Palladium-catalyzed aminoallylation of activated olefins with allylic halides and phthalimide

The three-component aminoallylation reaction of the activated olefins 2 with the phthalimide 1a and allyl chloride proceeded very smoothly in the presence of Pd(2)dba(3).CHCl(3) (5 mol %)/P(4-FC(6)H(4))(3) (40 mol %) and Cs(2)CO(3) (3 equiv against 2) in dichloromethane at room temperature to give the corresponding aminoallylated products, N-pent-4-enylphthalimides 3, in 58-99% yields. The reaction of oxazolidinone 1b also proceeded very smoothly to give N-(2,2-dicyano-1-phenylpent-4-enyl)oxazolidinone in a quantitative yield; however, the Tsuji-Trost-type allylation products 4 were obtained in the case of dibenzylamine, N-tosylaniline, and pyrrolidin-2-one. Further, 2 underwent cycloaddition with N-tosylvinylaziridine 9a in the presence of Pd(2)dba(3).CHCl(3) (5 mol %)/P(4-FC(6)H(4))(3) (40 mol %) in THF at room temperature, giving the corresponding pyrrolidines 11 in 69-99% yields.     

Palladium-catalyzed enantioselective 1,3-rearrangement of racemic allylic sulfinates: asymmetric synthesis of allylic sulfones and kinetic resolution of an allylic sulfinate

Described is an asymmetric synthesis of cyclic and acyclic allylic S-aryl and S-alkyl sulfones through a highly selective palladium(0)-catalyzed 1,3-rearrangement of racemic allylic sulfinates. Treatment of racemic cyclic and acyclic allylic S-tolyl- and S-tert-butylsulfinates with Pd(2)(dba)(3).CHCl(3) as precatalyst and N,N'-(1R,2R)-1,2-cyclohexanediylbis[2-(diphenylphosphino)benzamide] as ligand for the palladium atom afforded the corresponding isomeric allylic S-tolyl and S-tert-butyl sulfones of 93-99% ee in 82-96% yield. The rearrangement of the allylic sulfinates most likely proceeds in an intermolecular fashion via formation of a cationic pi-allylpalladium complex and the sulfinate ion. The racemic allylic sulfinates were obtained from the corresponding racemic alcohols and racemic tolylsulfinyl chloride and racemic tert-butylsulfinyl chloride, respectively, in high yields. Rearrangement of the racemic tert-butylsulfinic acid 2-cyclooct-1-enyl ester with Pd(2)(dba)(3).CHCl(3) and the bisphosphane was accompanied by a highly selective kinetic resolution of the substrate and gave at 50% conversion the (R)-configured sulfinate as mixture of the S(S) and R(S) diastereomers of 92% ee and 85% ee and the (S)-configured 3-tert-butylsulfonyl cyclooctene sulfone 15a with 98% ee in almost quantitative yields.     

Novel synthesis of 3-azabicyclo[3.1.0]hexanes by unusual palladium(0)-catalyzed cyclopropanation of allenenes

Novel stereoselective synthesis of 3-azabicyclo[3.1.0]hexanes from allenenes is presented. Treatment of N-protected 4-alkyl-4-(N-allyl)amino allenes with allyl carbonate and a catalytic amount of Pd(2)(dba)(3).CHCl(3) in MeCN leads to stereoselective formation of the 3-azabicyclo[3.1.0]hexane framework in moderate to good yields. [reaction: see text]     

Hetero-Diels-Alder reactions of alpha-aryl-beta-monohalo-alpha-nitrosoethylenes: diastereoselective synthesis of 6-substituted 3-aryl-4-halo-5,6-dihydro-4H-1,2-oxazines.

Treatment of alpha-aryl-beta-bromo(or chloro)-alpha-nitrosoethylene, prepared in situ from alpha-monobromo(or chloro)ketoximes and sodium carbonate in ether at rt, with allytrimethylsilane afforded exclusively trans-(4S,6S)- and trans-(4R,6R)-3-aryl-4-halo-6-[(trimethylsilyl)methyl]-5,6-dihydro-4H-1,2-oxazines 10 albeit in low yields. Similar treatment of beta-halo-alpha-nitrosoethylenes with ethyl vinyl ether, however, gave single stereoisomers, i.e., cis-(4S,6S)- and cis-(4R,6R)-6-ethoxy-4-halo-5,6-dihydro-4H-1,2-oxazines 11, in moderate to good yields. The result is in contrast to the reported predominant formation of trans-11a by a radical reaction. On the other hand, similar reactions with tert-butyl vinyl ether at 30 degrees C gave diastereomeric mixtures of cis-(4S,6S)-, cis-(4R,6R)-, trans-(4S,6R)-, and trans-(4R,6S)-6-(tert-butoxy)-4-halo-5,6-dihydro-4H-1,2-oxazines 12. In contrast to compounds 11, the major isomers have (4S,6R) and (4R,6S) configurations. The tendency of a [4 + 2] cycloaddition reaction is consistent with that observed in the Diels-Alder reaction with inverse-electron demand. The stereochemistries of compounds 10-12 were assigned on the basis of the (1)H NMR coupling constants, which were unambiguously determined by the decoupling experiments. All reactions leading to compounds 10-12 proceed with very high regioselectivity. Diastereoselectivity and high regioselectivity are understood in terms of the frontier orbital method. It has been found that cis-12g is isomerized to a mixture of stereoisomers in favor of the trans-isomer in the presence of HClO(4) (72%) in CHCl(3) at rt.     

