Deprotometalation of Substituted Pyridines and Regioselectivity-Computed CH Acidity Relationships

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Introduction
Pyridines are present in numerous biological key positions, with derivatives such as nicotine, nicotinamide (niacin), nicotinamide adenine dinucleotide phosphate (NADP) and pyridoxine (vitamin B 6 ). In addition to occurring in pharmaceuticals and agrochemicals, 1 pyridines are important part of organic materials. 2 To functionalize regioselectively these heterocycles, deprotonative lithiation 3 appears as a valuable tool; alkyllithiums and hindered lithium dialkylamides have been largely used for this purpose. 4 Nevertheless, the low compatibility between π-deficient heteroaromatics on the one hand, and either the alkyllithiums used as base or the heteroaryllithiums generated by deprotonation on the other hand, implies very low reaction temperatures and limits the scope of the method.
Alternative deprotometalation methods have since emerged with the use of metal additives allowing chemoselective reactions to be performed. 5 In the pyridine series, pioneering reagents combining alkyllithiums with LiDMAE (DMAE = 2-dimethylaminoethoxide) proved to direct the deprotonation to the 2 position. 6 In addition, (R) n (R') n' MLi-type reagents, in which M is a nonalkali metal (e.g. Cu, 7 Zn, 8 Cd 9 ), have been reported for their ability to deprotometalate sensitive aromatics including pyridines.
In this context, we have developed a lithium-zinc combination, prepared from ZnCl 2 ·TMEDA (TMEDA = N,N,N',N'-tetramethylethylenediamine) and LiTMP (TMP = 2,2,6,6-tetramethylpiperidino) in a 1:3 ratio, capable of accomplishing room-temperature deprotometalation of a large range of M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 3 substrates. 10 Probably in relation with high steric hindrance, this base proved by NMR and DFT studies to be a 1:1 mixture of the homometallic amides rather than a lithium zincate, 10a a result confirmed by DOSY NMR spectroscopy. 11 The idea of a deprotolithiation through LiTMP occurring first, followed by Zn(TMP) 2 -mediated transmetalation, was proposed in 2008 to rationalize its synergic behavior, 10a and supported by others who pinpointed LiTMP·2LiCl±TMEDA as the possible active lithiating base. 11 This "trans-metal trapping" 12 has since been extended to other pairs behaving synergically such as mixtures of LiTMP on the one hand, and ZnCl 2 ·2LiCl, MgCl 2 or CuCN·2LiCl on the other hand. 13 We here describe the use of this lithium-zinc combination for the deprotonative metalation of pyridines substrates and comment on the results, and notably on the regioselectivities observed, on the basis of the CH acidities in THF (THF = tetrahydrofuran).

