Steric Effects Compete with Aryne Distortion to Control Regioselectivities of Nucleophilic Additions to 3-Silylarynes

Abstract

We report an experimental and computational study of 3-silylarynes. The addition of nucleophiles yield ortho-substituted products as a result of aryne distortion, but meta-substituted products form predominately when the nucleophile is large. Computations correctly predict the preferred site of attack observed in both nucleophilic addition and cycloaddition experiments. Nucleophilic additions to 3-t-butylbenzyne, which is not significantly distorted, give meta-substituted products.

Despite once being a subject of controversy,¹ arynes are now a thriving area of chemical discovery.² Modern methods of aryne generation have led to greater control of reactivity, thus enabling the use of arynes in a host of synthetic applications.³ Nonetheless, the control and understanding of regioselectivity in reactions of unsymmetrical arynes remains an important area of research.²

The aryne distortion model, reported by our laboratories in 2010,⁴ shows that regioselectivity in nucleophilic additions and cycloadditions of arynes is governed by the inherent distortion present in unsymmetrical arynes and transition state distortion energies.⁵ The model allows for reliable regioselectivity predictions to be made using simple computations, and has been validated for ring-fused arynes and arynes that possess neighboring inductively withdrawing substituents.^4,6 In the case of 3-methoxybenzyne,⁷ the aryne is pre-distorted as suggested in Figure 1. Addition of the nucleophile occurs at the more electrophilic site, with flattening at the carbon undergoing attack, to give meta-substituted products.^8,9 As a means to further probe the aryne distortion model, we examined the influence of inductively donating silyl substituents on aryne regioselectivities.¹⁰ Our experimental and computational study demonstrates that the sense of regioselectivity in silylaryne reactions is variable, but aryne distortion can play a significant role. Computations correctly predict the preferred site of attack observed in both nucleophilic addition and cycloaddition experiments.

Figure 1.

Influence of 3-methoxy and 3-silyl substituents on aryne regioselectivity.

Geometry optimization of 3-triethylsilylbenzyne was conducted using DFT methods (B3LYP/6-311+G(d,p)).¹¹ The silyl group severely distorts the aryne, such that the internal angles at C2 and C1 are 134° and 122°, respectively.¹² Following the aryne distortion model, nucleophilic addition at C2, the more electropositive terminus of the aryne, is favored electronically; however, meta substitution should be preferred based on steric factors. Only few examples of silylaryne reactions have been reported, but it should be noted that additions of organolithium reagents to silylarynes occur with meta-selectivity,^10a,b,c whereas additions of amines are primarily ortho-selective.^10g,13

With the aim of studying regioselectivity patterns of silylarynes in a variety of nucleophilic addition and cycloaddition reactions, we prepared bis(silyl)triflate 5, which was envisioned to be a suitable precursor to triethylsilylbenzyne 1 (Scheme 1).¹⁴ Commercially available dibromophenol 2 was elaborated to known compound 3¹⁵ via a two-step procedure involving O-silylation followed by halogen-metal exchange-mediated O to C migration of the silyl substituent.¹⁶ Next, an analogous sequence was employed to install the triethylsilyl group, thus providing 4.¹⁷ Triflation of 4 afforded the desired bis(silyl)triflate 5.¹⁸

Scheme 1.

A comparative regioselectivity study was performed, where triethylsilylbenzyne 1 was generated in situ upon treatment of 5 with CsF in acetonitrile, in the presence of a variety of nucleophiles (Table 1).^19,20 Upon trapping of the aryne with benzylamine, reaction occurred to give a 1:2 ratio of products favoring ortho substitution (entry 1). However, when aniline was employed, the regioselective preference switched to favor meta addition (entry 2), which is consistent with the observations reported by Akai.^10g Other trapping agents that have not been used with silylbenzynes previously were also tested. Thiophenol based reagents also gave products of meta substitution predominantly (entries 3 and 4); in the later case, selectivity was 10:1. An enamine reagent, which functions as a carbon nucleophile, exclusively yielded the meta-substituted product (entry 5). Use of 4-t-Bu-benzoic acid, however, gave 1:3 selectivity, favoring ortho addition (entry 6).

Table 1.

Nucleophilic additions to triethylsilylbenzyne 1^a

entry	trapping agent	product(s)	ratio (yieldb)
1	H2N–Bn		1:2 (81% yield)
2			2:1 (99% yield)
3			4:1 (91% yield)
4			10:1 (77% yield)
5			(52% yield)
6			1:3 (53% yield)

^aSee Supporting Information for experimental details.

^bYields determined by ¹H NMR analysis with external standard.

Triethysilylaryne 1 was next evaluated in a series of cycloaddition reactions. As shown in Table 2, the selectivity patterns varied as a function of the trapping agent employed. A nitrone cycloaddition gave a 73% yield of a single regioisomer of product (entry 1), suggestive of ortho attack, as seen in previous nitrone cycloadditions of silylarynes.^10d Trapping of the silylaryne with pyridine N-oxide²¹ also proceeded with a significant preference for ortho addition (entry 2). Conversely, cycloaddition with a diazoester²² exclusively afforded the product resulting from initial meta attack (entry 3). Reaction with benzyl azide²³ gave a 6:1 ratio of products, favoring initial meta addition (entry 4). Despite variations in the initial site of nucleophilic attack, the major regioisomer observed in each cycloaddition is presumably that which arises from the least sterically encumbered transition state.

