Stereoselective follow-up reactions of (S)-2-sulfanyl nitriles

Article abstract of DOI:10.1016/S0957-4166(99)00155-X

Follow-up reactions of (S)-2-acetylthionitriles (S)-2 and (S)-2- benzylthionitriles (S)-4, respectively, are described. (S)-2- Acetylthionitriles were converted via Pinner reaction to ethyl (S)-2- mercaptocarboxylates (S)-3 almost without racemization. Two routes for the stereoselective preparation of 1,2-amino thiols (S)-5 have been investigated. Hydrogenation of (S)-2 with BH₃ THF gave (S)-5 which, however, could not be isolated directly under the reaction conditions, but, by reaction with phosgene in an alkaline medium, the 1,2-amino thiols (S)-5 could be trapped as (S)-5-alkylthiazolidinones (S)-7 in good yields without racemization. (S)- Benzylthioamines (S)-6, derived from (S)-4 by hydrogenation with LiA1H₄, were debenzylated with sodium in NH₃ to give (S)-5 which were isolated as hydrochlorides with high enantiomeric excesses. Optically active thiomorpholines (S)-12 are accessible starting from (S)-2-(2- hydroxyethylthio)nitriles (S)- 10 which are first chlorinated with SOCl₂ to yield (S)-2-(2-chloroethylthio)nitriles (S)-11 which after hydrogenation with LiAlH₄ cyclize to give thiomorpholines (S)12.

Full text of DOI:10.1016/S0957-4166(99)00155-X

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1777–1786
Stereoselective follow-up reactions of (S)-2-sulfanyl nitriles1
Sebastian Gaupp † and Franz Effenberger ∗
Institut für Organische Chemie der Universität Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart, Germany
Received 12 April 1999; accepted 21 April 1999
Abstract
Follow-up reactions of (S)-2-acetylthionitriles (S)-2 and (S)-2-benzylthionitriles (S)-4, respectively, are des-
cribed. (S)-2-Acetylthionitriles were converted via Pinner reaction to ethyl (S)-2-mercaptocarboxylates (S)-3
almost without racemization. Two routes for the stereoselective preparation of 1,2-amino thiols (S)-5 have been
investigated. Hydrogenation of (S)-2 with BH3·THF gave (S)-5 which, however, could not be isolated directly
under the reaction conditions, but, by reaction with phosgene in an alkaline medium, the 1,2-amino thiols (S)-5
could be trapped as (S)-5-alkylthiazolidinones (S)-7 in good yields without racemization. (S)-Benzylthioamines
(S)-6, derived from (S)-4 by hydrogenation with LiAlH4, were debenzylated with sodium in NH3 to give (S)-5
which were isolated as hydrochlorides with high enantiomeric excesses. Optically active thiomorpholines (S)-12
are accessible starting from (S)-2-(2-hydroxyethylthio)nitriles(S)-10 which are first chlorinated with SOCl2 to yield
(S)-2-(2-chloroethylthio)nitriles(S)-11 which after hydrogenation with LiAlH4 cyclize to give thiomorpholines (S)-
12. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
In the preceding publication1 we have described the stereoselective preparation of various (S)-2-
sulfanyl nitriles which have been obtained in high enantiomeric excesses starting from sulfonyl-activated
(R)-cyanohydrins by enzyme-catalyzed addition of HCN to aldehydes and ketones, respectively, and
subsequent sulfonylation. 2-Sulfanyl nitriles represent S-protected thiocyanohydrins whose synthetic
potential is assumed to be nearly as high as that of cyanohydrins.2 While follow-up reactions of optically
active cyanohydrins have been investigated extensively in recent years,2 nothing is known about reactions
of chiral thiocyanohydrins.
In the present publication we report on follow-up reactions of (S)-2-sulfanyl nitriles especially with
regard to stereoselectivity of the transformations.
∗
†
Corresponding author. E-mail: franz.effenberger@po.uni-stuttgart.de
Part of dissertation, Universität Stuttgart, 1998.
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00155-X

