Catalyzed Asymmetric Diels?Alder Reactions of Benzoquinone. Total Synthesis of (−)‐Ibogamine

The Diels? Alder reaction of 1,4‐benzoquinone with 1,3‐dienes catalyzed by Mikami's [Ti{(S)‐binol(2?)}Cl₂] complex (binol=[1,1′‐binaphthalene]‐2,2′‐diol) gives cycloadducts in good yield and in high enantiomer excess. A model is proposed to explain the observed absolute configuration of cycloadducts, and the reaction is used as the key step in an asymmetric synthesis leading to the alkaloid (?)‐ibogamine.     

Synthesis of indeno[2,1‐a]pyrrolo[3,4‐c]carbazole lactam regioisomers using ethyl cis‐β‐cyanoacrylate as a dienophile and lactam precursor

Reported here is the synthesis and characterization of the indenopyrrolocarbazole ring system utilizing a Diels‐Alder reaction with 2‐indenylindole and maleimide. Clemmensen reduction of imide 10 furnished the 5‐oxo ( 16 ) and 7‐oxo ( 17 ) lactam regioisomers. A new regiospecific route to 5‐oxo 16 was developed using ethyl cis‐β‐cyanoacrylate as the dienophile. The regio and stereochemical characterization of the cycloadducts was confirmed by X‐ray crystallography.     

Photocycloisomerization of Boc‐Protected 5‐Alkenyl‐2,5‐dihydro‐1H‐ pyrrol‐2‐ones

On irradiation (254 nm), the newly synthesized Boc‐protected 5‐alkenyl‐2,5‐dihydro‐1H‐pyrrol‐2‐ones 13 undergo regioselective intramolecular [2+2] photocycloadditions. While the allyl derivatives 13a – 13c afford mainly azatricyclo[3.3.0.0^2,7]octanones, i.e., crossed cycloadducts, the butenyl‐ and pentenyl‐substituted compounds 13d and 13e isomerize preferentially to straight cycloadducts.     

Microwave‐assisted One‐pot,Three‐component Regiospecific and Sterospecific Synthesis of Spiro Indanone Pyrrolidine/Piperidine Fused Nitrochromene Derivatives Through 1,3‐Dipolar Cycloaddition Reactions

A simple, straightforward, and versatile protocol for the synthesis of spiro indanone pyrrolidine/piperidine fused nitrochromene derivatives is described. The synthesis of a new series of spirocyclic molecules has been expediently accomplished via a one‐pot, three component 1,3‐dipolar cycloaddition reaction. 2‐Phenyl‐nitrochromene dipolarophiles were reacted with azomethine ylides, generated in situ by the condensation of dicarbonyl compound indane‐1,3‐dione and secondary amino acid (L‐proline/pipecolic acid), to produce the corresponding cycloadducts in good yields (85–90%) under classical as well as under microwave irradiation. The cycloaddition reaction was found to be highly regiospecific and diasterospecific. The regiochemical and sterochemical outcome of the cycloaddition reaction is ascertained by 2D NMR (COSY and NOESY) studies.     

Mechanochemical synthesis and cycloaddition reactions of fluoro nitrone under solvent‐free conditions and potential antimicrobial activities of the cycloadducts

Synthesis and cycloaddition reactions of fluoro nitrone under solvent‐free conditions using ball‐milling technique have been reported. Significant change in rate and yields of the cycloadducts have been noticed compared with solvent‐free microwave‐induced reactions of fluoro nitrones. The present study reports synthesis of N‐benzyl fluoro nitrone and its cycloaddition reactions with maleimides and few electron deficient alkynes under solvent‐free conditions. The synthesized fluoro cycloadducts were found to exhibit potential antimicrobial activities.     

A Facile One‐Pot Synthesis of Pyrrolo[1, 2‐a] Indoles by Intramolecular 1,3‐Dipolar Cycloaddition under Neat‐Microwave Irradiation

A straightforward and general approach for the stereoselective synthesis of fused pyrrolo[1,2‐a] indoles frameworks from>intramolecular 1,3‐dipolar cycloaddition using N‐alkylated Baylis–Hillman derivatives is presented. It was found that the cycloaddition proceeded efficiently under microwave irradiation in solvent‐free condition to afford highly stereoselective cycloadducts in good yield.     

