Initial investigations aimed to determine the origin of the issues encountered during the lithiation-selenation of bis-triazole 4, by studying the lithiation of N-bis(trifluoromethyl)phenyl-4-phenyl-1,2,3-triazole 5 (Figure ). Triazole 5 was treated with lithium diisopropylamide (LDA) at -78 °C and allowed to warm to room temperature over 3 hours. Upon addition of LDA, a deep red solution was produced, which upon warming quickly turned black. Analysis of the crude reaction product mixture by F NMR spectroscopy revealed that >15 different compounds were present, none of which were the starting triazole 5. Of these compounds, only the major product was successfully isolated and identified as amidine 6. Formation of this compound can be explained based on a combination of mechanistic pathways proposed in related work by Raap, Chang and Fokin (Figure ). Following deprotonation by LDA, the lithiated triazole 7 undergoes nitrogen extrusion to form lithium propargyl amide 8. Protonation (possibly by diisopropylamine) gives ketenimine 9, which can undergo nucleophilic attack from LDA to give, following protonation, the amidine product 6. Further studies showed that ~5% amidine forms within 5 minutes, even when the reaction is maintained at -78 °C. This highlights the instability of this lithiated triazole relative to those previously reported. Of interest, Cu-catalysed azide-alkyne cycloaddition reactions using N-sulfonyl azides have been shown to spontaneously undergo a similar nitrogen extrusion process from the cuprated triazole intermediate at room temperature (Figure ). Our work demonstrates that whilst the cuprated triazole bearing an N-bis(trifluoromethyl)phenyl substituent is sufficiently stable for the synthesis of triazole 5, the lithiated species is unstable, even at -78 °C. These results indicate that the stability of metalated triazoles are a function of both the electron-withdrawing nature of the N-substituent and the electropositivity of the associated metal. The lithiation of a range of triazoles was investigated through treatment with LDA at -78 °C, followed by the addition of D2O, where %D incorporation was used as a proxy for the extent of lithiation that had taken place (Figure ). A standard lithiation time of 5 mins was chosen as only trace levels of decomposition were observed when using N-bis(trifluoromethyl)phenyl-4phenyl-1,2,3-triazole 5 under these conditions. Lithiationdeuteration of triazoles 11 and 12 bearing electronically-neutral N-octyl and N-phenyl substituents was achieved with 88%D and 84%D incorporation, respectively (Figure ). The repeatability of lithiation-deuteration of N-octyl triazole 11 was assessed through 3 repeat experiments and provided a standard deviation of ±3%D. A similar level of error was assumed for all other entries. Lithiation-deuteration of N-bis(trifluoromethyl)phenylsubstituted triazole 5 resulted in 90% deuteration at the 5position of the triazole, in addition to 15%D in each of the orthopositions of the bis(trifluoromethyl)phenyl ring. To investigate this result further, the regioisomeric triazole 18, with an N-phenyl substituent and a bis(trifluoromethyl)phenyl group at C(4), was subjected to the lithiation-deuteration procedure (Figure ). Exclusive deuteration of the triazole was observed with 87%D incorporation. This suggests that lithiation of the aryl ring is not purely due to the moderate directing effect of the CF3 groups, but also due to directing and acidifying effects of the triazole. Further variation of electron-withdrawing N-aryl substituents demonstrated there was also competition between deuteration at the triazole and aryl C-H when an N-2,4,6-trichloro- (13) or N-3,4,5-trifluorophenyl substituent (14) was used (Figure ). Lithiation-deuteration of N-pentafluorophenyl triazole 15 required the use the more sterically-hindered lithiating agent, LiTMP (lithium tetramethylpiperidide), to provide deuterated triazole 15 with 92%D incorporation (Figure ). In contrast, when LDA was used, a mixture of compounds was produced (Figure , red box). Triazole 15 constituted ~60% of the reaction product mixture (80%D), with the next largest constituent (~30%) identified as aniline 16. This product presumably arises from nucleophilic aromatic substitution (SNAr) of the pentafluorophenyl substituent by LDA, directed through coordination of LDA to N(2) of the triazole. Whilst SNAr reactions of pentafluorophenyl groups generally take place in the less sterically-congested para-position, examples of