Catalytic asymmetric synthesis of chiral allylic amines. Evaluation of ferrocenyloxazoline palladacycle catalysts and imidate motifs

Palladium(II) catalysts based on a ferrocenyloxazoline palladacyclic (FOP) scaffold were synthesized and evaluated for the rearrangement of prochiral allylic N-(4-methoxyphenyl)benzimidates. When iodide-bridged dimer FOP precatalysts are activated by reaction with excess silver trifluoroacetate, the allylic rearrangement of both E and Z prochiral primary allylic N-(4-methoxyphenyl)benzimidates takes place at room temperature to give the corresponding chiral allylic N-(4-methoxyphenyl)benzamides in high yield and good ee (typically 81-95%). Several allylic imidate motifs were evaluated also. Because the corresponding enantioenriched allylic amide products can be deprotected in good yield to give enantioenriched allylic amines, allylic N-aryltrifluoroacetimidates were identified as promising substrates.     

Nickel-Catalyzed Preparations of Functionalized Organozincs

The reaction of primary alkyl bromides or chlorides with diethylzinc in the presence of Ni(acac)(2) (5 mol %) furnishes the corresponding alkylzinc halides (X = Br, Cl) via a halogen-zinc exchange reaction. The treatment of terminal alkenes with diethylzinc (neat, 25-60 degrees C) in the presence of Ni(acac)(2) as a catalyst (1-5 mol %) and 1,5-cyclooctadiene (COD) affords the corresponding dialkylzincs via a hydrozincation reaction. Whereas the conversion for simple alkenes bearing a remote functionality reaches 40 to 63%, the hydrozincation of allylic, homoallylic alcohols and allylic amines proceeds very efficiently (85-95% conversion). All the zinc organometallics obtained react with various electrophiles (allylic halides, enones, acid chlorides, alkynyl halides, ethyl propiolate) after transmetalation with CuCN.2LiCl. In the presence of the chiral catalyst 12, the dialkylzincs prepared add to aldehydes with high enantioselectivity.     

Regio- and enantioselective iridium-catalyzed intermolecular allylic etherification of achiral allylic carbonates with phenoxides

An enantioselective and regioselective iridium-catalyzed allylic etherification is described. The reaction of sodium and lithium aryloxides with achiral (E)-cinnamyl and terminal aliphatic allylic electrophiles in the presence of 2 mol % of an iridium-phosphoramidite complex provides chiral allylic aryl ethers in high yields and excellent levels of regio- and enantioselectivity. Lithium aryloxides containing a single substituent at an ortho, meta, or para position as well as sterically hindered phenoxides were tolerated. Reactions in THF displayed the most suitable balance of rate, regio-, and enantioselectivity. High ee's were also observed for the products from the reaction of alkyl (E)-allylic carbonates.     

A mild and efficient method for the stereoselective formation of C-O bonds: palladium-catalyzed allylic etherification using zinc(II) alkoxides

[reaction: see text] A highly chemo- and stereoselective palladium-catalyzed allylic etherification reaction is described. The use of zinc(II) alkoxides proved effective in promoting the addition of the oxygen nucleophile derived from aliphatic alcohols to eta(3)-allylpalladium complexes. Using diethylzinc (0.5 equiv), 5 mol % of Pd(OAc)(2), and 7.5 mol % of 2-di(tert-butyl)phosphinobiphenyl in THF, the cross-coupling reaction between various aliphatic alcohols and allylic acetates proceeded at ambient temperature to furnish allylic ethers with high stereoselectivity.     

Copper catalyzed enantioselective allylic substitution by MeMgX

Methyl Grignard undergoes highly regio (>90/10) and enantioselective (ee 91-96%) copper catalyzed allylic substitution on cinnamyl-type chlorides. CuBr (3%) and 3.3% of a chiral phosphoramidite ligand are sufficient for a complete reaction. The synthesis of a precursor of (+)-Naproxen is described. The reaction can be extended to alkyl substituted allylic chlorides (ee 72%).     

Catalytic asymmetric generation of (Z)-disubstituted allylic alcohols

A one-pot method for the direct preparation of enantioenriched (Z)-disubstituted allylic alcohols is introduced. Hydroboration of 1-halo-1-alkynes with dicyclohexylborane, reaction with t-BuLi, and transmetalation with dialkylzinc reagents generate (Z)-disubstituted vinylzinc intermediates. In situ reaction of these reagents with aldehydes in the presence of a catalyst derived from (-)-MIB generates (Z)-disubstituted allylic alcohols. It was found that the resulting allylic alcohols were racemic, most likely due to a rapid addition reaction promoted by LiX (X = Br and Cl). To suppress the LiX-promoted reaction, a series of inhibitors were screened. It was found that 20-30 mol % tetraethylethylenediamine inhibited LiCl without inhibiting the chiral zinc-based Lewis acid. In this fashion, (Z)-disubstituted allylic alcohols were obtained with up to 98% ee. The asymmetric (Z)-vinylation could be coupled with tandem diastereoselective epoxidation reactions to provide epoxy alcohols and allylic epoxy alcohols with up to three contiguous stereogenic centers, enabling the rapid construction of complex building blocks with high levels of enantio- and diastereoselectivity.     

