Enantio‐ and Diastereoselective Synthesis of Homopropargyl Amines by Copper‐Catalyzed Coupling of Imines, 1,3‐Enynes, and Diborons

Abstract

An efficient, enantio‐ and diastereoselective, copper‐catalyzed coupling of imines, 1,3‐enynes, and diborons is reported. The process shows broad substrate scope and delivers complex, chiral homopropargyl amines; useful building blocks on the way to biologically‐relevant compounds. In particular, functionalized homopropargyl amines bearing up to three contiguous stereocenters can be prepared in a single step.

Radical Carbonyl Propargylation by Dual Catalysis

“…Benzyl ethers (11), as well as esters (12)(13)(14)16)r anging from trifluoromethyl decorated ones (13,14)t os imple ethyl derivatives (16)s moothly afforded the desired coupling products.Avariety of aryl ethers containing functional groups spanning from natural product and drugs such as estrone (19) and paracetamol 20 (19,21), thus proving the inertness of enolizable moieties (19,20)and heterocycles (22). Finally,these examples (4-22)testify that our protocol is insensitive towards the alkyne substitution, which could vary from aryl (7,15,16)toa-heteroatom (4,8,10,13,(17)(18)(19)(20)(21)(22)and aliphatic (5,6,9,11,12,14). Ther elative stereochemistry of the major diastereoisomer was confirmed by single-crystal Xray analysis of asuitable specimen of 4,which showed an anti stereochemistry between the alcohol and the appended isobutyl substituent.…”

“…Remarkably,t he reaction proved suitable for the synthesis of highly sterically congested quaternary centers (7,33%)even in excellent yields (8,85%). In the former case, free alcohols were tolerated, thus making the protocol suitable to generate highly decorated 1,3- 7orremote diols (17)w ithout the need for protective groups.I na ddition to long aliphatic chain derivatives 9, both tosylamides (10)and the 1,3-enyne synthesized from the herbicide propyzamide (18)yielded the desired products in quantitative yield. Benzyl ethers (11), as well as esters (12)(13)(14)16)r anging from trifluoromethyl decorated ones (13,14)t os imple ethyl derivatives (16)s moothly afforded the desired coupling products.Avariety of aryl ethers containing functional groups spanning from natural product and drugs such as estrone (19) and paracetamol 20 (19,21), thus proving the inertness of enolizable moieties (19,20)and heterocycles (22).…”

“…In 2013, a Ni‐catalyzed three‐component coupling reaction of 1,3‐enynes, carbonyls, and dimethylzinc to construct allenyl alcohols was reported by Kimura (Scheme 1 B—route III) [17] . Later on, the elegant cross coupling reactions between 1,3‐enynes and carbonyls using a copper catalyst have been reported by Hoveyda, [18a] Buchwald [18b] and others (Scheme 1 B—route IV) [18c–g] . 1,3‐Enynes could also be used as radical acceptors to form substituted allenyl (1,4‐adducts) or alkynyl (1,2‐adducts) derivatives [19] .…”

Copper-catalyzed functionalization of enynes

“…In 2020, Procter and co-workers 19 developed the coppercatalyzed borylative 1,2-functionalization of 1,3-enynes 1 with aldimines 10 to give anti-homopropargylic amines 11 (Scheme 7). Interestingly, Ph-BPE L6 was again the ligand of choice.…”

Copper‐Catalyzed Borylative Couplings with C−N Electrophiles

“…In 2020, Procter and co‐workers [36] used a copper‐catalyzed borylative coupling of enynes 36 and aldimines 26 to prepare homopropargylic‐1,3‐aminoalcohols [37] 37 , containing up to three contiguous stereocenters, with high enantiocontrol (Scheme 10 A). Interestingly, ( S , S )‐Ph‐BPE L3 b ( c.f .…”