All Notebooks | Help | Support | About
16th June 2014 @ 00:46

See: Synthesis of N-(3-chlorophenyl)-3-(4-(difluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine-5-carboxamide (TM 14-1)

 

Using PIDA, TM 12-2 was cyclised to TM 14-2 in 39 % yield after purification. HSQC and HMBC spectra were used to completely assign 13C and 1H chemical shifts.

 

scheme

Using the method optimised by Jo (eg: see Synthesis of 5-chloro-3-(4-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyrazine (JU 8-2)

Purified Resynthesis of (E)-N-(3-chlorophenyl)-6-(2-(4-(difluoromethoxy)benzylidene)hydrazinyl)pyrazine-2-carboxamide (TM 12-2) (150 mg, 0.36 mmol) was stirred into DCM (6 mL), phenyliodine diacetate (PIDA) (1 eq, 0.36 mmol, 116 mg) added, and the reaction mixture stirred at RT for 5 hours, when TLC showed the reaction to be complete (product RF: 0.27 in EtOAc). The reaction mixture was washed with saturated NaHCO3 (2 x 10 mL), then the combined aqueous fractions were washed with DCM (4 x 10 mL). The combined organic fractions were dried over MgSO4, filtered, and the solvent removed under vaccum. A pearlescent white solid was observed on the glass frit used to remove MgSO4, which looked similar to the pure TM 14-1 obtained earlier: 65 mg were scraped off and recovered (NOTE: use more DCM next time, as the 50 mL used clearly wasn't enough to dissolve 150 mg of TM 14). By TLC this looked to be TM 14, and so was combined with the evaporated organic portion to give  136 mg of crude TM 14-1 after drying, as beige flakes with a brown deposit at the edges. Purification by automatic column chromatography gave pure TM 14-1 as a fine off-white powder (60 mg, 0.14 mmol, 39 %).

 

Crude NMR (1H, DMSO, 200 MHz):

TM 14-2 crude 1H DMSO 200 MHz.pdf

TM 14-2 crude.zip

Comparing the spectrum to that of pure TM 14-1 (

TM 14-1 pure 1H DMSO 400 MHz.pdf
, the crude looks to be nearly pure TM 14, making this method vastly superior to the low-yielding chloramine-T cyclisation.

 

Pure NMR spectra:

1H, DMSO, 400 MHz):

TM 14-2 1H DMSO 400 MHz.pdf

13C, DMSO, 400 MHz:

TM 14-1 pure 13C DMSO 400 MHz.pdf

(13C spectrum from TM 14-1. A quick carbon was acquired for 14-2 (and was in agreement), but acquisition was halted before a respectable S/N level was reached.)

HSQC, DMSO, 400 MHz:

TM 12-2 HSQC DMSO 400 MHz.pdf

HMBC, DMSO, 400 MHz:

TM 14-2 HMBC DMSO 400 MHz.pdf

Overlaid HSQC/HMBC for triazolopyrazine heterocyclic region:

TM 14-2 HSQC HMBC overlay TRIAZOLOPYRAZINE REGION.pdf

Overlaid HSQC/HMBC for homocyclic regions:

TM 14-2 HSQC HMBC overlay NORTHEAST REGION.pdf

GitHub issue discussing the assignment of NMR signals

From these, all proton and carbon peaks were assigned:

TM 14-2 peaks assigned

(1H peaks in red; 13C in blue)

Rationale:



From the 1D 1H spectrum, the following can be assigned: 10.88 (s, 1H) to 11 (characteristic shift; amidic proton has always been around here), 9.66 (s, 1H),  8.30 (s, 1H) to 1 and 3 as the only other singlets, also with characteristic shifts, 7.63 (dapp, J=8.73, 2H) and 7.15 (dapp, J=8.56, 2H) to pairs 12, 24, and 21, 23 as the only 2H doublet signals, 7.40 (t, J=1.92, 1H) to 15 (only finely split triplet signal), 7.29 (t, J=8.06, 1H) to 18 (only 3J triplet signal), and 7.11 (t, J=73.6, 1H) to 27, with characteristically large 2JHF splitting. This leaves two signals around 7.15 ppm but obscured by the large apparent doublet, corresponding to 17 and 19.

