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Synthesis of propargylamines and amides


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A copper(I) complex of i-Pr-pybox-diPh efficiently catalyzes the enantioselective one-pot three-component synthesis of propargylamines from aromatic aldehydes, anilines, and alkynes. A transition-state model has been proposed.
A. Bisai, V. K. Singh, Org. Lett., 2006, 8, 2405-2408.

π-Stacking can be used to increase the barrier to rotation in chiral atropisomers. Using this concept, an imidazole-based biaryl P,N-ligand has been designed and prepared as a single enantiomer. This ligand performs exceptionally well in the enantioselective A3-coupling.
F. S. P. Cardoso, K. Abboud, A. Aponick, J. Am. Chem. Soc., 2013, 135, 14548-14551.

A wide range of chiral propargylamines can be prepared in a one-pot three-component reaction between an alkyne, an aldehyde and a secondary amine at room temperature in the presence of CuBr and (R)-quinap in good yield and good enantioselectivity. Remarkably, the copper-catalyzed reaction is highly diastereoselective if a chiral amine or aldehyde is used.
N. Gommermann, C. Koradin, K. Polborn, P. Knochel, Angew. Chem. Int. Ed., 2003, 42, 5763-5766.

Coupling of an available pool of Brønsted acids, namely, amino acid derivatives, with tunable ligands on copper catalysts can be used to generate many different chiral environments simply by changing the amino acid or ligand employed and provides a scaffold for rapid screening for high enantioselectivity. The latter is illustrated in the copper-catalyzed alkynylation of imines in up to 99% ee.
. Lu, T. C. Johnstone, B. A. Arndtsen, J. Am. Chem. Soc., 2009, 131, 11284-11285.

A metal-free decarboxylative three-component coupling reaction was developed. When alkynyl carboxylic acids, paraformaldehyde, and amines were reacted in CH3CN at 65 °C for 3 h, the desired propargylamines were obtained in good yields. This coupling reaction also showed good yield in water solvent. This reaction showed higher selectivity toward alkynyl carboxylic acids than a terminal alkyne.
K. Park, Y. Heo, S. Lee, Org. Lett., 2013, 15, 3322-3325.

A copper-based system enables methylene insertion between an amine and an alkyne counterpart, via C-N bond cleavage of N,N-dimethylacetamide. The method gives an expedient access to a broad range of propargylic amines in good yields.
A. Rahaman, R. D. Shinde, S. Bhadra, J. Org. Chem., 2023, 88, 1884-1889.

A single Cu(II) catalyst couples a diverse range of nitrogen sources with various alkynes and aldehydes without the addition of ligand or base. Copper-catalyzed alkynylation involving p-toluenesulfonamide provides high yields of N-Ts-protected propargylamines. The superior activity of copper(II) triflate also allows this three-component alkynylation to incorporate a ketone.
C. E. Meyet, C. J. Pierce, C. H. Larsen, Org. Lett., 2012, 14, 964-967.

A highly efficient gold-catalyzed three-component-coupling of aldehydes, alkynes, and amines in water was developed. Excellent yields of the corresponding propargylamines were obtained in most cases for both aromatic and aliphatic aldehydes and various amines.
V. K.-Y. Lo, Y. Liu, M.-K. Wong, C.-M. Che, Org. Lett., 2006, 8, 1529-1532.

A BF3-mediated in situ generation of alkynyl imines followed by alkynylation or allylation with boronic esters enables an efficient synthesis of α-alkynyl- or α-allyl-substituted N-Boc-propargylic amines in good yields under mild conditions.
K. Yasumoto, T. Kano, K. Maruoka, Org. Lett., 2019, 21, 3214-3217.

The addition of dimethylalkynylaluminum reagents derived from terminal alkynes and trimethylaluminum to various N-activated α-amido sulfones provides the corresponding propargylamines in good yields. The use of stable, N-activated α-amido sulfone avoids the preparation and isolation of relatively unstable N-activated imines.
J.-H. Lee, S.-H. Lee, Synthesis, 2022, 54, 2233-2241.

