Oxazoline Palladacycles Research Articles

A General Protocol toward Oxindoles Bearing C3‐Allylic Quaternary Stereocenter via Domino Reaction: A Concise Synthesis of Heterocycle‐Fused Indoline Alkaloids

Comprehensive SummaryAn efficiently catalytic method toward the synthesis of indolin‐2‐ones featuring an allylic derived C3‐quaternary stereocenter via an intramolecular Heck cyclization/Suzuki coupling of N‐substituted‐N‐(2‐bromophenyl)acrylamides and organoboron reagents was successfully developed by using a 1,3‐bis(2,6‐diisopropylphenyl)acenaphthoimidazol‐2‐ylidene (AnIPr)‐ligated oxazoline palladacycle. It enabled a very broad substrate scope tolerating different functional groups, electronic properties and steric bulkiness. Notably, it revealed a great potential to build diverse heterocycle‐fused indoline alkaloids via the same intermediate 3‐allyl‐1,3‐dimethylindolin‐2‐ one.

A General Protocol toward Synthesis of 3-Methylindoles Using Acenaphthoimidazolyidene-Ligated Oxazoline Palladacycle.

An efficient catalytic strategy toward the synthesis of N-substituted 3-methylindoles from inactive o-dihaloarenes and N-allylamines was developed by using a 1,3-bis(2,6-diisopropylphenyl)acenaphthoimidazol-2-ylidene (AnIPr)-ligated oxazoline palladacycle. It enabled a very broad substrate scope tolerating different functional groups, electronic properties, and steric bulkiness and afforded desired products in good to excellent yields. Importantly, it showed great potential to synthesize several bioactive compounds and key intermediates of natural products in high yields.

Acenaphthoimidazolylidene‐ligated chiral oxazoline palladacycles: synthesis, structure, and application in intramolecular α‐arylation of amides towards 3,3′‐disubstituted oxindoles

AbstractA general catalytic protocol for the Pd‐catalyzed intramolecular arylations of N‐(2‐halogenoaryl) amides in eco‐friendly medium was successfully developed by using rationally designed acenaphthoimidazolylidene‐ligated chiral oxazoline palladacycles. Under the optimal reaction condition, a broad scope of substrates with various functional groups were well tolerated, leading to desired 3,3′‐disubstituted oxindoles in excellent yields (up to 98% yield).

Highly efficient α-arylation of aryl ketones with aryl chlorides by using bulky imidazolylidene-ligated oxazoline palladacycles.

α-Aryl derivatives of carbonyl compounds are important building blocks. Herein, we presented an efficient catalytic system for the α-arylation of aryl ketones with inactive aryl chlorides by firstly using N,N'-bis(2,6-diisopropylphenyl)-imidazol-2-ylidene (IPr)-ligated chiral oxazoline palladacycles, and tolerated a wide range of substrates at low catalyst loadings, leading to the desired products in good to excellent yields.

Rearrangement Reactions Leading to Optically Active α,α‐Disubstituted Primary Allylamines

Synthetic routes to α,α‐disubstituted allylamines have been examined. Racemic compounds were conveniently prepared by thermal Overman rearrangements of primary allylic alcohols with trisubstituted double bonds, but rearrangement of these substrates using the only commercially available compound known to catalyze enantioselective Overman rearrangements, the cobalt oxazoline palladacycle (R)‐COP‐Cl, failed. Instead, optically active secondary allylic alcohols with trisubstituted double bonds, obtained by Corey–Bakshi–Shibata reduction of the corresponding methyl ketones, were synthesized and converted into α,α‐disubstituted allylamines through a thermal Overman rearrangement or an allylic‐cyanate‐to‐isocyanate rearrangement. High chirality transfer (90–99 %) was obtained for both reaction sequences, but the yields were greatly improved when the allylic‐cyanate‐to‐isocyanate rearrangement was used.

Mechanism of the Cobalt Oxazoline Palladacycle (COP)-Catalyzed Asymmetric Synthesis of Allylic Esters

The catalytic enantioselective S(N)2' displacement of (Z)-allylic trichloroacetimidates catalyzed by the palladium(II) complex [COP-OAc](2) is a broadly useful method for the asymmetric synthesis of chiral branched allylic esters. A variety of experiments aimed at elucidating the nature of the catalytic mechanism and its rate- and enantiodetermining steps are reported. Key findings include the following: (a) the demonstration that a variety of bridged-dipalladium complexes are present and constitute resting states of the COP catalyst (however, monomeric palladium(II) complexes are likely involved in the catalytic cycle); (b) labeling experiments establishing that the reaction proceeds in an overall antarafacial fashion; (c) secondary deuterium kinetic isotope effects that suggest substantial rehybridization at both C1 and C3 in the rate-limiting step; and (d) DFT computational studies (B3-LYP/def2-TZVP) that provide evidence for bidentate substrate-bound intermediates and an anti-oxypalladation/syn-deoxypalladation pathway. These results are consistent with a novel mechanism in which chelation of the imidate nitrogen to form a cationic palladium(II) intermediate activates the alkene for attack by external carboxylate in the enantiodetermining step. Computational modeling of the transition-state structure for the acyloxy palladation step provides a model for enantioinduction.

