Direct access to 1,4-disubstituted 1,2,3-triazoles through organocatalytic 1,3-dipolar cycloaddition reaction of α,β-unsaturated esters with azides

Abstract

DBU-catalyzed organocatalytic 1,3-dipolar cycloaddition reactions of α,β-unsaturated esters with azides have been developed. This strategy generates 1,4-disubstituted 1,2,3-triazoles in high yields with high regioselectivities. It is demonstrated that some of these products can be transformed into important pharmaceutical agents.

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The 1,2,3-triazole core is a privileged scaffold that is featured in a abundant number of bioactive molecules and they exhibit considerable biological activities.¹ As shown in Fig. 1, tazobactam has been identified as a β-lactam antibiotic tazobactam.² Cefatrizine exhibits antibacterial activity.³ Rufinamide is an anticonvulsant drug developed in 2004 by Novartis.⁴ It is normally used to treat Lennox–Gastaut syndrome and other disorders. 1,2,3-Triazole moieties can also behave as antimicrobial agents.⁵

Fig. 1 Examples of important 1,2,3-triazoles.

The widely used protocol to synthesize 1,2,3-triazoles is the Huisgen 1,3-dipolar cycloaddition.⁶ However, this method requires high temperatures and proceeds with limited regioselectivity. In recent years, chemists have developed metal-catalyzed (copper,⁷ ruthenium,⁸ iridium⁹) azide–terminal alkyne cycloaddition (AAC). Although this strategy can provide a mild and efficient synthesis of 1,4-disubstituted 1,2,3-triazoles, the metal ions are potentially toxic for living organisms and can induce degradation of viruses.¹⁰ In recent years, Ramachary,¹¹ Bressy¹² and our group¹³ independently reported the organocatalytic regioselective synthesis of 1,4,5-trisubstituted 1,2,3-triazoles through an in situ enamine intermediate. This methodology provides a novel pathway to generate 1,2,3-triazoles in high yields and regioselectivities. However, these approaches are restricted to ketone or cyclic enone substrates and can only produce 1,4,5-trisubstituted 1,2,3-triazoles. Inspired by the success of the 1,4,5-trisubstituted 1,2,3-triazole synthesis,¹⁴ our efforts have moved to another highly important class of triazoles, 1,4-disubstituted 1,2,3-triazoles. As exemplified in Fig. 1, rufinamide and the antimicrobial agent have been identified as very important pharmaceuticals. In the beginning, we speculated that the reaction of ethyl acrylate 1c with azide 2a would give the 1,4-disubstituted 1,2,3-triazole 3ca under standard conditions. Surprisingly, the product arising from this reaction was undesirable pyrazoline 4 (Fig. 2). In this transformation (Fig. 2), the postulated mechanism suggested that the cycloaddition intermediate A of acrylate 1c and azide 2a would undergo an arrangement to generate the diazoester intermediate C,¹⁵ which further reacts with a second acrylate 1c to finally form undesirable pyrazoline 4. In order to achieve the triazole structure, we attempted to circumvent the ring opening step to avoid the conversion between B and C. After being confronted with this challenge, a thermodynamic control strategy was taken to solve the above problem. As indicated in Fig. 2 (this design), we can attach a suitable leaving group (LG) at the C5 position, which probably stimulates the competitive elimination reaction. This eventually induces the reaction to directly construct the desired product, the 1,4-disubstituted 1,2,3-triazole, driven by the forces of electron delocalization and aromaticity.

Fig. 2 Exploration of reactions to give 1,4-disubstituted 1,2,3-triazoles.

We began our initial investigation by employing active α,β-unsaturated ester 1a and phenyl azide 2a in the presence of various amine or phosphine catalysts. The screening results indicated that tertiary amine V was the best catalyst for this reaction (Table 1, entry 5). Other amine catalysts (I–IV, VI–VIII) can also give the desired product but the yields were not very high (Table 1, entries 1–4, 6–8). While if we utilized triphenylphosphine IX as the catalyst, very little of the desired product was obtained (Table 1, entry 9). After identifying catalyst V as the best catalyst, we next further screened the reaction mediums to improve yield. Further experimental results revealed that the solvent was one of the crucial factors for this reaction. The efficiency of reaction exhibited great difference between different solvents. For instance, when we conducted the reaction in DMF or DMA, the solvent influenced the reaction positively and the yields of desired product 3aa were improved to 61% and 63% (Table 1, entries 10 and 11). However, when we changed the solvent to methanol, toluene or CH₃CN, only moderate yields (42%, 53% and 56%) were observed (Table 1, entries 12–14). To our delight, when we utilized THF as the reaction medium, the yield increased to 89% (Table 1, entry 15). Further experiment revealed that CHCl₃ was the best solvent for this transformation. When we conducted the reaction using CHCl₃ as the solvent, an excellent yield (93%) was observed (Table 1, entry 16). Further extensive screening of temperature indicated that decreased T (°C) led to a slow conversion (entry 17, 50 °C, 53%, 48 h). It is worth noting that lowering the catalyst loading to 10 mol% resulted in a longer reaction time (24 h) with the yield of product 3aa maintained (Table 1, entry 18). Further reducing the catalyst loading to 5 mol% reduced the yield to 82% after 48 h (Table 1, entry 19). Finally, optimization of reaction parameters led us to identify DBU as a superb catalyst and CHCl₃ as an ideal medium for the desired transformation to give adduct 3aa in essentially high yield. Moreover, adduct 3aa could be obtained in absolute regioselectivity, which may be contributed to by the energy overlap of frontier molecular orbitals between the α,β-unsaturated ester 1a and the phenyl azide 2a.

