Sodium Dimethyl Malonate Research Articles

Asymmetric CC Bond‐Formation Reaction with Pd: How to Favor Heterogeneous or Homogeneous Catalysis?

The enantioselective allylic alkylation of (E)-1,3-diphenylallyl acetate was studied to clarify the heterogeneous or homogeneous character of the Pd/Al(2)O(3)-(R)-BINAP catalyst system. A combined approach was applied: the catalytic tests were completed with in situ XANES measurements to follow the oxidation state of Pd as a function of the reaction conditions. The study revealed that the oxidized Pd (after exposure to ambient air) is efficiently reduced by the solvents THF and dioxane, and by the nucleophile sodium dimethyl malonate, and thus these conditions prevent Pd leaching. The chiral modifier BINAP plays a dual role: a considerable coverage of the Pd surface by the bulky compound slows down the initial reduction of the surface oxides but BINAP itself may consume surface oxygen (through its conversion to BINAPO and BINAPO(2)) and contribute to the maintenance of the active metal surface during the reaction. Carrying out the reaction under pressure in an inert gas atmosphere is important to minimize the oxygen diffusion into the reaction mixture and to avoid leaching. The (known) effect of temperature is critical as well: our catalyst system is inactive at room temperature, which is a clear deviation from the behavior of the corresponding homogeneous system. In contrast, halogenated solvents are easily dehalogenated on Pd/Al(2)O(3) and thus they favor leaching of the metal and formation of soluble compounds, analogous to classical metal corrosion in the presence of halide ions. The frequently observed dissolution of Pd in the presence of halogenated substrates may be explained similarly.

Phosphino-(α-sulfinylalkyl)phosphonium ylide complexes (Rh, Pd) with a configurationally stable asymmetric ylidic carbon

The synthesis and structure of Rh(I) and Pd(II) complexes of chiral P,C-chelating phosphino-(α-sulfinylalkyl)phosphonium ylide ligands with a trisubstituted asymmetric ylidic center P +–C∗R(S∗(O) p-Tol)–M (R = alkyl group) have been investigated, and compared to those of the analogous disubstituted ylide complexes (R = H). Reaction of the ethyl onium ylide of o-bis(diphenylphosphino)benzene with (−)-menthyl-( S)- p-tolylsulfinate afforded the corresponding racemic erythro phosphino-(α-sulfinylethyl)phosphonium in 90% de (R = Me). The racemization process is interpreted by a Berry-like pseudorotation mechanism driven by the steric repulsion between the α-methyl substituent and the bulky menthyloxy S-substituent or sulfur lone pair in the intermediate ylide-sulfinyl adduct. The ylide of phosphino-(α-sulfinylethyl)phosphonium reacts with [Rh(cod) 2][PF 6] and PdCl 2(MeCN) 2 to afford the corresponding P,C∗-chelated threo-Rh(I) and erythro-Pd(II) mononuclear complexes in 70% yield and total diastereoselectivity. These respective complexes act as efficient catalytic precursors for the hydrogenation of ( Z)-α-acetamidocinnamic acid and allylic substitution of 3-acetoxy-1,3-diphenyl-1-propene with sodium dimethyl malonate. The bonding features of the erythro-Pd(II) complex exhibiting a sulfinyl O⋯Pd interaction are studied theoretically at the DFT level using ELF and MESP analyses. The η 2-P,C haptomeric form of the ylide ligand is estimated to compete at 19% with the η 1-C haptomeric form dominating at 81%.

