Pd-Catalyzed Modifiable Silanol-Directed Aromatic C–H Oxygenation

Transition metal-catalyzed C–H functionalizations have emerged as a powerful tool for the synthetic community.¹ One common strategy involves the use of directing groups to achieve high reactivity and selectivity.^1d-g As a broad spectrum of C–H functionalizations becomes a toolkit of choice, the expansion of substrate scope is therefore in a high demand. Recently, the employment of removable and/or modifiable directing groups has allowed an orthogonal diversification of C–H functionalized products.² This strategy illuminates an avenue for a quick functionalization of products obtained via C–H functionalization. Along the line of our development on silicon-tethered removable/modifiable directing groups,³ we have shown that silanol⁴ acts as a traceless directing group for the synthesis of catechols from phenols.^4a Herein, we wish to report the Pd-catalyzed, modifiable benzylsilanol-directed aromatic C–H oxygenation towards oxasilacycles, versatile intermediates for organic synthesis (vide infra).

Carbon-based silicon tethers have been shown to exhibit a high degree of diversification.^3,5 Thus, we started by searching a suitable carbon-based organosilanol for our method design. Given the similarity between silanol and alcohol and the generality of hydroxyl-directed C–H oxygenation⁶ reaction developed by Yu,⁷ three benzyl-bound silanols⁸ were tested under Yu’s oxidative C–O cyclization conditions (Table 1). Dimethylsilanol 1a, a well-established nucleophilic component in Hiyama-Denmark cross-coupling reaction,⁹ was tested first. However, the reaction with PhI(OAc)₂ and Li₂CO₃ in the presence of 10 mol % Pd(OAc)₂ in DCE at 100 °C led to decomposition of starting material, providing only trace amounts of cyclized product 2a (entry 1). Likewise, diphenylsilanol 1b¹⁰ also decomposed under these conditions (entry 2). However, bulkier diisopropyl benzylsilanol 1c, which was previously reported in an oxidative Heck reaction,^4c was stable yet reactive enough under the C–O cyclization conditions to produce five-membered oxasilacycle 2c in 35% GC yield (entry 3). The reactions under base-free conditions usually afforded higher yields of 2c (entries 3-6). Performing the reaction in PhCF₃ resulted in an increased yield (entry 7). The catalyst loading was reduced to 5 mol % without loss of efficiency (entry 9). Employment of Pd(OPiv)₂, which was previously found superior for phenoxysilanol-directed catechol synthesis,^4a resulted in a reduced yield (entry 10).¹¹

Table 1.

Optimization of Reaction Conditions.

#	Substrate	Pd [mol %]	Additive	Solvent	Yield [%][a]
1	1a (R=Me)	10	Li2CO3	DCE	trace
2	1b (R=Ph)	10	Li2CO3	DCE	0
3	1c (R=iPr)	10	Li2CO3	DCE	35
4	1c	10	none	DCE	46
5	1c	10	Li2CO3	PhMe	42
6	1c	10	none	PhMe	54
7	1c	10	none	PhCF3	73
8[b]	1c	10	none	PhMe	49
9	1c	5	none	PhCF3	73
10[c]	1c	5	none	PhCF3	60

^[a]GC yields.

^[b]The reaction concentration was 0.05 M.

^[c]5 mol % Pd(OPiv)₂ was used as the catalyst.

Next, the generality of this transformation was examined (Table 2). It was found that both alkyl and aryl groups can be tolerated at ortho-, meta- and para-positions of aromatic rings (entries 1-7). For meta-substituted substrates 1i-j, the oxygenation selectively goes to the less hindered C–H site. Besides, silanols 1m and 1n substituted at the benzylic position were also competent reactants in this transformation (entries 8-9). Moreover, naphthalene-based silanol 1o smoothly underwent oxidative cyclization to produce tricyclic product in 70% yield. Remarkably, tetralin (1p), chroman (1q), and benzosuberan (1r) derived silanols were efficiently transformed into their corresponding tricyclic products in good to high yields (entries 11-13). It deserves mentioning that the reaction can be easily scaled up to gram scale with comparable yields (entry 7).

Table 2.

Reaction Scope of Silanol-Directed C–H Oxygenation.

Entry	Substrate		Product		Yield [%][a]
1		1c		2c	72
2		1g		2g	87
3		1h		2h	74
4		1i		2i	50[b],[c] (72)
5		1j		2j	(71)[c]
6		1k		2k	(66)
7		1l		2l	68 (85) 83[b],[d]
8		1m		2m	69[b] (80)
9		1n		2n	58 (76)
10		1o		2o	70
11		1p		2p	77
12		1q		2q	58
13		1r		2r	90

^[a]Isolated by column chromatography on Florisil®. ¹H NMR yields are provided in the parentheses.

^[b]Isolated by Kugelrohr distillation.

^[c]Regioselectivity is >20:1.

^[d]Gram scale (5 mmol), isolated with 92% purity.

