Reaction of N′-(2-alkynylbenzylidene)hydrazide with tertiary amine: a concise synthesis of H-pyrazolo[5,1-a]isoquinolines

Abstract

The reaction of N′-(2-alkynylbenzylidene)hydrazide with tertiary amine via C–H bond activation in the presence of cooperative catalysis was reported, which generates H-pyrazolo[5,1-a]isoquinolines in good yields under mild conditions.

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Currently, the pursuit of practical and efficient approaches for the rapid generation of small molecules is of utmost urgency and importance in the studies of chemical genetics.¹ Recently, we have been involved in the development of methodologies for the construction of natural product-like compounds² for different biological evaluations. During the studies, we identified some hits of H-pyrazolo[5,1-a]isoquinolines as CDC25B, TC-PTP, and PTP1B inhibitors.³ Therefore, efficient approaches for the generation of diverse H-pyrazolo[5,1-a]isoquinolines are highly desirable. Recently, Li and co-workers reported an iron-catalyzed oxidation of tertiary amines in the presence of tert-butyl hydroperoxide (TBHP) for the synthesis of β-1,3-dicarbonyl aldehydes.⁴ During the reaction process, α,β-unsaturated aldehydes generated by tertiary amine oxidation in situ acted as key intermediates. Prompted by this result and our efforts in the tandem reactions⁵ for the synthesis of N-heterocycles, we conceived that the iron-catalyzed oxidation of tertiary amines could be applied in the reaction of N′-(2-alkynylbenzylidene)hydrazides as well for the generation of H-pyrazolo[5,1-a]isoquinolines. We envisioned that the isoquinolinium-2-yl amide⁶ and α,β-unsaturated aldehyde produced in situ would act as the intermediate in the transformation. The reaction would proceed through 6-endo cyclization, [3 + 2] cycloaddition, and aromatization to afford the desired product A. To our surprise, compound A was not obtained when a model reaction of N′-(2-alkynylbenzylidene)hydrazide 1a with triethylamine was studied in the presence of silver triflate and an iron catalyst with TBHP (Scheme 1). Instead, compound 3a was isolated in 8% yield, unexpectedly. No reaction occurred in the absence of iron catalyst or silver triflate. The presence of silver triflate has been demonstrated to promote the 6-endo cyclization of N′-(2-alkynylbenzylidene)hydrazide to form isoquinolinium-2-yl amide.⁶ With this interesting result in hand, we were curious to know the possible route for the formation of compound 3a.

Scheme 1 An unexpected result from an iron-catalyzed reaction of N′-(2-alkynylbenzylidene)hydrazide 1a with triethylamine.

It seems that the transformation is related to C–H activation^7–9 and C–N bond cleavage during the process. Catalytic dehydrogenative oxidation of the C–H bond adjacent to a nitrogen atom have been reported.^7,8 For instance, Loh and co-workers described a dioxygen–copper catalytic system for the production of α-amino acetals via a rearrangement of a tertiary amine through the oxidation of the aliphatic C–H bond.^8c We conceived that the result in Scheme 1 might proceed through a similar route in the presence of an iron catalyst. We reasoned that in the presence of an iron catalyst with TBHP, the tertiary amine would be transferred to an enamine through the oxidation of an aliphatic C–H bond of the tertiary amine, which then acted as a nucleophile to attack the in situ generated isoquinolinium-2-ylamide. The subsequent release of a tosyl group and aromatization would produce the H-pyrazolo[5,1-a]isoquinoline 3a. Based on these considerations, we started to explore the optimal conditions of this conversion.

The reaction of N′-(2-alkynylbenzylidene)hydrazide 1a with triethylamine 2a in 1,2-dichloroethane was investigated in the presence of silver triflate and an oxidant (Table 1). Only a trace amount of product 3a was detected when the iron catalyst was changed to FeCl₃, FeCl₂, or Fe(OTf)₃ (Table 1, entries 1–3). To our delight, the product was isolated in 76% yield by switching the catalyst to Fe(acac)₃ (Table 1, entry 4). In order to verify that the reaction proceeded through the isoquinolinium-2-yl amide intermediate B, the reaction of isoquinolinium-2-yl amide B with triethylamine 2a was performed under the Fe(acac)₃-catalysis conditions. As expected, H-pyrazolo[5,1-a]isoquinoline 3a was produced in 81% yield. The same outcome was generated when 5.0 equiv. of triethylamine was used. Reducing the amount of triethylamine to 2 equiv. decreased the yield. No difference was observed when 10 equiv. of triethylamine was employed (Table 1, entry 6). Lower yields were afforded when the reaction took place in other solvents (Table 1, entries 7–11). Other oxidants were screened. It was found that PhI(OAc)₂ was also effective in the conversion (Table 1, entry 12). The yield was higher when the reaction was exposed to air. Further surveys revealed that the reaction worked most efficiently in 1,2-dichloroethane in the presence of 5.0 equiv. of triethylamine.

