Enolates of 2-Isothiocyanatocarboxylic Esters: Synthesis of Thiazolo[5,4-d]-thiazole Derivatives and 2-Thioxo-1,3-thiazolidine-4-carboxylates

Abstract

An oxidative dimerization of titanium(IV) enolates derived from menthyl esters of 2-isothiocarboxylic acids leads to radical coupling followed by cyclization. This cascade reaction gives thiazolo[5,4-d]thiazole derivatives as pure enantiomers. Under similar conditions, 2-methylbutyl esters of 2-isothiocyanatocarboxylic acids undergo intermolecular oxidative dimerization to give mixtures of thiazolo[5,4-d]thiazoles and 2,3-diisothiocyanatosuccinates. Application of the soft enolization technique to dimethyl α,α′-diisothiocyanatodicarboxylic esters gives novel cyclic 1,2-diisothiocyanato-1,2-dicarboxylates. Sodium enolates of 2-isothiocyanatocarboxylates, on the other hand, form 5-imino-2-thioxo-1,3-thiazolidine-4-carboxylic esters by nonoxidative dimerization. The mechanisms of the two reaction pathways are discussed.

In synthesis, 2-isothiocyanatocarboxylic esters are mainly used in preparing five-membered heterocycles or acyclic thioureas. The earliest report on the reaction of ethyl 2-isothiocyanato-4-methylpentanoate with ammonia to give 2-thioxoimidazolidin-4-one appeared nearly 90 years ago.[ ¹ ] Later reports on preparations of 2-thioxoimidazolidin-4-ones describe reactions with amines,[ ² ] hydrazones,[ ³ ] and aminonitriles.[ ⁴ ] Syntheses of 1,2,3,4-thiatriazole[ ⁵ ] and some acyclic thioureas[ ⁶ ] have also been described. Thioureas derived from 2-isothiocyanatocarboxylates can serve as convenient reactants for preparation of chiral isothiazolidines that are potentially useful as antiviral agents.[ ⁷ ] Titanium(IV)-promoted oxidative coupling reactions of 2-isothiocyanatocarboxylic esters have been used in attempts to synthesize masked symmetric 2,3-diaminosuccinates[ ⁸ ] and 2-thioxoimidazolidine rings.[ ⁹ ] More recently, 2-isothiocyanatocarboxylic esters have been used as substrates in stereoselective Mannich additions leading to 2-thioxo-1,3-imidazolidines, which are derivatives of 2,3-diaminosuccinic acid.[ ¹⁰ ]

Titanium(IV) enolates of carboxylic esters can serve as very convenient and useful intermediates for C–C bond-formation reactions.[ ¹¹ ] Our research in the field of titanium(IV) enolates has focused on oxidative coupling reactions to form vicinal 2,3-diisothiocyanatosuccinates[ ⁸ ] and pyrrole derivatives.[ ¹² ] More recently, we found that titanium(IV) enolates derived from 2-nitrocarboxylic esters can be quantitatively chlorinated under oxidative conditions.[ ¹³ ] Our investigations on the mechanism of the oxidative coupling reaction have identified both the scope and limitations of this process. The oxidative dimerization of 2-isothiocyanatocarboxylic esters attracted our attention because the resulting 2,3-diisothiocyanato succinic acid derivatives could be regarded as masked 2,3-diamino acids­.

In continuation of our previous research on the diastereo­selectivity of the oxidative coupling reaction, we synthesized two novel 2-isothiocyanatocarboxylic esters, l-menthyl 2-isothiocyanatopropanoate (1a) and d-menthyl 2-isothiocyanatopropanoate (1b), that contain large chiral ester groups. Soft enolization of l-menthyl 2-isothiocyanatopropanoate (1a) with the titanium(IV) chloride–diisopropyl(ethyl)amine system led exclusively to a single oxidation product, but analysis of its NMR spectra and two-dimensional (2-D) NMR studies showed that this compound was not the expected 2,3-diisothiocyanatosuccinate, but was, in fact the thiazolo[5,4-d]thiazole 6a (Scheme [1]). The titanium(IV) enolates of d-menthyl 2-isothiocyanatopropanoate (1b) and endo-(1S)-bornyl 2-isothiocyanatoacetate (1c) also underwent oxidative coupling to give the same fused heterocyclic system in the products 6b and 6c, respectively.

The ¹³C NMR spectra of both the thiazolo[5,4-d]thiazole derivatives 6a and 6b exhibited double signals for all the nonequivalent carbon atoms. This suggested that the products might each consist of a mixture of two diastereoisomeric forms. However, the two products showed equal but opposite specific rotations, which is typical of enantiomers rather than diastereoisomers. Indeed, an X-ray crystal structure analysis of 6a showed that the C-2 and C-5 atoms have absolute configurations of R and S, respectively (Figure [1]), indicating that the oxidative coupling reactions of l- and d-menthyl 2-isothiocyanatopropanoates 1a and 1b are highly diastereoselective.

Our results suggested that the size of the ester group has a significant effect on the oxidative coupling of titanium(IV) enolates derived from 2-isothiocyanatocarboxylates and that the reaction can give either a 2,3-diisothiocyanatosuccinic ester or a fused thiazolo[5,4-d]thiazole system. To verify this, we prepared chiral (2S)-2-methylbutyl (2S)-2-isothiocyanatopropanoate (5d) in three steps from commercial N-(tert-butoxycarbonyl)alanine and (2S)-(–)-2-methylbutan-1-ol. Deprotection of the ester 3d by trifluoroacetic acid gave the nonisolable ester of l-alanine 4d, which was transformed into (2S)-2-methylbutyl (2S)-2-isothiocyanatopropanoate (5d) by the thiophosgene method. The designed ester group is smaller than the menthyl substituent, but is branched. Chiral isothiocyanato ester 5d was transformed into the corresponding titanium(IV) enolate, which underwent dimerization to give coupling products (Scheme [2]). Gas chromatography–mass spectrometric analysis of the reaction mixture showed that the reaction gave two products with the same molecular mass but different fragmentation patterns. NMR studies on the isolated products showed that the oxidative coupling had produced both the thiazolo[5,4-d]thiazole 6d and the 2,3-diisothiocyanatosuccinate derivative 7d. Titanium(IV) enolates of (2S)-2-methylbutyl (2S)-2-isothiocyanato-4-methylpentanoate (5e) and (2S)-2-methylbutyl (2S)-2-isothiocyanato-3-phenylpropanoate (5f) similarly gave dl-2,3-diisothiocyanatosuccinates 7e and 7f, respectively, as the main products. The dl-diastereo­selectivity of the coupling process was in excess of 95%. Traces of the meso forms 7e and 7f and of the fused thiazolo[5,4-d]thiazole derivatives 6e and 6f were detected by GC analysis of the reaction mixture. The cyclohexyl ester of 2-isothiocyanatopropanoate 5g gave dl-2,3-diisothiocyanatosuccinate 7g and meso-thiazolo[5,4-d]thiazole 6g in a 2:3 ratio.

An analysis of the competition between the two different oxidation processes showed that substituents at C-2 had an opposite effect on the dimerization reaction to that of the ester group. Branched and bulky ester groups apparently hindered the formation of 2,3-diisothiocyanatosuccinic esters and promoted the oxidative coupling to form thiazolo[5,4-d]thiazole derivatives, whereas medium-sized substituents at C-2 promoted the formation of the corresponding 2,3-isothiocyanatosuccinates. In each case, however, the final products consisted of equilibrium mixtures of the two types of dimer.

