MJE6- Ring closing C‐N Cross‐coupling Reaction

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MJE6a HIRAC- MJE6.docx

Source- Kondraganti, L.; Manabolu, S. B.; Dittakavi, R.. Synthesis of Benzimidazoles via Domino Intra and Intermolecular C‐N Cross‐coupling Reaction. ChemistrySelect 2018, 3 (42), 11744–11748. DOI: 10.1002/slct.201802754.

Reaction scheme-

Mechanism

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Method

29/05/23 4:00pm

1. Added DMSO (6mL), thiourea (0.288g, 3.8mmol), triethylamine (0.374g, 0.515mL, 3.69mmol), cobalt (II) chloride hexahydrate (0.441g, 1.85mmol).
2. Stirred for 1 hour.

5:15pm

• dissolved RM in DCM
• TLC 30% E/H- no spots stuck to baseline

30/05/23 9:30am

• dissolved RM, Cobalt, and thiourea in MeOH
• TLC 30% E/H with TA- no spots
• TLC 60% E/H with TA- no movement
• TLC 9% MeOH/DCM/NH4- no RM spot, thiourea Rf= 0.43

11:10 am

• started heating at 25C and continued stirring

1:15pm -Mass spec MJE6.crude.pdf MJE6.crude_1.zip

Notes- no product at 135

2pm

• increase temperature to 37C

3:15pm

• TLC 9% MeOH/DCM/NH4- RM spot coincides with thiourea spot

4pm

3. Added iodoaniline (0.2915g, 1mmol)- ADDED INCORRECT AMOUNT, SHOULD HAVE ADDED 1.122G, 3.78MMOL

5pm

• TLC 9% MeOH/DCM/NH4- RM spot coincides with thiourea spot, additional RM spot near solvent front

• TLC 80% E/H - spot near solvent front

  

• Mass spec MJE6.crude2.pdf 20230530-MJE6.crude200000.d.zip

Notes- positive 262+1, 346+1 Negative 295, 373, 424

31/05/23 10:30am

• TLC 80% E/H with TA- RM spot Rf= 0.87 Notes- reaction seems complete

11:40am

• IR to check functional groups Notes- Ranges primary amine (NH2); in starting material- 3500 N-H stretching, 3400-3300 N-H aliphatic secondary amine (NH); in product- 3350-3310 (broad peak at 3349) aromatic (C)- 2000-1650 imine/oxime (C=N)- 1690-1640 (peak at 1636)

1:20pm

• didn't dry solvents Et3N, DMSO

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MJE6a HIRAC- MJE6a.docx

Reaction mechanism

Mechanism

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Method

• NOTE- used Co2SO4.7H2O, not Co2SO4.H2O (GHS hazards and calculations adjusted on HIRAC)

01/06/23 9am

1. Added chlorobenzene (0.414g, 0.373mL, 3.70mmol), Cs2CO3 (1.81g, 5.55mmol), CoSO4.7H2O (0.0624g, 0.222mmol) and 1,10-phenanthroline (0.133g, 0.740mmol).
2. Heating and stirring at 11:15am

3pm

• dissolved chlorobenzene, phenanthroline and RM in MeOH for TLC
• TLC 10% E/H (from lit)- RM spot coincides with end product of 4-6

02/06/23 9:30am

• stopped reaction (22hrs)

• RM now changed colour from blue to black(as in lit).

• dissolved chlorobenzene, phenanthroline and RM in MeOH for TLC. However RM not very soluble in MeOH.

• TLC 10% E/H (from lit)- RM spot coincides with end product of 4-6

• TLC 9% MeOH/DCM/NH4- not clear

• TLC 60% E/H - too polar

• testing solubility MeOH- medium THF- medium DMF/MeOH- better

• TLC 10% E/H (from lit)- reaction not finished

12pm

• Mass spec MJE6a.crude.pdf 20230602_MJE4-7.crude.d.zip

06/06/23 9am

• try to dissolve RM DMF and MeOH- no MeOH and EtOAc- no H2O and MeOH- no DCM- no

• keep reaction going till MJE6 disappears

1:34pm

• partially dissolved RM in DMF/MeOH
• TLC 10% E/H- same spot as MJE6

07/06/23 9am

• switch off reaction

9:30am

• Mass spec MJE6a.crude2.pdf 20230607_MJE6a.crude2.d.zip

Note- seems like alternate product (MW: 287) made at 297 (287+ Na). Conclusion- redo reaction with correct iodoaniline and remove chlorobenzene

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Method 6-2

19/06/23 10:15am Notes- scale up 3x from HIRAC

• remember- not deuterated, correct iodoaniline, no chlorobenzene
• oven drying multi-neck flask

1:20pm

• grease vial and stoppers

2:15pm

1. Added dried DMSO (6mL), thiourea (0.2252g, 3.00mmol), triethylamine (417uL, 0.303g, 3.00mmol), cobalt (II) chloride hexahydrate (0.357g, 1.50mmol).
2. Started stirring.