Reaction of o‐Carboryne with Furans: Facile Synthesis of Carborane‐ Fused Oxanorbornenes and Their Derivatives

o‐Carboryne (1,2‐dehydro‐o‐carborane) is a very useful synthon for the synthesis of a variety of carborane‐functionalized molecules. Diels‐Alder reaction of o‐carboryne with furans gave a series of carborane‐fused oxanorbornenes in moderate to high yields using 1‐OTf‐1,2‐C₂B₁₀H₁₁ as carboryne precursor. The resultant cycloadducts can undergo hydrogenation, cyclic oxidation, bromination, [4 + 2]/[2 + 2] cycloaddition and nucleophilic ring opening reaction to afford a variety of highly functionalized carboranes that may find applications as useful basic units in medicine and materials science.     

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.     

Regioselective `One‐Pot' Synthesis of Antipodal Bis‐adducts by Heating of Solid [5,6]Fullerene‐C60‐Ih and Anthracenes,Preliminary Communication

Antipodal (`trans‐1') Diels‐Alder bis‐adducts 3 and 7 – 9 of [5,6]fullerene‐C₆₀‐I_h ( 1 ) with some anthracenes were prepared highly regioselectively by heating mixtures of the solid 1 and anthracene or of (one of) three alkyl‐substituted anthracenes in the absence of solvents (Scheme 2). Other bis‐cycloadducts were not detected, but lesser amounts of mono‐cycloadducts 2 and 4 – 6 , respectively, were also formed. Heating of solvent‐free mixtures of 1 and three other alkyl‐substituted anthracenes did not result in a detectable amount of (antipodal) bis‐cycloadducts. The antipodal bis‐adduct 7 of 1 and of 1‐methylanthracene was analyzed by X‐ray crystallography. The preparative outcome of heating of anthracenes and solid 1 parallels the result of the heating of the corresponding crystalline mono‐adducts of anthracenes and 1 . Both approaches reveal a remarkably consistent dependence of the reaction upon the presence and position of alkyl substituents at the anthracene unit. The regioselective assembly of antipodal bis‐adducts from anthracene(s) and 1 cannot be rationalized by their (inherent molecular) stability, but it indicates the crucial control of the lattice.     

Synthesis of New Spirocyclopropane and Oxadiazole Products

In explorations of synthesis and chemistry of spiroheterocycles, we found that the reaction of 2‐diazopropane with arylidene‐benzofuran‐2(3H)‐one and arylidene‐benzofuran‐3(2H)‐one derivatives generated the spirocyclopropane products. In addition to the expected cycloadducts, an unexpected oxadiazole was formed in some cases. The structures of the obtained adducts have been assigned by means of spectroscopic methods.     

Facile Access to Versatile Polyaromatic Building Blocks: Selectively Protected Benzocyclobutenedione Derivatives via Regioselective [2+2] Cycloaddition of α‐Alkoxybenzyne and Ketene Silyl Acetal

A facile, divergent access to highly oxygenated benzocyclobutene derivatives was developed via the regioselective [2+2] cycloaddition of α‐alkoxybenzynes and ketene silyl acetals. The cycloadducts could be converted to selectively protected alkoxybenzocyclobutenediones, an attractive class of compounds for the synthesis of polyaromatic compounds. As one possible application, divergent access to a regioisomer pair of sulfonylphthalides for the Hauser approach to polyaromatic compounds is described.     

One‐pot Regioselective Synthesis of Novel 1‐N‐Methyl‐spiro[2,3′]oxindole‐spiro[3,3″]‐1″‐N‐arylpyrrolidine‐2″,5″‐dione‐4‐arylpyrrolidines through Multicomponent 1,3‐Dipolar Cycloaddition Reaction of Azomethine Ylide

An atom economic and facile synthesis of novel dispiro–oxindole–pyrrolidines has been achieved via a three‐component tandem cycloaddition of azomethine ylide generated in situ from isatin and sarcosine by decarboxylative condensation with N‐aryl‐3‐benzylidene‐pyrrolidine‐2,5‐dione derivatives as dipolarophiles. The salient features of synthetic procedure are characterized by the mild reaction conditions, high yields, high regioselectivity and stereoselectivity, one‐pot procedure, and operational simplicity. This regioselectivity was assumed to be under the influence of π–π stacking interactions between the aromatic rings of azomethine ylide and N‐aryl‐3‐benzylidene‐pyrrolidine‐2,5‐diones that further control the exo–endo selectivity of the reaction 1,3‐dipolar cycloaddition. The regiochemistry and structures of the cycloadducts were determined with spectroscopic data.     

