Highly Enantioselective Zinc/Binol‐Catalyzed Alkynylation of N‐Sulfonyl Aldimines

Abstract

The catalytic enantioselective formation of new C À C bonds is an important class of organic reactions.[1] Among them, the asymmetric additions of terminal alkynes to C=O and C=N bonds are two of the most important objectives in organic synthesis; the resulting chiral propargylic alcohols and amines are versatile building blocks for the synthesis of a wide range of natural products and pharmaceuticals. Some excellent work has been reported on the asymmetric addition of alkynes to carbonyl compounds resulting in high ee values. [2] However, the practical enantioselective alkynylation of imines and imine derivatives to form propargylic amines is challenging because of the poor electrophilicity of the azomethine carbon. [3] In this context, most of the studies reported so far deal with the catalytic enantioselective alkynylation of N-aryl imines by using Cu I salts in combination with nitrogen-containing ligands. The leading studies of this reaction with N-aryl imines have been developed by Wei et al., [4] Bisai and Singh, [5] and Benaglia and co-workers [6] ; and Knochel and co-workers [7] and Carreira and co-workers [8] reported using iminium intermediates generated in situ in a three-component synthesis of propargylic amines.[9] Other methods, which do not make use of copper complexes as the catalyst, have also been described. Hoveyda and co-workers have used peptide-based ligands in combination with Zr-(OiPr) 4 ·HOiPr to catalyze the addition of preformed mixed alkynylzinc reagents to various N-aryl aromatic imines, which gives good results with trimethylsilylethyne and lower enantioselectivities with aryl-substitued alkynes.[10] Jiang and Si have described the addition of alkynes to a trifluoromethyl activated cyclic imine by using a stoichiometric amount of a chiral amino alcohol ligand.[11] Recently, Bolm and co-workers have described the use of dimethylzinc to catalyze the addition of terminal alkynes to N-aryl and N-protected imines in the absence of ligands.[12] An enantioselective version has been implemented by these authors for o-methoxyanilinederived imines by using a relatively large loading (40 mol %) of the amino alcohol ligands. [13] In contrast, N-acyl-and Nsulfonyl-protected imines show enhanced reactivity because of the electron-withdrawing character of the protecting group.The alkynylation of these substrates lead to protected propargylic amines. The highly enantioselective alkynylation of N-acyl imines has been carried out by using chiral alkynylboronates [14] and alkynylboranes, [15] which are based on the binol and the borabicyclo[3.3.2]decane scaffolds, respectively, as reagents. However, to the best of our knowledge, the enantioselective alkynylation of N-tosyl imines has not been reported so far. Because of the increased reactivity of N-sulfonyl imines and the findings reported by Bolm and co-workers, [12] we envisioned a dimethylzinc-mediated catalytic enantioselective alkynylation of N-sulfonyl imines by using an appropriate ligand (Scheme 1). Binol-type ligands were chosen in our stud...

Development of a syn‐Selective Mannich Reaction of Aldehydes with Propargylic Imines by Dual Catalysis: Asymmetric Synthesis of Functionalized Propargylic Amines

“…(2S,3R)-3-((4-Methoxyphenyl)amino)-2-methyl-5-phenylpentan-1ol (5):T oasolution of (2S,3S)-3-((4-methoxyphenyl)amino)-2methyl-5-phenylpent-4-yn-1-ol (4Ba; 1 11.8 mg, 0.38 mmol) in ethanol (1.1 mL) was added acetic acid (21.2 mL, 0.38 mmol) and 20 % wt of Pd/C (22.4 mg) at room temperature. The reaction mixture was stirred at 0 8Cu nder H 2 atmosphere (1 atm 5,142.1,141.9,128.4,126.0,115.6,115.0,66.7,57.0,55.9,37.6,34.5,33.2,11.3 ppm;H RMS (ESI): m/z calcd for C 19 H 26 NO 2 300.1964;found:300.1981.…”

“…[a] D 22 = À5.9 (c = 1, CH 2 Cl 2 ); 1 HNMR (CDCl 3 ,3 00 MHz) d = 7.36-7.14 (m, 6H), 6.80 (d, J = 9.0 Hz, 2H), 6.62 (d, J = 9.0 Hz, 2H), 4.45 (d, J = 5.4 Hz, 1H), 3.79 (d, J = 2.2 Hz, 3H), 3.39-3.34 (m, 6H), 2.70 (s, 4H), 1.70 ppm (d, J = 5.2 Hz, 3H); 13 CNMR (CDCl 3 ,7 5MHz) d = 152. 5,141.8,128.5,126.0,115.5,115.0,103.8,64.6,57.1,55.9,53.0,38.6,33.7,33.0,30.5 ppm;H RMS (ESI): m/z calcd for C 22 H 32 NO 4 374.2331;found:374.2336. (2S,3R,E)-3-((3-Methoxyphenyl)amino)-2-methyl-5-phenylpent-4en-1-ol (7):L iAlH 4 (45.6 mg, 1.2 mmol) was added to as olution of (2S,3S)-3-((3-methoxyphenyl)amino)-2-methyl-5-phenylpent-4-yn-1ol (4Ba;9 3.1 mg, 0.3 mmol) in THF (3 mL) at room temperature.…”

“…[1] In this context, propargylica mines not only are presenti nanumber of bioactive compounds, [2] but may also serve as versatile building blocks in synthesis [3] owing to the rich chemistry of both the amine anda lkyne moieties. Among the methods for their preparation (Figure 1), [4] the addition of terminala lkynes to imines, [5] and the 1,2-addition of organometallic reagents to propargylic imines [6] are especially attractive because the CÀC bond and stereocenter are generatedc oncurrently.A lthough, these standard catalytic and asymmetric methods usually allow for the generation of as ole stereocenter,t hey offer almost no chance to introduce additional functionality.…”

Recent Developments in Asymmetric Alkynylation of Imines

“…Making use of this effect, Pedro et al [68] have described very recently a dimethylzinc-mediated catalytic enantioselective alkynylation of N- sulfonyl imines 223 with dimethylzinc and terminal alkynes in the presence of binol-type ligands (225-230), which contained electron-withdrawing groups at the 3,3 and 6,6 positions, as well as a tetrahydrogenated ring. The reaction of phenylacetylene with N-tosyl benzaldimine was tested in the presence of 20 mol % of these ligands (Scheme 78).…”

[1,1′-Binaphthalene]-2,2′-diol, 3,3′-Bis[3,5-bis(trifluoromethyl)phenyl]-, (1R)-

“…Binaphthol 1 may be used as a catalyst for the enantioselective addition of alkynylzinc reagents to Nsulfonyl aldimines (eq 2). 5 The selectivity is much higher than that obtained with unsubstituted BINOL (8% ee). Other aryl aldimines also give good selectivities (64 to >99% ee with phenylacetylene) but alkyl aldimines give much lower (18-38% ee) selectivities.…”