Multicomponent Coupling Cyclization Access to Cinnolines via in Situ

Letter pubs.acs.org/OrgLett

Multicomponent Coupling Cyclization Access to Cinnolines via in Situ Generated Diazene with Arynes, and α‑Bromo Ketones Wen-Ming Shu, Jun-Rui Ma, Kai-Lu Zheng, and An-Xin Wu* Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Hubei, Wuhan 430079, P. R. China S Supporting Information *

ABSTRACT: A transition-metal-free multicomponent coupling cyclization reaction was explored involving arynes, tosylhydrazine, and α-bromo ketones. The reaction proceeds via a formal [2 + 2 + 2] cycloaddition, giving access to cinnoline derivatives in moderate yields under mild conditions. Three chemical bonds were formedtwo C−N bonds and one C−C bondin a single step.

I

Scheme 1. Strategic Access to Cinnolines

n the past decades, arynes have emerged as powerful synthons widely used in the synthesis of heterocycles and complex natural products.1 This is mainly because of the introduction of 2-(trimethylsilyl)aryl triflates as aryne precursors, which allow arynes to be generated under mild and easily controlled conditions, such as treatment with fluoride.2 Arynes can also proceed to various chemical reactions, including nucleophilic addition,3 cycloaddition,4 annulation,5 coupling,6 insertion,7 and others.8 When transition metals, such as palladium and nickel, were introduced into benzyne chemistry, many unprecedented transformations (such as [2 + 2 + 2] cycloaddition) were quickly developed.9 Cinnoline is an important nitrogen-containing heterocyclic compound, and its derivatives exhibit widespread potent biological and pharmaceutical activities, such as inhibitory activity toward CSF-1R, inhibited ulceration, anti-inflammatory, antitumor, and anticancer activity (Figure 1).10 As cinnoline analogues exhibit superior properties, there are various approaches for the synthesis of cinnolines.11 In recent years, Ge and co-workers reported distinguished work for the synthesis of cinnolines by copper-catalyzed aerobic dehydrogenative cyclization (Scheme 1a).12 In addition, the You group developed a general route to cinnolines through the rhodium-

catalyzed oxidative C−H activation/cyclization reaction (Scheme 1b).13 Furthermore, Willis and co-workers exploited a copper-catalyzed tandem C−N bond formation reaction for the efficient synthesis of functionalized cinnolines (Scheme 1c).14 More recently, Reddy and co-workers developed a directed C−H activation strategy for the synthesis of benzo[c]cinnolines through a sequential C−C and C−N bond formation.15 Herein, a transition-metal-free multicomponent coupling cyclization reaction was developed for direct access to cinnolines (Scheme Received: November 9, 2015

Figure 1. Selected biologically active cinnoline derivatives. © XXXX American Chemical Society

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DOI: 10.1021/acs.orglett.5b03236 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 2. Scope of α-Bromo Ketonesa

1d). Advantages of this method include the use of commercially available starting materials, mild reaction conditions, and the formation of three chemical bonds in a single step. Our initial investigations of this new route to cinnolines focused on the three-component reaction of 2-(trimethylsilyl)phenyl triflate (1a) and tosylhydrazine (2) with α-bromoacetophenone (3a). The desired product, 3-phenylcinnoline (4aa), was furnished with 34% yield when the reaction proceeded in the presence of 3.0 equiv of CsF at 80 °C for 3 h in CH3CN (entry 1). Encouraged by the aforementioned result, other reaction conditions were investigated, and the results are summarized in Table 1. First, the amount of CsF was examined (entries 1−4). Table 1. Optimization of the Reaction Conditionsa

entry

solvent

CsF (equiv)

temp (°C)

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13 14

CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN dioxane THF DCE toluene EtOAc

3 5 6 8 8 8 8 8 8 8 8 8 8 8

80 80 80 80 rt 40 60 70 90 80 70 80 80 80

34 46 57 63 24 46 51 60 69 trace 27 trace 35 14

a Reactions were carried out with 1a (0.5 mmol, 1.0 equiv), 2 (0.75 mmol, 1.5 equiv), 3 (0.5 mmol, 1.0 equiv), and CsF (8.0 equiv) in the CH3CN (4 mL) at 90 °C for 3 h in a sealed tube. Isolated products.

detected. In addition, when the substituents were heterocyclic (2-benzofuryl) and alkyl (methyl) groups, the desired products 4an and 4ao were not afforded. The structure of 4aa was identified by single-crystal X-ray diffraction (see Supporting Information (SI)). Encouraged by the results described above, the scope of 2(trimethylsilyl)aryl triflates (1) was subsequently examined (Scheme 3). First, symmetrically substituted aryne precursor

a

Reaction conditions: 1a (0.1 mmol, 1.0 equiv), 2 (0.15 mmol, 1.5 equiv), 3a (0.1 mmol, 1.0 equiv), CsF (0.8 mmol, 8.0 equiv), and solvent (2 mL) for 3 h in a sealed tube. bIsolated yields.