New example of Ramberg-Böcklund reaction initiated by Michael addition

Only isolated cases were reported [1–4] on the synthesis of functionalized olefins from α-haloalkyl vinyl sulfones through Ramberg–Bo..cklund reaction initiated by Michael addition. The limitations of this reaction evidently depend both on the structure of the initial substrate and on the nature of the used reagent. For instance, it was established in [5] that the treatment with potassium tert-butylate, a strong base but a weak nucleophile, of α-haloalkyl vinyl sulfones containing an allyl hydrogen atom promoted the so-called vinylogic Ramberg–Bo..cklund reaction leading to the formation of conjugated dienes. For instance, by this procedure nona-1,3diene was obtained in 72% yield proceeding from 1-(bromomethylsulfonyl)oct-1-ene. We showed in [6] that the treatment with the typical Michael reagents, enolates of CH-acids, of bromomethyl β-styryl sulfone led to the cyclization initiated by Michael addition giving tetrahydrothiophene S,S-dioxide derivative. We report here that at treating 1-(bromomethylsulfonyl)cyclohex-1-ene (I) with sodium dimethyl malonate (20°C, 17 h) from the three mentioned possible reaction routes proceeds the one consisting in the Ramberg–Bocklund reaction initiated by Michael addition: The functionalized derivative of methylenecyclohexane II is obtained. Unsaturated sulfone I was obtained in a two-stage process involving the addition of BrCH2SO2Br to cyclohexene (CH2Cl2, 10°C, 24 h, no special initiation was required) and the dehydrobromination of the adduct in a water-dioxane solution of Na2CO3 at heating (50°C, 30 h). SO2CH2Br

Resolution of the Atropochiral Biminap Ligand and Applications in Asymmetric Catalysis

Enantiomeric resolution of the rac-biminap ligand is achieved through fractional crystallization of four diastereoisomeric palladium complexes involving ortho-metallated enantiomerically pure (R)-dimethyl(1-naphthylethyl)amine as a chiral auxiliary. After decomplexation, the absolute configuration of (R)-biminap and (S)-biminap has been unambiguously attributed by single-crystal X-ray crystallography, and their stereochemical purity is confirmed by measurement of their optical rotation and by re-derivatization with the initial resolving chiral complex. Palladium complexes of biminap are shown to efficiently catalyze Tsuji-Trost allylic substitution of 3-acetoxy-1,3-diphenylpropene by sodium dimethyl malonate. In the asymmetric version using the enantiomerically pure (R)-biminap ligand, significant solvent and anion effects are evident, and an ee up to 90% is obtained.

Coordination Chemistry and Catalytic Application of Bidentate Phosphaferrocene−Pyrazole and −Imidazole Based P,N-Ligands

The synthesis of new planar chiral P,N-ligands based on 3,4-dimethylphosphaferrocene and either pyrazole or 1-methylimidazole is described. The coordination chemistry of the hemilabile pyrazole derivatives 3a and 3b (a features a methylene bridge between the heterocycles, b an ethylene bridge) was investigated and afforded complexes [Mo(3)(CO)5], cis-[Mo(3)2(CO)4], [Cp*RuCl(3)], [Cp*Ru(3)2]OTf, [Cp*RuCl(3)(PPh3)], and [Pd(η3-allyl)(3)]PF6. Reaction of the imidazole derivatives 4a and 4b with [Pd(η3-allyl)Cl]2 and TlPF6 yielded [Pd(η3-allyl)(4)]PF6. The Pd complexes of 3 and 4 were tested in the catalytic asymmetric allylic alkylation reaction of 1,3-diphenylallyl acetate with sodium dimethylmalonate. X-ray structures of one Ru complex and one Pd complex of 3a were determined.

Osmium-Catalyzed Allylic Alkylation

Complex [OsCl2(η6-p-cymene)]2 (1) reacts with (5,7-dioxa-6-phosphadibenzo[a,c]cyclohepten-6-yl)dimethylamine (L1) and (−)-(R)-(3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yl)dimethylamine (L2) to give OsCl2(η6-p-cymene)L (L = L1 (2), L2 (3)). Complexes 1−3 and OsCl2(η6-p-cymene){P(OPh)3} (4) are efficient catalyst precursors for the alkylation of 1-phenylallyl methylcarbonate (5a), 1-phenylallyl acetate (5b), cinnamyl methylcarbonate (6a), and cinnamyl acetate (6b) with sodium dimethylmalonate to afford 1-phenylallyl dimethylmalonate (7) and cinnamyl dimethylmalonate (8) with branched:linear molar ratios between 97:3 and 67:33. In the absence of sodium dimethylmalonate, the reaction of 1 with 5a leads initially to {OsCl(η6-p-cymene)}2(μ-OMe)2 (9) and subsequently to [{Os(η6-p-cymene)}2(μ-OMe)3][O2COMe] (10). In the absence of 5a, the reaction of 1 with sodium dimethylmalonate gives Os{κ1-C3-[CH(CO2Me)2]}{κ2-O,O-[CH(CO2Me)2]}(η6-p-cymene) (11). Complexes 9−11 are also efficient catalyst precursors for the alkylation of 5a with sodium dimethylmalonate. The activity of 9 and 10 is the same as that of 1. However, complex 11 is significantly less efficient than 1. In contrast to the latter, complexes 2 and 3 do not react with 5a in the absence of sodium dimethylmalonate. In the absence of the substrate, the reactions of 2 and 3 with sodium dimethylmalonate lead to Os{κ1-C3-[CH(CO2Me)2]}Cl(η6-p-cymene)L (L = L1 (12), L2 (13)), which further react with excess sodium dimethylmalonate to give 11. The catalytic behavior of 12 and 13 has been also studied. Their activities are the same as those of 2 and 3 and intermediate between those of 10 and 11. Complexes 3, 9, 11, and 12 have been characterized by X-ray diffraction analysis.

