Controllable access to trifluoromethyl-containing indoles and indolines: palladium-catalyzed regioselective functionalization of unactivated alkenes with trifluoroacetimidoyl chlorides

The synthesis of diverse products from the same starting materials is always attractive in organic chemistry. Here, a palladium-catalyzed substrate-controlled regioselective functionalization of unactivated alkenes with trifluoroacetimidoyl chlorides has been developed, which provides a direct but controllable access to a variety of structurally diverse trifluoromethyl-containing indoles and indolines. In more detail, with respect to γ,δ-alkenes, 1,1-geminal difunctionalization of unactivated alkenes with trifluoroacetimidoyl chloride enables the [4 + 1] annulation to produce indoles; as for β,γ-alkenes, a [3 + 2] heteroannulation with the hydrolysis product of trifluoroacetimidoyl chloride through 1,2-vicinal difunctionalization of alkenes occurs to deliver indoline products. The structure of alkene substrates differentiates the regioselectivity of the reaction.


Introduction
Transition-metal-catalyzed difunctionalization of alkenes has emerged as a powerful synthetic strategy for the assembly of structurally complex molecules. 1The transformation can forge two new C-C or C-X bonds for installing two different components into the C-C double bonds, which has aroused tremendous interest from many research groups.For the more difficult difunctionalization of unactivated alkenes, in recent years, the Engle group and others have developed a series of transitionmetal-catalyzed alkene 1,2-difunctionalization reactions with the assistance of the 8-aminoquinoline (AQ) auxiliary as a strongly coordinating bidentate directing group, including hydrofunctionalization, 2 dicarbofunctionalization, 3 carboamination, 4 carboboration and aminoboration, 5 and so on (Scheme 1a).In most cases of the above transformations, the nucleopalladated alkylpalladium(II) species stabilized by a bidentate directing group were initially generated, and then protodepalladation or oxidative addition with electrophiles occurred to afford the difunctionalizated products.2a,b Meanwhile, a competitive b-hydride elimination process was usually suppressed by the conformational rigidity of the directing group.
Compared with the rapid development of 1,2-vicinal difunctionalization protocols, reactions involving 1,1-geminal difunctionalization of unactivated alkenes have been rarely reported.To date, palladium-catalyzed 1,1-arylhalogenation, 1,1-diarylation and 1,1-arylborylation of alkenes have been explored by the use of prefunctionalized aryl sources. 6In 2019, Hong, Baik and their co-workers demonstrated a palladium(II)-catalyzed siteselective 1,1-difunctionalization of unactivated alkenes with two nucleophiles, wherein a regioselective b-H elimination of the cationic palladacycle and subsequent migratory insertion were involved (Scheme 1b). 7In the 1,1-difunctionalization reactions, the key step lies in the b-H elimination from a less stable sixmembered palladacycle to regenerate an olen moiety, thereby enabling the following olen insertion.2b We surmised that the structural exibility of the in situ formed palladacycle results in the regioselective difference of the 1,1-difunctionalization and 1,2-difunctionalization reactions.Pertinent to the present research, the utilization of difunctionalization of unactivated alkenes with two different electrophiles to produce structurally diverse heterocycles remains undeveloped and is of great signicance (Scheme 1c).
Triuoromethyl-substituted nitrogen-containing heterocycles as core skeletons widely exist in numerous bioactive and pharmaceutical molecules. 8Due to the unique properties of uorine atoms, the physicochemical and pharmacological properties of the parent heterocyclic molecules could be obviously improved. 9Tri-uoroacetimidoyl chlorides have been applied as a powerful and versatile uorinated synthon for the assembly of triuoromethylsubstituted N-heterocycles. 10Our group and others have developed a variety of synthetic methods for preparing various triuoromethyl-containing N-heterocycles by the employment of triuoroacetimidoyl chlorides as reactive partners. 11When the halogen atom was located at the ortho position of the aryl moiety of triuoroacetimidoyl chloride, it will serve as a 4-atom reaction precursor with two electrophilic reactive sites, which can be adopted as useful building blocks to construct triuoromethylsubstituted N-heterocycles.For instance, Zhu, Chen and coworkers demonstrated a palladium-catalyzed directed C-2 and C-3 dual C-H functionalization of N-(2-pyrimidyl)-indoles with tri-uoroacetimidoyl chlorides for accessing uorinated isocryptolepine analogues. 12Nevertheless, the more challenging task involving the combination of dual C-H functionalization of unactivated alkenes with triuoroacetimidoyl chlorides is still elusive.Herein, we report our research nding of a palladiumcatalyzed bidentate-directed 1,1-geminal and 1,2-vicinal difunctionalization of unactivated alkenes with triuoroacetimidoyl chlorides for the regioselective synthesis of biologically important triuoromethyl-containing indoles and indolines 13 (Scheme 1d).

