Chiral isothiocyanates-An approach to determination of the absolute configuration using circular dichroism measurement

Article abstract of DOI:10.1016/j.molstruc.2012.12.048

Chiral alkyl 2-isothiocyanates have been obtained from enantiopure, aliphatic amines. ECD measurements allowed us to correlate an absolute configuration at C-2 with a sign of the Cotton effect (CE) observed for n-π^- transition at the longer-wavelength range of the spectrum. Chirooptical data calculated for all enantiomers were consistent with the measured CE values and indicated that the weak absorption band at 240 nm could give an important information concerning the stereochemistry of simple, chiral isothiocyanates. Optically active esters of 2-isothiocyanatocarboxylic acids, prepared from α-amino acids, showed two absorption bands located over 195 nm. The more intensive band near 200 nm and the weak absorption located at 250 nm were related to n-π^- transitions in NCS group. TD DFT calculations carried out for methyl esters of 2-isothiocyanatocarboxylic acids showed the correlation between signs of CE determined for both absorption bands, and the absolute configuration on C-2.

Full text of DOI:10.1016/j.molstruc.2012.12.048

Journal of Molecular Structure 1037 (2013) 225–235
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Chiral isothiocyanates – An approach to determination of the absolute
configuration using circular dichroism measurement
b
Oskar Michalski a, , Dariusz Ciez
⇑
_
a Department of Chemistry and Physics, University of Agriculture, ul. Balicka 122, 31-149 Kraków, Poland
b Department of Chemistry, Jagiellonian University, ul. Ingardena 3, 30-060 Kraków, Poland
g r a p h i c a l a b s t r a c t
h i g h l i g h t s
"
"
"
"
Several chiral 2-isothiocyanates
were synthesized and their ECD
spectra were measured.
TD DFT calculations (B3LYP/6-
311+G(2d,p), PCM) reproduced all
observed Cotton effects.
Cotton effect in the range of 210–
230 nm depends on the
configuration of C-2.
Correlation between CE at 210–
230 nm and configuration of C-2 was
observed also in presence of other
stereogenic centers.
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 May 2012
Received in revised form 21 December 2012
Accepted 24 December 2012
Available online 4 January 2013
Chiral alkyl 2-isothiocyanates have been obtained from enantiopure, aliphatic amines. ECD measure-
ments allowed us to correlate an absolute configuration at C-2 with a sign of the Cotton effect (CE)
observed for n–pꢀ transition at the longer-wavelength range of the spectrum. Chirooptical data calculated
for all enantiomers were consistent with the measured CE values and indicated that the weak absorption
band at 240 nm could give an important information concerning the stereochemistry of simple, chiral iso-
thiocyanates. Optically active esters of 2-isothiocyanatocarboxylic acids, prepared from
a-amino acids,
Keywords:
showed two absorption bands located over 195 nm. The more intensive band near 200 nm and the weak
absorption located at 250 nm were related to n–pꢀ transitions in NCS group. TD DFT calculations carried
out for methyl esters of 2-isothiocyanatocarboxylic acids showed the correlation between signs of CE
determined for both absorption bands, and the absolute configuration on C-2.
Ó 2013 Elsevier B.V. All rights reserved.
Isothiocyanates
Absolute configuration
Cotton effect
CD spectroscopy
TD DFT calculations
1. Introduction
oxylates that have found applications not only as convenient reac-
tants for preparation of heterocyclic carboxylic acids [6–8] but also
For many years isothiocyanates have attracted considerable
attention because of their wide application in the organic synthe-
sis, easy of preparation, and stability. Simple aryl and alkyl isothio-
cyanates have been used for synthesis of thioureas and thioamides
[1], as well as precursors for various sulfur containing heterocycles
[2–5]. A particular interest was directed to 2-isothiocyanatocarb-
as precursors of 2,3-diaminoacids [9,10]. Our research on the oxi-
dative coupling of 2-isothiocyanatocarboxylic esters [9] prompted
us to look for a simple and easy method for determination of an
absolute configuration of the investigated 2-isothiocyanatoesters.
