# Lateral Deprotometallation-Trapping Reactions on Methylated Pyridines, Quinolines and Quinoxalines Using Lithium Diethylamide

Mohamed Hasyeoui, Peter Chapple, Frédéric Lassagne, Thierry Roisnel, Marie Cordier, Ali Samarat, Yann Sarazin, Florence Mongin

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Mohamed Hasyeoui, Peter Chapple, Frédéric Lassagne, Thierry Roisnel, Marie Cordier, et al. Lateral Deprotometallation-Trapping Reactions on Methylated Pyridines, Quinolines and Quinoxalines Using Lithium Diethylamide. European Journal of Organic Chemistry, 2023, 26 (35), 10.1002/ejoc.202300555. hal-04193393

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# Lateral Deprotometallation-Trapping Reactions on Methylated Pyridines, Quinolines and Quinoxalines Using Lithium Diethylamide

Mohamed Hasyeoui,[a,b] Peter M. Chapple,[a] Frédéric Lassagne,[a] Thierry Roisnel,[a] Marie Cordier,[a] Ali Samarat,[b] Yann Sarazin[a] and Florence Mongin*[a]

**Abstract:** The functionalization of methylated azines and diazines has aroused the interest of chemists given the structural diversity that it affords. Hindered lithium dialkylamides have in particular been used to deprotometallate these substrates chemoselectively. In contrast, it can be observed that, despite some promising work, lithium diethylamide has been used very little for this purpose. Our objective here is on the one hand to make an inventory of what reagents have been used to deprotometallate methylpyridines, - quinolines and -quinoxalines, and on the other hand to describe the results obtained by seeking to functionalize a series of substrates with lithium diethylamide (picolines, 2,4-lutidine, methylquinolines and 2-methylquinoxaline). Our efforts to take advantage of the use of an *in-situ* trap (a zinc chloride chelate) in these reactions are also described.

no further development has been investigated. However, one can wonder whether such a base could not find more applications in deprotolithiation reactions leading to α-lithiated products either stabilized in a tautomeric form with a metal-nitrogen bond,³a or even intercepted by *in-situ* traps.⁷

Azines like pyridines⁸ and quinolines,⁹ as well as diazines like quinoxalines,¹⁰ are heterocycles found in many compounds of biological interest or in organic materials. Given the structural diversity it affords access to, the selective functionalization of the methyl substituents found in these aromatic heterocycles remains topical.¹¹ We describe here our investigations on the use of LiNET₂, alone or in combination with an *in-situ* trap, to functionalize the methyl groups present on pyridines, quinolines and quinoxalines (Figure 1).

## Introduction

Alkali metal amides are bases widely used in organic synthesis. However, while small metal amides (e.g. NaNH₂ and KNH₂) and hindered N,N-disubstituted derivatives (especially lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidine and lithium bis(trimethylsilyl)amide) have been widely studied,¹ the use of lithium diethylamide in synthesis remains in its infancy.²

In 1999, Evans and co-workers were the first to evidence the specific role of lithium diethylamide (LiNET₂) for the functionalization of 4-substituted 2-methyloxazoles/thiazoles in tetrahydrofuran (THF) at low temperature. Unlike lithium diisopropylamide (LiDA) which gave mixtures of α- and ring-lithiated products, LiNET₂ mainly led to the more stable 2-oxazolylmethylsilium.³ To rationalize this result, they proposed a more pronounced equilibrium (mediated by the amine released *in-situ*) between the two possible organolithiums in the case of LiNET₂ (pKₐ of the formed diethylamine in THF: 31.7⁴) than in the case of LiDA (pKₐ of diisopropylamine in THF: 34.4⁴).

Although this original regioselective functionalization of oxazoles was used as the key step in the total syntheses of the antitumor phorboxazole B⁵ and the antiviral (–)-hennoxazole A,⁶

<figure><img src="image_2.png" /><figcaption>**Figure 1.** Substrates for which the behaviour towards LiNET₂ will be studied.</figcaption></figure>

## Results and Discussion

On the synthesis of [(LiNET₂)₄·(thf)₄]

Our initial interest in the field was triggered by our isolation of colourless crystals of the tetrameric [(LiNET₂)₄·(thf)₂] (A). The complex was prepared upon straightforward reaction of HNET₂ with a stoichiometric amount of n-BuLi in THF. Single-crystals suitable for XRD analysis were obtained in 79% yield (two fractions) by recrystallisation from a concentrated solution, and the molecular structure of the complex was unambiguously established (Figure 2). The compound loses one THF molecule upon thorough drying under dynamic vacuum, and the corresponding NMR data recorded in benzene-d₆ hence match the formulation [(LiNET₂)₄·(thf)] (A'). This monosolvated tetramer is characterised by a single resonance at δLi 1.75 ppm in the 7Li NMR spectrum recorded at 25 °C. NMR provided no evidence for the existence of a solution equilibrium between species with different nuclearity. The compounds A and A' are soluble in all common hydrocarbons and ethers.

