Copper-Catalyzed Oxidative [4 + 2]-Cyclization Reaction of Glycine

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Copper-Catalyzed Oxidative [4 + 2]-Cyclization Reaction of Glycine Esters with Anthranils: Access to 3,4-Dihydroquinazolines Jie Ren, Chao Pi,* Yangjie Wu, and Xiuling Cui* Department of Chemistry, Henan Key Laboratory of Chemical Biology and Organic Chemistry, Key Laboratory of Applied Chemistry of Henan Universities, Zhengzhou University, Zhengzhou 450052, P. R. China

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S Supporting Information *

ABSTRACT: An efficient and atom-economical approach for the synthesis of 3,4-dihydroquinazolines has been developed via copper-catalyzed oxidative cross-dehydrogenative [4 + 2]-cyclization of glycine derivatives with anthranils. This strategy features high efficiency and wide substrate tolerance under simple reaction conditions. Various 3,4-dihydroquinazoline derivatives could be easily obtained starting from titled products through chemical transformations, which further enhance its synthetic utility in organic synthesis and development of drugs.

imidazoles by employing a visible-light-induced iridiumcatalyzed aerobic oxidation/[3 + 2]-cycloaddition/aromatization cascade reaction of N-arylglycine with isocyanides.8 Since then, various oxidative cross-dehydrogenative [3 + 2]cyclization reactions of glycine derivatives with different substrates, such as 5-alkoxyoxazole,9 aziridine,10 α-angelicalatone,11 ethyl diazoacetate,12 and α-keto ester,13 have been established to access five-membered nitrogen-heterocycles. In these transformations, glycine derivatives were employed as two-atom synthons. On the other hand, anthranil as a new type of bifunctional aminating agent has been used to prepare functional molecules because it could simultaneously deliver a nucleophilic amino group and an electrophilic formyl group, which are normally difficult to introduce.14 We deduced that 3,4-dihydroquinazolines could be synthesized starting from glycine derivatives and anthranils through metal-catalyzed oxidative [4 + 2]-cyclization, in which glycine derivatives and anthranils work as two-atom and four-atom synthons, respectively. With our ongoing efforts to build heterocycles15 and clean C−H bond functionalizations,16 we explore a novel and atom-economical copper-catalyzed [4 + 2]-cyclization of glycine derivatives with anthranils for the synthesis of 3,4dihydroquinazolines under mild and simple reaction conditions. The title products could undergo further chemical

3,4-Dihydroquinazoline is an important fused nitrogen-heterocycle and has drawn considerable attention due to its excellent pharmacological and biological activities,1 and privileged structure in natural alkaloids,2 such as a T-type calcium channel blocking agent, trypanothione reductase (TryR) inhibitor, and antitumor activity. Generally, the traditional synthesis approaches fall into two strategies: (1) intramolecular cyclization of the carbodiimides bearing a Michael acceptor,3 (2) condensation of the 1,3-diamine with various electrophilic reagents.4 Unstable and harmful reagents, such as isocyanate3a,b and azide,4c,d and multiple steps are required. Mancheño recently accessed dihydroquinazoline via the C−N coupling/ cyclization/oxidation tandem reaction of N-substituted ptoluidine, but suffered from low functional-group tolerance.5 Glycine derivatives, as one of the simplest and cheapest nonnatural amino acids, have been used as important building blocks for the synthesis of complex and bioactive molecules. The generation of iminium intermediates from the glycine derivatives through the single electron (SET) oxidation pathway is involved in the cross-dehydrogenative coupling (CDC) reactions. Further transformations of these intermediates resulted in the facile construction and derivation of various nitrogen-containing compounds.6 Inspired by this elegant work, Mancheño and co-workers reported a direct oxidative cross-dehydrogenative [4 + 2] cyclization reaction of Narylglycines and alkenes to form substituted quinolines in 2011.7 N-Arylglycine was employed as a four-atom synthon in this procedure. Then, the Xiao group prepared the substituted © XXXX American Chemical Society

Received: April 10, 2019

A

DOI: 10.1021/acs.orglett.9b01246 Org. Lett. XXXX, XXX, XXX−XXX

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limitaion of glycine ester for the synthesis of 3,4-dihydroquinazoline derivatives (Scheme 1). Satisfyingly, it was observed

transformations for the synthesis of more useful nitrogenheterocycles. Glycine ester (1a) and anthranil (2a) were initially chosen as model substrates to verify this hypothesis. It was a pleasure to find that the corresponding product 3aa could be obtained in 33% yield when CuCl (10 mol %) was used as the catalyst in DCE (dichloroethane) at 80 °C under air for 12 h (Table 1,

