Suzuki–Miyaura coupling of aryl fluorosulfates in water: a modified approach for the synthesis of novel coumarin derivatives under mild conditions

Abstract

We herein report a modified, eco-friendly and atom-economical approach for the synthesis of a series of novel coumarin analogues via Suzuki–Miyaura cross-coupling methodology under mild conditions. The utilization of coumarin fluorosulfate as an atom-economical pseudohalide based electrophilic coupling partner was the key for success of our modified methodology. In addition, the use of water as a solvent, exceptionally milder reaction conditions and traditional catalytic systems further demonstrates the synthetic utility of the developed protocol. A comparative study of different pseudohalide leaving groups has been carried out in the later stage to understand the efficiency of aryl fluorosulfate. From this study, the increased hydrophilic nature of the fluorosulfate electrophilic coupling partner when compared to the other electrophiles has been realized. This allowed the increased solubility of the fluorosulfate electrophile in water under milder temperature conditions thereby furnishing the desired products in good to excellent yields.

GRAPHICAL ABSTRACT

KEYWORDS:

• Coumarin
• Suzuki–Miyaura coupling
• pseudohalide
• aryl fluorosulfate

1. Introduction

The current area of organic research is majorly focused on developing greener synthetic methodologies that allows waste minimization [1]. The need for developing greener protocols with low E-factors is highly important in organic synthesis owing to the diverse range of waste materials generated after complex organic reactions [2]. To address these issues, the adoption of greener techniques like use of catalytic reaction conditions, utilization of water as solvent media for performing organic reactions, development of energy efficient processes and employing atom-economical electrophiles are of immense potential [3]. The raising environmental concerns nowadays can be minimized to some extent by implementing these methods.

Coumarins are important heterocyclic compounds that occur in green plants and many natural products in free or combined state [4]. They exhibit a broad spectrum of biological and photo physical activities. The various applications of coumarins and their derivatives in medicinal chemistry and other related fields have encouraged the synthetic chemists around the globe to produce them in the laboratory. The pharmacological importance of coumarin derivatives have been underlined by their various therapeutic applications like photo chemotherapy, anti-tumor therapy and anti-HIV therapy [5]. Moreover, the coumarin analogues are also reported to possess anti-bacterial, anti-inflammatory and anti-coagulating activities. The presence of coumarin motif in many marketed drugs also emphasizes its importance in medicinal chemistry.

The transition metal catalyzed cross-coupling reactions have served as an excellent tool in the last three decades for synthesizing novel compounds with various applications [6–9]. Among the diverse transition metal catalyzed cross-coupling reactions discovered hitherto, the palladium-catalyzed cross-coupling reactions of aryl halides or pseudohalides with different boronic acids initially reported by Suzuki et al (commonly called as Suzuki–Miyaura coupling) is an important reaction used by synthetic chemists throughout the world for new C–C bond formation [10]. Over the past decades, the application of Suzuki cross-coupling has gained tremendous significance in various fields of research. The development of different palladium catalysts and electron-rich ligands further advanced the scope of this methodology in academic and industrial research [11]. However, considerable efforts are still made around the globe to make this reaction more facile and eco-friendly by decreasing the halide/pseudohalide waste and avoiding organic solvents containing hydrocarbons. In addition to this, the tedious purification processes for isolating the product also emphasize the need for developing more efficient, environmentally benign and facile approach for Suzuki–Miyaura coupling reactions. Recently, the utilization of supported palladium catalysts, environmentally benign solvents and non-conventional energy sources for these reactions have been reported by various research groups for circumventing these issues to some extent [12].

Among the various coumarin derivatives synthesized so far, 4-methyl-7-substituted coumarins have been found to demonstrate profound applications in fluorescent studies and medicinal chemistry [13]. In 2004, Revell and Ganesan reported the synthesis of polystyrene-tetrafluorosulfonate linker of 4-methyl-7-hydroxy coumarin and utilized it for Suzuki–Miyaura coupling with phenyl boronic acid for synthesizing 4-methyl-7-phenyl coumarin in DMF as the solvent [14]. Jin et al reported the synthesis of 4-methyl-7-phenyl coumarin by nickel-catalyzed reaction of corresponding heteroaryl ether and phenyl boronic acid in toluene as solvent [15]. The need for organic solvents and the generation of bulky pseudohalide wastes as byproducts are the major limitations of these protocols. Recently, we reported the synthesis of a series of 4-methyl-7-(hetero)aryl coumarins [16] by Suzuki–Miyaura cross-coupling of 4-methyl-7-nonafluorobutylsulfonyloxy coumarin with different boronic acids under microwave irradiation (Scheme 1). We utilized a combination of two organic solvents (Dimethoxyethane-MeOH) and Pd(OAc)₂/dppp catalytic system in that optimized methodology along with TBAF^.3H₂O as base. Although the reaction was successful in synthesizing an array of coumarin derivatives, the high amount of pseudohalide wastes generated and the need for organic solvents were certainly the limitations.

