Construction of poly-N-heterocyclic scaffolds via the controlled reactivity of Cu-allenylidene intermediates

Controlling the sequence of the three consecutive reactive carbon centres of Cu-allenylidene remains a challenge. One of the impressive achievements in this area is the Cu-catalyzed annulation of 4-ethynyl benzoxazinanones, which are transformed into zwitterionic Cu-stabilized allenylidenes that are trapped by interceptors to provide the annulation products. In principle, the reaction proceeds via a preferential γ-attack, while annulation reactions via an α- or β-attack are infrequent. Herein, we describe a method for controlling the annulation mode, by the manipulation of a CF3 or CH3 substituent, to make it proceed via either a γ-attack or an α- or β-attack. The annulation of CF3-substituted substrates with sulfamate-imines furnished densely functionalized N-heterocycles with excellent enantioselectivity via a cascade of an internal β-attack and an external α-attack. CH3-variants were transformed into different heterocycles that possess a spiral skeleton, via a cascade of an internal β-attack and a hydride α-migration followed by a Diels−Alder reaction.

Despite the rich reactivity of Cu-allenylidene intermediates such as I, annulation reactions that proceed via an αor β-attack rather than a γ-attack have remained scarce 39 . We have hypothesized that annulation mode B involving preferential αand β-attacks could be realized by controlling the steric and electric factors of suitable substituents X (X ≠ H). Thus, annulation mode B should arise from the pairwise combination of a successive internal β-attack and an external α-attack of I by the interceptor (Y − -Z + ). Subsequent formation of a Cγ-Z bond would provide the nonethynyl, poly-N-heterocycles with three new-bonds formation (Fig. 2c). During our research into the development of efficient synthetic methods for the synthesis of fluorine-containing heterocyclic compounds for drug discovery [46][47][48][49][50][51][52][53][54][55][56][57] , we noticed that the use of a CF 3 substituent as the X group can direct the reaction pathway from mode A to B 55 . Herein, we realize the idea of a cascade of inter-and intramolecular annulations (mode B), which involves both αand β-attacks by employing 4-ethynyl-4-CF 3benzoxazinanones 1 (X = CF 3 ) and cyclic sulfamate-imines 2 ( Fig. 2d; mode B). A wide variety of densely functionalized indoline heterocycles 3 that contain a CF 3 group can be obtained in high yield with excellent diastereoselectivity and enantioselectivity (up to 99% dr and 99% ee). Examples of reactions that generate allcarbon CF 3 quaternary stereocenters at the angular position are extremely rare 58,59 , and therefore the obtained results should accelerate corresponding areas of research, especially drugdiscovery. The copper-catalyzed asymmetric synthesis via a Cuallenylidene intermediate attracts much attention [60][61][62] . Substantial transformations of 3 into more complex molecules are also demonstrated.
The concept of altering the annulation mode by controlling the reactivity of the Cu-stabilized allenylidene intermediate I can also be applied to non-fluorinated substrates. Ethynyl benzoxazinanones 4 that contain a methyl (CH 3 ) group instead of a CF 3 group are transformed into very different poly-N-heterocycles with a spiral carbazole/indoline skeleton (5) in good yield with high regioselectivity (Fig. 2d; shunt mode B). The unusual formation of 5 occurs via a shunt pathway of mode B that involves the decarboxylative generation of I, followed by a cascade process that involves a cyclization, hydride-α-migration, and a Diels−Alder reaction. The series of spiral poly-N-heterocycles 5 generated here are also alkaloid-like indole-rich-molecules. Thus, this method can be expected to serve as a powerful tool for the generation of a drug-like space in a single step.

