One-Pot Suzuki-Hydrogenolysis Protocol for the Modular Synthesis of 2,5-Diaryltetrazoles

2,5-Diaryltetrazoles are a diverse range of compounds of considerable interest within the field of photochemistry as a valuable precursor of the nitrile imine 1,3-dipole. Current literature approaches toward this heterocycle remain unsuitable for the practical synthesis of a library of these derivatives. Herein, we disclose the development of a modular approach toward 2,5-diaryltetrazoles compatible with an array-type protocol, facilitated by a tandem Suzuki-hydrogenolysis approach.


■ INTRODUCTION
The recent resurgence of photochemistry as a unique and powerful method of forging and manipulating C−C bonds has stimulated the development and adaption of numerous synthetic protocols. 1 One such transformation is the photolysis of the 2,5-diaryltetrazole moiety to yield the versatile nitrile imine 1,3-dipole (Scheme 1a). 2−4 Owing to its facile reactivity with a number of functional groups including alkenes 4b, 5 and carboxylic acids, 6 the nitrile imine has recently found widespread application in fields where an orthogonal reactivity profile (click chemistry 7 ) is desirable, such as materials chemistry and chemical biology. 8,9 Due to the traceless reaction profile and inherent simplicity of photolyzing tetrazole systems, this protocol has become the most common method of nitrile imine generation. However, synthetic approaches toward 2,5-tetrazoles are limited relative to the requirement for structural diversity from the corresponding dipole precursors. In our laboratories, we were interested in the synthesis of a small library of 2,5diaryltetrazoles 10 and were surprised to find that the majority of recent reports on the preparation of these compounds rely on a cycloaddition-mediated approach reported by Kakehi (Scheme 1b) over 40 years ago. 11 While this robust synthesis is compatible with a range of substrates, it also typically employs hazardous reagents and often laborious purification protocols. An alternative approach was introduced by Liu in 2015; however, this route is somewhat limited by the commercial availability of the requisite aryl amidines. 12 The continuing limitation in the synthesis of these heterocycles appears to be simultaneous modification of both the N-and C-aryl rings of the tetrazole. Multiple procedures for the diversification of 5aryltetrazoles with a palette of N-aryl groups have been developed; 13 however, modification of the C-aryl ring itself is primarily restricted to classical syntheses via cycloaddition between the relevant benzonitrile and hydrazoic acid (Scheme 1b). 14 This approach again requires use of toxic and explosive reagents. More recently, Kamenecka disclosed a route toward 2-aryl-5-bromotetrazoles; however, this also requires the use of hazardous reagents, and subsequent derivatization to furnish C-aryl functionalized systems was not conducted. 15 While the existing approaches are well-suited to the focused synthesis of specific 2,5-diaryltetrazole species, we found most methods incompatible with an array-type approach toward a library of such compounds. We envisioned that a common intermediate containing the preformed tetrazole nucleus encoded with chemoselective functional handles would allow for simple, rapid modification of both the 2-and 5-positions of the heterocyclic ring system.
The use of 1-benzyl-5-bromotetrazole (1) as a starting material fulfilled all of the requirements discussed above for a facile and robust synthesis of tetrazole systems ready for further functionalization (Scheme 1c). Given our laboratory's previous efforts in the development of a tandem Suzukihydrogenation protocol in the synthesis of sp 3 -rich pharmaceutical building-blocks, 16 we reasoned that the treatment of 1 to similar conditions would facilitate modification of the 5position, while simultaneously unmasking the 2-position for derivatization using existing literature methodology. 13c Furthermore, 1 itself could be easily accessed on scale by alkylation and bromination of 1H-tetrazole, a commodity precursor, obviating the need for the hazardous synthesis of the heterocyclic constituent.

■ RESULTS AND DISCUSSION
The current study commenced with the investigation of the initial Suzuki coupling between 1 and aryl boronic acids. An initial literature search identified conditions reported by Yi in the coupling of similar substrates, using Pd(PPh 3 ) 4 as a catalyst. 17 As the presence of the triphenylphoshine ligand has previously been shown to be detrimental in one-pot Suzukihydrogenation methodology, 16 we sought to identify a suitable replacement Pd complex. Our optimization campaign began with the screening of six palladium precatalysts in combination with a number of different solvents and bases ( Figure 1).
XPhos Pd G3 was quickly identified as a potential alternative catalyst. When employed in conjunction with toluene, these reaction conditions afforded a substantially greater conversion than all other combinations examined.
