Recent Advances in the Synthesis and Applications of Isothiocyanates

doi:10.6023/cjoc202410008

Abstract

Isothiocyanates (ITCs) are an important class of organic compounds characterized by the functional group R—N= C=S. These functional groups are widely found in multiple natural products and pharmaceutical important drugs. Moreover, due to their high and versatile reactivity, they are widely used as an intermediate in organic synthesis. Keeping in view ITCs importance, this review summarizes their synthesis from nitrogen rich raw materials like amines, isocyanides, azides and some other compounds like oximes. Besides their synthesis, their application in organic compound synthesis as an intermediate will also be covered. Future research will likely focus on optimizing the synthesis of multifunctional isothiocyanates, understanding their complex biological mechanisms, exploring new applications, and highlighting the continued importance of isothiocyanates in modern chemistry and biotechnology.

Key words: isothiocyanates, primary amines, isocyanides, azide, isocyanates, cycloaddition

Cite this article

Zunqi Liu, Jahangir Khan, Muhammad Akram, Yasir Mumtaz. Recent Advances in the Synthesis and Applications of Isothiocyanates[J]. Chinese Journal of Organic Chemistry, 2025, 45(7): 2350-2366.

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Fig. & Tab. 53

Scheme 1. General synthetic pathways for the synthesis of ITCs

Scheme 2. ITCs synthesis from CS2 and amine in the presence of DMAP

Scheme 3. DMT/NMM/TsO－ as desulfurized agent for ITCs synthesis

Scheme 4. Synthesis of ITCs from R-NH2 and CS2 in the presence of DMAP or DABCO as a catalyst

Scheme 5. Copper catalyzed synthesis of ITCs

Scheme 6. ITCs synthesis from S8 in the presence of TMSCF3 and AgSCF3

Scheme 7. Synthesis of ITCs from RNH2 and CS2 using triphosgene as a dehydrosulfurizing agent

Scheme 8. (Me)4NSCF3, a solid sulfurizing reagent for the synthesis of ITCs

Buffer	Initial pH	Final pH	Yield/%
Buffer	Initial pH	Final pH	1a	1b
K₂HPO₄＋KH₂PO₄ (1 mol/L)	6	6.45	Trace	91
	7	7.44	5	88
	8	8.84	15	77
	9	9.45	65	22
	10	10.18	82	8

Table 1. Reaction of dithiocarbamate triethylammonium salt with methyl acrylate in aqueous buffer at different pH

Scheme 9. ITCs synthesis from amine using CBr4

Scheme 10. Synthesis of ITCs using DIB from amines

Scheme 11. (a) Reaction pathways toward the synthesis of ITCs involving S8 with isocyanide and (b) nucleophilic activation of S8

Scheme 12. Se and Te catalyzed the transformation of isocyanides to ITCs

Scheme 13. Molybdenum catalyzed the transformation of isocyanides to ITCs

Scheme 14. Molybdenum catalyzed the transformation of isocyanides to ITCs

Scheme 15. Rhodium catalyzed the transformation of isocyanides to ITCs using S8

Scheme 16. Mechanism of nucleophilic activation of S8

Scheme 17. Proposed mechanistic pathways for the synthesis of thioureas from isocyanides and amines

Scheme 18. Synthesis of ITCs using tertiary amine as a base

Scheme 19. Lawesson’s reagent catalyzed synthesis of ITCs from isocyanides

Scheme 20. Staudinger-aza-Witting reaction for the synthesis of gluco-ITCs

Scheme 21. Synthesis of N-protected amino alkyl-NCS from N-protected amino alkyl-N3

Scheme 22. Synthesis of ITCs using Lawesson’s reagent under microwave irradiation

Scheme 23. Synthesis of ITC from hydroximoyl chloride and thiourea

Figure 1. Synthetic applications of isothiocyanates

Scheme 24. Metal-free synthesis of 2-aminobenzothiazoles

Scheme 25. DBU-mediated synthesis of Z-selective heterocycles

Scheme 26. Silica gel promoted synthesis of 2-aminothiazoli- dines

Scheme 27. Synthesis of thiazolidine-2-imine via cascade alkynylation/hydrothiolation

