Fused Tetrazoles as Azide Surrogates in Click Reaction: Efficient Synthesis of N-Heterocycle-substituted 1,2,3-Triazoles

Abstract

It has been shown that various pyrido-, quinolino-, pyrazino- and qunoxalinotetrazoles can efficienly be used as azide components in the Cu-catalyzed click reaction with alkynes. This method allows for efficient synthesis of a wide variety of N-heterocyclic derivatives of 1,2,3-triazoles.

1,2,3-Triazoles are biologically important units.¹ Pyridotriazoles and quinolinotriazoles are particularly interesting as they exhibit a wide range of biological properties, including control of arthropod pests,^2a substance-related disorders,^2b ATP-competetive inhibition of vascular endothelial growth factor receptors I and II,^2c antibacterial,^2d and antimicrobacterial activity.^2e

Unarguably, the Cu-catalyzed click chemistry³ of azide with alkyne is the most efficient way to assemble the 1,2,3-triazole ring⁴ (eq. 1). However, preparation of pyrido- and quinolino- triazoles is not straightforward since these azides exist in equlibrium between closed form (tetrazole A) and open form (azide B) (eq. 2).⁵

(1)

(2)

Usually, the position of this equilibrium depends on several factors, such as nature of substituents,⁵ solvent⁶ and temperature.⁵ Thus, it has been reported^7a that NO₂ group at the C-6 position of tetrazole favors the open form (azide B). On the contrary, tetrazoles with NO₂, COOH, and Cl groups at the C-8 position, and unsubstituted tetrazole predominantly exist^7,8 in closed form A. It should be mentioned that pyridotetrazole has been employed in the preparation of organometallic complexes of late transition metals.^7a Furthermore, there have been contradictory reports^9,10 on the employment of tetrazoles in the click reaction. For instance, it has been shown that pyridotetrazoles, existing in closed form, are inert toward click reaction under standard conditions.⁹ By other hand, there have been two reports10a,b in which single examples of successful click reaction of generated in situ pyridotetrazoles with alkynes were demonstrated. Moreover, when this manuscript was under preparation, a paper describing successful click reaction of purinotetrazole, which mainly exists in open form, has appeared.^10c Accordingly, motivated by the high biological importance of pyridyl- and quinolinyl-containing triazoles² and intrigued by the contradictory results on employment of triazoles in click reaction,^9,10 we undertook investigation aming at the development of efficient method for employment of differently substituted tetrazoles in synthesis of heterocyclic derivatives of 1,2,3-triazoles. Herein, we wish to report that various pyrido- quinolino-, pyrazino- and qunoxalinotetrazoles 1 can efficiently be employed in click reaction with alkynes to give the corresponding heterocyclic derivatives of 1,2,3-triazoles 2 (eq. 3).

(3)

We first examined the reaction of tetrazole 1a with phenyl acetylene employing the most popular^[3b] click chemistry conditions (Table 1, entry 1). However, no formation of desired product 2a was observed. Employment of other copper salts was more effective. Thus, when the reaction was performed in the presence of 10 mol% CuI,^4a it afforded the product 2a in 10% yield (entry 2). Use of Cu(OTf)₂⁴ⁱ gave 5% of product (entry 3). A substantial improvement of the yield (52%) has been achieved with (CuOTf)₂•C₆H₆^4j (entry 4). Gratifyingly, analogous reaction at room temperature gave 81% of 2a (entry 5). THF was equally efficient as toluene in the reaction (entry 6). Switching to other solvents (entries 7 and 8) was not beneficial for this reaction.

Table 1.

Optimization of click reaction of tetrazoles.

no.	catalyst 10 mol %	solvent 0.25 M	t [°C]	time [h]	yield[a] [%]
1	CuSO4 • 5H2O, Na-ascorbate	DCM:H2O (1:1)	60	24	0
2	CuI	toluene	100	24	10
3	Cu(OTf)2	toluene	100	24	5
4	(CuOTf)2•C6H6	toluene	100	2	52[b]
5	(CuOTf)2•C6H6	toluene	rt	7	81
6	(CuOTf)2•C6H6	THF	60	12	76
7	(CuOTf)2•C6H6	DCE	100	24	0
8	(CuOTf)2•C6H6	1,4-dioxane	100	24	0

^aIsolated yields.

^bSome decomposition products were found.