Diastereoselective and Enantiospecific Synthesis of γ-Substituted α,β-Unsaturated Nitriles from O-Protected Allylic Cyanohydrins

gamma-Functionalized alpha,beta-unsaturated nitriles are prepared diastereoselectively and enantiospecifically from enantioenriched cyanohydrin-O-phosphates and carbonates derived from alpha,beta-unsaturated aldehydes, either by palladium or iridium-catalyzed nucleophilic allylic substitution reactions with different nucleophiles. Appropriate reaction conditions for dibenzylamine, benzylamine, sodium azide, NaOAc, tetra-n-butylammonium acetate (TBAA), the corresponding sodium salts of phenol and N-hydroxysuccinimide and the carbonucleophile sodium dimethyl malonate are described. Different substituted O-protected cyanohydrins, such as carbonates and phosphates, derived from crotonaldehyde, (E)-hex-2-enal, oct-2-enal, 2-methylbut-2-enal, and cinnamaldehyde are used as allylic substrates. The substitution takes place with total retention of the configuration for the (E)-gamma-functionalized nitriles and with inversion of the configuration for the Z-isomers. In general, cyanohydrin-O-phosphates are the materials of choice to get the highest E-diastereoselectivity. Dibenzylamine is the best nucleophile for the synthesis of gamma-nitrogenated alpha,beta-unsaturated nitriles in the presence of either palladium or iridium catalysts when aliphatic compounds and cinnamaldehyde derivative are used (up to 98% dr). For the synthesis of gamma-oxygenated alpha,beta-unsaturated nitriles sodium or TBAA the reagents are selected to avoid epimerizations in up to 76% dr. Finally, the Tsuji-Trost reaction with sodium malonate works only under palladium catalysis in up to 70% dr.

Steric Effects in Enantioselective Allylic Alkylation Catalysed by Cationic(η3‐Allyl)palladium Complexes Bearing Chiral Pyridine‐Aziridine Ligands

AbstractEnantiopure N,N′‐bidentate ligands (N,N′)*, containing substituted aziridine and aza‐aromatic rings, were prepared from imines derived from (S)‐valinol or (R)‐phenylglycinol and heteroaromatic aldehydes (2‐pyridine‐, 6‐benzyl‐2‐pyridine‐, 2‐ and 8‐quinolinecarbaldehyde) by the addition of iPrMgCl and subsequent cyclisation of the 1,2‐amino alcohol moiety to aziridine. Crystalline [(N,N′)*(η3‐allyl)Pd][SbF6] complexes were prepared from these ligands and used as catalysts in the alkylation of sodium dimethyl malonate with 1,3‐diphenyl‐2‐propenyl acetate and carbonate. By comparing the performances of two complexes bearing similar pyridine‐aziridine ligands but with a different C2‐aziridine substituent (Ph vs. iPr), a better enantioselectivity was provided by the Ph‐substituted ligand (90 % vs. 41 % ee), whereas the presence of a C6‐pyridine benzyl substituent caused inversion of the enantioselectivity. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Asymmetric Iridium(I)-Catalyzed Allylic Alkylation of Monosubstituted Allylic Substrates with Phosphinooxazolines as Ligands. Isolation, Characterization, and Reactivity of Chiral (Allyl)iridium(III) Complexes

IrI-catalyzed allylic alkylations of linear aryl-substituted allylic acetates proceed with enantiomeric excess of up to 95% ee using bidentate phosphinooxazolines as chiral ligands. The chiral (π-allyl)IrIII complexes 14 and 15 have been characterized by X-ray crystal structure analysis and spectroscopic data. The stoichiometric reaction between sodium dimethyl malonate and complex 14 proceeded with nucleophilic addition at the central allylic carbon as well as ligand exchange at Ir to give the iridacyclobutane complex 16, which was fully characterized. Complex 16 was transformed into (π-allyl)IrIII complexes by treatment with Lewis acid or iodine.

