First Higher‐Order Photocycloaddition to a CN Bond: 1,3‐Diazepines from Maleimides

Abstract

By comparison to C = O and C = C containing chromophores the photochemistry of the C = N bond has not received the same level of synthetic interest and mechanistic scrutiny. Excitation of the C=N bond is known to lead to isomerization, rearrangement, hydrolysis, oxidation, photoreduction, and photoalkylation. [1] Although olefins have been reported to undergo cycloaddition to photoexcited imines containing electron-withdrawing groups on the nitrogen atom, [1a-c, 2] generally useful preparative examples of [2+2] photocycloadditions to C=N bonds are very rare. Furthermore, the reverse situation in which the imine is the ground-state partner during the cycloaddition with a photoexcited alkene has, to our knowledge, yet to be reported. Herein, we report our findings in an area of maleimide photochemistry which have resulted in the realization of a [5+2] photocycloaddition that utilizes oximes and hydrazones as ground-state C=N components in the reaction. These results constitute the first reported examples of a higher-order photocycloaddition to a C=N bond.Previously we reported [3] the synthetic utility of the intramolecular [5+2] photocycloaddition [4] reaction of alkenyl-substituted maleimides 1 as a powerful method for the direct formation of the perhydroazaazulene ring system 3, which is common to a number of alkaloids. After pursuing an in-depth study, we proposed a singlet mechanism involving n!p* excitation with subsequent C À N a cleavage to give the biradical 2, which then underwent a [5+2] cycloaddition onto the alkene (Scheme 1). [5] Whereas the reaction is specific to the maleimide and phthalimide chromophores, a wide range of pendant alkene functionality can be used, including cyclic systems, a feature that we have exploited in alkaloid synthesis. [6] We were intrigued to see if similar reactivity would be displayed with maleimides using non-alkene substrates. Introducing a C = N based functionality to the maleimide photosubstrates 4 had the potential to extend the scope of the cycloaddition by enabling the formation of 1,3-diazepines 5, a class of diazepine that has rarely been reported. [7] We anticipated that an important factor when choosing the precursors 4 would be the stability of the C = N bond towards hydrolysis. Hydrazones and oximes were attractive as they are inherently more stable than imines with respect to isolation and additional manipulation. The preparation of the alcohols 6 a-c could be achieved by one of two routes (Scheme 2). Dimethylmaleimide and tetrahydrophthalimide derived alcohols 6 a and 6 b were prepared in excellent yield by condensation of the corresponding anhydrides with 4aminobutanol under Dean Stark conditions. The dichloromaleimide derivative 6 c was more problematic and was best prepared by a two-step sequence involving a Mitsunobu Scheme 1.[5+2] Photocycloadditions of N-substituted maleimides.Scheme 2. Synthesis of aldehydes 7, precursors to the oximes used for the [5+2] photocycloadditions. DMSO = dimethylsulfoxide, TBS = tertbutyldimethylsilyl, DIAD = diiso...

Recent Developments in the [5+2] Cycloaddition

“…With the aim of seeing if similar reactivity could be displayed with maleimides using non‐alkene substrates, these authors have discovered a new photochemically mediated intramolecular [5+2] photocycloaddition of maleimides to CN bonds 87. Indeed, introducing a CN‐based functionality to the maleimide photosubstrates 122a–l had the potential to extend the scope of the [5+2] cycloaddition by enabling the formation of 1,3‐diazepines 123a–l , a class of diazepines that has rarely been reported.…”

Synthesis of Tetracyclic 2,3-Dihydro-1,3-diazepines from a Dinitrodibenzothiophene Derivative

“…Since the last comprehensive survey of their synthesis 31 only a handful of new synthetic approaches have been reported for monocyclic, [32][33][34][35] singly- [36][37][38][39] or doubly-ringfused 1,3-diazepines. [40][41][42][43][44][45][46][47][48][49] In this work the introduction of sterically hindered nitro groups at the 1-and 9-positions of a dibenzothiophene-5,5-dioxide derivative provides access to a new two-electron accepting molecule, which is a precursor to luminescent four-ring-fused 2,3-dihydro-1,3-diazepines 6-8 using facile protocols in synthetically viable yields. To our knowledge these molecules represent the first examples of tetracyclic 1,3-diazepine derivatives.…”

The Profound Effect of the Ring Size in the Electrocyclic Opening of Cyclobutene‐Fused Bicyclic Systems

“…[4] Both strain and unfavorable entropic factors [5] mean that the synthesis by direct cyclization is often very difficult. [6] We have reported [7] extensively on the photocycloaddition reactions of maleimide and maleic anhydride derivatives and their use in synthesis. Such strategies involving 4-membered rings have proved to be a useful tool in total synthesis.…”

“…Medium to large carbocyclic rings are of great importance in organic chemistry and are commonly found as structural cores in an enormous range of biologically relevant natural products, including phorbol (7), [1] taxol (8), [2] byssochlamic acid (9), [3] eleutherobin (10). [4] Both strain and unfavorable entropic factors [5] mean that the synthesis by direct cyclization is often very difficult.…”

“…Such strategies involving 4-membered rings have proved to be a useful tool in total synthesis. [6] We have reported [7] extensively on the photocycloaddition reactions of maleimide and maleic anhydride derivatives and their use in synthesis. Ring opening and ring expansion of cyclobutanes, cyclobutenes, and cyclobutanones [8] has proved useful, for example, in the synthesis of the cyclooctane terpenoids asteriscanolide [9] and pachylactone.…”