The design and synthesis of bis(thiourea) ligands and their application in Pd-catalyzed heck and suzuki reactions under aerobic conditions

Article abstract of DOI:10.1002/ejoc.200500644

New, bulky N,N-disubstituted acyclic and cyclic bis(thiourea) ligands have been designed and synthesized. Their palladium(0) complexes are very stable and are active catalysts for Heck and Suzuki coupling reactions of aryl iodides and bromides under aerobic conditions. Good TONs and TOFs were achieved in the coupling reactions [for PhI, TONs up to 1000000 and TOFs up to 200000 (h ^-1); for activated aryl bromide, TONs up to 89000]. In addition, further studies were conducted to know more about the nature of these catalysts. The active catalyst was found to be the chelate complex containing the bis(thiourea) and Pd in a 1:1 ratio. However, unlike a monothiourea, further coordination can occur to give a coordinatively saturated complex when bis(thiourea) and Pd are combined in a 2:1 ratio; this complex is catalytically inactive in coupling reactions. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200500644

FULL PAPER
DOI: 10.1002/ejoc.200500644
The Design and Synthesis of Bis(thiourea) Ligands and Their Application in
Pd-Catalyzed Heck and Suzuki Reactions Under Aerobic Conditions
Wei Chen,[a] Rui Li,[b] Bo Han,[a] Bang-Jing Li,[b] Ying-Chun Chen,*[a] Yong Wu,[a]
Li-Sheng Ding,[b] and Dan Yang[c]
Keywords: Cross-coupling / Homogeneous catalysis / Palladium / S ligands
New, bulky N,N-disubstituted acyclic and cyclic bis(thio-
urea) ligands have been designed and synthesized. Their pal-
ladium(0) complexes are very stable and are active catalysts
for Heck and Suzuki coupling reactions of aryl iodides and
bromides under aerobic conditions. Good TONs and TOFs
were achieved in the coupling reactions [for PhI, TONs up to
1000000 and TOFs up to 200000 (h–1); for activated aryl bro-
mide, TONs up to 89000]. In addition, further studies were
conducted to know more about the nature of these catalysts.
The active catalyst was found to be the chelate complex con-
taining the bis(thiourea) and Pd in a 1:1 ratio. However, un-
like a monothiourea, further coordination can occur to give a
coordinatively saturated complex when bis(thiourea) and Pd
are combined in a 2:1 ratio; this complex is catalytically inac-
tive in coupling reactions.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Introduction
product. While the Pd complex of acyclic monothioureas
such as 7c show no activity in the Heck reaction,[8] we
found that a mixture of [Pd(dba)2] and acyclic 2a could ef-
ficiently catalyze the coupling of PhI with methyl acrylate.
Moreover, the complex between 2a and Pd exhibits excel-
lent thermal stability and no palladium black was formed
after heating at 150 °C for 24 h.[11] Considering the possibil-
ity that the two sulfur atoms of the bis(thiocarbamoyl chlo-
ride) 2a may coordinate to Pd to form the active com-
plex,[12] we decided to investigate if bulky chelating thiourea
ligands could form robust catalysts with transition metals
(Figure 1). Here we report the design and synthesis of
novel, bulky bis(thiourea) ligands and their application in
Pd-catalyzed Heck and Suzuki coupling reactions.
Palladium-catalyzed cross-coupling reactions are very
versatile protocols for C–C bond formation in organic syn-
thesis,[1] and bulky, electron-rich organophosphane com-
pounds have been found to behave as highly active ligands,
even for inert aryl chlorides.[2] However, their synthetic ap-
plications are significantly limited due to the air-sensitivity
of these ligands. Over the past few years considerable atten-
tion has been focused on the development of air-stable pal-
ladium catalysts,[3] amongst which palladacycles[4] and pal-
ladium–carbene complexes[5] are outstanding. On the other
hand, thioureas are generally air- and moisture-stable solids
and their structures can be easily tuned by varying the N-
substitution. Their potential application as ligands in me-
tal-catalyzed reactions has been reported recently.[6] Yang
et al.[7] and our group[8] have also demonstrated that bulky
monothiourea–Pd complexes are active catalysts for Heck[9]
and Suzuki[10] reactions of aryl halides or arenediazonium
salts.
During the synthesis of the bulky monothiourea 7a, we
isolated the bis(thiocarbamoyl chloride) 2a as a stable by-
[a] Department of Medicinal Chemistry, West China School of
Pharmacy, Sichuan University,
Chengdu 610041, China
[b] Chengdu Institute of Biology, Chinese Academy of Sciences,
Chengdu 610041, China
[c] Department of Chemistry, The University of Hong Kong,
Pokfulam Road, Hong Kong, China
E-mail: ycchenhuaxi@yahoo.com.cn
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Figure 1. Structures of thiourea ligands.
Eur. J. Org. Chem. 2006, 1177–1184
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1177

W. Chen, R. Li, B. Han, B.-J. Li, Y.-C. Chen, Y. Wu, L.-S. Ding, D. Yang
FULL PAPER
duction, and the crude product was subsequently treated
with thiophosgene without purification to give the bulky
bis(thiourea) systems 1e and 1f in good yields (Scheme 3).
Results and Discussion
Ligand Design and Synthesis
The bis(thiocarbamoyl chloride) 2 could be smoothly ob-
tained from the reaction of N,NЈ-diarylethylenediamine[13]
with excess thiophosgene. Subsequently, the acyclic bis(thio-
urea) ligands 1a–c were prepared by heating dichloride 2
with excess secondary amine in a pressure tube (Scheme 1).
Unfortunately, this reaction is quite sensitive to the struc-
tures of the secondary amines. Attempts to synthesize acy-
clic bis(thiourea) compounds using more bulky amines such
as dibenzylamine failed, probably owing to the steric hin-
drance and the low reactivity of the dichloride 2.
Scheme 3. Synthesis of cyclic bis(thiourea) ligands 1e and 1f.
