Enantioselective Copper‐Catalyzed Borylative Cyclization for the Synthesis of Quinazolinones

Abstract Quinazolinones are common substructures in molecules of medicinal importance. We report an enantioselective copper‐catalyzed borylative cyclization for the assembly of privileged pyrroloquinazolinone motifs. The reaction proceeds with high enantio‐ and diastereocontrol, and can deliver products containing quaternary stereocenters. The utility of the products is demonstrated through further manipulations.

Since the seminal reports of Hosomi [1] and Miyaura, [2] the copper-catalyzed borylative functionalization of olefins has emerged as a powerful method for stereocontrolled, complex molecule construction. [3] Subsequent studies by Ito and Sawamura,[4] and others, [5] have shown the utility of this process in cyclization reactions. In particular, several groups have used this strategy to construct valuable nitrogencontaining heterocycles, such as indolines [6] and tetrahydroquinolines [7] (Scheme 1 A). In particular, Lautens has recently described a copper-catalyzed stereoselective synthesis of tetrahydroquinolines through a conjugate borylation/Mannich cyclization cascade. [7a] This process illustrates the potential of copper-catalyzed borylative cyclizations by: 1) forming several stereocentres with high control; 2) incorporating a boron group that can undergo further derivatization; 3) preparing an important class of nitrogen-containing heterocycle, in this case tetrahydroquinolines Quinazolinones display important bioactivity. [8] In particular, pyrroloquinazolinones are common tricyclic motifs found in drug molecules and natural products (Scheme 1 B). It is important to prepare these compounds enantioselectively as quinazolinone enantiomers can display different bioactiv-ities. [9] Few current methods for the construction of quinazolinones are enantioselective, [8,10] and classical chiral resolution and chiral pool synthesis are typically used, for example, to access the enantiopure quinazolinones shown in Scheme 1 B. [11] More recently, dihydroquinazolinones have been prepared enantioselectively, typically from 2-aminobenzamide and aldehydes, [12] however, few enantioselective methods extend to the delivery of important pyrroloquinazolinone scaffolds. [12h] Thus, new enantioselective approaches to pyrroloquinazolinone building blocks are needed for the synthesis of known and as yet unknown bioactive targets. We recognized that the enantioselective, copper-catalyzed borylative cyclizations of substrates 1, involving intramolecular addition of an organocopper intermediate to a C=N electrophile, [3a] would constitute a valuable route to important enantiomerically enriched pyrroloquinazolinone derivatives 2 (Scheme 1 C). The resulting new process is highly enantioand diastereoselective, uses an inexpensive and non-toxic catalyst, and exploits commercially available chiral ligands. Furthermore, through subsequent derivatization, a variety of potentially bioactive quinazolinones can be accessed.
Interestingly, the addition of alcohols greatly influenced the yield of the process (Table 1, entries 7 and 8), and 2 a was isolated in high yield, with excellent diastereo-and enantiocontrol ( Table 1, entry 8). The exact role of the alcohol in this process remains unclear although it may facilitate catalyst turnover by protonation of a copper-amide intermediate to deliver product and regenerate a copper alkoxide. [15] Finally, we tested the phenyl-substituted substrate 1 b under our optimized conditions (Table 1, entries 9 and 10). Although ligand L3 was unsuccessful ( Table 1, entry 9), the product 2 b was isolated in excellent yield and with very high diastereoand enantiocontrol when using ligand L2 (Table 1, entry 10). Exposing substrate 1 a to the latter conditions gave 2 a in substantially reduced yield (Table 1, entry 11).