Results and discussion
Annulation reaction using 4-ethynyl CF 3 -benzoxazinanone 1. We commenced our investigation with an annulation reaction of 4-ethynyl CF 3 -benzoxazinanone 1a and sulfamate-derived cyclic imine 2a at room temperature in the presence of CuOTf·1/2 C 6 H 6 (10 mol%), a methyl-substituted Pybox ligand (L1, 20 mol%), and i-Pr 2 NEt (2.4 equiv) in toluene (Table 1, entry 1). To our delight, the reaction proceeded smoothly and delivered the polycyclic indoline (3aa) that bears a CF 3 group at the all-carbon quaternary centre. However, the yield of 3aa was only moderate and the enantioselectivity was poor (47% and 15% ee). Encouraged by this initial attempt, we systematically evaluated several chiral ligands (entries 2−4) and found that the phenyl-substituted Pybox ligand L2 stood out, producing the desired product 3aa in 70% yield with excellent enantioselectivity 96% ee (entry 2). Further results of the other ligands screened, such as L5 and (R)-BINAP are shown in Supplementary Table 1 in the Supporting Information. An investigation into the effect of the solvent on the reaction (Supplementary Table 2) revealed that toluene provides better reaction efficiency than other solvents. Gratifyingly, an evaluation of different Cu salts (entries 5−7 and Supplementary Table 3) revealed that Cu(OTf) 2 (5 mol%) and L2 (10 mol%) resulted in an improved reaction efficiency with a slightly lower yield (68%) and enhanced enantioselectivity (98% ee). A slightly improved yield was observed when the reaction was performed with 1.1 equiv of 2a (entry 8, 71% yield, 98% ee; for more details, see Supplementary Table 4). An evaluation of different bases (Supplementary Table 5) showed that i-Pr 2 NEt was superior to other  bases and the reaction efficiency was further improved by employing 0.5 equiv of the base (entry 9, 88% yield, 98% ee). The most favourable outcome was observed when the reaction was performed at 10°C (entry 10, 94% yield, >99% dr, >99% ee). Further experiments revealed that the presence of the base was necessary for this transformation to proceed (entry 11). The absolute configuration of 3aa, induced by L2, was determined by a single-crystal X-ray diffraction analysis (CCDC2026703).
Substrate scope. With the optimal catalyst identified and the standard conditions in hand, we studied the scope of the sulfamate-derived cyclic imines 2 for this enantioselective decarboxylative annulation reaction. The results are summarized in Fig. 3. Cyclic sulfamate imines (2a-2i) that bear a variety of substituents at different positions of the benzene ring, regardless of whether they are electron-donating or electron-withdrawing groups, were tolerated and delivered the annulated products (3aa-3ai) in good to excellent isolated yield (52−91%) with excellent enantioselectivity (>92% ee). The variation of the substituent pattern has thus merely a marginal impact on the selectivity. For instance, substrates that bear halogen substituents such as 6-F (2d), 6-Br (2e), or 7-Cl (2i) reacted smoothly and delivered the desired products in decent yield (71−91%) with respectable enantioselectivity. We observed that the selectivity was slightly decreased from 7-halo (3ai; 98% ee) substitution to 6-halo (3ad, 3ae; 95% ee) substitution. Although 6-NO 2 substituted cyclic imine 2 f led to a slightly lower yield, a high enantioselectivity was still achieved in this reaction (3af; 52%, 92% ee). Moreover, the naphthalene fused cyclic imine 2j reacted smoothly to produce the desired product in excellent yield and enantioselectivity (3aj; 87%, 99% ee).
Further experiments were performed in order to evaluate the generality of the reaction. Substituents were introduced at different positions on the benzoxazinanone moiety to create excellent reaction partners and resulted in the desired products with good yield and enantioselectivity. Substrates bearing electron-withdrawing groups, such as 7-CF 3 (1b), 6-F (1d), and 6-Cl (1e) reacted efficiently with different sulfamate-derived cyclic imines (2) and produced the desired products in good yield (>81%) with excellent enantioselectivity (up to 99% ee). Notably, the introduction of an ester group at the 7-position of the benzoxazinanone (1c), led to a similar product (3ca) in good yield (72%) with excellent diastereoselectivity (>99% dr) and enantioselectivity (96% ee). Nevertheless, this result should be noted due to the survival of the ester moiety under the applied reaction conditions. The reaction with an electron-donating substituent (CH 3 ) at the 6-position of the benzoxazinanone moiety gave the desired product in a decent yield with optimum enantioselectivity (3fa; 77%, 98% ee). The stereochemistry of these products was  assigned in analogy with 3aa. In all cases, the diastereoselectivity of 3 was found to be absolute.
Synthetic utility I. To further showcase the synthetic potential of this Cu-catalyzed decarboxylative annulation reaction, a gramscale synthesis of 3aa was carried out, which achieved an 85% isolated yield without deterioration of the optical purity (Fig. 4a). Gratifyingly, the Pd-catalyzed Suzuki coupling of bromosubstituted-indoline 3ae with phenylboronic acid afforded biphenyl product 6 in good yield under retention of the enantiopurity (Fig. 4b).