Heck Reactions under Aerobic Conditions
With the various bis(thiourea) ligands in hand, the cata-
lytic activity of the bis(thiourea)–Pd0 complexes was scre-
ened in the Heck reaction between iodobenzene and methyl
Scheme 1. Synthesis of acyclic bis(thiourea) ligands.
In order to introduce more bulky structures into the bis- acrylate at 100 °C (Table 1). The reactions were conducted
(thiourea) system, the cyclic bis(thiourea) ligands were de- in air and all the reagents were used directly as received.
signed and synthesized. In the first strategy, N-mesitylglycin- Initial studies showed that a 1:1 ratio of bis(thiourea) to
amide (3)[14] was reduced to the diamine, and subsequent reac- Pd is crucial to achieve high catalytic activity; an excess
tion with bis(bromomethyl)mesitylene[15] gave the tetraamine of bis(thiourea) ligand tended to dramatically decrease the
4. Although attempts to isolate pure 4 were unsuccessful, pure conversion rate. The structure of each bis(thiourea) ligand
bis(thiourea) 1d could be obtained after cyclization with thio- also has a great influence on the catalytic activity of its
phosgene in 11% yield for the three steps (Scheme 2).
palladium complex. Good catalytic efficacy was observed
for acyclic bis(thiourea)–Pd complexes, and the best activity
amongst these compounds was observed for bis(thiourea)
1c, derived from acyclic diethylamine (Table 1, entries 1–3).
Although the 1e–Pd complex exhibited lower catalytic ac-
tivity (entry 5), much better results were obtained when
more bulky ligands 1d or 1f were applied, and, indeed, the
1f–Pd complex displayed the highest catalytic activity (en-
try 6). It is notable that all bis(thiourea)–Pd0 catalysts dem-
onstrate excellent thermal stability, and high catalytic ac-
tivity was observed at elevated temperature. As indicated in
Table 1, high yields were obtained within 0.5 h at 150 °C
when 0.01 mol-% catalyst loading was applied for acyclic
bis(thiourea) derivatives 1a or 1c (entries 7 and 8). At a
higher temperature (180 °C), and with 1c as ligand, the cat-
alyst loading could be lowered even further, and quantita-
tive yields were obtained at 0.001 mol-% or 0.00033 mol-%
Scheme 2. Synthesis of cyclic bis(thiourea) ligand 1d.
Another process was also developed in order to improve Pd after 0.5 h or 3.5 h, respectively [entries 9 and 10, TOF
the synthesis of bis(thiourea) ligands. The N-arylglycine (h–1) up to 200000]. Furthermore, solvent-free conditions
5[14] was condensed with m-phenylenediamine in the pres- could be applied in our catalytic system (entries 11 and 12),
ence of EDCI and HOBt. The resulting bis(amide) 6 was and a very high TON (up to 1000000) was obtained in the re-
smoothly converted into the tetraamine by borane re- action with neat PhI, n-butyl acrylate, and NBu3 (entry 12).
1178
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1177–1184

Bis(thiourea) Ligands in Catalytic Heck and Suzuki Reactions
FULL PAPER
Table 1. Screening bis(thiourea) ligands for the palladium-catalyzed
Heck reaction.[a]
The reaction scope of the Heck reaction catalyzed by the
complex 1f–Pd0 was further explored with a number of aryl
halides and olefins. The results are summarized in Table 2.
For deactivated aryl iodides, complete conversion of the
substrate was observed within 3 h using 0.01 mol-% Pd cat-
alyst in the reaction with monosubstituted olefins such as
n-butyl acrylate (Table 2, entry 1). Under relatively harsh
condition (130 °C, 0.5 mol-% Pd), trisubstituted olefins[16]
could be prepared starting from 1,1- or 1,2-disubstituted
olefins (entries 2–4). Activated p-bromobenzaldehyde was a
suitable substrate at 0.1 mol-% Pd at 130 °C, and a high
isolated yield was obtained (entry 5). Better yields could be
achieved for other aryl bromides in the presence of 20 mol-
% TBAB (tetrabutylammonium bromide) and 0.1 mol-%
catalyst (entries 6–9).[17] Attempts to further decrease the
catalyst loading were also successful, and a high TON
(89000) could be obtained for the reaction of 3-nitrobro-
mobenzene and n-butyl acrylate when the reaction tempera-
ture was increased (entry 11). Deactivated p-bromoanisole
was smoothly coupled with styrene at 0.5 mol-% Pd catalyst
at higher temperature (160 °C) (entry 12). Unfortunately,
aryl chlorides were inert in this catalytic system, even in the
presence of TBAB/base (NaOAc, K2CO3, or KOtBu).[8]
Entry
Ligand
Pd
[mol-%]
T
[°C]
t
[h]
Yield[b]
[%]
TON
[×103]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.001
0.00033
0.0002
0.0001
100
100
100
100
100
100
150
150
180
180
180
180
6
6.5
4
4
4
86
64
95
99
45
99
89
92
99
99
99
99
8.6
6.4
9.5
10
4.5
10
8.9
9.2
100
300
500
1000
2
1a
1c
1c
1c
1f
0.5
0.5
0.5
3.5
5
9[c][d]
10[c][e]
11[c][f]
12[c][f]
1c
12
[a] Reactions were conducted under aerobic conditions. Unless
indicated otherwise, the reactions were conducted with 2.5 mmol
of PhI, PhI/acrylate/TEA, 1:1.2:1.2, [Pd(dba)2]/bis(thiourea), 1:1.
[b] Isolated yield. [c] NBu3 and n-butyl acrylate were used. [d] At
7.5 mmol scale in NMP. [e] At 12.5 mmol scale in NMP. [f] At
25 mmol scale in solven-free conditions.
