Hydroaminomethylation Beyond Carbonylation: Allene–Imine Reductive Coupling by Ruthenium‐Catalyzed Transfer Hydrogenation

Abstract

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...

Enantioselective three-component aminomethylation of α-diazo ketones with alcohols and 1,3,5-triazines

“…The resulting β-amino carbonyl compounds are versatile synthetic building blocks for a wide variety of natural products and biologically active compounds 9 . Different types of formaldehyde-derived imines or iminium salts, which are generally unstable and have to be in situ generated from formaldehyde with aromatic amines 10,11 , α-aminomethyl ethers [12][13][14][15][16][17] , N,O-acetals [18][19][20] , or 1,3,5-triaryl-1,3,5-triazines [21][22][23][24] , have been successfully applied. Within this context, enantioselective version of this transformation has also been achieved by catalytic asymmetric activation of the nucleophilic carbonyl compounds with either amine catalysts 10,11,14,16 or chiral Lewis acid 23,24 .…”

Ruthenium-Catalyzed Transfer Hydrogenation for C–C Bond Formation: Hydrohydroxyalkylation and Hydroaminoalkylation via Reactant Redox Pairs

“…In contrast, the development of corresponding late transition metal catalyzed amine C-H functionalizations has proven challenging. [92][93][94] Indeed, with the exception of the present authors work, [95][96][97][98][99] all other late transition metal catalyzed hydroaminoalkylations require pyridyl directing groups in combination with mono-olefin reactants. [100][101][102][103][104][105][106][107][108] In a significant departure from prior art, it was found that ruthenium catalyzed hydrogen transfer from 4-aminobutanol to 1-substituted-1,3-dienes results in the generation of dihydropyrrole-allylruthenium pairs, which combine to form products of hydroaminoalkylation with good to complete control of anti-diastereoselectivity (Scheme 18).…”

“…In contrast, 2-propanol-mediated reductive couplings of allenes or dienes with formaldimines (generated in situ from saturated 1,3,5-triazines) are efficient and selective processes. [95][96][97][98] Specifically, ruthenium catalyzed transfer hydrogenation of allenes in the presence of 1,3,5-tris(4-methoxyphenyl)-hexahydro-1,3,5-triazine provides products of hydroaminomethylation as single regioisomers. 96 Under similar conditions, butadiene and related 2-substituted dienes engage in regioselective reductive C-C coupling to furnish products of hydroaminomethylation.…”

“…[95][96][97][98] Specifically, ruthenium catalyzed transfer hydrogenation of allenes in the presence of 1,3,5-tris(4-methoxyphenyl)-hexahydro-1,3,5-triazine provides products of hydroaminomethylation as single regioisomers. 96 Under similar conditions, butadiene and related 2-substituted dienes engage in regioselective reductive C-C coupling to furnish products of hydroaminomethylation. 97 Here, higher temperatures (140 °C) are required to supress the competing aza-Diels-Alder reaction of formaldimine.…”

Enantioselective Generation of Adjacent Stereocenters in a Copper‐Catalyzed Three‐Component Coupling of Imines, Allenes, and Diboranes

“…[9] Fore xample,t he coupling of allenes and diboranes [10] with aldehydes or ketones [11] and allylic electrophiles [12] has been explored. [13][14][15][16] However,application to the synthesis of chiral non-racemic homoallylic amines has been surprisingly scarce, [17,18] given their importance,a nd this is likely due to the poor reactivity of imines. [6,7] Morkens seminal report is the only example of an enantioselective multicomponent reaction coupling allenes,imines,and B 2 pin 2 (Scheme 1B).…”