Iron-Catalyzed Synthesis of 2H-Imidazoles from Oxime Acetates and

Letter pubs.acs.org/OrgLett

Iron-Catalyzed Synthesis of 2H‑Imidazoles from Oxime Acetates and Vinyl Azides under Redox-Neutral Conditions Zhongzhi Zhu, Xiaodong Tang, Jianxiao Li, Xianwei Li, Wanqing Wu, Guohua Deng,* and Huanfeng Jiang* Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, P. R. China S Supporting Information *

ABSTRACT: A novel and versatile method for the synthesis of 2H-imidazoles via iron-catalyzed [3 + 2] annulation from readily available oxime acetates with vinyl azides has been developed. This denitrogenative process involved N−O/N−N bond cleavages and two C−N bond formations to furnish 2,4-substituted 2Himidazoles. This protocol was performed under mild reaction conditions and needed no additives or ligands. Furthermore, this is a green reaction involving oxime acetate as internal oxidant, acetic acid, and nitrogen as byproducts.

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Scheme 1. Synthesis of Substituted 2H-Imidazoles

n the past decades, transition-metal-catalyzed oxidative coupling has attracted much attention and provided an ideal synthetic mode for the formation of C−C and C−X bonds.1 Among the numerous catalysts explored in this field, noble metal catalysts including Pd, Rh, Ir, and Ru are often employed. However, due to the cost, toxicity, and sustainability, the first-row transition metals, especially abundant metals such as copper2 and iron,3 have increasingly attracted the attention of chemists. In this regard, iron, which is one of the most abundant, inexpensive, and environmentally friendly metals on the earth, has shown high reactivity and great potential in replacing precious metal catalysts for organic synthesis. 2H-Imidazoles are important motifs found in a broad spectrum of biologically active natural products4 as well as in organic synthesis.5 They could be used as chiral auxiliaries for organic synthesis reactions6a,b and for detection of a diradical intermediate.6c Despite their good synthetic utility, the synthesis of functionalized 2H-imidazoles is rarely reported. Classical methods for their synthesis involve Weiss’ protocols in which a series of 4,5-diphenyl-2H-imidazoles were structured from benzil, ketone, and ammonium acetate (Scheme 1, Figure 1a).7a The certain issues of this system are limited substrate scope and the use of large amounts of acid. After that, only two examples for the synthesis of 2H-imidazoles were reported. Chiba et al. employed KI as catalyst to synthesize this skeleton by electrolytic oxidation of ketones in ammoniacal methanol (Figure 1b).7b Thereafter, Auricchio’s group reported an alternative approach to nitrogen heterocycles by the cleavage of the azirine ring with poor selectivity and low yield (Figure 1c).7c However, the preparation of some practical and sensitive 2H-imidazoles is one of the continuing challenges among general preparative methods. Thus, the development of efficient transformations that exhibited mild conditions and good functional group tolerance for the synthesis of 2H-imidazoles is highly desirable. © XXXX American Chemical Society

In addition, considering the requirement of green and sustainable chemistry, using green oxidants such as O28 or internal oxidant9 will increase the value of the transformation very well. Oximes and their derivatives are a kind of internal oxidant that can be easily prepared by the reaction of ketone, hydroxylamine hydrochloride, and acetic anhydride. Originating from our continuous studies on oximes and oxime acetates as substrate and oxidant,10 herein we present an iron-catalyzed synthesis of polysubstituted 2H-imidazoles from oxime acetates and vinyl azides (Scheme 1d). At the outset, we used acetophenone oxime acetate (1a) and (1-azidovinyl)benzene (2a) as model substrates to screen iron salts and solvents under air atmosphere (Table 1). The desired product could be obtained in 72% GC yield when we used Fe(OAc)2 (5 mol %) as catalyst in CH3CN at 80 °C under air (entry 1). Various iron catalysts were examined, but they did not show apparent positive effects to this transformation Received: January 25, 2017

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DOI: 10.1021/acs.orglett.7b00203 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 1. Optimization of Reaction Conditionsa

Scheme 2. Substrate Scope of Oxime Acetatesa

entry

cat.

solvent

temp (°C)

yieldb (%)

1 2 3 4 5 6 7 8 9 10 11 12 13d 14 15e 16e 17e

Fe(OAc)2 FeSO4 FeF3 FeCl3 FeBr3 FeBr2 Fe(OAc)2 Fe(OAc)2 Fe(OAc)2 Fe(OAc)2 Fe(OAc)2 Fe(OAc)2 Fe(OAc)2

CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN toluene DMSO DCE DCE DCE DCE DCE DCE DCE DCE DCE

80 80 80 80 80 80 80 80 80 70 90 100 90 90 90 90 90

72 46 24 25 trace 24 21 11 81 62 94 (90)c 68 91 0 0 0 0

Zn(OTf)2 AgOAc Pd(OAc)2

a

Reaction conditions: unless otherwise noted, all reactions were performed with 1a (0.3 mmol), 2a (0.36 mmol), and catalyst (5 mol %) in solvent (2.0 mL) for 6 h. bYields and conversions analyzed by GC/MS and dodecane as internal standard are based on 1a. cIsolated yields. dUnder N2 atmosphere. eLewis acids (5 mol %).

a

Reactions were performed with 1 (0.3 mmol), 2a (0.36 mmol), and Fe(OAc)2 (5 mol %) in DCE (2 mL) at 90 °C for 6 h. Isolated yields.

Scheme 3. Substrate Scope of Vinyl Azidesa

(entries 2−6). Next, different solvents such as toluene, DMSO, and DCE were investigated, and DCE was found to be the optimal solvent (entries 7−9). Further examination of the temperature showed that 90 °C proved to be the best, affording 3aa in 94% GC yield and 90% isolated yield (entries 10−12). Moreover, we found that N2 atmosphere had no significant effect on the reaction (entry 13), and no reaction occurred in the absence of Fe(OAc)2 catalyst (entry 14). In addition, Lewis acids such as Zn(OTf)2, AgOAc, and Pd(OAc)2 could not catalyze this transformation (entries 15−17). Based on the optimization study, the substrate scope of oxime acetates was investigated (Scheme 2). Generally, this reaction proceeded smoothly and gave the desired products 3 in moderate to good yields (56−90%, Scheme 2). The acetophenone oxime acetates with group 4-NO2 and 4-CF3 were compatible with this conversion and the desired products were isolated in a slightly low yield (3aj, 3ak). Notably, the steric hindrance had little effect on the reaction (3ah and 3am, 3aa and 3an, 3ag, 3al, and 3ao). Moreover, oxime acetates derived from other aromatic ketones such as propiophenone, benzophenone, 3,4-dihydronaphthalen-1(2H)-one and 6,7,8,9tetrahydro-5H-benzo[7]annulen-5-one could be accessed through this route to generate the annulation products 3aq− at in good yields. In addition, the heteroarene oxime acetates were compatible with this transformation (3au−aw). When 1acetylnaphthalene oxime acetate was used as the substrate, 3ax could be isolated in 61% yield. Furthermore, the aliphatic oxime acetate also could be transformed into the desired product in moderate yields (3ay−bc). Next, we sought to investigate the scope of the vinyl azides (Scheme 3). In general, the azidovinylbenzenes with various functional groups, including methyl, tert-butyl, chloro, bromo, ester groups, were reacted under the optimal reaction conditions, and moderate to excellent yields of the desired

a

Reactions were performed with 1 (0.3 mmol), 2a (0.36 mmol), and Fe(OAc)2 (5 mol %) in DCE (2 mL) at 90 °C for 6 h. Isolated yields.

products were obtained (3bc−bh). Satisfactorily, with strong electron-withdrawing substituents (−NO2, −CF3) on the aromatic ring, the transformation proceeded smoothly to afford the desired products (3bi,bj). We also found that substitution at the ortho-, meta-, or para-position of the aromatic ring had a B

DOI: 10.1021/acs.orglett.7b00203 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

radical scavenger TEMPO, BHT, and 1,1-diphenylethylene to our standard reaction. We found that this conversion was not inhibited completely, but the yield of product 3aa was reduced significantly (eq 3). On the basis of previous reports and our preliminary results, a tentative mechanism for the iron-catalyzed [3 + 2] annulation of oxime acetates with vinyl azides is proposed in Scheme 7.

slight impact (3bk−bn). Moreover, naphthalene vinyl azide was also compatible in this reaction, affording the desired product 3bo in 65% yield. In addition, the aliphatic vinyl azide was also compatible in this transformation and afforded the desired product (3bp) in 68% yield. A gram-scale reaction of 1ab was carried out on a 10 mmol scale under the standard reaction conditions, providing 1.82 g of the desired product 3ab in 78% isolated yield (Scheme 4). Similar results were obtained when oxime acetate 1as was used under the standard conditions, and the desired 3as was achieved in 73% yield.

