Rhodium‐Catalyzed [3+2+2] and [2+2+2] Cycloadditions of Two Alkynes with Cyclopropylideneacetamides

It has been established that a cationic rhodium(I)/H₈‐binap complex catalyzes the [3+2+2] cycloaddition of 1,6‐diynes with cyclopropylideneacetamides to produce cycloheptadiene derivatives through cleavage of cyclopropane rings. In contrast, a cationic rhodium(I)/(S)‐binap complex catalyzes the enantioselective [2+2+2] cycloaddition of terminal alkynes, acetylenedicarboxylates, and cyclopropylideneacetamides to produce spiro‐cyclohexadiene derivatives which retain the cyclopropane rings.     

RhII‐Catalyzed [3+2] Cycloaddition of 2 H‐Azirines with N‐Sulfonyl‐1,2,3‐Triazoles

Rh^II‐catalyzed intermolecular [3+2] cycloaddition of 2 H‐azirines with N‐sulfonyl‐1,2,3‐triazoles is disclosed, in which a series of fully functionalized pyrroles is produced via rhodium azavinyl carbene intermediates. A distinct feature of this reaction is that the azavinyl carbene serves as a [2 C] equivalent, instead of as [1 C] or aza‐[3 C] synthons, which have been reported previously in cyclopropanations and [3+n] cycloadditions. Moreover, this methodology has also been successfully applied in the total synthesis of URB447 as well as the formal synthesis of Atorvastatin (Lipitor).     

Regioselective synthesis of mono- and bis-decahydrobenzocarbazoles via tandem reactions of α-diazo ketones

Regioselective intermolecular 1,3-dipolar cycloaddition reactions of rhodium generated carbonyl ylides with indoles are reported in this paper. Intermolecular 1,3-dipolar cycloaddition reactions of five-membered-ring cyclic carbonyl ylides with indole and substituted indoles afforded hexahydro-2H-carbazol-2-ones in a regioselective manner. Similarly, reactions of cyclic carbonyl ylides were carried out to afford decahydrobenzo[c]carbazoles or decahydrocyclopenta[c]carbazoles with high regioselectivity. Interestingly, the other possible regioisomer decahydrobenzo[a]carbazoles were also obtained by the reaction of cyclic carbonyl ylides and indoles having electron withdrawing substituents. The structure and stereochemistry of regioisomers 6,11c-epoxy-1,2,3,4,4a,5,6,6a,11b,11c-decahydro-4a-methyl-5-oxo-7H-benzo[c]carbazole and 11-benzenesulfonyl-6,11b-epoxy-2,3,4,4a,5,6,6a,11,11a,11b-decahydro-4a-methyl-5-oxo-1H-benzo[a]carbazole were unequivocally corroborated by single-crystal X-ray analyses. To advance this study, regioselective double 1,3-dipolar cycloaddition reaction of five-membered-ring cyclic carbonyl ylides has been demonstrated for the first time with biindoles having various aryl and alkyl spacers. This process constructed up to eight stereocenters, four carbon-carbon and two carbon-oxygen bonds in a single step with an excellent molecular complexity and stereoselectivity.     

Mechanistic Intricacies of Gold‐Catalyzed Intermolecular Cycloadditions between Allenamides and Dienes

The mechanism of the gold‐catalyzed intermolecular cycloaddition between allenamides and 1,3‐dienes has been explored by means of a combined experimental and computational approach. The formation of the major [4+2] cycloaddition products can be explained by invoking different pathways, the preferred ones being determined by the nature of the diene (electron neutral vs. electron rich) and the type of the gold catalyst (AuCl vs. [IPrAu]⁺, IPr=1,3‐bis(2,6‐diisopropylphenyl)imidazole‐2‐ylidene). Therefore, in reactions catalyzed by AuCl, electron‐neutral dienes favor a concerted [4+3] cycloaddition followed by a ring contraction event, whereas electron‐rich dienes prefer a stepwise cationic pathway to give the same type of formal [4+2] products. On the other hand, the theoretical data suggest that by using a cationic gold catalyst, such as [IPrAuCl]/AgSbF₆, the mechanism involves a direct [4+2] cycloaddition between the diene and the gold‐activated allenamide. The theoretical data are also consistent with the observed regioselectivity as well as with the high selectivity towards the formation of the enamide products with a Z configuration. Finally, our data also explain the formation of the minor [2+2] products that are obtained in certain cases.     

