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. 2026 Jan 14;6(1):497–506. doi: 10.1021/jacsau.5c01451

Pd(II)-Catalyzed Heteroarylative Difunctionalization of Unactivated Alkenes via Cascade Nucleopalladation of Alkynes

Jatin Patra 1, Rahul K Shukla 1, Chandra M R Volla 1,*
PMCID: PMC12848686  PMID: 41614152

Abstract

Herein, we unveil an efficient palladium­(II)-catalyzed three-component strategy for the regioselective difunctionalization of unactivated alkenes resulting in γ-selective heteroarylation via cascade cyclization of nucleophile-tethered alkynes. The developed protocol utilizes economically viable aryl, alkenyl, and alkyl halides as electrophilic coupling partners for β-selective incorporation. The reaction is distinguished by its operational simplicity, exhibits broad substrate scope, and retains high catalytic efficiency even in the presence of various pharmacologically relevant motifs. Furthermore, the synthetic approach was expanded to enable cascade borylation under oxidative conditions employing B2Pin2 providing access to C­(sp3)-B scaffolds. Notably, this work demonstrates cascade cyclization-driven dicarbofunctionalizations of unactivated alkenes, establishing a valuable synthetic tool for the streamlined assembly of complex heterocyclic molecular frameworks.

Keywords: difunctionalization, heteroarylation, unactivated alkene, cascade cyclization, palladium

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Introduction

Heterocycles represent a pivotal class of compounds owing to their extensive applications and profound biological significance. Among these, azaheterocycles and oxaheterocycles are especially prominent, as they are present in a variety of bioactive molecules, pharmaceuticals, agrochemicals, and natural products (Scheme A). Consequently, the pursuit of versatile and efficient strategies for constructing these heterocyclic scaffolds remains a central theme in the realm of modern synthetic chemistry. In this context, transition-metal-catalyzed intramolecular cyclization of nucleophile-tethered π-systems has emerged as an effective synthetic method for accessing structurally varied heterocyclic frameworks. This strategy becomes even more powerful when coupled with subsequent bond-forming events that introduce additional molecular complexity. , Among various catalyzed methods, palladium-catalyzed cascade cyclization is particularly notable for its precise regioselectivity and exceptional tolerance of diverse functional groups.

1. Overview of the Work; (A) Biological Significance of Heterocyclic Motifs; (B) State of the Art: Difunctionalization of Unactivated Alkenes; (C) Our Previous Work: Cascade Monofunctionalization; (D) Current Work: Cascade Difunctionalization.

1

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At the same time, alkenes are widely abundant and readily accessible feedstocks. As a result, their selective functionalization has attracted considerable attention, as it enables the generation of sp3-rich scaffolds by disrupting molecular planarity, a structural feature with key implications in drug design. In particular, catalytic three-component 1,2-vicinal difunctionalization of alkenes offers an efficient way to create intricate molecular structures by incorporating two distinct functionalities simultaneously. However, efforts to unlock their synthetic potential have frequently been hindered by challenges such as lower reactivity and regioselective control, especially with electronically unbiased alkenes. To address this, Engle and co-workers designed a directing group strategy for guiding regioselectivity in alkene difunctionalization by stabilizing the transient metallacycles (Scheme B, top). Two mechanistic manifolds have been delineated: an outer-sphere nucleometalation leading to Int-A, or an inner-sphere pathway involving transmetalation and subsequent migratory insertion proceeding via Int-B. Both these chelation-stabilized metal intermediates engage electrophiles to deliver bis-functionalized products with the nucleophile positioned at the terminal carbon. A complementary electrophile-initiated mechanistic strategy consisting of oxidative addition and migratory insertion, proceeding via Int-C and Int-D, was demonstrated independently by the groups of Engle, Giri, and Zhao under Ni-catalysis (Scheme B, middle). Key nickelacycle intermediate reacts with organometallic nucleophiles to afford bis-functionalized products with the electrophile at the terminal carbon. Together, these studies mark significant advances, underscoring the transformative potential of directing-group-assisted difunctionalization of unactivated alkenes. Efforts from other groups have further highlighted the versatility of this strategy.

