Palladium-catalyzed reaction of boronic acids with chiral and racemic alpha-bromo sulfoxides

Palladium-catalyzed cross-coupling reactions of racemic alpha-bromo sulfoxides with boronic acids are carried out in either aqueous or nonaqueous medium with formation of a new C sp(3)-C sp(2) bond. The arylation of chiral alpha-bromo sulfoxides occurs without racemization. The cross-coupling reaction is general and gives high yields with arylboronic acids substituted with either donor or acceptor groups but gives poor results with heteroarylboronic acids. The best yields are obtained using degassed solvents and CsF instead of aqueous base. The use of aqueous base and the presence of oxygen favor the homocoupling side reaction.     

Ring-opening reaction of unactivated 3-arylaziridine-2-carboxylates with nitrile reagents

Ring-opening reactions of unactivated 3-arylaziridine-2-carboxylates with nitrile reagents, using trans-1-benzyl-3-(3,4-methylenedioxyphenyl)aziridine-2-carboxylate as a typical aziridine substrate, were examined. Formation of azomethine ylide by C2-C3 bond cleavage was observed when the aziridine was treated with trimethylsilyl cyanide under thermal conditions. On the other hand the use of bromine cyanide (BrCN) and diethylaluminum cyanide (Et₂AlCN) led to N-C3 bond cleavage and the stereospecificity was found to be dependent on the reagent used. Additional aluminum-catalyzed ring-opening reactions disclosed that the potential cationic character of the C3 benzylic position and stereochemical requirements of substituents in the arylaziridine system control the reactivity. Furthermore, the synthetic utility of the ring-opening reaction was demonstrated not only by application to the cyclization of a ring-opened cyanopropanoate to an isoquinoline skeleton but also by the extension of other carbon nucleophile from nitrile (C1) to a ketene acetal (C2).     

Ir(I)-catalyzed enantioselective secondary sp3 C-H bond activation of 2-(alkylamino)pyridines with alkenes

A cationic Ir(I)-tolBINAP complex catalyzed an enantioselective C-C bond formation initiated by secondary sp(3) C-H bond cleavage adjacent to a nitrogen atom. The reaction of 2-(alkylamino)pyridines with various alkenes gave chiral amines in good yields with high enantiomeric excesses.     

Chiral nonracemic late-transition-metal organometallics with a metal-bonded stereogenic carbon atom: development of new tools for asymmetric organic synthesis

Transition-metal-catalyzed cross-coupling reactions and the Heck reaction have evolved into powerful tools for the construction of carbon-carbon bonds. In most cases, the reactive organometallic intermediates feature a carbon-transition-metal sigma bond between a sp(2)-hybridized carbon atom and the transition metal (Csp(2)--TM). New, and potentially more powerful approach to transition-metal-catalyzed asymmetric organic synthesis would arise if catalytic chiral nonracemic organometallic intermediates with a stereogenic sp(3)-hybridized carbon atoms directly bonded to the transition metal (C*sp(3)--TM bond) could be formed from racemic or achiral organic substrates, and subsequently participate in the formation of a new carbon-carbon bond (C*sp(3)-C) with retention of the stereochemical information. To date, only a few catalytic processes that are based on this concept, have been developed. In this account, both "classical" and recent studies on preparation and reactivity of stable chiral nonracemic organometallics with a metal-bonded stereogenic carbon, which provide the foundation for the future design of new synthetic transformations exploiting the outlined concept, are discussed, along with examples of relevant catalytic processes.     