The highly diastereoselective oxidative coupling reaction leading to the thiazolo[5,4-d]thiazole system appears to be a cascade radical process that commences with oxidation of the titanium(IV) enolate to a radical 8. This step is mediated by titanium(IV) ions that undergo reduction to titanium(III) species. We assume that the dimeric transition state that Matsumura[ ¹⁵ ] postulated as being typical of oxidative coupling reactions that lead to 2,3-diisothiocyanatosuccinates is not formed in the presence of large ester groups because of steric repulsion. The radical 8 undergoes intermolecular coupling to form a new C–C single bond between the two isothiocyanate groups, resulting in intermediate 10. This step initiates a cascade reaction involving double thiolation of the imine function to give 11, which finally undergoes ring closure to give the thiazolo[5,4-d]thiazole system 6 (Scheme [3]). This domino radical cyclization shows a very high diastereoselectivity in forming a thiazolo[5,4-d]thiazole core in which the C-2 and C-5 atoms have opposite configurations. This phenomenon can be explained in terms of a highly ordered transition state that forms three-dimensional structures in solution. The titanium(IV) enolates undergo self-assembly and self-organization processes in solution as a result of the coordination properties of the titanium ions. We propose a reaction mechanism based on a dimeric transition state, as previously suggested for oxidative coupling of phenylacetate derivatives,[15a] [b] except that in our model, we assume that two enolate subunits are linked by titanium(IV) ions and form a three-dimensional transition state 9 in which the bulky ester substituents are located in the opposite peripheral parts of the structure. The assumption that the bulky ester groups will be located opposite one another turns out to be helpful in explaining the diastereoselectivity of the reaction. The addition of the sulfur radical at the re-face of the enolate 11 is followed by attack of the second sulfur radical at the si-face. In this way, the reaction leads to the fused thiazolo[5,4-d]thiazole system with opposite configurations at the C-2 and C-5 positions.

Investigations of the competition between two oxidative coupling processes led us to conclude that 2,3-diisothiocyanatocarboxylic esters 7 can be obtained only when the 2-isothiocyanatocarboxylates contain small or medium-sized ester groups. The presence of bulky or branched ester substituents appears to change the reaction mechanism and leads to a domino process that gives the thiazolo[5,4-d]thiazole derivatives 6. This differences in reaction mechanism appear to arise from the presence of distinct transition states for each of the two processes and it precludes the use of chiral auxiliaries for stereoselective formation of 2,3-diisothiocyanatocarboxylic esters. We therefore designed some 2-isothiocyanatocarboxylic esters that contained bulky chiral ester groups but which were unable to form the thiazolo[5,4-d]thiazole system because of the presence of a rigid structure that prevented the formation of the transition state 9. These reactants, which were diesters of diols with 2-isothiocyanatocarboxylic acids, were prepared in three step from several chiral diols [(R)- and (S)-1,1′-binaphthalene-2,2′-diol, and 1,2;5,6-di-O-cyclohexylidene-d-mannitol] and protected amino acids. After esterification and deprotection, the amino groups were transformed into isothiocyanate functions by the thiophosgene method to give the desired diesters 12–15 (Figure [2]). We assumed that the chiral ester auxiliaries would promote enantioselective oxidative coupling of the 2-isothiocyanatocarboxylic fragments to give the corresponding chiral 2,3-diisothiocyanatosuccinic acid derivatives. However, reactions of diesters 12–15 with the titanium(IV) chloride/diisopropyl(ethyl)amine oxidizing system failed to give any dimerization products. Although the reactants readily formed double titanium(IV) enolates, oxidative coupling was restrained and only the starting material was recovered. As expected, the recovered reactants 13–15 showed nearly complete racemization at the α-positions in the 2-isothiocyanatocarboxylic fragments. The experiment proved that the formation of 2,3-diisothiocyanatosuccinates and thiazolo[5,4-d]thiazole derivatives is markedly dependent on the spatial structure of the transition state. The structure of the transition state is determined by interactions of the enolates derived from the 2-isothiocyanatocarboxylic esters. These results differ from those previously described by Periasamy[ ^15b ] for stereoselective oxidative coupling of chiral binaphth-2-yl arylacetates. It is likely that the titanium(IV) enolates formed from the isothiocyanatoacetates underwent isomerization before coupling and that they formed a complex that was unable to dimerize. Titanium(IV) enolates derived from binaphth-2-yl arylacetates, on the other hand, are more stable and therefore capable of giving the corresponding oxidative dimerization products. The labilities of titanium complexes and their stereochemical rearrangements are known and have been previously reported.[16a] [b]

Our next experiment was designed to confirm our observations concerning the chemo- and regioselectivity of the oxidative coupling. We investigated the oxidative dimerization of acyclic, enolizable diisothiocyanato esters derived from dicarboxylic acids. The substrates, which were esters of α,α′-diisothiocyanatosuberic and α,α′-diisothiocyanatosebacic acids, (19a and 19b, respectively), were prepared in several steps from the corresponding α,α′-dibromodicarboxylates 16a and 16b. We expected that the presence of a long hydrocarbon chain would hinder oxidative coupling to form the bicyclic thiazolo[5,4-d]thiazole (Scheme [4]) and would, instead, give the products of intramolecular cyclization. Indeed, our experiments showed that the double titanium(IV) enolates formed from dimethyl α,α′-diisothiocyanatodicarboxylates 19a and 19b or their diethyl analogues undergo an oxidative dimerization to give the corresponding cyclic 1,2-diisothiocyanato-1,2-dicarboxylates 20a and 20b, respectively, which represent a new group of cyclic dicarboxylic acids . Unlike the oxidative dimerization of simple 2-isothiocyanatocarboxylates, the degree of diastereoselectivity in the formation of the 1,2-diisothiocyanato-1,2-dicarboxylates 20a and 20b was low, and nearly equimolar amounts of the cis- and trans-diastereoisomers were obtained. Yields of products 20a and 20b were moderate, but we did not find any traces of thiazolo[5,4-d]thiazole derivatives. Because of their similar properties, it was impossible to separate the cis- and trans-forms of 1,2-diisothiocyanato-1,2-dicarboxylates 20a and 20b, and therefore the NMR spectra of these products included data for both diastereoisomers. On the basis of the integration data, we hypothesized that one diastereoisomer exists as two conformers. Analysis of the possible conformations of cis- and trans -20a showed that only the trans-diastereoisomer could have two different conformational energies corresponding to the two ring-flipped forms. These forms differ in terms of the spatial orientation of the vicinal isothiocyanate and ester groups, which can be either diaxial or diequatorial, respectively.

Unlike trans -20a, the second diastereoisomer, cis-20a, shows equivalent conformational energies for the two ring-flipped conformers.[ ¹⁷ ] We therefore assigned the double signals to the trans -20a diastereoisomer. Analysis of the NMR data recorded for the eight-membered 1,2-diisothiocyanato-1,2-dicarboxylate 20b showed an excess of one diastereoisomer, but the conformational diversity of the cyclooctane ring prevented us from identifying which diastereoisomer, cis- or trans-20b, is the main product of the oxidative coupling. An attempt to prepare chiral 1,2-diisothiocyanato-1,2-dicarboxylates failed: oxidative coupling of chiral l-menthyl or (2S)-2-methylbutyl diesters of α,α′-diisothiocyanatosebacic acid did not give any products, whereas the use of diethyl α,α′-diisothiocyanatosuberate or α,α′-diisothiocyanatosebacate led to oxidative dimerization. This experiment proved that the size of the ester group plays a major role in the intramolecular oxidative coupling reactions.

