Base promoted direct C4-arylation of 4-substituted-pyrazolin-5-ones with diaryliodonium salts

Abstract

A metal-free approach for the C4-arylation of 4-substituted-pyrazolin-5-ones with diaryliodonium salts was developed. The reaction proceeded smoothly at room temperature in the presence of DMAP (4-dimethylaminopyridine). As a result, a wide range of desired multi-substituted pyrazolin-5-one derivatives were obtained in good to excellent yields (20–98%).

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Hypervalent iodine chemistry is currently a field of intense development. Thanks to a variety of possible derivatives, diaryliodonium salts have been used widely in organic synthesis because of their low toxicity, stability, high reactivity, and availability.¹ Recently, metal-free arylation has become a rapidly growing area of extensive research for avoiding the drawbacks of organometallic chemistry, such as high economic cost, toxicity, and major problems regarding purification.² Amongst these methods, the arylation of nucleophiles by using diaryliodonium salts without transition-metal catalysts was achieved via an oxidative activation strategy.^1,3–12 The successful protocols included the α-arylation of enolates and azlactones,³ C-arylation of electron-rich aromatic compound,⁴ N-heteroarenes,⁵ naphthalene,⁶ and quinones;⁷ O-arylation of phenol, alcohols, carboxylic acids and oximes;⁸ N-arylation of anilines,^9a aqueous ammonia^9b and hydroxylamines;^9c S-arylation of arylsulfonic acid salts;¹⁰ and even the dearomatizating arylation of phenols¹¹ and indole derivatives.¹² Despite the significant progress that has been made in this area, new and efficient methods for metal-free arylation of various nucleophiles with diaryliodonium salts are still in great demand.

On the other hand, the pyrazolone-based skeleton is found in a variety of biologically important structural components and pharmaceuticals.¹³ Compounds containing this moiety frequently exhibit various applications as pharmaceutical agents,^14a–e synthetic scaffolds in combinatorial and medicinal chemistry,^14f,g chelating agents in coordination chemistry,^14h,i and analytical reagents in dye industry.^14j,k For example, edaravone is used in inhibiting protease-resistant prion protein accumulation.¹⁵ Consequently, inspired by the broad utility of pyrazolones, it is not surprising that great efforts have been directed toward developing synthetic approaches for the construction of the pyrazolone cores.¹⁶ Very recently, the development of asymmetric methodologies to access pyrazolone derivatives with a quaternary stereogenic center at C4 position has attracted considerable attention.¹⁷ To our knowledge, the direct arylation to the C4 position of the pyrazolone ring remains unexplored. Herein, we present our results on the first efficient C4-arylation of 4-substituted-pyrazolin-5-ones by using diaryliodonium salts under metal-free conditions at room temperature.

At the outset of the study, 4-benzyl-pyrazol-5-one (1a) and diphenyliodonium triflate (2a) were chosen as model substrates to establish the best reaction conditions (Table 1). A low conversion of 1a was obtained when either sodium carbonate or sodium hydroxide were used as the base (Table 1, entries 1 and 2). To our delight, with the treatment of 1a with 2 equiv. 2a in the presence of K₃PO₄ in toluene at room temperature for 6 h gave 93% yield of desired product (3aa, Table 1, entry 3). And other stronger bases were also efficient (Table 1, entries 4–6). Subsequently, a range of organic bases including NEt₃, DBU, DMAP were screened, and DMAP was found to be the most suitable base, which gave the product with excellent yield after 15 min (94%, Table 1, entries 7–9). Next, the screening of solvents revealed that the conversion to 3aa was more efficient in toluene than in DCE, 1,4-dioxane, CH₃CN, or DMF (Table 1, entries 10–13). Decreasing the amount of the base had a negative impact on yield (Table 1, entries 14 and 15). Furthermore, under the optimized conditions with the established model reaction of 4-benzyl-pyrazol-5-one and diphenyliodonium triflate, the influence of the counteranions of the diphenyliodonium salts was studied. Among all the tested reagents, diphenyliodonium triflate and p-toluenesulfonate furnished the desired product in excellent yields (Table 1, entries 9 and 17), whereas diphenyliodonium tetrafluoroborate gave a slightly lower yield and diphenyliodonium bromide only gave a trace amount of the desired product (Table 1, entries 16 and 18).