Catalytic Asymmetric Synthesis of Branched Chiral Allylic Phenyl Ethers from (E)‐Allylic Alcohols

The first di-μ-amidate dipalladium complexes and a new di-μ-carboxylate dipalladium complex of the COP (cobalt oxazoline palladacycle) palladium(II) catalyst family are reported and characterized crystallographically. The di-μ-amidate complex 3 or its enantiomer (ent-3) are the first asymmetric catalysts that allow commercially available, or readily accessible, (E)-2-alkene-1-ols to be transformed to enantioenriched branched allylic aryl ethers upon reaction of their trichloroacetimidate derivatives with phenols. The 3-aryloxy-1-alkene products are formed in high enantiomeric purity (typically 90-98% ee) and useful yields (61-88%).

The Asymmetric Aza‐Claisen Rearrangement: Development of Widely Applicable Pentaphenylferrocenyl Palladacycle Catalysts

Systematic studies have been performed to develop highly efficient catalysts for the asymmetric aza-Claisen rearrangement of trihaloacetimidates. Herein, we describe the stepwise development of these catalyst systems involving four different catalyst generations finally resulting in the development of a planar chiral pentaphenylferrocenyl oxazoline palladacycle. This complex is more reactive and has a broader substrate tolerance than all previously known catalyst systems for asymmetric aza-Claisen rearrangements. Our investigations also reveal that subtle changes can have a big impact on the activity. With the enhanced catalyst activity, the asymmetric aza-Claisen rearrangement has a very broad scope: the methodology not only allows the formation of highly enantioenriched primary allylic amines, but also secondary and tertiary amines; allylic amines with N-substituted quaternary stereocenters are conveniently accessible as well. The reaction conditions tolerate many important functional groups, thus providing stereoselective access to valuable functionalized building blocks, for example, for the synthesis of unnatural amino acids. Our results suggest that face-selective olefin coordination is the enantioselectivity-determining step, which is almost exclusively controlled by the element of planar chirality.

ChemInform Abstract: An Investigation into the Allylic Imidate Rearrangement of Trichloroacetimidates Catalyzed by Cobalt Oxazoline Palladacycles.

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An Investigation into the Allylic Imidate Rearrangement of Trichloroacetimidates Catalysed by Cobalt Oxazoline Palladacycles

Dimeric palladacycles, di-mu-X-bis[{eta(5)-(S)-((p)R)-2-[2'-(4'-methylethyl)oxazolinyl]cyclopentadienyl,1-C,3'-N}(eta(4)-tetraphenylcyclobutadiene)cobalt]dipalladium (COP-X), containing bridging groups X=OAc, Cl, Br, I, O(2)CCF(3), p-O(2)CC(6)H(4)F, were synthesised and compared as catalysts for the asymmetric allylic imidate rearrangement of (E)-Cl(3)CC(=NH)OCH(2)CH=CHR with R=nPr. The enantiomeric excess of the product (S)-Cl(3)CC(=O)NHCHRCH=CH(2) was essentially invariant of X (93-96%) and the yield increased in the sequence I<p-O(2)CC(6)H(4)F<OAc<O(2)CCF(3) approximately Br approximately Cl. With X=Cl (COP-Cl), the catalyst loading was reduced to 0.25 mol% (CH(3)CN/70 degrees C/48 h) and these conditions applied to various trichloroacetimidates (R=nPr, Me, CH(2)Ph, CH(2)CH=CH(2), CH(2)OTBDMS) to give the corresponding (S)-trichloroacetamides (68-88% yield, 84-94% ee; ee=enantiomeric excess). Addition of COP-Cl to triphenylphosphinobenzoyl NovaGel AM resin gave a recyclable catalyst in which the ee was maintained over three cycles (89-94%). Catalysis with COP-OAc displayed a small positive non-linear effect. The factors responsible for the activity of COP-X are discussed.

