Base-Mediated [3 + 4]-Cycloaddition of Anthranils with AzaoxyallylCations: A New Approach to Multisubstituted BenzodiazepinesJuan 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 ofMinistry of Education of China, Beijing, China§Beijing Laboratory of Biomedical Materials, Key Laboratory of Biomedical Materials of Natural Macromolecules (Beijing Universityof Chemical Technology), Ministry of Education, Beijing, China

*S Supporting Information

ABSTRACT: A new [3 + 4] cycloaddition of azaoxyallylcations and anthranils has been achieved for rapid access tomultisubstituted benzodiazepine derivatives. A variety ofanthranils and α-halo hydroxamates were both effectivesubstrates with simple operations under transition-metal-freeconditions. The intriguing features of this method include itsmild nature of the reaction conditions, high efficiency, broadsubstrate scope, and wide functional group compatibility.

Nitrogen heterocycles are widespread structural motifs inbioactive natural products, therapeutic agents, agro-

chemicals, and material molecules with significant activities.1

In particular, benzodiazepines, a member of the family ofprivileged scaffold, occupy a significant place in pharmaceuticalingredients.2 As representative examples shown in Figure 1,SB-214857 (lotrafiban), a potent glycoprotein IIb/IIIareceptor antagonist, displays antithrombotic activity.3 Diaze-pam, commercially known as Valium, is used to treat anxiety.2a

Abbemycin, isolated from Streptomyces sp. AB-999F-52, is anantibiotic.4 TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)-resistance could be overcome by use offuligocandin B.5 Circumdatin D and E are two quinazolino-benzodiazepine alkaloids isolated from the fungus Aspergillusochraceus.6 Given the rich biological profiles of the seven-membered nitrogen heterocycles in organic synthesis andmedical chemistry, the development of a novel method to

access benzodiazepine and related scaffolds remains highlydesirable.[3 + 4]-Cycloaddition reaction is an efficient strategy to

assemble seven-membered rings.7 In recent years, azaoxyallyl

Received: June 20, 2019Published: August 1, 2019

Figure 1. Selected biologically active molecules with the benzodia-zepine unit.

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

Letter

pubs.acs.org/OrgLettCite This: Org. Lett. 2019, 21, 6245−6248

© 2019 American Chemical Society 6245 DOI: 10.1021/acs.orglett.9b02118Org. Lett. 2019, 21, 6245−6248

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cations, as 1,3-dipoles, have been widely applied in [3 + 1]-,8

[3 + 2]-,9 and [3 + 3]-10 cycloaddition reactions. Because oftheir high reactivity profile, an azaoxyallyl cationic intermediatehas also recently emerged as a three-atom component in the [3+ 4]-11 cycloaddition reaction for synthesis of seven-memberedN-heterocycles. Jeffrey and co-workers had a continuinginterest in this emerging area of research. In 2011, Jeffreydisclosed the first [3 + 4]-cycloaddition reaction to constructseven-membered azacycles (Scheme 1a).11a Subsequently, anaza-[3 + 4] cycloaddition of diaza-oxyallyl cationic inter-mediates to furnish ureas has been realized by the same group(Scheme 1b).11b Following these successes, Jeffrey’s groupfurther developed the intramolecular [3 + 4] cycloaddition ofaza-oxyallylic cations with furans or N-Boc-pyrroles (Scheme1c).11c However, to the best of our knowledge, cycloadditionof anthranils with aza-oxyallylic cations, especially in the [3 +4]-cycloaddition toward the construction of benzodiazepinederivatives, has not yet been reported.Recently, we have successfully developed a [3 + 2]

cycloaddition reaction of azaoxyallyl cations and 1,2-benzisox-azoles, which enabled the efficient construction of oxazolinesderivatives.9i Inspired by this approach, we observed thatanthranils have been widely used as synthetically importantand useful motifs for the synthesis of pharmaceuticals andfunctional molecules due to their unique electronic proper-ties.12 It was envisioned that anthranils could serve as potentialprecursors for cycloaddition as four-atom components.12a,f,g