With the best-optimized conditions in hand, we tested the generality of the click reaction of tetrazoles (Table 2). To our delight, these newly developed conditions appeared to be very general for a spectrum of N-fused tetrazoles giving an easy access to 1,4-triazoles 2. Thus, reaction of ester-containing pyridotetrazole (1a) with varios alkynes proceeded smoothly at room temperature to produce differently substituted pyridyl-containing triazoles in good to excellent yields (entries 1–12). Reactions of unsubstituted (1b) and C-5 methyl-substituted (1c) tetrazoles were efficient at elevated temperatures (entries 13–21). It was also found that various N-fused heterocyclic tetrazoles, such as quinolinotetrazoles (1d, entries 22–28), pyrazinotetrazole (1e, entry 29 and 30) and qunoxalinotetrazole (1f, entries 31 and 32) successfully underwent click reaction to give the corresponding N-heterocycle-substituted 1,4-triazoles 2 in good yields. These reaction conditions appeared to be very general with respect to the alkyne component, as alkynes possessing various alkyl, aryl, alkenyl, benzyl, homobenzyl, ester, trimethylsilyl, alkyl chloride, secondary alcohol, acetal, thiophenyl, and even sugar groups provided good to high yields of triazoles 2.

Table 2.

Synthesis of functionalized 1,4-disubstituted triazoles.

no.	product	yield [%]b	no.	product	yield [%]b	no.	product	yield [%]b	no.	product	yield [%]b
1c	2a	81	9c	2i	64	17d	2q	37	25e	2y	68
2c	2b	88	10c	2j	84	18d	2r	74	26e	2z	62
3c	2c	70	11c	2k	50	19d	2s	88	27e	2aa	63
4c	2d	63	12c	2l	53	20d	2t	81	28e	2bb	54
5c	2e	60	13d	2m	62	21d	2u	81	29d	2cc	51
6c	2f	65	14d	2n	66	22e	2v	88	30d	2dd	57
7c	2g	86]	15d	2o	67	23e	2w	62	31d	2ee	73
8c	2h	72	16d	2p	58	24e	2x	77	32d	2ff	66

^aSee Supporting Information for details.

^bIsolated yield.

^cReactions performed at room temperature.

^dReactions performed at 100°C.

^eReactions performed at 125°C.

After developing the “tetrazole-clicking” approach for the synthesis of 1,4-triazoles, we next examined the possibility of employment of N-fused tetrazoles in the Ru-catalyzed¹¹ synthesis of 1,5-triazoles 5 (Table 3). However, when 1a was treated with phenyl acetylene in the presence of 5 mol% RuCpCl(PPh₃)₂ at 110°C for 24h in dioxane (entry 1), no desired product was formed. Employment of more active catalyst [RuCp*Cl(PPh₃)₂]¹¹ gave no reaction, as well (entry 2). Probably, the azide-coordinated Ru-catalyst, in contrast to the Cu-catalyst (entry 3), is deactivated by the chelation with the nitrogen atom of the pyridine ring.¹² To test this hypothesis, we performed reactions of 3-azido- and 4-azido- pyridines with this Ru(II) catalyst where no such type of chelation is possible. Indeed, it was found that 3-azidopyridine smoothly underwent cycloaddition reaction with phenyl acetylene (Table 3, entry 4) with RuCp*Cl(PPh₃)₂ providing inseparable mixture of 1,4-triazole and 1,5-triazole in 59% yield (1:1.5). Reaction of 4-azidopyridine gave 1,5-triazole as the major product (Table 3, entry 6). Expectedly, employment of Cu-catalysis for click reaction of 3-azido- and 4-azido- pyridines proceeded uneventfully providing 1,4-disubstituted triazoles in excellent yields (entries 5 and 7). Thus, it became evident that under the Ru-catalysis tested, pyridotetrazoles could not be used as precursors for 1,5-disubstituted triazoles.

Table 3.

Toward synthesis of 1,5-disubstituted triazoles.^a

no.	substrate	catalyst	4	5
1		RuCpCl(PPh3)2	-	-
2		RuCp*Cl(PPh3)2	-	-
3		(CuOTf)2C6H6	81%	-
4		RuCp*Cl(PPh3)2	23%	36%b
5		(CuOTf)2C6H6	91%	-
6		RuCp*Cl(PPh3)2	3%	56%
7		(CuOTf)2C6H6	87%	-

^aIsolated yield. Reaction conditions: 5 mol % catalyst, 1,4-dioxane 0.25 M, 110°C (entries 1, 2, 4 and 6); 10 mol % catalyst, PhMe 0.25 M, 100°C (entries 3, 5 and 7).

^bInseparable mixture of 4 and 5 (1:1.5).

(4)

In summary, it has been shown that pyrido-, quinilino-, pyrazino-, and qunoxalinotetrazoles, which exist in open/close form equilibrium (between 1 and 1′, eq. 4) can be employed as azide surrogates in the Cu-catalyzed click reaction. This reaction is efficient with a wide variety of alkynes to produce N-heterocyclic derivatives of 1,4-disubstituted triazoles 2. It has also been found that, probably due to deactivation of Ru-catalyst, pyridotetrazoles cannot be used as azide precursors in the synthesis of 1,5-disubstituted triazoles.