The molecular structure of the complex A, depicted in Figure 2, shows the complex to form a centrosymmetric, N-

<footnote>[a] M. Hasyeoui, Dr. P. M. Chapple, F. Lassagne, Dr. T. Roisnel, M. Cordier, Dr. Y. Sarazin, Prof. F. Mongin
Univ Rennes, CNRS, ISCR (Institut des Sciences Chimiques de Rennes) - UMR 6226, F-35000 Rennes, France
E-mail: florence.mongin@univ-rennes1.fr
https://iscr.univ-rennes1.fr/corint/florence-mongin</footnote>

<footnote>[b] M. Hasyeoui, Prof. A. Samarat
University of Carthage, Faculty of Sciences of Bizerte, LR18ES11,
Laboratory of Hetero-Organic Compounds and Nanostructured
Materials,
7021 Bizerte, Tunisia</footnote>

<footnote>Supporting information for this article is given via a link at the end of the document.</footnote>
bridged ladder-like arrangement, where each metal sits in a trigonal planar geometry (Σ<sub>θ</sub>(Li1) = 359.1° and Σ<sub>θ</sub>(Li2) = 360.1°). The Li atoms occupying the external positions are surrounded by one terminal THF and two bridging amido ligands, while those inside the ladder motive rest in an all-nitrogen environment. The geometry about each metal centre is trigonal planar. All Li-N and Li-O interatomic distances in the tetramer are unremarkable. Lithium amides are well known to generate original multimetallic structures in the solid state. The pattern of ladder-like sheets exhibited in **A** is known, and has for instance previously been seen in [(Li(pyrrolide)<sub>4</sub>.(TMEDA)<sub>2</sub>]<sup>12</sup> in lithium (2-(diethylamino)ethyl)(ethyl)amide,<sup>13</sup> or other lithium amides.<sup>14</sup>

<figure><img src="image_3.png" /><figcaption>**Figure 2.** ORTEP representation of the molecular solid-state structure of [(LiNET<sub>2</sub>)<sub>4</sub>(THF)<sub>2</sub>] (<b>A</b>). Ellipsoids at the 50% probability level. H atoms are omitted for clarity. Selected interatomic distances (Å) and angles (°): Li1-N1 = 2.044(6), Li1-N2 = 1.962(6), Li1-O1 = 1.882(6), Li2-N1 = 2.068(6), Li2-N2 = 1.979(6), Li2-N1' = 2.076(6); N1-Li1-N2 = 108.4(3), N1-Li1-O1 = 129.6(3), N2-Li1-O1 = 121.1(3), N1-Li2-N2 = 106.8(3), N1-Li2-N1' = 109.2(3), N1'-Li2-N2 = 144.1(3). Symmetry transformations used to generate equivalent atoms: -x, -y, -z, with T = [1, 1, 0].</figcaption></figure>

Functionalization in the pyridine series

The functionalization of 2- and 4-picolines by (lateral) α-deprotometallation-trapping sequences has been widely developed<sup>15</sup> (Figure 3). Among the many bases evaluated to α-deprotometallate 2-picoline, *n*-butyllithium in tetrahydrofuran (THF) is probably the most used. For example, it was employed by Vitagliano and co-workers who efficiently intercepted the intermediate 2-picolyllithium with chlorodiphenylphosphine.<sup>16</sup> By treating 2-picoline (also used as a solvent) with *n*-butyllithium in the presence of potassium *tert*-butoxide, Bart and co-workers also quantitatively isolated the 2-picolylpotassium.<sup>17</sup> In addition, the use of hindered lithium dialkylamides in THF also allowed for the easy α-deprotometallation of different 2-picolines.<sup>18</sup> This is of interest because LiDA<sup>18</sup> and lithium 2,2,6,6-tetramethylpiperidide (LiTMP), which have serendipitously also been used in heptane containing potassium *tert*-butoxide,<sup>19</sup> are more tolerant than alkyllithiums to substituents subject to nucleophilic attack.

<figure><img src="image_4.png" /><figcaption>**Figure 3.** Bases already employed to functionalize 2-, 4- and 3-picolines, and 2,4-lutidine.</figcaption></figure>

Compared to 2-picolines, 4-picolines have been α-functionalized by a greater number of bases. Like 2-picolines, they can be α-deprotometallated by using *n*-butyllithium; this was for example documented by Chung and co-workers who used this base in THF (at 40-45 °C) before reacting the intermediate 4-picolyllithium with 1-bromo-3-chloropropane (<-75 °C) towards the fibrinogen receptor antagonist MK-383.<sup>20</sup> Apart from alkyllithiums, hindered lithium dialkylamides have also been widely used. For example, in their synthesis of (+)-sesbanine, Tomioka and Koga employed LiDA in a 1:1 THF-hexamethylphosphoramide (HMPA) mixture at -78 °C for 2 h to generate the same 4-picolyllithium, finally trapped with methyl chloroformiate.<sup>21</sup> Pleasingly, the use of toxic HMPA can be avoided, as shown for example by Keene and co-workers by using LiDA in THF (0 °C, 1 h).<sup>22</sup> The possibility to use less basic alkali metal bis(trimethylsilyl)amides (Li,<sup>23</sup> Na,<sup>24</sup> K<sup>25</sup>) to α-deprotometallate 4-picolines has also been demonstrated.

