Synthesis of 2-trifluoromethylpyrazolo[5,1-a]isoquinolines via silver triflate-catalyzed or electrophile-mediated one-pot tandem reaction.

An efficient one-pot tandem cyclization/[3 + 2] cycloaddition reaction of N'-(2-alkynylbenzylidene)hydrazides with ethyl 4,4,4-trifluorobut-2-ynoate under silver triflate-catalyzed or electrophile-mediated conditions is described. Various trifluoromethylated pyrazolo[5,1-a]isoquinolines were afforded in moderate to excellent yield by this developed method.

Introduction

Isoquinolines and isoquinoline-derived heterocycles are prevalent structural motifs in natural products and pharmaceuticals that exhibit remarkable biological activities [1-2]. Therefore, great attention has been directed toward the development of efficient methods for the selective functionalization of the isoquinoline cores. Among these, pyrazolo[5,1-a]isoquinoline is an important class of isoquinoline derivatives. Recently, much effort has been spent on the synthesis of these compounds due to their promising biological activities [3-18]. For instance, in 2010, Wu and co-workers found some pyrazolo[5,1-a]isoquinoline derivatives showing activities for the inhibition of CDC25B, TC-PTP, and PTP1B [4].

It has been proved that the physical, chemical, and biological activity of organic molecules can be dramatically improved by substitution of hydrogen with fluorine atoms because of the strong electronegativity, the small size, the strength of the C–F bond, and the low polarizability of the fluorine atom. Statistically, more than 20% of the pharmaceuticals and 40% of the agrochemicals contain one or more fluorine atoms. Thus, there has been considerable interest in developing an efficient method for the synthesis of fluorinated heterocycles. Perfluoroalkynoate is a versatile and powerful building block for generating functionalized perfluoroalkylated compounds, especially fluorinated heterocycles, by tandem reactions [19-26]. For example, 2-perfluoroalkynoates have been widely used in synthesizing fluorinated heterocycles, such as benzodiazepines [22], chromenes [21,25], and 2-oxopyridine-fused 1,3-diazaheterocycles [26].

As part of our ongoing efforts in developing synthetic approaches for the functionalization of isoquinoline cores [11,14] and the synthesis of novel fluorinated heterocycles [27] with potential biological applications, herein, we describe an efficient method for the one-pot synthesis of trifluoromethylated pyrazolo[5,1-a]isoquinoline derivates via a Lewis acid (AgOTf) or an electrophile- (I2 or ICl) promoted annulation of N’-(2-alkynylbenzylidene)hydrazides followed by an 1,3-dipolar cycloaddition.

Results and Discussion

Based on Wu’s work on the silver triflate-catalyzed tandem reaction of N’-(2-alkynylbenzylidene)hydrazides with dimethyl acetylenedicarboxylate [28], we started our research by examining the reaction of N’-(2-alkynylbenzylidene)hydrazides 1a (0.3 mmol) and ethyl 4,4,4-trifluorobut-2-ynoate (2, 0.6 mmol) using NaOAc (0.45 mmol) as base, in the presence of AgOTf (5 mol %) and 4 Å MS (75 mg) in CH2Cl2 (3 mL) at room temperature overnight. Surprisingly, the unexpected [3 + 2] cycloaddition product pyrazolo[5,1-a]isoquinoline derivative 3a instead of the isoquinoline-based azomethine ylide [28] was obtained in good yield (84%, Table 1, entry 1). Similar yields were obtained when NaHCO3 or K2CO3 were used as base (83% and 86% yield, respectively, Table 1, entries 2 and 3). Several other inorganic or organic bases were examined, and the results showed that CsF was the best choice (91% yield, Table 1, entry 8). The control experiment also showed that the base was important for the reaction to proceed (8% yield, Table 1, entry 13). Subsequently, a range of solvents, such as acetonitrile, toluene, THF, dioxane and DMA were screened, and the results revealed that CH2Cl2 was the best one, and most of the others were exhibited good yields (Table 1, entry 8 and entries 14–18). The yield (65%) was reduced obviously when the loading of base was decreased to 1.0 equiv (Table 1, entry 19).

Table 1

Screening of conditions for the silver triflate-catalyzed reaction of N’-(2-alkynylbenzylidene)hydrazide 1a with ethyl 4,4,4-trifluorobut-2-ynoate 2a.

