First Synthesis of 3-Amino-2-arylimidazo[1,2-b]pyridazines by Groebke-Blackburn Reaction

Abstract

The Groebke-Blackburn transformation of an 3-aminopyridazine, a benzaldehyde, and an isocyanide allows the one-step assembly of so far unknown 3-amino-2-arylimidazo[1,2-b]-­pyridazines. Diversely substituted aldehydes and isocyanides can be used for this reliable three-component condensation, delivering biheterocyclic products with a broad range of different substituents in the imidazole moiety.

multicomponent reaction - Groebke-Blackburn reaction - heterocycles - imidazopyridazines - ring closure

References and Notes

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22

Representative Procedure
tert-Butyl isocyanide (4a, 200 mg, 2.4 mmol), benzaldehyde (5a, 233 mg, 2.2 mmol), and 3-amino-6-chloropyridazine (3, 260 mg, 2.0 mmo) are consecutively added to a solution of NH₄Cl (107 mg, 2.0 mmol) in MeOH (10 mL). The reaction mixture is stirred for 16 h at r.t. Subsequently, the solvent was removed in vacuo and the remainder taken up in EtOAc. This organic layer was washed with brine and H₂O, dried over Na₂SO₄ and evaporated. The residue was purified either by crystallization from Et₂O or by chromatography on silica gel, using cyclohexane-EtOAc (4:1) as eluent to deliver
3-tert-butylamino-6-chloro-2-phenylimidazo[1,2-b]pyrida-zine as yellow crystals (6a, 500 mg, 1.7 mmol, 83%); mp 219-222 ˚C. ^¹H NMR (400 MHz, CDCl₃): δ = 1.13 (s, 9 H), 3.44 (br s, 1 H), 6.95 (d, 1 H), 7.32 (t, 1 H), 7.43 (t, 2 H), 7.80 (d, 1 H), 8.22 (d, 2 H) ppm. LC-MS: t _R = 1.93 min, m/z = 301 [M + 1].

