A DFT-based theoretical investigation of the mechanism of the PtCl2-mediated cycloisomerization of allenynes

The mechanism of Pt(II)-catalyzed intramolecular cycloisomerization of allenyne systems has been extensively investigated by DFT calculations. Different mechanistic schemes have been proposed and discussed, including the Alder-ene reaction. The free energy results suggest that the kinetically preferred reaction pathway for precursors that are tri- and tetrasubstituted on the allene moiety should proceed by a five-step mechanism. This would involve formation of a platina(IV)cyclopentene intermediate by selective engagement of the external pi bond of the allene, which would undergo regioselective beta-H elimination from the equatorially disposed methyl group. A metal-induced H migration leads to a second octahedral Pt(IV)-chelate complex, which would yield the expected bicyclic system through an intramolecular migratory insertion step. Therefore, depending on the conformation of the initial eta(4)-reactant complex for trisubstituted patterns, two possible intermediates can be formed that would evolve through different paths. In these cases, the regio- and stereochemical outcomes predicted by the mechanistic scheme proposed agree with experimental data. Substituted precursors on the alkyne moiety follow a distinct, four-step, mechanism also involving an oxidative cyclometalation process to an octahedral Pt(IV) intermediate complex. Theoretical results reveal the kinetic preference for beta-H elimination from the allylic group rather than from the gem-dimethyl group, which should account for the observed regioselectivity.     

Studies on the Cu(I)-catalyzed regioselective anti-carbometallation of secondary terminal propargylic alcohols

A highly regioselective Cu(I)-catalyzed anti-carbometallation of secondary terminal propargylic alcohols with 1 degrees alkyl or aryl Grignard reagents affording 2-substituted allylic alcohols was developed. By using this method, optically active allylic alcohols can be prepared from the optically active propargylic alcohols without obvious loss of the enantiopurity. The cyclic organometallic intermediate formed may undergo an iodination or a Pd(0)-catalyzed coupling reaction to afford stereo-defined allylic alcohols.     

C-C bond-forming reactions of Ir(III)-alkenyls and nitriles or aldehydes: generation of reactive hydride- and alkyl-alkylidene compounds and observation of a reversible 1, 2-H shift in stable hydride-Ir(III) alkylidene complexes

Nucleophilic attack of the beta-carbon of an Ir(III)-alkenyl functionality onto the alpha-carbon of a coordinated nitrile- or aldehyde occurs intramoleculary to yield initially iridacyclic structures. Nitriles give rise to isolable complexes that contain delocalized five-membered rings (iridapyrroles, e.g. 3'-8') in a reaction catalyzed by H2O (for some of these syntheses, Ir(III)-eta 3-allyl derivatives may be used as the source of the Ir(III)-alkenyl moiety). In contrast, the alkenyl-to-aldehyde C-C coupling gives transient iridacycles that evolve by a fast alkyl-to-alkylidene migration and beta-H elimination. The end products (13* and 14*) contain an elaborated chelating alkoxide-olefin ligand. Addition of [H(OEt2)2][BAr'4] to the iridapyrroles effects stereospecific protonation of the beta-ring carbon. Those iridapyrroles which contain an additional metal-alkyl functionality (e.g. 3a*, alkyl = C2H5) afford highly reactive cationic alkyl-alkylidene intermediates that evolve instantaneously by migratory insertion/beta-H elimination. The end products also contain an elaborated, chelating ligand, although this time with an olefin and imine terminus compared with the previous ligand. Contrary to this result, protonation of the hydride-iridapyrrole complex 8a* in weakly coordinating solvents permits isolation of two unusual cationic cis-hydride-alkylidene compounds 11*, which undergo reversible 1,2-H shifts.     

Dual reactivity pattern of allenolates "on water": the chemical basis for efficient allenolate-driven organocatalytic systems

A study of the reactivity pattern associated with zwitterionic allenolates "on water" is reported. This study establishes the chemical basis for two organocatalyzed allenolate-driven reaction networks operating "on water". The first one is a chemodifferentiating three building block (ABB') three-component reaction (ABB' 3CR) manifold comprising terminal alkynoates and aldehydes. The manifold produces propargylic enol ethers 3 with higher average efficiency than their homologues in organic solvents. The second one is a novel organocatalytic system elicited by the reaction of alkynoates and nitrones in the presence of tertiary amines or phosphines. While terminal alkynoates afford 2,3,5-trisubstituted 2,3-dihydroisoxazoles 5 and propargylic N-hydroxylamines 6, internal alkynoates selectively afford the 2,3,4,5-tetrasusbstituted 2,3-dihydroisoxazaole 10. Importantly, in both cases, the 2,3-dihydroisoxazole ring is obtained as a sole regioisomer.     

