Efficient one-pot suzuki-miyaura double cross-coupling reactions using very low Pd(PPh3)4 catalyst loading

Article abstract of DOI:10.1080/00397910902898577

Suzuki-Miyaura double cross-coupling to form teraryls of interest as Schiff-base precursors can be achieved efficiently in near-quantitative yields using a low mol% amount of Pd(PPh3)4 and easily accessible dibromoaryls.

Full text of DOI:10.1080/00397910902898577

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Efficient One-Pot
Suzuki–Miyaura Double Cross-
Coupling Reactions Using Very
Low Pd(PPh3)4 Catalyst Loading
Almeqdad Y. Habashneh a , Othman O. Dakhil a ,
Ahmed Zein a & Paris E. Georghiou a
a Department of Chemistry , Memorial University
of Newfoundland, St. John's, Newfoundland and
Labrador , Canada
Published online: 29 Oct 2009.
To cite this article: Almeqdad Y. Habashneh , Othman O. Dakhil , Ahmed Zein &
Paris E. Georghiou (2009) Efficient One-Pot Suzuki–Miyaura Double Cross-Coupling
Reactions Using Very Low Pd(PPh3)4 Catalyst Loading, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 39:23,
4221-4229, DOI: 10.1080/00397910902898577
To link to this article: http://dx.doi.org/10.1080/00397910902898577
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Synthetic Communications1, 39: 4221–4229, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902898577
Efficient One-Pot Suzuki–Miyaura Double
Cross-Coupling Reactions Using Very Low
Pd(PPh3)4 Catalyst Loading
Almeqdad Y. Habashneh, Othman O. Dakhil, Ahmed Zein,
and Paris E. Georghiou
Department of Chemistry, Memorial University of Newfoundland,
St. John’s, Newfoundland and Labrador, Canada
Abstract: Suzuki–Miyaura double cross-coupling to form teraryls of interest as
Schiff-base precursors can be achieved efficiently in near-quantitative yields using
a low mol% amount of Pd(PPh3)4 and easily accessible dibromoaryls.
Keywords: Dibromoaryls, palladium-catalyzed cross-coupling, Suzuki–Miyaura,
teraryls
The Suzuki–Miyaura (SM) palladium-catalyzed cross-coupling
reaction,[1] as numerous authors have pointed out,[2] is one of the most
important and versatile synthetic transformations for the synthesis of
biaryl systems developed in the 20th century. Since the original metho-
dology was described, many modifications have been reported. These
include, for example, the use of different catalyst=ligand systems[3] and
solvents and the use by Molander and Ellis[2a] of trifluoroborates instead
of the usual boronic acid or ester components of the SM reaction. The
scope of the reaction has also been extended to the synthesis of bisaryl-
and bisnaphthyl-methanes.[4]
Noniterative,[5] one-pot, double-SM coupling reactions[6] with
dihalogenated arenes to form oligo- and polyaryl[5a] products, however,
Received December 18, 2008.
Address correspondence to Paris E. Georghiou, Department of Chemistry,
Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador,
Canada A1B 3X7. E-mail: parisg@mun.ca
4221

4222
A. Y. Habashneh et al.
have received relatively less attention. The main challenge in such
reactions is to achieve selectivity of single- over bis-coupling reactions. To
achieve a desired Pd-catalyzed, double-SM cross-coupling reaction, the
appropriate sequential steps of the oxidative addition–transmetalation
and reductive elimination catalytic cycle are required.
Dong and Hu[7] reported highly selective double-SM coupling (up to
99:1 double vs. mono-coupling) of different dihalobenzenes using equi-
molar amounts of o- or p-tolylboronic acid, or p-methoxyphenylboronic
acid and t-Bu3P (10%) with 2.5% Pd2(dba)3. These authors proposed that
the high selectivities were achieved via a preferential oxidative addition
pathway. In their mechanism, the Pd(0) released from the first reductive
elimination reacts preferentially in the oxidative addition reaction with
the already-formed first coupling product rather than with unreacted
dihalide starting material.
In general, however, relatively poor results for double-Suzuki
coupling[5a,8,9] have been reported using the more readily accessible
Pd(PPh3)4 catalyst. The results described in this article show that the ter-
aryl systems 1–3 (Fig. 1, Scheme 1) can be synthesized in quantitative
yields via one-pot double-SM coupling by using a low mol% of
Pd(PPh3)4. Teraryl compounds 1 and 2, which are of particular interest
to us as Schiff base[8f] precursors in the synthesis of novel calixsalen tar-
gets,[10] were obtained by the coupling reactions of boronic acid 4[8a] with
m- or p-dibromobenzene 5 or 6 in the presence of Pd(PPh3)4 and Ba(OH)2
as the base at 80ꢀC for 48 h. However, to optimize the reaction conditions
by examining the effect of changing the mol% of the Pd(0) catalyst
employed, m-dibromobenzene (5) was used as a model compound.
The results are summarized in Table 1: Using 1,2-dimethoxyethane
(DME)[11] as the solvent resulted in products 1 and 2 being formed in
45 and 76% yields from the reactions of 4 with 5 or 6, respectively
(Entries 1 and 2). In the case of 6, the corresponding single-coupling
product was also detected by 1H NMR monitoring of the reaction. When
dimethylacetamide (DMA)[8a,8e] was used as the solvent with all of the
other conditions being the same, teraryl product 1 was obtained with 5
in only 50% yields; increasing the reaction times or raising the reaction
temperature to 100ꢀC did not improve the yields. However, when the
mol% of the Pd catalyst was decreased to as low as only 0.025% and
DMA again was used as the solvent at 80ꢀC, with Ba(OH)2 as the base,
the yields of 1 were significantly improved from 50% to quantitative
(Entries 3–8). Similar results were obtained when the same conditions,
and only 0.025 mol% of the Pd catalyst was used in the reactions of 6
and 7 (Entries 7 and 8), forming 2 and 3 in 99 and 96% yields, respec-
tively. The results summarized in Table 1 clearly show that decreasing
the mol% of Pd(PPh3)4 to 0.025% in DMA as the solvent resulted in

