Meta-Selective C–H Arylation of Aromatic Alcohols with a Readily Attachable and Cleavable Molecular Scaffold

Abstract

The first example of meta-selective C–H arylations of arene alcohol-based substrates is described. The strategy involves the combination of the transient norbornene strategy with the quinoline-based acetal scaffold to achieve the formation of biaryl compounds. Both a two-step meta-arylation/scaffold cleavage process and a total telescoping procedure are described, highlighting the convenient attributes of attachment, removal, and recovery of the acetal scaffold. Moreover, the meta-arylated compounds can be further derivatized via ortho-selective functionalizations. These processes establish a foundation for catalytic polyfunctionalization of alcohol-based compounds.

Graphical abstract

Transition metal catalyzed site-selective C–H functionalization has been a broad and highly impactful enterprise in the fields of synthetic chemistry and materials science.^[1] A primary strategy to achieve site specificity is to employ substrates with directing capabilities that can position the catalytic complex to achieve selective bond functionalization. In terms of C(sp²)–H functionalization, this strategy has been widely executed for ortho-selective processes, as proximity effects are readily achieved. More recently, innovative approaches in directed C–H functionalization have now been achieved to attain meta-selectivity.^[2] Select strategies include designer templates that orient the metal in close proximity to a meta C–H bond,^[3] steric-controlled processes,^[4] or transformations that are predicated on a specific mechanistic pathway selective for meta reactivity.^[5] A separate approach using Pd catalysis was developed by the Yu and Dong groups independently,^[6,7] where they draw inspiration from the Catellani reaction involving norbornene insertion/deinsertion^[8] to achieve metalation at the meta position from an initial ortho-directed functionalization (Figure 1). Further studies illustrated the capacity of this palladium-catalyzed process to be utilized in derivatives of phenylacetic acids, phenethyl amines, benzyl amines, anilines, and phenols.^[9]

Figure 1.

Approach to alcohol-based scaffold to direct functionalization.

We^[10] and others^[11] have been interested in the catalytic C(sp²)–H functionalization of alcohol-based substrates, namely in the development of molecular scaffolds that can direct a metal species to a specific site.^[12] Our recent efforts have focused on the design of acetal-based scaffolds that feature pyridyl or quinolinyl groups for the functionalization of arene-based alcohols (Figure 1).^[10] These scaffolds are readily covalently attached to alcohols, and when attached will induce ortho-selective Pd-catalyzed C–H alkenylations and arylations. These scaffolds can circumvent some of the challenges encountered in directed functionalizations with alcohol-based substrates (e.g., oxidative decomposition pathways), and the facile attachment, cleavage, and recovery methods for these scaffolds enable straightforward processing and telescoping procedures. These processes were designed for ortho-selective reactivity; an analogous development in meta-functionalizations would significantly expand the scope of this methodology. Herein, we report the utilization of the norbornene strategy juxtaposed with our scaffolding protocol to achieve meta-selective functionalizations of alcohol-based substrates. To our knowledge, this represents the first meta-selective arylation of arene alcohol-based substrates.

We first evaluated the reaction of 3-methoxybenzyl alcohol with our respective heterocyclic scaffolds attached (1a, Scheme 1).^[13] When these substrates were treated under oxidative arylation conditions using norbornene as the transient mediator, minimal meta-arylation products (3aa) were observed. Additionally, we observed significant amounts of recovered starting material and observable quantities of a benzocyclobutane byproduct (4). We were still encouraged by this reactivity, albeit low, and anticipated that modifications may garner improved results. To our delight, we found that norbornene 5b (NBE-CO₂Me), developed by Yu for this transient strategy,^[9a-g] improved the arylation, with no observation of benzocyclobutane byproduct. The quinolinyl-based scaffold also afforded a significant enhancement in reactivity (49% vs. 15% yield), and this promising lead encouraged us to probe this reaction further.

Scheme 1.

Preliminary evaluation of meta-selective arylations using alcohol scaffold.

We next evaluated other parameters of the transformation (Table 1). Pd(TFA)₂ bolstered reactivity, affording the product in 65% yield (entry 1). 4 equiv each of PhI and AgOAc were optimal (entry 2), and different silver salts were minimally effective (entries 3-6). Investigations into ligands were revealing. 2-Hydroxypyridine ligands, oftentimes effective for similar meta-C–H functionalization processes,^[9b-f] did not improve reactivity here (entries 7-8). In evaluating amino acid derivatives, we found that both N-trifluoroacetylglycine (TFA-Gly-OH) and N-trifluoroacetyl-β-alanine (TFA-β-Ala-OH) were similarly optimal, affording the arylated product (3aa) in much improved yield (78%, with 8% rsm, Table 1, entries 17, 18). Considering availability of the amino acids, we chose using TFA-Gly-OH in the optimal conditions for further studies. The reaction could be performed without ligand in decreased but still measurable yield; AgOAc, however, was essential (entries 21, 22).^[14]

Table 1.

Optimization of the meta-C–H arylation of the QuA-attached scaffold.