Table 2. Heck reaction of aryl iodides and bromides with olefins.[a]
[a] [Pd(dba)2]/bis(thiourea), 1:1; ArX/olefin/base, 1:1.2:1.2. [b] Isolated yield. [c] E/Z = 4.5:1. [d] E/Z = 8.2:1. [e] E Product. [f] 20 mol-%
TBAB was added.
Eur. J. Org. Chem. 2006, 1177–1184
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1179

W. Chen, R. Li, B. Han, B.-J. Li, Y.-C. Chen, Y. Wu, L.-S. Ding, D. Yang
FULL PAPER
Suzuki Reactions under Aerobic Conditions
applied at 0.5 mol-% Pd at 120 °C (entry 8). Similar results
were gained when bulky, monodentate N,NЈ-bis(2Ј,5Ј-di-
The Pd-catalyzed Suzuki cross-coupling reaction of aryl tert-butylphenyl)ethylenethiourea (7a)[8] was used (entry 9).
halides with aryl boronic acids is a general and efficient However, the yield could be increased by adding 20 mol-
synthetic route to biaryl compounds and has found wide- % TBAB (entry 10). For 3,5-difluorophenylboronic acid, a
spread application in many areas of organic synthesis. The better result could be obtained by using TBAB as the ionic
operationally simple and air-stable nature of our thiourea/ solvent (entry 11). An acceptable yield was achieved for p-
Pd catalytic system inspired us to investigate its scope in nitrochlorobenzene with 1 mol-% Pd and 20 mol-% TBAB
the Suzuki reaction. As revealed in Table 3, an excellent iso- (entry 12 vs. entries 13 and 14). However, very low conver-
lated yield was obtained at a loading of 0.01 mol-% Pd at sions (Ͻ5%) were observed when other aryl chlorides were
100 °C after 3 h under aerobic conditions for p-iodoanisole applied. 1-Bromostyrene also displayed high reactivity
(Table 3, entry 1). A quantitative yield could also be towards phenylboronic acid in the bis(thiourea)–Pd system
achieved at 0.001 mol-% catalyst loading (entry 2). Encour- (entry 15). Potassium aryl trifluoroborates have been found
aged by these results, we began to evaluate the coupling to be more reactive than the corresponding organoboronic
reaction of aryl bromides with aryl boronic acids. For acti- acid,[18] and high yields were obtained at only 0.1 mol-% Pd
vated bromides, almost quantitative yields were achieved at 100 °C (entries 16 and 17). We also conducted the Suzuki
within 3 h in the presence of 0.1 mol-% Pd under the same reaction at further decreased catalyst loading (0.01 mol-%),
conditions (entries 3–7). On the other hand, only a low and a quantitative yield was obtained for 3-nitrobromoben-
yield was obtained when deactivated p-bromoanisole was zene at 120 °C in 3 h (entry 18).
Table 3. Suzuki coupling reaction catalyzed by 1f·Pd(dba)2.[a]
[a] [Pd(dba)2]/bis(thiourea), 1:1, ArX/Ar1B(OH)2/K2CO3, 1:1.2:2.0 in 25% H2O in NMP. [b] Isolated yield. [c] With ligand 7a. [d] 20 mol-
% TBAB was added. [e] The reaction was conducted in neat TBAB. [f] p-Nitrochlorobenzene/PhB(OH)2/K2CO3, 1:2.0:3.0.
1180
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1177–1184

Bis(thiourea) Ligands in Catalytic Heck and Suzuki Reactions
FULL PAPER
Complexes Study
9 [Pd0(7b)2 + H, m/z = 783.2, Figure 2, a] was observed,
even in the presence of excess ligand (4 equiv.).[8] Like 1c,
Since some difference in catalytic behavior was noted for chelate complex 10 (Pd0·1e + H, m/z = 621.3, Figure 2, b)
the bis(thiourea) catalysts compared with their monothio- was detected when cyclic bis(thiourea) 1e and [Pd(dba)2]
urea analogues,[8] more experiments were conducted to in- were combined in a 1:1 ratio.[20] In contrast, when another
vestigate the nature of the Pd complexes. As illustrated in equivalent of 1e was added, the ESI-MS study demon-
Scheme 4, we successfully isolated the chelate complex (8) strated the formation of Pd0·(1e)2 (M + H, m/z = 1135.0,
between bis(thiourea) 1c and PdCl2, which was well charac- Figure 2, c), which is completely inactive in the Heck reac-
terized by spectroscopic techniques. Moreover, a similar tion of PhI and methyl acrylate. Nevertheless, we were able
complex was detected for the 1c/Pd0 system (see Supporting to detect the formation of the trigonal palladium complex
Information). ESI-MS studies[19] were conducted to know 13 (Pd0·1e·7b + H, m/z = 959.2, Figure 2, d) when one
more about the coordinating difference between cyclic mon- equivalent of monothiourea 7b was added to the previously
othiourea and bis(thiourea) ligands (Scheme 4). As pre- prepared 10 (Scheme 4). Interestingly, this in situ prepared
viously reported, for monothiourea 7b only the 2:1 complex complex solution could efficiently catalyze the Heck reac-
Scheme 4. Preparation of thiourea–Pd complexes.
Figure 2. ESI mass spectra of thiourea–Pd0 complexes.
Eur. J. Org. Chem. 2006, 1177–1184
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1181

W. Chen, R. Li, B. Han, B.-J. Li, Y.-C. Chen, Y. Wu, L.-S. Ding, D. Yang
FULL PAPER
General Procedure for the Synthesis of Acyclic Bis(thiourea) Li-
gands: Bis(thiocarbamoyl chloride) 2 (0.5 mmol) and excess sec-
ondary amine (5 mmol) were heated at 100 °C in a sealed pressure
tube for 24 h. The solution was then diluted with EtOAc (10 mL)
and the organic phase was washed with dilute HCl and brine. The
organic layer was dried and concentrated. Flash chromatography
gave the pure bis(thiourea) derivatives 1a–c as white solids.
tion of PhI and methyl acrylate, with even better results
than with 10 (0.01 mol-% Pd, 4 h, 83% yield; cf. Table 1,
entry 5).[21] Therefore, coordinatively saturated complex 12
might be produced rather than the trigonal complex 11
when bis(thiourea) 1e and [Pd(dba)2] are combined in a 2:1
ratio, although the exact structure awaits further explora-
tion.[22,23]
Acyclic Bis(thiourea) 1a: Yield: 328 mg (95%). White solid, m.p.
