A practical and general synthesis of unsymmetrical terphenyls

Article abstract of DOI:10.1021/jo701308b

(Chemical Equation Presented) A synthetic procedure was developed that enables sequential chemoselective Suzuki-Miyaura cross-coupling of chlorobromobenzene with arylboronic acids. The first coupling is achieved at room temperature using a ligandless palladium catalyst. The chlorobiaryl product can then be subjected directly to the second coupling, facilitated by the SPhos ligand. Using this methodology, parallel synthesis of 32 unsymmetrical o-, m-, and p-terphenyl compounds was accomplished in good to excellent overall yields.

Full text of DOI:10.1021/jo701308b

bromides, through separate Pd- and Ni-catalyzed reactions,5
sequential Negishi cross-coupling reactions of diorganozinc
reagents with iodoaryl nonaflates6a and zinc phenoxides with
aryl triflates.6b Anhydrous reaction conditions are necessary in
these procedures, and purification of biaryl intermediates by
column chromatography is required. The reactivity of the
organometallic reagents can also be incompatible with certain
electrophilic functional groups (e.g., carbonyls, enones). Herein,
we describe a concise, practical, and high-yielding synthesis of
unsymmetrical terphenyls by employing sequential chemose-
lective Suzuki-Miyaura (SM) reactions.7 This is envisaged to
have a much broader scope; aryl precursors are widely available,
easy to handle, and most functional groups can be accom-
modated by the system.
A Practical and General Synthesis of
Unsymmetrical Terphenyls
Jose M. Antelo Miguez,† Luis Angel Adrio,
Antonio Sousa-Pedrares,† Jose M. Vila,† and
King Kuok (Mimi) Hii*
Department of Chemistry, Imperial College London, Exhibition
Road, South Kensington SW7 2AZ, U.K., and Departamento de
Qu´ımica Inorga´nica, Facultad de Qu´ımica, UniVersidad de
Santiago de Compostela, E-15782, Spain
mimi.hii@imperial.ac.uk
ReceiVed June 19, 2007
Success of the methodology is dependent on the chemose-
lectivity of the first arylation. Monoarylation of symmetrical
diiodo- and dibromoarenes is highly sensitive to the reaction
conditions.8 Equally, attempted monoarylation of bromoiodo-
benzene under harsh conditions can lead to mixtures of mono-
and diarylated products.9 In this work, the chemoselectivity of
monoarylation was achieved by using 4-, 3-, and 2-bromochlo-
robenzenes (1a, 1b, and 1c, respectively) as reactive substrates.
Selective substitution of the bromide can be achieved at room-
temperature using “ligandless” palladium catalysts:10 using Pd-
(OAc)2 (1.5 mol %) and K3PO4 as base, the coupling was
effected in a biphasic system (DMF-H2O) at room tempera-
ture,11 without phase-transfer reagents (Scheme 1). The reaction
appears to be insensitive to air and the organic solvent-DMF
can be substituted by toluene or THF, without noticeable
A synthetic procedure was developed that enables sequential
chemoselective Suzuki-Miyaura cross-coupling of chloro-
bromobenzene with arylboronic acids. The first coupling is
achieved at room temperature using a ligandless palladium
catalyst. The chlorobiaryl product can then be subjected
directly to the second coupling, facilitated by the SPhos
ligand. Using this methodology, parallel synthesis of 32
unsymmetrical o-, m-, and p-terphenyl compounds was
accomplished in good to excellent overall yields.
(4) For selected examples: (a) Zhang, C.; Ondeyka, J. G.; Herath, K.
B.; Guan, Z.; Collado, J.; Pelaez, F.; Leavitt, P. S.; Gurnett, A.; Nare, B.;
Liberator, P.; Singh, S. B. J. Nat. Prod. 2006, 69, 710-712. (b) Roberti,
M.; Pizzirani, D.; Recanatini, M.; Simoni, D.; Grimaudo, S.; Di Cristina,
A.; Abbadessa, V.; Gebbia, N.; Tolomeo, M. J. Med. Chem. 2006, 49,
3012-3018. (c) Simoni, D.; Giannini, G.; Roberti, M.; Rondanin, R.;
Baruchello, R.; Rossi, M.; Grisolia, G.; Invidiata, F. P.; Aiello, S.; Marino,
S.; Cavallini, S.; Siniscalchi, A.; Gebbia, N.; Crosta, L.; Grimaudo, S.;
Abbadessa, V.; Di, Cristina, A.; Tolomeo, M. J. Med. Chem. 2005, 48,
4293-4299. (d) Ohkanda, J.; Lockman, J. W.; Kothare, M. A.; Qian, Y.;
Blaskovich, M. A.; Sebti, S. M.; Hamilton, A. D. J. Med. Chem. 2002, 45,
177-188.
