Novel route to the synthesis of 4-quinolyl isothiocyanates Boyu Zhong, * Rima S. Al-Awar, Chuan Shih, John H. Grimes, Jr., Michal Vieth and Chafiq Hamdouchi Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, IN 46285, USA Received 8 December 2005; accepted 23 January 2006 Abstract—4-Quinolyl isothiocyanates were synthesized in a regiospecific fashion from the corresponding 4-chloroquinolines and sil- ver thiocyanate in refluxing toluene. The products were isolated in quantitative yield and high purity (>95%) by simple filtration and concentration. Reactivity and mechanism of the reaction are discussed. The new approach would provide a new mean which had been lacking for the synthesis of functionalized 4-quinolinyl isothiocyanate. Ó 2006 Elsevier Ltd. All rights reserved. Isothiocyanate is a very useful building block in syn- thetic chemistry, especially for constructing heterocycles such as thiodiazole, triazole, thiouracil, thioquinazo- lone, thiopyrimidine, etc. 1 It has been proven to be a key reagent in Edman peptide sequencing and other bio- logical assays of DNA and protein. 2 Due to their syn- thetic and biological importance, 3 several methods for the preparation of isothiocyanate have been reported. 4,5 Although these methods were shown to be highly effec- tive in alkyl and homocyclic systems, they suffered from the limited scope such as their applicability to hetero- cyclic systems. In fact, the synthesis of N-heterocyclic isothiocyanates has been a very challenging topic, 5,6 as they are prone to oligomerize by autocatalysis. As a result, they are generally generated in situ and trapped with amines or other reagents. Recently, 2-methyl-4- quinolyl isothiocyanate was synthesized. 7 Although the overall yield was as high as 80%, it required a two-step process including the isolation of a thiuronium salt intermediate, treatment with aqueous sodium hydroxide solution, and recrystallization in a nucleophilic solvent of aqueous alcohol. Nevertheless, it is the only 4-quin- olyl isothiocyanate ever reported. Our ongoing medicinal chemistry effort prompted us to undertake the synthesis of a variety of 4-quinolinyl isothiocyanates as key building blocks in the search for compounds with pharmacological importance. Our efforts using reported transformations starting from 4- aminoquinoline had led to failure. We turned to the di- rect replacement of the chlorine atom in 4-chloroquino- lines with inorganic thiocyanates, inspired by the previous work of Kristian. 8 Our use of silver thiocyanate turned out to be successful. In a typical reaction, a mix- ture of 4-chloroquinoline and silver thiocyanate in anhy- drous toluene was rapidly stirred at 110 °C for 12 h. 9 The reaction mixture was filtered and the filtrate was concentrated under vacuum to provide 4-quinolyl isothio- cyanate as an off-white solid in quantitative yield. 10 Attempts to purify the isothiocyanate on silica gel or recrystallization resulted in its decomposition. However, the crude product was sufficiently pure (>95%) for rou- tine synthetic uses. Representative examples of 4-quinolyl isothiocyanates that were successfully prepared using our new approach are listed in Tables 1 and 2. The data illustrate the broad scope of the reaction. The reaction was compatible with a variety of functional groups. Interestingly, the elec- tronic nature of the substitution did not significantly affect the reaction. For instance, the substrates with electron withdrawing groups, such as phenyl, fluorine, bromine, chlorine, trifluoromethyl, and carboxylic ester groups gave the products in similar yields and purities to those with electron-donating groups such as methyl, methoxy, and methylthio. The 4-chlorine is specifically activated during the reaction with no apparent effect on the other positions. The availability of these halo- quinolyl isothiocyanates was found to be valuable for further chemical transformations. The quantitative 0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2006.01.119 Keywords: 4-Quinolyl isothiocyanate; Thiocyanate; Silver thiocyanate. * Corresponding author. Tel.: +1 317 277 6024; fax: +1 317 277 3652; e-mail: zhong_boyu@lilly.com Tetrahedron Letters 47 (2006) 2161–2164