Visible light-mediated gold-catalyzed alkynylative cyclization of allenoates with iodoalkynes for the synthesis of β-alkynyl-γ-butenolides

Abstract

A method for the tandem cyclization/alkynylation of allenoates with iodoalkynes via gold catalysis under light irradiation is described. This transformation features a broad substrate scope, good functional group tolerance, and compatibility with heterocyclic substrates. The reaction proceeds smoothly at room temperature by using cheap, readily available acriflavine (ACF) as a photocatalyst, and offers β-alkynyl-γ-butenolides derivatives in moderate to good yields. Initial mechanistic studies suggest that a vinylgold(I) complex acts as a key intermediate, which would undergo photosensitization from the ACF singlet excited state. The corresponding energy transfer would promote the oxidative addition of the iodoalkyne partner to deliver C(sp²)–C(sp) coupling products after reductive elimination.

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Introduction

Homogenous gold catalysis has emerged as a powerful and versatile tool for a broad range of chemical transformations during the past decades. In these reactions, either gold(I) or gold(III) complexes most frequently act as a carbophilic π-acidity that activates carbon–carbon multiple bonds (such as alkenes, allenes, and especially alkynes) towards nucleophilic attack. The gold center does not change the oxidation state in the whole catalytic cycle.¹ Over the past few years, there has been intense interest in developing Au(I)/Au(III) catalytic processes to expand the scope of gold-catalyzed processes.² Due to the high redox potential of the Au(I)/Au(III) couple (1.41 V) (compared to Pd(0)/Pd(II)),³ stoichiometric and strong external oxidants are usually required to access Au(I)/Au(III) catalytic processes.⁴ However, some of the transformations require harsh conditions, costly and hazardous reagents. Therefore, there has been a necessity to devise new pathways that are more efficient to promote it.⁵ Firstly, the ligand design for gold(I) has emerged as a viable alternative, especially the use of hemilabile (P, N) ligands for versatile catalytic cross-coupling reactions that have been recently developed.⁶ Secondly, the groups of Glorius,⁷ Toste,⁸ and Hashmi⁹ have devised dual gold/photoredox catalytic systems, using aryl diazonium or iodonium salts easy to reduce as SET partners, to allow Au(I)/Au(III) catalytic cycles in arylation reactions under mild conditions. This methodology has been applied to various substrates, including ortho-alkynyl phenols as a flexible synthesis of 3-aryl benzofurans,¹⁰ while some of these reactions can proceed smoothly without photocatalysts.^11,12 Overall, the development of these dual gold/photoredox-catalyzed processes has been limited by the need for easily reduced radical precursors.

On the other hand, haloalkynes are widely used in synthetic chemistry, particularly as effective partners in transition metal-catalyzed cross-coupling reactions.¹³ Haloalkynes have been utilized in gold-catalyzed transformations without light activation or under light activation.¹⁴ In 2019, the Fensterbank group successfully replaced aryl diazoniums with alkynyl iodide partners in dual photo/gold-catalyzed alkynylative cyclization of o-alkynylphenols leading to valuable alkynylbenzofuran scaffolds. Further mechanistic and modeling studies support that photosensitized energy transfer takes place, rather than an electron transfer pathway, enabling the oxidative addition of iodoalkynes onto organogold intermediates in their excited triplet state (Scheme 1a, A).¹⁵ Recently, access to 2,3-disubstituted indoles from o-alkynyl aniline and iodoalkyne derivatives via a gold-catalyzed sequence under visible-light irradiation and in the absence of an exogenous photocatalyst was also developed. Mechanistic studies converge on the formation of potassium sulfonylamide emissive aggregates in the reaction medium (Scheme 1a, B).¹⁶ Extending the scope of possible partners for these transformations is highly desirable, particularly for the visible cyclization/alkynylation tandem of allenoates with iodoalkynes to generate β-alkynyl-γ-butenolides.

Scheme 1 Gold-catalyzed tandem cyclization/alkynylation.

