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Synlett 2022; 33(14): 1468-1472
DOI: 10.1055/s-0040-1719897
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Organic Chemistry in Thailand

Direct Synthesis of N-Monosubstituted Benzimidazol-2-ones via Ph3P–I2-Mediated Reaction of Hydroxamic Acids

Nittaya Wiriya
a   Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai, 50200, Thailand
,
Dolnapa Yamano
a   Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai, 50200, Thailand
,
Surat Hongsibsong
b   Environmental, Occupational Health Sciences and Non Communicable Diseases Center of Excellence, Chiang Mai University, Chiang Mai, 50200, Thailand
c   School of Health Science Research, Research Institute for Health Science, Chiang Mai University, Chiang Mai, 50200, Thailand
,
Mookda Pattarawarapan
a   Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai, 50200, Thailand
b   Environmental, Occupational Health Sciences and Non Communicable Diseases Center of Excellence, Chiang Mai University, Chiang Mai, 50200, Thailand
d   Research Center on Chemistry for Development of Health Promoting Products from Northern Resources, Faculty of Science, Chiang Mai University, Chiang Mai, 50200, Thailand
,
Wong Phakhodee  ∗
a   Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai, 50200, Thailand
b   Environmental, Occupational Health Sciences and Non Communicable Diseases Center of Excellence, Chiang Mai University, Chiang Mai, 50200, Thailand
d   Research Center on Chemistry for Development of Health Promoting Products from Northern Resources, Faculty of Science, Chiang Mai University, Chiang Mai, 50200, Thailand
› Author AffiliationsThis work is partially supported by Chiang Mai University, Thailand and the Thailand Research Fund through the Royal Golden Jubilee Ph.D. Program [PHD/0072/2559 (N.W.) and PHD/0023/2559 (D.Y.)].
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Abstract

A facile approach for the synthesis of benzimidazolones via a Ph3P–I2 promoted reaction of hydroxamic acids is reported. Upon Lossen-type rearrangement of the O-activated hydroxamic acids, the in situ generated isocyanates undergo an intramolecular attack by ortho N-nucleophiles producing the cyclized products in good yields under mild conditions. The method allows the direct preparation of a single regioisomer of N-monosubstituted derivatives using readily accessible starting materials and low-cost reagents with broad substrate scope.

Key words

benzimidazol-2-ones - hydroxamic acids - triphenylphosphine - iodine - Lossen rearrangement

Supporting Information

    Supplementary data (NMR spectra for all products) can be found in the online version, at doi: Supporting information for this article is available online at https://doi.org/10.1055/s-0040-1719897.
  • Supporting Information


