Synthesis of symmetrical terphenyl derivatives by PdCl 2-catalyzed Suzuki-Miyaura reaction of dibromobenzene using 3-(diphenylphosphino)propanoic acid as a ligand

Article abstract of DOI:10.1080/00397911.2015.1126606

A simple and efficient catalytic system for PdCl₂ catalyzing the Suzuki-Miyaura reaction of dibromobenzene and arylboronic acid has been developed by using 3-(diphenylphosphino)propanoic acid as a ligand in dimethylsulfoxide at 100 °C. Using this method, a series of symmetrical terphenyl derivatives were obtained with remarkably good yields, up to 93%.

Full text of DOI:10.1080/00397911.2015.1126606

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Synthesis of Symmetrical Terphenyl
Derivatives by PdCl2-Catalyzed Suzuki-
Miyaura Reaction of Dibromobenzene Using 3-
(Diphenylphosphino)propanoic Acid as a Ligand
Ningning Gu, Yashuai Liu, Ping Liu, Xiaowei Ma & Yan Liu
To cite this article: Ningning Gu, Yashuai Liu, Ping Liu, Xiaowei Ma & Yan Liu (2015): Synthesis
of Symmetrical Terphenyl Derivatives by PdCl2-Catalyzed Suzuki-Miyaura Reaction of
Dibromobenzene Using 3-(Diphenylphosphino)propanoic Acid as a Ligand, Synthetic
Communications, DOI: 10.1080/00397911.2015.1126606
To link to this article: http://dx.doi.org/10.1080/00397911.2015.1126606
View supplementary material
Accepted author version posted online: 02
Dec 2015.
Submit your article to this journal
Article views: 4
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=lsyc20
Download by: [Central Michigan University]
Date: 10 December 2015, At: 12:31

Synthesis of Symmetrical Terphenyl Derivatives by PdCl2-Catalyzed Suzuki-
Miyaura Reaction of Dibromobenzene Using 3-(diphenylphosphino)propanoic Acid
as a Ligand
Ningning Gu1, Yashuai Liu1, Ping Liu1, Xiaowei Ma1, Yan Liu1
1School of Chemistry and Chemical Engineering/Key Laboratory for Green Processing of
Chemical Engineering of Xinjiang Bingtuan, Shihezi University, P. R. China
Corresponding to Ping Liu, School of Chemistry and Chemical Engineering / Key
Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan, Shihezi
University, Shihezi 832003, China. E-mail: liuping1979112@aliyun.com
Abstract
A simple and efficient catalytic system for PdCl2 catalyzing the Suzuki-Miyaura reaction
of dibromobenzene and arylboronic acid has been developed by using 3-
(diphenylphosphino)propanoic acid as a ligand in DMSO at 100 ºC. Using this method, a
series of symmetrical terphenyl derivatives were obtained with remarkably high yields up
to 93%.
KEYWORDS: Terphenyls, Synthesis, P,O ligand, Palladium, Catalysis, Suzuki-Miyaura
reaction
INTRODUCTION
As an important structural motif, terphenyls can be found in a variety of natural
products[1] or as building blocks in different applications in medicinal chemistry [2-7] and
materials science [8-15]. Most notably, this is due to diverse biological activities and
1

unique optical and electronic properties [16, 17]. Thus, the development of convenient and
efficient methods for the synthesis of such compounds has therefore attracted
considerable attention. The general methods by which substituted terphenyls have been
obtained can be classified into four individual groups: (i) free-radical substitution of an
aromatic ring, (ii) Ullmann and related reactions, (iii) additions to dienes, and (iv)
condensation reactions of quinones [18]. However, this series of synthetic methods offers
limited applications due to a narrow substrate range that can be employed, the need for
harsh reaction conditions, long reaction times and particularly low yields obtained.
Recently, transition metal catalyzed coupling reactions proved to be the most practical
and versatile methods for the production of symmetrical and unsymmetrical o-, m- and p-
terphenyls [19]. In particular, the palladium-catalyzed Suzuki–Miyaura reaction has
become one of the most important and efficient synthetic technique for the production of
polyaryls (biaryls, teraryls, etc.). This is most notably due to the facts that aryl precursors
are widely available, easy to handle, and most functional groups can be accommodated
by these systems[20]. Related to previously published work by our group [21], in this article
we describe a simple, yet practical synthesis of symmetrical terphenyls by employing
Suzuki-Miyaura reactions. This strategy is believed to provide a much broader range of
synthetic applications in academia and industry.
RESULTS AND DISCUSSION
Our synthetic efforts started with 1,4-dibromobenzene and phenylboronic acid as model
substrates for the optimization of reaction conditions, including different palladium
sources, bases, solvents and ligands. The results for this are summarized in Table 1.
2

