Tandem copper-catalyzed enantioselective allylation-metathesis

Grignard reagents undergo enantioselective (up to 86% ee) copper-catalyzed S(N)2' substitution on achiral allylic chlorides. The reaction is wide in scope for both the Grignard reagent and the allylic substrate. The resulting terminal alkene could be submitted to intra- or intermolecular metathesis to afford new chiral synthons. The experimental conditions are compatible with a one-pot overall substitution-metathesis procedure without loss of enantioselectivity. [reaction: see text]     

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.     

Synthesis of Branched Alkylboronates by Copper‐Catalyzed Allylic Substitution Reactions of Allylic Chlorides with 1,1‐Diborylalkanes

Reported herein is a copper‐catalyzed S_N2′‐selective allylic substitution reaction using readily accessible allylic chlorides and 1,1‐diborylalkanes, a reaction which proceeds with chemoselective C?B bond activation of the 1,1‐diborylalkanes. In the presence of a catalytic amount of [Cu(IMes)Cl] [IMes=1,3‐bis(2,4,6‐trimethylphenyl)imidazole‐2‐ylidene] and LiOtBu as a base, a range of primary and secondary allylic chlorides undergo the S_N2′‐selective allylic substitution reaction to produce branched alkylboronates. The synthetic utilities of the obtained alkylboronates are also presented.     

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.     

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.     

Iridium-catalyzed asymmetric allylation of sodium triisopropylsilanethiolate: a new way to form chiral thiols

The iridium phosphoramidite complex-promoted regio- and enantioselective reaction of allylic carbonates with sodium triisopropylsilanethiolate produced allylic sulfides in 40-77% yields with up to 97 : 3 (branched?:?linear) and 89% ee, which were readily transformed into chiral thiol in 68% yield with 87% ee or disulfides with two chiral C-S bond centers in 40-73% yields with up to 90 : 10 dr and 99% ee.     

Palladium-catalyzed enantioselective allylic alkylation of thiocarboxylate ions: asymmetric synthesis of allylic thioesters and memory effect/dynamic kinetic resolution of allylic esters

The palladium-catalyzed allylic alkylation of KSAc and KSBz with racemic cyclic and acyclic allylic esters by using N,N'-(1R,2R)-1,2-cyclohexandiylbis[2-(diphenylphosphino)-benzamide] as ligand frequently gave the corresponding allylic thioesters with high ee values and yields. The reaction of the cyclic allylic carbonates with KSAc in the presence of H(2)O was accompanied by a partial palladium-catalyzed enantioselective "hydrolysis" of the substrates with formation of the corresponding enantioenriched allylic alcohols. The degree of the "hydrolysis" was strongly dependent on the solvent and the thiocarboxylate ion. Highly selective kinetic resolutions (KRs) were observed in the palladium-catalyzed reaction of the racemic cyclohexenyl and cycloheptenyl acetates with KSAc. While the KR of the cyclohexenyl acetate is characterized by a selectivity factor S = 72 +/- 19, that of the cycloheptenyl acetate afforded (R)-cycloheptenyl acetate of >or=99% ee in 48% yield and (S)-cycloheptenyl thioacetate of 98% ee in 50% yield. The palladium-catalyzed reaction of the racemic cyclopentenyl acetate with KSAc showed a strong "memory effect" (ME), that is, both enantiomers reacted with different enantioselectivities. The ME was probed by studying the palladium-catalyzed reactions of both the matched acetate of >or=99% ee and the mismatched acetate of >or=99% ee with KSAc. The acetates not only reacted with different enantioselectivities and rates but also suffered an unexpected and concomitant palladium-catalyzed racemization in the presence of the chiral ligand. This led in the case of the mismatched acetate to a temporary dynamic kinetic resolution (DKR) that featured a racemization of the mismatched acetate by the chiral catalyst. Studies of the palladium-catalyzed reaction of the racemic cyclopentenyl acetate, carbonate, and naphthoate with KSAc in the presence of the chiral ligand also showed the ME to be strongly dependent on the nucleofuge. This also allowed the synthesis of (S)-cyclopentenyl thioacetate of 92% ee in high yield from the racemic cyclopentenyl naphthoate.     