Mechanistic studies of the molybdenum-catalyzed asymmetric alkylation reaction.

Enantiomerically enriched, deuterated branched carbonates (Z)-(S)-PhCH(OCO(2)Me)-CH = CHD (1-D), (Z)-(R)-PhCH(OCO(2)Me)CH = CHD (2-D), and linear carbonate (E)-(S)-PhCH = CHCHD(OCO(2)Me) (3-D) were used as probes in the Mo-catalyzed asymmetric allylic alkylation with sodium dimethyl malonate, catalyzed by ligand-complex 11 derived from the mixed benzamide/picolinamide of (S,S)-transdiaminocyclohexane and (norbornadiene)Mo(CO)(4). The results of these studies, along with x-ray crystallography and solution NMR structural analysis of the pi-allyl intermediate, conclusively established the reaction proceeded by a retention-retention pathway. This mechanism contrasts with that defined for Pd-catalyzed allylic alkylations, which proceed by an inversion-inversion pathway. A proposed rationale for the retention pathway for nucleophilic substitution involves CO-coordination to form a tri-CO intermediate, followed by complexation with the anion of dimethyl malonate to produce a seven-coordinate intermediate, which reductively eliminates to afford product with retention of configuration.

Conclusive evidence for a retention-retention pathway for the molybdenum-catalyzed asymmetric alkylation.

Enantiomerically enriched, deuterated branched carbonates (Z)-(S)-PhCH(O2COMe)-CH=CHD (1a), (Z)-(R)-PhCH(O2COMe)CH=CHD (2a), and linear carbonate (E)-(S)-PhCH=CHCHD(O2COMe) (12) were employed as probes in the Mo-catalyzed asymmetric allylic alkylation with sodium dimethyl malonate, catalyzed by ligand complex 10 derived from the mixed benzamide/picolinamide of (S,S)-trans-diaminocyclohexane and (norbornadiene)Mo(CO)4. X-ray crystallography, along with solution NMR structural analysis of the pi-allyl intermediate and competition experiments, conclusively established the reaction proceeded via a retention-retention pathway. This mechanism contrasts with that defined for Pd-catalyzed allylic alkylations, which proceed via an inversion-inversion pathway.

A structure–activity relationship for pincer palladium(II) complexes—influence of ring-size of metallacycles on the activity in allylic alkylation

A series of new palladium(II) complexes derived from the well-known pincer complex [PdCl{(C 6 H 3 )(OP i Pr 2 ) 2 -2,6}] were synthesised: [PdX{(C 6 H 3 )(OP i Pr 2 ) 2 -2,6}] (X=Br − , I − , OAc − , OTf − ). A novel PCP′ pincer ligand 1-( i Pr 2 PO)-3-( i Pr 2 POCH 2 )(C 6 H 4 ) was prepared and complexed to palladium(II) to give [PdX{(C 6 H 3 )(OP i Pr 2 )-2-(CH 2 OP i Pr 2 )-6}] (X=Cl − , I − , OAc − , OTf − , BF 4 − ). The X-ray structure of [PdCl{(C 6 H 3 )(OP i Pr 2 )-2-(CH 2 OP i Pr 2 )-6}] was solved and is discussed. These complexes were applied to the catalytic reaction of cinnamyl acetate with sodium dimethyl malonate in order to evaluate the influence of the ligand structure and co-ordinating or non-co-ordinating anions on the regioselectivity. A detailed analysis shows that palladium(II) complexes of the unsymmetrical PCP′ bis(phosphinito) ligand are much more active when compared to related complexes of the symmetrical PCP bis(phosphinito) ligand. The origin of this difference in activity is discussed.

The unusual role of CO transfer in molybdenum-catalyzed asymmetric alkylations.

