Synthesis of sulfanyl derivatives of 1,2,4-triazoles via an acid catalyzed intramolecular cyclization of isothiosemicarbazones: structural characterization, E/Z isomerism, mechanistic insights and in vitro cytotoxicity
Snisha, Kallivalappil; Karthikeyan, Mano Chitra; Bhuvanesh, Nattamai; Arockiam, Antony Joseph Velanganni; Karvembu, Ramasamy; RSC Advances 16 (2026) 13433–13446; doi:10.1039/D6RA00822D

data_7251782
_publ_section_title
;
 Synthesis of sulfanyl derivatives of 1,2,4-triazoles via an acid
 catalyzed intramolecular cyclization of isothiosemicarbazones: structural
 characterization, E/Z isomerism, mechanistic insights and in vitro
 cytotoxicity
;
_journal_issue                   15
_journal_name_full               'RSC Advances'
_journal_page_first              13433
_journal_page_last               13446
_journal_paper_doi               10.1039/D6RA00822D
_journal_volume                  16
_journal_year                    2026
_chemical_formula_moiety         'C16 H16 N4 O2 S'
_chemical_formula_sum            'C16 H16 N4 O2 S'
_chemical_formula_weight         328.39
_space_group_crystal_system      monoclinic
_space_group_IT_number           4
_space_group_name_Hall           'P 2yb'
_space_group_name_H-M_alt        'P 1 21 1'
_atom_sites_solution_hydrogens   mixed
_atom_sites_solution_primary     dual
_audit_creation_date             2024-07-15
_audit_creation_method
;
Olex2 1.5
(compiled 2023.08.24 svn.re1ec1418 for OlexSys, GUI svn.r6817)
;
_audit_update_record
;
2025-11-28 deposited with the CCDC.	2026-03-04 downloaded from the CCDC.
;
_cell_angle_alpha                90
_cell_angle_beta                 90.8380(10)
_cell_angle_gamma                90
_cell_formula_units_Z            2
_cell_length_a                   9.24200(10)
_cell_length_b                   4.94600(10)
_cell_length_c                   17.0656(2)
_cell_measurement_reflns_used    12123
_cell_measurement_temperature    100.00(10)
_cell_measurement_theta_max      78.5650
_cell_measurement_theta_min      2.5620
_cell_volume                     780.00(2)
_computing_cell_refinement       'CrysAlisPro 1.171.43.98a (Rigaku OD, 2023)'
_computing_data_collection
'CrysAlisPro system (CCD 43.128a 64-bit (release 20-06-2024))'
_computing_data_reduction        'CrysAlisPro 1.171.43.98a (Rigaku OD, 2023)'
_computing_molecular_graphics    'Olex2 1.5 (Dolomanov et al., 2009)'
_computing_publication_material  'Olex2 1.5 (Dolomanov et al., 2009)'
_computing_structure_refinement  'SHELXL 2019/1 (Sheldrick, 2015)'
_computing_structure_solution    'SHELXT  (Sheldrick, 2015)'
_diffrn_ambient_environment      N~2~
_diffrn_ambient_temperature      100.00(10)
_diffrn_detector                 'Hybrid Pixel Array Detector'
_diffrn_detector_area_resol_mean 10.0000
_diffrn_detector_type            HyPix
_diffrn_measured_fraction_theta_full 1.000
_diffrn_measured_fraction_theta_max 0.998
_diffrn_measurement_details
;
List of Runs (angles in degrees, time in seconds):

  # Type    Start    End  Width  t~exp~   \w     \q     \k     \f   Frames
  1  \w    -12.00  29.00   0.50    0.10    --  -46.62  19.00  30.00   82
  2  \w    -49.00 -23.00   0.50    0.40    --  -91.75  45.00  30.00   52
  3  \w    -12.00  29.00   0.50    0.10    --  -46.62  19.00 -60.00   82