Stereochemical diversity in chiral ligand design: discovery and optimization of catalysts for the enantioselective addition of allylic halides to aldehydes

[reaction: see text] We have identified a new set of stereochemically diverse oxazoline ligands derived from simple amino acids that promote the Cr-catalyzed enantioselective addition of allylic halides to aldehydes in up to 95% ee. The Cr-catalyzed allylation using ligand 1d is rather insensitive to the nature of the allylic bromide (crotyl, allyl, and methallyl) in that >90% ee is observed for all three bromides evaluated in the addition to benzaldehyde.     

New enantioselective method for hydration of alkenes using cyclodextrins as phase transfer catalyst

A new enantioselective/inverse phase transfer catalysis (IPTC) reaction for the Markovnikov hydration of double bounds by an oxymercuration-demercuration reaction with cyclodextrins as catalysts was disclosed. Moderate ee (up to 32%) and yields (14-60%) were obtained for allylic amines and protected allylic alcohols as starting materials.     

Enantioselective synthesis of alpha-ionone derivatives using an anti S(N)2' substitution of functionalized zinc organometallics

[reaction: see text] The allylic substitution of sterically hindered (2-iodocycloalkyl)phosphates proceeds with complete anti S(N)2' stereoselectivity with mixed diorganozincs of the type RZnCH(2)SiMe(3) in the presence of CuCN.2LiCl. Only the group R of the copper-zinc reagent is transferred in the allylic substitution. This method was used to prepare odoriferous substances such as (R)-alpha-ionone in 97% ee and (R)-dihydro-alpha-ionone in 98% ee.     

Poly(vinyl chloride) stabilisation with organo-tin compounds—Part II: Catalysis of the dehydrochlorination by butyl-tin chlorides

The catalytic effect of the various butyl-tin chlorides on the dehydrochlorination reaction of chlorohexene, used as a model compound for allylic chlorides in poly(vinyl chloride), has been studied in tetrahydrofuran and dichloroethane solutions. The reaction follows an E2 mechanism, the rate determining step being the formation of a delocalised allylic carbocation. The catalytic power is directly related to the Lewis acidity of the tin chlorides and, further, RSnCl₃ is comparable with ZnCl₂, although it is more sensitive to complexing with weak Lewis bases. In the presence of poly(vinyl chloride) at 180°C, these butyl-tin chlorides show a retardation effect on dehydrochlorination, superimposed on a catalytic effect which increases with the Lewis acidity; however, in these conditions, RSnCl₃ is much less efficient than ZnCl₂ in catalysing the dehydrochlorination reaction.     

Features and applications of [Rh(CO)(2)Cl](2)-catalyzed alkylations of unsymmetrical allylic substrates

A novel regio- and stereoselective [Rh(CO)2Cl]2-catalyzed allylic alkylation of unsymmetrical allylic carbonates was discovered. The regioselectivity of the reaction favors product ratios in which substitution occurs at the carbon bearing the leaving group. When an enantiomerically enriched carbonate (> or = 99% ee) was examined, the Rh(I)-catalyzed allylic alkylation proceeded stereoselectively to provide the alkylation product with retention of absolute stereochemistry (98% ee). To establish the scope of the [Rh(CO)2Cl]2-catalyzed allylic alkylation, a variety of carbon and heteroatom nucleophiles were examined and the results described. As an application of the Rh(I)-catalyzed allylic alkylation, a series of novel domino reactions have been developed that couple the unique regio- and stereoselective [Rh(CO)2Cl]2-catalyzed alkylation of allylic trifluoroacetates with an intramolecular Pauson-Khand annulation, a cycloisomerization, or a [5+2] cycloaddition. A unique aspect of the method described is the use of a single catalyst to effect sequential transformations in which the catalytic activity is moderated simply by controlling the reaction temperature. Implementation of such processes provides a rapid and efficient entry to a variety of bicyclic carbon skeletons from simple precursors.     

