Yu, Diana

Detailed kinetic analysis for the Cu(I)-catalyzed Kinugasa reaction forming β-lactams has revealed an anomalous overall zero-order reaction profile, due to opposing positive and negative orders in nitrone and alkyne, respectively. Furthermore, the reaction displays a second-order dependence on the catalyst, confirming the critical involvement of a postulated bis-Cu complex. Finally, reaction progress analysis of multiple byproducts has allowed a new mechanism, involving a common ketene intermediate to be delineated. Our results demonstrate that β-lactam synthesis through the Kinugasa reaction proceeds via a cascade involving (3 + 2) cycloaddition, (3 + 2) cycloreversion, and finally (2 + 2) cycloaddition. Our new mechanistic understanding has resulted in optimized reaction conditions to dramatically improve the yield of the target β-lactams and provides the first consistent mechanistic model to account for the formation of all common byproducts of the Kinugasa reaction.

Continuing developments in the elucidation techniques of complex catalytic processes is of foremost importance to modern synthetic chemistry, and the identification of efficient synthetic techniques relies on precise, reliable, and adaptable methods to dissect the mechanism of a given transformation. Currently, methods of reaction development are grounded upon the systematic modification of specific variables—such as temperature, time, concentration, etc.—to account for and control the dynamic series of coupled equilibria within a catalytic environment. On the other hand, tandem reaction analytical methods that involve the concomitant use of different instruments to probe a reaction can provide time-resolved information regarding active chemical species and facilitate the interrogation and optimization of the system. Herein, we report our study applying tandem in situ ReactIR and HPLC-MS monitoring to the dysprosium(III) triflate-catalyzed aza-Piancatelli rearrangement of 2-furylcarbinols, a reaction that grants access to trans-4,5-disubstituted cyclopentenones—common motifs in important biologically relevant and natural compounds. With a prototype automated sampling apparatus, information was obtained about the intrinsic chemoselectivity of the reaction, and previously unseen intermediates were observed, allowing for a more detailed reaction mechanism to be substantiated. The advantages of applying this type of tandem measurement to study these types of systems are also discussed.

A mechanistic study of a new heterocycloisomerization reaction that forms annulated aminopyrroles is presented. Density functional theory calculations and kinetic studies suggest the reaction is catalyzed by trace copper salts and that a Z- to E-hydrazone isomerization occurs through an enehydrazine intermediate before the rate-determining cyclization of the hydrazone onto the alkyne group. The aminopyrrole products are obtained in 36–93% isolated yield depending on the nature of the alkynyl substituent. A new automated sampling technique was developed to obtain robust mechanistic data.

Kinetic studies were conducted on three unrelated reaction types using traditional and modified reaction monitoring tools. The Aza-Piancatelli rearrangement was studied through ReactIR and HPLC-MS to obtain a better understanding of why the substrate scope was limited. It was found that the Lewis acid catalyzed reaction is often zero-order, dependent on the lanthanide metal used. Off-cycle binding of the nucleophile to the Lewis acid was proposed to help explain the zero-order profile. Differences between Lewis and Brønsted acid catalysts were found through subsequent experiments assessing catalyst deactivation and the chemoselectivity of the products in the Aza-Piancatelli rearrangement. An automated sampling system was created for hands-free reaction monitoring and offline analysis by HPLC-MS to provide detailed information about more complicated reactions. The automated sampling system was modified for the study of microwave assisted reactions. This application allowed for more information to be derived from the field of poorly-understood microwave chemistry than allowed by previous technology. Comparisons were made between microwave-assisted and conventionally heated reactions, using a Claisen rearrangement as a model reaction. As expected, it was found that the Claisen rearrangement of allylphenyl ethers displayed similar kinetics between the two heating modes. The technology was also used briefly to search for the existence of non-thermal effects. It was shown that the sampling apparatus could be useful for collecting data observed from microwave-specific effects. Mechanistic studies were also conducted on the Kinugasa reaction to obtain a better understanding of why the reaction generally behaves poorly in regards to the formation of β-lactam product. To study the reaction, samples for HPLC-MS analysis were taken manually, then by a liquid handler, and then through direct-injection to the HPLC. It was found that its side-product formation was directly coupled to the desired product formation, suggesting that both the product and imine side-product stem from a common intermediate. Another little-known side-product was isolated, suggesting the common intermediate could be intercepted by select nucleophiles to form an amide. This finding will direct future attempts to find conditions to favor either β-lactam or amide formation.