Article pubs.acs.org/joc Functional Group Transformations in Derivatives of 1,4- Dihydrobenzo[1,2,4]triazinyl Radical † § † ∥ † ‡ † ⊥ Agnieszka Bodzioch, , Minyan Zheng, , Piotr Kaszynski,́ *, , and Greta Utecht , † Organic Materials Research Group Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235, United States ‡ Faculty of Chemistry, University of Łodź,́ Tamka 12, 91403 Łodź,́ Poland *S Supporting Information ABSTRACT: Transformations of functional groups OCOPh, ’ − OCH2Ph, I, NO2, and CO2Me in Blatter s radical derivatives 1 5 were investigated in order to develop synthetic tools for incorporation of the benzo[1,2,4]triazinyl system into complex molecular architectures. Thus, basic hydrolysis of OCOPh or Pd-catalyzed debenzylation of OCH2Ph gave phenol functionality, which was acylated and alkylated. Pd-catalyzed Suzuki, Negishi, Sonogashira, and Heck C−C cross-coupling reactions of iodo derivatives 1c, 1d, and 2d ffi were also successful and e cient. Reduction of NO2 in 1e led to aniline derivative 1t, which was reductively alkylated with hexanal and coupled to L-proline. Selected benzo[1,2,4]triazinyl radicals were characterized by EPR and electronic absorption spectroscopy, and the results were analyzed in tandem with DFT computational methods. Lastly, the mechanism for formation of the 1,4- dihydrobenzo[1,2,4]triazine ring was investigated using the B3LYP/6-31G(2d,p) method. ■ INTRODUCTION little attention, and only a handful of derivatives have been Stable π-delocalized radicals are becoming important structural reported in the literature. This situation changed several years elements of materials for solar cells,1 energy storage,2 ago when Koutentis began systematic development of synthetic − electronic,3,4 and biological5 8 applications.9,10 Their incorpo- access to this class of radicals. Since then, Koutentis optimized ration into more complex molecular architectures and tuning of the classic synthetic routes to the benzo[1,2,4]triazinyl skeleton,19 demonstrated Pd-catalyzed C−C cross-coupling properties can be accomplished through functional group − reactions of the 7-iodo derivatives,20 23 fused 5-membered transformations. In this context, we recently demonstrated a 17,24 number of chemical transformations on derivatives of the 1,3,5- heterocyclic rings at the 6,7 positions, and applied 11 benzo[1,2,4]triazinyls toward the synthesis of other hetero- triphenyl-6-oxoverdazyl radical (I, Figure 1). However, the 25 benzo[1,2,4]triazinyl radical appears even more interesting in cycles. More recently, he has developed another synthetic the context of developing new materials.12,13 pathway to the benzo[1,2,4]triazinyl, potentially widening the scope of substitution patterns on the heterocycle.18 While the structural variety of benzo[1,2,4]triazinyl derivatives has increased dramatically, there still remains a need for broader investigation of functionalized derivatives of the radical and functional group transformations in the presence of the unpaired electron. Such functionalized derivatives are required for the development of advanced materials and are of interest in our research program aimed at investigation of organic semiconductors. Figure 1. Structure and numbering scheme for 1,3,5-triphenyl-6- Herein, we report the investigation of functionalized oxoverdazyl (I) and 1,3-diphenyl-1,4-dihydrobenzo[1,2,4]triazinyl derivatives of Blatter’s radical II containing OCOPh (OBz), (Blatter’s radical, II). OCH2Ph (OBn), NO2,CO2Me, and I groups substituted on the phenyl rings (Chart 1). We focused on 7-(trifluoromethyl)- benzo[1,2,4]triazinyl radicals 1 and also prepared 7-iodo 1,3-Diphenylbenzo[1,2,4]triazinyl (II), also known as 26 ’ 14 derivatives 2a and 2d and report an attempted synthesis of Blatter s radical, is prototypical of a family of exceptionally fl stable organic radicals, which broadly absorb in the visible 7- uoro analogue 3d. We additionally describe two 7- range15,16 and exhibit reversible redox potentials with a relatively narrow electrochemical window.17,18 Due to its Received: April 22, 2014 inefficient and cumbersome synthesis, the radical has received Published: July 28, 2014 © 2014 American Chemical Society 7294 dx.doi.org/10.1021/jo500898e | J. Org. Chem. 2014, 79, 7294−7310 The Journal of Organic Chemistry Article Chart 1 a Scheme 1. Synthesis of Radicals 1−4 a fl Reagents and conditions: (i) (COCl)2, DMF (cat.), CH2Cl2, rt; (ii) 4-ZC6H4NH2,CH2Cl2,Et3N, rt; (iii) SOCl2 (excess), re ux; (iv) 4- XC6H4NHNH2 (19: a, X = OBz; b, X = OBn; c,X=I;e, X = H), Et3N, CH2Cl2/MeCN, rt; (v) air, DBU, Pd/C, CH2Cl2, rt. unsubstituted derivatives 4a and 4b and preparation of low hydrolytic stability of the ester under the reaction functionalized 6-trifluoromethyl derivatives 5f and 5h.We conditions. investigated transformations of these functionalities to esters, Radicals 1 and 2 were conveniently isolated by column ethers, amides, and alkylamines, and demonstrate Pd-catalyzed chromatography on SiO2. In