Despite these notable advancements, most studies remain confined to the installation of aryl or alkyl systems, and the incorporation of heteroaryl motifs has been underexplored. This is likely due to the need for prefunctionalized heteroaryl precursors and the competing coordination ability of heteroatoms. To address these challenges, we envisioned developing an intermolecular three-component cascade difunctionalization by combining intramolecular nucleophilic cyclization with alkene difunctionalization, which could serve as an attractive alternative. In situ-generated organometallic heterocyclic intermediates and electrophiles can strategically be integrated across the π-system of unactivated alkenes, bypassing the requirement of heteroaryl precursors (Scheme B, bottom). In 2021, our group reported a directing group-facilitated cascade hydro-heteroarylation, which enabled the regioselective monofunctionalization of unactivated alkenes (Scheme C). Building on these findings, we hypothesized that the key intermediate Int-E, formed after cascade cyclization, could undergo regioselective carbometalation leading to alkylmetal species Int-F, which can then be intercepted with diverse electrophiles, expanding the chemical space toward elusive carbo-heteroarylation of unactivated alkenes.

At the outset, we foresaw several challenges. Organopalladium intermediates generated after nucleophilic cyclization or migratory insertion could undergo facile protodepalladation or β-hydride elimination, leading to undesired side products including unfunctionalized heterocycles, monofunctionalization, or Heck-type olefination (Scheme B, below). Additional complications, such as alkene isomerization and competing cross-coupling processes with electrophiles, introduce further challenges. Addressing these issues, we hereby disclose a palladium-catalyzed, regioselective cascade aza-, carbo-, and oxa-cyclizations, enabling the difunctionalization of unbiased alkenes tethered with removable 8-aminoquinoline auxiliary (Scheme D). This protocol accommodates a diverse range of aryl, alkenyl, alkyl, and heteroaryl halides as coupling partners. Distinguished by its operational simplicity, it facilitates the incorporation of a wide array of heterocycles, such as indole, 2H-chromene, benzofuran, isochromenone, and 2,3-dihydro-1H-pyrrole, highlighting its broad synthetic applicability. Moreover, the methodology was also successfully extended to oxidative carboboration employing B2pin2, enabling the construction of valuable organoboron compounds.

Results and Discussion

Optimization

Our preliminary investigation commenced with butenamide 1a having a bidentate 8-aminoquinoline directing group, 4-methyl-N-(2-(phenylethynyl)­phenyl)­benzenesulfonamide 2a, and methyl 4-iodobenzoate 3a as the model substrates. During the initial screening, we were pleased to observe the selective formation of the desired product in 38% yield when Pd­(OAc)2 (10 mol %) and K2CO3 (2 equiv) were used in toluene (Table , entry 1). Other nonpolar solvents like DCE and 1,4-dioxane offered no improvement and were largely ineffective (entries 2 and 3). Remarkably, fluorinated solvents, particularly HFIP, substantially enhanced the reaction efficiency, delivering 4 in 78% (70% isolated yield; entry 5). In contrast, ethanol and DMF resulted only in trace product formation (entries 6 and 7). The optimal reaction temperature was found to be 70 °C as both higher and lower temperatures led to diminished yields (entries 8–10). Alternative bases, including Na2CO3, K3PO4, and NaHCO3 gave inferior results, with yields below 72% (entries 11–13). Other coordinating directing groups (1b–1e), such as acid, pyridyl, thioether, and oxazoline, failed to promote the three-component cascade difunctionalization, highlighting the unique ability of 8-aminoquinoline for stabilizing the palladalacycle (entry 14). Use of other Pd sources, such as Pd­(TFA)2, delivered a lower yield of 63% (entry 15), whereas reducing the base loading resulted in a decrease in the yield to 65% (entry 16).

1. Optimization of Reaction Conditions .

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s. no. base solvent temp yield (%)
1 K2CO3 toluene 70 38
2 K2CO3 DCE 70 12
3 K2CO3 1,4-dioxane 70 23
4 K2CO3 TFE 70 57
5 K 2 CO 3 HFIP 70 78 (70)
6 K2CO3 ethanol 70 trace
7 K2CO3 DMF 70 trace
8 K2CO3 HFIP 60 74
9 K2CO3 HFIP 80 68
10 K2CO3 HFIP 90 54
11 Na2CO3 HFIP 70 72
12 K3PO4 HFIP 70 54
13 NaHCO3 HFIP 70 30
14 K2CO3 HFIP 70 trace
15 K2CO3 HFIP 70 63
16 K2CO3 HFIP 70 65
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a

Reaction conditions: 0.1 mmol of 1a, 0.15 mmol of 2a, 0.2 mmol of 3a, 10 mol % Pd­(OAc)2, and 0.2 mmol of base in 1 mL solvent.

b

NMR yield using 0.1 mmol of 1,3,5-trimethoxybenzene as an internal standard.

c

Yield in parentheses refers to isolated yield after chromatography.

d

DGs 1b–1e instead of 1a.

e

10 mol % Pd­(TFA)2.

f

0.1 mmol of K2CO3.