1,3-Dipolar cycloaddition for selective synthesis of functionalized spiro[indoline-3,3'-pyrrolizines]

The 1,3-dipolar cycloaddition reaction of dimethyl hex-2-en-4-ynedioate with azomethine ylides derived from reaction of L-proline with various isatins in methanol selectively resulted in the formation of functionalized spiro[indoline-3,3'-pyrrolizine]acrylates as main products and spiro[indoline-3,3'-pyrrolizine]propiolates as minor products.This result indicated that the electron-deficient alkyne has higher reactivity than that of electron-deficient alkene in 1,3-dipolar cycloaddition reaction.     

Rapid Access for the Synthesis of 1‐N‐Methyl‐spiro[2.3′]oxindole‐spiro[3.7″] (3″‐Aryl)‐5″‐methyl‐3″,3a″,4″,5″,6″,7″‐hexahydro‐2H‐pyrazolo[4,3‐c]pyridine‐4‐aryl‐pyrrolidines Through Sequential 1,3‐Dipolar Cycloaddition and Annulation

The 1,3‐dipolar cycloaddition of an azomethine ylide, generated from isatin and sarcosine by a decarboxylative route with various p‐substituted 3,5 bis(aryl methylidene)N‐methyl‐4‐piperidinones in refluxing methanol, proceeded regioselectively to give novel dispiroheterocycles. The product on subsequent annulation with hydrazine hydrate afforded 1‐N‐methyl‐spiro[2.3′]oxindole‐spiro[3.7″](3″‐aryl)‐5″‐methyl‐3″,3a″,4″,5″,6″,7″‐hexahydro‐2H‐pyrazolo[4,3‐c]pyridine‐4‐aryl‐pyrrolidines in good yield.     

Rhodium(II)‐Catalyzed Cycloaddition Reactions of Non‐classical 1,5‐Dipoles for the Formation of Eight‐Membered Heterocycles

A new type of intermolecular rhodium(II)‐catalyzed [5+3] cycloaddition has been developed. This higher‐order cycloaddition between pyridinium zwitterion 1,5‐dipole equivalents and enol diazoacetates enables the formation of eight‐membered heterocyclic skeletons, which are otherwise difficult to construct. The optimized cycloaddition occurs efficiently under mild conditions with a wide range of pyridinium zwitterions and with high functional‐group tolerance.     

The Cyano Group as a Traceless Activation Group for the Intermolecular [3+2] Cycloaddition of Azomethine Ylides: A Five‐Step Synthesis of (±)‐Isoretronecanol

The cyano group was used as a traceless activation group for the [3+2] cycloaddition of azomethine ylides in a two‐step process, thereby providing a highly effective approach to 5‐unsubstituted pyrrolidines. The transformation includes the silver acetate catalyzed intermolecular 1,3‐dipolar cycloaddition of α‐iminonitriles and an unprecedented sodium borohydride induced reductive decyanation reaction. A diverse array of substrates is amenable to this transformation. The methodology was further extended to a five‐step total synthesis of the pyrrolizidine natural product isoretronecanol.     

Synthesis of dihydropyrazolo[3′,4′:3,4]pyrrolo[1,2-a]indoles and spiro-[3H-indole-3,3′-[Δ-1,2,4]-triazolin]-2-ones via intra and intermolecular 1,3-dipolar cycloadditions

A new class of dihydropyrazolo[3′,4′:3,4]pyrrolo[1,2-a]indoles and spiro[3H-indole-3,3′-[Δ²-1,2,4]-triazoline]-2-ones were synthesised via intra and intermolecular 1,3-dipolar cycloaddition reactions in good yields.     

An Efficient Four‐component Reaction for the Synthesis of Spiroheterocyclic Compounds

A series of 6‐amino‐8‐aryl‐3,4‐dihydro‐1H‐spiro[naphthalene‐2,2'‐[1,3] dioxolane]‐5,7‐dicarbonitrile and 8‐arylidene‐4‐aryl‐7,8‐dihydro‐5H‐spiro[quinazoline‐6,2'‐[1,3] dioxolan]‐2‐amine derivatives have been synthesized from the reactions of 1,4‐dioxaspiro[4.5] decan‐8‐one, aromatic aldehydes, and malononitrile (or guanidine carbonate) under different conditions with high yields. In this research, it was found the DBU–THF was efficient reaction condition for obtaining 6‐amino‐8‐aryl‐3,4‐dihydro‐1H‐spiro[naphthalene‐2,2'‐[1,3]dioxolane]‐5,7‐dicarbonitrile derivatives, while 95% EtOH and NaOH was the preferred condition for the synthesis of 8‐rylidene‐4‐aryl‐7,8‐dihydro‐5H‐spiro[quinazoline‐6,2'‐[1,3]dioxolan]‐2‐amine derivatives. To the best of our knowledge, these Spiroheterocycles were first reported in our research. The other advantages of this process were short‐reaction time, wide scope substrates, and simple set‐up.     