Scheme 28. Synthesis of 2-iminothiazolidines via telescoping reaction

Scheme 29. AlCl3-catalyzed annulation of DA cyclopropanes with ITCs

Scheme 30. Metal-free synthesis of 5-amino-1,2,4-thiadiazoles

Scheme 31. Cu-catalyzed synthesis of benzosultams

Scheme 32. BF3•OEt2-catalyzed denitrogenative transannulation

Scheme 33. Denitrogenative transannulation of 1-mesyl-1,2,3- triazoles

Scheme 34. Enantioselective synthesis of pyrrolidine based heterocyles

Scheme 35. Synthesis of functionalized tetrahydroquinazolines from o-haloanilines

Scheme 36. TfOH-promoted cascade trifluromethylation/cycli- sation

Scheme 37. Ring expansion of epoxy-sulfonamides with isothiocyanates

Scheme 38. [3＋2] umpolung annulations between 1,2,3-thia- diazoles and isothiocyanates

Scheme 39. Synthesis of thio-substituted phenanthridines from 2-biaryl isothiocyanates

Scheme 40. DABCO-catalyzed synthesis of 2-iminonaphtho- 1,3-oxathioles

Figure 2. Representation of electrophilic and nucleophilic center of ITCs

Scheme 41. Stereoselective synthesis of thioamides from ITCs and organolithium

Scheme 42. Use of ITCs as electrophile for electrophilic reaction of diazole

Scheme 43. Partial reduction of ITCs to thioformamides

Scheme 44. Synthesis of thiocarbamates and thiourea from ITCs

Scheme 45. Synthesis of unsymmetrical thiourea from ITCs at room temperature

Scheme 46. Trisubstituted unsymmetrical thiourea synthesis from ITCs

Scheme 47. Synthesis of unsymmetrical thiourea

Scheme 48. Synthesis of hydrazinecarbothioamides

Scheme 49. Synthesis of thiourea from ITCs

Scheme 50. Thioformamide synthesis followed by N-difluoromethyl amide synthesis

References 114

[42]	Arisawa M.; Ashikawa M.; Suwa A.; Yamaguchi M. Tetrahedron Lett. 2005, 46, 1727.
[43]	Boyarskiy V. P.; Bokach N. A.; Luzyanin K. V.; Kukushkin V. Y. Chem. Rev. 2015, 115, 2698. doi: 10.1021/cr500380d pmid: 25740195
[44]	Chakrabarty S.; Choudhary S.; Doshi A.; Liu F. Q.; Mohan R.; Ravindra M. P.; Shah D.; Yang X.; Fleming F. F. Adv. Snyth. Catal. 2014, 356, 2135.
[45]	Adam W.; Bargon R. M. Chem. Commun. 2001, 1910.
[46]	Adam W.; Bargon R. M.; Schenk W. A. J. Am. Chem. Soc. 2003, 125, 3871.
[47]	Arisawa M.; Ichikawa T.; Yamaguchi M. Org. Lett. 2012, 14, 5318. doi: 10.1021/ol302497m pmid: 23039101
[48]	Arisawa M.; Ichikawa T.; Yamaguchi M. Chem. Commun. 2015, 51, 8821.
[49]	Arisawa M.; Ichikawa T.; Tanii S.; Yamaguchi M. Synthesis 2016, 48, 3107.
[50]	Arisawa M.; Tanaka K.; Yamaguchi M. Tetrahedron Lett. 2005, 46, 4797.