Silver-Promoted Fluorination Reactions of α-Bromoamides

Silver-promoted C−F bond formation in α-bromoamides by using AgF under mild conditions is reported. This simple method enables access to tertiary, secondary, and primary alkyl fluorides involving biomolecular scaffolds. This transformation is applicable to primary and secondary amides and shows broad functional-group tolerance. Kinetics experiments revealed that the reaction rate increased in the order of 3°>2°>1° α-carbon atom. In addition, it was found that the acidic amide proton plays an important role in accelerating the reaction. Mechanistic studies suggested generation of an aziridinone intermediate that undergoes subsequent nucleophilic addition to form the C−F bond with stereospecificity (i.e., retention of configuration). The synthesis of sterically hindered alcohols and ethers by using Ag^I is also demonstrated. Examples of reactions of α-bromoamides with O nucleophiles are presented.     

Highly stereoselective palladium-catalyzed dithiocarbonylation of propargylic mesylates with thiols and carbon monoxide

Highly stereoselective dithiocarbonylation of propargylic mesylates with thiols and carbon monoxide has been developed by the use of tetrakis(triphenylphosphine)palladium(0) as the catalyst at 90 degrees C in THF. The reaction affords the corresponding dithioesters in good to excellent yields. For some secondary and tertiary propargylic alcohols with a terminal or internal triple bond, the reaction stereoselectively produces E-dithioesters as products. The dithiocarbonylation is believed to proceed via allenylpalladium and allenyl ester intermediates, and the high stereoselectivity might be rationalized by a mechanism where nucleophilic attack of a Pd(0)L(n) species on the allenyl sp carbon occurs from the less hindered side of an alkyl substituent.     

Zinc(II)-catalyzed redox cross-dehydrogenative coupling of propargylic amines and terminal alkynes for synthesis of N-tethered 1,6-enynes

The zinc(II)-catalyzed redox cross-dehydrogenative coupling (CDC) of propargylic amines and terminal alkynes proceeds to afford N-tethered 1,6-enynes. In the current CDC reaction, a C(sp)-C(sp(3)) bond is formed between the carbon adjacent to the nitrogen atom in the propargylic amine and the terminal carbon of the alkyne with reduction of the C-C triple bond of the propargylic amine, which acts as an internal oxidant.     

An Efficient Approach to Chiral Allyloxyamines by Stereospecific Allylation of Nitrosoarenes with Chiral Allylboronates

A novel and efficient approach to allyloxyamines by the allylation of nitrosoarenes with α‐chiral allylboronates is described. C? O bond formation occurs with high stereospecificity and the product allyloxyamines are easily transformed into valuable chiral building blocks such as isoxazolidines and allylic alcohols. The reaction features complete regioselectivity (O‐selectivity), high E/Z selectivity, and excellent chirality transfer.     

Mechanism of C[bond]H bond activation/C[bond]C bond formation reaction between diazo compound and alkane catalyzed by dirhodium tetracarboxylate

The B3LYP density functional studies on the dirhodium tetracarboxylate-catalyzed C-H bond activation/C-C bond formation reaction of a diazo compound with an alkane revealed the energetics and the geometry of important intermediates and transition states in the catalytic cycle. The reaction is initiated by complexation between the rhodium catalyst and the diazo compound. Driven by the back-donation from the Rh 4d(xz) orbital to the C[bond]N sigma*-orbital, nitrogen extrusion takes place to afford a rhodium[bond]carbene complex. The carbene carbon of the complex is strongly electrophilic because of its vacant 2p orbital. The C[bond]H activation/C[bond]C formation proceeds in a single step through a three-centered hydride transfer-like transition state with a small activation energy. Only one of the two rhodium atoms works as a carbene binding site throughout the reaction, and the other rhodium atom assists the C[bond]H insertion reaction. The second Rh atom acts as a mobile ligand for the first one to enhance the electrophilicity of the carbene moiety and to facilitate the cleavage of the rhodium[bond]carbon bond. The calculations reproduce experimental data including the activation enthalpy of the nitrogen extrusion, the kinetic isotope effect of the C[bond]H insertion, and the reactivity order of the C[bond]H bond.     