Scheme 1. Previously reported works on synthesis of 4-methyl-7-aryl/phenyl-coumarins and present work.

The aforementioned observations encouraged us to develop a modified, eco-friendly and facile approach for synthesizing a variety of novel coumarin derivatives under mild conditions. In our successful trials, we have employed coumarin fluorosulfate as the electrophilic coupling partner in water using traditional palladium catalyst to synthesize the desired coumarin analogues. In this letter, we report our modified methodology for accessing some novel coumarin derivatives in good yields. A comparative study of various pseudohalide leaving groups have also been carried out to understand the efficiency of fluorosulfate over other electrophilic coupling partners.

2. Results and discussion

As depicted in Scheme 2, we started our synthetic route by synthesizing the fluorosulfate intermediates 2a-i from corresponding phenols 1a-i by treating them with SO₂F₂ gas at room temperature. The generation of SO₂F₂ gas was achieved by performing a slight modification in the previously reported procedure (See Supporting Information) [17]. The fluorosulfate substrates 2a-i was then treated with various aryl boronic acids in view of synthesizing an array of novel coumarin analogues.

Scheme 2. Synthesis of fluorosulfate intermediates 2a-i.

As a model reaction, we employed o-tolylboronic acid 3a as the coupling partner for Suzuki coupling with coumarin fluorosulfate 2a. Recently, Sharpless and coworkers reported the ligand-free Suzuki coupling of aryl fluorosulfates and boronic acids in water at room temperature by utilizing Pd(OAc)₂ as catalyst and triethylamine (Et₃N) as base [18]. Our initial efforts for reaction optimization were based on the results of Sharpless under mild conditions. Accordingly, we screened different reaction parameters (catalyst, base, solvent and temperature) in view of obtaining the expected product 4aa in appreciably high yield. Unfortunately, we couldn’t obtain the desired product in good yield when the reaction was carried out in water at ambient temperature by employing Pd(OAc)₂ as catalyst and Et₃N as base under ligand-free conditions (Table 1, entry 1). The utilization of additional ligands did not help in improving the yield of the expected product 4aa (Table 1, entries 2–4). Increasing the reaction temperature to 60°C slightly improved the yield of the desired product (Table 1, entries 7,8). After a series of optimization studies, we obtained the desired product in reasonable yield when the reaction was carried out at 60°C and 30°C by employing Pd(PPh₃)₂Cl₂ as the catalyst, Na₂CO₃ as base and dioxane-H₂O (1:1) as the solvents (Table 1, entries 12,13). To our delight, we obtained the desired product in excellent yield when the reaction was carried out in water at 60°C (Table 1, entry 14). It is worth noting that the reaction was sluggish when dioxane and DMF was employed as solvents at 60°C (Table 1, entries 16,17). However, the desired product was obtained in 70% yield when the reaction was carried out at 100°C in DMF solvent (Table 1, entry 18). Moreover, decreasing the stoichiometry of the catalyst and base significantly decreased the yield of the expected product (Table 1, entries 19,20). Increasing the equivalents of base also afforded the desired product in slightly lower yield (Table 1, entry 21). Finally, the optimized reaction conditions were affixed as detailed in entry 14 of Table 1. The isolation of pure product was carried out by crystallization in ethanol without using column chromatography.

