Letter Cite This: Org. Lett. 2018, 20, 1216−1219
pubs.acs.org/OrgLett
Construction of Benzene Rings by Copper-Catalyzed Cycloaddition Reactions of Oximes and Maleimides: An Access to Fused Phthalimides Jie Yang, Bo Zhao, Yue Xi, Si Sun, Zhen Yang, Ying Ye, Kun Jiang,* and Ye Wei* College of Pharmacy, Third Military Medical University, Chongqing, 400038, China S Supporting Information *
ABSTRACT: A useful Cu-catalyzed cycloaddition protocol for the construction of benzene rings has been achieved. The reactions, utilizing readily available oximes and maleimides as starting materials, proceed under mild reaction conditions to generate a series of structurally interesting fused-phthalimides that are difficult to be prepared by conventional methods.
T
classic [2 + 2 + 2] cyclotrimerization of alkynes.3 In addition, cycloaddition reactions between alkynes and alkenes,4 between alkynes and ketone or β-keto esters,5 between alkynes and enol ether,6 and between alkenes7 have also been realized based on Pd, Rh, Re, or Mn catalysts. The other synthetic strategy toward the benzene ring formation involves the transitionmetal-catalyzed decarboxylative C−H bond functionalization (Scheme 1b).8 In such a protocol, carboxylic acids reacted with alkynes or alkenes via decarboxylation, C−H bond cleavage, and cyclization steps to produce polycyclic (hetero)aromatic compounds. Despite these great advances, these reactions still suffer from a few problems, including unsatisfactory chemoand/or regioselectivities and limited substrate scope. Therefore, the development of new synthetic protocols to construct structurally interesting and/or novel aromatic rings is greatly appealing. Oximes represent a class of useful synthons that can be readily accessed, and these reagents are generally nontoxic and nonexplosive, stable to air and moisture, easy to store, and simple to handle. Owing to the relatively low energy of the N− O bond,9 the oximes have been applied in various transformations,10 such as a Beckmann rearrangement11 and a Neber rearrangement.12 Note that much recent attention has been paid to the transition-metal-mediated oxime N−O bond transformations, because many transition metals are capable of triggering the oxime N−O bond cleavage to generate iminyl radicals or imino-metal intermediates via oxidative addition or single electron transfer (SET) pathways.13,14 As such, a variety of organic molecules, N-heterocycles in particular, can be produced based on the conversion of the iminyl radicals and imino-metal intermediates. Recently, our group realized an efficient approach to access spiropyrrolines based on a copper catalyst.15 The mechanistic investigation suggests that nucleophilic addition of a carbon radical to an activated alkene is involved in the reaction. Based on this point, we question
he benzene ring system represents a key structural component that occurs ubiquitously in a large majority of industrial chemicals, biologically active molecules, and functional materials.1 Consequently, the development of efficient synthetic methods toward the functionalized benzenes has already attracted a significant amount of attention from the chemistry community. Traditionally, substituted benzenes have been mainly prepared by stepwise introduction of substituents through electrophilic substitution reactions, such as Friedel− Crafts reaction.2 Given the fact that substituents on the benzene rings significantly influence both the reaction orientation and the substrate reactivity toward further substitution, careful choice of the reaction conditions and synthetic route is necessary to achieve high regioselectivity and reaction efficiency. Besides the modification of parent aromatic rings, one attractive approach to the substituted benzenes is transitionmetal-catalyzed cycloaddition reaction (Scheme 1a), such as the Scheme 1. Synthetic Methods for Benzene Ring Construction
Received: January 12, 2018 Published: February 7, 2018 © 2018 American Chemical Society
1216
DOI: 10.1021/acs.orglett.8b00141 Org. Lett. 2018, 20, 1216−1219
Letter
Organic Letters
