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_7251786
_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         'Br, C16 H17 N4 O2 S, H2 O'
_chemical_formula_sum            'C16 H19 Br N4 O3 S'
_chemical_formula_weight         427.32
_space_group_crystal_system      triclinic
_space_group_IT_number           2
_space_group_name_Hall           '-P 1'
_space_group_name_H-M_alt        'P -1'
_atom_sites_solution_hydrogens   mixed
_atom_sites_solution_primary     dual
_audit_creation_date             2024-05-22
_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                83.8980(10)
_cell_angle_beta                 78.1950(10)
_cell_angle_gamma                71.0320(10)
_cell_formula_units_Z            2
_cell_length_a                   6.81290(10)
_cell_length_b                   9.15510(10)
_cell_length_c                   15.64500(10)
_cell_measurement_reflns_used    27598
_cell_measurement_temperature    100.00(10)
_cell_measurement_theta_max      79.4190
_cell_measurement_theta_min      5.1130
_cell_volume                     902.482(19)
_computing_cell_refinement       'CrysAlisPro 1.171.43.98a (Rigaku OD, 2023)'
_computing_data_collection
'CrysAlisPro system (CCD 43.103a 64-bit (release 20-12-2023))'
_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 2018/2 (Sheldrick, 2018)'
_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 0.999
_diffrn_measured_fraction_theta_max 0.996
_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      0.00  28.00   0.50    0.10    --   18.00  65.00 159.76   56
  2  \w     -6.00  22.00   0.50    0.10    --   14.00  70.00  75.77   56
  3  \w      5.00  31.00   0.50    0.10    --   22.00  62.00 -11.22   52
  4  \w     35.00 119.00   0.50    0.10    --   47.91  47.00  21.07  168
  5  \w     35.00 119.00   0.50    0.10    --   47.91  47.00-164.40  168
  6  \w     42.00  67.00   0.50    0.40    --  113.25 -61.00   0.00   50
  7  \w     43.00  73.00   0.50    0.40    --  113.25 -61.00 -60.00   60
  8  \w     42.00  68.00   0.50    0.40    --  113.25 -61.00 -30.00   52
  9  \w     43.00  74.00   0.50    0.40    --  113.25 -61.00 120.00   62
 10  \w     41.00 102.00   0.50    0.10    --   47.91-137.00 156.00  122
 11  \w     42.00 121.00   0.50    0.40    --  113.25-137.00 156.00  158
 12  \w     42.00 121.00   0.50    0.40    --  113.25-137.00 156.00  158
 13  \w     39.00  99.00   0.50    0.10    --   47.91-133.00 -25.00  120
 14  \w     82.00 107.00   0.50    0.40    --  113.25-125.00-150.00   50
 15  \w     50.00  76.00   0.50    0.40    --  113.25-125.00-150.00   52
 16  \w     49.00  75.00   0.50    0.40    --  113.25-125.00 -90.00   52
 17  \w     45.00  75.00   0.50    0.40    --  113.25-125.00 -60.00   60
 18  \w     43.00 117.00   0.50    0.40    --  113.25-133.00 -25.00  148
 19  \w     79.00 106.00   0.50    0.40    --  113.25-125.00  90.00   54
 20  \w     83.00 110.00   0.50    0.40    --  113.25-125.00 120.00   54
 21  \w     44.00  69.00   0.50    0.40    --  113.25-125.00 120.00   50
 22  \w     43.00  69.00   0.50    0.40    --  113.25 -95.00 150.00   52
 23  \w     73.00  99.00   0.50    0.40    --  113.25 -95.00 150.00   52
 24  \w     45.00  73.00   0.50    0.40    --  113.25-125.00  90.00   56
 25  \w     46.00  72.00   0.50    0.40    --  113.25 -95.00  90.00   52
 26  \w     78.00 105.00   0.50    0.40    --  113.25 -95.00  90.00   54
