A One-Pot Approach to Pyridyl Isothiocyanates from Amines

A one-pot preparation of pyridyl isothiocyanates (ITCs) from their corresponding amines has been developed. This method involves aqueous iron(III) chloride-mediated desulfurization of a dithiocarbamate salt that is generated in situ by treatment of an amine with carbon disulfide in the present of DABCO or sodium hydride. The choice of base is of decisive importance for the formation of the dithiocarbamate salts. This one-pot process works well for a wide range of pyridyl ITCs. Utilizing this protocol, some highly electron-deficient pyridyl and aryl ITCs are obtained in moderate to good yields.

Numerous methods for preparing ITCs have been developed using different starting materials such as amines [13][14][15][16][17][18][19], tertiary alcohols [20], halides [21,22], nitrile oxides [23], azides [5], isocyanides [24,25]. Among these starting materials, amines are usually employed because of their broad availability and OPEN ACCESS versatility. Most reported methods are highly effective for the synthesis of alkyl and electron-rich aryl ITCs, but their applicability to pyridyl-substituted ITCs is limited due to the lower nucleophilicity of pyridyl amines. In fact, the synthesis of ITCs from pyridyl amines proved to be more difficult than that from aryl amines.
There are two main methods to convert substituted aminopyridines into the corresponding ITC analogue (Scheme 1). The most well-known method is based on thiophosgene [9], and later refinements of 'thiocarbonyl transfer' reagents such as thiocarbonyl-diimidazole [26] and dipyridyl-thionocarbonate [27]. The high toxicity and incompatability of thiophosgene with many functional groups limit its general use, furthermore, these 'thiocarbonyl transfer' reagents are not readily available and often do not work as desired due to the formation of thiourea byproducts. Another two-step approach, based on reagent-promoted decomposition of dithiocarbamate salts into ITCs, was first reported by Le Count [28] in 1977. The intermediate dithiocarbamate salts are generated by treatment of amines with carbon disulfide and Et 3 N. Although some desulfurylating reagents for this approach were developed [17,28], the first step, preparing the N-pyridyldithiocarbamate salts, was often neglected. Most of these methods are efficient only for electron-rich pyridyl ITCs, because electron-deficient aminopyridines lack enough reactivity to form dithiocarbamate salts, which results in low yield or excess (hundredfold) use of carbon disulfide. Thus, so far few efficient and general methods have been reported for the preparation of pyridyl ITCs, especially for those with highly electron-withdrawing groups. Therefore, research into an improved method for pyridyl ITCs, which can be used for a broad range of substituents, remains a topic of considerable interest. Scheme 1. Methods for conversion of amines to pyridyl ITCs.

