The Rational Design and Synthesis of Water-Soluble Thiourea Ligands for Recoverable Pd-Catalyzed Aerobic Aqueous Suzuki-Miyaura Reactions at Room Temperature

Article abstract of DOI:10.1055/s-0036-1589150

Eight precatalysts containing carboxylic-functionalized thiourea ligands are prepared and their activities and recyclability are evaluated in aerobic aqueous Suzuki-Miyaura reactions. A bulky monothiourea-Pd complex, functionalized with four carboxylic groups, shows the best activity and recyclability in the coupling of aryl bromides with arylboronic acids. The catalyst can be reused at least five times without any significant reduction in its catalytic activity. TEM analysis and the confirmed catalytic activity of the observed black precipitate reveal that Pd nanoparticles are formed during the reactions and are stabilized by the carboxylic-functionalized thiourea ligands.

Full text of DOI:10.1055/s-0036-1589150

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–L
paper
A
en
W. Chen et al.
Paper
Synthesis
The Rational Design and Synthesis of Water-Soluble Thiourea
Ligands for Recoverable Pd-Catalyzed Aerobic Aqueous Suzuki–
Miyaura Reactions at Room Temperature
Wei Chen*a
Xiao-Yan Lu*b
Bei-Hua Xua
Wei-guo Yua
Zi-niu Zhoua
Ying Hua
0
0
0
0
0-
0
0
2
6-
5
3
2
1-
5
2
1
Na2PdCl4
thiourea
(0.1%mol)
R1
R1
R2
B(OH)2
X
R2
+
KOH, H2O
r.t., under air
22 examples
15–99% yield
(hetero)aryl
(hetero)aryl
X = Br, Cl; R2 = H, alkyl, acyl, OMe
R1 = H, alkyl, acyl, CO2Et, CN, NO2, OMe, NH2
CO2H
High yields
N
N
Air- and moisture-stable
Recyclable catalyst
CO2H
CO2H
HO2C
a Department of Pharmaceutical Engineering, Zhejiang Pharmaceutical
College, 888 Yinxian Avenue Eastern Section, Ningbo, Zhejiang,
315100, P. R. of China
S
david_7788@sina.com
b Department of Pharmacy, Ningbo No. 2 Hospital, 41 Northwest
Street, Ningbo, Zhejiang, 315010, P. R. of China
xiao_yan_lu@163.com
Received: 31.08.2017
Accepted after revision: 14.10.2017
Published online: 04.01.2018
benes (NHCs) for Suzuki–Miyaura reactions in aqueous
solution have been frequently studied,4g,7 it is relatively dif-
ficult to conduct this reaction at room temperature.8 Nota-
bly, toxicity examinations of NHC ligands are extremely ra-
re.7r Therefore, the development of more stable, easy to re-
cycle and less toxic ligands is desirable. In continuation of
our studies on air- and moisture-stable cyclic bulky
monothiourea and bis(thiourea) ligands,9a–c we were inter-
ested in the area of undeveloped water-soluble and reus-
able thiourea–palladium complexes. Inspired by the toxici-
ty examinations of thioureas,10 we envisaged that the
preparation of water-soluble thiourea–palladium complex-
es as less toxic and recyclable catalysts would be possible. In
this work, we report the rational design and synthesis of
carboxylic-functionalized thiourea ligands, and evaluate
their performance as precatalysts in Suzuki–Miyaura reac-
tions in water. Furthermore, transmission electron micros-
copy (TEM) analysis revealed that Pd nanoparticles (PdNPs)
were formed during the reactions. The water-soluble
thiourea ligands serve as stabilizers of these nanoparticles.
It is a common strategy to make hydrophobic ligands
water-soluble by introduction of a carboxylate moiety.7l,11
Yang et al.12 and our group9 have also demonstrated that cy-
clic bulky monothiourea, N,N-disubstituted acyclic and cy-
clic bis(thiourea) ligands are active catalysts for Heck and
Suzuki reactions. Thus, the water-soluble and recyclable
carboxylic-functionalized thiourea ligand is designed to
meet the needs of activity and recyclability by introducing
two methyls and four carboxylates into the thiourea skele-
ton (Figure 1).
DOI: 10.1055/s-0036-1589150; Art ID: ss-2017-h0555-op
Abstract Eight precatalysts containing carboxylic-functionalized
thiourea ligands are prepared and their activities and recyclability are
evaluated in aerobic aqueous Suzuki–Miyaura reactions.
monothiourea–Pd complex, functionalized with four carboxylic groups,
shows the best activity and recyclability in the coupling of aryl bro-
mides with arylboronic acids. The catalyst can be reused at least five
times without any significant reduction in its catalytic activity. TEM
analysis and the confirmed catalytic activity of the observed black pre-
cipitate reveal that Pd nanoparticles are formed during the reactions
and are stabilized by the carboxylic-functionalized thiourea ligands.
A bulky
Key words water-soluble, thiourea, ligands, palladium-catalyzed,
Suzuki–Miyaura reactions
The palladium-catalyzed cross-coupling reaction is one
of the most powerful tools for forming carbon–carbon
bonds.1 A substantial challenge is the development of envi-
ronmentally friendly, safe and energy/resources-saving
protocols, which allow the cross-coupling reactions to be
performed in aqueous solution.2 With the increasing im-
portance of green chemistry, the development of water-sol-
uble Pd complexes as recyclable catalysts for cross-coupling
reactions in aqueous solution has become a current focus.3
Various water-soluble phosphine ligands have been applied
in phosphine–palladium catalysts,4 however, the air-sensi-
tivity of phosphine ligands significantly limits the catalyst
recycling and their synthetic applications.5 Accordingly,
current work is focused on the search for new catalytic sys-
tems overcoming the limitations of recyclability and stabil-
ity. The Suzuki–Miyaura reaction is a widely used and ver-
satile tool in organic synthesis.1b,6 Although a variety of
water-soluble palladium complexes of N-heterocyclic car-
Since the structure of each thiourea ligand has a signifi-
cant influence on the catalytic efficacy of its palladium
complex,9,12 eight carboxylic-functionalized thiourea li-
gands (1a–c and 1e–i) with different thiourea skeletons
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

B
W. Chen et al.
Paper
Synthesis
substitution of 2-bromo-N-arylacetamides13 with the cor-
carboxylic-functionalized:
excellent solubility and recyclability in
aqueous solvents under basic conditions
responding arylamine. The resulting amides
3 were
smoothly converted into the corresponding amines by bo-
rane reduction, and the crude products were subsequently
treated with thiophosgene without purification to give the
corresponding thioureas 2a–c, 2e and 2h–i in 31–69% yield
(two steps). Subsequent basic hydrolysis of thioureas 2
with NaOH in THF and H2O, followed by acidification to pH
1 with concentrated HCl solution gave rise to thiourea li-
gands 1a–c, 1e and 1h–i in good yields ranging from 65–
92%.
Me
CO2H
N
N
CO2H
CO2H
HO2C
S
Me
electronic and steric influence:
plays a key role in the catalytic activity
A precatalyst of carboxylic-functionalized thiourea ligand
Figure 1 Rational design of a water-soluble thiourea ligand
The carboxylic-functionalized thiourea ligand 1f was
prepared in a facile three-step synthesis (Scheme 3). Com-
pound 4f was easily prepared in 77% yield via nucleophilic
substitution of ethyl 2-bromoacetate with 4-[2-(4-hydroxy-
2,6-dimethylphenylamino)ethylamino]-3,5-dimethylphe-
nol.14 The diester 4f was subsequently treated with thio-
phosgene to give the thiourea 2f in 57% yield. Subsequent
basic hydrolysis of thiourea 2f with NaOH in THF and H2O,
followed by acidification to pH 1 with concentrated HCl
solution gave rise to thiourea ligand 1f in 96% yield. Carbox-
ylic-functionalized thiourea ligands 1a–c and 1e–i were
characterized by IR and NMR spectroscopy and mass spec-
trometry, and demonstrated good solubility in water under
basic conditions.
