetic approaches.
Aliphatic sulfones can be prepared from α,β-unsaturated
sulfone precursors10 through hydrogenation, including
asymmetric hydrogenations.11 In 1998, the Ranu group
reported the Pd/C-catalyzed hydrogenation of α,β-
unsaturated sulfones using ammonium formate.12 Inspired by
this study, an elegant enantioselective rhodium-catalyzed
hydrogenation of α,β-unsaturated sulfones was developed by
the Hou group in 2019 (Scheme 1a).13 In this procedure, both
the (E)- and (Z)-isomers gave excellent enantioselectivities
leading to opposite configurations of the products. The
synthesis of the (E)- and (Z)-α,β-unsaturated sulfone
precursors required 4 steps. In 2004, Lautens and coworkers
To develop the arylsulfonylation of styrenes, three crucial
requirements would need to be satisfied (Figure 1). First, a
sulfonyl radical source that is compatible with the catalyst and
intermediates in the arylsulfonylation would need to be
identified.18 Second, the competitive two-component coupling
between sulfonyl radicals and boronic acids would need to be
minimized (see byproduct 1, Figure 1).19 Finally, an
appropriate oxidant for the selective oxidation of Cu(I) to
Cu(II) must be chosen that would not oxidize other reactive
intermediates (such as oxidize a punitive benzyl radical to the
described
a
rhodium-catalyzed Heck-type coupling of
arylboronic acids with α,β-unsaturated sulfones.14 By
employing a rhodium catalyst bearing an enantioenriched
tetrafluorobenzobarrelene-based ligand, an enantioselective
1,4-addition of boronic acids to α,β-unsaturated sulfones was
accomplished by Hayashi and his group (Scheme 1b).15 Here
also, the requisite α,β-unsaturated sulfones required several
steps to prepare,15 reducing the overall synthetic efficiency.
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corresponding cation, leading to byproducts 2,10a 3,20 or 4,21
Figure 1).
acetone to DMF was 6 : 1, 74% AY of 4aa was obtained (Table
1, entry 10). In contrast, an acetone to DMF ratio of 8 : 1,
furnished the product in 66% AY (Table 1, entry 11). Upon
decreasing the temperature from 50 to 40 oC, 4aa was formed
in 82% AY and 80% isolated yield (Table 1, entry 12). When
the reaction was carried out at room temperature, the AY
dropped to 48% (Table 1, entry 13). We next examine the
catalyst loading. When reducing the catalyst loading to 5 mol %
(Table 1, entry 14) the AY dropped to 72%. Thus, subsequent
reactions were conducted with 10 mol % copper.
1
2
3
4
5
6
7
8
The choice of sulfonyl radical source is important to
develop user-friendly general methods to make C–S bonds.
Several commonly used sulfonyl radical sources suffer from
drawbacks that decrease their attractiveness. For instance,
sulfonyl chlorides require expensive silver salts to trap
chloride and prevent its undesired radical background
additions.22 The activation of sulfonyl hydrazides usually
employ high temperatures, and the release of nitrogen gas
raises safety concerns.23 For our difunctionalization of
styrenes to afford 2,2-diarylethylsulfone scaffolds, methyl
thiosulfonates were chosen as the sulfonyl radical source.24
Methyl thiosulfonates are readily available, odorless, and safe.
Herein, we report an unprecedented copper-catalyzed
intermolecular difunctionalization of styrenes with methyl
thiosulfonates and arylboronic acids to afford 2,2-
diarylethylsulfones (Figure 1). Our copper-catalyzed
difunctionalization reaction features: (a) commercially
available styrenes and arylboronic acids and readily available
methyl thiosulfonates as starting materials; (b) cheap and
abundant copper catalysts; and (c) mild reaction conditions
with broad functional group compatibility. It represents an
efficient and streamlined method to synthesize 2,2-
diarylethylsulfone scaffolds.
9
In a series of control experiments, Cu(I), dtbbpy and KHCO3
were demonstrated to be essential for the catalytic reaction.
