UPDATES DOI:10.1002/adsc.201500674 Synthesis of ortho-(Fluoro)alkylated Pyridines via Visible Light- Promoted Radical Isocyanide Insertion KunTong,a Tianyi Zheng,a YanZhang,a,*and Shouyun Yua,* a State KeyLaboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University,Nanjing 210093, Peoples Republic of China E-mail:[email protected] or [email protected] Supporting information for this article is availableonthe WWW under http://dx.doi.org/10.1002/adsc.201500674. Abstract: Aregiospecific synthesis of ortho- trifluoromethylated and ortho-(fluoro)alkylated pyr- idine derivatives has been developed. This strategy is enabled by visiblelight-promoted vinyl isocya- nide insertions with Umemotos reagent and elec- tron-deficient bromides at room temperature.The methodologypresentedhere provides an access to highly functionalized ortho-(fluoro)alkylated pyri- dine derivatives regiospecifically under mild condi- tions with good yields.The proposedmechanism was supported by TEMPO trappingexperiments, Stern–Volmer analysis andlight off/on andtime profile experiments. Figure1.Therationale for the synthesis of pyridines. Keywords: iridium;isocyanides;photochemistry; pyridines; trifluoromethylation synthetic technology (Figure 1a). Mechanistically,the imidoylradicals,[7] which are generated from isocya- nides with (pseudo)halides under visible light photo- redox catalysis,undergo homolytic aromatic substitu- Trifluoromethylated arenes are widely usedinnumer- tion (HAS)[8] to furnish phenanthridines and isoqui- ous fields,ranging from pharmaceuticals,agrochemi- nolines.[9] Based on these works,wespeculated that cals to materials.[1] Developing practical andgeneral the imidoylradicals could add onto C=Cdouble methodstointroduce the trifluoromethyl (CF3)group bonds intramolecularly,which wouldlead to ortho- into aromatic structures is especially important, as it substituted pyridine derivatives afteroxidation and [2] is notably absent in nature. Specifically, CF3-bearing deprotonation (Figure 1b). To the best of our knowl- pyridines are widely used as important intermediates edge,the regiospecific synthesisofortho-substituted and building blocks of numerous pharmaceuticals and pyridines employingradical isocyanide insertion has agrochemicals.[3] However, methods for the synthesis not been documented in the literature.Herein, we of these important motifsare very limited.[4,5] Direct wouldlike to report our efforts in the synthesis of trifluoromethylation of pyridine derivatives is the ortho-(fluoro)alkylated pyridines using visible light- most attractive strategy for accessing these com- promoted radical isocyanide insertion.[10] pounds.[5] However, it often results in amixture of re- Our initial effortfocused on the synthesis of ortho- [5a–f] gioisomers. Therefore,the regiospecific synthesis CF3-pyridine 3a from vinyl isocyanide 1a and Ume- [11] of CF3-pyridine derivatives is highly desirable,which motosreagent 2a. As shown in Table 1, when aso- remains alargely unsolved challenge. lution of 1a (1.0 equiv.) and 2a (2.0equiv.) in DMF In recent years,our group became interested in the was irradiated by 5W whiteLEDs in the presence of construction of functionalized nitrogen-containing ar- aphotocatalyst fac-Ir(ppy)3 (A)and Na2HPO4 for omatic compoundsusing visible light-promoted radi- 6h,wewere happy to find that the desired pyridine cal isocyanide insertions.