Entry	Base (1.5 equiv)	Solvent	Yield (%)b
1	NaOAc	CH2Cl2	84
2	NaHCO3	CH2Cl2	83
3	K2CO3	CH2Cl2	86
4	Cs2CO3	CH2Cl2	63
5	NaOH	CH2Cl2	51
6	t-BuOK	CH2Cl2	trace
7	KF	CH2Cl2	80
8	CsF	CH2Cl2	91
9	DABCO	CH2Cl2	60
10	NEt3	CH2Cl2	61
11	DBU	CH2Cl2	50
12	Pyridine	CH2Cl2	37
13	–	CH2Cl2	8
14	CsF	CH3CN	65
15	CsF	toluene	69
16	CsF	THF	71
17	CsF	dioxane	76
18	CsF	DMA	87
19	CsF (1.0 equiv)	CH2Cl2	65

aReaction conditions: N’-(2-alkynylbenzylidene)hydrazide 1a (0.3 mmol), AgOTf (5 mol %), solvent (3 mL), ethyl 4,4,4-trifluorobut-2-ynoate (2, 0.6 mmol, 2.0 equiv), base (1.5 equiv), 4 Å MS (75 mg), rt, overnight. bIsolated yield based on 1a.

To explore the scope of this tandem cyclization/[3 + 2] cycloaddition reaction, a range of N’-(2-alkynylbenzylidene)hydrazides 1a–j were prepared from the corresponding aldehydes and applied to the synthesis of trifluoromethylated pyrazolo[5,1-a]isoquinoline derivatives 3 under the optimized conditions (Table 1, entry 8). As shown in Table 2, for most cases, N’-(2-alkynylbenzylidene)hydrazides 1 reacted with ethyl 4,4,4-trifluorobut-2-ynoate 2 affording the corresponding products 3 in good to excellent yields. For instance, substrate 1b bearing an electron-donating substituent (methyl) reacted with 2 under the present reaction conditions gave the desired product 3b in good yield (86%, Table 2, entry 2). The structure of 3b was verified by 1H and 13C NMR, HRMS, as well as X-ray diffraction analysis (Figure 1, for details, see Supporting Information File 1). As expected, the substrates 1e–h with electron-withdrawing substituents are suitable partners in this process and the corresponding pyrazolo[5,1-a]isoquinolines 3e–h were obtained in good yields. Fortunately, alkyl-substituted N’-(2-alkynylbenzylidene)hydrazide was demonstrated to be good partner in the transformation. For instance, N’-(2-alkynylbenzylidene)hydrazide 1i reacted with 2, leading to the desired pyrazolo[5,1-a]isoquinoline 3i in 90% yield (Table 2, entry 9).

Table 2

Silver triflate-catalyzed tandem reactions of N’-(2-alkynylbenzylidene)hydrazides 1 with ethyl 4,4,4-trifluorobut-2-ynoate 2.

Entry	R1, R2/1	Product 3	Yield (%)a	Entry	R1, R2/1	Product 3	Yield (%)a
1	R1 = HR2 = Ph1a	3a	91	6	R1 = HR2 = 4-FC6H41f	3f	80
2	R1 = HR2 = 4-MeC6H41b	3b	86	7	R1 = HR2 = 4-AcC6H41g	3g	87
3	R1 = HR2 = 4-MeOC6H41c	3c	75	8	R1 = HR2 = 4-NO2C6H41h	3h	47
4	R1 = HR2 = 4-EtOC6H41d	3d	89	9	R1 = HR2 = cyclopropyl1i	3i	90
5	R1 = HR2 = 4-ClC6H41e	3e	85	10	R1 = 3-FR2 = Ph1j	3j	44

aIsolated yields based on N’-(2-alkynylbenzylidene)hydrazides 1.

Figure 1

ORTEP diagrams of 3b and 4h.

Subsequently, based on our previous reports on electrophile-mediated electrophilic cyclization reaction [28-29], one-pot tandem electrophilic cyclization/[3 + 2] cycloaddition of N’-(2-alkynylbenzylidene)hydrazides 1, electrophiles (I2 or ICl), and ethyl 4,4,4-trifluorobut-2-ynoate (2) were carried out under mild conditions. The results are summarized in Table 3. For all cases, this tandem reaction worked well leading to the corresponding iodinated fluorine-containing pyrazolo[5,1-a]isoquinolines 4 in moderate to excellent yields. Various functional groups, such as methyl, methoxy, ethoxy, halogen, acetyl, nitro, and cyclopropyl groups were tolerated under the reaction conditions. In general, substrates bearing electron-donating substituents show better reactivity than those with electron-withdrawing substituents. For instance, methyl-substituted N’-(2-alkynylbenzylidene)hydrazide 1b reacted with iodine and ethyl 4,4,4-trifluorobut-2-ynoate (2) in the presence of CsF and 4 Å MS leading to the desired product 4b in 90% yield (Table 3, entry 3). A relatively lower yield was obtained when nitro substituted N’-(2-alkynylbenzylidene)hydrazide 1h was used, and the desired product 4g was obtained in 50% yield (Table 3, entry 9). Alkyl-substituted product 4h was obtained in good yields when substrate 1i reacted with iodine or ICl (Table 3, entries 10 and 11), the structure of 4h was verified by 1H and 13C NMR, HRMS, as well as X-ray diffraction analysis (Figure 1, for details, see Supporting Information File 1). Based on this one-pot tandem electrophilic cyclization/[3 + 2] cycloaddition reactions, highly functionalized pyrazolo[5,1-a]isoquinolines can be obtained via palladium-catalyzed cross-coupling reaction.