Organocatalytic Enantioselective Higher‐Order Cycloadditions of In Situ Generated Amino Isobenzofulvenes

The [8+2] cycloaddition of indene‐2‐carbaldehydes and nitro olefins is described to provide benzonorbornene scaffolds in a highly peri‐, diastereo‐, and enantioselective fashion in the presence of a C₂‐symmetric aminocatalyst. This reaction, which proceeds through a transient semi‐aromatic amino isobenzofulvene, represents the first example of catalytic formation and transformation of these species. Quantum chemical calculations suggest a kinetically controlled stepwise mechanism where the stereochemistry is determined in the first bond‐forming event. Beyond the useful [8+2] cycloadducts, [10+4] cycloadducts have been identified in silico as potential off‐pathway intermediates.     

1,3‐Dipolar Cycloaddition of 4‐Chlorobenzonitrile Oxide with Some Dipolarophiles: Theoretical Analysis of Regioselectivity

Reaction of 4‐chlorobenzonitrile oxide ( 2 ) which was generated in situ with acrylo nitrile ( 3 ), vinyl acetate ( 4 ) and allyl bromide ( 5 ) as dipolarphile afforded the new cycloadducts 6a , 7a , and 8a compounds, respectively. Reactivity and regiochemistry of these reactions were investigated using activation energy calculations and density functional theory‐based reactivity indexes. The theoretical ¹³C NMR chemical shifts of the cycloadducts which were obtained by gauge‐invariant atomic orbital method were comparable with the observed values.     

New Studies on [2+3] Cycloadditions of Thermally Generated N‐Isopropyl‐ and N‐(4‐Methoxyphenyl)‐Substituted Azomethine Ylides

The thermal reaction of 1‐substituted 2,3‐diphenylaziridines 2 with thiobenzophenone ( 6a ) and 9H‐fluorene‐9‐thione ( 6b ) led to the corresponding 1,3‐thiazolidines (Scheme 2). Whereas the cis‐disubstituted aziridines and 6a yielded only trans‐2,4,5,5‐tetraphenyl‐1,3‐thiazolidines of type 7 , the analogous reaction with 6b gave a mixture of trans‐ and cis‐2,4‐diphenyl‐1,3‐thiazolidines 7 and 8 . During chromatography on SiO₂, the trans‐configured spiro[9H‐fluorene‐9,5′‐[1,3]thiazolidines] 7c and 7d isomerized to the cis‐isomers. The substituent at N(1) of the aziridine influences the reaction rate significantly, i.e., the more sterically demanding the substituent the slower the reaction. The reaction of cis‐2,3‐diphenylaziridines 2 with dimethyl azodicarboxylate ( 9 ) and dimethyl acetylenedicarboxylate ( 11 ) gave the trans‐cycloadducts 10 and 12 , respectively (Schemes 3 and 4). In the latter case, a partial dehydrogenation led to the corresponding pyrroles. Two stereoisomeric cycloadducts, 15 and 16 , with a trans‐relationship of the Ph groups were obtained from the reaction with dimethyl fumarate ( 14 ; Scheme 5); with dimethyl maleate ( 17 ), the expected cycloadduct 18 together with the 2,3‐dihydropyrrole 19 was obtained (Scheme 6). The structures of the cycloadducts 7b, 8a, 15b , and 16b were established by X‐ray crystallography.     

Photocycloaddition of Six‐Membered Cyclic Enones to Propen‐2‐yl Isocyanate

On irradiation in the presence of propen‐2‐yl isocyanate ( 4 ), six‐membered cyclic enones 3 are converted into regio‐ and stereoisomeric mixtures of [2+2] cycloadducts 5 – 10 ; the preferentially formed HT products, 5 – 8 , can be converted into the corresponding bicyclic amines by acid hydrolysis, whereas, under these conditions, the regioisomeric HH‐isocyanato derivatives undergo a retro‐Mannich reaction.     

The Synthesis of Naphthosultine and Benzodisultines and Their Pyrolysis with Dienophiles: Studies on o‐Naphthoquinodimethane and Bis‐o‐Quinodimethane

Sealed tube reactions of the naphthosultine 8 with a series of electron‐deficient dienophiles (fumaronitrile, N‐phenylmaleimide, dimethyl fumarate, and dimethyl acetylenedicarboxylate) in toluene at 180 °C gave corresponding 1:1 cycloadducts 11–14 in various amounts along with rearranged naphthosulfolene 7 in 67–95% yields. The reaction of 1,2,4,5‐tetra(bromomethyl)benzene with Rongalite (sodium form aldehyde sulfoxylate) and tetrabutylammonium bromide in DMF gave benzodisultines 17 and 18 in a combined yield of 56%. Sealed tube reactions of benzodisultines 17 and 18 with a series of dienophiles in xylene at 200 °C gave corresponding 1:1 and 1:2 cycloadducts 20–27 . The results suggested that thermal extrusion of sulfurdioxide from these sultines led to either o‐naphthoquinodimethane 6 (from 8 ) or bis‐o‐quinodimethane 19 (from 17 and 18 ); sub sequent trapping of these reactive intermediates by dienophiles and SO₂ gave various 1:1 and 1:2 Diels‐Alder ad ducts in modest to excellent yields.     