To date, several research groups have developed the synthesis of β-alkynyl-γ-butenolides via gold catalysis. In 2010, the Gouverneur group reported a gold(I)-catalyzed cascade cyclization-oxidative alkynylation of allenoates with various terminal alkynes using selectfluor acting as an external oxidant to prepare β-alkynyl-γ-butenolides (Scheme 1b, A).¹⁷ A few years later, the Hashmi group improved this method to avoid the use of any external oxidant. The cyclization–alkynylation reaction of allenoates was established for various alkynyl bromides via gold catalysis at 50 °C for 4 days (Scheme 1b, B).¹⁸ The Patil group reported the electrochemical redox gold catalysis for the oxy-alkynylation of allenoates with terminal alkynes (Scheme 1b, C).¹⁹ However, these approaches still suffered from the use of a strong external oxidant,¹⁷ long reaction time (4 days),¹⁸ or a special electrochemical system¹⁹ required. Very recently, Ma and co-workers developed Rh(III)/Cu(I) co-catalyzed cyclic oxy-alkynylation of 2,3-allenoic acids with alkyl alkynes to construct 4-alkynyl furan-2(5H)-one derivatives. Also, aryl-substituted acetylenes were able to produce the target products smoothly but with a lower yield.²⁰ Interestingly, our preliminary study^15a showed the feasibility of the photosensitized cross-coupling of the corresponding vinylgold(I) intermediate with an iodoalkyne to produce β-alkynyl-γ-butenolides. Herein, we report the successful development of a dual gold and photocatalytic system applicable to the intramolecular alkynylative cyclization of allenoates with iodoalkynes (Scheme 1c). In this work, we use cheap, readily available acriflavine (ACF) as a photocatalyst, and common gold complexes as catalysts, under visible light irradiation to achieve β-alkynyl-γ-butenolides derivatives.

Results and discussion

We initiated our investigation by utilizing ethyl 2-methyldeca-2,3-dienoate 1a and 1-fluoro-4-(iodoethynyl)benzene 2a as model substrates for this transformation under various conditions (see ESI Section III for detailed conditions optimization†). Based on the previous work protocol, using (p-CF₃Ph)₃PAuCl as gold catalyst, Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆ ([Ir–F]) as photocatalyst, K₂CO₃ as base in MeOH resulted in alkynylation product 3a yield of 37%, accompanied by a 23% of iodoindole 3aa as iodocyclization by-product (Table 1, entry 1). Subsequently, we explored alternative conditions which led to an increased yield of product 3a to 46% in the presence of Ph₃PAuCl (10 mol%), and Rhodamine B (RB) (5 mol%) in degassed MeOH (0.1 M) under blue LEDs irradiation (Table 1, entry 2). Other organic photocatalysts such as Eosin Y, 4CzIPN and Fukuzumi catalyst (FKC, 9-mesitylene-10-methylacridinium perchlorate) etc. were examined but they did not result in an improvement of the yield of 3a (Table 1, entries 3–5) (detail see ESI Section III.1†). We then turned our attention to acriflavine (ACF), a mixture of 3,6-diamino-10-methylacridinum chloride (trypaflavine) and 3,6-diaminoacridine (proflavine) in a 1 : 6 molar ratio. ACF is an old drug that was previously used as a trypanocidal agent during World War II,²¹ which has been extensively researched in the field of biomedical chemistry,²² yet its use as photosensitizer has not been reported in organic synthesis. The use of ACF increased the yield to 53% (Table 1, entry 6). Keeping with ACF, lower yields were obtained when NaHCO₃ was replaced by Na₂CO₃, Cs₂CO₃, or K₂HPO₄ (Table 1, entries 7–9). When cationic Au(I) complexes, such as Ph₃PAuNTf₂ and Ph₃PAuOTf, were utilized in the reaction, 55% and 61% yield of 3a were obtained respectively (Table 1, entries 10 and 11). The addition of 10 mol% of 1,10-phenanthroline as an additive increased the yield to 78% (Table 1, entry12), possibly due to some halogen bonding between phenanthroline and the alkynyl iodides might be at work.²³ Similarly, other amines such as 1,4-diazabicyclo[2.2.2] octane (DABCO) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were tested without improving the reaction (see ESI Section III.3†). When the amount of gold catalyst was decreased to 5 mol%, yield of 3a was reduced to 50% (Table 1, entry 13). In the control experiment, using proflavine (previously employed as photosensitizer)²⁴ instead of acriflavine reduced the yield of product 3a to 27% (Table 1, entry 14). The result is similar to that obtained without a PC (Table 1, entry 15). Furthermore, no product was detected when the reaction was performed in the absence of the gold catalyst (Table 1, entry 16). Additionally, significantly reduced yields of 3a were observed when acriflavine, 1,10-phenanthroline, or NaHCO₃ were absent (Table 1, entries 17 and 18). It is apparent that visible light and temperature play essential roles in this reaction. When the reaction was conducted in the dark at room temperature, only a 20% yield of product 3a was obtained (Table 1, entry 19), while increasing the temperature to 50 °C led to a yield of 40% (Table 1, entry 20).

