Catalytic enantioselective alkenylation–heteroarylation of olefins: stereoselective syntheses of 5–7 membered azacycles and oxacycles

Abstract

Catalytic enantioselective domino alkenylation–heteroarylation of nonconjugated iododienes proceeded with excellent stereoselectivity and broad scope of substrates. The reaction enables stereoselective syntheses of substituted azacycles such as piperidine, pyrrolidine azepine and dihydropyrans carrying new quaternary stereocenters. Mechanistically, C–H bonds of heterocycles were activated by lithium alkoxides via reversible deprotonation, rather than conventional palladium(II)-assisted metalation processes. Many types of heteroarenes can be used, including not only azoles (such as thiazoles, oxazoles, imidazoles and oxadiazoles), but also nonazoles (thiophene, furan and azine N-oxides).

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There is a resurgence of research interest in developing enantioselective domino coupling reactions initiated by Heck-type arylation of pendant alkenes.¹ For example, Zhu et al.² reported a stereoselective synthesis of stereodefined 3,3-disubstituted oxindoles via domino couplings of acroylamide ortho-triflates. The heteroarenes were limited to azoles having acidified C–H bonds such as benzothiazole, benzoxazole and 1,3,4-oxadiazole;³ they were activated via a palladium-based mechanism of nonconcerted metalation–deprotonation.⁴ However, analogous stereoselective domino couplings of alkenyl electrophiles proved to be much more difficult,⁵ due to side reactions such as Heck-type bicyclization onto the alkenyl groups after insertion to form [3.1.0]bicycles⁶ or subsequent ring expansion (see Fig. 1a).⁷

Fig. 1 (a) Domino arylation–heteroarylation of N-acroylamides for stereoselective synthesis of 3,3-disubstituted oxindoles. (b) Domino alkenylation–heteroarylation of olefins for asymmetric synthesis of azacycles of 5–7 ring sizes and 4,5-dihydropyran derivatives. (c) Examples of drugs containing piperidines and pyrrolidines.

We report herein a general method for catalytic domino alkenylation–heteroarylation to readily access 5–7 membered azacycles, as well as oxacyclic dihydropyran derivatives (see Fig. 1a and b).⁸ These saturated azacycles, pyrrolidines and piperidines are among the most frequently used rings in medicines, including both heterocycles and carbocycles (Fig. 1b).⁹ For example, anti-HIV agent nifeviroc contains a trisubstituted pyrrolidine and shows an IC₅₀ value of 2.9 nM against the CCR5 receptor, but the IC₅₀ value of its enantiomer was only 380 nM.¹⁰ The new reaction provides azacycles carrying quaternary stereocenters at C3 or C4 positions which are difficult to prepare from other catalytic reactions.¹¹ It also enabled asymmetric ring closure to form oxacyclic dihydropyrans (Fig. 1b).

In a model study of iododiene 1a and benzoxazole, we first explored a family of Josiphos ligands¹² to identify suitable ancillary ligands for palladium catalysts (see Scheme 1). In Pd^II complexes of Josiphos, switching from PAr₂ to PCy₂ (Ar = aryl; Cy = cyclohexyl) groups on the 1-ethyl sidearm is accompanied by not only electronic perturbation, but also a substantial conformational change in chelate rings formed by palladium and Josiphos, so as to avoid close contact of large PCy₂ rings with the ferrocene ring.¹³ Consequently, all four P-substituents will undergo a substantial conformational change; hence a significant change occurs in the chiral environment surrounding the palladium centers.

Scheme 1 Screening of Josiphos ligands on a model domino reaction of 1a and benzoxazole (GC yields on a 0.05 mmol scale in 0.3 mL of CH₂Cl₂). dba = dibenzylideneacetone.

The modularity and tunability of both steric and electronic properties of Josiphos ligands are very rewarding. This allowed us to quickly identify Josiphos L1 (ref. 14) which provides desired piperideine 2a in 88% yield and 92% ee, along with a small amount of an oxidative dimer of benzoxazole. If benzoxazole was omitted, the reaction pathway sidetracked to Heck bicyclization (41% 2a′ in 87% ee) and reductive Heck cyclization (27% 2a′′). The Heck bicyclization leading to 2a′ also eliminated PdH species, which can undergo ligand exchange with alkyl palladium complex C to form 2a′′via C–H reductive elimination (see Scheme 7c below). The Heck bicyclization has no parallelism in domino coupling reactions of aryl electrophiles (see Fig. 1a). Josiphos analogues L2–L4 carrying two diarylphosphines only afforded moderate 40–70% ees. In comparison, the Josiphos series having a strongly donating PCy₂ sidearm gave consistently higher ees than the former. On the other hand, the complex of L7 carrying two highly donating PCy₂ donors showed poor catalytic activity and afforded a low level of stereoselectivity. It is well known that in cationic Heck-type reactions, the key step of alkene insertion is accelerated by weakly donating ligands and retarded by strongly donating phosphines.¹⁵ Axially chiral biphosphines were also tested; for example, axially chiral BINAP and Segphos furnished 58% ee and 81% ee, respectively.

