Catalytic meta-selective C–H functionalization to construct quaternary carbon centres

Abstract

A catalytic meta-selective C–H functionalization of 2-phenylpyridines using a range of tertiary halides is described. The protocol is simple to perform and uses commercially available reagents to construct challenging quaternary carbon centres in a regioselective manner. Preliminary studies suggest the C–H functionalization proceeds through a radical process directed via a remote σ-activation.

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The transition-metal catalyzed cleavage and functionalization of inert C–H bonds is evolving into a fundamental methodology for the design of atom economical approaches to useful organic molecules.¹ While the direct functionalization at the ortho position of aromatic compounds by chelation assisted C–H bond cleavage has become well established in recent years, developing reactions with complementary regioselectivity continues to challenge contemporary catalytic methodology.² In this context, examples of meta selective catalytic C–H functionalization have been reported offering diversity in molecular design through alternative reaction strategies (Scheme 1a). These include substrate controlled systems,³ transient mediators such as a carboxylic acid⁴ or norbornene⁵ and covalent template strategies for remote activation.⁶ We first reported a novel catalytic σ-activation protocol for C–H functionalization that allows the meta sulfonation of 2-phenylpyridines via cyclometalated ruthenium intermediates.⁷ Interestingly, the catalytic σ-activation strategy proved effective for meta-alkylations with secondary alkyl halides⁸ whilst acyl halides and primary alkyl halides afford only the ortho-functionalized products consistent with a mechanism involving oxidative addition of the organohalide.⁹

Scheme 1 Catalytic meta-directed C–H functionalization.

Here we report a new catalytic meta-selective C–H functionalization of 2-phenylpyridines to construct quaternary carbon centres (Scheme 1b). The transition-metal catalyzed coupling of tertiary alkyl halides and aromatic C–H bonds is an especially challenging reaction due to the difficult oxidative addition of a metal complex into a bulky C–X bond.¹⁰ We hypothesized that a catalytic σ-activation strategy would therefore be amenable to establishing quaternary carbon centres by avoiding a general oxidative addition pathway.

In preliminary experiments, 2-phenylpyridine 1a was treated under conditions analogous to those developed in our meta-sulfonation reaction: [RuCl₂(p-cymene)]₂ (5 mol%) K₂CO₃ (2 equiv.), t-BuBr 2a (3 equiv.) using MeCN as the solvent.⁷ Unfortunately no coupled products were formed under these conditions however the desired meta-substituted product was observed in 12% conversion when the reaction solvent was changed to 1,4-dioxane (Table 1, entries 1 and 2). By simply changing the base from K₂CO₃ to various acetate salts, a significant increase in conversion was observed with KOAc proving the most effective (entry 6). In the absence of ruthenium complex, no product was observed (entry 11). This catalytic system was found to perform well in a range of solvents as well as under solvent free conditions and was completed in as little as 4 hours (entry 14). When t-BuCl 2b was used as the coupling reagent, a significant drop in conversion was observed, however by using a combination of K₂CO₃ and KOAc, the reaction performed competitively (entry 17).

Table 1 Optimization of catalytic meta tertiary alkylation

Entry	t-Bu-X	Base	Solvent	Conversion^a (%)
a Conversion of 1a to 3a by ^1H NMR. b With 30 mol% MesCOOH. c Without [RuCl2(p-cymene)]2. d Reaction in air. e [RuCl2(p-cymene)]2 (1 mol%). f Reaction time 4 h.
1	2a	K2CO3	MeCN	0
2	2a	K2CO3	1,4-Dioxane	12
3	2a	KOAc	Neat	69
4	2a	KOAc	2-Me-THF	68
5	2a	KOAc	2-Butanone	61
6	2a	KOAc	1,4-Dioxane	74
7^b	2a	K2CO3	1,4-Dioxane	60
8	2a	NaOAc	1,4-Dioxane	31
9	2a	CsOAc	1,4-Dioxane	64
10	2a	Bu4NOAc	1,4-Dioxane	13
11^c	2a	KOAc	1,4-Dioxane	0
12^d	2a	KOAc	1,4-Dioxane	25
13^e	2a	KOAc	1,4-Dioxane	50
14^f	2a	KOAc	1,4-Dioxane	72
15	2b	KOAc	1,4-Dioxane	20
16	2b	K2CO3	1,4-Dioxane	27
17	2b	KOAc (0.5 equiv.) K2CO3 (1.5 equiv.)	1,4-Dioxane	63
18^b	2b	K2CO3	1,4-Dioxane	62

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With optimized catalytic systems in hand, we then investigated how reaction conversions were affected when substituents at the 4-position of the aryl ring were varied (Scheme 2). It was found that electron donating substituents favoured the reaction whereas strongly electron withdrawing groups shut the reaction down entirely. The reaction was tolerant of halogen and ester substituents which is useful for further synthetic transformations. The reactions led to the sole formation of the mono substituted meta products with no decomposition or by-products observed although quantitative separation by conventional methods was not always possible (see ESI† for full analysis). Intriguingly, 1-bromoadamantane was found to be an effective coupling partner and product 4c was characterised by X-ray analysis confirming the regioselective meta substitution (Fig. 1).¹¹ Our procedure also effectively coupled a range of tertiary alkyl chlorides, reagents which are readily available and generally considered to be less reactive (Scheme 3). In these examples, it was found that the incorporation of longer alkyl chain lengths maintained high conversions and enabled better separation of the products by normal phase flash chromatography.

