Metal-Catalyzed Carbonylation: From the Industry to the Bench

Tom Hsieh Dong Research Group Organic and Biological Seminar Series Department of Chemistry, University of Toronto November 9, 2009 1 Outline

ƒ IntroductionIntroduction to cacarbonrbon mmonoxideonoxide (CO) ƒ Preparation of CO ƒ Uses of CO in some industrial processes ƒ Properties of the CO molecule

ƒ Reductive carbonylation of nitro compounds: use of CO as a stoichiometric redundant in the pppreparation of N-heterocycles

ƒ Carbonylative cross-coupling of organic ha lides: use o f CO as a C1 source in the preparation of carboxylic acid derivatives

2 Preparation of Carbon Monoxide

ƒ Burning elemental carbon in restricted supply of oxygen gas

ƒ Reduction of carbon dioxide with coke

ƒ Dehydration of formic acid (small scale for laboratory)

ƒ Water-gas shift reaction (preparation of synthesis gas)

Housecroft and Sharpe. Inorganic Chemisty. Prentice Hall: England 2001. 3 Industrial Process: FischerFischer--TropschTropsch Synthesis

ƒ Discovered in 1922 ƒ Commercialized in 1928 ƒ Heterogeneous catalysis ƒ Fe and Co catalysts ƒ 200-300 oC and 10-60 bar ƒ Highl y exoth erm ic ƒ 6.5 Mt / yr by 1944

ƒ Used as synthetic lubricants and Prof. Franz Fischer Dr. Hans Tropsch synthetic diesel/jet fuels

Housecroft and Sharpe. Inorganic Chemisty. Prentice Hall: England 2001. 4 Proposed FischerFischer--TropschTropsch Mechanism

Housecroft and Sharpe. Inorganic Chemisty. Prentice Hall: England 2001. 5 Industrial Process: Hydroformylation

ƒ Discovered and commercialized in 1938 by Otto Roelen at Ruhrchemie (Germany) ƒ Important industrial homogeneous catalysis ƒ Combined 7.2 Mt / yr ƒ 50% of world capacity located in Europe and 30% in USA ƒ Propene important olefin starting material

ƒ First acti ve cat al yst : [HC o (CO)3]

Hagen. Industrial Catalysis. Wiley-VCH: Weinheim 2006. 6 Industrial Process: Hydroformylation

Cat al yst s Co Co/phosphine Rh/phosphine Reaction 200-300 50-100 7-25 Pressure (()bar) Reaction 140-180 180-200 90-125 Temperature (°C) L:B of aldehyde 4:1 9:1 19:1

[HRh(CO)(PPh3)3] / Catalyst [HCo(CO)4] [HCo(CO)3(PBu3)] PPh3 up to 1:500 Main Products aldehydes alcohols aldehydes Hydrogenation to 1150.9 alkanes (%) Hagen. Industrial Catalysis. Wiley-VCH: Weinheim 2006. 7 Hydroformylation: Catalytic Cycle

β-H elimination β-H elimination

Migratory Migratory Coordination Insertion Insertion

Hydrorhodation Hydrorhodation

Hagen. Industrial Catalysis. Wiley-VCH: Weinheim 2006. 8 Use of [Rh] in Hydroformylation

ƒ Advantages of using [Rh] over [Co] ƒ [Rh] is 1000x more active

ƒ Excess of PPh3 allows high linear aldehyde selectivity

ƒ Use of PPh3 increases catalyst stability and prolongs its life ƒ [Rh] has low volatility so purification of product is simpler

ƒ [Rh] process is high cost: work up, catalyyygst recycling and corrosion ƒ Intensive research in developing heterogeneous [Rh] catalyst ƒ Two-phase technology: uses water-soluble [Rh] with TPPTS ƒ Improved L:B selectivity (> 19:1) ƒ Ease of [Rh] catalyst separation and recycling

Hagen. Industrial Catalysis. Wiley-VCH: Weinheim 2006. 9 Industrial Processes: Production of Acetic Acid

ƒ Commercialized in 1970 by Monsanto ƒ Important industrial catalytic process ƒ Combined 3.5 Mt / yr ƒ 60% of world’s acetyls ƒ One of few industrial catalytic processes whose kinetics are fully known

¯ ƒ Active catalyst: [RhI2(CO)2]