  4  \w     -6.00  30.00   0.50    0.10    --  -46.62  15.00-125.00   72
  5  \w     32.00 120.00   0.50    0.10    --   46.62  38.00 -60.00  176
  6  \w     32.00 120.00   0.50    0.10    --   46.62  38.00 -60.00  176
  7  \w     32.00 120.00   0.50    0.10    --   46.62  38.00  30.00  176
  8  \w     29.00 123.00   0.50    0.10    --   46.62  15.00-125.00  188
  9  \w     96.00 176.00   0.50    0.40    --  113.25  15.00-125.00  160
 10  \w    143.00 169.00   0.50    0.40    --  113.25  61.00 -60.00   52
 11  \w    112.00 167.00   0.50    0.40    --  113.25  77.00   0.00  110
 12  \w    109.00 135.00   0.50    0.40    --  113.25  61.00 -60.00   52
 13  \w    108.00 134.00   0.50    0.40    --  113.25  61.00  30.00   52
 14  \w    121.00 147.00   0.50    0.40    --  113.25  77.00  60.00   52
 15  \w    147.00 178.00   0.50    0.40    --  113.25  77.00 120.00   62
 16  \w    117.00 142.00   0.50    0.40    --  113.25  77.00 120.00   50
 17  \w    118.00 177.00   0.50    0.40    --  113.25  61.00 -30.00  118
 18  \w    101.00 126.00   0.50    0.40    --  113.25  45.00 -60.00   50
 19  \w     99.00 133.00   0.50    0.40    --  113.25  45.00 -90.00   68
 20  \w    145.00 178.00   0.50    0.40    --  113.25  45.00 -90.00   66
 21  \w    108.00 134.00   0.50    0.40    --  113.25  45.00 -30.00   52
 22  \w    103.00 128.00   0.50    0.40    --  113.25  30.00   0.00   50
 23  \w    102.00 128.00   0.50    0.40    --  113.25  30.00  30.00   52
 24  \w    105.00 131.00   0.50    0.40    --  113.25  45.00  60.00   52
 25  \w    147.00 177.00   0.50    0.40    --  113.25  45.00  60.00   60
 26  \w    144.00 175.00   0.50    0.40    --  113.25  15.00 -60.00   62
 27  \w     96.00 176.00   0.50    0.40    --  113.25  15.00-125.00  160
 28  \w     47.00  74.00   0.50    0.40    --  113.25 -61.00-180.00   54
 29  \w     43.00  75.00   0.50    0.40    --  113.25 -61.00-120.00   64
 30  \w     41.00  74.00   0.50    0.40    --  113.25 -61.00 -60.00   66
 31  \w     41.00  75.00   0.50    0.40    --  113.25 -61.00   0.00   68
 32  \w    -28.00   6.00   0.50    0.10    --   46.62 -15.00  63.00   68
 33  \w     42.00  71.00   0.50    0.40    --  113.25 -61.00 120.00   58
 34  \w     41.00  74.00   0.50    0.40    --  113.25 -61.00  90.00   66
 35  \w     47.00  73.00   0.50    0.40    --  113.25 -95.00 150.00   52
 36  \w     50.00  90.00   0.50    0.40    --  113.25-125.00  90.00   80
 37  \w     66.00 103.00   0.50    0.40    --  113.25 -95.00   0.00   74
 38  \w     64.00 105.00   0.50    0.40    --  113.25 -95.00 -30.00   82
 39  \w     67.00 109.00   0.50    0.40    --  113.25-125.00 -30.00   84
 40  \w     34.00  93.00   0.50    0.10    --   46.62-125.00-120.00  118
 41  \w   -122.00 -29.00   0.50    0.10    --  -46.62 -15.00  63.00  186
 42  \w   -119.00 -31.00   0.50    0.10    --  -46.62 -46.00 -51.70  176
 43  \w   -118.00 -31.00   0.50    0.10    --  -46.62 -47.00-110.98  174
 44  \w   -119.00 -31.00   0.50    0.10    --  -46.62 -46.00 -51.70  176
 45  \w   -119.00 -31.00   0.50    0.10    --  -46.62 -44.00-153.17  176
 46  \w    -47.00 -22.00   0.50    0.40    --  -91.75 125.00 -60.00   50
 47  \w    -85.00 -22.00   0.50    0.40    --  -91.75 125.00 -60.00  126
 48  \w   -167.00 -74.00   0.50    0.40    --  -91.75 -15.00  63.00  186