With the different thiourea ligands 1a–i in hand, the
catalytic activity of the thiourea–Pd complexes was
screened in aqueous Suzuki–Miyaura reactions between 4-
bromoanisole and phenylboronic acid in pure water at
100 °C, employing NaOH as the base (Table 1). The reactions
were conducted in air and all the reagents were used di-
rectly as received. Initial studies9 showed that a 1:1 ratio of
bis(thiourea) or a 2:1 ratio of monothiourea to Pd was cru-
were prepared (Figure 2). The synthetic pathways toward
the carboxylic-functionalized thiourea ligands 1a–c, 1e and
1g–i are summarized in Scheme 1 and Scheme 2. Amides 3
were easily prepared in yields of 57–88% via nucleophilic
R4
R1
R3
N
N
R4
R5
N
N
R1
R1
N
N
S
S
R2
S
R1
R3
R2
R2
R4
R3
R3
R1 R2
R3 R4
R5
1d Me Me
1e CO2H
Me
Me
H
H
H
Me
R1 R2 R3
R4
CO2H
H
Me
1a Me Me Me
1f Me OCH2CO2H Me
OCH2CO2H
1b Me
1c Me
H
H
CO2H CO2H
CO2H H
1g Me Me
H
H
H
CO2H H
1h Me CO2H
1i Me CO2H
CO2H H
CO2H CO2H
Figure 2 Structures of the thiourea ligands
Y
R1
O
Y
O
O
R1
N
N
R1
DIPEA
TBAI
(i) BH3.SMe2/THF
(ii) CSCl2, Na2CO3
H
H
X
NH
Br
+
NH
R2
HN
R2
H2N
NH2
R2
X
X
3a–c
Y
R4
N
N
N
N
(i) NaOH, H2O/THF
(ii) HCl
R1
R1
R1
R1
N
N
N
N
S
S
S
S
R2
R2
R2
R2
X
X
R3
R3
2a–c
1a–c
R1 R2 R3
1a Me Me Me
R1 R2
X
Y
R4
CO2H
3a/2a Me Me Me
CO2Et
3b/2b Me
3c/2c Me
H
H
CO2Me CO2Et
CO2Me H
1b Me H CO2H CO2H
1c Me H CO2H H
Scheme 1 Synthesis of carboxylic-functionalized thiourea ligands 1a–c
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

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W. Chen et al.
Paper
Synthesis
R1
O
R1
O
R3
Y
Y
R3
Y
Y
(i) BH3.SMe2/THF
(ii) CSCl2, Na2CO3
DIPEA
TBAI
X
NH
Br
X
NH HN
Z
+
H2N
Z
R1
R1
R3
R3
3e,g–i
R1
R3
R1
R3
Y
R4
R5
(i) NaOH, H2O/THF
(ii) HCl
N
N
N
N
X
Z
R2
S
S
R1
R3
R1
R3
Y
R4
1e,g–i
2e,g–i
R1 R2
R3 R4
R5
Me
R1
H
X
R3
Y
H
Z
1e
H
CO2H Me H
3e/2e
CO2Et Me
Me
H
1g Me Me
H
H
H
CO2H H
3g/2g Me Me
H
H
H
CO2Me
CO2Me
1h Me CO2H
1i Me CO2H
CO2H H
3h/2h Me CO2Et
3i/2i Me CO2Et
H
CO2H CO2H
CO2Me CO2Me
Scheme 2 Synthesis of carboxylic-functionalized thiourea ligands 1e and 1g–1i
cial to achieve high catalytic activity; an excess of thiourea
ligand tended to dramatically decrease the conversion rate.
As shown in Table 1, thiourea ligands 1a, 1d,9d and 1e–i dis-
played high catalytic activity, giving good to excellent yields
of coupled products within 20 hours in the first run (entries
2, 3 and 8–19). The other two thiourea ligands (1b and 1c)
Table 1 Comparison of Thiourea Ligands 1a–i in Aqueous Suzuki–
Miyaura Reactionsa
Pd-1 (0.1 mol%)
PhB(OH)2
MeO
Br
+
MeO
Ph
NaOH, H2O
100 °C
gave only traces to low yields within 24 hours in the first
runs (entries 4–7). Moreover, Pd(dba)2, PdCl2(MeCN)2 and
Na2PdCl4 were screened with thiourea ligands 1a–1i.
PdCl2(MeCN)2 and Na2PdCl4 exhibited better reactivity and
recyclability than Pd(dba)2 in the thiourea-ligand-assisted
aqueous Suzuki–Miyaura reaction (cf. entries 2, 3, 10, 11,
18 and 19 vs entries 1 and 9).
Entry
Ligand
Pd
Time (h)
Yield (%)b
1
2
1a
1a
1a
1b
1b
1b
1c
1d
1e
1e
1e
1f
Pd(dba)2
8
trace
PdCl2(MeCN)2
Na2PdCl4
20 (20c)
20 (20c)
8
84 (tracec)
90 (tracec)
trace
3
4
Pd(dba)2
5
PdCl2(MeCN)2
Na2PdCl4
24
trace
According to our previous studies,9a–c it is further en-
forced that the different catalytic activities of thiourea li-
gands 1a–i are attributed to the electronic and steric effects
of the thiourea moieties of the Pd complexes. In general, the
6
24
40
7
Pd(dba)2
8
trace
8
Pd(dba)2
8 (12c)
8 (12c)
8 (12c)
8 (12c)
8 (24c)
8 (24c)
8 (12c)
8 (12c)
8 (12c)
8 (12c)
8 (12c)
8 (12c)
95 (tracec)
92 (tracec)
99 (tracec)
99 (tracec)
79 (tracec)
90 (tracec)
97 (31c)
94 (tracec)
95 (46c)
90 (41c)
90 (67c)
91 (74c)
9
Pd(dba)2
10
11
12
13
14
15
16
17
18
19
PdCl2(MeCN)2
Na2PdCl4
NH HN
NaH
THF
BrCH2CO2Et
+
HO
OH
PdCl2(MeCN)2
Na2PdCl4
1f
NH HN
CSCl2, Na2CO3
THF
1g
1g
1h
1h
1i
PdCl2(MeCN)2
Na2PdCl4
EtO2CH2CO
OCH2CO2Et
OCH2CO2Et
4f
(i) NaOH,
H2O/THF
PdCl2(MeCN)2
Na2PdCl4
N
N
N
N
EtO2CH2CO
HO2CH2CO
(ii) HCl
S
PdCl2(MeCN)2
Na2PdCl4
2f
1i
a Reactions were conducted under aerobic conditions. Unless indicated oth-
erwise, the reactions were conducted with 5 mmol of aryl halide, 7.5 mmol
of phenylboronic acid, 10 mmol of NaOH and 5 mL of H2O, Pd/bis-thiourea
= 1:1, Pd/monothiourea = 1:2.
OCH2CO2H
S
1f
b Yield of isolated product.
c Second run.
Scheme 3 Synthesis of carboxylic-functionalized thiourea ligand 1f
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

D
W. Chen et al.
Paper
Synthesis
palladium complexes formed with relatively bulky thiourea
ligands (1a, 1d–i) exhibit higher catalytic activities. The rel-
atively poor activities of 1b and 1c may be associated with
the substituents of low steric hindrance (cf. entries 4–7 vs
entries 2 and 3). Moreover, monothiourea ligands 1d–i dis-
played higher catalytic activity than the bis(thiourea) li-
gand 1a (cf. entries 8–19 vs entries 1–3). As shown in Table
1, monothiourea ligand 1i displayed the best catalytic activ-
ity and recyclability, giving good yields even in the second
run (entries 18 and 19). This result supports the hypothesis
of the number of carboxylic groups having an important in-
fluence on the recyclability (cf. entries 18 and 19 vs entries
8–17). Since the electronic and steric properties of the li-
gands 1g, 1h and 1i are quite similar, it is reasonable to de-
duce that the solubility influence introduced by the four
carboxylic groups of ligand 1i played a key role in its high
recyclability (74% yield obtained in the second run) under
basic conditions (cf. entry 19 vs entries 14–17).
phenylboronic acid with 0.1 mol% of Pd-1i at 100 °C (en-
tries 1 and 2). A high yield (82%) was still observed within
12 hours in the fourth run using Na2PdCl4 as the Pd source
(entry 2). These results were significantly better than the
74% yield obtained in the second run catalyzed by Na2PdCl4-1i
in the presence of NaOH (see Table 1, entry 19). It is known
that the addition of tetra-n-butylammonium bromide
(TBAB) can accelerate the rate of aqueous Suzuki–Miyaura
reactions due to the formation of Bu4NPhB(OH)3.1e,7,15 The
addition of TBAB (1 equiv) to the coupling of 4-bromoan-
isole with phenylboronic acid increased the conversion
from 54% (0.4 equiv TBAB) to 90% within 24 hours at room
temperature (entries 4 vs 6). To our surprise, excellent
yields were also obtained even in the second run catalyzed
by Na2PdCl4-1i, using KOH as the base and within 24 hours
at room temperature when 1 equivalent of TBAB was used
as the additive (entry 8). The recyclability of the Na2PdCl4-
1i catalyst was further investigated using 4′-bromo-
acetophenone and 4-bromoanisole in aqueous Suzuki–
Miyaura couplings with phenylboronic acid (entries 9–11).
