Concise and efficient one-pot copper-catalyzed synthesis of H-pyrazolo[5,1-a]isoquinolines

Abstract

A new, concise and efficient one-pot copper-catalyzed method for the synthesis of H-pyrazolo[5,1-a]isoquinolines has been developed, and the H-pyrazolo[5,1-a]isoquinolines containing various functional groups were prepared in moderate to good yields. The method should provide a simple and practical strategy for this kind of N-fused heterocycles.

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N-Heterocycles widely occur in a variety of biologically active substances,¹ and they have been assigned as privileged structures in drug development because N-heterocyclic moieties often show improved solubility and can facilitate salt formation, both of which are important for oral absorption and bioavailability.² While pyrazoles are an important motif of man-made biologically active compounds such as celecoxib, fipronil, lonazolac, viagra, they are rarely found in natural products.³ The isoquinoline motif is commonly found in natural products⁴ and pharmaceutical compounds.⁵ For example, the isoquinoline derivatives were applied as potential PET radioligands for imaging peripheral benzodiazepine receptor,^6a and as orally bioavailable Kv1.5 antagonists for the treatment of atrial fibrillation.^6b The N-fused heterocycles of pyrazoles and isoquinoline frameworks, H-pyrazolo[5,1-a]isoquinolines (Fig. 1), exhibit promising biological activities for the inhibition of CDC25B, TC-PTP, and PTP1B,⁷ and some efficient methods for their synthesis have been developed by Wu^7,8 and other groups.⁹ Recently, there have been great achievements made in copper-catalyzed coupling reactions,¹⁰ and various N-heterocycles were constructed through these reactions by other groups¹¹ and us.¹² Herein, we report a novel, concise and efficient one-pot copper-catalyzed synthesis of H-pyrazolo[5,1-a]isoquinolines.

Fig. 1 H-Pyrazolo[5,1-a]isoquinoline as N-fused heterocycle of pyrazole and isoquinoline.

As shown in Table 1, a three-component reaction of 1-(2-bromophenyl)-3-phenylprop-2-yn-1-one (1a), hydrazine hydrochloride and ethyl 2-cyanoacetate (2b) was chosen as the model to optimize reaction conditions including copper-catalysts, ligands, bases, solvents and temperature under nitrogen atmosphere. Effect of ligands was investigated using 10 mol% as the catalyst, K₃PO₄ as the base, DMF as the solvent at 100 °C under nitrogen atmosphere (entries 1–6), and a highest yield (82%) was provided in the absence of ligand (entry 6). When CuBr (entry 7) and Cu(OAc)₂ (entry 8) were used as the catalysts, low yields were obtained. Other bases were also attempted (entries 9 and 10), and they showed weak results. DMSO, 1,4-dioxane and toluene were used as the solvents (entries 11–13), and they were inferior to DMF (entry 5). A lower yield was obtained when temperature was decreased to 80 °C (entry 14). Therefore, the standard conditions for the copper-catalyzed three-component reactions of substituted 1-(2-bromophenyl)-3-phenylprop-2-yn-1-ones, hydrazine hydrochloride and alkyl 2-cyanoacetates are as follows: 10 mol% CuI as the catalyst, K₃PO₄ as the base and DMF as the solvent, and the reactions were carried out at 100 °C under nitrogen atmosphere.

Table 1 Copper-catalyzed synthesis of ethyl 5-amino-2-phenyl-H-pyrazolo[5,1-a]isoquinoline-6-carboxylate (3b) via a three-component reaction of 1-(2-bromophenyl)-3-phenylprop-2-yn-1-one (1a), hydrazine hydrochloride and ethyl 2-cyanoacetate (2b): optimization of conditions^a

Entry	Cat.	Ligand	Base	Solvent	T/°C	Yield (%)^b
a Reaction conditions: 1-(2-bromophenyl)-3-phenylprop-2-yn-1-one (1a) (0.25 mmol), hydrazine hydrochloride (1.2 equiv, 0.3 mmol), ethyl 2-cyanoacetate (2b) (5 equiv, 1.25 mmol), catalyst (0.1 equiv, 0.025 mmol), ligand (0.2 equiv, 0.05 mmol), base (5 equiv, 1.25 mmol), solvent (2 mL) under nitrogen atmosphere. Reaction time (24 h). b Isolated yield. c PCA = piperidine-2-carboxylic acid.
1	CuI	PCA^c	K3PO4	DMF	100	69
2	CuI	L-proline	K3PO4	DMF	100	40
3	CuI	DMEDA	K3PO4	DMF	100	36
4	CuI	1,10-phen	K3PO4	DMF	100	21
5	CuI	Binol	K3PO4	DMF	100	75
6	CuI	—	K3PO4	DMF	100	82
7	CuBr	—	K3PO4	DMF	100	71
8	Cu(OAc)2	—	K3PO4	DMF	100	54
9	CuI	—	K2CO3	DMF	100	43
10	CuI	—	Li2CO3	DMF	100	trace
11	CuI	—	K3PO4	DMSO	100	62
12	CuI	—	K3PO4	1,4-Dioxane	100	17
13	CuI	—	K3PO4	Toluene	100	0
14	CuI	—	K3PO4	DMF	80	70

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As shown in Table 2, the substrate scope of the copper-catalyzed three-component reactions was investigated, and the examined substrates provided moderate to good yields. For substituent R¹, the substrates with electron-donating groups showed higher reactivity than those with electron-withdrawing groups. For substituent R², the aromatic substrates (1a–d) provided higher yields than aliphatic ones (1e–f), and the trimethylsilyl group was deprotected for substrate 1f (see product 3l). Interestingly, the synthesized products contain amino and carboxylate moieties, which provides opportunity for further derivatization in synthesis of diverse molecules. The method can tolerate functional groups in the substrates including ether (3d–f), C–Cl bond (3g–i), cyano (3j) and ester (3a–l).