No desired product was observed in the absence of any of
these components (Table 1, entries 15–17). Therefore, the
optimized conditions were: 10 mol % CuI and 15 mol%
dtbbpy as the catalyst, styrene (1a) as the limiting reagent, 2.0
equiv of thiosulfonate (2a), 2.5 equiv of 3a, 2.5 equiv of KHCO3,
and 3.0 equiv BzOOtBu as both oxidant and radical initiator in
a mix solvent of acetone and DMF (6 : 1 volume ratio) at 40 oC
for 12 h (for additional screening results, see SI).
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Table 1. Optimization of the Copper-Catalyzed
Difunctionalization of Styrene with 2a and 3aa
Ph
[Cu]/ligand
Ts
TsSMe
+
+ PhB(OH)2
Ph
Ph
base, solvent,
BzOOtBu
1a
2a
3a
4aa
O
OH
SO2Ar3
SO2Ar3
Ar1
Ar1
Byproduct 4
Byproduct 3
Oxidation
ref. 34-38
entry
catalyst
base
solvent
T/
℃
4aa
Coupling
Ar2B(OH)2
(AYb/%)
Ar2
O
S
Ar3
O
S
Ar3
O
S
Ar1
Ar3
LG
Ar1
Ar1
+
O
1c
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
CuBr
K2CO3
acetone 50
34
O
O
Key Intermediate
This work
Desired Product
Oxidation,
ref. 21
Coupling
Ar2B(OH)2
2 c
3 c
4 c
5 c
6 c
NaHCO3 acetone 50
17
ref. 31-33
Elimination
SO2Ar3
Ar1
Byproduct 2
Cs2CO3
KHCO3
KHCO3
KHCO3
acetone 50
acetone 50
acetone 50
acetone 50
N.P
48
Ar2SO2Ar3
Byproduct 1
Figure 1. Synthesis of 2,2-Diarylsulfones via
a
trace
40
Difunctionalization of Styrenes Strategy and the Potential
Challenges
Cu(CH3C
N)4PF6
For the reaction optimization, we chose styrene (1a), S-
methyl
4-methylbenzenesulfonothioate
(2a)
and
7 c
8
CuI
CuI
CuI
KHCO3
KHCO3
KHCO3
acetone 50
60
63
68
phenylboronic acid (3a) as the model substrates. When 2.0
equiv K2CO3 was used as base, 2.0 equiv BzOOtBu as oxidant,
10 mol % Cu(OTf)2 and 15 mol % 4,4'-di-tert-butyl-2,2'-
bipyridine (dtbbpy) as the catalyst at 50 oC in acetone, the
desired product 4aa was isolated in 34% AY (AY = assay yield,
determined by 1H NMR integration of the crude product
against an internal standard, Table 1, entry 1). Encouraged by
this result, three additional bases (NaHCO3, Cs2CO3, and
KHCO3) were examined. These experiments revealed that
KHCO3 was the top choice, generating 4aa in 48% AY (Table 1,
entry 4 vs. entries 1–3). Thus, KHCO3 was used for further
optimization. Three additional copper salts [CuBr,
Cu(NCCH3)4PF6, and CuI] were surveyed (Table 1, entries 5–7).
The yield of 4aa increased to 60% when CuI was utilized
(Table 1, entry 7). In subsequent solvent screens, N,N-
dimethylformamide (DMF) led to formation of 4aa in 63%
yield. This reaction also resulted in the formation of 20% AY
of 4-tolyl phenyl sulfone (4aa’) from the two-component
coupling side reaction between 2a and 3a (Table 1, entry 8).
