A General and Efficient Synthesis of Azaindoles and Diazaindoles

Abstract

The DBU-mediated cyclization of ortho-(Boc-amino)alkynyl pyridines, -pyridazines, -pyrimidines and -pyrazines ­efficiently generates azaindoles and diazaindoles, respectively. The reaction proceeds under mild conditions and in high yields. A ­variety of functional groups are tolerated.

azaindole - diazaindoles - cyclization - heterocycles - alkynes

References

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19

General Procedure for the Sonogashira Coupling.
To a solution of ortho-(Boc-amino)halogeno pyridine or diazine (1 mmol) in anhyd DMF (1 mL) and Et₃N (3 mL) was added copper iodide (0.10 mmol), Pd(PPh₃)₂Cl₂ (0.05 mmol) and the alkyne (1 mmol) under argon and the reaction stirred at r.t. for 15 h. The reaction was diluted with EtOAc (10 mL), washed with sat. aq NH₄Cl solution (2 × 5 mL) and the combined aqueous layers were extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (5 mL), dried over MgSO₄ and concentrated. Column chromatography (hexane-EtOAc) yielded ortho-(Boc-amino)alkynyl pyridines or diazines in 37-99% yield.
Data for Alkynes. Compound 7: prepared from (4-iodopyridin-3-yl)carbamic acid tert-butyl ester. [23] ¹H NMR (400 MHz, CDCl₃): δ = 9.35 (s, 1 H), 8.20 (d, J = 5.06 Hz, 1 H), 7.19 (d, J = 5.06 Hz, 1 H), 7.06 (s, 1 H), 2.51 (t, J = 7.07 Hz, 2 H), 1.72 (qt, J = 7.07 Hz, J = 7.33 Hz, 2 H), 1.55 (s, 9 H), 1.09 (t, J = 7.33 Hz, 3 H).
Compound 9: ¹H NMR data are in accordance with data reported in the literature. [7]
Compound 11: prepared from (2-bromopyridin-3-yl)carbamic acid tert-butyl ester. [22] ¹H NMR (400 MHz, CDCl₃): δ = 8.42 (d, J = 9.08 Hz, 1 H), 8.19 (dd J = 1.39 Hz, J = 4.67 Hz, 1 H), 7.18 (dd, J = 4.67 Hz, J = 8.57 Hz, 1 H), 2.53 (t, J = 7.08 Hz, 2 H), 1.74 (qt, J = 7.33 Hz, J = 7.08 Hz, 2 H), 1.54 (s, 9 H), 1.10 (t, J = 7.33 Hz, 3 H).
