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26th November 2015 @ 04:02

GitHub Issue #2

Repeat on same scale as Synthesis of (R)-2-amino-2-phenylethan-1-ol (AEW 174-1) as AEW 174-2 did not go to plan.

 

Procedure:

A 2-necked RB was charged with lithium aluminium hydride (1.3 g, 34.3 mmol, 2.1 equiv.) and cooled in an ice bath under Ar. THF (30 mL) was added slowly via syringee and the suspension was stirred at -5 ˚C. Phenylglycine (2.5 g, 16.6 mmol, 1 equiv.) was added portionwise over 10 mins and the reaction stirred at -5 ˚C for 0.5 h. Reaction mixture heated to reflux from 6.00 pm until 8.30 am. 

The reaction mixture was removed from the oil bath and allowed to cool to rt whilst open to the air. The grey slurry was then cooled in an ice bath and ether (40 mL) was added. followed by dropwise adddition of an aqueous solution of NaOH (2M, 10 mL) was added dropwise effervescene). The reaction mixture was left to stir for 15 minutes at rt - turned green to bright yellow slurry. The reaction mixture was filtered and the white cake washed with copious amounts of cool ether (~300 mL). The resulting yellow solution was concentrated at the Rotavap to give a yellow oil containing fine white swirls of powder. Ether (20 mL) was added and the reaction mixture cooled to -78 C. A small amount of white solid formed, mixture was sonicated for 30 seconds and the solid crashed out. Cooled to -78 C and then filtered to yield a white solid which was dried at the high vac (1.6 g, 11.7 mmol, 70% yield).

Hazard and Risk Assessment:

HIRAC AEW 174-1.pdf

InChi:

InChI=1S/C8H9NO2/c9-7(8(10)11)6-4-2-1-3-5-6/h1-5,7H,9H2,(H,10,11)/t7-/m1/s1

to 

InChI=1S/C8H11NO/c9-8(6-10)7-4-2-1-3-5-7/h1-5,8,10H,6,9H2/t8-/m0/s1


Data:

NMR

Literature:

Adapted from this procedure:

Dickman DA, Meyers AI, Smith GA, Gawley RE (1985) Reduction of   α-amino acids: L-valinol. Org. Synth. 63: 136–139. doi:10.15227/orgsyn.063.0136

See also: 

http://118.138.241.43/chiral_cat/2072/Reduction_of_Rphenylglycine_to_give_Rphenylglycinol_KAB991.html

26th November 2015 @ 01:16

Prepared following Chase Smith's procedure.

 

 

 

Crude AEW 262-1 (~1.59 mmol, 1 equiv.) and triphenylphosphine (626 mg, 2.39 mmol, 1.5 equiv.) were placed in a RBF under nitrogen followed by the addition of 40 mL of THF and 4 mL of water. The mixture was stirred at rt. No SM after 2 h, but stirred o/n at rt as per Chase's prep. TLC looked to have more spots next day.

When complete, the reaction was concentrated under reduced pressure and crude NMR recorded.

 purified via silica gel column chromatography eluting with a gradient of ethyl acetate and hexanes.


Data:

Crude proton NMR 200 MHz

AEW 264-1 crude.zip
AEW 264-1 crude.dx

Strings:

InChI=1S/C12H6F3N7O/c13-12(14,15)23-8-3-1-7(2-4-8)11-20-18-9-5-17-6-10(19-21-16)22(9)11/h1-6H

to

InChI=1S/C12H8F3N5O/c13-12(14,15)21-8-3-1-7(2-4-8)11-19-18-10-6-17-5-9(16)20(10)11/h1-6H,16H2

 

[N-]=[N+]=NC1=CN=CC2=NN=C(C3=CC=C(OC(F)(F)F)C=C3)N21

to

NC1=CN=CC2=NN=C(C3=CC=C(OC(F)(F)F)C=C3)N21

Attached Files
25th November 2015 @ 04:10

 

Procedure:

AEW 205 (200 mg, 0.674 mmol, 1 equiv.), potassium hydroxide (132 mg, 3.26 mmol, 3.5 equiv.) and 18-crown-6 (13 mg, 47.2 μmol, 0.07 equiv.) were stirred in toluene (6.7 mL) and then AEW 261-1 (111 mg, 0.674 mmol, 1 equiv.) was added. The reaction mixture was stirred at room temperature for 30 min. New spot started to form but still mainly SM. Heated to 40 deg and stirred for 1.45 h.

Cooled to RT, diluted with water and extracted with EtOAc (x 2). Combined organics washed with small quant. of water, brine, dried (MgSO4) filtered and evaporated to give a cloudy brown oil. 


