Potassium tert -Butoxide Mediated Reductive C-P Cross-Coupling of Arylvinyl Sulfides through C-S Bond Cleavage

Article abstract of DOI:10.1055/s-0040-1707319

A transition-metal-free t -BuOK-mediated reductive C-P cross-coupling reaction of arylvinyl sulfides with diarylphosphine oxides through C-S bond cleavage has been developed. This protocol not only permits the synthesis of diaryl(2-arylethyl)phosphine oxides, but also achieves an unprecedented construction of a C-P bond through C-S bond cleavage and reduction of a C-C double bond in one pot.

Full text of DOI:10.1055/s-0040-1707319

SYNLETT
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2020, 31, A–E
letter
A
en
J. Feng et al.
Letter
Synlett
Potassium tert-Butoxide Mediated Reductive C–P Cross-Coupling
of Arylvinyl Sulfides through C–S Bond Cleavage
Jie Fenga
Qiaoling Zhanga
Fuhai Lia
R2
P
Ar
R1
+
R2
t-BuOK, toluene
Ar
R22P(O)H
S
Ar, 120 °C, 24 h
O
11 examples
55–89 % yield
Lu Yangb
Ratnakar Reddy Kuchukullaa
Qingle Zeng*a
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3
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7
5
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X
a State Key Laboratory of Geohazard Prevention and Geoenviron-
ment Protection, College of Materials, Chemistry and Chemical
Engineering, Chengdu University of Technology, Chengdu
610059, P. R. of China
qinglezeng@hotmail.com
b Department of Chemistry, Graduate School of Science, Tohoku
University, 6-3 Azaaoba Aramaki, Aoba-ku, Sendai, 980-8578,
Japan
Corresponding Author
Received: 18.08.2020
Accepted after revision: 08.09.2020
Published online: 13.10.2020
by activation and cleavage of C–S bonds has attracted wide-
spread attention.15b,17 There have been reports on the cleav-
age of C–S bonds, with formation of carbon–heteroatom
bonds, by transition metals such as Pt,18 Rh,19 Fe,20 Co,21
Ni,9a,22 Pd,23 and Cu24 (Scheme 1A).
However, few transition-metal-free coupling reactions
have been reported.25 Only alkenylsilanes, sulfones, phos-
phine oxides, and nitroolefins have been prepared by radi-
cal-mediated C–S bond cleavage of arylvinyl sulfides
(Scheme 1B);26 the products of these reactions are import-
ant structural units in many natural products, pharmaceu-
ticals, and organic light-emitting materials.27
DOI: 10.1055/s-0040-1707319; Art ID: st-2020-v0457-l
Abstract A transition-metal-free t-BuOK-mediated reductive C–P
cross-coupling reaction of arylvinyl sulfides with diarylphosphine oxides
through C–S bond cleavage has been developed. This protocol not only
permits the synthesis of diaryl(2-arylethyl)phosphine oxides, but also
achieves an unprecedented construction of a C–P bond through C–S
bond cleavage and reduction of a C–C double bond in one pot.
Key words alkenyl sulfides, C–S bond cleavage, C–P bond formation,
potassium butoxide, transition-metal-free synthesis
During our researches in organosulfur chemistry28 and
coupling reactions,29 we occasionally observed transition-
metal-free, t-BuOK-promoted synthesis of diaryl(2-aryleth-
yl)phosphine oxides 3 by C–S bond cleavage and reductive
C–P cross-coupling of arylvinyl sulfides 1 and diarylphos-
phine oxides 2 (Scheme 1C).
Organophosphorus compounds have attracted consid-
erable attention due to their broad range of applications in
organic synthesis, materials science, bioorganic and medici-
nal chemistry, coordination chemistry, and catalysis, and as
flame retardants.1 In the 1980s, Hirao and colleagues re-
ported the construction of C–P bonds by palladium-cata-
lyzed reactions of aryl or alkenyl halides with dialkylphos-
phates.2 Since then, a range of organic and organometallic
compounds have been used to synthesize organophospho-
rus compounds, including organic halides,3 derivatives of
alcohols or phenols,4 diazonium salts,5 aryl hydrazines,6 bo-
ric acids,7 silanes,8 sulfides,9 aryl nitriles,10 aryl or alkenyl
carboxylic acids,11 amides,12 and aromatic esters.13
Conversion of C–X bonds into various C–Y bonds cata-
lyzed by transition metals is an essential process in organic
synthesis. Halogen compounds are commonly used in this
method.14 However, sulfur compounds have greater stabili-
ty and better availability than the halides used in conven-
tional methods.15 Sulfur is widely present in natural prod-
ucts, pesticides, and proteins; moreover, sulfur-containing
molecules can be precisely modified by highly selective ac-
tivation or functionalization of the C–S bond.16 The con-
struction of carbon–carbon and carbon–heteroatom bonds
(A) Transition-metal (TM)-catalyzed C–S bond cleavage with nucleophiles
TM (cat.)
