Letter Cite This: Org. Lett. XXXX, XXX, XXX-XXX
pubs.acs.org/OrgLett
Iridium-Catalyzed Enantioselective Synthesis of Dihydroimidazoquinazolinones by Elaborate Tuning of Chiral Cyclic Ligands Fei Peng, Hua Tian, Pengxiang Zhang, Can Liu, Xudong Wu, Xi Yuan, Haijun Yang, and Hua Fu* Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, China S Supporting Information *
ABSTRACT: A highly efficient, enantioselective intramolecular allylation of (E)-4-(alkyl(4-oxo-3,4-dihydroquinazolin-2-yl)amino)but-2-en-1-yl methyl carbonates was developed, and the corresponding dihydroimidazoquinazolinones were prepared in high yields and enantiomeric excess. The allylation was performed under catalysis of iridium-chiral cyclic phosphoramidite complexes, in which the reactivity and enantioselectivity of the substrates were elaborately tuned by our developed chiral cyclic phosphoramidite ligands with adjustable sizes of rings.
N
en-1-yl methyl carbonate (1a) leading to 1-benzyl-3-vinyl-2,3dihydroimidazo[2,1-b]quinazolin-5(1H)-one (2a) was used as the model to optimize conditions including ligands, solvents, bases, reaction temperature, and time. As shown in Table 1, a pair of racemates were obtained in 32% yield using [Ir(cod)Cl]2 as the catalysts, DMF as the solvent, and Cs2CO3 as the base under N2 at 50 °C in the absence of ligand (entry 1). Eight ligands were tested (entries 2−9), and our developed three chiral cyclic phosphoramidite ligands, (R)-CYC-8-NOL-PA ((R)-B), (R)-CYC-9NOL-PA ((R)-C), and (R)-CYC-8-NOL-PA ((R)-D), provided higher yields and ee values (entries 3−5). Next, the effect of solvents was investigated in the presence of ligand (R)-C containing a nine-membered ring (compare entries 4 and 10− 13), and the results showed that DMF was a suitable solvent (entry 4). Other bases were attempted (entries 14−19), and they were inferior to Cs2CO3 (compare entries 4 and 14−19). Variation of temperature, including rt, 35 °C, and 70 °C, was performed, and the experiments exhibited that the reaction at 50 °C gave the highest yield and ee value. We surveyed ratios of [Ir(cod)Cl]2 and (R)-C (compare entries 4, 23, and 24), and the results showed that it was suitable to use 2.5 mol % [Ir(cod)Cl]2 as the catalyst and 10 mol % (R)-C as the ligand. It is known that the catalytic reactivity and enantioselectivity are usually substratedependent, and there is no universal ligand in transition-metalcatalyzed asymmetric synthesis because subtle changes in steric, geometric, and/or electronic properties of chiral ligands can cause obvious variations in reactivity and enantioselectivity. Therefore, another two ligands, (R)-B containing an 8-membered ring and (R)-D containing a 10-membered ring, can be effective for other substrates. According to these results, we believe that (R)-B, (R)C, and (R)-D as the ligands, DMF as the solvents, and Cs2CO3 as
itrogen heterocycles are ubiquitous in natural products and biologically active molecules1 and have been assigned as privileged units in drug development,2 so their synthesis is a key goal in organic synthesis. Quinazolinone derivatives exhibit diverse biological properties such as anticancer,3 antimicrobial,4 antifungal,5 antiinflammatory,6 and AMPA receptor antagonist activities.7 In particular, polycyclic compounds with 2-amino-4quinazolinone cores show a wide range of biological functions8 such as antibroncholytic,9 antitumor,10 antihypertensive,11 and immunosuppressive activities. 