Synthesis of highly polysubstituted cyclopentadienes through an oxypalladation initiated domino Heck reaction of internal alkynes

Abstract

We describe a facile approach to prepare a variety of densely polysubstituted cyclopentadiene derivatives in good yields (52%–75%) through a palladium(II)-catalyzed oxypalladation initiated domino Heck reaction of internal alkynes with diverse carboxylic acids and phthalimide in the presence of glycine as the ligand. Control experiments revealed that the free NH₂ and COOH groups of glycine played an important role in accelerating the reaction. The reaction showed a broad substrate scope for carboxylic acids and was easily performed on a gram scale. The present method features high regioselectivity toward internal alkynes, enables the formation of four C–O/C–C bonds in a one-pot reaction, and is the first example of accessing cyclopentadiene scaffolds via an oxypalladation reaction.

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Cyclopentadiene scaffolds are an important class of cyclic molecules that are found in natural products and biologically active compounds and exhibit diverse biological activities; some representative examples, Guaiazulene, Urceoloids A, Oldhamine A, and Daphnicyclidins A, are shown in Fig. 1.¹ They serve not only as useful organic building blocks² but also as elegant diene-ligands (La–Ld, Fig. 1) that have been successfully applied in asymmetric C–H bond activation and related transformations.³ Given their significance, the development of novel strategies for the synthesis of cyclopentadienes has attracted much attention in the past decades.⁴ Consequently, a variety of synthetic methodologies have been developed for the synthesis of cyclopentadiene scaffolds (Scheme 1A), including [3 + 2] cycloadditions,⁵ [2 + 2 + 1] cycloadditions,⁶ cycloisomerization or annulation reactions,⁷ Alder–Ene reactions,⁸ rearrangement reactions,⁹ and other cascade transformations.¹⁰ However, these procedures are still limited by structural complexity, and the need for unstable reagents, complex starting materials, and harsh reaction conditions. Therefore, the development of novel methods to prepare cyclopentadiene scaffolds is still challenging, especially for densely polysubstituted cyclopentadienes owing to the steric hindrance on the five-membered ring.

Fig. 1 Natural products and ligands containing the cyclopentadiene unit.

Scheme 1 Strategies to prepare densely substituted cyclopentadienes.

Recently, domino reactions have been defined as chemical transformations that involve the formation of two or more bonds under the same conditions in a consecutive manner, due to their immense variety of applications and the multiple possible combinations of different individual steps. Domino reactions have proven themselves not only as efficient and economical strategies but also as an elegant concept in organic syntheses.¹¹ Among them, a highly versatile variant is the palladium-catalyzed domino Heck reaction.¹² The difficulty in this domino reaction lies in achieving consecutive carbon–carbon bond formation, wherein the intermediate organometallic species must be trapped through cross-couplings catalyzed by the same metal. Therefore, the development of highly selective domino Heck reactions is still challenging. On the other hand, palladium-catalyzed cascade transformations of alkynes involving oxypalladation as the key step remain a prominent and emerging strategy for the synthesis of structurally complex molecules in a single synthetic operation.¹³ The highly reactive σ-vinylpalladium intermediates generated in situ undergo further cascade transformations with various electrophiles to deliver diverse products.¹⁴ In traditional oxypalladation of alkynes, one molecule of alkyne always undergoes oxypalladation and is subsequently trapped by other electrophiles (including unsaturated carbonyl compounds, alkenes, nitriles, isonitriles, etc.) and oxidants to afford various scaffolds (Scheme 1B).¹⁵ However, up to now, oxypalladation initiated domino Heck reactions of alkynes, particularly triple Heck reactions involving three molecules of alkynes, is still unexplored. Based on our group's previous studies on Pd(IV) in the Heck reaction,¹⁶ herein, we report for the first time an unexpected oxypalladation-initiated domino Heck reaction of internal alkynes to prepare a variety of densely polysubstituted cyclopentadiene derivatives (Scheme 1C).