Table 1 Optimization of reaction conditions^a

Entry	[Au]	[PC]	Base	Ad.	3a yield (%)	3aa yield (%)
a Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol, 1.5 eq.), catalyst (10 mol%), photocatalyst (5 mol%), base (0.2 mmol, 1 eq.), additive (10 mol%), MeOH (2.0 mL), room temperature, blue LEDs, 24 h. Yields were determined by ^1H NMR using 1,3,5-trimethoxybenzene as the internal standard, the yield in parentheses is the isolated yield. b [Au-CF3] = (p-CF3Ph)3PAuCl (5 mol%); [Ir–F] = Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1 mol%). c 5 mol% of Ph3PAuOTf was used. d Reaction performed under darkness. e Reaction performed at 50 °C. f Isolated yield.
1^b	[Au-CF3]	[Ir–F]	K2CO3	—	37	23
2	Ph3PAuCl	RB	NaHCO3	—	46	17
3	Ph3PAuCl	Eosin Y	NaHCO3	—	35	14
4	Ph3PAuCl	4CzIPN	NaHCO3	—	45	20
5	Ph3PAuCl	FKC	NaHCO3	—	40	16
6	Ph3PAuCl	ACF	NaHCO3	—	53	18
7	Ph3PAuCl	ACF	Na2CO3	—	19	10
8	Ph3PAuCl	ACF	Cs2CO3	—	39	16
9	Ph3PAuCl	ACF	K2HPO4	—	23	12
10	Ph3PAuNTf2	ACF	NaHCO3	—	55	18
11	Ph3PAuOTf	ACF	NaHCO3	—	61	20
12	Ph 3 PAuOTf	ACF	NaHCO 3	Phen.	80 (78)	15
13^c	Ph3PAuOTf	ACF	NaHCO3	Phen.	50	13
14	Ph3PAuOTf	Proflavine	NaHCO3	Phen.	27	12
15	Ph3PAuOTf	—	NaHCO3	Phen.	25	12
16	—	ACF	NaHCO3	Phen.	Nr	10
17	Ph3PAuOTf	—	NaHCO3	—	16	20
18	Ph3PAuOTf	ACF	—	Phen.	15	10
19^d	Ph3PAuOTf	ACF	NaHCO3	Phen.	20	14
20^d^,^e	Ph3PAuOTf	ACF	NaHCO3	Phen.	40	16

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With the optimized reaction conditions in hand, summarized in Table 1, entry 12, we then explored the scope of this transformation, as shown in Table 2. Initially, a series of substituted aryl iodoalkynes 2 were reacted with ethyl 2-methyldeca-2,3-dienoate 1a. Aryl iodoalkynes 2 bearing electron-withdrawing groups such as F, Cl, Br, CF₃, and OCF₃, were coupled with allenoates 1a affording the corresponding products in good yields (Table 2, 3a–3g). The best results were obtained with aryl iodoalkynes 2 containing halogen substituent in the para position compared with the ortho or meta positions (3avs.3b, 3c). The presence of electron-donating groups (Me, t-Bu, OMe) or the absence of substitution, led the β-alkynyl-γ-butenolides in moderate (3n) to good (3h–3m, 3o) yields. When 2-(iodoethynyl)naphthalene was used, the corresponding product was formed in moderate yields (3p). We next explored various aliphatic iodoalkynes bearing sterically diversified alkyl groups to give target products in fairly good yields (3q–3v). Notably, aliphatic iodoalkyne substituted with a strongly electron-withdrawing group (OTs) worked well to give the desired 3s products in 45% yield. Even, aliphatic iodoalkynes bearing a benzylic alcohol and O-acyl hydroxylamine groups were also tolerated to afford the product in moderate yields (3t–3v). In addition, we were pleased to find that 3-(iodoethynyl)thiophene and 3-(iodoethynyl)pyridine also gave in moderate yields of the corresponding product 3w and 3x. Gratifyingly, this method is also effective when applied to iodinated ethisterone derivative, producing the corresponding product 3y in 40% yield.