Formation of 4-tolyl phenyl sulfone (4aa’) was not observed
in the prior experiments in acetone (entries 1–7). This
observation inspired us to turn to mix solvents with DMF and
acetone (Table 1, entries 9–11). When the volume ratio of
DMF
50
9
acetone 50
:
DMF
=
4:1d
10
11
12
13
CuI
CuI
CuI
CuI
KHCO3
KHCO3
KHCO3
KHCO3
acetone 50
:
74
DMF
=
6:1d
acetone 50
:
66
DMF
=
8:1d
acetone 40
:
82(80e)
48
DMF
=
6:1d
acetone R.T
:
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CuI (10 mol %)
dtbbpy (15 mol %)
DMF
6:1 d
=
Ar
1
2
3
Ph
1a
ArB(OH)2
+
+
TsSMe
Ts
KHCO3, BzOOtBu
acetone:DMF = 6:1
Cl
Ph
2a
3
4
14f
CuI
KHCO3
acetone 40
:
72
F
Br
4
5
DMF
=
6:1 d
6
7
8
9
15g
16
CuI
-
KHCO3
KHCO3
Acetone 40
:DMF =
6:1 d
trace
N.P
Ts
, 80%
CF3
Ts
, 83%
Ts
Ts
, 56%
CHO
Ph
4aa
Ph
4ab
Ph
4ac
Ph
4ad
, 65%
acetone 40
:
10
11
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OMe
DMF
=
6:1 d
R
Ts
, 60%
Ts
, R = F, 60%
Ts
, 71%
Ts
, 52%
17
CuI
-
acetone 40
:
N.P
Ph
4ae
Ph
4af
Ph
4ah
Ph
4ai
DMF
=
4ag
, R = Br, 57%
COOCH3
6:1 d
COCH3
aReaction conditions: 1a (0.1 mmol), 2a (2.0 equiv), 3a (2.5
equiv), base (2.5 equiv), BzOOtBu (3.0 equiv), copper catalyst
(10 mol %), dtbbpy (15 mol %), acetone (0.6 mL) and DMF
(0.1 mL), 40 C for 12 h. AY = Assay yield, determined by H
NMR analysis of the crude reaction mixtures using 0.1 mmol
S
S
o
b
1
Ts
, 86%
Ts
Ts
4al
, 32%
Ts
, 44%
Ph
4aj
Ph
4ak
Ph
Ph
4am
, 88%
c
CH2Br2 (7.0 μL) as internal standard. 3a (2.0 equiv), KHCO3
(2.0 equiv), BzOOtBu (2.0 equiv) and solvent (1.0 mL).
dVolume ratio. eIsolated yield. CuI (5 mol %), dtbbpy (7.5
aReaction conditions: 1a (0.1 mmol), 2a (2.0 equiv), 3 (2.5
equiv), KHCO3 (2.5 equiv), BzOOtBu (3.0 equiv), CuI (10
mol %), dtbbpy (15 mol %), acetone (0.6 mL) and DMF (0.1
mL), 40 oC for 12 h.
f
mol %). gWithout dtbbpy.
With the optimized conditions in hand, we evaluated the
substrate scope of arylboronic acids in the three-component
coupling reaction to generate 2,2-diarylethylsulfones. As
shown in Table 2, the parent phenylboronic acid gave the
product 4aa in 80% yield. Arylboronic acids with
electronegative or electron-withdrawing groups reacted
smoothly with 1a and 2a to give the target products 4ab, 4ac,
4ad and 4ae in 56–83% yields. Likewise, ortho- and meta-
substituted phenylboronic acids furnished the products 4af–h
in 57–71% yield. Of note, arylboronic acids possessing
aldehyde (3i), ketone (3j) and ester (3k), provided 4ai-k in
52–88% yields. Heterocycles are important in medicinal
chemistry, but often challenging to install.25 When 2-
thiophenyl and 3-thiophenyl boronic acids were employed,
4al and 4am were generated from 1a and 2a under our
standard reaction conditions in 32 and 44% yields,
respectively.