As the removal of a p-toluenesulfonyl (tosyl) group from an amide usually requires relatively harsh reaction conditions 63 , we were concerned prior to attempting the detosylation of 3 due to its high-density functional structure.
Interestingly, treatment of 3aa with Mg/MeOH under sonication generated another stereocenter, in which successive detosylation/ methoxylation reactions occur in a single step and result in the angular methoxylated product 7aa in 78% yield with outstanding stereoselectivity (>99% dr). The absolute configuration of 7aa was determined by single-crystal X-ray diffraction analysis (CCDC2026704, Fig. 4c). The scope of the detosylative methoxylation was extended to different substrates, and the results are summarized in Fig. 4c. Various substituents on the benzene ring with electronically different properties were well tolerated and gave the corresponding product 7 in moderate to good yield (>63%) with excellent stereoselectivity (up to 99% ee). Moreover, halo-substituted indolines (3db, 3ea) afforded the desired products 7db (60%) and 7ea (61%) in moderate yield with very good selectivity (99% ee). In all cases, the enantiopurity was retained at Synthetic utility II. To further explore the synthetic utility of this transformation, we decided to screen a number of acid-mediated substitution reactions of masked methoxy indole 7aa with the goal of introducing a substituent at the 2-position (Fig. 5). The Lewis-acid-mediated reaction of 7aa with allyltrimethylsilane afforded the desired allyl-substituted product 8 in 79% yield with 99% ee. Treatment of 7aa with trimethylsilyl cyanide (Me 3 Si-CN) and triethylsilane (Et 3 SiH) delivered the corresponding 2-cyanoproduct 9 and the reductive product 10 in 88 and 91% yield, respectively, without compromising the enantiopurity. The phosphoric-acid-catalyzed reaction of 7aa with indole furnished the sterically complex poly-N-heterocycle 11 in 82% yield under retention of the enantiopurity. These results suggest that methoxy poly-N-heterocycle 7 is a versatile compound that can be easily converted into synthetically challenging di-angular-substituted products in promising yields with optimum enantiopurity.
Annulation reactions using non-fluorinated, ethynyl CH 3benzoxazinanones. Next, we attempted the decarboxylative annulation of non-fluorinated, 4-ethynyl-4-CH 3 -benzoxazinanones 4 with 2 under the reaction conditions optimized for 1 (Fig. 6a). To our great surprise, a mixture of regioisomers of poly-N-heterocycles with a spiral carbazole/indoline skeleton 5a was obtained in 43% yield with high regioselectivity (2C/ 3C = 85:15). The expected cycloaddition product bearing the 2a sulfamate moiety was not formed in detectable quantities. The unique, alkaloid-like structure of 5a led us to investigate the scope of this regioselective transformation of 4 to 5. We thus treated 4a under the same catalytic conditions but without the addition of 2a. As expected, this transformation is generally applicable, and a variety of analogues of 4 were promptly converted into the corresponding spiro-carbazole/indoline molecules (Fig. 6b) in good to high yield (60−79%) with high 2C-regioselectivity (85:15-90:10). The poly-N-heterocyclic structure of 5 (2C) was determined unambiguously by single-crystal X-ray diffraction analysis of the brominated spiro-N-heterocycle 5c (2C). The X-ray crystal structure of 5c (2C) (CCDC2026705) and the HPLC analysis of 5a conclusively show that 5 is a racemate, which is useful information for the discussion of the reaction mechanism (vide infra). The transformation of 4a also proceeded smoothly with the non-chiral ligand 1,2-bis(diphenylphosphino)ethane (DPPE) to give the same spiro-carbazole/indoline 5a in similar yield (56%) and regioisomeric ratio (2C:3C = 88:12). The results using other ligands were also attempted and similar results were obtained (Supplementary Table 7). Removal of the tosyl group of 5a (2C) was achieved with Mg in MeOH/THF to yield spiro carbazole/indole derivative 12 with a 2-CH 3 -3H-indole skeleton (Fig. 6c). Suzuki−Miyaura coupling reaction of 5c (2C) with phenyl boronic acid (PhB(OH) 2 ) under Pd-catalysis gave the biscoupling product 13 in 56% yield (Fig. 6d).
