Palladium-Catalyzed Regio- and Stereoselective C–H Alkynylation of Conjugated Dienols

Abstract

The regioselective activation of alkenyl C–H bonds in conjugated dienols presents significant challenges due to the presence of multiple similarly reactive sites. In this study, we developed a palladium-catalyzed alkynylation method that is both regio- and stereoselective for the activation of internal alkenyl C–H bonds. This approach provides an efficient and versatile strategy for synthesizing dienyne derivatives with precise Z and E configurations. Stereocontrol is achieved through the introduction of acetate salts, which effectively modulate the reaction pathway, allowing for selective outcomes via either a C–H activation process or a Heck coupling mechanism. This innovative strategy not only enhances the specificity of the synthesis but also broadens the potential applications of the resulting dienyne derivatives in various fields.

Introduction

Conjugated 1,3-dien-5-ynes represent an important class of structural motifs found in numerous bioactive molecules and functional materials (Scheme a). These compounds serve as versatile synthetic building blocks owing to their high reactivity and facile transformation into valuable derivatives. However, the development of efficient methods for their regio- and stereoselective synthesis remains challenging, with limited systematic studies reported to date. Existing synthetic approaches face several limitations. Transition metal-catalyzed cross-coupling between alkynes and dienyl halides (Scheme b-i) often requires specialized starting materials, harsh conditions, and high catalyst loadings. Alternative methods employing alkynyl halides and organometallic alkenes (Scheme b-ii) are constrained by reagent toxicity and synthetic complexity. Other reported protocols (Scheme b-iii) typically involve tedious procedures with specialized reagents, yielding only limited dienyne derivatives with unsatisfactory efficiency. Recent decades have witnessed significant progress in transition metal-catalyzed direct C–H alkynylation of simple alkenes for constructing conjugated enynes via metallocycle intermediates. Since Chatani’s pioneering work in 2012 using 8-aminoquinoline as a directing group, various metal catalysts (Ir, Rh, Pd, Ni, Au, Fe) have been developed for this transformation. However, current methodologies predominantly focus on activated substrates (e.g., acrylamides, enamides) that form endometallacycles. Notably, the alkynylation of unactivated alkenes remains underdeveloped with only isolated examples reported by several research groups. These methods universally rely on 5- or 6-membered exometallacycles and strong chelating directing groups, while smaller, strained metallocycles remain largely unexplored.

1. Transition Metal-Catalyzed Diverse Hydrosilylation of Internal Alkynes.

Building on our prior studies of Pd-catalyzed alkenyl C–H functionalization via weak coordination, we now explore the directed C–H alkynylation of conjugated dienols, a challenging transformation requiring selective recognition of highly reactive sites while suppressing competitive intermolecular etherification. Through careful optimization of bases and additives, we achieved precise control over the reaction pathways, steering selectivity toward either Heck coupling or C–H activation via a strained 4-membered palladacycle. This strategy provides efficient, regio- and stereoselective access to conjugated dienynes from unprotected dienols, addressing a critical unmet need in the field.

Results and Discussion

Optimization of Reaction Conditions for the Alkynylation of (2Z,4E)-5-Substituted Penta-2,4-dien-1-ols

We aimed to identify the optimal reaction conditions using (2Z,4E)-5-phenylpenta-2,4-dien-1-ol (1a) as the model substrate, which contains a hydroxy directing group. When we subjected 1a and bromoalkyne 2a to Pd­(OAc)₂ and K₂CO₃ in ⁱ PrOAc as the solvent, we successfully synthesized enyne 4a, achieving a yield of 45% with a 4a:3a ratio of 16:1, presumably via the alkynyl-Heck pathway (Table , entry 1). The configuration of the olefin product was confirmed through NOESY analysis (Supporting Information). Solvent screening revealed that ⁱ PrOH effectively promoted the Heck reaction (entries 2–3). We ultimately determined the optimal conditions by extending the reaction time (entry 4). Surprisingly, the addition of NBu₄OAc increased the 3a:4a ratio to 2:1 (entries 5–7). Further screening of bases indicated that Et₃N was an effective promoter for the C–H activation reaction (entries 8–10). During the optimization process, we noted that the choice of additive significantly influenced the olefin configuration with LiOAc yielding the product in 53% yield with a stereoselectivity of 12:1 (3a:4a) (entries 11–13). Ultimately, the best results were achieved by conducting the reaction of 1a (1.0 equiv) with 2a (1.5 equiv) in the presence of Pd­(OPiv)₂ (7 mol %), Et₃N (2.0 equiv), and LiOAc (1.0 equiv) in ⁱ PrOH (0.2 M) at 60 °C for 48 h, resulting in a yield of 65% with a stereoselectivity of 12:1 (3a:4a) (Table , entry 14).

