Synthesis of novel palladacycles and their application in heck and Suzuki reactions under aerobic conditions

Article abstract of DOI:10.1021/ol048749s

(Chemical Equation Presented) Design and synthesis of a novel family of furancarbothioamide-based palladacycles are reported herein. These palladacycles are thermally stable, not sensitive to air or moisture, and are applied effectively in the Heck reaction of aryl halides with terminal olefins and in the Suzuki reaction of aryl halides with arylboronic acids. These reactions were performed under aerobic conditions, leading to turnover numbers (TONs) up to 1 × 10⁵.

Full text of DOI:10.1021/ol048749s

ORGANIC
LETTERS
2004
Vol. 6, No. 19
3337-3340
Synthesis of Novel Palladacycles and
Their Application in Heck and Suzuki
Reactions under Aerobic Conditions
,†
Zhengchang Xiong,† Nengdong Wang,† Mingji Dai,† Ang Li,† Jiahua Chen,* and
,†,‡
Zhen Yang*
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of
Education, College of Chemistry, Beijing 100871, China, Laboratory of Chemical
Genetics, Shenzhen Graduate School of Peking UniVersity, The UniVersity Town,
Shenzhen 518055, China, and ViVoQuest, Inc., 711 ExecutiVe BlVd,
Valley Cottage, New York 10989
zyang@chem.pku.edu.cn
Received July 1, 2004
ABSTRACT
Design and synthesis of a novel family of furancarbothioamide-based palladacycles are reported herein. These palladacycles are thermally
stable, not sensitive to air or moisture, and are applied effectively in the Heck reaction of aryl halides with terminal olefins and in the Suzuki
reaction of aryl halides with arylboronic acids. These reactions were performed under aerobic conditions, leading to turnover numbers (TONs)
up to 1 × 105.
Palladacycles are one of the most important and intensively
investigated classes of organometallic compounds, and some
are efficient catalysts or catalyst precursors in the Pd-
catalyzed C-C bond formation reactions.1
to both electronic and steric variations. Thus, the arylcar-
bothioamide-derived palladacycle was our primary choice
However, certain published phosphapalladacycles (1-4,
Figure 1) and phosphine-free N-heterocyclic carbenes (NHC)
(5-9, Figure 1) are air- and moisture-sensitive, and the
reactions have to be handled under an inert atmosphere.
Thiourea has been proven to be very useful in some Pd-
catalyzed reactions.2 One important aspect of the thiourea-
based ligand is its thermal stability and lack of sensitivity to
air and moisture. Our continuing interest in the development
of thiourea-related ligands in the Pd-catalyzed C-C bond
formation led us to explore the carbothioamide-derived
palladacycle because of its structural similarity with thiourea.
With the aim of studying C-C bond formation catalyzed
by the carbothioamide-derived palladacycle in a systematic
manner, we wanted our selected scaffolds to be amenable
† College of Chemistry, Beijing, and Shenzhen Graduate School of Peking
Figure 1. Selected existing palladacycles.
University, Shenzhen.
‡ VivoQuest, Inc.
10.1021/ol048749s CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/25/2004

