Scope and limitations of a DMF bio-alternative within Sonogashira cross-coupling and Cacchi-type annulation

Pd-catalysed C–C bond formation is an essential tool within the pharmaceutical and agrochemical industries. Many of these reactions rely heavily on polar aprotic solvents; however, despite their utility, these solvents are incompatible with the drive towards more sustainable chemical synthesis. Herein, we describe the scope and limitations of an alternative to DMF derived from renewable sources (CyreneTM) in Sonogashira cross-coupling and Cacchi-type annulations.


Introduction
The Sonogashira reaction [1,2] (Scheme 1) is a robust and broadly applicable Pd-catalysed bond-forming process that, alongside the Suzuki-Miyaura reaction [3], has steadily become an indispensible tool for C-C bond formation in the pharmaceutical industry [4]. While the Sonogashira reaction can be effec-tively carried out in a variety of media [1,2], in the general sense this process clearly relies upon the use of dipolar aprotic solvents, in particular DMF. Indeed, some 41% of all Sonogashira reactions reported using aryl iodides can be linked to the use of DMF as a solvent [5].
Based on its associated regulatory issues [24], it is perhaps no surprise that DMF continues to be a priority solvent for replacement. With legislation surrounding the use of DMF becoming increasingly stringent [24], numerous efforts have been made towards the use of alternative media in the Sonogashira reaction [25][26][27][28][29][30]. However, notwithstanding its issues, DMF is an excellent solvent for the Sonogashira reaction and its replacement frequently occurs at the expense of increased temperature (and therefore potentially substrate compatibility), reaction time, catalyst loading or the requirement for non-commercial/ expensive catalysts, and yield [25][26][27][28][29][30]. Consequently, poor choice of solvent replacement can result in one of industry's workhorse reactions becoming rather less predictable and robust.
In this regard, dihydrolevoglucosenone (Cyrene, Figure 1), accessed in two steps from cellulose [31,32], has been shown to possess similar physical properties to those of DMF and other dipolar aprotic solvents [31,32]. In addition to its renewability, Cyrene, as yet, has no associated pernicious effects and could potentially represent a direct and functional replacement in many of the fundamental reactions that typically employ DMF [31,32]. The replacement of solvents with regulatory issues with bio-derived alternatives has provided a series of advances within the cross-coupling arena [33], allowing efficient C-C bond formation via cornerstone Pd-based methods including Suzuki-Miyaura [34,35], Mizoroki-Heck [36,37], Sonogashira [38], Stille [39], Hiyama reactions [40], and hydroformylation reactions [41]. In the current study, we present the use of Cyrene as an alternative solvent (direct DMF replacement) for the Sonogashira reaction, as well as related Cacchi-type annulations [42,43], with an emphasis on scope and limitations of its application.

Results and Discussion
To explore the use of Cyrene in the context of the Sonogashira cross-coupling, we established a simple benchmark reaction using iodobenzene (1a) and phenylacetylene (2a) ( Table 1). A typical literature-derived catalyst system was employed (Pd(PPh 3 ) 2 Cl 2 with CuI additive [44,45]) and conversion to diphenylacetylene (3a) was monitored. Pleasingly, high conversion to product was immediately observed at room temperature in 5 h (94%, Table 1, entry 1). This high conversion was consistent across several reaction concentrations (Table 1, entries 2 and 3) allowing for a reduction in solvent volume, commensurate with the principles of green chemistry [46,47].
In attempts to further limit waste, we scanned a series of bases (see Supporting Information File 1); organic bases consistently performed more effectively and alternatives to Et 3 N provided no significant advantages. However, during this process we identified some potential limitations of this emerging solvent. Specifically, inorganic bases such as K 3 PO 4 and Cs 2 CO 3 ( Table 1, entries 4 and 5) resulted in the generation of a solid reaction mixture. Further analysis revealed that the aldol products 4a and 4b ( Figure 2) were generated under specific reaction conditions.
The manufacturers note that when using Cyrene, materials to avoid are strong acids, and strong oxidising and reducing agents. Since sensitivity to base was not specified, we surveyed a range of bases at various temperatures to evaluate the limitations of Cyrene under such conditions (Table 2).   (Table 2, entries 3, 5, 7, and 9-11). The extent of the reaction varied from the generation of additional components, such as 4a and 4b, to gelation or complete solidification of the reaction mixture. However, in a moderately basic reaction mixture (e.g., using Et 3 N) at mild reaction temperatures this issue could be entirely avoided. As such, optimisation of the Sonogashira process allowed complete conversion and 96% isolated yield in 1 h at 30 °C (Table 1, entry 8). Importantly, the Cyrene-based system compared very favourably upon comparison with standard solvents (THF and DMF; Table 1, entries 9 and 10, respectively).
Continuing with the primary investigation and with an optimised set of reaction conditions, we sought to explore the generality of Cyrene in the Sonogashira cross-coupling (Scheme 2). Significantly, a broad range of functionalised aryl and heteroaryl iodides were tolerated (Scheme 2a).
In addition, electron-deficient aryl bromides were accommodated, although with some variation in yield (3c, 3l, 3o, 3n). Functionality on the alkyne component was also typically well tolerated (Scheme 2b). While 3i and 3j required an extended reaction time, this was a substrate-specific problem for the use of 2a with these ortho-substituted aryl iodides that was not apparent for other alkyne/ortho-substituted iodoarene combinations (Scheme 2c).
Finally, with the viewpoint of generality of DMF substitution by Cyrene, the base/temperature sensitivity issue may have potential implications for further applications of Cyrene within well-used organic transformations. For example, the majority of many other standard cross-coupling processes employ inorganic or organic bases and heat (e.g., Suzuki-Miyaura, Heck). Accordingly, Cyrene may be projected to be incompatible with standard conditions for these reactions and its use would necessitate base-free or exceptionally mildly basic reaction conditions. In contrast, amide-bond formation is the most practiced reaction in the pharmaceutical industry [4] and these are routinely performed in DMF at room temperature in the presence of organic bases [53]. As such, Cyrene may offer considerable potential in this area. However, additional work will be required to validate the practicality of Cyrene as a viable DMF replacement in these applications.

Conclusion
In summary, we have developed a mild and robust method for the Sonogashira reaction, employing the bio-derived and sustainable alternative to DMF, Cyrene. In addition, we have shown the capacity for extension of the utility of this new solvent towards enabling the cascade synthesis of functionalised indoles and benzofurans via a Cacchi-type annulation. Perhaps more importantly, we have documented some of the limitations of the use of Cyrene as a solvent, providing guidance emerging in relation to the thermal and chemical (base) stabilities of this promising green solvent.

Supporting Information
Supporting Information File 1 Experimental procedures, analytical data, copies of NMR spectra, and single X-ray crystal diffraction data of 4b.