Umicore CX Catalysts Palladium Catalyzed Cross-Coupling Reactions 2 3

Umicore CX Catalysts Palladium catalyzed cross-coupling reactions 2 3

Specific, well-defined precatalysts and ready-made catalysts

UMICORE PMC WILL ASSIST YOU WITH OUR EXPERTISE IN ACTIVITY EXACTLY AS FAR AS IT IS NEEDED TO MEET YOUR NEEDS

Palladium catalyzed C-C- and C-X bond forming reactions have undergone remarkable developments in the last 25 years [1]. Numerous research groups, inspired by the 2010 Chemistry Nobel Prize awardees Heck, Negishi and Suzuki [2], have developed new palladium precursors, ligands and catalysts to fully utilize this versatile, synthetic tool in organic chemistry. Some of these palladium complexes have transitioned into a broad range of applications spanning from synthesis of agrochemicals, use in natural products and active pharmaceutical ingredients down to appearing in materials for electronic applications.

Umicore CX catalysts at glance:

• Alternative Palladium precursors

• Well-defined, ready-to-use Palladium phosphine complexes

• Selective & active Palladium N-heterocyclic carbene complexes

• Efficient Palladium recovery streams

[1] a) Handbook of Organopalladium Chemistry for Organic Synthesis, (Eds.: E. Negishi, F. Diederich) Wiley-VCH, 2002, b) Metal-Catalyzed Cross Coupling Reactions, (Eds.: A. de Meijere, F. Diederich) Wiley-VCH, 2004, c) Angew. Chem. Int. Ed. 2012, 51, 5062 [2] http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2010/popular-chemistryprize2010.pdf 4 5

CROSS-COUPLING REACTIONS ARE A TRANSITION METAL CATALYZED COUPLING OF AN ORGANIC ELECTROPHILE (I.E. ORGANIC HALIDE) WITH AN ORGANIC NUCLEOPHILE. SEVERAL NAME REACTIONS HAVE BEEN DEVELOPED USING ORGANOMETALLIC CARBON NUCLEOPHILES HALOGEN BONDS.

Kumada Sonogashira-Hagihara Stille Mizoroki-Heck Carbonylation Buchwald - Hartwig -Amination Cyanation Suzuki -Miyaura Negishi Hiyama

In addition to conventional product offerings Regardless of whether you need to perform a such as the palladium precursors and highly Suzuki coupling with strongly hindered and/or active phosphine catalysts, Umicore has deactivated substrates or a Negishi coupling developed a number of stable, user-friendly, with substrates carrying sensitive functional well-defined and powerful Palladium(0) and groups, or you are searching for a catalyst for LEGEND Palladium(II) N-heterocyclic carbene (NHC) a Buchwald-Hartwig Amination reaction, we catalysts that are commercially available at will provide you with the appropriate catalytic X = I, Br, Cl, or OTf industrial scale. active complex. 6 7

Examples

Buchwald-Hartwig amination reaction(3) Mizoroki-Heck Coupling(6)

OMe OMe 5 mol% [Pd(dppf)Cl2] 1.2 eq.NaOtBu + N THF, 3 h, 100 °C N substrate : substrate 2:1 substrate : substrate 1:1 I H2N O H 5 mol% Pd(OAc)2 2.5 mol% Pd2dba3 t N 1.2 eq. 96% yield 5 mol% HBF4*P Bu3 5 mol% XPhos t 1.5 eq. K2CO3 3 eq. NaO Bu N + toluene, 110 °C toluene, mW N O 45 min, 110 °C O Br O O 89% yield 79% yield 5 mol% [Pd(dppf)Cl2] 1.2 eq. NaOtBu + H2N THF, 3 h, 100 °C Br N H 1.2 eq. 96% yield

NC (7) NC 5 mol% [Pd(dppf)Cl2] Negishi Coupling 1.2 eq. NaOtBu + H2N THF, 3 h, 100 °C N Br H CN CN O 1.2 eq. 93% yield t Cl 2 mol% [Pd(P Bu3)2] + ClZn NMP/THF 18 h, 100 °C O O O O