Results and Discussion
In Le Count's work, iron(III) chloride has been proved to be effective for the decomposition of dithiocarbamate salts, but the preparation of N-pyridyldithiocarbamate salts was seldom investigated, so it became crucial for us to improve their preparation, because once the dithicarbamates were obtained, the desulfurylation step proceeded smoothly [13,16]. In the initial study, 3-amino-6-chloropyridine (1g) was chosen as a model substrate to prepare ITCs in a one-pot process (Table 1). At first, the effect of various bases was evaluated by performing the model reaction in tetrahydrofuran (entries 1-9). When inorganic bases (K 2 CO 3 , KOH) and organic bases like 1,8-bis(dimethylamino)naphthalene (Proton Sponge™) or pyridine were employed, the conversion of 1g was rather low, even after 12 h, giving less than 30% of 4g (entries 1-4). When triethylamine and potassium tert-butoxide was used, the conversion was significantly improved after 12 h (entries 5-6), however, a large amount of thiourea was formed in the case of t-BuOK. To our delight, when 1,8-diazabicyclo [5.4.0]-undec-7-ene (DBU), 4-dimethylaminopyridine (DMAP) or 1,4-diazabicyclo[2.2.2]octane (DABCO) were used as base, the conversion was complete within 4 h and 4g was obtained in excellent yield (entries 7-9). The results was summarized in Table 1 and could not be explained by the strength of the base (pK a ), for example, the substrate 1g reacted with CS 2 in the presence of DABCO (pK a 8.7) and Et 3 N (pK a 10.7), but it did not in the presence of pyridine (pK a 5.4) and Proton Sponge™ (pK a 12.1). The pK a values for protonated base are determined in polar solvents (water, MeCN, DMSO), in which they are dissociated as free ions [29]. However, THF is a nonpolar solvent and has a low dielectric constant, thus, the corresponding ammonium salts in nonpolar solvents are present entirely as ion pairs rather than free ions. To measure ion pairs basicity of some amines in THF, Streitwieser introduced the concept of pK ip [30], which refers to the equilibrium between the base and the acid with the H-bonded ion pair, and found that the pK ip values are inconsistent with their corresponding pK a values [31].  [32,33]; c The equilibrium between the base and acidic indicator hydrocarbons InH with the H-bonded ion pairs. pK ip = −logK ip [30].
A possible mechanism for the formation of pyridyl dithiocarbamate salts is proposed in Scheme 1. The first step, the attack of amine on carbon disulfide to form dithiocarbamic acid, is likely reversible. The driving force of the reaction is most likely the reaction of the dithiocarbamic acid with base to generate the stable dithiocarbamate salts. A greater ion pair basicity corresponds to a tighter ion pair, which facilitates the generation of dithiocarbamates, the ion pair basicities of Et 3 N (pK ip 2.1) and DABCO (pK ip 0.8) agree with their observed different reactivity. When we used DABCO as the base, an examination of different solvents showed that THF was the best solvent compared with DMF, acetone, MeCN, EtOH, CH 2 Cl 2 (entries [10][11][12][13][14]. Finally, with the optimized conditions for the formation of 2g, we then found that upon addition of aqueous FeCl 3 to unpurified 2g in one-pot, complete conversion to 4g was observed in about 1 h at room temperature. Under the reaction conditions outlined above (Table 1, entry 7), the substrate scope of various aminopyridines was examined next ( Table 2). The electronic effect of the substituents has a significant influence on the reaction outcome. For example, aminopyridines containing electron donating groups (Me, OMe) afforded good yields of 87%-91% in a relatively short reaction time (entries 2 and 8). Incidently, the corresponding ITCs from 2-aminopyridine and 2-amino-5-methylpyridine have been obtained as dimers, and such dimers slowly dissociate to monomers in hot organic solvent [34,35]. When the 2-or 4-aminopyridines contained halides (entries [3][4][5]9), longer reaction times and more equivalents of CS 2 were required to access 2, but the corresponding ITCs were still obtained in moderate to good yields, ranging from 73% to 83%. Meanwhile, the position of the amino group on the pyridine also exerted an influence on the reaction outcome; for example, the overall yield of C 6 H 3 ClN 2 S varies for 2-(3-or 4-)aminopyridines (entries 4,7,9), and a greater yield was obtained when the amino group is at the meta position with respect to the nitrogen atom in the pyridine (96%, entry 7). To our delight, several anilines with strong electron-withdrawing groups, such as NO 2 , CN, and CF 3 (entries 10-12), were also smoothly converted into the desired ITCs in 77%-87% yields. The approach also worked well for the fivemembered heterocyclic substrate (entry 13). However, the desired ITCs could not be detected when highly electron-deficient aminopyridines (such as those with NO 2 , CN, CO 2 Me substituents) were used. Only 5-trifluoromethylpyridyl-2-amine afforded the corresponding ITC in a low yield (42%, entry 6), even after prolonged reaction time and with excess CS 2 . For halide substituents in the ortho position of the amino group, no corresponding ITCs were observed. Thus, additional investigations are necessary to develop methods for the preparation of some highly electron-deficient pyridyl ITCs. The observed deficiencies in the synthesis of highly electron-deficient pyridyl ITCs inspired us to further optimize the process. The difficulty in the generation of dithiocarbamates is likely due to the weaker nucleophilicity of these amine substrates. In an effort to improve the reactivity, higher reaction temperatures in a variety of solvents were tested. Using methyl 6-aminonicotinate as a test substrate, we found that after 20 h of reflux in THF or DMF, only trace amounts of the corresponding ITCs were observed. We therefore investigated next the use of the strong base NaH to generate the more nucleophilic amide anions prior to CS 2 addition. After testing various solvents, the use of NaH in DMF was found to be the best choice. The amines was treated with NaH in DMF at 0 °C, then CS 2 was added, and after 6 h at room temperature, when the amines were fully consumed as monitored by TLC, the reaction mixtures were slowly treated with aqueous FeCl 3 . Using this process, we were able to obtain reasonable yields of several pyridyl ITCs with strong electron-withdrawing groups, such as NO 2 , CN, CO 2 Me, and 3,5-Cl 2 ( Table 3, entries 1-4, 31%-77% yield). This method was also effective for substrates bearing halide substituents in the ortho position of the amino moiety (entries 5-7, 49%-84% yield).

General Information
Tetrahydrofuran was redistilled in the presence of sodium/benzophenone. Unless otherwise stated, all reagents were commercially available and were used without purification. TLC was performed on pre-coated silica gel glass plates. Flash column chromatography was performed using flash silica gel (200-300 mesh) (Qingdao Haiyang, Qingdao, China). HPLC analyses were performed on an Agilent 1200 Series instrument (Santa Clara, CA, USA, column: Agilent Eclipse XDB-C18, 5 μm, 4.6 × 150 mm). Melting points were determined using a Stuart melting point apparatus and were uncorrected. 1 H-and 13 C-NMR spectra were recorded with a 300 MHz spectrometer (Bruker, Fallanden, Switzerland). HRMS and GC-MS were recorded on an Agilent mass spectrometer by the ESI and EI techniques, respectively. All yields given refer to isolated yields.

General Procedure for the Preparation of Isothiocyanates 4a-m
To a solution of amine 1 (8.0 mmol) and DABCO (16 mmol) in anhydrous THF (10 mL) was added dropwise a certain amount of CS 2 . The resulting mixture was stirred at r.t. for several hours until completion by TLC analysis. Then a solution of FeCl 3 ·6H 2 O (16 mmol) in water (15 mL) was added rapidly to the well suspended dithiocarbamate 2, and stirring was continued for 1 h. The aqueous layer was separated and extracted with EtOAc (2 × 10 mL). The combined organic phase was washed with water (2 × 10 mL), and dried over MgSO 4 . After removal of the solvent, the product was purified by flash column chromatography (petroleum ether-EtOAc) to give the corresponding ITCs 4.

Conclusions
In summary, we have developed a facile and environmentally friendly method for the preparation of various pyridyl ITCs from amines via a one-pot process. In comparison to existing methods, our procedure for the synthesis of highly electron-deficient pyridyl ITCs without using dangerous thiophosgene is simple yet efficient. The employed reagents are inexpensive and of low toxicity and the procedure is operationally simple, affording a wide range of pyridyl ITCs in moderate to excellent yields. Based on these characteristics, we envision that this method will be useful to the synthetic community.