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Synlett 2011(10): 1407-1412  
DOI: 10.1055/s-0030-1260568
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Regioselective and High-Yielding Method for Formaldehyde Inclusion in the 3CC Groebke-Blackburn-Bienaymé Reaction: One-Step Access to 3-Aminoimidazoazines

Anuj Sharma, Hong-yu Li*
College of Pharmacy, Department of Pharmacoloy/Toxicology, The University of Arizona, Tucson, AZ 85721, USA
Fax: +1(520)6260794; e-Mail: hongyuli@pharmacy.arizona.edu;
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Publikationsverlauf

Received 27 January 2011
Publikationsdatum:
16. Mai 2011 (online)

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Abstract

A regioselective, mild, convenient, and effective condition is developed for the inclusion of glyoxylic acid as formaldehyde equivalent in the 3CC reaction towards synthesis of 3-aminoalkyl imidazo-azines. In general, formaldehydes do not perform well with Ugi-type multicomponent sequences, and the method reported here is a regioselective and high-yielding one for the HCHO variant of Groebke-Blackburn-Bienaymé reaction.

Key words

Groebke-Blackburn-Bienaymé - multicomponent ­reaction - aminoimidazoazines - formaldehyde - glyoxylic acid

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10

Representative Procedure for the Synthesis of N -(2,6-dimethylphenyl)imidazo[1,2- a ]pyridin-3-amine (3b, Table 2)
To a solution of 2-aminopyridine (1b, 1.05 mmol) in MeOH (1.5 mL), was added glyoxylic acid (1.78 mmol) followed by HClO4 (0.105 mmol), and the solution was stirred for 10 min. 2-Isocyano-1,3-dimethylbenzene (1.05 mmol) was added to this mixture, and the solution was stirred for 12 h. MeOH was evaporated from the reaction mixture, and the crude was purified through silica gel chromatography to provide 3b in 77% yield. ¹H NMR (400 MHz, DMSO-d 6):
δ = 8.72 (d, J = 8 Hz, 1 H), 7.81 (d, J = 4 Hz, 2 H), 7.60 (s, 1 H), 7.52-7.48 (m, 1 H), 7.11 (d, J = 8 Hz, 2 H), 7.05-7.02 (m, 3 H), 2.09 (s, 6 H). ¹³C NMR (400 MHz, DMSO-d 6):
δ = 138.5, 136.4, 135.8, 133.4, 132.0, 131.7, 129.3, 128.0, 125.8, 125.3, 116.6, 112.9, 106.3, 18.1. HRMS: m/z calcd for C15H16N3: 238.13387; found: 238.13377. LC-MS (ES): 98.6% (λ = 214 nm).

11

Formation of regioisomer was observed during optimization studies using paraformaldehyde as formaldehyde source (entry 8, Table  [¹] ).

13

Nichol, G. S.; Sharma, A.; Li, H. Y. unpublished results.