3:45pm

• put reaction at 30C due to cold lab

4pm

• MS 20230619_MJE6-2.crude1.pdf 20230619_MJE6-2.crude1.zip Note- no product peak at 134 (thiourea cobalt complex).

• kept reaction going

20/06/23 9:30am

• TLC to check reaction progress (apparently TLC works in lit) 5% MeOH/DCM - streaked 9% MeOH/9% NH4OH/90% EtOAc- solid spot for thiourea and RM Rf=0.6

Note- thiourea still present

11am -MS 20230620_MJE6-2.crude2.pdf 20230620_MJE6-2.crude2.zip Note- no product at 134, therefore increase temperature to 40C

1pm

• TLC 9% MeOH/9% NH4OH/90% EtOAc- solid spot for thiourea and RM Rf=0.6

3:30pm

• TLC 9% MeOH/9% NH4OH/90% EtOAc- solid spot for thiourea and RM Rf=0.6

4. Added 4-bromo-2-iodoaniline (0.654g, 2.20mmol).

21/06/23 9am

• TLC 9% MeOH/9% NH4OH/90% EtOAc- RM same spots as thiourea and iodoaniline

12pm

• TLC 9% MeOH/9% NH4OH/90% EtOAc- RM same spots as thiourea and iodoaniline

  

• MS

  

  20230621_MJE6-2.crude3.zip

23/06/23 9am

• TLC 9% MeOH/9% NH4OH/90% EtOAc- only see thiourea and iodoaniline spots in RM

Method 6a-2

1. Added Cs2CO3 (1.471g, 4.51mmol), CoSO4.7H2O (0.0506g, 0.18mmol) and 1,10-phenanthroline (0.104g, 0.577mmol). Heating and stirring at 9:30am

12pm

• MS 20230623_MJE6a-2.crude1.pdf 20230623_MJE6a-2.crude1.zip

Note- peak at 210.97- intended product (yay)

3pm

2. Work up- vacuum filtration- rinse with diethyl ether, remaining dissolve into vial with MeOH
   • left to dry on filter paper for 2 days.

26/06/23 8:50am

• work up- continue drying
• situation- dried black solid in vial, filtrate
• solubility of black solid- MeoH- slightly
• DCM- no
• DMF- no

11:30am

• TLC 9% MeOH/9% NH4OH/90% EtOAc- no spot

  

• TLC 40% E/H- slight spot indicating iodoaniline

  

• TLC MeOH/DCM/NH4- no movement of RM

  

3pm

• NMR 6a-2 MJE6a-2.crude_1.zip MJE6a-2.dry.pdf

4pm

• MS filtrate 20230626_MJE6a-2.filtrate.pdf 20230623_MJE6a-2.filtrate.zip Note- product in filtrate (mix of black solid, DMSO, ether DMSO)

• plan to dissolve product in DCM (organic), liq-liq and then rotor vap organic layer to rid DMSO.

• attempted to dissolve filtrate in DCM and do liquid liquid separation, however was not soluble in DCM.

03/07/23 9:10am filtrate:

• ether, DMSO, water, DCM, product

• dried under N2- still wet (most likely DCM and ether gone)

• NMR

• Vial with dried black solid- has water, put under N2 solubility:

• MeOH- slightly

• toluene- no

• DMF- no

• chloroform- no

• acetone- no

• isopropanol- no

04/07/23 1:40pm

• TLC 9% MeOH/90% DCM/1% NH4 black solid- baseline filtrate + MeOH dried- 2 spots (IGNORE) wet filtrate - 1 spot - potentially product

• TLC 9% MeOH/90% DCM/1% NH4 Dry- Rf= 1 (iodo), Rf= 0.55 (IGNORE) Wet- Rf= 1, Rf= 0.55 Iodoaniline - Rf= 1

Note- after looking at MS of crude RM with product , no iodoaniline 297, guanidine 339, aromatic BZ 287, 1,10-phenanthroline possibly at 180

3:45pm

• MS wet filtrate due to less iodoaniline 20230705_MJE6a-2.Wet filtrate.pdf 20230705_MJE6a-2.wet filtrate.zip Note- product at 210.94

05/07/23 12pm

• dissolved wet filtrate in MeOH, filtered out black solid and filtrate straight into vial (15.800g).