Iridium-catalyzed allylic vinylation and asymmetric allylic amination reactions with o-aminostyrenes

An Ir-catalyzed allylic vinylation reaction of allyl carbonates with o-aminostyrene derivatives has been realized, providing skipped (Z,E)-diene derivatives. With (E)-but-2-ene-1,4-diyl dimethyl dicarbonate as the substrate, an efficient enantioselective synthesis of 1-benzazepine derivatives via an Ir-catalyzed domino allylic vinylation/intramolecular allylic amination reaction has been developed. Mechanistic studies of the allylic vinylation reaction have been carried out, and the results suggest that the leaving group of the allylic precursor plays a key role in directing the reaction pathway. Screening of various allylic precursors showed that Ir-catalyzed reactions of allyl diethyl phosphates with o-aminostyrene derivatives proceed via an allylic amination pathway. A subsequent ring-closing metathesis (RCM) reaction of the amination products led to a series of enantiomerically enriched 1,2-dihydroquinoline derivatives. Their utility is indicated by an asymmetric total synthesis of (-)-angustureine.     

Ru3(CO)12-catalyzed intramolecular allylic transfer reaction of tethered carbonyl group and allylic acetate moiety

A ruthenium catalyzed intramolecular allylic transfer reaction of allylic acetates containing aldehydes or ketones to form cis-homoallylic cyclopentanols and cyclohexanols as a major component is described. The use of Ru₃(CO)₁₂ (1 mol %) to promote reaction results in a convenient procedure for intramolecular allylation of carbonyl functionalities.     

From allylic alcohols to aldols through a new nickel-mediated tandem reaction: synthetic and mechanistic studies

Nickel hydride type complexes have been successfully developed as catalysts for the tandem isomerization-aldolization reaction of allylic alcohols with aldehydes. Optimization of the reaction conditions has shown that a cocatalyst, such as MgBr2, has a very positive effect on the kinetics of the reaction and in the yields of aldols. Under such optimized conditions {[NiHCl(dppe)] + MgBr(2) at 3-5 mol %)}, this reaction affords the aldols in good to excellent yields. It is a full-atom-economy-type reaction that occurs under mild conditions. Furthermore, it has a broad scope for the allylic alcohols and it is compatible with a wide range of aldehydes, including very bulky derivatives. The reaction is completely regioselective, but it exhibits a low stereoselectivity, except for allylic alcohols with a bulky substituent at the carbinol center. The use of chiral nonracemic catalysts was not successful, affording only racemic compounds. However, it was possible to use asymmetric synthesis for the preparation of optically active aldols. Various mechanistic studies have been performed using, for instance, a deuterated alcohol or a deuterated catalyst. They gave strong support to a mechanism involving first a transition-metal-mediated isomerization of the allylic alcohol into the free enol, followed by the addition of the latter intermediate onto the aldehyde in an "hydroxyl-carbonyl-ene" type reaction. These results confirm that allylic alcohols can be considered as new and useful partners in the development of the aldol reaction.     

Iridium complex-catalyzed allylic amination of allylic esters

Iridium complex-catalyzed allylic amination of allylic carbonates was studied. The solvent strongly affected the catalytic activity. The use of a polar solvent such as EtOH is essential for obtaining the products in high yield. The reaction of (E)-3-substituted-2-propenyl carbonate and 1-substituted-2-propenyl carbonate with pyrrolidine in the presence of a catalytic amount of [Ir(COD)Cl](2) and P(OPh)(3) (P/Ir = 2) gave a branch amine with up to 99% selectivity. Both secondary and primary amines could be used for this reaction. When a primary amine was used, selective monoallylation occurred. No diallylation product was obtained. The reaction of 1,1-disubstituted-2-propenyl acetate with amines exclusively gave an alpha,alpha-disubstituted allylic amine. This reaction provides an alternative route to the addition of an organometallic reagent to ketimines for the preparation of such amines. The reaction of (Z)-3-substituted-2-propenyl carbonate with amines gave (Z)-linear amines with up to 100% selectivity. In all cases, no (E)-linear amine was obtained. The selectivities described here have not been achieved in similar palladium complex-catalyzed reactions.     