With aromatic rings arranged differently in the two-
dimensional plane, o-, m-, and p-terphenyl compounds possess
unique photophysical properties that are often exploited in the
design of organic electroluminescent (OEL) devices1 and
liquid-crystalline materials.2 Terphenyls can also be found in
nature, predominantly as p-terphenyl derivatives,3 and synthetic
terphenyls are known to possess biological activities with
potential therapeutic values.4
(5) Cho, C. H.; Kim, I. S.; Park, K. Tetrahedron 2004, 60, 4589-4599.
(6) (a) Rottla¨nder, M.; Knochel, P. J. Org. Chem. 1998, 63, 203-208.
(b) Shimizu, H.; Manabe, K. Tetrahedron Lett. 2006, 47, 5927-5931.
(7) To the best of our knowledge, general synthesis of unsymmetrical
terphenyls by sequential Suzuki-Miyaura reactions has not been demon-
strated, although the regioselective cross-coupling of dihaloheteroaromatics
and arylboronic acids are known; see: (a) Beletskaya, I. P.; Tsvetkov, A.
V.; Latyshev, G. V.; Lukashev, N. V. Russian J. Org. Chem. 2003, 39,
1660-1667. (b) Cˇ ernˇa, I.; Pohl, R.; Klepeta´rˇva´, B.; Hocek, M. Org. Lett.
2006, 8, 5389-5392. (c) Conreaux, D.; Bossharth, E.; Monteiro, N.;
Desbordes, P.; Vors, J. P.; Balme, G. Org. Lett. 2007, 9, 271-274.
(8) (a) Sinclair, D. J.; Sherburn, M. S. J. Org. Chem. 2005, 70, 3730-
3733. (b) Uozumi, Y.; Kikuchi, M. Synlett 2005, 1775-1778. (c) Dong, C.
G.; Hu, Q. S. J. Am. Chem. Soc. 2005, 127, 10006-10007.
To date, general methodologies described for the synthesis
of unsymmetrical terphenyls include the coupling of bromoben-
zenesulfonates with arylboronic acids and arylmagnesium
† Universidad de Santiago de Compostela.
(9) (a) Liu, L.; Zhang, Y.; Xin, B. J. Org. Chem. 2006, 71, 3994-3997.
(b) Greenfield, A. A.; Butera, J. A.; Caufield, C. E. Tetrahedron Lett. 2003,
44, 2729.
(1) (a) Karastatiris, P.; Mikroyannidis, J. A.; Spiliopoulos, I. K.; Fakis,
M.; Persephonis, P. J. Polymer Sci. Part A: Polym. Chem. 2004, 42, 2214-
2224. (b) Ogawa, H.; Ohnishi, K.; Shirota, Y. Synth. Met. 1997, 91, 243-
245.
(10) (a) Felpin, F. X.; Ayad, T.; Mitra, S. Eur. J. Org. Chem. 2006,
2679-2690. See also: (b) Zim, D.; Monteiro, A. L.; Dupont, J. Tetrahedron
Lett. 2000, 41, 8199-8202. (c) Arcardi, A.; Cerichelli, G.; Chiarini, M.;
Correa, M.; Zorzan, D. Eur. J. Org. Chem. 2003, 4080-4086.
(11) The presence of water is crucial for this first SM reaction to proceed
at ambient temperature;the use of anhydrous DMF did not lead to any
significant product formation, unless the reaction temperature was raised
to >80 °C.
(2) For example: (a) Kula, P.; Dabrowski, R.; Kenig, K.; Chyczewska,
D. Ferroelectrics 2006, 343, 19. (b) Chen, B.; Baumeister, U.; Pelzl, G.;
Das, M. K.; Zeng, X.; Ungar, G.; Tschierske, C. J. Am. Chem. Soc. 2005,
127, 16578-16591. (c) Kiryanov, A. A.; Sampson, P.; Seed, A. J. J. Mater.
Chem. 2001, 11, 3068-3077.
(3) Liu, J. K. Chem. ReV. 2006, 106, 2209-2223.