1
225–226 °C. H NMR (400 MHz, CDCl3): δ = 7.37–7.34 (m, 2 H,
ArH), 7.21–7.18 (m, 2 H, ArH), 7.18–7.00 (m, 2 H, ArH), 4.87–
4.79 (m, 2 H, CHH), 4.15–4.11 (m, 2 H, CHH), 3.54–3.35 (m, 8
H, NCH2 of piperidinyl ring), 1.44–1.19 (m, 48 H, piperidinyl ring
+ tBu) ppm. 13C NMR (100 MHz, CDCl3): δ = 190.0, 149.1, 142.9,
141.3, 129.8, 127.4, 124.1, 54.0, 52.5, 35.6, 34.0, 32.0, 31.1, 25.2,
Conclusions
We have presented the synthesis of bulky N,N-disubsti-
tuted acyclic and cyclic bis(thiourea) ligands. These com-
pounds act as strong coordinating ligands for palladium
and the complexes demonstrate high thermal stability.
Good catalytic activity for aryl iodides and bromides in
24.2 ppm. IR (KBr): ν = 2958, 2865, 1609, 1440, 1397, 1362, 1244,
˜
1185, 1133, 1026 cm–1. EI-HRMS: calcd. for C42H66N4S2 690.4729;
found 690.4717. C42H66N4S2 (691.13): calcd. C 72.99, H 9.63, N
Heck and Suzuki coupling reactions was exhibited under 8.11; found C 72.90, H 9.52, N 8.13.
aerobic conditions for the bis(thiourea)–Pd catalysts, and
Acyclic Bis(thiourea) 1b: Yield: 220 mg (40%) for two steps. White
solid, m.p. 222–224 °C. H NMR (400 MHz, CDCl3): δ = 6.83 (s,
4 H, ArH), 4.29 (s, 4 H, CH2), 3.30–3.27 (m, 8 H, NCH2 of piperid-
inyl ring), 2.25 (s, 6 H, ArCH3), 2.18 (s, 12 H, ArCH3), 1.39–1.36
(m, 4 H, piperidinyl ring), 1.17–1.15 (m, 8 H, piperidinyl ring) ppm.
13C NMR (100 MHz, CDCl3): δ = 188.3, 141.3, 136.1, 134.3, 130.0,
1
high TONs and TOFs were achieved (for PhI, TONs up to
1000000 and TOFs up to 200000; for activated bromide,
TONs up to 89000). Moreover, spectroscopic investigation
of the bis(thiourea)–Pd complexes demonstrated that the
active catalyst is the chelating species in a 1:1 ratio. In the
presence of two equivalents of the bis(thiourea) ligand fur-
ther coordination gives the coordinatively saturated com-
plex, which is catalytically inactive in these coupling reac-
tions. Work is currently underway to develop recyclable
thiourea-Pd catalysts and extend the application of these
novel thiourea ligands in palladium- and other transition-
metal-catalyzed reactions.
51.9, 50.9, 25.2, 24.2, 20.7, 19.1 ppm. IR (KBr): ν = 2934, 1609,
˜
1473, 1422, 1369, 1131. EI-HRMS: calcd. for C32H46N4S2
550.3164; found 550.3158. C32H46N4S2 (550. 86): calcd. C 69.77, H
8.42, N 10.17; found C 69.52, H 8.44, N 10.09.
Acyclic Bis(thiourea) 1c: Yield: 200 mg (38%) for two steps. White
1
solid, m.p. 197–199 °C. H NMR (400 MHz, CDCl3): δ = 6.82 (s,
4 H, ArH), 4.29 (s, 4 H, CH2), 3.30 (q, J = 6.8 Hz, 8 H, CH2), 2.24
(s, 6 H, ArCH3), 2.21 (s, 12 H, ArCH3), 0.73 (t, J = 6.8 Hz, 12 H,
CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 188.2, 141.6, 136.4,
135.0, 51.3, 46.0, 20.8, 19.2, 11.7 ppm. IR (KBr): ν = 2963, 1651,
˜
1486, 1370, 1348, 1274, 1185, 1152, 1120 cm–1. EI-HRMS: calcd.
for C30H46N4S2 526.3164; found 526.3168. C30H46N4S2 (526.84):
calcd. C 68.39, H 8.80, N 10.63; found C 68.37, H 8.82, N 10.39.
Experimental Section
General Methods: Melting points were determined in open capillar-
ies and are uncorrected. The 1H and 13C NMR spectra were re-
corded at 400 MHz and 50 or 100 MHz (Bruker Avance), respec-
tively. The chemical shifts are reported in ppm downfield from
CDCl3 (δ = 7.27 ppm) for 1H NMR and relative to the central
CDCl3 resonance (δ = 77.0 ppm) for 13C NMR spectroscopy. ESI-
mass spectra were measured with a Finnigan LCQDECA ion trap
mass spectrometer. All reagents were used without purification as
commercially available.