We also compared our results pertaining to the properties and reactivities of titanium(IV) enolates with those for the corresponding sodium enolates of 2-isothiocyanatocarboxylates. We chose sodium as a counterion for enolate formation because the stability of the sodium enolates should prevent any accidental oxidative coupling processes. Unlike titanium(IV) enolates, alkali metal enolates tend to undergo oxidative coupling reactions only in the presence of oxidizing agents.[ ¹⁸ ] 2-Isothocyanatocarboxylates 1 readily gave the sodium enolates 21 on treatment with sodium hydride in anhydrous N,N-dimethylform­amide, but the enolates spontaneously underwent intermolecular dimerization to give the 5-imino-2-thioxo-1,3-thiazolidine-4-carboxylic esters 24 in moderate-to-good yields (Scheme [5]). Products 24 were isolated by pouring the reaction mixture into ice–water and neutralizing the resultant basic solution. Both the ester groups were stable and aqueous workup did not cause hydrolysis. The transformation could be described in terms of a two-step mechanism (Scheme [5]) involving addition of the sodium enolate 21 to the isothiocyanate group and subsequent cyclization of the intermediate 22 after repeated addition of the sulfur anion to the isothiocyanate function. The 5-imino-2-thioxo-1,3-thiazolidine-4-carboxylic ester product remains in an anionic form as the disodium salt 23, which can be readily converted into the desired product 24 by treatment with an acid. Our suggested mechanism, in which enolization at the chiral center of the 2-isothiocyanatocarboxylic ester is followed by racemization, explains the low stereoselectivity of this reaction. The use of a substoichiometric amounts of sodium hydride resulted in a dramatic decrease in the yield. This showed that the first step of the reaction, enolate attack on the isothiocyanate group, was only possible when the second reactant was also present as an enolate. In other cases, the enolate reacted with the α-hydrogen atom and did not undergo an addition to the isothiocyanate function of the 2-isothiocyanatocarboxylate.

NMR spectra of the 1,3-thiazolidine-4-carboxylic esters 24h–j derived from ethyl isothiocyanoacetates 1h–j, respectively, showed that the 2-thioxo-1,3-thiazolidines 24h–j exist mainly as the enamine tautomers formed by a 1,3-hydrogen shift from C-4 to the imine group (Scheme [6]). Unlike the dimers derived from isothiocyanatoacetates, 5-imino-2-thioxo-1,3-thiazolidine-4-carboxylic ester 24k, prepared from ethyl 2-isothiocyanatopropanoate (1k) existed exclusively as the imine. Moreover, the dimer 24k consisted of an equimolar mixture of diastereoisomers because the stereoselectivity of the intermolecular dimerization was poor. The pure enantiomers of 2-thioxo-1,3-thiazolidine-4-carboxylates 24i and 24j were obtained by dimerization of sodium enolates of l-menthyl and endo-(1S)-bornyl isothiocyanoacetates 1i and 1j, respectively.

The transformation of 5-imino-2-thioxo-1,3-thiazolidine-4-carboxylic esters 24 into carboxylic acids 25 was possible under basic or acidic conditions, but only one ester group underwent hydrolysis. Analysis of the MS/MS spectra of 25h proved that the 4-ethoxycarbonyl group was stable and remained unchanged whereas the N-amino acid fragment of the 1,3-thiazolidine ring was hydrolyzed (Scheme [6]). An attempt to hydrolyze both ester groups failed because the 1,3-thiazolidine ring decomposed under the harsh conditions that were required.

In summary, we found that the reactivity of 2-isothiocyanatocarboxylates is markedly dependent on their structure, permitting their use in syntheses of novel heterocyclic systems or vicinal diisothiocyanates. Titanium(IV) enolates of 2-isothiocyanatocarboxylic esters bearing bulky esters groups gave the previously unknown fused thiazolo[5,4-d]thiazole system in good yields. We proposed a mechanism for this transformation that involves three consecutive steps initiated by titanium(IV) ions. From the mechanistic point of view, the cyclization can be considered as a radical domino reaction. Steric repulsions between ester substituents resulted in the formation of thiazolo[5,4-d]thiazole derivatives in which the two ester groups were located on opposite sides of the molecule. The structure of the product reflected the structure of the transition state. Oxidative dimerization to give 2,3-diisothiocyanates occurred when the ester groups were small or medium-sized. An interesting result was obtained during enolization of dimethyl esters of α.α′-diisothiocyanatodicarboxylic acids; intramolecular cyclization led to derivatives of 1,2-diisothiocyanato-1,2-dicarboxylic acids, in agreement with Matsumura’s model of the transition state. Unfortunately, the diastereoselectivity of this process was very poor. Unlike titanium(IV) enolates, sodium enolates prepared from 2-isothiocyanatocarboxylates underwent dimerization followed by cyclization to give 5-imino-2-thioxo-1,3-thiazolidine-4-carboxylic esters in moderate-to-good yields. The resulting 2-thioxo-1,3-thiazolidines represent a new group of thiazolidine derivatives.

NMR spectra were recorded on a Bruker Avance II 300-MHz spectrometer with TMS as an internal standard. IR spectra were recorded on a Nicolet IR200 FT-IR spectrometer with a single-reflection attenuated total reflectance (ATR) head. Microanalyses were carried out by using a Vario MICRO Cube CHNS analyzer and the results were in good agreement with the calculated values. Column chromatography was performed on commercial Merck silica gel 60 (230–400 mesh ASTM). TLC analysis was carried out on Merck TLC silica gel 60 plates. GC was performed by using a Perkin-Elmer­ Clarus 500 chromatograph equipped with an Elite-5ms capillary column. GC/MS analyses were performed on a Thermo Scientific ISQ Single Quadrupole GC/MS equipped with an Elite-5ms capillary column, whereas EI-MS spectra were recorded on a Finnigan MAT 95S spectrometer. Optical rotations were measured by using a Jasco P-2000 polarimeter. Melting points were measured on an Electrothermal 9100 apparatus. X-ray diffraction data were collected at 110 K on a SuperNova diffractometer (Oxford Diffraction) with MoKα radiation (λ = 0.71073 Å).

endo-(1S)-Bornyl (2S)-2-isothiocyanatopropanoate (1c)[ ¹⁰ ] and cyclohexyl (2S)-2-[(tert-butoxycarbonyl)amino]propanoate (3g)[ ¹⁹ ] were prepared by the procedures described in the literature.

l-Menthyl (2R/2S)-2-Isothiocyanatopropanoate (1a); Typical Procedure

A 250-mL Erlenmeyer flask was placed on a magnetic stirrer and charged with CHCl₃ (45 mL), H₂O (25 mL), and l-menthyl dl-alaninate hydrochloride[ ¹ ] (1.86 g, 7.05 mmol). To the stirred soln were added Cl₂C=S (0.54 mL, 0.814 g, 7.08 mmol) and NaHCO₃ (1.78 g, 21.19 mmol) in one portion and the mixture was stirred vigorously until the orange soln became pale (40–70 min). When the Cl₂C=S had been consumed, the lower organic layer was separated, dried (MgSO₄), and concentrated. The crude oily product was purified by column chromatography [silica gel, cyclohexane–EtOAc (5:1)] to give a yellow oil; yield: 1.727 g (91%).

IR (ATR): 2955, 2928, 2870, 2059, 1741, 1454, 1374, 1289, 1205, 1151 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 0.77 and 0.76 (2d, J = 6.96 Hz, 3 H, CH-CH ₃), 0.87 (m, 1 H, 4-CH _aH_e), 0.91 (d, J = 7.00 Hz, 3 H, CH₃-CH-CH ₃), 0.92 (d, J = 6.52, 3 H, CH ₃-CH-CH₃), 1.05 (m, 2 H, 3-CH _aH_e, 6-CH _aH_e), 1.46 (m, 2 H, 5-CH-CH₃ and 2-CH), 1.58 (d, J = 7.09 Hz, 3 H, β-CH₃), 4.75 and 4.74 (m, 1 H, ABX spin system, OCH), 1.68 (m, 1 H, 4-CH_a H _e), 1.72 (m, 1 H, 3-CH_a H _e), 1.86 (m, 1 H, CH₃-CH-CH₃), 2.02 (m, 1 H, 6-CH_a H _e), 4.28 and 4.27 (2q, J = 7.09 Hz, 1 H, α-CH).