Table 1 Screening of the reaction conditions for metal-free arylation of 4-benzyl-pyrazol-5-one^a

Entry	X	Base	Solvent	Time (h)	Yield^b [%]
a Reaction conditions: 4-benzyl-pyrazol-5-one (0.2 mmol, 1 equiv.), diaryliodonium salts (0.4 mmol, 2 equiv.), base (0.4 mmol, 2 equiv.), solvent (3 mL).b Yield of isolated product.c DMAP (1.2 equiv.).d DMAP (0.3 equiv.).
1	OTf	Na2CO3	Toluene	6	Trace
2	OTf	NaOH	Toluene	6	49
3	OTf	K3PO4	Toluene	6	93
4	OTf	Cs2CO3	Toluene	6	89
5	OTf	^tBuOK	Toluene	6	81
6	OTf	NaH	Toluene	6	81
7	OTf	NEt3	Toluene	0.25	93
8	OTf	DBU	Toluene	0.25	88
9	OTf	DMAP	Toluene	0.25	94
10	OTf	DMAP	DCE	1	81
11	OTf	DMAP	1,4-Dioxane	1	68
12	OTf	DMAP	CH3CN	1	78
13	OTf	DMAP	DMF	1	78
14	OTf	DMAP^c	Toluene	1	84
15	OTf	DMAP^d	Toluene	12	29
16	Br	DMAP	Toluene	0.25	Trace
17	OTs	DMAP	Toluene	0.25	93
18	BF4	DMAP	Toluene	0.25	85

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With the optimized conditions in hand, the reaction scope of the C4-arylation of 4-benzyl-pyrazol-5-one by using a variety of symmetrical and unsymmetrical diaryliodonium salts was explored. As shown in Table 2, a number of substituted symmetrical diaryliodonium triflates such as di-(4-fluorophenyl)-iodonium triflate, di-(4-chlorophenyl)-iodonium triflate, di-(4-bromophenyl)-iodonium triflate, di-(4-tertbutylphenyl)-iodonium triflate, di-(4-methylphenyl)-iodonium triflate, di-(4-methoxyphenyl)-iodonium triflate and di-(3-methylphenyl)-iodonium triflate reacted efficiently with 4-benzyl-pyrazol-5-one (1a) to afford the corresponding arylation products with good to excellent yields (Table 2, entries 2–8). However, steric factors severely affected the reactivity, di-(2-methylphenyl)-iodonium triflate only gave desired product in 20% yield (Table 2, entry 9). Furthermore, almost no reaction took place with bis-(2,4,6-trimethyldiphenyl)iodonium triflate (2j) as the arylating reagent (Table 2, entry 10). Additionally, the use of unsymmetrical diaryliodonium salts was sequently investigated. 2k, 2l, and 2m preferentially transferred the aryl group with smaller steric hindrance to the 4-benzyl-pyrazol-5-one moiety in good yields (Table 2, entries 11–13), whereas 2n gave the desired product in moderate yield (Table 2, entry 14). In connection with the influence of the electronic properties on the reactivity, 4-methoxy-4′-nitrodiphenyliodonium salt (2o) was allowed to react with 1a under the standard conditions, selective transfer of p-nitrophenyl group to the desired product in excellent yield was observed (Table 2, entry 15), which is in accordance with the results of our previous report on metal-free arylation of hydroxylamines and oximes.^9c

Table 2 Direct coupling of 4-benzyl-pyrazol-5-one with various diaryliodonium salts^a

Entry	2	Ar^1	Ar^2	Time (min)	2	Yield^b [%]
a Reaction conditions: pyrazol-5-ones (0.2 mmol, 1 equiv.), diphenyliodonium salts (0.4 mmol, 2 equiv.), DMAP (0.4 mmol, 2 equiv.), toluene (3 mL).b Yield of isolated product.c OTs salt 2o used.
1	2a	Ph	Ph	15	3aa	94
2	2b	4-FC6H4	4-FC6H4	15	3ab	93
3	2c	4-ClC6H4	4-ClC6H4	60	3ac	85
4	2d	4-BrC6H4	4-BrC6H4	15	3ad	95
5	2e	4-^tBuC6H4	4-^tBuC6H4	15	3ae	93
6	2f	4-MeC6H4	4-MeC6H4	120	3af	95
7	2g	4-MeOC6H4	4-MeOC6H4	60	3ag	82
8	2h	3-MeC6H4	3-MeC6H4	60	3ah	92
9	2i	2-MeC6H4	2-MeC6H4	120	3ai	20
10	2j	Mesityl	Mesityl	120	3aj	Trace
11	2k	Mesityl	Ph	30	3aa	81
12	2l	Mesityl	4-MeC6H4	60	3af	86
13	2m	Mesityl	4-CO2Et	15	3ak	79
14	2n	Mesityl	4-NO2C6H4	120	3al	44
15	2o^c	4-MeOC6H4	4-NO2C6H4	60	3al	92