Publication History

Received: 23 December 2021

Accepted after revision: 26 January 2022

Article published online:
14 February 2022

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  • 20 General Procedure for the Synthesis of Hydroxamic Acid 1To a solution of N-substituted isatoic anhydride (0.613 mmol) in ethanol (5 mL) was added hydroxylamine hydrochloride (1.839 mmol) and sodium hydroxide (3.06 mmol) at 0 °C. After that, a few drops of water were added, and the reaction mixture was sonicated for 5 min before stirring at room temperature for 2–4 h. The crude mixture was concentrated under reduced pressure before dissolving in water. The pH was adjusted to 7 using 1 M HCl then extracted with EtOAc (3 × 10 mL). The combined organic layer was dried over anhydrous Na2SO4 before concentrated and purified by column chromatography (CC) using ethyl acetate/hexanes as the eluent. N-Hydroxy-2-[(4-vinylbenzyl)amino]benzamide (1a)White solid; mp 146–147 °C. 1H NMR (500 MHz, CDCl3): δ = 8.52 (s, 1 H), 7.34 (d, J = 8.5 Hz, 2 H), 7.30–7.25 (m, 4 H), 6.68 (dd, J = 17.5, 11.0 Hz, 1 H), 6.63 (dd, J = 8.5, 1.0 Hz, 1 H), 6.59 (td, J = 7.4, 1.0 Hz, 1 H), 5.71 (dd, J = 17.5, 1.0 Hz, 1 H), 5.22 (dd, J = 11.0, 1.0 Hz, 1 H), 4.38 (s, 2 H). 13C{1H} NMR (125 MHz, CDCl3): δ = 169.5, 149.3, 138.4, 136.6, 136.5, 133.8, 127.3, 127.0, 126.5, 115.5, 113.7, 112.4, 111.3, 46.9.
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  • 22 General Procedure for the Synthesis of Benzimidazolones 2To a solution of iodine (0.1514 g, 0.597 mmol) and triphenylphosphine (0.1566 g, 0.597 mmol) in freshly distilled dichloromethane (3 mL) was added hydroxamic acid 1 (0.398 mmol) at 0 °C under N2. After mixing for 5 min, triethylamine (0.22 mL, 1.59 mmol) was added before warming up to room temperature with continuous stirring. After completion of the reaction (2–16 h), the crude mixture was concentrated under reduced pressure before purification by column chromatography (CC) using ethyl acetate/hexanes as the eluent. Note: Six new compounds including 2a–f were fully characterized, while the spectral data of other known products were matched with the previously reported data. 1-(4-Vinylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (2a, Scheme [2])White solid (0.0817 g, 82% yield); mp 179–180 °C;Rf = 0.36 (40% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3): δ = 9.63 (s, 1 H), 7.36 (d, J = 8.5 Hz, 2 H), 7.29 (d, J = 8.5 Hz, 2 H), 7.11 (dd, J = 8.0, 1.5 Hz, 1 H), 7.02 (td, J = 8.0, 1.5 Hz, 1 H), 6.99 (td, J = 8.0, 1.5 Hz, 1 H), 6.86 (d, J = 8.0 Hz, 1 H), 6.68 (dd, J = 17.5, 11.0 Hz, 1 H), 5.71 (dd, J = 17.5, 1.0 Hz, 1 H), 5.23 (dd, J = 11.0, 1.0 Hz, 1 H), 5.08 (s, 2 H). 13C NMR{1H} (125 MHz, CDCl3): δ = 155.6, 137.1, 136.3, 135.7, 130.2, 127.9, 127.6, 126.6, 121.7, 121.4, 114.1, 109.6, 108.6, 44.3. HRMS (ESI/QTOF): m/z [M + H]+ calcd for C16H15N2O: 251.1179; found: 251.1183.6 -Methyl-1-(4-vinylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (2b, Scheme [2])White solid(0.0915 g, 87% yield); mp 179–181 °C;Rf = 0.35 (40% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3): δ = 9.11 (s, 1 H), 7.35 (d, J = 8.0 Hz, 2 H), 7.27 (d, J = 8.0 Hz, 3 H), 6.92 (s, 1 H), 6.80 (d, J = 8.0 Hz, 1 H), 6.72 (d, J = 8.0 Hz, 1 H), 6.67 (dd, J = 17.5, 11.0 Hz, 1 H), 5.71 (dd, J = 17.5, 1.0 Hz, 1 H), 5.22 (dd, J = 11.0, 1.0 Hz, 1 H), 5.05 (s, 2 H), 2.34 (s, 3 H). 