[51]	Németh A. G.; Szabó R.; Domján A.; Keserű G. M.; Ábrányi‐Balogh P. ChemistryOpen 2021, 10, 16.
[52]	Németh A. G.; Keserű G. M.; Ábrányi-Balogh P. Beilstein J. Org. Chem. 2019, 15, 1523.
[53]	Németh A. G.; Szabó R.; Orsy G.; Mándity I. M.; Keserű G. M.; Ábrányi-Balogh P. Molecules 2021, 26, 303.
[54]	[ Németh A. G.; Marlok B.; Domján A.; Gao Q.; Han X.; Keserű G. M.; Ábrányi‐Balogh P. Eur. J. Org. Chem. 2021, 25, 3587.
[55]	Nguyen T. B. Adv. Synth. Catal. 2017, 359, 1066.
[56]	Nguyen T. B. Adv. Synth. Catal. 2020, 362, 3448.
[57]	Liu S.; Deng G.-J.; Huang H. Synlett. 2021, 32, 142.
[58]	Davis R. E.; Nakshbendi H. F. J. Am. Chem. Soc. 1962, 84, 2085.
[59]	Chivers T.; Elder P. Chem. Soc. Rev. 2013, 42, 5996.
[60]	Thomson J. W.; Nagashima K.; Macdonald P. M.; Ozin G. A. Chem Soc Rev. 2011, 133, 5036.
[1]	Wu X.; Zhou Q.; Xu K. Acta Pharmacol. Sin. 2009, 30, 501.
[2]	Choudhari A. S.; Mandave P. C.; Deshpande M.; Ranjekar P.; Prakash O. Front. Pharmacol. 2020, 10, 1614.
[3]	Gupta P.; Kim B.; Kim S. H.; Srivastava S. K. Mol. Nutr. Food Res. 2014, 58, 1685.
[4]	Wang; N.; Saidhareddy; P.; Jiang, X. Nat. Prod. Rep. 2020, 37, 246.
[5]	Hanschen F. S.; Lamy E.; Schreiner M.; Rohn S. Angew. Chem., Int. Ed. 2014, 53, 11430.
[6]	Sugiyama R.; Li R.; Kuwahara A.; Nakabayashi R.; Sotta N.; Mori T.; Ito T.; Ohkama-Ohtsu N.; Fujiwara T.; Saito K.; Nakano R. T.; Bednarek P.; Hirai M. Y. Proc. Natl. Acad. Sci. 2021, 118, e2017890118.
[7]	Tarozzi A.; Angeloni C.; Malaguti M.; Morroni F.; Hrelia S.; Hrelia P. Oxid. Med. Cell. Longevity 2013, 2013, 415078.
[8]	Lawson A. P.; Long M. J.; Coffey R. T.; Qian Y.; Weerapana E.; El Oualid F.; Hedstrom L. Cancer Res. 2015, 75, 5130. doi: 10.1158/0008-5472.CAN-15-1544 pmid: 26542215
[61]	Bartlett P. D.; Cox E. F.; Davis R. E. J. Am. Chem. Soc. 1961, 83, 103.
[62]	Nguyen T. B.; Ermolenko L.; Al-Mourabit A. Synthesis 2014, 46, 3172.
[63]	Nickisch R.; Conen P.; Gabrielsen S.; Meier M. RSC Adv. 2021, 11, 3134. doi: 10.1039/d0ra10436a pmid: 35424261
[64]	Salami S. A.; Smith V. J.; Krause R. W. J. Sulphur Chem. 2023, 44, 269.
[65]	Garcı́a-Moreno M. I.; Dı́az-Pérez P.; Benito J. M.; Mellet C. O.; Defaye J.; Fernández J. M. Carbohydr. Res. 2002, 337, 2329.
[66]	Valette L.; Poulain S.; Fernandez X.; Lizzani-Cuvelier L. J. Sulphur Chem. 2005, 26, 155.
[67]	Nyoung K. J.; Ryu E. K. Tetrahedron Lett. 1993, 34, 8283.
[68]	Sajadikhah S. S.; Jazinizadeh E. Chem. Heterocycl. Compd. 2018, 54, 1020.
[69]	Barghash R. F.; Massi A.; Dondoni A. Org. Biomol. Chem. 2009, 7, 3319. doi: 10.1039/b908156a pmid: 19641791
