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30th May 2014 @ 03:43

As discussed in New Routes to Series 4 Triazolopyrazine Amides, the series 4 scheme could be improved by a pre-forming the triazolopyrazine ring, followed by a carbonylation to add the amide. There are a number of possible pathways to this, but due to their simplicity the conditions used by Ren, Emi and Yamane (Synthesis, 2011) seem a good place to start.

21-1 scheme

 

This reaction is a direct recreation of one from their paper, claimed to give 82 % yield. Method:


2-bromonaphthalene (103.5 mg, 0.50 mmol, 1 eq), phenol (70.5 mg, 0.75 mmol, 1.5 eq), Mo(CO)6 (26.4 mg, 0.10 mmol, 1.2 eq CO), and Bu3N (102 mg, 0.55 mmol, 1.1 eq) combined in diglyme (5 mL), and heated at 150 oC for 12 h under nitrogen. On completion, solvent removed under vacuum, and residue purified by chromatography (silica, 5 % EtOAc in hexane) to afford pure ester.

 

 

In the original paper, no mention is made of heterocyles or aryl chlorides as a substrate. If this reaction proves successful, chloropyrazine or 2-chloropyridine will be attempted next

 

HIRAC:

HIRAC.pdf

Revised HIRAC (2/6: more detail on heavy metals treatment)

HIRAC2.pdf
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29th May 2014 @ 07:32

Repeat of JU 1-6 for synthesis of key starting material.

Reaction Scheme

Procedure

Started 4:45pm

2,6-Dichloropyrazine (Aldrich, 5.0 g, 34 mmol) was dissolved in ethanol (50 mL) to give a clear solution.  Hydrazine hydrate (1.8 mL, 1.8 g, 36 mmol) was added resulting in a pale yellow solution. The resulting mixture was heated at reflux (bath temperature 80˚C) for 16.5 h. Analysis by TLC showed the reaction was near complete, and that a second product had begun to form in small amounts.

TLC JU 1-7 30:70 EtOAc:Hex 16.5 h.jpg

The reaction was stopped and cooled. The solvent was removed by rotary evaporation and the product dried in vacuo. The crude product was small crystals and orange in colour (6.76g, >100% yield). Previous attempts at the reaction gave a yellow product. The crude product was analysed by 1H NMR.

1H NMR, crude, DMSO, 200 MHz

JU 1-7 crude DMSO 200 MHz.pdf
JU 1-7 crude DMSO.zip

NMR showed the appearance of two new peaks compared to previous successful attempts at this reaction, and a shift in the two existing aromatic peaks downfield (see JU 1-6 for comparison). This indicates that a different product had been formed. Subsequent investigations of the hydrazine hydrate, dichloropyrazine and the ethanol water content are detailed in JU 1-8a/b and JU 1-9a/b.

06/06/2014

A possible structure for 1-7 is below.

An attempt to remove the possible hydroxy group was made by adding 2.8 M acidified MeOH (approx 125 mL) to the flask of JU 1-7 (~1 g was kept aside) and stirring for 2.25 hours. Analysis by TLC showed no change.

TLC JU 1-7 acidification 30:70 EtOAc:Hex 0.5 h.jpg
TLC JU 1-7 acidification 30:70 EtOAc:Hex 2.25 h.jpg

The reaction was not left longer due to the weekend. The solvent was removed by rotary evaporation and the flask refridgerated.

13C NMR, crude, DMSO, 400 MHz

JU 1-7 pure 13C 400 MHz.pdf
140702btodju1.zip

IR

JU 1-7.pdf

 

HIRAC & Risk Assessment

See JU 1-1

InChI strings

InChI=1S/C4H2Cl2N2/c5-3-1-7-2-4(6)8-3/h1-2H

to

InChI=1S/C4H5ClN4/c5-3-1-7-2-4(8-3)9-6/h1-2H,6H2,(H,8,9)

SMILES

ClC1=CN=CC(Cl)=N1

to

ClC1=CN=CC(NN)=N1

Attached Files
28th May 2014 @ 01:53

scheme

TM 21-1 (pure, from Synthesis of 6-chloro-N-(5-chloro-2-methylphenyl)pyrazine-2-carboxamide (TM 21-1): 495 mg, 1.75 mmol) combined with hydrazine hydrate (0.85 mL, 18 mmol, 10 eq) in ethanol (5 mL), and stirred at 80 oC for 18 h.

Solvents were removed under vacuum, and the crude product was dried on the highvac to give crude TM 22-1 as yellow chunks (621 mg, 128 % yield). As before, the crude likely still contains hydrazine, perhaps as a non-volatile hydrochloride salt from the HCl generated by substitution.

InChI:

InChI=1S/C12H9Cl2N3O/c1-7-2-3-8(13)4-9(7)17-12(18)10-5-15-6-11(14)16-10/h2-6H,1H3,(H,17,18)

to

InChI=1S/C12H12ClN5O/c1-7-2-3-8(13)4-9(7)17-12(19)10-5-15-6-11(16-10)18-14/h2-6H,14H2,1H3,(H,16,18)(H,17,19)

HIRAC:

HIRAC.pdf
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28th May 2014 @ 01:48

scheme

Pure TM 20-1 (550 mg, 1.92 mmol) was combined with hydrazine hydrate (0.94 mL, 19.2 mmol, 10 eq) in ethanol (5 mL), and stirred at 80 oC for ?? h.

InChI:

InChI=1S/C11H6Cl2FN3O/c12-6-2-1-3-7(10(6)14)17-11(18)8-4-15-5-9(13)16-8/h1-5H,(H,17,18)

to

InChI=1S/C11H9ClFN5O/c12-6-2-1-3-7(10(6)13)17-11(19)8-4-15-5-9(16-8)18-14/h1-5H,14H2,(H,16,18)(H,17,19)

HIRAC:

HIRAC.pdf

(see Synthesis of N-(3-chloro-2-fluorophenyl)-6-hydrazinylpyrazine-2-carboxamide (TM 15-1) for approval)

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28th May 2014 @ 01:44

scheme

TM 3-2 (525 mg, 1.86 mmol) dissolved in EtOH (4 mL) and hydrazine hydrate (0.89 mL, 17.7 mmol, 10 eq) added. Stirred at 80 oC for ?? h.

 

InChI:

InChI=1S/C12H9Cl2N3O/c1-7-8(13)3-2-4-9(7)17-12(18)10-5-15-6-11(14)16-10/h2-6H,1H3,(H,17,18)

to

InChI=1S/C12H12ClN5O/c1-7-8(13)3-2-4-9(7)17-12(19)10-5-15-6-11(16-10)18-14/h2-6H,14H2,1H3,(H,16,18)(H,17,19)

HIRAC:

HIRAC.pdf

 

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