1‐Phenyl‐1,2‐cyclohexadiene: Astoundingly High Enantioselectivities on Generation in a Doering–Moore–Skattebøl Reaction and Interception by Activated Olefins

The resolution of (1α,5α,6α)‐6‐bromo‐6‐fluoro‐1‐phenylbicyclo[3.1.0]hexane (rac‐ 5) provided the enantiomerically pure precursors (?)‐ 5 and (+)‐ 5 of 1‐phenyl‐1,2‐cyclohexadiene. On treatment of (?)‐ 5 with methyllithium in the presence of 2,5‐dimethylfuran, the pure (?)‐enantiomer of the [4+2] cycloadduct of 2,5‐dimethylfuran onto 1‐phenyl‐1,2‐cyclohexadiene was obtained exclusively. From this result, it is concluded that pure (M)‐1‐phenyl‐1,2‐cyclohexadiene ((M)‐ 7 ) emerged from (?)‐ 5 and was enantiospecifically intercepted to give the product. In the case of indene as trap for (M)‐ 7 , the (?)‐ and the (+)‐enantiomer of the [2+2] cycloadduct were formed in the ratio of 95:5. Highly surprising, remarkable enantioselectivities were also observed, when (M)‐ 7 was trapped with styrene to furnish two diastereomeric [2+2] cycloadducts. Hence, the achiral conformation of the diradical conceivable as intermediate cannot play a decisive part. The enantioselective generation of (M)‐ and (P)‐ 7 by the β‐elimination route was tested as well. Accordingly, 1‐bromo‐2‐phenylcyclohexene was exposed to the potassium salt of (?)‐menthol in the presence of 2,5‐dimethylfuran, and the enantiomeric [4+2] cycloadducts of the latter onto (M)‐ and (P)‐ 7 were produced in the ratio of 55:45.     

Diastereoselective 1,3‐Dipolar Cycloadditions of Chiral Derivatives of 2‐Oxoethanenitrile Oxide to Noncyclic Conjugated Symmetrical Alkenes

Asymmetric 1,3‐dipolar cycloadditions of chiral derivatives of the nitrile oxides 3a – 3c derived from (2R)‐bornane‐10,2‐sultam, (2R)‐10‐(dicyclohexylsulfamoyl)isoborneol, and (1R)‐8‐phenylmenthol, to either (E)‐stilbene 4 or dimethyl fumarate 5 , leading to the corresponding 4,5‐dihydroisoxazoles 6a – 6c and 7a – 7c in both moderate yields and diastereoselectivities, are presented. All cycloadducts were converted into the corresponding methyl esters 8 and 9 , which were used for determination of their enantiomeric purities via chiral HPLC analyses. In the case of both stilbene cycloadducts 6a and 6b , their absolute configurations were determined by X‐ray crystal‐structure analyses. These [3+2] cycloadditions suggest the participation of the thermodynamically less stable SO₂/CO syn‐conformer in the π_y approach along the C?O bond of the linear nitrile oxide 3a .     

Benzoannulation of Quinones by a Cycloaddition‐Fragmentation Approach. A Simple Synthesis of Methoxycarbonyl‐Substituted Polyacenoquinones

The cycloadducts 2A‐5A obtained from the Diels‐Alder cycloadditions of 1,2,3,4‐tetrachloro‐4,5‐dimethoxycyclopentadiene ( 1 ) with p‐benzoquinone ( 2 ), 1,4‐naphthoquinone ( 3 ), 1,4‐anthraquinone ( 4 ), and 2,3‐dicyano‐1,4‐benzoquinone ( 5 ) were subjected to the reaction with triethylamine in dichloromethane at room temperature. Cycloadducts 2A and 5A enolized to give the corresponding hydroquinones 2B and 5B , which were oxidized with DDQ to afford naphthoquinone ester 2D and anthraquinone ester 5D , respectively. In the cases of cycloadducts 3A and 4A , the enolization occurred concurrently with oxidation and fragmentation to produce directly the polyacenoquinone esters 3D and 4D , respectively. Under the same reaction condition, the unsymmetrical cycloadduct 6A derived from naphthoquinone ester 2D and 1 yielded isomeric polyacenoquinone esters 6Da and 6Db in a ratio of about 8:1.