The α-deprotometallation of the 3-picolines is less easy (Figure 3) because, although the resulting anion can be stabilized by resonance, the negative charge cannot be delocalized onto the ring nitrogen. For example, it was observed that it was more difficult to deprotometallate 3-picoline using an alkaline amide (e.g. KNH<sub>2</sub>) than 2- and 4-picolines.<sup>26</sup> A similar observation was made with (trimethylsilyl)methylsodium (in hexane containing *N*,*N*,*N*',*N''*,*N'''*-pentamethyldiethylenetriamine at room temperature) for the functionalization of 2- and 3-picolines with a Weinreb amide.<sup>27</sup> In the case of 3-picolines, alkyllithiums can only be employed for substrates benefiting from a heteroatom-containing substituent at the 2- or 4-position (for example, with 2-CONHtBu (*n*BuLi, THF, -40 °C),<sup>28</sup> 2- or 4-NHCOtBu (*n*BuLi, THF, 0 °C),<sup>29</sup> and 2-NHCO<sub>2</sub>tBu (*n*BuLi in THF at 0 °C)<sup>30</sup>). Alkali metal bis(trimethylsilyl)amides have been less successful and only employed at high temperature (e.g. KN(SiMe<sub>3</sub>)<sub>2</sub> in THF at 100 °C).<sup>31</sup> Probably due to the higher pK<sub>a</sub> value of the corresponding amine, LiDA in an ether solvent has been used in many examples, but with contrasting results.<sup>32</sup> However, in THF solutions also containing hexamethylphosphoramide (HMPA)<sup>33</sup> or less toxic 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidone (DMPU) as coordinating additives,<sup>34</sup> the reactions proved more efficient.

Our objective being to study the reactivity of LiNET<sub>2</sub> towards azines, we first treated the 2- and 4-picolines with this amide (1 equiv) in THF at -50 °C for 1 h before trapping the resulting species with 4-anisaldehyde. Under these conditions, inspired by the work of Evans and co-workers on 2,4-lutidine,<sup>3a</sup> the alcohol **1b** was formed from 2-picoline (**1a**) in a moderate 26% yield whereas the more acidic 4-picoline (**2a**) afforded the alcohol **2b** in 34% yield (as well as the ketone **2c**, which presumably results from its oxidation, in 13% yield; Scheme 1).
It is in fact likely that it is not the trapping step that limits the yield obtained from 2-picoline (1a); indeed, the teams of Mulvey and Robertson demonstrated a significant carbanionic character for the α-lithiated 2-picoline³⁵ which makes it a good nucleophile.

In order to confirm that 4-picoline (2a) is easier to functionalize than 2-picoline (1a), we carried out a competition experiment by treating a solution containing equimolar amounts of 1a and 2a in THF; this led to the unique formation of the alcohol 2b, consistent with greater stability of 4-picolyllithium. A similar result was obtained from isolated [(LiNET₂)₄·(thf)₂] (A).

<figure><img src="image_5.png" /><figcaption>**Scheme 1.** Use of LiNET₂ (1 equiv) to convert 2- and 4-picolines (1a and 2a) to the alcohols **1b** and **2b**.</figcaption></figure>

As the reactions shown in Scheme 1 gave the products in moderate yields, we next investigated the impact of base amount in the case of 2,4-lutidine (3a). Use of LiNET₂ (2 equiv) was beneficial, affording the alcohol 3b resulting from a functionalization of the methyl at C4 in 56% yield, and the corresponding ketone in 11% yield (Scheme 2; the rest is 3a).

<figure><img src="image_6.png" /><figcaption>**Scheme 2.** Use of LiNET₂ (2 equiv) to convert 2,4-lutidine (3a) to the alcohol 3b.</figcaption></figure>

N,N-diethyl-4-methylnicotinamide (4a1) was previously successfully functionalized on its methyl group by Chapleur and co-workers by using s-butyllithium in THF at -80 °C.³⁶ Moreover, hindered secondary lithium amides have also been used to α-functionalize the related ethyl nicotinate and nicotinonitrile.³⁷ Inspired by these results, we therefore decided to explore the functionalization of 4a1 by using LiNET₂ before carrying out the interception with 4-anisaldehyde. While the use of LiTMP (2 equiv, THF, -50 °C, 1 h) led to the expected alcohol 4b in 72% yield, the latter was formed in <20% yield by using LiNET₂ (2 equiv) due to 66% recovery of 4a1 and concomitant formation of an unidentified product (low yield).

We previously showed that ZnCl₂·TMEDA (TMEDA = N,N,N',N'-tetramethylethylenediamine) could be used as an in-situ trap to make the deprotometallation-trapping sequences

more efficient.³⁸ Therefore, the reaction using LiNET₂ was repeated in the presence of this chelate, resulting in the alcohol 4b in 52% improved yield (36% recovery of 4a1; Scheme 3, top). However, when the diethylcarboxamide group was replaced by a methyl ester, the function was also attacked by the base as expected when treating an ester with an unhindered lithium amide at a temperature between -78 °C and 20 °C,³⁹ leading to this same 4b in 54% yield (Scheme 3, bottom).

<figure><img src="image_7.png" /><figcaption>**Scheme 3.** Use of lithium dialkylamides (2 equiv) to convert the 3-substituted 4-picolines 4a1 and 4a2 to the alcohol 4b.</figcaption></figure>

When (dialkylaminomethyl)pyridines are sought from methylpyridines, the approach generally employed consists in α-halogenating the latter in order to carry out a nucleophilic substitution by the desired amine⁴⁰ (Scheme 4, top). Since diethylamine is present after deprotolithiation of picoline using LiNET₂, we felt that it would be possible to access the diethylaminomethylated pyridines from 1a and 2a by simply adding iodine instead of 4-anisaldehyde as an electrophile to generate the corresponding α-iodinated picolines in situ. However, since these α-iodinated picolines are likely to react with the α-metallated picolines, we considered a reverse addition for the trapping step as well as the use of an excess of iodine. Finally, we preferred to add additional diethylamine (3 equiv) at -50 °C before warming to room temperature to favour the substitution step (Scheme 4, bottom).

