Alkynylation of steroids via Pd-free Sonogashira coupling

Abstract

Cu-catalyzed Pd-free Sonogashira coupling has been proposed as a straightforward and convenient route to valuable steroidal enynes. A biligand catalyst system based on Ph3P and TMEDA has been designed. The protocol was utilized for the efficient coupling of iodosteroids with diverse terminal alkynes and 1-trimethylsilylalkynes. A possible role of an auxiliary ligand as a phase-transfer catalyst for a sparingly soluble inorganic base (K2CO3) was revealed.

Tri(1‐naphthyl)phosphine as a ligand in palladium‐free Sonogashira cross‐coupling of arylhalogenides with acetylenes

“…When both iodine and acetylenic reactants contain the electron-withdrawing groups (eg NO 2 , Ac), the crosscoupling in system B affords the target tolane 3a, 3b (94%-100%) according to GC-MS data (Table 1, entry 1, 3). It should be underlined that in the recently published paper, [7] the cross-coupling (Ph 3 P-CuI-K 2 CO 3 -TMEDA) of electronwithdrawing alkynes-1 does not result in the target acetylenes at all due to the side processes, that is, formation of the Michael adducts and further transformations. However, in the case of the system A the reaction is finished for 4 hours (entry 2).…”

“…According to GC‐MS data (entry 6), in 7 hours, in the reaction mixture, iodide 1a (14%), alkyne‐1 2d (5%), tolane 3e (62%), and buta‐1,3‐diyne 4a (18%) are detected. Noteworthy, earlier in various palladium‐free Cu(I)‐catalyzed Sonogashira cross‐couplings, the formation of buta‐1,3‐diyne was not observed . For the comparison purpose, we have implemented a similar reaction with the Ph 3 P (system A ) .…”

“…Predominant formation of buta‐1,3‐diynes, even in spite of the careful maintenance of an inert atmosphere, can be rationalized as follows. First, a complex Cu(III) is formed through the oxidative addition of iodoarene to copper acetylenide as described in (Schemes and ) . Further decomposition of this complex can occur via an alternative route, that is, reductive elimination of metal arene and iodoethynylarene likely due to the bulky ligand.…”

“…The first successful results in this area were disclosed by Miura et al who showed that triphenylphosphine (Ph 3 P) turned out to be the most efficient ligand in the Sonogashira reaction, while other phosphorus‐containing ligands, (PhO) 3 P, n ‐BuPPh 2 , and ( n ‐Bu) 3 P, exerted a significantly lower activity. At the moment, the search for new catalytic systems deprived from costly palladium catalysts with using different ligands keeps being continued …”

“…At the moment, the search for new catalytic systems deprived from costly palladium catalysts with using different ligands keeps being continued. [6][7][8] It is known that more sterically hindered tri(1-naphthyl) phosphine (Np 3 P) was found to be an excellent ligand for metal complex catalysts inducing many types of transformations (Heck, Suzuki, etc.). [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] However, the data on application of Np 3 P in the Sonogashira reaction are lacking in the literature.…”