A Highly Active Palladium(I) Dimer for Pharmaceutical Applications

Transcription

1 DI: / A Highly Active alladium(i) Dimer for harmaceutical Applications [d(µ-)( t Bu 3)] 2 AS A ACTICAL CSS-CULIG CATALYST By Thomas J. Colacot Johnson Matthey, Catalysis and Chiral Technologies, West Deptford, ew Jersey 08066, U.S.A.; colactj@jmusa.com The d(i) dimer [d(μ-)( t Bu 3)] 2 is one of the best third-generation cross-coupling catalysts for carbon carbon and carbon heteroatom coupling reactions. Information on its characterisation and handling are presented, including its decomposition mechanism in the presence of oxygen. The catalytic activity of [d(μ-)( t Bu 3)] 2 is higher than either ( t Bu 3)d(0) or the in situ generated catalyst system based on d 2(dba) 3 with t Bu 3. Examples of suitable reactions for which the d(i) dimer offers superior performance are given. Introduction The palladium(i) dimer, di-μ-bromobis(tri-tertbutylphosphine)dipalladium(i), [d(μ-)( t Bu 3)] 2, was synthesised and fully characterised by Mingos (1, 2). However, its potential as a unique C C and C coupling catalyst (3) was first explored by Hartwig (6). It has emerged as one of the best third-generation coupling catalysts for cross-coupling reactions, including C heteroatom coupling and α-arylations. In this review, the physical and chemical characteristics of the d(i) dimer as a catalyst material are discussed from a practical viewpoint, and up to date information on its applications in coupling catalysis is provided. Characteristics and Handling The d(i) dimer is a dark greenish-blue crystalline material, which gives a single peak in the 31 M spectrum at (δ) 87.0 ppm. The 1 H M spectrum gives a peak at (δ) 1.33 ppm (singlet; on expansion it appears as a distorted triplet) in deuterated benzene (1, 2). The compound decomposes in chlorinated solvents, especially in deuterated chloroform. The -ray crystal structure is reported in the literature as a dimer with d d bonding, stabilised by bromine atoms via bridge formation (1, 2). It can be handled in air as a solid for a short period of time, allowing the user to place it into a reactor in the absence of a solvent, degas and then carry out catalysis under inert conditions. However, this compound is highly sensitive to air and moisture in the solution phase. It can also decompose in the solid phase if not stored under strictly inert conditions. The solid state decomposition pattern over time was monitored in our laboratory at 0, 48 and 112 hours (Figure 1) (4). Its sensitivity towards oxygen is well understood, and is based on the formation of an oxygen-inserted product with the elimination of hydrogen (Scheme I) (5). Figure 2 shows the oxygen sensitivity of the d(i) dimer on a proton-decoupled 31 M spectrum recorded using a solvent which was not degassed. The peak at 107 ppm indicates the presence of the oxygeninserted decomposition product. Fig. 1 The solid state oxygen sensitivity of pure d(i) dimer, [d(μ-)( t Bu 3)] 2, with time (4) 0 h 48 h 112 h latinum Metals ev., 2009, 53, (4),