The prepared 2-isothiocyanate derivatives were usually amor-
phous solids or oils (and their conversion into crystalline form
needed additional chemical transformations). Thus we assumed
that chirooptical methods would be an efficient alternative for an
X-ray structure determination. However, published data concern-
ing applications of CD technique in the field of chiral isothiocya-
nates were rather limited.
⇑
Corresponding author.
E-mail addresses: o.michalski@ur.krakow.pl (O. Michalski), ciez@chemia.uj.
_
edu.pl (D. Ciez).
0022-2860/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molstruc.2012.12.048

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O. Michalski, D. Ciez / Journal of Molecular Structure 1037 (2013) 225–235
Fig. 1. Comparison of the measured and calculated UV–VIS and CD spectra of (3R)-3-isothiocyanato-2,2-dimethylbutane 1a.
The first attempt to investigate optical properties of
can be very useful for stereochemical investigations of chiral amine
derivatives.
Analysis of CD spectra including signs of Cotton effects and
chromophoric (cottonogenic) ANCS substituents in 2-isothiocy-
anatocarboxylates was made by Crabbé et al. [11] but precise mea-
surements and analysis of a weak CE were impossible because of
the technical reasons. After that report further investigations of
chirooptical properties of isothiocyanates have been virtually ne-
shape of absorption bands is nowadays the standard procedure
widely applied for determination of absolute configuration. Config-
uration of some chiral compounds can be however inferred only
from signs of Cotton effects according to two types of semiempir-
ical rules – sector rules and helicity (chirality) rules. The sector
rules have been assigned to inherently achiral chromophores and
based on three principal theories: the one-electron theory [13],
the coupled oscillator theory [14], and the electromagnetic (cou-
pling) theory [15]. The one-electron theory has been dedicated
´
glected. Fifty years after Crabbe’s work Gawronski et al. [12] pub-
lished very important article devoted to the circular dichroism of
chiral thioureas and isothiocyanates but focused mainly on exci-
ton-coupled CD spectra. The authors have compared experimental
and calculated UV and ECD spectra of some chiral 1,2-diaminocy-
clohexane derivatives and revealed that ANCS chromophoric group

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O. Michalski, D. Ciez / Journal of Molecular Structure 1037 (2013) 225–235
227
mainly to n–pꢀ transitions and stated the theoretical grounds for
the octant rule that allows to correlate the absolute configuration
of chiral ketones (including steroidal ketones) with measured CE
signs [16]. Development of the sector rules led to sector rule for
alkenes [17], bifurcated sector rule for chiral allenes [18], quadrant
rule proposed for chiral benzylic alcohols [19], chiral benzylic
derivatives (known as Brewster-Buta/Smith-Fontana sector rule)
[20] and mandelic acid derivatives [21], salicylideneamino chirality
rule designed for investigation of the absolute configuration of chi-
ral, primary amines [22] and benzoate sector rule designated for
determination of absolute configuration of chiral, cyclic secondary
alcohols [23]. The coupled oscillator theory described the optical
activity of chiral compounds bearing two or more achiral chro-
mophores characterized by strong electric transition moments.
The development of this theory in the case of two interacting chro-
mophores furnished the exciton splitting method that allowed to
easily deduce absolute configuration of a stereogenic center based
on analysis of bisignate CE couplets [24].
Helicity rules have been established for inherently chiral chro-
mophores that could be observed in unsaturated ketones, dienes,
twisted alkenes, disulfides and helicenes. The most important
semiempirical methods used for determination of absolute config-
uration are b,c-unsaturated ketone helicity rule [25a] (that can be
also applied for homoconjugated aldehydes and acid derivatives)
and diene helicity rule [25].
In this paper we report results of our research on application of
circular dichroism (CD) measurements to establishing absolute
configuration of chiral isothiocyanates. The measurements were
supported by TD DFT calculations of CD spectra.
