Titanium(IV) Isopropoxide Mediated Solution Phase Reductive Amination on an Automated Platform: Application in the Generation of Urea and Amide Libraries

Abstract

Amine libraries and their derivatives are important targets for high throughput synthesis because of their versatility as medicinal agents and agrochemicals. As a part of our efforts towards automated chemical library synthesis, a titanium(IV) isopropoxide mediated solution phase reductive amination protocol was successfully translated to automation on the Trident(TM) library synthesizer of Argonaut Technologies. An array of 24 secondary amines was prepared in high yield and purity from 4 primary amines and 6 carbonyl compounds. These secondary amines were further utilized in a split synthesis to generate libraries of ureas, amides and sulfonamides in solution phase on the Trident(TM). The automated runs included 192 reactions to synthesize 96 ureas in duplicate and 96 reactions to synthesize 48 amides and 48 sulfonamides. A number of polymer-assisted solution phase protocols were employed for parallel work-up and purification of the products in each step.

Copper (II)-Mediated Arylation with Aryl Boronic Acids for the N-Derivatization of Pyrazole Libraries

“…The copper mediated N-arylation reported here has not to our knowledge been previously employed for parallel solution- phase synthesis. The mild conditions and ease of product isolation should make it amenable for general use in the synthesis of medicinal chemistry libraries and for automated platforms, such as the Trident . Currently, the chemistry is not practicable with hindered or electron-deficient substrates.…”

“…Comparison of 1 H and 13 C NMR spectra of the species synthesized via the phenyl hydrazine route 31 and via phenylboronic acid cross-coupling 3 showed the two compounds to be identical. The chemical shifts for the C4-H of the products where only one isomer was obtained (3,4,(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)) are consistently around δ 5.3 ppm, whereas in the case of the reaction yielding two isomers (5), the C4-H shift for what is assumed to be the N-1 arylated isomer is around δ 5.5 ppm. Therefore, it is reasonable to propose that the N-2 aryl isomer is formed in each case, although it is not definitively established, with the only exception being the p-methoxy compound 5, which yielded a 1:5 mixture of N-1 and N-2 substituted compounds.…”

Green chemistry approaches as sustainable alternatives to conventional strategies in the pharmaceutical industry

“…9) has been investigated as having signicant anticancer activity against various tumors and is currently prescribed worldwide to treat the most aggressive forms of ovarian, lung and breast cancer as well as AIDS-related Kaposi's sarcoma. [45][46][47][48][49] It is a complex diterpenoid alkaloid originally isolated from the bark of the pacic yew tree Taxus brevifolia with a yield of 0.014%. 45,50 In addition, isolating paclitaxel required stripping the bark from the yew trees killing them in the process.…”

“…[45][46][47][48][49] It is a complex diterpenoid alkaloid originally isolated from the bark of the pacic yew tree Taxus brevifolia with a yield of 0.014%. 45,50 In addition, isolating paclitaxel required stripping the bark from the yew trees killing them in the process. Yews take 200 years to mature and are part of a sensitive ecosystem.…”

Combinatorial Approaches in Anticancer Drug Discovery: Recent Advances in Design and Synthesis

“…During the emerging days of combinatorial chemistry, solid-phase organic synthesis has been the leading strategy for the rapid production of large libraries for lead generation [3]. As combinatorial techniques for high throughput synthesis have evolved, the paradigm has shifted towards the assembly of smaller, target-oriented libraries containing discrete, pure compound [4]. In this context, library synthesis in solution-phase is gaining popularity due to the more demanding, complex multi-step chemistry.…”