Supplementary data of manuscript entitled
“An efficient L-proline catalysed synthesis of pyrazolo[3,4-e][1,4]thiazepine derivatives
and their in-vitro cytotoxicity studies”
Detailed interpretation of 4d using 2D NMR techniques
O
N
N NH
NH
O
O
S
O
The 1H NMR spectrum revealed that, the singlet at 10.13 ppm is due to the NH proton of amide part of thiazepinone
ring. The H,H-COSY of the 4d has revealed that the doublets at 6.78 and 6.69 ppm integrates for one proton each with
the coupling constant of 8.6 Hz, coupled with each other have been assigned as C-5′ and C-4′protons of pyridine ring.
Another set of doublet at 7.12 ppm and 6.56 ppm coupled with each other which also integrates for one proton each
with the coupling constant of 7.0 Hz revealed through H, H-COSY has been assigned as C-3" and C-4" of aryl
substituent. The singlet appeared at 6.52 ppm integrates for one proton has been due to C-6" proton of aryl ring. The
sharp singlets at 2.38, 3.65, 3.81 and 3.90 ppm which integrate for three protons each are due to the methyl and
methoxy groups of pyridine and aryl ring. The singlets at 3.65, 3.81 ppm has been assigned as methoxy protons of
aryls at C-5", C-2" respectively. The signal at 3.90 ppm has been assigned to protons of methoxy group at C-2' of
pyridine ring whereas other singlet at 2.38 ppm has assigned to the methyl protons at C-6' of pyridine ring. The
methine proton of thiazepinone ring appeared as singlet at 5.63 ppm. The methylene protons of thiazepinone ring
appeared as two doublets at 3.35 and 3.46 ppm with the coupling constant of 16 Hz. H, H-COSY spectrum of the
compound also supports the coupling of each other signal.
The
13
C NMR spectrum of the 4d shows the following
chemical shift values: 171.83, 159.71, 156.86, 153.17, 150.04, 146.59, 137.94, 136.37, 130.77, 116.05, 115.79,
112.64, 112.08, 108.79, 108.13, 56.37, 55.79, 53.65, 36.66, 32.74, 24.08; whereas the DEPT-135 spectrum of the
same compound shows the following signals: 137.94, 115.97, 115.71, 112.55, 112.00, 56.28, 55.70, 53.56, 36.57,
32.64, 23.99 and hence the remaining signals at 171.83, 159.71, 156.86, 153.17, 150.04, 146.59, 136.37, 130.77,
108.79, 108.13 have been tentatively assigned to non-proton bearing carbons. The down field signal at 171.83 ppm
has been assigned to carbonyl carbon. The carbons at C-2', C-2'', C-5'' bearing the methoxy substituent are appeared
at 159.71, 156.86, 153.17 ppm and the relatively down field signal at 159.71 ppm has been assigned to C-2' of
pyridine ring since it is placed between nitrogen and ipso carbon and hence it resonated at relatively down field. The
other two signals at 156.86, 153.17 ppm have been assigned to C-2'', C-5'' of aryl ring. The signals at 150.04 and
146.59 ppm have been assigned ipso carbons at C-3' of pyridine ring and C-1'' of aryl ring respectively. The signal at
136.37 ppm has been assigned to C-6' since it carries methyl group. The signal at 130.77 ppm is due to the carbon at
C-3 of pyrazole ring. The bridgehead carbons of pyrazolothiazepine appeared at 108.79 and 108.13 ppm. The signals
of proton bearing carbons have been assigned based on the HSQC spectrum of the compound 4d. The signals at
137.94, 116.05 and 115.79 ppm are due to the C-3'', C-6'' and C-5'' respectively of the aryl ring. The signals at 112.64,
112.08 ppm are due to the bridgehead carbons of pyrazolothiazepine ring. The methoxyl carbons at C-2'', C-5'' and C2' are appeared at 56.37, 55.79, 53.65 respectively. It is interesting to the relatively upfield carbon signal of the
methoxyl group at 53.56 ppm appears in relatively down field at 3.90 ppm and this difference may be due to the
anisotropic effect of either nitrogen or oxygen lone pair electon(s). In the aliphatic regions three different signals are
observed, among these the signal at 32.74 ppm observed in the negative part of the DEPT-135 spectrum and hence
assigned to methylene carbon of thiazepene ring. The signal at 36.66 ppm is due to the methine carbon at C-4 of the
thiazepine ring. The upfield signal at 24.08 ppm has been assigned to the methyl carbon at C-6' of the pyridine ring.
