Development of a fluorous, oxime-based palladacycle for microwave-promoted carbon-carbon coupling reactions in aqueous media

Article abstract of DOI:10.1039/c1gc16108c

A thermally stable, fluorous oxime-based palladacycle has been developed and was shown to efficiently promote various carbon-carbon bond formation reactions (Suzuki-Miyaura, Sonogashira and Stille) in aqueous media under microwave irradiation. The palladacycle gave extremely low levels of Pd leaching and could be reused five times with no significant loss of activity.

Full text of DOI:10.1039/c1gc16108c

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COMMUNICATION
Development of a fluorous, oxime-based palladacycle for
microwave-promoted carbon–carbon coupling reactions in aqueous media†
Woen Susanto,a Chi-Yuan Chu,b Wei Jie Ang,a Tzyy-Chao Chou,b Lee-Chiang Lo*b and Yulin Lam*a
Received 6th September 2011, Accepted 21st October 2011
DOI: 10.1039/c1gc16108c
A thermally stable, fluorous oxime-based palladacycle has
been developed and was shown to efficiently promote
various carbon–carbon bond formation reactions (Suzuki–
Miyaura, Sonogashira and Stille) in aqueous media under
microwave irradiation. The palladacycle gave extremely low
levels of Pd leaching and could be reused five times with no
significant loss of activity.
Theberge et al. have also reported a fluorous–aqueous biphasic
Suzuki–Miyaura coupling in droplets at room temperature in
0.75–8 h (Pd leaching: <0.5 ppm).8c Herein we report the
synthesis of a recyclable, fluorous, oxime-based palladacycle
1 (Scheme 1) and illustrate its application in the various
carbon–carbon coupling reactions under aqueous conditions
and microwave irradiation. An oxime-derived palladacycle was
chosen because it is known to be (i) thermally robust, (ii)
insensitive to air and moisture, (iii) a precatalyst with a high
ability to slowly release Pd(0) which suppresses the growth of
large Pd metal particles,9 and (iv) phosphines are not involved
in the reaction and thus problems involving phosphine oxide
and side-reactions arising from the coupling between phosphine
and aryl halide would be avoided.10
Palladacycle 1 was prepared by treating 4,4¢-dihydroxybenzo-
phenone 2 with allyl bromide at room temperature for a day
to give the allyl ether 3 in quantitative yield. Compound 3 was
then reacted with perfluorooctyl iodide (C8F17I) in the presence
of azobisisobutyronitrile (AIBN) in a radical reaction to give
compound 4 in 74% yield. Removal of the iodide in compound
4 was carried out using tributyltin hydride (Bu3SnH) and AIBN
in dichloroethane at refluxing temperature to give compound 5
in 89% yield. Subsequent condensation of 5 with hydroxylamine
hydrochloride (H2NOH·HCl) gave oxime 6 (87% yield) which in
turn was treated with tetrachlorolithiumpalladate (Li2PdCl4) in
the presence of a base to produce palladacycle 1.
For the synthesis of palladacycle 1, we had initially used the
reaction conditions reported by Alacid and Na´jera.11 However,
formation of Pd black was observed during the reaction and
palladacycle 1 was obtained in low yield (Table S1 in the
ESI†, entry 1). This could be attributed to the insolubility of
compound 6 in methanol. In order to optimize the reaction, we
varied the solvent and reaction time and found that the best
result was obtained in acetone. However at room temperature,
the reaction required 6 days to complete. This long reaction time
could be due to the poor solubility of sodium acetate in acetone.
Hence, we carried out the reaction under reflux and indeed, the
reaction time was shortened to 1 day and palladacycle 1 was
obtained in 90% yield (Table S1 in ESI†, entry 4).
