Lewis Acid Promoted Aerobic Oxidative Coupling of Thiols with Phosphonates by Simple Nickel(II) Catalyst: Substrate Scope and Mechanistic Studies

Article abstract of DOI:10.1021/acs.joc.9b00194

Exploring new catalysts for efficient organic synthesis is among the most attractive topics in chemistry. Here, using Ni(OAc)₂/LA as catalyst (LA: Lewis acid), a novel catalyst strategy was developed for oxidative coupling of thiols and phosphonates to phosphorothioates with oxygen oxidant. The present study discloses that when Ni(OAc)₂ alone was employed as the catalyst, the reaction proceeded very sluggishly with low yield, whereas adding non-redox-active metal ions such as Y³⁺ to Ni(OAc)₂ dramatically promoted its catalytic efficiency. The promotional effect is highly Lewis acidity dependent on the added Lewis acid, and generally, a stronger Lewis acid provided a better promotional effect. The stopped-flow kinetics confirmed that adding Y(OTf)₃ can obviously accelerate the activation of thiols by Ni(II) and next accelerate its reaction with phosphonate to generate the phosphorothioate product. ESI-MS characterizations of the catalyst disclosed the formation of the heterobimetallic Ni(II)/Y(III) species in the catalyst solution. Additionally, this Ni(II)/LA catalyst can be applied in the synthesis of a series of phosphorothioate compounds including several commercial bioactive compounds. This catalyst strategy has clearly supported that Lewis acid can significantly improve the catalytic efficiency of these traditional metal ions in organic synthesis, thus opening up new opportunities in their catalyst design.

Full text of DOI:10.1021/acs.joc.9b00194

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Article
Lewis acid promoted aerobic oxidative coupling
of thiols with phosphonates by simple nickel(II)
catalyst: Substrate scope and mechanistic studies
Jingwen Xue, Miao Zeng, Sicheng Zhang, Zhuqi Chen, and Guochuan Yin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00194 • Publication Date (Web): 14 Mar 2019
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Lewis acid promoted aerobic oxidative coupling of thiols with
phosphonates by simple nickel(II) catalyst: Substrate scope and
mechanistic studies
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Jing-Wen Xue, Miao Zeng, Sicheng Zhang, Zhuqi Chen, Guochuan Yin*
School of Chemistry and Chemical Engineering, Key laboratory of Material Chemistry for Energy
Conversion and Storage (Huazhong University of Science and Technology), Ministry of Education, Hubei Key
Laboratory of Material Chemistry and Service Failure, Huazhong University of Science and Technology,
Wuhan 430074, PR China.
O
O
O
Ni(OAc)2/Y(OTf)3
O2 balloon
Ni(OAc)2
R1-S
P
R3
R2
HP R2
R3
R2
R1-S
R1-SH
P
R3
O2 balloon
up to 88% yield
limited to 38% yield
Abstract: Exploring new catalyst for efficient organic synthesis is among the most attractive
topics in chemistry. Here, using Ni(OAc)2/LA as catalyst (LA: Lewis acid), a novel catalyst
strategy was developed for oxidative coupling of thiols and phosphonates to phosphorothioates
with oxygen oxidant. The present studies disclosed that when Ni(OAc)2 alone was employed as
the catalyst, the reaction proceeded very sluggishly with low yield, whereas adding
non-redox-active metal ions like Y3+ to Ni(OAc)2 dramatically promoted its catalytic efficiency.
The promotional effect is highly Lewis acidity dependent on the added Lewis acid, and generally,
a stronger Lewis acid provided a better promotional effect. The stopped-flow kinetics confirmed
that adding Y(OTf)3 can obviously accelerate the activation of thiols by Ni(II), and next accelerate
its reaction with phosphonate to generate the phosphorothioate product. ESI-MS characterizations
of the catalyst disclosed the formation of the heterobimetallic Ni(II)/Y(III) species in the catalyst
solution. Additionally, this Ni(II)/LA catalyst can be applied in synthesis of a series of
phosphorothioate compounds including several commercial bioactive compounds. This catalyst
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strategy has clearly supported that Lewis acid can significantly improve the catalytic efficiency of
these traditional metal ions in organic synthesis, thus opens up new opportunities in their catalyst
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designs.
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1. Introduction
In oxidative coupling reactions, palladium is one of the most popularly employed catalysts
because of its highly catalytic activity.1 In order to improve the catalytic efficiency of the Pd(II)
catalyst, Cu(II) was popularly employed as the co-catalyst or oxidant to regenerate the active
Pd(II) species from the reduced Pd(0), which was originally inspired from Wacker oxidations.2-5
In certain cases, organic ligands were also added to the Pd(II) catalyst through ligation to prevent
the formation of palladium black in the reaction.6 However, the drawback is that those organic
ligands generally caused the oxidative capability loss of the Pd(II) species because of their
electronic donation effect. Recently, it was found that binding Lewis acid (LA) or Brönested acid
to the redox metal ions can significantly increase their redox potentials, thus improve their
efficiency in oxidations,7, 8 and several Lewis acid promoted catalysis by redox metal complexes
were developed for sulfide oxidation, olefin epoxidation and benzene hydroxylation.7e, 7f, 8f, 8g We
further found that non-redox metal ions like Sc3+ can promote Pd(II)-catalyzed Wacker-type
oxidations even much better than Cu2+ does, implicating that the Lewis acid properties of Cu2+
may have played a significant role in Wacker-type oxidations in addition to its redox properties.9
Inspired by this finding, a Pd(II)/LA catalyst strategy was defined for organic synthesis, which has
been successful in a list of synthesis reactions and biomass transformations.10 Encouraged by the
successes in Pd(II)/LA catalysis, we suspect that this catalyst strategy can be expanded to those
organic synthesis catalyzed by other redox metal ions.
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Phosphorothioates are well known for their promising bioactivities in pesticides and
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drugs,11 and a list of efficient protocols were successfully explored for their synthesis through S-P
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bond formation.12,
Up to now, in phosphorothioate synthesis through oxidative S-P bond
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formation, stoichiometric oxidants or hydrogen acceptor were generally employed with only a
few exceptions using oxygen/air as oxidant.13 Therefore, exploring new catalysts which can utilize
aerobic oxygen as the oxidant is still highly desirable for this synthesis. The challenge is that thiols
could poison the transition metal ions like palladium (II), thereof, direct S-H activation by
palladium catalysts were quite rarely reported.12f, 14 On the other side, although nickel (II) can
tolerate the thiols to avoid poisoning, due to its relatively poor activity for oxidative coupling
reactions, its applications in the S-H activation reactions were also very limited,15 and no
application for S-P bond formation was reported until now. Inspired by that binding Lewis acid to
palladium (II) can significantly improve its catalytic efficiency in organic synthesis,9, 10 herein, we
report the first example of Lewis acid promoted simple Ni(II) catalyst for phosphorothioate
synthesis through the oxidative S-P bond formation with oxygen as the terminal oxidant. The new
protocol demonstrated here has not only provided an efficient method for phosphorothioate
synthesis, but also expanded the Pd(II)/LA catalysis to the cheap metal ions like nickel(II).
Table 1 Optimization of the reaction conditions for the model reaction a
Ni(OAc)2 10 mol%
Lewis acid 20 mol%
O
O
t-Bu
SH
HP OEt
OEt
t-Bu
S
P
OEt
Solvent, 70 o
O2 balloon, 24 h
C
OEt
1a
2a
Entry
Catalyst
Lewis acid
Solvent
Yield (%)b
1
2
3
4
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
--
DMF
DMF
DMF
DMF
4
NaOTf
Cu(OTf)2
Zn(OTf)2
8
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30
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Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Mg(OTf)2
Ca(OTf)2
Al(OTf)3
Sc(OTf)3
Yb(OTf)3
Y(OTf)3
Cu(OAc)2
Y(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
DMF
41
6
DMF
44
7
DMF
42
8
DMF
58
9
DMF
66
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15
DMF
72
DMF
36
DMA
DMSO
MeCN
THF
67
39
trace
n.d.
n.d.
