Mild and Rapid Pd‐Catalyzed Cross‐Coupling with Hydrazine in Continuous Flow: Application to the Synthesis of Functionalized Heterocycles

Abstract

Functionalized arylhydrazines are of widespread importance as intermediates in the syntheses of nitrogen-containing heterocycles. [1] In this regard, indoles, [1,2] arylpyrazoles/pyrazolones, [1,3] and aryltriazoles, [1,4] among others, [1] can be efficiently generated from arylhydrazines. These heterocyclic motifs are prevalent structural elements in numerous compounds of significant biological/medicinal value. [5] Among current strategies to generate arylhydrazines, nucleophilic aromatic substitution to an aryl halide (ArX) [6] or diazotization of an aniline followed by reduction of the diazonium salt [7] have long been preparative methods of choice [Eq. (1)]. However, the former method typically requires an arene activated by electron-withdrawing groups, while the diazotization/reduction sequence is redox-exhaustive and involves the generation of unstable diazonium intermediates.Modern cross-coupling technology has provided chemists with powerful tools to construct carbon-nitrogen bonds, [8] and thus presents an alternative method of synthesizing aryl hydrazines. [9] Accordingly, several such cross-coupling strategies have been reported utilizing hydrazine equivalents [10] such as benzophenone hydrazone [Eq. (2)].[10a-f] The only example of direct CÀN cross-coupling with hydrazine was recently reported by Stradiotto et al. [11] While this method represented a notable advance, the reactions were set up in a nitrogen-filled glovebox and required relatively high catalyst loading (3-10 mol % Pd). More importantly, signifi-cant safety issues exist with the use of hydrazine in the presence of transition metals, particularly with heating; many metal-hydrazine complexes are known to be powerful explosives. [12] We have recently demonstrated the feasibility of C À N cross-coupling reactions in continuous flow, [13] and this strategy represents an attractive solution to minimizing the hazards associated with hydrazine/transition metal mixtures. [14,15] Described herein is a mild and potentially scalable method for the direct cross-coupling of aryl chlorides with hydrazine through the use of continuous flow technology [Eq. (3)], and the application of this technology to the rapid construction of a range of heterocyclic scaffolds.We began our investigation by carrying out several smallscale ( 0.20 mmol) batch experiments to identify suitable reaction conditions; the cross-coupling reaction of 4-chlorotoluene and a commercially available 1.0 m solution of hydrazine in THF (2.0 equiv) was selected for optimization (Table 1). A screen of precatalysts [16] revealed tBuXPhos (L2) and BrettPhos (L3) as efficient ligands in promoting the desired monoarylation of hydrazine with 3 mol % catalyst loading at 60 8C for 1 h. Under these conditions, 4-tolylhydrazine 1 was formed in high yield with high selectivity over diarylated products 2 and 3 (entries 2-4). [17,18] We subsequently found that the BrettPhos-based catalyst was extremely active as it provided 1 in 84 % yield with 1.2 equiv of hydrazine at room temperature in only 3 min...

Room‐Temperature Hydrohydrazination of Terminal Alkynes Catalyzed by Saturated Abnormal N‐Heterocyclic Carbene–Gold(I) Complexes

“…In contrast, the use of unsubstituted hydrazine has remained relatively unexplored. One of the few examples is the palladium‐catalyzed direct CN cross‐coupling with hydrazine reported by Lundgren and Stradiotto15 in 2010 and by Buchwald and co‐workers16 in 2013 for a continuous flow system. Chen et al.…”

Flow Technology for Organometallic-Mediated Synthesis

“…However, safety concerns, related to the explosive nature of transition-metal hydrazine complexes, might be taken into consideration in batch processing. Buchwald and coworkers set up a mild and potentially scalable method for the direct cross-coupling of aryl chlorides with hydrazine through the use of continuous-flow technology [78]. Clogging issues, resulting from solids forming with the aryl amination, have been avoided by ultrasonication devices.…”

Modeling mesoscale reactors for the production of fine chemicals

“…Researchers interested in gram quantities or exploratory chemistries, will simply combine streams at a tee intersection [2,5,6,[35][36][37][38][39][40]. DeAngelis [35] demonstrated the safe production of several arylhydrazines via Pd-catalyzed cross-coupling reactions. Baumann [36] cited the convenience and safety benefits of flow chemistry for the fluorination of numerous compounds.…”