Several palladium catalysts (2 mol%) such as Pd(OH)2, Pd(OAc)2, and PdCl2 were tested
by using NaOH as the base in DMSO (2 mL) at 100 °C for 12 h. PdCl2 was found to be
the most promising species (Table 1, Entries 1–3). A variety of different bases have been
evaluated and K3PO4·H2O turned out to be the best choice in terms of isolated yields
(Table 1, Entries 4–6). Moreover, the use of toluene as well as DMF was found to be
superior to other solvents such as 1,4-dioxane and the coupling products were obtained in
yields of 87% and 86%, respectively(Table 1, Entries 7–9). Among the ligands used, 3-
(diphenylphosphino)propanoic acid (ligand 2) was found to be the preferred ligand for
this catalysis reaction, resulting in the formation of the desired product in 91% isolated
yield (Table 1, Entry 11). Remarkably, even when the catalyst loading was decreased
from 2 mol% to 1 mol%, the corresponding product was still obtained in 93% yield
(Table 1, Entry 12). Finally, the combination of PdCl2 (1 mol%)/ligand 2 (2 mol%),
K3PO4·H2O (4 equiv.) at 100 °C for 12 h in DMSO (2 ml) was found to be the most
efficient reaction conditions.
In general, most of arylboronic acids used readily reacted with 1, 4-dibromobenzene and
the desired products were obtained in good to excellent yields (Table 2). The coupling
reactions between arylboronic acids containing electron-donating groups such as 4-C3H7,
4-C5H11, and 1,4-dibromobenzene produced terphenyls in yields of 94% and 90%,
respectively (Table 2, Entries 1 and 2). Arylboronic acid species bearing electron-
withdrawing moieties reacted with 1,4-dibromobenzene, such as (4-fluorophenyl)boronic
acid, (4-(trifluoromethyl)phenyl)boronic acid and (3,4,5-trifluorophenyl)boronic acid.
Good yields were obtained for these reactions at similar reaction conditions (Table 2,
3

Entries 3-5). Furthermore, the substrate bearing carbonyl groups, such as (4-
formylphenyl)boronic acid, also resulted in a coupling reaction with 1,4-dibromobenzene
to afford the desired product in 75% yield (Table 2, Entry 6). When m-tolylboronic acid
was used as the coupling partner, a particularly high yield of 95% was obtained (Table 2,
Entry 7). Notably, the sterically demanding ortho substituents, such as o-tolylboronic
acid, did not impair the coupling reaction and resulted in the formation of the product in
95% yield (Table 2, Entry 8). To further ascertain the scope of this methodology, 1,2-
dibromobenzene and 1,3-dibromobenzene were employed. In contrast to 1,4-
dibromobenzene, when 1,2-dibromobenzene was subjected to react with various
arylboronic acids, the target products were obtained in considerably lower yields (Table
2, Entries 9-12). This is most likely due to the steric hindrance of intermediates formed,
namely derivatives of 2-bromo-1,1'-biphenyl. Similarly, the reactions of 1,3-
dibromobenzene with o-tolylboronic acid and (4-propylphenyl)boronic acid resulted in
the formation of the corresponding products in 76% and 39% yields, respectively (Table
2, Entries 13 and 14).
Moreover, a gram-scale synthesis was performed to substantiate potential practical
applications of this catalytic system. Fortunately, the reaction was performed using 5
mmol of 1,4-dibromobenzene and 6 mmol (4-propylphenyl)boronic acid, and proceeded
in a remarkably high 95% yield resulting in the production of 1.50 g of the desired
product 3b (Scheme 1).
EXPERIMENTAL SECTION
4