<figure><img src="image_8.png" /><figcaption>**Scheme 4.** Classical (top) and planned (bottom) approaches leading to (dialkylaminomethyl)pyridines.</figcaption></figure>

Under these conditions, the expected amines 1d and 2d were isolated, but in moderate 19% and 27% yield, respectively (Scheme 5). In contrast, starting from methyl 5-methylnicotinate (5a), an attempt (not shown) to apply the same protocol only led to the corresponding N,N-diethylcarboxamide 5b in 74% yield (58% yield in the absence of ZnCl₂·TMEDA). This result is as anticipated, as the corresponding anion charge cannot be delocalized on the ring nitrogen.
<figure><img src="image_9.png" /></figure>

1a

1) ZnCl₂·TMEDA (1 equiv)

2) LiNET₂ (2 equiv)

<figure><img src="image_10.png" /></figure>

<figure><img src="image_11.png" /></figure>

1d: 19%

<figure><img src="image_12.png" /></figure>

2a

3) I₂ (5 equiv), THF, -50 °C

(reverse addition)

4) Et₂NH (3 equiv)

-50 °C to rt

<figure><img src="image_13.png" /></figure>

2d: 27%

<caption>**Scheme 5.** Use of lithium dialkylamides (2 equiv) to convert 2- and 4-picolines (1a and 2a) to the amines 1d and 2d.</caption>

In order to confirm the greater reactivity at C4 compared to C2 observed in the presence of ZnCl₂·TMEDA (Scheme 5), we carried out a similar reaction starting from 2,4-lutidine (3a). When compared with the results depicted on Scheme 2, a mixture of the two isomers **3d1** and **3d2** was surprisingly formed under these conditions in a 74:26 ratio (35% yield; Scheme 6, top). Furthermore, a similar ratio was obtained when ZnCl₂·TMEDA was added after the deprotolithiation step (38% yield; Scheme 6, bottom).

<figure><img src="image_14.png" /><figcaption>**Scheme 6.** Use of lithium dialkylamides (2 equiv) to convert 2,4-lutidine (3a) to the amines **3d1** and **3d2**.</figcaption></figure>

These results led us to take a close interest in the studies already carried out on the deprotometallation of 2,4-lutidine (3a; Figure 3). Kaiser and co-workers observed back in 1973 that sodium (or potassium) amide in liquid ammonia, as well as LiDA in diethylether-hexane, were suitable methods to selectively access the 2,4-lutidine α-metallated at C4 (shown by subsequent trapping using various electrophiles).⁴¹ In contrast, the 2,4-lutidine α-metallated at C2 was instead obtained by using *n*-butyllithium in diethylether-hexane⁴¹ or sodium amide in THF.⁴² Additionally, while only the methyl at C2 is attacked with phenyllithium, a mixture (~80:20, this time in favour of the C4 deprotometallation) was obtained by Levine and co-workers when testing a stronger base, phenylsodium, in benzene.⁴²

These studies tend to indicate that the coordination of the base metal by the pyridine nitrogen (Li > Na) promotes a first reaction on the methyl at C2. Under kinetic conditions (non-reversible reaction; for example in the case of *n*-BuLi⁴¹ or when LiDA is used at -78 °C⁴³), it is therefore the 2,4-lutidine α-metallated at C2 which is formed and then intercepted by the electrophile. However, under thermodynamic conditions, for example when LiDA is used under conditions where the reaction is an equilibrium,⁴¹ or with less basic LiNET₂ at -50 °C³a (the use of -78 °C led to a ~80:20 mixture),⁴³ it is the more stable 2,4-lutidine α-metallated at C4 (higher acidity of the methyl at C4) which is eventually trapped.

Thus, when instead of LiNET₂, *n*-butyllithium was first added (deprotonation of the methyl at C2) followed by diethylamine (to

make the reaction reversible and go to the more stable lithiated product), the selective formation of the 4-functionalized product was observed.³a However, upon interception with different electrophiles, Ragan and co-workers obtained various yields from the 2,4-lutidine α-metallated at C4 using LiNET₂: no reaction with trialkylborates, diphenyldisulfide, dimethylcarbonate and carbon dioxide, but dimethylformamide, chlorotrimethylsilane and chloromethyldiphenylsilane gave the expected products.⁴⁴ One reason for these discrepancies could be the predominance of the metal enamide form over the picolylmetal form.¹¹c,⁴⁵ Moreover, the use of O-ethylchloroformiate having led only to the *N*,*N*-diethylcarbamate, the lithium amide and the α-lutidyllithium formed both seem likely to react with the electrophile.⁴⁴