Spectroscopic and crystallographic studies were undertaken to gain insight into the mechanism of the highly regio- and enantioselective allylic aklylation reaction catalyzed by molybdenum. The chiral ligand (L*) consisting of the mixed benzamide/picolinamide of (S,S,)-trans-1,2-diaminocyclohexane reacts with a typical Mo precatalyst, (norbornadiene)Mo(CO)4, to give a neutral complex L*Mo(CO)4 in which the ligand binds to the metal in a bidentate fashion through the pyridine and adjacent amide group. Reaction of this complex with the methyl carbonate of cinnamyl alcohol gives the corresponding pi-allyl complex L*(CO)2Mo(eta3-CH2=CH-CHPh). NMR and X-ray crystallographic characterization of this complex reveal the ligand binds in a facially capping tridentate fashion via the pyridine nitrogen, the nitrogen of the adjacent amide group, which has now been deprotonated, and the carbonyl oxygen of the remote amide. Surprisingly, the face of the allyl group open to attack with nucleophiles is that which would lead to the sense of stereochemistry opposite to that which is observed in catalytic reactions. Furthermore, the allyl complex in its isolated form is unreactive toward sodium dimethyl malonate. However, in the presence of a source of carbon monoxide (either Mo(CO)6 or gaseous CO), the allyl complex reacts with malonate to give the typically observed branched alkylated product in high yield and enantiomeric excess. The metal-containing product of this reaction is the molybdate complex [L*Mo(CO)4]-Na+. Reaction of the molybdate complex with linear or branched allylic carbonates regenerates the allyl complex, thus closing the catalytic cycle. Both the allyl complex and the molybdate complex are the only metal-containing species observed by NMR in typical catalytic reactions and thus appear to be catalyst resting states. Turnover of the catalytic cycle therefore involves shuttling of carbon monoxide between the two catalyst resting states. Coordination of CO appears to be necessary to activate the allyl complex toward nucleophilic attack, in effect stabilizing the molybdenum fragment as a leaving group.

Solvent-dependent dynamic kinetic asymmetric transformation/kinetic resolution in molybdenum-catalyzed asymmetric allylic alkylations.

Catalytic asymmetric alkylation reactions of branched racemic carbonates 1a and 1b with sodium dimethyl malonate, promoted by molybdenum and ligand 5, proceed by a kinetic resolution in toluene, THF, tetrahydropyran, i-PrOAc, 1,2-dichloroethane, and MeCN with k(rel) of 7-16. In THF, MeCN, tetrahydropyran, and i-PrOAc using the (S,S)-5 ligand, the fast reacting (S)-carbonate enantiomer provides the branched product with high ee (97-99.5%) and branched/linear selectivity, but the ee erodes as the reaction of the slow-reacting (R)-enantiomer takes place. This implies that the rate of equilibration of the oxidative addition complexes in these solvents is competitive with the subsequent malonate displacement step. In toluene and dichloroethane, the ee and branched/linear ratios diminish during the reaction of the slow-reacting (R)-isomer, but not nearly as much as in the other solvents. This is most likely due to either an increase in the rate of equilibration of the oxidative addition complexes relative to the malonate displacement step, or vice versa. Because of the minimal stereochemical memory effect in toluene and 1,2-dichloroethane, the reactions in these solvents can be carried to completion (dynamic kinetic asymmetric transformation) and still provide product with excellent ee (>95%). The anion of dimethyl methylmalonate also reacts via a kinetic resolution, although the ee's, rates, and k(rel) values differ from those of the reactions with dimethyl malonate.

Palladium-catalyzed allylic nucleophilic substitution reactions of ( E)-γ-acetoxy-α,β-unsaturated p-tolylsulfoxides

Regio- and diastereoselective nucleophilic allylic substitutions of optically pure ( E)-γ-acetoxy-α,β-unsaturated p-tolylsulfoxides 2 and 3 with sodium dimethyl malonate have been carried out. The reactivity of these substrates is controlled by both the chiral sulfinyl group and the size of the alkyl group attached at the γ-terminus of the allylic system. This process constitutes an example of palladium-mediated resolution of a 1:1 mixture of acetates 2 and 3.

