Chem. SCI: Jimmy Wu group of Dartmouth College realizes Beckmann splitting of nucleophile interception

Since the classical Beckmann rearrangement (Figure 1, conversion of ketoxime to corresponding amides) was reported in 1886, a variety of versions of the reaction have been developed subsequently, which can be roughly divided into two categories: 1) blocking the intermediate azaalkyne cation and / or iminate with nucleophiles other than water; 2) cracking to obtain nitriles These cleavage reactions involve similar Grob elimination processes to produce unsaturated groups such as olefins or carbonyls, with C-C bond breaking In addition, aldehyde oxime is usually directly eliminated by E2 to get nitrile (picture source: chem SCI.) in contrast, Beckman cleavage of ketoxime is rare and rarely reported for direct nucleophilic attack without elimination steps, but it may become a powerful means to construct highly functional dihydroindole Recently, the team of Jimmy Wu, Dartmouth College, USA, reported for the first time an example of Beckmann cracking of indolyoxime intercepted by nucleophiles That is to say, the synthesis of cyclohexyl [b] dihydroindole (EQ 1) containing four consecutive chiral centers by using a variety of nucleophiles will contribute to the rapid synthesis of indole alkaloids akuammiline and Koumine family natural products (Figure 2) This achievement was published in Chem SCI (DOI: 10.1039 / c9sc00926d) (picture source: chem SCI.) the author has been devoted to the development of new reactions involving indole and related heterocycles, and reported the [3 + 2] cyclization of 3-substituted indole with various α - haloketone derived oxo allyl cations to obtain bicyclone 3 (scheme 1) However, the typical Beckmann rearrangement products were not obtained after the conversion of ketone 3 to oxime The main product was cyanochlor4a (52%) and its regional isomer 5A (17%), whose structure was confirmed by sxrd and NMR (photo source: chem SCI.) for this unexpected discovery, the author wonders whether the reaction can be completely transformed In fact, the Beckmann cleavage blocked by nucleophiles has a wide range of substituents (r1-r3) and functional group tolerance (Table 1) Dihydroindole nitrogen can be replaced by methyl, benzyl and TBS atoms, its aromatic ring can also be replaced by various halogens, methyl or methoxy groups, and oxime derived from tryptamine and chromol can also react smoothly to obtain corresponding products When oxime derived from dihydroindole containing free hydrogen is used, it is easy to cause decomposition In any of the above reactions, no cleavage products similar to Grob were detected The range of regioselectivity between 4 and 5 is very wide (3:1 ~ 95:5), but the regioselectivity can be separated by column chromatography Based on the understanding of Beckmann rearrangement and product stereochemistry, the author proposed a possible reaction mechanism (scheme 2) It is well known that the electron absorbing groups on N with C = N compounds promote the mutual transformation between E and Z isomers Therefore, it is assumed that the equilibrium between (E) - 7 and (z) - 7 is fast and the subsequent cleavage rate is limited and irreversible, which can be carried out through a stereoscopic guidance process, i.e through the O-group participation of the non bonded electrons on the indolin nitrogen, a configuration reversed intermediate 8 of azopropionium can be obtained There is almost no stereo deviation between (E) - 7 and (z) - 7 Due to the requirement of the stereoelectricity of methanesulfonate, the leaving group and the transferred carbon atom are in the trans form The author thinks that the geometry of methanesulfonate oxime is the main determinant of the reaction region selection Therefore, a classical Curtin Hammett model has been established, in which the product distribution is controlled by the relative difference of (E) - 7 → 8 vs (z) - 7 → 9 transition state energy (ΔΔ g ≠) The experimental results show that the product distribution between 4 and 5 is always greater than the E / Z ratio of the corresponding oxime starting material (~ 1:1 DR) The main product 4A was obtained by the subsequent reversal of the chloride attack on n-propionium 8, and the formation of the secondary isomer 5A may be through the intermediate 9 of phenolic onium (picture source: chem SCI.) next, the author seeks to expand the scope of application of Beckmann cracking (Table 2) for nucleophile interception, including nucleophiles other than chlorides It is concluded that the initiator other than MscL can activate oxime for cleavage and provide different nucleophiles for the determination of ring opening of intermediates 8 and 9 Therefore, the expected cyano azides can be obtained by treating oxime 6 with DPPA In addition, the relatively weak nucleophiles produced by phntf 2, tfaa and MS 2O can also be used to obtain the corresponding products of trifluoromethylsulfonamide, trifluoroacetate and methanesulfonate, while the bromide can be obtained by MSBR (picture source: chem SCI.) in order to verify the effectiveness of the proposed intermediate 8, the author chose to study the stereochemistry results (scheme 3) of converting 10C and 12 into corresponding bromide The authors hypothesized that the activation of alcohol 12 could lead to the regeneration of the presumed intermediate 8 of aziridium and the subsequent ring opening by bromides, which would result in 10e However, if the reaction is carried out by free carbocation 14, the non enantiomers or olefin by-products can be obtained Therefore, after hydrolysis of trifluoroacetate 10C to produce 12, a single product 10e was obtained by pbr3 treatment, and no olefin or stereoisomer was detected (picture source: chem SCI.) conclusion: Jimmy Wu group first reported Beckmann rearrangement of dihydroindooxime intercepted by nucleophilic reagent The substrate of this reaction can withstand various functional groups, and can also use various initiators to introduce oxygen, nitrogen and halogen substituents into the final product The stereospecific cleavage of activated oxime was verified by the existing evidence, and the intermediate of azopropionium was obtained as a possible speed control step In addition, the reaction will also contribute to the synthesis of indoline alkaloids such as akuammiline and Koumine family natural products.