During condition optimization, we noticed that other reaction parameters were also important. The choice of metal alkoxides had a remarkable impact on the outcome. Without an added alkoxide, only 16% conversion of 1a was detected without any formation of 2a (Table 1, entry 2). LiOMe led to moderate yield and ee (entry 2); LiOt-Bu, NaOMe or KOMe proved to be the best bases in terms of both chemical yields and ees (entries 4 and 5); the more basic alkoxides NaOt-Bu or KOt-Bu gave poor yields of 2a probably due to fast deprotonation and ring opening of 2-metalated benzoxazole (entries 6 and 7).¹⁶ The use of silver phosphate was essential, without which the model reaction gave a complex mixture containing 2a in 48% yield and 81% ee (entry 8). Other silver salts, Ag₂CO₃, AgOAc or AgOTf can also provide 2a in 60–85% yields and ∼90% ees (entries 9–11). The result suggests that these silver salts may act as halide abstractors to create a coordination site for enantiofacial olefin insertion.

Table 1 The effect of reaction parameters on a model reaction of 1a and benzoxazole under conditions using Josiphos L1 (0.05 mmol scale in 0.3 mL of CH₂Cl₂. Calibrated GC conversion and yields and ees determined for pure samples). Ts = 4-toluenesulfonamide; dba = dibenzylideneacetone

Entry	Change of conditions	Conv. of 1a (%)	Yield of 2a (%)	Yield of 2a′ (%)
1	No change	100	88 (92% ee)	9
2	No LiOt-Bu	16	0	0
3	LiOMe	100	63 (58% ee)	12
4	NaOMe	100	89 (90% ee)	0
5	KOMe	100	73 (92% ee)	0
6	NaOt-Bu	33	12 (86% ee)	6
7	KOt-Bu	92	26 (85% ee)	5
8	No Ag3PO4	100	48 (81% ee)	<5
9	Ag2CO3	100	75 (92% ee)	12
10	AgOAc	100	59 (94% ee)	12
11	AgOTf	100	84 (90% ee)	8

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The Pd catalyst of Josiphos L1 can be applied to domino couplings of iododialkene 1a with many classes of heteroarenes (Scheme 2). We were gratified to find that the combination of lithium t-butoxide and silver phosphate enabled efficient activation of azoles including (benzo)thiazole, (benzo)oxazole, imidazoles and oxadiazole, but also nonazoles such as (benzo)thiophene,¹⁷ furan and azine N-oxides. In reactions of thiazoles (2h–i), polar groups, esters and nitrile were well tolerated. Notably, the C–H activation of C2-substituted thiazoles (2j–l) occurred regioselectively at C5 positions next to the sulfur atom. In the reactions of imidazoles (2n–o), (benzo)thiophenes (2q–t) and furan (2u), electron-withdrawing groups (e.g., ester, nitrile and trifluoroacetyl) were important to the activation and couplings of these heteroarenes. Notably, both pyridine and isoquinoline N-oxides were regioselectively activated at C2 positions to give products 2v–w in ∼70% ees under the standard conditions using L1. Switching from Ag₃PO₄ to AgOTf increased the stereoselectivity to >90% ees.

Scheme 2 Examples of azoles and non-azoles in enantioselective formation of piperidines (isolated yields from a 0.1 mmol scale in 0.5 mL of CH₂Cl₂).

Next, we studied structural variations of (Z)-1-iodo-1,6-dienes in stereoselective formation of piperideines (Scheme 3). The alkenyl fragment can tolerate different C5-substituents (ethyl, n-hexyl, isobutyl, cyclohexyl, benzyl and phenyl) (3a–f), while the C3 substituents of the iodoalkenyl fragment can be t-butyl, i-propyl, methyl, benzyl and phenyl (3g–k). Moreover, the N-tosylamide linker can be substituted by 2-thienylsulfonamide and N,N-dimethylsulfamate (3l–m). We also attempted to prepare piperidines carrying quaternary stereocenters at C4 positions, by using 2-iodo-1,7-diene 1n. At first, its reaction with benzoxazole failed to produce product 3n in a reasonable quantity. After switching from ligand L1 to L4 possessing a large di(1-naphthyl)phosphine sidearm, we succeeded in producing piperidines 3n–p from benzoxazole, oxazole and benzothiazole in satisfactory yields and with ∼90% ee (Scheme 3).

Scheme 3 Stereoselective formation of 6-membered piperideines and piperidines via domino couplings (isolated yields on a 0.1 mmol scale in 0.5 mL of CH₂Cl₂). Th = 2-thienyl.