Initially, 3-hexyne 1a was chosen as the model substrate to optimize the reaction conditions of the oxypalladation initiated domino Heck reaction to prepare polysubstituted cyclopentadienes. As shown in Table 1, when 3-hexyne 1a was reacted with 5.0 equiv. of acetic acid 2a in the presence of Pd(OAc)₂ (5 mol%) and PhI(OAc)₂ as an oxidant in DCE at 80 °C, the desired cyclopentadiene product 3aa was obtained in 30% yield (Table 1, entry 1). The structure of 3aa was confirmed as having Z-geometry for the exo-double bond based on the NOESY spectra. Replacing the oxidant PhI(OAc)₂ with Cu(OAc)₂ and H₂O₂ also afforded product 3aa in 24% and 14% yields, respectively (Table 1, entries 2 and 3). Next, the influence of substituted ArI(OAc)₂ was evaluated (Table 1, entries 4–8). When iodine(III) oxidants with electron-donating and electron-withdrawing groups such as 4-MeOC₆H₄I(OAc)₂ and 4-CF₃C₆H₄I(OAc)₂ were tested under the standard reaction conditions, product 3aa was obtained in 46% and 41% yields, respectively (Table 1, entries 4 and 5). Using 3,5-Me₂C₆H₃I(OAc)₂ and 3,5-(CF₃)₂C₆H₃I(OAc)₂ diminished the yields of 3aa (Table 1, entries 6 and 7). To our delight, 2,4,6-Me₃C₆H₂I(OAc)₂ obviously improved the yield of 3aa to 57% (Table 1, entry 8). The solvent screening trials revealed that DCE gave 3aa in a higher yield than toluene, THF, and MeCN, and the reaction did not work in MeOH (Table 1, entries 8 vs. 9–12). Several types of N- or N,O-ligands were tested. The addition of bipyridine L1 and bioxazoline L2 did not improve the yield of 3aa (Table 1, entries 13 and 14). Interestingly, the use of the amino alcohol ligand L3 furnished 3aa in 60% yield while glycine L4 obviously improved the yield of 3aa to 71% (Table 1, entries 15 and 16). Finally, the amino acid ligand screening trials demonstrated that ligands L5–L8 all gave 3aa in good yields but glycine L4 gave better results compared to L5–L8 (Table 1, entries 17–20). Other palladium(II)-catalysts, such as Pd(OOCCF₃)₂ and PdCl₂, delivered 3aa in 17% and 35% yields, respectively (Table 1, entries 21 and 22). Therefore, the optimal reaction conditions for the preparation of cyclopentadiene 3aa were 5 mol% of Pd(OAc)₂ combined with glycine L4 as the ligand and 2,4,6-Me₃C₆H₂I(OAc)₂ as the oxidant in DCE at 80 °C.

Table 1 Optimization of the reaction conditions^a

Entry	L	Oxidant	Solvent	3aa ^b (%)
a Reaction conditions: 1a (0.9 mmol), Pd(OAc)2 (5 mol%), ligand (10 mol%), HOAc 2a (5.0 equiv.), oxidant (2.0 equiv.), solvent (3.0 mL), 80 °C, 16–24 h. b Isolated yield. c Pd(OOCCF3)2 (5 mol%) was used. d PdCl2 (5 mol%) was used.
1	—	PhI(OAc)2	DCE	30
2	—	Cu(OAc)2	DCE	24
3	—	H2O2	DCE	14
4	—	4-MeOC6H4I(OAc)2	DCE	46
5	—	4-CF3C6H3I(OAc)2	DCE	41
6	—	3,5-Me2C6H3I(OAc)2	DCE	34
7	—	3,5-(CF3)2C6H3I(OAc)2	DCE	32
8	—	2,4,6-Me3C6H2I(OAc)2	DCE	57
9	—	2,4,6-Me3C6H2I(OAc)2	Toluene	37
10	—	2,4,6-Me3C6H2I(OAc)2	THF	42
11	—	2,4,6-Me3C6H2I(OAc)2	MeCN	10
12	—	2,4,6-Me3C6H2I(OAc)2	MeOH	—
13	L1	2,4,6-Me3C6H2I(OAc)2	DCE	54
14	L2	2,4,6-Me3C6H2I(OAc)2	DCE	35
15	L3	2,4,6-Me3C6H2I(OAc)2	DCE	60
16	L4	2,4,6-Me3C6H2I(OAc)2	DCE	71
17	L5	2,4,6-Me3C6H2I(OAc)2	DCE	65
18	L6	2,4,6-Me3C6H2I(OAc)2	DCE	68
19	L7	2,4,6-Me3C6H2I(OAc)2	DCE	59
20	L8	2,4,6-Me3C6H2I(OAc)2	DCE	70
21	L4	2,4,6-Me3C6H2I(OAc)2	DCE	17^c
22	L4	2,4,6-Me3C6H2I(OAc)2	DCE	35^d

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With the optimized conditions in hand, the substrate scope of the oxypalladation of internal alkynes with carboxylic acids to prepare polysubstituted cyclopentadienes was explored (Scheme 2). Symmetrical internal alkynes such as 3-hexyne (1a), 4-octyne (1b), 5-decyne (1c), and 6-dodecyne (1d) smoothly underwent the reaction to afford the corresponding products 3aa–3da in good yields ranging from 58% to 75%. To our delight, the unsymmetrical alkyne 1e was also tolerated, affording the desired product 3ea in 56% yield with high regioselectivity. When glycine L4 was replaced with the chiral amino acid ligand L8, product 3ea bearing a stereocenter was obtained in 40% yield but without any enantioselectivity at room temperature. To our surprise, diphenylacetylene (1f), methyl protected 2-butyne-1,4-diol (1g), and terminal alkyne (1h) were not compatible with this transformation and the reactions turned out to be messy. Next, the nucleophiles were evaluated. Using propanoic acid (2b) afforded the desired product 3ab in 73% yield accompanied by 3aa in 5% yield and these two mixed compounds could be easily separated cleanly by column chromatography. Benzoic acid (2c) as the nucleophile delivered 3ac in 69% yield accompanied by 3aa in 10% yield. Various substituted carboxylic acids bearing electron-donating groups and electron-withdrawing groups at the para-, meta-, and ortho-positions of the aryl ring reacted smoothly to afford the desired products 3ad–3am in good yields ranging from 52% to 73%. 2-Naphthoic acid 2n as the nucleophile furnished product 3an in 61% yield accompanied by 3aa in 9% yield. To our delight, 2-furoic acid 2o was tested under the standard conditions, affording the desired product 3ao in 56% yield accompanied by 3aa in 18% yield. Carboxylic acid 2p with a 2-nitro group delivered product 3ap in 72% yield accompanied by 3aa in 5% yield. Interesting, when HOAc was replaced with phthalimide 2q as the nucleophile, the desired product 3aq was also obtained in 54% yield but was accompanied by 3aa in 25% yield. Other N-atoms as nucleophiles, such as acetanilide (2r) and Ts-protected aniline (2s), could not deliver the corresponding cyclopentadienes 3ar and 3as, but product 3aa was obtained in 62% and 36% yields, respectively.