In order to verify whether this transformation, similarly to the previously developed silanol-directed oxygenation reaction (eq 1),^4a proceeds via an acetoxylated intermediate of type B, we performed a GC monitoring of the oxygenation reaction of 1c. Surprisingly, the reaction profile showed no formation of substantial amounts of acetoxylated intermediate 3c (< 3%) during the reaction course (Figure 1). Next, ¹⁸O-labeled silanol 4 was subjected to the reaction under the standard conditions. It was found that, accompanied by the formation of 2g, cyclized product 5 with ¹⁸O label was indeed formed. Moreover, the amount of ¹⁸O label in the cyclized products was lower than that of 4 and gradually decreased as the reaction proceeded. The test experiments indicated no ¹⁶O/¹⁸O scrambling in the starting silanol 4 throughout the reaction course occurred (Figure 2). Likewise, prolong (overnight) heating of the completed reaction did not change ¹⁸O-label incorporation in the cyclized products. We envisioned that the in situ generation and accumulation of HOAc¹³ during the reaction could be responsible for the observed downhill trend of ¹⁸O-label incorporation in the products. To verify the role of HOAc, we performed additional experiments with exogenous HOAc and in the presence of base (Li₂CO₃). As expected, the abundance of ¹⁸O label in the products was substantially lower under acidic conditions, but higher under the basic media compared to that under the additive-free reaction conditions (Figure 2).

Figure 1.

Reaction profile.¹² The reaction was monitored by GC/MS with tetradecane as the internal standard.

Figure 2.

The abundance of ¹⁸O incorporation in the starting silanol 4 shown with solid circles, the abundance of ¹⁸O incorporation in the cyclized products (additive-free conditions with solid squares; acidic conditions with solid triangles; basic conditions with hollow triangles).

Although the mechanistic details of this transformation are still unclear, the above observations indicate on two possible general pathways (Scheme 1). According to the first path, the partial loss of ¹⁸O label in the products suggests the possibility of the previously proposed reaction route, featuring an acetoxylation/cyclization sequence (path A).^4a Alternatively, the formation of ¹⁸O-enriched product 5 implies the possibility of a direct reductive C–O cyclization^7a (path B).¹⁴

Scheme 1.

Possible reaction pathways.

To test the feasibility of this oxygenation reaction on sp³ C–H systems, silanols D and E were subjected to the standard oxygenation reaction conditions. However, instead of benzylic C–H activation reaction toward silacycles D’ and E’, an ipso-acetoxydesilylation occurred, producing acyloxy benzenes D” and E” in 83% and 67% yields, respectively (eq 2). These results suggest that this method is effective for aromatic C–H oxygenation reaction only.¹⁵

We envisioned that the synthesized cyclic molecules, containing an easily cleavable Si–O bond and a potentially modifiable C–Si bond, could serve as a precursor for a variety of valuable products. Indeed, Tamao has showed in a single example that this type of oxasilacycles is useful to achieve functional group-compatible Kumada cross-coupling reactions.¹⁶ However, their synthetic usefulness has not yet been extensively exploited. Encouraged by our previous success on the modification of silicon-tethered directing groups,³ we were interested to investigate the synthetic potential of oxasilacycles as useful building blocks in organic synthesis. As expected, desilylation of cyclic product 2h with CsF in DMF resulted in phenol 8 in good yield (eq 3). In addition, thermodynamically stable cyclic structure 2 can be efficiently opened up with Meerwein salt in a single step (eq 3). In this hitherto unknown transformation, which we proposed to proceed via a cationic concerted asynchronous mechanism (supported by DFT calculations),¹² trimethyloxonium tetrafluoroborate plays a double duty: it delivers the methyl cation to the oxygen atom and the fluoride anion to the silicon atom. The oxygenation and ring opening steps could also be performed in a semi-one-pot manner, affording compound 9 from silanol 1i in 51% overall yield (eq 4).

The resulted fluorosilane 9 opened up broader opportunities for the subsequent modifications. As illustrated in Scheme 2, Tamao oxidation¹⁷ of 9 provided benzyl alcohol 10 in 76% yield. Fluoride-free Hiyama-Denmark cross-coupling of 9 with phenyl iodide, under conditions reported by Itami and Yoshida,¹⁸ afforded diarylmethane derivative 11 in 65% yield. Moreover, fluorosilane 9 in the presence of CsF can be employed as an equivalent of Grignard reagent in the reaction with aldehydes.¹⁹ Finally, an unprecedented transformation en route to nitrone derivative 13 was discovered upon treatment of benzylsilane 9 with nitrosobenzene in the presence of CsF.¹²

Scheme 2.

Further transformations.

In summary, we have developed Pd-catalyzed, benzylsilanol-directed ortho C–H oxygenation of aromatic rings. This method allows efficient synthesis of oxasilacycles, which are valuable synthetic intermediates. The synthetic usefulness was highlighted by an efficient removal of the silanol directing group and by its conversion into a variety of valuable functionalities. These transformations include known Tamao oxidation, Hiyama-Denmark cross-coupling, and nucleophilic addition, as well as unprecedented Meerwein salt-mediated ring-opening of oxasilacycles and nitrone formation from a benzylsilane and a nitroso compound.

Experimental Section

General procedure

An oven dried Wheaton V-vial (10 mL), containing a stirring bar, was charged with benzylsilanols 1 (0.5 mmol), Pd(OAc)2 (5.6 mg, 0.025 mmol), and PhI(OAc)₂ (0.6 – 0.75 mmol) under N₂ atmosphere. Dry α,α,α-trifluorotoluene (5 mL) was added via syringes and the reaction vessel was capped with pressure screw cap. The reaction mixture was heated at 100 °C for 7 h. The resulting mixture was cooled down to room temperature and filtered through a short layer of celite plug with the aid of EtOAc. The filtrate was concentrated under a reduced pressure. The residue was purified by column chromatography on Florisil® (eluent: hexanes/EtOAc) affording the corresponding cyclized products 2.

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