The PIFA-initiated oxidative cyclization of 2-(3-butenyl)quinazolin-4(3H)-ones – an efficient approach to 1-(hydroxymethyl)-2,3-dihydropyrrolo[1,2-a]quinazolin-5(1H)-ones

A regioselective method for the synthesis of 1-(hydroxymethyl)-2,3-dihydropyrrolo[1,2-a]quinazolin-5(1H)-ones – close structural analogs of naturally occurring vasicinone alkaloids – is described. The procedure is based on PIFA-initiated oxidative 5-exo-trig cyclization of 2-(3-butenyl)quinazolin-4(3Н)-ones, in turn prepared by thermal cyclocondensation of the corresponding 2-(pent-4-enamido)benzamides. The products obtained have a good natural product likeness (NPL) score and therefore can be useful for the design of natural product-like compound libraries.

A promising approach to the synthesis of 2,3-dihydropyrrolo[1,2-a]quinazolin-5(1H)-one derivatives substituted at the pyrrolidine ring (especially with functional groups) is annulation of the latter moiety to the quinazoline ring. Thus, a series of 1,5-disubstituted pyrroloquinazolines 3 were obtained by a three-component Sonogashira-type coupling of 2-chloro-4substituted quinazolines 4, propargylic alcohol, and secondary amines (see Scheme 1C) [10]. Appropriately 2-functionalized quinazolinones of type 5 might be good starting materials for the intramolecular cyclization providing the target compounds (see Scheme 1D); however, this approach was rarely used [33][34][35][36], possibly due to low regioselectivity of the ring formation at the two competing nucleophilic centers.
Our study commenced with the synthesis of key intermediates 7 bearing a homoallyl substituent at the C-2 position. Most of the methods for the preparation of 2-akyl-substitued quinazolin-4(3H)-ones [54] require the use of hardly available starting materials, expensive catalysts, and/or harsh reaction conditions [55], often intolerant to the unsaturated moieties. The known literature exceptions included synthesis of 2-alkynylquinazolines via acylation of anthranilamides with alkynylcarboxylic acids and further cyclocondensation under alkaline conditions [36], as well as formation of 2-alkenyl counterparts by a one-pot Yb(OTf) 3 -catalyzed microwave-or ultrasound-assisted reaction of 2-aminobenzonitrile and alkenoyl chlorides [56].
We have found that substrates 7 can be obtained efficiently by a two-step reaction sequence commencing from acylation of anthranilamides 8 with α-allylacetyl chloride 9 leading to benzamides 10. These intermediates appeared to be stable towards heating and underwent intramolecular cyclocondensation performed in diphenyl ether at 230 °C giving target products 7 in good to high yields (see Table 1).
Since it was not possible to predict a priori which of the nitrogen atoms of 7 would participate in PIFA-promoted heterocyclization, optimization of the reaction conditions was performed. The solvent, reaction temperature and time, as well as the reagent ratio were varied. Since CH 2 Cl 2 , CH 2 Cl 2 -TFA, and 2,2,2-trifluoroethanol (CF 3 CH 2 OH, TFE) are used most often for the reactions with PIFA, these solvents were evaluated in the study (see Table 2). It was found the reaction did not proceed with 1.5 equiv of PIFA in CH 2 Cl 2 or CH 2 Cl 2 -TFA at 0 °C over 2 h ( Table 2, entries 1 and 2), while in TFE, the conversion was 37% (Table 2, entry 3). To achieve full conversion of the starting material 7a in TFE at 0 °C, 2.5 equiv of the oxidant and 24 h reaction time were necessary (Table 2, entry 10).
The optimized conditions were applied to all quinazolones 7a-l, and target 1-(hydroxymethyl)-2,3-dihydropyrrolo[1,2-a]quinazolin-5(1H)-ones 6a-l were obtained in 75-83% yield (see Table 3). Their structural analysis showed that the reaction proceeded with high regioselectivity as 5-exo-trig cyclization. The substituent in the quinazoline ring had virtually no effect at the yield or selectivity of the heterocyclization. Two pathways seem to be possible for the oxidative heterocyclization of quinazolinones 7 (see Scheme 2). The first of them (pathway a) includes the formation of the nitrene cation 11 [41,42,44,45,53] under action of PIFA as an oxidant. A subsequent electrophilic attack at the double bond provides aziridinium cation 12 that undergoes selective ring opening with the trifluoroacetate anion to give intermediate 13. The formation of the last-mentioned can be achieved by an initial PIFA attack on the homoallyl C=C bond [41,42,57,58] through the possible intermediates 14 and 15 alternatively (pathway b). Finally, alkaline hydrolysis of 13 upon work-up of the reaction mixture leads to the formation of target product 6.
The structure of products 6 was confirmed by NMR spectroscopy; in addition to that, X-ray diffraction studies were performed with single crystals of compound 6f (see Figure 2).  Since the application of the obtained compounds in early drug discovery is anticipated, it is important to assess their suitability for the synthesis of compound libraries relevant to medicinal chemistry. While many chemoinformatic tools are available for that purpose, we have turned our attention to Ertl's natural product likeness (NPL) score since the target compounds were designed as natural product analogs [1][2][3][4]. In its essence, the NPL score for any molecule estimates its similarity to natural products vs synthetic molecules; it is based on the occurrence frequencies of the corresponding molecular fragments in the two series mentioned above. Zero value of the score is characteristic for the compounds equally similar to natural products and synthetic compounds, while positive values -for those more similar to natural products [1,4]. a Atom numbering as in starting compound 7. b Ertl's natural product likeness (NPL) score calculated using an online NaPLeS tool [4].

Scheme 2:
Plausible mechanism for the formation of 6.
It was found that most of the compounds 6a-l had the score values (-0.10 to 0.81; 0.46 on average, see Table 3) -even somewhat higher than natural vasicinone (0.30) and deoxyvasicinone (−0.01). Therefore, the products obtained in this work indeed fit into the natural product-like chemical space.

Experimental
Commercially available reagents and solvents were used without further purification. General procedure for the PIFA-mediated cyclization of compounds 7a-l: To a solution of quinazoline 7 (0.65 mmol) in TFE (5 mL), a solution of PIFA (0.70 g, 1.63 mmol) in TFE (20 mL) was added at 0 °С, and the mixture was stirred for 24 h at 0 °С. Saturated aq NaHCO 3 (20 mL) was added, the precipitate was filtered off, the filtrates were extracted with CH 2 Cl 2 (3 × 25 mL), dried over Na 2 SO 4 , and the solvent was removed in vacuo. The residue was recrystallized from MeOH to give product 6.

Supporting Information
Supporting Information File 1 Detailed experimental procedures for all compounds and precursors, X-ray structure determination, 1 H/ 13 C/ 19 F NMR spectra for all compounds.