2. Results and discussion
Our research has been divided into three parts – at the beginning
we studied chirooptical properties of simple alkyl 2-isothiocya-
nates. Measurements of UV and ECD spectra were followed by con-
formational analysis of alkyl 2-isothiocyanates and calculation of
their electronic spectra. The second step consisted of analysis of
methyl 2-isothiocyanatocarboxylic esters bearing an additional
chromophore attached to the stereogenic center. Simulated ECD
spectra were compared with those obtained in the experimental
way. Finally, our earlier observations and conclusions were verified
using chiral esters of 2-isothiocyanatocarboxylic acids with enantio-
pure alcohols and diols. These compounds served as test samples.
Structure optimization of (3R)-3-isothiocyanato-2,2-dimethyl-
butane 1a was performed using the density functional theory
Fig. 2. Key molecular orbitals involved in transitions calculated for ECD spectrum of
1a.
Table 1
TD DFT conformational analysis of alkyl 2-isothiocyanates (1a and 2a) and 2-isothiocyanatocarboxylates (3a–5a).
Compound
Conformer
Dihedral angles (°)
CANAC angle (°)
D
G (kJ/mol)
Population (%)
dh1a
dh2b
dh3c
dh4d
dh5e
1a
2a
cf1
cf1
cf2
cf3
cf1
cf2
cf1
cf2
cf1
cf2
172
–
–
–
–
–
–
–
–
–
–
–
58
75
60
61
–
–
–
–
–
–
151
150
149
150
144
147
145
144
144
148
100
ꢁ169
ꢁ171
ꢁ61
ꢁ61
ꢁ158
26
ꢁ157
ꢁ156
ꢁ160
30
0
61.2
20.6
18.1
52.7
47.3
73.3
26.7
67.3
32.7
161
2.696
3.019
0
0.270
0
2.505
0
1.788
ꢁ167
ꢁ36
ꢁ53
ꢁ33
ꢁ34
ꢁ23
ꢁ33
3a
4a
5a
ꢁ177
178
ꢁ177
ꢁ177
ꢁ177
178
ꢁ56
53
178
ꢁ179
a
b
c
CANAC2AC3 (1a and 2a), CANAC2AC1 (3a, 4a, and 5a).
NAC2AC3AC4 (2a), NAC2AC1AOMe (3a, 4a, and 5a).
C2AC1AOAC.
NAC2AC3AC4.
C2AC3AC4AH (4a), C2AC3AC4AC5 (5a).
d
e

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O. Michalski, D. Ciez / Journal of Molecular Structure 1037 (2013) 225–235
Fig. 3. Calculated and measured ECD spectra of (2R)-2-isothiocyanatoheptane 2a.
Fig. 4. Relationships between absolute configuration and signs of the Cotton effects observed for enantiopure alkyl 2-isothiocyanates.
(DFT) method at the B3LYP/6-311+G(2d,p) level. Calculations
provided significantly improved results. We decided to use the
polarized continuum (PCM) model. In this relatively simple meth-
od the solvent is considered as a continuum of uniform dielectric
constant and the molecule is located in a cavity defined as the un-
ion of a series of interlocking atomic spheres. All further ECD sim-
ulations were done in the same method (B3LYP/6-311+G(2d,p),
PCM/MeOH).
showed that there was only one conformer responsible for
absorption in the UV range. Isothiocyanate group was bent and
the calculated angle C2AN@C was 150°. Measured UV–VIS spec-
trum of 1a showed an absorption band at kmax = 244 nm as-
signed to the formally forbidden transition n–pꢀ in the ANCS
fragment of the alkyl isothiocyanate. The second absorption band
correlated with a
p–
pꢀ transition in the ANCS chromophore ap-
The first transition (HOMO ? LUMO, n–pꢀ) was forbidden and
with oscillator strength f = 0.0003 was not visible in UV spectrum.
