Ruthenium(II)-catalyzed hydrogen transfer from 2-propanol mediates reductive coupling of 1,1-disubstituted allenes with formaldimines with complete branch-regioselectivity,t hus representing an ew method for hydroaminomethylation beyond classical hydroformylation/reductive amination.
Hydroaminomethylation,[1] thes uccessive one-pot hydroformylation/reductive amination, is an important, atomefficient method for amine synthesis [Scheme 1, Eq. (1)].Subsequent to Reppes discovery of hydroaminomethylation at BASF in 1949, [2] relatively few studies were disclosed.[3]However,inthe last 15 years,due in large part to the elegant work of Eilbracht, [4] hydroaminomethylation has been intensively investigated [1] and utilized for the preparation of diverse pharmaceutical ingredients, [5] including cinacalcet (Sensipar, Mimpara), [5,6a] ibutilide (Corvert), [5, 6b] and fexofenadine (Allegra, Fexidine,T elfast, Fastofen, Tilfur,V ifas, Te lfexo,A llerfexo). [5,6c] Recent advances in hydroaminomethylation include the use of ammonia as ar eactant, [4c,7] regioselective reactions of terminal [8a] and internal [8b alkenes through ligand control [8] or the use of directing groups, [9] the evolution from rhodium-based to ruthenium-based catalysts, [10] and the emergence of noncarbonylative strategies, including hydroaminoalkylation [11] [Scheme 1, Eq. (2)] and photoredox catalysis [Scheme 1, Eq. (3)].[12] Thevast majority of hydroaminomethylation protocols apply to a-olefins.T o our knowledge,t he hydroaminomethylation of other punsaturated reactants,s uch as dienes or allenes,i s unknown.[13] Herein we report an ew strategy for hydroaminomethylation based on 2-propanol-mediated reductive coupling of 1,1-disubstituted allenes and formaldimines derived in situ from 1,3,5-tris(aryl)-hexahydro-1,3,5-triazines [Scheme 1, Eq. (4)].T hese processes deliver branched products of hydroaminomethylation bearing all-carbon quaternary centers. [13][14][15][16][17][18][19][20] Initial experiments were inspired by our earlier studies on the ruthenium-catalyzed reductive coupling of formaldehyde with allenes, [13,14] dienes, [13,15] and alkynes. [13,16] Using the allene 1a and hexahydro-1,3,5-triazine 2a,acrystalline solid prepared from paraformaldehyde and p-anisidine, [21] as eries of catalysts derived from the commercial ruthenium complex [HClRu(CO)(PPh 3 ) 3 ]w ere evaluated for their ability to induce reductive coupling by 2-propanol-mediated transfer hydrogenation (Table 1). In the absence of an exogenous ligand or upon use of tricyclohexylphosphine as al igand, small quantities of the desired homoallylic neopentyl amine 3a were formed as asingle regioisomer.Chelating phosphine ligands were more effective at enforcing higher conversion. Eventually,i tw as found that upon use of dCype as al igand, the desired homoallylic amine 3a could be obtained in 83 % yield.Under optimized reaction conditions using the ruthenium catalyst derived in situ from [HClRu(CO)(PPh 3 ) 3 ]and dCype, the scope of the allene partner was explored in...