Palladium-Catalyzed Allylic Transposition of (Allyloxy) Iminodiazaphospholidines: A Formal [3,3]-Aza-phospha-oxa-Cope Sigmatropic Rearrangement for the Stereoselective Synthesis of Allylic Amines

The synthesis of N-protected allylic amines has been achieved utilizing a palladium(II)-catalyzed, [3,3]-rearrangement of (allyloxy) iminodiazaphospholidines. This [3,3]-aza-phospha-oxa-Cope sigmatropic rearrangement reaction is thermodynamically driven by a P=N to P=O interconversion and is an alternative to the Overman rearrangement. The overall process involves the nucleophilic displacement of an allylic alcohol onto a P(III) precursor, followed by a Staudinger reaction to generate the (allyloxy) iminodiazaphospholidine precursors. Pd(II)-catalyzed [3,3]-aza-phospha-oxa-Cope rearrangement then gives a phosphoramide, which is readily hydrolyzed under acidic conditions to yield allylic amine derivatives. Pd(II) catalysis is believed to occur in a fashion analogous to that of the rearrangement of allylic imidates. The scope of racemic, diastereoselective, and enantioselective variants of this rearrangement is described. The use of chiral diamine auxiliaries in diastereoselective rearrangements is reported. Rearrangement of chiral N,N'-dimethyl cyclohexanediamine derived diazaphospholidines gives rise to phosphoramides with moderate diastereoselectivities (up to 3.5:1 dr). The same major diastereomeric product in these rearrangements was prepared irrespective of the starting allylic alcohol geometry. An enantioselective variant of the reaction was demonstrated for the rearrangement of cis-(allyloxy) iminodiazaphospholidines with cobalt oxazoline palladacycle (COP-X) catalysts (5 mol %) in high yield and enantioselectivity (up to 96% ee).

Monomeric Cobalt Oxazoline Palladacycles (COP). Useful Catalysts for Catalytic Asymmetric Rearrangement of Allylic Trichloroacetimidates.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of Planar Chiral Phosphapalladacycles by Highly Enantioselective Transcyclopalladation

The first highly enantioselective synthesis of planar chiral ferrocene phosphapalladacycles was performed by high-yielding asymmetric transcyclopalladation with cobalt oxazoline palladacycles (COP). Use of di-mu-acetatobis[(eta5-(S)-(pR)-2-(2'-(4'-isopropyl)oxazolinyl)cyclopentadienyl-C1,N3')(eta4-tetraphenylcyclobutadiene)cobalt]dipalladium(II), followed by acetate/chloride ligand exchange, gave (pS)-di-mu-chloro[2-(2-dicyclohexylphosphino)phenylferroene-C1,P)dipalladium(II) (95% ee). Similarly, diastereomeric di-mu-acetatobis[(eta5-(S)-(pS)-2-(2'-(4'-tert-butyl)oxazolinyl)cyclopentadienyl-C1,N3')(eta4-tetraphenylcyclobutadiene)cobalt]dipalladium(II) led to the enantiomeric (pR)-phosphapalladacycle (95% ee), revealing the control of these reactions by the element of planar chirality in COP. The reactions were extended to the synthesis of (pS)- and (pR)-di-mu-chloro[2-(2-diphenylphosphino)phenylferroene-C1,P)dipalladium(II) (78 and 92% ee, respectively). In all cases, the palladium-free precursors to COP were recovered for recycling.

Synthesis of tert-Leucine-Derived Cobalt Oxazoline Palladacycles. Reversal of Palladation Diastereoselectivity and Application to the Asymmetric Rearrangement of N-Aryl Trifluoroacetimidates

Starting from (η5-carboxycyclopentadienyl)(η4-tetraphenylcyclobutadiene)cobalt, (η5-(S)-2-(4-tert-butyl)oxazolinylcyclopentadienyl)(η4-tetraphenylcyclobutadiene)cobalt and (η5-(S)2-(4-methyl)oxazolinylcyclopentadienyl)(η4-tetraphenylcyclobutadiene)cobalt were synthesized in 70 and 79% yield, respectively. On heating with palladium acetate, only the former oxazoline resulted in the formation of a palladacycle (79% yield) that was determined to have an (S)-(pS)-configuration. Following ligand exchange (acetate to chloride to trifluoroacetate), the tert-butyl palladacycle was applied as a catalyst for the rearrangement of N-(4-methoxyphenyl)trifluoroacetimidates.

Monomeric Cobalt Oxazoline Palladacycles (COP). Useful Catalysts for Catalytic Asymmetric Rearrangement of Allylic Trichloroacetimidates

Cobalt oxazoline palladacycles (COP) containing acetylacetonate and hexafluoroacetylacetonate ligands were prepared as catalysts for the asymmetric rearrangement of allylic trichloroacetimidates. These monomeric catalysts are more soluble than the previously described chloride-bridged dimer COP-Cl (1). COP-hfacac (2) provides rearranged allylic trichloroacetamides with high enantiomeric purities (91-98% ee) in solvents of widely varying polarities: cyclohexane, toluene, 1,2-dichloroethane, ethyl acetate, acetone, acetonitrile, and THF. The first single-crystal X-ray structure of a COP catalyst is also reported.

The effect of face-blocking in the enantioselective aza-Claisen rearrangement of allylic imidates

A new cobaltocenyl oxazoline palladacycle compound was prepared for the enantioselective aza-Claisen rearrangement of allylic imidates. Studies on the effect of face-blocking and the mechanism of the reaction were carried out.