Transition metal-free coupling reactions of benzylic trimethylammonium salts with di(hetero)aryl disulfides and diselenides

Article abstract of DOI:10.1039/d0cc05633b

A new protocol was developed to synthesize (enantioenriched) thioethers and selenoethers from (chiral) benzylic trimethylammonium salts and di(hetero)aryl disulfides or diselenides. These syntheses were promoted by the presence of weak base and did not require the use of any transition metal, and resulted in the target products with good to excellent yields (72-94%). Using quaternary ammonium salts synthesized from enantiomerically enriched amines led to highly enantiopure benzylic thioethers and selenoethers (94-99% ee) with configurations reversed from those of their enantioenriched quaternary ammonium salts. This journal is

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DOI: 10.1039/D0CC05633B
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Transition Metal-Free Coupling Reaction of Benzylic
Trimethylammonium Salts with Di(hetero)aryl Disulfides and
Diselenides
Received 00th January 20xx,
Accepted 00th January 20xx
Fuhai Li,a Dan Wang,a Hongyi Chen,a Ze He,a Lihong Zhou,b and Qingle Zeng*a
DOI, 10.1039/x0xx00000x
A new protocol of transition metal-free, weak base-promoted been reported to fulfill catalytic transformation of C-N bond to
synthesis of (enantioenriched) thioethers and selenoethers from C-B,11 C-C,12 C-N,13 C-Si,14 C-S,15 C-P,16 and so on.
(chiral) benzylic trimethylammonium salts and di(hetero)aryl
There are very few reports to carry out C-N cleavage with
disulfides or diselenides with good to excellent yields (72%-94%) is transition metal catalysts. Tian found that in situ-formed N-
developed. If quaternary ammonium salts synthesized from phenyl-N,N-dimethylammonium salts from expensive 2-
enantiomerically enriched amines are adopted, highly (trimethylsilyl)phenyl triflate with higher activity may realize
enantiopure benzylic thioethers and selenoethers (94-99% ee) the C-N cleavage reaction without transition metal catalysis,17
with reverse configurations to their enantioenriched quaternary but this reaction is not applicable to trimethylammonium salts
ammonium salts are obtained.
with lower activity.
In our previous work, we have completed a series of studies
on benzylic quaternary ammonium salts.13,15a,18 Zeng and
coworkers completed the C-S coupling of quaternary
ammonium salts by using the Cu(I) catalyst.15a As an element
of the same group of sulfur, the C-Se bond formation reaction
is obvious of important research significance, since
organoselenium molecules demonstrate various interesting
bioactivities. During our exploration of a new C-Se formation
method from (enantioenriched) benzylic quaternary
ammonium salts, finally, we found that disulfides and
diselenides may be utilized in the C-S and C-Se coupling
reaction of (enantioenriched) benzylic trimethylammonium
salts without transition metal catalyst (Scheme 1).
Thioethers and selenoethers have a wide range of biological
activities.1 Thioethers have been reported as medicines to
treat diseases, such as diltiazem,2 mPEES-1 inhibitors.3 Both
selenoethers and thioethers are chalcogenides and thus has
similar physico-chemical properties, so selenoethers has great
potential application value, too.4 At present, to research on
selenoethers as drugs is getting more and more attention.
Among cancer cell redox modulators, selenium compounds
gained substantial attention. It has been shown that uridine
Se-nucleosides can induce reactive oxygen species (ROS)
generation and DNA damage, such as double-strand and
single-strand breaks in human HL-60 cells, thereby activating
the caspase cascade of apoptosis signals.5
As a class of important organic intermediates, the synthesis
of thioethers and selenoethers has aroused chemists’ great
interest. According to previous reports, thioethers and
selenoethers can be easily converted into other organic
compounds, such as C-X cracking,6 oxidation,7 imidization,8
salinization.9
Ar
N
X
OTf
Cs2CO3
Ar
X
Y

Y
+

X
Ar
MeCN, 80 o
C
R
R
Y = S, CH=CH, CH=N
X = S, Se
Ar = Aryl, Heteroaryl
78 examples
72-94% yield
94%-99% ee
In recent years, the research on the C-N bond cleavage
reaction of quaternary ammonium salts has grasped the focus
of many researchers.10 Transition metals Pd, Rh, Ir, Ni, Cu have
Scheme 1. Carbon-heteroatom bond formation of benzylic quaternary ammonium salts
via C-N bond cleavage
As our ongoing study of C-S coupling reaction,15a we used
transition metal catalysts such as Cu, Ni, Pd to investigate the
C-Se coupling reaction of arylselenols / alkylselenols and
quaternary ammonium salts. Due to the expensive, unstable-
in-air and malodor of arylselenols and alkylselenols, instead,
we adopted diselenides to react with benzyl quaternary
ammonium salts (Table 1). Indeed, this coupling reaction may
be carried out using transition metal catalysts but with low
a. State Key Laboratory of Geohazard Prevention and Geoenvironment Protection,
College of Materials, Chemistry & Chemical Engineering, Chengdu University of
Technology, Chengdu 610059, China. qinglezeng@hotmail.com.
