Metal- And Oxidant-Free Electrochemical Oxidative Desulfurization C-O Coupling of Thiourea-Type Compounds with Alcohols

Article abstract of DOI:10.1055/s-0039-1690837

An efficient desulfurization C-O coupling reaction of 3,4-dihydropyrimidine-2(1 H)-thiones (including thioureas) with alcohols was developed under electrochemical oxidation conditions. Herein, transition--metal catalysts and additives are not required and

Full text of DOI:10.1055/s-0039-1690837

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–I
paper
A
en
Z.-H. Zhu et al.
Paper
Synthesis
Metal- and Oxidant-Free Electrochemical Oxidative Desulfuriza-
tion C–O Coupling of Thiourea-Type Compounds with Alcohols
Zheng-He Zhu
Ar
Ar
Ming-Zhe Ren
Bao-Qian Cao
R1
R2
R1
R2
NH
N
C
Pt
R
N
H
S
Zheng-Jun Quan*
Xi-Cun Wang*
N
O
O
undivided cell
OH
H2
+
R
R
S
R'
R''
LiClO4 (0.1 M)
R'
R''
N
N
Gansu International Scientific and Technological Cooperation
Base of Water-Retention Chemical Functional Materials, College
of Chemistry and Chemical Engineering, Northwest Normal
University, Lanzhou, Gansu 730070, P. R. of China
quanzhengjun@hotmail.com
N
N
oxidant-free
metal-catalyst-free
room temperature
H
H
H
28 examples
wangxicun@nwnu.edu.cn
Received: 07.01.2020
Accepted after revision: 04.02.2020
Published online: 24.02.2020
C–S bond cleavage of thiomethyl-substituted N-heterocyclic
compounds.10 In 2014, Osuka and co-workers reported the
Pd-catalyzed C–N bond formation between aryl sulfides
and aromatic amines.11 In 2017, Morandi and co-workers
used a Pd-catalyzed desulfurization of arylthiophenols
with mercaptans or thiophenols to form C–S bonds.12 In
some cases of transition-metal-activated C–S bonds,13 sul-
fur atoms can bind tightly to the transition metal, resulting
in permanent deactivation of the transition metal, thus hin-
dering the reaction.14 To overcome these difficulties, an ac-
tive Grignard reagent was used as a nucleophile15 or an aryl
sulfide having a specific structure to promote efficient con-
version was employed.16,17 More recently, a gold-catalyzed
desulfurization of mercaptans with olefins to form C–C
bonds under photochemical conditions has been report-
ed.18 Pyrithione including pyrimidinethione entered our
field of view because of its special structure and as it is a
major component of many natural products and drugs, such
as the current cholesterol-lowering drug rosuvastatin
(Crestor)19 and the potent anticancer drug imatinib
(Gleevec).20 The main part of the compound is a pyrimidine
structure. Our group has reported a series of desulfuriza-
tion C–X (X = C, N) coupling reactions of 3,4-dihydropyrim-
idine-2(1H)-thiones (DHPMs) or their disulfides in a Pd–Cu
reaction system (Schemes 1A and 1B).21 Subsequently, Sohn
and co-workers reported the C–S bond activation/cleavage
of DHPMs to form C–C (Scheme 1A)22a and C–O bonds
(Scheme 1C)22b in a stoichiometric Cu system. These report-
ed methods have provided great progress for C–S bond acti-
vation/cleavage; however, some drawbacks are obvious. For
example, they need stoichiometric Cu reagent and transi-
tion-metal catalyst with/without the presence of stoichio-
metric oxidant. Furthermore, the reaction times are long
and temperatures are high.22c,d
DOI: 10.1055/s-0039-1690837; Art ID: ss-2020-g0012-op
Abstract An efficient desulfurization C–O coupling reaction of 3,4-di-
hydropyrimidine-2(1H)-thiones (including thioureas) with alcohols was
developed under electrochemical oxidation conditions. Herein,
transition-metal catalysts and additives are not required and the alco-
hol is both the solvent and the alkoxy donor.
Key words electrochemical oxidation, alkoxylation, alcohols, thioureas,
desulfurization
Recently, electrochemistry has been increasingly used
in organic synthesis. It can be used to substitute poisonous
or dangerous oxidizing or reducing agents.1 Electrochemical
oxidations have been successfully used for sulfur (SH)-
containing compounds to give disulfides1c,d or sulfonyl
compounds.1h However, desulfurization reactions of sulfur
compounds are still uncommon under electrochemical con-
ditions. Sulfur-containing compounds are widely found in
natural products, pesticides, proteins2 and functional mate-
rials.3 Their biological activities4 or reactivities5 play a
unique role in organic chemistry. Because the C–S bond is
relatively easier to activate and functionalize than other
carbon–heteroatom bonds (e.g., C–O, C–N),6 activation of
C–S bonds is important in organic chemistry.7 Generally,
transition metals have been used to catalyze C–S bond acti-
vation to construct new chemical bonds.8 Great progress
has been developed in this field, and some typical examples
are cited herein. In 2000, Liebeskind and Srogl first reported
a desulfurization C–C coupling reaction of thiol esters and
boric acids in the presence of copper(I) thiophene-2-car-
boxylate (CuTC) (1.5–3.0 equiv) and Pd2(dba)3.9 In 2009,
Knochel and co-workers reported the use of Pd-catalyzed
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Z.-H. Zhu et al.
Paper
Synthesis
Table 1 Optimization of the Reaction Conditionsa
C–S bond activation cleavage
Pd–Cu
N
CuSCN
CuTC
N
A
C
ArB(OH)2
B(OR)3 R = alkyl
Ar
OR
OR
C
Pt
N
NH
20 mA
EtO2C
Me
N
S
S
EtO2C
Me
or
NH
MeOH
+
N
LiClO4 (0.1 M)
Cs2CO3 (0.5 equiv)
undivided cell
S
Me
N
H
1a
S
N
O
D
this work
electrochemical
B
2a
3a
N
N
Pd–Cu
R1R2NH
NR2R1
Room temperature
Metal- and oxidant-free
OH
R1, R2 = aryl, alkyl
Entry Variation from the standard reaction conditions
Yield (%)b
R
1
2
3
4
5
6
7
8
9
none
81
Scheme 1 C–S bond activation/cleavage
n-Bu4NI, n-Bu4NBF4, instead of LiClO4
1.0 equiv, 0.8 equiv, 0.2 equiv of Cs2CO3
C(+)/C(–), instead of C(+)/Pt(–)
Pt(+)/Pt(–), instead of C(+)/Pt(–)
15 mA, instead of 20 mA,
10 mA, instead of 20 mA
60, 50
65, 71, 74
20
Herein, we report a metal- and oxidant-free procedure
to activate and cleave the C–S bond. The C–O bond is
formed by an electrochemical oxidative desulfurization C–O
coupling reaction of thiourea-type compounds with in-
expensive and readily available alcohols (Scheme 1D). We
have previously developed the C–O cross-coupling reac-
tions of pyrimidin-2-yl sulfonates with phenols23a and 2-
hydroxypyrimidines with OH nucleophiles.23b The current
method to form C–O bonds is simpler than the classical
Ullmann24a and Buchwald–Hartwig coupling reactions.24b
We tested our design using DHPM 1a and methanol (2a)
as model substrates (Table 1; for details, see Supporting In-
formation, Table S1). The optimal reaction conditions were
obtained under a constant current of 20 mA in an undivid-
ed, straight reaction tube containing carbon as an anode
and platinum as a cathode with reaction for 6 hours, to give
the desired product 3a in 81% yield (entry 1). A series of
electrolytes were chosen and found to give lower yields of
3a than that obtained by using LiClO4 (entry 2). The reac-
tion yield was best when Cs2CO3 (0.5 equiv) was used as the
base. In the absence of a base, 3a was obtained in 28% yield.