However, this transition was detected in the ECD spectrum as a
very weak, positive band located around 270 nm. Weak, negative
CE observed at 228 nm was assigned to formally forbidden n–pꢀ
transition. This transition had much higher oscillator strength
f = 0.0173 due to the same orientation in space and therefore better
overlap of the both involved molecular orbitals (Fig. 2). In calcu-
lated spectrum this absorption band is centered at 238 nm. Accord-
ing to calculations a positive band assigned to higher transition
peared below 195 nm, out of the range of recording (Fig. 1). Both
calculated and measured absorption bands assigned to the n–pꢀ
transitions appeared in the range of 210–250 nm. Thus, we re-
strained the recording region and selected methanol as the most
convenient solvent.
Calculated UV and ECD spectra using B3LYP/6-31+G(d), and
B3LYP/6-311+G(2d,p) basis sets were in reasonable agreement
with the experimental spectra of 1a in terms of sign, range, and rel-
ative intensity (Fig. 1). However modeling a molecule in solution

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O. Michalski, D. Ciez / Journal of Molecular Structure 1037 (2013) 225–235
229
Fig. 5. Calculated and measured UV and ECD spectra of methyl (2R)-2-isothiocyanatopropanoate 3a.
from the HOMO should be observed at 210 nm. In the experimental
ECD spectrum this band is partially covered by strong negative sig-
nals at shorter wavelengths.
recorded and calculated ECD spectra of the isothiocyanate 2a
showed a striking similarity. A weak, negative CE for n–pꢀ transi-
tion was observed at 229 nm whereas the simulated spectrum
showed this absorption band at 239 nm. The most intensive nega-
The bands correlated with p–
pꢀ transitions of the ANCS group
have not been observed in the experimental spectrum because
they appeared out of a measuring range – calculations showed
their position below 160 nm.
tive Cotton effect assigned to the p–
pꢀ transition of the ANCS
group was calculated to appear at 185 nm, which is below the
range of recording (Fig. 3).
Conformational analysis of (2R)-2-isothiocyanatoheptane 2a
indicated a presence of three major conformers and their relative
populations were summarized in Table 1. Similarly to 1a the isothi-
ocyanate moiety was bent giving the angle C2AN@C near 150°. The
simulated spectrum was obtained as a weighted mean of all
spectra calculated for examined conformers. Comparison of the
These two examples have pointed out that a sign of the CE as-
signed to formally forbidden transition n–pꢀ in ANCS group at the
stereogenic center C-2 can be correlated with the absolute configu-
ration at this center. This is of importance in the case when the
main absorption band of
exceeds a lower limit of the recording. The experiment carried
p–
pꢀ transition in the ANCS substituent

_
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O. Michalski, D. Ciez / Journal of Molecular Structure 1037 (2013) 225–235
Fig. 6. Calculated and measured ECD spectra of chiral (2R)-2-isothiocyanatocarboxylates 4a and 5a.
out for simple alkyl isothiocyanates showed that the positive CE can
be assigned to S enantiomers, whereas R enantiomers of alkyl iso-
thiocyanates give the negative CE (Fig. 4). Our observations were
consistent with those previously reported for chiral 1,2-diisothio-
cyanatocyclohexane [12]. The determined correlation remained
unchangeable for measured samples in methanol and acetonitrile.
The next phase of our research included analysis of chirooptical
behavior of methyl and ethyl 2-isothiocyanatocarboxylates. In
comparison with 2-alkylisothiocyanates investigated earlier 2-
isothiocyanatocarboxylates were more complex case for analysis.
They have two chromophores bonded to the same stereogenic cen-
ter and hence exhibit higher conformational diversity. Moreover
interactions between both cottonogenic moieties are possible.
Methyl (2R)-2-isothiocyanatopropanoate 3a obtained in two
steps from unnatural D-alanine has been chosen as the simplest
model of chiral 2-isothiocyanatoester. Conformational analysis of
3a showed two major conformers with an equilibrium ratio
52.7:42.3 (Table 1). Calculation of UV–VIS spectrum of 3a led us
to results similar to the experimental data. ECD spectrum recorded
for the methanolic solution of 3a exhibited a strong negative CE at
206.5 nm and very weak negative CE at 245 nm. It corresponds to
absorption bands – at 196 nm and at 250 nm – observed in UV–VIS
spectrum of 3a. The very weak, long-wave absorption is more
likely assigned to n–pꢀ transitions in ANCS group. Simulations
reproduced sign and shape of the both observed bands significantly
shifted to shorter wavelengths (Fig. 5).