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24

Further Spectroscopic Data Compound 6b: ^¹H NMR (400 MHz, CDCl₃): δ = 0.89 (t, 3 H), 1.38 (q, 2 H), 1.57 (q, 2 H), 3.15 (q, 2 H), 3.99 (t, 1 H), 6.85 (d, 1 H), 7.32 (t, 1 H), 7.44 (t, 2 H), 7.78 (d, 1 H), 8.03 (d, 2 H) ppm. LC-MS: t _R = 2.05 min, m/z = 301 [M + 1].
Compound 6c: ^¹H NMR (400 MHz, CDCl₃): δ = 1.12-1.89 (m, 10 H), 3.22 (q, 1 H), 3.89 (d, 1 H), 6.87 (d, 1 H), 7.32 (t, 1 H), 7.44 (t, 2 H), 7.78 (d, 1 H), 8.10 (d, 2 H) ppm. LC-MS: t _R = 2.15 min, m/z = 327 [M + 1].
Compound 6d: ^¹H NMR (400 MHz, CDCl₃): δ = 1.11 (s, 6 H), 2.20 (s, 3 H), 2.73 (s, 2 H), 3.96 (br s, 1 H), 6.96 (d, 1 H), 7.33 (t, 1 H), 7.42 (t, 2 H), 7.80 (d, 1 H), 8.21 (d, 2 H) ppm. LC-MS: t _R = 2.04 min, m/z = 347 [M + 1].
Compound 6e: ^¹H NMR (400 MHz, CDCl₃): δ = 1.03 (s, 6 H), 1.10 (s, 9 H), 1.18 (s, 2 H), 3.56 (br s, 1 H), 6.91 (d, 1 H), 7.31 (t, 1 H), 7.42 (t, 2 H), 7.78 (d, 1 H), 8.17 (d, 2 H) ppm. LC-MS: t _R = 2.32 min, m/z = 357 [M + 1].
Compound 6f: ^¹H NMR (400 MHz, CDCl₃): δ = 5.88 (br s, 1 H), 6.55 (d, 1 H), 6.64 (s, 1 H), 6.72-6.79 (m, 2 H), 7.05 (d, 1 H), 7.29-7.56 (m, 4 H), 7.91 (d, 1 H), 8.10 (d, 2 H) ppm. LC-MS: t _R = 1.89 min, m/z = 361 [M + 1].
Compound 6g: ^¹H NMR (400 MHz, CDCl₃): δ = 2.01 (s, 6 H), 5.69 (br s, 1 H), 6.81-6.93 (m, 4 H), 7.14-7.20 (m, 3 H), 7.58 (dd, 2 H), 7.82 (d, 1 H) ppm. LC-MS: t _R = 2.03 min, m/z = 349 [M + 1].
Compound 6h: ^¹H NMR (400 MHz, CDCl₃): δ = 4.30-4.39 (m, 3 H), 6.87 (d, 1 H), 7.19-7.36 (m, 6 H), 7.47 (t, 2 H), 7.78 (d, 1 H), 8.01 (d, 2 H) ppm. LC-MS: t _R = 1.98 min, m/z = 335 [M + 1].
Compound 6i: ^¹H NMR (400 MHz, CDCl₃): δ = 1.11 (s, 9 H), 3.46 (br s, 1 H), 6.99 (d, 1 H), 7.52-7.83 (m, 4 H), 8.47 (d, 1 H), 8.66 (d, 1 H) ppm. LC-MS: t _R = 2.19 min, m/z = 369 [M + 1].
Compound 6j: ^¹H NMR (400 MHz, CDCl₃): δ = 1.12 (s, 9 H), 3.43 (br s, 1 H), 6.97 (d, 1 H), 7.21-7.28 (m, 2 H), 7.80 (d, 1 H), 8.30 (d, 2 H) ppm. LC-MS: t _R = 2.20 min, m/z = 385 [M + 1].
Compound 6k: ^¹H NMR (400 MHz, CDCl₃): δ = 1.13 (s, 9 H), 2.31 (s, 3 H), 3.40 (br s, 1 H), 6.95 (d, 1 H), 7.22 (t, 1 H), 7.79 (d, 1 H), 7.92-7.98 (m, 2 H) ppm. LC-MS: t _R = 2.14 min, m/z = 333 [M + 1].
Compound 6l: ^¹H NMR (400 MHz, CDCl₃): δ = 1.16 (s, 9 H), 3.42 (br s, 1 H), 6.98 (d, 1 H), 7.43 (t, 1 H), 7.80 (d, 1 H), 8.03 (d, 1 H), 8.15 (d, 1 H) ppm. LC-MS: t _R = 2.23 min,
m/z = 353 [M + 1].
Compound 6m: ^¹H NMR (400 MHz, CDCl₃): δ = 1.04 (s, 9 H), 3.58 (br s, 1 H), 3.95 (s, 3 H), 6.88-7.04 (m, 2 H), 7.20 (t, 1 H), 7.39 (t, 1 H), 7.82 (d, 1 H) ppm. LC-MS: t _R = 1.92 min, m/z = 349 [M + 1].
Compound 6n: ^¹H NMR (400 MHz, CDCl₃): δ = 1.07 (s, 9 H), 3.58 (br s, 1 H), 3.96 (s, 3 H), 7.00 (d, 1 H), 7.27 (s, 1 H), 7.48 (d, 1 H), 7.83 (d, 1 H) ppm. LC-MS: t _R = 2.07 min, m/z = 383 [M + 1].
Compound 6o: ^¹H NMR (400 MHz, CDCl₃): δ = 1.04 (s, 9 H), 3.49 (br s, 1 H), 6.03 (s, 2 H), 6.95-7.00 (m, 2 H), 7.06 (s, 1 H), 7.81 (d, 1 H) ppm. LC-MS: t _R = 1.98 min, m/z = 379 [M + 1].
Compound 7: ^¹H NMR (400 MHz, CDCl₃): δ = 1.12 (s, 9 H), 3.33 (br s, 1 H), 3.48 (s, 3 H), 3.80 (t, 2 H), 4.49 (t, 2 H), 6.63 (d, 1 H), 7.28 (t, 1 H), 7.41 (t, 2 H), 7.72 (d, 1 H), 8.23 (d, 2 H) ppm. LC-MS: t _R = 1.58 min, m/z = 341 [M + 1].
Compound 8: ^¹H NMR (400 MHz, CDCl₃): δ = 3.75 (br s, 1 H), 7,11 (dd, 1 H), 6.95 (d, 1 H), 7.33 (t, 1 H), 7.45 (t, 2 H), 7.82-7.88 (m, 2 H), 7.97 (d, 1 H), 8.22 (d, 2 H) ppm.
LC-MS: t _R = 1.89 min, m/z = 355 [M + 1].
Compound 9: ^¹H NMR (400 MHz, CDCl₃): δ = 1.15 (s, 9 H), 3.45 (t, 4 H), 3.72 (t, 4 H), 3.51 (br s, 1 H), 6.89 (d, 1 H), 7.31 (t, 1 H), 7.43 (t, 2 H), 7.82 (d, 1 H), 8.26 (d, 2 H) ppm.
LC-MS: t _R = 1.77 min, m/z = 352 [M + 1].
Compound 10: ^¹H NMR (400 MHz, CDCl₃): δ = 4.41 (br s, 2 H), 6.83 (t, 1 H), 7.32 (t, 1 H), 7.40-7.52 (m, 2 H), 7.76 (t, 1 H), 7.92 (t, 2 H) ppm. LC-MS: t _R = 1.46 min, m/z = 245
[M + 1].
Compound 11: ^¹H NMR (400 MHz, CDCl₃): δ = 1.12 (s, 9 H), 3.56 (br s, 1 H), 3.77 (s, 6 H), 5.80 (s, 1 H), 7.31 (t, 2 H), 7.44 (t, 2 H), 7.82 (d, 1 H), 8.29 (d, 2 H) ppm. LC-MS: t _R = 2.12 min, m/z = 437 [M + 1].
Compound 12: ^¹H NMR (400 MHz, CDCl₃): δ = 1.18 (t, 3 H), 2.74 (q, 2 H), 3.56 (br s, 1 H), 6.97 (d, 1 H), 7.33 (t, 1 H), 7.40-7.48 (m, 2 H), 7.80 (d, 1 H), 8.30 (d, 2 H) ppm.
LC-MS: t _R = 1.67 min, m/z = 337 [M + 1].