indicated that O-trimethylacetyl oxime showed the best reactivity (entry 8). The combination of CuI (20 mol %) with Cu(OAc)2 (1 equiv) gave a lower yield (enter 11). By increasing the ratio of 1b to 2a from 1:2 to 1:1, the yield was improved from 26% to 37% (entry 8 vs 12). However, enhancing the ratio of 1b to 2a further showed no improvement. We also studied several additives, such as NaOAc, KOAc, and Na2SO3 (entries 13−15). The results indicated that the use of 1 equiv of NaOAc was beneficial to the reaction, with a 47% yield being obtained (entry 13). Pleasingly, the yield of 3a can be enhanced to 61% in the presence of 1 equiv of NaOAc and 1 equiv of KI (entry 16). More salts containing I− anion were also evaluated; however, the yield can not be increased further. For example, the replacement of KI with NaI or n-Bu4NI significantly suppressed the transformation (entry 17). With the optimized catalytic system in hand, we subsequently evaluated the reactions of a series of oximes with maleimide 2a (Scheme 2). Acetophenone-derived oximes bearing electron-
whether the reaction between oximes and alkenes can be developed to construct the benzene rings through a formal [2 + 2 + 2] cycloaddition process (Scheme 1c). To the best of our knowledge, such a synthetic strategy remains unexplored to date. Herein, we describe a Cu-catalyzed approach for the rapid construction of the benzene rings from readily accessible oximes and maleimides. Such an interesting transformation enables the synthesis of a series of fused-phthalimides that are of great importance in pharmaceutical 16 and material applications.17 Initially, we chose acetophenone O-acetyl oxime (1a) and Nbenzyl maleimide (2a) as model substrates to develop an effective catalytic system capable of the realization of the benzene ring formation (Table 1). Among the Cu(I) salts, CuI Table 1. Reaction Conditions Optimization for CuCatalyzed Benzene Ring Formationa
Scheme 2. Substrate Scope with Respect to Oximesa
additive
yield (%)b
entry
R
[Cu]
solvent
1 2 3 4 5 6 7 8 9 10 11d
Me Me Me Me Me Me Me t-Bu Ph 4-NO2-Ph t-Bu
THF THF THF THF DMSO DMF MeCN THF THF THF THF
none none none none none none none none none none none
trace 13 20 0 16 15 trace 26 19 18 22
12e 13e 14e 15e 16e,f 17e,h
t-Bu t-Bu t-Bu t-Bu t-Bu t-Bu
CuCl CuBr CuI Cu(II) saltc CuI CuI CuI CuI CuI CuI CuI/ Cu(OAc)2 CuI CuI CuI CuI CuI CuI
THF THF THF THF THF THF
none NaOAc KOAc Na2SO3 NaOAc/KI NaOAc/NaI or NaOAc/ n-Bu4NI
37 47 10 23 60(61)g trace
a
Reaction conditions: oxime 1 (0.1 mmol), N-benzyl maleimide 2a (0.2 mmol), copper salt (20 mol %), additive (0 or 1 equiv), solvent (1 mL), 60 °C, 12 h, under Ar. bDetermined by 1H NMR spectroscopy using 1,1,2,2-tetrachloroethane as an internal standard. cCu(OAc)2, CuCl2, CuBr2, and Cu(OTf)2 were used. dCuI (20 mol %) and Cu(OAc)2 (1 equiv) were used. e1b (0.2 mmol), 2a (0.2 mmol). f NaOAc (1 equiv)/KI (1 equiv) were used. gIsolated yield. hNaOAc (1 equiv)/NaI (1 equiv) or NaOAc (1 equiv)/n-Bu4NI (1 equiv) were used. a
Reaction conditions: oxime 1 (0.2 mmol), 2a (0.2 mmol), CuI (20 mol %), NaOAc (1 equiv), KI (1 equiv), THF (1 mL), 60 °C, 12 h, under Ar.
showed the best catalytic reactivity, giving rise to 3a in 20% yield (entry 3), while CuCl and CuBr displayed lower reactivity (entries 1 and 2). In addition, commonly used Cu(II) salts, including Cu(OAc)2, CuCl2, CuBr2, and Cu(OTf)2, were totally unreactive (entry 4). The reaction between 1a and 2a took place with DMSO or DMF as the solvent (entries 5 and 6), while it hardly proceeded in MeCN (entry 7). Considering the influence of the oxime group on the transformation, several O-subsituted oximes were screened (entries 8−10). The results
neutral, -donating, or -withdrawing substituents (e.g., Me, OMe, Cl, Br, I, and CF3) on the aryl ring gave rise to the corresponding fused-phthalimides in moderate yields (3b−3k). In the case of a 4-bromo substituted substrate, the structure of the desired product (3g) was unambiguously confirmed by single-crystal X-ray diffraction (CCDC 1811211). The 1217
DOI: 10.1021/acs.orglett.8b00141 Org. Lett. 2018, 20, 1216−1219
Letter
Organic Letters
generated in 46% yield (3y). Not only N-benzyl maleimides but also N-methyl maleimide can participate in this transformation to furnish the target product in 47% yield (3ab). Unfortunately, N-phenyl maleimide reacted with oxime sluggishly, with