Results and discussion
We commenced our studies by using triuoroacetimidoyl chloride 1a and 4-pentenoic acid derivative 2a with an 8-aminoquinoline directing group as the model substrate (Table 1).The reaction was performed at 80 C under N 2 atmosphere in different solvents in the presence of Pd(OAc) 2 , PPh 3 and Na 3 PO 4 .The results indicated that only THF could afford the 1,1-geminal difunctionalization product 3a with an alkenyl moiety at 3-position of indole in 37% yield (Table 1, entries 1-5).The exact structure of indole 3a was unambiguously conrmed by single X-ray diffraction analysis (CCDC: 2144265 †). 14Other bidentate directing groups were also examined, including 2-methyl-8-quinolinyl, pyridyl, picolyl and 2methylmercaptophenyl, and only trace of product 3a could be detected.The replacement of 8-quinolinyl with 1-naphthyl totally inhibited the reaction, highlighting the necessity of the 8-aminoquinoline directing group for the success of this reaction.Then, various bases were surveyed under the reaction system, which suggested the product 3a was obtained in 47% yield applying Na 2 CO 3 as the base (Table 1, entries 6-9).The reaction conditions were further optimized by the use of a series of palladium catalysts, and Pd(hfac) 2 could afford the best outcome (Table 1, entries 10-14).Furthermore, changing PPh 3 with other phosphine ligands failed to give a better result (Table 1, entries 15-18).Elevating or lowering the reaction temperature exerted a negative effect on the reaction (Table 1, entries 19 and  20).Gratifyingly, the employment of a mixed solvent of THF and PhCF 3 (v/v ¼ 4/1) promoted the reaction to deliver 3a in 58% yield (Table 1, entry 21).Further optimization of the reaction conditions was implemented by the addition of diverse additives, such as TBAI, BQ, AgOAc or TEMPO, but the desired product 3a was not detected.The relatively lower yield of this reaction came from the inevitable residue of alkene 2a and the susceptibility of triuoroacetimidoyl chloride 1a under the current reaction conditions.
With the establishment of the optimal reaction conditions, the scope and limitation of this 1,1-geminal difunctionalization reaction was explored by adopting a range of tri-uoroacetimidoyl chlorides (Table 2).In general, the tri-uoroacetimidoyl chlorides with electron-donating or electronwithdrawing groups in aryl moiety all could participate in this transformation to give rise to the corresponding 2-CF 3 -indole products 3b-m in low to moderate yields.In all cases, it was found that the g,d-alkene 2 remained and the excess tri-uoroacetimidoyl chloride 1 was decomposed under the current reaction conditions.Extensive effort towards the screening of the reaction conditions was devoted to fully consume the alkene substrate 2 but without success.Therefore, another group of yield data was provided in the parentheses calculated based on the recovery of alkene 2. Tri-uoroacetimidoyl chlorides bearing electron-donating groups 3b-g showed higher reactivity than that of substrates with electron-withdrawing groups 3h-m.The halogen substituents (F, Cl and Br) were also tolerated in this reaction (3h-m), but only lower efficiency was observed.Noteworthy is that other uoroalkyl groups, including CF 2 H, C 2 F 5 and C 3 F 7 , were also smoothly incorporated into the indole products 3n-p with moderate reactivity.Then, several substituted unactivated alkenes were evaluated to further explore the generality of the protocol.For instance, b-methyland phenyl-substituted 4-Scheme 1 Palladium-catalyzed difunctionalization of unactivated alkenes.
pentenoic amides reacted with 1a to deliver the indole products 3q-r in acceptable yields.a-Methyland cyclopropyl-substituted 4-pentenoic amides also acted as viable coupling partners (3st).Unfortunately, 1,2-and 1,1-disubstituted alkenes were not compatible with the reaction, presumably due to the remarkable steric factors.According to the structure of the obtained indole product 3, the presence of substituent at d-position of 4pentenoic amides will impede the formation of indole product.