 49  \w   -107.00 -81.00   0.50    0.40    --  -91.75 -47.00  12.76   52
 50  \w   -103.00 -77.00   0.50    0.40    --  -91.75 -46.00   2.82   52
 51  \w   -103.00 -77.00   0.50    0.40    --  -91.75 -46.00  -0.70   52
 52  \w   -110.00 -84.00   0.50    0.40    --  -91.75 -47.00 -77.05   52
 53  \w   -114.00 -88.00   0.50    0.40    --  -91.75 -48.00 -95.51   52
 54  \w   -117.00 -79.00   0.50    0.40    --  -91.75 -45.00-120.00   76
 55  \w   -115.00 -86.00   0.50    0.40    --  -91.75 -47.00 -64.23   58
 56  \w   -111.00 -85.00   0.50    0.40    --  -91.75 -45.00 -60.00   52
 57  \w   -164.00 -77.00   0.50    0.40    --  -91.75 -45.00 -90.00  174
 58  \w   -164.00 -77.00   0.50    0.40    --  -91.75 -45.00 -34.44  174
 59  \w   -102.00 -77.00   0.50    0.40    --  -91.75 -42.00 -54.19   50
 60  \w   -104.00 -77.00   0.50    0.40    --  -91.75 -45.00 -19.54   54
 61  \w   -102.00 -77.00   0.50    0.40    --  -91.75 -37.00  -0.96   50
 62  \w   -164.00-138.00   0.50    0.40    --  -91.75 -37.00  -0.96   52
 63  \w   -104.00 -78.00   0.50    0.40    --  -91.75 -37.00-145.83   52
;
_diffrn_measurement_device       'four-circle diffractometer'
_diffrn_measurement_device_type  'XtaLAB Synergy, Dualflex, HyPix'
_diffrn_measurement_method       '\w scans'
_diffrn_orient_matrix_type
'CrysAlisPro convention (1999,Acta A55,543-557)'
_diffrn_orient_matrix_UB_11      0.1563599000
_diffrn_orient_matrix_UB_12      0.0541265000
_diffrn_orient_matrix_UB_13      0.0283589000
_diffrn_orient_matrix_UB_21      0.0534679000
_diffrn_orient_matrix_UB_22      -0.0321241000
_diffrn_orient_matrix_UB_23      -0.0845707000
_diffrn_orient_matrix_UB_31      -0.0221250000
_diffrn_orient_matrix_UB_32      0.3050690000
_diffrn_orient_matrix_UB_33      -0.0138652000
_diffrn_radiation_monochromator  mirror
_diffrn_radiation_probe          x-ray
_diffrn_radiation_type           'Cu K\a'
_diffrn_radiation_wavelength     1.54184
_diffrn_reflns_av_R_equivalents  0.0241
_diffrn_reflns_av_unetI/netI     0.0170
_diffrn_reflns_Laue_measured_fraction_full 1.000
_diffrn_reflns_Laue_measured_fraction_max 0.998
_diffrn_reflns_limit_h_max       11
_diffrn_reflns_limit_h_min       -11
_diffrn_reflns_limit_k_max       6
_diffrn_reflns_limit_k_min       -4
_diffrn_reflns_limit_l_max       20
_diffrn_reflns_limit_l_min       -21
_diffrn_reflns_number            14972
_diffrn_reflns_point_group_measured_fraction_full 0.948
_diffrn_reflns_point_group_measured_fraction_max 0.932
_diffrn_reflns_theta_full        67.684
_diffrn_reflns_theta_max         74.431
_diffrn_reflns_theta_min         2.589
_diffrn_source                   'micro-focus sealed X-ray tube'
_diffrn_source_current           '1 mA'
_diffrn_source_type              'PhotonJet (Cu) X-ray Source'
_diffrn_source_voltage           '50 kV'
_exptl_absorpt_coefficient_mu    1.979
_exptl_absorpt_correction_T_max  1.000
_exptl_absorpt_correction_T_min  0.573
_exptl_absorpt_correction_type   gaussian
_exptl_absorpt_process_details
;
CrysAlisPro 1.171.43.98a (Rigaku Oxford Diffraction, 2023) 
Numerical absorption correction based on gaussian integration over 
a multifaceted crystal model 
Empirical absorption correction using spherical harmonics, 
implemented in SCALE3 ABSPACK scaling algorithm.