Stereoselective synthesis of 3-alkylideneoxindoles by palladium-catalyzed cyclization reaction of 2-(alkynyl)aryl isocyanates with organoboron reagents

A palladium(0)/monophosphine catalyst promotes a cyclization reaction of 2-(alkynyl)aryl isocyanates with organoboron reagents to produce stereodefined 3-alkylideneoxindoles. The alkynyl and isocyanato groups undergo oxidative cyclization with Pd(0) to form an oxapalladacycle intermediate. Subsequent transmetalation and reductive elimination afford the product.     

Azepine synthesis from alkyl azide and propargylic ester via gold catalysis

An efficient new method was developed to synthesize multisubstituted 4,5-dihydro-1H-azepine derivatives through the gold-catalyzed reaction of two molecules of propargylic esters with one molecule of alkyl azide. It was proposed that vinyl gold carbenoid, in situ generated from propargylic ester through gold-catalyzed 1,2-rearrangement, was trapped by alkyl azide to give vinyl imine intermediate. These, in turn, could undergo a formal [4 + 3] cycloaddition with another molecule of vinyl gold carbenoid to afford the desired azepine product.     

Ruthenium‐catalyzed cyclizations of enynes via a ruthenacyclopentene intermediate: Development of three novel cyclizations controlled by a substituent on alkyne of enyne

Three novel ruthenium‐catalyzed cyclizations of enynes were developed. In each cyclization, a ruthenacyclopentene derived from enyne and Cp*RuCl(cod) is a common intermediate. When an enyne having an alkyl, an ester, or a formyl group on an alkyne was reacted with Cp*RuCl(cod) under ethylene gas, ethylene was inserted into the ruthenium‐sp² carbon bond of ruthenacyclopentene to afford ruthenacycloheptene, and β‐hydrogen elimination followed by reductive elimination occurred to give a cyclic compound having a 1,3‐diene moiety. When an acyl group was placed on the alkyne, the carbonyl oxygen coordinated to the ruthenium metal of ruthenacyclopentene to produce a ruthenium carbene complex, which reacted with ethylene to give a cyclic compound having a cyclopropane ring on the substituent. On the other hand, when the substituent on the alkyne was pent‐4‐enyl, insertion of an alkene part into ruthenacyclopentene followed by reductive elimination gave a tricyclic compound by a ruthenium‐catalyzed [2 + 2 + 2] cyclization of diene and an alkyne. DOI 10.1002/tcr.201100003     

Efficient synthesis of 4-(3'-furanyl)butenolide derivatives via PdII-catalyzed oxidative heterodimeric cyclization reaction of 2,3-allenoic acids and 1,2-allenyl ketones

The oxidative cyclization/dimerization reaction between two classes of allenes with different functionalities was reported to provide an efficient route to polysubstituted 4-(3'-furanyl)-2(5H)-furanones, which are not readily available from the known methods. The highly optically active butenolides could be easily formed from the optically active 2,3-allenoic acids, which was obtained conveniently through chiral resolution with optically active amines, that is, cinchonidine or alpha-methyl benzylamine. A mechanistic study showed that the reaction proceeded via a matched double oxypalladation-reductive elimination process. The Pd(II) species may be regenerated via the subsequent cyclometallation of two equivalents of 1,2-allenyl ketones with Pd(0) and protonlysis of Pd enolates formed with the in situ generated HCl.     

Controllable highly stereoselective reaction of in situ generated magnesium dienolate intermediates with different electrophiles

In this paper, we have described an efficient controllable stereoselective alpha-acylation and -allylation reaction of the magnesium dienolate intermediates generated in situ from the Fe(III)-catalyzed reaction between 2,3-allenoates and Grignard reagents with different electrophiles to afford 2-acylated or allylated 3( Z)- or ( E)-alkenoates depending on the nature of the electrophiles and reaction conditions. The distinct stereoselectivity may be caused by the isomerization of metallic Z-1,3-dienoate to E-1,3-dienoate via the intermediacy of anti-allylic MgCl and syn-metallic species.     

RhI‐Catalyzed Bimolecular Cyclization between Two Different 1,5‐Bisallenes: A Combinatorial One‐Step Approach to Heterosteroids and Mechanistic Implications

In this paper, a bimolecular‐cyclization reaction between two different bis(allene)s with at least one heteroatom as the tether under the catalysis of trans‐[RhCl(CO)(PPh₃)₂] is described. This protocol provides an efficient entry to different heterocyclic 18,19‐norsteroid‐like scaffolds. The tricyclic product was formed highly selectively from the cyclization reaction of bis(2,3‐butadienyl)sulfide with dimethyl 2‐bis(2′,3′‐butadienyl)malonate, which sheds light on the mechanism involving the metalla‐[4.3.0]‐bicyclic intermediate formed by the cyclometallation of the terminal and the internal C=C bonds of each of the two allene moieties in 2‐bis(2′,3′‐butadienyl)malonate.     

