Functionalization of pyridyl ketones using deprotolithiation-in situ zincation

Abstract

The metallation of aryl ketones was achieved by using LiTMP in the presence of ZnCl₂·TMEDA, as evidenced by subsequent interception with iodine or by a palladium-catalysed cross-coupling reaction. One of the synthesized iodo ketones has been further elaborated to reach derivatives of biological interest.

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Pyridines play a large part in biological processes (nicotine, niacin, NADP, vitamin B₆…), in pharmaceuticals and agrochemicals,¹ as well as in organic materials.² In addition, pyridyl ketones bearing a halogen at the position adjacent to the carbonyl function are key intermediates to access heterocyclic scaffolds of interest such as azafluorenones,³ azaxanthones,⁴ naphthyridones,⁵ and thieno-,⁶ pyrazolo-⁷ and isoxazolo-pyridines.⁸

Even if deprotonative lithiation⁹ has been largely used to regioselectively functionalize pyridines,¹⁰ the method has never been extended to pyridyl ketones due to their low compatibility with organolithiums. Mixed lithium–nonalkali metal combinations have been developed to achieve chemoselective deprotometallation of aromatics.¹¹ In this context, the 1 : 1 mixture of homometallic amides LiTMP (TMP = 2,2,6,6-tetramethylpiperidino) and Zn(TMP)₂,¹² obtained by mixing in a 3 : 1 ratio LiTMP and ZnCl₂·TMEDA (TMEDA = N,N,N′,N′-tetramethylethylenediamine) in THF (THF = tetrahydrofuran), was successfully employed with a large range of sensitive substrates.¹³ Such a synergy, attributed to reversible deprotolithiation shifted by zinc-mediated transmetallation¹² (or ‘trans-metal trapping’¹⁴), has since been extended to the use of LiTMP in the presence of ZnCl₂·2LiCl, MgCl₂ or CuCN·2LiCl.¹⁵

Herein, we report the efficiency of aryl ketones as directing groups for LiTMP-mediated deprotometallation of pyridines and other arenes in the presence of ZnCl₂·TMEDA as in situ trap (Scheme 1, Table 1).

Scheme 1 Zincation of aryl ketones 1 using LiTMP in the presence of ZnCl₂·TMEDA followed by iodolysis or palladium-catalysed cross-coupling to afford ketones 2 and 2′m.

Table 1 Substrates 1a–l, calculated pK_a (THF) values for 1j and 1k, conditions used for the deprotolithiation-zincation, and iodinated aryl ketones 2a–l obtained

Entry	Substrate/n/temperature	Product/yield^a (%)
a Yield after purification by column chromatography.b 4-Benzoyl-3,5-diiodopyridine (2b′) was also obtained in 10% yield.c 1,5-Diiodo-4-azafluorenone (2j′) was also obtained in 20% yield.d 1,6-Diiodo-4-azaxanthone (2k′) was also obtained in 10% yield.
1
2
3
4
5
6
7
8
9
10
11
12

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Thus, after optimization of the reaction conditions (using four different reaction temperatures from −70 to −10 °C and different amounts of LiTMP from 1 to 3 equiv.), treatment of 2-benzoylpyridine (1a) in THF containing ZnCl₂·TMEDA (1 equiv.) with LiTMP (1.5 equiv.) at −30 °C for 15 min and then iodine led to the 3-iodo derivative 2a in 50% yield (entry 1). Similarly, 4-benzoylpyridine (1b) was converted to the 3-iodo derivative 2b by using LiTMP (2 equiv.); with this substrate benefiting from two free positions adjacent to the benzoyl group, a second deprotonation was observed to some extent, as evidenced by the competitive formation of the diiodo 2b′ (entry 2).

3-Benzoylpyridine (1c) is more prone to nucleophilic attack onto the ring than its 2- and 4-isomers.¹⁶ As a consequence, deprotolithiation-zincation could only be evidenced by subsequent iodolysis at temperatures below −50 °C. Using LiTMP (1.5 equiv.) at −55 or −70 °C for 15 min and then iodine provided the 4-iodo derivative 2c in 30 or 37% yield, respectively (entry 3).

When present at pyridine 2-position, halogens are known to acidify the 4-position, as shown by pK_a values calculated in THF.^13a The 2-halogeno 3-benzoylpyridines 1d–h were thus prepared.¹⁷ Accordingly, when similarly reacted by using LiTMP at −55 °C, the iodo derivatives 2d–g were isolated in improved yields, in line with the long range effects of fluorine and chlorine (entries 4–7). In contrast, the reaction from 1h proved more complex, giving the iodide 2h in a modest yield (entry 8).

The presence of a methoxy group at 2-position of 3-benzoylpyridine also had a positive impact on the course of the reaction since involving 1i in the sequence furnished the iodo derivative 2i in 88% yield (entry 9). Whereas this group does not acidify remote pyridine 4-position,^13b it acts by making the pyridine ring less sensitive towards competitive nucleophilic attack. Indeed, based on the ¹H NMR chemical shifts in CDCl₃ of 1c (8.12 and 8.82 ppm for H4 and H6, respectively) and 1i (7.72 and 8.32 ppm for H4 and H6, respectively), one can predict as shown by Handy and Zhang¹⁸ that the partial positive charges at C4 and C6 will be reduced for 1i.