¹³C NMR (75 MHz, CDCl₃): δ = 16.3, 16.0, 19.5, 20.8, 20.7, 21.9, 23.4, 23.3, 26.3, 26.2, 31.34, 34.1, 40.6, 46.9, 55.1, 55.0, 77.2, 76.9, 137.6, 137.4, 168.8, 168.7.

Anal. Calcd for C₁₄H₂₃NO₂S: C, 62.41; H, 8.61; N, 5.20. Found: C, 62.35; H, 8.60; N, 5.28.

d-Menthyl (2R/2S)-2-Isothiocyanatopropanoate (1b)

Yield: 2.29 g (85%); yellow oil.

GC-MS (EI, 70 eV): m/z (%) = 69 (68), 83 (100), 86 (53), 139 (88), 183 (19), 269 (3) [M]⁺.

Anal. Calcd for C₁₄H₂₃NO₂S: C, 62.41; H, 8.61; N, 5.20. Found: C, 62.49; H, 8.51; N, 5.33.

l-Menthyl Isothiocyanatoacetate (1i)

Yield: 2.50 g (76%); yellowish oil; [α]_D ²⁴ –75.9 (c 0.011, CHCl₃); R_f = 0.51 (cyclohexane–EtOAc, 5:1).

IR (ATR): 2957, 2928, 2871, 2073, 1748, 1455, 1370, 1271, 1210, 981, 958 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 0.77 (d, J = 6.90 Hz, 3 H, CH-CH ₃), 0.86 (m, 1 H, 4-CH _aH_e), 0.90 (d, J = 6.92 Hz, 3 H, CH₃-CH-CH ₃), 0.91 (d, J = 6.30 Hz, 3 H, CH ₃-CH-CH₃), 1.05 (m, 2 H, 3-CH _aH_e, 6-CH _aH_e), 1.50 (m, 2 H, 5-CH-CH₃ and 2-CH), 1.69 (m, 2 H, 3-CH_a H _e and 4-CH_a H _e), 1.83 (m, 1 H, CH₃-CH-CH₃), 2.03 (m, 1 H, 6-CH_a H _e), 4.18 (s, 2 H, CH ₂NCS), 4.78 (td, J = 4.41 and 10.1 Hz, 1 H, OCH).

¹³C NMR (75 MHz, CDCl₃): δ = 16.3, 20.7, 21.9, 23.4, 26.9, 34.0, 31.4, 40.7, 46.5, 46.9, 77.2, 138.6, 165.7.

Anal. Calcd for C₁₃H₂₁NO₂S: C, 61.14; H, 8.29; N, 5.48. Found: C, 61.21; H, 8.22; N, 5.55.

endo-(1S)-Bornyl Isothiocyanatoacetate (1j)

Yield: 1.55 g (51%); colorless oil; [α]_D ²⁴ –29.4 (c 0.007, CHCl₃); R_f  = 0.41 (cyclohexane–EtOAc, 5:1).

IR (ATR): 2956, 2882, 2083, 1752, 1454, 1350, 1270, 1211 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 0.86 (s, 3 H, CH₃), 0.89 (s, 3 H, CH₃), 0.91 (s, 3 H, CH₃), 1.01 (m, 1 H, 3-CH _endo ), 1.32 (m, 2 H, 5-CH _endo and 6-CH _exo ), 1.72 (m, 1 H, 4-CH), 1.76 (m, 1 H, 5-CH _exo ), 1.93 (m, 1 H, 6-CH _endo ), 2.40 (m, 1 H, 3-CH _exo ), 4.22 (s, 2 H, α-CH₂), 5.00 (m, 1 H, ABX spin system, OCH).

¹³C NMR (75 MHz, CDCl₃): δ = 13.5, 18.8, 19.7, 27.1, 28.0, 36.6, 44.8, 46.6, 48.0, 48.9, 82.9, 137.5, 166.4.

Anal. Calcd for C₁₃H₁₉NO₂S: C, 61.63; H, 7.56; N, 5.53. Found: C, 61.73; H, 7.36; N, 5.59.

(2S)-2-Methylbutyl (2S)-2-[(tert-Butoxycarbonyl)amino]propanoate (3d); Typical Procedure

A 100-mL Erlenmeyer flask was charged with CH₂Cl₂ (50 mL), N-Boc-l-alanine (2 g, 10.57 mmol), and DCC (2.177 g, 10.57 mmol), and the mixture was stirred at r.t. for 30 min. (2S)-(–)-2-Methylbutan-1-ol (1.20 mL, 0.983 g, 11.14 mmol) and DMAP (0.123 g, 1.01 mmol) were added and the mixture was stirred overnight then concentrated under reduced pressure. The residue was dissolved in EtOAc(80 mL), and the soln was filtered and washed successively with 5% aq HCl (36 mL) and brine (30 mL). The organic layer was dried (MgSO₄) and concentrated to give a crude product that was purified by column chromatography [silica gel, CHCl₃–MeOH (30:1)] to give a colorless oil; yield: 1.96 g (72%); [α]_D ²⁴ –4.1 (c 0.011, CHCl₃).

IR (ATR): 3361, 2967, 2935, 2880, 1712, 1505, 1455, 1366, 1248, 1160, 1064 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 0.89 (t, J = 7.42 Hz, 3 H, CH₂CH ₃), 0.91 (d, J = 6.75 Hz, 3 H, CHCH ₃), 1.18 (m, 1 H, CH_a H _b), 1.37 (d, J = 7.20 Hz, 3 H, CHCH ₃), 1.41 (m, 1 H, CH _aH_b), 1.43 (s, 9 H, CH₃), 1.70 (m, 1 H, CHCH₃), 3.94 (dd, J = 6.61 and 10.8 Hz, 1 H, OCH_a H _b), 3.98 (dd, J = 6.05 and 10.8 Hz, 1 H, OCH _aH_b), 4.30 (m, 1 H, CHNH), 5.05 (br s, 1 H, NH).

¹³C NMR (75 MHz, CDCl₃): δ = 11.2, 16.3, 18.8, 25.9, 28.3, 34.1, 49.3, 69.8, 79.7, 155.1, 173.4.

Anal. Calcd for C₁₃H₂₅NO₄: C, 60.21; H, 9.72; N, 5.40. Found: C, 60.15; H, 9.75; N, 5.51.

(2S)-2-Methylbutyl (2S)-2-[(tert-Butoxycarbonyl)amino]-4-methylpentanoate (3e)

Yield: 2.39 g (75%); colorless oil; [α]_D ²⁴ –3.2 (c 0.004, CHCl₃).

IR (ATR): 3352, 2961, 2933, 2875, 1712, 1505, 1462, 1366, 1249, 1160, 1047, 1048 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 0.87 (d, J = 7.42 Hz, 3 H, CHCH ₃), 0.91 (t, J = 5.30 Hz, 3 H, CH₂CH ₃), 0.92 (2d, J = 5.16 Hz, 6 H, CHCH ₃), 1.17 (sept, 1 H, CHMe₂), 1.42 (s, 9 H, CH₃), 1.46 (m, 1 H, CH_a H _b), 1.48 (m, 1 H, CH _aH_b), 1.71 (m, 3 H, CHCH₃ and CH ₂-i-Pr), 3.94 (dd, J = 6.76 and 10.8 Hz, 1 H, OCH_a H _b), 3.99 (dd, J = 5.88 and 10.8 Hz, 1 H, OCH _aH_b), 4.28 (m, 1 H, CHNH), 4.92 (br d, 1 H, NH).