16
CH3COOH
a
Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), solvent (2.0 mL), Ni(OAc)2 (10 mol%), Lewis acid (20
mol%), O2 balloon, 70 °C, 24 h. b Isolated yield.
2. Results and discussion
In the initial tests, p-tert-butylthiophenol (1a) and diethyl phosphite (2a) were employed as
model substrates for this Ni(II)/LA-catalyzed phosphorothioate synthesis. As shown in Table 1, in
the absence of Lewis acid, using 10 mol% Ni(OAc)2 alone with an atmospheric oxygen balloon as
the oxidant source, the catalyst showed very sluggish activity, giving only 4% yield of 3a after 24
h reaction at 70 °C in DMF (Table 1, entry 1). Subsequently, a list of Lewis acids were tested for
the Ni(OAc)2 catalyzed model reaction (Table 1, entries 2-11). As shown, adding 20 mol% NaOTf
to Ni(OAc)2 slightly improved the yield of 3a to 8% (Table 1, entry 2). When bivalent metal ions
including Cu2+, Zn2+, Mg2+ and Ca2+ were added to the catalytic system, the catalytic efficiency
was improved obviously (Table 1, entries 3-6). For examples, adding Ca(OTf)2 to Ni(OAc)2
provided 44% yield of 3a (Table 1, entry 5), and adding Cu(OTf)2 as the Lewis acid source also
gave 22% yield of 3a. Remarkably, adding trivalent metal ions such as Al3+, Sc3+, Yb3+ and Y3+ to
Ni(OAc)2 demonstrated much better promotional effects than these of adding bivalent metal ions
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(Table 1, entries 7-10). The best result was obtained from adding Y(OTf)3, which provided 72%
yield of 3a (Table 1, entry 10). It is worth mentioning that upon adding the reaction reagents
together in DMF solution, the solution turned to black immediately. With the reaction proceeding,
it turned back to clear gradually. Further tests confirmed that the color change to black was caused
by the reaction of Ni(II)/Y(III) catalyst with 1a rather than 2a. In literature, Cu(OAc)2 was
popularly proposed to serve as the oxidant in versatile Pd(II)/Cu(II)-catalyzed Wacker-type
oxidations and other organic synthesis reactions.2-5 Here, to specifically address the role of the
redox properties of Cu2+ cation in this oxidative coupling reaction in the case of using copper(II)
salt as a Lewis acid source, Cu(OAc)2 was also tested as the copper(II) source, which provided
only 36% yield of 3a (Table 1, entry 11), much less than these by adding trivalent non-redox metal
ions. This result unambiguously supported that the redox properties of Cu2+ was not essential for
this Ni(II)/LA-catalyzed oxidative coupling reaction. In particular, the promotional effects of
added Lewis acids were clearly related with their Lewis acidity, that is, a stronger Lewis acid
generally offered a better promotional effect; however, the non-redox Lewis acids alone were in
active for this reaction. This is similar to our previous studies with Pd(II)/LA catalysts,9, 10 and
also similar to those Lewis acid promoted stoichiometric and catalytic oxidations with iron and
manganese complexes as catalysts.7d, 7e, 7g 8a-8d A series of solvents were next investigated for this
reaction by adding Y(OTf)3 as the Lewis acid to Ni(OAc)2 catalyst. When DMA and DMSO were
employed as solvent, they provided 67% and 39% yields of 3a, respectively (Table 1, entries 12
and 13). Only trace amount of 3a were detected with acetonitrile as solvent (Table 1, entry 14),
and no 3a was detected in the case of using tetrahydrofuran or glacial acetic acid as solvent. The
influences of solvent on organic synthesis are always very complicated, including affecting the
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coordination environment, the potential hydrogen bond network, the redox potentials of the active
metal ions, and the stability of the intermediate, etc.16 The observed influence of solvent effect in
present studies could be the mixed apparent effects from different issues which are not fully
understood yet. Other parameters such as the ratio of substrate 1a and 2a, reaction temperature
were also screened, and a ratio of 1a/2a = 1.5/1 was identified as the best substrate molar ratio
with 70 °C as an optimal reaction temperature for this reaction (see Table S1 and S2).
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Then, the influence of the catalyst loading and the ratio of Ni(OAc)2 and Y(OTf)3 on the
efficiency of the model reaction were next evaluated (Table 2). As shown, with 5 mol%
Ni(OAc)2/Y(OTf)3 loading, it gave 62% yield of 3a (Table 2, entry 1). Having the amount of
Ni(OAc)2 at 5 mol% loading with increasing the Y(OTf)3 to 10 mol% made the yield of 3a
improving up to 79% (Table 2, entry 2). Increasing the Ni(OAc)2 loading to 10 mol% with
keeping Y(OTf)3 at 5 mol%, 78% yield of 3a was also obtained (Table 2, entry 3). Notably, the
best yield was obtained as 88% by adding 10% loading of Ni(OAc)2 with a 1:1 ratio of
Ni(OAc)2/Y(OTf)3 (Table 2, entry 4). The time course of this reaction also disclosed that adding
one equiv. of Y(OTf)3 to the Ni(OAc)2 catalyst could remarkably accelerate the reaction (Figure
1), whereas using Ni(OAc)2 alone was very sluggish. Further increasing the loading of Y(OTf)3
caused the yield slightly decrease. For example, using 10% Ni(OAc)2 with 30% Y(OTf)3 loading
led the yield decrease to 77% (Table 2, entry 6). It is worth mentioning again that using Lewis
acid alone as catalyst is inactive for this reaction (Table 2, entry 7).
Table 2 Ratio and amount of the catalyst loading for the model reaction a
O
O
Ni(OAc)2/Y(OTf)3
t-Bu
SH
HP OEt
OEt
t-Bu
S
P
OEt
DMF, 70 o
O2 balloon, 24 h
C
OEt
1a
2a
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Entry
Ni(OAc)2:Y(OTf)3 (mol%)
Yield (%)b
5
6
7
8
9
1
2
5:5
62
79
5:10
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3
4
5
6
7
10:5
10:10
10:20
10:30
0:10
78
88
86
77
ND
a
Reaction conditions: 1a (0.3 mmol), 2a (0.2 mmol), DMF (2.0 mL), Ni(OAc)2 (5-10 mol%), Y(OTf)3 (5-30
mol%), O2 balloon, 70 °C, 24 h. b Isolated yield.
Next, a series of control experiments were conducted under the optimal conditions to
identify the role of added Y(OTf)3 in this reaction (Table 3). When the reaction was catalyzed by
Ni(OAc)2 alone, only 20% yield of 3a was obtained under the standard conditions (Table 3, entry
1), which was much less than that by adding Y(OTf)3 to Ni(OAc)2 (88%, Table 3, entry 6 as the
standard conditions). Using Y(OTf)3 alone as a catalyst did not show any catalytic activity for this
reaction (Table 3, entry 2). These two experiments clearly supported that the added Lewis acid did
promote the Ni(II)-catalyzed oxidative coupling of thiol and phosphonate to phosphorothioate. In
order to distinguish the roles of OTf- anion and Y3+ cation from added Y(OTf)3 in this reaction,
three controlled experiments were designed by using Ni(OAc)2/HOTf, Ni(OTf)2, and
Ni(OTf)2/Y(OTf)3 as catalyst independently (Table 3, entries 3-5). As shown, adding 30 mol%
loading of HOTf , which provides the identical amount of OTf- anion to that of 10 mol%
Y(OTf)3), to Ni(OAc)2 as the catalyst provided only 9% yield of the 3a product. In addition, it is
worth mentioning that adding HOTf even suppressed the catalytic efficiency of Ni(OAc)2 (Table
3, 9% vs 20%, entries 1 vs 3). Subsequently, using Ni(OTf)2 as catalyst provided 14% yield of 3a
(Table 3, entry 4), and combining Ni(OTf)2 and Y(OTf)3) together as the catalyst also offered only
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29 % yield of 3a (Table 3, entry 5), much less than that of using Ni(OAc)2/Y(OTf)3, thus
excluding the anion exchange between Ni(OAc)2 and Y(OTf)3 to generate Ni(OTf)2 as the active
catalyst for this reaction. In order to address the role of OTf- in the reaction, two parallel
experiments were performed by using YCl3 and Y(OAc)3 to replace Y(OTf)3 for
Ni(OAc)2-catalyze model reaction, and 67% and 40% yield of 3a were obtained, respectively
(Table 3, entries 7 and 8). In a specific experiment using Zn(BF4)2 to replace Zn(OTf)2 in the
Ni(II)/Zn(II) catalyst, it also provided 27% yield of 3a, comparing to 30% yield with that of adding
Zn(OTf)2 (Table 3, entry 9 vs 10). Taken together, these results clearly supported that the Y3+
cation promoted the Ni(II)-catalyzed oxidative coupling reaction, and the counter anion of Y3+
affected the promotional effect through affecting the Lewis acidity of Y3+. Remarkably, the OAc-
anion is essential for this reaction as well as those in previous Pd(II)/LA catalysis.9, 10
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Ni(OAc)
2
Ni(OAc) +Y(OTf)
80
60
40
20
0
2
3
0
5
10
15
20
Reaction time (h)
Figure 1 The time course of Ni(OAc)2/Y(OTf)3 catalyzed oxidative S-P bond formation for phosphorothioate
synthesis. Reaction conditions: p-tert-butylthiophenol (0.3 mmol), diethyl phosphite (0.2 mmol), Ni(OAc)2 (10
mol%), Y(OTf)3 (10 mol%), DMF (2.0 mL), 70 °C.