From the 13C spectrum: 157.35 to 10 (carbonyl peak), 152.1 (t, J=3.20) to 22 (fine 3JCF coupling), 115.86 (t, J=258.3) to 27 (large 1JCFcoupling).

From HSQC and HMBC:

1H signal HSQC HMBC HMBC HMBC
9.66 146.15 145.71 d 130.19 d 124.35 s
8.30 130.19 146.15 d 157.3 s 124.35 d
7.63 d 2H 130.31 146.8 d 152.1 dd  
7.40 t 119.2      
7.29 t 130.25 132.8 dt? 138.6 dt?  
7.17d 118.1 119.2    
7.15 d 2H 118.2 d 124.0 dd 152.1 d  
7.15 d 124.3      
         

Triazolopyrazine ring:

Only (8.30, 130.19) can see the carbonyl signal at 157.3 ppm, so this must be 1. It follows that (9.66, 146.15) is 3. Carbon signal 124.35 can be assigned to 6, as it is a doublet from 2 but a faint singlet from 4. 4 sees a fine doublet (J = 15; likely 3JCH) at 145.7, which must therefore be 4. 9 cannot be assigned yet, but otherwise the triazolopyrazine ring is complete.

 

Directly-linked difluoromethoxyphenyl:

22 and 27 were assigned from 1d spectra earlier. By correlation to  (7.63, 130.31) and (7.15, 118.2), relevant carbon shifts for this system appear to be 146.8, 124.0, and 152.1 (already assigned 22). (7.63, 130.31) can be assigned to 12, 24 by the dd signal seen at 152.1, making (7.15, 118.2) 21, 23. 14 is then 124.0 ppm (dd from 21, 23), and 9 is at 146.8 ppm (seen from 1224).

 

Chloroanilide:

15 (119.2, 7.40) and 18 (7.29, 130.25) have been assigned from 1D spectra, and 17 and 19 can be assigned to the coupled signals (7.15, 124.3) and (7.17, 118.1) in some order. At this point, the only remaining carbon signals are 138.7 and 132.8, for 16 and 13. By chemical shifts, we can tentatively assign 138.7 to amidic position 13, leaving 132.8 to 16. I do not believe there is any evidence left to assign 17 and 19 properly, but on the basis of a simulation run with MNova by the NMR faculty have tentatively assigned (7.17, 118.1) to 19, and (7.15, 124.3) to 17.

 

Of these assignments, I am not completely confident about carbons {13 and 16}, and {17 and 19}: it is possible that the assigned signals for each pair should be swapped.

 

 

Raw NMR data:

TM 14-2 pure.zip

 

InChIs:

InChI=1S/C19H14ClF2N5O2/c20-13-2-1-3-14(8-13)25-18(28)16-10-23-11-17(26-16)27-24-9-12-4-6-15(7-5-12)29-19(21)22/h1-11,19H,(H,25,28)(H,26,27)/b24-9+

to

InChI=1S/C19H12ClF2N5O2/c20-12-2-1-3-13(8-12)24-18(28)15-9-23-10-16-25-26-17(27(15)16)11-4-6-14(7-5-11)29-19(21)22/h1-10,19H,(H,24,28)

 

HIRAC:

HIRAC.pdf

4JHH

Linked Posts
Attached Files
scheme.png
HIRAC.pdf
TM 14-2 crude 1H DMSO 200 MHz.pdf
TM 14-2 crude.zip
TM 14-2 HSQC HMBC overlay TRIAZOLOPYRAZINE REGION.pdf
TM 14-2 HSQC HMBC overlay NORTHEAST REGION.pdf
TM 12-2 HMBC DMSO 400 MHz.pdf
TM 12-2 HSQC DMSO 400 MHz.pdf
TM 14-2 HMBC DMSO 400 MHz.pdf
TM 14-2 1H DMSO 400 MHz.pdf
TM 14-2 HSQC DMSO 400 MHz.pdf
assignments.png
TM 14-2 pure.zip
TM 14-2 pure.zip