1 A novel selective synthesis of β-isothiocyanato ketones

A new selective two-step synthesis of β-isothiocyanato ketones from α,β-unsaturated ketones has been developed. This synthesis includes preparation of β-azidoketones with subsequent reaction of these with triphenylphosphine and carbon disulfide. This approach is especially useful for synthesis of β-unsubstituted β-isothiocyanato ketones, which are impossible to prepare with sufficient purity via commonly used procedures.


Scheme 1
However, reaction of -unsubstituted -unsaturated aldehydes or ketones (2, R 2 = R 3 = H) with thiocyanic acid proceeds with low selectivity, resulting in mixtures of isomeric isothiocyanates 3 and -thiocyanates 4 (up to 50 %) [20,21], which are difficult to separate because of similar physical properties.This drawback confines the use of -unsubstituted βisothiocyanato aldehydes and ketones in organic synthesis.
We hypothesized that -unsaturated aldehydes and ketones could be selectively transformed into respective β-isothiocyanato carbonyl compounds 1 and 3 by the addition of HN 3 to give -azido aldehydes and ketones [22,23] followed by transformation of the azido group into an isothiocyanato group using a Staudinger/aza-Wittig sequence [24][25][26][27][28][29][30].In our preliminary communication, an example of the application of this methodology has been described [31].Herein, we report full details of the selective synthesis of -unsubstituted isothiocyanato ketones from -unsaturated ketones.

Results and discussion
Starting β-azido ketones 5a and 5b were prepared according to the literature procedure based on the reaction of methyl vinyl ketone (6a) and isopropenyl methyl ketone (6b) with sodium azide in aqueous acetic acid at room temperature (Scheme 2) [23].
Azides 5a-5c were isolated from reaction mixtures as yellowish oils in 62-88 % yields after extraction with diethyl ether followed by neutralization of ether extracts with aqueous Na 2 CO 3 , drying and evaporation of solvent in vacuum.The purity of the crude 5a-5c was excellent (>95 % according to 1 H NMR data), and they were used in further transformations without additional purification.
First, transformation of the azido group of compounds 5a-5c into an isothiocyanato group was examined using azide 5a as a starting material.After treatment of this compound with one equivalent of triphenylphosphine in anhydrous THF at room temperature, nitrogen evolution via the Staudinger reaction was observed.Subsequent addition of excess of carbon disulfide to the obtained solution of iminophosphorane 7a gave the target isothiocyanate 8a (Scheme3).The latter was isolated after solvent removal and extraction of the residue with a petroleum etherdiethyl ether mixture (1:1).However, the yield of 8a did not exceed 30 %.

Scheme 3
A more convenient procedure of synthesis of 8a involved treatment of a solution of 5a in THF-CS 2 with triphenylphosphine at room temperature for several hours.Yield of 8a increased when after cessation of nitrogen evolution, the reaction mixture was refluxed for 1-1.5 h.Under optimal conditions (THF-CS 2 , rt, 1.5 h, then reflux, 1 h), the yield of oily 8a from azide 5a was 53 % after vacuum distillation.Oily isothiocyanate 8b and solid isothiocyanate 8c were prepared analogously from azides 5b and 5c in 82 and 52 % yields, respectively.Notably, the products of intramolecular aza-Wittig reaction of iminophosphoranes 7a-7c, azetines 9a-9c, were not detected in the studied reactions.Previously, Eguchi et al. [34] reported the formation of 2phenyl-1-azetine (9c) by the reaction of 5c with PPh 3 , however, in very low yield.
The reactions between azides 5a, 5c and triphenylphosphine (1 equiv.)with or without carbon disulfide in CDCl 3 were monitored by 1 H and 13 C NMR spectroscopy at 25 °C.
According to the 1 H NMR spectroscopy data (Table 1, Fig. 1), the reaction of 5a with PPh 3 in CDCl 3 was complete within 1.5 h to give iminophosphorane 7a and methyl vinyl ketone (6a) in a 62:33 ratio, respectively.Ketone 6a probably resulted from base-promoted elimination of hydrazoic acid from 5a under the action of 7a.Strong basic properties of iminophosphoranes are well documented in the literature [24][25][26][27][28][29].The formation of azetine 9a was not detected in the NMR experiment.The structure of iminophosphorane 7a was confirmed by its 1 H and 13 C NMR spectra.Thus, the 1 H NMR spectrum of 7a showed a singlet at 2.14 ppm because of the methyl group, a doublet of triplets at 3.24 ppm ( 3 J=6.7 and 3 J H,P =10.1 Hz) and a triplet at 2.97 ppm ( 3 J=6.7 Hz) assigned to the methylene groups of N-CH 2 -CH 2 fragment.In the 13  Table 2 and Fig. 2 show the 1 H NMR monitoring data for the reaction between 5a, PPh 3 (1 equiv.)and CS 2 at 25 °C in a mixture of CDCl 3 -CS 2 .Under these conditions, the rate of the formation of compound 8a was rather low.After 39 min, azide 5a, isothiocyanate 8a, iminophosphorane 7a and methyl vinyl ketone 6a in a 38:45:10:7 ratio were observed.After 4 h, the amount of isothiocyanato 8a increased to 62 %.Two unidentified products (or intermediates) were also formed in the reaction; however, the overall amount of these products did not exceed 15 %.ketones with full chemoselectivity.The prepared isothiocyanates 8a-8c were free from the corresponding isomeric thiocyanates 4, whereas the previously described 8a, 8b [35] were mixtures of the-isothiocyanato and -thiocyanato ketones in ratios of 50:50 and 65:35, respectively [21].

Table 2 .
Reaction of 5a with PPh 3 and CS 2 (CDCl 3 , 25 °C) a : dependence CDCl 3 was added at once to a 5 mm NMR tube charged with a solution of 5a (34.2 mg, 0.302 mmol) in 0.3 cm 3 CS2.The solution obtained was shaken carefully (gas evolution!).The progress of the reaction was monitored by 1H NMR spectroscopy (Bruker DPX-300).