Table 1 Initial studies for the iron-catalyzed reaction of N′-(2-alkynylbenzylidene)hydrazide 1a with triethylamine 2a

Entry	Oxidant	Et3N	Solvent	Yield (%)^a
a Isolated yield based on N′-(2-alkynylbenzylidene)hydrazide 1a.
1	FeCl3/TBHP	1 mL	ClCH2CH2Cl	trace
2	FeCl2/TBHP	1 mL	ClCH2CH2Cl	trace
3	Fe(OTf)3/TBHP	1 mL	ClCH2CH2Cl	trace
4	Fe(acac)3/TBHP	1 mL	ClCH2CH2Cla	76
5	Fe(acac)3/TBHP	5.0 equiv.	ClCH2CH2Cl	76
6	Fe(acac)3/TBHP	10.0 equiv.	ClCH2CH2Cl	77
7	Fe(acac)3/TBHP	5.0 equiv.	MeCN	58
8	Fe(acac)3/TBHP	5.0 equiv.	EtOH	52
9	Fe(acac)3/TBHP	5.0 equiv.	THF	63
10	Fe(acac)3/TBHP	5.0 equiv.	toluene	57
11	Fe(acac)3/TBHP	5.0 equiv.	1,4-dioxane	66
12	PhI(OAc)2	1 mL	ClCH2CH2Cl	60
13	PhI(OAc)2/air	1 mL	ClCH2CH2Cl	80
14	PhI(OAc)2/air	1.0 equiv.	ClCH2CH2Cl	56
15	PhI(OAc)2/air	2.0 equiv.	ClCH2CH2Cl	60
16	PhI(OAc)2/air	5.0 equiv.	ClCH2CH2Cl	75
17	PhI(OAc)2/air	5.0 equiv.	MeCN	65
18	PhI(OAc)2/air	5.0 equiv.	EtOH	28
19	PhI(OAc)2/air	5.0 equiv.	THF	44
20	PhI(OAc)2/air	5.0 equiv.	toluene	60
21	PhI(OAc)2/air	5.0 equiv.	1,4-dioxane	56

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Having demonstrated the viability of this conversion, we next investigated the scope of the transformation using an AgOTf/PhI(OAc)₂ system. To assess the impact of the structural and functional motifs on the reaction, we tested a range of N′-(2-alkynylbenzylidene)hydrazides 1 (Table 2). From the result, it seems that N′-(2-alkynylbenzylidene)hydrazides with an aliphatic group or an aryl group attached to the triple bond (R²) were all good partners in the reactions. Better results were obtained when N′-(2-alkynylbenzylidene)hydrazides 1 with an electron-withdrawing group attached on the aromatic ring were employed. For example, the reaction failed when N′-(2-alkynylbenzylidene)hydrazide 1m was utilized in the reaction with triethylamine 2a (Table 2, entry 23). In extending this useful transformation, reactions of N′-(2-alkynylbenzylidene)hydrazides 1 with tertiary amines 2 in the presence of silver triflate and iron catalyst were investigated in the meantime (Table 3). All reactions worked well to produce the expected H-pyrazolo[5,1-a]isoquinolines in good yields.