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.     

Asymmetric dihydroxylations of enynes with a trisubstituted C═C bond. An unprecedented route to γ-lactone building blocks with a quaternary stereocenter

En route to a comprehensive set of hydroxylactone building blocks (4R,5R)-, (4R,5S)-, (4S,5R)-, and (4S,5S)-5a, Sharpless asymmetric dihydroxylations of allylic chlorides (E)- and (Z)-9 were performed. They delivered the four stereoisomers of diol 10 with up to 92% ee and absolute configurations, which were proven to be in accordance with the Sharpless mnemonic.     

Synthesis and applications of the first polyfluorous proline derivative

Starting from trans-4-hydroxy-l-proline, a polyfluorinated proline derivative having a fluorine content of 54% has been prepared. It has been tested as a catalyst in the aldol reaction between p-nitrobenzaldehyde and acetone with 73% ee in BTF and in copper(I)-catalyzed allylic oxidation of cyclohexene with 20% ee in HFIP.     

Organocatalytic asymmetric allylic alkylation of sulfonylimidates with Morita-Baylis-Hillman carbonates

The asymmetric allylic alkylation reaction of sulfonylimidates with various Morita-Baylis-Hillman (MBH) carbonates was accomplished by the catalysis of commercially available cinchona alkaloids catalyst (DHQD)2AQN.The corresponding allylic alkylation products were obtained in good yields with high stereoselectivities (up to 99% ee,89:11 dr).     

Organocatalyzed regio- and enantioselective allylic trifluoromethylation of Morita-Baylis-Hillman adducts using Ruppert-Prakash reagent

The organocatalyzed regioselective allylic trifluoromethylation of Morita-Baylis-Hillman adducts using Ruppert-Prakash reagent was achieved in high to excellent yields via a successive S(N)2'/S(N)2' mode for the first time. The reaction was extended to the asymmetric allylic trifluoromethylation by the use of a bis-cinchona alkaloid catalyst with high enantioselectivities up to 94% ee.     

Malonate-type bis(oxazoline) ligands with sp hybridized bridge carbon: synthesis and application in Friedel-Crafts alkylation and allylic alkylation

A series of simple and new C₂-symmetric diphenylmethylidene malonate-type bis(oxazoline) ligands were synthesized and applied to the Friedel-Crafts reaction and allylic alkylation. The Cu(II) complex of ligand 4b bearing the benzyl group afforded good to excellent enantioselectivity for the F-C adducts (up to >99% ee) between indole and alkylidene malonate, and the palladium complex of ligand 4c bearing the phenyl group afforded excellent enantioselectivity (up to 94% ee) for the allylic alkylation product.     

C2-Symmetric 4,4′,5,5′-Tetrahydrobi(oxazoles) and 4,4′,5,5′-Tetrahydro-2,2′-methylenebis[oxazoles] as Chiral Ligands for Enantioselective Catalysis Preliminary Communication

The synthesis of a series of enantiomerically pure, C₂-symmetric 4,4′,5,5′-tetrahydro-2,2′-methylenebis[oxazoles] and 4,4′,5,5′-tetrahydro-2,2′-bi(oxazoles) is reported. Copper complexes with anionic tetrahydromethylenebis[oxazole] ligands are efficient catalysts for the enantioselective cyclopropane formation from olefins and diazo compounds (up to 96% ee in the reaction of styrene with menthyl diazoacetate). Tetrahydrobi(oxazole)iridium(I) complexes were found to catalyze transfer hydrogenations of aryl alkyl ketones with i-PrOH (up to 91% ee). Tetrahydrobi(oxazole)palladium complexes can be used as enantioselective catalysts for allylic nucleophilic substitution (up to 77% ee in the reaction of PhCH?CHCH(OAc)Ph with NaHC(COOMe)₂).     

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.