The above discussions clearly revealed the formation of the compound 4d. This has been supported by the observation
of m/z value at 426.1362 in HRMS spectrum.
Fig 1 1HNMR of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(2,5-dimethoxyphenyl)-1Hpyrazolo[3,4-e][1,4]thiazepin-7(4H,6H,8H)-one(4d)
:
Fig 2 13CNMR of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(2,5-dimethoxyphenyl)-1Hpyrazolo[3,4-e][1,4]thiazepin-7(4H,6H,8H)-one(4d) :
Fig 3 13CNMR of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(2,5-dimethoxyphenyl)-1Hpyrazolo[3,4-e][1,4]thiazepin-7(4H,6H,8H)-one(4d) :
Fig 4 HSQC of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(2,5-dimethoxyphenyl)-1Hpyrazolo[3,4-e][1,4]thiazepin-7(4H,6H,8H)-one(4d)
Fig 5 HSQC of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(2,5-dimethoxyphenyl)1Hpyrazolo[3,4-e][1,4]thiazepin-7(4H,6H,8H)-one(4d)
1
H NMR, 13C NMR and HRMS/LC-MS of Synthesized Compounds
Figure 6. 1H NMR of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(2-methoxyphenyl)-1H-pyrazolo [3, 4-e] [1, 4]
thiazepin-7(4H, 6H, 8H)-one (4a):
O
N
N NH
S
NH
O
O
C20H20N4O3S
Exact Mass: 396.1256
Figure 7. 1HNMR expansion of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(2-methoxyphenyl)-1H-pyrazolo [3,
4-e] [1, 4] thiazepin-7(4H, 6H, 8H)-one (4a):
Figure 8. 1HNMR expansion of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(2-methoxyphenyl)-1H-pyrazolo [3,
4-e] [1, 4] thiazepin-7(4H, 6H, 8H)-one (4a):
Figure 9. 13C NMR of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(2-methoxyphenyl)-1H-pyrazolo [3, 4-e] [1,
4] thiazepin-7(4H, 6H, 8H)-one (4a):
O
N
N NH
S
O
NH
O
Figure 10. HRMS of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(2-methoxyphenyl)-1H-pyrazolo [3, 4-e] [1, 4]
thiazepin-7(4H, 6H, 8H)-one (4a):
O
N
N NH
S
NH
O
O
C20H20N4O3S
Exact Mass: 396.1256
Figure 11. 1HNMR of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(3,4,5-trimethoxyphenyl)-1H-pyrazolo[3,4e][1,4]thiazepin-7(4H, 6H, 8H)-one(4b):
O
N NH
N
NH
O
O
S
O
O
Figure 12. 13C NMR of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(3,4,5-trimethoxyphenyl)-1H-pyrazolo[3,4e][1,4]thiazepin-7(4H, 6H, 8H)-one(4b):
O
N NH
N
NH
O
S
O
O
O
Figure 13. HRMS of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(3,4,5-trimethoxyphenyl)-1H-pyrazolo[3,4e][1,4]thiazepin-7(4H, 6H, 8H)-one(4b):
O
N NH
N
NH
O
S
O
O
C22H24N4O5S
Exact Mass: 456.1467
O