Materials And Instruments
Reagents were of analytical grade quality, purchased commercially and used as received.
All the reactions were carried out under air using magnetic stirring unless otherwise
noted. 1H NMR spectral data were recorded on a Bruker DPX–400 spectrometer using
TMS as internal standard and CDCl3 as solvent. Mass spectra were recorded on GC-MS
(Agilent 7890A/5975C) instrument under EI model. Column chromatography was
performed with silica gel (200-300 mesh) purchased from Qingdao Haiyang Chemical
Co., Ltd. Ligands 1 and 2 were synthesized by the literature methods (Figure 1).[22]
General Procedure For The Synthesis Of Symmetrical Terphenyl Derivatives (3a-
3o)
The Schlenk tube (5 mL) equipped with a stir bar was charged with PdCl2 (1.0 mol%),
Ph2P(CH2)2COOH (2.0 mol%), and K3PO4∙H2O (4.0 equiv.), then 1,4-dibromobenzene
(0.5 mmol), phenylboronic acid (1.20 mmol), and DMSO (2.0 ml) were added, and the
mixture was stirred at 100 ºC until the substrate was completely consumed. After cooling
to room temperature, the solution was quenched with water and extracted with EtOAc (3
× 10 mL). The combined EtOAc extracts were dried over anhydrous Na2SO4 and filtrated
and the solvent was removed under reduced pressure. The residue was purified by flash
column chromatography on silica gel with PE as the eluent to obtain the desired products.
4,4''-Dipropyl-1,1':3',1''-Terphenyl(3o)
white solid ,Isolated yield = 39%, Mp. 69.6-70.3 oC. 1H NMR (400 MHz, CDCl3): δ
(ppm) 7.79 (td, J = 1.8, 0.5 Hz, 1H), 7.58–7.52 (m, 6H), 7.45–7.20 (m, 5H), 2.67–2.61
5

(m, 4H), 1.69 (dt, J = 8.9, 7.5 Hz, 4H), 0.98 (t, J = 7.3 Hz, 6H). 13C NMR (100 MHz,
CDCl3): δ (ppm) = 141.9, 141.7, 138.6, 129.1, 128.9, 127.1, 125.8, 125.7, 37.7, 24.6,
13.9. HRMS (EI): m/z calcd for C24H26 [M]+ 314.2035, found 314.2031.
CONCLUSION
In summary, we have established a simple, yet efficient catalytic system for 3-
(diphenylphosphino)propanoic acid/PdCl2 catalyzing the Suzuki-Miyaura reaction of
dibromobenzene and arylboronic acid for the synthesis of terphenyl compounds in good
to excellent yields. Experimental data confirms that a broad range of different functional
groups can be used in this type of catalytic reaction. Furthermore, even substrates with
sterically hindered groups resulted in sufficient product formation at optimized reaction
conditions. The elegant approach presented here, as well as the option for efficient large
scale preparation, provide a convenient and more practical approach for a variety of
different future applications in academia or industry.
CONFLICT OF INTEREST
We state that none of the authors have any conflict of interest in the context of this
communication.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
ACKNOWLEDGMENT
6

We gratefully acknowledge financial support of this work by the National Natural
Science Foundation of China (No. 21563025, No. 21463022), the Doctor Foundation of
Xinjiang Bingtuan (No. 2012BB010), and Shihezi University Training Programme for
Distinguished Youth Scholars (No.2014ZRKXJQ05).
REFERENCES
1. Sawayama, Y.; Tsujimoto, T.; Sugino, K.; Nishikawa, T.; Isobe, M.; Kawagishi, H.
Syntheses of naturally occurring terphenyls and related compounds. Biosci. Biotechnol.
Biochem. 2006, 70, 2998.
2. Cali, V.; Spatafora, C.; Tringali, C. Sarcodonins and sarcoviolins, bioactive
polyhydroxy-p-terphenyl pyrazinediol dioxide conjugates from fruiting bodies of the
basidiomycete Sarcodon leucopus. Eur. J. Org. Chem. 2004, 592.
3. Orner, B.P.; Ernst, J.T.; Hamilton, A.D. Toward proteomimetics: Terphenyl
derivatives as structural and functional mimics of extended regions of an alpha-helix. J.
Am. Chem. Soc. 2001, 123, 5382.
4. Roberti, M.; Pizzirani, D.; Recanatini, M.; Simoni, D.; Grimaudo, S.; Cristina, D.;
Abbadessa, V.; Gebbia, N.; Tolomeo, M. Identification of a terphenyl derivative that
blocks the cell cycle in the G(0)-G(1) phase and induces differentiation in leukemia cells.
J. Med. Chem. 2006, 49, 3012.
5. Simoni, D.; Giannini, G.; Baraldi, P.G.; Romagnoli, R.; Roberti, M.; Rondanin, R.;
Baruchello, R.; Grisolia, G.; Rossi, M.; Mirizzi, D. A convenient synthesis of
unsymmetrically substituted terphenyls of biologically active stilbenes via a double
Suzuki cross-coupling protocol. Tetrahedron Lett. 2003, 44, 3005.
7