 27  \w     78.00 104.00   0.50    0.40    --  113.25 -95.00 120.00   52
 28  \w     75.00 106.00   0.50    0.40    --  113.25 -95.00 -60.00   62
 29  \w     49.00  89.00   0.50    0.40    --  110.00 -88.00-106.00   80
 30  \w     56.00 106.00   0.50    0.40    --  113.25 -95.00-150.00  100
 31  \w    102.00 133.00   0.50    0.40    --  110.00 -88.00-106.00   62
 32  \w    103.00 159.00   0.50    0.40    --  113.25  45.00-180.00  112
 33  \w    112.00 175.00   0.50    0.40    --  113.25  77.00 -30.00  126
 34  \w    139.00 177.00   0.50    0.40    --  113.25  61.00   0.00   76
 35  \w    106.00 133.00   0.50    0.40    --  113.25  61.00   0.00   54
 36  \w    110.00 140.00   0.50    0.40    --  113.25  77.00  60.00   60
 37  \w    141.00 167.00   0.50    0.40    --  113.25  61.00 150.00   52
 38  \w    106.00 134.00   0.50    0.40    --  113.25  61.00 150.00   56
 39  \w    108.00 178.00   0.50    0.40    --  113.25  61.00  90.00  140
 40  \w    153.00 178.00   0.50    0.40    --  113.25  61.00  60.00   50
 41  \w    152.00 178.00   0.50    0.40    --  113.25  45.00  30.00   52
 42  \w    106.00 140.00   0.50    0.40    --  113.25  61.00  60.00   68
 43  \w    150.00 177.00   0.50    0.40    --  113.25  45.00 120.00   54
 44  \w    101.00 130.00   0.50    0.40    --  113.25  45.00  30.00   58
 45  \w    103.00 140.00   0.50    0.40    --  113.25  45.00 120.00   74
 46  \w    109.00 155.00   0.50    0.40    --  113.25  61.00 -60.00   92
 47  \w    101.00 127.00   0.50    0.40    --  113.25  45.00-120.00   52
 48  \w    103.00 167.00   0.50    0.40    --  113.25  45.00-150.00  128
 49  \w    152.00 178.00   0.50    0.40    --  113.25  45.00 -90.00   52
 50  \w    106.00 176.00   0.50    0.40    --  113.25  61.00-120.00  140
 51  \w    101.00 131.00   0.50    0.40    --  113.25  45.00 -30.00   60
 52  \w    144.00 170.00   0.50    0.40    --  113.25  45.00 -30.00   52
 53  \w    103.00 131.00   0.50    0.40    --  113.25  45.00 -90.00   56
 54  \w    101.00 129.00   0.50    0.40    --  113.25  45.00 -60.00   56
 55  \w    101.00 150.00   0.50    0.40    --  113.25  45.00   0.00   98
 56  \w    101.00 127.00   0.50    0.40    --  113.25  45.00  60.00   52
 57  \w    102.00 147.00   0.50    0.40    --  113.25  45.00 150.00   90
 58  \w    118.00 158.00   0.50    0.40    --  113.25 125.00  60.00   80
 59  \w    116.00 170.00   0.50    0.40    --  113.25 125.00 150.00  108
 60  \w     90.00 178.00   0.50    0.40    --  113.25 133.00  41.00  176
 61  \w     87.00 178.00   0.50    0.40    --  113.25 137.00-140.00  182
 62  \w    -42.00 -15.00   0.50    0.10    --  -30.00 -55.00  73.01   54
 63  \w    -48.00 -20.00   0.50    0.10    --  -34.00 -52.00 137.01   56
 64  \w    -54.00 -28.00   0.50    0.10    --  -42.00 -50.00 115.87   52
 65  \w    -61.00 -28.00   0.50    0.10    --  -42.00 -48.00  29.99   66
 66  \w   -117.00 -33.00   0.50    0.10    --  -46.00 -47.00  20.04  168
 67  \w   -119.00 -35.00   0.50    0.10    --  -47.91 -46.00 -69.50  168
 68  \w    -54.00 -28.00   0.50    0.10    --  -42.00 -50.00-131.13   52
 69  \w    -54.00 -28.00   0.50    0.10    --  -42.00 -50.00-168.96   52
 70  \w   -119.00 -35.00   0.50    0.10    --  -47.91 -45.00-142.66  168
 71  \w   -119.00 -35.00   0.50    0.10    --  -47.91 -45.00-142.66  168
 72  \w   -122.00 -37.00   0.50    0.10    --  -50.00 -45.00  59.93  170
 73  \w   -122.00 -37.00   0.50    0.10    --  -50.00 -45.00  59.93  170