Table 1: Optimization of reaction conditions^a

Entry	Catalyst	Ligand	Base	Solvent	Temperature	Yield^b 4aa (%)
1	Pd(OAc)2	—-	Et3N	H2O	RT	10
2	Pd(OAc)2	PPh3	Et3N	H2O	RT	15
3	Pd(OAc)2	BINAP	Et3N	H2O	RT	0
4	Pd(OAc)2	Xantphos	Et3N	H2O	RT	0
5	Pd(PPh3)4	—-	Et3N	H2O	RT	0
6	Pd(PPh3)2Cl2	—-	Et3N	H2O	RT	10
7	Pd(OAc)2	—-	Et3N	H2O	60°C	25
8	Pd(OAc)2	PPh3	Et3N	H2O	60°C	35
9	Pd(PPh3)2Cl2	—-	Na2CO3	H2O	RT	20
10	Pd(PPh3)2Cl2	—-	Na2CO3	Dioxane	RT	0
11	Pd(PPh3)2Cl2	—-	Na2CO3	Dioxane-H2O (1:1)	RT	25
12	Pd(PPh3)2Cl2	—-	Na2CO3	Dioxane-H2O (1:1)	60°C	70
13	Pd(PPh3)2Cl2	—-	Na2CO3	Dioxane-H2O (1:1)	30°C	60
14^c	Pd(PPh3)2Cl2	—-	Na2CO3	H2O	60°C	90 (85)
15	Pd(PPh3)2Cl2	—-	Cs2CO3	H2O	60°C	80
16	Pd(PPh3)2Cl2	—-	Na2CO3	Dioxane	60°C	20
17	Pd(PPh3)2Cl2	—-	Na2CO3	DMF	60°C	25
18	Pd(PPh3)2Cl2	—-	Na2CO3	DMF	100°C	70
19^d	Pd(PPh3)2Cl2	—-	Na2CO3	H2O	60°C	60
20^e	Pd(PPh3)2Cl2	—-	Na2CO3	H2O	60°C	75
21^c,f	Pd(PPh3)2Cl2	—-	Na2CO3	H2O	60°C	85 (77)

^a Reaction conditions: 2a (1 mmol), 3a (1 mmol), catalyst (5 mol%), ligand (10 mol%), base (2 mmol), 2 mL solvent at given temperature for 6 h.

^b1 H NMR yield using terephthaldehyde as internal standard.

^c Isolated yield after crystallization in parenthesis.

^d 1 mol% of catalyst used.

^e 1 mmol of base used.

^f 3 mmol of base used.

After optimizing the suitable reaction conditions for obtaining the desired product 4aa in excellent yield, we decided to evaluate the generality of the developed protocol. Accordingly, we treated 2a with a series of boronic acids 3a-v in water at 60 °C by employing the catalyst Pd(PPh₃)₂Cl₂ and Na₂CO₃ base (Scheme 3). To our delight, we obtained the desired products 4aa-av in good to excellent yields. The boronic acids containing polyaromatic hydrocarbons like naphthalene, anthracene and pyrene furnished the corresponding products in excellent yields. However, the boronic acid with p-amino substituent afforded the desired product in satisfactory yield (70% isolated yield). The heteroaryl boronic acids also rendered the expected products in good to excellent yields. It is worth noting that the isolation of all the final products was successfully achieved by crystallization in ethanol.

Scheme 3. Scope of boronic acids in the synthesis of 4-methyl-7-(hetero)aryl coumarins. Reaction conditions: 2a (1 mmol), 3a-v (1 mmol), Pd(PPh₃)₂Cl₂ (5 mol%), Na₂CO₃ (2 mmol), 2 mL H₂O, 60 °C for 6-8 h. Isolated yield after crystallization in parenthesis. ^b Corresponding boronic acid pinacol ester used for the reaction. ^c Reaction carried out for 6 hours. ^d Reaction carried out for 7 hours. ^e Reaction carried out for 8 hours.

Our next attention was to evaluate the substrate scope of various coumarin/aryl fluorosulfates in our modified methodology. Accordingly, we treated different fluorosulfates 2b-i with 4-methoxyphenylboronic acid 3q in our optimized reaction conditions (Scheme 4). Gratifyingly, we obtained the desired products 4bq-iq in satisfactory to excellent yields. The coumarins containing electron-withdrawing substituents like COCH₃, CF₃ and COOEt procured the expected products in satisfactory yields whereas the fluorosulfate derived from β-naphthol and 4-nitrophenol afforded the corresponding products 4fq and 4gq in excellent yield. However, the fluorosulfate obtained from equol furnished the expected product 4hq in satisfactory yield only.

Scheme 4. Scope of aryl fluorosulfates in Suzuki coupling. Reaction conditions: 2b-i (1 mmol), 3q (1 mmol), Pd(PPh₃)₂Cl₂ (5 mol%), Na₂CO₃ (2 mmol), 2 mL H₂O, 60 °C for 6-8 h. Isolated yield after crystallization in parenthesis. ^a Reaction carried out for 6 hours. ^b Reaction carried out for 8 hours.

After the successful synthesis of a variety of final products, we directed our immediate attention to study the efficiency of aryl fluorosufate as a leaving group when compared to other pseudohalide leaving groups. Accordingly, we synthesized different pseudohalide leaving groups like triflate, nonaflate, mesylate etc. of corresponding 4-methyl-7-hydroxy coumarin and subjected them for our optimized Suzuki coupling conditions (Table 2). Among the different leaving groups screened, fluorosulfate was found to be superior to corresponding pentafluorobenzenesulfonates, imidazylates and nonaflates. It is noteworthy that the traditional leaving groups like mesylate, tosylate and triflate did not give the desired product in our optimized protocol.