Preparation of vinylogous 2-sulfonylindolines by the palladium-catalyzed heteroannulation of o-iodoanilines with dienyl sulfones and their further transformation to indoles and carbazoles.

The palladium-catalyzed heteroannulation of o-iodoanilines with dienyl sulfones provides a convenient route to vinylogous 2-sulfonylindolines 3. The reaction proceeds in DMF/water in the presence of potassium carbonate and catalytic palladium(II) acetate and is compatible with both electron-donating and -withdrawing substituents in the para position of the aniline, and with an alkyl substituent at C-2 of the dienyl sulfone. The indolines underwent oxidation with DDQ to afford the corresponding indoles 4. The latter were then employed as dienes in Diels-Alder reactions with dimethyl acetylenedicarboxylate (DMAD), methyl propiolate, or methyl acrylate. In the case of the latter two dienophiles, the cycloadditions were highly regioselective, affording the corresponding 1,3-products (with respect to the relative positions of the sulfone and ester groups), exclusively. The cycloadducts from acetylenic dienophiles were converted to the corresponding carbazoles by elimination of the sulfone moiety with DBU, and that from methyl acrylate was subjected to reductive desulfonylation and oxidation to the corresponding carbazole with DDQ. The method thus provides access to carbazoles with various substituents at the 3-, 4-, and 6-positions.     

Palladium-catalyzed 1,1-alkynylbromination of alkenes with alkynyl bromides

The palladium-catalyzed 1,1-alkynylbromination of terminal alkenes with a silyl-protected alkynyl bromide is reported. The method tolerates a diverse range of alkenes including vinylarenes, acrylates, and even electronically unbiased alkene derivatives to afford propargylic bromides regioselectively. Mechanistic studies and DFT calculations indicate that the 1,1-alkynylbromination reaction proceeds via the migration of the Pd center followed by the formation of a π-allenyl Pd intermediate, leading to the stereoselective reductive elimination of the C(sp³)–Br bond at the propargylic positon.

The first Pd-catalyzed 1,1-alkynylbromination of terminal alkenes using alkynyl bromides, which provides direct access to a variety of functionalized propargylic bromides without the need for an external brominating reagent, is reported.     

Direct Synthesis of Multi‐functional Pyrimidine,Pyrazine, and Pyridine Scaffolds via Inter‐ and Intramolecular Annulations of 3‐Amino‐thieno[2,3‐b]pyridine‐2‐carboxylate

The synthesis of a new series of annulated thieno[2,3‐b]pyridines was performed. Ester compound 1 underwent heterocyclization upon reaction with phenylisothiocyanate and formamide to afford pyrimidines 2 and 3 , respectively. Thienopyrimidine 5 was resulted via reaction of amino derivative 1 with triethyl orthoformate to afford the non‐isolable intermediate 4 , which allowed hydrazinolysis with hydrazine hydrate to afford the target compound. Pyrimidine type 5 was condensed with p‐nitrobenzaldehyde to afford Schiff base 6 . Refluxing of ester 1 with ethyl cyanoacetate and diethyl malonate followed by base‐mediated heterocyclization afforded condensed pyridines 8 and 9 , respectively. The tetracyclic pyrazine derivative 14 was obtained from the reaction of amino compound 1 with 2,5‐dimethoxytetrahydrofuran followed by hydrazinolysis to give carbohydrazide 11 , which undergo diazotization followed by Curtius rearrangement. The antibacterial results illustrated no significant results for the investigated compounds except compound 5 , which has moderate activity against Gram‐positive bacteria.     

Studies on Cu(I)-catalyzed synthesis of simple 3-substituted 1,2-allenes and optically active 2-substituted secondary 2,3-allenols

The sequential treatment of terminal alkynes or propargylic alcohols with n-BuLi and MOMCl afforded the corresponding propargylic methyl ethers, which would react with primary alkyl Grignard reagents under the catalysis of CuBr to afford 3-substituted 1,2-allenes or 2-substituted secondary 2,3-allenols, respectively. The reaction may be applied to the synthesis of optically active 2-substituted secondary 2,3-allenols with up to >99% ee without any protection to the free hydroxyl group in the starting 4-hydroxy-2-alkynyl methyl ethers.     