Synthesis of dibenzofurans directly from aryl halides and ortho-bromophenols via one-pot consecutive SNAr and intramolecular palladium-catalyzed aryl-aryl coupling reactions

A series of dibenzofurans were efficiently and conveniently synthesized via one-pot consecutive C(sp(2))-O bond formation reaction (SNAr) in the presence of anhydrous K(2)CO(3), followed by C(sp(2))-C(sp(2)) bond formation reaction (intramolecular palladium-catalyzed aryl-aryl coupling reaction) between aryl halides and ortho-bromophenols. The desired dibenzofurans were obtained in 32-99% isolated yields.     

Photoinduced Halophosphination of Unsaturated Compounds

Abstract

Comprehensive studies of photoinduced addition of phosphorus trihalides to unsaturated compounds, i.e. alkenes, alkynes, alkadienes, and enynes, were carried out. The addition of phosphorus trihalides to unsaturated C?C bonds is proved to be a radical chain process, the total reaction irate increasing with the increase of electron density on the unsaturated C?C bond. The photoinduced reaction of alkenes with PRr3 goes via Br atom attack on the least substituted C-atom of an unsaturated C?C bond and mainly results in the formation or dibromophosphines with a phosphorus atom in the second position of the carbon chain ?(1–2)-addition. In the case of polysubstituted alkenes an alternative direction of the reaction is realized, namely the photoinduced substitutional dibromophosphination to alkyl group. The reaction with alkynes results only in the formation of the products of (1–2)-addition. The Regioselectivity of the addition of phosphorous trihalide fragments to the substrate containing a heteroatom at the unsaturated C?C bond is determined by the stability of the secondary halogenoalkenyl(alky1) radical.     

Palladium-catalyzed, stereoselective, cyclizative alkenylboration of carbon-carbon double bonds through activation of a boron-chlorine bond

Palladium-catalyzed alkenylboration of carbon-carbon double bonds has been achieved using the reaction of chloro(diisopropylamino)boryl ethers of homoallylic alcohols with alkenylzirconium reagents. The reaction may proceed through an initial oxidative addition of the B-Cl bond, intramolecular insertion of the C═C bond into the B-Pd bond, transmetalation from the alkenylzirconium reagent, and reductive elimination of the products. The cyclization proceeds with high diastereoselectivity for the formation of cis-3,5- or trans-3,4-disubstituted-1,2-oxaborolane products. Cross-coupling of the resultant products with aryl iodides proceeds with retention of configuration at the boron-bound secondary carbon atom.     

Highly efficient copper-catalyzed nitro-Mannich type reaction: cross-dehydrogenative-coupling between sp3 C-H bond and sp3 C-H bond

A novel C-C bond formation method was developed via the cross-dehydrogenative-coupling (CDC) reaction catalyzed by using copper bromide in the presence of an oxidizing reagent, tert-BuOOH. The CDC reaction provides a simple and efficient catalytic method to construct beta-nitroamine via the reaction between sp3 C-H and sp3 C-H bonds.     

PtBr2-catalyzed transformation of allyl(o-ethynylaryl)carbinol derivatives into functionalized indenes. Formal sp3 C-H bond activation

The PtBr2-catalyzed reaction of 1-ethynyl-2-(1-alkoxybut-3-enyl)benzenes at 120 degrees C in CH3CN gave functionalized indenes in good to allowable yields. Most probably, the hydrogen at the terminal alkyne is transferred to the adjacent internal beta-carbon to form an (eta2-vinylidene)platinum carbene intermediate, which activates the sp3 C-H bond at the benzylic carbon. This reaction pathway is supported by DFT calculations which suggest that the formation of the Pt-vinylidene complex is the rate-limiting stage for the whole transformation.     

