The suzuki-miyaura reaction performed using a palladium-n-heterocyclic carbene catalyst and a weak inorganic base

Article abstract of DOI:10.1002/ejoc.201500043

N-Heterocyclic carbenes (NHCs) have been shown to be useful ligands for the Suzuki-Miyaura cross-coupling at low catalyst loadings. We now report that the commercially available and air-stable [Pd(IPr)(cin)Cl] pre-catalyst permits the formation of various functionalized biaryls from aryl chlorides and boronic acids (37 examples) under very mild conditions using a mixture of ethanol/water as solvent and an inorganic base. [Pd(IPr)(cin)Cl] permits an operationally simple Suzuki-Miyaura reaction under very mild conditions using a mixture of ethanol/water as solvent and an inorganic base.

Full text of DOI:10.1002/ejoc.201500043

Job/Unit: O50043
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Date: 17-02-15 18:25:15
Pages: 6
SHORT COMMUNICATION
DOI: 10.1002/ejoc.201500043
The Suzuki–Miyaura Reaction Performed Using a Palladium–N-Heterocyclic
Carbene Catalyst and a Weak Inorganic Base
Frédéric Izquierdo,[a] Martin Corpet,[a] and Steven P. Nolan*[a]
Keywords: Cross-coupling / N-heterocyclic carbenes / Palladium / Suzuki–Miyaura reaction
N-Heterocyclic carbenes (NHCs) have been shown to be
useful ligands for the Suzuki–Miyaura cross-coupling at low
formation of various functionalized biaryls from aryl chlor-
ides and boronic acids (37 examples) under very mild condi-
catalyst loadings. We now report that the commercially avail- tions using a mixture of ethanol/water as solvent and an inor-
able and air-stable [Pd(IPr)(cin)Cl] pre-catalyst permits the
ganic base.
are based on mixtures of organic solvents and water,[3b,3e,4]
as well as modifications of the ligand, including the ad-
Introduction
Palladium-catalyzed cross-coupling reactions are a popu- dition of functional groups, which secure the water solubil-
lar method of forming C–C bonds and have become a stan- ity of the catalyst (e.g., sulfonate) or use of phase-transfer
dard synthetic assembly tool in organic and organometallic reagents.[4b–4d,4f,4g,5] However, these solutions often require
chemistry.[1] Among these, the Suzuki–Miyaura reaction tedious synthetic procedures to obtain the desired pre-cata-
represents a preferred methodology. In an effort to reduce lysts.
the generation of hazardous substances, variations of the
While most of the early catalytic protocols involve phos-
Suzuki–Miyaura cross-couplings have been developed using phine ligands,[3e,3i,6] N-heterocyclic carbene (NHC) com-
green solvents,[2] particularly water.[3] These variations are plexes have shown remarkable catalytic performance,[7] in-
especially attractive as water is nontoxic, non-flammable, cluding in the Suzuki–Miyaura reaction.[4k,8] Numerous
inexpensive, and can be easily separated from organic prod- complexes of the [Pd(NHC)(cin)Cl] (cin = cinnamyl) family
ucts. Among the different approaches developed to reach are now commercially available, and these complexes have
greener reaction conditions, the most often used procedures proven effective in the Suzuki–Miyaura coupling, but
Scheme 1. Activation pathways of the [Pd(NHC)(cin)Cl] pre-catalyst.
[a] EaStCHEM School of Chemistry, University of St Andrews,
usually require the use of a strong base (e.g., KOtBu) to
St Andrews, KY16 9ST, UK
generate the catalytically active species, which limits the
functional group tolerance and the choice of solvent.[4k,8a,9]
Colacot and co-workers have shown that their Pd(allyl) sys-
tem could be activated using K2CO3 in a toluene/water mix-
E-mail: snolan@st-andrews.ac.uk
http://chemistry.st-and.ac.uk/staff/spn/group/SP%20Nolan/
Home.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500043.