Under the standard conditions, the substrate scope of thiophenols/aliphatic thiols and phosphates
to synthesize the thiophosphate products was examined. As summarized in Scheme 1, aromatic
thiols 1 having different ortho and para electron-donating groups like CH3 or CH3O were coupled
readily with diethyl phosphonate to generate the desired products in good yields (3b-3d,
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78-82%).When aromatic thiols bearing an electron-withdrawing groups (F, Cl, Br or NO2) were
employed, the corresponding products were also obtained in satisfactory yields (3e-3i, 70-86%).
The substrates having functional groups like amine and hydroxyl could also react with diethyl
phosphonate smoothly, giving the corresponding thiophosphate products in 40% and 75% yields,
respectively (3j and 3k). To our delight, both naphthalene-1-thiol and naphthalene-2-thiol were
also compatible for this Ni(II)/Y(III)-catalyzed S-P bond formation reaction, offering the desired
products in 86% and 76% yields, respectively (3l and 3m). When the thiophenols were replaced
with benzylthiophenol, this Ni(II)/Y(III)-catalyzed oxidative S-P bond formation also proceeded
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efficiently with diethyl phosphonate (3n and 3o).
Table 3 Control experiments for the model reaction a
O
O
Catalyst
t-Bu
SH
HP OEt
OEt
t-Bu
S P OEt
DMF, 70 o
O2 balloon, 16 h
C
OEt
1a
2a
Entry
Catalyst
Yield (%)b
1
2
3
4
5
6
7
8
9c
Ni(OAc)2
Y(OTf)3
20
ND
9
Ni(OAc)2+HOTf (30 mol%)
Ni(OTf)2
14
29
88
67
40
27
Ni(OTf)2+Y(OTf)3
Ni(OAc)2+Y(OTf)3
Ni(OAc)2+YCl3
Ni(OAc)2+Y(OAc)3
Ni(OAc)2+Zn(BF4)2
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10d
Ni(OAc)2+Zn(OTf)2
30
5
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9
a
Reaction conditions: 1a (0.3 mmol), 2a (0.2 mmol), DMF (2.0 mL), Ni(OAc)2 (10 mol%), Y(OTf)3 (10 mol%),
O2 balloon, 70 °C, 16 h. b Isolated yield. c Zn(BF4)2 (10 mol%) used as the Lewis acid. d Zn(OTf)2 (10 mol%) used
as the Lewis acid.
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Furthermore, aliphatic thiols also reacted well with diethyl phosphonate under the current
conditions (3p-3v). Cyclohexanethiol was coupled readily with diethyl phosphonate to give the
coupling product 3p in 72% yield. Aliphatic thiols such as octane-1-thiol, butane-1-thiol,
iso-butane-1-thiol, pentane-1-thiol, and ester functionalized chain aliphatic thiols were all
tolerated with this Ni(II)/Y(III) catalyst, giving 63-77% yields (3q-3v), respectively. Aside from
diethyl phosphonate, other phosphates such as diisopropyl and dibutyl phosphonate could also be
coupled with p-tert-butylthiophenol smoothly to give the corresponding products 3w and 3x in
good yields. In addition to dialkyl phosphates, diphenyl phosphine oxide and ethyl
phenylphosphinate were also tested as substrate to couple with p-tert-butylthiophenol, which gave
65% and 75% yields of the corresponding products (3y and 3z), respectively. Notably, in the
control experiments using Ni(OAc)2 alone as catalyst, the yields of the corresponding coupling
products were much lower than that obtained by Ni(III)/Y(III) catalyst (see the data in the
parentheses in Scheme 1). These data clearly highlights the crucial role of the added Lewis acid in
promoting the catalytic efficiency of Ni(II) in this oxidative coupling reaction, as well as those in
Pd(II)/LA catalysis.9, 10
In order to illustrate the practical applications of this Ni(II)/LA catalyst in phosphorothioate
synthesis, we applied this protocol in the synthesis of several commercial bioactive compounds as
shown in Scheme 2. Iprobenfos 3aa, a pesticide with excellent control effects on rice leaf blast
and ear mites,17 could be readily synthesized through the oxidative coupling of diisopropyl
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phosphonate and benzyl thiol with Ni(OAc)2/Y(OTf)3 catalyst in 62% yield. Similarly, inezin 3ab,
which has both preventive and therapeutic effects on rice diseases such as rice blast, stalk and rice
sclerotium,18 could also be afforded with 65% yield under the standard conditions. Demeton 3ac,
mainly used to prevent and cure sucker pests such as aphids and spider mites on cotton and fruit
trees,19 was also synthesized by this protocol with 72% yield. It is worth mentioning that, due to
the highly reactive of the ethylthiolyl group in 5 to organic oxidant in its oxidative synthesis, there
were only a few reports on the synthesis of 3ac.12d, 12e Finally, echothiopate, a drug that can be
used for the treatment of glaucoma with a long-lasting effect,20 could be easily synthesized from 6
through a two-step reaction, including oxidative coupling through this protocol to 3ad followed by
salinization with iodomethane,20b giving 69% and 85% of yields in two steps, respectively. Again,
the activity of Ni(OAc)2 alone in these synthesis was always much lower than these of
Ni(OAc)2/Y(OTf)3 catalyst as demonstrated in the parentheses of Scheme 2, thus highlighting the
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super activity of Ni(II)/LA catalyst as well as those of Pd(II)/LA catalysts.9, 10
Scheme 1 Substrate scope of Ni(II)/Y(III)-catalyzed oxidative coupling reactions a.
