Study of Reactivity in the 1,3-Dipolar Cycloaddition Reactions Leading to New Triazolopyrrolopyrazine Ring Systems

Abstract

The influence of the structural symmetry of the 2π double-reactive-sites component in the 1,3-dipolar cycloaddition reactions, involving nitrilimines as dipoles, was investigated. The experimental data showed that the loss of the symmetry leads to the formation of the monocycloadduct in good yields.

Key words

1,3-dipolar cycloaddition reactions - diazines - nitrilimine dipoles - triazolopyrrolopyrazines

References and Notes

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14

General Procedure for the 1,3-Dipolar Cycloaddition Reactions of 2-Phenyl[1 H ]pyrrolo[2,3- b ]pyrazine^¹5 (12) and Chlorophenylhydrazones^¹6,¹7 6′a-d (Method B)
Triethylamine (20.48 mmol) was added to a solution of
2-phenyl[1H]pyrrolo[2,3-b]pyrazine (12, 2.56 mmol,
0.5 g) and chlorophenylhydrazones 6′a-d (5.12 mmol) in anhydrous THF (20 mL). The mixture was stirred at r.t. for 96 h. In the case of the reaction of 12 and 6′a, methyl 3,7-diphenyl-5,6-dihydro-3H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-carboxylate (14a) was directly filtered from the mixture; yield 60%; mp 188-189 ˚C, from EtOH. IR: 3430-3093 (NH), 1731 (C=O), 1556 (C=N) cm^-¹. ^¹H NMR [200 MHz, (CD₃)₂ SO]: δ = 3.82 (s, 3 H, CH₃), 6.82 (s, 1 H, H-8), 7.04 (t, 1 H, 4-NC₆H₅, J = 6.6 Hz), 7.25-7.46 (m, 6 H, ArH), 8.03-8.05 (m, 1 H, 4-C₆H₅), 8.21-8.25 (m, 3 H, ArH, H-4), 10.82 (s, N H). ^¹³C NMR [50.3 MHz, (CD₃)₂ SO]: δ = 52.8 (q), 89.1 (d), 114.8 (d), 120.7 (s), 121.6 (s), 123.2 (d), 127.7 (d), 128.7 (d), 129.3 (d), 129.7 (d), 130.2 (d), 130.8 (s), 135.3 (s), 142.4 (s), 160.4 (s), 168.7 (s). Anal. Calcd for. C₂₁H₁₇N₅O₂: C, 67.91; H, 4.61; N, 18.86. Found: C, 67.96; H, 4.68; N, 18.92.
The solution was evaporated under reduced pressure, the residue was washed with EtOH (5 mL) and chromatog-raphed on a silica gel column using CH₂Cl₂ as the eluent. The first fraction eluted gave 3,9-dimethoxycarbonyl-1,6,11-triphenyl(1,11,11a,11b-tetrahydrobis-1,2,4-triazolo[3,4-c:4′,3′-a]-3H-pyrrolo[2,3-e]pyrazine) (13a); yellow solid, yield 13%; mp 214-215 ˚C, from EtOH. IR: 3407-3166 (NH), 1733, 1708 (C=O), 1594 (C=N) cm^-¹. ^¹H NMR [200 MHz, (CD₃)₂ SO]: δ = 3.91 (s, 3 H, CH₃), 3.96
(s, 3 H, CH₃), 5.83 (d, 1 H, H-11a, J = 7.6 Hz), 5.95 (d, 1 H, H-11b, J = 7.6 Hz), 6.75-6.77 (m, 3 H, H-5, 4-NC₆H₅), 7.07-7.23 (m, 10 H, ArH), 7.35-7.43 (m, 2 H, 3-NC₆H₅), 7.55-7.59 (m, 2 H, 3-NC₆H₅), 10.77 (s, NH). ^¹³C NMR [50.3 MHz, (CD₃)₂ SO]: δ = 52.8 (q), 53.0 (q), 73.3 (d), 74.6 (d), 97.5 (d), 110.0 (s), 113.1 (d), 113.2 (d), 115.0 (s), 120.8 (d), 120.9 (d), 123.2 (d), 124.9 (s), 125.9 (d), 128.8 (2 d), 128.9 (d), 132.2 (s), 140.6 (s), 142.8 (s), 143.4 (s), 144.2 (s), 158.4 (s), 158.6 (s). Anal. Calcd for C₃₀H₂₅N₇O₄: C, 65.80; H, 4.60; N, 17.91. Found C, 65.76; H, 4.65; N, 18.02.
The second fraction eluted with CH₂Cl₂-EtOAc (98:2)gave methyl 6-[methoxy-N-phenyl-2-oxoethanhydrazonyl]-3,7-diphenyl-5,6-dihydro-3H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-carboxylate (16a); yellow solid, yield 6%; mp 218-219 ˚C, from EtOH. IR: 3358-3021 (NH), 1739 (C=O), 1596 (C=N) cm^-¹. ^¹H NMR [200 MHz, (CD₃)₂ SO]: δ = 3.60 (s, 3 H, CH₃), 3.95 (s, 3 H, CH₃), 7.27 (s, 1 H, H-8), 7.37-7.56 (m, 11 H, ArH), 7.65 (d, 2 H, 2-C₆H₅, J = 7.0 Hz), 7.72 (d, 2 H, 2-C₆H₅, J = 7.8 Hz), 8.32 (d, 2 H, 3-C₆H₅, J = 7.8 Hz), 8.48 (s, 1 H, H-4). ^¹³C NMR (50.3 MHz, CDCl₃): δ = 52.8 (q), 52.9 (q), 108.3 (d), 110.9 (s), 120.0 (d), 120.9 (s)125.1 (d), 126.9 (d), 127.8 (d), 128.2 (d), 129.1 (d), 129.2 (d), 129.4 (d), 130.0 (d), 131.7 (s), 133.4 (d), 137.2 (s), 150.5 (s), 153.0 (s), 156.7 (s), 160.3 (s). Anal. Calcd for C₃₀H₂₅N₇O₄: C, 65.80; H, 4.60; N, 17.91. Found: C, 65.73; H, 4.57; N, 18.05.
Further fraction eluted with CH₂Cl₂-EtOAc (95:5), afforded methyl 3,7-diphenyl-3H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-carboxylate (15a); very bright orange solid, yield 10%; mp 254-255 ˚C, from EtOH. IR: 1735 (C=O), 1552 (C=N) cm^-¹. ^¹H NMR [200 MHz, (CD₃)₂ SO]: δ = 3.99 (s, 3 H, CH₃), 7.51 (s, 1 H, H-8), 7.61-7.72 (m, 5 H, ArH), 7.75 (d, 2 H, 2-NC₆H₅, J = 6.6 Hz), 8.04 (d, 2 H, 3-C₆H₅, J = 7.3 Hz), 8.45-8.47 (m, 2 H, ArH, H-4). ^¹³C NMR [50.3 MHz, (CD₃)₂ SO]: δ = 53.0 (q), 91.4 (d), 124.3 (2 d), 129.0 (2 d), 129.9 (d), 130.5 (d), 132.4 (d), 133.9 (s), 134.5 (s), 142.4 (s), 144.6 (s), 162.8 (s), 163.2 (s), 177.1 (s). Anal. Calcd for C₂₁H₁₅N₅O₂: C, 68.28; H, 4.09; N, 18.96. Found: C, 68.36; H, 4.16; N, 19.03. For the experimental details of all reactions see Supporting Information.