Computational aspects
The literature data on CH acidity of pyridines are scanty. 14 The main reasons are the necessity of using very strong bases at low temperatures and the side reactions of the azine carbanions generated. 4 A brief review of the papers devoted to experimental and theoretical investigation of azine CH acidities is presented in our previous publications. 10e,10h In the present work we report the values of CH acidity of pyridines both in gas-phase (∆ acid G) and in THF solution (pK a ), which were calculated by means of quantum chemistry.
Data on gas-phase acidity are important for the development of an acidity scale not depending on the basicity of the solvent in which the ionization takes place. Its recommended measure is the Gibbs energy (∆ acid G) of deprotonation of the substance: All the calculations were performed by using the Gaussian 03 software. Two different approaches, namely (i) the DFT B3LYP level of theory and (ii) the hybrid G3MP2B3 method, 15 As shown in Scheme 1, the values of the gas-phase acidity calculated at DFT B3LYP and G3MP2B3 levels are in excellent agreement (maximum deviation: 1.5 kcal mol −1 ), and are typical of those for very weak acids.
The solvent effects were treated by using the IEF formalism of polarized continuum model (PCM) with the default parameters for THF. The PCM energies were calculated at the B3LYP/6-311+G(d,p) level using geometries optimized for isolated structures.
The pK a values were further calculated by means of the following homodesmic reaction: where Py−H is bare pyridine, whose pK a value in THF (40.2, for position 4 of the ring) is known experimentally.
The homodesmic reaction Gibbs energy was calculated using the following equation: r s s s products reactants Further, it can be proved that: The CH acidity values for fluoro-and methoxy-pyridines in THF solution can be compared with those previously determined for chloro-and bromo-pyridines (  While the values of pK a (THF) of methoxypyridines are rather high and are of magnitude of monosubstituted benzenes, 16 the insertion of halogen makes the compounds much more acidic. When present at the 2 position, fluorine exerts a short range effect similar to that of chlorine; in contrast, positions remote from fluorine are less acidified (than with chlorine and, above all, bromine), in agreement with the electronic effects of the substituents. 17 The influence of the methoxy group is not quite that prominent. For molecules containing a methoxy group at the 2-, 4-and even 3-position, only adjacent sites are acidified. That the strongest acidifying effect is observed at both 2-and 4-sites, neighboring to the substituent, is a general trend for 3-substituted pyridines. In addition, this effect is stronger at the 4-position, which is far from the nitrogen lone pair, and also more affected because of concordant halogen/methoxy and nitrogen effects. In the case of 2,6-dihalogenated pyridines, the strongest acidifying effect is observed at the 3-and 5-positions of the ring. In addition, the 4-position also becomes much more acidic, notably compared to 2-monohalogenated substances, because of the cooperative long range electron-withdrawing effects of both halogens. With 2,6-dimethoxypyridine, the short range −I effects exhibited at the 3-and 5-position of the cycle by the methoxy groups are concealed by their stronger long range "para" electron-donating (+M) effects. From 2,3dimethoxypyridine, the "meta" electron-donating effect exhibited by the methoxy group at C2 does not offset the short range inductive acidifying effect exerted at C4 by the methoxy group at C3; as a result, the 4 position is more acidified for 2,3-dimethoxypyridine than for 2,6-dimethoxypyridine.
By using the computational approach described above, we also investigated the influence of substrate coordination to lithium species on the pK a (THF) values ( Figure 1). It is worth noting that, besides impacting the pK a (THF) values, complexation to lithium can favor the deprotonation at a neighboring M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 7 site through complex-induced proximity effect. 18 To this purpose, we considered 1:1 complexes of 3-, 4-and 2-methoxypyridine with LiCl and LiTMP. With LiCl, two types of coordination -namely through nitrogen and oxygen -were investigated, and several trends can be noted here. As expected, coordination of methoxypyridine to LiCl by nitrogen is more effective than by oxygen (with the corresponding isomeric complexes up to 8 kcal mol −1 more stable). In the case of O-Li complexation, the anions formed under deprotonation at positions adjacent to the methoxy group benefit from additional cyclic stabilization (values with asterisk on Figure 1). Finally, coordination of the metal by the ring nitrogen lone pair drastically increases CH acidity of the adjacent positions, making them competitive in deprotometalation processes.

Synthetic aspects
We first focused on the deprotometalation of 3-methoxypyridine (1a). 1a can be deprotolithiated regioselectively at its 2 position by using BuLi·TMEDA in THF at -40 °C, as evidenced by trapping with acetaldehyde to afford the expected alcohol in 49% yield. 19 A favored coordination of the metal of the base by the ring nitrogen (when compared to the methoxy substituent) is advanced to rationalize this result. By increasing the deprotometalation temperature to -23 °C, which proves possible by using less nucleophilic mesityllithium, 2-substituted 3-methoxypyridines are formed in higher yields. 20 Using The 1:1 mixture of LiTMP and Zn(TMP) 2 , obtained from ZnCl 2 ·TMEDA and LiTMP, 10a,11 was involved in the reaction with 1a in order to better understand the behavior of this combination ( Table   2). Upon treatment by the base (0.5 equiv of each metal amide) in THF for 2 h at room temperature (or 0 °C) and subsequent trapping with iodine, 1a was converted to a mixture of the 2-and 4-iodo derivatives (1b and 1c), both purified, isolated in 10 and 85% yield, respectively (entry 1). In order to see if this ratio could be modified, reactions were performed at a lower temperature or using a shorter reaction time. Whereas no reaction was noted at -40 °C (entry 2), shortening the reaction time to 10 min led to a mixture of 1b (50% yield) and 1c (25% yield) (entry 3). By keeping a 2 h contact at room temperature with the base, extending the base amount to 1 equiv of each metal amide led to the competitive formation of the 2,4-diiodo derivative 1d (30% yield, entry 4). With 2 equiv of each metal amide, 1c (58% yield) and 1d (35% yield) were the only products isolated (entry 5); in spite of caking of the reaction mixture, the formation of 1d proved favored by extending the contact time between base and substrate to 20 h (entry 6). 10h By using LiTMP (2 equiv) under similar reaction conditions, the 4iodo derivative 1c was obtained in 6% yield together with traces of 1b and the 4,4'-dimer 24 . Upon a similar treatment but in the presence of TMEDA (2 equiv), 1c and the 4,4'-dimer formed in 5 and 11% yield, respectively, together with traces of 1b. Table 2. Calculated pK a (THF) values for 3-methoxypyridine (1a), deprotometalation using in situ prepared 1:1 LiTMP-Zn(TMP) 2 followed by iodolysis and ORTEP diagram (30% probability) of 1d.  Some conclusions can be drawn from these data. The different results above confirm that the 2-and 4-metalated 3-methoxypyridines correspond to kinetic and thermodynamic products, respectively. The kinetic products are observed by using organolithiated (alkyl/aryl) bases, and coordination of the ring nitrogen to lithium favors reaction at C2 by both proximity effect 18a and strongly decreasing of the corresponding pK a values ( Figure 1). Results also evidence formation of transient 2-metalated 3methoxypyridines by using amido-containing bases such as LiDA, LiTMP and 1:1 LiTMP-Zn(TMP) 2 .
If chlorotrimethylsilane is not present to intercept the 2-metalated species, they change to presumably more stable 4-metalated derivatives (reversible reactions). Such an isomerization could also take place by using TMP-zincate, with lithium coordination by the pyridine nitrogen first giving rise to a 2metalated species, 25 provided that this conversion is faster than the consumption of generated H-TMP by the tert-butyl ligands. 26 The formation of 2,4-dimetalated species is only observed by using 1:1 LiTMP-Zn(TMP) 2 (1 or 2 equiv) for which "trans-metal trapping" 12 can take place. If lithium is coordinated by the pyridine nitrogen in the 2-metalated 3-methoxypyridine, methoxy could be still available to stabilize a 4metalated species. Similarly, if lithium is coordinated by the methoxy group in the 4-metalated 3methoxypyridine, pyridine nitrogen could be free to play a role in the formation of a 2-metalated derivative (Scheme 2).  (Table 3). After 2 h contact with the base (0.5 equiv of each metal amide) in THF at room temperature, iodolysis furnished a mixture of the 2-and 4-iodo derivatives (2b and 2c) in 57 and 37% yield, respectively (entry 1). Compared with methoxy (see above) and the other halogens (chlorine, bromine), 10e fluorine at C3 is less capable than the former and more than the latter of contributing to the stabilization of a 4-metalated species; thus, its ability to coordinate and stabilize a 4-metalated derivative seems to be intermediate between methoxy and the other halogens.
Increasing the base amount (to 1 equiv of each metal amide) allowed the diiodide 2d to be obtained in 46% yield together with the 4-iodo 2c (45% yield) and the 2-iodo 2b (9% yield). The experiment carried out by using 2 equiv of each metal amide quantitatively provided the diiodo 2d (entry 3); this result is different to what is observed from 1a, and can be in relation with lower pK a values.