In the present study, the addition of ZnCl₂·TMEDA at the start of the reaction was attempted in order to shift the equilibria towards the metallated derivatives of picolines or 2,4-lutidine, and this goal was achieved to some extent. However, in the latter case (**Test A**), the result of the reaction indicates that two α-metallated 2,4-lutidines are present before the trapping step. We therefore added ZnCl₂·TMEDA after 1 h at -50 °C in order to transmetallate the 2,4-lutidine selectively α-lithiated at C4 (**Test B**). However, the formation of the two products in a similar ratio seems to show closer stabilities for the two α-zincated 2,4-lutidines. Consistent with these results, it is worth noting that the two α-zincated 2,4-lutidines were also formed when Knochel and co-workers used TMPZnCl·LiCl in THF to perform the reaction.⁴⁶

In order to further investigate the role that ZnCl₂·TMEDA might play in these reactions, we decided to turn to the quinoline and quinoxaline series because these aromatic heterocycles are more prone to nucleophilic attacks than pyridines.⁴⁷

## Functionalization in the quinoline series

Like pyridines, methylquinolines have already been α-functionalized by deprotometallation-trapping using different bases¹³,³⁹ (Figure 4).¹⁵,⁴¹ As for 2-methylquinoline, *n*-butyllithium, for example, has been used successfully whether in diethylether⁴⁸ or THF.⁴⁹ Since the α-deprotometallated product is stabilized in its metal enamide form, weaker bases such as potassium amide in ammonia,⁵⁰ potassium bis(trimethylsilyl)amide in toluene,⁵¹ and LiDA in THF⁵² have also been employed.

Compared to its 2-isomer, the α-functionalization of 3- and 4-methylquinolines is less easy due to their sensitivity to nucleophilic attacks; therefore, organolithiums such as *n*-butyllithium and phenyllithium cannot be used.⁵³ However, less nucleophilic *N*,*N*-disubstituted metal amides such as LiDA,⁵⁴ as well as lithium,⁵⁵ sodium⁵⁶ and potassium⁵¹ bis(trimethylsilyl)amides have been successfully employed in THF in the case of 4-methylquinoline. From 3-methylquinoline, aroylation could be achieved by treatment with an excess of lithium bis(trimethylsilyl)amide and cesium fluoride in 2-methyltetrahydrofuran (2MeTHF) at 110 °C.⁵⁷
<figure><img src="image_15.png" /><figcaption>**Figure 4.** Bases already employed to functionalize 2-, 3- and 4-methylquinolines, and 2-methylquinoxaline.</figcaption></figure>

We started our study in the quinoline series with the 2-methylated derivative (6a). When treated successively with LiNET₂ (1 equiv) in THF at -50 °C for 1 h and 4-anisaldehyde from -50 °C to room temperature, the alcohol 6b was isolated in 60% yield (Scheme 7, top). The rest was recovered 6a and a product resulting from elimination. In contrast, using N,N-dimethylmethyleneiminium iodide (Eschenmoser's salt) as an electrophile did not afford the expected amine 6c but the alcohol 6d (41% yield; Scheme 7, middle), identified by ¹H, Jmod, HSQC and HMBC NMR, and HRMS data. However, replacing LiNET₂ with LiTMP, 6c was this time isolated in 44% yield (Scheme 7, bottom), which tends to indicate a non-innocent, although still unidentified, role of the amine.

<figure><img src="image_16.png" /><figcaption>**Scheme 7.** Use of LiNET₂ to convert 2-methylquinoline (6a) to the alcohols 6b and 6d, and use of LiTMP to convert 6a to the amine 6c.</figcaption></figure>

While 2-(aroylmethyl)quinolines can be prepared by the reaction between 2-quinolylmethylmetals and aromatic esters,⁵⁸ we were curious to see if other electrophiles could be used. O-Aroylated secondary hydroxylamines are capable of releasing either their dialkylamino or their aroyl group, depending on the reaction conditions. For example, McDonald and Wang showed that zinc enolates could react with them to provide 1,3-dicarbonylated compounds while the introduction of a copper catalyst led to α-aminated products.⁵⁹ Therefore, in order to obtain α-aminated compounds, we transmetallated the 2-quinolylmethylthyllithium formed in THF by deprotometallation using LiNET₂ into the 2-quinolylmethylzinc chloride, then treated by N-(benzoyloxy)morpholine in the presence of catalytic copper(II)

acetate. However, under these conditions, the expected amine did not form; instead, we obtained the ketone 6e in 67% yield, isolated in its enolic form.⁶⁰

Without a copper source, the reaction worked similarly (6e isolated in 65% yield), even when ZnCl₂·TMEDA was introduced before the base (62% yield; Scheme 8). However, when N-(benzoyloxy)morpholine was replaced by benzoyl chloride in the reaction without a copper source, the substrate 6a was completely recovered and we only obtained the N,N-diethylbenzamide resulting from the reaction between LiNET₂ and the electrophile. This result is consistent with that of Ragan and co-workers who noticed, during different electrophilic trappings of the 2,4-lutidine similarly α-lithiated at C4, that O-ethylchloroformiate did not behave as expected, only leading to the N,N-diethylcarbamate.⁴⁴

<figure><img src="image_17.png" /><figcaption>**Scheme 8.** Use of LiNET₂ to convert 2-methylquinoline (6a) to the ketone 6e.</figcaption></figure>

When 2-(dialkylaminomethyl)quinolines are required from 2-methylquinolines, oxidation of the methyl group to the aldehyde followed by reductive amination using sodium triacetoxyborohydride is usually preferred⁶¹ (Scheme 9, top).