Scheme 2 Catalytic meta functionalization using tertiary alkyl bromides. Numbers quoted are direct conversions to product by ¹H NMR. ^a Using KOAc (0.5 equiv.) and K₂CO₃ (1.5 equiv.).

Scheme 3 Catalytic meta functionalization using alkyl chloride reagents. Numbers quoted are direct conversions to product by ¹H NMR. ^a Numbers in brackets indicate isolated yields.

Fig. 1 The asymmetric unit in the crystal structure of 4c. Ellipsoids are illustrated at 30% probability.

In addition to the alkyl halide reagents outlined in Schemes 2 and 3, tertiary α-bromo ester 2c was effectively coupled, generating meta-substituted products 8a, 8c and 8d, compounds with a useful functional handle, in reasonable isolated yields (Scheme 4). This result provided key insight into the reaction mechanism and strongly suggested a radical type pathway, rather an S_EAr type mechanism previously proposed in our meta-sulfonation reaction.⁷

Scheme 4 Catalytic meta functionalization with α-bromo ester 2c. Numbers quoted are isolated yields.

Heterolytic cleavage of the C–X bond of 2c in an S_N1-type manner would result in a strongly disfavoured carbocation residing alpha to an electron withdrawing ester. It is therefore unlikely that reaction with the aromatic substrate would occur in this fashion. The possibility of S_N2 type reactivity can also be effectively ruled out given the steric effects of the tertiary alkyl halides used. The generation of tertiary alkyl radicals has however been widely reported with a range of transition metal catalysts and shown to be effective in the substitution of aromatics, heteroaromatics and olefins.¹²

In contrast to the reactions with simple alkyl-halides outlined in Schemes 2 and 3 which led to the sole formation of one product, reaction with 2c generated additional by-products. Compounds 9a, 9c and 9d were isolated along with spectroscopic evidence of trace higher oligomers which is consistent with a radical conjugate polymerisation pathway. We hypothesise that a tertiary carbon-centered radical species can add onto elimination products formed under the reaction conditions, which can in turn propagate onto a cyclometalated (σ-activated) substrate molecule to afford the observed by-products. Furthermore, the addition of radical scavenger TEMPO proved detrimental to the reaction with no desired product observed when stoichiometric quantities were used (see ESI†).

Further mechanistic work was conducted to provide additional insight into the interesting meta selectivity displayed by this reaction (Scheme 5). It has previously been proposed that initial ruthenium insertion into an ortho C–H bond to generate a cyclometalated complex is key to this type of reactivity.^7,8 In support of this, reaction of the ortho, ortho dimethyl substrate 1i resulted in no conversion to the desired meta substituted product. The importance of ruthenium σ-activation is also highlighted with the successful meta-selective reaction using pre-formed complex A. No meta-substituted product was observed when substrate 1j bearing a methyl group at the 3-position of the aromatic ring was used. Instead, the only product isolated was dimer 10 suggesting a competing reductive elimination of two coordinated substrate molecules when the site para to the C–Ru bond is blocked.¹³ Conformationally locked benzoquinoline 1j was however effectively alkylated generating 10 as the only isolated product.

Scheme 5 Mechanistic investigation. Numbers quoted are isolated yields.

Together these results suggest that substitution occurs preferentially at a position para to the C–Ru bond formed following cyclometalation. Interestingly, analogous reactivity has also recently been reported in a stoichiometric process on iridium complexes.¹⁴ In light of this work we now propose the following mechanism (Scheme 6). Initial ortho C–H insertion generates a cyclometalated complex, a process shown to be reversible and aided by carboxylate ligands.¹⁵ Substitution at the position para to the newly installed C–Ru bond then most likely occurs via a radical process whereby single-electron transfer (SET) from a ruthenium(II) species can generate a tertiary alkyl radical and the corresponding ruthenium(III)X species. The carbon-centered radical then adds to the aromatic ring to generate a cyclohexadienyl radical intermediate. Rearomatisation could occur via single-electron oxidation and deprotonation to regenerate a ruthenium(II) complex and furnish the meta alkylated product after proto-demetalation.

Scheme 6 Proposed catalytic cycle.

In summary, we have developed a novel meta selective catalytic C–H functionalisation of 2-phenylpyridine substrates for the installation of quaternary carbon centres. The procedure is operationally simple and was found to couple a useful range of tertiary alkyl bromides and more challenging tertiary alkyl chlorides. Mechanistic studies indicate that site selective radical addition occurs at the position para to the C–Ru bond formed following cyclometalation to afford products with net meta substitution. More detailed mechanistic studies are underway to determine the precise nature of the organometallic species and redox processes involved.

We are grateful to the University of Bath, EPSRC DTC in Sustainable Chemical Technologies and Novartis for funding. We acknowledge the valuable assistance of Dr Anneke Lubben (Mass Spectrometry, University of Bath), Dr John Lowe and Dr Catherine Lyall (NMR Spectroscopy, University of Bath).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Full experimental details. CCDC 1064109. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5cc03951g

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