1. Optimization of Reaction Conditions for the Alkynylation of (2Z,4E)-5-Phenylpenta-2,4-dien-1-ol .

entry	additive	base	solvent	ratio (4a:3a)	yield
1		K2CO3	i PrOAc	16:1	45%
2		K2CO3	DCM		trace
3		K2CO3	i PrOH	>20:1	56%
4		K2CO3	i PrOH	>20:1	73%
5	NBu4OAc	K2CO3	i PrOH	1:2	57%
6	NBu4BF4	K2CO3	i PrOH	2:1	72%
7	NBu4HSO4	K2CO3	i PrOH	4:1	42%
8	NBu4OAc	Na2CO3	i PrOH	1:2	43%
9	NBu4OAc	KOAc	i PrOH	1:4	58%
10	NBu4OAc	Et3N	i PrOH	1:5	51%
11	AcOH	Et3N	i PrOH	1:7	28%
12	NaOAc	Et3N	i PrOH	1:12	49%
13	LiOAc	Et3N	i PrOH	1:12	53%
14 , ,	LiOAc	Et3N	i PrOH	1:12	65%

^aConditions: 1a (0.2 mmol, 1.0 equiv), 2a (1.5 equiv), Pd­(OPiv)₂ (7 mol %), additive (1.0 equiv), and base (1.0 equiv) were stirred in ⁱ PrOH (0.2 M) under a N₂ atmosphere at 60 °C for 24 h. The yields were determined by crude ¹H NMR using 1,2-dibromoethane as an internal standard.

^b12 h, Pd­(OAc)₂ (10 mol %).

^cIsolated yield.

^d48 h.

^eEt₃N (2.0 equiv).

Substrate Scope of C–H Activation Reaction and Heck Reaction of (2Z,4E)-5-Substituted Penta-2,4-dien-1-ols

With the optimal reaction conditions established, we explored the scope of conjugated dienols (Scheme ). In both the C–H activation and Heck reactions, dienols bearing electron-donating groups (e.g., alkyl, alkyloxy) as well as electron-withdrawing groups (e.g., halogens, trifluoromethyl) produced the desired products with good yields and stereoselectivities (3b–3f, 4b–4f). Dienols substituted with polycyclic rings (e.g., naphthyl) and heteroaryl groups (e.g., thienyl) also showed favorable performance (3g, 3h, and 4g). Conversely, dienols with aliphatic substitutions exhibited lower reactivity, achieving only 33% conversion for the C–H activation reaction and 51% for the Heck reaction, even when the temperature was increased or the reaction time was extended. Fortunately, stereoselectivity was maintained in both cases (3i, 4i).

2. Scope of C–H Activation and Heck Reaction of (2Z,4E)-5-Substituted Penta-2,4-dien-1-ols .

^a Unless otherwise noted, C–H activation reactions were performed by using 1 (0.2 mmol, 1.0 equiv), 2a (1.5 equiv), Pd­(OPiv)₂ (7 mol %), LiOAc (1.0 equiv), and Et₃N (2.0 equiv) in ⁱ PrOH (0.2 M) at 60 °C for 48 h under a N₂ atmosphere. Heck reactions were performed by using 1 (0.2 mmol, 1.0 equiv), 2a (1.5 equiv), Pd­(OPiv)₂ (7 mol %), and K₂CO₃ (1.0 equiv) in ⁱ PrOH (0.2 M) at 60 °C for 24 h under a N₂ atmosphere.