<figure><img src="image_18.png" /></figure>

In search of a more straightforward approach (Scheme 9, bottom), we added iodine to the 2-quinolylmethylthyllithium formed by the reaction of 6a with LiNET₂. Instead of the desired amine, we observed the formation of the dimer 6f as one would expect⁶² (33% yield when 1 equiv of base was employed; Scheme 10, top and Figure 5, top). This indicates that, as soon as it is formed, 2-(iodomethyl)quinoline is attacked by 2-quinolylmethylthyllithium still present in the reaction medium. We therefore adapted the procedure used in the picoline series. Under the conditions of Scheme 5, 2-methylquinoline (6a) was converted to the expected amine 6g, but the latter could not be isolated due to the formation of another product of similar polarity (not shown). This led us to modify the procedure in order to favour the formation of 6g.

Accordingly, when ZnCl₂·TMEDA (1 equiv) was added to the 2-quinolylmethylthyllithium (formed by using 1 equiv of LiNET₂ at
–20 °C for 1 h), we also noticed the formation of **6g** after transfer to the solution of iodine (1 equiv) and subsequent reaction with diethylamine (1 equiv), this time successfully isolated in 40% yield (Scheme 10, bottom). However, despite other attempts (see experimental section), we could not improve this result due to inseparable remaining **6a** and unidentified products.

<figure><img src="image_19.png" /><figcaption>**Scheme 10.** Use of LiNET₂ to convert 2-methylquinoline (6a) to the dimer 6f and the amine 6g.</figcaption></figure>

<figure><img src="image_20.png" /><figcaption>**Figure 5.** ORTEP diagrams (30% probability) of 6f (top) and ZnI₂·6h (bottom).</figcaption></figure>

In an attempt to get an idea of the product of similar polarity formed in most of the reactions tested to obtain **6g**, a reaction inspired from Scheme 5, but using a different amine, was carried out from **6a**. Thus, by replacing diethylamine by morpholine in the last step, the by-product **6h** was isolated from the crude by column chromatography in 57% yield. Although its identification has proven difficult on the sole basis of its NMR spectra, crystals suitable for X-ray diffraction analysis were pleasingly collected to allow unambiguous attribution (Scheme 11 and Figure 5, bottom). The reasons for the formation of the morpholinomethylated **6h** instead of **6g** could be the destruction of LiNET₂⁶³ and possibly the corresponding amine⁶⁴ in contact with iodine (–50 °C to rt) and the excess morpholine employed. It should be noted that while zinc ligands incorporating 2-(aminomethyl)quinolines are known (e.g. for applications as fluorescent sensors),⁶⁵ such complexes with zinc iodide have, to our knowledge, never been reported.⁶⁶

<figure><img src="image_21.png" /><figcaption>**Scheme 11.** Use of LiNET₂ to convert 2-methylquinoline (6a) to the amine 6h</figcaption></figure>

(isolated as a complex).

In parallel, a few reactions were carried out from 4-methylquinoline (7a). Before knowing that it was possible to deprotometallate the substrate with LiNET₂ and perform the halide substitution with an amine other than diethylamine, we had tested other lithium dialkylamides. First, we had attempted to repeat the reaction depicted in Scheme 5 by replacing LiNET₂ and diethylamine with lithium morpholide⁶⁷ (LiM) and morpholine, respectively. Surprisingly, after subsequent heating at 60 °C overnight with morpholine (3 equiv), 4-formylquinoline (7b) was isolated in 40% yield instead of the expected amine (Scheme 12, top). To ensure that the oxygen was not coming from morpholine, the reaction was repeated with LiNET₂ and diethylamine; under the above conditions, the aldehyde 7b was again obtained (18% yield). However, in a parallel experiment scrupulously respecting the conditions of Scheme 5 with LiNET₂ and diethylamine, the aldehyde 7b was not formed but the expected amine (7e in Scheme 13; 70% yield). These results seem to show that the amine is formed, but is transformed in the reaction mixture during the prolonged heating to give the aldehyde 7b after the work-up.

Next, we replaced the LiNET₂ and diethylamine used in Scheme 5 with lithium pyrrolidide (LiPy) and pyrrolidine, respectively. This time, after subsequent heating at 60 °C overnight with pyrrolidine (3 equiv), it is the ethylenic product 7c which was isolated in 72% yield (Scheme 12, middle; Figure 6, top). As this compound is generally formed by reaction between 4-methylquinoline (7a) and 4-formylquinoline (7b),⁶⁸ it could also result here from a condensation reaction (addition of a 4-quinolylmethylzinc to 7b followed by elimination). Finally, although in a moderate 18% yield, we were able to isolate the expected amine 7d by using lithium piperidine (LiPi) and piperidine, provided the trapping conditions were made milder (Scheme 12, bottom).

<figure><img src="image_22.png" /><figcaption>**Scheme 12.** Use of lithium amides to convert 4-methylquinoline (7a) to the aldehyde 7b, the ethylenic product 7c, and the amine 7d.</figcaption></figure>
<figure><img src="image_23.png" /><figcaption>**Figure 6.** ORTEP diagrams (30% probability) of **7c** (top), **8b** (bottom left) and **8c** (bottom right).</figcaption></figure>

These results show a great potential for using lithium amides in combination with zinc-based *in-situ* traps to functionalize quinolines. However, this would require additional work that is beyond the scope of this study. We therefore refocused on our objective, which was to study the behaviour of these substrates towards $LiNEt_2$. By applying the conditions of *Test A* to functionalize 2,4-lutidine (**3a**) (Scheme 6), 2-(dimethylaminomethyl)quinoline (**7e**) was finally obtained from **7a** in 74% yield. To promote the formation of the dimer **7f**, instead of transferring the 4-quinolylmethylzinc into the iodine solution, the opposite was done instead, leading to the desired product **7f** in 80% yield (Scheme 13).