2 Fig. 2 The oxygen sensitivity of d(i) dimer, [d(μ-)( t Bu 3)] 2, as observed in the 31 M (ppm) spectrum recorded using non-degassed C 6D ppm Applications in Coupling Catalysis The high catalytic activity of the d(i) dimer [d(μ-)( t Bu 3)] 2 is due to its ease of activation, presumably to a highly active, coordinatively unsaturated and kinetically favoured 12-electron catalyst species, ( t Bu 3)d(0) (Scheme II). This renders the d(i) dimer more active than either the known 14-electron d(0) catalyst, ( t Bu 3) 2d(0), or the d(0) catalyst generated in situ by mixing d 2(dba) 3 with two molar equivalents of t Bu 3. The applications of the d(i) dimer in organic synthesis are described below. Carbon Heteroatom Coupling Hartwig identified the potential of the d(i) dimer as a highly active catalyst for C coupling using aryl chlorides as substrates with various amines at room temperature. A few examples are shown in Scheme III (6). Typically, aryl chloride coupling requires higher temperatures and longer reaction times when using the in situ generated d(0) catalyst, or even the ( t Bu 3) 2d(0) complex (7). Around the same time, rashad and coworkers at ovartis reported an amination reaction using [d(μ-)( t Bu 3)] 2 with challenging substrates such as hindered anilines (8). Scheme IV shows the coupling of -cyclohexylaniline with bromobenzene, comparing the performance of the d(i) dimer with those of in situ generated catalysts derived from d(ac) 2 with t Bu 3, BIA, antphos or DEphos. The performance of [d(μ-)( t Bu 3)] 2 is superior in each case. B r d d B r 2-2H 2H CH 2 d d(i) dimer d( I) d im e r CH M : 87 M M: : ppm M: 87 ppm M d Scheme I The oxygen sensitivity of d(i) dimer, [d(μ-)( t Bu 3)] 2, with the formation of an inactive d- species (5) d d d Scheme II The activation of d(i) dimer to a 12-electron catalyst species during coupling catalysis Highly active 12-electron species latinum Metals ev., 2009, 53, (4) 184

3 Cl H 0.5 mol% d(i) dimer a t Bu, T 15 min 1 h Scheme III Aryl chloride coupling at room temperature (6) = Bu, h or 2H = morpholine Yield 88 99% H d catalysts a t Bu, Toluene, 110 C Catalyst loading Yield [d(μ-)( t Bu 3)] mol% 93% d(ac) 2 t Bu mol% 86% d(ac) 2 BIA 0.5 mol% 27% d(ac) 2 antphos 0.5 mol% 27% d(ac) 2 DEphos 0.5 mol% none Scheme IV d(i) dimer-catalysed C coupling of -cyclohexylaniline (8) Hartwig s group subsequently conducted a detailed study to understand the activity and scope of [d(μ-)( t Bu 3)] 2 in the amination of fivemembered heterocyclic halides. Various combinations of d precursors with t Bu 3 were studied for a model system, the reaction of -methylaniline with 3-bromothiophene. The fastest reaction occurred with the d(i) dimer (9). More recently, Eichman and Stambuli reported a very interesting zinc-mediated d(i) dimercatalysed C S coupling, which should generate much interest in the area of C S coupling (Scheme V) (10). For the reactions of alkyl thiols with aryl bromides and iodides, potassium hydride was the best base, as illustrated in Scheme V. For the d-catalysed cross-coupling reactions of aryl bromides and benzenethiol using zinc chloride in catalytic amounts, with sodium tert-butoxide as the base, most of the reactions were sluggish and gave low yields. However, the addition of stoichiometric amounts of lithium iodide increased the rate of the reaction significantly, which is speculated to be due to the anionic effects proposed by Amatore and Jutand (11). Carbon Carbon Bond Formation Hartwig s group also studied the Suzuki coupling of sterically hindered tri-substituted aryl bromides. A d(i) dimer loading of 0.5 mol%, in the presence of alkali metal hydroxide base, gave good yields at room temperature within minutes (Scheme VI) (6). Ar- SH =, I ZnCl 2 (catalyst) KH (1.1 equiv.) mol% d(i) dimer THF Ar-S- Yield 46 99% = t Bu, n Bu, hch 2 Scheme V Zinc-mediated d(i) dimer-catalysed C S coupling (10) latinum Metals ev., 2009, 53, (4) 185

