Research Article Cite This: ACS Catal. 2019, 9, 5623−5630
pubs.acs.org/acscatalysis
Overcoming Scope Limitations in Cross-Coupling of Diazo Nucleophiles by Manipulating Catalyst Speciation and Using Flow Diazo Generation Ryan J. Sullivan, Garrett P. R. Freure, and Stephen G. Newman* Centre for Catalysis Research and Innovation, Department of Chemistry and Biomolecular Sciences, University of Ottawa, 10 Marie-Curie, Ottawa, Ontario K1N 6N5, Canada Downloaded via BUFFALO STATE on July 23, 2019 at 09:39:42 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
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ABSTRACT: The accessible scope of palladium-catalyzed diazo cross-coupling reactions has been expanded to include aryl chlorides by controlled diazo slow addition. The success of this strategy is based on manipulating speciation within the catalytic cycle through starvation of the diazo reagent to make the Pd(II) oxidative intermediate the resting state. The strategy is also applicable to cross-coupling reactions with aryl bromides and, in combination with safe, on-demand flow generation of nonstabilized diazo reagents, has been used to greatly expand the scope of applicable diazo compounds for this chemistry as well. Lastly, DFT calculations have provided insight into the mechanism and support for the proposed explanation for success of the slow addition strategy. KEYWORDS: palladium, diazo cross-coupling, slow addition, flow chemistry, nonstabilized diazo, DFT
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reported until 2010.11 This reaction was efficient only when using aryl iodides; extension to aryl bromides required high catalyst loadings, and aryl chlorides, which sluggishly undergo oxidative addition,12 have not yet been reported. Previous mechanistic studies on the Pd-catalyzed coupling of aryl halides with diazo compounds suggest that oxidative addition may be the rate-determining step,11 which precedes reaction with the diazo compound. Diazos are known to undergo numerous other reactions, including unimolecular decomposition13 and direct interaction with Pd(0).14 Given the sparsity of organobromides and the absence of aryl chlorides being used in Pd-catalyzed reactions with diazo compounds, substrate decomposition may be occurring faster than turnover-limiting oxidative addition with these less reactive organohalide electrophiles (Scheme 1b). Our group previously addressed a conceptually similar problem in Kumada−Corriu cross-coupling of aryl chlorides substituted with electrophilic groups (e.g., ketones, esters, etc.).15 Excellent selectivity for the cross-coupling product was achieved by manipulating the resting state of the catalyst through starvation of Grignard reagent, which was added dropwise at approximately the same rate as catalyst turnover. We hypothesized that a similar approach could be used to minimize exposure of diazo to reaction conditions in the absence of Pd(II) oxidative addition intermediate by manipulating the speciation along the catalytic cycle through
INTRODUCTION Despite being known for half a century, Pd-catalyzed crosscoupling reactions continue to grow in scope with an increasing diversity in the types of coupling partners. The use of N-tosylhydrazones is a recent, powerful example. First reported in 2007 by Barluenga and co-workers, these substrates react with catalytic Pd in the presence of strong base to form 1,1-disubstituted olefins (Scheme 1a).1 The reaction is proposed to occur by in situ formation of a diazo species, which reacts with the oxidative addition product of Pd(0) and an organohalide. Due to the high importance of polysubstituted olefins2 and the tendency for Mizoroki−Heck and related reactions to favor trans-1,2-substitution patterns with, e.g., styrene coupling partners,3 the reaction of N-tosylhydrazones with aryl halides has been used for the synthesis of diverse heterocycles, natural products, and bioactive molecules.4 Pioneering work by Van Vranken,5 Wang,6 and others has shown that diazo species can be used directly in Pd(0)catalyzed cross-coupling reactions,7 often in the absence of strong base and with shorter reaction times compared to analogous reactions of N-tosylhydrazones. We hypothesized that two scope limitations are hindering the more widespread application of this direct, efficient cross-coupling. First, most reports are limited to using stabilized diazo species such as αdiazocarbonyls. Second, only specific organohalides are reported, such as cis-vinyl iodides,8 benzyl or allyl halides,9 and, rarely, aryl iodides.10 While the two component coupling of traditional aryl halide electrophiles and diazo compounds is perhaps the most intuitive variant of this reaction, it was not © 2019 American Chemical Society
Received: March 21, 2019 Revised: May 6, 2019 Published: May 23, 2019 5623
DOI: 10.1021/acscatal.9b01180 ACS Catal. 2019, 9, 5623−5630
Research Article
ACS Catalysis
reagent decomposes while awaiting the rate-determining formation of the oxidative addition complex, further experiments were carried out with the ethyl 2-diazopropanoate added by syringe pump. With Pd(allyl)Cl dimer (2.5 mol %) and XPhos (10 mol %) as a catalyst, a strong correlation was observed between the addition rate of the diazo and the yield of the reaction (Scheme 2). While only trace product was observed when adding the diazo quickly, an 80% yield was achieved by adding over a period of 3 h.