¹³C NMR (75 MHz, CDCl₃): δ = 11.1, 16.3, 21.9, 22.7, 24.8, 25.9, 28.3, 34.1, 41.9, 52.1, 66.7, 79.7, 155.3, 173.5.

Anal. Calcd for C₁₆H₃₁NO₄: C, 63.76; H, 10.37; N, 4.65. Found: C, 63.65; H, 10.52; N, 4.69.

(2S)-2-Methylbutyl (2S)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropanoate (3f)

Yield: 2.52 g (71%); colorless oil; [α]_D ²⁴ +32.3 (c 0.004, CHCl₃).

IR (ATR): 3367, 2965, 2932, 2878, 1712, 1496, 1455, 1364, 1249, 1162, 1053, 1018 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 0.88 (m, 6 H, CHCH ₃ and CH₂CH ₃), 1.14 (m, 1 H, CH_a H _b), 1.38 (m, 1 H, CH _aH_b), 1.41 (s, 9 H, CH₃), 1.68 (m, 1 H, CHCH₃), 3.08 (m, 2 H, CH₂Ph), 3.86 (dd, J = 6.74 and 10.8 Hz, 1 H, OCH_a H _b), 3.99 (dd, J = 5.96 and 10.8 Hz, 1 H, OCH _aH_b), 4.58 (m, 1 H, CHNH), 4.98 (br d, 1 H, NH), 7.13 (m, 2 H, ArH), 7.25 (m, 3 H, ArH).

¹³C NMR (75 MHz, CDCl₃): δ = 11.1, 16.3, 25.9, 28.2, 33.9, 38.4, 54.4, 69.9, 79.8, 126.9, 128.5, 129.2, 136.1, 155.0, 171.9.

Anal. Calcd for C₁₉H₂₉NO₄: C, 68.03; H, 8.71; N, 4.18. Found: C, 67.95; H, 8.58; N, 4.22.

(2S)-2-Methylbutyl (2S)-2-Isothiocyanatopropanoate (5d); Typical Procedure

A three-necked 100-mL flask equipped with an argon inlet and protected against moisture was placed on a magnetic stirrer and charged with a soln of amino ester 3c (1.764 g, 6.80 mmol) in CH₂Cl₂ (55 mL). TFA (12.4 mL, 19.03 g, 167 mmol) was added and the mixture was stirred under argon at r.t. for 2.5 h. When the deprotection was completed, the CH₂Cl₂ and TFA were evaporated under reduced pressure at 45 °C and residue was transferred into a 250-mL Erlenmeyer flask and dissolved in CHCl₃ (40 mL). Next, Cl₂C=S (0.52 mL, 0.786 g, 6.80 mmol) was added dropwise to the flask followed by NaHCO₃ (1.714 g, 20.4 mmol) and H₂O (60 mL), and the mixture was intensively stirred for 1 h. The lower organic layer was separated, dried (MgSO₄), and concentrated to a crude oily product that was purified by distillation under reduced pressure (124–126 °C at 9 mmHg) to give a yellowish oil; yield: 0.75 g (55%); bp 124–126 °C (9 mmHg); [α]_D ²³ 17.8 (c 0.003, CHCl₃).

IR (ATR): 2964, 2935, 2878, 2059, 1743, 1458, 1379, 1289, 1198, 1149, 1054 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 0.91 (t, J = 7.42 Hz, 3 H, CH₂CH ₃), 0.95 (d, J = 6.76 Hz, 3 H, CHCH ₃), 1.22 (m, 1 H, CH_a H _b), 1.44 (m, 1 H, CH _aH_b), 1.59 (d, J = 7.10 Hz, 3 H, CHCH ₃), 1.77 (m, 1 H, CHCH₃), 4.01 (dd, J = 6.62 and 10.5 Hz, 1 H, OCH_a H _b), 4.08 (dd, J = 5.94 and 10.5 Hz, 1 H, OCH _aH_b), 4.33 (q, J = 7.10 Hz, 1 H, CHNCS).

¹³C NMR (75 MHz, CDCl₃): δ = 11.1, 16.3, 19.5, 25.9, 34.0, 54.9, 70.9, 137.3, 169.0.

GC-MS (EI, 70 eV): m/z (%) = 71 (57), 86 (100), 132 (9), 201 (8) [M]⁺.

Anal. Calcd for C₉H₁₅NO₂S: C, 53.70; H, 7.51; N, 6.96. Found: C, 53.78; H, 7.65; N, 7.05.

(2S)-2-Methylbutyl (2S)-2-Isothiocyanato-4-methylpentanoate (5e)

Yield: 1.10 g (67%); yellow viscous oil; [α]_D ²⁴ –45.6 (c 0.002, CHCl₃).

IR (ATR): 2961, 2933, 2875, 2058, 1744, 1464, 1387, 1316, 1269, 1192, 1149 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 0.94 (m, 12 H, CH₃), 1.22 (m, 1 H, CH_a H _b), 1.49 (m, 1 H, CH _aH_b), 1.80 (m, 4 H, CHCH₃, CH ₂-i-Pr, CHMe₂), 4.01 (dd, J = 6.65 and 10.8 Hz, 1 H, OCH_a H _b), 4.08 (dd, J = 5.91 and 10.8 Hz, 1 H, OCH _aH_b), 4.27 (m, 1 H, ABX spin system, CHNCS).

¹³C NMR (75 MHz, CDCl₃): δ = 11.2, 16.3, 21.2, 22.7, 25.1, 25.9, 34.0, 42.1, 58.1, 70.9, 136.8, 169.0.

Anal. Calcd for C₁₂H₂₁NO₂S: C, 59.22; H, 8.70; N, 5.76. Found: C, 59.15; H, 8.64; N, 5.86.

(2S)-2-Methylbutyl (2S)-2-Isothiocyanato-3-phenylpropanoate (5f)

Yield: 0.98 g (52%); orange oil; [α]_D ²³ –54.8 (c 0.013, CHCl₃).

IR (ATR): 2963, 2932, 2877, 2060, 1741, 1457, 1381, 1334, 1268, 1199, 1014 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 0.90 (t, J = 7.40 Hz, 3 H, CH₂CH ₃), 0.90 (d, J = 6.76 Hz, 3 H, CHCH ₃), 1.18 (m, 1 H, CH_a H _b), 1.38 (m, 1 H, CH _aH_b), 1.78 (m, 1 H, CHCH₃), 3.13 (dd, J = 8.12 and 13.8 Hz, 1 H, PhCH_a H _b), 3.26 (dd, J = 4.95 and 13.8 Hz, 1 H, PhCH _aH_b), 3.97 (dd, J = 6.61 and 10.5 Hz, 1 H, OCH_a H _b), 4.07 (dd, J = 5.93 and 10.5 Hz, 1 H, OCH _aH_b), 4.46 (m, 1 H, ABX spin system, CHNCS), 7.24 (m, 2 H, ArH), 7.32 (m, 3 H, ArH).

¹³C NMR (75 MHz, CDCl₃): δ = 11.1, 16.3, 25.8, 34.0, 39.7, 60.9, 71.0, 127.6, 128.7, 129.3, 135.1, 137.9, 168.0.

Anal. Calcd for C₁₅H₁₉NO₂S: C, 64.95; H, 6.90; N, 5.05. Found: C, 65.04; H, 6.78; N, 5.12.

Cyclohexyl (2S)-2-Isothiocyanatopropanoate 5g

Yield: 1.12 g (77%); yellow oil.