10.1021/jo701308b CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/24/2007
J. Org. Chem. 2007, 72, 7771-7774
7771

TABLE 1. Second Cross-Coupling of 2a-c Catalyzed by SPhosa
SCHEME 1. Monoarylation of Bromochlorobenzenes at
Room Temperature
conv (yield)c
entry precursor
Ar2
[Pd]b T (°C) t (h)
(%)
1d,e
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2b
2b
2a
2c
2c
Ph
Ph
Ph
Ph
Ph
Ph
0.5
0.5
1
0.5
1
1
0.5
1
rt
rt
3
3
2
16
24
24
3
21
21
23 f
72 (69)
100 (89)
93 (87)
63 (55)
91 (80)
100 (86)
100 (82)
100 (89)
60
60
30
60
60
60
60
SCHEME 2. Suzuki-Miyaura Cross-Coupling of
Chlorobiaryls by SPhos
4-F-C6H4
4-MeOC6H4
2-MeOC6H4
1
a General reaction conditions: 2a-c (1 equiv), arylboronic acid (1.1
equiv), Pd(OAc)2 (0.5 mol % or 1 mol %), SPhos (2 equiv/Pd), K3PO4 (3
equiv), THF-H2O (3:1), 24 h. b Pd(OAc)2 loading in mol %. c Conversions
were determined by 1H NMR spectroscopy. Isolated yield after column
chromatography/crystallization. d K3PO4‚H2O was used, as specified in ref
16. e Conducted with 1% water in THF. f Not isolated.
any problems, even with the sterically demanding 2-methox-
yphenylboronic acid (entry 9).
difference. In all cases, quantitative conversions to the corre-
sponding chlorobiphenyl compounds were obtained within 3
h.
Chemoselective cross-coupling of 2-bromochlorobenzene 1c
was previously achieved either by using Pd(PPh3)4 at reflux12
or at ambient conditions using a ferrocenylphosphine ligand.13
Thus, it was gratifying to find that the reaction proceeded equally
well under these conditions. These reactions were subsequently
replicated on a larger scale in a round-bottom flask opened to
air, without any deterioration in yield.
During this investigation, we uncovered an important depen-
dence of the reaction on the quality of the Pd(OAc)2 precursor:
while the first SM reaction is insensitive to the source of the
palladium precursor, a particular purified batch of Pd3(OAc)6
trimer appeared to perform noticeably better in the phosphine-
catalyzed coupling of the chlorobiaryl.17 Thus, we recommend
that Pd(OAc)2 of unspecified purity should be recrystallized
(e.g., from toluene) for use in these reactions.
Given that the first SM reaction proceeds with complete
consumption of the dihaloarene, the inorganic salts, spent
palladium catalyst, and slight excess of the arylboronic acid
reagent can be removed simply by an aqueous wash, to afford
compounds which can be used directly in the second coupling
without further purification. Thus, the synthesis of terphenyls
can be carried out in a simple synthetic sequence, which is
amenable to automation.
Utilizing this methodology, a small library of 22 unsym-
metrical p- and m-terphenyl compounds was synthesized from
a selection of simple arylboronic acids, chosen for their steric
and electronic properties (Schemes 3 and 4).
Unsymmetrical p-terphenyl compounds 3a-k are highly
crystalline solids, which can be purified by recrystallization.
However, compounds 3d and 3g are only sparingly soluble in
organic solvents. This affected their extraction from the reaction
mixture, resulting in slightly lower yields compared to the others,
which are obtained with an overall yield of ca. 85%. In
comparison, m-terphenyl compounds 4a-k are more soluble;
hence, column chromatography can be used to afford good to
excellent yields, typically >90%.
For the synthesis of the p- and m-terphenyls, neither of the
cross-coupling steps was sensitive to steric and electronic
characteristics of the substrates. In all cases, the chlorobiaryl
intermediates 2 were obtained in quantitative yields, i.e., the
overall yields of the terphenyl compounds were largely dictated
by the second step, which was relatively insensitive to the nature
of the arylboronic acid. For example, results obtained with
2-methoxyboronic acid are comparable with other less bulky
boronic acids.
With the first aryl group in place, the second arylation reaction
is considerably difficult as it involves cleavage of the stronger
C-Cl bond. The reaction can be catalyzed by ligandless Pd/C
using high temperature14 or microwave irradiation,15 but the
yield remained moderate to poor, especially for deactivated aryl
chlorides. Thus, we decided to effect the second coupling by
using 2-(2′,6′-dimethoxybiphenyl)dicyclohexylphosphine (SPhos),
a good universal ligand developed by Buchwald et al. for SM
reactions (Scheme 2).16
It was reported that the presence of a small amount of water
is needed to effect reactions catalyzed by SPhos under ambient
conditions. Adopting the literature procedure, the addition of a
small quantity of water to the catalytic solution caused the solid
base to form an insoluble paste, which impeded efficient mixing
of the reactants, giving unrepeatable results and a poor yield of
the product (Table 1, entry 1). However, by using a miscible
mixture of THF-H2O (3:1), a homogeneous mixture and a good
yield of the product can be obtained (entry 2). The yield can be
further improved by raising the temperature, enabling a low
catalytic loading (0.5 mol %) to be used (entries 3 and 4).
