MTCiting: Pharmaceutical R&D

The NLRP3 inflammasome is a multiprotein complex that functions as an immune-system sensor and modulating its activity has therapeutic potential in treating inflammatory and autoimmune disorders. Sulfonimidamides have emerged as attractive modulators enabling fine-tuning of inflammasome activity and these compounds can be diversified by coupling them to aryl isocyanates using a urea linker. To achieve this, anilines are converted to aryl isocyanates, which are in turn reacted with various sulfonimidamides to yield urea-bridged analogs. Whereas isocyanate formation and urea coupling are straightforward, scale-up of the tricyclo[6.2.0.0³,⁶]deca-1,3(6),7-trien-2-amine (aniline) building block synthesis is quite challenging.  

The work described in this paper focuses on a practical scalable route to the desired amine. The researchers report that the key step in this development uses a Parham cyclization, transforming a halogenated benzocyclobutene to the tricyclic aniline scaffold through intramolecular metal–halogen exchange and subsequent cyclization. In this route, an organolithium intermediate is synthesized at low temperature, and two successive ring closures yield the benzocyclobutene core. Optimizing this cyclization through careful reaction parameter control was critical to reduce competing E2 elimination pathways.

In kinetic studies using ReactIR and an EasyMax102 LT, it was determined that maintaining the reaction below –70 °C during halogen–metal exchange was critical to suppress E2 elimination, and provide the benzocyclobutene intermediate in excellent yield. At those temperatures, slow, controlled addition of 3.0 equivalents of n-butyllithium resulted in optimal reactivity and selectivity for the two back-to-back cyclizations, without significant side-product formation. The authors comment that discovering these conditions would have be quite difficult using traditional offline analysis methods. Further, they state “We believe this example highlights the value of in-situ FTIR technology as a powerful tool for process chemists to efficiently identify the critical reaction parameters−while minimizing the consumption of valuable intermediates in the early development space” 

Jermaks, J., Zhang, H., Malig, T. C., Lim, N., Burkhard, J. A., Han, C., & Gosselin, F. (2025). Optimization of a Parham Cyclization Aided by In Situ FTIR for an Enabling Synthesis of Tricyclo[6.2.0.03,6]deca-1,3(6),7-trien-2-amine. Organic Process Research & Development. https://doi.org/10.1021/acs.oprd.5c00181

Methods to produce saturated carbocycles with high diastereo- and enantiocontrol are important for the synthesis of pharmaceutical and natural products. The authors point out that cyclobutanes are achiral and cyclopentanes are part of steroid or prostaglandin frameworks. Further, the lack of diversity in synthesis is due to the difficulty in controlling stereochemistry and substitution pattern. They proposed that a stereospecific method to synthesize cycloalkyl boronic esters could result in the development of useful building blocks after derivatization of the C–B bonds. Though lithiation-borylations have been used in the synthesis of acyclic carbon chains, intramolecular lithiation-borylation has not been applied to the stereocontrolled synthesis of carbocycles. In this study, benzylic diethylcarbamates having a tethered vicinal bis‑boronic ester undergo lithium amide–mediated deprotonation, cyclization, and 1,2‑metallate rearrangement to form carbocycles. The intramolecular lithiation–borylation is fully regioselective and diastereoconvergent, preserving boronic ester stereochemistry while epimerizing the benzylic center. This yields carbocycles with high diastereo‑ and enantiocontrol from simple precursors.

In mechanistic investigations supporting this work, ReactIR measurements monitored the reaction of a diethylcarbamate with a tethered vicinal bis-boronic ester. The in-situ FTIR measurements performed at low temperature showed that the starting carbamate was rapidly consumed and that neither the pre-lithiation complex nor the lithiated carbamate were observed, but rather a second peak formed that was identified as a boronate intermediate complex.

Cope, C. J., Zanini, M., George, M. R. P., Otero, D., Sendra, J., Noble, A., Lefranc, J., Robiette, R., & Aggarwal, V. K. (2025). Intramolecular Lithiation‐Borylation for the stereoselective synthesis of cyclopentyl and cyclobutyl Bis‐Boronic esters. Angewandte Chemie International Edition. https://doi.org/10.1002/anie.202512896