meta‐ Rather than ortho‐Directed Metalations: Buttressing Effects Prejudicing the Proton Abstraction from (2,6‐Dihalophenyl)silanes

Abstract

(2,6-Dichlorophenyl)trimethyl-and -triethylsilane exhibit untypical reactivity patterns toward strong bases. When treated at -100°C with lithium 2,2,6,6-tetramethylpiperidide, they give rise to two, with sec-or tert-butyllithium even three, different organometallic intermediates which can be intercepted with standard electrophiles. The trialkylsilyl group intervenes in two respects. Exerting steric pressure on the neighboring chlorine atoms, it facilitates the permutational displacement of one of them against lithium, a side reaction which occurs whenever alkyllithium compounds are employed. At the same time it impedes the attack of hydrogen When applying the "toolbox" methods [1] to the regioexhaustive functionalization of 1,3-difluorobenzene [2] and 1,3-dichlorobenzene [3] we made an unexpected discovery. (2,6-Dichlorophenyl)trimethylsilane and (2,6-dichlorophenyl)triethylsilane underwent hydrogen/metal permutation ("metalation") at the 5-rather than the 4-position or, in other words, meta rather than ortho to the activating halogen. However, the yields of the trapping products, the 3,5-dichloro-4-(trialkylsilyl)benzoic acids (60-70 %), ranged far below our expectations, no matter whether sec-butyllithium or lithium 2,2,6,6-tetramethylpiperidide (LITMP) were employed as the base in tetrahydrofuran at -75°C. When (2,6-dibromophenyl)triethylsilane served as the substrate, 3,5-dibromo-4-(triethylsilyl)benzoic acid (2) was isolated in an even lower yield of only 52 %. We worried whether we might have missed a regioisomer or any other by-product derived from the dichlorinated or dibrominated starting materials. The reaction was therefore repeated under systematic variation of some key parameters and the resulting mixtures were carefully examined by gas chromatography. At -100°C in tetrahydrofuran, LITMP promoted mainly a bromine/lithium permutation and only to a minor extent remote deprotonation as evidenced by the formation of 39 % of 3-bromo-2-(triethylsilyl)benzoic acid (1) and 8 % of 3,5-dibromo-4-(triethylsilyl)benzoic acid (2). The relative atoms by the base in the immediate vicinity of the halogens due to relay transmission of steric hindrance. As a consequence, deprotonation occurs preferentially or exclusively at the 5-("meta") rather than the 4-("ortho")position. 4-Lithiated species, generated as by-products or separately by permutational halogen/metal interconversion, eliminate lithium chloride at -75°C to set free didehydrobenzenes ("arynes") which are trapped by their aryllithium precursors.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005) amounts of 1 and 2 were inverted to 11 % vs. 61 % and 5.6 % vs. 70 %, respectively, when LITMP was employed in the presence of N,N,NЈ,NЈЈ,NЈЈ-pentamethyldiethylenetriamine (PMDTA) alone or in the additional presence of potassium tert-butoxide. The latter "Faigl mix" [4] gave the dibromo acid 2 exclusively when the reaction was performed at -125°C in tetrahydrofuran or diethyl ether (15 and 4.1 %

Long‐Range Effects in the Metalation/Boronation of Functionalized 1,4‐Dihalobenzenes

“…[25,26] More advanced studies revealed that this is a purely kinetic phenomenon [27] whose synthetic potential is remarkable. [28] As expected, a comparison of product distributions 22/23 (2:1) and 24/25 (4:1) shows that this effect is more pronounced for the dibromo compound due to the increased van der Waals radius of this halogen. However, when the dibromo acetal was replaced with its more bulky diethyl analogue, the regioselectivity was not improved in favour of the product 23 due to a potential enhancement of the buttressing effect.…”

Fluorine‐Flanked Congested Sites: Minimal, Though Perceptible Buttressing Effects on the Proton Mobility of Arenes

“…In view of the thermal lability of ortho-lithiated (2,6dichlorophenyl)trimethylsilane, [17] we first tested the temperature sensitivity of lithiated (2,6-difluorophenyl)trimethylsilane (1a), (2,6-difluorophenyl)triethylsilane (1b) and (2,6-difluorophenyl)triisopropylsilane (1c). All three proved to be perfectly stable at -75°C, whereas slow decomposition started at -50°C and became fast above -25°C.…”

Substituent effects on the relative rates and free energies of ortho-lithiation reactions: families of fluorobenzenes as the substrates

“…In some cases (e.g. with X = SiMe 3 ), buttressing effects [34][35][36][37][38][39][40][41] (steric effects exerted by the X group through the fluoro group) 42 may compromise the reactivity of the 1,2-isomers 2. More importantly, the acidifying effect of substituents at meta positions is no longer the same as at ortho positions.…”