IR (ATR): 2936, 2859, 2058, 1739, 1450, 1287, 1201, 1150, 1010 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 1.41 (m, 6 H, cyclohexyl), 1.57 (d, J = 7.09 Hz, 3 H, CH₃), 1.73 (m, 2 H, cyclohexyl), 1.83 (m, 2 H, cyclohexyl), 4.28 (q, J = 7.09 Hz, 1 H, OCH), 4.86 (m, 1 H, ABX spin system, CHNCS).

¹³C NMR (75 MHz, CDCl₃): δ = 19.4, 23.4, 25.2, 31.3, 55.0, 75.1, 137.4, 168.4.

Anal. Calcd for C₁₀H₁₅NO₂S: C, 56.31; H, 7.09; N, 6.57. Found: C, 56.21; H, 7.20; N, 6.44.

Di-l-menthyl (2R,5S)-2,5-Dimethyl-2,5-dihydro[1,3]thiazolo[5,4-d][1,3]thiazole-2,5-dicarboxylate (6a); Typical Procedure

Ester 1a (1.954 g, 7.23 mmol) was dissolved in anhyd CH₂Cl₂ (30 mL) under argon and the soln was cooled to –96 °C. A soln of TiCl₄ (0.88 mL, 1.522 g, 8.02 mmol) in CH₂Cl₂ (5 mL) was added dropwise and the mixture was stirred for 30 min at –96 °C. When a yellow titanium(IV) complex had formed, a soln of DIPEA (1.40 mL, 1.04 g, 8.09 mmol) in CH₂Cl₂ (4 mL) was added dropwise to give a deep-blue titanium(IV) enolate. The mixture was stirred for 60 min at –96 °C then the cooling bath was removed and the soln was allowed to warm to r.t. After 24 h, the brown mixture was quenched with sat. aq NH₄Cl and the organic phase was dried (MgSO₄). The solvent was evaporated and the crude product was purified by column chromatography [silica gel, CHCl₃–MeOH (30:1)]. The product was isolated as the first fraction and crystallized (MeOH) to give colorless crystals;[ ¹⁹ ] yield: 1.43 g (76%); mp 122–123 °C; [α]_D ²³ –72.2 (c 0.01, acetone); R_f = 0.80 (CHCl₃–MeOH, 30:1).

IR (ATR): 3480, 2956, 2932, 2869, 1729, 1620, 1462, 1384, 1372, 1259, 1125 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 0.75 (d, J = 6.9 Hz, 3 H, CH₃-CH-CH ₃), 0.73 (d, J = 6.9 Hz, 3 H, CH₃-CH-CH ₃), 0.87 (m, 2 H, 4-CH _aH_e), 0.89 (m, 12 H, CH ₃-CH-CH₃ and CH-CH ₃), 1.05 (m, 4 H, 3-CH _aH_e, 6-CH _aH_e), 1.46 (m, 4 H, 5-CH-CH₃ and 2-CH), 1.66 (m, 2 H, 4-CH_a H _e), 1.70 (m, 2 H, 3-CH_a H _e), 1.86 (m, 2 H, CH₃-CH-CH₃), 2.02 (m, 2 H, 6-CH_a H _e), 2.05 (s, 3 H, β-CH₃), 2.01 (s, 3 H, β-CH₃), 4.69 (m, 2 H, ABX spin system, CH-O).

¹³C NMR (75 MHz, CDCl₃): δ = 16.2, 16.3, 20.6, 20.7, 21.9, 23.3, 23.5, 26.2, 26.3, 26.6, 27.1, 31.3, 34.1, 40.1, 40.2, 46.9, 77.1, 77.3, 98.9, 99.1, 168.1, 168.3, 177.9, 178.1.

MS (EI, 70 eV): m/z (%) = 83 (97), 139 (17), 171 (100), 216 (16), 261 (17), 399 (23), 537 (22) [M – H]⁺.

Anal. Calcd for C₂₈H₄₄N₂O₄S₂: C, 62.65; H, 8.26; N, 5.22. Found: C, 62.33; H, 8.52; N, 5.00.

Di-d-menthyl (2R,5S)-2,5-Dimethyl-2,5-dihydro[1,3]thiazolo[5,4-d][1,3]thiazole-2,5-dicarboxylate (6b)

Yield: 1.53 g (82%); colorless crystals; mp 122–123 °C; [α]_D ²³ +71.9 (c 0.01, acetone).

Anal. Calcd for C₂₈H₄₄N₂O₄S₂: C, 62.65; H, 8.26; N, 5.22. Found: C, 62.36; H, 8.48; N, 5.12.

Di-endo-(1S)-bornyl (2R,5S)-2,5-Dimethyl-2,5-dihydro[1,3]thiazolo[5,4-d][1,3]thiazole-2,5-dicarboxylate (6c)

Yield: 0.847 g (44%); yellow oil; R_f = 0.90 (CHCl₃–MeOH, 30:1).

IR (ATR): 2953, 2878, 1736, 1483, 1453, 1377, 1256, 1152, 1116 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 0.90 (m, 18 H, 6 CH₃), 1.00 (m, 2 H, 3-CH_endo), 1.31 (m, 4 H, 5-CH_endo and 6-CH_exo), 1.61 (m, 2 H, 4-CH), 1.76 (2 s, 6 H, α-CH₃), 1.98 (m, 4 H, 5-CH_exo and 6-CH_endo), 2.36 (m, 2 H, 3-CH_exo), 4.95 (m, 2 H, ABX spin system, CH-O).

¹³C NMR (75 MHz, CDCl₃): δ = 13.4, 13.5, 18.8, 19.6, 19.7, 26.2, 27.1, 27.3, 27.8, 27.9, 36.3, 44.8, 47.9, 48.0, 49.0, 49.1, 82.4, 82.5, 98.9, 99.0, 170.4, 176.6.

Anal. Calcd for C₂₈H₄₀N₂O₄S₂: C, 63.14; H, 7.60; N, 5.26. Found: C, 62.98; H, 7.75; N, 5.12.

Bis[(2S)-2-methylbutyl] (2R,5S)-2,5-Dimethyl-2,5-dihydro[1,3]thiazolo[5,4-d][1,3]thiazole-2,5-dicarboxylate (6d) and Bis[(2S)-2-methylbutyl] 2,3-Diisothiocyanato 2,3-dimethylsuccinate (7d)

A soln of isothiocyanatopropanoate 5c (0.652 g, 3.24 mmol) in CH₂Cl₂ (40 mL) was cooled to –96 °C under argon and TiCl₄ (0.39 mL, 0.675 g, 3.56 mmol) was added in one batch. The mixture was stirred for 20 min at –96 °C then a soln of DIPEA (0.62 mL, 0.463 g, 3.58 mmol) in CH₂Cl₂ (4 mL) was added dropwise. The soln turned deep blue owing to the formation of the titanium(IV) enolate. The mixture was stirred at –96 °C then the cooling bath was removed and soln was allowed to warm to r.t. After 4 h, when the substrate was fully consumed (GC), the mixture was poured into sat. aq NH₄Cl (80 mL). The lower organic phase was separated, dried (MgSO₄), and concentrated to give a crude mixture of dimers 6c and 7c, which were purified by column chromatography [silica gel, CHCl₃–MeOH (50:1)].

Bis[(2S)-2-methylbutyl] (2R,5S)-2,5-Dimethyl-2,5-dihydro[1,3]thiazolo[5,4-d][1,3]thiazole-2,5-dicarboxylate (6d)

Yield: 0.235 g (36%); colorless oil. R_f = 0.80 (CHCl₃–MeOH, 50:1).