Seven-membered azepane derivatives are important motifs in medicines,¹⁸ but catalytic asymmetric syntheses for these azacycles are still limited to date.¹⁹ Thus, the Pd catalyst of Josiphos L4 also promoted domino coupling of (Z)-1-iodo-1,7-diene 1q with benzothiazole via a rare 7-exo-trig cyclization (Scheme 4).²⁰ Asymmetric formation of tetrahydroazepine 3q was achieved in 70% yield and 84% ee (or 92 : 8 er). In contrast, the Pd/L1 catalyst failed to produce a significant amount of product 3q. The domino couplings using L4 proceeded well with 5-phenyloxazole and 3-cyanobenzothiophene, too (3t–3x).

Scheme 4 Stereoselective formation of tetrahydroazepines via domino couplings of 1q (isolated yields on a 0.1 mmol scale in 0.5 mL of CH₂Cl₂).

Furthermore, we successfully used the new method for stereoselective construction of trisubstituted pyrrolidines. Thus, a reaction of 2-iodo-1,6-diene 4a with benzoxazole generated 5a in 49% yield and 84% ee. After switching ligand L1 to Josiphos L2, a satisfactory result of 84% yield and 92% ee resulted. In this model reaction, Josiphos L3 and L4 also provided excellent yields and 90% ee (Scheme 5a). LiOtBu was important, without which only 26% conversion of 4a was detected, without any production of 5a. Additionally, when Ag₃PO₄ was omitted, the reaction afforded 5a in 31% yield and 71% ee, together with some premature coupling (26% yield of 5a′), hinting that the silver salt played a crucial role in halide abstraction to create a “vacant” site for enantiofacial olefin insertion.

Scheme 5 Stereoselective formation of substituted pyrrolidines via domino couplings (isolated yields on a 0.1 mmol scale in 0.5 mL of CH₂Cl₂): (a) the effect of Josiphos ligands and (b) examples of pyrrolidines obtained under conditions using Josiphos L2. Th = 2-thienyl.

The enantioselective formation of pyrrolidines tolerated well structural variations in iododienes (Scheme 5b), for example, ethyl and benzyl groups on olefinic units (5b–c) and acid-labile 2-thienylsulfonamide and N,N-dimethylsulfamate linkers (5d–e). Azoles such as benzoxazole, benzothiazole and 1,3,4-oxadiazole coupled well (5fi). Single crystals of 5d were obtained via vapor diffusion of hexane into a solution in DCM. X-ray crystallography thus established its absolute configuration to be 3R.†

We also attempted to prepare oxacycle 6avia a domino coupling of iodo-1,6-diene 6 (Scheme 6). Initially, we found that the Pd/L1 catalyst only provided 6a in a moderate yield and 53% ee, but after changing the ancillary ligand to (R)-xyl-Segphos, the result was readily improved to 80% yield and 95% ee. Thus, the Pd/xyl-Segphos catalyst efficiently enabled stereoselective formation of other oxacycles 6b–c from 5-phenyloxazole and 3-cyanobenzothiophene. The six-membered oxacycles are present in some medicines as core structures.²¹

Scheme 6 The effect of diphosphines on the formation of 6a and some examples of oxacycles obtained from domino couplings catalyzed by Pd/xyl-Segphos (isolated yields on a 0.1 mmol scale in 0.5 mL of CH₂Cl₂).

To gain insights into the activation of heteroarenes under catalytic conditions, we added 10 equiv. of CD₃CN (pK_a 31 in DMSO) to catalytic domino couplings of 1a with benzoxazole and 3-cyanobenzothiophene. Several observations were made. (a) 1a and benzoxazole (pK_a 25 in DMSO) reacted efficiently and almost full conversion was reached to give 86% yield of 2a after 2 h, while the recovered benzoxazole was 82% deuterated at the C2 position (see Scheme 7a). Treatment of benzoxazole with LiOtBu alone resulted in a comparable level of deuteration (85% after 2 h). A similar phenomenon was seen with deuteration of 3-cyanobenzothiophene (see Scheme 7b). (b) Parent thiophene and benzothiophene failed to participate in domino coupling; they did not undergo deuteration by LiOtBu and CD₃CN (<5%), either. Therefore, the electron-withdrawing groups are important for acidifying C–H bonds of (benzo)thiophenes and furan to allow reversible deprotonation to occur (e.g., 2q–u in Scheme 2). (c) Ag₂CO₃ complexes ligated by biarylphosphines were reported by others to catalyze deuteration of azoles, indoles and thiophenes using D₂O or CH₃OD.²² However, Ag₃PO₄ or Ag₂CO₃ together with Josiphos L1 only effected very low levels of deuteration in DCM after 2 h (2% and 11% for two heteroarenes). Thus, silver(I) heteroaryl complexes are probably not responsible for the activation and coupling of heteroarenes under our conditions. (d) Palladium(II) complexes were known to activate azoles and nonazoles via several different mechanisms, such as concerted metalation–deprotonation (CMD)²³ nonconcerted metalation–deprotonation^4a,b and electrophilic CMD,²⁴ depending on the nature of (hetero)arenes, ancillary ligands and conditions (such as bases and solvents). However, the extent of deuteration of the heteroarenes recovered from the two catalytic whole reactions (see Scheme 7) agreed well with those from control reactions with CD₃CN and LiOtBu in DCM. Thus, palladium(II) complexes did not play a significant role in activation of heteroarenes under our catalytic conditions. Thus, we concluded that the deuteration results point to a mechanistic scenario in which LiOtBu promoted reversible formation of lithiated heteroarenes.