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F. Izquierdo, M. Corpet, S. P. Nolan
SHORT COMMUNICATION
ture.[10] Recently, Hazari and co-workers have described the scope of the methodology. The optimized conditions are
preparation of the dinuclear PdI complex [Pd2(IPr)2- then 0.5 mol-% of A, 1 equiv. of boronic acid and 1.1 equiv.
(η3-cin)Cl] [IPr: 1,3-bis(2,6-diisopropylphenyl)imidazol-2- of K2CO3 in a 1:1 ethanol/water mixture at 80 °C in air.
ylidene] by the reduction of [Pd(IPr)(cin)Cl] in an EtOH/ Under these conditions, clean and complete conversion
K2CO3 system. In this report, it was proposed that this could be achieved in 4 h for methyl 4-chlorobenzoate, and
complex is in equilibrium with the catalytically active Pd0– in 16 h for p-chlorotoluene. Other commercially available
NHC intermediate by a disproportionation reaction. Based ethanol/water mixtures were tested and resulted in similar
on these studies the Hazari group proposed the mechanism high yields.[12,15]
depicted in Scheme 1 (A).[11] Similarly, Minakata and co-
workers showed that the [Pd(SIPr)(cin)Cl] [SIPr: 1,3-bis- scope and limitations of the transformation were studied
(2,6-diisopropylphenyl)imidazolin-2-ylidene] pre-catalyst (Scheme 2). Various aryl chlorides were coupled with phen-
With the optimized reaction conditions in hand, the
could also be activated using a mild base (Na2CO3) and ylboronic acid. The methodology allowed the coupling of a
boronic acid as a reductant in a toluene/water mixture wide range of aryl chlorides bearing different functional
(Scheme 1, B).[12]
groups in the para position with very good to excellent
yields (1a–1h, 65 to 99% isolated yield), nonetheless cou-
pling reaction involving alcohols or carboxylic acids could
not be achieved. In many cases, the final product was ob-
tained with a purity higher than 95% without the need for
further purification (1a–c, 2–4, 5b–c, 6a–b, 8, 15a and
Results and Discussion
With these interesting reports in mind, we decided to fur- 18).[13] With a non-activating group such as a methyl group,
ther investigate the use of alcohol solvents in the Suzuki– the desired product was obtained in very good yield but
Miyaura cross-coupling reaction with commercially avail- required a longer reaction time (1h, 88%). A broad range
able Pd–NHC pre-catalysts in the presence of mild inor- of boronic acids with varying electronic and steric proper-
ganic bases. We began our study examining the reaction of ties were next investigated. Following the same trend as its
phenylboronic acid and p-chlorotoluene in ethanol at 40 °C, phenyl derivative, the p-tolylboronic acid reacted cleanly
using the commercially available [Pd(NHC)(cin)Cl] pre- with a sulfone-functionalized chloride (2, 98%). The same
catalysts {NHC = IPr (A), SIPr (B), IPr* (C); IPr*: boronic acid was coupled with 2-chloropyridine to afford
1,3-bis[2,6-bis(diphenylmethyl)-4-methylphenyl]imidazol-2- the desired compound (3) after 16 h in 73% isolated yield
ylidene}.[13] Among these catalysts, the IPr- and SIPr-based as well as with methyl 4-chloro-3-methylbenzoate giving the
pre-catalysts showed good conversions with 65% and 64%, corresponding product in excellent yield (4, 98%). The
respectively, after 1 h. The pre-catalyst bearing the bulkiest more hindered o-tolylboronic acid reacted efficiently with
NHC, IPr*, gave low conversion (9%). The latter required p-chloroanisole (5a, 91%) after 16 h, while the reaction with
a longer reaction time to afford full conversion. This is activated substrates gave the desired product also in very
possibly due to a slower activation of the pre-catalyst due high yields (5b, 5c) after the standard 4 h reaction time.