[70]	Bedane K. G.; Singh G. S. ARKIVOC 2015, 206.
[9]	Dufour V.; Stahl M.; Baysse C. Microbiology 2015, 161, 229.
[10]	Petri L.; Szijj P. A.; Kelemen Á.; Imre T.; Gömöry Á.; Lee M. T.; Hegedűs K.; Ábrányi-Balogh P.; Chudasama V.; Keserű G. M. RSC Adv. 2020, 10, 14928.
[11]	Kulkarni P. M.; Kulkarni A. R.; Korde A.; Tichkule R. B.; Laprairie R. B.; Denovan-Wright E. M.; Zhou H.; Janero D. R.; Zvonok N.; Makriyannis A. J. Med. Chem. 2016, 59, 44.
[12]	Allen A. D.; Tidwell T. T. Chem. Rev. 2013, 113, 7287.
[13]	Norris B. C.; Bielawski C. W. Macromolecules 2010, 43, 3591.
[14]	Liao Y.-Y.; Deng J.-C.; Ke Y.-P.; Zhong X.-L.; Xu L.; Tang R.-Y.; Zheng W. Chem. Commun. 2017, 53, 6073.
[15]	Yu J.; Lin J. H.; Xiao J. C. Angew. Chem., Int. Ed. 2017, 56, 16669.
[16]	Scattolin T.; Klein A.; Schoenebeck F. Org. Lett. 2017, 19, 1831. doi: 10.1021/acs.orglett.7b00689 pmid: 28357864
[17]	Zhen L.; Fan H.; Wang X.; Jiang L. Org. Lett. 2019, 21, 2106.
[18]	Feng W.; Zhang X.-G. J. Chem. Commun. 2019, 55, 1144.
[19]	Santhosh L.; Durgamma S.; Sureshbabu V. V. Org. Biomol. Chem. 2018, 16, 4874. doi: 10.1039/c8ob01061g pmid: 29931019
[20]	Psurski M.; Janczewski Ł.; Świtalska M.; Gajda A.; Gosz- czyński T. M.; Oleksyszyn J.; Wietrzyk J.; Gajda T. Eur. J. Med. Chem. 2017, 132, 63.
[21]	Elhalem E.; Recio R.; Werner S.; Lieder F.; Calderón-Montaño J. M.; López-Lázaro M.; Fernández I.; Khiar N. Eur. J. Med. Chem. 2014, 87, 552.
[22]	Noshita T.; Kidachi Y.; Funayama H.; Kiyota H.; Yamaguchi H.; Ryoyama K. Eur. J. Med. Chem. 2009, 44, 4931.
[23]	Vermeulen M.; Zwanenburg B.; Chittenden G. J.; Verhagen H. Eur. J. Med. Chem. 2003, 38, 729. pmid: 12932904
[24]	Posner G. H.; Cho C.-G.; Green J. V.; Zhang Y.; Talalay P. J. Med. Chem. 1994, 37, 170. doi: 10.1021/jm00027a021 pmid: 8289191
[71]	Das B.; Dahiya A.; Patel B. K. Org. Biomol. Chem. 2024, 22, 3772.
[72]	Sharma S. Sulfur Rep. 1989, 8, 327.
[73]	Yang Z.; Cao T.; Liu S.; Li A.; Liu K.; Yang T.; Zhou C. New J. Chem. 2019, 43, 6465. doi: 10.1039/c9nj01419e
[74]	Zhang X.; Jia X.; Wang J.; Fan X. Green Chem. 2011, 13, 413.
[75]	Wang P.; Tang S.; Lei A. Green Chem. 2017, 19, 2092.
[76]	Liao J.-Y.; Selvaraju M.; Chen C.-H.; Sun C.-M. Org. Biomol. Chem. 2013, 11, 2473.
[77]	Ding Q.; Cao B.; Liu X.; Zong Z.; Peng Y.-Y. Green Chem. 2010, 12, 1607.
[78]	Ganesh K.; Sambasivam G.; Gavara G.; Ramraj S.; Rajendra G.; Karthikeyan S. Org. Biomol. Chem. 2023, 21, 564.
[79]	Zhang W.; Yue Y.; Yu D.; Song L.; Xu Y. Y.; Tian Y. J.; Guo Y. Adv. Synth. Catal. 2012, 354, 2283.