We postulated that cycloaddition of aza-oxyallylic cations withanthranils could be employed as a powerful method to prepareseven-membered heterocycles bearing an oxa-bridged ring

under metal-free conditions. Herein, we described our work onthe 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 promotingthis transformation, affording our designed [3 + 4] cycloadductin 35% yield in HFIP (Table 1, entry 1). The structure of 3awas determined by X-ray crystallographic study (CCDC1923224).13 Then, a systematic condition optimization wasperformed. As shown, among the several commonly usedinorganic and organic bases, K2CO3 was proven to be the bestchoice, affording 3a in an excellent yield of 94% (Table 1,entries 2−9). Next, the effect of solvent was examined. Byperforming the reaction under TFE, the yield of 3a sharplydecreased to 41% (Table 1, entry 10). Both i-PrOH andMeOH gave inferior results (Table 1, entries 11−12). Finally,it turned out that the yields failed to be enhanced comparedwith HFIP after evaluating a range of other solvents, includingTHF, dioxane, toluene, CH2Cl2, CH3CN, and DMF (Table 1,entries 13−18).

Table 1. Optimization of Reaction Conditionsa

entry base solvent time (h) yield (%)b

1 Na2CO3 HFIP 1 352 NaOH HFIP 0.5 773 NaHCO3 HFIP 24 trace4 K2CO3 HFIP 0.5 945 Cs2CO3 HFIP 1 746 t-BuOK HFIP 3 377 DBU HFIP 2 528 Et3N HFIP 9 599 DMAP HFIP 1 7710 K2CO3 TFE 0.5 4111 K2CO3 i-PrOH 24 trace12 K2CO3 MeOH 0.5 NR13 K2CO3 THF 24 trace14 K2CO3 dioxane 24 1515 K2CO3 toluene 24 2616 K2CO3 CH2Cl2 24 7017 K2CO3 CH3CN 6 8018 K2CO3 DMF 24 trace

aThe reactions were carried out with 0.2 mmol of 1a and 0.4 mmol of2a in 1.5 mL of solvent with 0.4 mmol of base at room temperature.bIsolated yield. HFIP = 1,1,1,3,3,3-hexafluoroisopropanol, DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene, DMAP = 4-dimethylaminopyridine,TFE = 2,2,2-trifluoroethanol, NR = No Reaction, THF = tetrahydro-furan, DMF = N,N-dimethylformamide.

Scheme 2. Substrate Scope of Anthranilsa,b

aAll reactions were performed with anthranil 1 (1.0 equiv) with α-halo hydroxamate 2a (2.0 equiv) and K2CO3 (2.0 equiv) dissolved inHFIP (7.5 M) at rt for 0.5−1.5h. bIsolated yield.

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Under the optimal conditions, the generality of anthranils 1were examined (Scheme 2). The cycloaddition reactions couldendure anthranils (1b−1c, 1e−1f) bearing various halidesubstituents (5-Cl, 5-Br, 6-Cl, 6-F), affording products in highyields (96−99%). In addition, electron-donating methyl groupsubstituted substrate 1d reacted smoothly to give 3d in 91%yield. Anthranils with an ethyl group (1g and 1h) and abromomethyl group (1i) at the C-3 position afforded [3 + 4]-cycloadducts (3g, 3h and 3i) in excellent yields. Moreover, theR2 substituent could be replaced by various aryl rings. Forsubstrate 3j bearing a phenyl group, the desired product wasobtained in 95% yield. The X-ray diffraction analysis firmly

confirmed the chemical structure of 3j (CCDC 1923225).Some other anthranils possessing trifluoromethyl or cyanidearyl substituents have showed comparable efficiency. We foundthat 3-(naphthalen-2-yl)benzo[c]isoxazole also behaved well,providing benzodiazepine derivative 3m in 60% yield. Whenthe R2-substituent was a pyrimidine group, this reaction alsosmoothly proceeded to provide the desired product with arelatively lower yield. However, when the anthranil bearing a Hatom at the C-3 position was tested, no desired product wasobtained (structures not shown).12a