6. Simoni, D.; Giannini, G.; Roberti, M.; Rondanin, R.; Baruchello, R.; Rossi, M.;
Grisolia, G.; Invidiata, F.P.; Aiello, S.; Marino, S. Studies on the apoptotic activity of
natural and synthetic retinoids: Discovery of a new class of synthetic terphenyls that
potently support cell growth and inhibit apoptosis in neuronal and HL-60 cells. J. Med.
Chem. 2005, 48, 4293.
7. Simoni, D.; Rondanin, R.; Baruchello, R.; Rizzi, M.; Grisolia, G.; Eleopra, M.;
Grimaudo, S.; Cristina, A.D.; Pipitone, M.R.; Bongiorno, M.R.; Arico, M.; Invidiata,
F.P.; Tolomeo, M. Novel terphenyls and 3,5-diaryl isoxazole derivatives endowed with
growth supporting and antiapoptotic properties. J. Med. Chem. 2008, 51, 4796.
8. Yashima, E.; Maeda, K.; Furusho, Y. Single- and Double-Stranded Helical Polymers:
Synthesis, Structures, and Functions. Acc. Chem. Res. 2008, 41, 1166.
9. Udayakumar, B.; Schuster, G.B. Photoisomerization of 2,2''-ethano-bridged m-
terphenyl derivatives: ring constraint activates an unreactive chromophore. J. Org.
Chem.1992, 57, 348.
10. Wright, R.S.; Vinod, T.K. Synthesis of m-terphenyl derivatives for potential use as
tectons in crystal engineering. Tetrahedron Lett. 2003, 44, 7129.
11. Liao, H.R.; Lin, Y.J.; Chou, Y.M.; Luo, F.T.; Wang, B.C. Theoretical study of optical
and electronic properties of p-terphenyls containing cyano substituents as promising
light-emitting materials. J. Lumin. 2008, 128, 1373.
12. Yu, G.; Gao, J.; Hummelen, J.C.; Wudl, F.; Heeger, A.J. Polymer photovoltaic cells-
enhanced efficiencies via a network of internal donor-acceptor heterojunctions. Science.
1995, 270, 1789.
8

13. Garnier, F.; Hajlaoui, R.; Yassar, A.; Srivastava, P. All-polymer field-effect transistor
realized by printing techniques. Science. 1994, 265, 1684.
14. Hide, F.; DÍaz-GarcÍa, M.A.; Schwartz, B.J.; Heeger, A.J. New Developments in the
Photonic Applications of Conjugated Polymers. Acc. Chem. Res. 1997, 30, 430.
15. Maya, F.; Tour, J.M. Synthesis of terphenyl oligomers as molecular electronic device
candidates. Tetrahedron. 2004, 60, 81.
16. Todd, M.H.; Balasubramanian, S.; Abell, C. Studies on the Synthesis,
Characterisation and Reactivity of Aromatic Diboronic Acids. Tetrahedron Lett. 1997,
38, 6781.
17. Corsico, E.F.; Rossi, R.A. Synthesis of Mono-, Di-, and Tri-phenyl Arenes by
Sequential Photostimulated SRN1 and Pd(0)-Catalyzed Cross Coupling Reactions on Aryl
Halides. ChemInform. 2000, 31.
18. Liu, J.K. Natural Terphenyls: Developments since 1877. Chem. Rev. 2006, 106, 2209.
19. Adrio, L.A.; Míguez, J.M.A.; Hii, K.K. Synthesis of Terphenyls. Org. Prep. Proced.
Int. 2009, 41, 331.
20. Miyaura, N.; Suzuki, A. Palladium-catalyzed cross-coupling reactions of organoboron
compounds. Chem. Rev. 1995, 95, 2457.
21. (a) Liu, Y.; Ma, X.; Xie, J.; Liu, P.; Dai, B.; He, R. Metallomicelles of palladium(II)
complexes as efficient catalysts for the Suzuki-Miyaura reaction in neat water. Appl.
Organomet. Chem. 2013, 27, 494; (b) Ma, X.; Liu, Y.; Liu, P.; Xie, J.; Dai, B.; Liu, Z.
Palladium-catalyzed direct arylation of polyfluoroarene and facile synthesis of liquid
crystal compounds. Appl. Organomet. Chem. 2014, 28, 180; (c) Ma, X.; Liu, Y.; Liu, P.;
Xie, J.; Dai, B.; Liu, Z. A rapid and efficient catalysis system for the synthesis of 4-
9

