Unusually Facile Thermal Homodienyl‐[1,5]‐Hydrogen Shift Reactions in Photochemically Generated Vinyl Aziridines

A range of photochemically generated tri‐ and tetracyclic vinyl aziridines have been found to undergo a general and surprisingly low temperature ring opening through a [1,5]‐hydrogen shift reaction. The rate of the process was found to be highly dependent on the structure and substitution around the azirdine ring and the alkene terminus, with some substrates being observed to undergo ring opening at temperatures as low as 25 °C. The rigid nature of these polycyclic systems precludes a conformational explanation of these rate differences, and an Eyring study confirmed a negligible entropic barrier to the reaction. However, the Eyring plots for two different aziridines systems showed a significant difference in their enthalpies of activation. It is therefore believed that the levels of aziridine ring strain, as well as electronic effects, are the dominant factors in this sequence.     

Regiodivergent Intermolecular [3+2] Cycloadditions of Vinyl Aziridines and Allenes: Stereospecific Synthesis of Chiral Pyrrolidines

The first rhodium‐catalyzed intermolecular [3+2] cycloaddition reaction of vinyl aziridines and allenes for the synthesis of enantioenriched functionalized pyrrolidines was realized. [3+2] cycloaddition with the proximal C=C bond of N‐allenamides gave 3‐methylene‐pyrrolidines in high regio‐ and diastereoselectivity, whereas, 2‐methylene‐pyrrolidines were obtained as the major products by the cycloadditions of vinyl aziridines with the distal C=C bond of allenes. Use of readily available starting materials, a broad substrate scope, high selectivity, mild reaction conditions, as well as versatile functionalization of the cycloadducts make this approach very practical and attractive.     

Silver(I)‐Catalyzed Hydroazidation of Ethynyl Carbinols: Synthesis of 2‐Azidoallyl Alcohols

The hydroazidation of alkynes is the most straightforward pathway to synthetically useful vinyl azides. However, a general hydroazidation of alkynes remains elusive. Herein, a chemo‐ and regioselective transformation of ethynyl carbinols into vinyl azides is described. This reaction produces a wide variety of 2‐azidoallyl alcohols with high efficiency and in good to excellent yields. These compounds constitute a new class of densely functionalized synthetic intermediates. Their synthetic potential has been demonstrated by further transformations into NH aziridines. The mechanistic aspects of the reaction will attract the attention of chemists working on alkyne chemistry and silver catalysis. The findings that are described in this paper represent significant advances in the regioselective hydroelementation of alkynes and open a new reaction manifold for exploitation.     

Modular Access to the Stereoisomers of Fused Bicyclic Azepines: Rhodium‐Catalyzed Intramolecular Stereospecific Hetero‐[5+2] Cycloaddition of Vinyl Aziridines and Alkenes

The first rhodium‐catalyzed intramolecular hetero‐[5+2] cycloaddition reaction of vinyl aziridines and alkenes was realized, wherein both internal and terminal alkenes were applicable. With this method, a variety of unique substituted chiral fused bicyclic azepines, bearing multiple contiguous stereogenic centers, were facilely accessed in a straightforward, high‐yielding, and highly stereoselective manner under mild reaction conditions. Notably, the E/Z geometry of the C?C bonds in the vinyl aziridine‐alkene substrates impact the cis/trans stereochemistry of the cycloadducts and up to six stereoisomers could be delivered.     

Catalytic Enantioselective Aza‐Benzoin Reactions of Aldehydes with 2H‐Azirines

The unprecedented enantioselective aza‐benzoin reaction of aldehydes with 2H‐azirines was developed by utilizing a chiral N‐heterocyclic carbene as the catalyst. A wide range of corresponding aziridines can be obtained in good yields with high enantioselectivities. The obtained optically active aziridines should be useful in the synthesis of other valuable molecules.     