Scheme 3. Scope of 2-(Trimethylsilyl)aryl Triflatesa

The desired product 4aa was satisfactorily afforded in 63% yield when 8.0 equiv of CsF were used in CH3CN at 80 °C (entry 4). Additionally, lowering the reaction temperature did not increase the yields of 4aa (entries 5−8). However, increasing the temperature to 90 °C resulted in the best yield (entry 9). Subsequently, various solvents were screened, revealing that CH3CN was the best choice for the reaction. A satisfactory yield of the desired product 4aa was not obtained in other solvents (dioxane, THF, DCE, toluene, and EtOAc) (entries 10−14). After optimizing the reaction conditions, we explored the substrate scope of α-bromo ketones (3), as shown in Scheme 2. It is noteworthy that the electronic properties of the substituents on the aromatic ring system were shown to have a significant influence on the efficiency of this transformation. The α-bromo ketones bearing electron-neutral (H), electron-donating (4-Me, 3-OMe, 4-OMe), and halo-substituted (4-F, 3-Cl, 4-Cl, 3,4-2Cl, 4-Br) groups attached to the benzene ring transformed smoothly into corresponding products in moderate to good yields (56%− 70%; 4aa−4ai). Much to our satisfaction, β-naphthyl and biphenyl group substrates were also compatible, giving the expected products 4al and 4am in 69% and 43% yield, respectively. However, the electron-withdrawing groups (4CN, 4-NO2) have a negative effect on this reaction, and the desired product 4aj had a low yield (48%), and 4ak was not

a

Isolated products.

1b was explored, and the corresponding product 4ba was obtained in moderate yield (43%). Moreover, when nonsymmetrical arynes derived from precursors 1d and 1e were used in the annulation, the products 4da/4da′ and 4ea/4ea′ were afforded as a mixture of two isomers in good yields (61% and 66%, respectively). However, the reaction of the 3-methoxy substituted aryne precursor 1c gained the sole regioisomers, and B

DOI: 10.1021/acs.orglett.5b03236 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters the corresponding products 4ca−4cf were obtained in 35%− 57% yields. To gain insight into the reaction process, control experiments were performed (Scheme 4). The reaction of benzyne precursor

Scheme 5. A Possible Mechanism

Scheme 4. Control Experimentsa

a

8 could be reduced by diazene A, transforming into diphenylhydrazine 7.18,21 We further explored the application of cinnolines in organic synthesis as shown in Scheme 6 (4aa as an example). 3-

Isolated products.

1a with tosylhydrazone 516,17 did not afford the target product 4aa under standard conditions. This result identified that compound 5 may not be the intermediate for this reaction (eq 1). Furthermore, the reaction between 1a and 2 proceeded smoothly to give 1-methyl-4-(phenylsulfonyl)benzene 6 in 75% yield together with small amounts of diphenylhydrazine 7 (12%) (eq 2). When 3.0 equiv of 1a and 1.0 equiv of 2 participated in this reaction, the main product was also compound 6 with a trace of 7 and a small quantity of (E)-1,2-diphenyldiazene 8 (7%) (eq 3). Moreover, the compound 8 could be reduced to 7 in 52% yield in the presence of tosylhydrazine 2 (eq 4). It was proven that diazene could be in situ generated in this reaction. In addition, other α-halo ketones have also been checked under standard conditions. The desired product 4aa was not afforded when using α-chloroacetophenone 9 as a substrate (eq 5). However, the product 4aa was obtained in 38% yield in the presence of α-iodoacetophenone 10 (eq 6). On the basis of the above-mentioned experimental results, a possible reaction mechanism for this reaction is proposed as shown in Scheme 5 (using 4aa as an example). Initially, 2(trimethylsilyl)phenyl triflate 1a furnishes the benzyne 1a′ in the presence of CsF. Meanwhile, tosylhydrazine 2 decomposes into the 4-methylbenzenesulfinate anion 11 and intermediate diazene A in the presence of CsF.18 Subsequently, the diazene A reacts with benzyne 1a′ and α-bromoacetophenone 3a through a coupling annulation reaction to afford intermediate B.19 Finally, intermediate B is converted to the desired product 4aa through an aromatization reaction with elimination of H2O. On the other hand, in the absence of 3a, the decomposed 4-methylbenzenesulfinate anion 11 and diazene A could capture benzyne 1a′ to give 1-methyl-4-(phenylsulfonyl)benzene 6, and (E)-1,2diphenyldiazene 8, respectively.20 The (E)-1,2-diphenyldiazene

Scheme 6. Synthetic Application (4aa as an Example)a

a

Isolated products.

Phenylcinnoline 4aa transformed into 3-phenylcinnolin-4-ol 12 in moderate yield (59%) through three-step reactions.10a Certain literature10a,d indicates that the cinnolin-4-ols are also very useful building blocks for the construction of pharmacologically active cinnoline derivatives. In summary, we have developed a novel transition-metal-free multicomponent coupling cyclization reaction for the efficient and convenient synthesis of cinnoline derivatives by simple treatment with CsF in the absence of catalyst. This method allows the formation of new C−C and C−N bonds in a single step. Further studies on this method for the synthesis of other bioactive compounds and applications are in progress in our laboratory.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.5b03236. C

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Organic Letters

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Experimental procedures, product characterizations, crystallographic data, and copies of the 1H and 13C NMR spectra (PDF) X-ray data for 4aa (CIF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the National Natural Science Foundation of China (Grants 21272085, and 21472056) for financial support. REFERENCES

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DOI: 10.1021/acs.orglett.5b03236 Org. Lett. XXXX, XXX, XXX−XXX