Table 1 Optimization of the reaction conditions^a

Entry	Cat.	Solvent	t/h	Yield^b (%)
a Reaction conditions: a mixture of 1a (0.10 mmol), 2a (0.20 mmol) and catalyst (20 mol%) in the solvent (0.3 mL) was stirred at 80 °C for 18 h.b Isolated yield.c The reaction was conducted at 50 °C.d 10 mol% catalyst used.e 5 mol% catalyst used.
1	I	DMSO	18	38
2	II	DMSO	18	41
3	III	DMSO	18	45
4	IV	DMSO	18	37
5	V	DMSO	18	54
6	VI	DMSO	18	21
7	VII	DMSO	18	31
8	VIII	DMSO	18	28
9	IX	DMSO	18	<5
10	V	DMF	18	61
11	V	DMA	18	63
12	V	MeOH	18	42
13	V	Toluene	18	53
14	V	CH3CN	18	56
15	V	THF	18	89
16	V	CHCl3	18	93
17^c	V	CHCl3	48	53
18^d	V	CHCl3	24	90
19^e	V	CHCl3	48	82

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With the optimized conditions in hand,‡ the generality of substrate scope of the 1,4-disubstituted 1,2,3-triazole synthesis was explored. As shown in Table 2, a diverse set of azides can be used in the transformation to produce the 1,4-disubstituted 1,2,3-triazoles in high to excellent yields. After obtaining the product 3aa in 90% yield, various aryl azides, regardless of electron-donating groups or electron-withdrawing groups in o, m, p-positions, all led to the desired products 3aa–am (Table 2, 82–94%). To our delight, aryl azides, which contained a naphthalene ring or a heterocyclic ring, could also be used for this transformation to afford the desired products 3an and 3ao in 85% and 88% yields respectively. It is worth noting that alkyl azides also afforded the expected adducts in high chemical yields, but under neat conditions (3ap and 3aq, 87% and 85%, respectively). The configuration of the products was assigned based on single-crystal X-ray analysis of 3ad.¹⁶

Table 2 Synthesis of 1,4-disubstituted 1,2,3-triazoles^a

a Reaction conditions: a mixture of 1 (0.10 mmol), 2 (0.20 mmol) and V (10 mol%) in CHCl₃ (0.3 mL) was stirred at 80 °C for 24 h.b Neat, 80 °C, 48 h.

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To further demonstrate the utility of this methodology, we performed a late-stage modification on several triazole analogues. As shown in Scheme 1, isonicotinoyl hydrazide 6 exhibited antimycobacterial activity against mycobacterium tuberculosis H37Rv Strain.¹⁷ DIBAL-H reduction of 3aa followed with an efficient PCC oxidation yielded the key intermediate aldehyde 5 (85% overall yield, 2 steps). Then aldehyde 5 reacted with isonicotinohydrazide (INH) at room temperature for 3 h to yield the desired isonicotinoyl hydrazide 6 in 82% yield.

Scheme 1 Synthesis of isonicotinoyl hydrazide 6.

After accomplishing the above synthesis, we embarked on the total synthesis of rufinamide, an anticonvulsant drug. The synthetic route to rufinamide started with the DBU-catalyzed [3 + 2] reaction (Scheme 2). Azide 7 reacted with α,β-unsaturated ester 1a to give triazole 8 in 85% yield (approximately 80 °C and 72 h). Next, ammonolysis of triazole 8 gave the corresponding rufinamide (89% yield, rt, 24 h).

Scheme 2 Synthesis of rufinamide.

The details of the postulated mechanism are illustrated in Scheme 3. 1a bearing a leaving group (MeO) was chosen to demonstrate the reaction process. DBU firstly reacts with 1a to form zwitterion D. Next addition of zwitterion intermediate D to phenyl azide 2a forms intermediate E. Elimination of E allows production of intermediate F, which undergoes a cascade sequence of electrocyclization and subsequent elimination to finally generate the cycloaddition product 3aa.

Scheme 3 Plausible mechanism for the synthesis of 3aa.

In summary, a DBU-catalyzed organocatalytic 1,3-dipolar cycloaddition of active α,β-unsaturated esters to azides has been developed. This methodology provides a straight-forward pathway to generate 1,4-disubstituted 1,2,3-triazoles, which exhibit considerable biological activity, in high yields and with good regioselectivity. Compared with the metal-based catalytic AAC systems, this methodology provides an important complementary method. Notably, the reaction proceeds efficiently when using a simple and cheap catalyst. Considering the ready availability of the starting materials (α,β-unsaturated esters) and the operational simplicity, we believe that this work will draw more research interest to organocatalytic synthesis of substituted 1,2,3-triazoles and other biologically active heterocycles. Such studies are actively under way in our laboratory, and more results will be reported in due course.

Acknowledgements

We thank the financial support from Qingdao University and National University of Singapore (Academic Research Grant: R143000480112, R143000443112).

Notes and references

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16. ESI†.
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Footnotes

† Electronic supplementary information (ESI) available. CCDC 1021699. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra19038j

‡ General procedure for 1,3-dipolar cycloadditions of α,β-unsaturated esters with azides: to a solution of CHCl₃ (0.3 mL) were added a α,β-unsaturated ester 1 (0.10 mmol), an azide 2 (0.20 mmol) and a catalyst V (0.01 mmol). The reaction mixture was stirred at 80 °C for 24 h and then the solvent was removed under vacuum. The residue was purified by silica gel chromatography to yield the desired product 3.

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