Intramolecular Schmidt Reaction Research Articles

Electrocatalytic conversion of ω-azido carboxylic acids to 1-pyrrolines via a combined process of oxidative decarboxylation and intramolecular Schmidt rearrangement

An efficient electrochemical oxidation of ω-azido carboxylic acids followed by an intramolecular Schmidt reaction for synthesis of 1-pyrroline has been reported.

Stereoselective Domino Semipinacol‐Schmidt Reaction: Diastereoselective Synthesis of 7 a‐epi‐(+)‐Lepadiformine C and Formal Synthesis of 7 a‐epi‐(−)‐Lepadiformine A

AbstractA concise approach has been developed for the diastereoselective synthesis of the azatricyclic core of (−)‐7 a‐epi‐lepadiformine A (8 a) and (−)‐7 a‐epi‐lepadiformine C (8 b) using stereoselective domino semipinacol‐Schmidt reaction as a key step. In presence of TiCl4, the oxaspiropentane‐azide derivatives underwent stereoselective domino cyclization to furnish the corresponding angularly fused azatricyclic cores in very good yields. Moreover, azatricyclic core of (−)‐7 a‐epi‐lepadiformine A has also been realized, in a stepwise manner, through the intramolecular Schmidt reaction of azido‐spirocyclobutanone intermediate. The synthetic utility of domino semipinacol‐Schmidt reaction is further shown in the diastereoselective synthesis of (+)‐7 a‐epi‐lepadiformine C (7).

Substituent effects on intramolecular Schmidt reactions: a theoretical study on the formation of bridged lactams.

The competitive formation of isomeric bridged lactams via acid-catalyzed intramolecular Schmidt reactions from 3-azidoethylcyclopentanones is explored using density functional theory (DFT) calculations, primarily performed at the M06-2X/6-311++G(d,p) level of theory. The results indicate that specific substituents installed at α-carbons can efficiently control the regioselectivity of the reaction by lone pair-cation interactions or steric hindrance reversing the main product preference, whereas cation-π interactions are not so effective.

Stereoselective and Stereospecific Triflate‐Mediated Intramolecular Schmidt Reaction: Ready Access to Alkaloid Skeletons**

AbstractThe stereoselectivity and stereospecificity of the triflate‐mediated intramolecular Schmidt reaction of substituted 3‐(1‐azidocyclohexyl)propanol derivatives leading to octahydro‐1H‐pyrrolo[1,2‐a]azepine, the structural skeleton of several important families of alkaloids such as the Stemona alkaloids, has been examined. The reaction involves an initial intramolecular SN2 reaction between the azide moiety and the triflate affording an intermediate spirocyclic aminodiazonoium salt that undergoes the expected 1,2‐shift/N2‐elimination followed by hydride‐mediated iminium salt reduction. Remarkably, chiral alcohols are converted to the azabicyclic derivative with no or limited racemization. The initial asymmetric alcohol center controls the diastereoselectivity of the whole process, leading to the formation of one out of the four possible diastereoisomers of disubstituted octahydro‐1H‐pyrrolo[1,2‐a]azepine. The origin of the stereoselectivity is rationalized based on theoretical calculations. The concise synthesis of (−)‐(cis)‐3‐propylindolizidine and (−)‐(cis)‐3‐butyllehmizidine, two alkaloids found in the venom of workers of the ant Myrmicaria melanogaster, is reported.

Stereoselective and Stereospecific Triflate-Mediated Intramolecular Schmidt Reaction: Ready Access to Alkaloid Skeletons*.

The stereoselectivity and stereospecificity of the triflate‐mediated intramolecular Schmidt reaction of substituted 3‐(1‐azidocyclohexyl)propanol derivatives leading to octahydro‐1H‐pyrrolo[1,2‐a]azepine, the structural skeleton of several important families of alkaloids such as the Stemona alkaloids, has been examined. The reaction involves an initial intramolecular SN2 reaction between the azide moiety and the triflate affording an intermediate spirocyclic aminodiazonoium salt that undergoes the expected 1,2‐shift/N2‐elimination followed by hydride‐mediated iminium salt reduction. Remarkably, chiral alcohols are converted to the azabicyclic derivative with no or limited racemization. The initial asymmetric alcohol center controls the diastereoselectivity of the whole process, leading to the formation of one out of the four possible diastereoisomers of disubstituted octahydro‐1H‐pyrrolo[1,2‐a]azepine. The origin of the stereoselectivity is rationalized based on theoretical calculations. The concise synthesis of (−)‐(cis)‐3‐propylindolizidine and (−)‐(cis)‐3‐butyllehmizidine, two alkaloids found in the venom of workers of the ant Myrmicaria melanogaster, is reported.