Synthesis of Cyclic Bis(thiourea) Ligand 1d
Compound 3: Ethyl (mesitylamino)acetate[14] (1.6 g, 7.2 mmol) in
methanol (20 mL) was added to a three-necked flask fitted with
gas inlet and ammonia was bubbled through it at 0 °C. The flask
was then sealed with septa. After standing at room temperature
for 48 h the solvent was removed under vacuum. Trituration with
petroleum ether gave 3 (1.22 g, 88%) as a white solid. M.p. 107–
1
Preparation of Dichloride 2: A solution of N,NЈ-diaryl diamine
108 °C. H NMR (400 MHz, CDCl3): δ = 7.02 (s, 1 H, NH), 6.84
(1.0 mmol) and NEt3 (0.42 mL, 3.0 mmol) in THF (10 mL) was (s, 2 H, ArH), 6.02 (s, 2 H, NH2), 3.62 (s, 2 H, CH2), 2.27 (s, 6 H,
added dropwise to a stirred solution of thiophosgene (0.3 mL,
3.0 mmol) in dry THF (10 mL) at 0 °C. After stirring at room tem-
perature overnight, the organic layer was washed with water, dried,
and concentrated. Compound 2a was recrystallized from ethanol
to give a stable white solid, whereas 2b was used directly in the next
step.
ArCH3), 2.23 (s, 3 H, ArCH3) ppm. 13C NMR (50 MHz, CDCl3):
δ = 173.1, 144.2, 129.6, 129.3, 128.2, 50.9, 20.3, 18.5 ppm. IR
(KBr): ν = 3413, 3178, 1682, 1487, 1390, 1321, 1220, 1157,
˜
1091 cm–1. ESI-LRMS: m/z = 193.1 [M + 1].
Cyclic Bis(thiourea) 1d: LiAlH4 (0.6 g, 16.2 mmol) was suspended
in dry THF (50 mL) and the amide 3 (1.0 g, 5.2 mmol) in THF
(10 mL) was added dropwise. After heating at reflux overnight, the
Dichloride 2a: Yield: 355 mg (60%). M.p. 200–202 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.42 (d, J = 8.5 Hz, 2 H, ArH), 7.29 (dd, reaction was quenched with 10% potassium hydroxide solution
J = 8.5, 2.2 Hz, 2 H, ArH), 6.74 (d, J = 2.2 Hz, 2 H, ArH), 5.33– (0.9 mL). The resulting solid was filtered through a pad of celite
5.28 (m, 2 H, CHH), 3.61–3.55 (m, 2 H, CHH), 1.30 (s, 18 H, tBu), and thoroughly washed with THF. HCl gas was introduced to pre-
1.17 (s, 18 H, tBu) ppm. 13C NMR (100 MHz, CDCl3): δ = 176.6,
cipitate the corresponding di-HCl salt (1.0 g, 90%). The diamine
salt was directly used in the next step. A solution of bis(bromome-
150.4, 141.0, 140.7, 130.4, 126.3, 125.5, 53.8, 35.6, 34.1, 31.9,
31.1 ppm. IR (KBr): ν = 2965, 1734, 1407, 1361, 1240, 1110 cm–1. thyl)mesitylene (0.72 g, 2.3 mmol) in CH3CN (10 mL) was added
˜
EI LRMS: m/z (%) = 592 (12) [M], 310 (100). EI-HRMS: calcd. slowly, at 80 °C, to a stirred mixture of the diamine salt (2.0 g,
for C32H46Cl2N2S2 592.2479; found 592.2467.
1182
9.2 mmol) and Na2CO3 (0.85 g, 8 mmol) in CH3CN (15 mL). The
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1177–1184

Bis(thiourea) Ligands in Catalytic Heck and Suzuki Reactions
FULL PAPER
resulting mixture was refluxed for 24 h. The mixture was then di-
luted with ethyl acetate and washed with brine, dried, and concen-
trated. The resulting oil was dissolved in THF (30 mL) and
Na2CO3 (1.27 g, 12 mmol) was added. Thiophosgene (0.7 mL,
9 mmol) in THF (10 mL) was added dropwise very slowly at room
temperature. After stirring overnight the THF was removed and
water (20 mL) and ethyl acetate (40 mL) were added. The organic
layer was washed with dilute HCl and brine, dried, and concen-
trated. The pure bis(thiourea) 1d was obtained by flash chromatog-
raphy (20% ethyl acetate/petroleum ether) as a white solid (150 mg,
11% for three steps). m.p. Ͼ 230 °C. 1H NMR (400 MHz, CDCl3):
δ = 6.97 (s, 1 H, ArH), 6.95 (s, 4 H, ArH), 4.97 (s, 4 H, ArCH2),
3.66 (t, J = 8.4 Hz, 4 H, CH2), 3.41 (t, J = 8.4 Hz, 4 H, CH2), 2.43
(s, 3 H, ArCH3), 2.40 (s, 6 H, ArCH3), 2.29 (s, 6 H, ArCH3), 2.22
(s, 12 H, ArCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 181.7,
138.6, 138.1, 137.8, 136.5, 134.7, 130.8, 130.7, 129.4, 46.9, 46.3,
room temperature overnight. The pure cyclic bis(thiourea) was ob-
tained as a white solid by flash chromatography and recrystalli-
zation from ethanol.
Cyclic Bis(thiourea) 1e: Yield: 208 mg (45%) for two steps. White
1
solid, m.p. Ͼ 230 °C. H NMR (400 MHz, CDCl3): δ = 8.20 (s, 1
H, ArH), 7.51–7.44 (m, 3 H, ArH), 6.97 (s, 4 H, ArH), 4.29 (t, J
= 8.4 Hz, 4 H, CH2), 3.91 (t, J = 8.4 Hz, 4 H, CH2), 2.31 (s, 6 H,
CH3), 2.28 (s, 12 H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ
= 180.7, 141.0, 138.3, 136.3, 134.7, 129.4, 128.6, 121.1, 120.2, 49.3,
47.2, 21.0, 17.8 ppm. IR (KBr): ν = 2917, 1604, 1489, 1421, 1306,
˜
1277, 1076 cm–1. ESI HRMS: calcd. for C30H34N4S2 + H 515.2303;
found 515.2294. C30H34N4S2 (514.75): calcd. C 70.00, H 6.66, N
10.88; found C 69.89, H 6.73, N 10.72.