A novel and general synthetic pathway to strychnos indole alkaloids: total syntheses of (-)-tubifoline, (-)-dehydrotubifoline,and (-)-strychnine using palladium-catalyzed asymmetric allylic substitution

A method of palladium-catalyzed asymmetric allylic substitution for synthesizing 2-substituted cyclohexenylamine derivatives was established. Treatment of a 2-silyloxymethylcyclohexenol derivative with ortho-bromo-N-tosylaniline in the presence of Pd(2)dba(3).CHCl(3) and (S)-BINAPO in THF afforded a cyclohexenylamine derivative with 84% ee in 80% yield. The Heck reaction was carried out to produce an indolenine derivative in good yield. Using this method, we synthesized indolenine derivative 7, which was recrystallized from EtOH to give an optically pure compound. From this compound, tetracyclic ketone 13, which should be a useful intermediate for the synthesis of indole alkaloids, could be synthesized. The total syntheses of (-)-dehydrotubifoline, (-)-tubifoline, and (-)-strychnine were achieved from 13. All ring constructions for the syntheses of these natural products were achieved using a palladium catalyst.     

Oxidative addition of allylic carbonates to palladium(0) complexes: reversibility and isomerization

The oxidative addition of a cyclic allylic carbonate to the palladium(0) complex generated from a [Pd(dba)2]+2 PPh3 mixture affords a cationic pi-allylpalladium(II) complex with the alkyl carbonate as the counter-anion. This reaction is reversible and proceeds with isomerization of the allylic carbonate at the allylic position. The equilibrium constant has been determined in DMF. The influence of the precursor of the palladium(0) is discussed.     

Synthesis of allyl cyanamides and N-cyanoindoles via the palladium-catalyzed three-component coupling reaction

The palladium-catalyzed three-component coupling reaction (TCCR) of aryl isocyanides, allyl methyl carbonate, and trimethylsilyl azide was conducted in the presence of Pd(2)(dba)(3).CHCl(3) (2.5 mol %) and dppe (1,2-bis(diphenylphosphino)ethane) (10 mol %). Allyl aryl cyanamides with a wide variety of functional groups were obtained in excellent yields. This palladium-catalyzed TCCR was further utilized for the synthesis of N-cyanoindoles. The reaction of 2-alkynylisocyanobenzenes, allyl methyl carbonate, and trimethylsilyl azide in the presence of Pd(2)(dba)(3).CHCl(3) (2.5 mol %) and tri(2-furyl)phosphine (10 mol %) at higher temperatures afforded N-cyanoindoles in good to allowable yields. (eta(3)-Allyl)(eta(3)-cyanamido)palladium complex, an analogue of the bis-pi-allylpalladium complex, is a key intermediate in the TCCR, and a pi-allylpalladium mimic of the Curtius rearrangement is involved to generate the (eta(3)-allyl)(eta(3)-cyanamido)palladium intermediate.     

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.     

Gold(I)/Chiral N,N′‐Dioxide–Nickel(II) Relay Catalysis for Asymmetric Tandem Intermolecular Hydroalkoxylation/Claisen Rearrangement

A highly efficient asymmetric cascade reaction between alkynyl esters and allylic alcohols has been realized. Key to success was the combination of a hydroalkoxylation reaction catalyzed by a π‐acidic gold(I) complex with a Claisen rearrangement catalyzed by a chiral Lewis acidic N,N′‐dioxide–nickel(II) complex. A range of acyclic α‐allyl β‐keto esters were synthesized in high yields (up to 99 %) with good diastereoselectivities (up to 97:3) and excellent enantioselectivities (up to 99 % ee ) under mild reaction conditions. These products can be easily transformed into optically active β‐hydroxy esters, β‐hydroxy acids, or 1,3‐diols.     