12 For example, imidazoquinazolinone derivatives are used as antiallergens and antivirals.13 Although a few methods for the synthesis of imidazoquinazolinone derivatives have been reported,13,14 the asymmetric synthesis of dihydroimidazoquinazolinones is still unknown. Recently, Ir-catalyzed enantioselective allylic substitution reactions have attracted much attention, and some valuable achievements have been gained.15−17 The results showed that the reaction enantioselectivity highly depended on the chiral ligands.18 At present, the common ligands for the iridiumcatalyzed enantioselective allylation are chiral phosphoramidites such as the Feringa19/Alexakis20 P,C ligands, Carreira P,olefin ligand,21 and You Me-THQphos ligand22 derived from 1,1′-bi-2naphthol (BINOL). Very recently, a new type of axially chiral cyclo-[1,1′-biphenyl]-2,2′-diol (CYCNOL) ligands with adjustable dihedral angles have been developed in our group,23 and the chiral cyclic phosphoramidite ligands derived from CYCNOL have been successfully used in iridium-catalyzed asymmetric arylation of unactivated racemic secondary allylic alcohols with aniline derivatives.24 Inspired by the excellent results, we herein report an iridium-catalyzed, enantioselective synthesis of dihydroimidazoquinazolinones by elaborate tuning of chiral cyclic phosphoramidite ligands with adjustable sizes of rings. Initially, Ir-catalyzed intramolecular asymmetric allylation of (E)-4-(benzyl(4-oxo-3,4-dihydroquinazolin-2-yl)amino)but-2© XXXX American Chemical Society
Received: October 16, 2017
A
DOI: 10.1021/acs.orglett.7b03230 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
With the optimized conditions determined, the substrate scope for the iridium-catalyzed intramolecular asymmetric allylation was investigated. As shown in Table 2, reactivity and
Table 1. Optimization of Conditions for Iridium-Catalyzed Intramolecular Asymmetric Allylation of (E)-4-(Benzyl(4oxo-3,4-dihydroquinazolin-2-yl)amino)but-2-en-1-yl Methyl Carbonate (1a) Leading to 1-Benzyl-3-vinyl-2,3dihydroimidazo[2,1-b]quinazolin-5(1H)-one (2a)a
entry
ligand
solvent
base
yield of 2a (%)b
ee of 2a (%)c
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20d 21e 22f 23g 24h
− (R)-A (R)-B (R)-C (R)-D (R)-E (R)-F (R)-G (R)-H (R)-C (R)-C (R)-C (R)-C (R)-C (R)-C (R)-C (R)-C (R)-C (R)-C (R)-C (R)-C (R)-C (R)-C (R)-C
DMF DMF DMF DMF DMF DMF DMF DMF DMF DMSO DCE dioxane MeCN DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF
Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 K2CO3 Li2CO3 NaOAc KOBut LiOBut NEt3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3
34 67 78 89 85 33 26 30 31 53 47 38 45 64 72 42 82 63 68 38 61 80 83 87
0 78 87 89 82 43 55 52 50 85 50 64 11 60 44 48 75 47 44 88 89 56 82 89
Table 2. Substrate Scope for the Iridium-Catalyzed Intramolecular Asymmetric Allylation of 1a
a
Reaction conditions: under N2, 1 (0.1 mmol), Cs2CO3 (0.1 mmol, 1.0 equiv), [Ir(cod)Cl]2 (2.5 μmol, 2.5 mol %), ligand (10 μmol, 10 mol %), DMF (2.0 mL), temperature (50 °C), time (3 h) in a sealed Schlenk tube. bIsolated yield. cThe ee values were determined by HPLC analysis. The absolute configurations of the products were determined by comparing structure of (R)-2c (the absolute configuration of (R)-2c was assigned by X-ray diffraction analysis). d Reaction time (3.5 h). eReaction time (4.0 h). fReaction time (15 h).
a
Reaction conditions: under N2, (E)-4-(benzyl(4-oxo-3,4-dihydroquinazolin-2-yl)amino)but-2-en-1-yl methyl carbonate (1a) (0.1 mmol), base (0.1 mmol, 1.0 equiv), [Ir(cod)Cl]2 (2.5 μmol, 2.5 mol %), ligand (10 μmol, 10 mol %), anhydrous solvent (2.0 mL), temperature (50 °C), time (3 h) in a sealed Schlenk tube. bIsolated yield. cThe ee values were determined by HPLC analysis. dAt rt (∼25 °C) for 12 h. eAt 35 °C for 10 h. fAt 70 °C for 2 h. g[Ir(cod)Cl]2 (2.5 μmol, 2.5 mol %), (R)-C (5.0 μmol, 5 mol %). h[Ir(cod)Cl]2 (1.0 μmol, 1.0 mol %), (R)-C (15 μmol, 15 mol %). Absolute configuration was determined by comparing structure of (R)-2c (the absolute configuration of (R)-2c was assigned by X-ray diffraction analysis). Bn = benzyl. DCE = 1,2-dichloroethane.