It is notable that the increment of temperature to 100 °C led
With the superior ligand 1i in hand, the aqueous Suzuki–
Miyaura reaction conditions were further optimized (Table
2). Firstly, we screened the commonly used water-soluble
base K2CO3 for the model reaction of 4-bromoanisole and
Table 2 Screening of Recoverable Reaction Conditions in Aqueous Suzuki–Miyaura Reactions Assisted by Ligand 1ia
Pd-1i (0.1 mol%)
+
PhB(OH)2
R
Br
R
Ph
base, H2O
r.t.–100 °C
Entry
R
Base
K2CO3
Pd
Time (h)
Yield (%)b
99 (99d/99e/76f)
1c
2c
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
Ac
PdCl2(MeCN)2
Na2PdCl4
8 (12d/12e/12f)
8 (12d/12e/12f)
24
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KOH
99 (99d/99e/82f)
64
3g,h
4g,h
5g,i
PdCl2(MeCN)2
Na2PdCl4
24
54
PdCl2(MeCN)2
Na2PdCl4
24
92
6g,i
24
90
7g,i
PdCl2(MeCN)2
Na2PdCl4
24 (24d)
24 (24d)
1 (1d/1e/1f)
1 (1d/1e/1f)
0.5 (0.5d/1e/1.5f)
24 (24d)
1 (1d/1e)
97 (40d)
8g,i
KOH
99 (90d)
9c,i
KOH
PdCl2(MeCN)2
Na2PdCl4
99 (99d/99e/92f)
99 (99d/99e/90f)
99 (99d/99e/99f)
95 (23d)
10c,i
11c,i
12g,i,j
13g,i,j
KOH
KOH
Na2PdCl4
OMe
OMe
KOH
Na2PdCl4
KOH
Na2PdCl4
>99 (73d/32e)
a Reactions were conducted under aerobic conditions. Unless indicated otherwise, the reactions were conducted with 5 mmol of aryl halide, 7.5 mmol of phenyl-
boronic acid, 10 mmol of base and 5 mL of H2O, Pd/1i = 1:2.
b Yield of isolated product.
c At 100 °C.
d Second run.
e Third run.
f Fourth run.
g At 25 °C.
h With the addition of TBAB (2 mmol).
i With the addition of TBAB (5 mmol).
j In the absence of thiourea ligand.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

E
W. Chen et al.
Paper
Synthesis
to excellent conversion into the desired products within 1.5
hours with 0.1 mol% of Na2PdCl4-1i loading, even in the
fourth run (entries 10 and 11).
Table 3 Substrate Scope of Na2PdCl4-1i in Catalytic Aqueous Suzuki–
Miyaura Reactionsa
Na2PdCl4-1i
(0.1 mol%)
R1
R2
Having established the optimum conditions, the scope
and limitations of the aqueous Suzuki–Miyaura reactions
was explored with various aryl halides and arylboronic
acids at room temperature. As revealed in Table 3, fifteen
different (hetero)aryl bromides were used and treated with
ten (hetero)arylboronic acids (entries 1–33). As a result,
both electron-deficient and electron-rich arylboronic acids
and aryl bromides gave the corresponding coupling prod-
ucts in excellent yields with 0.1 mol% of Na2PdCl4-1i loading
at room temperature (entries 1–11). For deactivated bro-
mides or hindered arylboronic acids, almost quantitative
yields were achieved within 12 hours in the presence of 0.1
mol% Pd at 100 °C (entries 12–17). We also conducted the
Suzuki–Miyaura reaction at a decreased catalyst loading
(0.01 mol%), and a quantitative yield was obtained for deac-
tivated 4-bromoanisole at 100 °C within 4 hours (entry 18).
For a hindered aryl bromide (entry 19), activation of 2-bro-
mo-1,3,5-trimethylbenzene with phenylboronic acid at
100 °C proved to be difficult and only traces of the desired
biaryl formed. For bulky substrates, the arylboronic acid
(entries 12–14) showed much higher reactivity compared
with the aryl halide (entry 19). It is known that the oxida-
tive addition is the rate-determining step of the catalytic
cycle in most cases.16a The concerted and SN2 mechanisms
are used to describe the oxidative addition process during
cross-coupling reactions, and both mechanisms consider
palladium(0) as a nucleophile and the organohalide as an
electrophile. The concerted mechanism requires a three-
centered transition state. On the other hand, if an SN2
mechanism is operative then the process generally involves
several steps. The reaction is initiated via nucleophilic at-
tack by the metal center at the less electronegative atom in
the substrate, leading to cleavage of the R–X bond to give a
[Pd–R]+ intermediate, which is followed by rapid coordina-
tion of the anion to the cationic metal center.16b,c For the
transmetalation in the Suzuki–Miyaura process, calcula-
tions show that the activation barrier is very high in the ab-
sence of a base, while transmetalation occurs easily in the
presence of a base.16c,d These theoretical results are in
agreement with the experimental observations in our
work. Moreover, as the concerted and SN2 mechanisms in
oxidative addition are both sensitive to steric hindrance, we
speculate that the coupling reactivity is mainly reliant on
the barrier to the oxidative addition reaction of the aryl ha-
lide to LnPd. On the other hand, steric hindrance in trans-
metalation (due to a bulky arylboronic acid) may have a mi-
nor influence on the coupling reactivity. This may explain
why the bulky arylboronic acid (in reactions with low steric
hindrance aryl halides, entries 12–14) showed much higher
reactivity than a bulky aryl halide (entry 19). Only a low
yield (28%) was obtained after 96 hours when activated
R1
X
B(OH)2
+
R2
KOH, H2O
(X = Br, Cl)
r.t., under air
Entry R1 (X)
R2
Time (h) Yield (%)b
1
2
4-Ac (Br)
H
24
24
24
24
24
24
24
24
24
48
24
12
1
>99
>99
>99
>99
>99
>99
>99
97
4-MeO (Br)
4-MeO (Br)
4-MeO (Br)
3-O2N (Br)
4-OHC (Br)
4-Me (Br)
2-Me
3-Ac
4-F3C
H
3
4
5
6
H
7
H
8
4-EtCO2 (Br)
3-Me (Br)
2-Me
2-Me
2-Me
2-Me
9
>99
>99
>99
93
10
11
12c
13c
14c
15c
16c
17c
2-NC (Br)
4-F3C (Br)
3-Me (Br)
2,6-(Me)2
4-Ac (Br)
2,6-(Me)2
2,6-(Me)2
2-Me
3-Ac
>99
95
4-MeO (Br)
4-MeO (Br)
4-MeO (Br)
4-MeO (Br)
5
2
>99
>99
>99
>99
trace
28
1
4-F3C
H
1
18c,d 4-MeO (Br)
4
19c
20
2,4,6-(Me)3 (Br)
H
12
96
10
10
12
12
18
18
1
4-O2N (Cl)
4-O2N (Cl)
4-O2N (Cl)
4-O2N (Cl)
4-O2N (Cl)
4-O2N (Cl)
4-Ac (Cl)
4-MeO
4-MeO
H
21c
22c
23c
24c
25c
26c
27c
28c
29c
30c
31c
32c
33c
>99
92
2-Me
4-F3C
2,6-(Me)2
H
>99
>99
trace
40
4-H2N (Br)
4-MeO (Br)
2-bromopyridine
4-MeO
>99
93
3-thiopheneboronic acid
H
3
16
4
45
3-bromothiophene 4-MeO
15
3-bromopyridine
4-Ac (Br)
4-Ac
2
trace
trace
trace
3-pyridylboronic acid
2-furanboronic acid
2
4-Ac (Br)
2
a Reactions were conducted under aerobic conditions. Unless indicated oth-
erwise, the reactions were conducted with 5 mmol of (hetero)aryl halide, 7.5
mmol of (hetero)arylboronic acid, 10 mmol of KOH, 5 mmol of TBAB and 5
mL of H2O, Pd/1i = 1:2.
b Yield of isolated product.
c At 100 °C.
d Na2PdCl4-1i (0.01 mol%) was added.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

F
W. Chen et al.
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Synthesis
4-nitrochlorobenzene was applied at room temperature
(entry 20). However, almost quantitative yields could be
achieved within 12 hours by increasing the reaction tem-
perature to 100 °C (entries 21–24). Attempts to couple acti-
vated 4-nitrochlorobenzene with hindered arylboronic ac-
ids such as 2,6-dimethylphenylboronic acid failed (entry
25). On the other hand, a moderate yield (40%) was ob-
served within 18 hours when activated 4′-chloroacetophe-
none and phenylboronic acid were applied at 100 °C (entry
26). Moreover, the optimum conditions could be applied for
an aryl halide bearing an active proton; an excellent yield
was obtained within 1 hour when 4-bromoaniline was cou-
pled with 4-methoxyphenylboronic acid at 100 °C (entry
27). These results reveal that Na2PdCl4-1i tolerates func-
tional groups on aryl bromides and arylboronic acids at
room temperature and is effective for coupling several de-
activated substrates in moderate to good yields at 100 °C.