Palladium-catalyzed selective synthesis of 2-allyltetrazoles

The palladium-catalyzed three-component coupling (TCC) reaction of cyano compounds, allyl methyl carbonate, and trimethylsilyl azide under a catalytic amount of Pd2(dba)3.CHCl3 (2.5 mol %) and tri(2-furyl)phosphine (10 mol %) gave various kinds of 2-allyltetrazoles in good to excellent yields. A pi-allylpalladium azide complex is proposed as a key intermediate in the TCC reaction.     

A route to 2-substituted tetrahydroquinolines via palladium-catalyzed intramolecular hydroamination of anilino-alkynes

The cyclization of amino-alkynes 1 in which an amino group is attached to the aromatic ring, proceeded smoothly using a catalytic amount of Pd(PPh3)4 and benzoic acid in toluene at 120 degrees C, leading to the formation of the 2-substituted tetrahydroquinolines 2. An asymmetric variant of the reaction using the chiral palladium catalyst (prepared in situ by mixing Pd2(dba)3.CHCl3 and (R,R)-RENORPHOS) was also explored. The absolute configuration of the enantiomerically enriched tetrahydroquinolines, obtained in this way, was determined by converting them to the known compounds and was found to be R. The alkaloids such as (+/-)-galipinine, (+/-)-angustureine, and their optically active form were synthesized by using this reaction as a key step.     

Synthesis of allenes via palladium-catalyzed hydrogen-transfer reactions: propargylic amines as an allenyl anion equivalent

Synthesis of allenes has been achieved by using palladium-catalyzed hydrogen-transfer reactions. Various propargylic amines, which were readily prepapred from iodobenzenes and propargylic amines by Sonogashira coupling reaction, underwent the hydrogen-transfer reaction in the presence of Pd2dba3.CHCl3/(C6F5)3P catalyst at 100 degrees C in dioxane for 24 h, giving the corresponding allenes in 43-99% yields. Various propargylic alcohols containing a propargylic aminomethyl group, synthesized by the addition of lithium acetylides of N,N-diisopropylprop-2-ynylamine to aldehydes and a ketone, also underwent the hydrogen-transfer reaction in the presence of Pd2dba3.CHCl3 catalyst and (C6F5)3P at 80 degrees C in dioxane, giving the corresponding allenes in 56-92% yields. In the current transformation, propargylic amines can be handled as an allenyl anion equivalent and introduced into various electrophiles to be transformed into allenes under palladium-catalyzed conditions.     

Stereoselective palladium-catalyzed carbocyclization of allenic allylic carboxylates

Palladium(0)-catalyzed reaction of allene-substituted allylic carboxylates 3-8 employing 2-5 mol % of Pd(dba)(2) in refluxing toluene leads to the carbocyclization and elimination of carboxylic acid to give bicyclo[4.3.0]nonadiene and bicyclo[5.3.0]decadiene derivatives (12-17). The carbon-carbon bond formation is stereospecific, occurring syn with respect to the leaving group. Addition of maleic anhydride as a ligand to the above-mentioned procedures changed the outcome of the reaction, and under these conditions 3-5 afforded cycloisomerized products 21-23. The experimental results are consistent with a mechanism involving oxidative addition of the allylic carboxylate to Pd(0) to give an electron-deficient (pi-allyl)palladium intermediate, followed by nucleophilic attack by the allene on the face of the pi-allyl opposite to that of the palladium atom. Furthermore, it was found that the Pd(dba)(2)-catalyzed cyclization of the trans-cycloheptene derivative (trans-8) can be directed to give either the trans-fused (trans-17) or the cis-fused (cis-17) ring system by altering the solvent. The former reaction proceeds via a nucleophilic trans-allene attack on the (pi-allyl)palladium intermediate, whereas the latter involves a syn-allene insertion into the allyl-Pd bond of the same intermediate. The products from the carbocylization undergo stereoselective Diels-Alder reactions to give stereodefined polycyclic systems in high yields.     

Stereocontrolled Photooxygenations–A Valuable Synthetic Tool§

The stereochemical course of the singlet-oxygen ene reaction with acyclic olefins may be controlled if in the substrate conformational fixation (1,3-allylic strain) an allyl-ic substituent for interaction with the attacking oxygen enophile aligns. Various substrates were chosen to elucidate the features of the olefin that are necessary to control the sense (threo versus erythro) and the extent of the ii-facial preference of the singlet-oxygen attack. Depending on the electronic properties of the double bond and the nature of the allylic substituent, threo or erythro selectivity may be imposed through hydrogen bonding, electrostatic and steric effects and stereoelectronic alignment. Such directing properties, especially that of the hydroxy group, were also confirmed in the other reaction modes of singlet oxygen, namely the [4+2] cycloaddition to chiral naphthylenic alcohols and the [2+2] cycloaddition to an adamantylidene-substituted allylic alcohol. The syntheses of the natural products Merucathin and Iso-dihydromahubanolide B are two examples in which such stereocontrolled photooxygenations have been used as key steps to build up the required chirality diastereose-lectively.     