Methyl (2R)-2-isothiocyanato-4-methylpentanoate 4a showed
a strong negative CE at 208.5 nm and very weak negative CE at
244 nm (Fig. 6). Geometry optimization showed three conformers
of 4a with an equilibrium ratio 89.8:7.7:2.5 (Table 1). Simulated

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O. Michalski, D. Ciez / Journal of Molecular Structure 1037 (2013) 225–235
231
Fig. 7. Correlations of signs of the Cotton effects and absolute configurations observed for enantiopure methyl 2-isothiocyanatocarboxylates.
Fig. 8. CD spectra of chiral esters derived from (2S)-2-isothiocyanatocarboxylates. The configuration of an ester group does not have any effect on a sign of the CE.
Fig. 9. CD spectrum measured for the chiral ester 10c shows the correlation between sign of the CE and absolute configuration on C-2 of 2-isothiocyanatocarboxylic acid. The
positive CE indicates S configuration at the C-2 stereogenic centers.

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O. Michalski, D. Ciez / Journal of Molecular Structure 1037 (2013) 225–235
232
ECD spectrum of 4a was very similar to the recorded one. Measure-
ment of ECD spectra of dimethyl (2R)-2-isothiocyanatopentanedio-
ate 5a provided very similar results showing two negative Cotton
effects at 208.5 and 244 nm. The calculated ECD spectrum of 5a
was nearly identical with the recorded spectrum (Fig. 6).
In general, the absolute configuration of chiral alkyl 2-isothiocy-
anatocarboxylic esters can be easily established based on a sign of
the CE in the range of 205–210 nm. Similarly to the alkyl isothiocy-
anates investigated earlier, 2-isothiocyanatocarboxylates show
strong negative CE for enantiomers R and the positive CE for their
optical antipodes (Fig. 7).
The third step of our investigations consisted of the synthesis of
some esters of enantiopure 2-isothiocyanatocarboxylic acids with
chiral alcohols and diols. We intended to clarify if any chiral ester
group could have an effect on a sign of the CE. Experiment that we
have carried out allowed us to verify applicability and find limita-
tions of the above-mentioned method. ECD spectra recorded for
Elite-5MS capillary column. GC/MS analyses were carried out using
Thermo Scientific ISQ Single Quadrupole GC–MS, equipped with
Elite-5MS capillary column. Column chromatography was per-
formed using commercial Merck silica gel 60 (230–400 mesh
ASTM) and TLC analysis was carried out using Merck TLC silica
gel 60 plates. Optical rotation measurements were performed
using Jasco P-2000 polarimeter. Melting points were measured
on an Electrothermal 9100 apparatus. CD and UV spectra were re-
corded using Jasco J-815 spectrometer with 10 mm (UV) and 2 mm
(CD) path lengths. The sample concentrations (mmol/L) for CD
measurements were as follows: 5.305 (1a), 3.319 (2a), 3.935
(3a), 4.866 (4a), 5.058 (5a), 4.112 (6), 12.20 (7), 5.650 (8), 4.570
(9b), 1.040 (10c).
4.2. Computations
All calculations were carried out with the GAUSSIAN 03W rev.
E.01 program [26]. Conformational analysis of all studied com-
pounds was performed with the use of B3LYP functional and 6-
31+G(d) basis set. The final optimization of the conformers found
was accomplished with B3LYP/6-311+G(2d,p) basis set for mole-
cules in vacuo. Then Gibbs energies of the conformers were calcu-
lated using the same DFT level and polarized continuum (PCM)
model for modeling of the solvent (methanol).
