Crabtree's Catalyst Research Articles

The development and use of novel iridium complexes as catalysts for ortho‐directed hydrogen isotope exchange reactions

AbstractThe preparation and application of groups of new iridium complexes are described. In particular, iridium complexes possessing phosphine ligands and a bulky N‐heterocyclic carbene have been shown to be robust and readily handled species and have been applied in a range of directed hydrogen–deuterium and –tritium exchange processes and, in particular, with drug‐like substrates or within ADMET‐related studies. Overall, these new iridium(I) complexes are shown to be highly active catalysts and display catalytic activity far in excess of the industry standard, Crabtree's catalyst, with excellent levels of labelling being achieved over short reaction times and at low metal complex loadings, while tolerating a wide range of functional moieties. Furthermore and again in contrast to systems employing Crabtree's catalyst, the low catalyst loadings and short reaction times made possible by these emerging iridium carbene complexes have delivered tritiated products with very good levels of labelling and without any appreciable by‐product waste production. Copyright © 2010 John Wiley & Sons, Ltd.

ChemInform Abstract: Homogeneous Hydrogenation with Iridium Complexes. Evidence for Polyhydride Intermediates in the Reduction of α-Pinene.

The hydrogenation of α-pinene by Crabtree's catalyst [(cycloocta-1,5-diene)(pyridine)(tricyclo-hexylphosphine)iridium hexafluorophosphate] in dichloromethane, occurs from the endo -face with high stereospecificity. Reaction is accompanied by reversible equilibration with β-pinene, which forms 2% of the equilibrium mixture. The hydrogenation of β-pinene is slower than its isomerization under these conditions. Reductions were carried out with deuterium in order to probe the reaction mechanism. Using the novel technique of 2H-decoupled 13C n.m.r., it was found that a complete analysis of the isotope distribution in the product could be obtained by analysis of the C1 signal, since the possible β-and y-perturbations gave rise to distinct spectral shifts. All possible isotopomers corresponding to deuterium substitution at C2, C3 and C10 were observed, and no other site of deuteration was detected. Analysis of the product demonstrated that iridium polyhydrides are likely to be involved, since the results are inconsistent with simpler mechanistic pathways.

Carbene-Metal Hydrides Can Be Much Less Acidic Than Phosphine-Metal Hydrides: Significance in Hydrogenations

Acidities of iridium hydride intermediates were shown to be critical in some transformations mediated by the chiral analogues of Crabtree's catalyst, 1-3. To do this, several experiments were undertaken to investigate the acidities of hydrogenation mixtures formed using these iridium-oxazoline complexes. DFT calculations indicated that the acidity difference for Ir-H intermediates in these hydrogenations were astounding; iridium hydride from the N-heterocyclic carbene catalyst 1 was calculated to be around seven pK(a) units less acidic than those from the P-based complexes 2 and 3. Consistent with this, the carbene complex 1 was shown to be more effective for hydrogenations of acid-sensitive substrates. In deuteration experiments, less "abnormal" deuteration was observed, corresponding to fewer complications from acid-mediated alkene isomerization preceding the D(2)-addition step. Finally, simple tests with pH indicators provided visual evidence that phosphine-based catalyst precursors give significantly more acidic reaction mixtures than the corresponding N-heterocyclic carbene ones. These observations indicate carbene-for-phosphine (and similar) ligand substitutions may impact the outcome of catalytic reactions by modifying the acidities of the metal hydrides formed.

Inside Cover: P-Chiral Ferrocenephospholanes: Synthesis, Reactivity, Metal Complex Chemistry and Application in the Asymmetric Hydrogenation of Olefins (Chem. Eur. J. 47/2009)

Enantiomerically pure P-chiral phospholanes can be readily prepared from (R)-N,N-dimethyl-1-ferrocenylethylamine by means of an ortho-lithiation procedure followed by a stereoconvergent hydrophosphination reaction. These mono- or bidentate ligands were converted to the corresponding Rh and Ir complexes, including a chiral version of Crabtree's catalyst, and tested in the asymmetric hydrogenation of olefins. For more details see the Full Paper by A. Pfaltz, B. Pugin et al. on page 12993 ff.

P‐Chiral Ferrocenephospholanes: Synthesis, Reactivity, Metal Complex Chemistry and Application in the Asymmetric Hydrogenation of Olefins

Starting from (R)-N,N-dimethyl-1-ferrocenylethylamine, a diastereoselective ortho-lithiation procedure and a stereoconvergent intramolecular hydrophosphination gave access to P-chiral ferrocenephospholanes. These mono- or bidentate ligands were converted to the corresponding rhodium and iridium complexes, including a chiral version of Crabtree's catalyst, and tested in the asymmetric hydrogenation of functionalized and unfunctionalized olefins. A significant reactivity difference between the rhodium-1,5-cyclooctadiene and the rhodium-norbornadiene complex was observed during catalyst activation.

