Chem. Comm.: regioselective [2 + 2] cycloaddition of cinnamates and related olefins

Cyclobutane skeletons are common in natural products, and they are found in plants, insects and microorganisms Most of these structures have biological activity, which makes them have potential in drug application There are many Cyclobutanes derived from cinnamic acid, such as β - Coca acid, piperarbornene D, sagerinic acid and so on In addition, some styrene derivatives, such as endiandrin a, di-o-methylendindrin a, magnosalin (trans) and andamanicin (CIS), can bind to glucocorticoid receptor (GR) and are widely used as anti-inflammatory drugs (Fig 1) Figure 1 Natural product source with cyclobutane structure: chemical communications recently, Oliver Reiser team from the Institute of organic chemistry, University of Regensburg, Germany published a paper in chemical communications, reporting an effective method to synthesize substituted cyclobutane from cinnamate, chalcone and styrene by using visible light triplet sensitization mode The new method has the advantages of mild conditions, high yield, wide range of substrate selection and no need for additional reaction AIDS (Fig 2) Fig 2 [2 + 2] cyclobutane synthesis by cycloaddition: the chemical communications author first selected different photocatalysts with ethyl cinnamate (1a) as the reaction substrate, and optimized the reaction conditions (Fig 3) Under the same reaction conditions (blue LED 455, O2), [IR {DF (CF 3) PPy} 2 (DTB bpy)] pf 6 showed the best photocatalytic effect (entry01-05) When the reaction atmosphere was replaced with inert gas N2, the yield was increased to 96% (entry 06) The amount of catalyst decreased from 1.0 mol% to 0.5 mol%, and the yield slightly decreased (entry 07) However, if the light source is replaced with 530nm rose red, and no photocatalyst or light source is used, the reaction will not succeed (entry 08-10) Figure 3 Source of catalyst screening and condition optimization: chemical communications next, the author expanded the reaction substrate, and the reaction results are shown in Figure 4 The enantioselectivity of 2B / 3b is better than that of ethyl cinnamate, but the yield is slightly lower Only δ - diastereomer 2C was obtained from the reaction of β - methyl cinnamate The enantioselectivity of Cinnamate with electron substituent in the benzene ring was decreased significantly (2I / 3i-2k / 3K) Ortho substituents can enhance the enantioselectivity of the reaction, and the ratio of 2P / 3P is 20:1 In addition, cinnamates with several substituents in benzene ring have good reactivity and enantioselectivity (2L / 3L and 2m / 3M) The substitution of benzene ring with furan, thiophene and N-Boc pyrrole was also successful, but the enantioselectivity was not obvious, and a small number of dimer by-products connected head to tail were also involved In addition, the reaction range was further extended to obtain the intramolecular cycloaddition products (2U / 3U) and chalcone cycloaddition products (2V / 3V and 2W / 3W) The new method also has limitations The yield of indole derivatives is not satisfactory (2t) Figure 4 Source of substrate expansion: further exploration by chemical communications authors found that this kind of intermolecular [2 + 2] dimerization is also applicable to styrene structure (Figure 5) It has been reported that the intermolecular cycloaddition of styrene is realized by photochemical olefin oxidation, but the reaction system is usually required to be electron rich But this method can realize the cycloaddition reaction of styrene which is electron deficient or even electron deficient Fig 5 [2 + 2] cycloaddition source of styrene: chemical communications authors also tried cross coupling cycloaddition of two different cinnamates (Fig 6) The results show that the cross coupling products account for a large proportion, but the enantioselectivity is not high, and the self coupling products of the same cinnamate can not be ignored Fig 6 Cross [2 + 2] cycloaddition source of cinnamate: chemical communications finally, the author gives the mechanism of this reaction according to the photodegradation principle of cinnamate proposed by Haag et al (Fig 7) The photo excited IR catalyst forms the excited state IR *, and then transfers the energy to substrate 1, forming the double free radical component 1 * 1 * dimers with another molecule 1 In order to stabilize the benzyl radical, intermediate a is selectively formed Under the strong action of π - π overlap of aromatic ring, the target product 2 of head to head connection is finally obtained Figure 7 Reaction mechanism source: chemical communications summary: Oliver Reiser team developed a new method to realize the photodegradation of cinnamate, styrene and chalcone, and obtained substituted cyclobutane with excellent yield and good enantioselectivity under mild conditions Paper link: http://pubs.rsc.org/en/content/article landing/2017/cc/c7cc06710k ා! Divabstract Reiser group link: http://www-oc.chemie.uni-regensburg.de/reiser/index﹐ e.html Reiser group 2017 Carnival photo