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5th February 2014 @ 00:25

Conclusions: The reaction was successful with a crude yield of 110%. The product was used in JU 3-1 without purifying.

Repeat of AEW 95-3 for scale up of key starting material for JU 3-1.

Reaction Scheme

Procedure

Started 3:40pm


JU 1-1 (crude, 1.207 g, 8.349 mmol) was stirred into a solution of AcOH (0.4 mL) and MeCN (12 mL). 4-formylbenzonitrile (0.892 g, 6.802 mmol) was added and the reaction was stirred at room temperature for 18 hours. The solvent was removed by rotary evaporation and dried in vacuo to yield a crude orange solid (1.931 g).

Data

-TLC (30% EtOAc in Hexane, 50% EtOAc in Hexane, and 100% EtOAc)

TLC JU 2-1 EtOAc:Hexane.jpeg
TLC JU 2-1 EtOAc.jpeg
TLC JU 2-1 EtOAc:Hexane 50:50.jpg


The TLC in 50:50 EtOAc and Hexane showed no starting material 1 (4-formylbenzonitrile) in the product lane therefore the reaction is complete.

-NMR

1H NMR of crude product, 200 MHz, CDCl3
A spectrum of the starting material 4-formylbenzonitrile was also run (same conditions).

JU 2-1 crude HNMR 200MHz CDCl3.pdf
JU 2-1.zip
JU 4-formylbenzonitrile.pdf
JU 4-formylbenzonitrile.zip

1H NMR of crude product (200 MHz, DMSO)

JU 2-1 crude DMSO 200 MHz.pdf
JU 2-1 crude DMSO.zip

13C and 2D NMR of crude product (400 MHz, DMSO) and analysis

140226btodju1.pdf
JU 2-1 2D NMR.zip

The 1H NMR shows four singlets and two doublets as expected which correspond to the product. Two much smaller doublets are also apparent and are due to an unidentified impurity. The 13C NMR shows twelve peaks, two of which appear smaller and likely correspond to the impurity. This leaves ten peaks as expected for the ten carbon environments in the compound.

The HSQC 2D NMR shows no correlation between the proton peak at 11.912 ppm and a carbon, so can be assigned as the amine proton. The amine proton has long range coupling signals in the HMBC 2D NMR which are most likely carbons 5, 6 and 7. Of these three peaks, one does not show coupling to a proton (152.5 ppm) and therefore is carbon 6. The second one at 141.0 ppm shows coupling to the aromatic protons and can be assigned as 5, leaving 7 to be the carbon peak at 129.6 ppm. Carbons 5 and 7 couple with a single proton in the HSQC NMR, 5 with the peak at 8.145 ppm and 7 with the peak at 8.636 ppm. This leaves one proton singlet at 8.112 ppm which must be at carbon 8. The HSQC shows direct coupling between this proton and the carbon peak at 133.6 ppm.

Of the remaining six carbon peaks, the taller two (133.1 and 127.6 ppm) must be the equivalent aromatic carbons and this is confirmed by the HSQC. The peak at 127.6 ppm couples to proton 5 in the HMBC spectrum and can be assigned as carbon 3. Carbon 2 is therefore the peak 133.1 ppm. Protons 7 and 8 show coupling in the HMBC to the carbon at 146.0 ppm which doesn’t have it’s own proton so must be carbon 9. Proton 5 couples to the carbon peak at 139.4 ppm, which must then be carbon 4. Carbon 1 is the peak at 111.5 ppm. This is because coupling over three bonds in aromatic systems is usually bigger than two and the peak at 111.5 ppm couples more strongly to the proton at carbon 3 than the one at 119.3 ppm does. This is in agreement with predicted carbon shifts for this molecule using MestReNova. The last peak at 119.3 can therefore be assigned to carbon 10.

Recrystallisation

Recrystallisation of the crude product was attempted as an alternative to purification by flash chromatography. EtOAc, MeCN and EtOH were all tried with no success. The product was somewhat soluble in 2-MeTHF however after gently boiling for 1 h not all the product would dissolve. The product was dissolved in >100 mL 2-MeTHF (not ideal) and left for 3 days in the fridge at which point a small amount of material could be recovered. 2-MeTHF was removed by roatry evaporation and in vacuo and the product was analysed by 1H NMR to check for the presence of impurities.

Toluene to be tried next.

JU 2-1 recrystallised DMSO 200 MHz.pdf
JU 2-1 recrys DMSO.zip

HIRAC

HIRAC JU 2-1.pdf

InChI strings

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

and

InChI=1S/C8H5NO/c9-5-7-1-3-8(6-10)4-2-7/h1-4,6H

to

InChI=1S/C12H8ClN5/c13-11-7-15-8-12(17-11)18-16-6-10-3-1-9(5-14)2-4-10/h1-4,6-8H,(H,17,18)/b16-6+

SMILES

ClC1=CN=CC(NN)=N1

and

[H]C(C1=CC=C(C#N)C=C1)=O

to

ClC1=CN=CC(N/N=C/C2=CC=C(C#N)C=C2)=N1

 

 

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Attached Files
Reaction Scheme JU 2-1.png
HIRAC JU 2-1.pdf
TLC JU 2-1 EtOAc.jpeg
TLC JU 2-1 EtOAc:Hexane.jpeg
JU 2-1 crude HNMR 200MHz CDCl3.pdf
JU 2-1.zip
TLC JU 2-1 EtOAc:Hexane 50:50.jpg
JU 4-formylbenzonitrile.pdf
JU 4-formylbenzonitrile.pdf
JU 4-formylbenzonitrile.zip
JU 2-1 crude DMSO 200 MHz.pdf
JU 2-1 crude DMSO.zip
140226btodju1.pdf
JU 2-1 2D NMR.zip
Screen shot 2014-03-06 at 10.18.22 PM.jpg
JU 2-1 recrystallised DMSO 200 MHz.pdf
JU 2-1 recrys DMSO.zip