^b 80 °C.

^c 100 °C, 48 h.

Optimization of Reaction Conditions for the Alkynylation of (2E,4E)-5-Substituted Penta-2,4-dien-1-ols

Building on our previous findings, we aimed to expand the substrate scope for C–H bond activation and alkynylation by using (2E,4E)-5-substituted penta-2,4-dien-1-ols as starting materials (Table ). We investigated various additives to modulate the stereoselectivity of the alkynylation product, which was obtained in 65% yield with more than 20:1 stereoselectivity when NBu₄OAc was used as the acetate additive (Table , entries 1–4). Further optimization indicated that lower loading levels of the additive were also effective (entry 5). By adjusting the amount of bromoalkyne 2a and the type of catalyst, we identified entry 7 as the optimal condition for synthesizing 4a, achieving a yield of 85% with more than 20:1 stereoselectivity (entries 6–7).

2. Optimization of Reaction Conditions for the Alkynylation of (2E,4E)-5-Phenylpenta-2,4-dien-1-ol .

entry	additive	catalyst	ratio (4a:3a)	yield
1	KOAc	Pd(OPiv)2	4:1	54%
2	NaOAc	Pd(OPiv)2	5:1	66%
3	NBu4PF6	Pd(OPiv)2	5:1	71%
4	NBu4OAc	Pd(OPiv)2	>20:1	65%
5	NBu4OAc	Pd(OPiv)2	>20:1	65%
6 ,	NBu4OAc	Pd(OPiv)2	>20:1	80%
7 , ,	NBu4OAc	Pd(OAc)2	>20:1	85%

^aConditions: 1a′ (0.2 mmol, 1.0 equiv), 2a (1.5 equiv), catalyst (7 mol %), additive (1.0 equiv), and K₂CO₃ (1.0 equiv) were stirred in ⁱ PrOH (0.2 M) under a N₂ atmosphere at 60 °C for 24 h. The yields were determined by crude ¹H NMR using 1,2-dibromoethane as an internal standard.

^bNBu₄OAc (0.5 equiv).

^c 2a (3.0 equiv).

^dIsolated yield.

Substrate Scope of C–H Activation Reaction of E-Dienols

Under the optimized conditions, we explored the substrate scope, as illustrated in Scheme . Phenyl rings bearing electron-donating groups (e.g., alkoxy, dimethylamino) or electron-withdrawing groups (e.g., halogens, trifluoromethyl, esters, and nitro) at the ortho or para positions were well tolerated, yielding the desired alkynylation products in 71–85% yield with excellent E-selectivities (4a, 4c, 4d, 4f, 4g, and 4j–4n). Notably, substrates containing bromo groups were also well tolerated, successfully undergoing alkynylation in a yield of 77% (4l). Bulky polycyclic rings substituted on (2E,4E)-5-substituted penta-2,4-dien-1-ols (e.g., naphthyl, biphenyl, tetrastyrene) and heteroaryl groups (e.g., furyl, indolyl, thienyl) were compatible as well (4g, 4o–4s). A variety of aliphatic-substituted dienols underwent alkynylation with moderate yields (4t–4v). Excellent stereoselectivity was achieved by extending the reaction time, resulting in conjugated polyenyne products 4x and 4y. Trisubstituted conjugated dienol compounds were also obtained in moderate yields by modulating the reaction conditions. Due to the instability of 1za, the product 4za was obtained in only 39% yield, but its stereoselectivity was still maintained (4y–4za). Conjugated dienols substituted with carbazole successfully underwent alkynylation under the standard conditions (4zb). The catalytic system was not limited to primary alcohols; we were pleased to find that easily oxidized secondary alcohols were also viable substrates in this reaction. Incorporation of alkyl and aryl groups at the α carbon adjacent to the hydroxyl group yielded good results (4zc, 4zd). Tertiary alcohols with high steric hindrance and diol compounds were able to undergo alkynylation in moderate yields (4ze, 4zf). Sterically demanding aryl substituents, such as 2,6-dichlorinated phenyl groups, were well tolerated and afforded 4zg in a 55% yield. Additionally, the Pd/OAc^– catalytic system was applicable to the regio- and stereoselective alkenyl C–H arylation of this type of dienol with alkoxy, amide, and benzofuranyl groups showing good tolerance in this system (5a–5d).

