One-Pot Synthesis of 1-Monosubstituted 1,2,3-Triazoles from Propargyl Alcohol

Abstract

A one-pot synthesis of 1-monosubstituted-1,2,3-triazoles from propargyl alcohol and various aryl azides was achieved. This simple method provides concise and efficient access to various 1-monosubstituted 1,2,3-triazole derivatives through a three-step one-pot ­sequence in good to excellent yields.

Key words

triazoles - propargyl alcohol - aryl azides - copper catalysis

As an important group of heterocyclic compounds containing a five-membered ring with three nitrogen atoms, 1,2,3-triazole derivatives are widely applied in many fields, such as biology,[1] materials science,[2] and medicinal[3] and synthetic organic chemistry.[4] In particular, in the last ten years many compounds of this type have found use as clinical and commercial drugs such as antibiotics,[5] indoleamine 2,3-dioxygenase (IDO) inhibitors,[6] antiviral drugs,[7] and ­histone deacetylase inhibitors (HDIs) (Figure [1]).[8]

Figure 1 Some 1,2,3-triazoles possessing various pharmaceutical ­activities

Owing to their wide range of uses, several strategies for the syntheses of 1,2,3-triazoles have been reported. The first method that was used to construct the 1,2,3-triazole ring was the Huisgen dipolar cycloaddition, which gives 1,4- and 1,5-disubstituted regioisomers without regioselectivity; in this reaction, an alkyne and an azide are mixed and heated.[9] In 2002, the Sharpless group[10] developed a copper-catalyzed 1,3-dipolar cycloaddition reaction of terminal alkynes and azides for the regioselective construction of 1,4-disubstituted 1,2,3-triazoles. This method is simple and vigorous. Subsequently, these compounds came into the limelight, attracting interested researchers who explored more-effective methods for the construction of this type of molecule through various approaches.[11] For example, the Fokin group[12] used a triazole ligand to stabilize Cu(I), which can vigorously catalyze the Huisgen cycloaddition reaction to form 1,4-substituted 1,2,3-triazoles at ­ambient temperatures. Orgueira et al.[13] found that active nanoparticulate copper also catalyzes the Huisgen cycloaddition reaction with high efficiency in a broad range of solvents, including THF, MeOH, MeCN, DMSO, and DMF.[14] ­Ramachary et al.[15] reported an organocatalytic enolate-mediated synthesis of 1,2,3-triazoles from aldehydes and aryl azides as starting materials, which constitutes an important alternative method. Meanwhile, syntheses of 1,5-disubstituted 1,2,3-triazoles were reported, in which ruthenium or a base was usually applied as a catalyst.[16] Recently, 1,4,5-trisubstituted 1,2,3-triazoles have been synthesized by using a three-​component system or from starting materials other than terminal alkynes and azides.[17] Some simple one-pot syntheses have been demonstrated that use aryldi­azonium silica sulfates,[18] arylboronic acids,[19] aryl halides,[20] or aromatic amines[21] as starting materials.

Scheme 1Methods for synthesizing 1-monosubstituted 1,2,3-triazoles

Owing to their recently identified particular biological activity, 1-monosubstituted 1,2,3-triazole derivatives have attracted a great deal of attention, especially in relation to their preparation, and they have been mainly prepared from azides and various acetylene sources, including ­acetylene[22] and its derivatives, such as acetylides [ethynyl(trimethyl)silane, ethynyl(tributyl)tin, sodium acetylide, or calcium carbide];[23] vinyl compounds (vinyl ­acetate, vinyl ethers, vinyl amines, or vinyl sulfoxides);[24] or propiolic acid (Scheme [1]).[25]

