Article Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
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Synergistic Effect of Copper and Ruthenium on Regioselectivity in the Alkyne−Azide Click Reaction of Internal Alkynes Sivaraj Ramasamy,† Chittibabu Petha,† Shankar Tendulkar,† Prantik Maity,† Martin D. Eastgate,‡ and Rajappa Vaidyanathan*,† †
Chemical Development and API Supply, Biocon Bristol-Myers Squibb Research and Development Center, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560099, India ‡ Chemical and Synthetic Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, New Jersey 08903, United States S Supporting Information *
ABSTRACT: Cu(I) salts have been shown to improve the regioselectivity and rate of the Ru-catalyzed alkyne−azide click reaction of internal alkynes with azides. While Cu and Ru individually provide complementary regioselectivity in the case of terminal alkynes, the synergistic effect of these two species in situ significantly improves regiochemical outcomes in the case of internal alkynes. The substrate scope of these new reaction conditions is also reported.
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INTRODUCTION The 1,2,3-triazole motif has gained widespread adoption as a structural feature within modern pharmaceuticals.1 The surge in this area can be attributed to the development of the alkyne− azide (3 + 2) cycloaddition reaction, which is also referred to as the alkyne−azide click (AAC) or the Hüisgen 1,3-dipolar cycloaddition reaction.2 Most of the initial work on this class of reactions centered on the coupling and cyclization of terminal alkynes with substituted azides to provide disubstituted 1,2,3triazoles. The original thermal cyclizations provided a mixture of regioisomeric triazoles (relative positions of the alkyl/aryl group on the acetylene and the substituent on the azide). Subsequently, the Cu-3 and Ru-mediated4 versions of this reaction (CuAAC and RuAAC, respectively) were developed to provide complementary regiochemical outcomes (Scheme 1).
RESULTS AND DISCUSSION We were interested in the regioselective synthesis of 1,4,5trisubstituted triazole 5, a key intermediate for a medicinal chemistry program. We envisioned that 5 could be accessed via a RuAAC reaction between propargylic alcohol 7 and TMSmethyl azide. Our initial attempts at this transformation provided a 2.5:1 mixture of regioisomeric triazoles 5 and 6 (entry 1, Scheme 2). As we sought to explore a larger-scale manufacturing route for this compound, we realized that this ratio needed significant enhancement. Moreover, the reaction required heating at >50 °C; the known thermal sensitivity of
Scheme 1
Scheme 2
are no reported examples of catalysis by copper (Scheme 1).2g,7,8
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The exclusive product in the CuAAC reaction is the 1,4regioisomer 1, and the RuAAC protocol furnishes the 1,5regioisomer 2. The mechanisms of these two complementary approaches have been extensively explored and elucidated by several groups.5 In the case of unsymmetrical internal alkynes bearing simple alkyl and aryl substituents, the RuAAC reaction provides regioisomers 3 and/or 4 in different ratios depending on the nature of R1 and R3,5b,6 whereas in stark contrast there © XXXX American Chemical Society
Received: May 24, 2018
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DOI: 10.1021/acs.oprd.8b00163 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Article
grinding of the insoluble material by the magnetic stir bar in the flask, and sought to overcome this problem by replacing CuI with a soluble Cu source. A few commercially available Cu salts were screened as additives in the reaction and provided only a modest enhancement in regioselectivity (entries 5−7, Table 1). Likewise, the addition of ligands with CuI did not exert any further beneficial effect on regioselectivity (entries 8 and 9). A major breakthrough was achieved upon the use of [nBu4N+]2[Cu2I4]2− generated in situ by premixing CuI and nBu4NI in equimolar amounts before the addition of 7, TMSmethyl azide, and [Ru(PPh3)2(Cp*)Cl].10 We were delighted to find that this soluble additive not only increased the regioselectivity to ∼11:1 (entry 10, Table 1) but also enhanced the reaction rate (complete conversion within 10 min at ∼55 °C or within 2 h at 35 °C). Reactions using the soluble Cu source in the absence of Ru did not proceed at all (entry 11) in line with literature reports. Similarly, the RuAAC reaction with n-Bu4NI did not improve the conversion or selectivity vis-à-vis the base case, confirming that Cu, not iodide, was responsible for the rate and selectivity enhancements (compare entries 12 and 1). These results implied that Ru is required for reactivity (Cu alone does not work), and the presence of Cu(I) augments both the regioselectivity and reaction rate. For obtaining further insight into the rate enhancement due to Cu with respect to the base case using Ru alone, four reactions were set up using 7, TMS-methyl azide, [Ru(PPh3)2(Cp*)Cl], and various Cu additives (Figure 1). It was found that the reaction using 10 mol % of premixed CuI and nBu4NI was faster (65% conv in 60 min; t1/2 = 46 min)11 than the reaction where these additives were added to the reaction mixture without premixing (53% conv in 60 min; t1/2 = 57 min). The reaction with just CuI was slower (35% conv in 60 min; t1/2 = 85 min), while the base case in the absence of any Cu additive was significantly slower (20% conv in 60 min; t1/2 = 133 min). These results clearly demonstrated the beneficial effect of Cu on the reaction rate12 as well as the superiority of the soluble complex [n-Bu4N+]2[Cu2I4]2− as an additive. A preliminary DSC examination of the reaction mixture during the conversion of 7 to 5 (and 6) under the Ru-alone conditions revealed a thermal event at ∼90 °C. The rate enhancement afforded by the addition of [n-Bu4N+]2[Cu2I4]2− allowed us to carry out the transformation at 30−35 °C as opposed to the 50−55 °C required for the Ru alone conditions, thus widening the safety window for executing the process. The new process using [n-Bu4N+]2[Cu2I4]2− was safely and successfully carried out on a 40 kg scale in the pilot plant.13 The scope and generality of this synergistic catalysis were then explored. To this end, several internal alkynes (each bearing one alkyl and one aryl substituent) were synthesized and subjected to the AAC reaction with either TMSCH2N3 or PhCH2N3 to provide the corresponding trisubstituted 1,2,3triazoles. The reactions were carried out with either 5 mol % [Ru(PPh3)2(Cp*)Cl] alone or a mixture of 5 mol % [Ru(PPh3)2(Cp*)Cl] and 10 mol % [n-Bu4N+]2[Cu2I4]2−. The reaction progress and ratios of the regioisomers were determined by HPLC analysis, and the results are summarized in Table 2. In all of the cases, the predominant regioisomer contained the aryl group at the 4-position of the triazole. The addition of [n-Bu4N+]2[Cu2I4]2− led to a significant increase in regioselectivity compared to the “Ru alone” conditions. The reactions with 2- and 3-alkynylpyridines exhibited a high degree of regioselectivity in the presence of added Cu (11a−c). The simple phenyl substituted analogues (11d−g) also followed this
alkyl-azides warranted further investigation to decrease the reaction temperature and increase the operating window for safe scale-up. As the synthetic development efforts progressed, we were intrigued by the fact that one of the batches of alkyne 7 provided a slightly higher ratio of regioisomers 5 and 6 (3.9:1) than the initial attempt (compare entries 1 and 2, Scheme 2). This variability could be attributed to several reaction parameters, one of which was the quality of starting material 7. Analysis of multiple batches of 7 for trace contaminants revealed that the batches exhibiting higher regioselectivity also contained higher levels of Pd and Cu, remnants from the Sonogashira coupling reaction used to produce 7. We therefore spiked small quantities of Pd2dba3, CuI, and CuSO4 into test reactions, starting with analytically pure samples of 7 (containing 99 >99 >99 >99 44 71 66 97 92 >99