3. Substrate Scope of C–H Activation Reaction of E-Dienols .

^a Unless otherwise noted, all reactions were performed by using 1′ (0.2 mmol, 1.0 equiv), 2 (0.6 mmol, 3.0 equiv), Pd­(OAc)₂ (7 mol %), NBu₄OAc (0.5 equiv), and K₂CO₃ (1.0 equiv) in ⁱ PrOH (0.2 M) at 60 °C for 24 h under a N₂ atmosphere.

^b 48 h.

^c 48 h at 80 °C.

^d 72 h, Pd­(OAc)₂ (10 mol %), NBu₄OAc (1.0 equiv), K₂CO₃ (2.0 equiv).

^e 72 h, Pd­(OAc)₂ (10 mol %).

^f 1a′ (0.2 mmol, 1.0 equiv), aryl iodide (1.5 equiv), Pd­(OPiv)₂ (7 mol %), NBu₄OAc (1.0 equiv), and KOAc (2.0 equiv) in ⁱ PrOH (0.4 M) at 80 °C for 24 h under a N₂ atmosphere.

Derivatization Reactions and Photophysical Property Investigations of Dienyne Derivatives

To evaluate the practicality of conjugated dienynes, various derivatization reactions were conducted (Scheme i). For example, treating product 4a with TBAF resulted in conversion to the corresponding terminal alkyne 6a. This was followed by palladium-catalyzed intercalation of terminal alkyne 6a, leading to esterification and forming 6b. Moreover, the Sonogashira cross-coupling reaction of 6a with iodobenzene successfully produced the arylated conjugated alkyne 6f, achieving an 81% yield. Additionally, 6a underwent a Sonogashira cross-coupling reaction with o-hydroxy iodobenzene, followed by O-attack, resulting in a 5-endo-dig cyclization that yielded benzofuran compound 6c. The coordination of the tosyl-protected amine group (NHTs) to palladium was also observed, leading to the generation of the cyclization product 6d. Furthermore, the intermolecular Glaser-Hay coupling reaction yielded bisalkyne 6e in an impressive 99% yield. The 1,3-dipolar cycloaddition reaction with (Z)-N-hydroxybenzimidoyl chloride produced oxazole 6g. Notably, the stereoselectivity of 6a was preserved throughout all transformations.

4. Derivatization Reactions and Photophysical Property Investigation .

^a (i) (a) TBAF, THF, H₂O; (b) Cs₂CO₃, PdI₂, thiourea, CBr₄, MeOH, CO; (c) CuI, Et₃N, Pd­(PPh₃)₂Cl₂, 2-iodophenol, DMF; (d) Pd­(PPh₃)₂Cl₂, CuI, Et₃N, N-Tosyl-2-iodoaniline, DMF; (e) TMEDA, CuI, DCM; (f) Pd­(PPh₃)₂Cl₂, CuI, Et₃N, PhI, DMF; (g) (Z)-N-hydroxybenzimidoyl chloride, KHCO₃, CuSO₄, Na ascorbate, ^t BuOH/H₂O (1/1). (ii) Emission spectra of 6f in tetrahydrofuran (10^–4 M) (λ_ex = 330 nm). (iii) Emission spectra of 4p in tetrahydrofuran with different water ratios (10^–4 M) (λ_ex = 350 nm).