Ni(OAc)2 10 mol%
Y(OTf)3 10 mol%
O
O
HP R1
R2
R
SH
R
S
P
R2
R1
DMF, 70 oC
O2 balloon
1
2
3
O
OMe
O
O
P
S
P
OEt
S
P
OEt
O
S
OEt
OEt
OEt
t-Bu
S-P OEt
OEt
OEt
MeO
3a
3b
14 h, 82% (36%)
3d
3c
15 h, 88% (32%)
6 h, 78% (24%)
6 h, 82% (28%)
O
O
O
Cl
O
P
S
P
OEt
Cl
S
P
OEt
S
P
OEt
S
OEt
OEt
OEt
OEt
OEt
F
Br
3h
3g
12 h, 70% (12%)
3e
3f
16 h, 86% (23%)
4 h, 72% (34%)
12 h, 76% (30%)
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O
P
O
O
P
O
S
OEt
S
P
OEt
S
OEt
S
P
OEt
OEt
OEt
OEt
OEt
H2N
O2N
HO
3l
3k
3j
3i
6 h, 75% (trace)
6 h, 86% (38%)
7
3 h, 71% (trace)
10 h, 40% (12%)
8
9
O
O
O
P
O
S
P
OEt
S
P
OEt
S
OEt
S
P
OEt
OEt
OEt
OEt
10
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OEt
MeO
3p
3o
3m
6 h, 76% (26%)
3n
18 h, 66% (36%)
12 h, 61% (20%)
16 h, 72% (trace)
O
O
O
S
P
OEt
S
P
OEt
S
P
OEt
OEt
OEt
OEt
3r
16 h, 68% (12%)
3q
16 h, 75% (20%)
3s
16 h, 70% (15%)
O
O
O
S
P
OEt
S
P
OEt
S
P
OEt
MeO2C
EtO2C
OEt
OEt
OEt
3t
3u
3v
16 h, 77% (18%)
16 h, 63% (8%)
16 h, 65% (16%)
O
P
O
O
O
S
On-Bu
S
P
Oi-Pr
S
P
Ph
S
P
Ph
On-Bu
Oi-Pr
Ph
OEt
t-Bu
t-Bu
t-Bu
t-Bu
3w
6 h, 73% (13%)
3x
6 h, 67% (16%)
3z
6 h, 75% (15%)
3y
3 h, 65% (trace)
a Standard conditions: 1 (0.3 mmol), 2 (0.2 mmol), DMF (2.0 mL), Ni(OAc)2 (10 mol%), Y(OTf)3 (10 mol%), O2
balloon, 70 °C. b Isolated yield. The values in parentheses were obtained with only Ni(OAc)2 as catalyst.
Scheme 2 Illustrated pesticide and drug synthesis by Ni(II)/Y(III) catalyst.
O
O
P
SH
HP OiPr
OiPr
Ph
S
OiPr
OiPr
3aa
iprobenfos
18 h, 62% (16%)
O
O
SH
HP OEt
Ph
Ph
S
P
OEt
Ph
3ab
inezin
16 h, 65% (trace)
O
O
HS
S
P
OEt
HP OEt
OEt
S
S
OEt
5
3ac
demeton
12 h, 72% (20%)
O
O
HS
S
P
OEt
N
HP OEt
OEt
N
OEt
6
3ad
16 h, 69% (22%)
Ref.19b
O
S
P
OEt
N
OEt
I
echothiopate 85%
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To gain insights into the mechanism of this Ni(OAc)2/Y(OTf)3-catalyzed oxidative coupling
reaction, mechanistic studies were next conducted by performing a list of control experiments
8
9
(Scheme 3). In literature, it has been proposed that all of S-centered radical,12d, 12e, 13a P-centered
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12e, 12g, 13a
radical,12d, 12e, 13a and disulfide
could serve as the intermediates in oxidative S-P bond
formation under certain conditions, and the existences of the radical intermediates were evidenced
by radical scavengers or trapped by olefin.12g Here, adding radical scavengers including
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and 2,6-di-tertbutyl-4-methylphenol (BHT) did
not quench the oxidative coupling between 1a and 2a under the standard conditions, which still
gave 3a in good yields (68% and 63%) (Scheme 3, eq. 1). In addition, the radical trapping
experiments by adding styrene to 1a or 2a under standard conditions also did not yield any radical
adduct as product (Scheme 3, eqs. 2 and 3). Therefore, these results clearly supported that the free
radical mechanism was not involved in this oxidative coupling reaction, and no P-centered
radicals or S-centered radicals was involved in phosphorothioate formation in present studies.
Next, in the absence of 2a, treating 1a under the standard conditions for 6 h led to the formation of
the disulfide 4a in 90% yield, whereas treating 2a itself did not lead the corresponding
homo-coupling product formation (Scheme 3, eqs. 4 and 5). This information implicated that the
disulfide 4a may exist in the reaction mixture and function as an intermediate in phosphorothioate
formation as well as those in literature.12e, 12g, 13a
Scheme 3 Experiments for mechanistic studies.
O
O
t-Bu
S
P
OEt (1)
standard conditions
t-Bu
SH
HP OEt
OEt
OEt
1a
2a
no additive
88%
TEMPO (2eq) 68%
BHT (2eq)
63%
standard conditions
t-Bu
SH
Ph
t-Bu
S
(2)
Ph
1a
0 %
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O
O
P
OEt
standard conditions
(3)
(4)
(5)
HP OEt
OEt
Ph
Ph
OEt
0 %
2a
7
8
9
standard conditions
t-Bu
SH
t-Bu
OEt
S
S
t-Bu
1a
4a
90 %
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O
O
P
O
EtO
P
standard conditions
HP OEt
OEt
OEOt Et
2a
0%
O
O
HP OEt
standard conditions
t-Bu
S
P
OEt
(6)
t-Bu
S
2
OEt
OEt
2a
4a
no additive
TEMPO (2eq) 50%
54%
0.15 mmol
0.2 mmol
Standard conditions: DMF (2.0 mL), Ni(OAc)2 (10 mol%), Y(OTf)3 (10 mol%), O2 balloon, 70 °C, 16 h.
In addition, it was reported that S-centered radical served as an intermediate for the
phosphorothioate formation under certain conditions.12d,
Consequently, this
12e,
13a
Ni(II)/Y(III)-catalyzed oxidative coupling reaction between 4a and 2a was conducted under the
standard conditions, and it did provide 3a in 54% yield. However, adding TEMPO only
demonstrated ignorable influence on this coupling, which still gave 50% yield (Scheme 3, eq. 6).
Apparently, the S-centered radical did not exist in the system to serve as the intermediate for 3a
formation. It is worth mentioning that, the reaction of 1a with 2a under the standard conditions
caused the solution turning to black immediately, whereas the solution color for 4a reacting with
2a changed to black much slower, indicating that they were two different reaction processes. Now,
these experiments also raise a new query, that is, whether 4a is an intermediate for the S-P bond
formation, since 4a may have chance to occur in the reaction medium as disclosed by Eq. 4. To
address this issue, the kinetic studies to compare the reactivity between 4a and 1a in their
reactions with 2a were conducted paralleling under the standard conditions (Fig. S1). As
displayed, in the whole time course, the yields of phosphorothioate product from 4a were always
much lower than that of using 1a as substrate, even in the case of adding identical equivalent of 4a
in place of 1a. If 4a were the intermediate for the phosphorothioate formation from 1a and 2a, the
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yield of phosphorothioate should be always not lower, even higher than that by using 1a as
substrate in the whole time course. Taken together, these experiments supported that 4a was not
on the pathway of 1a reacting with 2a to phosphorothioate. However, 4a may be generated in the
reaction mixture, and can be transferred to 3a under the standard conditions, that is, formation of
4a from 1a is reversible.
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0.10
0.09
0.08
Ni(OAc)2 5 mM
0.07
Ni(OAc)2 5 mM
0.08
0.06
0.04
0.02
0.00
0.06
0.05
0.04
+Y(OTf)3 5 mM
Y(OTf)3 5 mM
Ni(OAc)2 5 mM
360
380
400
420
440
+NaOTf 15 mM
NaOTf 15 mM
Ni(OTf)2 5 mM
300
400
500
600
700
800
900
Wavelength (nm)
Figure 2 UV-Vis spectra of Ni(OTf)2, Ni(OAc)2 and Y(OTf)3, NaOTf with their mixture in DMF at room
temperature.