Interestingly, a unexpected N-triuoroacetyl-substituted indoline product 4a was afforded in moderate yield when we used b,g-alkenes as substrates to further evaluate the generality of this transformation (Table 3).We speculated that the hydrolysis of triuoroacetimidoyl chlorides 1 occurs to give tri-uoroacetamides, which undergo [3 + 2] heteroannulation with 3-butenoic acid derivatives in a 1,2-vicinal difunctionalization manner.An analogous process involving palladium-catalyzed [3 + 2] heteroannulation of non-conjugated alkenyl amides and ortho-iodoanilines/phenols for preparing 2,3-dihydrobenzofurans and indolines was disclosed by Engle and co-workers. 15e next explored this protocol through slight modication of the reaction conditions by the addition of 2.0 equiv. of TEMPO, and the yield of product 4a was signicantly increased to 65%.The scope of this 1,2-difunctionalization reaction was examined with diverse triuoroacetimidoyl chlorides, and to our delight, the N-triuoroacetyl-substituted indoline products 4a-n was delivered in moderate to good yields (Table 3).
A wide variety of triuoroacetimidoyl chlorides were applicable to the reaction system, regardless of the electron properties of the aryl moiety.The halogen groups, even strong electron-withdrawing -CF 3 group, could survive well in the reaction (4g-m).Apart from triuoromethyl, other uoroalkyl groups were also compatible with the reaction for producing the corresponding indoline products 4o-r in 25-84% yields.The structure of product 4l was also determined by single X-ray diffraction analysis (CCDC: 2144260 †). 14In addition, b,galkene substrates bearing different substituents at the a-position were suitable substrates under the optimal conditions to provide the desired products 4s-w in reasonable yields with excellent stereoselectivity.However, when internal alkenes were tested under the standard conditions, no desired reaction occurred.The yields of the 1,2-vicinal difunctionalization reaction are generally higher than that of 1,1-geminal difunctionalization reaction.It is well-known that chelation-stabilized vemembered palladacycle species which either generated from  nucleopalladation of b,g-alkenes or from C-H activation of the corresponding aliphatic chains could favorably react with carbon electrophiles, which was pioneered by Daugulis and coworkers. 16n order to gain some deeper insight into the reaction pathway, a series of control experiments were performed as shown in Scheme 2. First, the reaction of alkene 2a with tri-uoroacetimidoyl chloride 1 0 without iodine substituent was carried out under standard conditions, but the coupling product 5 was not observed (Scheme 2a).The coupling reaction of 2a with iodobenzene proceeded smoothly to give the Heckcoupling product 6 in 36% yield (Scheme 2b).The above results indicated that the coupling reaction occurred initially between the alkene 2a and the C-I bond of triuoroacetimidoyl chloride.When deuterated water as an additive was subjected into the reaction, a Heck-coupling product 7 with an amide moiety was obtained in 14% yield with the concomitant formation of the product 3a in 48% yield (Scheme 2c).The N-H bonds of amide moiety and the C(sp 2 )-H bonds of alkene moiety were both partially deuterated.The replacement of Table 2 Substrate scope of 1,1-difunctionalization of g,d-alkenes a,b a Reaction conditions: 1 (0.4 mmol), 2 (0.2 mmol), Pd(hfac) 2 (10 mol%), PPh 3 (20 mol%), Na 2 CO 3 (2.0 equiv.) in THF/PhCF 3 (2.0 mL, v/v ¼ 4/1) at 80 C under N 2 atmosphere for 48 h.b Isolated yields and the yields in the parentheses were determined based on the recovery of alkene 2.