Selective synthesis of allylated oxime ethers and nitrones based on palladium-catalyzed allylic substitution of oximes

[reaction: see text] The viability of oximes as nucleophiles in transition-metal-catalyzed allylic substitution was examined. The oxygen atom of oxime acted as a reactive nucleophile in the reaction of a pi-allyl palladium complex. In the presence of Pd(PPh3)4, the allylic substitution of oximes with allylic carbonate afforded the linear O-allylated oxime ethers selectively without a base. In contrast, the palladium-catalyzed reaction with allylic acetate proceeded smoothly in the presence of K2CO3 or Et2Zn as a base. Selective formation of nitrones was achieved by using palladium(II) catalyst. In the presence of Pd(cod)Cl2, the allylic substitution of oximes with allylic acetate afforded the N-allylated nitrones under solvent-free conditions, as a result of the reaction with the nitrogen atom of oximes.     

Facile, efficient, and enantiospecific syntheses of 1,1'-N-linked pseudodisaccharides as a new class of glycosidase inhibitors

This article describes an efficient synthesis of a potent trehalase inhibitor, 1,1'-N-linked pseudodisaccharide 1 (consisting of two valienamines), in 14 steps with an overall yield of 12% and a first synthesis of 2 (consisting of two 2-epi-valienamines) in 15 steps with an overall yield of 24% from (-)-quinic acid. The synthesis involves a stereospecific palladium-catalyzed coupling reaction between an allylic amine and an allylic chloride as the crucial step. The acetonide blocking groups were shown to be the best hydroxyl protecting groups, compatible with the palladium-catalyzed allylic amination reaction that afforded high yields of the 1,1'-N-linked pseudodisaccharides with a minimum amount of an elimination diene side product.     

Allylic alkylations catalyzed by palladium-bis(oxazoline) complexes derived from heteroarylidene malonate derivatives

A series of simple heteroarylidene malonate-type bis(oxazoline) ligands 4 and 5 were applied to the palladium-catalyzed allylic alkylation reaction, and the ligand 4a bearing a phenyl group afforded excellent enantioselectivity (up to 96% ee) for the allylic alkylation product. Other substrates were also examined, giving the allylic alkylated products in high yield but with poor ee values.     

Pd-catalyzed asymmetric allylic amination using aspartic acid derived P-chirogenic diaminophosphine oxides: DIAPHOXs

[reaction: see text] A Pd-catalyzed asymmetric allylic amination using aspartic acid derived P-chirogenic diaminophosphine oxides (DIAPHOXs) is described. Asymmetric allylic amination of both linear and cyclic substrates proceeded at room temperature to give the chiral allylic amines in 72-99% ee.     

In Situ Generation of Formaldehyde and Triphenylphosphine from (Hydroxymethyl)triphenylphosphonium and Its Application in Wittig Olefination

The reaction of (hydroxymethyl)triphenylphosphonium with benzylic or allylic halide under basic conditions at room temperature affords terminal alkenes in 61–89% yields. In this reaction, both formaldehyde and triphenylphosphine are in situ generated from (hydroxymethyl)triphenylphosphonium and further undergo Wittig olefination with benzylic or allylic halide.     

Highly selective palladium catalyzed kinetic resolution and enantioselective substitution of racemic allylic carbonates with sulfur nucleophiles: asymmetric synthesis of allylic sulfides,allylic sulfones,and allylic alcohols

We describe the highly selective palladium catalyzed kinetic resolutions of the racemic cyclic allylic carbonates rac-1 a-c and racemic acyclic allylic carbonates rac-3 aa and rac-3 ba through reaction with tert-butylsulfinate, tolylsulfinate, phenylsulfinate anions and 2-pyrimidinethiol by using N,N'-(1R,2R)-1,2-cyclohexanediylbis[2-(diphenylphosphino)-benzamide] (BPA) as ligand. Selectivities are expressed in yields and ee values of recovered substrate and product and in selectivity factors S. The reaction of the cyclohexenyl carbonate 1 a (>/=99 % ee) with 2-pyrimidinethiol in the presence of BPA was shown to exhibit, under the conditions used, an overall pseudo-zero order kinetics in regard to the allylic substrate. Also described are the highly selective palladium catalyzed asymmetric syntheses of the cyclic and acyclic allylic tert-butylsulfones 2 aa, 2 b, 2 c, 2 d and 4 a-c, respectively, and of the cyclic and acyclic allylic 2-pyrimidyl-, 2-pyridyl-, and 4-chlorophenylsulfides 5 aa, 5 b, 5 ab, 6 aa-ac, 6 ba and 6 bb, respectively, from the corresponding racemic carbonates and sulfinate anions and thiols, respectively, in the presence of BPA. Synthesis of the E-configured allylic sulfides 6 aa, 6 ab, 6 ac and 6 bb was accompanied by the formation of minor amounts of the corresponding Z isomers. The analogous synthesis of allylic tert-butylsulfides from allylic carbonates and tert-butylthiol by using BPA could not be achieved. Reaction of the cyclopentenyl esters rac-1 da and rac-1 db with 2-pyrimidinethiol gave the allylic sulfide 5 c having only a low ee value. Similar results were obtained in the case of the reaction of the cyclohexenyl carbonate rac-1 a and of the acyclic carbonates rac-3 aa and rac-3 ba with 2-pyridinethiol and lead to the formation of the sulfides 5 ab, 6 ab, and 6 bb, respectively. The low ee values may be ascribed to the operating of a "memory effect", that is, both enantiomers of the substrate give the substitution product with different enantioselectivities. However, in the reaction of the racemic carbonate rac-1 a as well as of the highly enriched enantiomers 1 a (>/=99 % ee) and ent-1 a (>/=99 % ee) with 2-pyrimidinethiol the ee values of the substrates and the substitution product remained constant until complete conversion. Similar results were obtained in the reaction of the cyclic carbonates rac-1 a, ent-1 a (>/=99 % ee) and ent-1 c (>/=99 % ee) with lithium tert-butylsulfinate. Thus, in the case of rac-1 a and 2-pyrimidinthiol and tert-butylsulfinate anion as nucleophiles the enantioselectivity of the substitution step is, under the conditions used, independent of the chirality of the substrate; this shows that no "memory effect" is operating in this case. Hydrolysis of the carbonates ent-1 a-c, ent-3 aa and ent-3 ba, which were obtained through kinetic resolution, afforded the enantiomerically highly enriched cyclic allylic alcohols 9 a-c (>/=99 % ee) and acyclic allylic alcohols 10 a (>/=99 % ee) and 10 b (99 % ee), respectively.     