3-Aza-cope rearrangement of quaternary N-allyl enammonium salts. Stereospecific 1,3 allyl migration from nitrogen to carbon on a tricyclic template

N-Allyl enamines can undergo a [3,3] sigmatropic rearrangement known as a 3-aza-Cope (or amino-Claisen) reaction. We explored a 3-aza-Cope reaction involving 1,3 allylic migration from nitrogen to carbon in N-allyl enammonium quaternary salts, exemplified by benzo[a]quinolizine 8 and pyrrolo[2,1-a]isoquinoline 13, with an interest in stereochemistry and mechanism. Salts 8 and 13 were accessed, respectively, through stereospecific allylation of hydroxy amines 4 and 11a/11b to give 7 and 12a/12b, which were dehydrated with trifluoroacetic acid. Allylic migration in these tricyclic tetrahydroisoquinolines occurred with high stereospecificity, with the major products 9 (from 8) and 15a (from 13) apparently deriving from a concerted suprafacial [3,3] rearrangement. The rearrangement of 8 to 9 was facile at 23 degrees C (t(1/2) = ca. 5 h) and was >98% stereospecific, whereas the rearrangement of 13 to 15a/15b required heating between 50 and 100 degrees C, with ca. 90-95% stereospecificity (t(1/2) = ca. 0.3 h at 100 degrees C). A deuterium-labeling experiment with 21 ((2)H-13) confirmed that allylic inversion accompanies the 1,3 migration en route to major isomer 22a ((2)H-15a), supporting the predominance of a concerted [3, 3] sigmatropic mechanism. However, the 5-10% loss of stereospecificity in the rearrangements of the pyrroloisoquinolines 13 and 21, reflected by formation of minor isomers 15b and 22b, respectively, indicates a minor nonconcerted reaction pathway.     

Asymmetric Synthesis of 1,3‐Butadienyl‐2‐carbinols by the Homoallenylboration of Aldehydes with a Chiral Phosphoric Acid Catalyst

Asymmetric C(sp)? C(sp²) bond formation to give enantiomerically enriched 1,3‐butadienyl‐2‐carbinols occurred through a homoallenylboration reaction between a 2,3‐dienylboronic ester and aldehydes under the catalysis of a chiral phosphoric acid (CPA). A diverse range of enantiomerically enriched butadiene‐substituted secondary alcohols with aryl, heterocyclic, and aliphatic substituents were synthesized in very high yield with high enantioselectivity. Preliminary density functional theory (DFT) calculations suggest that the reaction proceeds via a cyclic six‐membered chairlike transition state with essential hydrogen‐bond activation in the allene reagent. The catalytic reaction was amenable to the gram‐scale synthesis of a chiral alkyl butadienyl adduct, which was converted into an interesting optically pure compound bearing a benzo‐fused spirocyclic cyclopentenone framework.     

A theoretical investigation of the Co(CO)4--catalyzed carbonylative ring expansion of N-benzoyl-2-methylaziridine to beta-lactams: reaction mechanism and effect of substituent at the aziridine Calpha atom

The reaction mechanism of the Co(CO)4--catalyzed carbonylative ring expansion of N-benzoyl-2-methylaziridine to afford N-benzoyl-4-methyl-2-azetidinone and N-benzoyl-3-methyl-2-azetidinone was investigated by using the B3LYP density functional theory methodology in conjunction with the conductor polarizable continuum model/united atom Kohm-Sham method to take into account solvent effects. Computations predict that the most favorable reaction mechanism differs from the experimental proposals except for the nucleophilic ring-opening step, which is the rate-determining one. The regioselectivity and stereospecificity experimentally observed is explained in terms of the located reaction mechanism. The substitution of the methyl group at the carbon alpha of aziridine by the phenyl one gives rise to the obtaining of an only product that corresponds to the CO insertion into the C(substituted)-N bond in accordance with experimental findings. When the ethyl group replaces the methyl one the CO insertion occurs into the two C-N bonds, but the regioselectivity of the process is higher than that of the methyl substituent.     