Figure 14. 1H NMR of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(3-nitrophenyl)-1H-pyrazolo[3,4e][1,4]thiazepin-7(4H, 6H, 8H)-one(4c):
O
N
N NH
NH
S
O
NO2
Figure 15. 1HNMR expansion of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(3-nitrophenyl)-1H-pyrazolo[3,4e][1,4]thiazepin-7(4H, 6H, 8H)-one(4c):
Figure 16. 1HNMR expansion of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(3-nitrophenyl)-1H-pyrazolo[3,4e][1,4]thiazepin-7(4H,6H,8H)-one(4c):
Figure17. 13CNMR of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(3-nitrophenyl)-1H-pyrazolo[3,4e][1,4]thiazepin-7(4H, 6H, 8H)-one(4c):
O
N
N NH
NH
S
NO2
O
Figure 18. HRMS of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(3-nitrophenyl)-1H-pyrazolo[3,4e][1,4]thiazepin-7(4H, 6H, 8H)-one(4c):
O
N NH
N
NH
S
NO2
C19H17N5O4S
Exact Mass: 411.1001
O
Figure 29. 1HNMR of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(2,5-dimethoxyphenyl)-1H-pyrazolo[3,4e][1,4]thiazepin-7(4H,6H,8H)-one(4d):
O
N
N NH
NH
O
S
O
O
Figure 20. 13CNMR of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(2,5-dimethoxyphenyl)-1H-pyrazolo[3,4e][1,4]thiazepin-7(4H,6H,8H)-one(4d) :
Figure 21. HRMS of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(2,5-dimethoxyphenyl)-1H-pyrazolo[3,4e][1,4]thiazepin-7(4H, 6H, 8H)-one(4d) :
O
N
N NH
NH
O
O
S
O
C21H22N4O4S
Exact Mass: 426.1362
Figure 22. 1HNMR of 4-(2,5-dichlorophenyl)-3-(2-methoxy-6-methylpyridin-3-yl)-1H-pyrazolo[3,4e][1,4]thiazepin-7(4H, 6H, 8H)-one(4e) :
O
N
N NH
NH
Cl
S
Cl
O
Figure 23 13CNMR of 4-(2,5-dichlorophenyl)-3-(2-methoxy-6-methylpyridin-3-yl)-1H-pyrazolo[3,4e][1,4]thiazepin-7(4H, 6H, 8H)-one(4e) :
O
N
N NH
NH
Cl
S
Cl
O
Figure 24. HRMS of 4-(2,5-dichlorophenyl)-3-(2-methoxy-6-methylpyridin-3-yl)-1H-pyrazolo[3,4e][1,4]thiazepin-7(4H, 6H, 8H)-one(4e) :
O
N
N NH
NH
Cl
S
Cl
C19H16Cl2N4O2S
Exact Mass: 434.0371
O
Figure 35. 1HNMR of 4-(4,6,7,8-tetrahydro-3-(2-methoxy-6-methylpyridin-3-yl)-7-oxo-1H-pyrazolo[3,4e][1,4]thiazepin-4-yl)benzonitrile(4f) :
O
N
N NH
NH
S
NC
O
Figure 46. 13CNMR of 4-(4,6,7,8-tetrahydro-3-(2-methoxy-6-methylpyridin-3-yl)-7-oxo-1H-pyrazolo[3,4e][1,4]thiazepin-4-yl)benzonitrile(4f) :
O
N
N NH
NH
S
NC
O
Figure 27. HRMS of 4-(4,6,7,8-tetrahydro-3-(2-methoxy-6-methylpyridin-3-yl)-7-oxo-1H-pyrazolo[3,4e][1,4]thiazepin-4-yl)benzonitrile(4f) :
O
N
N NH
NH
S
NC
C20H17N5O2S
Exact Mass: 391.1103
O