For the electrode material, it was experimentally proven
that the selection of carbon rod as anode and platinum as
cathode are the best choice (entries 4 and 5). When the op-
erating current was reduced to 15 mA or 10 mA, the yield of
3a decreased significantly (entries 6 and 7). Further studies
showed that when the reaction was carried out in a
MeCN/MeOH (1:1) mixture, 3a was formed in 25% yield
(entry 8). No product 3a was observed in the absence of
current (entry 9).
35
64
51
MeCN/MeOH (1:1), instead of MeOH
no electric current
25
n.d.c
a Standard reaction conditions: 1a (0.2 mmol), 2a (6 mL), LiClO4 (0.1 M),
Cs2CO3 (0.5 equiv), carbon rod anode, platinum cathode, undivided cell,
20 mA constant current, rt, 6 h, under air.
b Isolated yields.
c Not detected.
substrate with an isopropyl substituent at the C6 position
afforded the desired product 3s in a moderate yield of 50%.
Simple pyrimidinethiones also reacted with alcohols to give
the desired products 3t, 3u and 3v in 53%, 41% and 35%
yield, respectively. When 2-mercaptobenzothiazole was
used as a substrate, reaction with methanol provided 2-me-
thoxybenzothiazole (3w) in 33% yield (Scheme 2B). In com-
parison, the yields of products 3a–3v obtained by using the
corresponding disulfides as substrates were higher (Scheme
2A, yields in square brackets). When simple 4-methylthio-
phenol was used as a substrate, no desulfurization product
was obtained, rather methyl 4-methylbenzenesulfinate was
obtained.25
Guanidine compounds are widely used in medicine,
chemistry and other industries due to their strong basicity,
high stability and good biological activity.26 Generally,
guanidines are prepared by the addition of amines to cyan-
amide and iso(thio)urea. Therefore, we selected N-benzoyl-
N′-phenylthiourea and N-phenyl-N′-(pyridin-2-yl)thiourea
as substrates for the reaction with alcohols (MeOH, EtOH,
n-PrOH) to synthesize alkoxy products. Fortunately, the
corresponding isourea compounds 5a–5e were obtained in
fair yields (Scheme 2C).
Under the optimal reaction conditions, multiple alco-
hols (Scheme 2; MeOH, EtOH, n-PrOH, i-PrOH) were tested
and found to give the corresponding products 3a–3d in
moderate to good yields (Scheme 2A). Next, we evaluated
the reaction range of the DHPM substrate by changing the
aryl substituent at the C4/C6 position. Both the electronic
and steric effects of the C4 aryl substituent on the product
yields are slight (Scheme 2A, 3e–3n). When the C4 aryl
para-substituent was methoxy, the product was obtained in
a lower yield (Scheme 2A, 3h). When C5 was substituted by
a methyl ester, isobutyl ester or tert-butyl ester group, the
desired product 3o–3r was obtained in moderate yield. The
To gain insight into the details of electrocatalytic desul-
furization of pyrimidinethiones, control experiments were
performed. In the first place, cyclic voltammetry experi-
ments with 1a, and with 1a and base in argon, were carried
out separately (Figure 1). An oxidation peak of 1a was ob-
served at 1.55 V (blue line), and at 1.63 V (red line) for 1a in
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

C
Z.-H. Zhu et al.
Paper
Synthesis
N
C
N
Pt
NH
R4OH
S
+
or
S
R4
O
3
S
N
2
A. Substrate scope with different DHPMs,a disulfidesb and alcohols
Me
Me
Me
EtO2C
Me
EtO2C
Me
EtO2C
Me
EtO2C
Me
EtO2C
OMe
EtO2C
EtO2C
Me
N
N
N
N
N
N
N
N
N
On-Pr
N
Oi-Pr
N
OMe
Me
N
OEt
Me
N
OMe
N
OMe
3a, 81% [88%]
3d, 40% [57%]
3g, 71% [79%]
3b, 63% [80%]
3c, 56% [70%]
3f, 67% [76%]
3e, 64% [73%]
F
Cl
Cl
OMe
F
Cl
Br
F
EtO2C
N
EtO2C
EtO2C
Me
EtO2C
EtO2C
EtO2C
Me
EtO2C
N
N
N
N
N
N
Me
N
OMe
Me
N
OMe
N
OMe
Me
N
OMe
Me
N
OMe
N
OMe
Me
N
OMe
3h, 48% [53%]
3j, 52% [61%]
3i, 60% [70%]
3k, 66% [73%]
3l, 67% [75%]
3m, 70% [79%]
3n, 64% [73%]
Cl
Me
Me
Br
MeO2C
Me
i-BuO2C
t-BuO2C
Me
EtO2C
MeO2C
N
N
N
N
N
N
N
N
N
OMe
Me
N
OEt
Me
N
OMe
N
OMe
N
Oi-Pr
i-Pr
N
OMe
N
OEt
Me
N
OMe
3o, 61% [69%]
3v, 35% [43%]
3p, 57% [65%]
3s, 50% [57%]
3u, 41% [50%]
3q, 50% [59%]
3r, 55% [64%]
3t, 53% [63%]
B. 2-Mercaptobenzothiazole and methanol
C
Pt
N
N
LiClO4 (0.1 M)
10 mA, rt, 6 h
MeOH
6 mL
OMe
SH
+
S
S
0.2 mmol
3w, 33%
C. Substrate scope with different thioureas and alcoholsc
R4
N
O
S
R5
N
H
5
R6
R5
R6
C
Pt
R4OH
+
N
H
N
H
4
2
O
O
O
O
O
O
N
N
N
N
N
N
H
H
H
5a, 52%
5b, 38%
5c, 27%
O
O
N
N
N
N
N
N
H
H
5d, 43%
5e, 30%
Scheme 2 Substrate expansion of the desulfurization C–O coupling reaction of thiones and disulfides with alcohols 2. a Reagents and conditions: DHPM
(0.2 mmol), 2 (6 mL), LiClO4 (0.1 M), Cs2CO3 (0.5 equiv), carbon rod anode, platinum cathode, undivided cell, 20 mA constant current, rt, 6 h; isolated
yields. b Reagents and conditions: disulfide (0.1 mmol), 2 (6 mL), LiClO4 (0.1 M), carbon rod anode, platinum cathode, undivided cell, 20 mA constant
current, rt, 6 h; isolated yields in square brackets. c Reagents and conditions: 4 (0.2 mmol), 2 (6 mL), LiClO4 (0.1 M), carbon rod anode, platinum cathode,
undivided cell, 8 mA constant current, rt, 6 h; isolated yields.
the presence of base. Next, when 1a and base were exposed
to air, oxidation peaks of 1a were observed at 1.21 and
1.42 V (green line). Therefore, DHPMs are more susceptible
to oxidize in the presence of air.