Suzuki–Miyaura Double Cross-Coupling
4223
Figure 1. Structures of aryl- and naphthyl halides, and boronic acids employed in
this study.
quantitative formation of the desired double-SM products, 1–3.
Compounds 1–3 all showed accurate mass measurements for their
respective structural formulas.
Scheme 1. General scheme for the Suzuki–Miyaura double cross-coupling
reactions.

4224
A. Y. Habashneh et al.
Table 1. Effect of mol% of catalyst on yields using using boronic acid 4
Entry Starting material Mol% of catalyst Solvent Product Yield (%)a
1
2
3
4
5
6
7
8
6
5
5
5
5
5
6
7
13
13
13
1
0.05
0.025
0.025
0.025
DME
DME
DMA
DMA
DMA
DMA
DMA
DMA
2
1
1
1
1
1
2
3
76
45
50
70
82
100
99
96
aYields reported are based upon isolated yields. Experimental details are
included in the Experimental section.
A possible explanation to account for these results is to consider that
when Pd(0) is present in the reaction solution in relatively high concentra-
tions, inactive black Pd-Pd clusters[12] are preferentially formed. Dark-
colored reaction mixtures indicative of the formation of such black Pd–Pd
clusters could be observed in our reactions when the amount of Pd was
used in the higher mol% quantities. As a consequence of such cluster
formation, the presence or effectiveness of active Pd(0) intermediates
involved in the catalytic cycle of the SM reaction decreased, resulting
in the lesser yields of the double-SM coupling products. Conversely,
when the concentrations of Pd(0) in the reaction solution are low, the
potential of forming such inactive Pd–Pd clusters is minimized and the
relative amounts of the active Pd(0) are greater, allowing the preferential
oxidative pathway proposed by Dong and Hu to occur efficiently when
low Pd(0) concentrations are used.
To determine whether the observed reaction conditions are also more
generally applicable, reactions were conducted with the less-reactive
chloro analogs, o- and m-dichlorides 5a and 6a. Because boronic acid 4
is expected to be relatively electron-rich and could therefore be more reac-
tive under the conditions developed, some other representative less
electron-rich boronic acids such as 4a–4c were also tried. The results are
summarized in Table 2. In the reactions of dichloro precursors 5a and
6a with phenylboronic acid 4a, the yields of m- and p-terphenyls 1a and
2a were less (39 and 40%, respectively) than those obtained with the cor-
responding dibromides 5 and 6 (69 and 68%, respectively). With the less
reactive phenylboronic acid, biphenyl 8 itself was the major by-product
in each of the reactions studied, along with the mono-coupled products
8a–d formed from the respective chloro- or bromo- precursors. With
3-nitrophenylboronic acid (4b), none of the corresponding terphenyls were
obtained. Instead, unexpectedly, 3,30-dinitrobiphenyl (9) in 62–74% yields