We next turned our attention to the substrate scope of
styrenes in the three-component difunctionalization with 2a
and 3a. Overall, this method proved general with respect to
the styrenes, providing access to a wide range of 2,2-
diarylethylsulfones (Table 3). Styrenes with electron-donating
groups, such as para-tBu, -OMe or -Ph were well tolerated,
providing 5aa-c in 70–87% yields. Styrenes bearing electron-
withdrawing 4-F, 4-CF3, and 4-NO2 (1e–g) were good coupling
partners, delivering the desired products 4ab, 4ae and 5ad in
62–66% yields. When sterically hindered 2-methyl styrene
(1h) was utilized as the coupling partner, the corresponding
product 5ae was afforded in 65% yield. In addition, meta-
bromostyrene (1i) exhibited good reactivity generating the
expected product 5af in 79% yield. 1-(Chloromethyl)-4-
vinylbenzene is a substrate that would react rapidly with any
anionic sulfur-based nucleophiles. This substrate was suitable
for the multicomponent reaction, affording 5ag in 64% yield,
leaving the para-chloromethyl group for further modification.
As noted earlier, heterocycles are important in medicinal
chemistry.25 Our catalytic protocol proved applicable to a
variety of heterocyclic styrene derivatives.2 Pyridyl (1k, 1l),
thiophenyl (1m, 1n), furanyl (1p), quinolonyl (1q),
isoquinolonyl (1r), and indolyl (1s) alkenes furnished the
desired 2,2-diarylethylsulfones (5ah-I, 4al-m, and 5aj-n) in
30–64% yields. The internal styrene derivative, indene (1t),
was successfully applied to this transformation, delivering the
Table 2. Substrate Scope of Arylboronic Acids in the
Copper-Catalyzed Difunctionalization with 1a and 2aa
corresponding trans-sulfone product 5ao as
diastereomer in 42% yield.
a single
Table 3. Substrate Scope of Styrenes in Copper-Catalyzed
Difunctionalization with 2a and 3aa
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CuI (10 mol %)
dtbbpy (15 mol %)
Ph
+
SO2Ar
+ ArSO2SMe
PhB(OH)2
1
2
3
4
5
6
7
8
Ph
Ph
KHCO3, BzOOtBu
acetone:DMF = 6:1
Ph
1a
2
3a
6
O
F
Cl
O
Ph
Ph
Ph
Ph
O
O
O
S
O
S
O
S
S
Ph
Ph
Ph
Ph
O
O
O
6aa
6ab
6ac
6ad
, 61%
, 70%
, 76%
, 73%
Br
CF3
Ph
Ph
Ph
O
O
Ph
Ph
O
O
S
S
O
S
S
Ph
Ph
Ph
O
9
O
O
6ae
6af
6ag
6ah
, 60%
, 51%
, 73%
, 75%
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11
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S
Ph
Ph
O
O
S
O
S
Ph
O
6ai
6aj
, 50%
, 62%
aReaction conditions: 1a (0.1 mmol), 2 (2.0 equiv), 3a (2.5
equiv), KHCO3 (2.5 equiv), BzOOtBu (3.0 equiv), CuI (10
mol %), dtbbpy (15 mol %), acetone (0.6 mL) and DMF (0.1
mL), 40 ℃ for 12 h.
To explore the potential synthetic utility of our method,
late-stage functionalization of bioactive natural products was
conducted. Alkenes bearing cromaril, estrone and tocol, three
well known bioactive natural products, proceeded smoothly
under the optimized reaction conditions to provide 5ap, 5aq,
and 5ar in synthetically useful yields (40–52%) (Scheme 2).
aReaction conditions: 1 (0.1 mmol), 2a (2.0 equiv), 3a (2.5
equiv), KHCO3 (2.5 equiv), BzOOtBu (3.0 equiv), CuI (10
mol %), dtbbpy (15 mol %), acetone (0.6 mL) and DMF (0.1
mL), 40 oC for 12 h.