Figure 28. 1H NMR of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(2-nitrophenyl)-1H-pyrazolo[3,4e][1,4]thiazepin-7(4H, 6H, 8H)-one(4g) :
O
N
N NH
NH
S
NO2
O
Figure 29. 13CNMR of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(2-nitrophenyl)-1H-pyrazolo[3,4e][1,4]thiazepin-7(4H, 6H, 8H)-one(4g) :
O
N
N NH
NH
S
O
NO2
Figure 30. HRMS of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(2-nitrophenyl)-1H-pyrazolo[3,4e][1,4]thiazepin-7(4H, 6H, 8H)-one(4g) :
Figure 31. 1H NMR of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(3,4-dimethoxyphenyl)-1H-pyrazolo[3,4e][1,4]thiazepin-7(4H, 6H, 8H)-one(4h) :
O
N
N NH
NH
S
O
O
O
Figure 32. 13CNMR of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(3,4-dimethoxyphenyl)-1H-pyrazolo[3,4e][1,4]thiazepin-7(4H, 6H, 8H)-one(4h) :
O
N
N NH
NH
S
O
O
O
Figure 33. HRMS of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(3,4-dimethoxyphenyl)-1H-pyrazolo[3, 4e][1,4]thiazepin-7(4H, 6H, 8H)-one(4h) :
O
N
N NH
NH
S
O
O
C21H22N4O4S
Exact Mass: 426.1362
O
Figure 34. 1H NMR of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(2, 4, 6-trimethoxyphenyl)-1H-pyrazolo[3,4e][1,4]thiazepin-7(4H, 6H, 8H)-one (4i) :
O
N
N NH
O
NH
O
S
O
O
Figure 35. 13CNMR of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(2, 4, 6-trimethoxyphenyl)-1H-pyrazolo[3,4e][1,4]thiazepin-7(4H, 6H, 8H)-one (4i) :
O
N
O
N NH
S
O
O
NH
O
Figure 36. LC-MS of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(2, 4, 6-trimethoxyphenyl)-1H-pyrazolo[3,4e][1,4]thiazepin-7(4H, 6H, 8H)-one (4i) :
Figure 37. 1HNMR of 4-(4-chlorophenyl)-3-(2-methoxy-6-methylpyridin-3-yl)-1H-pyrazolo[3,4e][1,4]thiazepin-7(4H,6H,8H)-one (4j):
O
N
N NH
NH
S
Cl
O
Figure 38. 13CNMR of 4-(4-chlorophenyl)-3-(2-methoxy-6-methylpyridin-3-yl)-1H-pyrazolo[3,4e][1,4]thiazepin-7(4H,6H,8H)-one (4j):
O
N
N NH
NH
S
Cl
O
Figure 39. HRMS of 4-(4-chlorophenyl)-3-(2-methoxy-6-methylpyridin-3-yl)-1H-pyrazolo[3,4e][1,4]thiazepin-7(4H,6H,8H)-one (4j):
O
N
N NH
NH
S
Cl
C19H17ClN4O2S
Exact Mass: 400.0761
O
Figure 40. 1HNMR of 4-(2-fluorophenyl)-3-(2-methoxy-6-methylpyridin-3-yl)-1H-pyrazolo[3,4e][1,4]thiazepin-7(4H, 6H, 8H)-one(4k):
O
N
N NH
NH
S
F
O
Figure 41. 13CNMR of 4-(2-fluorophenyl)-3-(2-methoxy-6-methylpyridin-3-yl)-1H-pyrazolo[3,4e][1,4]thiazepin-7(4H, 6H, 8H)-one(4k):
O
N
N NH
NH
S
F
O
Figure 42. HRMS of 4-(2-fluorophenyl)-3-(2-methoxy-6-methylpyridin-3-yl)-1H-pyrazolo[3,4e][1,4]thiazepin-7(4H, 6H, 8H)-one(4k):
O