1.5 eq. 76% yield

t s (4) Cl 2 mol% [Pd(P Bu3)2] Bu + ClZn sBu Palladium catalyzed decarboxylation NMP/THF 24 h, 100 °C

t 5 mol% Pd[P( Bu3)]2 H 1.5 eq. 70% yield 1 eq. TBACl N N O 1.5 eq. Cs2CO3 N Ph + PhBr + DMF, µW, Ph OH 8 min, 170 °C Ph 2 eq. 74% yield trace

Newman-Kwartz rearrangement(8)

O NMe2 S NMe2 t 2 mol% [Pd(P Bu3)2] S toluene, 4 h, 100 °C O Palladium catalyzed oxidative coupling(5) F3C F3C > 99% yield

OH 5 mol% Umicore CX21 OH t 2.2 eq.KO Bu O NMe S NMe + 2 t 2 toluene, 1.5 h, 80 °C 2 mol% [Pd(P Bu3)2] Cl S toluene, 4 h, 100 °C O

2.1 eq. 92% yield > 99% yield

[3] J. Am. Chem. Soc. 1996, 118, 7217 [6] J. Am. Chem. Soc. 2008, 130, 3266 [4] J. Am. Chem. Soc. 2006, 128, 11350 [7] J. Am. Chem. Soc. 2001, 123, 2719 [5] J. Org. Chem. 2011, 76, 1390 [8] Angew. Chem. Int. Ed. 2009, 48, 7612 8 9

Suzuki-Miyaura Coupling(9,10) First Class Palladium metal 50 ppm Umicore CX21 N Cl t 1.1 eq. KO Bu N + (HO)2 B tech. grade IPA 3 h, 80 °C recycling technology 1.05 eq. 92% yield UMICORE’S PRECIOUS METAL RECYCLING CAPABILITIES CAN GIVE 1 mol% Umicore CX32 (HO)2B 1.1 eq. KOtBu MORE VALUE TO YOUR PROCESS. THE SOONER THE BETTER! + Br tech. grade IPA 1.5 h, rt

1.05 eq. 92% yield Planning to associate a metal recycling loop to your industrial scale Palladium catalyzed cross-coupling reaction will bring significant additional cost effective- Cl 50 ppm Umicore CX21 1.1 eq. KOt Bu ness to your process. The earlier we speak, the better + (HO)2B tech. grade IPA we can adjust the separation and recycling processes 3 h, 80 °C to offer you maximized precious metal savings. Con-

1.05 eq. 92% yield tact us to discover the accuracy and efficiency of our Palladium recycling technologies and their impact on the economics of your chemical synthesis.

Palladium catalyzed oxidative carbonylation(11)

[Pd]/ligand O H 0.5 eq. TBP + OH + CO 16 h, 120 °C O Umicore PMC cross-couplings

15 eq. 10 atm 81% yield with 5 mol% PdCl2 and 5 mol% Xantphos 80% yield with 2 mol% Pd(Xantphos)Cl2 precatalysts and ready-to-use catalysts

ADVANTAGES READY TO USE EMPIRICAL FORMULA CHEMICAL NAME CAS-No PRODUCT-No

VERSUS IN SITU FORMED CATALYSTS: +2 Palladium(II) chloride 7647-10-1 3000036292 PdCl2 • higher reactivity +2 • consistent reactivity profile for optimum reactivity control Diacetylacetonatopalladium(II) 14024-61-4 3000034510 [Pd(acac)2]

• no catalytically inactive palladium-ligand species +2 Bis(acetonitrile)dichloropalladium(II) 14592-56-4 3000036037 • higher subsequent end-product purity level [Pd(CH3CN)2Cl2]

+2 • no impurities from palladium precursor and no ligand by Bis(benzonitrile)dichloropalladium(II) 14220-64-5 3000036142 incomplete in situ transformation [Pd(C6H5CN)2Cl2]

+2 • efficient utilization of stable, pure & active catalyst with Dichloro(1,5-cyclooctadiene)palladium(II) 12107-56-1 3000034509 correct stoichiometry [Pd(cod)Cl2]

+2 • no loss of palladium and ligand by incomplete in situ Palladium(II) acetate 3375-31-3 3000034514 transformation or ligand decomposition [Pd(OAc)2]3