In order to address the active species and the reaction details for the oxidative S-P bond
formation by Ni(OAc)2/Y(OTf)3 catalyst, a series of UV-Vis studies were conducted with the
DMF solution of Ni(OAc)2/Y(OTf)3. As shown in Figure 2, Ni(OAc)2 alone in DMF
demonstrated two distinct absorbance bands which can be attributed to the
metal-ligand-charge-transfer (MLCT) transition having maximum band around 405 nm (ε = 16
M-1 cm-1) and d-d transition having a broad band around 680-760 nm (ε = 5.6 M-1 cm-1),
respectively. Adding one equiv. of Y(OTf)3 to Ni(OAc)2 in DMF caused a minor but
non-ignorable blue-shift of the d-d transition band, however, it did not change the shape of the
band, implicating a slight coordination environment change of the Ni(II) species, for example, a
plausibly slight d-d gap increase, caused by adding Y(OTf)3. Similarly, a much weaker, but also
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non-ignorable blue-shift of the MLCT band was also observed for the same solution as well. To
eliminate the possibility of the absorbance band migration caused by the OTf- anion exchange, the
UV-Vis measurements were also conducted by using three equiv. of NaOTf to replace one equiv.
of Y(OTf)3 in the solution; unsurprisingly, no absorbance band migration was observed as shown
in Figure 2. Unexpectedly, Ni(OTf)2 in DMF demonstrated a flat curve with no obvious MLCT
and d-d transition band. These results clearly supported that the OTf- anion exchange can be
excluded to generate Ni(OTf)2 from Ni(OAc)2/Y(OTf)3, at least, to a significant level, since
adding Y(OTf)3 to Ni(OAc)2 in DMF did not weaken its absorbance, whereas Ni(OTf)2 has no
obvious band in this area.
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As well as the phenomena observed from above oxidative coupling reactions, that is,
adding 1a to the catalyst solution containing Ni(OAc)2/Y(OTf)3 led to the immediate color change
to black, here, the UV-Vis spectrum also disclosed the formation a new species having the
absorbance band occurring around 490 nm, and simultaneously, the original d-d transition band of
the Ni(II) decayed (Figure S3). In the stoichiometric treatment of 1a with Ni(OAc)2/Y(OTf)3 in
DMF solution, along with the concentration of 1a increasing, the absorbance intensity of the new
band increased as well (Figure S3). In the controlling experiment using Ni(OAc)2 alone, a similar
new band was also observed immediately when treating it with 1a. However, compared with the
new band generated by treating 1a with Ni(OAc)2, the band from 1a with Ni(OAc)2/Y(OTf)3
demonstrated a slightly blue-shift as well as the influence of Y(OTf)3 to Ni(OAc)2 in DMF
solution (Figure 2 vs 3). This new band can be rationally assigned to the absorbance of the
RS-Ni(II) or RS-Ni(II)/Y(III) intermediate by the reaction of 1a with Ni(OAc)2 or
Ni(OAc)2/Y(OTf)3, respectively, in which the presence of the Y3+ made the absorbance slightly
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blue-shifted. Following the general procedures reported for kinetic studies in literature,21 the
stopped-flow kinetics for the formation of this intermediate disclosed that the presence of Y(OTf)3
accelerated its formation rate, giving the k2 values of 3.14 × 10-3 mM-1 s-1 for Ni(OAc)2/Y(OTf)3
and 4.15 × 10-4 mM-1 s-1 for Ni(OAc)2 alone, respectively (Figure 4). Remarkably, the stability of
this intermediate was significantly improved by the presence of Y(OTf)3 (Figure S7). That is, the
presence of Y(OTf)3 made the formation of the RS-Ni(II)/Y(III) intermediate faster than that of
the corresponding RS-Ni(II) intermediate, meanwhile it also stabilized the RS-Ni(II)/Y(III)
intermediate to make its decay slower than that of the corresponding RS-Ni(II) intermediate.
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1.0
Ni(II)/Y(III)+1a
Ni(II)+1a
0.8
0.6
0.4
0.2
0.0
400
500
600
700
800
Wavelength (nm)
Figure 3 UV-Vis spectra of Ni(OAc)2 with 1a in the presence (black) and absence (red) of Y(OTf)3 from kinetic
process tested by the stopped-flow instrument. [Catalyst] = 1 mM, [1a] = 1 mM, solvent: DMF, room temperature.
In the similar treatment of 2a with the catalytic solution, there was no color change
observed and the UV-Vis spectrum also remained no change, indicating that in the oxidative
coupling S-P formation with Ni(OAc)2/Y(OTf)3 catalyst, the catalyst first reacted with 1a which
consequently reacted with 2a to generate the product. Consequently, the reaction kinetics of 2a
with the in-situ generated RS-Ni(II) or RS-Ni(II)/Y(III) intermediate was investigated with the
stopped-flow instrument. As displayed in Figure 5, the presence of Y(OTf)3 accelerated the
reaction of this intermediate with 2a, making the 2a dependent decay faster than that of in the
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absence of Y(OTf)3, that is, the slope of the concentration dependence is larger for the catalysts
system with Y(OTf)3, giving k2 values of 3.32 × 10-5 mM-1 s-1 for Ni(OAc)2/Y(OTf)3 and 1.62 ×
10-5 mM-1 s-1 for Ni(OAc)2 alone, respectively (Figure 5). It is worth mentioning that, there exists
two pathways for the decay of both RS-Ni(II) and RS-Ni(II)/Y(III) intermediates; one is to
generate disulfide as mentioned earlier (eq. 4, vide supra), the other is to react with 2a to generate
the target phosphorothioate products (if 2a were added). Therefore, the kobs in Figure 5 is not the
real kobs for the phosphorothioate formation, but the total decaying kobs for both disulfide and
phosphorothioate formations. The larger slope of the concentration dependence for the reaction
between the RS-Ni(II)/Y(III) intermediate and 2a than that of the RS-Ni(II) intermediate and 2a in
Figure 5 indicated that the reaction between 2a and RS-Ni(II)/Y(III) intermediate is faster than
that of the RS-Ni(II) intermediate with 2a (k2 value of 3.32 × 10-5 vs 1.62 × 10-5 mM-1 s-1), thus
Y(OTf)3 accelerates the second step of the reaction. Taken together, these kinetic data clearly
confirmed that adding Y(OTf)3 to Ni(OAc)2 accelerated its reaction with 1a, and next also
accelerated it further reaction with 2a to the corresponding phosphorothioate product.
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Ni(II)+1a
Ni(II)/Y(III)+1a
0.20
0.15
0.10
0.05
0.00
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55
Concentration of 1a (mM)
Figure 4 Correlation of substrate concentration with the kobs constant for the formation of RS-Ni(II) or
RS-Ni(II)/Y(III) intermediates by the reaction of Ni(OAc)2 with 1a in the absence (black) and presence (red) of
Y(OTf)3.
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0.004
0.003
0.002
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Ni(II)+1a+2a
Ni(II)/Y(III)+1a+2a
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Concentration of 2a (mM)
Figure 5 Correlation of substrate concentration with the kobs constant for the disappearance of the RS-Ni(II)/Y(III)
or RS-Ni(II) intermediate when their reacting with 2a.
In clarifying the reactivity between the disulfide compound 4a and the Ni(II)/Y(III) catalyst, it
was found that the color of the reaction solution turned black gradually in 10 minutes at 70 °C,
which was much slower than that of reaction with 1a. In the UV-Vis tests at room temperature, the
characteristic bands of the Ni(II) species remained unchanged after adding 4a to the DMF solution
of the Ni(II)/Y(III) catalyst (Figure S4), and no new band was observed for the corresponding
RS-Ni(II)/Y(III) species as that from the reaction of 1a with the Ni(II)/Y(III) catalyst. These
results supported that thiophenol 1a is more feasibly activated by Ni(II)/Y(III) catalyst than the
disulfide compound 4a. Taken together, although 4a can react with 2a to generate the
corresponding phosphorothioate product under the catalytic conditions, the UV-Vis studies
disclosed that its kinetic behaves was different from that of 1a reacting with Ni(II)/Y(III) catalyst.
Thus, 4a may be generated from 1a under the catalytic conditions as displayed by Eq. 4, and can
be further transformed to the corresponding phosphorothioate product as shown in Eq. 6; however,
it is not on the pathway of 1a reacting with 2a to the phosphorothioate product.
