Solvent control of product diversity in palladium-catalyzed addition of arylboronic acid to aryl aldehydes Tuluma Das, Amarnath Chakraborty, Amitabha Sarkar ⇑ Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India article info Article history: Received 6 June 2014 Revised 17 July 2014 Accepted 18 July 2014 Available online 24 July 2014 Keywords: Palladium Addition reaction Carbinol Symmetrical ether Fluorene abstract In Pd-catalyzed arylboronic acid addition to aryl aldehydes, the expected carbinol or asymmetrical ether can be obtained as the major product by altering aqueous solvent composition. Exploiting this method- ology with 2-formylbiphenyls as reaction partner, a fluorene scaffold can be readily constructed in two steps. Ó 2014 Elsevier Ltd. All rights reserved. Diarylcarbinol derivatives are important intermediates for the synthesis of natural products, pharmacologically active com- pounds as well as new materials. 1 Transition metal catalyzed addi- tion of organometallic reagents to aldehydes is a mild and efficient method widely used for the synthesis of substituted carbinols. Among organometallic compounds, organoboron reagents 2 have achieved prominence because of their air and moisture stability, low toxicity, and ease of handling. Transition metal catalyzed 1,2-addition of organoboron reagents to aldehydes has drawn much attention since Miyaura and co-workers reported Rh-cata- lyzed addition of arylboronic acid to aldehydes. 3 Subsequently, various catalytic systems were developed and they are primarily based on Rh 4 and Pd. 5 As a part of our ongoing research with palladium-ligand chem- istry in catalysis, we investigated Pd-catalyzed 1,2-addition reac- tion of boronic acids and aldehydes as a model reaction. In our laboratory, pyrazole based ligands were successfully used in palla- dium-catalyzed coupling reactions. 6 In the present work, we describe the use of 3,5-dimethyl-1-(2 0 -pyridyl)pyrazole (L) 7 as a ligand in Pd-catalyzed addition of arylboronic acids to aryl alde- hydes. We demonstrate that the reaction medium plays a decisive role in determining the product formation from the same combina- tion of reactants. Initially, we selected phenylboronic acid and 4-methylbenzalde- hyde as reaction partners and Pd(OAc) 2 as the metal catalyst precursor in the presence of different bases and solvents (Scheme 1). No reaction occurred until triflic acid (TfOH) was used as an additive instead of a base and water as the solvent. The starting aldehyde was consumed in 8 h at 60 °C to generate ether 4a as the only product in high yield (see entry-13, Table S1 of Supplementary data). It is pos- sible that the symmetrical ether 4a was formed in situ by the acid catalyzed self-condensation of the initially formed 1,2 addition product that is, phenyl(p-tolyl)methanol (3a). The formation of this undesired product 4a led us to explore alternative conditions to pre- pare the desired carbinol 3a from this reaction. Interestingly, we found that compound 3a was produced in 10% yield along with compound 4a (61%) (see entry-17, Table S1) in dioxane/water (1:1). Formation of compound 3a prompted us to play with the ratio of dioxane and water in the addition reaction with TfOH as an additive. Gratifyingly, we observed that dioxane/ water (5:1) was the best solvent system at 80 °C to furnish carbinol 3a exclusively in 81% yield. http://dx.doi.org/10.1016/j.tetlet.2014.07.073 0040-4039/Ó 2014 Elsevier Ltd. All rights reserved. ⇑ Corresponding author. Tel.: +91 33 2473 4971; fax: +91 33 2473 2805. E-mail address: ocas@iacs.res.in (A. Sarkar). Ar CHO Ph B(OH) 2 additive solvent, 60 °C Ar Ph OH 3a 4a Pd(OAc) 2 ,L 1a 2a O Ph Ar Ar Ph N N N L= Ar= 4-CH 3 -C 6 H 4 Scheme 1. Addition of phenylboronic acid to 4-methylbenzaldehyde. Tetrahedron Letters 55 (2014) 5174–5178 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet