Note pubs.acs.org/joc
PhI(OCOCF3)2‑Mediated Cyclization of o‑(1-Alkynyl)benzamides: Metal-Free Synthesis of 3‑Hydroxy-2,3-dihydroisoquinoline-1,4dione Chao Yang,† Xiang Zhang,† Daisy Zhang-Negrerie,† Yunfei Du,*,†,‡ and Kang Zhao*,† †
Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China ‡ Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China S Supporting Information *
ABSTRACT: The synthesis of an undocumented skeleton of 3hydroxy-2,3-dihydroisoquinoline-1,4-diones has been discovered and reported. The reaction consists of an intramolecular cyclization of o(1-alkynyl)benzamides in MeCN/H2O, mediated by metal-free, hypervalent reagent of PhI(OCOCF3)2, followed by an oxidative hydroxylation reaction. The mechanism consisting of two pathways has been proposed and discussed.
T
he intramolecular cyclization of alkynes possessing a nucleophilic moiety in the proximity of the carbon−carbon triple bond1 has been reported to be a convenient and effective process for the construction of a variety of heterocycles.2 Among these transformations is the construction of N-containing heterocycles through intramolecular cyclization reactions between an amide moiety and the carbon−carbon triple bond. For this reason, during the past decades o-(1-alkynyl)benzamide derivatives have been widely studied as a basic enyne-amide system for exploring novel and useful cyclization transformations.3 The existing strategies mainly involve the Nnucleophilic or O-nucleophilic attack of the amide group onto the nearby carbon−carbon triple bond, giving rise to the five- or six-membered heterocyclic compounds through 5-exo-dig or 6endo-dig cyclization, respectively.4 For examples, upon treatment with electrophilic oxidants such as I2, ICl, NBS and PhSeCl, o-(1alkynyl)benzamides could be converted into isobenzofuranimine and isochromenimine compounds, with the electrophilic E+ being incorporated into the products (Figure 1, route a).5 Interestingly, in the presence of AgSbF6 or AgOTf as catalyst, the reaction provided isochomenimines with excellent regioselectivity with no formation of the five-membered isobenzofuranimine compounds (route b).4c,d On the other hand, in the presence of a base4a or mediated by AlCl3 and acyl chlorides,4b o-(1alkynyl)benzamides were converted into isoindolinone compounds I, obviously resulting from the nucleophilicity of the amide group instead while going through the similar reactions as in routes a and b (route c). Moreover, by the combining Cs2CO3 and catalytic amount of Cu(OAc)2,4e or InBr34f,g as Lewis acids, o(1-alkynyl)benzamides could be transformed into isoquinolinones II (route d). It was also reported that with ZnCl2 as catalyst and DMF as solvent, and the reaction temperature at 100 °C, both I and II were formed.6 It is worth noting that for o-(1alkynyl)benzamide derivatives bearing certain types of R2 © XXXX American Chemical Society
Figure 1. Existing intramolecular cyclization of o-(1-alkynyl)benzamides.
substituents, cascade heteroannulation could occur leading to the formation of various fused heterocylic compounds such as indole[3, 2-c]isoquinoliones, 7 3,4-dihydro-1H-benzo[c]chromen-6(2H)-imine8 derivatives, and indeno[1,2-c]azepin3(2H)-ones9 (not shown). These reported transformations showed that o-(1-alkynyl)benzamides could be converted into various interesting heterocycles, the particular type of which depended on the reaction conditions and substitution pattern of the starting substrates. In this communication, we report a novel transformation, which yielded products carrying the skeleton of 3-hydroxy-2,3dihydroisoquinoline-1,4-dione, a structure that has never been Received: March 13, 2015
A
DOI: 10.1021/acs.joc.5b00576 J. Org. Chem. XXXX, XXX, XXX−XXX
Note
The Journal of Organic Chemistry reported before to the best of our knowledge, by treating o-(1alkynyl)benzamide derivatives with hypervalent iodine reagent,10 i.e., phenyl iodide bistrifluoroacetate (PIFA) in a mixture of MeCN and H2O as solvent. As part of our ongoing effort in searching for new methods to construct heterocyclic compounds utilizing hypervalent iodine reagents,11 we launched the study of potential cyclization reactions of o-(1-alkynyl)benzamides mediated by suitable hypervalent iodine reagents.12 During those first trials, we used the readily available N-methoxy-2-(phenylethynyl)benzamide 1a (1.0 equiv) as the model substrate, PIFA (1.2 equiv) as the hypervalent iodine reagent, and DCE as the solvent, one of the most frequently chosen solvents for the types of reactions involving hypervalent iodine(III) reagents. However, the reaction provided a complex mixture of products. By switching the solvent to the more polar acetonitrile, the reaction furnished 3-hydroxy-2,3-dihydroisoquinoline-1,4-dione (the structure of which was unambiguously confirmed through X-ray crystallographic analysis) as the major product in 10% yield, with 80% of the starting material recovered. This initial result indicated that the reaction sequence involved not only a cyclization reaction, but also a sequential oxidative hydroxylation reaction. This finding gave rise to the synthesis of a brand new class of heterocyclic compounds, namely, the 3-hydroxy-2,3-dihydroisoquinoline-1,4-dione derivatives. As the yield from the initial reactions were far from satisfactory, we set out the study of reaction conditions in order to maximize the yields. The results are summarized in Table 1. When 2.1
solvent containing a mixture of acetonitrile and water was applied, the reaction yield was greatly improved. A satisfactory 85% yield of the desired product was achieved when the volume ratio of acetonitrile to water was 1:1 (Table 1, entry 7). Further solvents screening showed that the solvent system of 1,4dioxane/water (1:1 v/v) gave only 10% yield of the product and reactions in methanol/water (1:1 v/v) or trifluoroethanol (TFE)/water (1:1 v/v) only provided a complex mixture with no desired product formed. Screens of other hypervalent iodine reagents were also carried out, but results showed that none of the ones tested (PIDA, PhIO and IBX) gave better yield than with PIFA. Under the optimal conditions (Table 1, entry 7), a series of substituted o-(1-alkynyl)benzamides were prepared (see Supporting Information for details) to investigate the scope of this novel method (Table 2). Reaction-yield data show that the Table 2. Synthesis of 3-Hydroxy-2,3-dihydroisoquinoline-1,4dione via PIFA-Mediated Cyclization and Oxidative Hydroxylationa
Table 1. Optimization of the Reaction Conditionsa
entry
oxidant (equiv)
solvent (v/v)
time (h)
yield (%)b
1 2 3 4 5 6 7 8 9 10 11 12 13
PIFA (1.2) PIFA (1.2) PIFA (2.1) PIFA (2.1) PIFA (2.1) PIFA (2.1) PIFA (2.1) PIFA (2.1) PIFA (2.1) PIFA (2.1) PIDA (2.1) PhIO (2.1) IBX (2.1)
DCE CH3CN CH3CN CH3CN (dried) CH3CN/H2O (10:1) CH3CN/H2O (5:1) CH3CN/H2O (1:1) 1,4-dioxane/H2O (1:1) MeOH/H2O (1:1) TFE/H2O (1:1) CH3CN/H2O (1:1) CH3CN/H2O (1:1) CH3CN/H2O (1:1)
1 1.5 1.5 1.5 0.5 0.5 0.5 0.5 0.5 0.5 2 5 0.5
−c 10 42 − 62 78 85 10 − − 68 58