The palladium-catalyzed carbon–carbon coupling reaction is an
important tool for the synthesis of symmetric and nonsymmetric
biaryls and over the decades, a wide variety of homogeneous
catalytic systems have been developed for this transformation.1
Although homogeneous catalysts have many advantages, the
difficulties surrounding the separation and recovery of the cata-
lyst, and product contamination with traces of heavy metals are
common problems encountered, which restrict their applications
in certain industries.2 This inherent limitation of homogeneous
catalysis has thus resulted in the development of new strategies
for transition-metal catalysis that facilitates catalyst recovery
and recycling.3,4 One of these strategies which has attracted much
interest involves fluorous chemistry.4 However, these methods of
catalysis are typically conducted in organic or perfluorocarbon
solvents.5 From the environmentally benign viewpoint, the use
of water as a solvent in transition-metal catalysis offers many
advantages.6 Although various catalytic systems in aqueous
solutions have been developed,7 very few examples of fluo-
rous palladium-based catalysis in aqueous media have been
reported.8 In 2008, a recyclable polymer-supported fluorous
catalyst (Amberlyst A-21-Pd(OPf)2, 1 mol% Pd) was shown to
promote the Sonogashira reaction in water at 80 ◦C in 1–18 h (Pd
leaching: 3.6–11.6 ppm)8a and recently, recyclable fluoro silica
gel-supported perfluoro-tagged palladium nanoparticles (0.1
mol% Pd) were used to catalyze the Suzuki–Miyaura reaction
in water at 100 ◦C in 8–12 h (Pd leaching: <10 ppm).8b In 2009,
aDepartment of Chemistry, National University of Singapore, 3 Science
Drive 3, Singapore, 117543. E-mail: chmlamyl@nus.edu.sg;
Fax: 65-67791691; Tel: 65-65162688
bDepartment of Chemistry, National Taiwan University, No. 1, Sec. 4
Roosevelt Road, Taipei, 106, Taiwan. E-mail: lclo@ntu.edu.tw;
Fax: 886-223636359; Tel: 886-233661669
Initial assessment of the catalytic activity of palladacycle 1
(0.05 mol% Pd) was conducted using the Suzuki–Miyaura reac-
tion between phenylboronic acid 7 and 4-bromobenzotrifluoride
with K2CO3 as the base, water as the solvent, TBAB as an
† Electronic supplementary information (ESI) available: Experimental
procedures, Tables S1–S4 and full spectroscopic data for all new
compounds. See DOI: 10.1039/c1gc16108c
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Scheme 1 Synthesis of palladacycle 1.
Table 1 Suzuki–Miyaura reaction of phenylboronic acid 7 with aryl
Table 2 Recycling of palladacycle 1 in the Suzuki–Miyaura reaction
and benzyl halidesa
Entry
1
ArX
Time (min)
2
Product (Yieldb)
Pd leaching
(ppm)b
Recovered 1
(wt%)
Cycle
Time (min)
Yield (%)a
2
3
6 (2.5 hc)
3.5 (1 hd)
1
2
3
4
5
2
3
4
6
7
98
96
95
95
92
0.031
0.033
0.027
0.023
0.027
90
93
91
89
88
a Isolated yield. b Determined by ICP-OES of the crude product.
4
2
(Table 1). To determine the catalytically active species in the
reaction, we carried out the mercury drop test and another test
using substoichiometric amounts of CS2. Results from both tests
(Table S2†, entries 11 and 12) strongly suggest that the palladium
nanoparticles are the catalytic species in the reaction. A com-
parison of palladacycle 1 with its polymer-supported analog
showed that the Suzuki–Miyaura reaction with palladacycle 1
occurred more rapidly and gave a higher yield of the product
(Table 1, entries 2–3). It was also gratifying to note that our
reaction protocol could be applied successfully to the synthesis
of diarylmethanes (Table 1, entry 3), as such syntheses have been
reported to be difficult using various homogeneous palladium
catalyst systems12 and was only recently made more accessible
via palladium–phosphine catalysts.13
Next, we investigated the possibility of recovering and reusing
palladacycle 1. 4-Bromobenzotrifluoride and 7 were used for
the model study under the optimized reaction conditions. The
recycling experiments were carried out over 5 runs and the
time taken for the reaction to reach completion was 2–7 min
to produce 8a in 92–98% yields (Table 2). In addition, ICP-OES
analysis of Pd leaching in the crude product was very low (0.023–
0.033 ppm over 5 cycles). It is worth noting that the amount of
palladium leaching is much much lower than that observed for
the polymer-supported oxime-based palladacycle analog (14.4–
20.2 ppm over 7 cycles)14 and the three earlier reported fluorous
Pd-catalysts which were applied to the cross-coupling reactions
in aqueous media (vide supra).8
a Palladacycle 1 (0.05 mol% Pd), K2CO3, TBAB, H2O, 140 ◦C, M.W.
b Isolated yield. c Using polymer-supported oxime-based palladacycle:1
0.1 mol% Pd, K2CO3, H2O, 100 ◦C. d Using polymer-supported oxime-
based palladacycle:1 0.1 mol% Pd, KOH, TBAB, acetone–H2O (3 : 2),
50 ◦C.