Ring transformations of heterocyclic compounds. XIX. Spiro[dihydropyridine‐indolines] novel heterocycles with two spiro‐condensed N‐containing subunits easy accessible by 1,3‐oxazinium ring transformation

The synthesis of hitherto unknown 1‐benzoyl‐1′,3′,3′‐trimethyl‐4,6‐diphenylspiro[1,2‐dihydropyridine‐2,2′‐indolines] 5 from 2,4,6‐triphenyl‐1,3‐oxazinium tetrafluoroborate ( 1b ) and 1,3,3‐trimethyl‐2‐methyleneindolines 2 (used as such or generated in situ from the corresponding 3H‐indolium salts 4 ) in the presence of triethylamine in anhydrous acetonitrile by a 3,6‐[C₃N+C₂] 1,3‐oxazinium ring transformation is reported. Structure elucidation is performed by an X‐ray structure determination of the spiro[dihydropyridine‐indoline] 5a . Spectroscopic data of the transformation products and their mode of formation are discussed.     

The Effect of Position Replacement of Functional Groups on the Stepwise character of 1,3‐Dipolar Reaction of a Nitrile Oxide and an Alkene

It is a well‐known fact that by changing the 1,3‐dipolar cycloaddition (1,3‐DC) reaction mechanism from concerted to stepwise, the stereospecificity is lost; since in synthesizing the required heterocyclic molecules that reaction is a requisite, it is important to study the concertedness of that reaction. Several papers on this subject have already stated that the existence of electron withdrawing groups (EWG) or electron donor groups (EDG) on dipole or dipolarophile leads to a high‐energy differentiation between the dipole HOMO and dipolarophile LUMO (or vice versa) as well as the emergence of an intermediate in the reaction pathway. This paper seeks answering the question of when an EWG on dipole and an EDG on dipolarophile could be a factor in making the reaction mechanism stepwise, and does repositioning of functional groups in replacing dipole and dipolarophile switches the reaction mechanism from stepwise into concerted or vice versa?     

Highly Enantioselective Intramolecular 1,3‐Dipolar Cycloaddition: A Route to Piperidino‐Pyrrolizidines

Enantioselective catalytic intermolecular 1,3‐dipolar cycloadditions are powerful methods for the synthesis of heterocycles. In contrast, intramolecular enantioselective 1,3‐dipolar cycloadditions are virtually unexplored. A highly enantioselective synthesis of natural‐product‐inspired pyrrolidino‐piperidines by means of an intramolecular 1,3‐dipolar cycloaddition with azomethine ylides is now reported. The method has a wide scope and yields the desired cycloadducts with four tertiary stereogenic centers with up to 99 % ee. Combining the enantioselective catalytic intramolecular 1,3‐dipolar cycloaddition with a subsequent diastereoselective intermolecular 1,3‐dipolar cycloaddition yielded complex piperidino‐pyrrolizidines with very high stereoselectivity in a one‐pot tandem reaction.     

Rh‐Catalyzed [5+1] and [4+1] Cycloaddition Reactions of 1,4‐Enyne Esters with CO: A Shortcut to Functionalized Resorcinols and Cyclopentenones

We have developed novel Rh‐catalyzed [n+1]‐type cycloadditions of 1,4‐enyne esters, which involve an acyloxy migration as a key step. The efficient preparation of functionalized resorcinols, including biaryl derivatives, from readily available 1,4‐enyne esters and CO was achieved by Rh‐catalyzed [5+1] cycloaddition accompanied by 1,2‐acyloxy migration. When enyne esters had an internal alkyne moiety, the reaction proceeded by a [4+1]‐type cycloaddition involving 1,3‐acyloxy migration, leading to cyclopentenones.     

Tandem Insertion–[1,3]‐Rearrangement: Highly Enantioselective Construction of α‐Aminoketones

An enantioselective synthesis of α‐aminoketone derivatives were readily available through a tandem insertion–[1,3] O‐to‐C rearrangement reaction. The rhodium salt and chiral N,N′‐dioxide‐indium(III) complex make up relay catalysis, which enables the O?H insertion of benzylic alcohols to N‐sulfonyl‐1,2,3‐triazoles, and asymmetric [1,3]‐rearrangement of amino enol ether intermediates, subsequently. Preliminary mechanistic studies suggested that the [1,3] O‐to‐C rearrangement step proceeded through an ion pair pathway.     