Dynamic Effects in Intramolecular Schmidt Reactions: Entropy, Electrostatic Drag, and Selectivity Prediction.

Electrostatic drag in the intramolecular Schmidt reactions of azidopropylcyclohexanones is characterized using density functional theory (DFT) calculations and direct dynamics simulations. Despite resulting from enthalpically favorable interactions, electrostatic drag slows down N2 loss during formation of bridged lactam products, an effect with implications for controlling product selectivity.

An Intramolecular Schmidt Reaction of δ-Azido N-Acylbenzotriazoles.

A Lewis acid promoted intramolecular Schmidt reaction of N-acylbenzotriazoles with alkyl azides was designed and realized. The benzotriazole was not only employed as an efficient activator for initiating the Schmidt rearrangement but also used as a powerful terminator for the subsequent nucleophilic trapping of the isocyanate ion and/or N-acyliminium ion from the rearrangement. Thirteen δ-azido N-acylbenzotriazoles were investigated, and the conversion afforded the desired benzotriazole-1-carboxamides and lactams with good to excellent yields.

Intramolecular Schmidt Reaction of Alkyl Azides with Pentafluorophenyl Esters

Intramolecular Schmidt Reaction of Alkyl Azides with Pentafluorophenyl Esters

Designing Reactions with Post-Transition-State Bifurcations: Asynchronous Nitrene Insertions into C–C σ Bonds

Summary Discoveries of chemical reactions with potential energy surfaces with post-transition-state bifurcations are increasing in frequency. Although such potential energy surface features are often discovered accidentally, we demonstrate here that they can be designed rationally. We describe a process for designing such reactions and apply it to the design of a nitrene addition/alkyl-shift reaction with a post-transition state bifurcation. We examine substituent effects on this reaction and propose a dynamics-based model for selectivity control.

Tf2O-Promoted Intramolecular Schmidt Reaction of the ω-Azido Carboxylic Acids.

A designed Tf2O-promoted intramolecular Schmidt reaction of 2-substituted ω-azido carboxylic acids was demonstrated. Tf2O was used as an activation reagent for the carboxylic acid, and ω-azido anhydride was in situ generated, releasing a molecular TfOH, which acted as an acid promoter for the Schmidt process. A series of 2-substituted pyrrolidines was produced and acetylated for better purification. The strategy was also efficient for conversion of a 4-substituted ω-azido carboxylic acid to the tricyclic lactam.

Divergent Synthesis of Solanidine and 22-epi-Solanidine.

A divergent synthesis of solanidine and 22-epi-solanidine, two 25S natural steroidal alkaloids, from 25R-configured diosgenin acetate, is described. Initially, solanidine was synthesized through a series of transformations including a cascade ring-switching process of furostan-26-acid, an epimerization of C25 controlled by the conformation of six-membered lactone ring, an intramolecular Schmidt reaction, and an imine reduction/intramolecular aminolysis process. To address the epimerization issue during Schmidt reaction, an improved synthesis was developed, which also led to a synthesis of 22-epi-solanidine. In this synthesis, selective transformation of azido lactone to azido diol and amino diol was realized through a reduction relay tactic. The azido diol was transformed to solanidine via an intramolecular Schmidt reaction/N-alkylation/reduction process and to 22-epi-solanidine via an intramolecular double N-alkylation process.

Synthesis of Demissidine and Solanidine.

Demissidine and solanidine, two steroidal alkaloids, are synthesized in eight steps from tigogenin acetate and diosgenin acetate, respectively, which involve the replacement of three C-O bonds with C-N bonds. Key transformations include a cascade ring-switching process of furostan-26-acid, an epimerization of C25, an intramolecular Schmidt reaction, and an imine reduction/intramolecular aminolysis process.