additive and under microwave irradiation at 140 ◦C. The reaction
proceeded efficiently to give the biphenyl product 8a in 98% yield
within 2 min (Table 1, entry 1). It is worth noting that other
solvent systems, including THF which is commonly used for the
homogeneous palladium-catalyzed Suzuki–Miyaura reaction,
gave lower yields of the product (Table S2†, entries 3–6). We next
examined the effects of the bases on the reaction. Two inorganic
bases (K2CO3 and KOH) and an organic base (Cy2NMe) were
investigated, and K2CO3 was found to be the most effective
base for the reaction (Table S2†, entries 1, 7–8). The reaction
temperature was also varied and the experimental data obtained
(Table S2†, entries 1, 9–10) indicated that although the reaction
completed more rapidly under microwave irradiation conditions,
raising the temperature to 170 ◦C resulted in a lower yield of the
product. Finally, we tried to reduce the precatalyst loading to
0.005 mol% Pd. This afforded 8a in 98% yield (corresponding
to 2 ¥ 104 TON) and the reaction time was only slightly longer
than the reaction with 0.05 mol% Pd (Table S2†, entries 1 and
2). However, when 0.005 mol% Pd was applied to the cross-
coupling of 7 with benzyl chloride under microwave irradiation
at 140 ◦C, the reaction required nearly an hour to complete.
Thus, a precatalyst loading of 0.05 mol% Pd was used for
the remaining Suzuki–Miyaura reactions with palladacycle 1
Encouraged by these results, we extended our studies to the
Stille and copper-free Sonogashira coupling reactions. Attempts
to carry out the Sonogashira coupling of p-nitrophenyl bromide
and phenylacetylene 9 with palladacycle 1 (0.05 mol% Pd) and
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Table 3 Sonogashira reaction for phenylacetylene 9 with aryl halidesa
Table 4 Stille reaction of tributyl(4-methoxyphenyl)stannane 11 with
aryl halidesa
Entry
1
ArX
Time (min)
2
Product (Yieldb)
Entry
1
ArX
Time (min)
2
Product (Yieldb)
2
3
4
7
2
10
14
12
3
4
1.5
4
a Palladacycle 1 (0.5 mol% Pd), pyrrolidine, H2O, 140 ◦C, M.W. b Isolated
yield. c Ref. 17.
a Palladacycle 1 (0.005 mol% Pd), H2O, TBAB, 100 ◦C, M.W. b Isolated
yield.
◦
different bases under microwave irradiation at 140 C resulted
Conclusion
in a sluggish reaction (Table S3†, entries 1, 3–5). Hence the
precatalyst loading was increased to 0.5 mol% Pd and the best
yield was obtained when pyrrolidine was used as the base (Table
S3†, entries 1–5). Next, we varied the solvent and found that
water proved to be the best solvent (Table S3†, entries 5–9).
These results were gratifying as Sonogashira coupling reactions
in neat water and in the absence of additives15 are rare and
low yielding because of the poor solubility or instability of the
catalysts and coupling reagents in aqueous media.16 For our
experiments into the Sonogashira coupling reaction in aqueous
media, we had initially used undegassed water for the reaction.
This resulted in the homocoupled product of 9 being formed
as a side-product (Table S3†, entry 9). To circumvent this
problem, we tried degassed water and found that not only was
the homocoupled product absent but the reaction time was also
reduced. To demonstrate the versatility of palladacycle 1 for
copper-free Sonogashira coupling reactions, we have applied it
to other substrates which also gave good yields of the desired
product (Table 3).
Next, we investigated the applicability of palladacycle
1 to the Stille coupling reaction. In our initial studies,
palladacycle 1 (0.05 mol% Pd) was added to tributyl(4-
methoxyphenyl)stannane 1118 and o-bromobenzaldehyde in
different solvents (Table S4 in the ESI†, entries 1–4). The best
yield was obtained when water was used as the reaction solvent
but the reaction time was 28 min. To reduce the reaction time, we
tried increasing the reaction temperature but this gave a poorer
yield of the desired product. Thus we introduced TBAB as an
additive and this resulted in a higher yield (91%) and a significant
reduction in reaction time (2 min) (Table S4†, entry 6). Further
experimentation showed that the reaction proceeded equally
well at a lower temperature (100 ◦C) and precatalyst loading
(0.005 mol% Pd), giving the product in both a comparable yield
and reaction time (Table S4†, entry 8). Using these optimized
conditions, we have extended the study to other substrates
which also gave good to excellent yields of the desired products
(Table 4).
In summary, a fluorous oxime-based palladacycle 1 was synthe-
sized and shown to promote the Suzuki–Miyaura, Sonogashira
and Stille coupling reactions in aqueous media. Palladacycle 1
could be used under microwave irradiation at high temperatures
which significantly shortened the reaction time. Recycling was
also possible with palladacycle 1 which was reused five times in
a Suzuki–Miyaura reaction without significant loss of activity.
Palladium leaching was also very low.
Acknowledgements
This research is supported by grants from the National Univer-
sity of Singapore (R-143-399-112 to Y. L.) and National Science
Council of Taiwan (NSC 98-2113-M-002-009-MY3 to L.-C.L.).