Scheme 2 Substrate scope for the preparation of polysubstituted cyclopentadienes 3. (Reaction conditions: 1 (0.9 mmol), Pd(OAc)₂ (5 mol%), glycine L4 (10 mol%), NuH 2 (5.0 equiv.), 2,4,6-Me₃C₆H₂I(OAc)₂ (2.0 equiv.), DCE (3.0 mL), 80 °C, 16–24 h; isolated yield; ^a rr = regioselectivity ratio; ^b glycine L4 was replaced with L8; ^c the yield of 3aa.)

To better understand the role of the ligand, control experiments were performed (Scheme 3). When methyl glycinate L9 was used as the ligand, product 3aa was obtained only in 41% yield, suggesting that the COOH group in glycine played an important role (Scheme 3-1). Boc-glycine L10 afforded 3aa in 47% yield under the standard conditions (Scheme 3-2). Surprisingly, methyl Boc-glycinate L11 gave 3aa only in 26% yield (Scheme 3-3). These results revealed that the free NH₂ and COOH groups had a great impact on the reaction. When a 1 : 1 mixture of 2b with 4-OMe and 2i with 4-NO₂ was subjected to the standard conditions, it was found that the initial ratio of products 3ab and 3ai was 1 : 4, indicating that the benzenecarboxylic acid with electron-withdrawing groups reacted faster than that with electron-donating groups (Scheme 3-4).

Scheme 3 Control experiments.

Based on the oxypalladation and Heck reaction pathways, a possible mechanism for the formation of cyclopentadiene 3aa from 1a and HOAc 2a was proposed (Scheme 4). Initially, Pd(OAc)₂ combined with glycine L4 to give the active species Pd(II)/L, which then coordinated with 3-hexyne 1a to form intermediate A. Oxypalladation of intermediate A with HOAc afforded the vinylpalladium species B and the insertion of B into the second molecule of 1a through the Heck reaction provided intermediate C. Then, intermediate C underwent the Heck reaction with the third molecule of 1a, producing intermediate D and sequential intramolecular insertion of the vinylpalladium to the double bond through exo-cyclization afforded intermediate E. Finally, β-H elimination of E gave product 3aa and released the Pd(II)–H species F, which underwent reductive elimination and oxidative addition with the iodine(III) oxidant to complete the catalytic cycle. Therefore, the oxidative ability of the iodine(III) reagent had a great impact on the reaction efficiency, which might be dependent on the substituent effect of iodine(III) reagents.

Scheme 4 Proposed mechanism.

To show the utility of this oxypalladation initiated domino Heck reaction for the preparation of polysubstituted cyclopentadienes, a gram scale reaction was performed. As shown in Scheme 5-1, when 1.23 g of 3-hexyne 1a (15.0 mmol) was used under the standard conditions, product 3aa was obtained in 65% yield (0.988 g). Interestingly, when cyclopentadiene 3aa was treated with K₂CO₃ in MeOH at room temperature, the corresponding polysubstituted cyclopentadiene scaffold was obtained in 89% yield. Its structure was determined using 2D NMR spectroscopy and is proposed to form via deprotection and keto–enol tautomerism. Finally, the reduction of compound 4 with LiAlH₄ afforded alcohol 5 in 84% yield (Scheme 5-2).

Scheme 5 Gram scale preparation of 3aa and its transformations.

In summary, we have developed a facile method to prepare various highly polysubstituted cyclopentadienes in moderate to good yields and high regioselectivity from internal alkynes through an oxypalladation initiated domino Heck reaction strategy. Glycine was identified as an efficient ligand and played important roles in this domino reaction. The cyclopentadiene product can be easily prepared on a gram scale and converted into functionalized polysubstituted cyclopentadiene scaffolds.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data underlying this study are available in the published article and its supplementary information (SI). Supplementary information: experimental details and characterization of all compounds and copies of ¹H and ¹³C NMR for new compounds. See DOI: https://doi.org/10.1039/d5qo01231g.

Acknowledgements

Financial support provided by the National Natural Science Foundation of China (22571050), the Natural Science Foundation of Guangxi (2025GXNSFGA069003 and 2023GXNSFDA026025), and the Guangxi Bagui Youth Program is greatly appreciated.

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Footnote

† These authors contributed equally to this work.

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