Asymmetric Allylic Substitution Reactions with a Xylophos-Pd Catalyst

The chiral diphosphine ligand xylophos (1) was tested as an auxiliary in palladium catalyzed allylic substitution reactions. Whereas its activity was found to be generally good only in the case of 1,3-diphenylprop-2-en-1-yl acetate, a fair level of asymmetric induction was achieved with sodium dimethyl malonate (83%ee) and benzylamine (66%ee) as nucleophiles.

Asymmetric Palladium-Catalyzed Allylic Alkylation Using Bis(Oxazoline) Ligands: Phenomenal Reversal of Enantioselectivity with a Single Chiral Backbone

Chiral bis(oxazoline) ligands with four stereogenic centers were tested in the asymmetric palladium-catalyzed allylic alkylation of the rac-1,3-diphenyl-2-propenyl esters with sodium dimethyl malonate. A remarkable effect on the enantioselectivity was observed: the dihydroxy bis(oxazoline) ligands gave the (S)-product with 92% ee, while the diester led to the (R)-product with 90% ee. This change in direction of chiral induction sense with the dihydroxy ligand is due to the regioselection of the nucleophilic attack on the palladium(II) π-allyl complex. Implication of the interaction of a hydroxy group with the dimethyl malonate anion is considered to explain the change in the regiochemistry of the nucleophilic attack. X-ray structures of the η3-1,3-diphenylallyl-[(2,2-bis[2-((4S)-((1S)-1-hydroxy-1-phenylmethyl)-1,3-oxazolinyl)]propane)-N,N‘]palladium(II) tetrafluoroborate 7 and the η3-1,3-diphenylallyl-[(2,2-bis[2-((4S)-((1S)-1-methyloxy-1-phenylmethyl)-1,3-oxazolinyl)]propane)-N,N‘]palladium(II) tetrafluoroborate 8 are presented, which clearly show the occurrence of hydrogen bonding in complex 7.

Palladium-catalyzed asymmetric alkylation of 2-azaallyl acetates for the synthesis of β-carboxyaspartic acid derivatives

Palladium-catalyzed asymmetric alkylation of 2-azaallyl acetate, N-(diphenylmethylene)acetoxyglycine ester with a sodium salt of malonate ester was successfully carried out. High enantioselectivities were achieved using sodium dimethyl methylmalonate (98%ee) or sodium dimethyl malonate (93%ee) as a nucleophile with t-butyl ester of 2-azaallyl acetate in the presence of ( S)-BINAP in acetonitrile.

A Repetitive Approach to the Synthesis of Medium and Large Ring Compounds with a Ring-Opening/Ring-Closure Cascade Reaction of Siloxycyclopropane Derivatives as Crucial Step

Starting from siloxycyclopropyl-substituted dimethyl malonates 1 and 2 a chain elongation was performed to give new malonates 8, 9, 10, and 18 in reasonable overall yield. Further elongation by five carbon atoms transforms 10 into 15. Precursor 21 was prepared by alkylation of cyclopropanecarboxylate 20 with dibromide 17 and subsequent treatment with sodium dimethyl malonate. Compounds 8, 9, 10, 15, 18, and 21 were subjected to cesium fluoride under high dilution which induced a ring-opening/ring-closure cascade reaction giving cyclopentadecanone derivatives 11, 12, 13, cycloeicosanone derivative 16, cyclotetradecanone derivative 19 and cyclononane derivative 22 (together with 23). The efficiency of this reaction including an intramolecular Michael addition is discussed. The sequence allows efficient synthesis of medium and large carbocycles by a highly flexible building block system involving in principle unlimited repetition of construction steps. An X-ray analysis of 19 reveals its crown-like conformation which is slightly distorted to a more planar skeleton compared with a ten-membered ring analog 24.

New chiral rhenium complexes of unsaturated alcohols: preparation and reactivity

New chiral rhenium complexes of allylic, homoallylic and propargylic alcohols have been prepared and their reactivity versus various reagents has been studied. Starting from the allyl alcohol complex, a multistep sequence involving a chemoselective oxidation, a Wittig reaction and a reduction led without bond-shift to conjugated dienone and dienol. The complexed allyl acetate, prepared by reaction of acetic anhydride on the complexed allyl alcohol reacted with sodium dimethylmalonate in a diastereoselective fashion.