All Notebooks | Help | Support | About
27th February 2017 @ 19:30

Synthesis of (E)-4-(2-((2-(6-chloropyrazin-2-yl)hydrozono)methyl)-phenyl)morpholine (FS-04-01); Cyclisation Step.

FS-04-01

 

Scheme:

 

FS-04-01 Scheme.jpg

 

Reagents

Quantities

Moles

Equivalents

FS-03-01

0.3138 g

0.9875 mmol

1

PIDA

0.3185 g

0.9888 mmol

1

DCM

50 mL

-

-

NaHCO3

25 mL

-

-

 

Procedure:

 

PIDA (0.3185 g, 0.99 mmol) was added to a stirring mixture of FS-03-01 (0.3138 g, 0.99 mmol) in DCM (20 mL). Left to stir, at room temperature, over night.

The resultant mixture was separated with NaHCO3 (~25 mL) in deionised water.

The organic phase was extracted and the aqueous phase was washed with DCM (3x10 mL).

The crude yield was 96.28%

 

Purification:

 

The crude product was purified via column chromatography, using a 1:9 EtOAc to petroleum ether eluent.  The polarity was increased incrementally, every 500 mL, by 5% - with the final elutions being at 35% EtOAc. From 25% EtOAc onwards, hexane was used instead of petroleum ether.

The final yield was 24.7% (0.0772 g) with four distinct compounds being eluted; FS-04-01-1, FS-04-01-2, FS-04-01-3 and FS-04-01-4. The product was assumed to be FS-04-01-2 with a yield of 10.26% (0.032 g)

cyclisation.jpg
 

NMR Analysis:

 

FS-04-01-1 and FS-04-01-4 appeared to contain starting material and solvent. 

FS-04-01-2 and FS-04-01-3 seemed the most promising, with FS-04-01-2 being analysed in depth via 1H NMR, 13C NMR, mass spectrometry and IR.

FS-04-01-PROTON.jpg
FS-04-01- Carbon.jpg
FS-04-01- DEPT.jpg

FS-04-01-2DNMR.jpg
FS-04-01.jpg
FS-04-01-4.jpg

FS-04-01-2.jpg
FS-04-01-1.jpg

FS-04-01-2.jpg

FS-04-01-2 MS.pdf
FS-04-01-2 MS (1).pdf
FS-04-01-2 MS (Infused Neg).pdf

 

The results were inconclusive (at present), though a small quantity of the intended final product was seen in the mass spec.

 

References:

 

OSM: Synthesis of 5-chloro-3-(4-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyrazine (JU 8-2), http://malaria.ourexperiment.org/triazolopyrazine_se/9986/, Date accessed: 12/11/16.

Attached Files
27th February 2017 @ 19:23

Synthesis of (E)-4-(2-((2-(6-chloropyrazin-2-yl)hydrozono)methyl)-phenyl)morpholine (FS-03-01); Condensation Step.

FS-03-01

 

Scheme:

 

FS-03-01 scheme.jpg

 

Reagents

Quantity

Moles

Equivalents

2-chloro-6-hydrazinylpyrazine

0.1562 g

1.05 mmol

1

2-morpholinylbenzaldehyde

0.2 g

1.05 mmol

1

EtOH

4 mL

67 mmol

62

 

Procedure:

 

2-choloro-6-hydrazinylpyrazine (0.1562 g, 1.05 mmol) was added to a stirring solution of 2-morpholinylbenzaldehyde (0.2 g, 1.05 mmol) in ethanol (4.0 mL, 67 mmol).

The mixture was left to stir, after Ca. 2 hours a TLC (1:1 pet. ether to EtOAc) of the mixture against diluted 2-morpholinylbenzaldehyde showed the reaction had reached completion.

 

Condensation.jpg

 

The product was rotary evaporated to give a yield of 93.95% (0.3138g, 0.9875 mmol)

 

NMR analysis:

 

FS-03-01.jpg

 

Reference:

 

OSM: Synthesis of (E)-2-chloro-6-(2-(napthalen-2-ylmethylene)hydrazinyl)pyrazine (TY 2-1).

http://malaria.ourexperiment.org/triazolopyrazine_se/9268/Synthesis_of_E2chloro62naphthalen2ylmethylenehydrazinylpyrazine_TY_21.html , Date accessed: 10/11/16.