to steric congestion of the metal center.[14] At 0.5 mol-% Furthermore, using activated boronic acid such as o-meth-
catalyst loading, the conversion remained nearly the same oxyphenylboronic acid gave excellent yields (6a–b). Its p-
if the temperature was increased to 80 °C. Different solvent/ methoxy derivative allowed the coupling with many aryl
base combinations were also studied. Lower conversions partners (7–11), even with the less common p-chlorophen-
were observed with other inorganic bases such as Na2CO3 ylacetone (7, 86%). The intermediate of diflunisal[16] (8)
or K3PO4. Poorer conversions were also obtained using was achieved in very good yield (82%), without the need
other alcohols.[13]
for any additional purification steps. On the other hand, the
Further optimization was performed on a more activated reaction of p-methoxyphenylboronic acid was less efficient
substrate, methyl 4-chlorobenzoate, to gauge the viability of with 2-chlorothiophene and 2-chloronaphthalene, affording
the inorganic base with more reactive substrates.[13] Under the products in good to moderate yields (9 and 10, 74%
the previously described conditions, full conversion of start- and 52%), presumably due to steric hindrance in the latter
ing material was observed with this substrate. However, case. The same boronic acid reacted very efficiently with
transesterification with the solvent proved to be problem- benzyl chloride to afford the expected compound (11) in
atic leading to a 63:37 ratio of methyl/ethyl ester. Decreas- 84% isolated yield. The p-trimethylsilylphenylboronic acid
ing the amount of boronic acid was found to be detrimental coupled very well with both unactivated and activated aryl
affording an unfavorable ratio (Me/Et = 23:77). As the for- chlorides (12a–b, 89 and 96%) as well as with methyl p-
mation of the transesterification product can be associated chlorocinnamate (13, 90%). Unactivated boronic acids were
with the excess base used, we were pleased to observe al- then investigated (14–19). Boronic acid bearing a p-meth-
most no by-product using 1.1 equiv. of base (Me/Et = 93:7). oxycarbonyl group reacted efficiently with 2-chlorothio-
In order to develop greener conditions and to possibly in- phene (14, 78%) and with functionalized aryl chlorides
crease further the reactivity of the boronic acid, different (15a–b and 16a–b, 61 to 98%). Another unactivated boronic
ethanol/water ratios were studied. Finally, a ratio of eth- acid, functionalized with a cyano group in the para posi-
anol/water of 1:1, gave full conversion with no observed tion, reacted smoothly with p-chloroacetophenone to afford
transesterification, and thus was chosen to evaluate the the desired product after 16 h (17, 94%). The cross-cou-
2
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Suzuki–Miyaura Reaction with a Pd–NHC Catalyst and a Weak Inorganic Base
pling reaction between o-formylphenylboronic acid and p- treated with p-chlorophenyl methyl sulfone and yielded 19
chlorobenzotrifluoride led to the Xenalipin intermediate[17] in a moderate 49% isolated yield. 2-Naphthylboronic acid
(18) in excellent yield without further purification. The also reacted efficiently with activated aryl chlorides (20 and
more challenging p-acetamidophenylboronic acid was 22).
Scheme 2. Scope and limitations of the Suzuki–Miyaura coupling with [Pd(IPr)(cin)(Cl)].
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F. Izquierdo, M. Corpet, S. P. Nolan
SHORT COMMUNICATION
In comparison with previous work, Nechaev describes a
similar method using a six-membered ring derivative of IPr
with a phase-transfer agent in water at reflux. This method
appears limited to unfunctionalized heteroaromatic com-
pounds.[18] The present method appears much more versa-
tile and is straightforward to launch.
Finally, the robustness of the methodology was tested on
a multigram scale for a selection of products (Table 1). We
were pleased to see that 1a (Table 1, Entry 1) was obtained
in excellent yield after workup using only 0.25 mol-% of
catalyst. Compound 1b was isolated in 90% yield after col-
umn chromatography. The reaction afforded 1c (Entry 3) in
excellent yield after recrystallisation from hot ethyl acetate.
