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4th December 2017 @ 15:40

NH1-008

Synthesis of final product using Buchwald-Hartwig cross-coupling - on a larger scale

Mechanism

 

 
mechanism final step.jpg
Compound Data(mr/density) 

 Amount

 mMol Eqv 
NH1-007 412.9  0.100g  0.24 
Toluene 4.00ml  -
Pyrrollidine  71.2/0.85g/ml  0.048ml 0.28 1.2 
NaOtBu 96.1  0.0323g  0.34  1.4 
Pd(dBA)2  575.00 0.00069g  0.0012  0.50% 
Johns Phos 298.40 0.00322g 0.0108 4.5%

Procedure- NH1-008

NH1-007 (0.100g, 0.24mmol) was dissolved in degassed toluene (4.00mL). Pyrrolidine (0.048mL,0.28mmol) was added dropwise. John Phos (0.00322g, 0.0108mmol) was added followed by the base, NaOtBu (0.0323g, 0.34mmol). Pd(dBA)2 (0.00069g, 0.0012mmol) was added and the reaction was left to stir at 80 degrees for 7 days.

NH1-008 was separated using HCl and EtOAc. This was then dried using MgSO4, filtered and dried in vacuo. TLC was carried out (5% MeOH/95% DCM) and is shown below.

final TLC.jpg

1H NMR of NH1-008 was taken in chloroform. The NMR did not show the significant product peaks. To confirm this, NH1-008 was purified via flash column chromatography (2% MeOH/98% DCM). The TLC concluded a potential product in vials from 9-16. These were collected and dried in vacuo. 1HNMR was taken but unfortunately the analysis concluded that this reaction did not work as the spectra was same as the starting material.

Attached Files
4th December 2017 @ 15:08
NH1-007

SNAr reaction 

Mechanism

 
week 3.jpg


Reagent Equivalent Molecular Weight mMol Quantity
4-flurophenylethan-1-ol 2 140.00 7.10 0.9mL
Sodium Hydride 2 24.00 14.06 540.00mg
Triazolopyrazine 1 309.55 3.55 1100.00mg
THF - - - 30.00mL

Procedure

THF (30.00mL) was added to Triazolopyrazine (1100.00mg, 3.5mmol) and the mixture was stirred under a nitrogen atmosphere. 4-flurophenylethan-1-ol (0.9mL, 7.10mmol) was added and the mixture was cooled in ice. NaH (540.00mg, 14.06mmol) was added and the dark brown mixture was stirred and left under a nitrogen atmosphere for 2 hours (RMTP).  

 
nitrogen atmosphere.jpg

TLC analysis (Petroleum ether/EtOAc 25:75) confirmed that the reaction had worked.

HCl (2M) and EtOAc (60.00mL) were added to separate the solution, the sample was filtered. The solution was dried over MgSO4 which was filtered off and rinsed with EtOAc. The solution was evaporated in vacuo. 

The crude was purified via flash column chromatography (100% Ethyl acetate). TLC analysis (100% ethyl acetate) showed that test tubes 19-57 contained the product.

repeat 1-15.jpg
repeat 17-32.jpg
repeat 33-47.jpg
repeat final 57.jpg

The product was collected and dried in vacuo. This formed golden crystals.

1H NMR of the product NH-1-007 was taken in chloroform. The NMR showed the desired structure.

The product was weighed and dissolved in CDCl3 to ensure that no product was left in the round bottom flask. This was left to dry. The product was re-weighed (360.00mg, 0.87mol, 24%)

Analysis of product NH-1-004

δH(400 MHz, CDCl3: 9.01 (3H, s, CHAr), 7.61 (4H, d, CHAr), 6.91 (2H, d, CHAr), 6.78 (2H, d, CHAr) 4.42 (6H, s, CHAr) and 2.94 (6H, s, CHAr).

 

Attached Files
4th December 2017 @ 13:24
NH1-005-3= NH1-006

Further Analysis of NH1-006

Mechanism

mechanism final step.jpg
 

Procedure

TLC was carried out in three different solvents which is shown below. The first plate was carried out in 100% EtOAc, the second plate was carried out in 5% MeOH/ 95% DCM and the third plate was carried out in 50% EtOAC/ 50% Pet.Ether.

TLC 3 different solvents.jpg

NH1-006 was purified via flash column chromatography (2% MeOH/ 98% DCM) on a small scale.

small scale FCC.jpg

The TLC concluded a potential product in vials 3-6.  These vials were collected and dried in vacuo.

TLC NH-006 fluoro.jpg

1H NMR and 19F NMR of the product NH-1-006 was taken in chloroform.

Analysis of product NH-1-006

δH(400 MHz, CDCl3: 9.95 (1H, s, CHAr), 7.52 (4H, d, CHAr), 6.80 (5H, q, CHAr), 6.60 (5H, q, CHAr) 4.37 (2H, d, CHAr), 3.36 (4H, s, CHAr), 2.97 (2H, d, CHAr) and 2.05 (5H, s, CHAr).

δF(370Mhz), CDCl3: -115.4 (1F)

The reaction showed a potential product. However, as this reaction was carried out using such a small scale it is difficult to confirm that the reaction had worked to completion. Therefore this reaction needs to be repeated on a larger scale.