because both electronic and steric effects can be addressed
effectively by changing different electron-donating and
-withdrawing groups (R1) on the aromatic ring (electronic
effect) and by changing various substitutions (R2) on the
nitrogen (steric effect), respectively (Figure 2).
Table 1. Palladacycle-Catalyzed Heck Reaction of
Iodobenzene with Methyl Acrylatea
entry
palladacycle
mol % Pd
t (h)
yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
13
14
15
16a
16b
16c
16d
17
13
14
15
16a
16b
16c
16d
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.001
0.001
0.001
0.001
0.001
0.001
0.001
2
2
2
2
2
2
2
2
8
8
8
6
6
6
6
97%
97%
97%
97%
97%
97%
97%
97%
97%
97%
97%
97%
97%
97%
97%
Figure 2. Carbothioamide-derived palladacycles.
As a matter of fact, such a furancarbothioamide-based
palladacycle 13 (Figure 3) was synthesized 25 years ago,
a Reaction conditions: 3 mmol of Phl, 4.5 mmol of methyl acrylate, 3.6
mmol of Et3N, 2 mL of DMA. b Isolated yields.
of furancarbothioamide-based palladacycles (13-17, Figure
3) and evaluate them in the Heck and Suzuki reactions. We
herein report the preliminary results of our research.
The preparation of the palladated complexes 13-17 was
accomplished using a similar procedure described in the
literature. Accordingly, these palladacycles were prepared
by addition of furancarbothioamides to a methanol solution
of Li2PdCl4 at room temperature.4 The furancarbothioamides
were made by thiolation with Lawesson’s reagent from their
corresponding furancarbamides,5 which were easily synthe-
sized from the commercially available furans.6 Thus, eight
different palladacycles 13-17 (Figure 3) with a variety of
steric and electronic properties were made.
Palladacycles 13-17 are slightly soluble in hexanes,
chloroform, and dichloromethane and moderately soluble in
polar solvents such as DMF, DMA (dimethyl acetamide),
and DMSO.
The catalytic efficacy of the synthesized palladacycles 13-
17 was tested in the Heck cross-coupling reaction between
phenyl iodide and methyl acrylate at 130 °C. The reactions
Figure 3. Structures of the synthesized furancarbothioamide-
derived palladacycles.
and its structure was fully characterized by X-ray diffraction.3
However, its catalytic activity for C-C bond formation was
not evaluated, which encouraged us to synthesize a number
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3338
Org. Lett., Vol. 6, No. 19, 2004

were conducted in air7,2h with all the reagents being used
directly as received.
stress that the DMA stock solution of palladacycle 16a was
utilized for these coupling reactions and retained its activity
even after standing in air at room temperature for weeks.
We then evaluated the catalytic efficacy of palladacycle
16a in the Heck reaction with aryl bromides and chlorides
as the substrates. In general, higher catalyst loading and
longer reaction times were required to push to completion
the reaction of aryl bromides, compared to the corresponding
iodides. For phenyl bromide or activated bromides (entries
1-4, Table 3), complete conversions of the substrates were
Table 1 illustrates the coupling results. Good to excellent
yields were obtained within 1-3 h when 0.01 mol %
palladacycles were applied. Reducing the catalyst loading
to 0.001 mol % led to longer reaction times but did not
influence the reaction conversion markedly (see entries 9-12,
Table 1). Interestingly, the palladacycles formed with bulky
substituents (such as 16a-d) exhibit enhanced catalytic
activities (cf. entries 12-15 vs entries 9-11). Moreover, no
discernible influence was observed when the furan substituent
was changed from H to nitro (cf. 12-15) or replacement of
furan (entry 4) with benzofuran (entry 8).
Table 3. Palladacycle 16a-Catalyzed Heck Coupling Reaction
of Aryl Bromides with Terminal Olefinsa
It is noteworthy that all the palladacycles demonstrated
good thermal stability, showing no decomposition (monitored
1
by H NMR) when heated in DMSO-d6 for 4 h at 100 °C.
Due to its catalytic efficacy in the Heck reaction, palla-
dacycle 16a was studied further in the coupling of a number
of aryl iodides and olefins. Table 2 indicates that high yields
Table 2. Palladacycle 16a-Catalyzed Heck Coupling Reaction
of Aryl Iodides with Terminal Olefinsa
a Reaction conditions: 1 mmol of Phl, 1.5 mmol of methyl acrylate, 1.2
mmol of Et3N, 2.0 mL of DMA. b Isolated yields. c Reaction conditions:
1.0 mmol of ArBr, 1.3 mmol of methyl acrylate, 1.2 mmol of NaOAc, 0.2
mmol of n-Bu4NBr, 2.0 mL of DMA.
observed within 4-15 h in the presence of 0.1-0.5 mol %
Pd using DMA as the solvent and Et3N as the base. n-Butyl
acrylate displayed a higher reactivity than styrene (cf. entries
1, 3, 6 vs 2, 4, 7). Under the “Jeffery conditions”,8 improved
results were obtained for entries 6 and 7, using 0.2 equiv of
Bu4NBr in DMA and NaOAc as the base. On the other hand,
we observed a low yield when a deactivated bromide (entry
8) was employed, and no reaction occurred using an aryl
chloride as a substrate.
a Reaction conditions: 3 mmol of Phl, 4.5 mmol of methyl acrylate, 3.6
mmol of Et3N, 2.0 mL of DMA. b Isolated yields.
The Pd-catalyzed Suzuki cross-coupling reaction is a useful
method for C-C bond formation. Recent notable advances
have been achieved in the Suzuki reaction under aerobic
conditions with some novel palladium complexes (such as
the complexes derived from diazabutadiene,9 oxime,10 N-
acylamidine,11 and di-2-pyridylmethylamine12) or even with
were obtained within 1-3 h using 0.01 mol % catalyst. We
(7) (a) For recent reports on Heck reactions using catalysts that are air-
and moisture-stable, see: (a) Buchmeiser, M. R.; Wurst, K. J. Am. Chem.
Soc. 1999, 121, 11101. (b) Silberg, J.; Schareinia, T.; Kempe, R.; Wurst,
K.; Buchmeiser, M. R. J. Organomet. Chem. 2001, 622, 6. (c) Masllorens,
J.; Moreno-Manas, M.; Pla-Quintana, A.; Roglans, A. Org. Lett. 2003, 5,
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5588 and related references therein.
Org. Lett., Vol. 6, No. 19, 2004
3339