enantioselectivity of the substrates are closely related to structures of ligands in the presence of catalyst [Ir(cod)Cl]2. Similar to substrate 1a, ligand (R)-C containing a nine-membered ring showed higher reactivity and enantioselectivity than (R)-B containing an eight-membered ring and (R)-D containing a ten-membered ring in synthesis of 2b. In contrast, (R)-B and (R)D provided higher ee values than (R)-C in the synthesis of 2c
the base are feasible in the Ir-catalyzed intramolecular asymmetric allylation. B
DOI: 10.1021/acs.orglett.7b03230 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters containing 8-OMe, and (R)-B was the most suitable ligand, providing 92% ee. For substrates with fluorine at the 6-, 7-, and 8sites, their reactivity was similar to each other, but the enantioselectivity exhibited smaller differences with variation of ligands (2d, 2e, and 2f). The substrates with 6- and 7-F were preferred to (R)-C in enantioselectivity (2d and 2e), and the three ligands, (R)-B, (R)-C, and (R)-D, exhibited a smaller difference for the substrate with 8-F (2f). For the synthesis of 2g with 7-Cl, the three ligands were all effective, and (R)-B and (R)-C seemed to be more suitable ligands in the synthesis of 2h with 8-Cl. For the synthesis of 2i, 2j, and 2l with two substituent groups on the phenyl rings, our developed three cyclic chiral ligands all displayed high reactivity and enantioselectivity, and (R)-B and (R)-C were better. (R)-C was a more effective ligand in enantioselectivity for the synthesis of 2k containing 7-Br. The three ligands were highly efficient in reactivity and enantioselectivity for the synthesis of 2m with 7-I. Three substrates containing electron-withdrawing groups, including trifluoromethyl and nitro groups, were attempted, and their reactivity was high. However, the enantioselectivity showed differences depending on the ligands (2n, 2o, and 2p). When the phenyl ring in 2a was replaced with a naphthyl ring, the enantioselectivity obviously increased (compare 2a and 2q). Introduction of an S-heterocycle did not affect the reactivity and enantioselectivity of the substrate when (R)-B and (R)-C were used as the ligands, respectively (2r). Variation of substituent groups on the N-benzyl was attempted, and no evident changes were observed in enantioselectivity (2s and 2t). When an allyl group replaced the benzyl on the N atom in 1a, ligand (R)-C provided a satisfactory result, but (R)-B and (R)D were not suitable ligands (2u). In general, the enantioselectivity exhibited various differences with variation of ligands for the synthesis of 2r, 2t, and 2u, and the effect of substituent R2 on the nitrogen was also evident in the enantioselectivity. According to these results, our chiral cyclic phosphoramidite ligands with variation of ring sizes are very useful in enantioselectivity for the present iridium-catalyzed intramolecular asymmetric allylation. The reaction showed tolerance of some functional groups, including C−F, C−Cl, C−Br, and C−I bonds, ether, nitro and CF3 groups, and S- and N-heterocycles. To explore the absolute configurations of our newly synthesized dihydroimidazoquinazolinones (2), the single crystal of (R)-2c was prepared in a mixed solvent of hexane and dichloromethane, and its absolute configuration was detected and unambiguously confirmed by X-ray diffraction analysis (Figure 1) (see Supporting Information for details). According to our experiments and the related references,15−17,24,25 a possible mechanism on the iridium-catalyzed intramolecular asymmetric allylation is proposed in Scheme 1 (here, compound 1a was used as the example). First, treatment of
Scheme 1. A Possible Mechanism for the Ir-Catalyzed Intramolecular Asymmetric Allylation
1a with Cs2CO3 provides the corresponding salt I and CsHCO3, coordination of the allyl part in I with in situ formed IrXL* of [Ir(cod)Cl]2 and chiral cyclic phosphoramide ligand (L*) gives complex II,25 and desorption of carbon dioxide (CO2) in II affords an allyl−iridium cation intermediate III and a methoxy anion. Intramolecular cyclization of III in the presence of a methoxy anion donates the target product (2a) and MeOCs, regenerating catalyst complex IrXL*. In addition, the experiments for the gram scale synthesis of (R)1-benzyl-3-vinyl-2,3-dihydroimidazo[2,1-b]quinazolin-5(1H)one (2a) and the reduction of 2b and 2n were effectively performed (see Supporting Information for details). The results showed that the iridium-catalyzed intramolecular asymmetric allylation was an efficient protocol for the construction of chiral Nheterocycles, and the synthesized products (2) could be further modified into diverse N-heterocycles. In summary, we have developed a highly efficient and enantioselective Ir-catalyzed asymmetric synthesis of (R)dihydroimidazoquinazolinones. The Ir-catalyzed intramolecular asymmetric allylation method shows some advantages, including use of the readily available starting materials, synthesis of useful products, an operationally simple protocol, high reactivity and enantioselectivity, and tolerance of some functional groups. Importantly, the reactivity and enantioselectivity of the substrates were elaborately tuned by our developed chiral cyclic phosphoramidite ligands with adjustable ring sizes. We think that the present method will find wide application for asymmetric synthesis of chiral N-heterocycles.
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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.7b03230. Experimental details and NMR data (PDF) Accession Codes
CCDC 1576771 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 data_
[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
Hua Fu: 0000-0001-7250-0053 Notes
The authors declare no competing financial interest.
Figure 1. Crystal structure of (R)-2c. C
DOI: 10.1021/acs.orglett.7b03230 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
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ACKNOWLEDGMENTS The authors would like to thank Dr. Mrs Haifang Li in this department for her great help in high resolution mass spectrometry analysis and the National Natural Science Foundation of China (Grant Nos. 21372139 and 21772108) for financial support.
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