S
+
Nu–
R1 Nu
R1
R2
– R2S–
(B) Radical C–S bond cleavage of aryl alkenyl sulfides
Ar
Y = Si, SO2, PO, NO2
Ar
+
RY
SAr
YR
– ArS
(C) This work: t-BuOK-mediated reductive C–P cross-coupling of alkenyl sulfides
t-BuOK
Ar
Ar
R1
+
R22P(O)H
2
P(O)R2
S
2
3
1
Scheme 1 Methods for activating C–S bonds
Initially, the reductive cross-coupling of 4-methylphenyl
styryl sulfide (1a) with diphenylphosphine oxide (2a) was
chosen as a model system for optimizing the reaction con-
ditions (Table 1). The effects of various solvents on the reac-
tion were investigated in the presence of t-BuOK (Table 1,
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
J. Feng et al.
Letter
Synlett
entries 1–9). The reaction did not proceed at room tem-
perature under any of the reaction conditions tested, but af-
ter heating, some product 3a was formed, except for the re-
actions in DMF, propane-1,3-diol, or DCE (Table 1). Screen-
ing of various solvents and bases at various temperatures
revealed that the best yield of 3a (82%) was obtained at 120
°C in toluene with t-BuOK as the base (entries 18 and 21).
At lower temperatures, the reaction was significantly slow-
er and lower yields were observed after 24 hours (entry 18
versus entries 2 and 15–17). Therefore, the optimal reac-
tion conditions were found to involve toluene as solvent
with 2.5 equivalents of t-BuOK as base under an argon at-
mosphere at 120 °C.30,31
stituents on the aromatic ring, arylvinyl sulfides 1b and 1c
(entries 2 and 3) with an electron-donating group afforded
lower yields of the reductive cross-coupling products than
did the electron-deficientyy substrates 1d–g (entries 4–7).
To our surprise, 2-pyridylethene (1h) with a hetaryl group
afforded the target product 3h in a yield as high as 87% (en-
try 8).
Table 2 Reaction of Alkenyl Sulfides 1 with Diarylphosphine Oxides 2a
t-BuOK
Ar
R1
+
Ar
R22P(O)-H
P(O)R2
S
2
toluene, 120 °C
3
2
1
Entry Ar
R1
4-Tol
R2
Product Yield (%)
Table 1 Screening of Reaction Conditionsa
1
2
Ph
4-Tol
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
3a
3b
3c
3d
3e
3f
82
71
65
86
85
83
85
87
79
81
89
86
81
56
73
63
59
51
55
69
55
4-Tol
O
H
3
4-EtC6H4
4-FC6H4
3-FC6H4
2-FC6H4
4-ClC6H4
2-pyridyl
Ph
4-Tol
P
base
P
+
4
4-Tol
S
O
solvent
3a
5
4-Tol
2a
1a
Base (equiv)
6
4-Tol
Entry
Solvent
Temp (°C)
Yield (%)
7
4-Tol
3g
3h
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
1
2
t-BuOK (2.0)
t-BuOK (2.0)
t-BuOK (2.0)
t-BuOK (2.0)
t-BuOK (2.0)
t-BuOK (2.0)
t-BuOK (2.0)
t-BuOK (2.0)
t-BuOK (2.0)
t-BuONa (2.0)
K2CO3 (2.0)
KOH (2.0)
1,4-dioxane
toluene
DMSO
110
110
110
110
80
23
51
32
0
8
4-Tol
9
4-BrC6H4
4-ClC6H4
4-FC6H4
3-FC6H4
2-FC6H4
4-MeOC6H4
2-naphthyl
t-Bu
3
10
11
12
13
14
15
16
17
18
19
20
21
Ph
4
DMF
Ph
5
MeCN
10
0
Ph
6
propane-1,3-diol
xylene
110
110
80
Ph
7
43
0
Ph
8
DCE
Ph
9
EtOAc
80
12
13
0
Ph
10
11
12
13
14
15
16
17
18
19
20
21
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
110
110
110
110
110
40
Ph
2-pentyl
Bu
Ph
11
0
Ph
cyclopentyl
cyclohexyl
4-Tol
K3PO4 (2.0)
Et3N (2.0)
Ph
0
Ph
3,5-Me2C6H3 (2b) 3i
a Reaction conditions: 1 (1 mmol), 2 (2 mmol), t-BuOK (2.50 mmol), toluene
(12 mL), 120 °C, 24 h.