Table 2 Scope of iodoalkynes^a,b

a Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol, 1.5 eq.), Ph₃PAuOTf (10 mol%), Acriflavine (5 mol%), NaHCO₃ (0.2 mmol, 1 eq.), 1,10-phenanthroline (10 mol%), MeOH (2.0 mL), room temperature, blue LEDs, 24 h. b Isolated yield.

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In a second step, the scope and limitations of the reaction of various allenoates 1 with 1-fluoro-4-(iodoethynyl)benzene 2a were explored, as shown in Table 3. Various sterically alkyl-substituted allenoates in the R1 position afforded the corresponding products (4a–4d) in yields ranging from 38 to 80%. When using the methyl-substituted allenoate at R1, the corresponding product 4a was obtained in 80% yield. However, when the allenoate was substituted by two methyl groups at this position, the reaction gave the expected product 4d in lower yield. In particular, allenoate substituted with a bulky tert-butyl group gives the desired product 4c in moderate yield. To our delight, when we used allenoic acids instead of allenoates, providing desired product 4c in 90% yield. Furthermore, allenoates with other substituents in the R1 position, such as bromoethyl, benzyl and allyl, provided the corresponding alkynylating cyclization products (4e–4g) in equally appreciable yields. And the structure of product 4f was confirmed by X-ray diffraction analysis, Cambridge Crystallographic Data Centre (CCDC) accession code no. 2374591.† Interestingly, when the methyl group was replaced by benzyl in the R2 position of the allenoates, the reaction proceeded smoothly and gave the desired product in a 45% yield (4h). We also tested phenylated or unsubstituted allenoates in position R1, but only a trace amount of corresponding products (4i–4j) was formed under these reaction conditions. A similar result was obtained when R2 was replaced by H-atom (4k).

Table 3 Scope of allenoates^a,b

a Reactions were performed with allenoates 1, unless otherwise noted. Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol, 1.5 eq.), Ph₃PAuOTf (10 mol%), Acriflavine (5 mol%), NaHCO₃ (0.2 mmol, 1 eq.), 1,10-phenanthroline (10 mol%), MeOH (2.0 mL), room temperature, blue LEDs, 24 h. b Isolated yield. c Allenoic acids instead of allenoates.²⁷

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In order to find a reasonable mechanism for this transformation, a series of control experiments was carried out (Scheme 2). Firstly, vinylgold(I) complex 5 was prepared in 92% yield by an independent route involving 1a, PPh₃AuCl and AgOTf,^15a,25 as shown in Scheme 2a. ³¹P NMR spectroscopy showed the expected single peak at 44 ppm. We were then able to confirm the formation of 5 using PPh₃AuOTf as the source of gold(I) by ³¹P NMR spectroscopy and the same peak at 44 ppm was observed (Scheme 2b). Finally, we showed that 5 was instantaneously and selectively formed from allenoate 1a under standard reaction conditions in the presence of iodoalkyne 2a. Accordingly, we did not observe by ³¹P NMR any peak corresponding to gold(III)-acetylide (Scheme 2c). These results indicated that vinylgold(I) complex 5 was a key intermediate for this transformation. Secondly, we performed the experiment of vinylgold(I) complex 5 with iodoalkyne 2a under photocatalyzed conditions for 3 h, yielding target product 3a almost quantitatively (Scheme 2d). However, a lower yield of 3a was obtained under direct irradiation conditions (without acriflavine) (Scheme 2e and entry 15, Table 1). Consistent with previous reports,^15,16 these results suggest that the reaction involves an energy transfer process. Finally, we observed a decrease in the acriflavine luminescence signal when the concentration of vinylgold 5 was increased, suggesting that 5 acts as a quencher of the acriflavine excited state (Fig. 1a). We also determined that the lifetime of acriflavine, obtained from the fluorescence lifetime decay (λ_ex = 450 nm, λ_em = 636 nm) curve of acriflavine, was 3.18 ns (see ESI V.3†), which suggests that the excited state of acriflavine is a singlet state. The corresponding Stern–Volmer linear plot is shown in Fig. 1b. The value of the kq bimolecular quenching rate constant was estimated at 6.65 × 10¹¹ mol⁻¹ L s⁻¹ from respectively the luminescence intensity (I₀/I) and lifetime (t₀/t) Stern–Volmer plots (see inset of Fig. 1b and ESI Section V.3†). This very high value, is reminiscent of our precedent study that established a static quenching instead of a dynamic one.¹⁶ Moreover, we also conducted the light/dark experiment, the desired product 3a formed only under continuous irradiation (see ESI Section V.6†).