The generality of methyl thiosulfonates in copper-catalyzed
difunctionalization with 1a and 3a was next investigated
(Table 4). The parent 2,2-diphenylethyl phenyl sulfone (6aa)
was generated in 70% yield. The electron-donating 4-methoxy
substituent exerts a negligible effect on the outcome of the
transformation, affording 6ab in 76% yield. Aryl
thiosulfonates with electronegative or electron-withdrawing
groups, such as 4-F, 4-Cl, 4-Br and 4-CF3, coupled under the
standard conditions, providing 6ac–6af in 51–73% yields.
Using sterically demanding 2-methyl thiosulfonate (2h) as
coupling partner in the difunctionalization led to formation of
6ag in 75% yield. An acetyl group on the phenyl sulfone (2i)
was tolerated owing to the mild reaction conditions,
furnishing the product 6ah in 60% yield. 2,2-Diphenylethyl 2-
thiophenyl sulfone (6ai), a heteroaryl sulfone, was produced
in 62% yield. It is noteworthy that methyl thiosulfonate 2j, an
example of an alkyl thiosulfonate, also exhibited good
reactivity in the copper-catalyzed difunctionalization with 1a
and 3a, providing 6aj in 50% yield under the optimized
conditions.
Scheme 2. Late-Stage Functionalization of Natural
Products
Difunctionalization of Styrenes with 2a and 3a
Based
on
Copper-Catalyzed
Several experiments to probe the mechanism of this
catalytic transformation were performed (Scheme 3). First,
Table 4. Substrate Scope of Thiosulfonates in Copper-
Catalyzed Difunctionalization with 1a and 3aa
when
2
equiv
of
radical
scavenger
2,2,6,6-
tetramethylpiperidinyl-1-oxide (TEMPO) was added to the
reaction under otherwise standard conditions, the formation
of product 4aa was inhibited and 1a was recovered in near
quantitative assay yield, as determined by GC (Scheme 3a).
Both p-methyl benzene sulfonate anion (7a) and 2,2,6,6-
tetramethylpiperidine (8a) were detected in the reaction
mixture via HRMS analysis (see Scheme S1). Based on these
observations, we speculate that TEMPO captured the sulfonyl
radical, which was followed by reduction to 7a and 8a. These
results are consistent with a radical pathway. When 2.0 equiv
of the spin trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO) was
added to the model reaction, the formation of 9a was
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confirmed by HRMS (Scheme 3b) and electron paramagnetic
resonance spectroscopy (EPR) (Scheme 3c). This result
supports the intermediacy of the sulfonyl radical in this
(dtbbpy)CuI (A), which reacts with BzOOtBu to generate the
copper(II) complex B, and •OCMe3 (E).27 Then •OCMe3 (E)
abstracts hydrogen from DMF to generate the formyl radical
F.28 A radical relay process between 2a and the formyl radical
1
2
3
4
5
6
7
8
process (Scheme 3b). In addition,
a series of UV−vis
experiments was performed to probe the oxidation states of
the copper catalyst (Scheme 3d). When copper(I) iodide was
mixed together with dtbbpy ligand, the UV absorption of Cu(I)
complex is ca. 431 nm (Scheme 3d). However, the UV band
shifted to 703 nm when copper(I) iodide and dtbbpy were
mixed together with BzOOtBu, which is consistent with the d-d
transition of Cu(II) species.26 To verify the existence of Cu(II)
species, the solution of CuI, dtbbpy and BzOOtBu was
monitored by EPR, which clearly exhibited signals for a Cu(II)
species (see Figure S1 in the SI). When the reaction mixture
was monitored by UV, the copper absorption is approximately
684 nm, which was attributed to a Cu(II) species as the
catalyst resting state.