13C NMR{1H} (125 MHz, CDCl3): δ = 155.5, 137.1, 136.3, 135.8, 131.6, 128.01, 127.88, 127.6, 126.6, 122.0, 114.1, 110.1, 108.3, 44.3, 21.4. HRMS (ESI/QTOF): m/z [M + H]+ calcd for C17H17N2O: 265.1335; found: 265.1335.5-Chloro-1-(4-vinylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (2c, Scheme [2])White solid(0.0884 g, 78% yield); mp 185–186 °C;Rf = 0.36 (40% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3): δ = 9.78 (s, 1 H), 7.37 (d, J = 8.0 Hz, 2 H), 7.27 (d, J = 8.0 Hz, 2 H), 7.11 (d, J = 2.0 Hz, 1 H), 6.97 (dd, J = 8.5, 2.0 Hz, 1 H), 6.75 (d, J = 8.5 Hz, 1 H), 6.68 (dd, J = 17.5, 11.0 Hz, 1 H), 5.72 (dd, J = 17.5, 1.0 Hz, 1 H), 5.24 (dd, J = 11.0, 1.0 Hz, 1 H), 5.05 (s, 2 H). 13C NMR{1H} (125 MHz, CDCl3): δ = 155.5, 137.3, 136.2, 135.2, 128.73, 128.69, 127.6, 127.3, 126.7, 121.5, 114.3, 110.1, 109.3, 44.4. HRMS (ESI/QTOF): m/z [M + H]+ calcd for C16H14ClN2O: 285.0789; found: 285.0791.5-Fluoro-1-(4-vinylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (2d, Scheme [2])White solid(0.0694 g, 65% yield); mp 160–161 °C;Rf = 0.38 (40% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3): δ = 9.70 (s, 1 H), 7.37 (d, J = 8.5 Hz, 2 H), 7.27 (d, J = 8.5 Hz, 2 H), 6.87 (dd, J = 8.5, 2.5 Hz, 1 H), 6.76–6.65 (m, 3 H), 5.72 (d, J = 17.5 Hz, 1 H), 5.24 (d, J = 11.0 Hz, 1 H), 5.06 (s, 2 H). 13C NMR{1H} (125 MHz, CDCl3): δ = 159.80, 157.91 (d, 1JCF = 236.6 Hz), 155.8, 137.3, 136.2, 135.3, 128.41, 128.31(d, 3JCF = 12.6 Hz), 127.6, 126.7, 126.3, 114.3, 108.85, 108.78 (d, 3JCF = 9.5 Hz), 108.11, 107.92 (d, 2JCF = 24.0 Hz), 98.08, 97.86 (d, 2JCF = 28.3 Hz), 44.4. HRMS (ESI/QTOF): m/z [M + H]+ calcd for C16H14FN2O: 269.1085; found: 269.1085.5-Nitro-1-(4-vinylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (2e, Scheme [2])White solid(0.0586 g, 57% yield); mp 215–216 °C;Rf = 0.35 (40% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3): δ = 10.13 (s, 1 H), 8.03 (s, 1 H), 8.02 (dd, J = 9.5, 2.0 Hz, 1 H), 7.39 (d, J = 8.5 Hz, 2 H), 7.29 (d, J = 8.5 Hz, 2 H), 6.94 (d, J = 8.5 Hz, 1 H), 6.68 (dd, J = 17.5, 11.0 Hz, 1 H), 5.73 (dd, J = 17.5, 1.0 Hz, 1 H), 5.26 (dd, J = 11.0, 1.0 Hz, 1 H), 5.13 (s, 2 H). 13C NMR{1H} (125 MHz, CDCl3): δ = 155.8, 143.0, 137.7, 136.0, 135.1, 134.3, 127.73, 127.68, 126.88, 118.6, 114.7, 107.9, 105.6, 44.8. HRMS (ESI/QTOF): m/z [M + H]+ calcd for C16H14N3O3: 296.1030; found: 296.1028.5,6-Dichloro-1-(4-vinylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (2f, Scheme [2])White solid(0.1029 g, 81% yield); mp 241–242 °C;Rf = 0.38 (40% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3 + CD3OD): δ = 7.38 (d, J = 8.0 Hz, 2 H), 7.24 (d, J = 8.0 Hz, 1 H), 7.14 (s, 1 H), 6.91 (s, 1 H), 6.69 (dd, J = 17.5, 11.0 Hz, 1 H), 5.73 (dd, J = 17.5, 1.0 Hz, 1 H), 5.25 (dd, J = 11.0, 1.0 Hz, 1 H), 4.99 (s, 2 H). 13C NMR{1H} (125 MHz, CDCl3 + CD3OD): δ = 155.3, 137.4, 136.1, 134.8, 129.6, 127.5, 126.7, 125.3, 124.9, 114.4, 111.0, 109.9, 44.4. HRMS (ESI/QTOF): m/z [M + H]+ calcd for C16H13Cl2N2O: 319.0399; found: 319.0403.
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