Notes and references
1 (a) J. Tsuji, Palladium Reagents and Catalyst: Innovations in Organic
Synthesis, 1996, John Wiley & Sons Ltd, Chichester, England; (b) T.
Hayashi, J. Organomet. Chem., 2002, 653, 41; (c) I. Moreno, R. San
Martin, M. T. Herrero and E. Dominguez, Curr. Top. Catal., 2009, 8,
91; (d) J. Dupont, F. R. Flores, Handbook of Green Chemistry, 2009,
Wiley-VCH, Weinheim, Germany, pp 319.
2 (a) E. B. Mubofu, J. H. Clark and D. Macquarrie, Green Chem., 2001,
3, 23; (b) D. Rosario-Amorin, X. Wang, M. Gaboyard, R. Cle´rac, S.
Nlate and K. Heuze´, Chem.–Eur. J., 2009, 15, 12636.
3 (a) N. E. Leadbeater and M. Marco, Chem. Rev., 2002, 102, 3217;
(b) T. J. Dickerson, N. N. Reed and K. D. Janda, Chem. Rev., 2002,
102, 3325; (c) Q.-H. Fan, Y.-M. Li and A. S. C. Chan, Chem. Rev.,
2002, 102, 3385; (d) A. Molna´r, Chem. Rev., 2011, 111, 2251.
4 I. T. Horva´th and J. Ra´bai, Science, 1994, 266, 72.
5 N. Audic, P. W. Dyer, E. G. Hope, A. M. Stuart and S. Suhard, Adv.
Synth. Catal., 2010, 352, 2241 and references therein.
6 C.-J. Li, Chem. Rev., 2005, 105, 3095.
7 (a) G. Hamasaka, T. Muto and Y. Uozumi, Angew. Chem., Int. Ed.,
2011, 50, 4876; (b) M. Lamblin, L. Nassar-Hardy, J.-C. Hierso, E.
Fouquet and F.-X. Felpin, Adv. Synth. Catal., 2010, 352, 33; (c) Y.
Uozumi and Y. M. A. Yamada, Chem. Rec., 2009, 9, 51; (d) K. H.
Shaughnessy, Chem. Rev., 2009, 109, 643.
8 (a) Z.-W. Ye and W.-B. Yi, J. Fluorine Chem., 2008, 129, 1124; (b) L.
Wang and C. Cai, J. Mol. Catal. A: Chem., 2009, 306, 97; (c) A. B.
This journal is
The Royal Society of Chemistry 2012
Green Chem., 2012, 14, 77–80 | 79
©

View Article Online
Theberge, G. Whyte, M. frensel, L. M. Fidalgo, R. C. R. Wootton
and W. T. S. Huck, Chem. Commun., 2009, 6225.
9 N. T. S. Phan, M. Van Der Sluys and C. W. Jones, Adv. Synth. Catal.,
2006, 348, 609.
10 (a) I. P. Beletskaya and A. V. Cheprakov, J. Organomet. Chem., 2004,
689, 4055; (b) D. A. Alonso, C. Na´jera and M. C. Pacheco, Org. Lett.,
2000, 2, 1823.
11 E. Alacid and C. Na´jera, Adv. Synth. Catal., 2007, 349, 2572.
12 (a) L. Botella and C. Na´jera, J. Organomet. Chem., 2002, 663, 46;
(b) D. A. Alonso, C. Na´jera and M. C. Pacheco, J. Org. Chem., 2002,
67, 5588.
13 (a) N. Henry, C. Enguehard-Gueiffier, I. Thery and A. Gueiffier, Eur.
J. Org. Chem., 2008, 28, 4824; (b) I. A. Fairlamb, P. Sehnal and R. J.
K. Taylor, Synthesis, 2008, 2009, 508.
14 E. Alacid and C. Na´jera, J. Organomet. Chem., 2008, 694,
1658.
15 Additives are added to solubilize the reagents and cata-
lysts: D. Rosario-Amorin, M. Gaboyard, R. Cle´rac, S. Nlate
and K. Heuze, Dalton Trans., 2011, 40, 44 and references
therein.
16 (a) B. Liang, M. Dai, J. Chen and Z. Yang, J. Org. Chem., 2005,
70, 391; (b) B. Ine´s, R. San Martin, F. Churruca, E. Dominguez,
M. K. Urtiaga and M. I. Arriortua, Organometallics, 2008, 27,
2833.
17 F. Habib, I. Nasser and G. Mohammad, J. Mol. Catal. A: Chem.,
2010, 321, 110.
18 Synthesis of 11: L. S. Liebeskind and J. Wang, Tetrahedron, 1993, 49,
5461.
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