Table 2. Screening of different leaving groups for Suzuki coupling^a.

Entry	Compound	R	Yield^b 4aa (%)
1	2a	F	85
2	2ab	CH3	0
3	2ac	CF3	0
4	2ad		0
5	2ae		30
6	2af		40
7	2ag		35

^a Reaction conditions: 2a-ag (1 mmol), 3a (1 mmol), Pd(PPh₃)₂Cl₂ (5 mol%), Na₂CO₃ (2 mmol), 2 mL H₂O, 60 °C for 6 h.

^b Isolated yield after crystallization.

The utilization of aryl fluorosulfates 2a-i as the key electrophilic coupling partner has indeed reduced the generation of bulky pseudohalide wastes in our developed protocol. Our experiments clearly indicated the superior reactivity of fluorosulfate based electrophile in aqueous medium, highlighting its increased hydrophilicity when compared to the other pseudohalide coupling partners. The superior polarity of this electrophilic coupling partner when compared to the other electrophiles could be the possible reason for its enhanced aqueous solubility which eventually led to the higher yields of the final products [18,19]. The utilization of water as solvent also contributed to the overall efficiency and eco-friendliness of our reactions. To understand the environmental friendliness of our methodology, we decided to calculate the E-factor for the formation of desired products in our reactions (Table 3). Taking this into account, the E-factor for the formation of 4aa-av and 4bq-iq was calculated using the known mathematical formula (See Supporting Information for more details) [20]. To our delight, the E-factor of most of the reactions has been found to be between 1 and 3 which underlines the eco-friendliness of our reactions developed.

Table 3. Evaluation of E-factor for the synthesized compounds^a.

Entry	Product	Isolated yield (%)	E-factor
1		85	2.01
2		87	1.75
3		75	2.37
4		77	2.18
5		80	1.77
6		85	1.90
7		70	2.65
8		80	1.84
9		77	1.56
10		82	1.54
11		85	2.12
12		87	1.49
13		80	1.90
14		86	1.56
15		86	1.78
16		80	2.09
17		90	1.74
18		85	1.76
19		90	2.17
20		88	2.10
21		85	2.10
22		90	1.94
23		86	1.96
24		82	1.70
25		80	1.69
26		84	1.66
27		90	1.96
28		90	2.01
29		80	1.66
30		83	1.73

^a The calculation is given in Supporting Information.

Our next attention was to compare the efficiency of our optimized protocol with previously reported methodologies (Table 4). Taking this into consideration, we selected the synthesis of 4av and compared our results with previously reported ones. To our delight, our optimized reaction conditions afforded the required product in better yield at lower temperature. Moreover, our reaction conditions were found to be milder in terms of catalyst loading, utilization of eco-friendly solvent (H₂O) and the stoichiometry of boronic acid and base employed.

Table 4. A comparative study of previously reported works and present work

Entry	X =	Ph-B(OH)2 Equiv.	Catalyst Equiv.	Ligand Equiv.	Base Equiv.	Solvent	Temperature	Yield^a 4av (%)
This work	OSO2F	1	0.05	—	2	H2O	60°C	90
Revell et al [14]		3	0.1	—	3	DMF	80°C	76
Jin et al [15]		4	0.05	—	7	Toluene	110°C	84
M.N. Joy et al [16]		1.5	0.05	0.1	3	DME-MeOH (3:1)	80°C	93

^a Isolated yield.

3. Conclusion

In summary, we have developed a modified approach for accessing some novel coumarins 4aa-av and 4bq-iq in good to excellent yields under mild conditions. The utilization of aryl fluorosulfate as the electrophilic coupling partner and the use of traditional Pd(PPh₃)₂Cl₂ catalyst in water as solvent are the main highlights of our developed protocol. The screening of different pseudohalide leaving groups emphasized the importance of fluorosulfate to be employed as the substrate for obtaining the desired products under exceptionally milder conditions. The generation of less bulky pseudohalide byproduct and lower E-factor for the formation of desired products also highlights eco-friendliness of this developed methodology. This methodology can be utilized for the Suzuki cross-coupling reactions of more complex heterocycles containing hydroxyl groups in future.

Conflicts of interest statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

Grigory Zyryanov is thankful to Ministry of Science and Higher Education of the Russian Federation (Agreement # 075-15-2022-1118, dated 29 June 2022). Sougata Santra is thankful to Russian Science Foundation (Grant # 24-23-00516). This study is supported via funding from Prince Satam bin Abdulaziz University project number (PSAU/2023/R/1444).