MJE 8-1- Free amine synthesis with trichloroacetonitrile

[memm0740]

HIRAC- MJE8-1.docx

[memm0740]

Method

03/07/23 11:20am

1. Added diamine (0.277g, 1.49mmol), trichloroacetonitrile (198uL, 0.285g, 2.00mmol), Cu(OAc)2 (0.0189g, 1.04mmol), THF (2mL).
2. switched on stirring at 12:30pm - under nitrogen

2:30pm

• dissolved RM and diamine in MeOH
• TLC in 20% E/H

5pm

• TLC in 20% E/H

5:45pm

• MS 20230703_MJE8-1.crude.1.pdf 20230703_MJE8-1.crude.1.d.zip Note- no product at 211
• left reaction to stir overnight

04/07/23 9:30am

• RM black tar like substance
• TLC 20% E/H- streaking
• TLC 40% E/H- slightly higher Rf

11am

• TLC 40% E/H with triethylamine- too high
• TLC 20% E/H with triethylamine - on baseline
• left reaction to stir at 30C

12pm

• TLC 9% MeOH/90% DCM/NH4- higher Rf

3:45pm

• MS 20230705_MJE8-1.crude2.pdf 20230705_MJE8-1.crude2.zip

• Note- no product at 211, two peaks at 210?, largest peak at 289

• left overnight at 30C

05/07/23 9am -MS shows peak at 289 (not sure)

• TLC 40% E/H to check state of reaction- less spots, presence of yellow spot
• TLC 60% E/H- see yellow spot better

11am

3. Work up- following HIRAC diluted with DCM (3mL) and aq NH4Cl (3mL) and left to stir for 30 min.

11:52am

• stopped very hard to see layers formed, so transferred to separating funnel
• added more DCM and NH4Cl
• left for 1 hr to see if layers form

1:30pm New work up:

• RM now has black solid, DCM and NH4Cl

• Filter using sinter to separate black solid and filtrate.

• MS Black solid 20230705_MJE8-1.black solid.pdf 20230706_MJE8-1.black solid.zip Note- no 211, strong peak at 289

Bright orange filtrate 20230705_MJE8-1.orange filtrate.pdf 20230705_MJE8-1.orange filtrate.zip

• No 211, 289, something at 285

• mini liquid-liquid extraction with orange filtrate - orange particulates suspended in aqueous phase (dissolved water) top layer, DCM bottom clear layer.

• check solubility of black solid - MeOH very good (289)

• orange filtrate - in water

06/07/23 9am

• NMR black solid- needs to be more concentrated

3pm

• NMR orange filtrate in deuterated MeOH

10/07/23 12pm

• continuing work up filtered the orange filtrate as there was solid in it. Using sintered funnel, separated black solid to orange filtrate.

• MS orange filtrate 2 230710_MJE8-1.filtrate 2.pdf 230710_MJE8-1.orange filtrate2.zip

• MS filter cake 2 230710_MJE8-1.solid filtercake2.pdf 230710_MJE8-1.filtercake2.zip

Note- presence of intended product potentially at 211

• put black solid from first filter into vial ( 15.422g)- drying under vacuum

11/07/23 9am

• vial + product of black solid= 15.521g yield %=

3pm

• more concentrated 8-1 black solid NMR

14/07/23 5pm

• RV orange filtrate 2 to remove THF and DCM
• left under N2 to blow down water (NH4Cl and Brine)

17/07/23 8-1 solid= 94.4mg 8-1 solid 2= 2.7mg filtrate = should have been 180mg (dropped!)

[memm0740]

Method 8-2

17/07/23 11:30am

• oven dried flask for 1.5 hr

1. Added diamine (g, mmol), trichloroacetonitrile (198uL, 0.285g, 2.00mmol), Cu(OAc)2 (0.0180g, mmol), THF (2mL). Switched on stirring at 1:00pm - under nitrogen

Dissolved RM and diamine in MeOH

• TLC in 20% E/H 30% E/H

  

• MS 230717_MJE8-2.crude1.pdf 230717_MJE8-2.crude1.d.zip Note- double peaks at 257 +1 and small double at 289

• leave overnight

18/07/23 9am

• MS 230718_MJE8-2.crude2.pdf 230718_MJE8-2.crude2.d.zip Note- tiny amount at 211, not visible on MS but shown.
• TLC 30% E/H- SM gone.