Table 1 Selected Optimizations of the Reaction Conditions^a

Entry	Solvent	Oxidant 1 (2.5 equiv)	Base (1.5 equiv)	Catalyst (mol%)	Oxidant 2 (2 equiv)	Yieldb (%)
1	DMF	–	–	–	–	62c
2	DMF–H2O (8:1)	–	–	–	–	76c
3	MeCN–H2O (8:1)	–	–	–	–	68c
4	MeCN	–	–	–	–	96c
5	MeCN	t BuOOH	–	–	–	74d
6	MeCN	K2S2O8	–	–	–	88d
7	MeCN	KMnO4	–	–	–	72d
8	MeCN	KMnO4	KOH	–	–	82d
9	MeCN	KMnO4	K2CO3	–	–	86d
10	MeCN	KMnO4	Na2CO3	–	–	92d
11	MeCN	KMnO4	Na2CO3	PdCl2 (20)	Cu(OAc)2	0e
12	MeCN	KMnO4	Na2CO3	Pd(OAc)2 (20)	Cu(OAc)2	25e
13	MeCN	KMnO4	Na2CO3	AgOAc (20)	Cu(OAc)2	30e
14	MeCN	KMnO4	Na2CO3	AgOAc (20)	K2S2O7	36e
15	MeCN	KMnO4	Na2CO3	Ag2CO3 (20)	K2S2O7	30e
16	MeCN	KMnO4	Na2CO3	AgNO3 (20)	K2S2O7	52e
17	MeCN	KMnO4	Na2CO3	Ag2O (20)	K2S2O7	86e
18	MeCN	KMnO4	Na2CO3	Ag2O (20)	(NH4)2S2O7	74e
19	MeCN	KMnO4	Na2CO3	Ag2O (20)	KMnO4	26e
20	MeCN	KMnO4	Na2CO3	Ag2O (20)	–	32e
21	MeCN	KMnO4	Na2CO3	Ag2O (10)	K2S2O7	88e
22	MeCN	KMnO4	Na2CO3	Ag2O (5)	K2S2O7	65e

^a Reaction conditions: (1) 1-azido-4-methylbenzene (1a; 0.3 mmol), propargyl alcohol (2; 0.36 mmol), CuI (0.03 mmol), NaAsc (0.06 mmol), solvent (2 mL) solvent, 15 mL sealed pressure tube, stirring, 80 °C; (2) oxidant 1 (0.75 mmol), base (0.45 mmol), stirring, 80 °C; (3) catalyst and oxidant 2 (0.6 mmol), stirring, 100 °C.

^b Isolated yield.

^c Yield of [1-(4-tolyl)-1H-1,2,3-triazol-4-yl]methanol.

^d Yield of 1-(4-tolyl)-1H-1,2,3-triazole-4-carboxylic acid.

^e Yield of 1-(4-tolyl)-1H-1,2,3-triazole (3a).

As part of our continuing interest in the synthesis and modification of various 1,2,3-triazole derivatives,[26] we describe a convenient and efficient one-pot three-step method for the preparation of monosubstituted 1,2,3-triazoles 3 by using aryl azides 1 and propargyl alcohol (2) as starting materials.

Table 2 Substrates scope^a,b

3a; 88%	3b; 83%	3c; 81%
3d; 83%	3e; 93%	3f; 87%
3g; 79%	3h; 73%	3i; 70%
3j; 70%	3k; 76%	3l; 73%
3m; 75%	3n; 81%	3o; 77%
3p; 80%	3q; 82%

^a Reaction conditions: (1) azide 1 (0.3 mmol), propargyl alcohol (2; 0.36 mmol), CuI (0.03 mmol), NaAsc (0.06 mmol), MeCN (2 mL), sealed 15 mL pressure tube, 80 °C, 5 h. (2) KMnO₄ (0.75 mmol), Na₂CO₃ (0.45 mmol), 80 °C, 8 h; (3) Ag₂O (0.03 mmol), K₂S₂O₇ (0.6 mmol), 100 °C, 24 h.[27]

^bYields of the isolated products after column chromatography are reported.

We chose the reaction of 1-azido-4-methylbenzene (1a) and propargyl alcohol (2) as a model system (Table [1]). Initially, we explored the first step of the process by using CuI and sodium ascorbate (NaAsc) as a catalyst system in various solvents, and we obtained the intermediate product [1-(4-tolyl)-1H-1,2,3-triazol-4-yl]methanol in 62% yield by using DMF as a solvent, through a Cu-catalyzed azide–alkyne Huisgen cycloaddition (Table [1], entry 1). DMF–H₂O (8:1), MeCN–H₂O (8:1), and MeCN were also examined as solvents, and an excellent yield of 96% was obtained in MeCN after five hours (entries 2–4). We then studied the second process of oxidizing the intermediate product [1-(4-tolyl)-1H-1,2,3-triazol-4-yl]methanol to 1-(4-tolyl)-1H-1,2,3-triazole-4-carboxylic acid by using various oxidants and bases (entries 5–10). A combination of KMnO₄ and Na₂CO₃ was the best choice, giving a 92% yield after eight hours (entry 10). t-BuOOH, K₂S₂O₈, KMnO₄, KMnO₄–KOH, and KMnO₄–K₂CO₃ gave inferior results as oxidants (entries 5–9). Encouraged by these results, we screened various catalysts and oxidants for the final step of the process (entries 11–20). None of the target molecule was detected when we used PdCl₂ as a catalyst and Cu(OAc)₂ as the oxidant (entry 11). When the PdCl₂ catalyst was replace with Pd(OAc)₂, the reaction gave 1-(4-tolyl)-1H-1,2,3-triazole (3a) in 25% yield (entry 12). We then investigated other catalysts (AgOAc, Ag₂CO₃, AgNO₃, and Ag₂O) (entries 13–17) and we found that Ag₂O was the most efficient. Oxidant screening showed that K₂S₂O₇ was the best choice, giving an 86% yield (entry 17). An oxidant is essential for this coupling, as a very low yield was obtained in the absence of an oxidant (entry 20). Next, we examined the amount of Ag₂O and we found that 10% AgNO₃ was efficient in this transformation, affording the desired product 3a in 88% yield (entry 21); reducing the amount to 5% an inferior result was obtained(entry 22).