In order to eliminate known systematic errors in Gibbs energies
a scaling factor (0.9877) was used for zero-point energies calcula-
tions [27]. ECD calculations were performed with the TD DFT
method at B3LYP/6-311+G(2d,p) level with the PCM/methanol sol-
vent model. The ECD spectra of all significant conformers were
constructed from Gauss curves with the bandwidth 0.25 eV at
1/e peak height. The final simulated spectra were composed of
appropriate spectra of conformers weighted according to their
relative population.
endo-(1S)-bornyl (S)-2-isothiocyanatopropanoate 6,
L-menthyl
(S)-2-isothiocyanato-4-methylpentanoate 7, D-mentyl (S)-2-isoth-
iocyanato-4-methylpentanoate 8 and (2S)-2-methylbutyl (2S)-2-
isothiocyanatopropanoate 9b showed in the region 205–210 nm
strong, positive CE (Fig. 8) indicating absolute configuration S at
the stereogenic center C-2.
Chiral diester, 1,2,5,6-di-O-cyclohexylideno-D-mannitol-3,4-di-
O-[(2S)-2-isothiocyanatopropanoate] 10c gave the ECD spectrum
with the positive CE at 207.6 nm confirming an absolute configura-
tion S at the both stereogenic centers C-2 of 2-isothiocyanatopro-
panoate (Fig. 9).
3. Conclusion
Absolute configuration of chiral alkil isothiocyanates can be
established by means of circular dichroism (CD) measurements.
Analysis of the chirooptical properties of simple R and S alkyl iso-
thiocyanates bearing –NCS group at the stereogenic center showed
that a sign of the Cotton effect observed in the range of 220–230 nm
depends on the absolute configuration at this center. Although this
longer-wavelength absorption related to a forbidden n–pꢀ transi-
tion in the ANCS group is weak it could play an important role when
other, stronger absorption bands cannot be observed. In particular,
calculated ECD spectra with the TD DFT method show that the
4.3. Syntheses of enantiopure alkyl isothiocyanates and 2-
isothiocyanatocarboxylic esters
(Tables 2 and 3).
4.3.1. (3R)-3-Isothiocyanato-2,2-dimethylbutane 1a and (3S)-3-
isothiocyanato-2,2-dimethylbutane 1b
(3R)-3-isothiocyanato-2,2-dimethylbutane 1a and (3S)-3-isoth-
iocyanato-2,2-dimethylbutane 1b have been prepared according to
the literature data [28,29].
strong p–
pꢀ absorption of the ANCS moiety can be usually observed
below 190 nm – this short-wavelength range imposes essential
limitations for solvents and measurement conditions. On the other
hand chiral 2-isothiocyanatocarboxylic esters derived from a-ami-
4.3.2. Representative synthesis of (2R)-(-)-2-isothiocyanatoheptane 2a
A mixture of commercial (2R)-(-)-2-aminoheptane (0.431 g;
3.74 mmol), chloroform (40 mL), and water (30 mL) was treated
with thiophosgene (0.31 mL; 0.467 g; 4.06 mmol) and sodium
bicarbonate (0.691 g; 8.22 mmol). The resulting mixture was stir-
red for 2 h. Then the lower organic layer was separated and dried
over Na2SO4. Next, the mixture was concentrated and crude oily
product was purified using column chromatography (silica gel,
cyclohexane – ethyl acetate 5:1) to give pure (2R)-(-)-2-isothiocy-
no acids show a strong absorption band over 200 nm assigned to n–
pꢀ transition in the NCS chromophore. The sign of a Cotton effect
observed near 210 nm is correlated with absolute configuration at
C-2 and it is independent on the configuration of any chiral ester
group. Circular dichroism spectra of methyl 2-isothiocyanatocarb-
oxylic esters can be easily reproduced using TD DFT method at
the B3LYP/6-311+G(2d,p) level with the PCM/methanol solvent
model with very high accuracy.