Entry	Ligand	Additive	Time (h)	Yield [%][a]	Rsm [%][a,b]
1	Ac-Gly-OH	AgOAc	46	65	17
2[c]	Ac-Gly-OH	AgOAc	72	59	21
3	Ac-Gly-OH	Ag2CO3	46	26	65
4	Ac-Gly-OH	AgOPiv	46	12	82
5	Ac-Gly-OH	AgOTf	46	nd	nd
6	Ac-Gly-OH	AgTFA	22.5	nd	nd
7		AgOAc	24	33	52
8		AgOAc	24	23	69
9	Ac-Ala-OH	AgOAc	46	57	20
10	Ac-t-Leu-OH	AgOAc	46	64	12
11	Ac-Phe-OH	AgOAc	46	53	24
12	Ac-β-Ala-OH	AgOAc	46	66	8
13	Boc-Gly-OH	AgOAc	46	69	8
14	Formyl-Gly-OH	AgOAc	46	49	35
15	Bz-Gly-OH	AgOAc	46	23	61
16	TFA-Gly-OH	AgOAc	46	75	7
17	TFA-β-Ala-OH	AgOAc	24	78	8
18	TFA-Gly-OH	AgOAc	24	78	8
19	TFA-Gly-OH	AgOAc	15	74	13
20	none	AgOAc	24	60	9
21	TFA-Gly-OH	KOAc	24	4	95
22	TFA-Gly-OH	none	24	0	66

^[a]NMR yield using 1-octene as a standard. nd: Not detected.

^[b]Rsm: recovered starting material.

^[c]3 equiv each 2a, AgOAc.

The substrate scope was then ascertained (Scheme 2). We first evaluated the aryl iodide component, and we found that a variety of substituted aromatic groups could be employed. Both electron rich and electron poor aryl iodides were reactive, and the transformation showed good functional group compatibility (e.g., ether, ester, ketone, carbamate, nitro, trifluoromethyl, halogen). Aryl iodides bearing a para-, meta-, or ortho-substituent afforded the corresponding products in good to excellent yields. An alkyl iodide could also be utilized, although the alkylated arene was obtained in only modest yield (3ao).

Scheme 2.

Iodide scope in meta-selective arylations.

[a] Isolated with 9% rsm. [b] Ethylenediamine workup was not performed. [c] Isolated with 5% rsm. [d] Isolated with 13% rsm. [e] Isolated with 18% rsm.

A range of scaffold-attached benzylic alcohol substrates were also evaluated (Scheme 3), using iodobenzoates as the coupling agent.^[15] The transformation tended to work better for compounds bearing electron rich substituents, such as ethers, alkyls, arenes, and carbamates. Electron withdrawing groups (e.g., halides in 3gp, 3jn) were still tolerated, however. This procedure appeared to work most effectively with meta-substituted benzylic alcohol-based substrates; ortho-substituted cases were also competent but in diminished yields (3hp, 3in, 3jn, 3kp, 3mn). The 3,4-methylenedioxy group was effective (3ln, 61% yield), as was a heterocyclic compound (3mn, 47% yield). The meta-arylation could be extended to secondary alcohol-based compounds (3np, 75% yield). Finally, for cases where mono- and di-arylation were possible, both products were observed.^[16]

Scheme 3.

Arene alcohol substrate scope in meta-selective arylations.

[a] Using 20 mol % Pd(TFA)2 and 40 mol % TFA-Gly-OH. [b] Estimated 85% purity. [c] Yield refers to isolation of the corresponding alcohol after scaffold cleavage.

A primary attribute in our scaffolding approach is the capitalization on the lability of the acetal for direct scaffold cleavage and recovery. Scheme 4 is illustrative in the context of this meta-arylation. A sequential procedure of arylation with immediate subsequent scaffold cleavage afforded biaryl alcohol 6an in 83% yield.^[17] Methyl acetal-derived scaffold (QuAOMe, 7) was also recovered in 94% yield; we have shown that this compound can be reused in further attachment sequences.^[10b] Furthermore, a telescoping procedure for this meta-arylation process using our quinolinyl scaffold could also be executed. Benzylic alcohol 8a was converted to the meta-arylated alcohol (6an) in 74% yield without any intermediate purifications.

Scheme 4.

Scaffold cleavage and telescoping protocol.

Our scaffolding approach to meta-arylation complements our existing ortho-functionalization strategies. To that end, we have demonstrated that the meta-arylated products can undergo subsequent functionalizations (Scheme 5). Under our previously described conditions, the ortho-C–H arylation of compound 3an affords the secondary arylated product (10) in 67% yield. Olefination was also successful; the C–H alkenylation of compound 3ah affords alkene product 12 in 66% yield. We envision our scaffold could be utilized for the facile diversified syntheses of polysubstituted arene alcohols via select functionalization strategies.

Scheme 5.

Polyfunctionalization via the scaffolding strategy.

In summary, we have developed the site selective meta-C–H arylation of benzylic alcohols via palladium catalysis by incorporating the norbornene transient mediator strategy into our quinoline-based acetal scaffold. The particular use of amino acid-based ligands for this reaction is distinct in the norbornene strategy, and suggests a unique cooperation of ligand and scaffold in this functionalization process. The transformation shows considerable scope and functional group compatibility, and the desired biaryl compounds can be obtained in generally moderate to high yields. Scaffold cleavage and recovery, in addition to a telescoping protocol, could be achieved in good yields without purification of any intermediates. The meta-arylation can also be combined with ortho-arylation or olefinations to afford polysubstituted arenes, establishing a foundational platform for ready diversifications of aromatic systems. Considering the synthetic versatility of the alcohol functional group, we anticipate this scaffolding strategy toward functionalization will enable the facile and direct syntheses of an array of arene compounds. Studies on further reactivity based on our approach will be reported in due course.