Asymmetric Alkynylation of Seven-Membered Cyclic Imines by

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Asymmetric Alkynylation of Seven-Membered Cyclic Imines by Combining Chiral Phosphoric Acids and Ag(I) Catalysts: Synthesis of 11-Substituted-10,11-dihydrodibenzo[b,f ][1,4]oxazepine Derivatives Yuan-Yuan Ren, You-Qing Wang,* and Shuang Liu Provincial Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng, Henan, 475004, China S Supporting Information *

ABSTRACT: Asymmetric alkynylation of seven-membered cyclic imine dibenzo[b,f ][1,4]oxazepines is successfully achieved by combining chiral phosphoric acid and Ag(I) catalysts. Various arylacetylenes, conjugated enynes, and terminal 1,3-diynes are good substrates for this reaction, and aliphatic hexyne is also a suitable donor at elevated temperature. Optimization of this approach has provided a facile method to synthesize optically active 11-substituted10,11-dihydrodibenzo[b,f ][1,4]oxazepine derivatives containing a carbon−carbon triple bond with 63−99% ee. Subsequent transformations of the carbon−carbon triple bond for the heterocyclic products have been disclosed.

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ketimines was reported by Zhou et al.3 Therefore, the research for other catalytic asymmetric reactions to synthesize these seven-membered cyclic optically active compounds is highly desirable. Asymmetric alkynylation of imines is one of the most efficient methods for obtaining chiral propargylamines,4 which are important synthetic intermediates for the construction of biologically active nitrogen-containing compounds5 and natural products.6 While catalytic enantioselective addition to imines provides the most efficient method for the synthesis of chiral nitrogen-containing compounds,7 the direct use of alkynes as carbon nucleophiles continues to be desired. Research more typically focuses on the use of acyclic imines and related CN electrophiles as substrates, which are prepared prior to use8 or generated in situ from aldehydes and amines.9 However, the asymmetric alkynylation of cyclic imines is rarely reported, despite the fact that it is a potentially powerful method for the construction of optically active polyfunctional nitrogencontaining heterocycles.10 In 2004, Jiang et al. described the highly enantioselective alkynylation of six-membered cyclic Nacyl trifluoromethyl-activated imine using stoichiometric Zn(OTf)2 and amino alcohol as a chiral ligand.11 Recently, the same cyclic imines were employed for the asymmetric diynylation reaction with chloramphenicol-amine derivatives as chiral additives.12 Two catalytic asymmetric methods used previously include the alkynylation of cyclic iminium derived from dihydroisoquinoline catalyzed by CuBr/Quinap13 and the combined system of CuOAc/Ph-pybox with an axially chiral dicarboxylic acid.14 To the best of our knowledge, there has

ver the past decade, considerable attention has been given to 11-substituted-10,11-dihydrodibenzo[b,f ][1,4]oxazepine derivatives, which play an important role in synthetic organic chemistry and pharmaceutical science,1,2 such as antihistaminics I,1a dibenzazepines II analogous to Sintamil,1b and progesterone receptor agonist III (Scheme 1).1c Despite the availability of several published methods for the construction of these structures,1b,2 a catalytic method that offers high enantioselectivity is highly desired as different enantiomers or diastereomers of a molecule often have different biological activity. So far, only Ir-catalyzed asymmetric hydrogenation of the corresponding seven-membered cyclic Scheme 1. Construction of Dibenzo[b,f ][1,4]oxazepine Derivatives via Catalytic Asymmetric Reaction

Received: September 25, 2014

© XXXX American Chemical Society

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dx.doi.org/10.1021/jo5022037 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Note

of catalysis, we focused on the combined chiral Brønsted acids and Ag(I) catalysts.18 Combining chiral phosphoric acid (CPA)19 C-1 and AgOAc catalysts in toluene at room temperature resulted in a 20% yield of the desired product 3aa with 38% ee (entry 1). Further assessment of solvents revealed that 1,4-dioxane was proven to be the most favorable solvent (75% yield, 58% ee) (entry 5). Several silver salts were also examined, and AgOAc was yet the best choice (entries 7− 11). Subsequently, a screening for CPA was undertaken (entries 12−16), resulting in the bulky substituted CPA C-6 making a significant improvement in both reactivity and enantioselectivity (entry 16). Notably, when the AgOAc loading was reduced to 5 mol %, the product 3aa was obtained in full conversion within a shorter time (24 h, as opposed to 72 h) (entry 17). Finally, the ee value was further improved to 87% by decreasing the reaction temperature to 15 °C (entry 18).20 Once the reaction conditions were optimized, the scope of this reaction was then evaluated, as summarized in Table 2.

been no report of catalytic asymmetric alkynylation of sevenmembered imines. In the course of our research on the catalytic enantioselective addition of cyclic imines to construct chiral Nheterocycles,15 very recently, we reported organocatalyzed asymmetric direct Mannich reaction of dibenzo[b,f ][1,4]oxazepines.15c Inspired by those achievements, in this note, we described a highly enantioselective alkynylation of dibenzo[b,f ][1,4]oxazepines by combining chiral phosphoric acids and Ag(I) catalysts (Scheme 1). Various arylacetylenes, conjugated enynes, and terminal 1,3-diynes were tolerated in the reaction. Furthermore, the carbon−carbon triple bond introduced herein is an important functional group for further chemical transformation, and the corresponding reductions to obtain separately (Z)- and (E)-alkenes without loss of enantioselectivities were realized. Optimization studies were performed with the alkynylation reaction of seven-membered cyclic imine 1a and phenylacetylene 2a as the model substrates, and the results are listed in Table 1. Cooperative catalytic models based on chiral Brønsted acids and metal catalysis16 have been previously employed in the asymmetric alkynylation of acyclic imines.17 In order to achieve high activity and stereoselectivity, two welldifferentiated and parallel catalytic cycles were used, the addition of metallic alkynylides to imines and the use of chiral Brønsted acids as imine activators. As such, for the investigation

Table 2. Addition of Different Alkynes to Imine 1aa

Table 1. Optimization of Reaction Conditionsa

entry

R (2)

3

yield [%]b

ee [%]c

1 2 3 4 5d 6 7e 8 9 10f

Ph (2a) p-MeC6H4 (2b) p-MeOC6H4 (2c) p-FC6H4 (2d) o-FC6H4 (2e) 3-thienyl (2f) n-butyl (2g) 1-cyclohexenyl (2h) 2-propenyl (2i) (E)-CHCHC6H5 (2j)

3aa 3ab 3ac 3ad 3ae 3af 3ag 3ah 3ai 3aj

88 83 92 91 65 74 38 92 74 44

87 85 88 89 93 90 78 95 91 90

a

entry

solvent

AgX

CPA

yield [%]b

ee [%]c

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17d,e 18e,f

toluene benzene CH2Cl2 THF dioxane MeOH dioxane dioxane dioxane dioxane dioxane dioxane dioxane dioxane dioxane dioxane dioxane dioxane

AgOAc AgOAc AgOAc AgOAc AgOAc AgOAc AgO AgNO3 AgBF4 AgCO2CF3 AgOTf AgOAc AgOAc AgOAc AgOAc AgOAc AgOAc AgOAc

C-1 C-1 C-1 C-1 C-1 C-1 C-1 C-1 C-1 C-1 C-1 C-2 C-3 C-4 C-5 C-6 C-6 C-6

20 40 11 30 75