Table 2 Copper-catalyzed synthesis of alkyl 5-amino-2-alkyl-H-pyrazolo[5,1-a]isoquinoline-6-carboxylates (3) via a three-component reaction^a

3, Yield^b
a Reaction conditions: substituted 1-(2-bromophenyl)-3-alkylprop-2-yn-1-one (1) (0.25 mmol), hydrazine hydrochloride (1.2 equiv, 0.3 mmol), alkyl 2-cyanoacetate (2) (5 equiv, 1.25 mmol), CuI (0.1 equiv, 0.025 mmol), K3PO4 (5 equiv, 1.25 mmol), DMF (2 mL) under nitrogen atmosphere. Reaction time (24 h). b Isolated yield.

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As shown in Scheme 1, we attempted control experiments in order to explore the copper-catalyzed three-component reaction mechanism. Coupling of 1-(2-bromophenyl)-3-phenylprop-2-yn-1-one (1a) with hydrazine hydrochloride in the presence of K₃PO₄ led to 4-(5-(2-bromophenyl)-1H-pyrazol-3-yl)benzonitrile in 87% yield (Ia) (Scheme 1A), whose structure was confirmed by NMR and MS. Copper-catalysis with Ia and ethyl 2-cyanoacetate (2b) provided product 3b in 91% yield under the standard conditions (Scheme 1B). Therefore, a possible mechanism for this copper-catalyzed three-component reaction of substituted 1-(2-bromophenyl)-3-phenylprop-2-yn-1-ones, hydrazine hydrochloride and alkyl 2-cyanoacetates leading to alkyl 5-amino-2-alkyl-H-pyrazolo[5,1-a]isoquinoline-6-carboxylates (3) is proposed in Scheme 2. First, coupling of substituted 1-(2-bromophenyl)-3-phenylprop-2-yn-1-one (1) with hydrazine hydrochloride provides I in the presence of base (K₃PO₄). Copper-catalyzed coupling of I with alkyl 2-cyanoacetate (C-arylation) gives II, intramolecular nucleophilic attack of the NH of the pyrazolo group to cyano in II leads to III, and isomerization of III affords the target product (3).

Scheme 1 (A) Coupling of 1-(2-bromophenyl)-3-phenylprop-2-yn-1-one (1a) with hydrazine hydrochloride leading to 5-(2-bromophenyl)-3-phenyl-1H-pyrazole (Ia). (B) Copper-catalyzed of Ia with ethyl 2-cyanoacetate (2b) leading to 3b.

Scheme 2 Possible mechanism for synthesis of alkyl 5-amino-2-alkyl-H-pyrazolo[5,1-a]isoquinoline-6-carboxylates (3).

We extended the three-component reactions to other substrates including malononitrile (2d), pentane-2,4-dione (2e) and ethyl 3-oxobutanoate (2f). Unfortunately, some by-products were observed. A major reason was that hydrazine could react with 2d–f during treatment of 1 with hydrazine. Therefore, one-pot two-step reactions of three-components were performed as shown in Table 3: coupling of 1 with hydrazine hydrochloride led to intermediate I (see Scheme 2) in DMF in the presence of K₃PO₄ or Cs₂CO₃ at 80 °C for 12 h, and then treatment of I with 2d–f provided the target product (3) under copper-catalysis at 100 °C for 24 h. The one-pot two-step reactions exhibited the similar results to Table 2. In addition, the synthesized products possess amino, cyano, carbonyl and ester groups.

Table 3 Synthesis of other 1H-pyrazolo[5,1-a]isoquinolines (3) via one-pot two-step reactions of three-components^a

3, yield^b
a Reaction conditions: substituted 1-(2-bromophenyl)-3-alkylprop-2-yn-1-one (1) (0.25 mmol), hydrazine hydrochloride (1.2 equiv, 0.3 mmol), alkyl 2-cyanoacetate (2) (5 equiv, 1.25 mmol), CuI (0.1 equiv, 0.025 mmol), K3PO4 for 3m–p (5 equiv, 1.25 mmol), Cs2CO3 for 3q–x (5 equiv, 1.25 mmol), DMF (2 mL) under nitrogen atmosphere. Reaction time for the first step (12 h); for the second step (24 h). b Isolated yield for the two steps.

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In summary, we have developed a convenient and efficient copper-catalyzed method for synthesis of H-pyrazolo[5,1-a]isoquinolines from the readily available starting materials. The synthesized H-pyrazolo[5,1-a]isoquinolines own various key functional groups including halo, amino, ester, cyano and carbonyl, which provided opportunity for the construction of diverse biologically active molecules.

Acknowledgements

The authors wish to thank the National Natural Science Foundation of China (Grant Nos. 20972083 and 21172128), and the Ministry of Science and Technology of China (Grant No. 2012CB722605) for financial support.

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Footnote

† Electronic supplementary information (ESI) available: General procedure for synthesis, characterization data, and ¹H and ¹³C NMR spectra of compounds 3a–x. See http://dx.doi.org/10.1039/c2ra21305b/

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