A convenient synthesis of 5-(1,2,4-oxadiazol-5-yl)pyrimidine-2,4(1H,3H)-diones

The synthesis of 5-heteroaryl-substituted uracil derivatives is presented. The 1,3-dipolar cycloaddition reaction was applied for the construction of a heterocyclic ring. The nitrile oxides were obtained from the appropriate 4-substituted benzaldoximes using N-chlorosuccinimide (NCS) under basic conditions. [2+3] Cycloaddition of nitrile oxides with 5-cyanouracil as a dipolarophile gave the corresponding 5-(3-substituited-1,2,4-oxadiazol-5-yl)uracils in satisfactory yields under mild conditions. 5-Substituted uracils having an additional heterocyclic ring were obtained as a result of the [2+3] cycloaddition of 5-cyanouracil to nitrile oxides generated from thiophene-2-carbaldehyde and 5-formyluracil derivatives.     

Synthesis of pyrrolidine-fused [34]- and [36]octaphyrins via 1,3-dipolar cycloaddition

[reaction: see text] The utility of expanded porphyrins as a dipolarophile in cycloaddition reactions has been investigated. The 1,3-dipolar cycloaddition of meso-octakis(pentafluorophenyl)[36]octaphyrin(1.1.1.1.1.1.1.1) with an azomethine ylide provides mono- and bis-pyrrolidine-fused octaphyrins regio- and stereoselectively. Treatment of the cycloadduct with MnO(2) afforded [34]octaphyrin quantitatively.     

A Convenient 1,3‐Dipolar Cycloaddition Reaction for the Synthesis of Spirooxindoles and Some Other Spirocompounds Containing the 1,3,4‐Oxadiazole Moiety

A series of spiro[indoline‐3,2′‐[1,3,4]oxadiazol]‐2‐ones were prepared from the reaction of isatin derivatives and hydrazonoyl chlorides through the 1,3‐dipolar cycloaddition reaction. This method has some important aspects, such as mild reaction condition, easy purification, and high yield of products. Also, the synthesis of spiro[acenaphthylene‐1,2′‐[1,3,4]oxadiazol]‐2‐one and spiro[[1,3,4]oxadiazole‐2,9′‐phenanthren]‐10′‐one were studied under the same condition. The structures were confirmed spectroscopically (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS) and by elemental analyses. A plausible mechanism for this reaction is proposed.     

Rhodium-catalyzed intra- and intermolecular [5 + 2] cycloaddition of 3-acyloxy-1,4-enyne and alkyne with concomitant 1,2-acyloxy migration

A new type of rhodium-catalyzed [5 + 2] cycloaddition was developed for the synthesis of seven-membered rings with diverse functionalities. The ring formation was accompanied by a 1,2-acyloxy migration event. The five- and two-carbon components of the cycloaddition are 3-acyloxy-1,4-enynes (ACEs) and alkynes, respectively. Cationic rhodium(I) catalysts worked most efficiently for the intramolecular cycloaddition, while only neutral rhodium(I) complexes could facilitate the intermolecular reaction. In both cases, electron-poor phosphite or phosphine ligands often improved the efficiency of the cycloadditions. The scope of ACEs and alkynes was investigated in both the intra- and intermolecular reactions. The resulting seven-membered-ring products have three double bonds that could be selectively functionalized.     

Rhodium(II)‐Catalyzed Annulation of Azavinyl Carbenes Through Ring‐Expansion of 1,3,5‐Trioxane: Rapid Access to Nine‐Membered 1,3,5,7‐Trioxazonines

The rhodium(II)‐catalyzed denitrogenative coupling of N‐alkylsulfonyl 1,2,3‐triazoles with 1,3,5‐trioxane led to nine‐membered‐ringed trioxazonines in moderate‐to‐good yields. 1,3,5‐Trioxane, acting as an oxygen nucleophile, reacted with the α‐aza‐vinylcarbene intermediate, giving rise to ylide formation, which was probably the key step in the reaction. Triazoles that contained aryl substituents with various electronic and steric features on the C4 carbon atom were well‐tolerated. The synthesis of trioxazonine derivatives was achieved through a one‐pot, two‐step procedure from 1‐mesylazide and a terminal alkyne by combining Cu^I‐catalyzed 1,3‐dipolar cycloaddition and rhodium‐catalyzed transformations.