Hagen. Industrial Catalysis. Wiley-VCH: Weinheim 2006. 10 The Monsanto Process: Catalytic Cycle

Oxidative Migratory Addition Insertion

Reductive Ligand Elimination Exchange

Hagen. Industrial Catalysis. Wiley-VCH: Weinheim 2006. 11 The Monsanto Process

ƒ Process is licensed worldwide ƒ Mild reaction conditions: 30-40 bar and 150-200 °C ƒ Numerous columns needed for product isolation ƒ Stainless steel needed for all plant components due to corrosiveness of iodide ƒ In 1996, the Cativa Process introduced by BP Chemicals ƒ Higher reactivity about 3x ƒ Up to 0.5 Mt / yr via this modification

Hagen. Industrial Catalysis. Wiley-VCH: Weinheim 2006. 12 Carbon Monoxide

“carbene-like” “dinitrogen-like”

ƒ Colorless and odorless gas ƒ Highly flammable and toxic ƒ Bond length: 112.8 pm ƒ Bond energy: 257 kcal/mol ƒ Dipo le moment: 0. 112 D ƒ Insoluble in water (26 mg/L)

ƒ HOMO is lone pair on C (σ3)

13 Carbon Monoxide

C≡ON≡NHC≡CH O=OO=C=OMe2C=O Bond Energy 257 226 200 119 193 193 (kcal/mol) Bond Length 112.8 109.7 120.3 121.0 116.0 121.3 (pm) Dipole 0.112 0 0 0 0 2.91 Moment (D)

14 Use of Carbon Monoxide in Synthesis

Aldehydes Acyl halides Aldoximes Nitriles Ketones Anhydrides Ketenes Carbonates Ketoximes Carbamates CO Metal-Catalyzed Esters Isocyanates + Carbonylation Lactones Ureas Substrate Carboxylic acids Amines AidAmides AdAzo compounds Lactams Heterocycles 1,2-Dicarbo n yl s Car bocycl es 1,4-Dicarbonyls Metal complexes 15 Reductive Carbonylation of Nitro Compounds

16 Reductive Carbonylation

ƒ The use of CO for the reduction of chemical bonds while forming

CO2, for example:

ƒ NO2 reduced to nitroso and/or nitrene

ƒ CO oxidized to CO2 – a stoichiometric reductant

17 First Example of Reductive Carbonylation

ƒ In 1949, Buckley and Ray reported the first reductive carbonylation

ƒ Trace amounts of reduction occurred at 200 oC or < 2500 atm ƒ Nickel and cobalt catalysts had no effect

Buckley and Ray. J. Chem. Soc. 1949, 1154. 18 Towards Catalysis

ƒ In 1965, Kmiecik identified Fe(CO)5 as a efficient catalyst for the reductive carbonylation of nitrobenzene

ƒ KiKmiec ikiltdik isolated azoxy benzene as a possible intermediate

Kmiecik. J. Org. Chem. 1965, 30, 2014. 19 Synthesis of Isocyanates

ƒ In 1967, Hardy and Bennett reported the first reduction of nitro aromatics to generate isocyanates catalytically

ƒ R = EDG and EWG ƒ Solvents: nonpolar ƒ Catalysts: Pd, Rh/Al, Rh/C

ƒ Lewis acids: FeX3, AlX3, SnCl4, CuCl2

Hardy and Bennett. Tetrahedron Lett. 1967, 11, 961. 20 Advancements in Reductive Carbonylation

ƒ Since this discovery, research in this area of reductive carbonylation has greatly increased

ƒ Big push for the formation of other targets including isocyanates, carbtbamates, ureas, an did amines

Chem. Rev. 1996, 96, 2035. and Curr. Org. Chem. 2006, 10, 1479. 21 Isocyanates from Phosgenation

ƒ > 2 Mt produced per year ƒ TDI and MDI account for > 95% of the world’s diisocyanates made ƒ Important precursors to numerous polyurethanes ƒ Phosgene is highly toxic ƒ LtfLarge amounts of corrosive HCl proddduced

The Polyurethanes Book; Wiley: New York, NY, 2003. and Dalton Trans. 2009, 6251. 22 Reductive Carbonylation Mechanism

Chem. Rev. 1996, 96, 2035. 23 Diversity of Nitroarenes in Reductive Carbonylation