polymer-incarcerated palladium,13 which inspired us to test
the palladacycle 16a in the Suzuki reaction under aerobic
conditions in consideration of its beneficial air- and moisture-
stable properties.
Table 5. Parallel Synthesis of Biaryl Molecules by
Palladacycle 16a-Catalyzed Suzuki Coupling Reactiona
Aryl bromides are cheaper and more readily available
substrates than the corresponding iodides but are more
reluctant to undergo the catalytic Suzuki reaction. Therefore,
we tested the catalytic efficacy of palladacycle 16a in the
Suzuki reaction using aryl bromides as the substrates. To
this end, eight aryl bromides with four aryl boronic acids
were selected for the coupling reaction with palladacycle 16a
as a catalyst under aerobic conditions, and the coupling
results are listed in Table 4. Under the optimized conditions,
Table 4. Palladacycle 16a-Catalyzed Suzuki Coupling of Aryl
Bromides and Arylboronic Acida
a Reaction conditions: 1 mmol of Ar1Br, 1.2 mmol of Ar2B(OH)2, 2.0
mmol of K2CO3, 2 mL of 25% H2O in DMA, 100 °C. b Isolated yield.
perfomred by simply mixing the reagents in flasks under
aerobic conditions, and the reactions were finished in 2 h at
100 °C. It is noteworthy that the same coupling reactions
were tried using the other palladium complexes (such as Pd-
(Ph3P)4 and PdCl2(Ph3P)2) in the same way as above, but no
satisfying results were obtained, presumably due to their air
sensitivity.
In summary, we have synthesized a novel family of
furancarbothioamide-derived palladacycles, and their cata-
lytic activities were tested in the Heck and Suzuki coupling
reactions with aryl halides and terminal olefins or aryl
boronic acids. These novel palladacycles are air- and
moisture-stable, and the reaction can be readily conducted
under aerobic conditions. Further studies of their applicability
in other synthetic transformations are currently under inves-
tigation.
a Reaction conditions: 1 mmol of Ar2Br, 1.2 mmol of Ar2B(OH)2, 2.0
mmol of K2CO3, 2 mL of 25% H2O in DMA, 100 °C. b 16a (mol%).
c Isolated yield.
Acknowledgment. We gratefully acknowledge financial
support of this work by the National Science Foundation of
China (Grants 20142004 and 20242002), and VivoQuest,
Inc., through the sponsored research program.
the selected aryl bromides were coupled with the typical
boronic acids, and good to excellent yields were obtained.
To verify its unique role in the Pd-catalyzed Suzuki
reaction, 16a was employed in the Suzuki reaction to build
up the biaryl fragments in our SAG14 library in a parallel
format. To this end, eight coupling reactions were selected,
and the results are shown in Table 5. All the reactions were
Supporting Information Available: Experimental pro-
cedures and NMR and LC-MS spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL048749S
(11) Eberhardt, J. K.; Fro¨hlich, R.; Wu¨rthwein, E.-U. J. Org. Chem. 2003,
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