Merging photoredox with copper catalysis enables an efficient decarboxylative alkynylation of N-(acetoxy)phthalimides of α-amino acids with terminal alkynes at room temperature to provide valuable propargylamines in very good yields. This [Ru(bpy)3]Cl2/CuI catalyzed simple protocol offers mild reaction conditions and high efficiency.
H. Zhang, P. Zhang, M. Jiang, H. Yang, H. Fu, Org. Lett., 2017, 19, 1016-1019.

9,10-Dicyanoanthracene as the photoredox catalyst enables a metal-free, visible-light-induced photocatalytic decarboxylative alkynylation of a broad scope of α-amino acids, α-oxo acids, and α-keto acids at room temperature under an atmosphere of argon.
C. Yang, J.-D. Yang, Y.-H. Li, X. Li, J.-P. Chen, J. Org. Chem., 2016, 81, 12357-12363.

The reaction between N-Boc-aminals and organomagnesium reagents provides previously inaccessible N-Boc-protected propargylic and allylic amines via in situ generated N-Boc-imine intermediates. The obtained N-Boc-propargylic amines could be readily converted into unprecedented N-Boc-ketimines by oxidation with manganese dioxide.
T. Kano, R. Kobayashi, K. Maruoka, Org. Lett., 2016, 18, 276-279.

A novel InBr3-Et3N reagent system promotes the alkynylation of not only a variety of aromatic/heterocyclic or bulky aliphatic aldehydes but also N,O- or N,S-acetals. The reaction of N-silyl-N,O-acetals with 1-alkynes gives primary propargylic amines in good yields.
N. Sakai, R. Kanada, M. Hirasawa, T. Konakahara, Tetrahedron, 2005, 61, 9298-9304.

Copper-catalyzed Mannich reactions of terminal alkynes and secondary amines with aqueous formaldehyde is accelerated by the use of a catalytic amount of an imidazole ligand carrying a long alkyl chain.
T. Okamura, K. Asano, S. Matsubara, Synlett, 2010, 3053-3056.

N. Sakai, R. Kanada, M. Hirasawa, T. Konakahara, Tetrahedron, 2005, 61, 9298-9304.

Mediated by copper/diethyl azodicarboxylate, regioselective alkynylation of unactivated aliphatic tertiary methylamine with terminal alkyne was successfully established. The alkynylation reaction described here has the advantage of simple operation, mild reaction conditions, good to excellent yields, and no need to exclude air and moisture.
X. Xu, X. Li, Org. Lett., 2009, 11, 1027-1029.

A one-pot reaction for the transformation of common secondary amides into amines with C-C bond formation consists of in situ amide activation with Tf2O followed by partial reduction and addition of C-nucleophiles. The method is general in scope and allows the use of both hard nucleophiles (RMgX, RLi) and soft nucleophiles, as well as enolates. With soft nucleophiles the presence of ester, cyano, nitro, and tertiary amide groups are tolerated.
P.-Q. Huang, Y.-H. Huang, K.-J. Xiao, Y. Wang, X.-E. Xia, J. Org. Chem., 2015, 80, 2861-2868.

A simple and effective copper-catalyzed oxidative cross-coupling of dimethylanilines with alkynes in the presence of tert-BuOOH allows the construction of propargylamines via a combination of sp3 C-H bond and sp C-H bond activations followed by C-C bond formation.
Z. Li, C.-J. Li, J. Am. Chem. Soc., 2004, 126, 11810-11811.

Highly enantioselective direct alkyne-imine additions catalyzed by Cu(I)OTf and Evan's pybox ligands were developed in water and in toluene. The process is simple and allows the synthesis of various propargylic amines in high ees and good yields.
C. Wei, C.-J. Li, J. Am. Chem. Soc., 2002, 124, 5638-5639.

An economical and efficient Cu(I)-catalyzed one-pot reaction of enaminones with terminal alkynes provides symmetrical and asymmetrical 3-amino diynes in good yield under mild conditions.
C. Zhang, H. Guo, L. Chen, J. Zhang, M. Guo, X. Zhu, C. Shen, Z. Li, Org. Lett., 2021, 23, 8169-8173.

Propargylamines have been synthesized by a gold(III) salen complex-catalyzed three-component coupling reaction of aldehydes, amines, and alkynes in water in excellent yields at 40°C. With chiral prolinol derivatives as the amine component, excellent diastereoselectivities have been attained.
V. K.-Y. Lo, Y. Liu, M.-K. Wong, C.-M. Che, Org. Lett., 2006, 8, 1529-1532.

