Deciphering complexity in Pd-catalyzed cross-couplings

Abstract

Understanding complex reaction systems is critical in chemistry. While synthetic methods for selective formation of products are sought after, oftentimes it is the full reaction signature, i.e., complete profile of products/side-products, that informs mechanistic rationale and accelerates discovery chemistry. Here, we report a methodology using high-throughput experimentation and multivariate data analysis to examine the full signature of one of the most complicated chemical reactions catalyzed by palladium known in the chemical literature. A model Pd-catalyzed reaction was selected involving functionalization of 2-bromo-N-phenylbenzamide and multiple bond activation pathways. Principal component analysis, correspondence analysis and heatmaps with hierarchical clustering reveal the factors contributing to the variance in product distributions and show associations between solvents and reaction products. Using robust data from experiments performed with eight solvents, for four different reaction times at five different temperatures, we correlate side-products to a major dominant N-phenyl phenanthridinone product, and many other side products.

Fig. 1. Synthesis of N-substituted phenanthridinones 2 from 2-bromo-benzamides 1—a formal redox-neutral dimerization and deamidation process.

Key: The blue color in structures 1 and 2 shows the origin of the benzo-moiety. The colored disconnection bonds show different bond sites for activation by the catalyst system. Other generic colors are used to guide the eye to multiple products being formed and HTE screening positions in batch mode.

Fig. 2. Proposed reaction mechanism for the formation of N-substituted phenanthridinones 2, along with confirmatory studies (this work).

The blue color in compounds shows the origin of the benzo-moiety. A Catalytic cycle as proposed by Porée et al.—we note that discrete steps connecting D and E are required. B Reported by-products and side-products. Note: that the relationship of PPh₃ to all intermediates is not shown, but it is likely involved in various steps. C Synthesis of N-phenyl phenanthridinones 2a, 2a-d₅ and 2b. D Reaction of 1a at 80 °C in DMF mediated by Pd(OAc)₂/dppe (1:1, 5 mol%) under two different pre-catalyst regimes. The normalized kinetics show loss of 2-bromo-N-phenylbenzamide 1a at 1324 cm⁻¹ monitored using a Mettler-Toledo ReactIR/silicon probe. Red square - catalyst pre stir at 20 °C; black square—catalyst pre-stir at 80 °C.

Fig. 3. A full survey of the reaction products detected by analytical methods (LC-MS and GC-MS).

The blue color in compounds shows the origin of the benzo-moiety.

Fig. 4. Scores plots for the first two principal components obtained with UV-scaled data from experiments performed in 8 different solvent systems.

The plot in (A) shows experiments performed at 110 °C for four different reaction times whereas (B) shows 2-h reactions performed at five different temperatures. The loadings, shown as vectors in the insets, indicate the contribution of the various products to the principal components.

Fig. 5. Scores plots for the first two principal components obtained after removing outliers from UV-scaled data from experiments performed in 8 different solvent systems.

The plot in (A) shows experiments performed at 110 °C for four different reaction times whereas (B) shows 2-h reactions performed at five different temperatures. In both cases, 13 observations were removed. The loadings, shown as vectors in the insets, indicate the contribution of the various products to the principal components.

Fig. 6. Further data analysis.

A Correspondence analysis biplot showing associations between solvents and reaction products. Key: Dim = dimension. The number of experiments (after combining replicate analyses) with high (black), medium (orange), and low (light green) quantities for each product are used in the analysis. B Bubble plot showing the number of experiments with quantities above two-thirds of the range for the product by solvent. Bubble sizes are proportional to the number of experiments, also shown where the maximum possible is 20 (i.e., 5 temperatures for 4 reaction times).

Fig. 7. Heatmap showing correlations between products across reactions, including all solvents, reaction times and temperatures.

Median values of replicate observations were used in the analysis. Key: red boxes are positive correlations and blue boxes are negative correlations (see color bar, upper left). The reaction products are ordered using hierarchical clustering, resulting in the dendrograms shown in the margins, so that similar products cluster together. The map colors show the strength of correlation, as indicated by the color bar. Specific clusters of compounds are highlighted by colored boxes, representing selected interactions.

Fig. 8. Stoichiometric palladium reactivity studies using substrate 1a.

³¹P NMR (203 MHz, DMF-d₇) spectral changes and confirmation of derived (pseudo)molecular ions by ESI-MS: (1) Pd₂dba₃·CHCl₃ and dppe taken at rt, t = 0 min; (2) taken after addition of 2-bromo-benzamide 1a at rt, t = 5 min; (3) taken after 45 min heating at 80 °C; (4) taken after 16 h heating at 80 °C. We have assigned species to five phosphorus species, cross-referenced with the ESI-MS analysis (simulated ions shown in red; experimental ions in blue). The species at δ 57.35 is a trace product, derived from the formation of Pd⁰(dba)(dppe)/Pd⁰(dppe)₂, which is distinct to the species at δ 56.77 ppm, formed at higher temperature, assigned to PdBr₂(dppe) VIII.

Fig. 9. Detailed catalytic cycle for the formation of phenanthridinone 2a.

Key: O.A. oxidative addition, R.E. reductive elimination, RDS is rate determining step. We expect all steps resulting in loss of HBr to involve base. Potential catalytic cycles for selected side-products, based on the correlations revealed by the rich data analysis (from heat maps and hierarchical clustering; highlighted by appropriate colors). We expect all steps resulting in loss of HBr to involve base. We do not preclude dppeO being an alternative ligand for Pd in these catalytic cycles, especially in solvents where there is no other potential reductant, i.e., where phosphine ligand becomes the obvious reductant. The blue color in the chemical structures shows the origin of the benzo-moiety.