b. College of Environment and Ecology, Chengdu University of Technology, Chengdu
610059, China.
Electronic Supplementary Information (ESI) available: [Experimental procedures,
1H, 13C NMR and MS characterization data and spectra of all products]. See
DOI: 10.1039/x0xx00000x
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yields (Table 1, entries 1-3). However, surprisingly, reaction temperature was tested. Pleasingly, shortening the time to 12
View Article Online
without catalyst even provided higher yield than that with h did not decrease the yield at 80 °C (EntDryOI1: 510)..1039/D0CC05633B
transition metal catalysts (Table 1, entries 4 vs 1-3). Moreover, In order to study the effect of various counter anions of benzyl
for highly enantioenriched benzylic trimethylammonium quaternary ammonium salts, benzyl trimethyl ammonium
triflate (S)-4a (Table 1, entries 5-6), the addition of transition chloride, bromide, and iodide were examined under the
metal catalyst CuI caused severer racemization than no optimized conditions (Entries 16-18). The results show that
catalyst. Therefore, no transition metal catalyst was adopted benzyl trimethylammonium salts with Cl﹣, Br﹣, I﹣ as counter
for the following reactions.
anions gave lower yields than that with triflate (Entries 16-18
vs 15). Therefore, benzylic trimethylammonium triflates were
adopted in the following research.
Table 1. Optimization of Reaction Conditions a
With the optimized condition in hand, the transition metal-
free coupling reactions of various substituted benzyl
quaternary ammonium triflates with diphenyl disulfide and
diphenyl diselenide were investigated (Scheme 2). Perhaps
due to low steric hindrance of benzylic quaternary ammonium
salts, all thioethers and selenoethers were obtained with good
to high yields from the reaction of the corresponding
substituted benzyl quaternary ammonium salts.
Se
base, solvent
T, 24h
Se
N
+
X
Se
3aa-Se or 5ab
2b
1 or 4
Ph
N
OTf
Br
Ph
N
Cl Ph
N
Ph
N
OTf
I
Ph
N
(S)-4a
1b
1c
1d
1a
Entry
1 or 4
Catalyst
Base
Solvent Temp Yield ee%
(ºC)
80
80
80
80
80
80
80
80
80
80
80
80
40
60
80
80
80
80
(%)b
35
26
29
36
34
35
75
80
90
23
70
0
1
1a
1a
CuI
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
t-BuOK
KOH
MeCN
MeCN
MeCN
MeCN
MeCN
-
-
2
NiCl2
OTf
Cs2CO3 (2.0 equiv)
X
N
X
Ph
Y
+
Y
Ph
X
3
1a
Pd(PPh3)4
-
MeCN (5 mL)
80 oC, 12 h
R'
R'
4
1a
-
-
1
2
3
5
(S)-4a
(S)-4a
1a
CuI
78
96
-
Se
6
-
-
-
-
-
-
-
-
-
-
-
-
-
S
MeCN
MeCN
R'
R'
7
R'= H, 3aa-Se, 90%
R'= H, 3aa-S, 89%
R'= 4-Me, 3ba-Se, 91%
R'= 3-Me, 3ca-Se, 90%
R'= 2-F, 3da-Se, 87%
R'= 2-Cl, 3ea-Se, 88%
R'= 2-Br, 3fa-Se, 86%
R'= 4-F, 3ga-Se, 88%
R'= 4-Cl, 3ha-Se, 89%
R'= 4-Br, 3ia-Se, 86%
R'= 4-I, 3ja-Se, 72%
8
1a
MeCN
MeCN
toluene
DMSO
H2O
-
R'= 4-Me, 3ba-S, 90%
R'= 4-F, 3ca-S, 88%
R'= 4-Cl, 3da-S, 89%
R'= 4-Br, 3ea-S, 88%
R'= 4-(t-Bu), 3fa-S, 92%
R'= 4-OMe, 3ga-S, 94%
R'= 4-CF3, 3ha-S, 85%