Cyclic Bis(thiourea) 1f: Yield: 242 mg (41%) for two steps. White
1
solid, m.p. Ͼ 230 °C. H NMR (400 MHz, CDCl3): δ = 8.24–8.22
(m, 1 H, ArH), 7.53–7.43 (m, 3 H, ArH), 7.38 (d, J = 2.0 Hz, 2 H,
ArH), 7.35 (d, J = 2.0 Hz, 2 H, ArH), 7.11 (s, 2 H, ArH), 4.29–
4.18 (m, 4 H, CH2), 4.13–4.07 (m, 2 H, CH2), 4.01–3.93 (m, 2 H,
CH2), 1.48 (s, 18 H, tBu), 1.34 (s, 18 H, tBu) ppm. 13C NMR
(100 MHz, CDCl3): δ = 184.1, 150.5, 145.0, 141.2, 139.6, 128.8,
128.7, 128.2, 127.5, 125.5, 121.8, 121.6, 121.2, 52.6, 49.4, 35.4, 34.3,
45.5, 21.0, 20.4, 17.7, 16.2 ppm. IR (KBr): ν = 2917, 1609, 1489,
˜
1437, 1408, 1326, 1309, 1273, 1233, 1033 cm–1. ESI-LRMS: m/z
(%) = 585.2 (100) [M + 1]. ESI-HRMS: calcd. for C35H44N4S2 +
Na 607.2905; found 607.2883. C35H44N4S2 (584.88): calcd. C 71.88,
H 7.58, N 9.58; found C 71.72, H 7.53, N 9.50.
Synthesis of Cyclic Bis(thiourea)s Ligands 1e and 1f
31.9, 31.2 ppm. IR (KBr): ν = 2960, 1604, 1559, 1475, 1414, 1297,
˜
1084 cm–1. ESI-LRMS: m/z (%) = 655.4 (37) [M + 1], 639.5 (100).
ESI-HRMS: calcd. for C40H54N4S2 + H 655.3868; found 655.3864.
C40H54N4S2 (655.01): calcd. C 73.35, H 8.31, N 8.55; found C
73.27, H 8.43, N 8.33.
Preparation of Compound 6: 1,3-Phenylenediamine dihydrochloride
(0.18 g, 1 mmol), 5[13] (2.2 mmol), 1-[3-(dimethylamino)propyl]-3-
ethylcarbodiimide hydrochloride (EDCI; 0.46 g, 2.4 mmol) and 1-
hydroxybenzotriazole (HOBt; 0.14 g, 1 mmol) were stirred in DCM
(20 mL) at 0 °C. After 5 min NEt3 (5 mmol) was added and the
mixture was stirred at room temperature under argon and moni-
tored by TLC. After completion, solvent was removed under vac-
uum and ethyl acetate (30 mL) was added. The organic layer was
washed with saturated NaHCO3 and brine, dried, and concen-
trated. Pure 6 was obtained by flash chromatography or recrystalli-
zation from ethanol.
Synthesis of 1c·PdCl2 Complex 8: Dichloromethane (2 mL) was
added to
a vial containing 1c (38.2 mg, 0.073 mmol) and
[PdCl2(CH3CN)2] (18.8 mg, 0.073 mmol). After the solids had dis-
solved an immediate color change to red was observed. The solu-
tion was stirred for 0.5 h. All volatile components were then re-
moved in vacuo, and the resulting solid was treated with diethyl
ether (5 mL). The resulting powder was washed with toluene and
dried under vacuum to give 8 as an orange solid. Yield: 41 mg
(80%). m.p. Ͼ 220 °C. 1H NMR (400 MHz, CDCl3): δ = 6.76 (s, 2
H, ArH), 6.52 (s, 2 H, ArH), 5.55 (br. s, 2 H, CH2), 3.50–3.45 (m,
8 H, CH2), 2.81 (br. s, 2 H, CH2), 2.21 (s, 6 H, ArCH3), 2.04 (s, 6
H, ArCH3), 1.63 (s, 6 H, ArCH3), 1.27–1.19 (m, 12 H, CH3) ppm.
13C NMR (50 MHz, [D6]DMSO+CD2Cl2): δ = 184.8, 137.5, 133.1,
Diamide 6e: Yield: 390 mg (85%). White solid, m.p. 188–189 °C.
1H NMR (300 MHz, CDCl3): δ = 9.56 (s, 2 H, NH), 7.92 (s, 1 H,
ArH), 7.44–7.41 (m, 2 H, ArH), 7.30–7.25 (m, 1 H, ArH), 6.86 (s,
4 H, ArH), 3.81 (s, 4 H, CH2), 2.32 (s, 12 H, ArCH3), 2.25 (s, 6 H,
ArCH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.4, 157.3, 141.6,
138.1, 133.0, 129.8, 129.0, 115.5, 110.7, 52.5, 20.5, 18.3 ppm. IR
(KBr): ν = 3314, 2917, 1664, 1608, 1523, 1486, 1425, 1305,
˜
130.2, 129.1, 67.2, 52.8, 25.2, 20.2, 18.6, 18.1 ppm. IR (KBr): ν =
˜
1225 cm–1. ESI-LRMS: m/z = 459.2 [M + 1].
2971, 1636, 1459, 1400, 1076 cm–1. ESI-HRMS: calcd. for
C30H46Cl2N4PdIIS2
– Cl2 – H 631.2120; found 631.2115.
1
Diamide 6f: Yield: 538 mg (90%). White solid, m.p. 90–92 °C. H
C30H46Cl2N4PdS2 (704.17): calcd. C 51.17, H 6.58, N 7.96; found
C 51.08, H 6.69, N 8.24.