With respect to heteroaryl substrates such as (hetero)aryl
bromides or (hetero)arylboronic acids (entries 28–33), cou-
pling of (hetero)aryl bromides with (hetero)arylboronic ac-
ids at 100 °C proved to be difficult, and only a trace or low
yields (15–45%) of the desired products were formed (en-
tries 29–33). However, a good yield of 93% was obtained
within 3 hours when 4-bromoanisole was coupled with 3-
thiopheneboronic acid at 100 °C (entry 28).
hours. However, a low yield (27%) was observed. Further-
more, the isolated black solid (obtained from 0.1 mol% of
Na2PdCl4-1i) was directly applied in the catalytic coupling
of 4′-bromoacetophenone and phenylboronic acid in water
at 100 °C over a period of 2 hours, and a quantitative yield
of the coupling product was obtained in the second run.
Moreover, no obvious loss of catalytic activity was observed
even after the black solid had been used five times. It is
known that active Pd nanoparticles are usually involved in
palladium-catalyzed
cross-coupling
reactions.3c,7l,8a,17
Therefore, TEM analysis was performed after the first and
the fifth runs of the coupling reactions between 4′-bromo-
acetophenone and phenylboronic acid. Following the cou-
pling reactions, the black precipitate was isolated by cen-
trifugation and was washed with methanol (5 × 3 mL) and
water (5 × 3 mL). The black precipitate was again centri-
fuged and dispersed in ethanol for TEM analysis.7l,8a The
TEM images in Figure 3 clearly reveal the presence of PdNPs
both after the first run and the fifth run (Figures 3a,b and
3c,d). The water-soluble thiourea ligand 1i acts as a stabiliz-
er of the nanoparticles in water. Furthermore, no obvious
aggregation of Pd nanoparticles was visually observed after
five consecutive cycles (Figure 3, c and d). We report here
characterization using TEM analysis for the size and distri-
Since the formation of a black precipitate is observed
during the coupling reactions, more experiments were de-
signed to investigate the nature of the water-soluble
thiourea–Pd complexes in water. A black precipitate due to
Pd nanoparticles (PdNPs) can be visually observed during
the coupling reactions in the absence of TBAB (Table 2, en-
tries 1 and 2). After the coupling reactions, moderate to
good yields (76–82%) were still observed within 12 hours in
the fourth run using Na2PdCl4 as the Pd source in the ab-
sence of TBAB (Table 2, entries 1 and 2). On the other hand,
the black precipitate was not obtained from the Pd catalyst
and thiourea ligands under the reaction conditions without
both the halide and the boronic acid. A clear solution was
still obtained when Na2PdCl4 was treated with water-solu-
ble thiourea ligands at 100 °C over a period of 2 hours in the
absence of both the halide and boronic acid. Moreover,
when 4-bromoanisole and phenylboronic acid were treated
with Na2PdCl4 and TBAB under the reaction conditions in
the absence of the thiourea ligand (Table 2, entries 12 and
13), an obvious decrease in the activity was observed after
two (at r.t., Table 2, entry 12) or three (at 100 °C, Table 2,
entry 13) consecutive cycles. These results further confirm
that PdNPs are formed from the stabilization of thiourea li-
gands.
After the aqueous coupling reactions of 4′-bromoace-
tophenone and phenylboronic acid, the black solid (ob-
tained from 0.1 mol% of Na2PdCl4-1i) was isolated by cen-
trifugation. The resulting supernatant solution was directly
applied in the catalytic coupling of 4′-bromoacetophenone
and phenylboronic acid in water at 100 °C over a period of 2
Figure 3 TEM images of PdNPs generated from the Na2PdCl4-1i com-
plex: (a) and (b) after the first run of the coupling reaction of 4′-bromo-
acetophenone and phenylboronic acid; (c) and (d) after the fifth run of
the coupling reaction of 4′-bromoacetophenone and phenylboronic ac-
id. In all, >100 particles were counted in each case using ‘Nano Measur-
er’ software.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

G
W. Chen et al.
Paper
Synthesis
bution of Pd nanoparticles. Both sets of nanoparticles
formed in consecutive coupling reactions were observed to
have an estimated average size of 4 ± 1 nm (Figure 3, a,b and
c,d). These results further confirm the hypothesis that the
coupling reaction is catalyzed by Pd nanoparticles.
Dimethyl 5-{[2-(Mesitylamino)-2-oxoethyl]amino}isophthalate
(3g)
Yield: 4.06 g (88%); white solid; mp 209–210 °C.
IR (KBr): 3259, 2952, 1728, 1668, 1609, 1529, 1439, 1359, 1241, 1134,
1000, 756 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.12 (s, 1 H), 7.86 (s, 1 H), 7.56 (d, J =
1.2 Hz, 2 H), 6.84 (s, 2 H), 4.99 (t, J = 4.8 Hz, 1 H), 4.03 (d, J = 5.3 Hz, 2
H), 3.91 (s, 6 H), 2.22 (s, 3 H), 2.11 (s, 6 H).
13C NMR (151 MHz, CDCl3): δ = 168.4, 166.3, 147.3, 137.2, 135.0,
131.6, 130.3, 128.9, 121.1, 118.0, 52.3, 48.3, 20.9, 18.3.
In summary, a series of eight precatalysts of carboxylic-
functionalized thiourea ligands has been synthesized in a
straightforward manner. Complex Na2PdCl4-1i, functional-
ized with four carboxylic groups, displayed the best catalyt-
ic activity and recyclability. Moreover, the coupling of aryl
bromides and phenylboronic acids can even be conducted
at room temperature while the catalyst can be recycled in
at least five consecutive runs. TEM analysis shows that Pd
nanoparticles form during the reactions. These novel wa-
ter-soluble thiourea ligands are air- and moisture-stable,
and the resulting Pd nanoparticles can be readily recycled
in water under air. Work is in progress in our laboratory to
extend the applications of water-soluble thiourea ligands in
palladium- and other transition-metal-catalyzed reactions.
HRMS (ESI): m/z [M + H]+ calcd for C21H25N2O5: 385.1758; found:
385.1737.
Dimethyl 5-[(2-{[4-(Ethoxycarbonyl)-2,6-dimethylphenyl]amino}-
2-oxoethyl)amino]isophthalate (3h)
Yield: 3.77 g (71%); white solid; mp 220–221 °C.
IR (KBr): 3249, 2962, 1720, 1671, 1527, 1419, 1258, 1114, 1009, 763
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.17 (t, J = 1.3 Hz, 1 H), 7.96 (s, 1 H),
7.74 (s, 2 H), 7.60 (d, J = 1.3 Hz, 2 H), 4.81 (t, J = 5.4 Hz, 1 H), 4.35 (q, J =
7.1 Hz, 2 H), 4.10 (d, J = 5.5 Hz, 2 H), 3.93 (s, 6 H), 2.22 (s, 6 H), 1.38 (t,
J = 7.1 Hz, 3 H).
All reagents were used as supplied from commercial sources without
further purification. TLC was performed on Yucheng chemical glass-
backed silica plates. Column chromatography was performed using
Yucheng chemical silica gel (200–300 mesh) eluting with EtOAc and
petroleum ether (PE). Melting points were obtained using a X-4A dig-
ital micro melting point apparatus (made by Gongyi City Kerui Instru-
ment Co., Ltd.). IR spectra were recorded using a Perkin-Elmer 1600
Series FTIR. 1H NMR spectra were recorded at 600 or 400 MHz, and
13C NMR spectra were recorded at 150 or 100 MHz using tetramethyl-
silane as the internal standard. Chemical shifts are reported in parts
per million (ppm), and the residual solvent peak was used as an inter-
nal reference: proton (chloroform, δ 7.26; DMSO, δ 2.50), carbon
(chloroform, δ 77.0; DMSO, δ 39.5). Multiplicities are indicated as fol-
lows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd
(doublet of doublets), br s (broad singlet). Coupling constants are re-
ported in hertz (Hz). High-resolution mass spectrometry (ESI) was
performed with a Finnigan LCQDECA ion-trap mass spectrometer.