9
1a
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
-
10
11
12
13
14
15 c
16
17
18
1a
-
1a
-
1a
-
R'= 4-(t-Bu), 3ka-Se, 90%
R'= 4-OMe, 3la-Se, 92%
R'= 3-OMe, 3ma-Se, 89%
R'= 2-OMe, 3na-Se, 90%
R'= 4-CF3, 3oa-Se, 84%
1a
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
21
45
90
10
16
24
-
S
S
1a
-
3ia-S, 91%
1a
-
1b
-
Se
S
1c
-
3pa-Se, 88%
1d
-
3ja-S, 90%
S
a Unless otherwise noted, the reactions were performed with 1a (1.0 mmol), 2b (1.2
mmol), base (2.0 mmol) and solvent (5 mL) in a sealed test tube with sleeve rubber
stopper under argon atmosphere. b Isolated yield. c The reaction time was shortened to
12 h.
Se
3qa-Se, 90%
Se
N
3ra-Se, 73%
Scheme 2. Scope of benzyl quaternary ammonium salts
Then we further explored various bases (entries 7-9), and
we found that the reaction can proceed well under strong
bases such as potassium tert-butoxide. As a weaker base,
cesium carbonate even obtained a higher yield than strong
bases potassium tert-butoxide and KOH (Entries 9 vs 7-8).
Considering that strong bases are more likely to cause
elimination reaction of benzylic ammonium salts and to
decrease functional group tolerance of substrates, we chose
the most effective cesium carbonate as the base.
Screening of some other common solvents shows acetonitrile
is the best one (Entries 9 vs 10-12). At lower temperature (40
°C and 60 °C), the reaction was not complete within 24 h
(Entries 13-14). Considering that the boiling point of
acetonitrile is only 81.6 °C, for safety reasons, no higher
Next, the scope of disulfides and diselenides were screened
in the reaction with benzyl trimethylammonium triflate 1a
(Scheme 3). For disulfides, we first investigated the reaction of
various 4-substituted diaryl disulfides, and found that the
reaction has good tolerance to both electron donating groups
and electron withdrawing groups. 1,2-Bis(benzo[d]thiazol-2-
yl)disulfanes (3ag-S) and 1,2-di(pyridin-2-yl)disulfanes (3ah-S)
were also investigated, and the yields were all excellent.
2 | J. Name., 2012, 00, 1-3
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Table 2. Scope of reaction of enantioenriched benzylic ammonium salts with diphenyl
View Article Online
R2
Cs2CO3 (2.0 equiv)
MeCN (5 mL)
N
OTf
X
DOI: 10.1039/D0CC05633B
R2
X
disulfides and diselenides
+
X
R2
80 o
C 12 h
3
1
2
N
*
X
OTf
Cs2CO3 (2.0 equiv)
MeCN (5 mL)
X
*
X
R''
+
S
R''
Se
80 o
C
12 h
R3
N
S
S
R3
2 (X = S, Se)
4
5
R''= H, 3aa-Se, 90%
3ag-S, 84%
R''= H, 3aa-S, 89%
R''= 4-Me, 3ab-Se, 91%
R''= 3-Me, 3ac-Se, 90%
R''= 2,4,6-Me, 3ad-Se, 93%
R''= 4-OMe, 3ae-Se, 91%
R''= 4-F, 3af-Se, 88%
*
N
*
OTf
N
*
R''= 4-Me, 3ab-S, 87%
R''= 4-Cl, 3ac-S, 90%
R''= 4-OMe, 3ad-S, 85%
R''= 4-NO2, 3ae-S, 82%
R''= 4-OH, 3af-S, 86%
N
OTf
OTf
R
S
N
R = H,
R = MeO, 4b
R = Br, 4c
4a
R''= 4-Cl, 3ag-Se, 89%
R''= 4-Br, 3ah-Se, 88%
R''= 4-CF3, 3ai-Se, 88%
R''= 3,5-CF3, 3aj-Se, 83%
R''= 4-(t-Bu), 3ak-Se, 90%