To further study the reaction mechanism, a series of
control experiments was carried out (Scheme 3). When the
radical-trapping agent TEMPO or BHT was added to the re-
action of 1a with methanol, only a trace or 20% yield of 3a
was obtained (Scheme 3a). Further, after the addition of
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

D
Z.-H. Zhu et al.
Paper
Synthesis
were detected by mass spectrometry (see Supporting Infor-
mation). At the same time, the desired product 3a was ob-
tained in 88% and 93% yield by using 7 and 9, respectively,
as substrate (Scheme 3c). Therefore, it is speculated that 7
and 9 are intermediates of the reaction.
According to the literature and our experimental re-
sults, a C–O cross-coupling mechanism of electrochemical
oxidative desulfurization is proposed in Scheme 4. First, 1a
is deprotonated by the action of the base, and further oxi-
dized at the anode to form disulfide 7 by dimerization of
the sulfur radical 6.28 At the same time, on the cathode,
methanol (2a) is reduced to produce H2 and methoxy anion.
Then, a nucleophilic attack of compound 7 by methoxy an-
ion occurs to form 8. By two consecutive oxidation steps, 8
is further oxidized to methyl pyrimidinesulfonate 10. Then,
9 or 10 reacts with methoxide anion to obtain product 3a
and methyl sulfonate.
Figure 1 Cyclic voltammograms of 1a
1,1-diphenylethylene (Scheme 3b), the corresponding sul-
fur radical and methoxy product were detected by mass
spectrometry (see Supporting Information); thus, the for-
mation of radicals in the reaction is presumed. These obser-
vations indicate the presence of an S radical in intermediate
6 (see Scheme 4).1c,d,h,27 Meanwhile, the possibility of an SET
process forming disulfide 7 cannot be ruled out, because
TEMPO can be oxidized at a potential lower than substrates
1. The lack of product formation could be a result of prefer-
ential oxidation of these radical inhibitors. Methoxy radi-
cals are difficult to produce, so it is presumed that a meth-
oxy anion is formed. When the reaction of 1a with meth-
anol was carried out for 1 hour, the dimerized product 7
and methyl pyrimidinesulfinate 9 were isolated (Scheme
3c), and methyl pyrimidinesulfonate and methyl sulfonate
In summary, we have reported the reaction of thiourea-
type compounds with alcohols to form ether compounds by
electrochemical oxidative cleavage of C–S bonds. The reac-
tion can perform well using various thioureas and primary
alcohols (MeOH, EtOH, n-PrOH) and i-PrOH as coupling
agents. It does not require transition-metal catalysis or oxi-
dant. Mechanism studies have confirmed that the oxidation
of the thiourea to disulfide is important.
Reactions were carried out in a constant current mode using a poten-
tiostat from Xiamen Bodong Biotechnology Co., Ltd. Cyclic voltammo-
grams were recorded on a CHI 660E workstation. Column chromatog-
raphy was carried out on silica gel (200–300 mesh) and TLC analysis
was performed on silica gel GF254 plates. 1H NMR and 13C NMR data
were recorded using Varian Mercury plus-400 and Agilent 600 MHz
LiClO4 (0.1 M), Cs2CO3 (0.5 equiv)
C(+)/Pt(–), MeOH, 20 mA, 6 h
3a
trace
TEMPO
5 equiv
a)
1a
1a
+
+
LiClO4 (0.1 M), Cs2CO3 (0.5 equiv)
3a
BHT
C(+)/Pt(–), MeOH, 20 mA, 6 h
O
20%
5 equiv
Ph
Me
Ph
Ph
O
Ph
Ph
LiClO4 (0.1 M), Cs2CO3 (0.5 equiv)
C(+)/Pt(–), MeOH, 20 mA, 6 h
EtO
Me
N
b)
c)
1a
+
+
Ph
N
S
Ph
Detected by MS
5 equiv
O
Ph
N
O
Ph
LiClO4 (0.1 M)
O
Ph
N
Cs2CO3 (0.5 equiv)
EtO
N
EtO
N
EtO
Me
N
+
1a MeOH
+
HSO CH
3 3
+
+
O
S
O
C(+)/Pt(–)
20 mA, 1 h
O
Me
S
Me
Me
N
Me
S
2
O
O
7 (30%)
LiClO4 (0.1 M)
9 (17%)
Detected by MS
+
3a
7
9
MeOH
MeOH
C(+)/Pt(–), 20 mA, 4 h
LiClO4 (0.1 M)
88%
+
3a
93%
C(+)/Pt(–), 20 mA, 3 h
Scheme 3 Control experiments
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

E
Z.-H. Zhu et al.
Paper
Synthesis
O
Ph
O
Ph
HSO3CH3
+
EtO
Me
NH
EtO
Me
N
Me
N
H
1a
S
N
3a
O
e–
H
H2
O
Ph
EtO
N
O
Ph
N
MeO
Me
O
N
6
Ph
S
EtO
N
O
S
H
dimerization
O
O
Me
Me
Me
O
10
EtO
Me
N
O
N
S
2
O
Ph
MeOH
O
Ph
e–
7
EtO
Me
N
EtO
Me
N
O
MeO
O
N
S
N
S
Me
O
8
9
Scheme 4 Proposed mechanism
DD2 instruments, with CDCl3 as solvent and TMS as an internal stan-
dard. Chemical shifts are reported in  units (ppm), with the TMS res-
onance in the 1H NMR spectra specified as 0.00 ppm. 1H NMR data are
reported as follows: chemical shift, multiplicity (s = singlet, d = dou-
blet, t = triplet, q = quartet, m = multiplet), coupling constant in Hz
(J value) and integration. Chemical shifts of the 13C NMR spectra from
TMS were recorded using the central peak of CDCl3 (77.0 ppm) as an
internal standard. Melting points were measured using an XT-4 appa-
ratus. High-resolution mass spectrometry (ESI) was obtained using a
Thermo Scientific Q Exactive mass spectrometer to record the exact
mass of the molecular ion + hydrogen ([M + H]+).
1H NMR (400 MHz, CDCl3):  = 7.64–7.60 (m, 2 H), 7.45–7.40 (m, 3 H),
4.49 (q, J = 6.8 Hz, 2 H), 4.13 (q, J = 7.2 Hz, 2 H), 2.56 (s, 3 H), 1.43 (t, J =
7.2 Hz, 3 H), 1.01 (t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 168.6, 168.3, 166.4, 164.1, 137.9,
130.0, 128.3, 128.2, 119.7, 63.7, 61.5, 22.7, 14.4, 13.6.