Second Generation Synthesis of C27−C35 Building Block of E7389, a Synthetic Halichondrin Analogue

A practical method is reported to synthesize E7389 C27-C35 building block 13 from 1,2-O-isopropylidene-alpha-D-5-deoxyglucurono-6,3-lactone (3). This synthesis relies on two key processes: (1) C34/C35-diol is introduced via asymmetric dihydroxylation with dr = 3:1, with the undesired C34-diastereomer effectively removed by crystallization of 11, and (2) the C30 PhSO2CH2 group is introduced stereoselectively (>100:1) via hydrogenation of 12 in the presence of the Crabtree catalyst. The reported synthesis is practically free from chromatographic separation.

Synthesis of Vicinal Dimethyl Chirons by Asymmetric Hydrogenation of Trisubstituted Alkenes

Roche ester derivatives were converted to trisubstituted alkenes with allylic chiral centers. Hydrogenation of these substrates with chiral analogues of Crabtree's catalyst, specifically, an optically active carbene oxazoline derivative, were found to be mostly catalyst controlled. However, the peripheral functionalities and protecting groups had significant effects and could be adjusted to give high stereoselectivities. The upshot of this work is that alpha,omega-functionalized chirons to introduce 1,2-dimethyl functionalities into acyclic chains have been developed.

The effect of adding Crabtree's catalyst to rhodium black in direct hydrogen isotope exchange reactions

AbstractA new catalytic system based on rhodium black using Crabtree's catalyst as an additive for direct hydrogen isotope exchange in aromatic compounds has been investigated. The level of deuterium incorporation can be improved from for example 16 to 93%. The new catalyst mixture tolerates a variety of solvents. Copyright © 2009 John Wiley & Sons, Ltd.

Functional Group Compatibility. Propargyl Alcohol Reduction in the Presence of a Vinyl Iodide

Vinyl iodides are stable to the reduction of propargyl alcohols to cis allylic alcohols by hydrogen over Pd/CaCO(3) in hexane. They are also stable to the reduction of propargyl alcohols to saturated alcohols by hydrogen over Crabtree's iridium catalyst in CH(2)Cl(2).

Iridium Catalysis for CH Bond Arylation of Heteroarenes with Iodoarenes

Efficient couplings using equimolar quantities of each coupling partner and multiple C-H bond arylation reactions are achieved with an Ir-based catalytic system for the C-H bond arylation of electron-rich heteroarenes with iodoarenes to construct extended pi-systems. The dramatic ligand effect on reaction efficiency leads to the discovery that Crabtree's catalyst (see scheme) is the optimal catalyst precursor.

Synthesis of the tritiated isotopomers of enzastaurin and its N‐des‐pyridylmethyl metabolite for use in ADME studies

AbstractEnzastaurin (3‐(1‐methyl‐1H‐indol‐3‐yl)‐4‐[1‐[1‐(2‐pyridinylmethyl)‐4‐piperidinyl]‐1H‐indol‐3‐yl]‐1H‐pyrrole‐2,5‐dione, 1), an agent with potential utility in the treatment of solid tumors, is currently in phase II clinical trials. Enzastaurin undergoes metabolism in vitro and in vivo to several products of oxidative metabolism, the major one of which is 3‐(1‐methyl‐1H‐indol‐3‐yl)‐4‐(1‐piperidin‐4‐yl‐1H‐indol‐3‐yl)‐1H‐pyrrole‐2,5‐dione (2). In a model study, the attempted synthesis 1‐[2H] by reaction of 1 with deuterium gas in the presence of Ir[(COD)(Cy3P)pyr]PF6 (Crabtree's catalyst) was unsuccessful. Alternatively, it was decided to prepare tritiated 2 as both a final product and the starting material for the tritiation of 1. We have reported herein a route that was developed for use in the preparation of tritium‐labeled 2‐[3H] and its successful conversion to 1‐[3H]. Copyright © 2008 John Wiley & Sons, Ltd.

Homogeneous Hydrogenation of Tri‐ and Tetrasubstituted Olefins: Comparison of Iridium‐Phospinooxazoline [Ir‐PHOX] Complexes and Crabtree Catalysts with Hexafluorophosphate (PF6) and Tetrakis[3,5‐bis(trifluoromethyl)phenyl]borate (BArF) as Counterions

AbstractFour iridium complexes with achiral phosphino‐oxazoline (PHOX) ligands were readily prepared in two steps starting from commercially available phenyloxazolines. The air‐stable complexes with tetrakis[3,5‐bis(trifluoromethyl)phenyl]borate (BArF) as counterion showed high reactivity in the hydrogenation of a range of tri‐ and tetrasubstituted olefins. The best results were obtained with an iridium complex (11) derived from a dicyclohexylphosphino‐oxazoline ligand bearing no additional substituents in the oxazoline ring. With several substrates, which gave only low conversion with the Crabtree catalyst, [Ir(Py)(PCy3)(COD)]PF6, full conversion was observed. The productivity of the Crabtree catalyst could be strongly increased by replacing the hexafluorophosphate anion with tetrakis[3,5‐bis(trifluoromethyl)phenyl]borate. In one case, in the hydrogenation of a tetraalkyl‐substituted CC bond, [Ir(Py)(PCy3)(COD)]BArF gave higher conversion than catalyst 11. However, with several other substrates complex 11 proved to be superior.