Gratifyingly, a direct comparison between the previously reported conditions and this emerging approach furnished nearly identical yields (Table 1, entries 1 and 2). Furthermore, this was accomplished over a much shorter time frame of 3 h; however, the catalyst loading remained higher. Both electrondonating and mildly electron-deficient boronic acids were shown to be compatible substrates (Table 1, entries 3 and 4); however, 4-cyanophenylboronic acid proved recalcitrant to product formation (Table 1, entry 5). In an effort to determine the compatibility of strongly electron-deficient boron species within the reaction manifold, a second screening effort was conducted, using an array of relevant variables selected based on the results of the initial screen ( Figure 2). These results suggested that while the nitrile derivative remained intolerant to the reaction conditions, the improved performance of 4-(trifluoromethyl)-phenylboronic acid indicated that this issue was substrate-specific, rather than a consequence of electronic factors. Throughout this additional screen, XPhos was again shown to represent the most favorable precatalyst, while cesium was identified as the carbonate counterion.
With optimal discrete variables in hand, we turned our attention to the catalyst loading. Preliminary efforts proved frustrating, with a significant decrease in yield observed upon reduction of catalyst loading (Table 2, entries 1−3). However, a concurrent Design of Experiments study 18,19 highlighted an unanticipated correlation between the water stoichiometry of the reaction, relative to the overall concentration, and the Scheme 1. (a) Application of 2,5-Tetrazoles as a Nitrile Imine Source; (b) Previous Efforts toward the Synthesis of Functionalized Tetrazoles; (c) This Work: Modular Synthesis of 2,5-Diaryltetrazoles via a Two-Step Tandem Pd and Cu Catalysis Approach Figure 1. Initial catalyst screening identified XPhos Pd G3 as a suitable candidate for further study. a Conversion was determined by HPLC with reference to an internal standard. All reactions were performed on a 2.5 μmol scale using 1.5 equiv of PhB(OH) 2 , 2 equiv of base, and a 4:1 solvent/H 2 O ratio (0.8 M). observed conversion (Figure 3, see the Supporting Information for full details). Exploiting this finding successfully furnished the optimized reaction conditions for the Suzuki component of the proposed process, with a catalyst loading of 3 mol % ( Table 2, entries 4−9). Studies into the subsequent debenzylation protocol proved to be more straightforward. A screen of eight Pd/C catalysts from three different sources afforded in many cases examples of quantitative conversion, with ethanol identified as an appropriate solvent (Figure 4). Further investigations highlighted Evonik's Noblyst P1071 Pd/C catalyst as a desirable option to mediate the transformation (see the Supporting Information for further details). A final optimization found that a 2.5 mol % loading of catalyst facilitated quantitative conversion under only 4 bar of hydrogen gas (Table 3, entries 1−3). It was also determined that gentle heating of the reaction mixture to 40°C was essential for enabling full conversion (Table 3, entry 4).
Translation of this methodology into a one-pot procedure proved challenging, with preliminary attempts affording only moderate turnover. Gratifyingly, further reducing the pressure of hydrogen gas was found to increase this yield to synthetically useful levels ( Table 4, entries 1 and 2). Consistent with our previous work, 16 the catalyst ratio was found to be a crucial factor in maximizing product formation. While the isolated debenzylation conditions required only a 2.5 mol % Pd/C loading, any reduction below 10% Pd/C significantly impacted conversion within the one-pot manifold ( Table 4, entry 3). Attempts to circumvent the addition of ethanol as a cosolvent at the midpoint of the reaction also failed to furnish improved conversions (Table 4, entries 4−6). However, satisfactory conditions were identified with a total Pd catalyst loading of 13 mol %, furnishing a 65% isolated yield of 3a in 22 h.
With fully optimized reaction conditions in hand, we next sought to investigate the scope of this one-pot procedure with respect to the boronic acid substituent (Table 5a). Additional screen of electron-deficient boron species indicated that some substrates were compatible with the conditions, while Cs 2 CO 3 represented a minor improvement over K 2 CO 3 . a Conversion was determined by LCMS with reference to caffeine as an internal standard. All reactions were performed on a 50 μmol scale using 1.5 equiv of PhB(OH) 2 , 2 equiv of base, and 50 equiv of H 2 O at a concentration of 0.1 M.   Introduction of electronically deficient and neutral moieties were found to be well-tolerated, with minimal impact on yield (cf. 3b−3d). Similarly, meta-and ortho-substitution of the aryl component was found to be compatible (cf. 3e and 3f), although the reduced yield of the meta analogue 3e remains more difficult to rationalize. More sterically encumbered substrates 3g and 3h were also successfully isolated. The modest yield associated with 3h can likely be attributed to the increased size of the tetrazole hindering adsorption of the substrate onto the surface of the Pd/C catalyst. Reaction conditions were also found to be amenable to scale-up, with substrates 3a, 3b, 3f, and 3g successfully synthesized in good yield on a 2.5 mmol scale. While the one-pot generation of 5-aryltetrazoles is preferable from a practical perspective, the yields of certain substrates were found to benefit from a directly related two-pot procedure (Table 5b). This approach enabled the robust synthesis of electron-rich analogue 3i, a key pharmacophore of a reported allosteric potentiator of the metabotropic glutamate 2 receptor. 20 Vinyl boronic acids were also found to be compatible, with the synthesis of 3j in good yield, providing access to alkyl tetrazole derivatives via a formal sp 2 −sp 3 coupling. Biaryl substrates 3k and 3l represent examples of an important subset of nitrile imine precursors with extended π-systems with a diminished yield in the case of the bulkier ophenyl species. While low-yielding, methoxy ester substrate 3m provides a valuable functional handle for further derivatization. To exhibit the versatility of this procedure, the debenzylation step of this scope exploited the ex situ generation of H 2 gas in a two-chambered reaction vessel known as COware, 21 attaining the required pressure of H 2 without the need for more specialized apparatus.