To explore the potential application of alkynylation products in photoluminescence, we conducted further research on the optical properties of compounds 6f and 4p (Scheme ). Initially, we examined the fluorescence emission properties of 6f, as illustrated in Scheme ii. The maximum emission wavelength of compound 6f in THF was found to be approximately 407 nm. The CIE coordinates indicated that 6f emits deep blue fluorescence when excited by light (CIE x, y (0.06, 0.05)). In recent years, aggregation-induced emission (AIE) has been utilized in various fields, including OLED materials and fluorescent probes and has become a growing area of research. Consequently, we further investigated whether our synthetic compounds exhibit AIE properties. The fluorescent emission behavior of compound 4p was tested in THF with varying water ratios. Notably, as the water fraction increased, compound 4p demonstrated a significantly enhanced fluorescence emission (Scheme iii). In fact, at a water content of 90%, the emission intensity was approximately 15 times greater than that in pure THF solution. These results indicate that compound 4p possesses AIE properties.

Mechanistic Investigation

Parallel reactions of substrate 1a′ and deuterated 1a′ with bromoalkyne 2a were conducted (Scheme a). The obtained KIE data (kinetic isotope effect k _H/k _D = 2.5), derived from their initial rate constants, suggested that the C–H cleavage step is likely the rate-determining step for the alkynylation process. To investigate whether an Z/E isomerization process occurred among the starting materials and products during the reaction, we shortened the reaction time for the C–H activation of 1a. The results showed that both the remaining 1a and product 3a maintained a single configuration. To rule out the possibility that 1a was converted to 1a′ within the reaction system, followed by a rapid transformation of 1a′ to 3a via the Heck coupling process, we added 1a′ under C–H activation conditions and detected only product 4a. The results indicate that no isomerization of the starting material occurs during the reaction. Meanwhile, the possibility that 1a is first converted to 4a and then isomerized to 3a is excluded.

5. Mechanistic Studies.

To rule out the possibility that 1a first forms 3a in the Heck reaction and then rapidly isomerizes to the thermodynamically more stable 4a, we added 3a to the Heck reaction system. It was observed that the Z/E stereoselectivity of 3a remained >20:1. Therefore, these results indicated that the Z/E isomerization of the products did not occur during the reaction (Scheme b). To ascertain whether the reaction pathway involves C–H activation or anti-β-H elimination, we tested whether 1a′-D could undergo C–H bond cleavage in the absence of 2a. Since allyl alcohols can be readily oxidized to aldehydes in the catalytic system, we observed a decrease in the deuteration ratio of the alkenyl C–H bond from 95% to 68% when AcOH was used as a quenching reagent (Scheme c). This data supports the conclusion that the reaction mechanism involves C–H activation through a four-membered cyclic palladium intermediate.

Based on the experimental results and related literature reports, a plausible mechanism is proposed in Scheme . In the presence of an acetate ion as an additive, deprotonation occurs with the −OH group acting as a directing group, leading to the formation of intermediate I. During this process, acetate ions serve as an intramolecular base to assist in the cleavage of C–H bonds and promote the progression of the C–H activation reaction. The oxidative addition of the palladacycle intermediate with the alkynyl bromide then takes place, yielding Pd­(IV) species II′. Subsequent reductive elimination results in desired product 3. Alternatively, alkyne migratory insertion into palladacycle II may occur, followed by β-Br elimination to release the final products. In the absence of additives, the oxidative addition of Pd(0) with the alkynyl bromide leads to the formation of Pd­(II), which is followed by migratory insertion, C–C bond rotation, and subsequent syn β-H elimination to yield product 4.

6. Proposed Reaction Pathway.

Conclusion

In summary, we have developed a palladium-catalyzed alkynylation reaction of conjugated dienols. This novel method offers a straightforward and efficient approach for synthesizing a diverse range of compounds with dienyne scaffolds, showcasing an impressive substrate scope that accommodates various functional groups and structural motifs. One of the key features of this method is its precise control over both stereoselectivity and regioselectivity, which are essential for producing compounds with the desired configurations. Furthermore, we have found that the introduction of acetate ions into the catalytic system serves as an effective strategy for modulating product stereoselectivity. This capability enables the fine-tuning of reaction conditions to optimize the formation of specific stereoisomers, thereby enhancing the overall utility of the method. Ultimately, this approach provides a reliable and effective strategy for constructing valuable dienyne compounds with promising applications in various fields.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacsau.5c01417.

• Experimental procedures; characterization data for all new compounds (PDF)

All authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.