However, this is rather dependent on the nature of the
substrate: while the reaction with 2b required both higher
temperature and catalytic loading (entries 5 and 6), coupling of
2a with 4-fluorophenylboronic acid was complete within 3 h,
using just 0.5 mol % of the catalyst (entry 7). Likewise, cross-
coupling of the 2c with other arylboronic acids did not present
(12) (a) Lehmler, H. J.; Robertson, L. W. Chemosphere 2001, 45, 137-
143. (b) Mazzanti, A.; Lunazzi, L.; Minzoni, M.; Andersen, J. E. J. Org.
Chem. 2006, 71, 5474-5481.
(13) Kataoka, K.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org. Chem.
2002, 67, 5553-5566.
(14) Lyse´n, M.; Ko¨hler, K. Synthesis 2006, 692-698.
(15) Arvela, R. K.; Leadbeater, N. E. Org. Lett. 2005, 7, 2101-2104.
(16) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J.
Am. Chem. Soc. 2005, 127, 4685-4696.
(17) Similar observations had been reported by others in related
chemistry: (a) Bianchini, C.; Meli, A.; Oberhauser, W. Organometallics
2003, 22, 4281-4285. (b) Bakhmutov, V. I.; Berry, J. F.; Cotton, F. A.;
Ibragimov, S.; Murillo. C. A. Dalton Trans. 2005, 1989-1992.
7772 J. Org. Chem., Vol. 72, No. 20, 2007

SCHEME 3. Synthesis of 11 Unsymmetrical p-Terphenylsa
SCHEME 5. Synthesis of 10 Unsymmetrical o-Terphenylsa
a Aryl groups are colored red and blue, according to the order of their
installation (first and second, respectively). Conditions: (A) Pd(OAc)2 (1.5
mol % of Pd), DMF-H2O (1:1), 4 h, rt; (B) Pd3(OAc)6 (1 mol % of Pd),
SPhos (2 mol %), THF-H2O (3:1), 21 h, 60 °C. Isolated yields of the
terphenyls were calculated over two steps (based on bromochlorobenzene).
SCHEME 4. Synthesis of 11 Unsymmetrical m-Terphenylsa
a See footnote a, Scheme 1. *Heated at 110 °C in toluene-H2O for 24 h.
these conditions. While the failure of 2m to react may be
attributed to greater difficulty of palladium to access the
o-chloride, the reason for the failure of 2l to undergo any
reaction appears to be strictly electronic, since the reactions
between 2c, 2j, and 2k with 2-methoxyphenylboronic acid had
proceeded successfully to afford the products (5d, 5g, and 5h)
in high yields. The unfavorable effect was overcome eventually
by conducting these reactions at 110 °C in a mixed toluene-
water system: the reaction between 2l and 2-methoxyphenyl-
boronic acid proceeding to give 5j (83%). Nevertheless, the
reaction between 2m and 4-methoxyboronic acid only afforded
a low yield (23%) of the same product.
These observations led to the following conclusions: (1) The
ligand-assisted cross-coupling is more sensitive to steric and
electronic effects on the chlorobiaryl, than the arylboronic acid
substrate; therefore, (2) o-terphenyl compounds, such as 5j, are
assembled more efficiently by installing the sterically more
demanding aryl group in the second SM reaction via its
corresponding arylboronic acid, and (3) for substrates containing
electron-donating substituents, higher reaction temperatures
should be adopted for the second step.
The electro-optic properties of terphenyl molecules are
dependent upon their conformations in the solid state,18 which
are, in turn, dependent upon intermolecular and intra-ring
torsional interactions. While the former favors a planar con-
formation for better crystal packing, the torsional forces favors
the twisted form.19 Some of these features are displayed in the
crystal structure of the p-terphenyl compound 3k (Supporting
a See footnote a, Scheme 1.
Finally, 10 unsymmetrical o-terphenyls were similarly con-
structed (Scheme 5). The synthesis of o-terphenyls may be
envisaged to be more challenging due to the proximity of the
reactive sites, which may impose unfavorable steric or coopera-
tive effects. To examine this, five different arylboronic acids
were employed in the coupling with 2-bromochlorobenzene.
Again, under the “ligandless” protocol at ambient temperature,
the first coupling proceeded smoothly in all cases, to furnish
very good yields of the chlorobiaryls, irrespective of the
electronic or steric nature of the substratessyields of g93%
were obtained for all these reactions.