IR (ATR): 3480, 2960, 2933, 2867, 1730, 1620, 1460, 1383, 1375, 1257, 1120 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 0.90 (t, J = 7.70 Hz, 6 H, CH₂CH ₃), 0.91 (d, J = 5.91 Hz, 6 H, CH ₃CH), 1.17 (m, 2 H, CH_a H _b), 1.38 (m, 2 H, CH _aH_b), 1.75 (m, 2 H, CH₃CH), 2.04 (s, 6 H, β-CH₃), 4.04 (m, 4 H, OCH₂).

¹³C NMR (75 MHz, CDCl₃): δ = 11.2, 16.3, 25.9, 26.7, 34.0, 71.0, 98.9, 168.6, 178.2.

Anal. Calcd for C₁₈H₂₈N₂O₄S₂: C, 53.97; H, 7.05; N, 6.99. Found: C, 53.88; H, 7.15; N, 7.08.

Bis[(2S)-2-methylbutyl] 2,3-Diisothiocyanato 2,3-dimethylsuccinate (7d)

Yield: 0.280 g (43%); colorless oil. R_f = 0.70 (CHCl₃–MeOH, 50:1).

IR (ATR): 2963, 2933, 2877, 2022, 1740, 1459, 1382, 1257, 1095, 961 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 0.93 (t, J = 7.45 Hz, 6 H, CH₂CH ₃), 0.98 (d, J = 6.77 Hz, 6 H, CH ₃CH), 1.25 (m, 2 H, CH_a H _b), 1.47 (m, 2 H, CH _aH_b), 1.74 (s, 6 H, β-CH₃), 1.79 (m, 2 H, CH₃CH), 4.08 (m, 4 H, OCH₂).

¹³C NMR (75 MHz, CDCl₃): δ = 11.1, 16.4, 22.5, 25.9, 34.0, 70.5, 72.0, 140.6, 167.9.

GC-MS (EI; 70 eV): m/z (%) = 71 (100), 130 (33), 200 (24), 201 (31), 401 (2) [M + H]⁺.

Anal. Calcd for C₁₈H₂₈N₂O₄S₂: C, 53.97; H, 7.05; N, 6.99. Found: C, 53.85; H, 7.14; N, 6.92.

Dimethyl 2,7-Diisothiocyanatosuberate (19a); Typical Procedure

A 250-mL Erlenmeyer flask was placed on a magnetic stirrer and charged with a suspension of dimethyl 2,7-diaminosuberate dihydrochloride 18a (1.801 g, 5.90 mmol) in CHCl₃ (60 mL). Cl₂C=S (0.99 mL, 1.493 g, 12.98 mmol) and NaHCO₃ (3.272 g, 38.95 mmol) were added to the stirred soln followed by H₂O (40 mL) added carefully in a dropwise manner. The mixture was then stirred for 2.5 h. The organic layer was separated, dried (MgSO₄), and concentrated under reduced pressure. The crude product was purified by column chromatography [silica gel, CHCl₃– MeOH (30:1)] to give a yellowish waxy solid; yield: 1.55 g (83%); mp 47–48 °C; R_f (TLC plates) = 0.90 (CHCl₃–MeOH, 30:1).

IR (ATR): 2956, 2935, 2862, 2066, 1745, 1436, 1220, 1168, 986 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 1.48 (m, 4 H, CH₂), 1.92 (m, 4 H, CH₂), 3.81 (s, 6 H, OCH₃), 4.29 (m, 2 H, ABX spin system, CHNCS).

¹³C NMR (75 MHz, CDCl₃): δ = 24.8, 33.1, 53.2, 59.2, 137.7, 168.7.

Anal. Calcd for C₁₂H₁₆N₂O₄S₂: C, 45.55; H, 5.10; N, 8.85. Found: C, 45.67; H, 5.20; N, 8.66.

Dimethyl 2,9-Diisothiocyanatosebacate (19b)

Yield: 1.524 g (75%); yellow oil; R_f = 0.90 (CHCl₃–MeOH, 30:1).

IR (ATR): 2931, 2859, 2059, 1744, 1437, 1331, 1265, 1206, 1176, 986 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 1.36 (m, 4 H, CH₂), 1.43 (m, 4 H, CH₂), 1.88 (m, 4 H, CH₂), 3.81 (s, 6 H, OCH₃), 4.28 (m, 2 H, ABX spin system, CHNCS).

¹³C NMR (75 MHz, CDCl₃): δ = 25.3, 28.4, 33.4, 53.1, 59.4, 137.2, 168.9.

Anal. Calcd for C₁₄H₂₀N₂O₄S₂: C, 48.82; H, 5.85; N, 8.13. Found: C, 48.74; H, 5.90; N, 8.24.

Dimethyl cis- and trans-1,2-Diisothiocyanatocyclohexane-1,2-dicarboxylate (20a)

A soln of diester 19a (1.451 g, 4.58 mmol) in CH₂Cl₂ (40 mL) was cooled to –96 °C under argon and TiCl₄ (1.11 mL, 1.920 g, 10.1 mmol) was added in one batch. The mixture was stirred for 20 min at –96 °C before a soln of DIPEA (1.74 mL, 1.300 g, 10.1 mmol) in CH₂Cl₂ (4 mL) was added in a dropwise manner. The soln turned deep blue as a result of the formation of the titanium(IV) enolate. The mixture was stirred at –96 °C for 30 min and then the cooling bath was removed and soln was allowed to warm to r.t. After 5 h, when the substrate was fully consumed (TLC), the mixture was poured into sat. aq NH₄Cl (80 mL). The lower organic phase was separated, dried (MgSO₄), and concentrated. The resulting crude product was purified by column chromatography [silica gel, CHCl₃–MeOH (30:1)] to give a yellow solid; yield: 0.88 g (61%; near equimolar mixture of cis- and trans-diastereoisomers); R_f = 0.85 (CHCl₃–MeOH, 30:1).

IR (ATR): 2936, 2865, 2032, 1741, 1466, 1368, 1233, 1180, 1095, 1015 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 1.70 (m, 4 H, CH₂), 1.96 (m, 2 H, CH₂), 2.29 (m, 2 H, CH₂), 3.91, 3.86 and 3.84 (s, 6 H, OCH₃).

¹³C NMR (75 MHz, CDCl₃): δ = 22.5, 20.2 and 20.0 (CH₂), 33.5, 32.0 and 31.9 (CH₂), 54.3, 53.9 and 53.6 (OCH₃), 75.2, 73.1, and 69.3 (α-C), 142.2 and 139.4 (NCS), 167.7 (COO).

Anal. Calcd for C₁₂H₁₄N₂O₄S₂: C, 45.85; H, 4.49; N, 8.91. Found: C, 45.94; H, 4.67; N, 8.84.

Dimethyl cis- and trans-1,2-Diisothiocyanatocyclooctane-1,2-dicarboxylate (20b)

Yield: 0.84 g (54%); yellow solid; R_f = 0.85 (CHCl₃–MeOH, 30:1).

IR (ATR): 2935, 2863, 2035, 1740, 1465, 1368, 1238, 1183, 1097, 1018 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 1.11 (m, 2 H, CH₂), 1.34 (m, 6 H, CH₂), 1.88 (m, 2 H, CH₂), 2.03 (m, 2 H, CH₂), 3.87, 3.85, 3.82, and 3.81 (s, 6 H, OCH₃).

¹³C NMR (75 MHz, CDCl₃): δ = 25.2, 24.6, and 24.4 (CH₂), 28.8 and 28.1 (CH₂), 34.1 and 33.4 (CH₂), 54.1, 53.9, and 53.1 (OCH₃), 75.9 (α-C), 141.1, 140.8, and 140.4 (NCS), 167.8, 167.7 and 167.2 (COO).

