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Synlett 2011(12): 1740-1744  
DOI: 10.1055/s-0030-1260940
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Clemens Lamberth*
Syngenta Crop Protection AG, Research Chemistry, Schaffhauserstr. 101, 4332 Stein, Switzerland
Fax: +41(62)8660860; e-Mail: clemens.lamberth@syngenta.com;
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Received 1 April 2011
Publikationsdatum:
05. Juli 2011 (online)

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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.

Key words

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

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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].

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].