Reaction of Vinyl Aziridines with Arynes: Synthesis of Benzazepines and Branched Allyl Fluorides

Abstract

We report the cycloaddition betweenv inyl aziridines and arynes. Depending on the reactionc onditions and the choice of the aryne precursor,t he aziridinium intermediate can be trapped through two distinct mechanistic pathways. The first one proceeds through af ormal [5+ +2] cycloaddition to furnish valuable multi-substituted benzazepines. In the second pathway,t he aziridinium is interceptedb yafluoride ion to afford allylic fluoridesi n good yields. Both reactions proceed stereospecifically and furnish enantiopure benzazepines and allylic fluorides.The ongoing resurgencei na ryne chemistry can be attributed to the development of modern methodologies that enable the efficient generation of arynesins itu under mild reaction conditions. [1] This advancementh as allowed the scope of aryne chemistry to expand significantly into the areaso ft ransitionmetal catalysis and multicomponent reactions, among others. [2] Amination reactions are an area in which aryne chemistry has been particularly successful. As ar esult,a minations of arynes have found great utility in the total synthesis of alkaloids. [3] As ap art of our ongoing programs in aryne chemistry [4] and the synthesis of aza-heterocycles from aziridines, [5] we werei nterested in exploringt he reactivity of vinyl aziridines toward arynes. We envisioned that the [5+ +2] cycloaddition between an aryne and av inyl aziridine couldp roceed through af ormal cycloaddition [6] reactiont of urnish valuableb enzazepines (Figure 1a). [7] The 7-membered aza-heterocyclei sa ni mportant scaffold in medicinal chemistrya nd is found in aw ider ange of bioactive compounds, [8] naturalp roducts, [9] dipeptide mimics, [10] and dyes [11] (Figure 1b). Due to the importance of this class of heterocycle, several methods have been developed for the synthesis of this and similarscaffolds. [12] We initiated our study by screening differentc onditions for benzyne generation in the presence of 1-benzyl-2-vinyl aziridine (2a)a samodel vinyl aziridine (Scheme 1). Utilizing the conditions developed by Kobayashi, [13] we only observed trace amountso ft he desired benzazepine 3a.H owever,w eo bserved the formationo fa llylic fluoride 6a,w hich is most likely formed from an attack of the fluoridea nion onto the internal allylic positiono ft he electrophilic aziridinium cation.T his led us to screen methods for fluoride-free aryne generation. Utilizing the aryne precursor 1b and iPrMgCl·LiCl, [14] only 2a was recovered.I th as been reported that magnesiated 1b is highly reactive and decomposest ot he aryne at À78 8C, presumably before nucleophilic attack of 2a.W ew ere pleasedt os ee that by utilizing the same conditions, but switching to the more stable aryne precursor 1c, [15] we werea ble to observe the formation of benzazepine 3a in an encouraging 45 %y ield. [16] After this initial hit, further optimization of the annulation reaction was performed (Table 1). Switching the solventf rom Et 2 OtoT HF hadadeleterious effect (34 %, entry 1). Exchanging Figure 1. (a) Reactionofv inyl ...

Aromatic Aza‐Claisen Rearrangement of Arylpropargylammonium Salts Generated in situ from Arynes and Tertiary Propargylamines

“…In 2009, Greaney and co‐workers reported an elegant charge‐accelerated aromatic aza‐Claisen rearrangement of allylarylammonium salts, generated in situ by nucleophilic addition of tertiary allylamines to arynes, to yield 2‐allylanilines (Scheme 1 A). [7, 8] This aryne‐mediated rearrangement was later extended to diallylarylamines, [9] 2‐vinylazetidines, [10] and 2‐vinylaziridines [11] for the synthesis of various nitrogen‐containing heterocycles. In sharp contrast to tertiary allylamines, [12] much less attention has been paid to tertiary propargylamines in the aryne‐mediated sigmatropic rearrangements [13] .…”

Synthesis of Stannylated Aryl Imines and Amines via Aryne Insertion Reactions into Sn−N Bonds

“… A) Aryl amine synthesis using transition metal catalysis. B) Arene C−N bond formation through arynes [18–27] . C) Aryne insertion into the N−Sn bond of a stannylated benzophenone imine.…”

“…An elegant route towards 2‐allylanilines was presented by Greany and coworkers using allylamines as starting materials [23] . Moreover, benzazepines can be prepared by the reaction of in situ generated arynes with vinyl aziridines [24] . Note that the latter two processes do not rely on direct σ‐bond insertion reactions.…”

“…[23] Moreover, benzaze-pines can be prepared by the reaction of in situ generated arynes with vinyl aziridines. [24] Note that the latter two processes do not rely on direct σ-bond insertion reactions. Moreover, various methods for the construction of CÀ N and CÀ Sn bonds involving aryne intermediates are known.…”

“…B) Arene CÀ N bond formation through arynes. [18][19][20][21][22][23][24][25][26][27] C) Aryne insertion into the NÀ Sn bond of a stannylated benzophenone imine. The scope with respect to the aryne component was studied next using imine 2 b as the amination reagent (Scheme 4).…”