R''= 4-CN, 3al-Se, 85%
4d
4e
3ah-S, 90%
entry
4
product 5
yield(%)
ee(%)
rac-4a
(R)-4a
(S)-4a
rac-4a
(R)-4a
(S)-4a
rac-4b
(R)-4b
(S)-4b
rac-4b
(R)-4b
(S)-4b
rac-4c
(R)-4c
(S)-4c
rac-4c
(R)-4c
(S)-4c
rac-4d
(R)-4d
(S)-4d
rac-4d
(R)-4d
(S)-4d
rac-4e
(R)-4e
(S)-4e
rac-4e
(R)-4e
(S)-4e
X = S, rac-5aa
X = S, (S)-5aa
X = S, (R)-5aa
88%
88%
89%
84%
85%
84%
1
--
2
97
96
--
3
X = Se, rac-5ab
X = Se, (S)-5ab
X = Se, (R)-5ab
X = S, rac-5ba
X = S, (S)-5ba
X = S, (R)-5ba
X = Se, rac-5bb
X = Se, (S)-5bb
X = Se, (R)-5bb
X = S, rac-5ca
X = S, (S)-5ca
X = S, (R)-5ca
X = Se, rac-5cb
X = Se, (S)-5cb
X = Se, (R)-5cb
X = S, rac-5da
X = S, (S)-5da
X = S, (R)-5da
X = Se, rac-5db
X = Se, (S)-5db
X = Se, (R)-5db
4
5
98
96
--
96
98
--
94
96
--
99
99
--
99
99
--
99
99
--
98
99
--
Se
N
6
7
93%
93%
93%
90%
90%
90%
90%
90%
90%
88%
88%
89%
87%
88%
87%
87%
88%
87%
8
9
3am-Se, 85%
10
11
12
13
S
Se
14
15
16
17
18
19
20
21
22
23
3an-Se, 90%
Scheme 3. Scope of di(hetero)aryl disulfides and diselenides
For diaryl diselenides, the position and quantity of methyl
substitution on the benzene have little effect on the yield
(3ab-Se, 3ac-Se, 3ad-Se), and the steric hindrance factor is
negligible. Then, the effects of different substituent about
halogen, methoxy, trifluoromethyl, tert-butyl, and cyano were
also investigated, and the yield was still excellent.
Furthermore, the reaction also has good tolerance to pyridine
(3am-Se) and thiophene (3an-Se).
Next, the reactions of various highly enantioenriched
benzylic trimethylammonium triflates with diphenyl diselenide
and diphenyl disulfide were studied (Table 2). In all reactions,
the target products were obtained with excellent yields and
excellent enantiopurities. By comparing the orientation of the
optical rotation and HPLC eluent peak orders of our
corresponding products 5aa, 5ab and 5ca and the reported
highly enantioenriched products,17 the absolute configurations
of our products were set. As we known, chiral points of chiral
amines did not involve in the process of preparation of chiral
quaternary ammonium triflates, so chiral quaternary
ammonium triflates and chiral amines have the same absolute
configuration. By comparison of the known absolute
configuration of commercially available amines with our
products, we found that the product configurations were
totally reversed. It seems that this reaction occurs via an SN2
substitution. These phenomena were also reported in other
transition metal catalyzed coupling reaction or non-transition
metal involved substitution.11a, 11b, 14, 17
24
25
X = S, rac-5ea
X = S, (S)-5ea
X = S, (R)-5ea
X = Se, rac-5eb
X = Se, (S)-5eb
X = Se (R)-5eb
92%
92%
92%
89%
89%
90%
26
27
28
29
30
99
98
--
98
99
In order to check the effectiveness of this synthetic method,
a scale-up reaction was carried out. The 10 mmol-scaled
reaction provided the desired product in 78% yield.
