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Reports: UR152858-UR1: Effective, Catalyzed and Electrophilic Cyclization Reactions Leading to Highly and Diversely Substituted Fluoroheterocycles

Roman Dembinski, Oakland University

Reaction of alk-3-yn-1-ones (propargyl ketones) with o-phenylenediamines was investigated. We have demonstrated that at a room temperature the reaction leads to enaminones (3-amino-2-alkenones, 70–99%). The protocol with the same set of reagents at elevated temperature in microwave-accelerated conditions proceeds in ethanol in the absence of a catalyst and leads to 1,5-benzodiazepines with good yields (70–92%). This combination of non-catalyzed amination reaction with subsequent condensation reaction provides effective access with high atom economy to diverse 2,4-disubstituted 1,5-benzodiazepines. The methodology allows for the introduction of benzyl-type substituents at the C-2 position of benzodiazepine that is not easily carried out by current methods. The catalyst-free conditions provide an appealing protocol that includes the formation of two C=N bonds and does not require the isolation of the enaminone. The overall formal amination reaction proceeds with anti-Markovnikov regiochemistry relative to the initial alkyne bond. With a high degree of rearrangement, this reaction provides a convenient and temperature-controlled synthetic method for the synthesis of benzodiazepines. En route, enaminones with the stereoselective positioning of o-phenylenediamine across the double bond can be manufactured with no need to protect the second amino function.

The crystal structure of 2-(4-methylbenzyl)-4-phenyl-3H-benzo[b][1,5]-diazepine (orthorhombic, P 21/21/21, a/b/c = 10.2819(9)/10.7707(9)/15.6284(14), Z = 4) was acquired and confirmed diazepine tautomer formed.

The crystal structure of (Z)-3-[(2-amino-4,5-dimethylphenyl)amino]-4-(4-tert-butylphenyl)-1-(4-chlorophenyl)but-2-en-1-one (monoclinic, P 21/n, a/b/c = 5.7713(9)/16.573(2)/25.145(4), Z = 4) documents regiochemistry of amination of a triple bond and Z stereochemistry of enaminone.

So far two undergraduate students were involved in this project and enjoyed summer research opportunity. Both are remaining in the PI’s laboratory, while pursuing theirs B.S. degree in Chemistry (ACS accredited). The M.S. student involved successfully graduated and joined an industrial chemistry company (Henkel, and subsequently BASF).

I am grateful to participate in this program, since it provided me with the unique opportunity to carry out research with undergraduate students and to have an impact for their future careers.