Propargylic amine formation

TABLE 10.6. Propargylic Amine Formation from Aldehydes and Alkynes... 

The ability of allylzinc bromide to add to terminal alkynes was first observed with acetylenic amines as substrates. Thus, the propargylic amine 290 underwent addition of allylzinc bromide in refluxing THF and afforded after hydrolysis the allylic amine 291. This reaction occurred much more easily compared to the case of ethylenic amines (see Section III.A) and the regioselectivity was also noteworthy as a branched product was obtained predominantly82,105. It was suggested that metallation of the terminal alkyne was responsible for the observed regioselectivity. Indeed, the formation of an alkenyl... 

The PdCb-catalysed cyclocarbonylation of propargylic amines (70) with CuCl2 and p-benzoquinone afforded ( )-o -chloroalkylidene-/3-lactams (71) in moderate to good yields. The formation of the corresponding Z-isomers or five-membered ring products was not observed. The stereoselectivity in this reaction is different from that observed with propargylic alcohols a mechanistic rationale has been proposed.83... 

An enantioselective version of this reaction has been reported by Rueping et al.102 Treatment of an a-iminoester and an alkyne with silver acetate and a binol phosphate derivative gave propargylic amines with the highest enantiomeric ratio (er) reported as 96 4. Although the proposed catalytic cycle invoked the in situ formation of the... 

Scheme 9.8 Silver-catalysed formation of propargyl amines...

Pd(ll)-catalyzed reaction of propargyl alcohols or propargyl amines with a-sulfonyl-a,/3-unsaturated ketones leads to the formation of furo[3,4- ] heterocyclic derivatives (Equation 33) <2000JOC3223>. 

Finally, in analogy to the chalcone formation by CIR, the use of Ai-tosyl propargyl amines 20 leads to the formation of A/ -tosyl enimines 21 in moderate to excellent yields (Scheme 12) [85]. 

Balme has reported a one-pot threecomponent alkene carboamination between propargylic amines, alkylidene malonates, and aryl halides [43]. For example, treatment of N-methyl propargylamine (2 equiv), dimethyl benzylidene malonate (2 equiv) and 1,4-diiodobenzene (1 equiv) with n-BuLi and a palladium catalyst provided 43 as a single diastereomer (Eq. (1.20)) [43a]. The formation of the C—N bond in this process does not appear to be metal catalyzed. Instead, initial conjugate addition of the nitrogen nucleophile to the activated alkene affords a malonate anion, which undergoes carbopalladation followed by reductive elimination to afford the pyrrolidine product. 

The ahphatic aldehydes reacted efficiently toward the formation of propargyl-amine. However, a lack of reactivity was observed with aromatic aldehydes (1 to 2 days), requiring longer reaction time, higher catalyst loading (3 mol%), and temperature (50 to 70 °C versus RT). 

Over the past 5 years Cu(I)-catalyzed addition of terminal acetylenes to imines has been an intense area of research for the synthesis of chiral propargyl amines. Two mechanistic proposals have been put forth which utilize Cu(I) complexes as Lewis acids in these additions. Benaglia and coworkers reported a mechanism for reactions utilizing preformed imines (Scheme 17.37). The chiral Cu(I) salt (171) initially coordinates imine (172) to generate complex (173). Subsequent coordination of the terminal acetylene (174) affords complex (175). Formation of requisite copper acetylide results in the formation of complex (176), which facilitates intramolecular addition of the acetylide to the imine. Decomplexation of the resulting propargyl imine from (177) regenerates the catalytic Cu(I) species. 

An analogous propargylation/amination/cycloisomerization sequence with pyrrole formation was established for propargylic alcohols 92, 1,3-dicarbonyl compounds and primary amines with catalysis of In(III) chloride [128]. 

As described in preface, the author found that the reaction of iV-tosylated 2-ethynylaniline la with parafonnaldehyde 2a and diisopropylamine 3a in dioxane in the presence of copper(I) bromide afforded a 2-(aminomethyl)indole derivative 7a in 92% yield (Scheme 1). This reaction can be rationalized by Mannich-type MCR followed by indole formation through intramolecular hydroamination toward the activated alkyne moiety of a plausible intermediate 6. Actually, the reaction of the identically prepared propargyl amine 8 with CuBr (5 mol.%) gave the expected indole 7b in quantitative yield (Scheme 2). 

An important variant for transition metal-catalyzed carbon-nitrogen bond formation is allylic substitution (for reviews, see1,la lh). Nucleophilic attack by an amine on an 7r-allyl intermediate, generated from either an allylic alcohol derivative,2 16,16a 16f an alkenyloxirane,17-19,19a-19d an alkenylaziridine19,19a 19d, or a propargyl alcohol derivative,21,21a 21d gives an allylic amine derivative. 

---