Base-Mediated [3 + 4]-Cycloaddition of Anthranils with Azaoxyallyl

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Base-Mediated [3 + 4]-Cycloaddition of Anthranils with Azaoxyallyl Cations: A New Approach to Multisubstituted Benzodiazepines Juan Feng,†,‡,§ Meng Zhou,† Xuanzi Lin,† An Lu,† Xiaoyi Zhang,†,‡,§ and Ming Zhao*,†,‡,§ †

School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing, China § Beijing Laboratory of Biomedical Materials, Key Laboratory of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology), Ministry of Education, Beijing, China Downloaded via UNIV AUTONOMA DE COAHUILA on August 1, 2019 at 14:54:22 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

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ABSTRACT: A new [3 + 4] cycloaddition of azaoxyallyl cations and anthranils has been achieved for rapid access to multisubstituted benzodiazepine derivatives. A variety of anthranils and α-halo hydroxamates were both effective substrates with simple operations under transition-metal-free conditions. The intriguing features of this method include its mild nature of the reaction conditions, high efficiency, broad substrate scope, and wide functional group compatibility.

N

Scheme 1. Base Mediated [3 + 4] Cycloadditions with Azaoxyallyl Cations

itrogen heterocycles are widespread structural motifs in bioactive natural products, therapeutic agents, agrochemicals, and material molecules with significant activities.1 In particular, benzodiazepines, a member of the family of privileged scaffold, occupy a significant place in pharmaceutical ingredients.2 As representative examples shown in Figure 1, SB-214857 (lotrafiban), a potent glycoprotein IIb/IIIa receptor antagonist, displays antithrombotic activity.3 Diazepam, commercially known as Valium, is used to treat anxiety.2a Abbemycin, isolated from Streptomyces sp. AB-999F-52, is an antibiotic.4 TRAIL (tumor necrosis factor-related apoptosisinducing ligand)-resistance could be overcome by use of fuligocandin B.5 Circumdatin D and E are two quinazolinobenzodiazepine alkaloids isolated from the fungus Aspergillus ochraceus.6 Given the rich biological profiles of the sevenmembered nitrogen heterocycles in organic synthesis and medical chemistry, the development of a novel method to

access benzodiazepine and related scaffolds remains highly desirable. [3 + 4]-Cycloaddition reaction is an efficient strategy to assemble seven-membered rings.7 In recent years, azaoxyallyl Figure 1. Selected biologically active molecules with the benzodiazepine unit. © XXXX American Chemical Society

Received: June 20, 2019

A

DOI: 10.1021/acs.orglett.9b02118 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 1. Optimization of Reaction Conditionsa

Scheme 2. Substrate Scope of Anthranilsa,b

entry

base

solvent

time (h)

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Na2CO3 NaOH NaHCO3 K2CO3 Cs2CO3 t-BuOK DBU Et3N DMAP K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3

HFIP HFIP HFIP HFIP HFIP HFIP HFIP HFIP HFIP TFE i-PrOH MeOH THF dioxane toluene CH2Cl2 CH3CN DMF

1 0.5 24 0.5 1 3 2 9 1 0.5 24 0.5 24 24 24 24 6 24

35 77 trace 94 74 37 52 59 77 41 trace NR trace 15 26 70 80 trace

a

The reactions were carried out with 0.2 mmol of 1a and 0.4 mmol of 2a in 1.5 mL of solvent with 0.4 mmol of base at room temperature. b Isolated yield. HFIP = 1,1,1,3,3,3-hexafluoroisopropanol, DBU = 1,8diazabicyclo[5.4.0]undec-7-ene, DMAP = 4-dimethylaminopyridine, TFE = 2,2,2-trifluoroethanol, NR = No Reaction, THF = tetrahydrofuran, DMF = N,N-dimethylformamide.