Scheme 1. Scope of the Glycine Estersa

Table 1. Optimization of the Reaction Conditionsa

entry

cat. (mol %)

oxidant

solvent

yieldb (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19c

CuCl − CuCl2 Cu(OTf)2 Cu(OAc)2 CuO CuI CuCl2 CuCl2 CuCl2 CuCl2 CuCl2 CuCl2 CuCl2 CuCl2 CuCl2 CuCl2 CuCl2 CuCl2

air air air air air air air air air air air O2 DTBP TBHP m-CPBA oxone BPO DDQ BPO

DCE DCE DCE DCE DCE DCE DCE toluene DMSO CCl4 DCM DCM DCM DCM DCM DCM DCM DCM DCM

33% NR 42% 24% 35% NR Trace Trace Trace 21% 48% 61% 41% 37% 46% 66% 84% 41% 93%

a

Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), CuCl2 (10 mol %), BPO (1 equiv) and DCM (2 mL) at 80 °C for 12 h under air. Isolated yields.

that the desired products (3aa−3ia) were obtained in 66−96% yields with both electron-donating and -withdrawing groups at the para-position of the phenyl ring in substrates 1. Whereas, only a trace amount of the desired product was observed for para-CF3 phenyl glycine ester and 4-cyano substituted phenylglycene ester also failed to give the product, probably due to its strong electron-withdrawing ability (3ja−3ka). The meta- and ortho-substituted (such as, F, Cl, Br, Me, and OMe) phenyl glycine esters were all compatible in this transformation, affording the corresponding products in 58−93% yields (3la− 3qa). Meanwhile, this transformation also displayed an excellent tolerance toward the polysubstituted glycine esters (3ra−3ta). This result indicated that the steric hindrance on the benzene ring had no significant effect on this transformation. Moreover, the substrates with different ester groups were investigated, which proceeded smoothly to afford the desired products in moderate yields (3ua−3wa). The scope of anthranils was also evaluated (Scheme 2). To our delight, various substituents, including electron-withdrawing or electron-donating groups (for example, halides, CF3, Me, and OMe) at the C-4 position of anthranils were well tolerated and gave the desired products in 57−71% yields (3ab−3af). The structure of the compound 3ae was confirmed by the single-crystal X-ray analysis (see the Supporting Information). When halogen (including F, Cl, and Br) and OMe were at the C-5 position of anthranils, this transformation showed satisfactory tolerance in 46−72%% yields (3ag−3j), which provide opportunity for further trans-

a

Reaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), catalyst (10 mol %), oxidant (1 equiv) and solvent (2 mL), 80 °C, 12 h, air. b Isolated yields. NR: no reacrion. c2a (0.2 mmol).

entry 1). Inspired by this positive result, the reaction conditions were optimized using the condensation of glycine ester (1a) and anthranil (2a) as a model reaction (Table 1). The reaction failed to afford 3aa in the absence of a copper salt (entry 2). Then, copper salts were tested next, including CuCl2, Cu(OTf)2, Cu(OAc)2, CuO, and CuI (entries 3−7). CuCl2 gave the highest yield of 42% yield. A series of solvents were screened, and DCM (dichloromethane) proved to be the best choice for the transformation (entries 8−11). To our delight, the yield of the desired product 3aa increased to 61% when O2 was used as the oxidant instead of air (entry 12), indicating that an oxidant was essential for this reaction. Encouraged by this preliminary result, a brief screen of commonly used oxidants showed that benzoyl peroxide (BPO) was the best of choice and gave an 84% yield (entries 13−18). However, other oxidants, such as di-tert-butyl peroxide (DTBP), tert-butyl hydroperoxide (TBHP), 3-chloroperoxybenzoic acid (mCPBA), potassium peroxomonosulfate (oxone), and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) also produced the desired product, but in lower yields. Gratifyingly, when 2a was increased to 2 equiv, the desired product could be provided in 93% yield (entry 19). With the optimized reaction conditions in hand (entry 19, Table 1), we then investigated the substrate scope and B

DOI: 10.1021/acs.orglett.9b01246 Org. Lett. XXXX, XXX, XXX−XXX

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5aa in good yields (Scheme 3b and c). Both large-scale reaction and further transformations confirmed the practicability of this current developed protocol. In order to further probe the reaction mechanism, a series of control experiments were carried out (Scheme 4). When BHT Scheme 4. Control Experiments

a

Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), CuCl2 (10 mol %), BPO (1 equiv) and DCM (2 mL), 80 °C, 12 h, air. Isolated yields.