 74  \w   -118.00 -68.00   0.50    0.10    --  -47.91-133.00 -25.00  100
 75  \w   -161.00 -68.00   0.50    0.40    --  -91.75-133.00 -25.00  186
 76  \w   -119.00 -66.00   0.50    0.10    --  -47.91-137.00 156.00  106
 77  \w   -158.00 -66.00   0.50    0.40    --  -91.75-137.00 156.00  184
 78  \w   -104.00 -78.00   0.50    0.40    --  -91.75 -39.00 111.39   52
 79  \w   -134.00 -49.00   0.50    0.10    --  -62.00 -47.00 168.40  170
 80  \w   -134.00 -49.00   0.50    0.10    --  -62.00 -47.00 -73.60  170
 81  \w   -134.00 -49.00   0.50    0.10    --  -62.00 -47.00 -73.60  170
 82  \w   -134.00 -49.00   0.50    0.10    --  -62.00 -47.00 -26.13  170
 83  \w   -134.00 -49.00   0.50    0.10    --  -62.00 -47.00 -26.13  170
 84  \w    -91.00 -57.00   0.50    0.10    --  -70.00 -47.00-129.76   68
 85  \w   -111.00 -83.00   0.50    0.40    --  -91.75 -47.00-100.50   56
 86  \w    -90.00 -57.00   0.50    0.10    --  -70.00 -47.00  28.36   66
 87  \w   -109.00 -83.00   0.50    0.40    --  -91.75 -47.00   9.14   52
 88  \w   -112.00 -81.00   0.50    0.40    --  -91.75 -47.00 111.11   62
 89  \w   -108.00 -82.00   0.50    0.40    --  -91.75 -47.00 158.51   52
 90  \w   -138.00 -53.00   0.50    0.10    --  -66.00 -47.00 122.74  170
 91  \w   -137.00-110.00   0.50    0.10    --  -66.00 -47.00 122.74   54
 92  \w   -162.00-124.00   0.50    0.40    --  -91.75 -45.00  90.00   76
 93  \w    -96.00 -57.00   0.50    0.10    --  -70.00 -45.00  38.95   78
 94  \w   -108.00 -81.00   0.50    0.40    --  -91.75 -46.00 -10.74   54
 95  \w   -116.00 -79.00   0.50    0.40    --  -91.75 -45.00  90.00   74
 96  \w    -83.00 -57.00   0.50    0.10    --  -70.00 -45.00  71.83   52
 97  \w   -105.00 -79.00   0.50    0.40    --  -91.75 -45.00  60.00   52
 98  \w   -105.00 -79.00   0.50    0.40    --  -91.75 -45.00  30.00   52
 99  \w   -113.00 -80.00   0.50    0.40    --  -91.75 -45.00 -60.00   66
100  \w   -144.00-118.00   0.50    0.40    --  -91.75 -45.00-120.00   52
101  \w   -104.00 -79.00   0.50    0.40    --  -91.75 -45.00-150.00   50
102  \w   -106.00 -80.00   0.50    0.40    --  -91.75 -46.00-167.63   52
103  \w   -163.00-125.00   0.50    0.40    --  -91.75 -45.00-150.00   76
104  \w   -161.00-118.00   0.50    0.40    --  -91.75 -45.00 -90.00   86
105  \w   -108.00 -81.00   0.50    0.40    --  -91.75 -45.00-120.00   54
106  \w   -106.00 -80.00   0.50    0.40    --  -91.75 -45.00 -90.00   52
107  \w    -98.00 -72.00   0.50    0.40    --  -86.00 -44.00 -89.07   52
108  \w   -130.00 -44.00   0.50    0.10    --  -58.00 -44.00-170.40  172
109  \w   -126.00 -41.00   0.50    0.10    --  -54.00 -44.00  12.54  170
110  \w   -126.00 -41.00   0.50    0.10    --  -54.00 -44.00  12.54  170
111  \w    -89.00 -57.00   0.50    0.10    --  -70.00 -45.00  52.12   64
112  \w    -80.00 -54.00   0.50    0.10    --  -66.00 -44.00 136.82   52
113  \w    -94.00 -68.00   0.50    0.40    --  -82.00 -43.00 131.63   52
114  \w   -110.00 -78.00   0.50    0.40    --  -90.00 -42.00 169.05   64
115  \w   -146.00-120.00   0.50    0.40    --  -82.00 -43.00 131.63   52
116  \w    -85.00 -59.00   0.50    0.10    --  -70.00 -41.00 178.45   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      0.0676201000
_diffrn_orient_matrix_UB_12      -0.0147320000
_diffrn_orient_matrix_UB_13      -0.0996913000
_diffrn_orient_matrix_UB_21      -0.1453106000
_diffrn_orient_matrix_UB_22      0.1657733000