Catalytic Reductive Carbonylation of Organic Nitro Compounds. Kluwer Academic Publishers: Netherlands, 1997. Benzimidazoles via [Ru] Catalysis

Entry Solvent T (oC) % A % B % C

1 Benzene 220 86 4 ---

2 Benzene 170 34 trace 47

3 (no [Ru]) Benzene 220 ------85

4 CH3CN 170 82 --- 4

ƒ Limited number of stable imines ƒ ClbdiththiidCan also be done with the imine made iitin situ

Cenini and coworkers. J. Mol. Catal. 1992, 72, 283. Benzimidazoles via [Pd] Catalysis

o EtEntry R Time (h) T(T ( C) PCO (t(atm ) %A% A %B% B 1 Ph 5 180 40 83 trace

2 Ph 5 180 20 81 ---

3 Ph 5 160 40 78 11

4 Ph 5 140 40 55 10

5 p-ClC6H4 2 180 40 55 45

6 p-OMeC6H4 3 180 40 80 10

ƒ 2,4,6-Trimethylbenzoic acid (TMBH) is required or else no reaction

Cenini and coworkers. J. Mol. Catal. 1994, 59, 3375. Carbazoles via [Pd] Catalysis

o ƒ Previous forcing conditions: Ru3(CO)12, 50 atm CO , 220 C ƒ Low Catalyst loading: 0.5 mol % Pd, 3.5 mol % phen, 97% yield

Smitrovich and Davies. Org. Lett. 2004, 6, 533. 27 Merck’s Kinase Inhibitors

quantitative yield

Pd(TFA)2 (0. 1 mol %) TMphen (1.0 mol %) CO (1 atm) DMF, 70 oC

ƒ Conditions: Pd(OAc)2 (6 mol %), PPh3 (24 mol %), CO (4 atm) ƒ Difficult purification required development of new reaction conditions

Davies and coworkers. Tetrahedron. 2005, 61, 6425. 28 Substrate Scope of Merck’s Conditions

Varying Conditions

Pd(OAc)2 or Pd(TFA)2 0.1 – 1.5 mol% phen or TMphen 0.7 – 3 mol % CO (1 – 2 atm) 70 – 80 oC

Davies and coworkers. Tetrahedron. 2005, 61, 6425. 29 Proposed Mechanism for Indole Formation

Davies and coworkers. Tetrahedron. 2005, 61, 6425. 30 Nitroalkenes in Reductive Carbonylation

ƒ Proposal: extension to Nitroalkenes ƒ ItInteres tdited in accessi ng vari ous N-htheterocycl es

31 Synthesis of Nitroalkenes

ƒ Preparation of the model nitroalkene substrate

ƒ Preparation of symmetrical arylnitroalkenes

32 Substrate Scope

a Isolated yield. b Regioselectivity (based on 1H NMR integrations) is 47:53.

Electron-rich substrates are tolerated 33 Substrate Scope

a Isolated yield. c Regioselectivity is 42:58. d Regioselectivity is 51:49.

Electron-poor substrates are tolerated 34 Regioselective CC––HH Bond Amination

Structure solved by Dr. Alan Lough 35 Indoles via Reduction of Nitroalkenes with CO

ƒ Tolerant of both electron-rich and electron-poor substrates – 10 examples, 58–98% ƒ Versatile methodology for making indoles ƒ Fe, Rh, Pt and Pd catalysts ƒ Bidentate N- and P-based ligands ƒ New strategy for the synthesis of nitroalkenes

Hsieh and Dong. Tetrahedron. 2009, 65, 3062 (Invited Article). 36 Carbonylative cross-coupling of organic halides

37 Biologically Active Compounds via Carbonylation

38 Biologically Active Compounds via Carbonylation

Seeberger and coworkers. Org. Lett. 2002, 4, 2965.

Kogen and coworkers. Tetrahedron. 2005, 61, 2075. 39 Biologically Active Compounds via Carbonylation

Desmaele and coworkers. Tetrahedron Lett. 2005, 46, 2201.