contrast, radicals 4 partially C−C coupling reactions. We also characterize selected radicals decomposed under the same conditions, and pure compounds by electrochemical and spectroscopic methods and briefly were obtained using SiO2 passivated with Et3N. investigate the effect of the substituent on the phenyl rings on The requisite amidrazones 6−9 were obtained from 4- electronic absorption and EPR spectra. The experimental data substituted benzoic acids 10, which were converted to amides are augmented with DFT computational results, which also 11−14 and subsequently to imidoyl chlories 15−18 using − include mechanistic studies of the formation of the 1,3- SOCl2 (Scheme 1). Reactions of chlorides 15 18 with an 11 diphenyl-1,4-dihydrobenzo[1,2,4]triazine. appropriate arylhydrazine 19 gave the desired amidrazones 6−9, respectively, isolated in 29−85% yield after chromatog- ■ RESULTS raphy. In general, reactions with 4-iodophenylhydrazine (19c) gave higher yields of amidrazones, while the lowest yield of 29% Synthesis of Radicals 1-5. Benzo[1,2,4]triazinyls 1−4 was obtained for 6a containing the benzoyloxy group. with a substituent at the C(7) position were prepared following Reactions of benzoyloxy imidoyl chloride 15a with 15 the classical Neugebauer route, which involves oxidative hydrazines 19b (X = OBn) and 19g (X = CO2H) gave cyclization of the corresponding amidrazones 6−9 (Scheme 1). complex mixtures of products from which no amidrazones 6f The aerial oxidation of 6, 7, and 9 in the presence of catalytic and 6g could be isolated. Amidrazones 6a, 6b, and 7a were amounts of Pd/C and DBU, according to a general method,19 obtained conveniently by reacting appropriate imidoyl chloride gave the expected radicals 1, 2,26 and 4, respectively, in yields with hydrazine hydrochloride 19a·HCl (X = OBz) in the fl 11 ranging from 32% to 89%. No 7- uorobenzo[1,2,4]triazinyl 3d presence of an additional 1 equiv of Et3N. was obtained from fluoroamidrazone 8d under these Amidrazones 6−9 had limited stability to purification on conditions, and only a complex mixture of products was SiO2 and storage, which hampered complete characterization observed by TLC. The low yields obtained for radicals efforts. For instance, within several hours, amidrazone 6c containing the benzoyloxy group are presumably due to the underwent partial oxidation in the solid state giving a number 7295 dx.doi.org/10.1021/jo500898e | J. Org. Chem. 2014, 79, 7294−7310 The Journal of Organic Chemistry Article a Scheme 2. Synthesis of Radicals 5 a fl ° → fl Reagents and conditions: (i) C6H5CHO, EtOH, re ux, 2h for 19c or C6H5CHO, EtOH, 0 C rt, overnight for 19b; (ii) 4- uoro-3- fl ·• ° nitro(tri uoromethyl)benzene (21), K2CO3, DMSO, rt, 16h; (iii) NH2OH HCl, pyridine, 80 C, 20 h; (iv) ArCOCl from 10d or 10h,Et3N, ° → → fl CH2Cl2,0 C rt, 20 h; (v) Sn, AcOH, rt 30 min re ux 10 min; (vi) air, base or NaIO4, rt. of products including radical 1c, as demonstrated by TLC radical 5h in nearly quantitative yield. Although leuco 25h analysis. Most amidrazones underwent slow decomposition appeared stable in air, it undergoes quick aerial oxidation to 5h during recrystallization; however, no radicals were detected by upon treatment with 1 equiv of KOH, in analogy to the first TLC. reported synthesis of Blatter’s radical II.14 The overall yields for benzo[1,2,4]triazinyls 1, 2, and 4 range The preparation of the benzyloxy hydrazide 24f was from 12% to 25% based on acid 10. Exceptionally high overall problematic. Attempts at acylation of hydrazine 23b with acid yields of about 53% were obtained for iodo radicals 1c and 1d. chloride derived from 4-benzyloxybenozic acid (10b) using ff Benzo[1,2,4]triazinyls 5f and 5h, with the CF3 substituent at several di erent reaction conditions (CH2Cl2 and Et3N, neat the C(6) position, were obtained according to a new, recently pyridine cold or warm) resulted in the appearance of a new, described procedure18 (Scheme 2). Thus, arylation of unidentified major product, similar to that observed during the hydrazones 20b and 20c with 1-fluoro-2-nitro-4- preparation of 24h. Unfortunately, the expected hydrazide 24f fl (tri uoromethyl)benzene (21) in DMSO containing K2CO3 and the unknown side product could not be separated by gave the corresponding products 22b and 22c in 99% and 60% chromatography, and this approach was abandoned. Another yield, respectively. The double activation of the fluorine atom in preparation of hydrazide 24f was attempted starting with 18 21 by the NO2 and CF3 substituents for nucleophilic aromatic bisbenzyloxy hydrazide 26. Unfortunately, arylation of 26 substitution permitted the arylation to be conducted at ambient with 21 in sec-butanol containing K2CO3 gave a complex temperature rather than at 100 °C.18 Treatment of hydrazones mixture of products from which 24f could not be isolated. · 18 22 with an excess NH2OH HCl in hot pyridine, removed the benzal group and hydrazines 23b and 23c was obtained in 64% and 77% yield, respectively.