NMR (400 MHz, CDCl3): δ = 8.50 (s, 2 H, NH), 7.71 (s, 1 H,
ArH), 7.32–7.23 (m, 5 H, ArH), 6.85 (dd, J = 8.4, 2.0 Hz, 2 H,
ArH), 6.61 (d, J = 2.0 Hz, 2 H, ArH), 4.62 (s, 2 H, NH), 3.99 (d,
J = 5.2 Hz, 4 H, CH2), 1.49 (s, 18 H, tBu), 1.24 (s, 18 H, tBu) ppm.
13C NMR (100 MHz, CDCl3): δ = 169.3, 150.5, 144.9, 137.9, 131.8,
129.6, 126.3, 116.3, 116.1, 111.5, 110.5, 50.4, 34.3, 33.8, 31.2,
Supporting Information Available (for details see the footnote on
the first page of this article): Procedure for ESI MS study of the
thiourea-Pd complex. 1H NMR spectroscopic data for coupling
products; Spectra of bis(thiourea) ligands and complex 8.
30.3 ppm. IR (KBr): ν = 3449, 3349, 2961, 1689, 1610, 1561, 1524,
˜
1416, 1363, 1306, 1258, 1233, 1163, 915 cm–1. ESI-LRMS: m/z =
599.4 [M + 1].
Acknowledgments
General Procedure for Preparation of 1e and 1f: Borane–dimethyl
sulfide (2  in THF) (3.6 mL, 7.2 mmol, 8 equiv.) was added to a
solution of 6 (0.9 mmol) in THF (20 mL) at 0 °C and the solution
was refluxed overnight. After cooling to room temperature, meth-
anol was added very slowly to destroy the excess borane and the
solvent was removed. Methanol (10 mL) was added and removed
again under reduced pressure. The resulting tetraamine was directly
used in the next step. A dilute solution of thiophosgene (0.23 mL,
2.3 mmol) in THF (15 mL) was added very slowly to a stirred mix-
ture of the tetraamine obtained above and Na2CO3 (0.46 g,
5.4 mmol) in dry THF (20 mL). The mixture was then stirred at
This project was sponsored by SRF for ROCS, SEM, China. Y.C.C.
is grateful to Sichuan University for financial support.
[1] A. de Meijere, F. Diederich, Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed., volumes 1 and 2, Wiley-VCH, Weinheim,
2004.
[2] a) A. F. Littke, G. C. Fu, Angew. Chem. Int. Ed. 2002, 41, 4176–
4211; b) G. C. Fu, J. Org. Chem. 2004, 69, 3245–3249 and refer-
ences cited therein.
[3] a) M. R. Buchmeiser, K. Wurst, J. Am. Chem. Soc. 1999, 121,
11101–11107; b) J. Silberg, T. Schareina, R. Kempe, K. Wurst,
Eur. J. Org. Chem. 2006, 1177–1184
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1183

W. Chen, R. Li, B. Han, B.-J. Li, Y.-C. Chen, Y. Wu, L.-S. Ding, D. Yang
FULL PAPER
M. R. Buchmeiser, J. Organomet. Chem. 2001, 622, 6–18; c)
G. A. Grasa, A. C. Hillier, S. P. Nolan, Org. Lett. 2001, 3,
1077–1080; d) J. Masllorens, M. Moreno-Mañas, A. Pla-Quin-
tana, A. Roglans, Org. Lett. 2003, 5, 1559–1561; e) G. Y. Li, J.
Org. Chem. 2002, 67, 3643–3650 and references cited therein.
For recent reports on air-stable phosphane ligands, see: f) M.
Feuerstein, H. Doucet, M. Santelli, J. Org. Chem. 2001, 66,
5923–5925; g) N. Kataoka, Q. Shelby, J. P. Stambuli, J. F. Hart-
wig, J. Org. Chem. 2002, 67, 5553–5566; h) J. F. Jensen, M.
Johannsen, Org. Lett. 2003, 5, 3025–3028; i) T. J. Colacot,
H. A. Shea, Org. Lett. 2004, 6, 3731–3734.
[10] For recent reviews on the Suzuki coupling, see: a) J. Hassan,
M. Sévignon, C. Gozzi, E. Schulz, M. Lemaire, Chem. Rev.
2002, 102, 1359–1470; b) M. Miura, Angew. Chem. Int. Ed.
2004, 43, 2201–2203.
[11] Some Pd black deposited when the Pd complex of monothio-
urea 7a was heated under the same conditions.
[12] ESI-MS study of the solution of 2a with [Pd(dba)2] (1:1) indi-
cated the formation of complex Pd0·2a (m/z = 720.7 [M + Na]).
[13] a) A. J. Arduengo, R. Krafczyk, R. Schmutzler, H. A. Craig,
J. R. Goerlich, W. J. Marshall, M. Unverzagt, Tetrahedron
1999, 55, 14523–14534; b) S. Lee, J. F. Hartwig, J. Org. Chem.
2001, 66, 3402–3415.
[4] For recent reviews on palladacycles, see: a) J. Dupont, M.
Pfeffer, J. Spencer, Eur. J. Inorg. Chem. 2001, 1917–1927; b)
[14] K. Turnbull, J. Heterocycl. Chem. 1985, 22, 965–968.
R. B. Bedford, Chem. Commun. 2003, 1787–1796; c) A. Zapf, [15] A. W. Van der Made, R. H. Van der Made, J. Org. Chem. 1993,
M. Beller, Chem. Commun. 2005, 431–440; d) J. Dupont, C. S.
Consorti, J. Spencer, Chem. Rev. 2005, 105, 2527–2571.
[5] For recent reviews on N-heterocyclic carbene–palladium cata-
lysts, see: a) W. A. Herrmann, Angew. Chem. Int. Ed. 2002, 41,
1290–1309; b) B. S. Yong, S. P. Nolan, Chemtracts: Org. Chem.
2003, 205–227; c) V. César, S. Bellemin-Laponnaz, L. H. Gade,
Chem. Soc. Rev. 2004, 33, 619–636.
58, 1262–1263.
[16] C. Gurtler, S. L. Buchwald, Chem. Eur. J. 1999, 5, 3107–3112
and references cited therein.