_diffrn_orient_matrix_UB_23      -0.0140737000
_diffrn_orient_matrix_UB_31      0.1828027000
_diffrn_orient_matrix_UB_32      0.0634157000
_diffrn_orient_matrix_UB_33      0.0014749000
_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  0.0487
_diffrn_reflns_av_unetI/netI     0.0208
_diffrn_reflns_Laue_measured_fraction_full 0.999
_diffrn_reflns_Laue_measured_fraction_max 0.996
_diffrn_reflns_limit_h_max       8
_diffrn_reflns_limit_h_min       -7
_diffrn_reflns_limit_k_max       11
_diffrn_reflns_limit_k_min       -11
_diffrn_reflns_limit_l_max       19
_diffrn_reflns_limit_l_min       -19
_diffrn_reflns_number            31293
_diffrn_reflns_point_group_measured_fraction_full 0.999
_diffrn_reflns_point_group_measured_fraction_max 0.996
_diffrn_reflns_theta_full        67.684
_diffrn_reflns_theta_max         74.501
_diffrn_reflns_theta_min         5.113
_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    4.393
_exptl_absorpt_correction_T_max  1.000
_exptl_absorpt_correction_T_min  0.556
_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            yellow
_exptl_crystal_colour_primary    yellow
_exptl_crystal_density_diffrn    1.573
_exptl_crystal_description       block
_exptl_crystal_F_000             436
_exptl_crystal_size_max          0.223
_exptl_crystal_size_mid          0.091
_exptl_crystal_size_min          0.054
_refine_diff_density_max         0.365
_refine_diff_density_min         -0.500
_refine_diff_density_rms         0.057
_refine_ls_extinction_coef       0.0014(2)
_refine_ls_extinction_expression Fc^*^=kFc[1+0.001xFc^2^\l^3^/sin(2\q)]^-1/4^
_refine_ls_extinction_method     'SHELXL-2019/1 (Sheldrick 2019)'
_refine_ls_goodness_of_fit_ref   1.067
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     228
_refine_ls_number_reflns         3698
_refine_ls_number_restraints     0
_refine_ls_restrained_S_all      1.067
_refine_ls_R_factor_all          0.0226
_refine_ls_R_factor_gt           0.0225
_refine_ls_shift/su_max          0.001
_refine_ls_shift/su_mean         0.000
_refine_ls_structure_factor_coef Fsqd
_refine_ls_weighting_details
'w=1/[\s^2^(Fo^2^)+(0.0301P)^2^+0.5131P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.0596
_refine_ls_wR_factor_ref         0.0597
_reflns_Friedel_coverage         0.000
_reflns_number_gt                3692
_reflns_number_total             3698
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            d6ra00822d2.cif
_cod_data_source_block           rk_skvtl5
_cod_database_code               7251786
_shelx_shelxl_version_number     2019/1
_chemical_oxdiff_formula         CHNOS
_shelx_estimated_absorpt_t_max   0.797
_shelx_estimated_absorpt_t_min   0.441
_olex2_refinement_description
;
1. Fixed Uiso
 At 1.2 times of:
  All C(H) groups, All C(H,H) groups, All N(H) groups, All O(H,H) groups
 At 1.5 times of:
  All C(H,H,H) groups
2.a Riding coordinates:
 N2(H2), O1W(H1WA,H1WB)
2.b Secondary CH2 refined with riding coordinates:
 C1(H1A,H1B)
2.c Aromatic/amide H refined with riding coordinates:
 N1(H1), C3(H3), C4(H4), C5(H5), C6(H6), C7(H7), C10(H10), C12(H12), C13(H13),
 C15(H15), C16(H16)
2.d Idealised Me refined as rotating group:
 C9(H9A,H9B,H9C)
;
_shelx_res_checksum              98790
_olex2_submission_original_sample_id RKB_240517_SDc_SKVTL5
_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 1.624
_oxdiff_exptl_absorpt_empirical_full_min 0.732