By using the optimized reaction conditions, we then explored the scope of the aryl azide in this transformation (Table [2]). A broad spectrum of substrates bearing various substituents was investigated. All the reactions proceeded smoothly and they consistently gave the target molecules 3a–q in good to excellent yield, regardless of whether the substrates bore electron-donating or electron-withdrawing substituents (Table [2, 3a–q]). The reactions of aryl azides with electron-donating groups such as methyl or methoxy in the ortho-, meta-, or para-position all gave the corresponding products in good yields (3a–f). Substrates with an electron-withdrawing group such as as sulfonamide, nitro, fluoro, chloro, or bromo also reacted smoothly, although the yields were somehow lower (2g–q).

Aryl azides with substituents in the para-position produced higher yields than did those bearing groups in the meta- or ortho-position, probably owning to the steric effects (Table [2, 3a] versus 3c and 3d or 3e versus 3f). Note that substrates possessing more-electron-rich groups gave higher yields of the corresponding products. Furthermore, a substrate bearing group a sulfonamido group was also suitable for this transformation, giving a good yield of the corresponding product 3g.

In summary, we successfully synthesized 1-monosubstituted 1,2,3-triazoles from propargyl alcohol and various aryl azides as starting materials. The 1-monosubstituted 1,2,3-triazole derivatives were readily prepared in good to excellent yields by a simple three-step one-pot sequence.

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• 27 1-Substituted 1H-1,2,3-Triazoles; General Procedure Aryl azide 1 (0.3 mmol), propargyl alcohol (2; 0.36 mmol), CuI (0.03 mmol), NaAsc (0.06 mmol), and MeCN (2 mL) were added to a 15 mL pressure tube. The tube was sealed and the mixture was stirred at 80 °C for 5 h until the reaction was complete. KMnO₄ (0.75 mmol) and Na₂CO₃ (0.45 mmol) were added, and the mixture was stirred at 80 °C for 8 h. Ag₂O (0.03 mmol) and K₂S₂O₇ (0.6 mmol) were then added, and the mixture was heated at 100 °C for 24 h until the reaction was complete (TLC). H₂O (25 mL) was added, and the mixture was extracted with EtOAc (3 × 20 mL). The organic layers were combined, washed with brine (3 × 5 mL), dried (Na₂SO₄), and concentrated under reduced pressure to afford a crude product that was purified by column chromatography [silica gel, EtOAc–PE (1:3)]. 1-(4-Tolyl)-1H-1,2,3-triazole (3a) White solid; yield: 42 mg (88%); mp 85.5–86.5 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.96 (d, J = 0.8 Hz, 1 H), 7.83 (s, 1 H), 7.62 (d, J = 8.4 Hz, 2 H), 7.32 (d, J = 8.2 Hz, 2 H), 2.43 (s, 3 H). 1-(2-Methoxyphenyl)-1H-1,2,3-triazole (3f) White solid; yield: 46 mg (87%); mp 81–82.3 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.13 (d, J = 1.0 Hz, 1 H), 7.82 (d, J = 1.0 Hz, 1 H), 7.79 (dd, J = 7.9, 1.7 Hz, 1 H), 7.46–7.41 (m, 1 H), 7.14–7.08 (m, 2 H), 3.89 (s, 3 H). 4-(1H-1,2,3-Triazol-1-yl)benzenesulfonamide (3g) White solid; yield: 53 mg (79%); mp 187–187.5 °C. ¹H NMR (500 MHz, CDCl₃): δ = 8.93 (s, 1 H), 8.14 (d, J = 8.6 Hz, 2 H), 8.04 (d, J = 6.1 Hz, 3 H), 7.55 (s, 2 H). 1-(3-Chlorophenyl)-1H-1,2,3-triazole (3m) White solid; yield: 40 mg (75%); mp 91.6–92.4 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.02 (d, J = 1.1 Hz, 1 H), 7.86 (d, J = 1.0 Hz, 1 H), 7.80 (t, J = 2.0 Hz, 1 H), 7.66 (ddd, J = 7.9, 2.0, 1.3 Hz, 1 H), 7.51–7.40 (m, 2 H).