Cu-catalyzed, Mn-mediated propargylation and allenylation of aldehydes with propargyl bromides

A simple, practical, and high chemo-selective method for the synthesis of propargyl alcohol and allenyl alcohols via Cu-catalyzed, Mn-mediated propargylation and allenylation of aldehydes with propargyl bromides has been established. When 3-bromo-1-propyne was conducted under the standard condition, the aldehydes were transformed to the corresponding propargylation products completely, while when 1-bromo-2-pentyne was used, allenic alcohol was the only product. Variety of homopropargyl alcohols and allenyl alcohols were obtained in high yields and the reaction is compatible with broad substrate scopes. In addition, the large-scale reaction could also be proceeded smoothly indicating the potential synthetic applications of this transformation. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1186/s13065-022-00803-3.

As we known, Cu catalyst, is not only abundant, easy to utilize, and relatively insensitive to water and air, but also has advantageous for the controllable access to Cu(0), Cu(I), Cu(II), and Cu(III) oxidation states [46,47]; possibly because of its single-electron transfer (SET) and two-electron processes (TEPs) pathway [48,49]; which make the catalytic system with high catalytic activities and rate. Moreover, Manganese has been widely used in organic reactions by virtue of its environmentally benign and sustainable nature, low cost and versatile reactivity [50,51]. Up to now, there were only few examples had been reported, but they showed the activity of Mn in the proparylation reaction. So will the combination of Cucatalyst and Mn powder increase the catalytic efficiency in the proparylation of propargyl bromide with aldehyde?
In this paper, we developed the first example of Cu-catalyzed and Mn-mediated propargylation and allenylation of aldehydes with propargyl bromides under a novel catalytic system, which is covered with advantages of high efficiency, good chemo-selectivity, and wide substrates scopes under mild reaction conditions (Fig. 1).
We initiated our investigation using benzaldehyde (1a) and propargyl bromide (2a) as model substrates which catalyzed by copper salts and Mn powder (Table 1). Without Mn, only trace amount of desired product was observed which indicated that Mn powder is indispensable (Table 1, entry 1). While in the absence of CuBr 2 , 16% of 3a was produced which demonstrated the great importance of Cu catalyst (entry 2). Screening of different solvents illustrated that MeCN is the best reaction medium, giving the desired product 3a in 47% yield (entry 3). While, only trace amount of product was observed in THF or DCM and 24% in EtOH (entries 4-6). The yield of products dropped sharply when the reaction was carried out in the open system (entry 7). Meanwhile, without the addition of CF 3 COOH, only 13% yield of 3a was achieved (entry 8). Subsequently, extensive experiments were conducted to investigate the effects of different copper salts on the reaction. Series of Cu catalysts, including CuSO 4 , CuCl, CuCl 2 , CuBr and CuI were tested and CuCl gave the best result (entries 9-13). Adding 5 equiv. Mn powder, a remarkable increase has been presented (entry 14). Simultaneously, a light increase of yield was observed by increasing the amount of catalyst (entry 15). Further studies indicated that extending the reaction time to 24 h, 1a can be transformed to 3a completely under the standard conditions (entry 16).
When 1-bromo-2-butyne (4a) was used instead of propargyl bromide, the rearrangement product allenyl alcohol was achieved with good yield under the same reaction conditions (Table 3). Importantly, the direct propargylation product was not detected in this catalytic system, which indicated that the chemo-selectivity for this reaction is quite good. For example, substrates (5a-5c) which substituted by isopropyl-, methyl-and Table 1 The effect of different parameters on the reaction of 1a and 2a. a a Reaction conditions: All reactions were performed with 1a (0.5 mmol), 2a (1.5 equiv.), copper catalyst (10 mol%), Mn powder (3 equiv.), CF 3 COOH (25 mol%), solvent (2 mL), at room temperature under N 2 atmosphere. b Yield was determined by GC with dodecane as internal standard based on 1a. c Reaction in the air. d Without CF 3 COOH. e 5.0 equiv. of Mn was added. f CuCl (20 mol%) was added.   fluoro-groups on the aromatic ring, reacted well and provided the corresponding products in moderate yields. In addition, heteroaromatic aldehyde (5d) is also worked for the transformation and an allenyl substituted alcohol (5e) was obtained with 85% yield.

Entry
To demonstrate the synthetic applications of our protocols, we tried to scale up the reaction of benzaldehyde (1a) with 3-bromo-1-propyne (2a) or 1-bromo-2-pentyne (4a) independently under standard conditions (Fig. 2). The corresponding products 3a or 5a was obtained in a gram-scale, which highlightened the potential applicability of this transformation in organic synthesis.
Based on the above results and studies reported in the previous reference, a tentative mechanism for the Cu-Catalyzed, Mn-mediated propargylation and allenylation of aldehydes with propargyl bromides was proposed in Fig. 3 [52][53][54][55][56]. Mn, which is severed as a strong reducing agent, reduced the Cu I to Cu 0 in an active form in situ. Insertion of Cu 0 to propargyl bromides gives the crucial intermediate progargyl metal species (Int-I) and allenyl metal species (Int-II). Then, nucleophilic addition of aldehydes conducted smoothly with metal species to deliver the Int-III and Int-IV. Finally, desired products were obtained in the presence  of CF 3 COOH. The Cu II complex was reduced to Cu 0 with Mn powder to continue the next catalytic cycle.
In conclusion, the practical propargylation and allenylation of propargyl bromide has been discovered. The unique combination of the Cu catalyst and Mn powder present a novel and effective catalyst system in the preparation of homopropargylation alcohols and allenyl alcohols. Wide substrates compatibility has been exhibited with a variety of different substituent. This process represents a rare example of propargylation reaction and opens a new area of research. Further mechanistic studies and synthetic applications of this reaction are under progress in our laboratory.