Scheme 2 Control experiments.

Fig. 1 Mechanistic investigations: (a) Quenching of acriflavine by vinylgold(I) complex 5 monitored by steady-state fluorimetry; (b) Stern–Volmer linear fitting of the quenching described in panel (a).

Taking all these results into account, and based on literature precedents for visible-light-mediated energy transfer catalysis including our reported work,^15,16,26 a possible mechanism cycle has been proposed, as shown in Scheme 3. First, the gold(I) species coordinates to allenoate 1, and cyclization leads to the organogold(I) complex A in the presence of the base. Meanwhile, acriflavine acts as a photosensitizer, absorbing visible light to produce the excited singlet state. At this stage, energy transfer can take place to produce electronically excited gold(I) species A* in its singlet state while simultaneously regenerating the ground state of acriflavine. After easy intersystem crossing due to the heavy atom effect of gold, the triplet excited gold(I) species A* undergoes oxidative addition to iodoalkynes 2 to produce the gold(III) complex B. Subsequent reductive elimination provides β-alkynyl-γ-butenolides 3 and the active catalyst through the formation of the new C–C bond, and complete the catalytic cycle.

Scheme 3 Proposed reaction mechanism.

Conclusions

We have reported an original approach to β-alkynyl-γ-butenolides by gold-catalyzed tandem cyclization/alkynylation of allenoates with iodoalkynes under visible light irradiation at room temperature. This transformation features a broad substrate scope, good functional group tolerance, and compatibility with heterocyclic substrates. Mechanistic studies suggest that acriflavine acts as a photosensitizer, promoting the excitation of the vinylgold(I) intermediate through an energy transfer process and aiding the oxidative addition of an iodoalkyne. Such a dual catalytic process opens a new method for the synthesis of β-alkynyl-γ-butenolides with potential biological activity.

Author contributions

Y. H., Y. Z., M. B. M., J. C. H. L., W. M. and Y. H. performed the synthetic experiments, prepared the starting materials and purified the products. M. B. M., J. H. L., C. O., V. M. M. and L. F verified the experiment. C. O., V. M. M., L. F, F. Z., Z. X. and B. F. designed the experiments. All authors analyzed the data, discussed the results, commented on the manuscript, and approved the final version of the manuscript.

Data availability

The data supporting this article have been included as part of the ESI.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

Financial support from the National Natural Science Foundation of China (22201019; 22061048), and Yunnan Provincial Science and Technology Department (202401CF070075, 202401BC070018), and Yunnan Key Laboratory of Chiral Functional Substance Research and Application (202402AN360010). We thank also Sorbonne Université, CNRS, IUF, ANR-20-CE07-0038 LuxOr, and Generalitat Valenciana (CIAPOS/2022/174) for financial support.

References

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27. CCDC 2374591 (4f) contains the supplementary crystallographic data for this paper.†.

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Footnote

† Electronic supplementary information (ESI) available: Experimental details, compound characterization, and NMR spectra. CCDC 2374591. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4qo01153h

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