Substrate Scope

After having the optimized reaction conditions in hand, we systematically examined the scope of the cascade 5-endo-dig N-cyclization, employing a series of N-protected 2-(ethynyl)­aniline derivatives with 1a and methyl 4-iodobenzoate 3a (Scheme ). 4-Methyl-substituted alkyne led to the formation of the corresponding product 5 in 69%. Substitution of the phenyl group with a 2-naphthyl group resulted in the formation of 6 as a 1:1 mixture of diastereomers in 65% yield, due to an additional chiral axis. Aliphatic alkynes had no discernible impact on the reaction’s progress, as indole derivatives having cyclopentylmethyl 7, cyclopropyl 8 and n-butyl 9 were isolated in 65–68% yields. A cyano substituent at the 4-position of aniline was well accommodated, providing 10 in 71%. Furthermore, variations in N-sulfonyl groups corroborated the efficacy of different protecting groups (11 and 12). Next, we directed our efforts toward investigating the scope of aryl iodides, which exhibit broad versatility and effectiveness. Aryl iodides bearing various electron-rich, electron-poor, as well as unsubstituted derivative, furnished the corresponding products 13–17 in moderate to good yields. Notably, the protocol also demonstrated excellent tolerance for heteroaryl iodides such as 4-iodo-1H-pyrazole and N-tosyl 5-iodo-indole, leading to the formation of bis-heteroaryl derivatives 18–19 in good yields (72–76%). Delightfully, the carboindolation process proved effective with other electrophiles such as E-, Z-, and cyclic alkenyl iodides, providing synthetically valuable β-alkenyl derivatives 20–24 in good yields (63–82%), further expanding the scope and utility of this methodology. We then proceeded to investigate methyl iodide as a potential electrophile in this reaction, which resulted in the formation of indole 25 in moderate yield. Other alkyl iodides were found to be not amenable to the transformation (see Supporting Information), likely due to steric considerations. To our delight, N-tosyl-protected homopropargyl amine underwent a cascade 5-endo-dig aminopalladation/C–C bond formation to provide dihydropyrrole 26 in 58% yield as a 1:1 mixture of diastereomers.

2. Substrate Scope of the Cascade Difunctionalization of Unactivated Alkenes.

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Following the success of cascade aminopalladation–carboindolation, we pondered whether the generality of our current methodology could be extended to 6-endo-dig C-cyclization using substituted phenyl propargyl ethers (Scheme B). Gratifyingly, a range of substituted aryl propargyl moieties enabled the successful synthesis of 4-(2H-chromen-3-yl)­butanamide derivatives 27–34 in good yields (69–81%), encompassing a broad range of electronic and steric substitution patterns. We next sought to enhance the synthetic efficiency of the transformation by reacting 3-butenamide 1a with alkynes bearing oxygen nucleophiles (Scheme C). This strategy led to the formation of structurally distinct oxaheterocyclic derivatives. 2-(Phenylethynyl)­phenol 2b delivered benzofuran derivative 35 in 70% yield using methyl 4-iodobenzoate as the coupling partner. The synthesis of highly substituted 3-phenyl-1H-isochromen-1-one 36 was accomplished from methyl 2-(p-tolylethynyl)­benzoate 2c under similar catalytic conditions. However, the reaction of acetylenic aldehyde 2d failed to yield the desired isochromenol derivative 37 under the optimized reaction conditions, likely due to its inherent instability or competitive side reactions.

Subsequently, we examined the scope of unactivated alkenes using 4-methyl-N-(2-(phenylethynyl)­phenyl)­benzenesulfonamide 2a and methyl 4-iodobenzoate 3a (Scheme D). We were pleased to find that (Z)-internal alkene 1f could be successfully converted into the cascade difunctionalized product 38, albeit in a relatively modest 38% yield with a 10:1 diastereomeric ratio. Considering the syn-migratory insertion of alkene, the stereochemistry of the major diastereomer of was anticipated as shown in Scheme . In contrast, no desired cascade product was obtained from the E-configured internal alkenes 1g–1i. Instead, monofunctionalized products derived from the cascade cyclization and protodepalladation were isolated in the cases of the Me- and Et-substituted E-internal alkenes. 1,1-Disubstituted alkene 1j proved completely unreactive. Similarly, the α-methyl-substituted terminal alkene 1k was unproductive under the optimized conditions, affording only monofunctionalized product 42 in 55% yield. Our efforts to engage unactivated alkene 1l having γ,δ-unsaturation met with no success, as neither desired difunctionalization nor anticipated monofunctionalization was observed. Instead, 1l reacted with aryl iodide, leading to a mixture of 44 and 45.