Compound 13: prepared from (3-iodopyridin-2-yl)carbamic acid tert-butyl ester. [24] ¹H NMR (400 MHz, CDCl₃): δ = 8.36 (dd, J = 5.05 Hz, J = 1.77 Hz, 1 H), 7.60 (dd, J = 7.58 Hz, 1.77 Hz, 1 H), 7.57 (s, 1 H), 6.90 (dd, J = 7.58 Hz, J = 5.05 Hz, 1 H), 2.49 (t, J = 7.07 Hz, 2 H), 1.69 (qt, J = 7.33 Hz, J = 7.07 Hz, 2 H), 1.54 (s, 9 H), 1.09 (t, J = 7.33 Hz, 3 H).
Compound 15: ¹H NMR (400 MHz, CDCl₃): δ = 9.74 (br s, 1 H), 9.29 (br s, 1 H), 6.90 (s, 1 H), 2.99 (t, J = 7.58 Hz, 2 H), 1.69 (m, 11 H), 0.99 (t, J = 7.33 Hz, 3 H).
Compound 17: ¹H NMR (400 MHz, CDCl₃): δ = 8.97 (br s, 1 H), 7.92 (br s, 1 H), 6.74 (s, 1 H), 2.99 (t, J = 7.58 Hz, 2 H), 1.69 (qt, J = 7.58 Hz, J = 7.58 Hz, 2 H), 1.63 (s, 9 H), 1.01 (t, J = 7.58 Hz, 3 H).
Compound 19: ¹H NMR (400 MHz, CDCl₃): δ = 9.41 (s, 1 H), 8.73 (s, 1 H), 6.96 (br s, 1 H), 2.49 (t, J = 7.08 Hz, 2 H), 1.66 (qt, J = 7.33 Hz, J = 7.08 Hz, 2 H), 1.48 (s, 9 H), 1.03 (t, J = 7.33 Hz, 3 H).
Compound 21: ¹H NMR (400 MHz, CDCl₃): δ = 8.34 (br s, 1 H), 8.24 (br s, 1 H), 6.46 (br s, 1 H), 2.96 (t, J = 7.58 Hz, 2 H), 1.69 (qt, J = 7.58 Hz, J = 7.34 Hz, 2 H), 1.62 (s, 9 H), 0.99 (t, J = 7.34 Hz, 3 H).
Compound 23: ¹H NMR (400 MHz, CDCl₃): δ = 9.32 (s, 1 H), 8.14 (d, J = 5.03 Hz, 1 H), 7.16 (d, J = 4.80 Hz, 1 H), 6.97 (s, 1 H), 4.53 (s, 2 H), 1.46 (s, 9 H).
Compound 25: ¹H NMR (400 MHz, CDCl₃): δ = 9.26 (br s, 1 H), 8.12 (d, J = 5.05 Hz, 1 H), 7.25 (s, 1 H), 7.11 (d, J = 5.05 Hz, 1 H), 3.79 (t, J = 5.71 Hz, 2 H), 2.60 (t, J = 6.95 Hz, 2 H), 1.85 (tt, J = 6.95 Hz, J = 5.71 Hz, 2 H), 1.48 (s, 9 H).
Compound 27: ¹H NMR (400 MHz, CDCl₃): δ = 9.28 (s, 1 H), 8.14 (d, J = 5.05 Hz, 1 H), 7.13 (d, J = 5.05 Hz, 1 H), 6.98 (s, 1 H), 3.41 (s, 1 H), 1.60 (s, 6 H), 1.46 (s, 9 H).
Compound 29: ¹H NMR (400 MHz, CDCl₃): δ = 9.35 (s, 1 H), 8.21 (d, J = 5.05 Hz, 1 H), 7.25-7.52 (m, 6 H), 7.04 (br s, 1 H), 1.49 (s, 9 H).
Compound 31: ¹H NMR (400 MHz, CDCl₃): δ = 8.85 (s, 1 H), 8.10 (d, J = 5.05 Hz, 1 H), 7.32 (d, J = 5.05 Hz, 1 H), 7.23 (d, J = 8.85 Hz, 2 H), 6.57 (s, J = 8.85 Hz, 2 H), 1.45 (s, 9 H).
Compound 33: ¹H NMR (400 MHz, CDCl₃): δ = 9.41 (s, 1 H), 8.22 (d, J = 5.06 Hz, 1 H), 7.20 (d, J = 5.06 Hz, 1 H), 7.04 (s, 1 H), 4.86 (s, 1 H), 4.22 (d, J = 5.56 Hz, 2 H), 1.56 (s, 9 H), 1.48 (s, 9 H).