We then moved toward investigating the reactivity of an α-halo hydroxamates partner. As depicted in Scheme 3,substrates (2b−2e) with variation of protecting groups onthe nitrogen atom tend to provide benzodiazepine derivativesin 85−97% yields (3o−3r). Additionally, cyclohexyl-substi-tuted hydroxamate afforded 3s in 75% yield. When the R3 andR4 groups were different alkyl chains, the N-benzyloxy α-bromoamides 2g yielded product 3t with a diastereomeric ratio(d.r. = 7:1) in 60% combined yield. However, the cyclo-addition reaction did not take place with N-benzyl-2-bromo-2-methylpropanamide as the substrate, which might arise fromthe low stability of the azaoxyallyl cation.10f,11d,13 Moreover,some other combinations of anthranils and α-halohydrox-amates were also compatible, providing functionalizedbenzodiazepine derivatives (3v−3x) in excellent yields.In order to address the viability and potential synthetic

application of this [3 + 4] cycloaddition, gram-scale reactionsand several chemical transformations of product 3a werecarried out. The product was obtained in 94% (1.2 g scale) and90% (5.8 g scale) yields, respectively (Scheme 4A). This resultindicates that there is no loss of efficiency during the scale-upoperation 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/Cin methanol solvent (Scheme 4B). Hydrogenation in ethylacetate could be completed to provide 5 without cleavage ofthe N−O bond. X-ray analysis of product 5 determined itschemical structure (CCDC 1923226). Under more strenuousconditions, when 3a was treated with Mo(CO)6, N-unprotected 6 could be achieved through deprotection of thebenzyl group and cleavage of the N−O bond. In addition, theN−O bond could also be cleaved by zinc under acidicconditions, providing 7 in 71% yield.A plausible mechanism of the above transformation is

proposed in Scheme 5. First, azaoxyallyl cation intermediate Awas formed from α-halohydroxamate 2a in the presence of

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

aAll reactions were performed with anthranil 1 (1.0 equiv) with α-halo hydroxamate 2 (2.0 equiv) and K2CO3 (2.0 equiv) dissolved inHFIP (7.5 M) at rt for 0.5−1.5h. bIsolated yield.

Scheme 4. Synthetic Applications

Scheme 5. Proposed Reaction Mechanism

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K2CO3. Next, anthranil 1a reacted with intermediate Agenerating zwitterionic intermediate B. Finally, the [3 + 4]-cycloadduct 3a was observed through intramolecular nucleo-philic addition of B.In summary, aza-oxyallyl cations generated in situ and

anthranils undergo a [3 + 4] cycloaddition to providesynthetically useful benzodiazepine derivatives in averagegood yields. The new method was both concise and mild,which exhibited good functional group tolerance. Moreimportantly, the process was performed without addition of atransition-metal catalyst, which further rendered the approachattractive and valuable. The application of the cycloadditionreaction in the synthesis of biological benzodiazepinemolecules is ongoing in our laboratory.

■ ASSOCIATED CONTENT*S Supporting Information

The Supporting Information is available free of charge on theACS Publications website at DOI: 10.1021/acs.or-glett.9b02118.

Procedures, NMR spectra, and X-ray crystallographicstructures of 3a, 3j, and 5 (PDF)

Accession Codes

CCDC 1923224−1923226 contain the supplementary crys-tallographic data for this paper. These data can be obtainedfree of charge via www.ccdc.cam.ac.uk/data_request/cif, or byemailing data_request@ccdc.cam.ac.uk, or by contacting TheCambridge Crystallographic Data Centre, 12 Union Road,Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

■ AUTHOR INFORMATIONCorresponding Author

*E-mail: maozhao@126.com.ORCID

Juan Feng: 0000-0002-7224-2696Notes

The authors declare no competing financial interest.

■ ACKNOWLEDGMENTSWe acknowledge the financial support from the Special Projectof China (2018ZX097201003) and the National ScienceFoundation of China (81703332).

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