In contrast, the second coupling at the ortho position is much
more sensitive to the constituents of the chloro intermediate:
while the cross-coupling with the electronically deficient and
neutral (2c, 2j, and 2k) substrates proceeded with high yields,
attempts to access the dimethoxy-substituted compound 5j, by
the coupling of either 2l or 2m with the corresponding
methoxyphenylboronic acid, did not afford any product under
(18) Heimel, G.; Puschnig, P.; Oehzelt, M.; Hummer, K.; Koppelhuber-
Bitschnau, B.; Porsch, F.; Ambrosch-Draxl, C.; Resel, R. J. J. Phys:
Condens. Matter 2003, 15, 3375-3389.
(19) Baranyai, A.; Welberry, T. R. Mol. Phys. 1992, 75, 867-879.
J. Org. Chem, Vol. 72, No. 20, 2007 7773

(20.5 mg, 0.05 mmol, 2 equiv) were mixed in degassed THF-
H2O (3/1, 5 mL). The mixture was sonicated for 6 min to generate
the active catalyst. Meanwhile, a Radley reaction tube was charged
with the chlorobiaryl, base (1.5 mmol, 3 equiv), and arylboronic
acid Ar2B(OH)2 (0.55 mmol), placed in the carousel, and purged
and filled with N2. A mixture of THF-H2O (1.5 mL) was added,
and the temperature of the solution was raised to 60 °C, whereupon
1 mL of the catalyst solution was injected. The reaction mixture
was stirred, typically overnight. The solution was then allowed to
cool to room temperature, and extracted with CH2Cl2 (3 × 15 mL).
The combined layers were dried over Na2SO4, filtered, and
evaporated. For products with limited solubility, these were
collected and washed with an EtOAc-hexane mixture (4/1, 5 mL).
Alternatively, purification was achieved by column chromatography.
For reactions at high temperatures, the catalyst was generated in
degassed toluene, and degassed water was added to the reaction
mixture before the reaction temperature was raised to 100 °C.
Information). In the solid state, the molecule exhibits two
different torsional angles between adjacent rings, with a smaller
angle between the central arene and tolyl (34.4°) than that found
between the central ring and the o-anisole (50.7°). Within each
unit cell, the distance between the molecules and the orientation
of the phenyl rings precludes any π interactions between the
rings. Thus, the intra-ring torsional interaction overrides inter-
molecular interactions in 3k. Preliminary studies of the UV
absorption spectra of the compounds (Supporting Information)
revealed discernible trends that can be correlated to the chemical
structures, which may be explored further to design rigid
molecules with novel optical properties.
Experimental Section
First Suzuki-Miyaura Coupling. A Radley tube was charged
with a stir bar, Pd(OAc)2 (1.5 mol %), bromochlorobenzene (95
mg, 0.5 mmol), the appropriate arylboronic acid R1B(OH)2 (0.55
mmol, 1.1 equiv), and K3PO4 (1 mmol, 2 equiv). The reaction vessel
was positioned in the carousel and purged and filled with N2, before
the addition of a mixture of DMF-H2O (1/1, 3 mL) by syringe.
The reaction mixture was stirred at room temperature for 3 h, after
which a solution of EtOAc-hexane (1/4, 15 mL) was added. The
layers were separated, and the aqueous layer was extracted with
EtOAc-hexane (1/4, 15 mL × 2). The combined organic extracts
were washed with H2O (15 mL), dried (Na2SO4), and evaporated.
The residue was used directly in the next step without further
purification.
Acknowledgment. We thank the Ministerio de Educacio´n
y Ciencia for financial support (Project No. CTQ2006-15621-
C02-01/BQU) and Xunta de Galicia for providing fellowships
to L.A.A. and J.M.A.M.; the latter was also a recipient of a
fellowship from the Fundacio´n Gil Da´vila. We are grateful to
Johnson Matthey plc for the loan of Pd salts and AstraZeneca
for the gift of SPhos.
Supporting Information Available: Characterization data for
all compounds, X-ray crystallographic data and CIF files for
compounds 3k, and copies of 1H and 13C NMR spectra of all novel
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
This reaction was subsequently conducted on a larger scale in
air, using a round-bottom flask and reagent-grade THF (in place
of DMF), with no noticeable deterioration in yield.
Second Suzuki-Miyaura Coupling. In a 5 mL volumetric flask
flushed with N2, Pd3(OAc)6 (5.6 mg, 0.025 mmol in Pd) and S-Phos
JO701308B
7774 J. Org. Chem., Vol. 72, No. 20, 2007