Ammonia → (4E)-N-methyl-5-(5-oxazolo[5,4-b]pyridinyl)-4-penten-2-amine

HRID 514301Notes

Reaction equation

HRID 514301 reaction equation
NC1C(O)=CC(Br)=CN=1.N.Br[C:12]1[N:17]=[C:16]2[O:18][CH:19]=[N:20][C:15]2=[CH:14][CH:13]=1.BrC1C=C2OC=NC2=NC=1.[CH3:31][N:32](C(OC(C)(C)C)=O)[CH:33]([CH2:35][CH:36]=[CH2:37])[CH3:34]>>[CH3:31][NH:32][CH:33]([CH2:35]/[CH:36]=[CH:37]/[C:12]1[N:17]=[C:16]2[O:18][CH:19]=[N:20][C:15]2=[CH:14][CH:13]=1)[CH3:34]

Participants

6

Reactant 5

HCID 222AmmoniaHCID 116940412-Amino-5-bromo-3-hydroxypyridineHCID 15546849N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amineHCID 219640536-Bromo-[1,3]oxazolo[4,5-b]pyridineHCID 219641115-Bromooxazolo[5,4-b]pyridine

Product 1

HCID 22714612(4E)-N-methyl-5-(5-oxazolo[5,4-b]pyridinyl)-4-penten-2-amine

Procedure

In another example, 6-bromooxazolo[4,5-b]pyridine, when submitted sequentially to palladium catalyzed coupling to N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine and deprotection with trifluoroacetic acid, gives (4E)-N-methyl-5-(6-oxazolo[4,5-b]pyridinyl)-4-penten-2-amine. The requisite 6-bromooxazolo[4,5-b]pyridine can be produced from 2-amino-5-bromo-3-pyridinol by condensation with formic acid or a trialkyl orthoformate, using methodology similar to that of M-C. Viaud et al., Heterocycles 41: 2799-2809 (1995). The use of other carboxylic acids produces 2-substituted-6-bromooxazolo[4,5-b]pyridines, which are also substrates for the Heck reaction. The synthesis of 2-amino-5-bromo-3-pyridinol proceeds from furfurylamine (Aldrich Chemical Company). Thus, 5-bromo-3-pyridinol (produced from furfurylamine according to U.S. Pat. No. 4,192,946) can be chlorinated, using methods described by V. Koch et al., Synthesis, 499 (1990), to give 2-chloro-5-bromo-3-pyridinol, which in turn can be converted to 2-amino-5-bromo-3-pyridinol by treatment with ammonia. 5-Bromooxazolo[5,4-b]pyridine, isomeric by orientation of ring fusion to the previously described 6-bromooxazolo[4,5-b]pyridine, can also be used in the Heck coupling with N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine. Subsequent removal of the tert-butoxycarbonyl protecting group provides (4E)-N-methyl-5-(5-oxazolo[5,4-b]pyridinyl)-4-penten-2-amine. The 5-bromooxazolo[5,4-b]pyridine can be synthesized from 3-amino-5-bromo-2-pyridinol (3-amino-5-bromo-2-pyridone) by condensation with formic acid (or a derivative thereof) as described above. 3-Amino-5-bromo-2-pyridinol can be made by bromination (using techniques described by T. Batkowski, Rocz. Chem. 41: 729-741 (1967)) and subsequent tin(II) chloride reduction (according to the method described by S. X. Cai et al., J. Med. Chem. 40(22): 3679-3686 (1997)) of commercially available 3-nitro-2-pyridinol (Aldrich Chemical Company).

Workup

  1. customSubsequent removal of the tert-butoxycarbonyl protecting group

Sources & evidence

ORD record
ord-f0f48835cf3445ebb576438a31cf7ed1
Source dataset
uspto-grants-2015_08
Patent number
US09107915B2

Reaction notes

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