Attached Files
26th October 2017 @ 15:18

 

NH1-005-1/2/3

Reaction 5 - NH1-005-1/2/3

Synthesis of final product using Buchwald-Hartwig cross-coupling 

Mechanism

mechanism final step.jpg
Compound Data(mr/density) 

 Amount

 mMol Eqv 
NH1-004 412.9  0.050g  0.12 
Toluene 10.00ml  -
Pyrrollidine  71.2/0.85g/ml  0.0102g /0.012ml 0.14  1.2 
NaOtBu 96.1  0.0161g  0.16  1.4 
BINAP - (NH1-005-1)  622.7  0.00056g  0.0009  0.75% 
Pd(dBA)2    0.00055g  0.0006  0.50% 
Pd(OAc)2 915.7  0.000808g  0.0036  3.00% 
 Cs2CO3 325.82  0.05g  0.168  1.4 
 Pet.Ether Excess  Excess 
Diethyl Ether  Excess  Excess 
BINAP (NH1-005-2)  622.7  0.00336g  0.0054  4.5% 
Johns Phos 298.40 0.00161g 0.0054 4.5%

Procedure- NH1-005-1

NH1-004 (0.0572g,0.12mmol) was dissolved in degassed toluene (2mL). Pyrrolidine (0.012mL,0.14mmol) was added dropwise. BINAP (0.00056g, 0.0009mmol) was added followed by the base, NaOtBu (0.0161g, 0.16mmol). Pd(dBA)2 (0.0055g) was added and the reaction was left to stir at 80 degrees for 14 days.

Procedure- NH1-005-2

NH1-004 (0.0552g,0.12mmol) was dissolved in degassed toluene (2mL). Pyrrolidine (0.012mL,0.14mmol) was added dropwise. BINAP (0.000336g, 0.0054mmol) was added followed by the base, Cs2CO3 (0.055g, 0.168mmol). Pd(OAc)2 (0.0008g) was added and the reaction was left to stir at 80 degrees for 14 days.

Procedure- NH1-005-3

NH1-004 (0.0520g,0.12mmol) was dissolved in degassed toluene (2mL). Pyrrolidine (0.012mL,0.14mmol) was added dropwise. John Phos (0.0016g, 0.0054mmol) was added followed by the base, NaOtBu (0.0161g, 0.16mmol). Pd(dBA)2 (0.0055g) was added and the reaction was left to stir at 80 degrees for 14 days.

 

TLC analysis was carried out for all three reactions. Each vial was separated using a pipette using HCl and EtOAc. Each vial was dried using MgSO4, filtered and dried in vacuo. TLC carried out (5% MeOH/95% DCM) after 2 weeks is shown below.

1 2 3.jpg

TLC 123.jpg

1H NMR of each product was taken in chloroform. The NMR for NH1-005-1 and NH1-005-2 did not show any change for the starting material. However the NMR for NH1-005-3 showed a potential peak that could be a product. This concluded that further analysis for NH1-005-3 needed to be carried out.

Attached Files
16th October 2017 @ 13:36

NH1-004-

Reaction 4 - NH1-004

SNAr reaction 

Mechanism

week 3.jpg


Reagent Equivalent Molecular Weight mMol Quantity
4-flurophenylethan-1-ol 2 140.00 2.38 0.3mL
Sodium Hydride 2 24.00 5.60 224.00mg
Triazolopyrazine 1 309.55 1.19 369.00mg
THF - - - 10.00mL

Procedure

THF (10.00mL) was added to Triazolopyrazine (369.00mg, 1.19mmol) and the mixture was stirred under a nitrogen atmosphere. 4-flurophenylethan-1-ol (0.3mL, 2.38mmol) was added and the mixture was cooled in ice. NaH (224.00mg, 5.60mmol) was added and the dark brown mixture was stirred and left under a nitrogen atmosphere for 2 hours (RMTP). 

nitrogen atmosphere.jpg

TLC analysis (Petroleum ether/EtOAc 50:50) confirmed that the reaction had worked. 

TLC week 3.jpg

HCl (2M) and EtOAc (20.00mL) were added to separate the solution, the sample was filtered. The solution was dried over MgSO4 which was filtered off and rinsed with EtOAc. The solution was evaporated in vacuo. 

The crude was purified via flash column chromatography (100% Ethyl acetate). TLC analysis (100% ethyl acetate) showed that test tubes 9-17 contained the product.

FCC.jpg
TLC week 3 no 2.jpg
TLC week 2 no 3.jpg

The product was collected and dried in vacuo. This formed golden crystals.

crystals 2.jpg
crystals 3.jpg
crystals 1.jpg
 

1H NMR, 13C NMR and 19F NMR of the product NH-1-004 was taken in chloroform. The NMR showed the desired structure. The 1H NMR of the starting material was also taken.

The product was weighed and dissolved in CDCl3 to ensure that no product was left in the round bottom flask. This was left to dry. The product was re-weighed (245.00mg, 0.6mol, 68%)

Analysis of product NH-1-004

δH(400 MHz, CDCl3: 9.01 (2H, s, CHAr), 7.61 (4H, q, CHAr), 6.90 (2H, t, CHAr), 6.78 (2H, t, CHAr) 4.91 (2H, t, CHAr) and 2.94 (2H, t, CHAr)

δC(100Mhz), CDCl3: 160.9 (CAr-F), 147.7 (CAr), 146.5 (CAr), 143.7 (CAr-O), 136.5 (CHAr), 131.8(CHAr), 131.7 (CAr), 130.0 (CHAr), 129.9 (CHAr), 126.6 (CAr-Br), 124.7 (CAr), 115.6(CHAr), 108.3 (CAr), 71.1(CHAr)and 33.7 (CHAr).

δF(370Mhz), CDCl3: -115.4 (1F)

Attached Files