Transmission electron microscopy (TEM) was performed on a JEOL
JEM-2100F electron microscope operating at 200 kV. The TEM sam-
ples were prepared by pipetting a drop of an EtOH solution of the
PdNPs on copper grids covered with a Quantifoil Multi A holey carbon
film with a 2-nm carbon film on top.
13C NMR (100 MHz, CDCl3): δ = 168.0, 166.4, 166.3, 147.2, 137.5,
135.5, 132.0, 129.6, 129.4, 121.8, 118.3, 61.1, 52.6, 48.7, 18.7, 14.5.
HRMS (ESI): m/z [M + H]+ calcd for C23H27N2O7: 443.1818; found:
443.1806.
Trimethyl 5-[(2-{[4-(Ethoxycarbonyl)-2,6-dimethylphenyl]ami-
no}-2-oxoethyl)amino]benzene-1,2,3-tricarboxylate (3i)
Yield: 3.42 g (57%); white solid; mp 148–149 °C.
IR (KBr): 3315, 2952, 1735, 1602, 1436, 1254, 1205, 1136, 1031, 800,
773, 704 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 9.25 (s, 1 H), 8.26 (s, 2 H), 7.69 (s, 2 H),
4.57 (br s, 1 H), 4.34 (q, J = 7.1 Hz, 2 H), 3.98 (s, 3 H), 3.90 (s, 2 H), 3.88
(s, 6 H), 2.35 (s, 6 H), 1.39 (t, J = 7.1 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 169.7, 169.3, 166.8, 164.7, 149.8,
138.4, 131.8, 130.7, 129.0, 127.6, 124.1, 123.4, 60.6, 53.0, 52.8, 51.5,
18.7, 14.3.
HRMS (ESI): m/z [M + H]+ calcd for C25H29N2O9: 501.1868; found:
501.1858.
Method B: Amides 3a–c,e
A mixture of the arylamine (12 mmol), 2-bromo-N-arylacetamide13
(for amides 3a–c: 26.4 mmol; for amide 3e: 13.2 mmol), TBAI (222
mg, 0.6 mmol), MeCN (60 mL) and N,N-diisopropylethylamine
(DIPEA) (for amides 3a–c: 3.72 g, 28.8 mmol; for amide 3e: 1.86 g,
14.4 mmol) was refluxed for 12–24 h. Upon completion, the MeCN
was removed and H2O (50 mL) was added. The mixture was then ex-
tracted with EtOAc (3 × 50 mL) and washed with brine, dried
(Na2SO4), and concentrated. The pure amide 3 was obtained as a
white or pale-yellow solid through flash chromatography (PE/EtOAc,
5:1 to 1:1).
Amides 3a–c,e,g–3i; General Procedures
Two methods were used for the synthesis of amides 3.
Method A: Amides 3g–i
A mixture of the arylamine (12 mmol), 2-bromo-N-arylacetamide13
(13.2 mmol), TBAI (222 mg, 0.6 mmol) and N,N-diisopropylethyl-
amine (DIPEA) (1.86 g, 14.4 mmol) was stirred at 130 °C for 2 h, then
after cooling to 80 °C, EtOH (60 mL) and H2O (60 mL) were added. The
mixture was then stirred at r.t. for 2 h. The resulting precipitate was
collected by filtration and washed with EtOH (3 × 15 mL). The pure
amide 3 was obtained as a white or pale-yellow solid through flash
chromatography (PE/EtOAc, 3:1 to 1:1).
Ethyl 3,5-Bis{[2-(mesitylamino)-2-oxoethyl]amino}benzoate (3a)
Yield: 5.48 g (86%); white solid; mp 119–120 °C.
IR (KBr): 2976, 2859, 1664, 1610, 1509, 1239, 1108, 1032, 851, 768
cm–1
.
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W. Chen et al.
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Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.94 (s, 2 H), 6.87 (d, J = 1.5 Hz, 2 H),
6.82 (s, 4 H), 6.24 (s, 1 H), 4.32 (q, J = 7.1 Hz, 2 H), 3.92 (s, 4 H), 2.22 (s,
6 H), 2.09 (s, 12 H), 1.34 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.2, 166.8, 148.3, 137.3, 135.1,
132.8, 130.6, 129.1, 105.4, 102.5, 61.2, 48.6, 21.0, 18.5, 14.4.
To a stirred mixture of the amine obtained above and Na2CO3 (for bis-
thioureas 2a–c: 763 mg, 7.2 mmol, 2.4 equiv; for monothioureas
2e,g–i: 382 mg, 3.6 mmol, 1.2 equiv) in dry THF (20 mL) was added a
dilute solution of thiophosgene (for bisthioureas 2a–c: 828 mg, 7.2
mmol, 2.4 equiv; for monothioureas 2e,g–i: 414 mg, 3.6 mmol, 1.2
equiv) in THF (10 mL) over about 12 h. After stirring at r.t. overnight,
THF was removed under vacuum, and H2O (30 mL) and EtOAc (30 mL)
were added. The organic layer was washed with brine (10 mL), dried
(Na2SO4) and concentrated. The pure thiourea 2 was obtained as a
white or pale-yellow solid through flash chromatography (PE/EtOAc,
5:1 to 1:1) and recrystallization from methanol.
HRMS (ESI): m/z [M + H]+ calcd for C31H39N4O4: 531.2971; found:
531.2971.
Dimethyl 4,4'-[(2,2′-{[5-(Ethoxycarbonyl)-1,3-phenylene]-
bis(azanediyl)}bis(acetyl))bis(azanediyl)]bis(3-methylbenzoate)
(3b)
Yield: 5.74 g (81%); pale-yellow solid; mp 104–105 °C.
IR (KBr): 2952, 1716, 1610, 1526, 1438, 1276, 1124, 767 cm–1
Ethyl 3,5-Bis(3-mesityl-2-thioxoimidazolidin-1-yl)benzoate (2a)
Yield: 915 mg (52%, two steps); white solid; mp >240 °C.
.
1H NMR (400 MHz, CDCl3): δ = 8.59 (s, 2 H), 8.17 (d, J = 8.5 Hz, 2 H),
7.86 (d, J = 8.5 Hz, 2 H), 7.77 (s, 2 H), 6.91 (s, 2 H), 6.16 (s, 1 H), 4.44–
4.22 (m, 4 H), 3.96 (d, J = 5.2 Hz, 4 H), 3.88 (s, 6 H), 2.04 (s, 6 H), 1.35
(t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 168.5, 166.8, 166.4, 148.3, 139.5,
133.3, 131.9, 128.8, 127.1, 126.2, 120.6, 106.3, 102.0, 61.4, 52.1, 49.6,
17.3, 14.4.
IR (KBr): 2972, 2915, 1713, 1602, 1476, 1421, 1273, 1247, 1110, 1026,
856, 771, 695 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.62 (t, J = 2.0 Hz, 1 H), 8.09 (d, J = 2.0
Hz, 2 H), 6.97 (s, 4 H), 4.40 (q, J = 7.1 Hz, 2 H), 4.36–4.27 (m, 4 H),
3.97–3.87 (m, 4 H), 2.31 (s, 6 H), 2.28 (s, 12 H), 1.40 (t, J = 7.1 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 180.8, 165.9, 141.1, 138.6, 136.4,
134.6, 131.4, 129.6, 125.0, 121.7, 61.5, 49.3, 47.3, 21.2, 18.0, 14.5.
HRMS (ESI): m/z [M + H]+ calcd for C31H35N4O8: 591.2455; found:
591.2440.
HRMS (ESI): m/z [M + H]+ calcd for C33H39N4O2S2: 587.2514; found:
587.2527.
Methyl 4-(2-{[3-({2-[(4-Acetoxy-2-methylphenyl)amino]-2-oxo-
ethyl}amino)phenyl]amino}acetamido)-3-methylbenzoate (3c)
Dimethyl 4,4′-{[5-(Ethoxycarbonyl)-1,3-phenylene]bis(2-thioxo-
imidazolidine-3,1-diyl)}bis(3-methylbenzoate) (2b)
Yield: 4.67 g (75%); pale-yellow solid; mp 184–185 °C.
Yield: 893 mg (46%, two steps); pale-yellow solid; mp 123–124 °C.
IR (KBr): 2962, 1609, 1523, 1256, 1120, 768 cm–1
.