4 2 hb(h) mol% d(i) dimer KH, THF 15 min, T = ; = H, C, CF 3, CH 3 or CH 3; 2, = H or CH 3 h 2 Yield 84 95% Scheme VI oom temperature Suzuki coupling of sterically bulky aryl bromides (6) esearch work from yberg at Astra Zeneca (12) demonstrated a very practical, clean method for C C coupling using the d(i) dimer [d(μ-)( t Bu 3)] 2 to produce 3 kg to 7 kg of product routinely (Scheme VII). During the initial in situ studies, d 2(dba) 3 in combination with commercial ligands such as Q-hos, t Bu 2biphenyl or Cy 2-biphenyl gave poor results, although with proper process tweaking improvements were made. The conventional ligands, such as h 3 and dppf, were not useful. However, the (o-tol) 3/d 2(dba) 3 system behaved somewhat well with the formation of some byproducts. The d loading was as high as 5 mol% (12). For the α-arylation (13) of fairly challenging carbonyl compounds, Hartwig identified the d(i) dimer [d(μ-)( t Bu 3)] 2 as one of the best catalysts, especially for amides and esters. The work from Hartwig s group provided general conditions for α-arylations of esters and amides (14 16). The coupling reactions of aryl halides with esters are summarised in Scheme VIII (17). For aryl bromides, lithium dicyclohexylamide (LiCy 2) was the best base, while sodium hexamethyldisilazide (ahmds) was required for aryl chloride substrates. Intermolecular α-arylation of H H d(i) dimer, Zn(C) 2 Zn, DMF 50ºC, 1 3 h C H H Scheme VII The d(i) dimer-catalysed cyanation reaction, which may be carried out on a kilogram scale (12) 2 (i) LiCy 2 ( = ) or ahmds ( = Cl) Toluene, T, 10 min (ii) d(i) dimer T 100ºC, 4 h 2, 2 = Me, H; = Me, t Bu =, Cl; = Me, Me, F Yield 71 88% Scheme VIII α-arylation of esters under milder conditions using the d(i) dimer catalyst (17) latinum Metals ev., 2009, 53, (4) 186

5 in situ generated zinc enolates of amides was also reported in excellent yield under eformatsky conditions using the d(i) dimer, (Scheme I) (18). The appropriate choice of base for the substrate is critical for this reaction. The α-vinylation of carbonyl compounds has been reported recently by Huang and coworkers at Amgen, catalysed by the d(i) dimer in conjunction with lithium hexamethyldisilazide (LiHMDS) base (Scheme ) (19). The same catalytic system can be extended to the α-vinylation of ketones and esters. The combination of d 2(dba) 3 with Buchwald ligands such as -hos and S-hos gave inferior results, as did in situ catalysis with ligands such as antphos, (S)-M, BIA and Ir-HCl (carbene) in the presence of d 2(dba) 3. Amgen researchers also reported a stereoselective α-arylation of 4-substituted cyclohexyl esters using the d(i) dimer at room temperature, with lithium diisopropylamide (LDA) as the base. Diastereomeric ratios, dr, of up to 37:1 were achieved (Scheme I) (20). Me 2 (i) 1.5 equiv. Zn* THF, T, 30 min (ii) 2.5 mol% d(i) dimer Me 2 Yield 94% Scheme I α-arylation of amides under eformatsky conditions (18); Zn* = activated zinc species ' ''' '' 2 =, Tf, Ts d(i) dimer, LiHMDS Toluene, 80ºC, 24 h ' '' ''' 2 Yield 48 95% Scheme α-vinylation reaction using d(i) dimer catalyst (19); Tf = trifluoromethane sulfonate; Ts = tosylate Glossary Ligand BIA t Bu 2-biphenyl t Bu 3 Cy 2-biphenyl dba DEphos dppf Ir-HCl (carbene) (S)-M Ac (o-tol) 3 h 3 Q-hos S-hos antphos -hos Full name 2,2' -bis(diphenylphosphino)-1,1' -binaphthyl 2-(di-tert-butylphosphino)biphenyl tri-tert-butylphosphine 2-(dicyclohexylphosphino)biphenyl dibenzylideneacetone bis(2-diphenylphosphinophenyl)ether 1,1' -bis(diphenylphosphino)ferrocene 1,3-bis-(2,6-diisopropylphenyl)imidazolium chloride 2-(diphenylphosphino)-2' -methoxy-1,1' -binaphthyl acetate tri(o-tolyl)phosphine triphenylphosphine 1,2,3,4,5-pentaphenyl-1' -(di-tert-butylphosphino)ferrocene 2-dicyclohexylphosphanyl-2',6' -dimethoxybiphenyl 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene 2-dicyclohexylphosphino-2',4',6' -triisopropylbiphenyl latinum Metals ev., 2009, 53, (4) 187