cations, as 1,3-dipoles, have been widely applied in [3 + 1]-,8 [3 + 2]-,9 and [3 + 3]-10 cycloaddition reactions. Because of their high reactivity profile, an azaoxyallyl cationic intermediate has also recently emerged as a three-atom component in the [3 + 4]-11 cycloaddition reaction for synthesis of seven-membered N-heterocycles. Jeffrey and co-workers had a continuing interest in this emerging area of research. In 2011, Jeffrey disclosed the first [3 + 4]-cycloaddition reaction to construct seven-membered azacycles (Scheme 1a).11a Subsequently, an aza-[3 + 4] cycloaddition of diaza-oxyallyl cationic intermediates to furnish ureas has been realized by the same group (Scheme 1b).11b Following these successes, Jeffrey’s group further developed the intramolecular [3 + 4] cycloaddition of aza-oxyallylic cations with furans or N-Boc-pyrroles (Scheme 1c).11c However, to the best of our knowledge, cycloaddition of anthranils with aza-oxyallylic cations, especially in the [3 + 4]-cycloaddition toward the construction of benzodiazepine derivatives, has not yet been reported. Recently, we have successfully developed a [3 + 2] cycloaddition reaction of azaoxyallyl cations and 1,2-benzisoxazoles, which enabled the efficient construction of oxazolines derivatives.9i Inspired by this approach, we observed that anthranils have been widely used as synthetically important and useful motifs for the synthesis of pharmaceuticals and functional molecules due to their unique electronic properties.12 It was envisioned that anthranils could serve as potential precursors for cycloaddition as four-atom components.12a,f,g We postulated that cycloaddition of aza-oxyallylic cations with anthranils could be employed as a powerful method to prepare seven-membered heterocycles bearing an oxa-bridged ring

All reactions were performed with anthranil 1 (1.0 equiv) with αhalo hydroxamate 2a (2.0 equiv) and K2CO3 (2.0 equiv) dissolved in HFIP (7.5 M) at rt for 0.5−1.5h. bIsolated yield. a

under metal-free conditions. Herein, we described our work on the aforementioned reaction. We commenced our investigations by using anthranil (1a) and α-halo hydroxamate (2a) as standard substrates (Table 1). Initially, it was found that Na2CO3 was effective in promoting this transformation, affording our designed [3 + 4] cycloadduct in 35% yield in HFIP (Table 1, entry 1). The structure of 3a was determined by X-ray crystallographic study (CCDC 1923224).13 Then, a systematic condition optimization was performed. As shown, among the several commonly used inorganic and organic bases, K2CO3 was proven to be the best choice, affording 3a in an excellent yield of 94% (Table 1, entries 2−9). Next, the effect of solvent was examined. By performing the reaction under TFE, the yield of 3a sharply decreased to 41% (Table 1, entry 10). Both i-PrOH and MeOH gave inferior results (Table 1, entries 11−12). Finally, it turned out that the yields failed to be enhanced compared with HFIP after evaluating a range of other solvents, including THF, dioxane, toluene, CH2Cl2, CH3CN, and DMF (Table 1, entries 13−18). B

DOI: 10.1021/acs.orglett.9b02118 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 3. Substrate Scope of α-Halo Hydroxamatesa,b