vinylbiphenyl derivatives. Appl. Organomet. Chem. 2013, 27, 707; (d) Liu, P.; Zhang, W.;
He, R. Preparation and catalytic properties of bis(imino)pyridine palladium(II) complexes
as efficient catalysts for Suzuki cross-coupling reaction in water. Appl. Organomet.
Chem. 2009, 23, 135; (e) Liu, P.; Zhou, L.; Li, X.; He, R. Bis(imino)pyridine
palladium(II) complexes: Synthesis, structure and catalytic activity. J. Organomet. Chem.
2009, 694, 2290. (f) P. Liu, M. Yan, R. He. Bis(imino)pyridine palladium(II) complexes
as efficient catalysts for the Suzuki-Miyaura reaction in water. Appl. Organomet. Chem.
2010, 24, 131.
22. Liu, Y.S.; Liu, Y.; Ma, X.W.; Liu, P.; Xie, J.W.; Dai, B. 3-
(Diphenylphosphino)propanoic acid: an efficient ligand for the Cu-catalyzed N-arylation
of imidazoles and 1H-pyrazole with aryl halides. Chin. Chem. Lett. 2014, 25, 775.
10

Table 1. Optimization of the reaction conditionsa
Entry
Catalyst
Pd(OH)2 (2%)
Solvent
Base
Yield/%b
trace
11
1
2
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
1,4-dioxane
toluene
DMF
NaOH
Pd(OAc)2 (2%)
PdCl2 (2%)
NaOH
3
NaOH
82
4
PdCl2 (2%)
Cs2CO3
20
5
PdCl2 (2%)
NEt3
trace
87
6
PdCl2 (2%)
K3PO4·H2O
K3PO4·H2O
K3PO4·H2O
K3PO4·H2O
K3PO4·H2O
K3PO4·H2O
K3PO4·H2O
7
PdCl2 (2%)
33
8
PdCl2 (2%)
87
9
PdCl2 (2%)
86
10c
11
12
PdCl2 (2%)/Ligand 1 (4%)
PdCl2 (2%)/Ligand 2 (4%)
PdCl2 (1%)/Ligand 2 (2%)
DMSO
DMSO
DMSO
80
91
93
aReaction conditions: 1,4-dibromobenzene 0.5 mmol, phenylboronic acid 1.2 mmol, base 2.0
mmol, solvent 2 mL, 100 °C, 12 h.
b Isolated yields.
c 80 °C.
11

Table 2. Suzuki-Miyaura reactions of dibromoarenes catalyzed by palladiuma
Entry
1
R/1
4-C3H7/1b
4-C5H11/1c
4-F/1d
4-CF3/1e
3,4,5- trifloro/1f
4-CHO/1g
3-CH3/1h
2-CH3/1i
H/1a
2
Product
3b
3c
Yield(%)b
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2c
2c
94
90
90
85
76
75
95
95
43
60
58
57
76
39
2
3
3d
3e
4
5
3f
6
3g
7
3h
3i
8
9
3j
10
11
12
13
14
1e
3k
3l
1g
1d
3m
3n
3o
1i
1b
aReaction conditions: arylbromide 0.5 mmol，arylboronic acid 1.2 mmol, PdCl2 1% mol, ligand 2
2% mol, K3PO4·H2O 2.0 mmol, DMSO 2 mL, 100 °C, 12 h.
b Isolated yields
12

Scheme 1. A gram-scale synthesis of 3b
13

Figure 1. Ligands used in this study
14