Finally, the Diflusinal (Table 1, Entry 4) and Xenalipin in-
termediates (Entry 5) were isolated in good yields after ex-
traction, without the need of chromatography.
Experimental Section
General Procedure for the Suzuki–Miyaura Reaction in Ethanol/
Water: Under normal atmosphere, in a vial equipped with a stirring
bar and sealed with a screw cap fitted with a septum, were added
the boronic acid (0.5 mmol, 1 equiv.), K2CO3 (76 mg, 0.55 mmol,
1.1 equiv.) and the aryl or heteroaryl chloride (0.5 mmol). Then,
were added successively distilled water (0.5 mL) and [Pd(IPr)-
(cin)(Cl)] (1.62 mg, 2.5ϫ10–3 mmol, 0.5 mol-%) in solution in
EtOH (0.5 mL). After reaction at 80 °C, the mixture was cooled to
room temperature. An equal volume of water and CH2Cl2 (10 mL)
was added, and the aqueous phase was extracted with CH2Cl2 (3ϫ
10 mL). The combined organic phases were dried with MgSO4, and
the solvent was removed under vacuum. As a function of the sub-
strate, the desired product may or may not require further purifica-
tion, but usually does not.
Acknowledgments
Table 1. Scale up of the Suzuki–Miyaura cross-coupling using
[Pd(IPr)(cin)Cl].[a]
We gratefully acknowledge the European Commission (EC) for
funding through the seventh framework program SYNFLOW, the
European Research Council (ERC) (Advanced Investigator Award
“FUNCAT” to S. P. N.) and the The Engineering and Physical Sci-
ences Research Council (EPSRC). We thank the EPSRC National
Mass Spectrometry Service Center in Swansea for mass spectromet-
ric analyses. S. P. N. is a Royal Society Wolfson Research Merit
Award holder.
[1] N. Miyaura in Metal-Catalyzed Cross-Coupling Reactions, 2nd
ed. (Eds.: A. de Mejeire, F. Diederich), Wiley-VCH, Weinheim,
2008, pp. 41–123), .
[2] D. Prat, J. Hayler, A. Wells, Green Chem. 2014, 16, 4546–4551.
[3] a) M. O. Simon, C. J. Li, Chem. Soc. Rev. 2012, 41, 1415–1427;
b) H. D. Velazquez, F. Verpoort, Chem. Soc. Rev. 2012, 41,
7032–7060; c) Á. Molnár, Chem. Rev. 2011, 111, 2251–2320; d)
J. Magano, J. R. Dunetz, Chem. Rev. 2011, 111, 2177–2250; e)
K. H. Shaughnessy, Chem. Rev. 2009, 109, 643–710; f) C. J. Li,
Chem. Rev. 2005, 105, 3095–3166; g) C. J. Li, Acc. Chem. Res.
2002, 35, 533–538; h) D. Wang, D. Astruc, Chem. Rev. 2014,
114, 6949–6985; i) V. Polshettiwar, A. Decottignies, C. Len, A.
Fihri, ChemSusChem 2010, 3, 502–522.
[4] a) J. W. Byun, Y. S. Lee, Tetrahedron Lett. 2004, 45, 1837–1840;
b) S. Roy, H. Plenio, Adv. Synth. Catal. 2010, 352, 1014–1022;
c) T. Tu, X. Feng, Z. Wang, X. Liu, Dalton Trans. 2010, 39,
10598–10600; d) T. E. Schmid, D. C. Jones, O. Songis, O.
Diebolt, M. R. L. Furst, A. M. Z. Slawin, C. S. J. Cazin, Dal-
ton Trans. 2013, 42, 7345–7353; e) M. Charbonneau, G. Ad-
doumieh, P. Oguadinma, A. R. Schmitzer, Organometallics
2014, 33, 6544–6549; f) X. Ma, H. Wang, W. Chen, J. Org.
Chem. 2014, 79, 8652–8658; g) F. Rajabi, W. R. Thiel, Adv.