M A N U S C R I P T
A C C E P T E D ACCEPTED MANUSCRIPT Table 3. Calculated pK a (THF) values for 3-fluoropyridine (2a), and deprotometalation using in situ prepared 1:1 LiTMP-Zn(TMP) 2 followed by iodolysis and ORTEP diagram (30% probability) of 2d. We next focused on 4-and 2-methoxypyridines (3a and 4a). Concerning 4-methoxypyridine (3a), using LiDA in THF in the presence of chlorotrimethylsilane leads to the 3-silylated derivative (61% yield) together with the 3,5-disilylated (16%). 20 Deprotolithiation can be carried out at the 3 position more efficiently by using either mesityllithium in THF at -23 °C 20 or phenyllithium in THF at 0 °C. 31 Due to lower LUMO levels, 2-methoxypyridine (4a) is more prone to nucleophilic attacks than 3-and 4-methoxypyridines (1a and 3a). 32 Using BuLi in THF with 4a at temperatures between 0 and 20 °C leads to both deprotolithiation and nucleophilic addition. 33 Conducting the reaction by using LiDA and chlorotrimethylsilane as an in situ trap quantitatively furnishes the 3-trimethylsilyl derivative. 32 To make efficient this LiDA-promoted deprotometalation, and extend it to other kinds of electrophilic trapping, it is possible to consume the diisopropylamine formed by reaction either with MeLi 32 or with PhLi. 34 As for 3-methoxypyridine (1a), mesityllithium can be used in THF at room temperature. 20 Bimetallic combinations such as 1:1 LiTMP-Al(iBu) 3 ("trans-metal trapping" 12 in THF at -78 °C), 35 putative LiCo(TMP) 3 (in THF at room temperature), 36 LiCu(TMP) 2 (in THF at room temperature) 37 and putative LiFe(TMP) 3 (in THF at room temperature), 38 can be employed for the same purpose. The regioselectivity of the reaction can be switched from the more acidic 3 to the less acidic 6 position by recourse to BuLi-LiDMAE in hexane at 0 °C, conditions that favor coordination-over acidity-driven reaction. 39

