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Deprotonative Metalation of Five-Membered Aromatic Heterocycles Using Mixed Lithium-Zinc Species J.M

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Deprotonative Metalation of Five-Membered Aromatic Heterocycles Using Mixed Lithium-Zinc Species J.M Deprotonative metalation of five-membered aromatic heterocycles using mixed lithium-zinc species J.M. l’Helgoual’Ch, Anne Seggio, Floris Chevallier, M. Yonehara, Erwann Jeanneau, Masanobu Uchiyama, Florence Mongin To cite this version: J.M. l’Helgoual’Ch, Anne Seggio, Floris Chevallier, M. Yonehara, Erwann Jeanneau, et al.. Deproto- native metalation of five-membered aromatic heterocycles using mixed lithium-zinc species. Journal of Organic Chemistry, American Chemical Society, 2007, 73 (1), pp.177-183. 10.1021/jo7020345. hal-00784514 HAL Id: hal-00784514 https://hal.archives-ouvertes.fr/hal-00784514 Submitted on 5 Feb 2014 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Deprotonative metalation of five-membered aromatic heterocycles using mixed lithium-zinc species Jean-Martial L'Helgoual'ch,† Anne Seggio,† Floris Chevallier,† Mitsuhiro Yonehara,‡ Erwann Jeanneau,§ Masanobu Uchiyama,*,‡ and Florence Mongin*,† Synthèse et ElectroSynthèse Organiques, UMR 6510 CNRS, Université de Rennes 1, Bâtiment 10A, Case 1003, Campus Scientifique de Beaulieu, 35042 Rennes, France, The Institute of Physical and Chemical Research, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan, and Centre de Diffractométrie Henri Longchambon, Université Claude Bernard Lyon 1, 69622 Villeurbanne, France [email protected], [email protected] RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required according to the journal that you are submitting your paper to) † UMR 6510 CNRS, Université de Rennes 1. ‡ RIKEN. § Centre de Diffractométrie Henri Longchambon, Université Lyon 1. 1) 0.5 equiv ZnCl2·TMEDA + 1.5 equiv LiTMP THF, rt, 2 h Ar H Ar I 2) I2 Ar-H = benzoxazole, benzothiazole, benzo[b]thiophene, benzo[b]furan, N-Boc indole, N-Boc pyrrole, N-phenylpyrazole: 52-73% 1 Abstract: Deprotonation of benzoxazole, benzothiazole, benzo[b]thiophene, benzo[b]furan, N-Boc protected indole and pyrrole, and N-phenylpyrazole using an in situ mixture of ZnCl2·TMEDA (0.5 equiv) and lithium 2,2,6,6-tetramethylpiperidide (1.5 equiv) in THF at room temperature was described. The reaction was evidenced by trapping with iodine, regioselectively giving the expected functionalized derivatives in 52 to 73% yields. A mixture of mono- and disubstituted derivatives was obtained starting from thiazole. Cross-coupling reactions of 2-metalated benzo[b]thiophene and benzo[b]furan with heteroaromatic chlorides proved possible under palladium catalysis. A reaction pathway where the lithium amide and zinc diamide present in solution behave synergically was proposed for the deprotonation reaction, taking account of NMR and DFT studies carried out on the basic mixture. ___________________________________________________________________________________ Introduction Substituted five-membered aromatic heterocycles are structural units present in many natural products and pharmaceutical synthetic intermediates.1 Among the methods used to functionalize them,1 deprotonation reactions using lithiated bases have been developed.2 This methodology often requires low temperatures and can not be used when reactive functional groups are present. In addition, unlike organoboron, organotin, organozinc and organomagnesium compounds, organolithiums can hardly be involved in cross-coupling reactions.3 Organomagnesium compounds have been prepared by deprotonation at higher temperatures.4 Nevertheless, because of the limited reactivity of the magnesium amide or diamide used to deprotonate functionalized substrates, an excess has in general to be employed to ensure good yields.5 In addition, even if the use of mixed lithium-magnesium amides seems more promising,6 it is still not extendable to very sensitive substrates. 2 The deprotonation reactions of sensitive aromatics such as alkyl benzoates, ethyl thiophenecarboxylates, ethyl 2-furancarboxylate, pyridine, quinoline and isoquinoline using t 7 Bu2Zn(TMP)Li (TMP = 2,2,6,6-tetramethylpiperidino) as a base were first described in 1999. More i recently, the use of the aluminium ate base Bu3Al(TMP)Li and the copper ate bases R(TMP)Cu(CN)Li2 (R = alkyl, aryl, or TMP) have been developed in order to generate functionalized aromatic compounds including heterocycles.8 The reactions performed in tetrahydrofuran (THF) proved to be chemoselective, but require 1 or 2 equiv of base.9 Several examples of deprotonation using lithium amidozincates in hexane have been reported by Mulvey since 2005.10 The term alkali-metal-mediated