1,2-Diamination of Alkenes via 1,3-Dipolar Cycloadditions with Azimines

SPECIFIC AIMS. 1,2-Diamines are useful in medicinal chemistry as bioactive compounds and as ligands or precursors thereto in catalysis.1, 2 The 1,2-diamination of an alkene represents an attractive synthetic route to 1,2-diamines, because a large variety of alkenes are commercially available and inexpensive. However, despite many efforts, most described 1,2-diaminations of alkenes are challenged by poor scope, stereospecificity, or reagent safety or availability. Our long-term goal is to enable new drug development to proceed at an increased pace by providing greater access to a wider variety of 1,2-diamines. A cycloaddition of an NXN compound (where X is a tether) with an alkene in a cycloaddition reaction, followed by excision of X to give the 1,2-diamine, is an attractive approach to 1,2-diamination, because the two new C–N bonds form simultaneously and hence stereospecifically. Our group was the first to publish a 1,2-diamination method that used this strategy. Our NXN compound, an azidium ion, ArN=N+=NAr, underwent a 1,3-dipolar cycloaddition (DCA) with an alkene to give a triazolinium ion, and excision of the middle N gave the 1,2-diamine.3 The cycloaddition step was stereospecific, with the two new C–N bonds forming in concerted fashion. However, the 1,2-diamines that our method provided bore N-aryl groups, whose resistance to removal was an obstacle to our method’s adoption. To address this issue, we have been developing a 1,2-diamination of alkenes via alkene–azimine DCA.4 Azimines such as BocN=N(Ph)+–N(Boc)– are surprisingly easy to make and are surprisingly stable. These 1,3-dipoles undergo DCA with both electron-poor and electron-neutral alkenes at 60–70 °C to give 1,2,3- triazolidines, saturated five-membered rings with three contiguous N atoms. Reductive cleavage of the N–N bonds of the 1,2,3-triazolidine then provides a 1,2-diamine bearing a Boc group on each N. Unlike our previous method,3 our new one provides 1,2-diamines bearing easily removed protecting groups (Boc).5 Building on these promising results, the goal of this proposal is to establish the scope and applicability of azimine-mediated 1,2-diamination of alkenes, which we will achieve by fulfilling the following specific aims: Specific aim 1: Develop further the 1,2-diamination of alkenes via DCA with azimines. We have already found that azimines BocN=N(Ar)+–N(Boc)– (Ar = Ph or p-anisyl) undergo DCAs with both electron-poor (ethyl acrylate, dimethyl fumarate) and electron-neutral (cyclopentene, allylbenzene) alkenes to give 1,2,3- triazolidines. Very recently, we have also found that we can cleave the N–N bonds of the 1,2,3-triazolidine derived from norbornene by high-pressure hydrogenation (1000 psi) over Raney Ni, affording a 1,2-diamine with Boc protection of both N atoms. We will investigate further the DCA of azimines with alkenes that have diverse substitution patterns, stereochemistry, and functional groups, and we will subject the 1,2,3-triazolidines prepared by these DCAs to Raney Ni-catalyzed hydrogenolysis under high pressure. We have also learned how to prepare less symmetrical azimines such as BocN=N(Ph)+–N(Cbz)– and BocN=N(Ph)+–N(COCF3)–, and we will investigate whether these azimines are more suitable for the 1,2-diamination of alkenes. Specific aim 2: Develop a tethered 1,2-diamination of alkenes and apply it to the synthesis of a natural product. We have developed a method for preparing azimines connected to an alkene by a tether. These alkene- tethered azimines undergo intramolecular DCA (IDCA) at room temperature to give bicyclic 1,2,3-triazolidines. High-pressure hydrogenation (300 psi) of the triazolidines over Raney Ni then cleave the N–N bonds, providing 1,2-diamines partly embedded in nitrogen-containing heterocycles. We will investigate the scope of the tethered 1,2-diamination, particularly with substrates in which the alkene is embedded in a ring, and we will illustrate its utility by applying it to a total synthesis of the naturally occurring 1,2-diamine, (+)-loline. Specific aim 3: Develop a catalytic asymmetric 1,2-diamination via azimines. Many Lewis acids catalyze DCAs by coordinating to an electron-withdrawing group on the dipolarophile, thereby lowering the energy of the dipolarophile’s LUMO.6, 7 Lewis acid catalysts may have the same effect on the alkene–azimine DCA, which proceeds rather slowly when not catalyzed (6–18 h at 60 °C). If they do, we will determine to what extent chiral, enantiopure Lewis acid catalysts will induce electron-poor alkenes to undergo an enantioselective cycloaddition with an azimine to give an enantioenriched 1,2,3-triazolidine and, after reduction, an enantioenriched 1,2- diamine. From a purely intellectual point of view, our proposed method for 1,2-diamination of alkenes via cycloaddition with azimines is innovative, because chemists have barely studied azimines at all, let alone investigated their potential for the synthesis of 1,2-diamines. From a practical point of view, the development of our method will provide synthetic chemists with a simple and general route to diamines that bear easily removed protecting groups. We envision that the availability of these diamines will enable much quicker and more economical syntheses of drug substances, catalysts, and other compounds which contain a 1,2-diamine motif.