M A N U S C R I P T
A C C E P T E D ACCEPTED MANUSCRIPT Table 6. Calculated pK a (THF) values for 2-fluoropyridine (5a), and deprotometalation using in situ prepared 1:1 LiTMP-Zn(TMP) 2 followed by iodolysis. Compared with 2-methoxypyridine (4a), 2,6-dimethoxypyridine (6a) is less prone to nucleophilic attacks. BuLi can thus be employed to functionalize efficiently the 3 position. 42 The bimetallic base LiCo(TMP) 3 can also be used in THF at room temperature for the same purpose. 36 In the case of 2,3dimethoxypyridine (7a), 2 equiv of BuLi are required to perform an efficient functionalization at the 4 position. 43 Both compounds 6a and 7a could be quantitatively deprotometalated next to the methoxy group by I OMe Scheme 3. Calculated pK a (THF) values for 2,6-dimethoxypyridine (6a) and 2,3-dimethoxypyridine (7a), deprotometalation using in situ prepared 1:1 LiTMP-Zn(TMP) 2 followed by iodolysis and ORTEP diagram (30% probability) of 6c and 7b.

M A N U S C R I P T
A C C E P T E D ACCEPTED MANUSCRIPT 16 We finally studied the behavior of 2,6-difluoropyridine (8a). 8a can be cleanly deprotolithiated at its 3 position upon treatment with LiDA in THF at -75 °C. 44,41b,c A similar reaction is also possible by using Li 2 (TMP)MgBu 3 in THF at -10 °C. 30 In contrast to what can be observed by employing LiDA, using 1:1 LiTMP-Zn(TMP) 2 in THF at room temperature led either to mono or to dideprotonation (0.5 or 1 equiv of each metal amide, respectively) of 2,6-difluoropyridine (8a), as demonstrated by subsequent interception with iodine to furnish either the monoiodide 8b (66% yield) or the diiodide 8c (85% yield) ( Table 7). Table 7. Calculated pK a (THF) values for 2,6-difluoropyridine (8a), and deprotometalation using in situ prepared 1:1 LiTMP-Zn(TMP) 2 followed by iodolysis. Compared with 2,6-dimethoxypyridine (6a), 8a is more prone to dimetalation, probably in relation with lower pK a values. Compared with 8a, pyridines bearing heavier halogens (chlorine, bromine) give under similar reaction conditions more than one product, 10e a result probably resulting from both steric and longer range acidifying effects. 45 Finally, we have shown that it is possible to associate deprotometalation-iodination of pyridines with N-arylation of azoles for the generation of C,N'-linked bis-heterocycles. To this purpose, after hydrolysis and work-up, we involved the crude containing the iodide 5b in the reaction with pyrazole (2 equiv) using metal copper (0.2 equiv) as transition metal, cesium carbonate (2 equiv) as base, and acetonitrile as solvent at its reflux temperature for 24 h. 46 Under these conditions, both substitution of fluorine and N-arylation were noted, as evidenced with the formation of 5d in 70% yield (Scheme 4).

Conclusion
In summary, the basic mixture prepared from 1:3 ZnCl 2 ·TMEDA-LiTMP, and supposed to be a 1:1 mixture of LiTMP and Zn(TMP) 2 , allows reactions that are not reached by its lithium precursor.
Besides more efficient monodeprotonations, for example from 2-methoxypyridine, dideprotonations can be efficiently achieved for substrates benefiting from lower pK a values such as 3-fluoropyridine and 2,6-difluoropyridine. Such results are in accordance with a "trans-metal trapping" 12 allowing the pyridyllithiums to be trapped by zinc species as they are formed.

General
All the reactions were performed in Schlenk tubes under an argon atmosphere. THF was distilled over sodium/benzophenone. Liquid chromatography separations were achieved on silica gel Merck-Geduran Si 60 (63-200 µm). Melting points were measured on a Kofler apparatus. IR spectra were taken on a Perkin-Elmer Spectrum 100 spectrometer. 1 H and 13 C Nuclear Magnetic Resonance (NMR) spectra were recorded on a Bruker Avance III spectrometer at 300 and 75 MHz, respectively. 1 H chemical shifts (δ) are given in ppm relative to the solvent residual peak, and 13 C chemical shifts are relative to the central peak of the solvent signal. The sample was studied with graphite monochromatized Mo-Kα radiation (λ = 0.71073 Å). The Xray diffraction data were collected by using either APEXII, Bruker-AXS diffractometer (compounds 1d, 2d and 5d) or D8 VENTURE Bruker AXS diffractometer (compounds 6c and 7b). The structure was solved by direct methods using the SIR97 program, 48 and then refined with full-matrix least-square methods based on F 2 (SHELX-97) 49 with the aid of the WINGX program. 50  Purification by chromatography on silica gel (the eluent is given in the product description) led to the compounds described below. Purification by chromatography on silica gel (the eluent is given in the product description) led to the compounds described below.