HETEROCYCLES

Communication | Regular issue | Vol. 91, No. 1, 2015, pp. 41-48
Received, 11th November, 2014, Accepted, 22nd December, 2014, Published online, 7th January, 2015.
DOI: 10.3987/COM-14-13124

■ One-Pot Synthesis of [1,2,3]Triazolo[1,5-a]pyrazine Derivatives from Ynones and Amino Azide

Shinichi Koguchi,* Azusa Sakurai, and Kosuke Niwa

Faculty of Science, Tokai University, Kitakaname 4-1-1, Hiratsuka, Kanagawa, 259-1292, Japan

Abstract

A new procedure is described for the synthesis of [1,2,3]triazolo[1,5-a]pyrazine derivatives via a one-pot cycloaddition.

1,3-Dipolar cycloaddition is one of the widely used reactions in synthetic chemistry and has been extensively studied for heterocyclic formation. Numerous methods have been developed for the synthesis of 1,2,3-triazoles from azides and alkynes (Huisgen reaction). The most versatile 1,4-disubstituted 1,2,3-triazole synthetic method employs acetylene and azide with a copper catalyst, as developed by Sharpless et al. (copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) or click chemistry).1 Few works have described the selective synthesis of 1,5-disubstituted triazoles.2 Fokin and co-workers reported the ruthenium(II)-catalyzed [CpRu-Cl(PPh3)2], regioselective synthesis of 1,5-disubstituted 1,2,3-triazoles from azides and alkynes.3 Coats and colleagues described click reactions using a silylacetylene derivative for the synthesis of 1,5-disubstituted products.4 Recently, we reported the synthesis of novel 1,5-disubstituted 1,2,3-triazoles from a triazolium salt.5 Herein, we describe the Huisgen-based, one-pot synthesis of [1,2,3]triazolo[1,5-a]pyrazine derivatives from ynones and amino azide via 1,5-disubstituted, 4-protected 1,2,3-triazoles (Scheme1).
The use of imidazopyrazine derivatives as inhibitors and their syntheses have been studied extensively.6 Based on these studies, triazolopyrazine derivatives are expected to be significant physiologically active compounds. However, the synthesis of [1,2,3]triazolo[1,5-a]pyrazine derivatives has not been reported.

We initially investigated the regioselective synthesis of 3-protected-4-phenyl-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazine derivatives (1). The desired compound, 4-phenyl-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazine (1a), was not obtained by reacting 1-phenylprop-2-yn-1-one with 2-azidoethanamine (Table 1, Entry 1). We developed cycloaddition reactions using silyl-protected ynone derivatives for the synthesis of 3-protected-4-phenyl-6,7-dihydro-[1,2,3]triazolo[1,5-a] pyazines. The reactions occurred favorably in all instances (Table 1, Entries 2 and 3). However, low reactivity was observed in cycloaddition using 1-phenyl-3-(triisopropylsilyl)prop-2-yn-1-one, most likely due to steric hindrance (Table 1, Entry 4).

Next, we devised a method for selectively deprotecting silyl-protected compounds in the same vessel. We examined the deprotection of 3-protected-4-phenyl-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazine derivatives using a number of developed deprotection methods. Trifluoroacetic acid efficiently cleaved the silyl group in our synthetic methodology. A mixture of 1-substituted-3-(trimethylsilyl)prop-2-yn-1-one (0.5 mmol), 2-azidoethanamine (1.5 mmol), and toluene (1 mL) was sealed in a glass vial and warmed to 120 °C overnight. Product formation was confirmed by thin-layer chromatography (TLC), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at 120 °C for 5 h. Then, 1 M-NaOH (1 mL) was added to the reaction mixture. The mixture was stirred for 1 h at room temperature and then extracted with CHCl3 and washed with water. The organic layer was dried and evaporated under vacuum, and the product was isolated by silica gel column chromatography to afford 4-substituted-6, 7-dihydro-[1,2,3]triazolo[1,5-a]pyrazine derivatives in excellent yields.
To investigate the substrate generality of this synthetic method, nine different [1,2,3]triazolo[1,5-a]pyrazine derivatives were synthesized using silyl-protected ynones and amino azide (Table 2). The silyl protecting group was substituted with trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS), and triisopropylsilyl (TIPS) in Entries 1-3 in Table 2. 1-Phenyl-3-(trimethylsilyl)prop-2-yn-1-one and 3-(tert-butyldimethylsilyl)-1-phenylprop-2-yn-1-one were obtained quantitatively as the desired products (Table 2, Entries 1 and 2). However, low reactivity was observed in the reaction using 1-phenyl-3-(triisopropylsilyl)prop-2-yn-1-one (Table 2, Entry 3), analogous to that in Table 1. The synthesis of 4-aryl-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazine generally proceeded well (Table 2, Entries 1-8). The synthesis of 4-alkyl-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazine also generally proceeded well. (Table 2, Entries 9-11) Thus, the developed reaction occurred favorably in all instances.7