Synthesis of nonracemic allylic hydroxy phosphonates via alkene cross metathesis

Allylic hydroxy phosphonates and their derivatives can be interconverted by using cross metathesis with second generation Grubbs catalyst. The absolute stereochemistry of the starting phosphonate is conserved in the product. Cross metathesis reaction of the acrolein-derived phosphonate 2a yields a series of functionalized allylic hydroxy phosphonates. However, the cross metathesis reaction is often accompanied by competing dimerization and alkene migration reactions leading to a reduction in yield. The cinnamaldehyde- and crotonaldehyde-derived phosphonates 2b and 2c were also examined. In general, the metathesis reactions of phosphonates 2b and 2c are considerably slower than those for phosphonate 2a leading to mixtures. Several hydroxyl-protected derivatives of the phosphonate 2a (methyl carbonate 3a, acetate 4a, N-tosyl carbamate 5a, TBDMS 6a, and acetoacetate 7a) undergo metathesis without competing side reactions to give substituted allylic phosphonates in good to excellent yield.     

Palladium-catalyzed deracemization of allylic carbonates in water with formation of allylic alcohols: hydrogen carbonate ion as nucleophile in the palladium-catalyzed allylic substitution and kinetic resolution

The palladium-catalyzed deracemization of racemic cyclic and acyclic allylic methyl carbonates in water in the presence of N,N'-(1R,2R)-1,2-cyclohexanediylbis[2-(diphenylphophino)benzamide] proceeds with high enantioselectivities to give the corresponding allylic alcohols in high yields. This deracemization involves a palladium-catalyzed allylic substitution with the in-situ-formed hydrogen carbonate ion and an irreversible decomposition of the intermediate allylic hydrogen carbonates, with formation of the corresponding allylic alcohols. The palladium-catalyzed reaction of racemic cyclic allylic acetates with potassium hydrogen carbonate in water in the presence of the chiral bisphosphane proceeds with a highly selective kinetic resolution to give the corresponding allylic alcohols and allylic acetates.     

Enantioselective Syntheses of (-)- and (+)-Homocitric Acid Lactones

Highly enantioselective syntheses of enantiomers of homocitric acid lactones (R)-5a and (S)-5b are described. Thermal Diels-Alder cycloadditions of 2a and 2b to 1,3-butadiene produced adducts 3a and 3b, respectively. Oxidative ozonolysis of latter adducts gave products 4a and 4b which after acid treatment afforded a mixture with 5a and 5b as major component. Acid lactones 5a and 5b were converted into their dimethyl esters 6a and 6b which were purified by chromatography. After saponification, the products obtained were crystallized to yield (-)- and (+)-homocitric acid lactones ((R)-5a and (S)-5b). Diastereomeric excess (de) of Diels-Alder adducts 3a and 3b was determined by means of Mosher esters of glycols 8a, 8b, and racemic 8. Diels-Alder cycloaddition products of lactones 2a and 2b to 1,3-butadiene showed a diastereoselectivity of 96%.     

Proline catalyzed two-component, three-component and self-asymmetric Mannich reactions promoted by ultrasonic conditions

The proline catalyzed two-component and three-component asymmetric Mannich reaction with hydroxyacetone and self-Mannich reaction with propanal were performed successfully under ultrasonic conditions in 1 h to afford Mannich products in 90-98% isolated yields and 81-99% ees with excellent diastereoselectivities.     

Palladium-catalyzed intramolecular asymmetric hydroamination, hydroalkoxylation, and hydrocarbonation of alkynes

A conceptually novel approach for asymmetric intramolecular hydroamination, hydroalkoxylation and hydrocarbonation of alkynes using chiral palladium catalysts are described. The reactions of the aminoalkynes 5, alkynols 7, and alkynylmethines 9 in the presence of Pd2(dba)3 x CHCl3/PhCOOH/renorphos 4 in benzene (or benzene-hexane) at 100 degrees C gave the corresponding cyclization products (nitrogen heterocycles 6, oxygen heterocycles 8, and carbocycles 10) in good yields with good enantioselectivities. The origins of enantioselectivities in the hydroamination reaction are discussed based on DFT computations.     

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.