<figure><img src="image_24.png" /><figcaption>**Scheme 13.** Use of $LiNEt_2$ to convert 4-methylquinoline (7a) to the amine 7e and the dimer 7f.</figcaption></figure>

The role of $ZnCl_2 \cdot TMEDA$ in the reaction giving amines such as 7e is fundamental. Indeed, when the reaction of Scheme 13, top was carried out in the absence of this chelate, 7e was not formed and the dimer 7f was found to be the main product (71% yield); this result is similar to that observed when iodine was

added to the formed 4-quinolylmethylthium (72% yield; Scheme 14).

<figure><img src="image_25.png" /><figcaption>**Scheme 14.** Use of $LiNEt_2$ without $ZnCl_2 \cdot TMEDA$ to convert 4-methylquinoline (7a) to the dimer 7f.</figcaption></figure>

For comparison purpose, additional reactions were also studied with an alkyllithium. When the reaction in Scheme 13, top was performed with *n*-butyllithium (1 equiv) instead of $LiNEt_2$, no reaction took place, probably because the base first attacks $ZnCl_2 \cdot TMEDA$ (not shown). When *n*-butyllithium (1 or 2 equiv) was added before $ZnCl_2 \cdot TMEDA$, for a reaction carried out in the presence of catalytic diethylamine (0.2 equiv), the dimer **7f** and the butylated product **7g** were formed (not shown). However, the latter became the major product (isolated in 69% yield) when *n*-butyllithium was added to **7a** before $ZnCl_2 \cdot TMEDA$ (Scheme 15); this is a logical outcome since the 2- or 4-unsubstituted quinolines are heterocycles subject to nucleophilic attack.⁴⁷b

<figure><img src="image_26.png" /><figcaption>**Scheme 15.** *n*BuLi-mediated conversion of 4-methylquinoline (7a) to the butylated 7g.</figcaption></figure>

As observed previously from its 2-isomer **6a**, the use of aroyl chlorides (benzoyl and 3-methoxybenzoyl chlorides) to intercept the 4-quinolylmethylthium (prepared according to Scheme 11) failed to delivering the *α*-aroylated products. Indeed, after 12 h at room temperature, the substrate **7a** was recovered while the corresponding *N*,*N*-diethylbenzamide derivatives were the only products formed (by reaction between $LiNEt_2$ and the electrophile; not shown). Thus, we instead used *N*-(*benzoyloxy*)morpholine, under the conditions of *Test D* (Scheme 8), to test the reactivity of the *α*-metallated derivative of 2-chloro-4-methylquinoline (**8a**). Surprisingly, the expected ketone **8b** was only obtained in ~20% yield (due to inseparable starting material) while the product **8c** resulting from the substitution of the chloro group by the released benzoyloxide was isolated in 43% yield. Fortunately, crystals of the latter have been obtained, allowing its structure to be unambiguously confirmed by X-ray diffraction (Scheme 16; Figure 6, bottom). Indeed, very few compounds of this type have already been described (e.g. 2-(*tert*-butyl)-3-phenyl-2,3-dihydroisoxazolo[5,4-*b*]pyridine, obtained by intercepting a benzyne intermediate by a nitrone).⁶⁹
<figure><img src="image_27.png" /><figcaption>**Scheme 16.** Use of LiNET₂ to convert 2-chloro-4-methylquinoline (8a) to the ketone 8b.</figcaption></figure>

These data suggest that after deprotolithiation using LiNET₂, the reactivity of the α-lithiated derivative of 4-methylated quinolines is lower than that of the 2-methylated ones. This was further confirmed by reacting the 4-quinolylmethyl lithium with 4-anisaldehyde towards the alcohol 7h (39% yield). In contrast, by replacing LiNET₂ with LiTMP, 7h was obtained in a high yield of 82% (Scheme 17, top). Similarly to the results obtained from 6a (Scheme 7), deprotolithiation of 4-methylquinoline (7a) using LiNET₂ followed by treatment with Eschenmoser's salt as an electrophile (–50 °C to rt and 12 h at rt) did not lead to the expected amine (not shown). A few more control experiments using LiTMP were then carried out from 8a. By using this lithium amide which favours the deprotolithiated species, the alcohol 8d and the amine 8e could be isolated in 88% and 39% yield, respectively (Scheme 17, bottom).

<figure><img src="image_28.png" /><figcaption>**Scheme 17.** Use of LiNET₂ or LiTMP to convert 4-methylquinoline (7a) to the alcohol 7h, and use of LiTMP to convert 2-chloro-4-methylquinoline (8a) to the alcohol 8d and the amine 8e.</figcaption></figure>

## Functionalization in the quinoxaline series

Since quinoxalines without substituent in position C2 or C3 are prone to nucleophilic attack,⁴⁷a only non-nucleophilic bases can be used (Figure 4). For example, to prepare 1-phenyl-2-(2-quinoxalyl)ethanol from 2-methylquinoxaline (9a), Yu and coworkers efficiently employed LiDA in THF at room temperature before quenching with benzaldehyde.⁷⁰ Thus, we decided to investigate whether LiNET₂ and LiTMP could be used in a similar way.