Practical Electrochemical Anodic Oxidation of Polycyclic Lactams for Late Stage Functionalization.

Electrochemistry provides a powerful tool for the late-stage functionalization of complex lactams. A two-stage protocol for converting lactams, many of which can be prepared through the intramolecular Schmidt reaction of keto azides, is presented. In the first step, anodic oxidation in MeOH using a repurposed power source provides a convenient route to lactams bearing a methoxy group adjacent to nitrogen. Treatment of these intermediates with a Lewis acid in dichloromethane permits the regeneration of a reactive acyliminium ion that is then reacted with a range of nucleophilic species.

Practical Electrochemical Anodic Oxidation of Polycyclic Lactams for Late Stage Functionalization

AbstractElectrochemistry provides a powerful tool for the late‐stage functionalization of complex lactams. A two‐stage protocol for converting lactams, many of which can be prepared through the intramolecular Schmidt reaction of keto azides, is presented. In the first step, anodic oxidation in MeOH using a repurposed power source provides a convenient route to lactams bearing a methoxy group adjacent to nitrogen. Treatment of these intermediates with a Lewis acid in dichloromethane permits the regeneration of a reactive acyliminium ion that is then reacted with a range of nucleophilic species.

ChemInform Abstract: Intramolecular Schmidt Reaction of Acyl Chlorides with Alkyl Azides: Preparation of Pyrrolizine by Intramolecular Capture of Intermediates with Alkenes or Alkynes.

AbstractThe intramolecular capture of the corresponding isocyanate ions, generated from (I), (IV) and (VIII), as well as the N‐acyliminium ion from (VI) with alkene and alkyne units is described.

ChemInform Abstract: Total Synthesis of Unsaturated Imine Venom Alkaloids of Costa Rican Ant by Way of Schmidt Reaction via Allyl/Pentadienyl Cations.

Total synthesis of α,β-, and α,β,γ,δ-unsaturated imine ant venom alkaloids is described. The labile two conjugated imine alkaloids were synthesized by late stage intramolecular Schmidt reaction via allyl and pentadienyl cation intermediates.

Intramolecular Schmidt reaction of acyl chlorides with alkyl azides: preparation of pyrrolizine by intramolecular capture of intermediates with alkenes or alkynes.

The preparation of substituted pyrrolizines through the Schmidt reaction of acyl chlorides with alkyl azides has been realized. Intramolecular capture of the isocyanate ion and N-acyliminium ion intermediates from the Schmidt process with alkene or alkyne units was achieved, and the efficiency of the conversion with respect to ring construction and bond formation was demonstrated.

Temperature dependence of turnover in a Sc(OTf)3-catalyzed intramolecular Schmidt reaction Dedicated to the memory of Harry Wasserman, an inspirational person and a most elegant scholar

Temperature dependence of turnover in a Sc(OTf)3-catalyzed intramolecular Schmidt reaction Dedicated to the memory of Harry Wasserman, an inspirational person and a most elegant scholar

Temperature dependence of turnover in a Sc(OTf)3-catalyzed intramolecular Schmidt reaction

The intramolecular Schmidt reaction of ketones and tethered azides is an efficient method for the generation of amides and lactams. This reaction is catalyzed by Lewis acids, which tightly bind the strongly basic amide product and result in product inhibition. We report herein conditions to achieve a catalytic Schmidt reaction using substoichiometric amounts of the heat-stable Lewis acid Sc(OTf)3. This species was shown to effectively release products of the Schmidt reaction in a temperature-dependent fashion. Thus, heat was able to promote catalyst turnover. A brief substrate scope was conducted using these conditions.

ChemInform Abstract: Intramolecular Schmidt Reaction of Acyl Chlorides with Alkyl Azides: Capture of N‐Acyliminium Ion Intermediates with Aromatic Rings.

Intramolecular Schmidt reaction of acyl chlorides with alkyl azides through N-acyliminium ion intermediates is designed and realized. The intramolecular capture of the intermediates with aromatic rings affords several nitrogen-containing tricyclic skeletons. The important feature of the domino process is the efficiency in bond reorganization and ring formation.