1:30pm

• RV MeOH
• left on vacuum overnight.

06/07/23 10am

• MS dry black solid (didn't show potential product on TLC, stuck to base) 230706_MJE6a-2.drysolid.pdf 230706_MJE6a-2.drysolid.zip

Note- doesn't show on MS but slight amount of 211 product. Conclusion- product potentially soluble in aqueous as higher present in filtrate with water and had slight orange tinge.

06/07/23 3pm

• NMR dry black solid again DMSO
• NMR wet filtrate in deuterated MeOH

[memm0740]

Method 6-3

10/07/23 10am Notes- scale up 3x from HIRAC remember- not deuterated, correct iodoaniline, no chlorobenzene oven drying 25mL flask

12pm

1. Added dried DMSO (6mL), thiourea (0.2279g, 3.00mmol), triethylamine (417uL, 0.303g, 3.00mmol), cobalt (II) chloride hexahydrate (0.3548g, 1.50mmol).
2. Started stirring at 1:11pm.

• dissolved thiourea and RM in methanol TLC in 9% MeOH/9% NH4OH/90% EtOAc- same spot as thiourea

3:15pm

3. Added 4-bromo-iodoaniline (0.658g, 2.20mmol).

11/07/23 9:30am

• dissolved RM, thiourea and bromo-iodoaniline in MeOH
• TLC in MeOH/ NH4OH/ 90% EtOAc- both thiourea and aniline present

10am

• MS 230711-MJE6-3.crude1.pdf 230711_MJE6-3.crude1.d.zip Note- no intended product at 339

• TLC in MeOH/ NH4OH/ 90% EtOAc- both thiourea and aniline present

  

1:45pm MS 230711_MJE6-3.crude2.pdf 230711-MJE6-3.crude2.d.zip Note- no product at 339. Going to add rest of reagents to make free amine BZ.

2:30pm Method 6a-3

1. Added Cs2CO3 (1.471g, 4.51mmol), CoSO4.7H2O (0.0506g, 0.18mmol) and 1,10-phenanthroline (0.104g, 0.577mmol). Heating and stirring at 2:51pm.

• left overnight at 120C.

12/07/23 9am

• MS 230712_MJE6-3.crude3.pdf 230712_MJE6-3.crude3.d.zip Note- largest peak at 211- yay product formed. Time to work up.

11:30am TLC MeOH/ NH4OH/ 90% EtOAc- Rm shows no more thiourea, iodoaniline slightly present 60%- messy, shows presence of step 1 and iodoaniline 80%- same as first TLC

1pm

2. Work up- ink black RM solubility of black solid-
   • acetonitrile- yes
   • ether- no
   • DCM- slightly

• vacuum filtration- filter cake, filtrate, residue (in flask rinsed with DCM and put through filtration)

2:45pm

• MS of filtrate 230712_MJE6-3. filtrate.pdf 230712_MJE6-3.filtrate.zip

• MS of solid 230712_MJE6-3.solide.pdf 230712_MJE6-3.solide.d.zip Note- seems product at 211 is present in both filtrate and filter cake. Therefore going to dry solid filter cake on high vac and conduct liquid-liquid to extract product from filtrate.

• continue work up

• acetonitrile completely soluble in water, therefore can't do liquid -liquid

• attempted to rotovap acetonitrile off (currently in filtrate acetonitrile, DCM,DMSO, product). (vial= 15.81g)

• left filter cake to dry on vacuum filtration

13/07/23 11:30pm

• continue rotovapping

• collect solid into vial (15.997g)

• MS of dried solid 20230713_MJE6-3.dried solid.pdf 230713_MJE6-3dried solid.zip Note- product much higher in filtrate, not in dried filtrate as much.

3pm

• NMR -filtrate dissolved in MeOD, not in CD3CN or (CD3)2CO (acetone) MJE6-3.filtrate.pdf MJE6-3.filtrate_1.zip

• solid struggled to dissolve in DMSO, MeOD, DCM. Dissolved in TFA, waiting for deuterated TFA to arrive.

• put filtrate under high vacuum.

14/0723 9am -put under N to blow down nitrogen

[memm0740]

Method 6-4

18/07/23 9am Notes- scale up 3x from HIRAC remember- not deuterated, correct iodoaniline, no chlorobenzene oven drying 25mL flask 1hr

1. Added dried DMSO (6mL), thiourea (0.2279g, 3.00mmol), triethylamine (417uL, 0.303g, 3.00mmol), cobalt (II) chloride hexahydrate (0.3580g, 1.50mmol). 2.Started stirring at 10:30am.