Anal. Calcd for C₁₄H₁₈N₂O₄S₂: C, 49.11; H, 5.30; N, 8.18. Found: C, 48.95; H, 5.43; N, 8.28.

Ethyl 5-[(2-Ethoxy-2-oxoethyl)amino]-2-thioxo-2,3-dihydro-1,3-thiazole-4-carboxylate (24h)

A 250-mL Erlenmeyer flask, protected from moisture by a CaCl₂ guard tube, was placed on a stirrer and charged with anhyd DMF (90 mL) and ethyl isothiocyanatoacetate (3.77 g, 0.026 mol). The mixture was cooled to 0 °C on an ice bath. NaH (0.834 g, 0.035 mol) was carefully added in several portions to the stirred soln and then the ice bath was removed and the mixture was stirred for 2 h at r.t. The red-brown soln was poured into cold H₂O and acidified to pH 5 with 10% aq HCl aq. The resulting yellow precipitate was filtered off and crystallized (EtOH) to give the pure pale-yellow product. The filtrate was extracted with EtOAc (2 × 100 mL), and the organic layers were washed successively with H₂O (80 mL) and brine (50 mL) then dried (MgSO₄) and concentrated. The brown residue was crystallized (EtOH) to give a second portion of the product; total yield: 2.45 g (65%); mp 188 °C.

IR (ATR): 3362, 3077, 2974, 2913, 1742, 1652, 1592, 1511, 1428, 1211, 1183, 1020 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 1.31 (t, J = 7.15 Hz, 3 H, CH₃), 1.36 (t, J = 7.14 Hz, 3 H, CH₃), 3.90 (d, J = 5.78 Hz, 2 H, CH₂), 4.27 (q, J = 7.15 Hz, 2 H, OCH₂), 4.32 (q, J = 7.14 Hz, 2 H, OCH₂), 7.11 (br s, 1 H, NH), 9.77 (br s, 1 H, NH).

¹³C NMR (75 MHz, CDCl₃): δ = 14.1 (CH₃), 14.4 (CH₃), 48.1 (CH₂), 61.3 (OCH₂), 62.2 (OCH₂), 106.2 (C=C), 153.9 (C=C), 158.5 (CO₂Et), 168.1 (CO₂Et), 176.8 (C=S).

Anal. Calcd for C₁₀H₁₄N₂O₄S₂: C, 41.37; H, 4.83; N, 9.65. Found: C, 41.45; H, 4.73; N, 9.82.

Acknowledgment

We are grateful to the Polish Ministry of Science and Higher Education (Grant No. N N204 310037) and the European Regional Development Fund in the framework of the Polish Innovation Economy Operational Program (contract no. POIG.02.01.00-12-023/08) for financial support.

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• 20 Crystallographic data for compound 6a have been deposited with the accession numbers CCDC 862700 and can be obtained free of charge from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: +44(1223)336033; E-mail: deposit@ccdc.cam.ac.uk; Web site: www.ccdc.cam.ac.uk/conts/retrieving.html

• References

• 1 Kodama H. Chem. Zentralbl. 1923; 94: 206
  Search in Google Scholar
• 2a Berlin AYa, Levi IS. J. Gen. Chem. USSR (Engl. Transl.) 1963; 33: 846
  Search in Google Scholar
• 2b Tsogoeva SB, Hateley MJ, Yalalov DA, Meindl K, Weckbecker C, Huthmacher K. Bioorg. Med. Chem. 2005; 13: 5680
  CrossrefSearch in Google Scholar
• 2c Floch L, Uher M, Lesko J. Collect. Czech. Chem. Commun. 1989; 54: 206
  CrossrefSearch in Google Scholar
• 2d Dobosz M, Pachuta-Stec A. Acta Pol. Pharm. 1994; 51: 457
  Search in Google Scholar
• 2e Ryczek J. J. Heterocycl. Chem. 2003; 40: 665
  CrossrefSearch in Google Scholar
• 2f Chowdhury AZ, Shaifullah M, Shibata Y. Chem. Pharm. Bull. 2001; 49: 391
  CrossrefSearch in Google Scholar
• 3a Bates SR. E, Guthrie DJ. S, Elmore DT. J. Chem. Res., Miniprint 1993; 2: 0201
  Search in Google Scholar
• 3b Foye WO, Dabade SV, Kelley CJ, Lebrun E, Rapenbusch R. Med. Chem. Res. 1998; 8: 542
  Search in Google Scholar
• 4a Masquelin T, Sprenger D, Baer R, Gerber F, Mercadal Y. Helv. Chim. Acta 1998; 81: 646
  CrossrefSearch in Google Scholar
• 4b Cabon G, Gaucher B, Gegout A, Heulle S, Masquelin T. Chimia 2003; 57: 248
  CrossrefSearch in Google Scholar
• 5 Floch L, Martvoň A, Uher M, Leško J, Weis W. Collect. Czech. Chem. Commun. 1977; 42: 2945
  CrossrefSearch in Google Scholar
• 6a Dobosz M, Pitucha M, Wujec M. Acta Pol. Pharm. 1996; 53: 31
  Search in Google Scholar
• 6b Veverka M, Marchalin M. Collect. Czech. Chem. Commun. 1987; 52: 113
  CrossrefSearch in Google Scholar
• 7a Cież D, Szneler E. Monatsh. Chem. 2005; 136: 2059
  CrossrefSearch in Google Scholar
• 7b Cież D, Szneler E. J. Chem. Res. 2007; 200
• 8 Cież D. Tetrahedron 2007; 63: 4510
  CrossrefSearch in Google Scholar
• 9 Cież D, Kalinowska-Tłuścik J, Peyrat S, Touko EP, Trzewik B, Zwoliński K. Synthesis 2008; 3261
  Thieme Connect
• 10 Cież D, Kalinowska-Tłuścik J, Marchewka J. Aust. J. Chem. 2012; in press;
  Search in Google Scholar
• 11 Periasamy M. ARKIVOC 2002; (vii): 151
  Search in Google Scholar
• 12 Cież D. Org. Lett. 2009; 11: 4282
  CrossrefSearch in Google Scholar
• 13 Cież D, Kalinowska-Tłuścik J. Synlett 2012; 23: 267
  Thieme ConnectSearch in Google Scholar
• 14 Farrugia LJ. J. Appl. Crystallogr. 1997; 30: 565
  Search in Google Scholar
• 15a Matsumura Y, Nishimura M, Hiu H, Watanabe M, Kise N. J. Org. Chem. 1996; 61: 2809
  CrossrefPubMedSearch in Google Scholar
• 15b Rao VD, Periasamy M. Tetrahedron: Asymmetry 2000; 11: 1151
  CrossrefSearch in Google Scholar
• 16a Weingarten H, Miles MG, Edelmann NK. Inorg. Chem. 1968; 7: 879
  CrossrefSearch in Google Scholar
• 16b Ribeiro N, Fetzer L, Streiff S, Désaubry L. Synlett 2010; 2928
  Thieme Connect
• 17 Penn JH, Plants RC, An L. Chem. Commun. (Cambridge) 1999; 2359
• 18 Alvarez-Ibarra C, Csákÿ AG, Colmenero B, Quiroga ML. J. Org. Chem. 1997; 62: 2478
  CrossrefSearch in Google Scholar
• 19 Hayashida O, Sebo L, Rebek J. J. Org. Chem. 2002; 67: 8291
  CrossrefSearch in Google Scholar
• 20 Crystallographic data for compound 6a have been deposited with the accession numbers CCDC 862700 and can be obtained free of charge from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: +44(1223)336033; E-mail: deposit@ccdc.cam.ac.uk; Web site: www.ccdc.cam.ac.uk/conts/retrieving.html

• Supplementary Material