Suppressing the Anionic Fries Rearrangement of Aryl Dialkylcarbamates; the Isolation of a Crystalline ortho‐Deprotonated Carbamate

Abstract

In the presence of organolithium bases phenyl dialkylcarbamates have previously been shown to undergo facile rearrangement to yield the corresponding salicylamides. However, heterometallic lithium diethyl(2,2,6,6-tetramethylpiperidido)zincate achieves the clean directed ortho-metallation (DoM) of phenyl dialkylcarbamates, with [C 6 H 4 {OC(O)-Strategies aimed at achieving directed ortho-metalation (DoM) have been developed over a number of years, [1] and now represent a core tool in the elaboration of complex aromatic compounds. While organolithium reagents have historically been used to achieve this chemistry, their nucleophilicity has brought with it the risk of competing reactions at the directing group. The need to circumvent this issue has led to the design of the heterometallic bases R 2 Zn(TMP)Li [R = Et, tBu (1); TMP = 2,2,6,6-tetramethylpiperidide]. These have been successfully used to elaborate functionalised aromatic compounds incorporating directing groups normally susceptible to nucleophilic degradation. [2] Moreover, initial questions over whether these bases effect alkyl or amido basicity [3] appear to have now been resolved, with recent density functional theory (DFT) work establishing the view that they exhibit a kinetic preference for amido ligand exchange [4] according to a stepwise reaction mechanism.[4c] We have also used this idea to explain the experimentally observed polybasicity of 1 (R = Et, tBu). [4c,5] [a] Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, U.K. NMe 2 }{Zn(µ-TMP)Et}Li] 2 having been structurally characterized. DFT studies point to a stepwise deprotonative mechanism in which the zincate reagent exhibits kinetic amido basicity.

Evaluating cis‐2,6‐Dimethylpiperidide (cis‐DMP) as a Base Component in Lithium‐Mediated Zincation Chemistry

“…DA was effective in this H–Zn/Zn–I double exchange process producing a yield (76 %) intermediate to that of 1 and the TMP variant in hexane solution, but gave lower yields than the cis- DMP and TMP mixtures in THF solution. As expected from previous reports of the use of “[LiZn(TMP)Et 2 ]” for deprotozincations of N,N -diisopropylbenzamide, N,N -diisopropylnaphthamide[ 10a ] and phenyl dimethylcarbamate[ 34 ] a TMP base mixture effectively metallated 3 , giving the best yield of the amides studied in hexane solution (82 %, 15 % higher than that achieved by 1 ). Increasing the number of equivalents of base to two, in THF solution, the results achieved by 1 were comparable to those with the TMP mixture.…”

Closer Insight into the Reactivity of TMP−Dialkyl Zincates in Directed ortho-Zincation of Anisole: Experimental Evidence of Amido Basicity and Structural Elucidation of Key Reaction Intermediates

“…2 In addition to this high functional group tolerance, reactions can be carried out under much milder conditions (generally at room temperature) than when traditional organolithium reagents such as t BuLi or LiTMP are employed, where other undesirable reactions such as nucleophilic addition can compete with the desired metalation. 3 The structural elucidation of the THF-supported mixed-metal base [(THF)Li(TMP)( t Bu)Zn( t Bu)] ( 1 ) 4 and of some key zincated intermediates of its reaction with DoM substrates such as the tertiary aromatic amide N , N -diisopropyl benzamide, 5 anisole (Scheme 1) 6 or phenyl dialkyl carbamates 7 have unequivocally established that these metalations are genuine direct zincations, where the position previously filled by a hydrogen atom in the aromatic molecule is now occupied by zinc. This reactivity is in stark contrast to the low kinetic basicity found for conventional homometallic zinc reagents.…”

Trapping of Transient Organolithium Compounds

“…In 2008, Wheatley and Uchiyama reported the direct iodination of carbamate 37 utilizing Et 2 Zn(TMP)Li as a base (Scheme 7). [23] Carbamate 37 underwent a smooth deprotonation at room temperature to generate the corresponding organozinc species, which was transformed to the desired aryl iodide 38 in 99% yield without the anionic Fries rearrangement. The zincation provides direct access to the functionalized aromatic compounds with the combination of recently developed reactions of organozinc species, [24] whereas this example is limited to iodination.…”

“…The anionic Fries rearrangement is promoted by the highly reactive organolithium. In 2008, Wheatley and Uchiyama reported the direct iodination of carbamate 37 utilizing Et 2 Zn(TMP)Li as a base (Scheme ) . Carbamate 37 underwent a smooth deprotonation at room temperature to generate the corresponding organozinc species, which was transformed to the desired aryl iodide 38 in 99% yield without the anionic Fries rearrangement.…”