The cascade difunctionalization offered a sophisticated platform for the chemo- and regioselective construction of intricately substituted indole and 2H-chromene bioconjugates, including natural product scaffolds (Scheme A). Under the established reaction conditions, carboindolation of unactivated alkene 1a with ethisterone-tethered 2-(ethynyl)­aniline afforded the compound 49 in 71% yield, and its structure was unequivocally confirmed from single-crystal X-ray analysis (CCDC: 2487304). Similarly, alkynes derived from naturally occurring alcohols, such as thymol, (L)-menthol, and β-citronellol, underwent cascade N-cyclization to furnish the corresponding indoles 50–53 in 67–76% yield. Furthermore, reaction of propargyl alkynes derived from thymol and sesamol with alkenyl iodides led to the formation of the corresponding chromene derivatives 54 and 55 in satisfactory yields (78–80%) via C-cyclization. The protocol was also found to be effective with aryl iodides tethered with geraniol and α-tocopherol, producing 56 and 57 in 65 and 46% yields, respectively.

3. Substrate Scope of Heteroarylation, Borylation, and Further Functionalization.

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Organoboron compounds are regarded as valuable synthetic intermediates owing to their remarkable ability to engage in a diverse array of C–C and C-heteroatom bond-forming reactions. Among various strategies for organoborane synthesis, alkene difunctionalization with boron-based coupling partners is particularly noteworthy, as it not only generates molecular complexity but also allows for the formation of a C­(sp3)-B stereocenter. To our delight, a slight modification of the standard reaction conditions allowed the successful application of the developed strategy for the cascade heteroarylative borylation of the unactivated alkene 1a with a series of aniline derivatives substituted at the para-position of the ethynyl phenyl ring to deliver boron compounds 59–63 in 57–65% yield (Scheme B). Compound 59 was crystallized, and single-crystal X-ray analysis unambiguously confirmed the structure of the borylated product (CCDC: 2487302).

The practicality of the Pd­(II)-catalyzed alkene boroindolation method was illustrated on a 2.3 mmol scale of 1a to isolate 0.77 g of 59 (59% yield) (Scheme C). Further transformations were performed on the alkyl pinacol boronate to expand the synthetic value of the difunctionalized derivatives. Removal of the 8-aminoquinoline directing group using p-TSA in methanol led to the formation of ester derivative 64 in a 64% yield. Under mild oxidative conditions, pinacol boronate 59 was readily converted into alcohol derivative 65. Subsequent directing group removal under acidic conditions furnished β-hydroxy ester 66 in 61%.

Mechanistic Studies

To elucidate the chelation effect of the 8-aminoquinoline directing group, we performed a control experiment with N-phenyl-but-3-enamide 1m (Scheme A). The lack of reactivity with this unactivated alkene substrate, together with the directing group screening in Table (entry 14), highlights the key role of the 8-aminoquinoline directing group in enabling the transformation. Moreover, the inert behavior of 2-phenyl-1-tosyl-1H-indole 67 under the reaction conditions provides compelling evidence that the catalytic cycle proceeds specifically through a Pd­(II)-indolyl intermediate, reinforcing its role as the crucial active species driving the transformation (Scheme B). Further insights were obtained from a competitive experiment between aryl iodide 3a and alkenyl iodide 3b. The results showed that 3b undergoes oxidative addition significantly more readily, furnishing products 21/4 in a 10:1 ratio (Scheme C). In a parallel competition between N-nucleophile 2a and C-nucleophile 68, the products 4/29 were formed in a 1:0.9 ratio, indicating that both nucleophiles display nearly comparable reactivity under the standard conditions (Scheme D). An additional experiment was conducted to investigate the competition between aminopalladation (5-endo-dig) and oxypalladation (6-endo-dig) employing 69 as the model substrate (Scheme E). Notably, both pathways were operative, yielding aminopalladation product 70 alongside oxypalladation product 71, with a combined overall yield of 73%. This outcome suggests that under the given conditions, both reaction channels are accessible, potentially influenced by subtle electronic or steric factors governing palladium-mediated selectivity.