Synth. Catal. 2014, 356, 1873–1877; h) J. C. Shi, H. Yu, D.
Jiang, M. Yu, Y. Huang, L. Nong, Q. Zhang, Z. Jin, Catal.
Lett. 2014, 144, 158–164; i) L. Liu, Y. Dong, N. Tang, Green
Chem. 2014, 16, 2185–2189; j) X. X. Zhou, L.-X. Shao, Synthe-
sis 2011, 3138–3142; k) N. Marion, O. Navarro, J. Mei, E. D.
Stevens, N. M. Scott, S. P. Nolan, J. Am. Chem. Soc. 2006, 128,
4101–4111.
[5] a) I. Özdemir, N. Gürbüz, Y. Gök, E. Çetinkaya, B. Çetinkaya,
Synlett 2005, 2394–2396; b) F. Godoy, C. Segarra, M. Poyatos,
E. Peris, Organometallics 2011, 30, 684–688; c) D. Schönfelder,
O. Nuyken, R. Weberskirch, J. Organomet. Chem. 2005, 690,
4648–4655; d) B. Inés, R. SanMartin, M. J. Moure, E. Domíng-
uez, Adv. Synth. Catal. 2009, 351, 2124–2132; e) F. Churruca,
R. SanMartin, B. Inés, I. Tellitu, E. Domínguez, Adv. Synth.
Catal. 2006, 348, 1836–1840; f) H. Ohta, T. Fujihara, Y. Tsuji,
Dalton Trans. 2008, 379–385; g) A. Tudose, L. Delaude, B.
André, A. Demonceau, Tetrahedron Lett. 2006, 47, 8529–8533;
[a] Reaction conditions: In a flask fitted with a septum and a stir-
ring bar, were added successively all the reagents, the pre-catalyst
and the solvents. The mixture was heated at 80 °C for 4 h. [b] Iso-
lated yield. [c] Reaction conducted with 0.25 mol-% of catalyst. [d]
After purification, providing gram quantities of isolated products.
Conclusion
We have described a very user-friendly methodology for
the Suzuki–Miyaura reaction under non-inert conditions,
using a commercially available Pd–NHC complex as pre-
catalyst at low catalyst loading. The reactions were opti-
mized in a 1:1 water/ethanol mixture in the presence of a
mild and inexpensive inorganic base that permits to extend
the scope of the Suzuki–Miyaura reaction using Pd–NHC
as pre-catalysts. We have shown that this system can couple
a wide range of aryl chlorides and boronic acids in good to
excellent yields and have exemplified this with a number of
examples conducted on a multigram scale.
4
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Suzuki–Miyaura Reaction with a Pd–NHC Catalyst and a Weak Inorganic Base
h) C. Fleckenstein, S. Roy, S. Leuthäußer, H. Plenio, Chem.
Commun. 2007, 2870–2872; i) M. Meise, R. Haag, ChemSus-
124, 3370; f) S. Würtz, F. Glorius, Acc. Chem. Res. 2008, 41,
1523–1533.
Chem 2008, 1, 637–642; j) G. Papini, M. Pellei, G. Gioia Lob- [8] a) N. Marion, O. Navarro, J. Mei, E. D. Stevens, N. M. Scott,
bia, A. Burini, C. Santini, Dalton Trans. 2009, 6985–6990; k)
S. Gu, H. Xu, N. Zhang, W. Chen, Chem. Asian J. 2010, 5,
1677–1686; l) F.-T. Luo, H.-K. Lo, J. Organomet. Chem. 2011,
696, 1262–1265; m) H. Türkmen, L. Pelit, B. Çetinkaya, J. Mol.
Catal. A 2011, 348, 88–93; n) P. Karthikeyan, A. Vanitha, P.
Radhika, K. Suresh, A. Sugumaran, Tetrahedron Lett. 2013,
54, 7193–7197; o) L. A. Schaper, S. J. Hock, W. A. Herrmann,
F. E. Kühn, Angew. Chem. Int. Ed. 2013, 52, 270–289; Angew.
Chem. 2013, 125, 284; p) Z. Wang, Y. Yu, Y. X. Zhang, S. Z.