anatoheptane 2a as a yellow oil possessing mushroom-like odor
ꢁ 79.8° (c 0.012 M in CHCl3); 1H NMR
24
4. Experimental
(0.505 g, 86%); [
a]
D
(300 MHz, CDCl3): dH 0.91 (t, J 6.9 Hz, 3H), 1.30 (m, 4H), 1.34 (d, J
6.5 Hz, 3H), 1.57 (m, 4H,), 3.75 (ddq, J 6.4, 6.4 and 6.5 Hz, 1H)
ppm; 13C NMR (75 MHz, CDCl3): dC 13.9, 21.8, 22.4, 25.7, 31.2,
37.5, 54.0, 129.7 ppm; Anal. Calcd. for C8H15NS: C, 61.09; H, 9.61;
N, 8.91. Found: C, 61.00; H, 9.68; N, 8.83.
4.1. General methods
NMR spectra were recorded on a Bruker Avance II 300 MHz
spectrometer (using TMS as an internal standard). IR spectra were
measured using a FT-IR spectrometer Nicolet IR200 with a single-
reflection ATR head. Microanalyses were carried out using CHNS
Vario Micro-Cube analyzer and their results were in good agree-
ment with the calculated values. Gas chromatography was per-
formed using PerkinElmer Clarus 500 apparatus equipped with
4.3.3. (2S)-(+)-2-isothiocyanatoheptane 2b
(2S)-(+)-2-isothiocyanatoheptane 2b has been prepared analo-
gously to the above-mentioned procedure. Column chromatogra-
phy afforded pure 2b as a yellow oil having disagreeable smell;

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O. Michalski, D. Ciez / Journal of Molecular Structure 1037 (2013) 225–235
233
Table 2
Chiral alkyl isothiocyanates and 2-isothiocyanatocarboxylates – optical rotations and synthetic methods.
R
R0
C-2 configuration
[
a]
D
Literature
1a
1b
2a
2b
3a
3b
4a
4b
5a
5b
6
CH3
tertBu
R
S
R
S
R
S
R
S
R
S
S
S
S
S
ꢁ36.6
+36.9
ꢁ79.8
+80.9
ꢁ23.9
+23.4
+17.9
ꢁ18.0
+18.7
ꢁ18.8
+168.0
+92.1
+204.0
+17.8
[15]
[16]
–
tertBu
CH3
CH3
nC5H11
CH3
nC5H11
–
CH3
CO2Me
CH3
[18]
[19]
–
[20]
–
[21]
–
–
CO2Me
CH2AiPr
CO2Me
CO2Me
CH2AiPr
CO2Me
CH2CH2CO2Me
CH3
CH2CH2CO2Me
CO2Me
CO2-endo-(1S)-bornyl
CO2-
CO2-
7
8
9b
L
-menthyl
-menthyl
CH2AiPr
CH2AiPr
CH3
D
–
–
CO2-(2S)-2-methylbutyl
Table 3
was treated with thiophosgene (2.10 mL; 3.17 g; 27.7 mmol) and
sodium bicarbonate (6.83 g; 81.3 mmol). The resulting mixture
was stirred vigorously until the orange solution turns pale yellow
(40–70 min.). After the thiophosgene was consumed, the lower or-
ganic layer was separated and dried over MgSO4. Next, the mixture
was concentrated and crude oily product was purified using col-
umn chromatography (silica gel, cyclohexane – ethyl acetate 5:1)
to give pure endo-(1S)-bornyl (2S)-2-isothiocyanatopropanoate 6.
Chiral 1,2,5,6-di-O-cyclohexylideno-D-mannitol-3,4-O-diesters – configurations and
optical rotations.
R
G
C-2 configuration
[a]
D
10a
10b
10c
CH3
CH3
CH3
NHCO2tertBu
NHþ3 Clꢁ
NCS
S
S
S
+42.9
+41.2
+41.2
Yellowish oil (1.050 g, 79%); [
a]
D + 168.0° (c 0.12 M in acetone).