Scheme 7. Proposed Mechanism

Scheme 4. Large-Scale Synthesis of 3

To demonstrate the practical utility of this novel method, further transformations of 3 are illustrated in Scheme 5. Scheme 5. Further Transformations of 3 First, imine anion intermediate A was produced via reduction of 1a by an Fe(II) species with a two-step, single electron-transfer process.12f,k Next, a nucleophilic attack may occur between anion intermediate A and 2H-azirine 4a12b,g−j or Michael addition−elimination of the A to the vinyl azides2a,12d,e to form the intermediate B. Then, intermediate C was formed via intramolecular cyclization of intermediate B.12a Finally, oxidative dehydrogenation of C by Fe(III) species gave the product 3 (path a). There was an alternative approach that intermediate B was first oxidized by Fe(III) to form the imine radical intermediate D, which cyclized to intermediate E. Finally, the product 3 was obtained via sequential oxidation/ deprotonation process (path b). In summary, an efficient and external-oxidant-free ironcatalyzed [3 + 2] annulation of oxime acetates with vinyl azides has been developed, providing rapid access to a series of functionalized 2H-imidazoles. The reaction involves N−O/N− N bond cleavages and two new C−N bond formations. The advantages of this protocol include low-cost catalyst, facile conditions, easy handling, and high atom economy. Various 2,2,5-trisubstituted 2H-imidazoles were formed in good yields. Further studies to explore asymmetric synthesis and new transformations of oxime acetates are in progress in our laboratory.

Compound 3 could be effectively oxidized to 6a and 6b with acetic acid peroxide.11 In addition, compound 3 also could be restored to 7 with lithium aluminum hydride smoothly in good yields (7a−d). To gain more insight into the reaction mechanism, several experiments were performed in Scheme 6. First, the aryl-2HScheme 6. Control Experiments

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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.7b00203. Experimental procedures, condition screening table, characterization data, and copies of NMR spectra for all products (PDF)

azirine 4a, which was considered to be a possible intermediate generated from aryl vinyl azides, was reacted with 1 under the optimal conditions, 3aa and 3ah could be obtained in high yields, and we also detected trace amount of 3ab, which came from the self-coupling of 4a (eq 1). Moreover, treatment of 2a with isolable imines 5 under the standard conditions in the absence of 1ar afforded 3ar in 84% yield. This result indicated that the generation of imine or imine intermediates was involved in this transformation. Thereafter, we added 5 equiv of

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. C

DOI: 10.1021/acs.orglett.7b00203 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters *E-mail: [email protected].

F. V.; Slivo, C.; Swahn, B.-M.; Olsson, L.-L.; Johansson, P.; Eketjäll, S.; Fälting, J. J. Med. Chem. 2012, 55, 9297. (12) (a) Shen, M.; Driver, T. G. Org. Lett. 2008, 10, 3367. (b) Chiba, S.; Wang, Y.-F.; Lapointe, G.; Narasaka, K. Org. Lett. 2008, 10, 313. (c) Tang, W.; Capacci, A.; Sarvestani, M.; Wei, X.; Yee; Senanayake, N. K. J. Org. Chem. 2009, 74, 9528. (d) Wang, Y.-H.; Chiba, S. J. Am. Chem. Soc. 2009, 131, 12570. (e) Chen, W.; Hu, M.; Wu, W.; Zou, H.; Yu, Y. Org. Lett. 2010, 12, 3863. (f) Guan, Z.-H.; Zhang, Z.-Y.; Ren, Z.H.; Wang, Y.-Y.; Zhang, X. J. Org. Chem. 2011, 76, 339. (g) Chen, F.; Shen, T.; Cui, Y.; Jiao, N. Org. Lett. 2012, 14, 4926. (h) Deb, I.; Yoshikai, N. Org. Lett. 2013, 15, 4254. (i) Donthiri, R. R.; Pappula, V.; Reddy, N. N. K.; Bairagi, D.; Adimurthy, S. J. Org. Chem. 2014, 79, 11277. (j) Xiang, L.; Niu, Y.; Pang, X.; Yang, X.; Yan, R. Chem. Commun. 2015, 51, 6598. (k) Zhao, M. N.; Ren, Z.-H.; Yu, L.; Wang, Y.-Y.; Guan, Z.-H. Org. Lett. 2016, 18, 1194.

ORCID

Huanfeng Jiang: 0000-0002-4355-0294 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Key Research and Development Program of China (2016YFA0602900), the National Natural Science Foundation of China (21420102003), and the Fundamental Research Funds for the Central Universities (2015ZY001) for financial support.

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DOI: 10.1021/acs.orglett.7b00203 Org. Lett. XXXX, XXX, XXX−XXX