HRMS (ESI): m/z [M + H]+ calcd for C16H18N2O3: 287.1390; found:
287.1392.
Ethyl 4-Methyl-6-phenyl-2-propoxypyrimidine-5-carboxylate
(3c)22b
Yield: 33.6 mg (56%); colorless oil.
1H NMR (600 MHz, CDCl3):  = 7.63–7.60 (m, 2 H), 7.45–7.39 (m, 3 H),
4.38 (t, J = 6.6 Hz, 2 H), 4.12 (q, J = 7.2 Hz, 2 H), 2.55 (s, 3 H), 1.87–1.80
(m, 2 H), 1.04–0.99 (m, 6 H).
13C NMR (150 MHz, CDCl3):  = 168.6, 168.3, 166.4, 164.3, 137.9,
130.0, 128.3, 128.2, 119.7, 69.5, 61.5, 22.7, 22.2, 13.6, 10.5.
Ethyl 2-Methoxy-4-methyl-6-phenylpyrimidine-5-carboxylate
(3a);22b Typical Procedure
1a (55.2 mg, 0.2 mmol), Cs2CO3 (32.6 mg, 0.1 mmol, 0.5 equiv), LiClO4
(63.8 mg, 0.6 mmol) and MeOH (6 mL) were added to a straight reac-
tion tube, which was equipped with a graphite rod (Ø 6 mm) as an
anode and a platinum plate (10 × 10 × 2 mm) as a cathode. Electroly-
sis was performed using a constant current of 20 mA, with stirring at
room temperature under an air atmosphere until the substrate was
completely consumed (detected by TLC). Then, silica gel was added
and the solvent was removed under reduced pressure. The residue
was purified by column chromatography on silica gel (ethyl acetate/
petroleum ether, 1:20) to give pure product 3a as a colorless oil; yield:
44.1 mg (81%). All products 3 and 5 were synthesized according to
this procedure.
HRMS (ESI): m/z [M + H]+ calcd for C17H20N2O3: 301.1547; found:
301.1546.
Ethyl 2-Isopropoxy-4-methyl-6-phenylpyrimidine-5-carboxylate
(3d)22b
Yield: 24.0 mg (40%); colorless oil.
1H NMR (600 MHz, CDCl3):  = 7.64–7.61 (m, 2 H), 7.46–7.40 (m, 3 H),
5.44–5.37 (m, 1 H), 4.13 (q, J = 7.2 Hz, 2 H), 2.55 (s, 3 H), 1.41 (d, J = 6.0
Hz, 6 H), 1.02 (t, J = 7.2 Hz, 3 H).
1H NMR (600 MHz, CDCl3):  = 7.64–7.63 (m, 2 H), 7.45–7.40 (m, 3 H),
13C NMR (150 MHz, CDCl3):  = 168.7, 168.4, 166.4, 163.7, 138.0,
129.9, 128.3, 128.2, 119.4, 70.6, 61.5, 22.8, 21.9, 13.6.
HRMS (ESI): m/z [M + H]+ calcd for C17H20N2O3: 301.1547; found:
301.1544.
4.13 (q, J = 7.2 Hz, 2 H), 4.06 (s, 3 H), 2.56 (s, 3 H), 1.02 (t, J = 7.2 Hz, 3
H).
13C NMR (150 MHz, CDCl3):  = 168.7, 168.3, 166.5, 164.5, 137.8,
130.0, 128.4, 128.3, 119.9, 61.6, 55.0, 22.8, 13.6.
HRMS (ESI): m/z [M + H]+ calcd for C15H16N2O3: 273.1234; found:
273.1232.
Ethyl 2-Methoxy-4-methyl-6-(p-tolyl)pyrimidine-5-carboxylate
(3e)
Ethyl 2-Ethoxy-4-methyl-6-phenylpyrimidine-5-carboxylate
(3b)22b
Yield: 36.6 mg (64%); colorless oil.
1H NMR (400 MHz, CDCl3):  = 7.55 (d, J = 8.4 Hz, 2 H), 7.23 (d, J = 8.0
Hz, 2 H), 4.17 (q, J = 6.8 Hz, 2 H), 4.06 (s, 3 H), 2.55 (s, 3 H), 2.39 (s, 3
H), 1.08 (t, J = 7.2 Hz, 3 H).
Yield: 36.1 mg (63%); colorless oil.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

F
Z.-H. Zhu et al.
Paper
Synthesis
13C NMR (100 MHz, CDCl3):  = 168.8, 168.7, 166.5, 164.7, 140.7,
135.1, 129.3, 128.5, 119.9, 61.9, 55.2, 23.0, 21.6, 13.9.
HRMS (ESI): m/z [M + H]+ calcd for C16H18N2O3: 287.1390; found:
287.1392.
13C NMR (150 MHz, CDCl3):  = 169.9, 166.7, 164.6, 163.3, 160.5,
158.8, 131.4, 131.4, 130.8, 130.8, 126.4 (d, J = 15.0 Hz), 124.3, 124.3,
120.4, 115.4, 115.2, 61.3, 55.1, 23.7, 13.5.
HRMS (ESI): m/z [M + H]+ calcd for C15H15FN2O3: 291.1139; found:
291.1137.
Ethyl 2-Methoxy-4-methyl-6-(o-tolyl)pyrimidine-5-carboxylate
(3f)
Ethyl 4-(3-Fluorophenyl)-2-methoxy-6-methylpyrimidine-5-car-
boxylate (3k)
Yield: 38.3 mg (67%); colorless oil.
Yield: 38.3 mg (66%); colorless oil.
1H NMR (600 MHz, CDCl3):  = 7.40–7.37 (m, 3 H), 7.17–7.13 (m, 1 H),
4.17 (q, J = 7.2 Hz, 2 H), 4.06 (s, 3 H), 2.56 (s, 3 H), 1.07 (t, J = 7.2 Hz, 3
1H NMR (400 MHz, CDCl3):  = 7.47 (s, 1 H), 7.41 (d, J = 7.6 Hz, 1 H),
7.33–7.25 (m, 2 H), 4.15 (q, J = 7.2 Hz, 2 H), 4.06 (s, 3 H), 2.56 (s, 3 H),
2.39 (s, 3 H), 1.05 (t, J = 6.8 Hz, 3 H).
H).
13C NMR (150 MHz, CDCl3):  = 168.5, 168.3, 166.6, 164.5, 138.1,
137.7, 130.8, 128.9, 128.2, 125.3, 119.9, 61.6, 55.0, 22.7, 21.4, 13.6.
HRMS (ESI): m/z [M + H]+ calcd for C16H18N2O3: 287.1390; found:
287.1391.
13C NMR (150 MHz, CDCl3):  = 169.0, 167.9, 164.9 (d, J = 3.0 Hz),
164.5, 163.4, 161.8, 139.9 (d, J = 7.5 Hz), 129.9 (d, J = 9.0 Hz), 124.0 (d,
J = 3.0 Hz), 119.9, 117.0, 116.9, 115.5, 115.4, 61.7, 55.1, 22.8, 13.6.