N
N NH
NH
S
O
F
C19H17FN4O2S
Exact Mass: 384.1056
Figure 43. 1HNMR of 3-(2-methoxy-6-methylpyridin-3-yl)-4-p-tolyl-1H-pyrazolo[3,4-e][1,4]thiazepin7(4H, 6H, 8H)-one (4l) :
O
N
N NH
NH
S
O
Figure 44. 1HNMR expansion of 3-(2-methoxy-6-methylpyridin-3-yl)-4-p-tolyl-1H-pyrazolo[3,4e][1,4]thiazepin-7(4H, 6H, 8H)-one (4l) :
O
N
N NH
NH
S
O
Figure 45. 1HNMR expansion of 3-(2-methoxy-6-methylpyridin-3-yl)-4-p-tolyl-1H-pyrazolo[3,4e][1,4]thiazepin-7(4H, 6H, 8H)-one (4l) :
O
N
N NH
NH
S
O
Figure 56. 13 CNMR of 3-(2-methoxy-6-methylpyridin-3-yl)-4-p-tolyl-1H-pyrazolo[3,4-e][1,4]thiazepin7(4H, 6H, 8H)-one (4l) :
O
N
N NH
NH
S
O
Figure 67. HRMS of 3-(2-methoxy-6-methylpyridin-3-yl)-4-p-tolyl-1H-pyrazolo[3,4-e][1,4]thiazepin-7(4H,
6H, 8H)-one (4l) :
O
N
N NH
NH
S
C20H20N4O2S
Exact Mass: 380.1307
O
Figure 78. 1HNMR of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(4-methoxyphenyl)-1H-pyrazolo [3, 4e][1,4]thiazepin-7(4H, 6H, 8H)-one (4m):
O
N
N NH
NH
S
H3CO
O
Figure 49. 1HNMR expansion of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(4-methoxyphenyl)-1H-pyrazolo
[3, 4-e] [1,4]thiazepin-7(4H, 6H, 8H)-one (4m):
O
N
N NH
NH
S
H3CO
O
Figure 50. 1HNMR expansion of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(4-methoxyphenyl)-1H-pyrazolo
[3, 4-e] [1,4]thiazepin-7(4H, 6H, 8H)-one (4m):
O
N
N NH
NH
S
H3CO
O
Figure 51. 13CNMR of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(4-methoxyphenyl)-1H-pyrazolo [3, 4-e] [1,
4] thiazepin-7(4H, 6H, 8H)-one (4m):
O
N
N NH
NH
S
H3CO
O
Figure 52. HRMS of 3-(2-methoxy-6-methylpyridin-3-yl)-4-(4-methoxyphenyl)-1H-pyrazolo [3, 4-e] [1, 4]
thiazepin-7(4H, 6H, 8H)-one (4m):
O
N
N NH
NH
S
H3CO
C20H20N4O3S
Exact Mass: 396.1256
O
Figure 53 1HNMR spectrum of methyl 2-methoxy-6-methylpyridine-3-carboxylate (compound 1):
O
OCH3
N
OCH3
Figure 54. 13CNMR spectrum of methyl 2-methoxy-6-methylpyridine-3-carboxylate (compound 1):
O
OCH3
N
OCH3
Figure 55 LC-MS spectrum of methyl 2-methoxy-6-methylpyridine-3-carboxylate (compound 1):
O
OCH3
N
OCH3
C9H11NO3
Exact Mass: 181.0739
Figure 86. 1H NMR of 3-(2-methoxy-6-methylpyridin-3-yl)-1H-pyrazol-5-amine (compound 2):
O
N
N NH
NH2
Figure 97. 13CNMR of 3-(2-methoxy-6-methylpyridin-3-yl)-1H-pyrazol-5-amine (compound 2):
O
N
N NH
NH2
Figure 108. HRMS of 3-(2-methoxy-6-methylpyridin-3-yl)-1H-pyrazol-5-amine ( compound 2):
NH2
NH
N
N
OCH3
Chemical Formula: C10H12N4O
Exact Mass: 204.10