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2. Preparation of optically active 2-mercaptocarboxylic acid esters (S)-3
2-Mercaptocarboxylic acids and their esters are of particular interest as components of pharmacolo-
gically active oligopeptides (e.g., ACE3 or renin inhibitors4). Chiral 2-mercaptocarboxylic acids are
accessible starting from either naturally occurring amino acids4,5 or from 2-hydroxycarboxylic acid
derivatives.6
We now describe an alternative route to optically active 2-mercaptocarboxylates starting from (R)-
2-(sulfonyloxy)nitriles (R)-1 by reaction with potassium thioacetate to yield the corresponding (S)-
2-acetylthionitriles (S)-2 which can be converted directly under conditions analogous to the Pinner
reaction7 to give (S)-2-mercaptocarboxylates (S)-3 as outlined in Scheme 1.
Scheme 1.
As can be seen from the results summarized in Table 1, the reaction proceeds almost without
racemization. It was not possible to decide whether removal of the acetyl group or Pinner reaction occurs
first.
With the conversion of compounds (R)-1 to (S)-3 it could also be proved that the reaction of (R)-1 with
KSAc to 2-acetylthionitriles (S)-2, described in the preceding publication,1 proceeded with complete
inversion of configuration. A comparison of the optical rotation sign of (S)-3b with literature data4
unambiguously confirms its (S)-configuration.
3. Preparation of optically active 1-amino-2-thiols (S)-5
Optically active 1,2-amino thiols (S)-5, which are of increasing interest as N,S-chelate ligands8
and as intermediates in the synthesis of chiral heterocycles, have been prepared so far from L-amino
acids.9 In recent times 1,2-amino thiols have been investigated especially with respect to their biological
activities as aminopeptidase N-inhibitors.9,10 The preparation of (S)-1-amino-2-thiols (S)-5, as illustrated
in Scheme 2, starts from (S)-acetylthio- and benzylthionitriles (S)-2 and (S)-4, respectively.1
Preliminary investigations have shown that 2-acetylthionitriles 2 could be reacted with LiAlH4 in
diethyl ether to give the corresponding amino thiols. The required aqueous workup, however, is di-
Table 1
Conversion of acetylthionitriles 2 to ethyl 2-mercaptocarboxylates 3 under Pinner reaction conditions

S. Gaupp, F. Effenberger / Tetrahedron: Asymmetry 10 (1999) 1777–1786
1779
Scheme 2.
Table 2
5-Alkylthiazolidin-2-ones (S)-7 from 2-acetylthionitriles (S)-2 via 1,2-amino thiols (S)-5 by reduction
with BH3·THF and subsequent reaction with phosgene
sadvantageous since amino thiols exist in aqueous media mainly in zwitterionic form,11 resulting in an
extremely difficult extraction and isolation in neutral form. Therefore, LiAlH4 was replaced by BH3·THF.
In this case, the reduction could be terminated with methanol, whereby excess borane was converted
to methyl borate which could be removed under vacuum. We first investigated this reaction by using
racemic 2-acetylthiopentanenitrile (RS)-2a. After 14 h reaction time, neither the cyano nor the acetyl
group were detected any more by NMR spectroscopy. The hydrogenation of (RS)-2a with BH3·THF
afforded a product mixture from which the desired 1-aminopentane-2-thiol (RS)-5a could not be isolated
by distillation, chromatography or recrystallization of the hydrochloride.
Analogous to the preparation of 1,3-oxazolidin-6-ones12 we treated the crude amino thiol (RS)-5a with
a solution of phosgene in toluene13 in an alkaline medium to yield the stable 5-propyl-1,3-thiazolidin-2-
one (RS)-7a. Compound 7a could be purified by chromatography. By applying these reaction conditions
to optically active 2-acetylthionitriles (S)-2 the corresponding (S)-5-alkylthiazolidin-2-ones (S)-7 were
obtained without any racemization (Scheme 2, Table 2).
Since the isolation of (S)-1-amino-2-thiols (S)-5 failed by this method, we have investigated an
alternative route starting from (S)-2-benzylthionitriles (S)-4 as outlined in Scheme 2. The cyano group in
(S)-4 could easily be hydrogenated to the amino function with LiAlH4 in diethyl ether within 1 h. The
(S)-1,2-benzylthioamines (S)-6, which were obtained thereby in a GC purity of >96% and high chemical
yields (Table 3), could be debenzylated without further purification.
The removal of the benzyl group by using sodium in NH3 has already been described for racemic
2-benzylthioamines.14 Based on the published method, sodium was added to (S)-2-benzylthioamines
(S)-6 in liquid NH3 at −35°C, and the reaction was terminated with NH4Cl. After nonaqueous workup,

