Divergent Regioselectivity in the Synthesis of Trisubstituted Allylic Alcohols by Nickel‐ and Ruthenium‐Catalyzed Alkyne Hydrohydroxymethylation with Formaldehyde

Abstract

Dedicated to Professor Barry M. Trost on the occasion of his 70th birthday.Trisubstituted allylic alcohols [1,2] are ubiquitous in natural products and are readily converted into diverse chiral building blocks by enantioselective epoxidation, [2a,b] cyclopropanation, [2a,c] hydrogenation, [2a,d] and allylic substitution. [2a,e] Among methods for the regio-and stereoselective synthesis of trisubstituted primary allylic alcohols, alkyne hydrometalation or carbometalation mediated by stoichiometric organometallic reagents has found broad use. [3][4][5][6][7] For example, in seminal studies by Corey et al. (1967), [4c] the regio-and stereoselective hydroalumination of propargyl alcohols was used to construct vinyl iodides, which were converted into trisubstituted allylic alcohols upon exposure to lithium dialkyl cuprates. Similarly, alkyne hydromagnesiation and carbomagnesiation with Grignard reagents delivered trisubstituted allylic alcohols regio-and stereoselectively. [6,7] Although alkyne functionalization through hydrometalation and carbometalation remains at the forefront of research, [3][4][5][6][7] the development of equivalent transformations that avoid stoichiometric metal reagents is clearly desirable. Conversely, whereas related nickel-catalyzed alkyne-carbonyl reductive couplings can be highly regioselective, such processes require terminal reductants that are metallic, pyrophoric, or highly mass intensive (e.g. ZnR 2 , BEt 3 , HSiR 3 ; Scheme 1), [8][9][10] although nickel-catalyzed alcoholmediated alkyne-enone couplings were recently disclosed. [11] Hence, the discovery of alkyne-carbonyl (or alkyneimine) reductive couplings under hydrogenation conditions is significant. [12,13] More recently, an alkyne-carbonyl reductive coupling by ruthenium-catalyzed transfer hydrogenation was developed; however, regioselectivity in such processes remains largely unexplored. [14,15] Herein, we report the regio-and stereoselective synthesis of trisubstituted primary allylic alcohols from alkynes in the absence of stoichiometric metallic reagents. In this reaction, paraformaldehyde is used as a C 1 feedstock and, more remarkably, as a reductant under conditions of transfer hydrogenation with nickel and ruthenium catalysts, which exhibit complementary regioselectivity (Scheme 2).In response to the lack of efficient methods for diene hydroformylation, [16] we recently developed a process for diene hydrohydroxymethylation under the conditions of ruthenium-catalyzed transfer hydrogenation using paraformaldehyde as a C1 feedstock; [17] paraformaldehyde was itself prepared from synthesis gas (via methanol). As the development of efficient catalysts for alkyne hydroformylation remains an unmet challenge, [18] we undertook the current investigation into alkyne-paraformaldehyde reductive coupling. Initial studies focused on the reductive coupling of 1-phenylpropyne (1 a) with paraformaldehyde. We explored the nickel-catalyzed reductive coupling of 1 a with paraformaldehyde in the absence of a reducing agent. [8][9][10] Re...

Formation of C–C bonds via ruthenium-catalyzed transfer hydrogenation

“…Using Ru(O 2 CCF 3 ) 2 (CO)(PPh 3 ) 2 as a precatalyst, hydrogen is transferred from a primary alcohol to 2-butyne to generate aldehyde-vinylruthenium pairs, which react to give allylic alcohols [29]. At higher reaction temperatures, the initially formed allylic alcohols undergo dehydrogenation to form α,β-unsaturated ketones.…”

“…At higher reaction temperatures, the initially formed allylic alcohols undergo dehydrogenation to form α,β-unsaturated ketones. Thus, intermolecular alkyne hydroacylation is achieved from the alcohol oxidation level (Scheme 6) [29b]. …”

“…It was found that the specific combination of iodide and carboxylate counterions at ruthenium enabled highly regioselective reductive to occur under transfer hydrogenation conditions employing formic acid as terminal reductant [29a]. Related regioselective carbonyl vinylations from the alcohol oxidation level are currently under investigation (Scheme 7).…”

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

“…[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.…”

Hydroxymethylation beyond Carbonylation: Enantioselective Iridium-Catalyzed Reductive Coupling of Formaldehyde with Allylic Acetates via Enantiotopic π-Facial Discrimination

“…Merging the chemistry of transfer hydrogenation and carbonyl addition, 7 formaldehyde (or methanol 11b ) mediated hydrohydroxymethylations of diverse π-unsaturated reactants (allenes, 11a,b,c dienes 11d,e and alkynes 11f ) were developed. 11,12,13 While these processes are efficient and regioselective in contexts where carbonylation/hydroformylation is not, enantioselective variants have not been established, nor has the hydroxymethylation of allylic acetates been explored.…”