Song and coworkers. J. Org. Chem. 2001, 66, 605. 40 Carbonylation of Aryl Halides

TilCditiTypical Conditions

ƒ X = Cl, Br, I, OTf, OMs and OTs

ƒ [Pd] = Pd(0) and Pd(II)

ƒ L = mono- and bidentate phosphines

ƒ Base = organic and inorganic

ƒ T = 100 to 180 °C

ƒ PCO = 1 to 40 bar

Organometallics. 2008, 27, 5402. and Angew. Chem. Int. Ed. 2009, 48, 4114. 41 Profen Drugs: Chiral Carboxylic Acids

ƒ Sub-class of the non-steroidal anti-inflammatory drugs (NSAIDs) ƒ Compared to aryl-X, small amounts of research done with 2° alkyl-X. ƒ Lack of efficient methods of preparing profens enantioselectively

42 State of the Art: Asymmetric Profen Preparation

ƒ Hydrocarboxylation and Hydroesterification

ƒ Primarily palladium catalysis ƒ Typical enantioselectivities < 60% ee ƒ Reggypioselectivity problem – linear and branched products ƒ Difficult to obtain high levels of both regio- and enantioselectivity

Dalton Trans. 2008, 853. and Top Organomet. Chem. 2006, 18, 97. 43 Stoichiometric Alkoxycarbonylation

90% inversion of stereochemistry

Stille and coworkers. J. Am. Chem. Soc. 1974, 96, 4983. 44 Stereoconvergent Catalytic Hydroxycarbonylation

ƒ Mild conditions: rt, 4-12 h, CO (1 atm) ƒ 9 different ligands were tested ƒ LidLow conversion and ee ƒ No substrate scope

Arzoumanian and coworkers. Organometallics 1988, 7, 59. 45 Stereospecific Catalytic Hydroxycarbonylation

ƒ Poor Regioselectivity ƒ Significant amount of homobenzyl acid, vinylarene and alkylarene byproducts ƒ High enantioselectivity at low conversions ƒ Best result: 36% yield, 91% ee ƒ High pressure of CO (43 atm)

Sparacino and coworkers. J. Org. Chem. 1991, 56, 1928. 46 Alkoxycarbonylation of 2° Alkyl Halides

ƒ Proposal

ƒ Two possibilities for asymmetric induction ƒ Stereoconvergent: a chiral catalyst facilitates the transformation of racemic substrates to enantioenriched products ƒ Stereospecific: an achiral catalyst facilitates the transformation of enantioenriched substrates to enantioenriched products with either retention or inversion of stereochemistry

Charles Yeung 47 PdPd--CatalyzedCatalyzed Enantioselective Alkoxycarbonylation

ƒ New catalytic transformation

ƒ Pd(0) and Pd(II) successfully catalyze this transformation ƒ Ni, Rh, Ru, Pt and Fe are ineffective catalysts ƒ Conventional bidentate ligands are ineffective ƒ e.g. BINAP, BIPHEP, SEGPHOS and DUPHOS

ƒ Initial hit with Pd(OAc)2, Et3N, CH2Cl2, MeOH

ƒ P(2-frl)furyl)3 – 46% GC yield ƒ (R)-Monophos – 48% GC yield, 33% ee 48 Carbonylation of Benzylic Bromides

R = R' = Ph MeOH, 67%, 21% ee R = Ar, R' = Ar' MeOH, 20%, 49% ee i-PrOH, 12%, 72% ee

Ar = Ar' =

ƒ High yields with low ee and vice versa ƒ Reactions with i-PrOH generally give higher ee than with MeOH ƒ Product distribution differ between MeOH and i-PrOH ƒ Substitution is the major competing pathway with MeOH ƒ β-H elimination is the major competing pathway with i-PrOH

49 Summary and Conclusion

ƒ Carbon monoxide is used throughout synthetic chemistry ƒ Industrial pp()rocesses (Mt scale) and academic research (g)(mg scale)

ƒ Major advancements in reductive carbonylation ƒ 1949 – no catalyy,sis, 250 °C, and 3000 atm of CO ƒ 2009 – numerous catalysts (0.1 mol %), 70 °C and 1 atm of CO ƒ Significant improvements – possible industrial applications soon ƒ Beyond nitroarenes

ƒ Carbonylative cross-coupling of many R-X electrophiles ƒ Aryl, vinyl, benzyl and alkyl ƒ Halides, sulfonates, acetates, carbonates, etc. ƒ Directed carbonylation of sp2 C–H is also known ƒ Enantioselective variants are in development

50 Acknowledgements

Prof. Vy M. Dong Charles Yeung Dong Research Group 51