Li, H. Qian, Z. Y. Lin, Green Chem. 2015, 17, 413–420; q) R.
Zhong, A. Pothig, Y. Feng, K. Riener, W. A. Herrmann, F. E.
Kuhn, Green Chem. 2014, 16, 4955–4962; r) T. Liu, X. Zhao,
Q. Shen, L. Lu, Tetrahedron 2012, 68, 6535–6547; s) B. Karimi,
P. Fadavi Akhavan, Inorg. Chem. 2011, 50, 6063–6072; t) G.
Nan, F. Ren, M. Luo, Beilstein J. Org. Chem. 2010, 6, 70.
a) K. W. Anderson, S. L. Buchwald, Angew. Chem. Int. Ed.
2005, 44, 6173–6177; Angew. Chem. 2005, 117, 6329; b) A.
Konovets, A. Penciu, E. Framery, N. Percina, C. Goux-Henry,
D. Sinou, Tetrahedron Lett. 2005, 46, 3205–3208; c) A. S. Gu-
ram, A. O. King, J. G. Allen, X. Wang, L. B. Schenkel, J. Chan,
E. E. Bunel, M. M. Faul, R. D. Larsen, M. J. Martinelli, P. J.
Reider, Org. Lett. 2006, 8, 1787–1789; d) L. Wu, B.-L. Li, Y.-
Y. Huang, H.-F. Zhou, Y.-M. He, Q.-H. Fan, Org. Lett. 2006,
8, 3605–3608; e) M. Blug, C. Guibert, X.-F. Le Goff, N. Me-
zailles, P. Le Floch, Chem. Commun. 2008, 203; f) H. Doucet,
Eur. J. Org. Chem. 2008, 2013–2030; g) L. Wu, Z.-W. Li, F.
Zhang, Y.-M. He, Q.-H. Fan, Adv. Synth. Catal. 2008, 350,
846–862; h) A. N. Marziale, S. H. Faul, T. Reiner, S. Schneider,
J. Eppinger, Green Chem. 2010, 12, 35–38; i) V. Polshettiwar,
A. Decottignies, C. Len, A. Fihri, ChemSusChem 2010, 3, 502–
522; j) S. L. Mao, Y. Sun, G.-A. Yu, C. Zhao, Z.-J. Han, J.
Yuan, X. Zhu, Q. Yang, S. H. Liu, Org. Biomol. Chem. 2012,
10, 9410–9417; k) K. Wójcik, C. Goux-Henry, B. Andrioletti,
K. M. Pietrusiewicz, E. Framery, Tetrahedron Lett. 2012, 53,
5602–5604.
S. P. Nolan, J. Am. Chem. Soc. 2006, 128, 4101–4111; b) O.
Navarro, N. Marion, J. Mei, S. P. Nolan, Chem. Eur. J. 2006,
12, 5142–5148; c) C. J. O’Brien, E. A. B. Kantchev, C. Valente,
N. Hadei, G. A. Chass, A. Lough, A. C. Hopkinson, M. G.
Organ, Chem. Eur. J. 2006, 12, 4743–4748; d) L. Wu, E. Drin-
kel, F. Gaggia, S. Capolicchio, A. Linden, L. Falivene, L. Cav-
allo, R. Dorta, Chem. Eur. J. 2011, 17, 12886–12890; e) G. Al-
tenhoff, R. Goddard, C. W. Lehmann, F. Glorius, Angew.
Chem. Int. Ed. 2003, 42, 3690–3693; Angew. Chem. 2003, 115,
3818.
[9] a) A. Chartoire, A. Boreux, A. R. Martin, S. P. Nolan, RSC
Adv. 2013, 3, 3840–3843; b) A. Chartoire, M. Lesieur, L. Faliv-
ene, A. M. Z. Slawin, L. Cavallo, C. S. J. Cazin, S. P. Nolan,
Chem. Eur. J. 2012, 18, 4517–4521; c) A. R. Martin, A. Char-
toire, A. M. Z. Slawin, S. P. Nolan, Beilstein J. Org. Chem.