Scheme 1. Development of Cross-Coupling Reactions Involving Pd-Carbene Intermediates
Scheme 2. Effect of Diazo Addition Rate on Product Yield for the Cross-Coupling of Ethyl 2-Diazopropanoate with Aryl Chloridesa
starvation of diazo nucleophile. In this way, the Pd(II) oxidative addition intermediate becomes the catalyst resting state, ensuring its continuous presence to react with incoming diazo compound that is added dropwise. Herein, we describe how this strategy enables productive cross-coupling reactions with unactivated aryl chlorides and bromides at reasonable catalyst loadings. Furthermore, the limitations on the types of diazo coupling partners that can be used are simultaneously addressed. While nonstabilized diazos are hazardous and prone to decomposition, reports from Ley, Charette, Kappe, and others have demonstrated that these species can be safely and efficiently used if generated ondemand, for example, by continuously oxidizing well-behaved hydrazones over MnO2 and immediately using the reactive products.16 This strategy lends itself to highly exothermic reactions that benefit from slow addition, as is the case with diazo cross-couplings. These two strategieson-demand diazo synthesis and artificial manipulation of the catalyst resting stateprovide a substantial expansion in the scope of this reaction, which is reported for the first time using diverse nonstabilized diazo reagents and with aryl bromides and chlorides (Scheme 1c).
a
Conditions: 0.2 mmol of ArCl, 3 equiv of iPr2NH, [Pd(allyl)Cl]2 (2.5%), XPhos (10%) in toluene (1 mL) at 100 °C, 1.5 equiv of ethyl 2-diazopropanoate in toluene (1 mL) added by syringe pump and stirred 15 additional min after addition was complete. Yield determined by proton NMR of crude mixture with 1,3,5trimethoxybenzene as internal standard. Dotted lines are added for assistance with visualization only.
To further investigate the relationship between the diazo addition rate and yield, reactions between ethyl 2-diazopropanoate with an electron-poor (4-chlorobenzonitrile) and electron-rich (4-chloroanisole) aryl chloride were investigated. As was the case with chlorobenzene, both substrates exhibited an increase in yield with controlled diazo addition, with substantially different optimal rates depending on the electronic nature of the substituent on the aryl chloride. For 4-chlorobenzonitrile, a 63% yield could already be achieved if the diazo reagent was added in one dose at the start of the reaction, whereas only trace product could be achieved in this manner when using 4-chloroanisole. With diazo reagent added over a period of 30 min or longer, ∼90% yield was achieved for 4-chlorobenzonitrile, while for 4-chloroanisole only moderate yield was achieved even with diazo added over 5 h. These results provided strong support for both initial hypotheses. Desired products could be produced from aryl chlorides as long as diazo was added slowly over the duration of the reaction. The optimal addition rate may be approximating catalyst turnover rate, ensuring that the Pd(II) oxidative addition intermediate is always present to react with
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RESULTS AND DISCUSSION The cross-coupling of ethyl 2-diazopropanoate with chlorobenzene was initially examined as a challenging reaction due to the reluctancy of aryl chlorides to undergo oxidative addition. Reaction conditions developed by Wang and coworkers for related couplings of aryl bromides were found to be ineffective.11 On the basis of the hypothesis that the diazo 5624
DOI: 10.1021/acscatal.9b01180 ACS Catal. 2019, 9, 5623−5630
Research Article
ACS Catalysis
Attention was next turned to expanding the scope of the diazo compounds with the use of nonstabilized diazo reagents. It is unsurprising that previous reports on these direct crosscoupling reactions are primarily limited to well-behaved αdiazo carbonyl compounds, since these species are isolable, less prone to decomposition, and, in many cases, commercial. Nonstabilized diazo reagents on the other hand present considerable safety risks during their preparation and isolation due to a tendency to (explosively) decompose.17 For crosscoupling with aryl halides, these less stable diazo species should also be particularly challenging substrates due to faster background decomposition reactions than the stabilized analogues. Nonetheless, we believed that these challenges could be overcome with the combination of slow diazo addition and flow chemistry for safe, “on-demand” diazo generation. We selected the strategy reported by Ley and co-workers for the generation of nonstabilized α-aryl diazo compounds by the continuous flow oxidation of hydrazones over MnO2 for this purpose.16d,e The literature protocol reported the production of diazo compounds in methylene chloride using short contact times (