+2 • no in situ catalyst preformation step Palladium(II) pivalate 106224-36-6 3000020655 [Pd(OOCtBu) ] • Easy catalyst operation for improved 2 3 process safety & simplicity +2 Bis(η3-allyl)di(μ-chloro)dipalladium(II) 12012-95-2 3000034516 [Pd(allyl)Cl]2

+2 Di(μ-chloro)bis(η3-cinnamyl)dipalladium(II) 12131-44-1 3000034515 [Pd(cinnamyl)Cl]2

0 Tris(dibenzylideneacetone)dipalladium(0) 51364-51-3 3000034523 [9] [Pd (dba) ] x dba Chem. Eur. J. 2006, 12, 5142 2 3 [10] J. Am. Chem. Soc. 2006, 128, 4101 [11] J. Am. Chem. Soc. 2012, 134, 9902 10 11

READY TO USE PALLADIUM PHOSPHINE CATALYSTS PALLADIUM N-HETEROCYCLIC CARBENE CATALYSTS

Palladium Vinylsiloxane TRADE NAME EMPIRICAL FORMULA CAS-No PRODUCT-No TRADE NAME EMPIRICAL FORMULA CAS-No PRODUCT-No Catalysts

0 Si Si O Umicore CX11 NHC = IPr 649736-75-4 3000034519 Si Si [(IPr)Pd(NQ)] O 0 O 2 O Pd Pd O Umicore CX61 252062-59-2 3000036051 Pd(vs)c NHC Pd Pd NHC Si Si O 0 Umicore CX12 NHC = IMes 467220-49-1 3000034521 O [(IMes)Pd(NQ)]2 iPr i 0 P Pr US 6 316 380 and Umicore CX14 NHC = SIMes 955998-76-2 3000036042 Si WO 2004 014550 apply. [(SIMes)Pd(NQ)]2 O Fe Pd 0 Si Umicore CX62 1708984-17-1 3000036052 +2 P [Pd(dippf)(vs)tol] Umicore CX21 NHC = IPr 478980-03-9 3000034520 iPr NHC [(IPr)Pd(allyl)CI] iPr Pd WO2015 059049 and foreign equivalents apply. +2 Umicore CX22 NHC = IMes 478980-04-0 3000034522 Cl [(IMes)Pd(allyl)CI] Palladium Monodentate TRADE NAME EMPIRICAL FORMULA CAS-No PRODUCT-No +2 Phosphine Catalysts US 6 316 380, WO 2004 014550 and Umicore CX23 NHC = SIPr 478980-01-7 3000034526 foreign equivalents apply. [(SIPr)Pd(allyl)CI] PPh3 NHC +2 0 Pd PPh3 Umicore CX31 NHC = IPr 884879-23-6 3000034528 Pd-Tetrakis 14221-01-3 3000034517 Pd Ph3P [(IPr)Pd(cinnamyl)CI] [Pd(PPh3)4] Cl PPh3 +2 Umicore CX32 NHC = SIPr 884879-24-7 3000034527 [(SIPr)Pd(cinnamyl)CI] 0 P Pd P Fu catalyst 53199-31-8 3000034529 t US 6 316 380, WO 2004 014550 and +2 [Pd[P( Bu3)]2] Umicore CX33 NHC = IPr* 1380314-24-8 3000036301 foreign equivalents apply. [(IPr*)Pd(cinnamyl)CI]