Proposed reaction mechanisms. Based on the experimental results and our own hypotheses, we propose a feasible reaction mechanism to rationalize the formation of polycyclic merged indolines 3 from the reaction of 4-ethynyl 4-CF 3 -benzoxazinanones 1 with cyclic sulfamate imines 2 (Fig. 7a). Initially, a Cu catalyst (stabilized by its ligands) reacts with 1a in the presence of a base (i-Pr 2 NEt) to generate Cu acetylide A. Subsequently, the decarboxylation reaction of A generates zwitterionic Cu-allenylidene intermediate I. Due to the presence of the sterically demanding CF 3 group at the γ-allenyl position, the cyclic sulfamate imine 2a does not smoothly approach the expected γposition of I for the annulation mode A. A double-helical, pseudo-C2-symmetrical architecture of Cu-complex I optimized by DFT calculations is displayed with their selected atomic charge distributions (Fig. 7b, see more details in Supplementary Fig. 1). Ligand L1 was used for computations. The computed optimized conformation supports the fact that the CF 3 group highly blocks the Cγ-position of I. Thus, a conventional γ-attack would be unfavourable. Besides, the nitrogen atom is close to the β-carbon  (Fig. 7c). The unexpected transformation of the non-fluorinated ethynyl Me-benzoxazinanones 4 into spiro-carbazole/indolines 5 can also be explained based on the proposed mechanism (Fig. 8). The first half of the process for the generation of Cu indoline zwitterionic intermediate II' from 4a via zwitterionic Cu-allenylidene intermediate I′ is the same as the process for the formation of Cu indoline zwitterionic intermediate II in Fig. 7. Namely, the mode A is unfavourable due to the steric Me group based on the DFT calculation of I′ (with L1). The nitrogen atom is close to the βcarbon of Cu-allenylidene intermediate I′ (N---Cβ: 2.59749 Å), resulting in the intramolecular cyclization to Cu-indoline II. While the γ-anion is stabilized in the CF 3 -containing intermediates I and II by negative hyperconjugation (Fig. 7), that in the non-fluorinated Cu zwitterionic intermediates I′ and II′ (II′′) is unstable due to the positive inductive effect by Me group. The atomic charge distributions are shown in Fig. 8b D spontaneously dimerizes via a Diels−Alder cyclization pathway to furnish the structurally complex spiro-carbazole-indoline 5a. The lack of asymmetric induction observed in the synthesis of 5a supports a pathway where D spontaneously dimerizes independently from the Cu-catalyzed catalytic cycle (Fig. 8a).
To shed further light on the possibility of controlling the annulation mode by altering the conformation of Cu-allenylidene zwitterionic intermediate I, we conducted the reaction of the nonsubstituted ethynyl benzoxazinanone 14 with two cyclic sulfamate imines (2a and 2e) under the same Cu-catalysis conditions.  Remarkably, ethynyl substrate 14 could be transformed, via a Cucatalyzed decarboxylative [4 + 2] annulation, into two tetracyclic 4-ethynyl-quinazoline derivatives (15a and 15e) in good yield (>52%) with excellent diastereoselectivity (19:1 dr) (Fig. 9a). An X-ray diffraction analysis of single crystals of 15a confirmed a tetracyclic quinazoline skeleton with a cis-stereochemical assignment (CCDC2026702). This result is consistent with our proposed mechanism, i.e., that the annulation reaction of the unsubstituted, non-steric, ethynyl 12 with 2 proceeds via mode A, which involves a Cu-allenylidene intermediate I′′ and a preferential γ-attack of interceptor 2 on I′′, to furnish the ethynyl-N-heterocycles 15 (Fig. 9b). Mode B, which involves the intramolecular β-attack, was not observed when non-substituted ethynyl benzoxazinanones 14 are used. The optimized conformation of the Cu-allenylidene intermediate I′′ with the atomic charge distributions (selected) by DFT calculations are shown (Fig. 9c, Supplementary Fig. 2). The γ-position is obviously opened to the nucleophile while the β-carbon is rather sterically shielded, which is in good agreement with the experimental observation mentioned above. Interestingly, however, the βcarbon is the most positive (Cα: −0.851; Cβ: 0.248; Cγ: −0.232). This fact suggests the balance of electronic and steric factor at Cuallenylidene intermediate is crucial for the reactivity and reaction mode of the annulation reactions.