Finally, we investigated the reaction pathway of our synthetic methodology, that is, whether triazole formation (Path A) or imine formation (Path B) occur first.

We prepared 1-phenyl-3-(trimethylsilyl)prop-2-yn-1-one (silyl-protected ynone) and tert-butyl (2-azidoethyl)carbamate (Boc-protected azide) to verify Path A. The silyl-protected ynone reacted with the Boc-protected azide to form the triazole intermediate in good yield (4). Subsequent deprotection of triazole intermediate (4) afforded the [1,2,3]triazolo[1,5-a]pyrazine derivative (1a) in good yield (Scheme 3).

We prepared 1-phenyl-3-(trimethylsilyl)prop-2-yn-1-one and 2-bromoethanamine to verify Path B. The silyl-protected ynone reacted with 2-bromoethanamine to form the imine intermediate (5) (E/Z isomer mixture). Subsequent azidation of the imine intermediate (5) afforded [1,2,3]triazolo[1,5-a]pyrazine derivative (1a) in only trace yields. We could not obtain the desired product in good yield (Scheme 4).

Accordingly, the reaction pathway is suggested in Scheme 2 as Path A, in which the first stage is triazole formation and the second stage is imine formation.

In summary, we have demonstrated the one-pot synthesis of [1,2,3]triazolo[1,5-a]pyrazine derivatives from ynones and amino azide. Our synthetic method was effective in generating a variety of [1,2,3]triazolo[1,5-a]pyrazine derivatives, and we determined the reaction pathway for this synthetic methodology.

ACKNOWLEDGEMENTS
We thank Drs. Makoto Oba, Mikio Watanabe and Taichi Nakano. This study was supported by Tokai University Supports Association Research.

