Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. 2018, 20, 3465−3468
Stereoselective Synthesis of Fully-Substituted Acrylonitriles via Formal Acylcyanation of Electron-Rich Alkynes Bing Liu,†,§,∥ Yong Wang,‡,∥ Ying Chen,§ Qian Wu,§ Jing Zhao,*,§ and Jianwei Sun*,‡
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†
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China ‡ Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China § State Key Laboratory of Coordination Chemistry, Institute of Chemistry and BioMedical Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China S Supporting Information *
ABSTRACT: A Sc(OTf)3-catalyzed formal acylcyanation of electron-rich alkynes for the efficient synthesis of fully-substituted acrylonitriles is described. By means of alkyne carbonyl metathesis, the reaction features mild conditions, high regio- and stereoselectivity, and a broad scope. The strong preference of the nitrile group for inward rotation in the torquoselective ring opening of the oxetane intermediate determines the remarkable Z selectivity of this process.
fficient synthesis of stereodefined tetrasubstituted olefins is an important and challenging topic in organic synthesis.1 In particular, cyano-substituted olefins, i.e., acrylonitriles, are well-known versatile monomers for the synthesis of useful polymers. Multisubstituted acrylonitriles are also useful precursors toward other functionalized olefins because of their ease of conversion to a wide range of functional groups.2 Consequently, general strategies for the efficient and stereoselective synthesis of multisubstituted acrylonitriles are highly desirable but remain underdeveloped. During the past few decades, extensive efforts have been devoted to the synthesis of fully-substituted acrylonitriles, resulting in several notable catalytic systems, with direct cyanation of alkynes being the most direct approach (Scheme 1a).3 Among them, acylcyanation is particularly attractive for the assembly of carbonyl-substituted acrylonitriles. However, regio- and stereoselective intermolecular examples have not been well-established. Nakao and Hiyama pioneered the intermolecular Ni-catalyzed acylcyanation of electron-neutral alkynes with a Lewis acid as the necessary activator of the acylnitrile (Scheme 1b).4 Unfortunately, while this process can be achieved with excellent syn addition stereoselectivity, for unsymmetrical alkynes excellent regioselectivity is limited to highly sterically biased alkynes (e.g., Me vs tBu). Recently, Ohmiya and co-workers reported another elegant example of acylcyanation of electron-deficient alkynes using phosphine catalysis, resulting in the anti addition products with moderate to good stereoselectivities (Scheme 1c).5 Because of the involvement of C−CN bond cleavage, these two approaches require either additional Lewis acid activation or relatively elevated temperature.
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© 2018 American Chemical Society
Scheme 1. Overview of Acrylonitrile Synthesis from Alkynes
Moreover, although success with electron-neutral and electron-deficient alkynes has been achieved, acylcyanation Received: April 13, 2018 Published: June 6, 2018 3465
DOI: 10.1021/acs.orglett.8b01180 Org. Lett. 2018, 20, 3465−3468
Letter
Organic Letters
resulted in the identification of an optimal set of conditions, leading to 94% yield at room temperature in the presence of 5 mol % Sc(OTf)3 (entry 20). Notably, the product was obtained as a single isomer regarding the double-bond configuration, and the Z configuration was confirmed by NOE experiments and X-ray crystallography.
of electron-rich alkynes remains unknown. In continuation of our efforts on the study of electron-rich alkynes,6 herein we report a mild Lewis acid-catalyzed formal acylcyanation of these alkynes, leading to the efficient synthesis of fullysubstituted acrylonitriles with complete regio- and stereocontrol. Different from the previous acylcyanations, the present reaction employs an alkyne−carbonyl metathesis mechanism via the [2 + 2] cycloaddition adduct oxtene as an intermediate. Since no C−CN bond cleavage is involved, we expect that this process can be achieved under mild conditions without additional activation of the nitrile functional group. Initially, internal ynamide 1a was chosen as the representative substrate, and benzoyl cyanide (2a) was employed as the cyanation reagent. We evaluated a range of Lewis acids, including those based on Ag, Zn, La, Y, etc. Unfortunately, most of them did not show good catalytic ability when the reaction was run in chlorobenzene (0.25 M) at 70 °C for 12 h. Gratifyingly, we did observe the formation of the desired product 3aa in some of the entries (Table 1). We found that in many cases the ynamide substrate readily decomposed in the presence of these promoters.
With the optimized conditions in hand, we next examined the substrate scope of ynamides (Table 2). Different internal ynamides with various N-protecting groups all reacted smoothly with benzoyl cyanide to form the desired fullysubstituted acrylonitriles with excellent syn selectivity. Indeed, essentially a single isomer was observed in almost all cases. In Table 2. Scope of Various Ynamidesd
Table 1. Evaluation of the Reaction Conditions
entry
catalyst
solvent
t/°C
conv./%a
yield/%a
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18b 19c 20b,d
AgNTf2 AgOTf Zn(OTf)2 In(OTf)3 La(OTf)3 Y(OTf)3 Yb(OTf)3 Hf(OTf)3 Dy(OTf)3 Cu(OTf)2 Sc(OTf)3 HNTf2 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3
PhCl PhCl PhCl PhCl PhCl PhCl PhCl PhCl PhCl PhCl PhCl PhCl toluene DCM CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3
70 70 70 70 70 70 70 70 70 70 70 70 70 45 70 40 rt rt rt rt
100 100 20 100 48 36 100 90 88 100 100 100 100 100 100 100 100 100 100 100
