Fourfold homologous anionic ortho-Fries rearrangement on a partially bridged resorc[4]arene Oskar Middel, Willem Verboom, and David N. Reinhoudt Abstract: Fourfold homologous anionic ortho-Fries rearrangement in the twofold bridged tetra-O-carbamate 3 gave the tetrakis(carboxamidomethyl)resorc[4]arene 4 in 68% yield. Compound 3 was prepared by selective carbamoylation of methylresorc[4]arene 1, followed by the bridging of the remaining OH groups in tetra-O-carbamate 2. Key words: resorc[4]arenes, selective functionalizations, homologous anionic ortho-Fries rearrangement. Résumé : Le réarrangement ortho-Fries anionique homologue quaternaire du tétra-O-carbamate 3 à pont binaire conduit à la formation du tétrakis(carboxamidométhyl)résorc[4]arène, 4, avec un rendement de 68%. Le composé 3 a été préparé par carbamoylation sélective du méthylrésorc[4]arène, 1, suivie de la formation d’un pont des groupes OH résiduels du tétra-O-carbamate 2. Mots clés : résorc[4]arènes, fonctionnalisation sélective, réarrangement ortho-Fries anionique homologue. [Traduit par la Rédaction] Middel et al. 1527 Over a time period of about 20 years the directed ortho- metalation strategy (DoM) (for recent examples see ref. 1a, 1b; for a review see ref. 1c) has developed as a common synthetic concept in aromatic chemistry. The Snieckus group is one of the leaders in this emerging field in synthetic or- ganic chemistry and by their contemporary developments and collaborations, this synthetic concept has been applied in pharmaceutical chemistry, industrial processes, and the to- tal syntheses of complex natural products. Recently, we (2) introduced the DoM concept in supramolecular chemis- try as the first synthetic tool for the direct, selective intro- duction of functional groups at the lateral positions of the calix[4]arene skeleton. Resorc[4]arenes (for a review see ref. 3) (octols), are the cyclic condensation products of aldehydes and resorcinol and the insertion of methylene bridges between adjacent phenolic moieties results in the formation of cavitands (3, 4). Only a few (selective) resorc[4]arene functionalizations, other than methylene bridge formation (4), are known, e.g., the Mannich reaction (5), radical aromatic bromination (6), and the alkylation (7) and (sulfonate) esterification (8, 9) of the phenolic groups. In this communication, we report our first results on the application of the DoM concept for the introduction of upper rim functional groups via a unique fourfold anionic ortho-Fries rearrangement (10) at the par- tially bridged resorc[4]arene 3. Results and Discussion Synthesis 2 Reaction of resorc[4]arene 1 (11) with diisopropyl- carbamoyl chloride (20 equiv) in the presence of a large ex- cess of NaH as a base in DMF at 65°C for 72 h afforded a mixture of tetra-O-carbamate regioisomers. Fractional crys- tallization of this mixture from MeOH–H 2 O gave regio- isomer 2, having two diametrical pairs of substituted adjacent phenol groups, in 32% isolated yield. 3 The predom- inant formation of 2 is probably due to a stabilizing effect of the hydrogen bond between adjacent phenol groups. The se- lective formation of (tetrasulfonate) esters of resorc[4]arenes described by Shivanyuk and co-workers (8a), in which on two diametrical aryl rings two sulfonate esters were intro- duced, was explained by the formation of a strong hydrogen bond between a sulfonate ester and an adjacent phenol moiety. 4 Can. J. Chem. 79: 1525–1527 (2001) © 2001 NRC Canada 1525 DOI: 10.1139/cjc-79-11-1525 Received March 1, 2001. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on October 19, 2001. Dedicated to Professor Victor Snieckus for his contributions to Canadian chemistry. O. Middel, W. Verboom, and D.N. Reinhoudt. 1 Laboratory of Supramolecular Chemistry and Technology, MESA + Research Institute, University of Twente, P.O. Box 217, NL-7500 AE Enschede, The Netherlands. 1 Corresponding author (fax: +31 534894645; e-mail: smct@ct.utwente.nl). 2 Experimental and spectroscopic data of resorc[4]arenes 2–5 have been deposited as supplementary material. Supplementary material may be purchased from the Depository of Unpublished Data, Document Delivery, CISTI, National Research Council Canada, Ottawa, ON K1A 0S2, Canada (http://www.nrc.ca/cisti/irm/unpub_e.shtml for information on ordering electronically). 3 Octols having lower rim substituents gave complicated reaction mixtures of multiple substitutions. Other examples giving other regioisomers: see ref. 8. 4 In the case of esters, a dependence on solvent, base, and acylating agents was observed: see ref. 8b.