6 C 2Et d(i) dimer, LDA Toluene, T, 3 24 h 1 C 2Et Yield 37 85% Up to 37:1 dr Scheme I oom temperature diasteroselective α-arylation of 4-substituted cyclohexyl esters using d(i) dimer (20) Conclusions The d(i) dimer [d(μ-)( t Bu 3)] 2 stands out as unique among the third generation catalysts for cross-coupling. It has a higher activity than other catalysts, a fact which can be attributed to its ability to form a 12-electron ligand-d(0) species during the activation step in the catalytic cycle. Its application to a wide variety of C C, C and C S cross-coupling reactions will enable higher yields and better product selectivities under relatively mild conditions. Acknowledgements Fred Hancock and Gerard Compagnoni of Johnson Matthey s Catalysis and Chiral Technologies are acknowledged for their support of this work. eferences 1. Vilar, D. M.. Mingos and C. J. Cardin, J. Chem. Soc., Dalton Trans., 1996, (23), V. Durà-Vilà, D. M.. Mingos,. Vilar, A. J.. White and D. J. Williams, J. rganomet. Chem., 2000, 600, (1 2), T. J. Colacot, Di-μ-bromobis(tri-tert-butylphosphine)dipalladium(I), to be included in 2009 in e-es Encyclopedia of eagents for rganic Synthesis, eds. L. A. aquette, D. Crich,. L. Fuchs and G. Molander, John Wiley & Sons Ltd., published online at: wiley.com/eros (Accessed on 30th July 2009) 4 Johnson Matthey Catalysts, Coupling Catalysis Application Table, West Deptford, ew Jersey, U.S.A.: (Accessed on 30th July 2009) 5 V. Durà-Vilà, D. M.. Mingos,. Vilar, A. J.. White and D. J. Williams, Chem. Commun., 2000, (16), J.. Stambuli,. Kuwano and J. F. Hartwig, Angew. Chem. Int. Ed., 2002, 41, (24), Kuwano, M. Utsunomiya and J. F. Hartwig, J. rg. Chem., 2002, 67, (18), M. rashad,. Y. Mak, Y. Liu and. epic, J. rg. Chem., 2003, 68, (3), M. W. Hooper, M. Utsunomiya and J. F. Hartwig, J. rg. Chem., 2003, 68, (7), C. C. Eichman and J.. Stambuli, J. rg. Chem., 2009, 74, (10), C. Amatore and A. Jutand, Acc. Chem. es., 2000, 33, (5), yberg, rg. rocess es. Dev., 2008, 12, (3), C. C. C. Johansson and T. J. Colacot, Angew. Chem., 2009, in press 14 T. Hama and J. F. Hartwig, rg. Lett., 2008, 10, (8), T. Hama and J. F. Hartwig, rg. Lett., 2008, 10, (8), T. Hama,. Liu, D. A. Culkin and J. F. Hartwig, J. Am. Chem. Soc., 2003, 125, (37), T. Hama and J. F. Hartwig, Synfacts, 2008, (7), T. Hama, D. A. Culkin and J. F. Hartwig, J. Am. Chem. Soc., 2006, 128, (15), J. Huang, E. Bunel and M. M. Faul, rg. Lett., 2007, 9, (21), E. A. Bercot, S. Caille, T. M. Bostick, K. anganathan,. Jensen and M. F. Faul, rg. Lett., 2008, 10, (22), 5251 The Author Dr Thomas J. Colacot is a esearch and Development Manager in Homogeneous Catalysis (Global) of Johnson Matthey s Catalysis and Chiral Technologies business unit. Since 2003 his responsibilities include developing and managing a new catalyst development programme, catalytic organic chemistry processes, scale up, customer presentations and technology transfers of processes globally. latinum Metals ev., 2009, 53, (4) 188