t-BuOK (2.0)
t-BuOK (2.0)
t-BuOK (2.0)
t-BuOK (2.0)
t-BuOK (1.0)
t-BuOK (1.5)
t-BuOK (2.5)
0
60
0
80
42
65
0
We continued to investigate the effect on the yield of
the reaction of alkyl or aryl substituents R1 on substrate 1.
When R1 was a substituted phenyl group, electronic effects
of the substituents on the benzene ring were obvious. Elec-
tron-withdrawing substituents were beneficial to the reac-
tion (Table 2, entries 9–13). Moreover, the more electroneg-
ative the halo group, the higher the yield (entries 9–11). An
electron-donating methoxy group on the benzene ring
sharply decreased the yield (entry 14). Overall, aromatic R1
groups afforded higher yields than aliphatic R1 groups (en-
tries 9–15 versus 16–20). In this reaction, a styryl thioether
provided moderate yields, regardless of whether the R1
120
120
120
120
31
82
a Reaction conditions: 1a (1 mmol), 2a (2 mmol), base, solvent (12 mL), 24 h.
With the optimized reaction conditions in hand, we
next evaluated the scope of the substrate (Table 2). Various
arylvinyl sulfides 1 successfully coupled with the diphenyl-
phosphine oxides 2 to produce the corresponding (-ary-
lethyl)phosphine oxides 3a–i in moderate to high yields (Ta-
ble 2, entries 1–21). Because of electronic effects of the sub-
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

C
J. Feng et al.
Letter
Synlett
group was a bulky tert-butyl group or a smaller group, or
was linear or cyclic (entries 16–20).
To explore the reaction mechanism, we designed a se-
ries of control experiments (Scheme 4). We found that
when the ratio of the reaction starting materials was 1:1,
the presence of the target product was barely detectable
(Scheme 4a). We therefore believe that in this reaction, di-
phenylphosphine oxide acts as both a reactant and a reduc-
ing agent that can be oxidized to diphenylphosphinic acid
(6) under alkaline conditions. We then repeated the experi-
ment under the optimized conditions. After workup of the
reaction, the aqueous phase was acidified with hydrochlo-
ric acid; subsequent extraction of the aqueous phase af-
forded a white solid confirmed to be diphenylphosphinic
acid (6) by NMR and mass spectrometry (Scheme 4b). Fur-
thermore, we presumed that the alkenyl(diphenyl)phos-
phine oxide 7 was the key intermediate before reduction, so
we subjected compound 7 to the standard conditions and,
as expected, we obtained the desired product 3a in 76%
yield (Scheme 4c).
Finally, we carried out a reaction with bis(3,5-dimethyl-
phenyl)phosphine oxide (2b) as the substrate under the
same conditions, and the corresponding target product 3i
was obtained with a lower yield (Table 2, entry 21). This re-
sult might be due to the presence of the electron-donating
methyl substituents on the benzene ring of 2b.
This reaction was also carried out on a 10 mmol scale
without a decrease in the reaction efficiency (Scheme 2).
Thus, heating a mixture of 1a (10 mmol), 2a (20 mmol), and
t-BuOK (25 mmol) in toluene (50 mL) at 120 °C for 24 hours
gave product 3a in 76% yield.
t-BuOK
H
O
(2.5 equiv)
+
P
P
toluene
120 °C, 24 h
O
S
Based on these experimental results, a plausible mecha-
nism for the reductive C–P cross-coupling between arylvi-
nyl sulfides and diarylphosphine oxides was proposed
(Scheme 5). Tautomer 2a′ of 2a is protonated by t-BuOK to
give the 2a′ anion. Nucleophilic attack by the 2a′ anion on
1a then produces sulfide 8. Through electron transfer, 8 re-
leases a TolS– anion and affords 7. Addition of an excess of
diphenylphosphine oxide (2a) to 7 generates 5, which is at-
tacked by tert-butoxide and then eliminates t-butyl diphen-
ylphosphinate (9) to give an anion of product 3. Finally, the
anion of 3 is protonated by tert-butanol to produce the de-
sired product 3a. The diphenylphosphinic acid (6) men-
tioned above is generated from tert-butyl diphenylphosphi-
nate (9) during the workup with aqueous HCl.
