Meta-Selective C-H Functionalization using a Nitrile based Directing Group and Cleavable Si-Tether

Abstract

A nitrile-based template that enables meta-selective C-H bond functionalization was developed. The template is applicable to a range of substituted arenes and tolerates a variety of functional groups. The directing group uses a silicon atom for attachment allowing for a facile introduction/deprotection strategy increasing the synthetic practicality of this template.

C-H functionalization is an area that has seen enormous growth over the past 30 years.¹ Given the ubiquity of C-H bonds in organic molecules, selectivity in C-H functionalization is a critical element to any successful methodology. The three main approaches to controlling selectivity have been to use either sterics,² inherent reactivity,³ and directing groups^1b-f to differentiate C-H bonds. Between these approaches, directing groups have been the most widely applied; however, this strategy has generally been limited to activating positions ortho to the directing functionality on aromatic rings. In a pioneering report, Yu and co-workers have demonstrated that meta-selective C-H activation⁴ is possible using a directing group appended to both alcohol and acid substrates.⁵ In this case the strain associated with forming the requisite metallocyclophane is alleviated by the application of a linear nitrile.

Herein we report a silicon based directing/protecting group⁶ for meta-selective C-H activation of aromatic rings (Scheme 1). The advantage of our methodology is that the directing group is easily incorporated onto alcohol-based substrates and removed under standard fluoride or acid catalyzed deprotection conditions. Moreover, the directing group is synthesized in 3 steps from inexpensive reagents and is recyclable. The expansion of meta-selective C-H activation to alcohol-based substrates enriches the synthetic utility of these nitrile-based directing groups.

Scheme 1. Development of silicon based directing group.

As a first step towards developing a practical directing group for meta selective C-H activation, we synthesized a series of silicon based directing groups and tested them in the oxidative C-H coupling to olefins. After preliminary optimization of the reaction conditions (see Supp. Info.), we found that placing the nitrile meta to the silicon atom results in a significant amount of meta functionalization of the aromatic ring (o:m:p = 7:81:12, Table 1, entry 1). It is worth noting that the relative position of the silicon tether and nitrile is different from the Yu group's carbon based directing group. We reasoned that the larger size of the silicon atom along with elongated Si-C and Si-O bonds may require greater separation between the directing nitrile and reacting aromatic group. The para isomer 2 provides the product in low yield and with selectivity that is typical for a sterically driven C-H functionalization reaction (o:m:p = 22:43:35, Table 1, entry 2).⁷ Furthermore, this reaction serves as a control reaction, verifying the necessity of having the nitrile properly positioned in the substrate for meta selectivity.

Table 1. Optimization of ligand structure^a.

entry	substrate	o:m:pb	product	yield [%] (mono/di)
1	1a	7:81:12	3a	43 (5.1:1)
2	2	22:43:35	4	8c
3	1b	6:81:13	3b	52 (4.8:1)
4	1c	5:86:9	3c	42 (5:1)
5	1d	6:88:6	3d	62 (3.4:1)
6	1e	4:90:6	3e	54 (2.6:1)
7	1f	4:92:4	3f	57 (3.6:1)
8	1g	6:90:4	3g	50 (5.3:1)
9d	1f	2:96:2	3f	84 (1.74:1)

^areaction conditions: 0.1 mmol substrate, 1.5 equiv ethylacrylate, 10 mol % Pd(OAc)₂, 20 mol % AcGly-OH, 2.0 equiv AgOAc in 1 mL DCE, 90°C, 24 h.

^bRatio was determined by ¹H NMR.

^cNMR yield

^dReaction time was 6 h using 3.0 equiv. HFIP and 3.0 equiv AgOAc.

With this initial success, we took advantage of the modular nature of the silicon-based directing group to further optimize the reaction. To improve the meta directing ability, we varied the groups adjacent to the nitrile in order to examine how compressing and expanding the bond angle (α) between the phenyl ring and nitrile affects the selectivity (Table 1). Changing the geminal methyl groups to a cyclopropane, which should expand α, affords comparable results to 1a (Table 1, entry 3). A contraction of α by expanding ring size (1c) results in an increase in the meta selectivity. Switching to bulkier acyclic groups in order to further compress α improves the meta selectivity. This trend was observed from methyl (1a) to sec-butyl group (1d-f, Table 1, entries 5-7), which provided the maximum selectivity. More ortho product was obtained with cyclohexyl groups (1g, Table 1, entry 8) on the benzylic position, suggesting that optimum angle for meta selectivity had been exceeded. Although the reaction is highly meta selective with optimal substrate 1f, the conversion of the reaction was found to be modest. Upon further optimization, higher conversion was achieved by the addition of 3.0 equiv of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) without any deterioration in selectivity (Table 1, entry 9).