4. Mechanistic Studies; (A) Role of Directing Group; (B) Mechanistic Evidence of Cascade Cyclization; (C) Competitive Experiments with Electrophiles; (D) Competitive Experiment with N-Nucleophile vs C-Nucleophile; (E) Competitive Experiment with N-Nucleophile vs O-Nucleophile; (F) Plausible Mechanism for Cascade Heteroarylation; (G) Plausible Mechanism for Cascade Carboboration.

4

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Based on our preliminary mechanistic studies and prior literature reports, , a plausible catalytic cycle for the cascade heteroarylation is depicted in Scheme F. In agreement with the known coordinating characteristics of Pd­(II) with the directing group, intermediate A is formed through anion exchange, which subsequently engages in π-coordination with alkyne 2 to form intermediate B. An outer-sphere intramolecular nucleopalladation of the alkyne then furnishes 3-indolyl-palladium­(II) intermediate C. Regioselective migratory insertion of an alkene with Int C affords the five-membered palladacycle D. Oxidative addition of the organohalide 3 to the alkyl-palladium­(II) intermediate D produces the Pd­(IV) species E. Finally, reductive elimination and protonation delivers the desired product 4 and regenerates the catalytically active Pd­(II) species, thus completing the catalytic cycle.

An oxidative catalytic sequence operates in the cascade carboboration process, as outlined in Scheme G. Following the formation of intermediate A, coordination of the alkyne and subsequent outer-sphere intramolecular nucleopalladation generates Pd­(II) species F. Regioselective migratory insertion of an alkene with this intermediate results in five-membered palladacycle G. Subsequent base-assisted transmetalation with B2Pin2, produces intermediate H, which undergoes reductive elimination to deliver the carboborated product 59 along with Pd(0). The external oxidants present in the reaction mixture then reoxidize Pd(0) back to Pd­(II), thereby regenerating the active catalytic species and completing the catalytic cycle.

Conclusions

In summary, we have developed a cascade strategy for the regioselective dicarbofunctionalization of unactivated alkenes utilizing a removable 8-aminoquinoline directing group. This method leverages chelation-stabilized migratory insertion with alkyne-tethered nucleophiles to enable the β,γ-difunctionalization of 3-butenoic acid derivatives. The approach allows for selective γ-functionalization with a diverse range of heterocycles, including indole, 2H-chromene, benzofuran, isochromenone, and 2,3-dihydro-1H-pyrrole, alongside β-selective incorporation of electrophilic partners, including aryl, alkenyl, and alkyl halides. Furthermore, the efficient trapping of organopalladium intermediates with B2Pin2 under oxidative conditions provided valuable C­(sp3)-B motifs, serving as versatile synthons for further functional group transformations. The reaction proved to be scalable and compatible with numerous valuable functional groups, effectively retaining its performance even with structures relevant to medicinally significant structures. The directing group was also effectively removed via hydrolysis, highlighting the method’s practicality. Overall, this work introduces an efficient approach for cascade cyclization-driven intermolecular three-component difunctionalization of unactivated alkenes, significantly expanding the toolbox for constructing complex molecular architectures.

Experimental Section

General Procedure for Palladium-Catalyzed Carboindolation of Alkenamides

To an oven-dried screw-cap reaction tube equipped with a stir bar, alkenamide 1a (0.1 mmol), 2 (0.15 mmol), 3 (0.2 mmol), Pd­(OAc)2 (10 mol %), and K2CO3 (0.2 mmol) were added sequentially, followed by HFIP (1 mL). The reaction mixture was heated for 7–8 h at 70 °C. The completion of the reaction was confirmed by checking TLC under a UV detector. Then, the organic phase was evaporated under reduced pressure, and the product was purified by using silica-gel column chromatography (eluent: hexane/ethyl acetate = 8/2).

Supplementary Material

au5c01451_si_001.pdf (10.8MB, pdf)

Acknowledgments

This activity is supported by ANRF, India (CRG/2023/004060). We also would like to thank DST-FIST (SR/FST/CS-II/2017/37). J.P. would like to thank P.M.R.F. for the fellowship.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacsau.5c01451.

  • Experimental procedures and analytical data (1H, 13C NMR, and 19F NMR, HRMS) (PDF)

J.P. and R. K. S. designed and conducted all experiments and characterized the novel compounds. J.P. and C. M. R. V. wrote the manuscript. C. M. R. V. directed the research.

The authors declare no competing financial interest.

References

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