IR (KBr): 2950, 2892, 1719, 1602, 1474, 1425, 1305, 1109, 770, 718,
1H NMR (400 MHz, CDCl3): δ = 8.75 (s, 2 H), 8.24 (d, J = 8.5 Hz, 2 H),
7.88 (dd, J = 8.5, 1.9 Hz, 2 H), 7.78 (d, J = 1.4 Hz, 2 H), 7.09 (t, J = 8.0 Hz,
1 H), 6.23 (dd, J = 8.1, 2.2 Hz, 2 H), 6.03 (t, J = 2.1 Hz, 1 H), 4.46 (t, J =
5.4 Hz, 2 H), 3.93 (d, J = 5.5 Hz, 4 H), 3.89 (s, 6 H), 2.02 (s, 6 H).
678 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.58–8.51 (m, 1 H), 8.10 (d, J = 1.8 Hz, 2
H), 8.01 (s, 2 H), 7.96 (d, J = 8.1 Hz, 2 H), 7.35 (d, J = 8.2 Hz, 2 H), 4.39
(q, J = 7.1 Hz, 2 H), 4.36–4.26 (m, 4 H), 4.01 (t, J = 8.7 Hz, 4 H), 3.92 (s,
6 H), 2.39 (s, 6 H), 1.39 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 168.8, 166.8, 148.2, 139.6, 131.8,
131.1, 128.9, 126.7, 125.9, 120.2, 105.6, 98.8, 52.2, 49.9, 17.1.
HRMS (ESI): m/z [M + H]+ calcd for C28H31N4O6: 519.2244; found:
519.2229.
13C NMR (150 MHz, CDCl3): δ = 181.3, 166.6, 165.7, 143.4, 140.9,
137.3, 132.8, 131.6, 130.3, 128.7, 128.3, 125.6, 122.3, 61.6, 52.4, 49.5,
49.1, 18.2, 14.5.
HRMS (ESI): m/z [M + H]+ calcd for C33H35N4O6S2: 647.1998; found:
647.1990.
Ethyl 4-[2-(Mesitylamino)acetamido]benzoate (3e)
Yield: 3.11 g (76%); white solid; mp 75–76 °C.
Dimethyl 4,4′-[1,3-Phenylenebis(2-thioxoimidazolidine-3,1-di-
yl)]bis(3-methylbenzoate) (2c)
IR (KBr): 3241, 2978, 1703, 1677, 1523, 1486, 1409, 1277, 1178, 1109,
1028, 853, 770 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 9.56 (s, 1 H), 8.04 (d, J = 8.7 Hz, 2 H),
7.70 (d, J = 8.7 Hz, 2 H), 6.87 (s, 2 H), 4.37 (q, J = 7.1 Hz, 2 H), 3.73 (s, 2
H), 3.10 (br s, 1 H), 2.29 (s, 6 H), 2.25 (s, 3 H), 1.39 (t, J = 7.1 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 169.8, 166.3, 141.9, 141.6, 133.3,
131.0, 130.1, 130.0, 126.3, 118.7, 61.0, 52.8, 20.7, 18.4, 14.5.
Yield: 534 mg (31%, two steps); pale-yellow solid; mp >230 °C.
IR (KBr): 2950, 1714, 1604, 1478, 1426, 1277, 1200, 1110, 772 cm–1
1H NMR (600 MHz, CDCl3): δ = 8.13 (t, J = 1.9 Hz, 1 H), 8.01 (s, 2 H),
7.96 (dd, J = 8.2, 1.5 Hz, 2 H), 7.55–7.48 (m, 2 H), 7.45 (dd, J = 9.1, 6.7
Hz, 1 H), 7.35 (d, J = 8.2 Hz, 2 H), 4.28 (t, J = 8.4 Hz, 4 H), 3.99 (t, J = 8.8
Hz, 4 H), 3.92 (s, 6 H), 2.40 (s, 6 H).
.
HRMS (ESI): m/z [M + H]+ calcd for C20H25N2O3: 341.1865; found:
341.1861.
13C NMR (150 MHz, CDCl3): δ = 181.3, 166.6, 143.5, 140.8, 137.3,
132.8, 130.2, 129.0, 128.7, 128.3, 121.9, 121.1, 52.4, 49.8, 49.1, 18.2.
HRMS (ESI): m/z [M + H]+ calcd for C30H31N4O4S2: 575.1787; found:
Thioureas 2a–c,e,g–i; General Procedure
To a solution of amide 3 (3 mmol) in THF (30 mL) was added
BH3·SMe2 (2 M in THF, for bisthioureas 2a–c: 12 mL, 24 mmol, 8
equiv; for monothioureas 2e,g–i: 6 mL, 12 mmol, 4 equiv) at 0 °C. The
solution was refluxed for 6 h then, after cooling to r.t., MeOH (15 mL)
was added dropwise in order to destroy the excess BH3. The solvent
was removed, and the resulting amine was used directly in the next
step.
575.1798.
Ethyl 4-(3-Mesityl-2-thioxoimidazolidin-1-yl)benzoate (2e)
Yield: 685 mg (62%, two steps); pale-yellow solid; mp 165–166 °C.
IR (KBr): 2971, 1706, 1605, 1421, 1264, 1106, 765 cm–1
.
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W. Chen et al.
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Synthesis
1H NMR (600 MHz, CDCl3): δ = 8.07 (d, J = 8.8 Hz, 2 H), 7.85 (d, J = 8.8
Hz, 2 H), 6.97 (s, 2 H), 4.37 (q, J = 7.1 Hz, 2 H), 4.32–4.25 (m, 2 H),
3.94–3.87 (m, 2 H), 2.31 (s, 3 H), 2.26 (s, 6 H), 1.39 (t, J = 7.1 Hz, 3 H).
then slowly quenched with H2O (30 mL). The organic layer was
washed with brine, dried (Na2SO4) and concentrated in vacuo. The
residue was purified via recrystallization from petroleum ether.
13C NMR (150 MHz, CDCl3): δ = 180.2, 166.2, 144.8, 138.6, 136.2,
Yield: 364 mg (77%); pale-yellow solid; mp 112–113 °C.
134.5, 130.1, 129.6, 126.6, 122.2, 60.9, 48.8, 47.0, 21.2, 17.9, 14.4.
HRMS (ESI): m/z [M + H]+ calcd for C21H25N2O2S: 369.1637; found:
IR (KBr): 3369, 2936, 1751, 1600, 1482, 1209, 1155, 1091, 1024, 857,
829, 714 cm–1
.
369.1614.
1H NMR (600 MHz, CDCl3): δ = 6.60 (s, 4 H), 4.55 (s, 4 H), 4.27 (q, J =
7.1 Hz, 4 H), 3.09 (s, 4 H), 2.29 (s, 12 H), 1.30 (t, J = 7.1 Hz, 6 H).
Dimethyl 5-(3-Mesityl-2-thioxoimidazolidin-1-yl)isophthalate
(2g)
13C NMR (150 MHz, CDCl3): δ = 169.4, 153.2, 139.9, 132.0, 115.0, 65.9,
61.4, 49.4, 18.8, 14.3.
HRMS (ESI): m/z [M + H]+ calcd for C26H37N2O6: 473.2652; found:
473.2646.
Yield: 854 mg (69%, two steps); white solid; mp 176–177 °C.
IR (KBr): 2950, 1729, 1605, 1455, 1356, 1311, 1239, 1129 1076, 996,
754 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.56 (d, J = 1.4 Hz, 2 H), 8.53 (t, J = 1.4
Hz, 1 H), 6.98 (s, 2 H), 4.36–4.29 (m, 2 H), 3.99–3.92 (m, 8 H), 2.31 (s, 3
H), 2.28 (s, 6 H).
13C NMR (150 MHz, CDCl3): δ = 180.7, 165.9, 141.4, 138.6, 136.2,
134.3, 130.9, 129.5, 128.8, 127.5, 52.5, 48.9, 47.1, 21.1, 17.9.
Diethyl 2,2′-{[(2-Thioxoimidazolidine-1,3-diyl)bis(3,5-dimethyl-
4,1-phenylene)]bis(oxy)}diacetate (2f)
To a stirred mixture of amine 4f (1.42 g, 3 mmol) and Na2CO3 (382
mg, 3.6 mmol, 1.2 equiv) in dry THF (20 mL) was added a dilute solu-
tion of thiophosgene (414 mg, 3.6 mmol, 1.2 equiv) in THF (10 mL)
over about 12 h. After stirring at r.t. overnight, the THF was removed
under vacuum, and H2O (30 mL) and EtOAc (30 mL) were added. The
organic layer was washed with brine (10 mL), dried (Na2SO4) and con-
centrated. The residue was purified through flash chromatography
(PE/EtOAc, 3:1 to 1:1) and recrystallization from EtOH.
HRMS (ESI): m/z [M + Na]+ calcd for C22H24N2O4SNa: 435.1349; found:
435.1317.