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Intens.
x10
+MS, 0.1-1.5min #(3-92)
710.82
5
708.83
A
B
712.82
709.83
711.82
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C12H20F6N2NiO12S2Y, M,708.88
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708.88
C
4
3
2
1
0
710.87
711
CH3
709.88
710
711.88 712.87
O
O
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DMF
DMF
OTf
OTf
708
709
712
m/z
Ni(II)
Y(III)
O
O
708.83
CH3
CH3
781.88
O
DMF
OTf
O
DMF
DMF
Ni(II)
Y(III)
O
O
OTf
CH3
635.85
532.91
500
854.93
900
600
700
800
m/z
Figure 6 ESI-MS spectrum with plausible structures of (a) Ni(OAc)2/Y(OTf)3 in DMF at 70 oC for 20 minutes. (b)
Ni(II)/Y(III) dimeric structure at m/z = 708.83, and (c) its theoretical isotopic peak distribution.
In previous studies, the heterobimetallic structures were was even proposed for the
Pd(II)/LA catalyzed organic synthesis based on NMR and UV-Vis characterizations, in which two
acetate bridge linked the Pd(II) and LA together,9, 10 and similar heterobimetallic palladium(II)
complexes were isolated with X-ray characterizations in literature.22 Here, as implicated from the
synthetic results and UV-Vis studies, a new nickel (II) species may have been in-situ generated in
the catalytic solution of Ni(OAc)2/Y(OTf)3, and is responsible for the improved catalysis. Indeed,
the electrospray ionization mass spectrometry (ESI-MS) analysis of above catalytic solution
disclosed a major mass peak at m/z=708.83 (Figure 6). Based on the similarly crucial role of
acetate in both Pd(II)/LA and Ni(II)/Y(III) catalysis, the structure of this mass peak could be
assigned to the acetate bridged heterobimetallic Ni(II)/Y(II) structure as well as those in Pd(II)/LA
catalysts. This mass spectrum agreed well with the theoretical prediction of the corresponding
isotopic peak distribution patterns, thus provided valuable evidence to support the existence of a
heterobimetallic Ni(II)/Y(III) species in the catalytic solution. In addition to the mass peak at
m/z=708.83, another peak at m/z=781.88 can be assigned to the Ni(II)/Y(III) dimeric structure
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with one more DMF ligated, and also agreed well with the theoretical prediction of the
corresponding isotopic peak distribution patterns. Due to the paramagnetic properties of the Ni(II)
cation, the NMR characterizations of the Ni(II)/Y(III) species were not accessible.
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R-SH
Ni(II)/Y(III)
1
O2
k2=3.14x10-3 mM-1s-1
H
H2O2
Ni(0)/Y(III)
R
S
Ni(II)/Y(III)
O
P
I
R
S
OEt
O
OH
P
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HP OEt
OEt
3
k2=3.32x10-5 mM-1s-1
OEt
OEt
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2
R
S Ni(II)/Y(III)
R
S
Ni(II)/Y(III)
EtO
P
O
EtO
P
OH
OEt
III
EtO
II
H
Scheme 4 A plausible mechanism for Ni(II)/Y(III) catalyzed oxidative coupling S-P formation reaction to
phosphorothioate (R: p-tert-butylphenyl).
According to above studies with the reported mechanisms in literatures,12f, 12g a simplified
mechanism was proposed for this Ni(II)/Y(III)-catalyzed oxidative coupling reaction as shown in
Scheme 4. In this mechanism, a heterometallic Ni(II)/Y(III) species (abbreviated as Ni(II)/Y(III))
was in-situ generated in the catalytic solution, which served as the activity species for the
oxidative coupling reaction. Initially, the Ni(II)/Y(III) species activated the S-H bond of
thiophenol 1 to generate the RS-Ni(II)/Y(III) intermediate I. Subsequently, the ligation of 2’ (the
tautomerization structure of 2 12g, 13a) to the intermediate I generated the intermediate II which
gave the intermediate III via proton release. Next, the reductive elimination of the intermediate III
to produce the final product 3 with Ni(0)/Y(III) complex. Finally, the Ni(0)/Y(III) species was
oxidized by oxygen to regenerate the active Ni(II)/Y(III) species to achieve the catalytic cycle as
well as those in other Ni(II)-catalyzed synthesis.23 In the whole catalytic cycle, the formation of
the heterobimetallic Ni(II)/Y(III) species accelerated the formation of the intermediate I, and next
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accelerated its reaction with 2’, thus improving the catalytic efficiency. In addition, through HPLC
analysis of H2O2 generation, it was found that adding Y(OTf)3 to Ni(OAc)2 substantially increased
the H2O2 formation in the catalytic solution (Figure S12). Since detecting the Ni(0) and
Ni(0)/Y(III) species was not successful in the catalytic solution, the direct evidence to confirm the
presence of Lewis acid accelerating the aerobic oxidation of Ni(0) was not available. However, the
increased H2O2 formation may have implicated that the presence of Lewis acid also accelerated
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the oxidation of Ni(0) back to the active Ni(II)/Y(III) species.
3. Conclusion
The present work illustrated a novel Ni(II)/LA catalyst strategy for the oxidative coupling
of thiols and phosphonates to phosphorothioates. The presence of certain non-redox metal ions as
Lewis acid could significantly improve the catalytic efficiency of the simple nickel (II) salt, and
the promotional effect was highly the Lewis acidity dependent on the added Lewis acid. That is, a
stronger Lewis acid provided a better promotional effect. The kinetic studies also disclosed that
the presence of Y(OTf)3 could obviously accelerate the activation of thiol by Ni(II) to generate the
RS-Ni(II)/Y(III) intermediate, and further accelerate the next oxidative coupling with phosphonate
to generate the corresponding phosphorothioate product. ESI-MS characterizations of the
Ni(OAc)2/Y(OTf)3 in DMF solvent disclosed the formation of a heterobimetallic Ni(II)/Y(III)
species which is responsible for the improved catalysis. This Ni(II)/Y(III) catalyst also
demonstrated a wide substrate scope for the S-P formation through oxidative coupling, and was
successfully exampled in several commercial bioactive compound synthesis. The present
Ni(II)/Y(III) catalyst not only demonstrated its applications in phosphorothioate synthesis through
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oxidative coupling, but also convinced that the Pd(II)/LA catalysis can be expanded to other redox
metal ions, which opens up new opportunity for the catalyst design in versatile organic synthesis.
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4. Experimental Section
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4.1 Materials and analytical methods
Unless otherwise noted, all reagents were purchased from commercial suppliers and used
without further purification. Compound 5 and 6 were synthesized following the literatures with
modifications.24 UV-Vis spectra were collected on Agilent Technologies Cary-8454 UV-Vis
spectrometer. UV-Vis kinetic analyses were performed on the Stopped-Flow Reaction
Analyzer-SX20 (Applied Photophysics). The reactions were monitored by TLC with Haiyang
GF-254 silica gel plates (Qingdao Haiyang chemical industry Co. Ltd, Qingdao, China) using UV
light or KMnO4 as visualizing agents as needed. Flash column chromatography was performed
using 200-300 mesh silica gel at increased pressure. H NMR spectra and 13C NMR spectra were
1
respectively recorded on Brüker AV-400 spectrometers. Chemical shifts (δ) were expressed in
ppm with TMS as the internal standard, and coupling constants (J) were reported in Hz.
High-resolution mass spectra were obtained on mass spectrometer by using ESI FT-ICR Mass.
4.2 General procedure for the synthesis of 5 (2-(ethylthio)ethane-1-thiol).
A mixture of 2-(ethylthio)ethan-1-ol (20 mmol) and thiourea (20 mmol) in 48% aq. HBr (4.25
mL) was refluxed overnight under argon. Then the reaction was cooled down to room
temperature. Next, concentrated aq. NaOH (1.6 g, 40 mmol) was added carefully, and the resulting
mixture was refluxed overnight under Ar. After that, the reaction solution was cooled down to
room temperature, neutralized with concentrated HCl, and extracted with CH2Cl2 (100 mL). The
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organic phase was separated, washed with water, dried over Na2SO4, and evaporated to give 5 as
5
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7
colorless oil, which was used without further purification (1.98 g, 81% yield).
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4.3 General procedure for the synthesis of 6 (2-(dimethylamino)ethane-1-thiol).