Crabtree's catalyst revisited; Ligand effects on stability and durability

The extent of time-dependent deactivation of monophosphine monoamine iridium hydrogenation catalysts by trimer formation is strongly dependent on ligand structure; attempts to counter this process lead to the observation of an oligomerisation resistant catalyst.

Hydrogen isotope exchange at alkyl positions using Crabtree's catalyst and its application to the tritiation of methapyrilene

Hydrogen isotope exchange at alkyl positions using Crabtree's catalyst and its application to the tritiation of methapyrilene

Tritium‐labelling via an iridium‐based solid‐phase catalyst

AbstractA solid‐phase, iridium‐based ortho‐exchange catalyst has been developed, with the aim of producing cleaner, more efficient, systems for tritium and deuterium labelling. The catalyst, which is a solvated polystyrene‐bound triphenylphosphine complex of cyclooctadienyliridium(I) hexafluorophosphate, was evaluated with respect to more conventional catalysts such as CODIr(PPh3)2PF6 and the Crabtree catalyst using simple model compounds as substrates. Labelling of drug candidate molecules proceeds with high regioselectivity and, after a simple filtration step, affords products with high radiochemical purities directly from the exchange reaction. The solid‐phase catalyst functioned well with a variety of traditional directing groups including nitro, amide, benzophenone and N‐heterocycles. Copyright © 2007 John Wiley & Sons, Ltd.

Well-Defined Chiral Spiro Iridium/Phosphine−Oxazoline Cationic Complexes for Highly Enantioselective Hydrogenation of Imines at Ambient Pressure

New chiral phosphine-oxazoline ligands (7, SIPHOX) with a rigid and bulky spirobiindane scaffold were synthesized, starting with optically pure 7-diphenylphosphino-7'-trifluoromethanesulfonyloxyl-1,1'-spirobiindane, in four steps in 40-64% overall yield. Iridium complexes of 7, the chiral analogues of the Crabtree catalyst, were generated by coordination of ligands 7 and [Ir(COD)Cl](2) in the presence of sodium tetrakis-3,5-bis(trifluoromethyl)phenylborate. The complexes were characterized by NMR, ESI-MS, and X-ray diffraction analysis. The Ir-SIPHOX complexes can catalyze the hydrogenation of acyclic N-aryl ketimines under ambient pressure with excellent enantioselectivities (up to 97% ee) and full conversions. This result represents the highest enantioselectivity and the first example of the hydrogenation of imines catalyzed by chiral analogues of the Crabtree catalyst at ambient pressure. Studies on the stability of the catalysts revealed that the catalysts Ir-SIPHOX are very stable and resistant to the formation of inactive trimers under hydrogenation conditions. On the basis of the X-ray diffraction analysis of the structures of catalysts and amine products, a rational explanation for the enantiocontrol of the chiral catalysts in the hydrogenation of imines is proposed.

Rh(I) and Ir(I) Derivatives of a P(S),N-Substituted Indene Ligand: Synthetic, Structural, and Catalytic Alkene Hydrosilylation Studies

Treatment of 1-PiPr2-indene or 1-PiPr2-2-NMe2-indene (1a) with elemental sulfur afforded 3-iPr2P(S)-indene or 1-iPr2P(S)-2-NMe2-indene (4a) in 81% and 85% isolated yield, respectively. Addition of 4a to [(COD)M(THF)2]+BF4- afforded the corresponding [(COD)M(kappa2-N,S-4a)]+BF4- complexes (M = Rh, 5a, 76%; M = Ir, 5b, 59%; COD = eta4-1,5-cyclooctadiene), which were found to exhibit temperature-dependent NMR spectral features that were rationalized in terms of a dynamic process involving M-NMe2 dissociation, rotation about the indenyl-NMe2 bond, inversion at nitrogen, and re-coordination to M. Analysis of variable-temperature NMR data collected for 5a and 5b each yielded a value for DeltaG(double dagger) of ca. 14 kcal/mol for this process. Exposure of 5a or 5b to NaN(SiMe3)2 generated the corresponding (COD)M(kappa2-C,S-1-iPr2P(S)-2-NMe2-(C1-indenyl)) complex (M = Rh, 6a, 70%; M = Ir, 6b, 86%) in which the metal is incorporated into an M-C-P-S ring via coordination to the indenyl ring in an eta1-fashion, as well as to sulfur. Alternatively, complex 6b was prepared cleanly via lithiation of 4a followed by treatment with 0.5 equiv of [(COD)IrCl]2. The ability of 5a,b and 6a,b to mediate the addition of triethylsilane to styrene was also explored, and their performance was compared with that of Wilkinson's Catalyst ((PPh3)3RhCl) and Crabtree's catalyst ([(COD)Ir(PCy3)(Py)]+PF6-; Cy = cyclohexyl; Py = pyridine). Single-crystal X-ray diffraction data are provided for 4a, 2-NMe2-3-iPr2P(S)-indene (4b), 6a, and 6b.