Dimethyl 5-{3-[4-(Ethoxycarbonyl)-2,6-dimethylphenyl]-2-thioxo-
imidazolidin-1-yl}isophthalate (2h)
Yield: 293 mg (57%); pale-yellow solid; mp 176–177 °C.
Yield: 734 mg (52%, two steps); pale-yellow solid; mp 197–198 °C.
IR (KBr): 2986, 2956, 1752, 1595, 1489, 1316, 1272, 1217, 1159, 1094,
IR (KBr): 2917, 1734, 1594, 1435, 1318, 1247, 1121, 1025, 757 cm–1
.
1011, 850 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.56 (d, J = 1.5 Hz, 2 H), 8.54 (t, J = 1.5
Hz, 1 H), 7.85 (s, 2 H), 4.45–4.31 (m, 4 H), 4.02–3.88 (m, 8 H), 2.37 (s, 6
H), 1.39 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 180.5, 166.2, 165.9, 141.2, 141.1,
137.3, 131.2, 130.7, 130.1, 129.0, 127.8, 61.2, 52.7, 49.2, 46.9, 18.2,
14.5.
1H NMR (600 MHz, CDCl3): δ = 6.68 (s, 4 H), 4.59 (s, 4 H), 4.28 (q, J =
7.1 Hz, 4 H), 3.96 (s, 4 H), 2.30 (s, 12 H), 1.32 (t, J = 7.1 Hz, 6 H).
13C NMR (150 MHz, CDCl3): δ = 181.4, 169.0, 157.2, 138.4, 131.1,
114.6, 65.4, 61.4, 47.7, 18.2, 14.2.
HRMS (ESI): m/z [M + H]+ calcd for C27H35N2O6S: 515.2210; found:
515.2185.
HRMS (ESI): m/z [M + H]+ calcd for C24H27N2O6S: 471.1590; found:
471.1582.
Thioureas 1a–c,e–i; General Procedure
Thiourea 2 (1 mmol), excess NaOH (600 mg, 15 mmol), H2O (20 mL)
and THF (20 mL) were stirred at r.t. for 24 h. The solution was then
diluted with Et2O (20 mL) and the organic phase was washed with
H2O (5 mL). The aqueous layer was collected and slowly acidified with
concentrated HCl solution to pH = 1. The resulting precipitate was
collected by filtration and washed with H2O (5 mL). The pure thiourea
1 was obtained as a white or pale-yellow solid through flash chroma-
tography (CH2Cl2/MeOH, 10:1 to 1:1) or by recrystallization from
EtOAc.
Trimethyl 5-{3-[4-(Ethoxycarbonyl)-2,6-dimethylphenyl]-2-thioxo-
imidazolidin-1-yl}benzene-1,2,3-tricarboxylate (2i)
Yield: 777 mg (49%, two steps); pale-yellow solid; mp 222–223 °C.
IR (KBr): 2952, 1742, 1604, 1480, 1434, 1241, 1136, 1009, 798, 773
cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.62 (s, 2 H), 7.86 (s, 2 H), 4.41–4.36
(m, 4 H), 3.99 (s, 3 H), 3.99–3.95 (m, 2 H), 3.93 (s, 6 H), 2.36 (s, 6 H),
1.40 (t, J = 7.1 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 179.9, 168.5, 166.1, 164.9, 141.2,
140.8, 137.1, 133.3, 130.7, 130.0, 129.0, 128.2, 61.1, 53.0, 52.9, 48.7,
46.6, 18.1, 14.4.
3,5-Bis(3-mesityl-2-thioxoimidazolidin-1-yl)benzoic Acid (1a)
Yield: 369 mg (66%); pale-yellow solid; mp >240 °C.
HRMS (ESI): m/z [M + H]+ calcd for C26H29N2O8S: 529.1639; found:
529.1628.
IR (KBr): 2916, 1713, 1688, 1600, 1476, 1423, 1307, 1271, 1075, 1032,
854, 775, 693 cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 13.12 (s, 1 H), 8.29 (s, 1 H), 8.23 (s,
2 H), 6.97 (s, 4 H), 4.36 (t, J = 8.7 Hz, 4 H), 3.92 (t, J = 8.6 Hz, 4 H), 2.27
(s, 6 H), 2.20 (s, 12 H).
Diethyl 2,2′-({[Ethane-1,2-diylbis(azanediyl)]bis(3,5-dimethyl-4,1-
phenylene)}bis[oxy])diacetate (4f)
To a suspension of NaH (60% dispersion in mineral oil, 120 mg, 3
mmol) in dry THF (10 mL) at 0 °C was added 4-[2-(4-hydroxy-2,6-di-
methylphenylamino)ethylamino]-3,5-dimethylphenol14 (300.4 mg, 1
mmol) in THF (10 mL). After 10 min, ethyl 2-bromoacetate (334 mg, 2
mmol) was added and the mixture was stirred at r.t. for 4 h. Upon
completion, the reaction solution was diluted with EtOAc (30 mL) and
13C NMR (150 MHz, DMSO-d6): δ = 179.3, 166.8, 141.2, 137.3, 136.1,
134.9, 130.5, 128.9, 122.1, 121.0, 48.8, 46.8, 20.6, 17.4.
HRMS (ESI negative ion): m/z [M – H]+ calcd for C31H33N4O2S2:
557.2045; found: 557.2035.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

J
W. Chen et al.
Paper
Synthesis
4,4′-[(5-Carboxy-1,3-phenylene)bis(2-thioxoimidazolidine-3,1-di-
13C NMR (150 MHz, DMSO-d6): δ = 179.7, 166.8, 142.0, 137.9, 136.5,
yl)]bis(3-methylbenzoic Acid) (1b)
135.3, 131.8, 129.4, 128.5, 126.5, 48.9, 47.3, 21.1, 17.9.
HRMS (ESI negative ion): m/z [M – H]+ calcd for C20H19N2O4S:
Yield: 484 mg (82%); pale-yellow solid; mp >240 °C.
IR (KBr): 2961, 1710, 1605, 1476, 1419, 1306, 1278, 775, 681 cm–1
.
383.1071; found: 383.1073.
1H NMR (400 MHz, DMSO-d6): δ = 12.93 (br s, 3 H), 8.29 (t, J = 2.0 Hz,
1 H), 8.22 (d, J = 2.0 Hz, 2 H), 7.92 (s, 2 H), 7.86 (dd, J = 8.2, 1.7 Hz, 2 H),
7.48 (d, J = 8.2 Hz, 2 H), 4.35 (dd, J = 18.6, 9.8 Hz, 4 H), 4.05 (dd, J =
15.3, 7.9 Hz, 4 H), 2.35 (s, 6 H).
5-[3-(4-Carboxy-2,6-dimethylphenyl)-2-thioxoimidazolidin-1-
yl]isophthalic Acid (1h)
Yield: 269 mg (65%); white solid; mp >230 °C.
IR (KBr): 2966, 1714, 1602, 1453, 1311, 1237, 901, 761, 678 cm–1
.
13C NMR (100 MHz, DMSO-d6): δ = 179.7, 166.9, 166.7, 143.5, 141.0,
1H NMR (600 MHz, DMSO-d6): δ = 8.52 (s, 2 H), 8.30 (s, 1 H), 7.74 (s, 2
H), 4.45 (t, J = 8.8 Hz, 2 H), 4.02–3.90 (m, 2 H), 2.29 (s, 6 H).
137.1, 131.8, 130.8, 130.4, 128.5, 128.0, 122.0, 121.7, 49.1, 48.8, 17.7.
HRMS (ESI): m/z [M + H]+ calcd for C29H27N4O6S2: 591.1372; found:
13C NMR (151 MHz, DMSO-d6): δ = 179.2, 167.2, 166.6, 141.5, 137.5,
591.1367.
137.4, 131.8, 130.7, 129.5, 128.4, 126.6, 49.0, 46.7, 17.7.
4,4′-[1,3-Phenylenebis(2-thioxoimidazolidine-3,1-diyl)]bis(3-
methylbenzoic Acid) (1c)
HRMS (ESI negative ion): m/z [M – H]+ calcd for C20H17N2O6S:
413.0813; found: 413.0816.
Yield: 377 mg (69%); pale-yellow solid; mp 218–219 °C.
IR (KBr): 2923, 1697, 1606, 1423, 1280, 775 cm–1
.