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Table 3
Hydrogenation of (S)-2-benzylthionitriles (S)-4 with LiAlH4 to (S)-2-benzylthioamines (S)-6 and their
conversion to (S)-1-amino-2-thiols (S)-5 with sodium in NH3
(S)-1-amino-2-thiols (S)-5 were precipitated as hydrochlorides (Scheme 2, Table 3). A direct gas
chromatographic separation of the enantiomers of both 6 and 5 was not possible. Enantiomeric excesses
of 5 were therefore determined again after cyclization to 5-alkyl-2-thiazolidinones 7. As can be seen from
Table 3, both reactions — hydrogenation of (S)-4 and subsequent debenzylation of benzylthioamines (S)-
6 to (S)-5 — proceed without racemization.
4. Preparation of 5-alkyl-2,4-thiazolidinediones 9
Numerous synthetic routes starting from thiocyano derivatives have been published for the preparation
of thiazole, thiazoline and thiazolidine derivatives.15 2,4-Thiazolidinediones with substituents at the 5-
position are known as components of a new class of antidiabetic agents.16 Syntheses published so far
afford, however, only racemic 2,4-thiazolidinediones.16b–g
(S)-2-Thiocyanatonitriles1 appear to open an access to chiral sulfur–nitrogen heterocycles of this type.
Therefore, we have investigated the preparation of 2,4-thiazolidinediones by intramolecular cyclization,
using first racemic 2-thiocyanatopentanenitrile (RS)-8 as outlined in Scheme 3.
Scheme 3.
Owing to the high acidity of the proton at the 5-position of thiazolidinediones,16g the acid-catalyzed
cyclization seems to be most suitable with respect to the preparation of optically active compounds 9.
Compound (RS)-8 was heated in concentrated HCl/ethanol to 80°C for 14 h, and after chromatographic
purification 5-propyl-2,4-thiazolidinedione (RS)-9 was obtained in 57% yield. Under these reaction
conditions, however, (S)-thiocyanatopentanenitrile (S)-8 reacted with complete racemization. Neither
shorter reaction times nor lower temperatures or replacement of conc. HCl by 10% HCl could prevent
racemization. In all cases, conversion to 9 decreased and the formation of by-products became dominant.
Obviously, racemization occurs by an acid-catalyzed keto–enol tautomerism. H–D exchange experiments
also indicate deprotonation in acidic media. With increasing acidity of the medium, H–D exchange and
racemization was accelerated.

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5. Preparation of optically active 2-alkylthiomorpholines (S)-12
A further interesting class of compounds available from 2-sulfanyl nitriles are thiomorpholines,
which were investigated recently with respect to their biological and pharmacological properties.17
Numerous synthetic approaches to racemic thiomorpholines have been described in the literature.18 (S)-
2-(2-Hydroxyethylthio)nitriles1 should present suitable chiral starting compounds for the synthesis of
optically active thiomorpholines. Scheme 4 illustrates the synthetic pathway to chiral thiomorpholines
starting from (S)-2-(2-hydroxyethylthio)nitriles (S)-10.
Scheme 4.
In the first step, (S)-2-(2-hydroxyethylthio)nitriles (S)-10 were converted with thionyl chloride to the
corresponding (S)-2-(2-chloroethylthio)nitriles (S)-11 in high chemical yields after chromatographic
purification (Table 4). Compounds (S)-11 should react, after hydrogenation of the cyano group to
the amine, intramolecularly to give thiomorpholines 12. Nonaqueous workup is favorable in order to
prevent hydrolysis of (S)-11 to starting (S)-10. The determination of enantiomeric excesses of (S)-11 by
gas chromatography has failed so far. The nearly constant optical rotation values, however, indicate a
racemization-free reaction.
By hydrogenation of nitriles 11 at 0°C with LiAlH4, the primarily formed 1,2-(20-chloroethyl-
thio)amines spontaneously cyclized to the desired 2-alkylthiomorpholines 12 (Scheme 4). Compound
(S)-11a was reacted as a single enantiomer to (S)-12a while 11b,c were reacted as racemates. The
enantiomeric excess of (S)-12a could be determined by gas chromatography on a β-cyclodextrin phase
after acetylation. Compound (S)-12a was obtained in 92% yield with only 62% ee (determined from
crude free thiomorpholine). In order to achieve this result (R)-1a (88% ee) was reacted at room
temperature with mercaptoethanol to give (S)-10a, and then (S)-11a, obtained from (S)-10a as described
above, was hydrogenated directly with LiAlH4 without further purification by distillation. While 12b
was obtained as the hydrochloride in analytically pure form with 62% yield, the cyclohexyl derivative
12c could not be isolated as the hydrochloride or as the free thiomorpholine.
Table 4
(S)-2-(2-Chloroethylthio)nitriles (S)-11 prepared from (S)-2-(2-hydroxyethylthio)nitriles (S)-10 by
reaction with SOCl2