F
affords sulfonyl radical (G), and generates the
thiocarbamate, which was formed in 72% AY by 1H NMR
spectroscopy (and fully characterized, see SI for details). Ts•
(G) undergoes addition to styrene 1a, generating the benzyl
radical H. Meanwhile, the Cu(II) complex B reacts with
arylboronic acid 3a via transmetallation to form the aryl
copper(II) species C, which then undergoes oxidative trapping
with the benzylic radical H to afford a reactive Cu(III)
intermediate D.29 Complex D undergoes reductive elimination
to furnish 4aa and regenerate the copper(I) species A to close
the catalytic cycle. As mentioned earlier, the reaction forming
5ag, containing a benzylic chloromethyl group, suggests that
anionic sulfur species are unlikely to be intermediates in this
process. Anionic sulfur compounds undergo rapid SN2
reactions with benzyl chloride derivatives.
9
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a) Radical trapping experiments with TEMPO
CuI (10 mol %)
dtbbpy (15 mol %)
Ph
Ts
PhB(OH)2
TsSMe
+
Ph
+
KHCO3, BzOOtBu
acetone:DMF = 6:1
TEMPO 2 equiv.
Ph
N
O
O
4aa
not detected
1a
2a
3a
Ts
H
NMe2
Me2N
tBuO
E
1a
was completely recovered as determined by GC.
decomposed
O
PhCO2OtBu
+
TsO
PhCO2 CuII
N
H
F
TsSMe
2a
B
7a
8a
8a
CuI
A
O
7a
and
were confirmed by HRMS.
PhB(OH)2
3a
Me2N
SMe
11a
b) EPR studies with DMPO
Ph
Ts
Ts
G
CuI (10 mol %)
dtbbpy (15 mol %)
N
Ph
4aa
Ph CuII
O
Ts
PhB(OH)2
Ph
TsSMe
+
+
N
C
KHCO3, BzOOtBu
acetone:DMF = 6:1
(2 equiv.)
CuIII Ph
Ts
1a
2a
3a
O
9a
Ph
1a
Ph
D
HRMS (ESI, m/z): calcd. for
Ts
Ph
C13H18NO3S [M]: 268.1007, found: 268.1004
H
c) EPR spectra of 9a (the fitting data and experimental data)
Figure 2. Proposed Mechanism of Copper-Catalyzed
Difunctionalization of Styrenes
In summary,
difunctionalization of styrenes with arylboronic acids and
methyl thiosulfonates has been developed. variety of
a novel copper-catalyzed intermolecular
A
styrenes, methyl thiosulfonates and arylboronic acids were
compatible with the catalytic conditions, resulting in rapid
d) UV-Vis spectra studies
access to 2,2-diarylethylsulfone derivatives in
a one-pot
procedure. Key to success of this three component coupling
hinges on the use of methyl thiosulfonates as sulfonyl radical
source, which suppress the direct arylation of sulfonyl radical
with arylboronic acids when reactions are conducted in
acetone/DMF solvent systems. Importantly, owing to mild
reaction conditions, our method is suited for the late-stage
functionalization of complex natural products. The
mechanistic studies point toward a sulfonyl radical initialized
radical relay pathway. The development of enantioselective
version of the strategy described herein is currently ongoing
in our laboratory.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Detailed experimental procedures, characterization data, and
NMR spectra of new compounds (PDF).
Scheme 3. Control Experiments to Probe the Reaction
Mechanism
Based on the experimental results above, and related
literature reports,16c
a
plausible reaction mechanism is
illustrated (Figure 2). CuI binds the ligand dtbbpy to give
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Page 6 of 7
Heteroarylalkylsulfones with Carbonyl Compounds. J. Chem. Soc.,
Perkin Trans. 1 2002, 2563-2585.
(10) (a) Fang, Y.; Luo, Z.; Xu, X. M. Recent Advances in the
Synthesis of Vinyl Sulfones. RSC Adv. 2016, 6, 59661-59676. (b)
Liwosz, T. W.; Chemler, S. R. Copper-Catalyzed Oxidative
Amination and Allylic Amination of Alkenes. Chem. Eur. J. 2013,
19, 12771-12777.
AUTHOR INFORMATION
Corresponding Author
1
2
3
4
*E-mail: jiatz@sustech.edu.cn
Notes
The authors declare no competing financial interest.