5-[3-(4-Carboxy-2,6-dimethylphenyl)-2-thioxoimidazolidin-1-
yl]benzene-1,2,3-tricarboxylic Acid (1i)
1H NMR (600 MHz, DMSO-d6): δ = 12.72 (br s, 2 H), 8.08 (s, 1 H), 7.91
(s, 2 H), 7.85 (d, J = 7.7 Hz, 2 H), 7.61 (d, J = 7.9 Hz, 2 H), 7.52–7.37 (m,
3 H), 4.43–4.20 (m, 4 H), 4.10–3.97 (m, 4 H), 2.34 (s, 6 H).
13C NMR (150 MHz, DMSO-d6): δ = 180.2, 167.4, 144.1, 141.3, 137.6,
132.2, 130.7, 128.9, 128.6, 128.4, 121.5, 119.8, 49.8, 49.2, 18.2.
Yield: 344 mg (75%); pale-yellow solid; mp 239–241 °C.
IR (KBr): 2980, 1702, 1604, 1430, 1245, 896, 776, 671 cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 8.40 (s, 2 H), 7.74 (s, 2 H), 4.49–
4.40 (m, 2 H), 3.99–3.92 (m, 2 H), 2.29 (s, 6 H).
13C NMR (150 MHz, DMSO-d6): δ = 179.0, 168.7, 167.2, 166.8, 141.4,
141.0, 137.5, 133.1, 130.7, 130.6, 129.6, 127.4, 48.8, 46.8, 17.8.
HRMS (ESI negative ion): m/z [M – H]+ calcd for C28H25N4O4S2:
545.1317; found: 545.1319.
HRMS (ESI negative ion): m/z [M – H]+ calcd for C21H17N2O8S:
457.0706; found: 457.0708.
4-(3-Mesityl-2-thioxoimidazolidin-1-yl)benzoic Acid (1e)
Yield: 310 mg (91%); white solid; mp >240 °C.
IR (KBr): 2978, 1701, 1606, 1422, 1273, 1131, 776 cm–1
.
Suzuki Reactions of Aryl Halides with Boronic Acids; General Pro-
cedure
1HNMR (600 MHz, DMSO-d6): δ = 12.85 (br s, 1 H), 8.00 (s, 4 H), 6.99
(s, 2 H), 4.37 (d, J = 8.1 Hz, 2 H), 3.93 (t, J = 8.4 Hz, 2 H), 2.29 (s, 3 H),
2.20 (s, 6 H).
13C NMR (150 MHz, DMSO-d6): δ = 179.2, 167.4, 145.2, 137.9, 136.4,
135.3, 129.9, 129.4, 126.7, 122.4, 48.9, 47.1, 21.1, 17.9.
The aryl halide (5.0 mmol), arylboronic acid (7.5 mmol), base (10.0
mmol), the calculated amount of thiourea, Pd and H2O (5 mL) were
added to a flask containing a magnetic stir bar under air. The flask
was sealed with a rubber septum and the contents were stirred at the
specified temperature for the appropriate period of time. Upon com-
pletion, the reaction mixture was extracted using Et2O (3 × 10 mL).
The solvent was removed on a rotary evaporator and the residue was
purified by flash chromatography on silica gel to afford the desired
product. The coupling products were characterized by 1H NMR and
13C NMR spectroscopy (see the Supporting Information). The identi-
ties of the products were confirmed by comparison with literature
spectroscopic data.18
HRMS (ESI): m/z [M + H]+ calcd for C19H21N2O2S: 341.1324; found:
341.1313.
2,2′-{[(2-Thioxoimidazolidine-1,3-diyl)bis(3,5-dimethyl-4,1-
phenylene)]bis(oxy)}diacetic Acid (1f)
Yield: 440 mg (96%); white solid; mp >230 °C.
IR (KBr): 2923, 1736, 1493, 1314, 1279, 1166, 1093, 848, 695 cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 6.68 (s, 4 H), 4.66 (s, 4 H), 3.94 (s, 4
H), 2.20 (s, 12 H).
13C NMR (150 MHz, DMSO-d6): δ = 180.6, 170.7, 157.2, 138.4, 131.4,
Recycling of Catalyst 1i-Na2PdCl4 in Aqueous Suzuki–Miyaura
Reactions
The catalyst 1i (1 mol%, 4.6 mg), Na2PdCl4 (0.5 mol%, 1.5 mg), phenyl-
boronic acid (914.5 mg, 7.5 mmol), KOH (561 mg, 10.0 mmol), TBAB
(5 mmol, 1.61 g) and the aryl halide (5.0 mmol) were added to a flask
containing a magnetic stir bar. H2O (5 mL) was added and the mixture
was stirred at 25 °C or 100 °C for the appropriate period of time. Upon
completion, the mixture was extracted with Et2O (3 × 10 mL). The or-
ganic solvent was collected by centrifugation and removed on a rota-
ry evaporator. The residue was purified by flash chromatography on
silica gel to give the product. The aqueous phase from the centrifuga-
tion was evaporated under reduced pressure to remove any residual
Et2O. The aqueous catalytic system was recharged with the same sub-
strates and base for the next run.
114.2, 64.8, 47.8, 18.0.
HRMS (ESI): m/z [M + H]+ calcd for C23H27N2O6S: 459.1590; found:
459.1584.
5-(3-Mesityl-2-thioxoimidazolidin-1-yl)isophthalic Acid (1g)
Yield: 354 mg (92%); white solid; mp >230 °C.
IR (KBr): 2956, 1735, 1600, 1436, 1306, 1279, 1214, 760, 669 cm–1
1H NMR (600 MHz, DMSO-d6): δ = 8.52 (d, J = 1.5 Hz, 2 H), 8.29 (t, J =
1.5 Hz, 1 H), 6.95 (s, 2 H), 4.43–4.37 (m, 2 H), 3.93–3.87 (m, 2 H), 2.25
(s, 3 H), 2.18 (s, 6 H).
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

K
W. Chen et al.
Paper
Synthesis
Funding Information
(6) (a) Suzuki, A. J. Organomet. Chem. 1999, 576, 147. (b) Wolfe, J. P.;
Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999,
121, 9550. (c) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron
2002, 58, 9633.
We are grateful for the financial support from the National Natural
Science Foundation of China (21502172), Zhejiang Provincial Natural
Science Foundation of China (LQ13B020005, LQ15H300001), the Sci-
ence and Technology Innovation Team Project of Ningbo Science and
Technology Bureau, China (2015C110027), the Key Laboratory of
Ningbo, China (2016A22002) and the Ningbo Natural Science Founda-
(7) (a) Schonfelder, D.; Nuyken, O.; Weberskirch, R. J. Organomet.
Chem. 2005, 690, 4648. (b) Churruca, F.; SanMartin, R.; Ines, B.;
Tellitu, I.; Dominguez, E. Adv. Synth. Catal. 2006, 348, 1836.
(c) Fleckenstein, C.; Roy, S.; Leuthaeusser, S.; Plenio, H. Chem.
Commun. 2007, 2870. (d) Meise, M.; Haag, R. ChemSusChem
2008, 1, 637. (e) Ines, B.; SanMartin, R.; Moure, M. J.;
Dominguez, E. Adv. Synth. Catal. 2009, 351, 2124. (f) Turkmen,
H.; Can, R.; Çetinkaya, B. Dalton Trans. 2009, 7039. (g) Roy, S.;
Plenio, H. Adv. Synth. Catal. 2010, 352, 1014. (h) Tu, T.; Feng, X.;
Wang, Z.; Liu, X. Dalton Trans. 2010, 39, 10598. (i) Godoy, F.;
Segarra, C.; Poyatos, M.; Peris, E. Organometallics 2011, 30, 684.
(j) Karimi, B.; Akhavan, P. F. Chem. Commun. 2011, 47, 7686.
(k) Karimi, B.; Akhavan, P. F. Inorg. Chem. 2011, 50, 6063. (l) Li, L.
Y.; Wang, J. Y.; Zhou, C. S.; Wang, R. H.; Hong, M. C. Green Chem.
2011, 13, 2071. (m) Turkmen, H.; Pelit, L.; Çetinkaya, B. J. Mol.
Catal. A: Chem. 2011, 348, 88. (n) Benhamou, L.; Besnard, C.;
Kündig, E. P. Organometallics 2013, 33, 260. (o) Gupta, S.; Basu,
B.; Das, S. Tetrahedron 2013, 69, 122. (p) Kolychev, E. L.;
Asachenko, A. F.; Dzhevakov, P. B.; Bush, A. A.; Shuntikov, V. V.;
Khrustalev, V. N.; Nechaev, M. S. Dalton Trans. 2013, 42, 6859.
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(r) Schaper, L.-A.; Hock, S. J.; Herrmann, W. A.; Kühn, F. E.
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Baquero, E. A.; Silbestri, G. F.; Gonzalez-Arellano, C.; de Jesús, E.;
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Rev. 2015, 115, 4607.
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