Article Cite This: J. Org. Chem. 2019, 84, 204−215
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Cascade Reaction of Arylboronic Acids and 2′-Cyano-biaryl-2aldehyde N‑Tosylhydrazones: Access to Functionalized 9‑Amino-10arylphenanthrenes Yueqiang Liu, Lingjuan Chen, Zhong Wang, Ping Liu,* Yan Liu,* and Bin Dai
J. Org. Chem. 2019.84:204-215. Downloaded from pubs.acs.org by UNIVERSITE DE SHERBROOKE on 01/11/19. For personal use only.
School of Chemistry and Chemical Engineering, the Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan, Shihezi University, Shihezi City, 832004, China S Supporting Information *
ABSTRACT: An efficient, general, and convenient protocol for the synthesis of functionalized 9-amino-10-arylphenanthrene derivatives using a catalystfree cascade reaction of arylboronic acids and 2′-cyano-biaryl-2-aldehyde Ntosylhydrazones is described. The synthesis was carried out via simple experimental conditions using Na2CO3 in 1,4-dioxane as a solvent. Moreover, the 9-amino-10-arylphenanthrene compounds were also obtained on a gram scale and further derivatized to synthesize the fused phenanthrene derivatives.
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INTRODUCTION 9-Aminophenanthrene proves to be an important structural scaffold frequently found in natural products,1 medicinal chemistry,2 and functional materials.3 Furthermore, 9-aminophenanthrene derivatives represent important synthons widely used in organic reactions due to the presence of easily accessible amino groups and other active sites.4 Classical ways to access 9-aminophenanthrenes include nitro-reduction,5 amide-hydrolysis,6 and intramolecular cyclization.7 More recently, amination reactions of phenanthryl boronic acids or phenanthryl halides have been reported.8 In addition, coupling reactions prove to be effective for the construction of 9aminophenanthrene derivatives.9 Despite significant advances that have been achieved in this field, the methods developed to date often suffer from limitations including poor accessibility of the starting materials, harsh reaction conditions, a narrow substrate scope, and the use of transition metal catalysts and/ or organometallic reagents. Therefore, the development of an efficient, general, and convenient protocol toward the synthesis of functionalized 9-aminophenanthrene derivatives remains a desirable target in synthetic organic chemistry. N-Tosylhydrazones, a class of readily accessible and excellent bench-stable diazo precursors, have been extensively used in organic synthesis.10,11 Since 2012, numerous applications have been reported in the literature describing the use of N-tosylhydrazones as starting materials in crosscoupling, insertion, olefination, alkynylation, and other reaction types.12−14 In particular, reactions generating various structurally important units in a one-pot and cascade manner prove to be critical in this field. Likewise, cyclization reactions using N-tosylhydrazone substrates offer an important method for the construction of phenanthrene ring systems. Wang et al. developed a Cu-catalyzed tandem reaction between Ntosylhydrazones and terminal alkynes to generate substituted phenanthrenes (Scheme 1a and b).15,16 In addition, a metalcatalyzed cyclization of bis(N-tosylhydrazone)s provided © 2018 American Chemical Society
Scheme 1. Synthesis of Phenanthrene Derivatives via Cyclization Reactions Involving N-Tosylhydrazones
various polycyclic aromatic compounds (Scheme 1c).17,18 In 2013, Wang et al. reported a new cyclization process involving a diazo carbon insertion into a keto C−C bond as the key step to afford 9-hydroxy-phenanthrene derivatives (Scheme 1d).19 However, to the best of our knowledge, tandem reactions involving N-tosylhydrazones to construct 9-aminophenanthrene derivatives have never been reported to date. In 2016, Valdés et al. reported the carbocyclization of γ- or δ-cyano-N-tosylhydrazones with alkenylboronic acids to afford a series of cyclic ketone products.20 The mechanism proposed for this cascade reaction involved the addition of boronic acid to the diazo compound, nucleophilic attack of the allylboronic acid II to the cyano group, and hydrolysis of the imine III that provided the final product IV (Scheme 2a). Inspired by this work, we envisioned that the cascade reaction of boronic acid with 2′-cyano-biphenyl-2-aldehyde N-tosylhydrazones could proceed in a similar manner to provide intermediate III′. Instead of the formation of ketone IV′ via hydrolysis (Scheme 2b, route 1), intermediate III′ was hypothesized to form intermediate VI′ via tautomerization due to the stabilization of Received: October 9, 2018 Published: December 11, 2018 204
DOI: 10.1021/acs.joc.8b02605 J. Org. Chem. 2019, 84, 204−215
Article
The Journal of Organic Chemistry