HRMS (ESI): m/z [M + H]+ calcd for C15H15FN2O3: 291.1139; found:
291.1137.
Ethyl 2-Methoxy-4-methyl-6-(m-tolyl)pyrimidine-5-carboxylate
(3g)
Ethyl 4-(4-Chlorophenyl)-2-methoxy-6-methylpyrimidine-5-car-
boxylate (3l)29
Yield: 40.6 mg (71%); colorless oil.
1H NMR (400 MHz, CDCl3):  = 7.49–7.47 (m, 1 H), 7.44–7.41 (m, 1 H),
7.34–7.27 (m, 2 H), 4.16 (q, J = 7.2 Hz, 2 H), 4.08 (s, 3 H), 2.57 (s, 3 H),
2.40 (s, 3 H), 1.06 (t, J = 7.2 Hz, 3 H).
Yield: 41.0 mg (67%); colorless oil.
1H NMR (600 MHz, CDCl3):  = 7.58–7.56 (m, 2 H), 7.40–7.37 (m, 2 H),
4.16 (q, J = 7.2 Hz, 2 H), 4.04 (s, 3 H), 2.55 (s, 3 H), 1.08 (t, J = 7.2 Hz, 3
H).
13C NMR (150 MHz, CDCl3):  = 168.9, 168.0, 165.1, 164.5, 136.4,
136.2, 129.7, 128.6, 119.7, 61.7, 55.1, 22.8, 13.7.
13C NMR (150 MHz, CDCl3):  = 168.5, 168.3, 166.6, 164.5, 138.1,
137.7, 130.8, 128.9, 128.2, 125.3, 119.9, 61.6, 55.0, 22.7, 21.4, 13.6.
HRMS (ESI): m/z [M + H]+ calcd for C16H18N2O3: 287.1390; found:
287.1391.
HRMS (ESI): m/z [M + H]+ calcd for C15H15ClN2O3: 307.0844; found:
307.0841.
Ethyl 2-Methoxy-4-(4-methoxyphenyl)-6-methylpyrimidine-5-
carboxylate (3h)29
Ethyl 4-(3,4-Dichlorophenyl)-2-methoxy-6-methylpyrimidine-5-
carboxylate (3m)
Yield: 29.0 mg (48%); colorless oil.
1H NMR (600 MHz, CDCl3):  = 7.66–7.63 (m, 2 H), 6.95–6.92 (m, 2 H),
4.20 (q, J = 7.2 Hz, 2 H), 4.06 (s, 3 H), 3.84 (s, 3 H), 2.54 (s, 3 H), 1.12 (t,
J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 168.7, 168.3, 165.5, 164.4, 161.4,
130.1, 130.0, 119.4, 113.8, 61.6, 55.4, 54.9, 22.7, 13.8.
Yield: 47.6 mg (70%); colorless oil.
1H NMR (600 MHz, CDCl3):  = 7.75 (d, J = 1.8 Hz, 1 H), 7.49 (d, J = 8.4
Hz, 1 H), 7.45 (dd, J = 8.4, 1.8 Hz, 1 H), 4.20 (q, J = 7.2 Hz, 2 H), 4.05 (s,
3 H), 2.55 (s, 3 H), 1.13 (t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 169.2, 167.7, 164.5, 163.7, 137.5,
134.5, 132.8, 130.4, 130.3, 127.5, 119.8, 61.9, 55.2, 22.9, 13.8.
HRMS (ESI): m/z [M + H]+ calcd for C16H18N2O4: 303.1339; found:
303.1337.
HRMS (ESI): m/z [M + H]+ calcd for C15H14Cl2N2O3: 341.0454; found:
341.0456.
Ethyl 4-(4-Fluorophenyl)-2-methoxy-6-methylpyrimidine-5-car-
boxylate (3i)
Ethyl 4-(3-Bromophenyl)-2-methoxy-6-methylpyrimidine-5-car-
boxylate (3n)
Yield: 34.8 mg (60%); colorless oil.
1H NMR (600 MHz, CDCl3):  = 7.67–7.60 (m, 2 H), 7.12–7.07 (m, 2 H),
4.16 (q, J = 7.2 Hz, 2 H), 4.04 (s, 3 H), 2.54 (s, 3 H), 1.07 (t, J = 7.2 Hz, 3
H).
13C NMR (150 MHz, CDCl3):  = 168.8, 168.2, 165.1, 164.8, 164.4,
163.1, 133.9 (d, J = 3.0 Hz), 130.4 (d, J = 7.5 Hz), 119.7, 115.5, 115.4,
61.7, 55.0, 22.7, 13.7.
Yield: 44.8 mg (64%); colorless oil.
1H NMR (600 MHz, CDCl3):  = 7.79 (d, J = 1.8 Hz, 1 H), 7.59–7.56 (m, 1
H), 7.55–7.53 (m, 1 H), 7.29 (t, J = 7.8 Hz, 1 H), 4.17 (q, J = 7.2 Hz, 2 H),
4.06 (s, 3 H), 2.56 (s, 3 H), 1.08 (t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 169.1, 167.8, 164.8, 164.5, 139.7,
133.0, 131.3, 129.8, 126.9, 122.4, 119.9, 61.8, 55.1, 22.8, 13.7.
HRMS (ESI): m/z [M + H]+ calcd for C15H15BrN2O3: 351.0339; found:
HRMS (ESI): m/z [M + H]+ calcd for C15H15FN2O3: 291.1139; found:
291.1136.
351.0336.
Ethyl 4-(2-Fluorophenyl)-2-methoxy-6-methylpyrimidine-5-car-
boxylate (3j)
Methyl 4-(4-Chlorophenyl)-2-methoxy-6-methylpyrimidine-5-
carboxylate (3o)
Yield: 30.2 mg (52%); colorless oil.
Yield: 35.6 mg (61%); white solid; mp 85–87 °C.
1H NMR (600 MHz, CDCl3):  = 7.59–7.57 (m, 2 H), 7.42–7.39 (m, 2 H),
4.06 (s, 3 H), 3.69 (s, 3 H), 2.55 (s, 3 H).
1H NMR (600 MHz, CDCl3):  = 7.59–7.56 (m, 1 H), 7.44–7.39 (m, 1 H),
7.25–7.21 (m, 1 H), 7.10–7.06 (m, 1 H), 4.12 (q, J = 7.2 Hz, 2 H), 4.05 (s,
3 H), 2.65 (s, 3 H), 1.01 (t, J = 7.2 Hz, 3 H).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

G
Z.-H. Zhu et al.
Paper
Synthesis
13C NMR (150 MHz, CDCl3):  = 169.0, 168.6, 165.0, 164.6, 136.5,
2-Ethoxy-4-methylpyrimidine (3u)22b
136.1, 129.6, 128.7, 119.4, 55.1, 52.5, 22.8.
HRMS (ESI): m/z [M + H]+ calcd for C14H13ClN2O3: 293.0687; found:
293.0685.
Yield: 11.3 mg (41%); colorless oil.