Crude NMR 200 MHz

AEW 263-1 roton crude 200 MHz.pdf
AEW 264-1 crude.zip
AEW 263-1 crude.dx


Column:

Mix major TLC spot:

AEW 263-1 mix.pdf
AEW 263-1 mix.dx

 

Strings:

InChI=1S/C12H7ClF2N4O/c13-9-5-16-6-10-17-18-11(19(9)10)7-1-3-8(4-2-7)20-12(14)15/h1-6,12H

and

InChI=1S/C10H15NO/c1-11(2)10(8-12)9-6-4-3-5-7-9/h3-7,10,12H,8H2,1-2H3

to

InChI=1S/C22H21F2N5O2/c1-28(2)18(15-6-4-3-5-7-15)14-30-20-13-25-12-19-26-27-21(29(19)20)16-8-10-17(11-9-16)31-22(23)24/h3-13,18,22H,14H2,1-2H3

 

ClC1=CN=CC2=NN=C(C3=CC=C(OC(F)F)C=C3)N21

and

OC[C@@H](C1=CC=CC=C1)N(C)C

to

FC(F)OC(C=C1)=CC=C1C2=NN=C3N2C(OC[C@@H](C4=CC=CC=C4)N(C)C)=CN=C3

Attached Files
25th November 2015 @ 00:34

Using Procedure Developed by Chase Smith.

 

 

AEW 251-1 (500 mg, 1.59 mmol, 1 equiv.) and sodium azide (413 mg, 6.36 mmol, 4 equiv.) were stirred in anhydrous DMF (10.5 mL) at room temperature for 2.5 h.

The mixture was  then diluted with EtOAc (50 mL) and placed in a separating funnel. The organic layer was washed with a saturated aqueous sodium bicarbonate (50 mL). Organic layers were separated and the aqueous layer extracted with EtOAc (50 mL). Combined organic layers were washed with water (50 mL)  followed by brine (50 mL) then dried over sodium sulfate, filtered and concentrated to give a crude black solid (550 mg).

 

Crude NMR looks good (residual DMF present though)

200 MHz

AEW 262-1 crude.dx
AEW 262-1 crude.pdf

Data: 

TLC (4:1 EtOAc/Hexane) 2.5 h

AEW 262-1 4:1 EtOAc:Petrol.JPG

 

Strings:

InChI=1S/C12H6ClF3N4O/c13-9-5-17-6-10-18-19-11(20(9)10)7-1-3-8(4-2-7)21-12(14,15)16/h1-6H

to

InChI=1S/C12H6F3N7O/c13-12(14,15)23-8-3-1-7(2-4-8)11-20-18-9-5-17-6-10(19-21-16)22(9)11/h1-6H

 

ClC1=CN=CC2=NN=C(C3=CC=C(OC(F)(F)F)C=C3)N21

to

[N-]=[N+]=NC1=CN=CC2=NN=C(C3=CC=C(OC(F)(F)F)C=C3)N21

Attached Files
18th November 2015 @ 23:54

GitHub Issue #2

Procedure:

A 100 mL RB was charged with lithium aluminium hydride (2.6 g, 68.6 mmol, 2.1 equiv.) and cooled in an ice bath under Ar. THF (60 mL) was added slowly via syringee and the suspension was stirred at -5 ˚C. Phenylglycine (5.0 g, 33.2 mmol, 1 equiv.) was added portionwise over 10 mins and the reaction stirred at -5 ˚C for 0.5 h. Reaction mixture heated to reflux from 

The reaction mixture was removed from the oil bath and allowed to cool to rt whilst open to the air. The grey slurry was then cooled in an ice bath and ether (80 mL) was added. followed by dropwise adddition of an aqueous solution of NaOH (2M, 20 mL) was added dropwise effervescene). The reaction mixture was left to stir for 30 minutes at rt - turned green to bright yellow slurry. The reaction mixture was filtered _ very slow and the cake remained green/yellow rather than forming white cake seen in previous attempt. The cake washed with copious amounts of cool ether (~700 mL). The resulting yellow solution was concentrated at the Rotavap to give a yellow oil containing fine white swirls of powder. Ether (20 mL) was added and the reaction mixture cooled to -78 C. A small amount of white solid formed, mixture was sonicated for 30 seconds and the solid crashed out. Cooled to -78 C and then filtered to yield a white solid which was dried at the high vac (1.6 g, 11.7 mmol, 70% yield).

Hazard and Risk Assessment:

For twice the scale

HIRAC AEW 174-1.pdf


InChi:

InChI=1S/C8H9NO2/c9-7(8(10)11)6-4-2-1-3-5-6/h1-5,7H,9H2,(H,10,11)/t7-/m1/s1

to 

InChI=1S/C8H11NO/c9-8(6-10)7-4-2-1-3-5-7/h1-5,8,10H,6,9H2/t8-/m0/s1


Data:

low resolution 200 MHz NMR from Synthesis of (R)-2-amino-2-phenylethan-1-ol (AEW 174-1)  

AEW 74-1.pdf
amino alcohol.zip

Literature:

Adapted from this procedure:

Dickman DA, Meyers AI, Smith GA, Gawley RE (1985) Reduction of   α-amino acids: L-valinol. Org. Synth. 63: 136–139. doi:10.15227/orgsyn.063.0136

See also: 

http://118.138.241.43/chiral_cat/2072/Reduction_of_Rphenylglycine_to_give_Rphenylglycinol_KAB991.html