12pm

• MS 230718_MJE6-4.crude1.pdf 230718_MJE6-4.crude1.d.zip Note- no 134, peak at 138.11 (possibly thiourea-cobalt complex).

2:50pm

3. Added iodoaniline (0.6959g, 2.34mmol)

3:15pm

• MS 230718_MJE6-4.crude2.pdf 230718_MJE6-4.crude2.d.zip

Note- product at 339, largest peak at 362 (not sure). Still SM iodoaniline at 297 left so keep reaction stirring no heat.

20/07/23 9am

• TLC - slight amount of iodoaniline left

  

• MS 230720-MJE6-4.crude3.pdf 230720-MJE6-4.crude3.d.zip

Note- no peak at 339, but also no SM at 297

10:30am Method 6a-4

1. Added Cs2CO3 (1.471g, 4.51mmol), CoSO4.7H2O (0.0537g, mmol) and 1,10-phenanthroline (0.101g, mmol).
2. Switched on heating and stirring.

12:20pm

• RM still dark blue (same as before added 6a)
• solubility: MeOH/EtOAc DCM- better IsOH- yes
• TLC - iodoaniline left

4:30pm MS 230720_MJE6-4.crude4.pdf 230720_MJE6-4.crude4.d.zip

• TLC- iodoaniline still present

31/07/23 (left RM in flask for a week- due to personal surgery)

• MS and TLC shows iodoaniline still present but in lower quantity, compared to product.

1pm

• Work up- vac filtration
• left to dry till 5pm

5pm

• MS of solid- high in 211 230731_MJE6-4 solid.pdf

01/08/23 9:30am

• MS filtrate- 211, 300 230801_MJE6-4.filtrate.pdf 230801_MJE6-4.filtrate.d.zip

11am

• put solid into vial= 15.7994g
• vial + product= 17.046g
• trying to figure out 8-2 solubility to proceed with this reaction. Trying to see if amine soluble in aqueous, to then do aqueous work up.

07/08/23

• Work up: from 8-2 added HCl (10mL)

• added 2.5M NaOH (3mL) to get pH 14

• extract by 10mL DCM x3

• RV DCM

• MS DCM- none

• top layer clear aq- no

• bottom grey ag- little

• work up did not work

08/08/23

• to freeze dry aq layer, dissolved in 1:1 acetonitrile to water.

09/0823 9am

• left on vac for freeze drying

11/08/23 12:30pm

• NMR unsuccessful
• check sol of filtrate as it contains 211, best to worst: TFA, DCM, EtOAc, toluene.

Conclusion- struggling to isolate 211 in aq or organic phases due to DMSO

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09/089/23 10am Method 6-5 oven drying 25mL flask 1hr

1. Added dried DMSO (6mL), thiourea (0.2206g, mmol), triethylamine (417uL, 0.303g, 3.00mmol), cobalt (II) chloride hexahydrate (0.3608g, mmol). 2.Started stirring at 11:50am.

3:15pm MS (138 peak like last time) 230809_MJE6-5.crude.pdf 230809_MJE6-5.crude.d.zip

4pm

• TLC 7.5% MeOH/92.5% DCM
• thiourea present

3. Added iodoaniline (0.6969g, mmol)

11/08/23 9am

• MS- does not look the same as 6-4 at this stage 230811_MJE6-5.crude2.pdf 230811_MJE6-5.crude2.d.zip

4. Added Cs2CO3 (1.4739g, mmol), CoSO4.7H2O (0.0567g, mmol) and 1,10-phenanthroline (0.102g, mmol). Switched on heating and stirring.

4pm

• MS - reaction done 230811-MJE6-5crude3.pdf 230811-MJE6-5crude3.d.zip

4:30pm

5. Work up- vac filtration (rinse with DMSO)
   • left to dry on vac filtration

14/08/23 10am

• solid doesn't look like purple powder from 6-4, possible pyrrolysis

15/08/23 10am

• blow down DMSO in filtrate
• solubility of filtrate: toluene, EtOAc, Hexane-no DMF and TFA - yea MeOH and DCM- partially

16/08/23 10am

• MS of filtrate 230816_MJE6-5.filtrate.pdf 230816_MJE6-5.filtrate.d.zip

• weight of solid= 707mg

• weight of filtrate= 21469mg

• cont to blow down filtrate