[25]	Kim S.; Yi K. Y. J. Med. Chem. 1985, 26, 1661.
[26]	Larsen C.; Harpp D. N. Org. Chem. 1981, 46, 2465.
[27]	Kim S.; Yi K. Y. J. Org. Chem. 1986, 51, 2613.
[28]	Rong H.-J.; Chen T.; Xu Z.-G.; Su T.-D.; Shang Y.; Wang Y.-Q.; Yang C.-F. Tetrahedron Lett. 2021, 68, 152868.
[29]	Janczewski Ł.; Kręgiel D.; Kolesińska B. Molecules 2021, 26, 2740.
[30]	Munch H.; Hansen J. S.; Pittelkow M.; Christensen J. B.; Boas U. Tetrahedron Lett. 2008, 49, 3117.
[31]	Liu P.; Li C.; Zhang J.; Xu X. Synth. Commun. 2013, 43, 3342.
[32]	Thomas S.; Alexander K.; Franziska S. Org. Lett. 2017, 19, 1497.
[33]	Jamir L.; Ali A. R.; Ghosh H.; Chipem F. A.; Patel B. K. Org. Biomol. Chem. 2010, 8, 1674.
[80]	Savarimuthu S. A.; Prakash D. L.; Thomas S. A.; Gandhi T.; Bera M. K. Org. Biomol. Chem. 2020, 18, 3552. doi: 10.1039/d0ob00083c pmid: 32342068
[81]	Singh R. P.; Gout D.; Lovely C. J. Eur. J. Org. Chem. 2019, 2019, 1726. doi: 10.1002/ejoc.201801505
[82]	Viart H.-F.; Larsen T.; Tassone C.; Andresen T. L.; Clausen M. H. Chem. Commun. 2014, 50, 7800.
[83]	Ranjan A.; Mandal A.; Yerande S. G.; Dethe D. H. Chem. Commun. 2015, 51, 14215.
[84]	Coin G.; de Ferrier de Montal O.; Dubourdeaux P.; Latour J. M. Eur. J. Org. Chem. 2021, 3, 443.
[85]	Sun Y.; Yang G.; Chai Z.; Mu X.; Chai J. Org. Biomol. Chem. 2013, 11, 7859.
[86]	Sandeep K.; Reddy A. S.; Swamy K. K. Org. Biomol. Chem. 2019, 17, 6880. doi: 10.1039/c9ob00994a pmid: 31270513
[87]	Kumar R.; Ginoya V.; Semwal R.; Adimurthy S. J. New J. Chem. 2021, 45, 20547.
[88]	Chuprakov S.; Kwok S. W.; Fokin V. V. J. Am. Chem. Sci. 2013, 135, 4652.
[34]	Techapanalai S.; Annuur R. M.; Sukwattanasinitt M.; Wacharasindhu S. ChemistrySelect 2023, 8, 8667.
[35]	Ghosh H.; Yella R.; Nath J.; Patel B. K., Eur. J. Org. Chem. 2008, 6189.
[36]	Boyer J.; Ramakrishnan V. J. T. J. Org. Chem. 1972, 37, 1360.
[37]	Tanaka S.; Uemura S.; Okano M. Bull. Chem. Soc. Jpn. 1977, 50, 2785.
[38]	Fujiwara S.-i.; Shin-Ike T.; Okada K.; Aoki M.; Kambe N.; Sonoda N. Tetrahedron Lett. 1992, 33, 7021.
[39]	Fujiwara S.-i.; Shin-Ike T.; Sonoda N.; Aoki M.; Okada K.; Miyoshi N.; Kambe N. Tetrahedron Lett. 1991, 32, 3503.
[40]	Adam W.; Bargon R. M.; Bosio S. G.; Schenk W. A.; Stalke D. J. T. J. Org. Chem. 2002, 67, 7037.
[41]	Farrell W. S.; Zavalij P. Y.; Sita L. R J. Organomet. Chem. 2016, 35, 2361.
[89]	Haung J.-Y.; Barve I. J.; Sun C.-M. Org. Biomol. Chem. 2019, 17, 3040.
[90]	Attanasi O. A.; Favi G.; Giorgi G.; Majer R.; Perrulli F. R.; Santeusanio S. Org. Biomol. Chem. 2014, 12, 4610. doi: 10.1039/c4ob00676c pmid: 24848196