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6. Experimental
6.1. Materials and methods
1
Melting points were determined on a Büchi SMP-20 and are uncorrected. H NMR spectra were
recorded on a Bruker AC 250 F (250 MHz) with TMS as an internal standard. Column chromatography
was performed with glass columns of different sizes packed with silica gel S (Riedel–de Haen) or
silica gel 60 (Merck), grain size 0.032–0.063 mm. Optical rotations were determined in a Perkin–Elmer
polarimeter 241 LC. GC for determination of enantiomeric excess: Hewlett–Packard 6890 Series with
FID, 0.9 bar hydrogen, column 30 m×0.32 mm, phase Chiraldex B-TA (ICT).
6.2. Preparation of ethyl (S)-2-mercaptocarboxylates (S)-3 from 2-acetylthionitriles (S)-2; general
procedure
To a solution of 2 (6.4–17.5 mmol) in diethyl ether (10–20 mL) at 0°C an ice-cooled 10% solution
of HCl in ethanol (10–20 mL) (for 2a) or a saturated solution of HCl in ethanol (20–40 mL) was
slowly added dropwise. The stirred reaction mixture was allowed to warm to room temperature (14 h),
hydrolyzed with ice-water and extracted with diethyl ether. The combined extracts were dried (MgSO4),
and concentrated in vacuo. The residue was chromatographed on silica gel with petroleum ether/ethyl
acetate.
6.3. Preparation of (S)-5-alkyl-1,3-thiazolidin-2-ones (S)-7 from (S)-2; general procedure
To a 1 M solution of 2 (3.2–10 mmol) in THF at 0°C was added dropwise within 10 min a 1 M
solution of BH3·THF (2 equiv.). After being stirred for 36 h, the reaction was terminated with methanol
(2 mL/mmol 2), and the solvent was removed in vacuo. The residue was taken up in water:toluene (1:1)
(2 mL/mmol 2), and K2CO3 (3 equiv. based on 2) was added. The reaction mixture was cooled to 0°C,
and a 2 M solution of phosgene in toluene (2 equiv.) was added. After being stirred vigorously for 0.5
h, the reaction mixture was extracted with diethyl ether. The combined extracts were dried (MgSO4),
and concentrated in vacuo. The residue was chromatographed on silica gel with petroleum ether/ethyl
acetate.
6.4. Preparation of (S)-2-benzylthioamines (S)-6 from (S)-2-benzylthionitriles (S)-4; general procedure
A solution of 4 (4a,c: 10 mmol, 4b: 13 mmol) in diethyl ether (15 mL (4a) or 40 mL) was added
dropwise within 1 h to LiAlH4 (1.3 equiv.) in diethyl ether (15–40 mL) at 0°C, and the reaction
mixture was stirred for 14 h at room temperature. Water was added until Al–Li-hydroxides coagulated.
The organic phase was decanted, dried (MgSO4), and concentrated. The remaining colorless to light
yellow oils (GC purity >96%) were distilled in vacuo. Compounds 6 were reacted to 5 without further
purification.
6.5. Preparation of (S)-1-amino-2-thiols (S)-5 from (S)-6; general procedure
According to Carroll et al.14 sodium metal was added in small portions to 6 (5.4–7.7 mmol) in liquid
NH3 at −35°C until a permanent blue color remained for 45 min. Then NH4Cl was added to decompose
excess sodium, and the reaction mixture was allowed to warm up for removal of NH3. After addition of