We next explored the performance of various arylsubstituted alkenes 1 b-1 k in the process (Scheme 2). In almost all cases, borylative cyclization and construction of two adjacent stereocentres-including a quaternary stereocentre-proceeded efficiently to deliver pyrroloquinazolinones 2 b-k with very good to excellent enantio-and diastereocontrol. For example, aryl groups bearing electron-rich substitu- ents at both meta-and para-positions gave products with very high enantiocontrol (2 c-2 f). Ortho-, meta-and para-halogenated aryl groups were also well tolerated (2 g-2 i). Finally, substrates bearing 2-napthyl and 2-thienyl groups gave the desired products in high yield and with excellent enantiocontrol (2 j, 2 k). Additional substrates bearing heteroaryl groups gave rise to unstable products (see Supporting Information). The relative and absolute stereochemistry of the products was determined by X-ray crystallographic analysis of a derivative of 2 e and 2 f. [16] Various substitution on the aryl ring of the amidine component of 1 was also tolerated (Scheme 3). For example, the methyl-and fluorine-containing products 2 l and 2 m were obtained in high yield and with good to excellent enantiocontrol. A thiophene-fused substrate was also compatible with our standard conditions to give 2 n with moderate enantiocontrol. Building on our initial optimization ( Table 1, entry 8), we investigated the scope of the process with additional monosubstituted alkene substrates 1 o-r. The product 2 o was obtained in high yield and with excellent diastereo-and enantiocontrol, thus suggesting that electronrich substrates are particularly well-suited to the process. Halogenated substrates were also tested (2 p-2 r); borylative cyclization proceeded well, albeit with lower enantiocontrol for substrates 1 q and 1 r. The relative and absolute stereochemistry of the products 2 a, 2 o-2 r was assigned after X-ray crystallographic analysis of a derivative of 2 a. [16] Substrates bearing substitution at the terminus of the alkene proved unreactive (see Supporting Information).
The functionality in the dihydroquinalozinone products 2 presents opportunities for further transformations (Scheme 4). The material (2 b) for these transformations was obtained by performing the enantioselective, borylative cyclization on a gram-scale; essentially identical yield, enantio-and diastereocontrol were observed (c.f. Table 1, entry 10). We first converted product 2 b into the trifluoroborate salt 3, [17] and the alcohol 4; the latter by oxidation with H 2 O 2 . Methylation of the free amine group was also carried out to give product 5. Finally, oxidation with DDQ provided pyrroloquinazolinone product 6. It is noteworthy that judicious choice of oxidant (H 2 O 2 or DDQ) leads selectively to either product 4 or 6. Products related to 6 are common in medicine (Scheme 1 B) [8] and our preparation of 6 represents a rare example of an enantioselective approach to this class of compound.
We propose a tentative mechanism and stereochemical model to rationalize the observed outcome of the cyclization of aryl-substituted alkene substrates 1 b (Scheme 5). Upon formation of copper-boryl species II, enantioselective borocupration occurs across the double bond of the alkene to give III. Our stereochemical model (Scheme 5 B) suggests this addition occurs with the smaller methylene group (R) oriented towards the ligand P-aryl ring, rather than the larger phenyl group on the substrate (TS-1 a vs. TS-1 b). Based Scheme 4. Gram-scale reaction and derivatizations of 2 b. Conditions: (i) see Scheme 2; (ii) KHF 2 4 equiv, MeOH/H 2 O, 0 8C to RT; (iii) H 2 O 2 2 equiv, K 2 CO 3 2 equiv, THF, À20 8C; (iv) NaH 1.5 equiv, MeI 1.5 equiv, THF, 0 8C to RT; (v) DDQ 1.5 equiv, CH 2 Cl 2 , 08C to RT. on previous reports, a favourable face-to-face interaction between the phenyl group on the alkene of the substrate and the P-aryl ring might further stabilize TS-1 a, whereas unfavourable edge-to-face interactions might be present in TS-1 b. [18] The diastereoselective, CÀC bond-forming cyclization of III can then proceed via TS-2 to give the intermediate IV. We suggest that copper coordinates to the nitrogen atom during this step, in agreement with previous reports. [19] Finally, in line with the positive influence of alcohols on reactivity, we suggest that R'OH (R' = iPr, tBu) protonates intermediate IV to give the desired product 2 b and regenerate the active copper alkoxide catalyst I.
A highly enantio-and diastereoselective copper-catalyzed borylative cyclization constructs two adjacent stereocentresincluding a quaternary stereocentre-and delivers a range of pyrroloquinazolinone derivatives that are currently difficult to access. The new process exploits an inexpensive and nontoxic copper catalyst and commercially available chiral phosphine ligands. Selective manipulation of the products allows access to enantiomerically enriched quinazolinones of medicinal relevance.