Suzuki–Miyaura Double Cross-Coupling
4225
Table 2. Yields of coupling products obtained with phenylboronic
acid (4a) and 3-nitrophenylboronic acid (4b)a
Entry
1
Starting material
Boronic acid
Product
Yield (%)
5
4a
1a
8
69
25
8b
1a
8
4
39
30
Trace
68
25
5
40
2
3
4
5a
6
4a
4a
4a
8d
2a
8
8a
2a
8
6a
31
8c
3a
8
Trace
65
21
63
33
68
62
74
5
6
7
5
4a
4b
9
9a
9
7
8
9
6
4b
4b
4b
6a
7
9
9
aYields reported are based upon isolated yields. Compounds other
than those reported in the Experimental section are based upon com-
parisons with those same compounds reported in the literature.
was obtained. In the case of the reaction of 4b with m-dibromobenzene (5),
the mono-coupled product 9a was also obtained. With p-formylphenyl-
boronic acid, no product formation with either dibromo- or dichloroben-
zene was observed under the conditions examined.
Despite the longer reaction times required (which were not necessa-
rily optimized) and some of the limitations noted herein, an advantage
of the methodology reported herein (besides the reduction in the amounts
of expensive Pd catalyst required) is that it is also applicable to the more
easily accessible and less expensive dibrominated aryl precursors. Further
investigation of the exact mechanism for the observations noted in this
communication is warranted and is ongoing in our laboratory.
EXPERIMENTAL
Boronic acids 4a–c and dihaloaryl compounds 5, 5a, 6, and 6a were
purchased from Sigma-Aldrich. Boronic acid 4 was prepared as

4226
A. Y. Habashneh et al.
described in Ref. 8a, and 2,7-dibromonaphthalene (7) was prepared
as described in Ref. 13.
Suzuki Coupling Reactions: General Procedure
A mixture of the respective dibromoaryl compound (3.21 mmol), boronic
acid (6.7 mmol), barium hydroxide monohydrate (2.42 g, 12.8 mmol),
N,N-dimethylacetamide (25 mL), and H2O (5 mL) was thoroughly
degassed by a nitrogen stream before the addition of Pd(PPh3)4 (2 mg,
0.0016 mmol). The mixture was heated at 80ꢀC for 48 h under nitrogen.
The resultant mixture was cooled, and dichloromethane (25 mL) was
added. The organic phase was separated, washed with 10% hydrochloric
acid (25 mL ꢁ 4), dried over MgSO4, and filtered, and the solution was
concentrated by a rotary evaporator. The product was purified using
silica-gel chromatography and eluted with 5% dichloromethane–hexane.
Synthesis of 1,3-Bis(3-tert-butyl-4-methoxyphenyl)benzene (1)
The product 1 was collected as colorless crystals in quantitative yield: mp
106–108ꢀC; 1H NMR (C6D6) d 1.69 (s, 18H), 3.36 (s, 6H), 6.82
(d, J ¼ 8.0 Hz, 2H) 7.39 (t, 1H), 7.48 (dd, J ¼ 3.0, 8.0 Hz, 2H), 7.60 (dd,
J ¼ 2.0, 8.0 Hz, 2H), 7.81 (d, J ¼ 2.0 Hz, 2H), 8.07 (t, J ¼ 1.5 Hz, 1H);
13C NMR (CDCl3) d 30.36, 35.57, 55.69, 112.43, 125.78, 126.22,
126.25, 126.41, 129.54, 133.99, 139.06, 142.63, 158.77; MS (APCI) m=z
403.1 (M þ H), calcd. for C28H34O2 402.3.
Synthesis of 1,4-Bis(3-tert-butyl-4-methoxyphenyl)benzene (2)
The product 2 was collected as colorless crystals in 99% yield: mp
218–220ꢀC; 1H NMR (CDCl3) d 1.45 (s, 18H), 3.90 (s, 6H), 6.98
(d, J ¼ 8.0 Hz, 2H), 7.46 (dd, J ¼ 2.0, 8.0 Hz, 2H), 7.56 (d, J ¼ 2.0 Hz,
2H), 7.62 (s, 4H); 13C NMR (CDCl3) d 30.25, 35.46, 55.61, 112.34,
125.86, 126.05, 127.58, 133.35, 138.95, 140.289, 158.60; MS (APCI)
m=z 403.3 (M þ H), calcd. for C28H34O2 402.3.
Synthesis of 2,7-Bis(3-tert-butyl-4-methoxyphenyl)naphthalene (3)
The product 3 was collected as colorless crystals in 96% yield: mp
1
210–212ꢀC; H NMR (CDCl3) d 1.49 (s, 18H), 3.93 (s, 6H), 7.03 (d,
J ¼ 8.5 Hz, 2H), 7.59 (dd, J ¼ 2.5, 8.5 Hz, 2H), 7.70 (d, J ¼ 2.5 Hz, 2H),

Suzuki–Miyaura Double Cross-Coupling
4227
7.73 (dd, J ¼ 1.5, 8.5 Hz, 2H), 7.91 (d, J ¼ 8.5 Hz, 2H), 8.05 (s, 2H); 13C
NMR (CDCl3) d 30.03, 35.26, 55.42, 112.17, 125.42, 125.63, 126.06,
126.12, 128.19, 131.30, 133.35, 134.34, 138.84, 139.44, 158.50; MS (APCI)
m=z [M þ H] 453.4, calcd. for C32H36O2 452.3.
ACKNOWLEDGMENTS
This work was supported by Memorial University of Newfoundland
and National Sciences and Engineering Research Council of Canada
(NSERC). Prof. G. Bodwell is thanked for his insightful comments.
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