Attached Files
27th February 2017 @ 19:15

 

Scaled-up - Amination of 2-fluorobenzaldehyde, via SNAr, with DMF to produce 2-morpholinylbenzaldehyde.

FS-02-02 

Scheme:

 

FS-02-02 Scheme.jpg
 

 

Reagents

Quantity

Moles

Equivalents

2-fluorobenzaldehyde

2.1 mL

20 mmol

1

Morpholine

3.46 mL

40 mmol

2

K2CO3

4.1 g

29.7 mmol

1.5

DMF

20 mL

259 mmol

13

 

Procedure:

 

To a stirring mixture of K2CO3 (4.1 g, 29.7 mmol) in DMF (20 mL), 2-fluorobenzaldehyde (2.1 mL, 20 mmol) and morpholine (2.6 mL, 30 mmol) were added. The mixture was heated to ~100 oC, condensing under air and left overnight.

A mini work-up and TLC (1:1 EtOAc to petroleum ether) was done, showing the reaction was incomplete.

To force the reaction to completion, a further 10 mmol of morpholine was added to the reaction mixture, bringing the overall reactant equivalents to 1:2 with morpholine in excess.

 

The reaction didn’t reach completion after 3 hours so it was left for a further week.

 

Purification:

 

Diethyl ether (~70 mL) in a 1:1 solution of water in brine (15 mL/15 mL) was used to dilute and bring about separation.

 

The organic phase was washed once more with a solution of diethyl ether and water in brine (10 mL diethyl ether and 20 mL (1:1) water and brine).

 

The aqueous phase was washed with diethyl ether (~20 mL).

 

The combined organic phases were washed with brine (20 mL) and the extracted organic phase was evaporated in vacuo to give the crude product (3.9g).

The pure product was eluted via column chromatography with an eluent of EtOAc to petroleum ether (1:9).

125 fractions were eluted in total with the product showing, via TLC, in fractions’ 61-113.

 

2-morpholinylbenzaldehyde was successfully synthesised to give a yellow, crystalline, solid with a yield of 37.7% (1.44 g).

 

FS-02-02 product.jpg

 

NMR Analysis:

 

1H NMR (400 MHz, CDCl3) δ 10.3 (1H, s, CHO), 7.83 – 7.81 (1H, d, J 7.7 Hz, HAr), 7.69 – 7.53 (1H, m, HAr), 7.17 – 7.11 (2H, m, HAr), 3.92 – 3.89 (4H, t, CH2OCH2), 3.10 – 3.08 (4H, t, CH2NCH2).

 

FS-02-02 NMR Proton crude.JPG

 

FS-02-02 MS.pdf

 

FS-02-02.jpg

 

References:

 

X. Xia, X. Shu, K. Ji, et al., Journal of Organic Chemistry, 2010, 75(9), 2893 – 2902.

 

Attached Files
27th February 2017 @ 19:05

 

Amination of 2-fluorobenzaldehyde, via SNAr, in DMF to produce 2-morpholinylbenzaldehyde.

 

FS-02-01

 

Scheme:

 

 

FS-02-01 scheme.jpg

 

Reagents

Quantities

Moles

Equivalents

2-fluorobenzaldehyde

0.2 mL, 0.24 g

1.898 mmol

1

Morpholine

0.19 mL, 0.19 g

2.196 mmol

1.2

K2CO3

0.3 g

2.171 mmol

1.1

DMF

2.0 mL

25.94 mmol

13.7

 

Procedure:

2-fluorobenzaldehyde (0.2 mL, 1.9 mmol) and morpholine (0.19 mL, 2.2 mmol) were added to a stirring mixture of K2CO3 (0.312 g, 2.2 mmol) in DMF (2.0 mL, 26 mmol). The mixture was refluxed (~100 oC; condensing under air, with no water) for Ca. 6 days.

The mixture was an opaque, pale, yellow colour.

 

 

Picture2.jpg

 

After reflux, the mixture was dark orange. A mini work-up was done with diethyl ether and brine to bring about clear separation.

 

Picture3.jpg

Initial TLC was carried out (pet. ether/EtOAc, 5:5) with clear separation and fluorescence being seen at 366 nm (UV).

 

Picture4.jpg
 

 

Mixture was diluted in diethyl ether (10 mL), phase separation was forced by addition of water then washed, twice, in diethyl ether (~3 mL followed by ~4 mL) and water.