ortho-alkylation, amination and alkoxylation have been reported using oxazinyl and oxazolinyl directing groups. In contrast, when the regioisomeric triazole 19 was subjected to the lithiationdeuteration conditions using LDA, no SNAr products were obtained, despite the potential for this process to be directed through coordination of LDA to the N(3) position (Figure ). This suggests that the SNAr process is not only directed through proximal coordination of LDA, but also promoted through connection of the pentafluorophenyl group to the triazole at the electron-withdrawing N(1) atom. Finally, the attempted lithiationdeuteration of N-trifluoromethyltriazole 17 resulted in no detectable deuterium incorporation and significant (~80%) decomposition (Figure )). This result implies that once lithiated, the triazole undergoes rapid decomposition, and is in line with the expected reduction in stability of this metalated triazole, as predicted computationally by Ariafard. N The utility of the developed lithiation conditions was investigated through lithiation-functionalisation of two selected triazoles (Figures 4, 5). N-Pentafluorophenyl triazole 15 was chosen due to the potential sensitivity of the pentafluorophenyl group; whilst N-bis(trifluoromethyl)phenyl-4-phenyl-1,2,3-triazole 5 was chosen to assess if regioselective functionalisation could be achieved despite the imperfect regioselectivity of lithiation (as shown by the lithiation-deuteration studies). Preparative isolation of deuterated triazole 15 was achieved in 67%, despite a 99% yield determined by 1 H NMR using an internal standard. This demonstrates that although no side-products were formed, isolation of these triazoles can pose a challenge. Halogenation was also successful, with iodo-and bromotriazoles 20 and 21 obtained in 57% and 50%, respectively. Alkylation, ethoxycarbonylation and sulfenylation were also achieved to give 22-24 in low to moderate yields. Selenation using diphenyldiselenide gave selenated triazole 25 in 13%, in addition to diselenated product 26 in 22%. This side-product presumably arises following SNAr of product 25 by the phenylselenide anion released during triazole selenation. In line with this proposal, side-product 26 could be completely supressed by using phenylselenyl bromide as the selenating agent. Finally, the use of either benzaldehyde or benzophenone led to cyclised products 27 and 28. These products presumably form through intramolecular SNAr of the pentafluorophenyl ring by the oxyanion intermediate. These results further highlight the sensitivity of the pentafluorophenyl ring to nucleophilic attack. Whilst electrophiles containing halogen and sulfinate leaving groups are compatible, more nucleophilic leaving groups (and intermediates) such as alkoxides and selenides can result in competitive SNAr processes. Next, lithiation-functionalisation of N-bis(trifluoromethyl)phenyl-4phenyl-1,2,3-triazole 5 was investigated to determine if regioselective functionalisation could be achieved despite lithiation taking place on both the triazole and the bis(trifluoromethyl)phenyl ring (Figure ). First, selenation using diphenyldiselenide at -78 °C and warming to room temperature over 2 hours resulted in a mixture of selenated triazole 29 and diselenated triazole 30 in 22% and 37% yield, respectively. Improved selectivity for the mono-selenated product 29 could be achieved by maintaining the reaction temperature at -78 °C for 1 hour, followed by quenching with water at this temperature (29: 53%; 30: 4%). These conditions were then applied for further functionalisations using benzaldehyde and benzophenone, to give triazoles 31 and 32 in 43% and 57%, respectively. No evidence of functionalisation on the aryl ring was observed in either case. These examples demonstrate that although lithiation takes place on both the triazole and the aryl ring, careful control of the reaction conditions can allow selective functionalisation of the triazole and expand the range of products that can be accessed. Finally, the optimised lithiation-selenation conditions were applied to bis-triazole 2, leading to the formation and isolation of bis-selenated product 4 in 5% yield (Figure ). This low yield was in part due to challenges associated with isolation; however it still provides a significant improvement upon the literature conditions initially applied (Figure ). Further work, and alternative approaches, are currently being investigated to provide more efficient access to these novel architectures.