20

Typical Procedure for the Cyclization.
To a solution of ortho-(Boc-amino)alkynyl pyridine or diazine (1 mmol) in MeOH-H₂O (5 mL, 3:1) was added DBU (5 mmol) and the reaction heated to 65-85 °C for 1-14 h. Then, MeOH was removed under vacuum and the solution cooled in an ice-water bath; H₂O was added dropwise to precipitate the azaindole or diazaindole. Compounds 16, 18, 28, and 30 did not solidify from aqueous solution. In these cases the H₂O-DBU mixture was decanted from the oil. The oil is then dissolved in MeOH and the precipitation procedure repeated. Compound 28 was purified by chromatography. The precipitate was collected by filtration, washed with H₂O and dried to give the desired products (>95% purity). Yields 62%-97%.
Data for Azaindoles and Diazaindoles. Compound 8: mp (MeOH-H₂O) 158 °C. ¹H NMR (400 MHz CDCl₃): δ = 8.71 (s, 1 H), 8.20 (d, J = 5.31 Hz, 1 H), 7.43 (d, J = 5.31 Hz, 1 H), 6.28 (s, 1 H), 2.80 (t, J = 7.58 Hz, 2 H), 1.81 (qt, J = 7.58 Hz, J = 7.33 Hz, 2 H), 1.03 (t, J = 7.33 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 145.22, 137.99, 134.03, 133.50, 132.73, 99.02, 30.45, 22.36, 13.90. HRMS (APCI): m/z calcd for C₁₀H₁₃N₂ [M + 1]: 161.1073; found: 161.1075.
Compound 10: ¹H NMR data are in accordance with data reported in the literature. [25]
Compound 12: mp (MeOH-H₂O) 123 °C. ¹H NMR (400 MHz, CDCl₃): δ = 10.43 (s, 1 H), 8.40 (dd, J = 1.26 Hz, 4.80 Hz, 1 H), 7.59 (d J = 8.08 Hz, 1 H), 7.02 (dd, J = 4.80 Hz, 8.08 Hz, 1 H), 6.44 (s, 1 H), 2.80 (t, J = 7.58 Hz, 2 H), 1.76 (qt, J = 7.33 Hz, J = 7.58 Hz, 2 H), 0.98 (t, J = 7.33 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 147.27, 145.08, 141.98, 129.39, 117.72, 115.63, 99.68, 30.70, 22.37, 13.85. HRMS (APCI): m/z calcd for C₁₀H₁₃N₂ [M + 1]: 161.1073; found: 161.1076.
Compound 14: mp (MeOH-H₂O) 65 °C. ¹H NMR (400 MHz, CDCl₃): δ = 12.37 (s, 1 H), 8.21 (d, J = 4.55 Hz, 1 H), 7.83 (dd, J = 7.83 Hz, J = 1.26 Hz, 1 H), 7.03 (dd, J = 7.83 Hz, J = 4.80 Hz, 1 H), 6.20 (s, 1 H), 2.86 (t, J = 7.58 Hz, 2 H), 1.86 (qt, J = 7.58 Hz, J = 7.33 Hz, 2 H), 1.04 (t, J = 7.33 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 149.33, 141.78, 140.18, 127.63, 122.00, 115.38, 97.17, 30.84, 22.46, 13.99. HRMS (APCI): m/z calcd for C₁₀H₁₃N₂ [M + 1]: 161.1073; found: 161.1073.
Compound 16: mp (MeOH-H₂O) 154 °C. ¹H NMR (400 MHz, CDCl₃): δ = 9.46 (br s, 1 H), 9.28 (br s, 1 H), 6.35 (s, 1 H), 2.89 (t, J = 7.46 Hz, 2 H), 1.81 (qt, J = 7.45 Hz, J = 7.33 Hz, 2 H), 0.95 (t, J = 7.33 Hz, 3 H). ¹³C NMR (100 MHz, MeOH-d ₄): δ = 148.43, 145.51, 137.86, 133.96, 126.91, 99.78, 30.95, 23.37, 14.09. HRMS (APCI): m/z calcd for C₉H₁₂N₃ [M + 1]: 162.1025; found: 162.1032.
Compound 18: mp (MeOH-H₂O) 177 °C. ¹H NMR (400 MHz, CDCl₃): δ = 10.02 (br s, 1 H), 8.83 (br s, 1 H), 7.44 (br s, 1 H), 6.64 (s, 1 H), 2.81 (t, J = 7.46 Hz, 2 H), 1.79 (qt, J = 7.46 Hz, J = 7.34 Hz, 2 H), 0.97 (t, J = 7.34 Hz, 3 H). ¹³C NMR (100 MHz, MeOH-d ₄): δ = 151.68, 149.60, 130.76, 107.23, 97.11, 29.69, 21.40, 12.47. HRMS (APCI): m/z calcd for C₉H₁₂N₃ [M + 1]: 162.1025; found: 162.1032.