Scope and limitations of ether-directed, metal-catalysed aza-Claisen rearrangements; improved stereoselectivity using non-coordinating solvents

In an effort to understand and enhance the stereochemical outcome of the MOM-ether directed rearrangement of allylic trichloroacetimidates we have investigated various reaction conditions for this process. A range of Pd(ii) and other metal catalysts have been shown to effectively catalyse the rearrangement providing the subsequent allylic amides in high selectivity (up to 11 : 1 ratio of diastereomers). The replacement of THF as a solvent in this reaction with non-coordinating solvents such as toluene has led to an enhancement of the directing effect resulting in a significant increase in the diastereoselective outcome (15 : 1 ratio). The reaction was also carried out for the first time, using a highly coordinating ionic solvent which disrupts binding of the Pd(ii)-catalyst to the MOM-ether yielding the allylic amide in only moderate diastereoselectivity. These results provide further evidence for the ether directed aza-Claisen rearrangement of allylic trichloroacetimidates.     

Fluorinated alcohols as promoters for the metal-free direct substitution reaction of allylic alcohols with nitrogenated, silylated, and carbon nucleophiles

The direct allylic substitution reaction using allylic alcohols in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) and 2,2,2-trifluoroethanol (TFE) as reaction media is described. The developed procedure is simple, works under mild conditions (rt, 50 and 70 °C), and proves to be very general, since different nitrogenated nucleophiles and carbon nucleophiles can be used achieving high yields, especially when HFIP is employed as solvent and aromatic allylic alcohols are the substrates. Thus, sulfonamides, carbamates, carboxamides, and amines can be successfully employed as nitrogen-based nucleophiles. Likewise, silylated nucleophiles such as trimethylsilylazide, allyltrimethylsilane, trimethylsilane, and trimethylsilylphenylacetylene give the corresponding allylic substitution products in high yields. Good results for the Friedel-Crafts adducts are also achieved with aromatic compounds (phenol, anisole, indole, and anilines) as nucleophiles. Particularly interesting are the results obtained with electron-rich anilines, which can behave as nitrogenated or carbon nucleophiles depending on their electronic properties and the solvent employed. In addition, 1,3-dicarbonyl compounds (acetylacetone and Meldrum's acid) are also successfully employed as soft carbon nucleophiles. Studies for mechanism elucidation are also reported, pointing toward the existence of carbocationic intermediates and two working reaction pathways for the obtention of the allylic substitution product.     

Diastereoselective palladium-catalyzed formate reduction of allylic carbonates as a new entry into propionate units

[reaction: see text] The diastereoselective palladium-catalyzed formate reduction of allylic carbonates is described. Reduction of allylic carbonates under mild conditions (Pd(OAc)(2) (2.5-5 mol %), [n-Bu(3)PH]BF(4) (2.5-5 mol %), HCO(2)H/Et(3)N (1:2) (3 equiv), CH(3)CN (0.05M), 40 degrees C) affords the terminal olefin as the syn isomer in good yields and modest to excellent diastereoselectivity. These compounds, which are useful building blocks for the synthesis of polypropionate units, are the synthetic equivalent of the products obtained from an aldol reaction of an alpha-methyl-beta,gamma-unsaturated aldehyde.     

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).