To further exemplify the advantages afforded by this modular approach, we targeted the synthesis of a diverse matrix consisting of 16 2,5-diaryltetrazoles (Table 6). N-Aryl substituents were selected on the basis of their unique influence on the properties of the resulting heterocycle, such as the incorporation of a handle for further covalent modification (e.g., 4f) or the manipulation of λ max properties (e.g., 4k). The current approach was found to be highly effective, with the synthesis of 15 of the 16 tetrazoles accomplished in good to excellent yields in conjunction with the established copper-mediated N-arylation protocol. 13c The practicality of this approach represents a significant advance over existing methods in the synthesis of a diverse library of nitrile imine precursors. One of the most beneficial aspects is the absence of time-consuming purification procedures. Owing to the acidic character of 3, appropriate moderation of pH during reaction workup afforded all 5-aryl-1H-tetrazoles at a sufficient level of purity for subsequent manipulation without the need for additional decontamination. Commencing from 5bromotetrazole 1, the synthesis of 2,5-tetrazoles 4a−p required only one chromatographic purification step prior to the isolation of the final product. The synthesis of tetrazole 4a on a 6 mmol also demonstrated the scalability of the procedure, meaning that the entire route was shown to afford an overall yield of greater than 50% on a multimillimolar scale. The unexpected failure of substrate 4j can be perhaps be attributed to a lower thermal stability of the tetrazole due to the enhanced push−pull system generated by the substituents. 22

■ CONCLUSIONS
In conclusion, we have developed a convenient and widely applicable Suzuki-hydrogenolysis protocol enabling the expedient synthesis of 2,5-diaryltetrazoles, valuable precursors of the nitrile imine 1,3-dipole. The scope of the reaction was shown to be tolerant of a range of steric and electronic parameters and was further expanded through the accommodation of a hyphenated, two-pot procedure. Facile synthesis of a diverse palette of 2,5-tetrazoles in combination with existing Cu-catalyzed methodology has underlined the utility of this reaction, which offers a complementary means of accessing the 2,5-diaryltetrazole scaffold in comparison to previous reports. We intend to further utilize this transformation in our continued investigations into the reactivity of the pleiotropic nitrile imine dipole.
■ EXPERIMENTAL SECTION General Information. All reagents and solvents were obtained from commercial suppliers and were used without further purification  Reactions performed on a 0.5 mmol scale using 1.3 equiv of PhB(OH) 2 , 1.5 equiv of Cs 2 CO 3 , and 100 equiv of H 2 O at a concentration of 0.1 M. b Conversions were determined by LCMS with reference to caffeine as an internal standard. c EtOH (2.5 mL) was added as a cosolvent prior to the hydrogenolysis step of the reaction. d Isolated yield.
unless otherwise stated. Purification was carried out according to standard laboratory methods. All reactions were conducted using round-bottom flasks or microwave vials of appropriate volume, unless otherwise stated. Reactions were carried out at elevated temperatures using a temperature-regulated hot plate/stirrer with a sand bath unless otherwise stated. Phase separation was conducted using IST Isolute Phase Separator Cartridges.
Flash chromatography was carried out manually using ZEOprep 60 HYD 40−63 μm silica gel or using a Teledyne ISCO CombiFlashRF+ apparatus with RediSep silica cartridges.
Fourier transform infrared (FTIR) spectra were obtained using a PerkinElmer Spectrum One Fourier Transform spectrometer with samples used neat. 1 H, 19 F, and 13 C NMR spectra were obtained on a Bruker DRX 500, Bruker AVI, or Bruker Nano spectrometer at 400 or 500, 471 or 376, and 100 or 126 MHz, respectively. Chemical shifts are reported in ppm and coupling constants are reported in Hz with CDCl 3 referenced at 7.26 ( 1 H) and 77.16 ppm ( 13 C) and DMSO-d 6 referenced at 2.50 ( 1 H) and 39.52 ppm ( 13 C). Signal assignment of novel compounds was instructed using relevant 2D NMR experiments. High-resolution mass spectra were obtained on a Waters XEVO G2-XS QTof instrument (100−1200 AMU) in positive ionization mode. Reversed-phase HPLC data was obtained using a Waters CSH C18 column. LCMS spectra were obtained using an Acquity UPLC CSH C18 column (50 mm × 2.1 mm i.d. 1.7 μm packing diameter) at 40°C. The solvents employed were a 0.1% v/v solution of formic acid in water and a 0.1% v/v solution of formic acid in acetonitrile. The UV detection was a summed signal from wavelengths 210 nm −360 nm. Mass spectral data was acquired using a Waters QDA instrument (100−1000 AMU at 5 Hz) with an alternate-scan positive and negative electrospray ionization mode.