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A 100 mL round bottom flask was dried, degassed, and refilled with argon. Then,
dimethylamine (10 mL, 2 M solution in THF) was added in and next solidified into the white solid
in a liquid nitrogen bath. Then the liquid nitrogen bath was replaced by an ice bath, ethylene
sulfide (1.3 eq., 26 mmol) in 20 mL THF was added into above dimethylamine solution dropwise.
The reaction solution was next stirred for 2 hours at 0 °C under nitrogen. Finally, the solution was
concentrated via rotary evaporation at 40 °C to yield the corresponding product 6 as a colorless
liquid (1.47 g, 70% yield).
4.4 General procedure for oxidative coupling reaction with Ni(OAc)2/Y(OTf)3 catalyst in
DMF
In a typical procedure, Ni(OAc)2 (3.5 mg, 0.02 mmol) and Y(OTf)3 (10.7 mg, 0.02 mmol) were
dissolved in DMF (2 mL) in a glass tube. After pre-stirring the prepared solution for 20 min under
70 °C, 1 (0.3 mmol) and 2 (0.2 mmol) were added in. The glass tube was next connected with an
O2 balloon, and stirred at 70 °C for desired reaction time. After the reaction, 5 mL H2O was added
into the reaction mixture, which was next extracted by ethyl acetate (3 × 10 mL) for three times.
The combined organic phase was dried over anhydrous Na2SO4, and next the solvent was removed
under reduced pressure. The crude products were purified by column chromatography on a silica
gel (petroleum ether/EtOAc: 1/1–5/1) to give the desired products. Control experiments were
carried out carefully, and the results are summarized in Table 1 and Table 3.
4.5 General procedure for UV-Vis experiments in DMF
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In a typical UV-Vis experiment to characterize the catalyst, Ni(OAc)2 (5 mmol) and Y(OTf)3 (5
mmol) were dissolved in DMF in a glass tube, which was pre-stirred for 20 min under 70 °C, then
cooled down to room temperature for UV-Vis studies. The UV-Vis scans were carried out by
using Ni(OAc)2 (5 mmol), Ni(OTf)2 (5 mmol), Y(OTf)3 (5 mmol) and Ni(OAc)2 /Y(OTf)3 (5
mmol) in DMF at room temperature independently.
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4.6 General procedure for the stopped-flow experiments in DMF
(a) In a typical kinetic experiment to determine the formation rate of the RS-Ni(II) or
RS-Ni(II)/Y(III) species, 1 mM Ni(II) or Ni(II)/Y(III) catalyst with excess of 1a (20, 30, 40, and
50 mM) were dissolved in DMF separately, then, the in-situ generation kinetics of the RS-Ni(II) or
RS-Ni(II)/Y(III) species was monitored at 490 nm with the stopped-flow instrument by detecting
their reaction at room temperature. The kobs constants for the formation of the RS-Ni(II) or
RS-Ni(II)/Y(III) species were calculated according to the first-order reaction, and the k2 value was
calculated from a set of the kobs constants with different 1a concentrations, including 20, 30, 40,
and 50 mM.
(b) To investigate the reaction kinetics of 2a with the RS-Ni(II) or RS-Ni(II)/Y(III) species, 1 mM
Ni(II) or Ni(II)/Y(III) catalyst were dissolved in DMF as one sample, and 1 mM 1a with excessive
2a (30, 40, 50, and 60 mM) were dissolved in DMF in another sample. The decay of the in-situ
generated RS-Ni(II) or RS-Ni(II)/Y(III) species was monitored with the stopped-flow instrument
at 490 nm through the in-situ reaction of two samples at room temperature. The kobs constants for
the decay of the RS-Ni(II) or RS-Ni(II)/Y(III) species were calculated according to the first-order
reaction, and the k2 value was calculated from a set of the kobs constants with the different 2a
concentrations, including 30, 40, 50, and 60 mM.
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S-(4-(tert-butyl)phenyl) O,O-diethyl phosphorothioate (3a) 12f Colorless oil (53.2 mg, 88% yield);
1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 6.7 Hz, 2H), 7.36 (d, J = 8.3 Hz, 2H), 4.31-4.05 (m,
4H), 1.32 (m, 15H). 13C{1H} NMR (101 MHz, CDCl3) δ 152.4 (d, J = 3.1 Hz), 134.3 (d, J = 5.1
Hz), 126.5 (d, J = 2.1 Hz), 122.8 (d, J = 7.2 Hz), 64.0 (d, J = 6.1 Hz), 34.7), 31.2, 16.0 (d, J = 7.2
Hz). 31P NMR (162 MHz, CDCl3) δ 23.4.
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O,O-diethyl S-(4-methoxyphenyl) phosphorothioate (3b) 12f, 13b colorless oil (45.3 mg, 82% yield);
1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 6.8 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 4.30-4.07 (m,
4H), 3.80 (s, 3H), 1.31 (t, J = 7.0 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 160.5 (d, J = 2.8
Hz), 136.3 (d, J = 4.7 Hz), 116.6 (d, J = 7.3 Hz), 115.0 (d, J = 2.4 Hz), 63.9 (d, J = 6.3 Hz), 55.4,
16.0 (d, J = 7.1 Hz).
O,O-diethyl S-(2-methoxyphenyl) phosphorothioate (3c) 13b colorless oil (45.5 mg, 82% yield); 1H
NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.6 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 6.93 (dd, J = 14.4,
7.8 Hz, 2H), 4.22 (dq, J = 14.3, 7.1 Hz, 4H), 3.88 (s, 3H), 1.31 (t, J = 7.0 Hz, 6H). 13C{1H} NMR
(101 MHz, CDCl3) δ 159.5 (d, J = 5.0 Hz), 136.9 (d, J = 4.4 Hz), 130.9 (d, J = 2.8 Hz), 121.3 (d, J
= 2.3 Hz), 114.5 (d, J = 7.0 Hz), 111.5 (d, J = 2.2 Hz), 63.8 (d, J = 5.8 Hz), 55.9, 16.0 (d, J = 7.5
Hz).
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O,O-diethyl S-(p-tolyl) phosphorothioate (3d) 12f, 13b colorless oil (40.6 mg, 78% yield); H NMR
(400 MHz, CDCl3) δ 7.44 (d, J = 6.8 Hz, 2H), 7.15 (d, J = 7.7 Hz, 2H), 4.29-4.08 (m, 4H), 2.34 (s,
3H), 1.31 (t, J = 7.0 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 139.3 (d, J = 3.0 Hz), 134.6 (d,
J = 5.1 Hz), 130.2 (d, J = 2.3 Hz), 122.8 (d, J = 7.3 Hz), 64.08 (d, J = 6.2 Hz), 21.2, 16.0 (d, J =
7.2 Hz).
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S-(4-bromophenyl) O,O-diethyl phosphorothioate (3e) 13b colorless oil (49.4 mg, 76% yield); H
NMR (400 MHz, CDCl3) δ 7.46 (dd, J = 18.5, 7.9 Hz, 4H), 4.20 (dt, J = 12.6, 8.3 Hz, 4H), 1.32 (t,
J = 7.0 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 136.0 (d, J = 5.2 Hz), 132.5 (d, J = 2.1 Hz),
125.9 (d, J = 7.2 Hz), 123.6 (d, J = 3.5 Hz), 64.3 (d, J = 6.4 Hz), 16.0 (d, J = 7.1 Hz).
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S-(2-chlorophenyl) O,O-diethyl phosphorothioate (3f) 13b colorless oil (48.3 mg, 86% yield); H
NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.4 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.35-7.21 (m, 2H),
4.33-4.14 (m, 4H), 1.32 (t, J = 7.0 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 137.9 (d, J = 6.9
Hz), 136.8 (d, J = 4.0 Hz), 130.3 (dd, J = 5.7, 2.4 Hz), 127.5 (d, J = 2.3 Hz), 126.4 (d, J = 6.9 Hz),
64.4 (d, J = 6.3 Hz), 16.0 (d, J = 7.3 Hz).