[17] a) T. Jeffery, Tetrahedron Lett. 1985, 26, 2667–2670; b) M. T.
Reetz, E. Westermann, Angew. Chem. Int. Ed. 2000, 39, 165–
168.
[18] a) S. Darses, G. Michaud, J.-P. Genêt, Eur. J. Org. Chem. 1999,
1875–1883; b) G. A. Molander, B. W. Katona, F. Machrouhi,
J. Org. Chem. 2002, 67, 8416–8423; c) S. Darses, J.-P. Genet,
Eur. J. Org. Chem. 2003, 4313–4327; d) G. A. Molander, B.
Biolatto, Org. Lett. 2002, 4, 1867–1870; e) T. E. Barder, S. L.
Buchwald, Org. Lett. 2004, 6, 2649–2652.
[19] For recent reports on the use of ESI-MS in Pd-catalyzed
mechanism studies, see: a) C. Markert, A. Pfaltz, Angew. Chem.
Int. Ed. 2004, 43, 2498–2500; b) D. M. Tomazela, F. C. Gozzo,
G. Ebeling, P. R. Livotto, M. N. Eberlin, J. Dupont, Inorg.
Chim. Acta 2004, 357, 2349–2357; c) A. A. Sabino, A. H. L.
Machado, C. R. D. Correia, M. N. Eberlin, Angew. Chem. Int.
Ed. 2004, 43, 2514–2518l; d) C. Chevrin, J. Le Bras, F. Henin,
J. Muzart, A. Pla-Quintana, A. Roglans, R. Pleixats, Organo-
metallics 2004, 23, 4796–4799.
[20] The palladium catalytic precursor in the Heck reaction is gen-
erally postulated as a coordinatively unsaturated 14-electron
species (PdL2), see ref.[9b]
[21] The same results were obtained when the Heck reaction of PhI
and methyl acrylate was catalyzed by the in situ prepared solu-
tion of 10 and 2 mol 7b, so we believe that the coordinatively
saturated complex Pd0·1e·(7b)2 could not be formed owing to
the steric hindrance.
[6] a) G. De Munno, B. Gabriele, G. Salerno, Inorg. Chim. Acta
1995, 234, 181–183; b) B. Gabriele, G. Salerno, M. Costa, G. P.
Chiusoli, J. Organomet. Chem. 1995, 503, 21–28; c) F. Touch-
ard, F. Fache, M. Lemaire, Tetrahedron: Asymmetry 1997, 8,
3319–3326; d) F. Touchard, P. Gamez, F. Fache, M. Lemaire,
Tetrahedron Lett. 1997, 38, 2275–2278; e) F. Touchard, M. Ber-
nard, F. Fache, F. Delbecq, V. Guiral, P. Sautet, M. Lemaire,
J. Organomet. Chem. 1998, 567, 133; f) F. Touchard, M. Ber-
nard, F. Fache, M. Lemaire, J. Mol. Catal. A: Chem. 1999, 140,
1–11; g) T. Y. Zhang, M. J. Allen, Tetrahedron Lett. 1999, 40,
5813–5816; h) M. L. Tommasino, M. Casalta, J. A. J. Breuzard,
M. Lemaire, Tetrahedron: Asymmetry 2000, 11, 4835–4841; i)
J. A. J. Breuzard, M. L. Tommasino, F. Touchard, M. Lemaire,
M. C. Bonnet, J. Mol. Catal. A: Chem. 2000, 156, 223–232; j)
Y. Nan, H. Miao, Z. Yang, Org. Lett. 2000, 2, 297–299; k) H.
Miao, Z. Yang, Org. Lett. 2000, 2, 1765–1768; l) Y. Hu, Z.
Yang, Org. Lett. 2001, 3, 1387–1390; m) D. Kovala-Demertzi,
P. N. Yadav, M. A. Demertzis, J. P. Jasiski, F. J. Andreadaki,
I. D. Kostas, Tetrahedron Lett. 2004, 45, 2923–2926; n) Y. Tang,
L. Deng, Y. Zhang, G. Dong, J. Chen, Z. Yang, Org. Lett.
2005, 7, 593–595 and references cited therein.
[7] a) M. Dai, B. Liang, C. Wang, J. Chen, Z. Yang, Org. Lett.
2004, 6, 221–224; b) M. Dai, B. Liang, C. Wang, Z. You, J.
Xiang, G. Dong, J. Chen, Z. Yang, Adv. Synth. Catal. 2004,
346, 1669–1673. For furancarbothioamide-based palladacycles,
see: c) Z. Xiong, N. Wang, M. Dai, A. Li, J. Chen, Z. Yang,
Org. Lett. 2004, 6, 3337–3340.
[8] D. Yang, Y.-C. Chen, N.-Y. Zhu, Org. Lett. 2004, 6, 1577–1580.
[9] For recent reviews on the Heck reaction, see: a) I. P. Belets-
kaya, A. V. Cheprakov, Chem. Rev. 2000, 100, 3009–3066; b)
N. J. Whitcombe, K. K. Hii, S. E. Gibson, Tetrahedron 2001,
57, 7449–7476; c) A. B. Dounay, L. E. Overman, Chem. Rev.
2003, 103, 2945–2964; d) V. Farina, Adv. Synth. Catal. 2004,
346, 1553–1582.
[22] The same ESI-MS results were obtained with bis(thiourea) li-
gand 1f.
[23] Trigonal or coordinatively saturated Pd complexes can be pro-
duced from diphosphane ligands and palladium. The latter
complexes also display low catalytic activity in the Heck reac-
tion. See: a) M. Portnoy, D. Milstein, Organometallics 1999,
18, 1655–1664; b) M. Portnoy, Y. Ben-David, I. Rousso, D.
Milstein, Organometallics 1994, 13, 3465–3479.
Received: August 25, 2005
Published Online: December 13, 2005
1184
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1177–1184