in 1,4-dioxane at 110 °C for 5 h afforded the targeted cyclization product 3a in 56% yield and the coupling byproduct 3a′ in 33% yield (entry 1). In an effort to further improve the yield of intermediate 3a, various bases and solvents were screened. Among the studied bases, Na2CO3 provided the highest yield of compound 3a (76%, entry 9). Other bases, including Cs2CO3, K3PO4, Li2CO3, NaHCO3, CH3COONa, t-BuOK, and organic bases, did not result in a further yield increase (entries 2−8). Moreover, the use of different solvents (entries 10−13) did not lead to a further increase in yield. Further adjustments of the reaction temperature resulted in lower reaction yields (entries 14− 16). 4,4,5,5-Tetramethyl-2-phenyl-1,3,2-dioxaborolane proved to be ineffective for this reaction (entry 17). When N-4methoxybenzenesulfonyl hydrazone derived from 4-methoxybenzenesulfonyl hydrazine with 2′-formyl-4′,5′-dimethoxy[1,1′-biphenyl]-2-carbonitrile was employed instead of Ntosylhydrazone 2a, the yield was not improved (entry 18). The optimal condition was obtained using Na2CO3 as a base and 1,4-dioxane as a solvent at a reaction temperature of 110 °C (entry 9). Scope and Limitations of Substrates. Using optimized reaction conditions, the substrate scope of this reaction was explored via screening of a series of arylboronic acids (Table 2). Different arylboronic acids bearing −Me, −OMe, and −F groups were screened, and the expected tandem reaction with N-tosylhydrazones of 2′-formyl-4′,5′-dimethoxy-[1,1′-biphenyl]-2-carbonitrile proceeded smoothly to provide the corresponding products 3b−d in 51−69% yields. However, the use of thiophen-3-ylboronic acid afforded the corresponding product 3e in lower yield. Fortunately, using naphthalen-2ylboronic acid resulted in a good reactivity and provided the desired product 3f in 74% yield. Next, we investigated the N-tosylhydrazone species 1 bearing one parent aromatic ring (Table 3). The Ntosylhydrazone with 2′-formyl-[1,1′-biphenyl]-2-carbonitrile as a substrate was allowed to react with p-tolylboronic acid to provide the desired product 3g in only 40% yield. In comparison, the reaction was found to be affected by the substituents on the aryl formaldehyde moiety. Both electronwithdrawing and electron-donating groups were determined to be tolerated, providing the corresponding cyclization products 3h−p in 48−65% yields. Moreover, the position of the substituent had no significant effect on the cyclization reactivity of the N-tosylhydrazone 2. To further ascertain the scope of this reaction system, the N-tosylhydrazone series 2 with two different parent aromatic rings was employed as a reactant. In regard to the substituents on the aryl cyanide, the reaction of the substrate with an electron-donating group proved to deliver improved results compared to the substrate bearing an electron-withdrawing group (i.e., compounds 3q, 3u, and 3y). In addition, when an electron-withdrawing group
Scheme 2. Cyclization Reactions of Cyano-Ntosylhydrazones with Boronic Acids
the entire conjugated structure. Subsequent hydrolysis may furnish the 9-aminophenanthrene compound VII′ (Scheme 2b, route 2). Herein, we report the realization of this hypothesis and the corresponding 9-amino-10-arylphenanthrene derivatives were readily synthesized through the catalyst-free tandem reaction of arylboronic acid and 2′-cyano-biaryl-2-aldehyde Ntosylhydrazones.
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RESULTS AND DISCUSSION Optimization of the Reaction Conditions. Various 2′formyl-[1,1′-biaryl]-2-carbonitrile derivatives 1 as starting material could be readily prepared in good yields by Suzuki− Miyaura reaction. The corresponding derivatives could then be transformed to N-tosylhydrazones in almost quantitative yields via reaction with p-toluenesulfonyl hydrazine in methanol. The solvent was then removed by rotary evaporation, and the residual was dried in vacuo to obtain the tosylhydrazone 2. The latter compound was then used in the next step without further purification (Scheme 3). The reaction of N-tosylhydrazone 2a with phenylboronic acid was employed as a model reaction to assess the optimal reaction conditions (Table 1). Using K2CO3 as a base, reaction
Scheme 3. Preparation of 2′-Formyl-[1,1′-biaryl]-2-carbonitrile Derivatives
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DOI: 10.1021/acs.joc.8b02605 J. Org. Chem. 2019, 84, 204−215
Article
The Journal of Organic Chemistry Table 1. Optimization of the Reaction Conditionsa
entry
solvent
base
yield/3aa (%)
yield/3a′ a (%)
1 2 3 4 5 6 7 8b 9 10 11 12c 13 14c 15d 16e 17f 18g
1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane toluene DME THF 1,4-dioxane/H2O (3:1) 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane
K2CO3 Cs2CO3 K3PO4 Li2CO3 NaHCO3 CH3COONa t-BuOK other bases Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3
56 55 26 0