Scheme 5. Proposed Reaction Mechanism

confirmed the chemical structure of 3j (CCDC 1923225). Some other anthranils possessing trifluoromethyl or cyanide aryl substituents have showed comparable efficiency. We found that 3-(naphthalen-2-yl)benzo[c]isoxazole also behaved well, providing benzodiazepine derivative 3m in 60% yield. When the R2-substituent was a pyrimidine group, this reaction also smoothly proceeded to provide the desired product with a relatively lower yield. However, when the anthranil bearing a H atom at the C-3 position was tested, no desired product was obtained (structures not shown).12a We then moved toward investigating the reactivity of an αhalo hydroxamates partner. As depicted in Scheme 3, substrates (2b−2e) with variation of protecting groups on the nitrogen atom tend to provide benzodiazepine derivatives in 85−97% yields (3o−3r). Additionally, cyclohexyl-substituted hydroxamate afforded 3s in 75% yield. When the R3 and R4 groups were different alkyl chains, the N-benzyloxy αbromoamides 2g yielded product 3t with a diastereomeric ratio (d.r. = 7:1) in 60% combined yield. However, the cycloaddition reaction did not take place with N-benzyl-2-bromo-2methylpropanamide as the substrate, which might arise from the low stability of the azaoxyallyl cation.10f,11d,13 Moreover, some other combinations of anthranils and α-halohydroxamates were also compatible, providing functionalized benzodiazepine derivatives (3v−3x) in excellent yields. In order to address the viability and potential synthetic application of this [3 + 4] cycloaddition, gram-scale reactions and several chemical transformations of product 3a were carried out. The product was obtained in 94% (1.2 g scale) and 90% (5.8 g scale) yields, respectively (Scheme 4A). This result indicates that there is no loss of efficiency during the scale-up operation of the present methodology. We found that both the N−O bond and the benzyl group of 3a were readily transformed through hydrogenation with Pd/C in methanol solvent (Scheme 4B). Hydrogenation in ethyl acetate could be completed to provide 5 without cleavage of the N−O bond. X-ray analysis of product 5 determined its chemical structure (CCDC 1923226). Under more strenuous conditions, when 3a was treated with Mo(CO)6, Nunprotected 6 could be achieved through deprotection of the benzyl group and cleavage of the N−O bond. In addition, the N−O bond could also be cleaved by zinc under acidic conditions, providing 7 in 71% yield. A plausible mechanism of the above transformation is proposed in Scheme 5. First, azaoxyallyl cation intermediate A was formed from α-halohydroxamate 2a in the presence of

a All reactions were performed with anthranil 1 (1.0 equiv) with αhalo hydroxamate 2 (2.0 equiv) and K2CO3 (2.0 equiv) dissolved in HFIP (7.5 M) at rt for 0.5−1.5h. bIsolated yield.

Scheme 4. Synthetic Applications

Under the optimal conditions, the generality of anthranils 1 were examined (Scheme 2). The cycloaddition reactions could endure anthranils (1b−1c, 1e−1f) bearing various halide substituents (5-Cl, 5-Br, 6-Cl, 6-F), affording products in high yields (96−99%). In addition, electron-donating methyl group substituted substrate 1d reacted smoothly to give 3d in 91% yield. Anthranils with an ethyl group (1g and 1h) and a bromomethyl group (1i) at the C-3 position afforded [3 + 4]cycloadducts (3g, 3h and 3i) in excellent yields. Moreover, the R2 substituent could be replaced by various aryl rings. For substrate 3j bearing a phenyl group, the desired product was obtained in 95% yield. The X-ray diffraction analysis firmly C

DOI: 10.1021/acs.orglett.9b02118 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

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K2CO3. Next, anthranil 1a reacted with intermediate A generating zwitterionic intermediate B. Finally, the [3 + 4]cycloadduct 3a was observed through intramolecular nucleophilic addition of B. In summary, aza-oxyallyl cations generated in situ and anthranils undergo a [3 + 4] cycloaddition to provide synthetically useful benzodiazepine derivatives in average good yields. The new method was both concise and mild, which exhibited good functional group tolerance. More importantly, the process was performed without addition of a transition-metal catalyst, which further rendered the approach attractive and valuable. The application of the cycloaddition reaction in the synthesis of biological benzodiazepine molecules is ongoing 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.9b02118. Procedures, NMR spectra, and X-ray crystallographic structures of 3a, 3j, and 5 (PDF) Accession Codes

CCDC 1923224−1923226 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Juan Feng: 0000-0002-7224-2696 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge the financial support from the Special Project of China (2018ZX097201003) and the National Science Foundation of China (81703332).

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REFERENCES

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DOI: 10.1021/acs.orglett.9b02118 Org. Lett. XXXX, XXX, XXX−XXX