[91]	Saito T.; Sonoki Y.; Otani T.; Kutsumura N. Org. Biomol. Chem. 2014, 12, 8398.
[92]	Cai H.; Zhou Y.; Zhang D.; Xu J.; Liu H. Chem. Commun. 2014, 50, 14771.
[93]	Trillo P.; Slagbrand T.; Tinnis F.; Adolfsson H. Chem. Commun. 2017, 53, 9159.
[94]	Gui H.-Z.; Wei Y.; Shi M. Org. Biomol. Chem. 2018, 16, 9218.
[95]	Saraswat P.; Jeyabalan G.; Hassan M. Z.; Rahman M. U.; Nyola N. K. Synth. Commun. 2016, 46, 1643.
[96]	Hou X.-Q.; Wen J.-B.; Yan L.; Du D.-M. Org. Biomol. Chem. 2021, 19, 7181.
[97]	Frankowski S.; Gajda T.; Albrecht Ł. Adv. Synth. Catal. 2018, 360, 1822.
[98]	Saunthwal R. K.; Patel M.; Danodia A. K.; Verma A. K. Org. Biomol. Chem. 2015, 13, 1521. doi: 10.1039/c4ob02286f pmid: 25485697
[99]	Zhao C.-L.; Han Q.-Y.; Zhang C.-P. Org. Lett. 2018, 20, 6480.
[100]	Anitha M.; Swamy K. K. Org. Biomol. Chem. 2018, 16, 402.
[101]	Dong Z.; Ma M.-Y.; Xu J.; Yang Z. Chem. Commun. 2022, 58, 7980.
[102]	Guo W.; Li S.; Tang L.; Li M.; Wen L.; Chen C. Org. Lett. 2015, 17, 1232.
[103]	Nguyen T. B.; Retailleau P. Org. Lett. 2022, 24, 6676. doi: 10.1021/acs.orglett.2c02736 pmid: 36048584
[104]	Pace V.; Monticelli S.; de la Vega-Hernández K.; Castoldi L. Org. Biomol. Chem. 2016, 14, 7848.
[105]	Anisimova V.; Zhukovskaya O.; Spasov A.; Kuznetsova V.; Kosolapov V.; Yakovlev D.; Solov’eva O.; Sorotskii D.; Brigadirova A.; Vorob’ev E. J. Pharm. Chem. 2016, 49, 653.
[106]	de la Vega-Hernández K.; Senatore R.; Miele M.; Urban E.; Holzer W.; Pace V. Org. Biomol. Chem. 2019, 17, 1970. doi: 10.1039/c8ob02312c pmid: 30362485
[107]	Perveen S.; Yasmin A.; Khan K. M. Nat. Prod. Res. 2010, 24, 18.
[108]	Begum S.; Choudhary M. I.; Khan K. M. Nat. Prod. Res. 2009, 23, 1719.
[109]	Viana G. M.; Soares D. C.; Santana M. V.; do Amaral L. H.; Meireles P. W.; Nunes R. P.;da Silva, L. C. R. P.; de Sequeira Aguiar, L. C.; Rodrigues, C. R.; de Sousa, V. P. Chem. Pharm. Bull. 2017, 65, 911.
[110]	Koohgard M.; Sarvestani A. M.; Hosseini-Sarvari M. New J. Chem. 2020, 44, 14505. doi: 10.1039/d0nj02197k
[111]	Sousa-Pereira D.; Chaves O. A.; Dos Reis C. M.; de Oliveira M. C.; Sant'Anna C. M. R.; Netto-Ferreira J. C.; Echevarria A. Bioinorg. Chem. 2018, 81, 79.
[112]	Wibowo J. P.; Xiao Z.; Voet J. M.; Dekker F. J.; Quax W. J. Bioorg. Med. Chem. Lett. 2020, 30, 127409.
[113]	Hu C.; Jiang L.; Guo Z.; Mumtaz Y.; Liu J.; Qin J.; Chen Y.; Lin Z.; Yi W. Angew. Chem. 2024, 136, e202319758.
[114]	Wang L.; Wang J.; Ye S.; Jiang B.; Guo Z.; Mumtaz Y.; Yi W. Angew. Chem., Int. Ed. 2022, 61, e202212115.

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