triuoroacetimidoyl chloride 1a with its hydrolysis product 8 to react with alkene 2a under the standard conditions could afford the coupling product 7 in 31% yield without generation of the [3 + 2] heteroannulation indoline product (Scheme 2d).For the indoline synthesis using b,g-alkenes, the addition of water into the reaction could give improved yields, whereas the reaction yield decreased in the absence of TEMPO or with higher loading of water (Scheme 2e).Combined with the yield data of standard conditions (65%) or without TEMPO (42%), it is evident that TEMPO greatly promotes the reaction, but the exact role of TEMPO in the reaction is still unclear.We also utilized the hydrolysis product 8 as the coupling partner in the optimal conditions or in the absence of TEMPO, the comparable poor yields were obtained (Scheme 2f), which revealed that tri-uoroacetimidoyl chloride was possibly not rapidly transformed into amide 8 to participate in the reaction.Notably, the alkene 2l with the longer chain was unreactive in the reaction system, presumably due to the very unstable palladacycle intermediate (Scheme 2g).Only trace of the desired product could be detected when bromide or chloride analogues of tri-uoroacetimidoyl chlorides were tested (Scheme 2h).Finally, reactions between triuoroacetimidoyl chloride and TEMPO were also carried out to exclude the possible reaction pathway (Scheme 2i).
Based on the mechanistic investigation and the precedent literature, 2g,12,15-17 the plausible reaction mechanisms of two different difunctionalizations of unactivated alkenes were proposed as depicted in Scheme 3.For the 1,1-difunctionalization reaction, the oxidative addition of C-I bond of tri-uoroacetimidoyl chloride 1a to Pd(0) generated imidoyl Pd(II) intermediate A, which coordinated with the directing group in the alkene 2a to form complex B.Then, the 1,2-migratory insertion of B afforded the 6-membered palladacycle intermediate C, followed by the b-H elimination to deliver the alkenetethered triuoroacetimidoyl chloride D. Subsequently, the second sequence of oxidative addition of C-Cl bond of D, migratory insertion of E and b-H elimination of F occurred to give the 3H-indole G, which underwent the double bond isomerization process to furnish the desired 2-CF 3 -indole product 3a.For the 1,2-difunctionalization reaction, a similar Pd(II)/ Pd(IV) catalytic pathway based on the Engle's work was reasonable. 15Initially, the hydrolysis of triuoroacetimidoyl chloride in the presence of trace amount of water in reaction system occurred to produce amide 8.The alkene coordination with Pd(II) catalyst generated Pd(II) species H, which underwent nucleopalladation with 8 to afford Pd(II) complex I.Then, the oxidative addition of C-I bond of aryl moiety to Pd(II) center delivered Pd(IV) intermediate J, followed by the reductive elimination step to give rise to the nal indoline product 4a.Although the exact role of TEMPO in the 1,2-difunctionalization reaction is still unclear, we propose that TEMPO reoxidize Pd(0) that was formed from during the reaction to the catalytically active Pd(II) form.
We also explored the practicability of the reaction by performing a scale-up reaction.The reaction could be easily reproducible at 1.0 mmol scale for product 4n with slightly decreased efficiency (66%) and the triuoroacetyl group of 4n could be readily removed in the presence of NaBH 4 (Scheme 4a).With regard to product 4q with a CF 2 Br moiety, a palladiumcatalyzed radical annulation reaction with isocyanide 18 was conducted for incorporating a phenanthridine scaffold into the indoline 4q to afford compound 10, albeit with low yield (Scheme 4b).

Conclusions
In conclusion, we have developed a straightforward approach for the regioselective synthesis of structurally diverse triuoromethyl-containing indoles and indolines via a palladium-catalyzed dual functionalization of unactivated alkenes with triuoroacetimidoyl chlorides.The structure of alkene substrates controls the regioselectivity of the annulation Scheme 3 Plausible reaction mechanism.reaction, which enables the divergence of 1,1-geminal and 1,2vicinal difunctionalization of unactivated alkenes.Several control experiments have been conducted to elucidate the reaction mechanism.Further efforts towards the additional application of triuoroacetimidoyl chlorides as versatile coupling partners in the C-H functionalization eld should be pursued in future.

Scheme 4
Scheme 4 Scale-up reaction and synthetic transformations.

Table 1
Optimization of reaction conditions a