Addition of terminal alkynes to imines

The Cu(I)-catalyzed direct addition of terminal alkynes to imines generated in situ from aldehydes and amines affords synthetically useful propargylamines. This metal-catalyzed carbon-carbon bond formation is best performed in toluene but water is also a convenient solvent. While the achiral process is mediated by the bimetallic catalytic system RuCls/CuBr, CuOTf in conjunction with chiral bis(oxazolines) has been found optimal for enantioselective additions (eq 119). 

C. Wei, C.-J. Li, J. Am. Chem. Soc. 2002, 124, 5638-5639. Enantioselective direct-addition of terminal alkynes to imines catalyzed by copper(I)pybox complex in water and in toluene. 

Wei, C., Mague, J. T., Li, C.-J. (2004). Cu(I)-catalyzed direct addition and asymmetric addition of terminal alkynes to imines. Proceedings of the National Academy of Sciences of the United States of America, 101, 5749-5754. 

Combined use of ZnCh, EtaN, and MeaSiCl promotes a direct addition of terminal alkynes to imines to give propargylamines [140]. MeaSiCl activates imines to accelerate the addition of zinc acetylides generated from the alkynes. Dialkylzincs also adds efficiently to imines with the aid of Mea SiCl [141]. 

Another example of the addition of terminal alkynes to C=N in water is the coupling of alkynes with in-situ-generated A-acylimines (Eq. 4.32) and A-acyliminium ions (Eq. 4.33). In 2002, Li et al. developed a coupling reaction of alkynes with A-acylimines and A-acyliminium ions mediated by Cu(I) in water to generate propargyl amide derivatives.57 Either an activated imine derivative or imininum derivative was proposed as the intermediate, respectively. 

Benaglia and coworkers have developed a number of chiral ligands based on binaphthyl diamine (190) for CuOTf-catalyzed additions of terminal alkynes to preformed imines (Scheme 17.39) [51]. In a screen of the parent binaphthyl diamine (190) and N-alkylated derivatives, ligand (190) was found to provide moderate enantioselectivity in the addition of phenylacetylene (189) to imine (188). The selectivity could be improved by using bis-imine derivative (191) as the chiral ligand in the reaction [52]. 

Addition of lithiated alkoxy ethynyl anion with chiral Al-sulfinyl imines proceeds with dr >95 5, which can be reversed in the presence of BF3. Excellent diastereoselec-tivity has been reported for zinc-mediated addition of methyl and terminal alkynes to chiral IV-f-butanesulfinyl ketimines (to form 3-amino oxindoles). Zinc-BINOL complexes have been used to achieve enantioselective addition of terminal alkynes to N-(diphenylphosphinoyl)imines (up to 96% cc) and terminal 1,3-diynes to IV-arylimines to trifluoropyruvates (up to 97% yield and 97% ee). ... 

On the basis of the same principle, we developed a three-component synthesis of macrocycles starting from azido amide (46), aldehyde (47) and a-isocyanoaceta-mide (48) (the cx-isocyanoacetamides are easily available, see [84—86]) bearing a terminal triple bond (Scheme 11) [87]. The sequence is initiated by a nucleophilic addition of isonitrile carbon to the in situ generated imine 50 led to the nitrilium intermediate 51, which was in turn trapped by the amide oxygen to afford oxazole 52 (selected examples [88-94]). The oxazole 52, although isolable, was in situ converted to macrocycle 51 by an intramolecular [3+2] cycloaddition upon addition of Cul and diisopropylethylamine (DIPEA). In this MCR, the azido and alkyne functions were not directly involved in the three-component construction of oxazole, but reacted intramolecularly leading to macrocycle once the oxazole (52) was built up. The reaction created five chemical bonds with concurrent formation of one macrocycle, one oxazole and one triazole (Scheme 15). 

It is assumed that cyclization proceeds by Cu-promoted intramolecular nucleophilic addition of the imine moiety to the triple bond (77 —78) with loss of the tBu group by formation of isobutene. The imines 77 are accessible from (2-halogeno)benzaldehydes 80 (X = Br, I) by Sonogashira coupling with terminal alkynes and imine formation with (CH3)3C-NH2 or vice versa. 

A number of actinide complexes have been investigated with respect to their catalytic activity in the intermolecular hydroamination of terminal alkynes with primary ahphatic and aromatic amines [98, 206-209]. Secondary amines generally do not react and the reaction is believed to proceed via an metal-imido species similar to that of group 4 metal complexes. The reaction of Cp 2UMc2 with sterically less-demanding aliphatic amines leads exclusively to the anti-Markovnikov adduct in form of the -imine (31) [207] however, sterically more demanding amines, e.g., t-BuNH2, result in exclusive alkyne dimerization. The ferrocene-diamido uranium complex 12 (Fig. 4) catalyzes the addition of aromatic amines very efficiently (32) [98]. 