1H NMR (600 MHz, CDCl3):  = 8.29 (d, J = 4.8 Hz, 1 H), 6.73 (d, J = 4.8
Hz, 1 H), 4.36 (q, J = 7.2 Hz, 2 H), 2.41 (s, 3 H), 1.38 (t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 169.9, 165.0, 158.4, 114.3, 63.1, 24.0,
14.4.
HRMS (ESI): m/z [M + H]+ calcd for C7H10N2O: 139.0866; found:
139.0864.
Methyl 4-(4-Bromophenyl)-2-methoxy-6-methylpyrimidine-5-
carboxylate (3p)
Yield: 38.3 mg (57%); white solid; mp 88–89 °C.
1H NMR (600 MHz, CDCl3):  = 7.57–7.55 (m, 2 H), 7.51–7.49 (m, 2 H),
4.05 (s, 3 H), 3.68 (s, 3 H), 2.54 (s, 3 H).
13C NMR (150 MHz, CDCl3):  = 169.1, 168.6, 165.1, 164.6, 136.5,
131.7, 129.8, 124.9, 119.3, 55.1, 52.6, 22.8.
HRMS (ESI): m/z [M + H]+ calcd for C14H13BrN2O3: 337.0182; found:
2-Isopropoxypyrimidine (3v)22b
Yield: 9.7 mg (35%); colorless oil.
1H NMR (600 MHz, CDCl3):  = 8.46 (d, J = 4.8 Hz, 2 H), 6.85 (t, J = 4.8
Hz, 1 H), 5.28–5.21 (m, 1 H), 1.37 (d, J = 6.0 Hz, 6 H).
337.0185.
13C NMR (150 MHz, CDCl3):  = 164.8, 159.2, 114.4, 70.2, 21.8.
HRMS (ESI): m/z [M + H]+ calcd for C7H10N2O: 139.0866; found:
139.0867.
Isobutyl 2-Methoxy-4-methyl-6-(p-tolyl)pyrimidine-5-carboxyl-
ate (3q)
Yield: 31.4 mg (50%); colorless oil.
2-Methoxybenzo[d]thiazole (3w)30
1H NMR (600 MHz, CDCl3):  = 7.57–7.55 (m, 2 H), 7.24–7.21 (m, 2 H),
4.17 (q, J = 7.2 Hz, 2 H), 4.06 (s, 3 H), 3.22–3.15 (m, 1 H), 2.39 (s, 3 H),
1.31 (s, 3 H), 1.30 (s, 3 H), 1.09 (t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 176.2, 168.7, 166.1, 164.9, 140.3,
135.0, 129.1, 128.2, 119.2, 61.6, 54.8, 33.1, 21.6, 21.4, 13.7.
Yield: 10.9 mg (33%); white solid; mp 68–70 °C.
1H NMR (400 MHz, CDCl3):  = 8.18 (d, J = 8.0 Hz, 1 H), 8.01 (d, J = 8.4
Hz, 1 H), 7.63–7.51 (m, 2 H), 3.74 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 175.1, 153.8, 136.3, 127.4, 127.4,
125.2, 122.6, 51.6.
HRMS (ESI): m/z [M + H]+ calcd for C8H7NOS: 166.0321; found:
166.0320.
HRMS (ESI): m/z [M + H]+ calcd for C18H22N2O3: 315.1703; found:
315.1701.
tert-Butyl 2-Methoxy-4-methyl-6-phenylpyrimidine-5-carboxyl-
ate (3r)
Methyl (Z)-N-Benzoyl-N′-phenylcarbamimidate (5a)31
Yield: 26.4 mg (52%); colorless oil.
Yield: 33.0 mg (55%); colorless oil.
1H NMR (600 MHz, CDCl3):  = 12.05 (s, 1 H), 8.32–8.29 (m, 2 H),
7.54–7.51 (m, 1 H), 7.47–7.43 (m, 2 H), 7.36 (d, J = 2.4 Hz, 2 H), 7.35 (s,
2 H), 7.20–7.16 (m, 1 H), 4.13 (s, 3 H).
13C NMR (150 MHz, CDCl3):  = 177.8, 161.1, 137.3, 136.2, 132.0,
129.4, 129.1, 128.0, 125.2, 122.3, 55.0.
1H NMR (400 MHz, CDCl3):  = 7.68–7.64 (m, 2 H), 7.47–7.42 (m, 3 H),
4.05 (s, 3 H), 2.57 (s, 3 H), 1.35 (s, 9 H).
13C NMR (150 MHz, CDCl3):  = 168.2, 167.2, 166.0, 164.2, 137.9,
129.9, 128.5, 128.3, 121.5, 82.6, 54.9, 27.6, 22.7.
HRMS (ESI): m/z [M + H]+ calcd for C17H20N2O3: 301.1547; found:
301.1546.
HRMS (ESI): m/z [M + H]+ calcd for C15H14N2O2: 255.1128; found:
255.1129.
Ethyl 4-Isopropyl-2-methoxy-6-(p-tolyl)pyrimidine-5-carboxyl-
ate (3s)
Ethyl (Z)-N-Benzoyl-N′-phenylcarbamimidate (5b)
Yield: 20.4 mg (38%); colorless oil.
Yield: 31.4 mg (50%); colorless oil.
1H NMR (600 MHz, CDCl3):  = 12.12 (s, 1 H), 8.29–8.26 (m, 2 H),
7.53–7.49 (m, 1 H), 7.46–7.42 (m, 2 H), 7.37–7.33 (m, 4 H), 7.18–7.14
(m, 1 H), 4.66 (q, J = 7.2 Hz, 2 H), 1.47 (t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 177.8, 160.6, 137.5, 136.5, 132.0,
129.3, 129.0, 128.0, 125.0, 122.1, 64.3, 14.5.
1H NMR (600 MHz, CDCl3):  = 7.56 (d, J = 8.4 Hz, 2 H), 7.22 (d, J = 7.8
Hz, 2 H), 4.17 (q, J = 7.2 Hz, 2 H), 4.06 (s, 3 H), 3.22–3.17 (m, 1 H), 2.39
(s, 3 H), 1.31 (d, J = 6.6 Hz, 6 H), 1.09 (t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 176.2, 168.7, 166.1, 164.9, 140.3,
135.1, 129.1, 128.2, 119.2, 61.6, 54.8, 33.1, 21.6, 21.4, 13.7.
HRMS (ESI): m/z [M + H]+ calcd for C16H16N2O2: 269.1285; found:
269.1283.
HRMS (ESI): m/z [M + H]+ calcd for C18H22N2O3: 315.1703; found:
315.1705.
2-Ethoxypyrimidine (3t)22b
Propyl (Z)-N-Benzoyl-N′-phenylcarbamimidate (5c)
Yield: 15.2 mg (27%); colorless oil.
Yield: 13.2 mg (53%); colorless oil.