The behaviour of the ketones 1j–l, possessing reduced flexibility on carbonyl direction, was similarly examined. 4-Azafluorenone (1j) was converted to the 1-iodo derivative 2j in a moderate yield, similar to that obtained from 3-benzoylpyridine (1c). In the case of 1j, the phenyl ring was also attacked to a lesser extent at a position facing the pyridine nitrogen to afford the diiodide 2j′ (entry 10, Fig. 1). In contrast with the reaction from 1j, the sequence using 4-azaxanthone (1k) and 4-azathioxanthone (1l) provided the iodides 2k and 2l in higher 60% yields (entries 11 and 12).

Fig. 1 ORTEP diagrams (30% probability) of compounds 2j′ and 2k′.

In order to evaluate the scope of the method, we chose other aromatic substrates.¹⁹ When compared with its 4-aza analogue 1k, xanthone (1m) similarly led to the 1-iodo 2m in 72% yield. On the contrary, as previously noted between 1j and 1k, the reaction from 1n was less efficient than from 1m. Indeed, 1-iodofluorenone (2n) was obtained in 52% yield, but together with the ketone 2n′ (35% yield) resulting from an addition of the metallated product to 1n (Scheme 1, Table 2). As organozincs hardly react with ketones, the product 2n′ could rather result from an addition of 1-lithiofluorenone to 1n more rapid than its trapping by the zinc species. These results suggest that the carbonyl direction in the metallated derivative coming from 1n is less prone to stabilize a 1-lithio compound than that from 1m.

Table 2 Substrates 1m and 1n and their calculated pK_a (THF) values, conditions used for the deprotolithiation-zincation, iodinated aryl ketones 2m and 2n obtained, and ORTEP diagram (30% probability) of compound 2n′

Entry	Substrate/n/temperature	Product/yield^a (%)
a Yield after purification by column chromatography.
1
2
3

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Interestingly, the deprotolithiation-in situ zincation could be combined with a subsequent Negishi cross-coupling reaction.²⁰ Thus, using catalytic amounts of PdCl₂ as palladium source and 1,1′-diphenylphosphinoferrocene (dppf) as ligand with 2-chloropyridine^12a allowed 2′m to be formed from 9-xanthone (1m) in 76% yield (Scheme 1).

CH acidities are in general useful data to better understand deprotometallation outcomes, in particular regarding regioselectivity issues. We thus calculated selected pK_a values in THF solution by means of quantum chemistry at the DFT B3LYP level of theory.¹³ After geometry optimization and calculation of the vibrational frequencies by using the 6-31G(d) basis set, the single point energies were obtained using the 6-311+G(d,p) basis set. The solvent influence was treated through the polarized continuum model (PCM) with the default parameters for THF. Finally, the pK_a values were reached from the Gibbs energy of the homodesmic reaction between the studied and probe heterocycles.

That both sets of CH acidity values for 1m and 1n are rather similar (Table 2) supports the role of the carbonyl direction on the course of the reaction through coordination. Analogously, the difference observed between the pK_a values of 1j and 1k is not significant enough to allow for a rationalization of the distinct yields noted, rather suggesting a more efficient stabilization of the metallated compound by the carbonyl group in the case of 1k at the origin of the higher yield. Besides, the formation of dimetallated products from 1j and 1k, as demonstrated by isolation of 2j′ and 2k′ (Fig. 1), could be favoured for the former by a nitrogen assistance and, for the latter, by a relatively low pK_a value (35.6) at the 6-position (Table 1).

Finally, when 2-benzoylthiophene (1o) was submitted to LiTMP in the presence of ZnCl₂·TMEDA as before, the reaction took place next to sulphur to afford after iodolysis the iodo derivative 2o in 80% yield (Scheme 2).

Scheme 2 Zincation of phenyl 2-thienyl ketone (1o) using LiTMP in the presence of ZnCl₂·TMEDA followed by iodolysis to afford the iodinated 2-thienyl ketone 2o.

To move towards nitrogen-containing derivatives of biological interest, 2-benzoyl-3-iodopyridine (2a) was involved in further reactions (Scheme 3). A catalyst–base system was first optimized to perform guanidine copper-catalysed N-arylation.²¹ Upon treatment with K₃PO₄ as base and CuI as catalyst source in the presence of DMSO, the iodide 2a was converted to the pyrido[3,2-d]pyrimidine 3a in 77% yield. Besides, cyclizing Suzuki coupling²² was performed from the ketone 2a and 2-aminophenylboronic acid under palladium catalysis to provide 5-phenylbenzo[f][1,7]naphthyridine (4a)²³ in 68% yield.

Scheme 3 Conversion of 2-benzoyl-3-iodopyridine (2a) to derivatives of biological interest.

In summary, we have reported a short and simple access to iodinated aryl ketones. Additionally, transition metal-mediated reactions occurring with cyclization led to elaborated scaffolds. Applications towards the synthesis of libraries of compounds for biological evaluation are currently under investigation in our laboratory.

Acknowledgements

We thank the Ministère de l'Enseignement supérieur et de la Recherche scientifique Algérien (M. H.), the Centre national de la recherche scientifique and the Institut Universitaire de France (F. M.). We acknowledge FEDER founds (D8 VENTURE Bruker AXS diffractometer) and Thermo Fisher (generous gift of 2,2,6,6-tetramethylpiperidine). This research has been partly performed as part of the CNRS PICS project “Bimetallic synergy for the functionalization of heteroaromatics”.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available: General procedures, experimental procedures and compound characterizations, ¹H and ¹³C NMR spectra of the new compounds, and X-ray crystallographic data. CCDC 1475309 (2j′), 1475009 (2k′) and 1475010 (2n′). For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra11370b

‡ Present address: Département de Chimie, Faculté des Sciences, Université Hassiba Benbouali de Chlef, Hay Es-Salem, RN 19, 02000 Chlef, Algeria.

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