Table 2 Reactions of N′-(2-alkynylbenzylidene)hydrazides 1 with tertiary amines 2 in the presence of silver triflate and PhI(OAc)₂

Entry	R^1, R^2	R^3, R^4	Yield (%)^a
a Isolated yield based on N′-(2-alkynylbenzylidene)hydrazide 1.
1	H, Ph (1a)	H, Et (2a)	75 (3a)
2	H, Ph (1a)	H, ^iPr (2b)	73 (3a)
3	H, Ph (1a)	Me, ^nPr (2c)	57 (3b)
4	H, Ph (1a)	Et, ^nBu (2d)	73 (3c)
5	H, 4-MeC6H4 (1b)	H, Et (2a)	77 (3d)
6	H, 4-MeOC6H4 (1c)	H, Et (2a)	57 (3e)
7	H, 4-MeOC6H4 (1c)	Me, ^nPr (2c)	45 (3f)
8	H, 4-ClC6H4 (1d)	H, Et (2a)	67 (3g)
9	H, 4-ClC6H4 (1d)	Me, ^nPr (2c)	55 (3h)
10	H, cyclopropyl (1e)	H, Et (2a)	78 (3i)
11	5-Cl, cyclopropyl (1f)	H, Et (2a)	67 (3j)
12	4-F, C6H5 (1g)	H, Et (2a)	84 (3k)
13	4-F, 4-MeC6H4 (1h)	H, Et (2a)	78 (3l)
14	4-F, n-Bu (1i)	H, Et (2a)	73 (3m)
15	5-F, C6H5 (1j)	H, Et (2a)	73 (3n)
16	5-F, C6H5 (1j)	Me, ^nPr (2c)	49 (3o)
17	5-Me, C6H5 (1k)	H, Et (2a)	71 (3p)
18	5-Me, C6H5 (1k)	Me, ^nPr (2c)	55 (3q)
19	5-Me, C6H5 (1k)	Et, ^nBu (2d)	64 (3r)
20	4-OMe, C6H5 (1l)	H, Et (2a)	41 (3s)
21	4-OMe, C6H5 (1l)	Me, ^nPr (2c)	52 (3t)
22	4-OMe, C6H5 (1l)	Et, ^nBu (2d)	45 (3u)
23	4,5-(OMe)2, 4-MeOC6H4 (1m)	H, Et (2a)	trace

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Table 3 Reactions of N′-(2-alkynylbenzylidene)hydrazides 1 with tertiary amines 2 in the presence of silver triflate and iron catalyst

Entry	R^1, R^2	R^3, R^4	Yield (%)^a
a Isolated yield based on N′-(2-alkynylbenzylidene)hydrazide 1.
1	H, Ph (1a)	H, Et (2a)	76 (3a)
2	H, Ph (1a)	Me, ^nPr (2c)	68 (3b)
3	H, Ph (1a)	Et, ^nBu (2d)	72 (3c)
4	H, 4-MeC6H4 (1b)	H, Et (2a)	83 (3d)
5	H, 4-MeOC6H4 (1c)	H, Et (2a)	61 (3e)
6	H, 4-ClC6H4 (1d)	H, Et (2a)	68 (3g)
7	H, cyclopropyl (1e)	H, Et (2a)	67 (3i)
8	5-Cl, cyclopropyl (1f)	H, Et (2a)	72 (3j)
9	4-F, C6H5 (1g)	H, Et (2a)	70 (3k)
10	5-F, C6H5 (1j)	Me, ^nPr (2c)	56 (3o)
11	5-Me, C6H5 (1j)	H, Et (2a)	72 (3p)
12	5-Me, C6H5 (1j)	Me, ^nPr (2c)	67 (3q)
13	4-OMe, C6H5 (1k)	H, Et (2a)	46 (3s)
14	4-OMe, C6H5 (1k)	Me, ^nPr (2c)	67 (3t)

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In conclusion, we have reported an unexpected reaction of N′-(2-alkynylbenzylidene)hydrazide with a tertiary amine via C–H bond activation in the presence of cooperative catalysis. H-Pyrazolo[5,1-a]isoquinolines are generated in good yields under mild conditions. During the reaction process, three bonds are formed with the concurrent cleavage of a C–N bond of the tertiary amine. Currently, studies of catalytic dehydrogenative oxidation of the C–H bond adjacent to a nitrogen atom for the synthesis of other N-heterocycles is under investigation in our laboratory.

Acknowledgements

Financial support from the National Natural Science Foundation of China (21032007) and Jiangxi Normal University is gratefully acknowledged.

References

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Footnote

† Electronic supplementary information (ESI) available: experimental procedures, characterization data, ¹H and ¹³C NMR spectra of compounds 3. See DOI: 10.1039/c2ra20899g

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