Table 2.

Cycloaddition reactions with triethylsilylbenzyne 1^a

entry	trapping agent	product(s)	ratio (yieldb)
1			(73% yield)
2			1:9 (60% yield)
3			(65% yield)
4	N3–Bn		6:1 (85% yield)

^aSee Supporting Information for experimental details.

^bYields determined by ¹H NMR analysis with external standard.

These results demonstrate that nucleophilic additions and cycloadditions of 3-triethylsilylbenzyne do occur with significant regioselectivities, but the orientation of attack varies as a function of the trapping agent. DFT calculations were carried out to provide additional insights into the origins of these observations. All geometry optimizations were performed using Gaussian 09²⁴ using the B3LYP density functional and the 6-311+g(d,p) basis set. A frequency calculation was performed on all reactants and transition states to verify minima and first order saddle points, respectively, and an ultra fine grid was used for all numerical integration. Unscaled zero-point energies were used, and Truhlar’s anharmonic correction was applied to frequencies that are less than 100 cm⁻¹.²⁵ Trimethylsilylbenzene was used as a model for triethylsilylbenzyne.²⁶

Figure 2 shows optimized transition states for the nucleophilic additions of benzylamine and aniline to 3-trimethylsilylbenzyne. The barrier for attack of benzylamine at C2 is predicted to be 0.7 kcal/mol lower than for attack at C1. Addition at C2 is favored because the aryne’s pre-distorted bond angles favor nucleophilic attack at the flatter, more electrophilic carbon, which is C2 in this case. During the attack, the aryne has to undergo geometric changes, including an increase of the CCC angle at the site of attack and compression of the other terminus of the aryne. The larger angle, like C2 in triethylsilylbenzyne, will be attacked preferentially. In contrast, for aniline, attack is predicted to be favored at C1 rather than C2 by 3.7 kcal/mol. Because aniline is a more bulky nucleophile, it suffers from more steric hindrance with the silyl group of the benzyne. As shown in Figure 2, the H–H distance of the two closest hydrogens in the C2 attack of aniline are very close at 2.13 Å. In the case of benzylamine the closest H–H distance is 2.52 Å. This steric interaction is overriding the aryne distortion preference for attack at C2. Although the magnitude of selectivity is exaggerated, computations correctly predict experimental regioselectivities.²⁷

Figure 2.

Transition states for nucleophilic additions of benzylamine and aniline to 3-trimethylsilylbenzyne.

The cycloaddition of methylazide with 3-trimethylsilylbenzyne was also examined computationally, with methylazide serving as a model for benzylazide. Transition states are shown in Figure 3. C1 attack is favored, which is consistent with experimental results, by 0.7 kcal/mol. Aryne distortion would favor attack of the nucleophilic substituted terminus at C2, but steric hindrance overrides this electronic preference leading to preferential attack at C1.

Figure 3.

Cycloaddition of methylazide with 3-trimethylsilylbenzyne.

For comparison, we studied 3-t-butylbenzyne (6),²⁸ which is sterically similar to 3-triethylsilylbenzyne (1), but varies electronically (Figure 4). The geometry optimized structure of 6 (B3LYP/6-311+G(d,p)) revealed internal angles of 129° and 127° at C2 and C1, respectively. Given the minimal distortion present, 6 was predicted to undergo sterically-guided attack at C1 to give meta-substituted products.

Figure 4.

Geometry optimized structure of 3-t-butylbenzyne 6 and predicted regioselectivity.

A silyltriflate precursor to aryne 6 was prepared from o-t-Bu-phenol and examined in nucleophilic addition reactions (Table 3).²⁹ When aniline was used as the trapping agent, formation of the meta-substituted product was preferred (entry 1), similar to the trend observed in the reaction of 3-triethylsilylbenzyne. Benzylamine and 4-t-Bu-benzoic acid were also tested with aryne 6. In contrast to the outcome seen in reactions of 1, only meta substitution was observed (entries 2 and 3). These results support the notion that aryne distortion plays a significant role in reactions of 3-silylaryne 1. Quantum chemical calculations were performed for the reaction of 6 with aniline and benzylamine, and in both cases the attack at C1 was strongly favored.²⁹

Table 3.

Nucleophilic additions to t-butylbenzyne 6^a

entry	trapping agent	productb	ratio (yieldc)
1			(66% yield)
2	H2N–Bn		(61% yield)
3			(50% yield)

^aSee Supporting Information for experimental details.

^bortho-Substituted products were not observed.

^cYields determined by ¹H NMR analysis with external standard.

The effects of the inductively donating silyl group on arynes have been studied both experimentally and computationally. It has been shown that if the incoming nucleophile is not bulky, the aryne distortion model holds true and the flatter terminus of the aryne is the site of attack. If however, there is sufficient steric bulk on the nucleophile, then attack on the more accessible carbon of the aryne is favored. When the substituent adjacent to the aryne is an alkyl group, steric effects dominate, since there is no significant differential distortion of the aryne bond angles.