Table 3

One-pot tandem reactions of N’-(2-alkynylbenzylidene)hydrazides 1, electrophiles, and ethyl 4,4,4-trifluorobut-2-ynoate (2)a.

Entry	1	X2	4	Yield (%)b	Entry	1	X2	4	Yield (%)b
1	1a	I2	4a	71	7	1f	I2	4e	62
2	1a	ICl	4a	78	8	1g	I2	4f	84
3	1b	I2	4b	90	9	1h	ICl	4g	50
4	1b	ICl	4b	82	10	1i	I2	4h	85
5	1c	I2	4c	80	11	1i	ICl	4h	62
6	1d	I2	4d	88	12	1j	I2	4i	50

aReaction conditions: N’-(2-alkynylbenzylidene)hydrazide 1a (0.3 mmol), I2 or ICl (1.3 equiv), solvent (3 mL), ethyl 4,4,4-trifluorobut-2-ynoate (2, 0.6 mmol, 2.0 equiv), base (1.5 equiv), 4 Å MS (75 mg), rt, overnight. bIsolated yields based on N’-(2-alkynylbenzylidene)hydrazides 1.

Conclusion

In conclusion, we have developed an efficient one-pot tandem cyclization/[3 + 2] cycloaddition reaction of N’-(2-alkynylbenzylidene)hydrazides with ethyl 4,4,4-trifluorobut-2-ynoate under silver triflate-catalyzed or electrophiles-mediated conditions. Highly functionalized pyrazolo[5,1-a]isoquinolines can be synthesized in moderate to excellent yield by this developed method.

Experimental

General

All reactions were performed in test tubes under N2-atmosphere. Flash column chromatography was performed with silica gel (200–300 mesh). Analytical thin-layer chromatography was performed on glass plates pre-coated with 0.25 mm 230–400 mesh silica gel impregnated with a fluorescent indicator (254 nm). Thin-layer chromatography plates were visualized by exposure to ultraviolet light. Organic solutions were concentrated on rotary evaporators at 25–35 °C. Commercial reagents and solvents were used as received. 1H and 13C NMR spectra were recorded on a Bruker AV 400 at 400 MHz (1H) and 100 MHz (13C) at ambient temperature. Chemical shifts are reported in parts per million (ppm) on the delta scale (δ) and referenced to tetramethylsilane (0 ppm). HRMS analyses were performed in ESI mode on a Bruker mass spectrometer.

General procedure for the silver triflate-catalyzed one-pot tandem reaction of N’-(2-alkynylbenzylidene)hydrazide 1 with ethyl 4,4,4-trifluorobut-2-ynoate 2: A mixture of N’-(2-alkynylbenzylidene)hydrazide 1 (0.30 mmol, 1.0 equiv) and silver triflate (5 mol %) in anhydrous dichloromethane (3.0 mL) was stirred at room temperature overnight. Then a solution of ethyl 4,4,4-trifluorobut-2-ynoate (2, 0.60 mmol, 2.0 equiv) in dichloroethane (2.0 mL), 4 Å MS (75 mg) and CsF (0.45 mmol, 1.5 equiv) were added and stirred for another 3 h. After completion of the reaction as indicated by TLC, the reaction mixture was purified by flash column chromatography on silica gel to provide the corresponding product 3.

General procedure for the electrophile-mediated one-pot tandem reaction of N’-(2-alkynylbenzylidene)hydrazide 1 with ethyl 4,4,4-trifluorobut-2-ynoate (2): A mixture of N’-(2-alkynylbenzylidene)hydrazide 1 (0.30 mmol, 1.0 equiv) and electrophiles (I2 or ICl) (0.36 mmol, 1.2 equiv) in anhydrous dichloromethane (3.0 mL) was stirred at room temperature overnight. Then a solution of ethyl 4,4,4-trifluorobut-2-ynoate (2, 0.60 mmol, 2.0 equiv) in dichloroethane (2.0 mL), 4 Å MS (75 mg) and CsF (0.45 mmol, 1.5 equiv) were added and stirred for another 3 h. After completion of the reaction as indicated by TLC, the reaction mixture was purified by flash column chromatography on silica gel to provide the corresponding product 4. For details, see Supporting Information File 1.

Characterization data and NMR spectra.

X-ray data for compound 3b.

X-ray data for compound 4h.