Ring‐Opening Reactions of 3‐Aryl‐1‐benzylaziridine‐2‐carboxylates and Application to the Asymmetric Synthesis of an Amphetamine‐Type Compound

Nucleophilic ring‐opening reactions of 3‐aryl‐1‐benzylaziridine‐2‐carboxylates were examined by using O‐nucleophiles and aromatic C‐nucleophiles. The stereospecificity was found to depend on substrates and conditions used. Configuration inversion at C(3) was observed with O‐nucleophiles as a major reaction path in the ring‐opening reactions of aziridines carrying an electron‐poor aromatic moiety, whereas mixtures containing preferentially the syn‐diastereoisomer were generally obtained when electron‐rich aziridines were used (Tables 1–3). In the reactions of electron‐rich aziridines with C‐nucleophiles, S_N2 reactions yielding anti‐type products were observed (Table 4). Reductive ring‐opening reaction by catalytic hydrogenation of (+)‐trans‐(2S,3R)‐3‐(1,3‐benzodioxol‐5‐yl)aziridine‐2‐carboxylate (+)‐trans‐ 3c afforded the corresponding α‐amino acid derivative, which was smoothly transformed into (+)‐tert‐butyl [(1R)‐2‐(1,3‐benzodioxol‐5‐yl)‐1‐methylethyl]carbamate((+)‐ 14 ) with high retention of optical purity (Scheme 6).     

Visible‐Light‐Enabled Stereodivergent Synthesis of E‐ and Z‐Configured 1,4‐Dienes by Photoredox/Nickel Dual Catalysis

A stereodivergent reductive coupling reaction between allylic carbonates and vinyl triflates to furnish both E‐ and Z‐configured 1,4‐dienes has been achieved by visible‐light‐induced photoredox/nickel dual catalysis. The mild reaction conditions allow good compatibility of both vinyl triflates and allylic carbonates. Notably, the stereoselectivity of this synergistic cross‐electrophile coupling can be tuned by an appropriate photocatalyst with a suitable triplet‐state energy, providing a practical and stereodivergent means to alkene synthesis. Preliminary mechanistic studies shed some light on the coupling step as well as the control of the stereoselectivity step.     

Synthesis of Functionalized Novel α‐Amino‐β‐alkoxyphosphonates through Regioselective Ring Opening of Aziridine‐2‐phosphonates

Aziridines are highly useful compounds as building blocks for the synthesis of important organic compounds. Amino acid synthesis by aziridine ring opening reaction is a good example to the use of aziridines. Although this reaction is studied by many groups, the synthesis of amino phosphonic acids is less explored. In this study, we have carried out the ring opening reaction of aziridinyl phosphonates with a variety of alcohols including the more functional propargylic and allylic alcohols. These reactions provided functionalized α‐amino‐β‐alkoxyphosphonates in 40–91 % yield.     

Efficient Access to Chiral Trisubstituted Aziridines via Catalytic Enantioselective Aza‐Darzens Reactions

Herein, we report a Zn‐ProPhenol catalyzed aza‐Darzens reaction using chlorinated aromatic ketones as nucleophilic partners for the efficient and enantioselective construction of complex trisubstituted aziridines. The α‐chloro‐β‐aminoketone intermediates featuring a chlorinated tetrasubstituted stereocenter can be isolated in high yields and selectivities for further derivatization. Alternatively, they can be directly transformed to the corresponding aziridines in a one‐pot fashion. Of note, the reaction can be run on gram‐scale with low catalyst loading without impacting its efficiency. Moreover, this methodology was extended to α‐bromoketones which are scarcely used in enantioselective catalysis because of their sensitivity and lack of accessibility.     

Desymmetrization of meso‐N‐Sulfonylaziridines with Chiral Nonracemic Nucleophiles and Bases

The cyclohexene‐derived aziridine 7‐tosyl‐7‐azabicyclo[4.1.0]heptane ( 1 ) reacts with Grignard reagents in the presence of chiral nonracemic Cu‐catalysts to afford sulfonamides 3a – e (Scheme 3) in up to 91% ee under optimized conditions (Table 2). No activation of the aziridine by Lewis acids is required. The reaction may be extended to other bicyclic N‐sulfonylated aziridines, but aziridines derived from acyclic olefins, cyclooctene, and trinorbornene are unreactive under standard conditions (Scheme 5). Exposure of 1 to s‐BuLi in the presence of (−)‐sparteine (2.8 equiv.) affords the allylic sulfonamide 31 in 35% yield and 39% ee (Scheme 6). Under the same conditions, the aziridines 33 and 35 yield products 34 and 36 derived from intramolecular carbenoid insertion with 75 and 43% ee, respectively.     