The requisite silicon chloride 8 is synthesized in 3 steps from inexpensive starting materials, and can be made in multi-gram quantities (Scheme 2). First, 2-(3-bromophenyl)-acetonitrile 5 was dialkylated using potassium tert-butoxide and sec-butyl iodide, followed by lithium-halogen exchange mediated silylation produced intermediate silane 7 in good yield. Conversion to silyl chloride 8 was accomplished by trichloroisocyanuric acid in excellent yield.

Scheme 2. Preparation of directing group and installation.

With the optimized conditions and template structure in hand, the substrate scope was investigated. Various benzyl alcohols with electron withdrawing or donating substituents were prepared from the corresponding alcohols and silyl chloride in one step (Scheme 2). Although we could not avoid formation of bis-substituted products for 2-substituted substrates (Table 2, 9a-9c), high meta selectivity was observed regardless of substrate's electronic nature. The result for 3-substituted substrates clearly shows this method is applicable to a wide variety of functional groups. Compound 9d afforded the highest yield maintaining high selectivity. All the halogens from fluoride to bromide are well tolerated (9e-9g), resulting in good yields and selectivity. The presence of a strongly electron withdrawing CF₃ group led to diminished yield (50%) but the highest selectivity (meta:others=97:3, 10h) was observed. C-H activation of 9i, which contains a methoxy substitutent, results in inferior selectivity. Competition experiments with other ortho-directing groups present suggested that the directing ability of the nitrile group is superior to that of an ester (compound 9k)⁸ but not of an acetoxy group (compound 9j).⁹ Meta selectivity decreased slightly with 4-substituted compounds (9l-9n) due to steric hindrance. In the case of methoxy substitution, the electronic effect and directing group worked in concert to enhance meta selectivity (10n, meta:others=98:2). Interestingly, among the seven aromatic C-H bonds in 1-naphthyl methanol 9o, the C-H bond at C-3 is activated and affords the product in 53% yield. We were also able to apply this method toward secondary α-methylbenzyl alcohol substrates with similar levels of selectivity and yield in the C-H activation step (9p-r).

Table 2. Substrate Scope^a.

^areaction conditions: 0.1 mmol substrate, 1.5 equiv ethylacrylate, 10 mol % Pd(OAc)₂, 20 mol % AcGly-OH, 3.0 equiv AgOAc, 5.0 equiv HFIP in 1 mL DCE, 90 °C, 24 h. Isomeric ratio was determined by ¹H NMR.

^b20.0 equiv HFIP were used.

^c10 equiv HFIP, 3.0 equiv acrylate were used.

^dinseperable mixture with side product from metal-halogen exchange

Further investigation with various olefin partners revealed that electron deficient olefins bearing amide, ketone, and sulfone groups produced functionalized compounds with moderate yields and high selectivity (11a-c). 1,2-disubstituted trans-methyl crotonate also proceeded well affording a single stereoisomer 11d as the major product.

To probe the mechanism of the reaction an intermolecular competition experiment was performed. A kinetic isotope effect of 2.5 was estimated by NMR spectroscopic analysis after cleavage of the silicon directing group (Scheme 3). This value suggests C-H bond activation is the rate determining step and a bent transition state is expected to be involved.¹⁰

Scheme 3. Kinetic isotope effect.

An additional advantage of this chemistry is the potential to reuse the silicon directing group. The template was easily cleaved by tetrabutylammonium fluoride at room temperature within an hour after filtration of the silver and palladium precipitates without additional purification step (Table 2, compound 10d′). Alternatively, when the purified C-H activation product is treated with wet ethanol in the presence of a catalytic amount of para-toluenesulfonic acid, the free benzyl alcohol 10d′ is obtained and the template is recovered as silanol 12 (Scheme 4). Silanol 12 can be used to prepare protected starting material 9d in moderate yield.

Scheme 4. Template regeneration.

In summary, we have developed an efficient meta directing group based on a silicon tether. Introduction of the template was performed using standard silicon protection conditions and in-situ cleavage was demonstrated as feasible. C-H activation was successful for all substitution patterns on the aromatic ring, and the template could be applied to primary and secondary alcohols with equal efficacy. Because of the reversible nature of the silicon oxygen bond, investigations are underway to develop conditions that will facilitate catalytic use of our template.

Table 3. Reaction with various olefins^a.

^areaction conditions: 0.1 mmol substrate, 1.5 equiv ethylacrylate, 10 mol % Pd(OAc)₂, 20 mol % AcGly-OH, 2.0 equiv AgOAc, 5.0 equiv HFIP in 1.0 mL DCE, 90 °C, 24 h. Isomeric ratio was determined by ¹H NMR.

^b10 equiv HFIP was used.