The combined organic phases were washed with brine. The extracted organic phase was then dried over MgSO4 and rotary evaporated to give the crude product (0.4204 g).

 

The TLC of the crude product (1:9 EtOAc/pet. ether) showed clear separation:

Rf1 = 0.087 => with fluorescence seen at 366 nm; presumed to be the product.

Rf2 = 0.33 => Presumed to be the starting material.

Clear separation via TLC (mobile phase at the ratio 1:9) gave an indication of the eluent ratio required to resolve the pure product via column chromatography.

 

Purification:

 

Silica gel was added to the diluted crude product (in EtOAc) and rotary evaporated to give a free-moving, yellow, solid:

 

 

Picture5.jpg

 

Pure product was eluted via column chromatography, 10% EtOAc in petroleum ether with ~200 mL of solvent used in total,  with TLC’s being taken of the eluted solvent/product.

Picture6.jpg
 

 

30 fractions were produced in total:

 

 

Picture7.jpg
 

 

The first 10 fractions showed nothing under UV (254nm or 366nm); fractions 11-23 showed spots at 366nm and so were combined and rotary evaporated to give the pure product, a yellow oil, which was then submitted for NMR analysis. 

 

NMR analysis:

Indepth analysis showed that 2-morpholinylbenzaldehyde was successfully synthesised via the SNAr method.

1H NMR (400 MHz, CDCl3) δ 10.3 (1H, s, CHO), 7.82 – 7.80 (1H, d, J 7.6 Hz, HAr), 7.6 – 7.5 (1H, m, HAr), 7.2 – 7.1 (2H, m, HAr), 3.9 (4H, s, CH2OCH2), 3.09 – 3.08 (4H, d, J 3.1 Hz, CH2NCH2).

 

18thDEPT.jpg

18thPureCarbon.jpg

18thProton - use OSM.jpg

18thHSQC-CH.jpg

18thHMBC-CH.jpg

 

References:

 

X. Xia, X. Shu, K. Ji, et al., Journal of Organic Chemistry, 2010, 75(9), 2893 – 2902.

 

Attached Files
10th November 2016 @ 15:27

 

Preparation of (ortho) amine-substituted benzaldehyde via Buchwald-Hartwig amination.

FS-01-01

Scheme:

FS-01-01 scheme.jpg



Reagent

Quantities

Moles/ mmol

Equivalents

2-bromobenzaldehyde

0.13 mL, 0.2 g

1.1

1

Morpholine

0.2 mL,

0.2 g

2.3

2.1

Caesium carbonate

0.28 g

0.9

0.82

Rac-BINAP

6.4 mg

0.0103

0.009

Pd(II) acetate

2.1 mg

0.0094

0.0086

Toluene

5.0 mL

 

 

 

Procedure:

 

Morpholine (0.2 mL, 2.3 mmol) was added to 2-bromobenzaldehyde (0.13 mL, 1.1 mmol) in toluene (5.0 mL) under inert atmosphere (nitrogen.) Caesium carbonate (0.28 g, 0.9 mmol), BINAP (6.4 mg, 0.0103 mmol) and, Pd(II) acetate (2.1 mg, 0.0094 mmol) were then added sequentially and the reaction mixture was then degassed (ca. 10 minutes), then heated at reflux for 21 hours and 35 minutes.

 

fs-01-01(1).jpg

fs-01-01(2).jpg

The resultant mixture was dark yellow, slightly opaque, with sediment.

fs-01-01(3).jpg

fs-01-01(4).jpg

 

TLC analysis:

 

After this time TLC analysis (50% EtOAc/pet. ether) showed that there was still starting material remaining, however it was decided to quench the reaction.

fs-01-01(5).jpg

Work-up and extraction:

 

The mixture was poured into half-saturated K2CO3 and extracted into CH2Cl2 (3 x 20 mL). The combined organic phases were washed with brine (10 mL), dried over MgSO4, filtered and the solvent removed by rotary evaporation to give a yellow oil.

 

Analysis by 1H NMR showed substantial amounts of starting material so an alternative approach was sought. (FS-1-01 crude).

4thOCT.jpg

References:

 

Constantin Rabong, Christian Hametner and Kurt Mereiter, Heterocycles, 2008, 75, 813


Attached Files