10:15am

• RV off THF (learnt THF miscible in DCM and NH4Cl and therefore need to get rid before work up)

11:30am

• added 4mL DCM and NH4Cl
• stir started

12pm

• stopped stir and transferred to sep funnel for layers to separate

• extract by adding DCM (amines should be in aqueous layer- orange) 4 x 3mL DCM

• MS

• orange filtrate 230718_MJE8-2.orange filtrate.pdf 230718_MJE8-2.orangefiltrate.zip

• black solid 230718_MJE8-2.black solid.pdf 230718_MJE8-2.blacksolid.zip

Note- didn't see 211 in either

20/07/23 9am

• continued RV ammonium chloride in filtrate
• NMR solid and put into vial = 16.0047g 8-2.solid.pdf MJE8-2.solid_1.zip

Note- hard to determine structure from NMR

31/07/23 2pm

• Continuing work up Extraction 1 of Filtrate

• added 4mL HCL to NH4Cl filtrate (in vial), extract with 3x3mL DCM

• ended with organic, aq and filtered out ammonium chloride salt

• MS

• organic - no significant peaks

• aq filtrate (salt)- no 211 230801_MJE8-2. aq filtrate (salt).pdf MJE8-2.aq filtrate salt.zip

Note- due to no presence of product assumed in aqueous phase.

01/08/23 9am Extraction 2 of filtrate

• Chemistry- amines remain protonated at lower pH and therefore pass in aqueous layer. By increasing pH by adding NaHCO3, to get NH2, and pass into organic phase, easier to isolate.
• added NaHCO3 to aq phase made up to 150mL (pH 9)
• washed with DCM x3
• ended up with 75mL organic phase, 110mL aq phase
• RV organic phase - weight 0.0482g

1:30pm

• MS organic 230801_MJE8-2.organic 2.pdf MJE8-2.organic2.zip

  

• MS aq 230801_MJE8-2.aq 2.pdf MJE8-2.aq2.zip

  

  Note- small amount of 211 for both- but not showing up in pdf.

  Extraction 3 of Filtrate

• added NaOH to increase pH to 14. Possibly pKa of amines higher and therefore need to increase pH further to deprotonate.

• 3x 40mL DCM

• ended up with 170mL aq, 120ml DCM

• RV organic phase- weight-

• MS organic 230803_MJE8-2.ext3.pdf 230803_MJE8-2.ext3.d.zip Note- small amount of 211

Extraction 4

• 3 x 75mL EtOAc

• ended up with 150mL aq, 200mL organic

• RV organic

• MS organic 230803_MJE8-2.Extfour.pdf 230803_MJE8-2.Extfour.d.zip Note- tiny amount of 211

03/08/23

• NMR Ext2 MJE8_2 ext 2.pdf MJE8_2 ext 2_1.zip Note0 NMR shows many peaks- some promising in aromatic region.

• NMR Ext3 MJE8_2 ext 3.pdf MJE8-2.EXT3_1.zip Note- NMR shows no peaks.

04/08/23

• MS aqueous 230804_MJE8-2.ext4aq.pdf 230804_MJE8-2.ext4aq.d.zip Note- nothing

08/08/23 9am

• column conditions 34.6mg

• TLC 40% E/H, 80% E/H

  

• 9% MeOH/ 90% DCM/ 1% NH4 (no pic)

• 7.5% MeOH/ 92.5% DCM (no pic- best Rf)

11/08/23 10am

• did prep TLC
• isolated 4 bands and roto vapped
• TLC of 4 bands in 7.5%MeOH/ 92.5%DCM

14/08/23 9am

• MS of 4 bands 1: 230814_MJE8-2.1.pdf 230814_MJE8-2.1.d.zip

2: 230814_MJE8-2.2.pdf 230814_MJE8-2.2.d.zip

3: 230814_MJE8-2.3.pdf 230814_MJE8-2.3.d.zip

4: 230814_MJE8-2.4.pdf 230814_MJE8-2.4.d.zip

Note- only 211 in 3.

15/08/23

• NMR 3 and 4 8-2. Bands 3 and 4.pdf MJE8-2.3_1.zip MJE8-2.4_1.zip

Note- aromatic peaks possibly matching to benzene ring of BZ core in band 3.

• put into vials
• band 3 weight-
• band 4 weight-

Conclusion- crude RM did not show 211 initially so possibly should have let reaction go for longer or figured out different way.