;
_exptl_crystal_colour            orange
_exptl_crystal_colour_primary    orange
_exptl_crystal_density_diffrn    1.398
_exptl_crystal_description       needle
_exptl_crystal_F_000             344
_exptl_crystal_size_max          0.497
_exptl_crystal_size_mid          0.053
_exptl_crystal_size_min          0.043
_refine_diff_density_max         0.260
_refine_diff_density_min         -0.205
_refine_diff_density_rms         0.037
_refine_ls_abs_structure_details
;
 Flack x determined using 1167 quotients [(I+)-(I-)]/[(I+)+(I-)]
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
;
_refine_ls_abs_structure_Flack   0.000(8)
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.054
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     209
_refine_ls_number_reflns         2972
_refine_ls_number_restraints     1
_refine_ls_restrained_S_all      1.054
_refine_ls_R_factor_all          0.0239
_refine_ls_R_factor_gt           0.0235
_refine_ls_shift/su_max          0.000
_refine_ls_shift/su_mean         0.000
_refine_ls_structure_factor_coef Fsqd
_refine_ls_weighting_details
'w=1/[\s^2^(Fo^2^)+(0.0401P)^2^+0.1496P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.0638
_refine_ls_wR_factor_ref         0.0642
_reflns_Friedel_coverage         0.665
_reflns_Friedel_fraction_full    0.882
_reflns_Friedel_fraction_max     0.848
_reflns_number_gt                2933
_reflns_number_total             2972
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            d6ra00822d2.cif
_cod_data_source_block           rk_skvtlsd
_cod_database_code               7251782
_shelx_shelxl_version_number     2019/1
_chemical_oxdiff_formula         C16H16N4O2S
_shelx_estimated_absorpt_t_max   0.920
_shelx_estimated_absorpt_t_min   0.440
_olex2_refinement_description
;
1. Fixed Uiso
 At 1.2 times of:
  All C(H) groups, All C(H,H) groups, All N(H) groups
 At 1.5 times of:
  All C(H,H,H) groups
2.a Riding coordinates:
 N3(H3)
2.b Secondary CH2 refined with riding coordinates:
 C10(H10A,H10B)
2.c Aromatic/amide H refined with riding coordinates:
 C2(H2), C4(H4), C5(H5), C7(H7), C8(H8), C12(H12), C13(H13), C14(H14),
 C15(H15), C16(H16)
2.d Idealised Me refined as rotating group:
 C9(H9A,H9B,H9C)
;
_shelx_res_checksum              45218
_olex2_exptl_crystal_mounting_method
'The crystal was mounted on a MITIGEN holder'
_olex2_submission_original_sample_id RKB_240705_SDc_SKVTLSD
_olex2_submission_special_instructions 'No special instructions were received'
_oxdiff_exptl_absorpt_empirical_details
;
Empirical correction (ABSPACK) includes:
- Absorption correction using spherical harmonics
- Frame scaling
- Detector area scaling
;
_oxdiff_exptl_absorpt_empirical_full_max 1.171
_oxdiff_exptl_absorpt_empirical_full_min 0.869