1H NMR (600 MHz, CDCl3):  = 12.12 (s, 1 H), 8.29–8.27 (m, 2 H),
7.53–7.50 (m, 1 H), 7.46–7.42 (m, 2 H), 7.38–7.33 (m, 4 H), 7.18–7.15
(m, 1 H), 4.56 (t, J = 6.6 Hz, 2 H), 1.89–1.83 (m, 2 H), 1.05 (t, J = 7.8 Hz,
3 H).
13C NMR (150 MHz, CDCl3):  = 177.8, 160.8, 137.5, 136.5, 131.9,
129.3, 129.0, 128.0, 125.0, 122.1, 70.0, 22.1, 10.6.
1H NMR (400 MHz, CDCl3):  = 8.50 (d, J = 4.8 Hz, 2 H), 6.91 (t, J = 4.8
Hz, 1 H), 4.41 (q, J = 7.2 Hz, 2 H), 1.43 (t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 165.2, 159.2, 114.7, 63.3, 14.4.
HRMS (ESI): m/z [M + H]+ calcd for C6H8N2O: 125.0709; found:
125.0708.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

H
Z.-H. Zhu et al.
Paper
Synthesis
HRMS (ESI): m/z [M + H]+ calcd for C17H18N2O2: 283.1441; found:
283.1443.
Chem. Res. 2020, in press; DOI 10.1021/acs.accounts.9b00603.
(f) Qiu, Y.-A.; Struwe, J. L.; Ackermann, L. Synlett 2019, 30, 1164.
(g) Meyer, T. H.; Finger, L. H.; Gandeepan, P.; Ackermann, L.
Trends Chem. 2019, 1, 63. (h) Laudadio, G.; de A Bartolomeu, A.;
Verwijlen, L. M. H. M.; Cao, Y.; de Oliveira, K. T.; Noël, T. J. Am.
Chem. Soc. 2019, 141, 11832.
Methyl (Z)-N′-Phenyl-N-(pyridin-2-yl)carbamimidate (5d)
Yield: 19.5 mg (43%); colorless oil.
1H NMR (400 MHz, CDCl3):  = 12.28 (s, 1 H), 8.27 (dd, J = 4.8, 2.0 Hz, 1
H), 7.62–7.56 (m, 1 H), 7.32 (d, J = 4.4 Hz, 4 H), 7.10–7.04 (m, 2 H),
6.90–6.85 (m, 1 H), 3.99 (s, 3 H).
13C NMR (150 MHz, CDCl3):  = 160.3, 154.3, 145.6, 138.3, 137.6,
128.8, 123.4, 121.6, 121.2, 116.9, 53.8.
(2) Pan, F.; Shi, Z.-J. ACS Catal. 2014, 4, 280.
(3) (a) Yeh, V. S. C. Tetrahedron 2004, 60, 11995. (b) Palmer, D. C.
Oxazoles: Synthesis, Reactions, and Spectroscopy, Vol. 1; Wiley:
New Jersey, 2003. (c) Turchi, I. J.; Dewar, M. J. S. Chem. Rev.
1975, 75, 389.
(4) (a) Block, E. Advances in Sulfur Chemistry; JAI Press: Greenwich,
1994. (b) Cremlyn, R. J. An Introduction to Organosulfur Chemis-
try; Wiley: Chichester, 1996. (c) Organic Sulfur Chemistry:
Structure and Mechanism; Oae, S., Ed.; CRC Press: Boca Raton,
1991.
(5) (a) Furukawa, N.; Sato, S. In Organosulfur Chemistry II; Page, P.
C. B., Ed.; Springer: Heidelberg, 1999, 89. (b) Rayner, C. M.
Advances in Sulfur Chemistry, Vol. 2; JAI Press: Greenwich, 2000.
(c) Wei, J.; Liang, H.-M.; Ni, C.-F.; Sheng, R. Org. Lett. 2019, 21,
937.
HRMS (ESI): m/z [M + H]+ calcd for C13H13N3O: 228.1131; found:
228.1130.
Ethyl (Z)-N′-Phenyl-N-(pyridin-2-yl)carbamimidate (5e)
Yield: 14.5 mg (30%); colorless oil.
1H NMR (400 MHz, CDCl3):  = 12.34 (s, 1 H), 8.29–8.25 (m, 1 H),
7.62–7.57 (m, 1 H), 7.37–7.30 (m, 4 H), 7.10–7.02 (m, 2 H), 6.90–6.84
(m, 1 H), 4.50 (q, J = 7.2 Hz, 2 H), 1.42 (t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 153.8, 145.6, 138.5, 137.5, 128.9,
128.8, 123.1, 121.3, 121.2, 116.7, 62.6, 14.5.
(6) Cherkasov, A.; Jonsson, M. J. Chem. Inf. Comput. Sci. 2000, 40,
1222.
HRMS (ESI): m/z [M + H]+ calcd for C14H15N3O: 242.1288; found:
242.1289.
(7) (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107,
174. (b) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147.
(c) Ackermann, L. Chem. Commun. 2010, 46, 4886. (d) Xu, L.-M.;
Li, B.-J.; Yang, Z.; Shi, Z.-J. Chem. Soc. Rev. 2010, 39, 712.
(8) Otsuka, S.; Nogi, K.; Yorimitsu, H. Top. Curr. Chem. 2018, 376,
199.
Ethyl 2-(Methoxysulfinyl)-4-methyl-6-phenylpyrimidine-5-car-
boxylate (9)
Yield: 10.9 mg (17%); colorless oil.
(9) Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122, 11260.
(10) Metzger, A.; Melzig, L.; Despotopoulou, C.; Knochel, P. Org. Lett.
2009, 11, 4228.
(11) Sugahara, T.; Murakami, K.; Yorimitsu, H.; Osuka, A. Angew.
Chem. Int. Ed. 2014, 53, 9329; Angew. Chem. 2014, 126, 9483.
(12) Lian, Z.; Bhawal, B. N.; Yu, P.; Morandi, B. Science 2017, 356,
1059.
1H NMR (400 MHz, CDCl3):  = 7.73 (d, J = 7.6 Hz, 2 H), 7.56–7.46 (m, 3
H), 4.26 (q, J = 7.2 Hz, 2 H), 3.79 (s, 3 H), 2.75 (s, 3 H), 1.12 (t, J = 7.2 Hz,
3 H).
13C NMR (150 MHz, CDCl3):  = 169.7, 167.5, 166.9, 164.7, 136.2,
130.9, 128.7, 128.6, 127.3, 62.4, 52.5, 22.7, 13.6.
HRMS (ESI): m/z [M + H]+ calcd for C15H16N2O4S: 321.0904; found:
321.0903.
(13) (a) Dubbaka, S. R.; Vogel, P. Angew. Chem. Int. Ed. 2005, 44, 7674;
Angew. Chem. 2005, 117, 7848. (b) Prokopcov, H.; Kappe, C. O.
Angew. Chem. Int. Ed. 2008, 47, 3674; Angew. Chem. 2008, 120,
3732. (c) Wang, L.; He, W.; Yu, Z. Chem. Soc. Rev. 2013, 42, 599.
(14) Otsuka, S.; Yorimitsu, H.; Osuka, A. Chem. Eur. J. 2015, 21, 14703.
(15) (a) Mehta, V. P.; Modha, S. G.; Van der Eycken, E. J. Org. Chem.