S. Gaupp, F. Effenberger / Tetrahedron: Asymmetry 10 (1999) 1777–1786
1783
diethyl ether (50 mL), the remaining NH3 was removed by heating the solution on a hot water bath. The
reaction mixture was cooled to 0°C, HCl saturated ethanol (2 mL/mmol 6) was added, and the reaction
mixture stirred for at least 2 h at 0°C. The solid was filtered off and extracted with isopropanol. The
combined extracts were concentrated in vacuo, diethyl ether was added, and the hydrochlorides were
allowed to precipitate at −20°C.
6.6. Determination of enantiomeric excesses by conversion to 1,3-thiazolidin-2-ones 7
To a solution of 5 (20 mg) in concentrated K2CO3 solution (1 mL) toluene (1 mL) and a 2 M solution
of phosgene in toluene (20 µL) were added, and the reaction mixture was shaken for 10 min. The reaction
was extracted with ethyl acetate (2 mL). The extract was filtered through a silica gel column (3×0.5 cm)
with ethyl acetate (2 mL). The enantiomeric excess was determined directly from the filtrate.

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6.7. 5-Propyl-2,4-thiazolidinedione 9 by acid-catalyzed cyclization of 2-thiocyanatopentanenitrile 8
A solution of 8 (1.0 g, 7.13 mmol) in ethanol was added dropwise to a solution of conc. HCl in ethanol
(30:30 mL), and the reaction mixture was heated to 80°C for 14 h. Then it was set to pH 5–6 with
NaHCO3 and extracted with diethyl ether. The combined extracts were dried (MgSO4), and concentrated
in vacuo. The residue was chromatographed on silica gel with petroleum ether/ethyl acetate to give 0.64
1
g (57%) 9 as a colorless oil. H NMR (CDCl3): δ 0.99 (t, J=7.3 Hz, 3H, CH3), 1.33–1.61 (m, 2H,
CH2CH3), 1.83–2.23 (m, 2H, CH2CH), 4.29 (dd, J=9.3, 4.2 Hz, 1H, CH). Anal. calcd for C6H9NO2S
(159.2): C, 45.27; H, 5.69; N, 8.80; S, 20.14. Found: C, 45.36; H, 5.70; N, 8.55; S, 20.14.
6.8. Preparation of (S)-2-(2-chloroethylthio)nitriles (S)-11 from (S)-2-(2-hydroxyethylthio)nitriles
(S)-10; general procedure
To a solution of 10 (8.8–9.8 mmol) in dichloromethane (20–40 mL) at 0°C SOCl2 (ca. 1.5 equiv. with
respect to 10) was slowly added dropwise, and the reaction mixture was stirred at room temperature for

S. Gaupp, F. Effenberger / Tetrahedron: Asymmetry 10 (1999) 1777–1786
1785
12 h. Solvent and excess SOCl2 were removed in vacuo, and the residue was chromatographed on silica
gel with petroleum ether/dichloromethane.
6.9. Preparation of 2-alkylthiomorpholines 12 from 2-(2-chloroethylthio)nitriles 11; general procedure
A solution of 11 (11a: 5.6 mmol, 11b: 8.9 mmol) in diethyl ether (11a: 10 mL, 11b: 20 mL) was slowly
added dropwise to a suspension of LiAlH4 (1.6 equiv. with respect to 11) in diethyl ether (10 or 20 mL)
at 0°C. After being stirred for 3 h, water was added until Li–Al salts coagulated. The organic phase was
decanted, dried (MgSO4), and concentrated in vacuo. In the case of 12a, yield and enantiomeric excess
were determined from the concentrate. Compound 12b crystallized as the hydrochloride without addition
of HCl, and was sonified in diethyl ether to result in analytically pure form.
6.10. Determination of enantiomeric excess of 12a
A solution of crude 12a (10 µL), pyridine (10 µL) and acetic anhydride (50 µL) in dichloromethane
(0.2 mL) was heated to 60°C for 3 h. The reaction mixture was filtered through a silica gel column (3×0.5
cm) with dichloromethane (2 mL). The enantiomeric excess was determined directly from the filtrate.
Acknowledgements
We would like to thank the Bundesministerium für Bildung und Forschung (Zentrales Schwerpunkt-
programm Bioverfahrenstechnik, Stuttgart) and the Fonds der Chemischen Industrie for financial support.
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