Conclusion
In summary, we have demonstrated a strategy for controlling the annulation mode of ethynyl benzoxazinanones based on the reactivity of the Cu-allenylidene zwitterionic intermediate I that is formed during the reaction. Via a Cu-catalyzed decarboxylative annulation reaction of 4-ethynyl 4-CF 3 -benzoxazinanones 1 with cyclic sulfamate imines 2, densely functionalized indoline scaffolds 3, which bear a trifluoromethylated all-carbon quaternary centre, were constructed in excellent yield and enantioselectivity (up to 99% ee). The key step in the transformation is the unique generation of a Cu-indoline zwitterionic intermediate II from a Cu-allenylidene zwitterionic intermediate I by intramolecular βattack. The obtained poly-N-heterocycles contain a chiral C-CF 3 bond at an angular position; the synthesis of these types of molecules is usually very challenging. Notably, the chemical transformation of the CF 3 -poly-N-heterocycles 3 resulted in various types of derivatives with excellent selectivity. Significantly, this protocol represents the first example of the construction of optically pure trifluoromethylated merged indoline frameworks. These molecules will most likely become prospective drug candidates. The concept was extended to non-fluorinated, 4-ethynyl 4-CH 3 -benzoxazinanones 4. Under the same Cu-catalyzed decarboxylation conditions, CH 3 -substituted Cu-indoline zwitterionic intermediates II′ (II′′) were generated. The II′′ was promptly converted regioselectively into the alkaloid-like, spirocarbazole-indoline derivatives 5 via a cascade process of internal β-attack and hydride α-migration (shunt-mode B) followed by a spontaneous Diels−Alder cyclization. This method is generally applicable to a variety of substrates, all of which are attractive for drug-discovery research. Although significant effort has already been devoted to control the reactivity of the α, β, and γ-positions of the Cu-allenylidene, the hitherto reported results are fragmented and no clear strategy has emerged. Our concept, which is based on exploiting the reactivity of the Cu-allenylidene zwitterionic intermediate I, may be substantially expanded to synthesize complex polycyclic molecules. The number of permutations and combinations of potential reactants and interceptors that can be used in this cascade annulation will lead to a rich variety of heterocyclic skeletons. Moreover, the concept could be extended to not only use Cu-catalysis but to also use Pdcatalysis and 4-vinyl-benzoxazinanones 87,88 . Further studies on the extension of this concept are currently in progress in our laboratory.

Methods
Computational methods. The ligand framework of zwitterionic Cu-allenylidene intermediates I (X = CF 3 ), I′ (X = Me) and I′′′ (X = H) adopted a double-helical, pseudo-C2-symmetrical architecture according to the reported works of X-ray structure of [Cu 2 Cl(pybox) 2 ] − [CuCl 2 ] − 89-91 , and computed structure of Cuallenylidene complexed with L1 92 . Ligand L1 was used instead of L2 for computation to simplify their calculations. The geometry optimizations and energy calculations were carried out at the B3LYP/6-311 G** level with Grimme's dispersion correction methods of the D3. Atomic charge distributions were calculated from the B3LYP/6-311 G** level wave functions by electrostatic potential fitting using General procedure for preparation of CF 3 -poly-N-heterocycles 3. In an argon filled glove box, a flame-dried 10 mL Schlenk tube was charged with copper(II) trifluoromethanesulfonate (1.81 mg, 0.005 mmol, 5 mol%), 2,6-bis[(4 R)-phenyl-2oxazolin-2-yl]-pyridine L2 (3.69 mg, 0.01 mmol, 10 mol%) and anhydrous Toluene (1 mL). The resulting solution was stirred for 1 h at 80°C. In an argon filled glove box, ethynyl benzoxazinanones 1 (0.1 mmol), benzoxathiazine 2 (0.11 mmol), and DIPEA (8.7 μL, 0.05 mmol, 0.5 equiv) were added. The resulting solution was stirred at 10°C until the complete conversion of ethynyl benzoxazinanones (monitored by TLC). The reaction was quenched by saturated NH 4 Cl aqueous solution (2 mL). The resulting solution was extracted with ethyl acetate (5 mL × 3). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated under vacuum. The diastereomeric ratio and crude yield were determined by 19 F NMR analysis of the crude reaction mixture. The residue was purified by flash silica gel chromatography (Toluene) to afford the title compound 3. Full experimental details can be found in the Supplementary Methods.

Data availability
All characterization data including 1 H, 13