Compound 20: mp (MeOH-H₂O) 176 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.87 (s, 1 H), 8.63 (s, 1 H), 6.39 (s, 1 H), 2.79 (t, J = 7.46 Hz, 2 H), 1.75 (qt, J = 7.46 Hz, J = 7.46 Hz, 2 H), 0.95 (t, J = 7.46 Hz, 3 H). ¹³C NMR (100 MHz, MeOH-d ₄): δ = 151.10, 150.11, 148.43, 137.04, 127.43, 98.08, 29.75, 21.46, 12.33. HRMS (APCI): m/z calcd for C₉H₁₂N₃ [M + 1]: 162.1025; found: 162.1031.
Compound 22: mp (MeOH-H₂O) 156 °C. ¹H NMR (400 MHz, CDCl₃): δ = 10.26 (br s, 1 H), 8.36 (br s, 1 H), 8.08 (br s, 1 H), 6.40 (s, 1 H), 2.81 (t, J = 7.58 Hz, 2 H), 1.79 (qt, J = 7.58 Hz, J = 7.34 Hz, 2 H), 0.99 (t, J = 7.34 Hz, 3 H). ¹³C NMR (100 MHz, MeOH-d ₄): δ = 149.67, 143.79, 141.70, 137.77, 136.53, 98.67, 31.67, 23.26, 14.09. HRMS (APCI): m/z calcd for C₉H₁₂N₃ [M + 1]: 162.1025; found: 162.1031.
Compound 24: mp (MeOH-H₂O) 185 °C. ¹H NMR (400 MHz, MeOH-d ₄): δ = 8.60 (s, 1 H), 8.00 (d, J = 5.56 Hz, 1 H), 7.43 (d, J = 5.81 Hz, 1 H), 6.44 (s, 1 H), 4.79 (s, 2 H). HRMS (APCI): m/z calcd for C₈H₉N₂O [M + 1]: 149.0709; found: 149.0711.
Compound 26: mp (MeOH-H₂O) 161 °C. ¹H NMR (400 MHz, MeOH-d ₄): δ = 8.52 (s, 1 H), 7.96 (d, J = 5.56 Hz, 1 H), 7.44 (d, J = 5.56 Hz, 1 H), 6.29 (s, 1 H), 3.62 (t, J = 6.32 Hz, 2 H), 2.90 (t, J = 7.71 Hz, 2 H), 1.98 (tt, J = 6.32 Hz, J = 7.71 Hz, 2 H). HRMS (APCI): m/z calcd for C₁₀H₁₃N₂O [M + 1]: 177.1022; found: 177.1026.
Compound 28: oil. ¹H NMR (400 MHz, MeOH-d ₄): δ = 8.60 (s, 1 H), 8.01 (d, J = 5.56 Hz, 1 H), 7.50 (d, J = 5.65 Hz, 1 H), 6.43 (s, 1 H), 1.57 (s, 6 H). HRMS (APCI): m/z calcd for C₁₀H₁₁N₂ [M - H₂O + 1]: 159.0916; found: 159.0917.
Compound 30: mp (MeOH-H₂O) 205 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.92 (s, 1 H), 8.14 (d, J = 5.56 Hz, 1 H), 7.80 (d, J = 7.96 Hz, 2 H), 7.50 (d, J = 5.31 Hz, 1 H), 7.41 (dd, J = 7.58 Hz, J = 7.58 Hz, 2 H), 7.33 (dd, J = 6.81 Hz, J = 6.81 Hz, 2 H), 6.79 (s, 1 H). HRMS (APCI): m/z calcd for C₁₃H₁₁N₂ [M + 1]: 195.0916; found: 195.0921.
Compound 32: mp (MeOH-H₂O) 188 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.76 (s, 1 H), 8.22 (d, J = 5.56 Hz, 1 H), 7.53 (d, J = 8.59 Hz, 2 H), 7.46 (d, J = 5.30 Hz, 1 H), 6.77 (d, J = 8.33 Hz, 2 H), 6.65 (s, 1 H), 3.49 (br s, 2 H). HRMS (APCI): m/z calcd for C₁₃H₁₂N₃ [M + 1]: 210.1031; found: 210.1034.
Compound 34: mp (MeOH-H₂O) 64 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.75 (s, 1 H), 8.22 (d, J = 5.56 Hz, 1 H), 7.45 (dd, J = 5.56 Hz, J = 1.01 Hz, 1 H), 6.33 (s, 1 H), 5.15 (s, 1 H), 4.41 (d, J = 6.06 Hz, 2 H), 1.49 (s, 9 H). HRMS (APCI): m/z calcd for C₁₃H₁₈N₃O₂ [M + 1]: 248.1393; found: 248.1384.

21

Unpublished results: pyridines and diazines with substituents such as NMe₂, OMe, or CN are well tolerated in this reaction.

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