Michal Sienkiewicz

Application of triazenes for protection of secondary amines

Abstract Use of the phenyldiazenyl group, which serves as a protecting group for secondary amines is described in detail. The triazene protected amine is compatible with oxidative and reductive conditions as well as with strong bases (LDA, tert-butyllithium) and alkylating reagents. The amine is regenerated by action of trifluoroacetic acid and a suitable reducing agent (EtOH or NaH2PO2).

Studies on Aldol Reactions of Nortropinone Derivatives in Solution and on Solid Phase

Polymer-anchored (Merrifield, trityl chloride, Wang p-nitrophenyl carbonate and triazene supports) nortropinone, or N-protected nortropinone derivatives in solution, were subjected to deprotonation with LDA or chiral lithium amides, and the resulting lithium enolates were trapped with an aldehyde. The aldols were obtained with moderate to good yields (44-84%) and enantioselectivities (44-86% ee).

Solid-phase Synthesis of Tertiary N-Methyl Amines Including Tropanes

Synthesis on solid phase is one of modern methodologies especially useful in parallel and combinatorial syntheses. Tertiary amine functionalities are found in many important classes of catalysts, reagents and biologically active compounds. The tertiary N-methyl group is also present in structures of tropane alkaloids and majority of synthetic tropane derivatives with potential biological activity. Despite of well-defined tropane scaffold structure, which is present in known or potentially bioactive functionalized tropane derivatives only a few approaches to tropanes libraries and supported synthesis have been studied. Our approach to supported synthesis of tropane derivatives is based on anchoring nortropinone (1, Scheme 1), a secondary amine which naturally required a postcleavage N-methylation with one of the known procedures. Although secondary amines can be anchored reversibly via several well-known linkers including activated Wang carbonate, and triazene T2, we also looked for other methods. The linkers preserving the amine character of the anchored nitrogen atom, such as REM (via Michael addition-Hofmann elimination), amino acetals (DSEM and POEM), BAL-type, BOBA and several widely available polymeric gels (Merrifield, trityl chloride), could offer certain advantages. The motivation for seeking such anchors was an observation that the reactions of lithium enolates of tropinone and N-benzylnortropinone (both tertiary amines) in solution were more stereoselective and higher yielding than reactions of corresponding N-diazaphenyl (triazene) or carbobenzyloxy (uretane) derivatives. Therefore, we undertook a study on anchoring, and cleavage of nortopinone (1) on various polymeric supports with emphasis on methods for conversion of immobilized nortropane scaffold to tertiary amines such as tropane (2, Scheme 1). Solid-phase methods for synthesis of tertiary amines including N-methyl amines have been reported by Andersson. Others reported solid-phase alkylation and cleavage of tertiary amines by Hofmann type elimination from REM-type resins. An interesting method for debenzylating cleavage of quaternized amines from the Merrifield support based on nucleophilic displacement was reported by Cai. In our report, we wish to describe a novel method for preparation of N-methylated tertiary amines, including tropanes, based on quaternization and nucleophilic debenzylation of so formed ammonium salts immobilized via benzyl amine linkage on a widely available solid support, the Wang gel. We also report results of our approaches to reversible immobilization of nortropinone on polystyrene type supports with MOM analogue, BOM analogue, Wang type, PAL-type, Merrifield, para-C3-T2 triazene, carbamate Wang, and trityl linkers (Figure 1). Reversible Anchoring of the Amino Ketone. The cyclic secondary amines like nortropinone (1) could, in principle, be immobilized in a form of a tertiary amine via several linkers such as REM, Wang, and BAL linkers. The REM linker could not be used for our purposes because of its incompatibility with the basic conditions of enolate reactions, such as the directed aldol reaction. The Wang and BAL type linkers are typically used for releasing amine derivatives, usually amides or sulfonamides. However, the recent reports prompted us to investigate their use for immobilization of amino ketones such as nortropinone. We found that even though nortropinone could be anchored to Wang polymer (to give 6) and the 2,6-dimethoxy Wang polymer (to give 10, PAL type linker) very effectively (87-100%, Table 1, Figure 1), cleavage of this amino ketone was not feasible. Attempted oxidative cleavage of the Wang linker 6 (with DDQ) and simple benzylamine linker 7 derived from Merrifield polymer (with ceric(IV) ammonium nitrate, CAN), in our hands, did not provide any amine products (Figure 1). Therefore, we investigated amino acetal linkers analogous to MOM and BOM protecting groups for amines (8 and 9, Figure 1). Preparation of similar linkers by two different methods was reported. Unfortunately, we were able to obtain only modest loadings of the test amine, 4-benzylpiperidine or nortropinone 1, via such linkers prepared by either method (Figure 1). The cleavage provided poor loadings of released amines (17 and 9%, Table 1) despite using trifluoroacetic acid (TFA) at different concentrations, addition of water, prolonged cleavage times, and ultrasound. The only practical method for reversible linking of the amino ketone 1 to polymers in the form of a tertiary amine was the reactions with Merrifield gel or trityl chloride gel to form loaded polymers 7 and 3, respectively (Figure 1). The amino ketone could however be cleaved off the Merrifield support only by the procedure of Leysen et al. (action of 1-chloroethyl chloroformate (ACE-Cl) in 1,2dichloropropane (DCP), followed by methanolysis) in an analogy to the known reactions in solution, albeit with moderate yield (37% of the theoretical loading). As expected, nortropinone was very efficiently anchored and cleaved from supports with trityl linker 3 and carbamate Wang linker 4, (ca. 100% of the theoretical loadings). Immobilization and

(2R)-8-Benzyl-2-[(S)-hy­droxy(phen­yl)meth­yl]-8-aza­bicyclo­[3.2.1]octan-3-one

The crystal of the title compound, C21H23NO2, was chosen from a conglomerate formed by a racemic mixture. An intramolecular hydrogen bond is formed between hydroxy group and heterocyclic N atom of the azabicyclo[3.2.1]octan-3-one system. The crystal structure is stabilized by C—H⋯O interactions between aliphatic C—H groups and the carbonyl O atom. For the title chiral crystal, the highly redundant and accurate diffraction data set collected with low energy copper radiation gave a Flack parameter of 0.12 (18) for anomalous scattering effects originating from O atoms.