Multistep synthetic routes to eight structurally diverse and medicinally relevant targets were planned autonomously by the Chematica computer program, which combines expert chemical knowledge with network-search and artificialintelligence algorithms. All of the proposed syntheses were successfully executed in the laboratory and offer substantial yield improvements and cost savings over previous approaches or provide the first documented route to a given target. These results provide the long-awaited validation of a computer program in practically relevant synthetic design.

Although much current research focuses on developing new boron reagents and identifying robust catalytic systems for the cross-coupling of these reagents, the fundamental preparations of the nucleophilic partners (i.e., boronic acids and derivatives) has been studied to a lesser extent. Most current methods to access boronic acids are indirect and require harsh conditions or expensive reagents. A simple and efficient palladium-catalyzed, direct synthesis of arylboronic acids from the corresponding aryl chlorides using an underutilized reagent, tetrahydroxydiboron B 2 (OH) 4 , is reported. To insure preservation of the carbon-boron bond, the boronic acids were efficiently converted to the trifluoroborate derivatives in good to excellent yields without the use of a workup or isolation. Further, the intermediate boronic acids can be easily converted to a wide range of useful boronates. Finally, a two-step, one-pot method was developed to couple two aryl chlorides efficiently in a Suzuki-Miyaura-type reaction.The Suzuki-Miyaura cross-coupling reaction has become of immense utility and thus importance,1 , 2 and yet there does not exist a simple, robust, catalytic, and functional group tolerant method that provides direct access to the boronic acid, with straightforward conversion to related derivatives. Thus, arylboronic acids are normally accessed by hydrolysis of boronate esters, and consequently many other boronic acid derivatives (e.g., organotrifluoroborates) are derived ultimately from these same boronate esters. The boronate esters can be accessed in a number of ways, including iridium-catalyzed C-H activation with bis(pinacolato)diboron3 and transmetalation from reactive organometallics.4 The harsh reaction conditions used in the latter approach severely limit functional group incorporation into the boronic acid derivatives.5 Another common method makes use of bis(pinacolato)diboron or related reagents to access arylboronates catalytically according to Miyaura's widely used protocol.6 -12 When boronic acids are the targets required in any of these protocols, the boronate esters must be converted by way of oxidation,13 hydrolysis,14 reduction, 15 or transesterification. 16 These methods are inherently inefficient both in terms of atom economy and step economy, employ harsh reaction conditions (NaIO 4 , aq HCl, LAH, diethanolamine, BBr 3 ), or require the use of excess polymer-supported boronic acid. 16,17 Further, the transformation of pinacol boronate esters to the analogous trifluoroborates often suffers from difficulties in purification, rendering these protocols exceedingly tedious. 18,19 In this communication, the development of the first direct synthesis of boronic acids via palladium-catalyzed cross-coupling of aryl chlorides with tetrahydroxydiboron B 2 (OH) 4 (1) is outlined. [20][21][22][23] This protocol allows the direct synthesis and isolation of arylboronic acids and also permits the preparation of trifluoroborates and diverse boronate analogs without the use of highly reactive organomet...

The Suzuki-Miyaura reaction has become one of the more useful tools for synthetic organic chemists. Until recently, there did not exist a direct way to make the most important component in the coupling reaction, namely the boronic acid. Current methods to make boronic acids often employ harsh or wasteful reagents to prepare boronic acid derivatives and require additional steps to afford the desired boronic acid. The scope of the previously reported palladium-catalyzed, direct boronic acid synthesis is unveiled, which includes a wide array of synthetically useful aryl electrophiles. It makes use of the newly available second generation Buchwald XPhos preformed palladium catalyst and bis-boronic acid (BBA). For ease of isolation and to preserve the often sensitive C-B bond, all boronic acids were readily converted to their more stable trifluoroborate counterparts.

The use of bis-boronic acid for the direct synthesis of boronic acids has greatly facilitated the two-step, one-pot borylation/Suzuki cross-coupling reaction between aryl- and heteroaryl halides. Making use of Buchwald’s second generation XPhos preformed catalyst, high yields of cross-coupled products were obtained for most substrates. The method also allows an efficient two-step, one-pot synthesis, providing access to three distinct cross-coupled products after column chromatography. The method also provides a rapid and convenient route to teraryl compounds.

A modified Pd-catalyzed method of forming aryl- and heteroarylboron species and a two-step, one-pot borylation/Suzuki-Miyaura cross coupling using the atom economical tetrahydroxydiboron (bis-boronic acid, BBA) is reported. By using ethylene glycol as an additive, the new method results in increased yields, lower BBA loading, faster reaction times, and a broader reaction scope, including previously problematic substrates such as heterocycles.