In order to explore the mechanism, we conducted a few
control experiments (Scheme 4). In the radical trapping
experiment, three equivalents of TEMPO were added to the
reaction, but had little effect on the yield, indicating that the
reaction was likely not a radical process. In our normal
experiments, in addition to the desired products selenoethers
and thioethers, the by-products 6 and 7 were also been
detected, respectively. But when no benzylic quaternary
ammonium salt was added in the reaction, 6 and 7 were not
obtained. This suggests that the reaction may be a synergistic
reaction of the three components, and the acetonitrile may
also play a certain role in promoting the reaction by promoting
the generation of nucleophiles.
Cs2CO3 (2.0 equiv)
TEMPO (3.0 equiv)
N
Se
OTf
+
Se
Se
MeCN (5 mL)
80 oC, 12h
2b
3aa-Se, 85%
1
1
1
Cs2CO3 (2.0 equiv)
CN
N
S
OTf
+
S
+
3aa-S
MeCN (5 mL)
80 oC, 12h
S
S
2a
89%
6, 36%
Cs2CO3 (2.0 equiv)
Se
N
Se
CN
3aa-Se
+
+
OTf
Se
MeCN (5 mL)
80 oC, 12h
90%
7, 52%
2b
Scheme 4. Control experiments
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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(c)N. Metanis, E. Keinan and P. E. Dawson, J. Am. Chem. Soc.
Based on the above experimental results, we propose a
possible mechanism (Scheme 5). Disulfide or diselenide is
polarized under the action of acetonitrile, and the negatively
charged atoms attack the benzylic quaternary ammonium salt.
This process is an SN2 process, and thus the configuration of
the product is reversed. At the same time, Cs2CO3 turns
acetonitrile into its anion. Acetonitrile anion reacts with
polarized RXXR (X = Se or S) to produce 7 or 6′. The by-product
6′ produced by disulfide will continue to react due to the
activity of methylene hydrogen and produce 6. Both 6 and 7
were collected and characterized by NMR.
View Article Online
2006, 128, 16684.
DOI: 10.1039/D0CC05633B
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7
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NMe3OTf
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

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
H
CH2CN
CH2CN
S
S
Ar
ArS
R1
R1
CN
SN2 inversion
Ar
R2
Ar
Ar
R2
Ar
S
Ar
TfOMe3N
S
S
6
Scheme 5. A proposed mechanism
In summary, we have developed a strategy to synthesize
(enantioenriched) benzylic selenoethers and thioethers via the
transition metal-free coupling reaction of (enantioenriched)
benzylic quaternary ammonium salts with di(hetero)aryl
diselenides and disulfides. This method has wide scope of
substrates and generally high yields. Moreover, when
enantiopure benzylic quaternary ammonium salts are
adopted, chiral benzylic thioethers and selenoethers in reverse
configuration with extremely high enantiomeric purity are
obtained, as is a good way to prepare enantiopure benzylic
thioethers and selenoethers. A synergistic reaction mechanism
is proposed to explain the role of acetonitrile.
This work was supported by the National Natural Science
Foundation of China (No. 21372034) and the State Key
Laboratory of Geohazard Prevention and Geoenvironment
Protection (No. SKLGP2018Z002).
Conflicts of interest
There are no conflicts to declare.
Notes and references
1
(a)R. A. Nugent, S. T. Schlachter, M. J. Murphy, G. J. Cleek, T. J.
Poel, D. G. Wishka, D. R. Graber, Y. Yagi, B. J. Keiser, R. A.
Olmsted, L. A. Kopta, S. M. Swaney, S. M. Poppe, J. Morris, W. G.
Tarpley and R. C. Thomas, J. Med. Chem. 1998, 41, 3793; (b)L.
Flohe, W. A. Günzler and H. H. Schock, FEBS Lett. 1973, 32, 132;
4 | J. Name., 2012, 00, 1-3
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Table of contents entry
DOI: 10.1039/D0CC05633B
Ar
X
N
OTf
Cs2CO3
Ar
X
Y

Y
+

X
Ar
MeCN, 80 o
C
R
R
Y = S, CH=CH, CH=N
X = S, Se
Ar = Aryl, Heteroaryl
78 examples
72-94% yield
94%-99% ee
Benzylic thioethers and selenoethers with high (enantiopurity and) yield are synthesized via transition
metal-free coupling reaction of benzylic trimethylammonium salts.