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S-(3-chlorophenyl) O,O-diethyl phosphorothioate (3g) 13b colorless oil (39.3 mg, 70% yield); H
NMR (400 MHz, CDCl3) δ 7.49 (s, 1H), 7.39 (d, J = 7.4 Hz, 1H), 7.23 (dt, J = 15.6, 7.9 Hz, 2H),
4.23-4.04 (m, 4H), 1.25 (t, J = 7.0 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 134.8 (d, J = 2.3
Hz), 134.1 (d, J = 5.4 Hz), 132.5 (d, J = 5.3 Hz), 130.3 (d, J = 2.0 Hz), 129.2 (d, J = 2.6 Hz),
128.5 (d, J = 7.1 Hz), 64.3 (d, J = 6.3 Hz), 16.0 (d, J = 7.1 Hz).
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O,O-diethyl S-(4-fluorophenyl) phosphorothioate (3h) 12f, 13b colorless oil (38 mg, 72% yield); H
NMR (400 MHz, CDCl3) δ 7.63-7.48 (m, 2H), 7.05 (t, J = 8.5 Hz, 2H), 4.28-4.10 (m, 4H), 1.32 (t,
J = 7.0 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 164.6 (d, J = 3.3 Hz), 162.1, 136.7 (dd, J =
8.4, 5.0 Hz), 121.7 (d, J = 3.7 Hz), 116.6 (dd, J = 22.1, 2.2 Hz), 77.4, 77.1, 76.8, 64.2 (d, J = 6.4
Hz), 16.0 (d, J = 7.1 Hz).
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O,O-diethyl S-(4-nitrophenyl) phosphorothioate (3i) 12f, 13b colorless oil (41.4 mg, 71% yield); H
NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.5 Hz, 2H), 7.77 (d, J = 7.4 Hz, 2H), 4.36-4.13 (m, 4H),
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1.35 (t, J = 7.0 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 147.8, 136.3 (d, J = 6.6 Hz), 134.1
(d, J = 6.0 Hz), 124.1, 64.7 (d, J = 6.5 Hz), 16.0 (d, J = 7.0 Hz).
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S-(4-aminophenyl) O,O-diethyl phosphorothioate (3j) 12f, 13b pale yellow oil (21 mg, 40% yield);
1H NMR (400 MHz, CDCl3) δ 7.24 (d, J = 6.7 Hz, 2H), 6.55 (d, J = 8.2 Hz, 2H), 4.18-4.01 (m,
4H), 3.72 (s, 2H), 1.24 (t, J = 7.0 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 146.7 (d, J = 2.6
Hz), 135.3 (d, J = 4.6 Hz), 114.7 (d, J = 2.4 Hz), 111.9, 62.9 (d, J = 6.3 Hz), 15.0 (d, J = 7.2 Hz).
O,O-diethyl S-(4-hydroxyphenyl) phosphorothioate (3k) 12f, 13b colorless oil (39.2 mg, 75% yield);
1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 7.22 (dd, J = 8.5, 2.0 Hz, 2H), 6.56 (d, J = 8.2 Hz,
2H), 4.21-4.03 (m, 4H), 1.27 (t, J = 7.0 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 157.6 (d, J =
3.1 Hz), 135.7 (d, J = 4.7 Hz), 116.1 (d, J = 2.4 Hz), 112.2 (d, J = 7.2 Hz), 63.6 (d, J = 6.8 Hz),
15.0 (d, J = 7.0 Hz).
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O,O-diethyl S-(naphthalen-1-yl) phosphorothioate (3l)
colorless oil (51 mg, 86% yield); H
NMR (400 MHz, CDCl3) δ 8.53 (d, J = 8.4 Hz, 1H), 7.97-7.78 (m, 3H), 7.60 (t, J = 7.4 Hz, 1H),
7.52 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 4.21-4.02 (m, 4H), 1.18 (t, J = 7.0 Hz, 6H).
13C{1H} NMR (101 MHz, CDCl3) δ 135.3 (d, J = 5.6 Hz), 134.7 (d, J = 4.1 Hz), 134.3 (d, J = 2.2
Hz), 130.3 (d, J = 3.4 Hz), 128.6, 127.1, 126.5, 125.9, 125.7 (d, J = 3.4 Hz), 123.8 (d, J = 8.1 Hz),
64.2 (d, J = 6.6 Hz), 16.0 (d, J = 7.1 Hz).
O,O-diethyl S-(naphthalen-2-yl) phosphorothioate (3m) 13b colorless oil (45 mg, 76% yield); 1H
NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.80 (dd, J = 8.4, 5.1 Hz, 3H), 7.61 (d, J = 8.5 Hz, 1H),
7.50 (dd, J = 6.1, 3.2 Hz, 2H), 4.30-4.12 (m, 4H), 1.30 (t, J = 7.0 Hz, 6H). 13C{1H} NMR (101
MHz, CDCl3) δ 134.4 (d, J = 6.8 Hz), 133.6 (d, J = 2.2 Hz), 133.1 (d, J = 1.9 Hz), 130.9 (d, J =
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4.1 Hz), 129.0, 127.7 (d, J = 3.2 Hz), 127.1, 126.8, 123.8 (d, J = 7.4 Hz), 64.2 (d, J = 6.3 Hz), 16.1
(d, J = 7.1 Hz).
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S-benzyl O,O-diethyl phosphorothioate (3n) 13b colorless oil (34.4 mg, 66% yield); H NMR (400
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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
MHz, CDCl3) δ 7.41-7.22 (m, 5H), 4.19-3.94 (m, 6H), 1.28 (t, J = 7.0 Hz, 6H). 13C{1H} NMR
(101 MHz, CDCl3) δ 137.5 (d, J = 5.4 Hz), 128.9, 128.7, 127.6, 63.5 (d, J = 5.7 Hz), 35.0 (d, J =
3.9 Hz), 16.0 (d, J = 7.4 Hz).
O,O-diethyl S-(4-methoxybenzyl) phosphorothioate (3o) 13b colorless oil (35.4 mg, 61% yield); 1H
NMR (400 MHz, CDCl3) δ 7.28 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 4.19-3.95 (m, 6H),
3.80 (s, 3H), 1.30 (t, J = 7.0 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 159.1, 130.1, 129.5 (d, J
= 5.7 Hz), 114.0, 63.5 (d, J = 5.8 Hz), 55.3, 34.6 (d, J = 3.8 Hz), 16.0 (d, J = 7.3 Hz).
12f, 13b
1
S-cyclohexyl O,O-diethyl phosphorothioate (3p)
colorless oil (36.3 mg, 72% yield); H
NMR (400 MHz, CDCl3) δ 4.16 (dt, J = 15.5, 8.6 Hz, 4H), 3.28 (dd, J = 21.6, 10.5 Hz, 1H), 2.08
(d, J = 9.9 Hz, 2H), 1.78-1.71 (m, 2H), 1.63-1.46 (m, 3H), 1.45-1.24 (m, 9H). 13C{1H} NMR (101
MHz, CDCl3) δ 63.4 (d, J = 6.1 Hz), 45.6 (d, J = 3.5 Hz), 35.3 (d, J = 6.0 Hz), 25.9, 25.3, 16.1 (d,
J = 7.3 Hz).
O,O-diethyl S-octyl phosphorothioate (3q) 12f, 13b colorless oil (42.4 mg, 75% yield); 1H NMR (400
MHz, CDCl3) δ 4.34-4.07 (m, 4H), 2.90-2.74 (m, 2H), 1.68 (dt, J = 14.9, 7.4 Hz, 2H), 1.34 (dd, J
= 25.8, 18.7 Hz, 16H), 0.88 (t, J = 6.5 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 63.4 (d, J =
5.9 Hz), 31.8, 30.9 (dd, J = 14.5, 4.9 Hz), 29.0 (d, J = 13.2 Hz), 28.6, 22.6, 16.1 (d, J = 7.3 Hz),
14.1.
1
S-butyl O,O-diethyl phosphorothioate (3r) 13b colorless oil (30.8 mg, 68% yield); H NMR (400
MHz, CDCl3) δ 4.32-4.04 (m, 4H), 2.84 (dt, J = 14.5, 7.4 Hz, 2H), 1.74-1.61 (m, 2H), 1.40 (dt, J =
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