Efficient Synthesis of 1,3‐Dithiol‐2‐one Derivatives via 4,5‐Bis(dibromomethyl)‐1,3‐dithiol‐2‐one

A series of 1,3‐dithiol‐2‐one derivatives via [4 + 2] Diels–Alder cycloaddition reaction of 4,5‐bis(dibromomethyl)‐1,3‐dithiol‐2‐one with vinyl‐substituted compounds have been synthesized. Structures of all the newly synthesized compounds are well supported by spectral data such as ¹H‐NMR, MS, and elemental analysis. The structures of IVf and IVg have been analyzed by X‐ray crystallography.     

Solid‐Phase Organic Synthesis of 1,4‐N‐Vinyl‐ and 1,4‐N‐Allyl‐Triazoles with the Sulfonate Linker

Polymer‐supported 2‐azidoethyl sulfonate and 3‐azidopropyl sulfonate reagents have been developed and applied to the solid‐phase organic synthesis of 1‐vinyl‐ and 1‐allyl‐1,2,3‐triazoles, respectively, by CuI‐mediated azide‐alkyne cycloadditions and subsequent cleavage from the polymer support through elimination reaction promoted by DBU. The advantages of this new synthetic method include simple operation and high yield of the products, as well as good stability of the reagents.     

Double Stereodifferentiation in the Catalytic Asymmetric Aziridination of Imines Prepared from α‐Chiral Amines

The catalytic asymmetric aziridination of imines and diazo compounds (AZ reaction) mediated by boroxinate catalysts derived from the VANOL and VAPOL ligands was investigated with chiral imines derived from five different chiral, disubstituted, methyl amines. The strongest matched and mismatched reactions with the two enantiomers of the catalyst were noted with disubstituted methyl amines that had one aromatic and one aliphatic substituent. The synthetic scope for the AZ reaction was examined in detail for α‐methylbenzyl amine for cis‐aziridines from α‐diazo esters and for trans‐aziridines from α‐diazo acetamides. Optically pure aziridines could be routinely obtained in good yields and with high diastereoselectivity and the minor diastereomer (if any) could be easily separated. The matched case for cis‐aziridines involved the (R)‐amine with the (S)‐ligand, but curiously, for trans‐aziridines the matched case involved the (R)‐amine with the (R)‐ligand for imines derived from benzaldehyde and n‐butanal, and the (R)‐amine with the (S)‐ligand for imines derived from the bulkier aliphatic aldehydes pivaldehyde and cyclohexane carboxaldehyde.     

Chiral Brønsted Acid‐Catalyzed Asymmetric Synthesis of N‐Aryl‐cis‐aziridine Carboxylate Esters

We report a multi‐component asymmetric Brønsted acid‐catalyzed aza‐Darzens reaction which is not limited to specific aromatic or heterocyclic aldehydes. Incorporating alkyl diazoacetates and, important for high ee's, ortho‐tert‐butoxyaniline our optimized reaction (i.e. solvent, temperature and catalyst study) affords excellent yields (61–98 %) and mostly >90 % optically active cis‐aziridines. (+)‐Chloramphenicol was generated in 4 steps from commercial starting materials. A tentative mechanism is outlined.     

Visible‐Light‐Promoted Nickel‐ and Organic‐Dye‐Cocatalyzed Formylation Reaction of Aryl Halides and Triflates and Vinyl Bromides with Diethoxyacetic Acid as a Formyl Equivalent

A simple formylation reaction of aryl halides, aryl triflates, and vinyl bromides under synergistic nickel‐ and organic‐dye‐mediated photoredox catalysis is reported. Distinct from widely used palladium‐catalyzed formylation processes, this reaction proceeds by a two‐step mechanistic sequence involving initial in situ generation of the diethoxymethyl radical from diethoxyacetic acid by a 4CzIPN‐mediated photoredox reaction. The formyl‐radical equivalent then undergoes nickel‐catalyzed substitution reactions with aryl halides and triflates and vinyl bromides to form the corresponding aldehyde products. Significantly, besides aryl bromides, less reactive aryl chlorides and triflates and vinyl halides serve as effective substrates for this process. Since the mild conditions involved in this reaction tolerate a plethora of functional groups, the process can be applied to the efficient preparation of diverse aromatic aldehydes.     