MgI2 as an additive enables a dramatic improvement in the [IrCl(COD)]2-catalyzed addition reaction of silylacetylenes and imines. This general and convenient reaction provides various amine products in excellent yields and can be conducted in THF as well as in the absence of solvent.
C. Fischer, E. M. Carreira, Synthesis, 2004, 1497-1503.

A highly enantioselective, catalytic three-component coupling of aldehydes, alkynes, and 4-piperidone hydrochloride hydrate affords the corresponding tertiary propargylamines in useful yields. A selective cleavage of the piperidone protecting group is possible using either ammonia/EtOH or a polymer-supported scavenger amine.
P. Aschwanden, C. R. J. Stephenson, E. M. Carreira, Org. Lett., 2006, 8, 2437-2440.

A Zn(OTf)2-mediated solvent-free synthesis of propargylamines proceeds effectively via A3 coupling of aldehydes, amines, and phenylacetylene. The protocol tolerates a broad range of substituted benzaldehydes, enolizable aldehydes, and formaldehyde. Recyclability of the catalyst, low catalyst loading, and use of inexpensive catalyst are the key features.
P. B. Sarode, S. P. Bahekar, H. S. Chandak, Synlett, 2016, 27, 2209-2212.

A three-component coupling between an aldehyde, alkyne and amine is catalyzed by silver iodide to generate propargylic amines in high yields in water without cocatalyst or activator. This method is especially effective for reactions involving aliphatic aldehydes.
C. Wei, Z. Li, C.-J. Li, Org. Lett., 2003, 5, 4473-4475.

Treatment of various aromatic and aliphatic aldimines with a mixture of a terminal alkynes and dimethylzinc solution in toluene yields the corresponding protected propargylic amines in moderate to excellent yields. A three-component synthesis of propargylic amines with an aldehyde, ortho-methoxyaniline and phenylacetylene through in situ formation of the corresponding imine in the presence of dimethylzinc was developed.
L. Zani, S. Alesi, P. G. Cozzi, C. Bolm, J. Org. Chem., 2006, 71, 1558-1562.

A copper(I)-catalyzed direct three-component coupling of ethyl glyoxylate, p-anisidine, and terminal alkynes provides β,γ-alkynyl α-amino acid derivatives in good yields.
Z. Shao, A. S. C. Chan, Synthesis, 2008, 2868-2870.

A modified binaphthol catalyzes an asymmetric conjugate alkynylation of β-enaminones with potassium alkynyltrifluoroborates via in situ generated organodifluoroboranes. Mechanistic studies revealed the impact of molecular sieves on efficiency and stereocontrol. Additional functionalization provides a diverse set of valuable β-alkynyl-β-amino carbonyl scaffolds.
J.-F. Wang, X. Meng, C.-H. Zhang, C.-M. Yu, B. Mao, Org. Lett., 2020, 22, 7424-7426.

L. Zani, S. Alesi, P. G. Cozzi, C. Bolm, J. Org. Chem., 2006, 71, 1558-1562.

A copper-catalyzed coupling of imines with alkynes and acid chlorides provides an efficient and general three-component coupling method to prepare propargylamides. The coupling can also be diversified to allow the formation of N-carbamate-protected propargylamines with the use of chloroformates.
D. A. Black, B. A. Arndtsen, Org. Lett., 2004, 6, 1107-1110.

A mild, copper(I)/Quinap-catalyzed addition of functionalized alkynes to enamines in high yields and with up to 90% ee is reported. Some selective transformations of the propargylamine products show the potential synthetic utility of this method.
C. Koradin, K. Polborn, P. Knochel, Angew. Chem. Int. Ed., 2002, 41, 2535-2538.

An expeditious and convenient method gives γ-amino-ynamides via nucleophilic addition of lithiated ynamides to aryl imines. This work also features an aza-variant of a Meyer–Schuster rearrangement of γ-amino-ynamides and their synthetic utility in intramolecular ketenimine [2+2] cycloadditions.
R. Qi, X.-N. Wang, K. A. DeKorver, Y. Tang, C.-C. Wang, Q. Li, H. Li, M.-C. Lv, Q. Yu, R. P. Hsung, Synthesis, 2013, 45, 1749-1758.