Highly selective synthesis of bicyclic quinolizidine alkaloids and their analogues via double RCM reaction of N-alkynyl-N-(1,omega)-alkadienyl acrylamides

The double ring-closing metathesis reaction of N-alkynyl-N-(1,omega)-alkadienyl acrylamides 1 using first- or second-generation Grubbs' catalyst afforded, in a highly selectively manner, the fused bicyclic quinolizidine alkaloid derivatives and their analogues bearing a 1,3-diene moiety, which may further undergo a Diels-Alder reaction with a dienophile to afford N-containing polycyclic compounds. The excellent selectivity of fused/dumbbell-mode cyclization has been realized by the higher reactivity of the electron-rich C=C bond or carbon-carbon triple bond combined with the lower reactivity of the electron-deficient C=C bond toward metallocarbenes and the thermodynamically more stable nature of fused bicyclic compounds 3 vs dumbbell-type bicyclic compounds 4.     

Efficient synthesis of carbazoles via PtCl2-catalyzed RT cyclization of 1-(indol-2-yl)-2,3-allenols: scope and mechanism

A detailed study on the scope of the efficient PtCl(2)-catalyzed synthesis of carbazoles from 1-(indol-2-yl)-2,3-allenols is described. Through isotopic labeling experiments, it is confirmed that the reaction proceeds through a unique metal carbene intermediate, which undergoes subsequent highly selective 1,2-hydrogen migration to afford carbazoles. The reaction shows wide scope and allows the introduction of a variety of different substituents at different positions on the carbazole due to the substituent-loading capability of both indole and the allene moiety.     

Palladium-catalyzed construction of poly-substituted indolizinones

We have developed a highly efficient one-pot approach to poly-substituted indolizinones from tertiary propargylic alcohols by using a palladium-catalyzed domino reaction. This reaction is proposed to proceed via successive aminopalladation, reductive elimination, and 1,2-shift. While our previous effort to the same skeleton via 2-iodoindolizinones selected α,β-unsaturated esters, terminal acetylenes, or boronic acids as coupling partners, this strategy introduces new functional groups at the C2 position of indolizinone core with (hetero)aryl halides or diallyl carbonate, expanding the substrate scope for decoration at the C2 site. Furthermore, a new preparation route to tertiary propargylic alcohols for this study is described to rapidly diversify the molecular framework.     

Palladium-catalyzed heteroannulation of cyclic alkenes by functionally substituted aryl iodides

Indolines and 2,3-dihydrobenzofurans are produced in good yields by the Pd(0)-catalyzed heteroannulation of cyclic and bicyclic alkenes by o-amino- and o-hydroxyaryl iodides. These processes are only successful with cyclic olefins in which the key alkylpalladium intermediate cannot undergo facile palladium β-hydride elimination. These reactions appear to involve: (1) oxidative addition of the aryl iodide to the palladium catalyst, (2) arylpalladation of the olefin, (3) possible coordination of the internal nucleophile to the palladium, (4) formation of a six-membered palladacycle, and (5) reductive elimination of the organopalladium intermediate to give the heteroannulation product and regenerate Pd(0).     

Palladium acetate-catalyzed cyclization reaction of 2,3-allenoic acids in the presence of simple allenes: an efficient synthesis of 4-(1'-bromoalk-2'(Z)-en-2'-yl)furan-2(5H)-one derivatives and the synthetic application

We have realized a cyclization reaction of 2,3-allenoic acids 1 in the presence of simple alkyl- or aryl-substituted allenes 3. In this reaction, the cyclic oxypalladation of 2,3-allenoic acid with Pd(II) would afford the furanonyl palladium intermediate 2, which could be trapped by the simple allene to afford a pi-allylic intermediate anti-9. This intermediate anti-9 could be nucleophilically attacked by Br- to yield 4-(1'-bromoalk-2'(Z)-en-2'-yl)furan-2(5H)-one derivatives Z-5 and Pd(0). The in-situ formed Pd(0) was efficiently converted to the catalytically active Pd(II) species by benzoquinone in HOAc. The functional groups, such as malonate, acetoxyl, and phthalic amide in allene 3, are tolerable under the current conditions. High efficiency of chirality transfer was observed when optically active 2,3-allenoic acids were used, which reveals that the formation of the intermediates 2 was a highly stereoselective anti-oxypalladation process. The highly selective formation of Z-isomer may be explained by face-selective coordination of allene 3 with the palladium atom in intermediate 2: the palladium atom coordinates to the terminal C=C double bond of allene 3 from the face opposite to the substituent group to avoid the steric congestion. The products Z-5 could be further elaborated via the S(N)2 nucleophilic substitution with amine or sodium benzenesulfinate, the reduction of the C-Br bond by NaBH(4), and the CuBr.SMe(2)-catalyzed S(N)2'-substitution with CH(3)MgBr.     

Ionic diamine rhodium complex catalyzed reductive N-heterocyclization of 2-nitrovinylarenes

Ionic diamine rhodium complex (1) catalyzes the reductive N-cyclization of 2-vinylnitroarenes using carbon monoxide as a reducing agent to afford functionalized indoles. The catalytic system allows direct access to indoles with ester and ketone groups at the 2- or 3-position, in good yields.