Letter pubs.acs.org/OrgLett
Metal-Free [2 + 1 + 2]-Cycloaddition of Tosylhydrazones with Hexahydro-1,3,5-triazines To Form Imidazolidines Pei Liu, Guangyang Xu, and Jiangtao Sun* Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology and School of Pharmaceutical Engineering & Life Science, Changzhou University, Changzhou 213164, P. R. China S Supporting Information *
ABSTRACT: A novel protocol toward imidazolidines has been accomplished using tosylhydrazones and hexahydro-1,3,5-triazines as the substrates under metal-free reaction conditions. Importantly, the role of LiOtBu has been confirmed not only to release the diazo but also to promote the cycloaddition. Further mechanistic investigations reveal that the reaction proceeds through a stepwise [2 + 1 + 2] process.
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Scheme 2. Initial Attempts and Our Strategy
s stable and readily available starting materials, tosylhydrazones have been extensively employed as diazo precursors to synthesize structurally diverse molecules in modern organic synthesis.1 Not surprisingly, generation of a diazo moiety in situ from tosylhydrazones has enabled the development of versatile novel reactions under transition-metal catalysis,2,3 or even more appealing, under metal-free reaction conditions.4−8 For example, in 2009, Barluenga and Valdés demonstrated an elegant C−C bond formation by reductive coupling of boronic acids and tosylhydrazones under metal-free conditions (Scheme 1a).4 Later, they further extended this Scheme 1. Previous Reports
heterocycle. The initial unsuccessful attempts prompted us to develop an effective protocol to circumvent this challenge. In continuation of our ongoing interest in diazo chemistry and triazine involved cycloadditions,10 we report here a basepromoted cycloaddition from tosylhydrazones via a [2 + 1 + 2] process under metal-free reaction conditions (Scheme 2c). At the outset, we utilized tosylhydrazone 1a and hexahydro1,3,5-triazine 2a as model substrates to establish the optimal reaction conditions (Table 1). When the reaction was performed in toluene at 60 °C, the use of 2 equiv of Cs2CO3 afforded 3a in 40% yield associated with a small amount of azine 4a (entry 1), while K2CO3 gave a much lower yield (entry 2). Gratifyingly, when LiOtBu was employed, 3a was obtained in 84% yield (79% isolated yield) together with a 7% yield of 4a (entry 3). Switching the base to KOtBu, NaOtBu, and NaH resulted in moderate yields (entries 4−6), while the use of KOH and NaOMe gave very low yields (entries 7 and 8). Then, the solvent was screened. First, the formation of similar
protocol to forge C−C, C−O, and C−N bonds.5 Wang and coworkers successfully developed metal-free C−B and C−Si bonds formation by using tosylhydrazones as ideal substrates.6 The Jiang group also reported tosylhydrazones involved metalfree carbamation and cyclopropanation (Scheme 1b).7 Despite these advances, new reactions using tosylhydrazones as starting materials under metal-free conditions are still needed from the viewpoints of cost and sustainability. Recently, we reported a gold-catalyzed cycloaddition of donor/acceptor diazo compounds with hexahydro-1,3,5triazines9 to prepare five-membered N-heterocycles (Scheme 2a).10a Unfortunately, this protocol was not applicable to donor/donor diazo substrates. Under gold catalysis, the expected cyclization product was not obtained but rather the coupling products azine and olefin (Scheme 2b). Moreover, the use of rhodium complexes also did not produce the desired © XXXX American Chemical Society
Received: March 1, 2017
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DOI: 10.1021/acs.orglett.7b00600 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Optimization of Reaction Conditionsa
entry
base
solvent
t (°C)
yield (%)b 3a/4a/5a
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Cs2CO3 K2CO3 LiOtBu KOtBu NaOtBu NaH KOH NaOMe LiOtBu LiOtBu LiOtBu LiOtBu LiOtBu LiOtBu LiOtBu LiOtBu
toluene toluene toluene toluene toluene toluene toluene toluene dioxane DCE CH2Cl2 THF p-xylene toluene toluene toluene
60 60 60 60 60 60 60 60 60 60 60 60 60 110 80 25
40/6/