2009, 74, 6870. (b) Hintermann, L.; Schmitz, M.; Chen, Y. Adv.
Synth. Catal. 2010, 352, 2411. (c) Eberhart, A. J.; Imbriglio, J. E.;
Procter, D. J. Org. Lett. 2011, 13, 5882. (d) Murakami, K.;
Yorimitsu, H.; Osuka, A. Angew. Chem. Int. Ed. 2014, 53, 7510;
Angew. Chem. 2014, 126, 7640.
(16) (a) Liebeskind, L. S.; Srogl, J. Org. Lett. 2002, 4, 979. (b) Alphonse,
F.-A.; Suzenet, F.; Keromnes, A.; Lebret, B.; Guillaumet, G. Org.
Lett. 2003, 5, 803. (c) Counceller, K. L.; Stambuli, J. P. C. M. Org.
Lett. 2009, 11, 1457. (d) Begouin, J.-M.; Gosmini, C. Chem.
Commun. 2010, 46, 5972. (e) Melzig, L.; Metzger, A.; Knochel, P.
Chem. Eur. J. 2011, 17, 2948. (f) Modha, S. G.; Trivedi, J. C.;
Mehta, V. P.; Ermolat’ev, D. S.; Van der Eycken, E. J. Org. Chem.
2011, 76, 846.
(17) (a) Hooper, J. F.; Young, R. D.; Pernik, I.; Weller, A. S.; Willis, M.
C. Chem. Sci. 2013, 4, 1568. (b) Pan, F.; Wang, H.; Shen, P.-X.; Shi,
Z.-J. Chem. Sci. 2013, 4, 1573. (c) Creech, G. S.; Kwon, O. Chem.
Sci. 2013, 4, 2670.
(18) Zhang, L.-M.; Si, X.-J.; Yang, Y.-Y.; Witzel, S.; Sekine, K.; Rudolph,
M.; Rominger, F.; Hashmi, A. S. K. ACS Catal. 2019, 9, 6118.
(19) Watanabe, M.; Koike, H.; Ishiba, T.; Okada, T. Bioorg. Med. Chem.
1997, 5, 437.
Funding Information
We are thankful for the financial support from the National Natural
Science Foundation of China (No. 21562036) and the LongYuan Youth
Innovative and Entrepreneurial Talents Project (the Key Talent Proj-
ects of Gansu Province, [2019]39).
N
ati
o
n
a
lNaturalS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
of
C
h
i
n
a
(2
1
5
6
2
0
3
6)
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690837.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orti
n
gInformati
o
n
References
(1) (a) Frontana-Uribe, B. A.; Little, R. D.; Ibanez, J. G.; Palma, A.;
Vasquez-Medrano, R. Green Chem. 2010, 12, 2099. (b) Wiebe, A.;
Gieshoff, T.; Möhle, S.; Rodrigo, E.; Zirbes, M.; Waldvogel, S. R.
Angew. Chem. Int. Ed. 2018, 57, 5594; Angew. Chem. 2018, 130,
5694. (c) Folgueiras-Amador, A. A.; Qian, X.-Y.; Xu, H.-C.; Wirth,
T. Chem. Eur. J. 2018, 24, 487. (d) Huang, C.; Qian, X.-Y.; Xu, H.-C.
Angew. Chem. Int. Ed. 2019, 58, 6650; Angew. Chem. 2019, 131,
6722. (e) Jiao, K.-J.; Xing, Y.-K.; Yang, Q.-L.; Qiu, H.; Mei, T.-S. Acc.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

I
Z.-H. Zhu et al.
Paper
Synthesis
(20) (a) Capdeville, R.; Buchdunger, E.; Zimmermann, J.; Matter, A.
Nat. Rev. Drug Discovery 2002, 1, 493. (b) Quan, Z.-J.; Zhang, Z.;
Da, Y.-X. Chin. J. Org. Chem. 2009, 29, 876.
(24) (a) Theil, F. Angew. Chem. Int. Ed. 1999, 38, 2345; Angew. Chem.
1999, 111, 2493. (b) Tolnai, G. L.; Petho, B.; Krall, P.; Novk, Z.
Adv. Synth. Catal. 2014, 356, 125.
(21) (a) Quan, Z.-J.; Hu, W.-H.; Jia, X.-D.; Zhang, Z.; Da, Y.-X. Adv.
Synth. Catal. 2012, 354, 2939. (b) Yan, Z.-F.; Quan, Z.-J.; Da, Y.-X.;
Zhang, Z. Chem. Commun. 2014, 50, 13555. (c) Quan, Z.-J.; Lv, Y.;
Jing, F.-Q.; Jia, X.-D.; Huo, C.-D. Adv. Synth. Catal. 2014, 356, 325.
(22) (a) Phan, N. H. T.; Kim, H.; Shin, H.; Lee, H.-S.; Sohn, J.-H. Org.
Lett. 2016, 18, 5154. (b) Kim, H.; Lee, J.; Shin, H.; Sohn, J.-H. Org.
Lett. 2018, 20, 1961. (c) Matloobi, M.; Kappe, C. O. J. Comb. Chem.
2007, 9, 275. (d) Gershon, H.; Grefig, A. T.; Scala, A. A. J. Hetero-
cycl. Chem. 1983, 20, 219.
(25) Ai, C.-R.; Shen, H.-W.; Song, D.-G.; Li, Y.-J.; Yi, X.; Wang, Z.; Ling,
F.; Zhong, W.-H. Green Chem. 2019, 21, 5528.
(26) (a) Berlinck, R. G. S.; Kossuga, M. H. Nat. Prod. Rep. 2005, 22, 516.
(b) Berlinck, R. G. S.; Burtoloso, A. C. B.; Trindade-Silva, A. E.;
Romminger, S. Nat. Prod. Rep. 2010, 27, 1871.
(27) Sauermann, N.; Meyer, T. H.; Tian, C. J. Am. Chem. Soc. 2017, 139,
18452.
(28) Huang, P.-F.; Wang, P.; Tang, S.; Fu, Z.-J.; Lei, A.-W. Angew. Chem.
Int. Ed. 2018, 57, 8115; Angew. Chem. 2018, 130, 8247.
(29) Wang, L.; Ma, Z.-G.; Wei, X.-J.; Meng, Q.-Y.; Yang, D.-T.; Du, S.-F.;
Chen, Z.-F.; Wu, L.-Z.; Liu, Q. Green Chem. 2014, 16, 3752.
(30) Yoon, S. B.; Chun, E. J.; Noh, Y. R. Bull. Korean Chem. Soc. 2013,
34, 2819.
(23) (a) Quan, Z.-J.; Jing, F.-Q.; Zhang, Z.; Da, Y.-X.; Wang, X.-C. Chin. J.
Chem. 2013, 31, 1495. (b) Wang, X.-C.; Yang, G.-J.; Jia, X.-D.;
Zhang, Z.; Da, Y.-X.; Quan, Z.-J. Tetrahedron 2011, 67, 3267.
(31) Bruce, W. M. J. Am. Chem. Soc. 1904, 26, 449.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I