In a manner analogous to classic nitrile iinines, the additions of trifluoro-methylacetonitrile phenylimine occur regiospecifically with activated terminal alkenes but less selectively with alkynes [39], The nitnle imine reacts with both dimethyl fumarate and dimethyl maleate m moderate yields to give exclusively the trans product, presumably via epimenzation of the labile H at position 4 [40] (equation 42) The nitrile imine exhibits exo selectivities in its reactions with norbornene and norbornadiene, which are similar to those seen for the nitrile oxide [37], and even greater reactivity with enolates than that of the nitnle oxide [38, 41], Reactions of trifluoroacetomtrile phenyl imine with isocyanates, isothiocyanates, and carbodiimides are also reported [42]... 

Terminal alkynes readily react with coordinatively unsaturated transition metal complexes to yield vinylidene complexes. If the vinylidene complex is sufficiently electrophilic, nucleophiles such as amides, alcohols or water can add to the a-carbon atom to yield heteroatom-substituted carbene complexes (Figure 2.10) [129 -135]. If the nucleophile is bound to the alkyne, intramolecular addition to the intermediate vinylidene will lead to the formation of heterocyclic carbene complexes [136-141]. Vinylidene complexes can further undergo [2 -i- 2] cycloadditions with imines, forming azetidin-2-ylidene complexes [142,143]. Cycloaddition to azines leads to the formation of pyrazolidin-3-ylidene complexes [143] (Table 2.7). 

Furthermore, when trimethylsilylacetylene 40 was used as an alkyne in the [IrCl(cod)]2-catalyzed reaction, propargyUc amines (where the alkyne was added to the double bond of imine) were obtained (Equation 10.7) [21, 23]. It is probable that the reaction proceeds through oxidative addition of the terminal C—H bond of alkyne to the Ir complex, followed by the insertion of imine to the resulting Ir-H complex. The crosscoupling reachon of trimethylsilyl (TMS)-acetylene with aldimines took place by [IrCl(cod)]2, leading to the corresponding adducts (Equahon 10.8) [24]. 

In an analogous late-stage arylation approach, terminal alkyne 31 was envisioned as a versatile intermediate. Slow addition of 4-pentynoyl chloride to imine 3 and (n-Bu)3N at reflux (efficient condenser, 100°C, 12 h, 1 1 toluene heptane) afforded only trace amounts of 31. Reaction of 4-pentynoyl chloride with triethylamine in methylene chloride under preformed ketene conditions ( 78°C, 1 h), followed by addition of 3 and warming to — 10°C over 4 h, afforded a complex mixture of products. Since high-yield preparation of 31 remained elusive, access to internal alkynyl analogs (type 33) was accomplished by preassembly of the appropriate arylalkynyl acid substrate for the ketene-imine cycloaddition reaction (Scheme 13.9). 

Recently, Nakamura and coworkers described a related reaction of the zinc enolates derived from /3-aminocrotonamides of type 395256. In the presence of a stoichiometric amount of Et2Zn, the latter underwent smooth addition to terminal alkynes upon heating in hexane and afforded the corresponding tetrasubstituted 2-alkylidene acetoacetamides 396 (after acidic hydrolysis of the imine) with high (Z)-stereoselectivity (equation 173). 

Radical cyclizations to carbon-nitrogen multiple bonds resemble additions to carbon-carbon multiple bonds in that they usually give products of irreversible exo cyclization. To date, the most useful acceptors have been oximes189 and nitriles,190 and one example of each type of cyclization is given in Scheme 45.191 Nitriles are useful because the intermediate imines are readily hydrolyzed by mild acid to ketones. Although this route to ketones is shorter than the two-step sequence of alkyne cyclization/ozo-nolysis, nitriles are slightly poorer acceptors than terminal alkynes, and much poorer acceptors than activated alkynes. Thus, when slow cyclizations are involved, the two-step protocol is preferable. 

Catalytic hydroamination of imsaturated carbon-carbon bonds has a strong potential for the access to a large variety of amines, enamines or imines [90]. The first addition of a N-H bond to alkynes catalyzed by a ruthenium catalyst was described in 1995 by Watanabe et al. [91], and involved a ruthenium-catalyzed addition of the N-H bond of N-formyl anilines to terminal alkyne (Scheme 8.29). 

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