Hydrogen‐Mediated Reductive Coupling of Conjugated Alkynes with Ethyl (N‐Sulfinyl)iminoacetates: Synthesis of Unnatural α‐Amino Acids via Rhodium‐Catalyzed C—C Bond Forming Hydrogenation.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Hydrogen-Mediated Reductive Coupling of Conjugated Alkynes with Ethyl (N-Sulfinyl)iminoacetates: Synthesis of Unnatural α-Amino Acids via Rhodium-Catalyzed C−C Bond Forming Hydrogenation

Rhodium-catalyzed hydrogenation of 1,3-enynes 1a-8a and 1,3-diynes 9a-13a at ambient temperature and pressure in the presence of ethyl (N-tert-butanesulfinyl)iminoacetate and ethyl (N-2,4,6-triisopropylbenzenesulfinyl)iminoacetates, respectively, results in reductive coupling to afford unsaturated alpha-amino acid esters 1b-13b in good to excellent yields with exceptional levels of regio- and stereocontrol. Further hydrogenation of the diene containing alpha-amino acid esters 1b-8b using Wilkinson's catalyst at ambient temperature and pressure results in regioselective reduction to afford the beta,gamma-unsaturated alpha-amino acid esters 1c-8c in good to excellent yields. Exhaustive hydrogenation of the unsaturated side chains of the Boc- and Fmoc-protected derivatives of enyne and diyne coupling products 14b-16b occurs in excellent yield using Crabtree's catalyst at ambient temperature and pressure providing the alpha-amino acid esters 14d-16d, which possess saturated side chains. Finally, cross-metathesis of the Boc-protected reductive coupling product 14b with cis-1,4-diacetoxy-2-butene proceeds readily to afford the allylic acetate 14e. Isotopic labeling studies that involve reductive coupling of enyne 1a and diyne 9a under an atmosphere of elemental deuterium corroborate a catalytic mechanism in which oxidative coupling of the alkyne and imine residues is followed by hydrogenolytic cleavage of the resulting metallacycle. A stereochemical model accounting for the observed sense of asymmetric induction is provided. These studies represent the first use of imines as electrophilic partners in hydrogen-mediated reductive carbon-carbon bond formation.

Studies on the Synthesis of (±)-Stenine: A Combined Intramolecular [4 + 2]-Cycloaddition/Rearrangement Cascade

Several cyclic 2-(methylthio)-5-amidofurans containing tethered unsaturation were prepared via the reaction of dimethyl(methylthio)sulfonium tetrafluoroborate (DMSTF) with beta-alkoxy-gamma-dithiane lactams. Thermolysis of these furans resulted in an intramolecular Diels-Alder reaction (IMDAF). The resulting oxa-bridge cycloadducts underwent a subsequent 1,2-methylthio shift to form tricyclic lactams in high yield. Furan 9, annealed to an azepine ring, underwent the IMDAF reaction at or below room temperature. Conformational effects imposed by the placement of a carbonyl group within the tether, combined with a rotational bias about the C(2)-N bond, enhances the rate of the IMDAF reaction of the seven-ring system so that it occurs readily at 25 degrees C. The feasibility of using the cascade sequence in the context of a total synthesis of the Stemona alkaloid (+/-)-stenine was explored. The eventual synthesis of (+/-)-stenine was carried out by an intramolecular Diels-Alder reaction of a 2-amido-5-methylthio-substituted furan containing a trans-pent-3-enoic acid methyl ester side chain in order to create the desired azepinoindole skeleton. This was followed by a series of reductions to set the syn-anti stereochemical relationship at the incipient ring fusion sites present in stenine. All six stereocenters at the azepinoindole core were derived in high stereoselectivity from the functionality present in the rearranged cycloadduct 10. Compound 10 was converted to stenine in 11 additional steps via a sequence that features a Crabtree's-catalyst directed hydrogenation, iodolactonization, and a Keck allylation.