5
6
7
8
(11) (a) Zhou, T.; Peters, B.; Maldonado, M. F.; Govender, T.;
Andersson, P. G. Enantioselective Synthesis of Chiral Sulfones by
Ir-Catalyzed Asymmetric Hydrogenation: A Facile Approach to the
Preparation of Chiral Allylic and Homoallylic Compounds. J. Am.
Chem. Soc. 2012, 134, 13592-13595. (b) Jiang, J.; Wang, Y.; Zhang,
X. Rhodium-Catalyzed Asymmetric Hydrogenation of β-
Acetylamino Acrylosulfones: A Practical Approach to Chiral β-
Amido Sulfones. ACS Catal. 2014, 4, 1570-1573. (c) Peters, B. K.;
Zhou, T.; Rujirawanich, J.; Cadu, A.; Singh, T.; Rabten, W.;
Kerdphon, S.; Andersson, P. G. An Enantioselective Approach to
the Preparation of Chiral Sulfones by Ir-Catalyzed Asymmetric
Hydrogenation. J. Am. Chem. Soc. 2014, 136, 16557-16562. (d) Shi,
L.; Wei, B.; Yin, X.; Xue, P.; Lv, H.; Zhang, X. Rh-Catalyzed
Asymmetric Hydrogenation of α-Substituted Vinyl Sulfones: An
Efficient Approach to Chiral Sulfones. Org. Lett. 2017, 19, 1024-
1027.
(12) Ranu, B. C.; Guchhait, S. K.; Ghosh, K. Chemoselective
Hydrogenation of α,β-Unsaturated Sulfones and Phosphonates via
Palladium-Assisted Hydrogen Transfer by Ammonium Formate. J.
Org. Chem. 1998, 63, 5250-5251.
(13) Yan, Q.; Xiao, G.; Wang, Y.; Zi, G.; Zhang, Z.; Hou, G. Highly
Efficient Enantioselective Synthesis of Chiral Sulfones by Rh-
Catalyzed Asymmetric Hydrogenation. J. Am. Chem. Soc. 2019,
141, 1749-1756.
(14) Lautens, M.; Mancuso, J.; Grover, H. Rhodium-Catalyzed
Heck-Type Coupling of Boronic Acids with Activated Alkenes in
An Aqueous Emulsion. Synthesis 2004, 2006-2014.
(15) Nishimura, T.; Takiguchi, Y.; Hayashi, T. Effect of Chiral
Diene Ligands in Rhodium-Catalyzed Asymmetric Addition of
Arylboronic Acids to α,β-Unsaturated Sulfonyl Compounds. J. Am.
Chem. Soc. 2012, 134, 9086-9089.
(16) (a) Evano, G.; Blanchard, N. Copper-Mediated Cross-Coupling
Reactions. Wiley: New Jersey, 2014. (b) Shaughnessy, K. H.;
Ciganek, E.; DeVasher, R. B. Copper-Catalyzed Amination of Aryl
and Alkenyl Electrophiles Wiley: New Jersey, 2017. (c) Wang, F.;
Chen, P.; Liu, G. Copper-Catalyzed Radical Relay for Asymmetric
Radical Transformations. Acc. Chem. Res. 2018, 51, 2036-2046.
(17) (a) Lan, X.-W.; Wang, N.-X.; Xing, Y. Recent Advances in
Radical Difunctionalization of Simple Alkenes. Eur. J. Org. Chem.
2017, 5821-5851. (b) Zhang, J.-S.; Liu, L.; Chen, T.; Han, L.-B.
ACKNOWLEDGMENT
We thank the Science and Technology Innovation
Commission
of
Shenzhen
Municipality
9
(JCYJ20180302180256215) to provide financial support.
SUSTech is greatly appreciated for providing startup fund to
TJ. We are also very grateful to Dr. Yang Yu (SUSTech) for
HRMS and Dr. Zhou Tang (SUSTech) for EPR fitting data. PJW
thanks the US NSF (CHE-1902509).
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