Recyclization of furan in the synthesis of pyrrolo[1,2-d][1,4]diazepinone

Abstract

Pyrrolodiazepines are an important class of heterocyclic compounds due to their broad spectrum of pharmacological activity [1][2][3][4]. Additionally, the pyrrolodiazepinone framework is the basic structural fragment of natural anthramycin alkaloids which show antitumor activity [5]. All of this is responsible for the high interest in developing synthetic methods for these compounds. However, the Paal-Knorr reaction has been virtually unused in the preparation of pyrrolodiazepinones. Only two examples of its use have been reported. The first involves successive closing of the pyrrole and diazepinone rings [6] and the second a simultaneous formation of both rings [7]. This is likely associated with the fact that the synthesis of suitable 1,4-dicarbonyl compounds as precursors of the pyrrolodiazepinones is a multistage and laborious process [7].It is well known that furan derivatives in the presence of acids can serve as precursors of 1,4-diketones [8]. This property of furan compounds allowed us to develop a simple and efficient method for preparing pyrrolo[1,2-a][1,4]diazepinones based on the recyclization of N-(furfuryl)anthranilamides [9]. This process is a one-pot domino reaction in which opening of the furan ring and the formation of the diazepinone and pyrroles ring occur. We now report the use of this methodology for preparing pyrrolo[1,2-d][1,4]diazepinones.Acylation of the furylethylamine 1 by the 2-phthalimidoacetyl chloride 2 in benzene gave amide 3, treatment of which with hydrazine hydrate in ethanol led to the removal of the phthalimido protection and formation of the amine 4. Holding compound 4 in a mixture of acetic and hydrochloric acids for 1 day at room temperature and subsequent work up of the reaction mixture with an aqueous solution of NaHCO 3 gave the target compound 6. Evidently the reaction takes place via intermediate formation of the diketone 5.The yield of the pyrrolodiazepinone 6 is 21% which compares with the results in the study [6]. However, bearing in mind the simplicity of these procedures in our proposed method, it can be used in the preparation of other pyrrolo[1,2-d] [1,4]diazepinones and in further work we intend to carry out an optimization of the method. 1 H and 13 C NMR spectra were recorded on a Bruker DPX-300 spectrometer (300 and 75 MHz respectively) using CDCl 3 as solvent. The standards used were the residual protons of the deuterated solvent CDCl 3 (7.25 ppm for 1 H and 77.0 ppm for 13 C). Mass spectra were obtained on a Kratos MS-30 spectrometer by EI with ionizing energy 70 eV and ionization chamber temperature 200ºC.

A General Synthetic Route to Isomeric Pyrrolo[1,2-x][1,4]diazepinones

“…To demonstrate a general characteristic of the developed one-pot method, we applied it for the synthesis of isomeric pyrrolo­[1,2- d ]­[1,4]­diazepin-4­(5 H )-ones . We disclosed that the model reaction between 2-(5-methylfuran-2-yl)­ethylamine ( 11a ) and N -Boc-glycine ( 12a ) proceeded efficiently affording pyrrolo­[1,2- d ]­[1,4]­diazepin-4­(5 H )-one 13a in 64% yield (Scheme ).…”

Furan's Gambit: Electrophile‐Attack‐Triggered Sacrifice of Furan Rings for the Intramolecular Construction of Azaheterocycles

“…The acid‐induced rearrangement of β‐alanine N ‐furfurylamide 59 was shown above to afford pyrrolo[1,2‐ a ][1,4]diazepine 60 (see Scheme ). The isomeric pyrrolo[1,2‐ d ][1,4]diazepine 75 was synthesized under the same reaction conditions from glycine N ‐(2‐furylethyl)amide 74 (Scheme ) 29. However, this reaction proceeded in low yield.…”