HPLC analysis was performed using a gradient method, eluting with 5−90% MeCN/H 2 O over 1 min at a flow rate of 1 mL/min when employing standalone HPLC, and eluting with 3−98% MeCN/ H 2 O (+ formic acid modifier) over 2 min at a flow rate of 1 mL/min when used in conjunction with MS. Reactions using an internal standard required prior HPLC calibration using samples containing varying molarities of product and caffeine, allowing calculation of the response factor by substituting values into eq 1. Screening reactions were then conducted using a known molarity of caffeine internal standard.  (1) General Procedure for the Synthesis of Compounds 3a−3h. To a 10 mL Biotage Endeavor reaction vessel was added Evonik Noblyst P1071 20% palladium on carbon (10 mol %). 1-Benzyl-5bromo-1H-tetrazole (1, 1 equiv), an aryl boronic acid (1.3 equiv), and XPhos Pd G3 (3 mol %) were then added as a solution in toluene (0.1 M). To the resulting suspension was added cesium carbonate (1.5 equiv) as a solution in water (100 equiv), at which point the vessel was purged with nitrogen and stirred at 100°C for 4 h. Upon cooling to room temperature, ethanol (50% volume of toluene) was added before the vessel was placed under a hydrogen atmosphere and heated at 40°C for a further 18 h. Upon reaction completion, the mixture was passed through Celite and partitioned between ethyl acetate (30 mL) and water (30 mL). The organic phase was washed twice more with water (2 × 30 mL) before the aqueous phases were combined and acidified using 2 M HCl solution (20 mL). The acidic aqueous phase was then washed three times with ethyl acetate (3 × 30 mL) before all organic layers were then combined, passed through a phase separator, and concentrated under reduced pressure to yield the product.
General Procedure for the Synthesis of Compounds 3i−3m. To a microwave vial containing 1-benzyl-5-bromo-1H-tetrazole (1, 1 equiv), an aryl or vinyl boronic acid (1.5 equiv), and XPhos Pd G3 (3 mol %) was added toluene (0.2 M). The vessel was purged with nitrogen, and cesium carbonate (2 equiv) and water (10 equiv) were added. The mixture was stirred at 100°C for 2 h before being cooled to room temperature. The mixture was diluted with ethyl acetate (10 mL) and passed through a Celite plug, which was then washed with a further portion of ethyl acetate (10 mL). The solution was concentrated under reduced pressure and purified by column chromatography. Isolation of the intermediate 1-benzyl-5-aryltetrazole was confirmed by 1 H NMR spectroscopy before the species was added to chamber A of a 2 × 10 mL COware reaction vessel 21a as a solution in ethanol (0.1 M). Evonik Noblyst P1071 20% palladium on carbon (10 mol %) was also added to chamber A, while chamber B was charged with zinc powder (1.8 mmol, 118 mg) and 36% hydrogen chloride solution (343 μL, 4 mmol). The vessel was sealed and stirred at 40°C for 18 h. The mixture was cooled to room temperature, diluted with ethyl acetate (10 mL) and passed through a Celite plug, which was washed with a further portion of ethyl acetate (10 mL). This organic phase was washed twice with water (2 × 30 mL), before the aqueous phases were combined and acidified using 2 M HCl solution (20 mL). The acidic aqueous phase was then washed three times with ethyl acetate (3 × 30 mL), before all organic layers were then combined, passed through a phase separator and concentrated under reduced pressure to yield the product.
General Procedure for the N-Arylation of 5-aryltetrazoles. In accordance with previous literature precedent, 13c 5-aryltetrazole (3,1 equiv), an aryl boronic acid (2 equiv), copper(I) oxide (5 mol %), and DMSO (0.13 M) were added to a microwave vial. The reaction mixture was stirred under an oxygen atmosphere at 100°C for 16 h. The solution was cooled to room temperature and partitioned between ethyl acetate (20 mL) and 1 M HCl solution (20 mL). The aqueous layer was backwashed with an additional portion of ethyl acetate (20 mL) before the combined organic layers were combined, washed with brine (40 mL), passed through a phase separator and concentrated under reduced pressure. The crude product was then purified by column chromatography.