Scheme 7 Catalytic domino couplings of 1a with (a) benzoxazole and (b) 3-cyanobenzothiophene in the presence of CD₃CN. (c) A putative catalytic cycle of domino coupling of model substrate 1a and a heteroarene and the formation of side products (Ar = heteroaryl).

In a productive catalytic cycle (see Scheme 7c), silver phosphate or carbonate abstracted the halide ion from oxidative-addition complex A to produce cationic alkenyl complex B. It quickly underwent asymmetric olefin insertion to form alkyl palladium species C which, in turn, was intercepted by a lithio heteroarene. Final C–C reductive elimination of species D completed the catalytic cycle of domino coupling. The lithiation, we believe, may the rate-limiting step, at least in reactions of furans, thiophenes and benzothiophenes. When complex C was not trapped by an organometallic reagent, it was sidetracked to bicyclization forming side product 2a′. The Heck bicyclization forming 2a′ also eliminated PdH species, which can undergo ligand exchange with alkyl palladium complex C and subsequent C–H reductive elimination to form 2a′′ (see Scheme 7c below).

As a showcase of synthetic utility, product 5a was readily converted to other compounds via transformations of its olefinic group (see Scheme 8). (a) Stirring 5a with Co₂(CO)₈ in refluxing xylene led to olefin isomerization to a more stable isomer, 2-pyrroline 7avia an allyl cobalt hydride species.²⁵ (b) Treatment with in situ formed KPPh₂, however, resulted in olefinic isomerization with ring opening of benzoxazole (7b).²⁶ (c) Moreover, RuCl₃-catalyzed oxidative cleavage using NaIO₄ (ref. 27) provided ketone 7c under mild conditions. (d) Catalytic hydrogenation over Pd/C occurred facioselectively to give 7d in a dr of 12 : 1, using the benzoxazole ring as a directing group. The configuration of cis-3,4-dimethyl pyrrolidine was established with NOESY analysis. (e) Iron-catalyzed radical hydrofluorination of 5a under Boger's conditions²⁸ produced a regioselectively Markovnikov adducts 7e (as two distereomers in a ratio of 1.5 : 1).

Scheme 8 Product derivatization: (a) Co₂(CO)₈, mesitylene, 130 °C, 24 h; (b) HPPh₂, KOH, DMSO, 90 °C, 1 h; (c) cat. RuCl₃, NaIO₄, EtOAc/MeCN/H₂O 1 : 1 : 1, RT, 15 h; (d) 5% Pd/C, H₂ (balloon), MeOH, RT, 16 h; (e) Fe(NO₃)₃·9H₂O, NaBH₄, Selectfluor, MeCN/H₂O 1 : 1, 0 °C, 2 h.

In conclusion, we report enantioselective domino alkenylation–heteroarylation reactions in excellent enantioselectivity. The reactions produced 5–7 membered azacycles (pyrrolidine, piperidine and tetrahydroazepine) containing new quaternary stereocenters, which are not easily accessible from other methods. We found that many types of heteroarenes, both azoles and nonazoles, are suitable substrates, including (benzo)thiazole, (benzo)oxazole, imidazole, oxadiazole, (benzo)thiophene, furan and azine N-oxides. Mechanistically, deuteration experiments indicated that both azoles and nonazoles were activated by regioselective, reversible lithiation by LiOtBu. This mechanism is distinct from nCDM previously reported by Zhu et al. in catalytic arylation–heteroarylation.

Data availability

Experimental and NMR data (both in pdf) have been included.

Author contributions

ZM conducted all catalytic experiments and compound characterization and LS conducted derivatization reactions described in Scheme 8. JSZ drafted the manuscript.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We acknowledge financial support from the National Natural Science Foundation of China (22271007), Peking University Shenzhen Graduate School, State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics and Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs for JSZ. Hao Xie at PKUSZ conducted X-ray diffraction and data collection.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, characterization of isolated products and CIF files of crystallographic data. CCDC 2152684 (5d). For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d2sc07117g

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