One-Pot Synthesis of 1,4-Benzodiazepin-3-ones

The group of Peter Andreana from Wayne State University, Michigan, has developed a one-pot two-step synthesis of regiochemically differentiated 1,4-benzodiazepin-3-ones (Org. Lett. 2008, 10, 4541. ). The first step involves the Ugi four-component coupling reaction to form α-acylaminoamides which are subsequently converted to benzodiazepines by a reductive (NO₂ → NH₂) aza-Michael cyclization employing Fe(0)/NH₄Cl in aqueous media as reducing agent. With bifunctional o-nitrobenzaldehyde 1 exclusively C2, N4, C5-substituted benzodiazepines 2 are obtained whereas with o-nitrobenzylamine 3 the C2, N4-substituted derivatives 4 are formed. The reduction reaction gave higher yields in shorter times compared to more conventional reactions performed in a sealed-tube with oil-bath heating. It has to be noted that at higher temperatures either decomposition or a 6-exo aza-Michael cyclization to form 2,5-diketopiperazines occurred.

High-Temperature Zincation of Functionalized (Het)Aromatics

Paul Knochel and Stefan Wunderlich from Ludwig-Maximilians-Universität, Munich, have reported on the direct zincation of highly functionalized aryl and heteroaryl derivatives using the complex base (tmp)₂Zn•2MgCl₂•2LiCl (Org. Lett. 2008, 10, 4705. ). With microwave heating, a tremendous time saving could be achieved − e.g. for derivatives with R¹ = CO₂Et, R² = R³ = H, R⁴ = Cl, Br the reaction time could be reduced from 110 h at 25 °C to 2 h at 80 °C. Interestingly, for substrates with R¹ = CO₂Et, CONEt₂, R² = R³ = R⁴ = H, microwave heating is crucial since under oil-bath heating at the same temperature a very low yield is obtained (10-20% vs. >90%). Importantly, sensitive functional groups are well tolerated under the reaction conditions. This zincation protocol was further successfully applied to heterocyclic systems such as pyridines, benzothiophene or benzofuran. In a post-derivatization step, the bis-zincated species were further transformed via Cu-mediated or Pd-catalyzed reactions.

Synthesis of Symmetrical and Unsymmetrical 2,5-Diketopiperazines

The phosphorous-promoted coupling of unprotected amino acids toward the one-step synthesis of 2,5-diketopiperazines was disclosed by Stefan Bräse and his group from the Universität Karlsruhe, Germany (Eur. J. Org. Chem. 2008, ASAP. ). Symmetrical and unsymmetrical 2,5-diketopiperazines are generated by the condensation of amino acids with methyldichlorophosphite in toluene. The ionic liquid (IL) 1,3-dimethylimidazolium dimethyl phosphate needs to be used as a heating aid in order to reach the 145°C. Unsymmetrical derivatives are obtained by the combination of proline, sarcosine, indoline- and octahydroindolecarboxylic acids without the formation of any by-products (1.2 equiv excess of one amino acid is crucial in this case). Advantages of this protocol are excellent yields, complete retention of the stereochemistry, tolerance of base-stable protecting groups and a simple work-up procedure (only filtration).

Suzuki-Miyaura Coupling of Unprotected 2-Chlorobenzimidazoles

Brad Savall and Jill Fontimayor from Johnson & Johnson Pharmaceutical Research & Development, San Diego, have synthesized a series of 2-arylbenzimidazoles via Suzuki-Miyaura couplings of unprotected 2-chlorobenzimidazoles (Tetrahedron Lett. 2008, 49, 6667. ). Higher yields could be achieved when switching from arylboronic acids to aryltrifluoroborate salts as coupling partners. To overcome the problem with homocoupling of pyridylboronic acids, a change in the catalyst system to PdCl₂(dppf)•CH₂Cl₂ and the use of aryltrifluoroborate salts was advantageous.

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