1a
2a
3a
20 mmol
2.021 g
10 mmol
2.263 g
2.328 g, 76%
Scheme 2 Gram-scale experiment
A further transformation of product 3e is shown in
Scheme 3. In the presence of catalytic amounts of p-tolue-
nesulfonamide and molecular iodine, [2-(3-fluorophe-
nyl)ethyl](diphenyl)phosphine oxide and (diacetoxyio-
do)benzene (DIB) in DCE at 60 °C gave the oxidative cou-
pling product 4 in 54% yield.32,33 This is a metal-free direct
arylation of an aromatic C–H bond; in other words, a regio-
specific dimerization of arenes through oxidative C–H bond
activation, which has not been previously reported.
In summary, we have discovered a transition-metal-free
t-BuOK-promoted C–S cleavage and, consequently, a reduc-
tive C–P cross-coupling reaction. Various diaryl(2-aryleth-
yl)phosphine oxides were synthesized from a wide range of
arylvinyl sulfides and diarylphosphine oxides in the pres-
ence of t-BuOK. The products can be synthesized on a gram
scale and transformed further into other interesting mole-
DIB (2.5 equiv)
I2 (0.2 equiv)
TsNH2 (0.2 equiv)
F
O
P
O
F
P
P
F
O
DCE (5 mL)
60 °C, 10 h
3e
4, 54%
Scheme 3 Reaction expansion through oxidative cross-coupling
Ph
Ph
P
H
S
t-BuOK (2.5 equiv)
Ph
Ph
P
+
+
O
Ph
(a)
(b)
O
toluene
120 °C, 24 h
Ph
3a, trace
1a, 1 mmol
2a, 1 mmol
Ph
P
Ph
Ph
organic
layer
O
Ph
H
S
t-BuOK (2.5 equiv)
Ph
Ph
3a
P
Ph
O
O
toluene
120 °C, 24 h
H
aqueous
layer
HCl (aq)
P
1a, 1 mmol
2a, 2 mmol
Ph
O
6, 45%
O
P
Ph
Ph
H
Ph
t-BuOK (2.5 equiv)
Ph
+
O
P
P
(c)
Ph
Ph
O
Ph
toluene
120 °C
Ph
7, 1 mmol
2a, 2 mmol
3a, 76%
Scheme 4 Control experiments
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

D
J. Feng et al.
Letter
Synlett
O
P
Tol
Ph
O
P
O
H
S
OH
P
Ph
Ph
Ph
O
P
t-BuO
– RS
1a
Ph
Ph
Ph
P
R'
Ph
Ph
Ph
Ph
– t-BuOH
S
Ph
Ph
2a
2a'
2a' anion
7
8
Ph2P(O)H (2a)
t-BuO
Ph
Ph
O
Ph
P
O
Ph
Ph
Ph
Ph
P
O
Ph
t-BuO
t-BuOH
t-BuO
P
P
Ph
Ph
Ph
Ph
Ph
Ph
9
– t-BuOP(O)Ph2 ( )
O
O
P
O
P
3a
3a anion
Ph
Ph
5
t-BuO
O
O
HCl (aq)
Ot-Bu
O
P
P
H
Ph
Ph
Ph
Ph
9
6
(detected)
Scheme 5 Postulated reaction mechanism
cules. A reasonable mechanism is proposed based on con-
trol experiments.
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Funding Information
This work was supported by the State Key Laboratory of Geohazard
Prevention and Geoenvironment Protection (No. SKLGP2018Z002).
S
ate
K
e
y
L
aboratory
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f
Ge
o
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azardPreventio
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entProtecti
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n(SKLG
P
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8
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= 2.9, 1.8 Hz). 19F NMR (376 MHz, CDCl3):  = –113.15. 31P NMR
(162 MHz, CDCl3):  = 31.22. HRMS (ESI-MS): m/z [M + Na]+
calcd for C20H18FNaOP: 347.0972; found: 347.0951.
(29) (a) Zeng, Q.; Zhang, L.; Zhou, Y. Chem. Rec. 2018, 18, 1278.
(b) Yang, L.; Feng, J.; Qiao, M.; Zeng, Q. Org. Chem. Front. 2018, 5, 24.