Gold‐Catalyzed Annulations of 2‐Alkynyl Benzaldehydes with Vinyl Ethers: Synthesis of Dihydronaphthalene,Isochromene, and Bicyclo[2.2.2]octane Derivatives

With the suitable selection of a gold catalyst as well as the appropriate control of the reaction conditions, various new gold‐catalyzed cyclizations of 2‐alkynyl benzaldehyde with acyclic or cyclic vinyl ethers have been developed. Acetal‐tethered dihydronaphthalene and isochromenes were obtained from the reactions of 2‐alkynyl benzaldehydes with acyclic vinyl ethers under mild conditions. And, more interestingly, the gold‐catalyzed reactions of 2‐alkynyl benzaldehyde with a cyclic vinyl ether afforded the bicyclo[2.2.2]octane derivative involving two molecules of cyclic vinyl ethers. These products contain interesting substructures that have been found in many biologically active molecules and natural products. In addition, a gold‐catalyzed homo‐dimerization of 2‐phenylethynyl benzaldehyde 1 a was observed when the reaction was carried out in the absence of vinyl ether, affording a set of separable diastereomeric products. Plausible mechanisms for these transformations are discussed; a gold‐containing benzopyrylium was regarded as the crucial intermediate by which a number of these new transformations took place.     

Continuous‐Flow Synthesis and Derivatization of Aziridines through Palladium‐Catalyzed C(sp3)−H Activation

A continuous‐flow synthesis of aziridines by palladium‐catalyzed C(sp³)?H activation is described. The new flow reaction could be combined with an aziridine‐ring‐opening reaction to give highly functionalized aliphatic amines through a consecutive process. A predictive mechanistic model was developed and used to design the C?H activation flow process and illustrates an approach towards first‐principles design based on novel catalytic reactions.     

Efficient Trapping of 1,2‐Cyclohexadienes with 1,3‐Dipoles

1,2‐Cyclohexadienes are transient intermediates that undergo rapid dimerization and intermolecular trapping with activated olefins and heteroatomic nucleophiles. Fluoride‐mediated desilylative elimination of readily accessible 6‐silylcyclohexene‐1‐triflates allows the mild, chemoselective, and functional‐group tolerant generation of cyclic allene intermediates, which undergo efficient trapping reactions with stable 1,3‐dipoles. The reactions proceed with high levels of both regio‐ and diastereoselectivity. The reaction of cyclic allenes with azides is accompanied by the facile loss of dinitrogen, resulting in the formation of tetrahydroindoles or polycylic aziridines depending on the azide employed.     

Comparing Cyclophellitol N‐Alkyl and N‐Acyl Cyclophellitol Aziridines as Activity‐Based Glycosidase Probes

The synthesis and evaluation as activity‐based probes (ABPs) of three configurationally distinct, fluorescent N‐alkyl cyclophellitol aziridine isosteres for profiling GH1 β‐glucosidase (GBA), GH27 α‐galactosidase (GLA) and GH29 α‐fucosidase (FUCA) is described. In comparison with the corresponding acyl aziridine ABPs reported previously, the alkyl aziridine ABPs are synthesized easily and are more stable in mild acidic and basic media, and are thus easier to handle. The β‐glucose‐configured alkyl aziridine ABP proves equally effective in labeling GBA as its N‐acyl counterpart, whereas the N‐acyl aziridines targeting GLA and FUCA outperform their N‐alkyl counterparts. Alkyl aziridines can therefore be an attractive alternative in retaining glycosidase ABP design, but in targeting a new retaining glycosidase both N‐alkyl and N‐acyl aziridines are best considered at the onset of a new study.     

Catalyst‐Controlled 1,2‐ and 1,1‐Arylboration of α‐Alkyl Alkenyl Arenes

Two methods are reported for the 1,2‐ and 1,1‐arylboration of α‐methyl vinyl arenes. In the case of 1,2‐arylboration, the formation of a quaternary center occurred through a rare cross‐coupling reaction of a tertiary organometallic complex. 1,1‐Arylboration was enabled by catalyst optimization and occurred through a β‐hydride elimination/reinsertion cascade. Enantioselective variants of both processes are presented as well as mechanistic investigations.