The influence of a cyano-substituent on an alkyliron isomerization reaction

The complex CpFe(CO)PPh₃)(σ-CH₂CH₂CN) cleanly undergoes an isomerization reaction to Cpfe(CO)PPH₃)(σ-CH(CH₃)CN) when heated in solution at 95°C. The electron-withdrawing cyano group thus stabilizes a secondary alkylmetal complex in preference to the isomer containing a primary carbon to iron bond.     

Ligand-tuned regioselectivity of a cobalt-catalyzed Diels-Alder reaction. A theoretical study

Quantum chemical calculations at the BP86/def2-SVP levels of theory have been carried out for the reaction pathways of the [Co(L)] (+)-catalyzed Diels-Alder reaction of isoprene with phenylacetylene, with L = dppe, iminA, iminB. The calculations suggest that the reactions take place in a stepwise fashion, starting with the formation of the complex [Co(L)(isoprene)(phenylacetylene)] (+) as precursor for the consecutive C-C bond formation. The actual Diels-Alder ring-closing reaction proceeds as an intramolecular addition of the ligands isoprene and phenylacetylene, yielding a metallacyclic intermediate after generation of the first carbon-carbon bond, which determines the regioselectivity of the reaction. There are four different conformations of the starting complexes [Co(L)(isoprene)(phenylacetylene)] (+) which initiate four different pathways yielding the 1,3-cyclohexadiene product. The energetically most stable conformations do not lead to the reaction pathways that have the lowest activation energies. All conformations and the associated pathways must be considered in order to obtain the kinetically most favorable reaction course. The calculated values for the regioselectivities of the [Co(L)] (+)-catalyzed Diels-Alder reaction agree exceptionally well with the experimental values. The calculations concur with the experimental finding that the para product is kinetically favored for L = dppe while the formation of the meta product is kinetically favored when L = iminA or iminB. The different regioselectivies for L = dppe and L = iminA or iminB come from (a) the steric interactions of the bidentate ligands with the isoprene and phenylacetylene moieties in [Co(L)(isoprene)(phenylacetylene)] (+), which determine the distance between the carbon atoms forming the C-C bond, and (b) the relative energies of the different starting complexes. The first C-C bond formed in the rate-determing step of the [Co(dppe)] (+)-catalyzed reaction yielding the para product is the C4-C1' bond, and for the meta product it is the C1-C1' bond. The opposite order is found for the [Co(iminA)] (+)- and [Co(iminB)] (+)-catalyzed reactions, where the C1-C2' bond formation is the initial step toward the para product, while the C4-C2' bond is first formed in the reaction yielding the meta product. The calculations suggest that a less polar solvent should reduce the preference for formation of the meta product in the [Co(iminA)] (+)- and [Co(iminB)] (+)-catalyzed reactions but would enhance the formation of the para product in the [Co(dppe)] (+)-catalyzed reaction. Experimental tests using toluene as solvent instead of dichloromethane confirm the theoretical predictions.     

Double elimination protocol for synthesis of 5,6,11,12-tetradehydrodibenzo[a,e]cyclooctene

A new method for constructing 5,6,11,12-tetradehydrodibenzo[a,e]cyclooctene is described on the basis of one-pot double elimination protocol. The target molecule, which is the smallest cyclophane with alternate arylene-ethynylene linkage, is synthesized in 61 % yield through oxidative dimerization of ortho-(phenylsulfonylmethyl)benzaldehyde. The initial carbon-carbon bond formation between sp(3) carbons followed by stepwise conversion to sp(2) and finally sp carbons bypasses the difficulty encountered in direct coupling of the sp carbon in the terminal acetylene. The mechanism of this process is discussed. The Wittig-Horner-type coupling is a key reaction employed for the carbon-carbon bond formation. Generation of (E)-vinylsulfone moiety in the first coupling between alpha-sulfonyl anion and aldehyde functions is crucial for the effective second coupling to complete the cyclization. The syn-elimination of the (E)-vinylsulfone moieties in the cyclized intermediate furnishes the acetylenic bonds.