zincation has been introduced to depict these reactions because the reactivity ("synergy") exhibited by the zincates can not be attained by the homometallic compounds on their own.11 Herein, we report a new chemoselective deprotonation tool for regio-controlled functionalization of five-membered aromatic heterocycles using a basic mixture obtained from a lithium base and TMEDA- chelated zinc chloride. Results and Discussion To develop new chemoselective deprotonation reactions of five-membered aromatic heterocycles, our approach capitalizes on the high chemoselectivity of organozincate reagents, which allows flexible design and fine-tuning by modifying the ligation environment. In the initial screening of suitable zincates, benzoxazole (1) was selected as a model substrate because this substrate can be readily metalated by alkyllithiums, but the 2-lithiated species is well-known to be in equilibrium with the corresponding lithium phenolate, even at extremely low temperature.12 We therefore focused on the stability of intermediary aromatic zincates (relative to their lithium analogues) which is well-known to prevent from subsequent rearrangement13 or side-reactions.14 We assumed that it might allow the 3 regioselective zincation of five-membered aromatic heterocycles and the isolation of 2-zincate intermediates without any successive side-reactions. Previous NMR studies on 2-metallo benzoxazole have shown the equilibrium was completely on the side of the open isomer with lithium, whereas transmetalation to the organozinc derivative favored the ring closure.15 Then, we performed a preliminary DFT study on the stability of 2-metallo benzoxazoles and their rearrangement pathways by means of the B3LYP/6-31+G* method. Figure 1 shows the energy changes for each path, and the geometries of the transition states, intermediates and products. While the transition state (TS) and the product (PD) of 2-lithio derivatives were kinetically and thermodynamically stable, those of the 2-zincio compounds were found to be more unstable compared with 2-zincio reactant (RT), which was consistent with the experimental observations. These big energetic changes by the difference of metal species prompted us to further survey on whether the zincate bases could be used for chemoselective metalation of aromatic heterocycles. E N 1.30 109.6° 1.86 Li 1.94 N 1.49 89.7° 1.92 O Li 1.34 2.44 110.1° 66.8° N 1.18 1.38 TS 31.8° O 10.0 55.1° 3.18 2.22 22.9 125.2° RT Li O 1.74 PD E N 1.22 69.6° 101.2° 1.93 1.92 N 1.18 O 2.19 ZnCl 42.1° 72.4° N 2.82 2.14 1.30 TS 134.0° 1.93 ZnCl 114.0° ZnCl 25.8 O 1.89 1.39 33.1 2.88 O 119.4° PD RT FIGURE 1. Calculated structures for the reactants, transition states and products, and energy changes. Bond lengths and energy changes at the B3LYP/6-31+G* level are shown in Å and kcal/mol, respectively. 4 The deprotonation reaction of 1 was then examined using various zincate reagents (Table 1). The addition of one molar equiv (per lithium) of TMEDA or THF to a bulk nonpolar hydrocarbon in order to increase the opportunity for crystal growth proved to favor the deprotonation reactions of N,N- diisopropylcarboxamide10b,c and anisole10d using lithium amidozincates. We therefore decided to prepare 16 bases from ZnCl2·TMEDA, much less hygroscopic than ZnCl2, and 3 (or 4) equiv of alkyllithium or lithium dialkylamide, and to study their ability to deprotonate benzoxazole (1) (Table 1). TABLE 1. Deprotonation of benzoxazole (1) using in situ prepared mixtures of ZnX2·TMEDA and 3 (or 4) equiv of alkyllithium or lithium dialkylamide 1) ZnX2·TMEDA (n1 equiv) N + RLi (n2 equiv) + R'Li (n3 equiv) N O solvent, rt, 2 h O I 2) I2 1 2 entry X n1 R n2 R' n3 solvent yield (%) 1 Cl 1.0 Me 3.0 - - THF 28 2 Cl 1.0 Bu 3.0 - - THF 10 3 Cl 1.0 Bu 4.0 - - THF 32 4 Cl 1.0 Bu 2.0 TMP 1.0 THF 35 5 Cl 1.0 sBu 2.0 TMP 1.0 THF 38 6 Cl 1.0 Me 2.0 TMP 1.0 THF 44 7 Cl 0.50 TMP 1.5 - - THF 57 8 Cl 0.33 TMP 1.0 - - THF 60 9 Cl 0.40 TMP 1.2 - - THF 55 10 Cl 0.40 TMP 1.2 - - hexane 55 11 Br 0.33 TMP 1.0 - - THF 58 The first experiments were carried out with bases obtained by mixing 1 equiv of ZnCl2·TMEDA and 3 equiv of methyl- or butyllithium, and assumed to be lithium trimethylzincate and lithium tributylzincate, respectively.17 When used in THF at room temperature for 2 h, these mixed Li-Zn compounds hardly 5 metalated benzoxazole (1), giving the 2-substituted derivative 2 in low yields of 28 and 10%, respectively, after trapping with iodine (Entries 1 and 2). Since dilithium tetraalkylzincates have been shown to exhibit a higher reactivity compared to lithium trialkylzincates in various reactions including halogen-metal exchange,18 we decided to use 4 equiv of butyllithium instead of 3.
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