(30) Trisubstituted Phosphine Oxides 3a–i; General Procedure
An oven-dried standard 25 mL ground-mouth test tube
equipped with a stirrer bar was charged with the appropriate
disubstituted phosphine oxide 2 (2.0 mmol, 2.0 equiv), alkenyl
sulfide 1 (1.0 mmol, 1.0 equiv), t-BuOK (2.5 mmol, 2.5 equiv),
and toluene (12 mL). The test tube was sealed with a sleeve
rubber stopper and then evacuated and refilled with argon for
three cycles. The mixture was stirred at 120 °C for 24 h, then
cooled to r.t. The mixture was diluted with EtOAc and washed
with H2O, and the aqueous layer was extracted with EtOAc (×3).
The combined organic layer was dried (MgSO4) and concen-
trated under vacuum on a rotary evaporator, and the residue
was purified by column chromatography (silica gel, PE–EtOAc
gradient).
(31) [2-(3-Fluorophenyl)ethyl](diphenyl)phosphine Oxide (3e)
White crystals; yield: 276 mg (85%); mp 101–102 °C. 1H NMR
(400 MHz, CDCl3):  = 7.81–7.67 (m, 4 H), 7.54–7.39 (m, 6 H),
7.22–7.11 (m, 1 H), 6.98–6.87 (m, 1 H), 6.87–6.78 (m, 2 H),
2.97–2.81 (m, 2 H), 2.60–2.47 (m, 2 H). 13C NMR (101 MHz,
CDCl3):  = 162.84 (d, JC–F = 246.0 Hz), 143.57 (dd, JC–P = 15.2 Hz,
JC–F =7.2 Hz), 132.50 (d, JC–P = 98.7 Hz), 131.88 (d, JC–P = 2.7 Hz),
(32) [(6,6′-Difluorobiphenyl-2,2′-diyl)bis(ethane-2,1-
diyl)]bis(diphenylphosphine) Dioxide (4)
An oven-dried standard 25 mL ground-mouth test tube
equipped with a stirrer bar was charged with phosphine oxide
3e (0.324 g, 1.0 mmol), (diacetoxyiodo)benzene (0.805 g, 2.5
mmol), I2 (0.051 g, 0.2 mmol), p-toluenesulfonamide (0.034 g,
0.2 mmol), and DCE (5 mL). The test tube was sealed with a
sleeve rubber stopper and then evacuated and refilled with
argon for three cycles. The mixture was stirred at 60 °C for 10 h,
then cooled to r.t. The reaction was quenched with aq Na2S2O3,
and the mixture was extracted with EtOAc and washed with
H2O. The aqueous layer was extracted with EtOAc (×3), and the
combined organic layer was dried (MgSO4) and concentrated in
vacuum on a rotary evaporator. The residue was purified by
column chromatography (silica gel, PE–EtOAc gradient) to give a
white solid; 349 mg (54%); mp 101–102 °C.
1H NMR (400 MHz, CDCl3):  = 7.86–7.73 (m, 8 H), 7.67 (dd, J =
8.7, 5.7 Hz, 2 H), 7.58–7.41 (m, 12 H), 6.96 (dd, J = 9.4, 3.0 Hz, 2
H), 6.62 (td, J = 8.3, 3.0 Hz, 2 H), 3.06–2.92 (m, 4 H), 2.54 (ddd,
J = 10.8, 8.9, 4.7 Hz, 4 H). 13C NMR (101 MHz, CDCl3):  = 163.05
(d, JC–F = 248.2 Hz), 145.84 (dd, JC–P = 14.9 Hz, JC–F =7.2 Hz),
140.55 (d, JC–F = 7.8 Hz), 132.74 (s), 131.95 (d, JC–F = 2.8 Hz),
131.75 (s), 130.84 (d, JC–P = 9.5 Hz), 128.70 (d, JC–P = 11.7 Hz),
116.83 (d, JC–F = 22.2 Hz), 115.68 (d, JC–F = 21.7 Hz), 32.97 (s),
30.10 (d, JC–P = 69.4 Hz). 19F NMR (376 MHz, CDCl3):  = –113.56
to –113.67 (m). 31P NMR (162 MHz, CDCl3):  = 31.46 (s). HRMS
130.70 (d, JC–P = 9.3 Hz), 130.03 (d, JC–F = 8.3 Hz), 128.73 (d, JC–P
=
11.6 Hz), 123.73 (d, JC–F = 2.8 Hz), 114.92 (d, JC–F = 21.2 Hz),
113.19 (d, JC–F = 21.0 Hz), 31.53 (d, JC–P = 70.0 Hz), 27.30 (dd, JC–P
(ESI-MS): m/z [M
922.9984; found: 922.9956.
+ Na +
I2]+ calcd for C40H34F2I2NaO2P2:
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E