For this purpose, 9a was successively treated with a lithium amide (2 equiv) in THF at –50 °C for 1 h and 4-anisaldehyde (1.2 equiv). While LiTMP afforded the expected alcohol 9b in

67% yield, the use of LiNET₂ led to the same product less efficiently, notably due to the formation of the elimination product 9c (Scheme 18, top). Both reactions were also carried out by adding the lithium amide (2 equiv) to a solution of 9a containing ZnCl₂·TMEDA (1 equiv). Under these conditions, a different result was observed, the diol 9d being the main product formed. Similar yields between LiNET₂ and LiTMP were recorded this time (Scheme 18, middle), and these yields for this bis-functionalized product are excellent given that 4-anisaldehyde was used at 1.2 equivalents. Such results suggest that the second deprotometallation takes place during the trapping step, and that the trapped intermediate might be sufficiently activated (Scheme 18, bottom).

Of note, our attempt to replace 4-anisaldehyde with N-(benzoyloxy)morpholine after reaction with LiTMP failed to deliver a ketone (9a recovered), suggesting a highly electrophile-dependent reaction. Additionally, when LiNET₂ (1 equiv) was employed, no alcohol was obtained in significant amounts, either with or without ZnCl₂·TMEDA.

<figure><img src="image_29.png" /><figcaption>**Scheme 18.** Use of LiNET₂ or LiTMP to convert 2-methylquinoxaline (9a) to the alcohol 9b or the diol 9d.</figcaption></figure>

## Conclusion

Here, we presented a detailed study on the use of lithium diethylamide in the deprotometallation of aromatic substrates. Consistent with the lower pKₐ value of diethylamide compared to more hindered secondary amines such as diisopropylamine and 2,2,6,6-tetramethylpiperidine, deprotometallation reactions using LiNET₂ preferentially lead to the most stable metallated derivatives. However, the observed conversions are in general lower, and it is often necessary to use either an excess of base or an *in-situ* trap to shift the equilibrium towards the formation of the expected metallated derivatives.

Furthermore, we evidenced that the use of iodine as an electrophile requires care, as it otherwise leads to the formation of dimers. Interestingly, by using ZnCl₂·TMEDA as an *in-situ* trap and adding the reaction mixture to the iodine used in excess, we succeeded in excluding formation of this dimer and in reacting
the iodinated derivative with a secondary amine, ultimately
leading to aminomethylated derivatives.

However, due to this more pronounced equilibrium with LiNEt₂ than with more hindered lithium dialkylamides, subsequent electrophilic trapping can be complicated. For example, aroyl chlorides are more easily attacked by the lithium amide than by the metallated derivative. Finally, the fact that the α-metallated derivative is stabilized in a tautomeric form where the metal is fixed on the ring nitrogen (metal enamide) also complicates the trapping step.

We believe that this study will ease the introduction of this
small lithium amide into the toolbox of organic reagents to
promote reactions otherwise difficult to perform.

Experimental Section

General information, preparation and analyses of the compounds, as well
as NMR spectra of the products A', **3b**, **4b**, **5b**, **6b**, **6d**, **6f**, **6g**, ZnI₂·6h,
**7c**, **7e**, **7h**, **8c**, **8d**, **8e**, **9b** and **9d**.

Crystallographic data

Deposition Number 2267122 (for A), 2267236 (for 6f), 2267237 (for ZnI2·6h), 2267238 (for 7c), 2267239 (for 8b), 2267240 (for 8c) contain the supplementary crystallographic data for this paper. These data are provided free of charge by the joint Cambridge Crystallographic Data Centre and Fachinformationszentrum Karlsruhe Access Structures service.

Acknowledgements

We thank the Université de Rennes, the Centre National de la
Recherche Scientifique (CNRS), the Fondation d'Entreprise
Grand Ouest and the Tunisian Ministry of Higher Education and
Scientific Research (grant for M. H.) for supporting this research.
We acknowledge the Fonds Européen de Développement
Régional (FEDER; D8 VENTURE Bruker AXS diffractometer)
and Thermofisher (generous gift of 2,2,6,6-tetramethylpiperidine).
Financial support from the Agence Nationale de la Recherche is
acknowledged (PhD grant to P.M.C., ANR-17-CE07-0017-01).
F. M. would like to thank Dr. W. Erb for his technical assistance,
his critical review of this document and his valuable suggestions.

Keywords: lithium diethylamide; α-deprotometallation; pyridine; quinoline; quinoxaline

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Entry for the Table of Contents

FULL PAPER

<figure><img src="image_30.png" /></figure>

The behaviour of methylated heterocycles (picolines, 2,4-lutidine, methylquinolines and 2-methylquinoxaline) in deprotometallation-trapping sequences using lithium diethylamide was studied.

Lithium dialkylamide

Mohamed Hasyeoui, Peter M. Chapple,
Frédéric Lassagne, Thierry Roisnel, Marie
Cordier, Ali Samarat, Yann Sarazin and
Florence Mongin*

Page No. – Page No.

Lateral Deprotometallation-Trapping
Reactions on Methylated Pyridines,
Quinolines and Quinoxalines Using
Lithium Diethylamide