+2 Br NHC Cl Cl Umicore CX41 NHC = IPr 444910-17-2 3000034518 +1 [(IPr)PdCI ] tBu P Pd Pd PtBu Pd Pd 2 2 3 3 Umicore CX71 t 185812-86-6 3000036049 [PdBr[P( Bu3)]]2 Cl Cl NHC Br +2 US 6 316 380, WO 2004 014550 and Umicore CX42 NHC = SIPr 627878-09-5 3000034610 +2 foreign equivalents apply. [(SIPr)PdCI2]2 Umicore CX72 29934-17-6 3000034513 R1= PCy3 [Pd(PCy ) CI ] 3 2 2 NHC 0 Umicore CX51 NHC = IPr 478019-87-3 3000036038 +2 Pd [(IPr)Pd(vs)] R1= PPh3 Umicore CX73 13965-03-2 3000034512 [Pd(PPh3)2CI2] 0 Umicore CX52 NHC = IMes 441018-46-8 3000036039 +2 Si Si [(IMes)Pd(vs)] Cl R1 R1= P(o-tol)3 Umicore CX74 40691-33-6 3000034511 O Pd [Pd[P(o-tol)3]2CI2] R1 Cl US 6 316 380, WO 2004 014550 and 0 +2 Umicore CX54 NHC = SIMes 1004291-85-3 3000036043 foreign equivalents apply. R = P(tBu )Ph Umicore CX81 t 34409-44-4 3000034531 [(SIMes)Pd(vs)] 1 2 [Pd[P( Bu2)Ph]2CI2] NHC +2 t Cl Pd Cl +2 R = P( Bu)Cy Umicore CX82 t 104889-13-6 3000027105 1 2 [Pd[P( Bu)Cy ] CI ] PEPPSI IPr NHC = IPr 905459-27-0 3000036041 2 2 2 N [(IPr)Pd(3-CI-py)CI2] +2 t n R = P( Bu )( Bu) Umicore CX83 t n 1444507-24-7 3000036046 Cl 1 2 [Pd[P( Bu2)( Bu)]2CI2] US 6 316 380, WO 2004 014550 and +2 t t foreign equivalents apply. Quantities PEPPSI SIPr NHC = SIPr 927706-57-8 3000036044 Bu Cl Bu Ph Ph up to 1kg are exclusively sold [(SIPr)Pd(3-CI-py)CI2] +2 i i i i Me2N P Pd P NMe2 Umicore CX84 887919-35-9 3000034530 by Sigma Aldrich. Pr Pr Pr Pr Ph Ph tBu Cl tBu [Pd(amphos)2CI2] N N N N N N iPr iPr iPr iPr Ph Ph LEGEND FOR PRODUCTS Ph Ph IPr Palladium Bidentate SIPr IPr* TRADE NAME EMPIRICAL FORMULA CAS-No PRODUCT-No Ph Ph i i i i Phosphine Catalysts Pr Pr Pr Pr Ph Ph N N N N N N N N N N Ph +2 n = 1 Umicore CX91 19978-61-1 3000034609 iPr iPr iPr iPr Ph Ph P Ph [Pd(dppe)CI ] Cl 2 Ph Ph Pd SIPr IPr IPr* SIMes IMes ! (CH2)n P Cl +2 Ph n = 2 Umicore CX92 59831-02-6 3000036040 Ph [Pd(dppp)CI2] N N N N +2 R1 = Ph Umicore CX93 72287-26-4 3000034524 R1 [Pd(dppf)CI2] R1 P SIMes IMes Cl +2 ! Fe Pd Cl R1 = Ph Umicore CX94 95464-05-4 3000034525 [Pd(dppf)CI2] x CH2CI2 P R1 Please visit our website at www.pmc.umicore.com to see our updated product list. R1 +2 R = tBu Umicore CX96 95408-45-0 3000034532 1 [Pd(dtbpf)CI ] 2 If you have still not found what you are looking for, please ask our team for advice on how to innovate your powerful cross coupling reaction technology. We have the solution for your needs. +2 O Umicore CX97 205319-10-4 3000036050 [Pd(Xantphos)CI ] The information and statements contained herein are provided free of charge. They are believed to be accurate at the time of publication, but Umicore makes Ph2P PPh2 2 Pd no warranty with respect thereto, including, but not limited to, any results to be obtained or the infringement of any proprietary rights. Use or application of Cl Cl such information or statements is at the user´s sole discretion, without any liability on the part of Umicore. Nothing herein shall be construed as a license or recommendation for use, which infringes upon any proprietary rights. All sales are subject to Umicore´s General Conditions of Sale and Delivery. © 2017 Umicore AG & Co. KG. Version 03/2017. Printed in the Federal Republic of Germany. If you have still not found what you are looking for, please ask our team for advice on how to innovate your powerful cross coupling reaction technology. We have the solution for your needs.

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