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To further probe the scope of this reaction, a wide variety of pyrazolone derivatives bearing a benzyl group at the C4 position were investigated. Pyrazol-5-ones with fluoro-, chloro-, and bromo-groups on the aromatic ring of the R group reacted smoothly with 2a and formed the corresponding products in excellent yields (Table 3, entries 2–4). 4-Substituted pyrazol-5-ones containing electron-withdrawing substituents (4-CF₃, 4-NO₂) also gave the products in excellent yields (Table 3, entries 5 and 6). And the electron-donating methyl-group afforded the desired product in good yield (Table 3, entry 7). Especially, for the substrate containing an H at R in the pyrazolin-5-one ring system, diarylated product (3ha) was obtained in 72% yield (Table 3, entry 8). It is worth pointing out that the C4-arylation of 4-substituted pyrazol-5-ones successfully occurred when the R substituent was a linear group (Table 3, entries 9–11). The corresponding products 3ia–3ka were generated in good yields. In addition, substrate 1l with Phenyl group at R¹ in the pyrazolin-5-one ring system reacted well, and the desired product was obtained in 83% yield (Table 3, entry 12), Furthermore, substrates, bearing a p-tolyl group or 4-(trifluoromethyl)phenyl group, also reacted smoothly with 2a to furnish the corresponding products in good yields (Table 3, entries 13 and 14).

Table 3 Direct coupling of diaryliodonium salt with various pyrazol-5-ones^a

Entry	1	R	R^1	R^2	3	Yield^b [%]
a Reaction conditions: pyrazol-5-ones (0.2 mmol, 1 equiv.), diphenyliodonium salts (0.4 mmol, 2 equiv.), DMAP (0.4 mmol, 2 equiv.), toluene (3 mL).b Yield of isolated product.
1	1a	Benzyl	Me	Ph	3aa	94
2	1b	4-F-benzyl	Me	Ph	3ba	98
3	1c	4-Cl-benzyl	Me	Ph	3ca	91
4	1d	4-Br-benzyl	Me	Ph	3da	95
5	1e	4-CF3-benzyl	Me	Ph	3ea	94
6	1f	4-NO2-benzyl	Me	Ph	3fa	92
7	1g	4-Me-benzyl	Me	Ph	3ga	88
8	1h	H	Me	Ph	3ha	72
9	1i	Me	Me	Ph	3ia	91
10	1j	Et	Me	Ph	3ja	90
11	1k	Allyl	Me	Ph	3ka	82
12	1l	Benzyl	Ph	Ph	3la	90
13	1m	Benzyl	Me	4-MeC6H4	3ma	83
14	1n	Benzyl	Me	4-CF3 C6H4	3na	95

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Conclusions

In summary, we have disclosed the first C4-arylation of 4-substituted-pyrazolin-5-ones with diaryliodonium salts mediated by DMAP. The procedure is capable of tolerating a relatively wide range of substrates, and excellent results (up to 98% yield) can be obtained. Furthermore, this experimentally simple process, starting from readily available starting materials, facilitates the access to multiply substituted pyrazolin-5-ones derivatives, which are potential biologically active molecules.

Experimental section

A mixture of 4-substituted-pyrazolin-5-ones 1 (0.2 mmol, 1 equiv.), diaryliodonium salt 2 (0.4 mmol, 2 equiv.), DMAP (0.4 mmol, 2 equiv.), and toluene (3 mL) was taken in a 10 mL reaction tube at room temperature for 15–120 min under vigorous stirring. After completion of the reaction, as indicated by TLC, the reaction mixture was concentrated under reduced pressure, and the crude compound was purified by chromatography on a silica gel column (ethyl acetate/petroleum ether (1/10)) to afford the desired product 3.

Acknowledgements

The work was supported by the National Nature Science Foundation of China (NSFC, 21272069, 21202186) and the Fundamental Research Funds for the Central Universities, Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra03819g

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