References

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7. 7. General procedure for the synthesis of compounds 1a, 2a-h; A solution of silyl protected ynones (0.5 mmol) in toluene (1 mL) was added 2-azidoethanamine (1.5 mmol). The mixture was stirred for 24 h at 120 °C in a sealed tube. Then the reaction mixture was confirmed using TLC and added trifluoroacetic acid (1 mL) and the mixture was stirred for 5 h at room temperature. Then to the reaction mixture was added 1M-NaOH aq (1 mL), and the whole was stirred 1 h at room temperature. The mixtuer was extracted with CHCl3 and washed with water. Organic layer was dried and evaporated. The solvent was removed under vacuum and the product was isolated by silica gel column chromatography.
Compound 1a: Yellow oil; 1H-NMR (500 MHz, CDCl3): δ=4.24 (t, 2H, J =7.5), 4.56 (t, 2H, J =7.5), 7.54 (m, 3H), 7.82 (m, 2H), 7.87 (s, 1H). 13C-NMR (125 MHz, CDCl3): δ=42.7, 48.2, 126.8, 127.5(2C), 128.9(2C), 131.3, 132.3, 136.0, 157.0. HRMS (APCI): m/z [M+H]+ calcd for C11H10N4: 199.0987; found; 199.0903.
Compound 2a: Yellow oil. 1H-NMR (500 MHz, CDCl3): δ=2.32 (s, 3H), 4.30 (t, 2H, J =7.0Hz), 4.57 (t, 2H, J =7.0Hz), 7.26-7.38 (m, 4H), 7.54 (s, 1H). 13C-NMR (125 MHz, CDCl3): δ=20.3, 42.6, 48.3, 126.0, 128.2, 129.3, 129.9, 131.0, 132.3, 135.7, 136.1, 152.7. HRMS (APCI): m/z [M+H] + calcd for C12H13N4: 213.1140; found; 213.1073.
Compound 2b: Orange oil. 1H-NMR (500 MHz, CDCl3): δ=2.43 (s, 3H), 4.23 (t, 2H, J =6.5Hz), 4.55 (t, 2H, J =6.5Hz), 7.37-7.65 (m, 4H), 7.87 (s, 1H). 13C-NMR (125 MHz, CDCl3): δ=21.4, 42.7, 48.2, 124.7, 126.8, 128.0, 128.7, 132.1, 132.4, 135.9, 138.8, 157.1. HRMS (APCI): m/z [M+H]+ calcd for C12H13N4: 213.1140; found; 213.1060.
Compound 2c: White solid, mp 92 °C. 1H-NMR (500 MHz, CDCl3): δ=2.44 (s, 3H), 4.22 (t, 2H, J =6.5Hz), 4.55 (t, 2H, J =6.5Hz), 7.31 (d, 2H, J =8.0Hz), 7.72 (d, 2H, J =8.0Hz), 7.86 (s, 1H). 13C-NMR (125 MHz, CDCl3): δ=21.4, 42.7, 48.0, 127.2, 129.2, 132.2, 133.2, 141.7, 156.7, 161.7. HRMS (APCI): m/z [M+H]+ calcd for C12H13N4: 213.1140; found; 213.1069.
Compound 2d: Yellow oil. 1H-NMR (500 MHz, CDCl3): δ=4.39 (t, 2H, J =7.5), 4.59 (t, 2H, J =7.5), 7.39 (m, 2H), 7.44 (m, 2H), 7.57 (s, 1H). 13C-NMR (125 MHz, CDCl3): δ=42.6, 48.6, 127.2, 129.9, 130.3, 131.3, 132.2, 132.2, 135.4, 156.5, 156.6. HRMS (APCI): m/z [M+H]+ calcd for C11H10ClN4: 233.0594; found; 233.0479.
Compound 2e: Orange oil. 1H-NMR (500 MHz, CDCl3): δ=4.31 (t, 2H, J =7.5), 4.58 (t, 2H, J =7.5), 7.51 (m, 4H), 7.73 (s, 1H). 13C-NMR (125 MHz, CDCl3): δ=41.5, 48.8, 115.4, 115.5, 126.4, 129.2, 131.2, 131.3, 131.5, 160.0, 160.6. HRMS (APCI): m/z [M+H]+ calcd for C11H10FN4: 217.0889; found; 217.0793.
Compound 2f: White solid, mp 128 °C. 1H-NMR (500 MHz, CDCl3): δ=2.40 (s, 3H), 4.05 (t, 2H, J =7.0), 4.43 (t, 2H, J =7.0), 7.83 (s, 1H). 13C-NMR (125 MHz, CDCl3): δ=22.9, 42.4, 47.7, 128.0, 130.7, 155.8. HRMS (APCI): m/z [M+H]+ calcd for C6H9N4: 216.1140; found 213.1069.
Compound 2g: Orange oil. 1H-NMR (500 MHz, CDCl3): δ=0.86-0.89 (m, 5H), 1.25-1.28 (m, 9H), 1.62-1.73 (m, 3H), 2.64-2.67 (m, 2H), 4.05 (t, 2H, J =7.0), 4.42 (t, 2H, J =7.0), 7.81 (s, 1H). 13C-NMR (125 MHz, CDCl3): δ=14.1, 22.6, 26.4, 29.3, 29.4, 31.8, 36.5, 38.8, 38.9, 42.5, 50.9, 127.7, 130.5, 159.5. HRMS (APCI): m/z [M+H]+ calcd for C14H25N4: 249.2079; found 249.1961.
Compound 2h: Orange oil. 1H-NMR (500 MHz, CDCl3): δ=0.84-0.0.86 (m, 8H), 1.23-1.66 (m, 13H), 2.63-2.64 (m, 2H), 4.04 (t, 2H, J =7.0), 4.38 (t, 2H, J =7.0), 7.79 (s, 1H). 13C-NMR (125 MHz, CDCl3): δ=14.0, 22.5, 27.0, 29.2, 29.4, 29.5, 31.8, 34.1, 36.0, 36.8, 38.7, 42.5, 50.6, 127.6, 130.4, 159.4. HRMS (APCI): m/z [M+H]+ calcd for C16H29N4: 277.2392; found 277.2258.