2012, 8, 1637–1643; d) A. Chartoire, X. Frogneux, S. P. Nolan,
Adv. Synth. Catal. 2012, 354, 1897–1901; e) S. Meiries, G.
Le Duc, A. Chartoire, A. Collado, K. Speck, K. S. A. Arach-
chige, A. M. Z. Slawin, S. P. Nolan, Chem. Eur. J. 2013, 19,
17358–17368.
[10] C. C. C. Johansson Seechurn, S. B. L. Parisel, T. J. Colacot, J.
Org. Chem. 2011, 76, 7918–7932.
[11] D. P. Hruszkewycz, D. Balcells, L. M. Guard, N. Hazari, M.
Tilset, J. Am. Chem. Soc. 2014, 136, 7300–7316.
[12] Y. Takeda, Y. Ikeda, A. Kuroda, S. Tanaka, S. Minakata, J.
Am. Chem. Soc. 2014, 136, 8544–8547.
[13] For more details, see the Supporting Information.
[14] a) L. Cavallo, A. Correa, C. Costabile, H. Jacobsen, J. Or-
ganomet. Chem. 2005, 690, 5407–5413; b) H. Clavier, S. P. No-
lan, Chem. Commun. 2010, 46, 841–861.
[15] The reaction can also be carried out in single malt whisky. This
led to a 97% conversion of the desired product under optimised
reaction conditions and an 87% isolated yield.
[16] C. Giordano, L. Coppi, F. Minisci, US Patent 5312975, 1994.
[17] a) C. Dupuis, K. Adiey, L. Charruault, V. Michelet, M. Savig-
nac, J.-P. Genêt, Tetrahedron Lett. 2001, 42, 6523–6526; b)
L. N. B. Bell, M. T. Hodgson Jr., G. L. Shumaker, T. K. 1982;
c) K. Koch, R. J. Chambers, M. S. Biggers, Synlett 1994, 347–
348.
[6]
[7] a) Y. Fort, C. Comoy, in N-Heterocyclic Carbenes (Ed.: S. Diez-
Gonzalez), Royal Society of Chemistry, London, 2011, pp.
284–316; b) S. Díez-González, N. Marion, S. P. Nolan, Chem.
Rev. 2009, 109, 3612–3676; c) G. C. Fortman, S. P. Nolan,
Chem. Soc. Rev. 2011, 40, 5151–5169; d) N. Marion, S. P. No-
lan, Acc. Chem. Res. 2008, 41, 1440–1449; e) C. Valente, S.
Çalimsiz, K. H. Hoi, D. Mallik, M. Sayah, M. G. Organ, An-
gew. Chem. Int. Ed. 2012, 51, 3314–3332; Angew. Chem. 2012,
[18] E. L. Kolychev, A. F. Asachenko, P. B. Dzhevakov, A. A. Bush,
V. V. Shuntikov, V. N. Khrustalev, M. S. Nechaev, Dalton Trans.
2013, 42, 6859–6866.
Received: January 12, 2015
Published Online: ᭿
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F. Izquierdo, M. Corpet, S. P. Nolan
SHORT COMMUNICATION
Suzuki–Miyaura Reactions
F. Izquierdo, M. Corpet,
S. P. Nolan* ...................................... 1–6
The Suzuki–Miyaura Reaction Performed
Using a Palladium–N-Heterocyclic Carb-
ene Catalyst and a Weak Inorganic Base
Keywords: Cross-coupling / N-heterocyclic
carbenes / Palladium / Suzuki–Miyaura re-
action
[Pd(IPr)(cin)Cl] permits an operationally
simple Suzuki–Miyaura reaction under
very mild conditions using a mixture of
ethanol/water as solvent and an inorganic
base.
6
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