[6] Aseries of 6-functional- 3a could be isolated in 65% yield (Table 1, entry 1). ized phenanthridine and 1-functionalized isoquinoline This promising result prompted us to optimize the re- derivatives were prepared regiospecifically using this action conditions further. It was found that other pho- Adv.Synth. Catal. 2015, 357,3681 –3686 2015 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim 3681 Kun Tong et al. UPDATES Table 1. Optimization of the reactionconditions.[a] ical precursors,such as Tognis reagent 2b and CF3SO2Cl (2c), were then investigated, but noneof them gaveimproved yields (entries17and 18). The dosageof2a could be reduced to 1.5 equivalents with- out affecting the yield (entries 19 and 20). Controlex- periments verifiedthe necessityofthe base,irradia- tion andphotocatalyst (entries 21–23). Avariety of vinyl isocyanides was synthesized in order to explore the scope of this transformation under the established optimized conditions (Table 2). Generally,all vinyl isocyanides reacted with Umemo- [a] Entry Photocatalyst Base Solvent Yield [%] tos reagent 2a quite well and the desired ortho-CF3- pyridines 3a–3n were generatedinsatisfactory yields 1 A Na2HPO4 DMF 65 (34–90%). 3-Arylpyridines 3a–3f were found to be 2 B Na2HPO4 DMF 50 3 C Na2HPO4 DMF 35 4 D Na2HPO4 DMF 56 [a,b] Table 2. Synthesis of o-CF3-pyridines. 5 E Na2HPO4 DMF 55 6 F Na2HPO4 DMF 31 7 A Na2HPO4 DMA 70 8 A Na2HPO4 CH3CN 62 9 A Na2HPO4 DCM 60 10 A Na2HPO4 DMSO 50 11 A Na2HPO4 MeOH 77 12 A Na2HPO4 EtOH 75 13 A Na2CO3 MeOH 66 14 A NaHCO3 MeOH 68 15 A Cs2CO3 MeOH trace 16 A K2HPO4 MeOH 64 [c] 17 A Na2HPO4 MeOH 50 [d] 18 A Na2HPO4 MeOH 52 [e] 19 ANa2HPO4 MeOH 77 [f] 20 A Na2HPO4 MeOH 53 21 A noneMeOH 23 22 none Na2HPO4 MeOH NR [g] 23 A Na2HPO4 MeOH NR [a] Reaction conditions: Asolution of 1a (0.1 mmol, 1.0 equiv.), 2a (0.2 mmol, 2.0 equiv.), base (0.2 mmol, 2.0 equiv.) and photocatalyst (0.0025 mmol, 2.5 mol%) in the indicated solvent (2.0 mL) was irradiated with 5W white LEDs for 6h. [b] Isolated yield. [c] 2b insteadof2a. [d] 2c instead of 2a. [e] 1.5 equiv.of2a. [f] 1.2 equiv.of2a. [g] No irradiation. NR= no reaction. tocatalysts,such as Ir(ppy)2(dtbbpy)PF6 (B), Ir(dFCF3ppy)2(dtbbpy)PF6 (C), Ru(bpy)3Cl2 (D), Ru(phen)3(PF6)2 (E)and fluorescein(F), were not as efficient as photocatalyst A and no more than 65% yield wasobserved(entries 2–6). Thesolvent effect [a] Reaction conditions: was then investigated (entries 7–12). To our delight, asolution of 1a (0.2 mmol, 1.0 equiv.), 2a (0.3 mmol, 1.5 equiv.), Na HPO when the reactionwas conducted in MeOH, an im- 2 4 (0.3 mmol, 1.5 equiv.) and fac-Ir(ppy)3 (0.002 mmol, provedyield of 3a (77%) was obtained (entry 11). 1.0 mol%)indry MeOH (2.0 mL) was irradiated by 5W Different bases,such as Na2CO3,NaHCO3,Cs2CO3 white LEDs. [b] and K2HPO4,were also tested, but none of them Isolated yield. [c] could give better results (entries 13–16). TheCF3C rad- DMF instead of MeOH. 3682 asc.wiley-vch.de 2015 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Adv.Synth. Catal. 2015, 357,3681 –3686 UPDATES Synthesis of ortho-(Fluoro)alkylated Pyridines Scheme 1. Synthesis of 2,4,6-trisubstituted pyridines. more suitable in this transformation with 66–90% could be provided by the radical insertion of isocya- yields.3-(2-Naphthyl)-and furylpyridines 3g (53% nides with EtO2CCF2Br and PhSO2CF2Br,respective- yield) and 3h (48% yield) were preparedinDMF due to the instability of the corresponding isocyanides in Table 3. Synthesis of o-(fluoro)alkylatedpyridines.