(3 equiv, BHT = 2,6-di-tert-butyl-4-methylphenol) as a radical trapper was added to the reaction of 1a and 2a, the yield of 3aa dramatically decreased to 17% (Scheme 4a). This result implies that a radical process might be involved in the reaction. In addition, according to the results of this transformation, the glycine imine 4 was predicted as a key intermediate. Therefore, the reaction of anthranil 2a and glycine imine 4 was further investigated. However, under the optimal reaction conditions (condition a), no desired product 3aa was observed, which demonstrates that BPO may inhibit this transformation. When PhCOOH (2 equiv) instead of BPO was added to the reaction system of 4 and 2a, the desired product 3aa was obtained in 66% yield (condition b). We deduced that BPO was converted to PhCOOH, which worked as a proton donor to improve the electrophilicity of the imine intermediate and facilitate the following nucleophilicity procedure between imine and anthranil. When TEMPO (3 equiv, TEMPO = 2,2,6,6tetramethylpiperidinyl) as a radical trapper was added to the reaction system, 3aa was obtained in 52% yield, which demonstrates that the radical process might not involve cleavage of the weak N−O bond of anthranil reagent (condition c). Moreover, no desired product 3aa was observed in the absence of CuCl2 (condition d). This result suggested that copper salt was necessary for the cycloaddition reaction. On the basis of the results of the control experiments and previous reports,9,11,12 a possible reaction mechanism of the [4 + 2] cycloaddition reaction is proposed in Scheme 5. First, the glycine ester 1a was oxidized to generate imine intermediate 4 under the combined effects of the copper salt and BPO. Subsequently, the electron-rich nucleophile of 2a attacked imine 4, which was activated by the copper salt, to afford the intermediate A. Then A underwent intramolecular N−O bond cleavage to deliver a nitrene intermediate B.14b Finally, the reactive intermediate B underwent a second nucleophile addition to form product 3aa.14a,g In summary, we have developed a straightforward and efficient copper-catalyzed oxidative dehydrogenative [4 + 2] cyclization of glycine derivatives with anthranils. Multisubstituted 3,4-dihydroquinazoline derivatives were prepared in an atom-economical manner from easily available starting

formations. Meanwhile, the C-6 position of anthranil also performed well, affording the product in 81% yield (3ak). These results indicated that both the electron density and steric hindrance of anthranils did not dramatically influence this transformation. To demonstrate the application of the method in organic synthesis, 3,4-dihydroquinazoline 3aa was synthesized in gram scale in 74% yield under the standard reaction conditions (Scheme 3a). In addition, a series of chemical transformations Scheme 3. Scale-up Reaction and Chemical Transformations

of 3aa were subjected. Organic compounds containing carbon−nitrogen (C−N) and carbon−phosphorus (C−P) have shown broad practical application in medicinal chemistry and material science, and C4-substituted 3,4-dihydroquinazolines showed different types of biological activities.1c,f,g The direct coupling of C−OH and N−H/P−H bonds via dehydrogenative cross-coupling reaction provided 4aa and C

DOI: 10.1021/acs.orglett.9b01246 Org. Lett. XXXX, XXX, XXX−XXX

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Scheme 5. Proposed Reaction Mechanism

materials under simple reaction conditions using cheap copper salt as a catalyst. Moreover, the products obtained are subjected to various chemical transformations to afford different 3,4-dihydroquinazoline derivatives, demonstrating the synthetic utility of this developed protocol. Further application of the nitrogen heterocyclic frameworks is currently underway.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01246. General information; catalytic procedure; characterization of products (PDF) Accession Codes

CCDC 1898865 (3ae) contains 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 Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Yangjie Wu: 0000-0002-0134-0870 Xiuling Cui: 0000-0001-5759-766X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We greatly acknowledge partial financial support from the Mi ni str y of Sci ence and T echno logy of C hi na (2016YFE0132600).

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REFERENCES

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