[a,b] MeOH. 3-Alkylpyridines 3i–3k were also preparedin fair yields (48–56%). Thesubstitution on C-4 could be varied and 4-unsubstituted (3i,34% yield), propyl (3m,51% yield) and isobutyl (3n,60% yield) pyridine derivatives were accessible by means of this method. Fluorinated b-carboline derivative 3o can also be ob- tained by this strategy (80% yield). Very interestingly,when isocyanide 1p was subject- ed to the cyclization, 2,4,6-trisubstituted pyridine 3p was isolated in 67% yield instead of thetetrasubstitut- ed one 3p’ (Scheme1). It wasenvisaged that pyridine 3p was generated from fragmentation of the radical intermediate I with the loss of an isopropyl radical. Given that the tert-butyl radical is more stable than the isopropylradical, it was not surprising that when isocyanide 1q was employed, pyridine 3p was pro- duced with an improvedyield (81%). Thestereochemistry of vinylisocyanide was crucial to this transformation.When 1a’ was subjected into the standard conditions,the desired product could be isolated, but with poorer yield (33%, Scheme 2). Thesuccess with the preparation of ortho-CF3-pyri- dines inspired us to explore the possibility of prepar- ing other ortho-(fluoro)alkylated pyridines using asimilar strategy.AsshowninTable 3, ortho- difluoromethylated pyridines 5a–5d (42–63% yields) [a] Reaction conditions: 1 (0.2 mmol, 1.0 equiv.), 4 (0.6 mmol, 3.0 equiv.), Na2HPO4 (0.3 mmol, 1.5 equiv.) and fac-Ir(ppy)3 (0.002 mmol, 1.0 mol%) in dry DMF (2.0 mL) wasirradiated by 5W white LEDs. Scheme 2. Synthesis of 3a from 1a’. [b] Isolated yield. Adv.Synth. Catal. 2015, 357,3681 –3686 2015 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim asc.wiley-vch.de 3683 Kun Tong et al. UPDATES Scheme 3. TEMPO trappingexperiments.The yields are based on 19FNMR analysis. ly,under slightly modified standard conditions (a changeinthe solvent from MeOH to DMF). ortho- Monofluoromethylated pyridines 5e–5h could also be accessedwith the assistance of this method. ortho-Per- fluoroalkylatedpyridines 5i–5k were also compatible in this transformation. Several bromides without any fluorine were tested. To our delight, the correspond- ing ortho-alkylatedpyridines 5l–5m were generatedin 41–57% yields. To gainfurther insights into the reactionmecha- nism, aseries of TEMPO trappingexperiments was employed. As showninScheme 3, when Umemotos reagent 2a was treated with the radical scavenger TEMPO in the dark, only atrace of trappingproduct 6 was detected based on 19FNMR analysis.Instead, the adduct 6 was observed in about 34% NMR yield when the trappingreactions were carriedout under visible light irradiation. When isocyanide 1a was in- troducedinto the trappingexperiments,asimilar resultwas observed. These observations strongly sug- gest that the generation of the CF3C radical from Ume- motosreagent can be achieved under visible light ir- radiation. We then carried out the fluorescence quenching ex- periments (Stern–Volmer studies) of fac-Ir(ppy)3.It was observed that the fluorescence intensity de- creasedwith increasing concentration of 2a (Figure 2 a). As shown in Figure 2b,alinearrelationship be- tween I0/I and the concentration of 2a was observed at low concentrations (I0 and I are the fluorescence intensitiesbefore and after the addition of 2a).