IR (ATR): 2981, 2954, 2048, 1736, 1218 cmꢁ1
;
1H NMR (300 MHz,
CDCl3): dH 0.86 (s, 3H), 0.89 (s, 3H), 0.91 (s, 3H), 1.01 (m, 1H),
1.30 (m, 2H), 1.59 (d, J 7.1 Hz, 3H), 1.72 (m, 1H), 1.77 (m, 1H),
1.91 (m, 1H), 2.40 (m, 1H), 4.31 (q, J 7.1 Hz, 1H), 4.97 (m, 1H)
ppm; 13C NMR (75 MHz, CDCl3): dC 13.5, 18.8, 19.5, 19.6, 27.1,
28.0, 36.7, 44.8, 48.0, 48.9, 55.0, 82.5, 137.5, 169.2 ppm; GC–MS
(EI): m/z 267 (M+), 181, 137, 136, 121, 95, 81; Anal. Calcd. for
(0.481 g, 82%); [a]
24 + 80.9° (c 0.011 M in CHCl3); Anal. Calcd. for
D
C8H15NS: C, 61.09; H, 9.61; N, 8.91. Found: C, 61.15; H, 9.72; N,
C14H21NO2S: C, 62.88; H, 7.92; N, 5.24. Found: C, 62.95; H, 7.79;
N, 5.30.
8.92.
4.3.4. Methyl 2-isothiocyanatocarboxylic esters 3–5
Methyl 2-isothiocyanatocarboxylic esters 3–5 have been ob-
tained from appropriate a-amino acid methyl esters in accordance
4.3.6. (+)
L
-menthyl (2S)-2-isothiocyanato-4-methylpentanoate 7
-leucine- -menthyl ester hydro-
chloride [31] based on the described above protocol. Yellowish
oil (0.972 g, 74%); [
24 + 92.1° (c 0.12 M in acetone). IR (ATR):
2956, 2928, 2058, 1740, 1269 cmꢁ1
Ester has been prepared from
L
L
with procedure described for 2a [30].
a
]
D
;
1H NMR (300 MHz, CDCl3):
4.3.4.1. Methyl (2R)-(-)-2-isothiocyanatopropanoate 3a. [31],
dH 0.76 (d, J 7.0 Hz, 3H), 0.87 (m, 1H), 0.91 (d, J 7.0 Hz, 3H), 0.91
(d, J 6.5 Hz, 3H), 0.95 (d, J 6.5 Hz, 3H), 0.98 (d, J 6.4 Hz, 3H), 1.04
(m, 1H), 1.44 (m, 3H), 1.67 (m, 3H), 1.82 (m, 3H), 4.22 (q, 1H),
1.98 (m, 1H), 4.75 (dt, J 4.4 and 10.9 Hz, 1H) ppm; 13C NMR
(75 MHz, CDCl3): dC 16.2, 20.7, 21.1, 21.9, 22.7, 23.3, 25.1, 26.2,
31.4, 34.1, 40.6, 42.0, 46.8, 58.2, 76.8, 136.9, 168.4 ppm; GC–MS
(EI): m/z 311 (M+), 183, 174, 139, 138, 97, 83; Anal. Calcd. for
[
a]D ꢁ 23.9° (c 0.020 M in CHCl3).
4.3.4.2. Methyl (2S)-(+)-2-isothiocyanatopropanoate 3b. [32],
[a]D + 23.4° (c 0.022 M in CHCl3).
4.3.4.3. Methyl (2R)-(+)-2-isothiocyanato-4-methylpentanoate 4a.
Methyl (2R)-(+)-2-isothiocyanato-4-methylpentanoate 4a and di-
methyl (2R)-(+)-2-isothiocyanato-pentanedioate 5a have not been
yet described in the literature. Both esters have been synthesized
in accordance with the Floch method [30] and purified by vacuum
distillation.
C17H29NO2S: C, 65.56; H, 9.38; N, 4.50. Found: C, 65.65; H, 9.45;
N, 4.61.
4.3.7. (+) -menthyl (2S)-2-isothiocyanato-4-methylpentanoate 8
D
Ester has been prepared from
chloride [31].
Yellow oil (0.856 g, 81%); [
(ATR): 2959, 2931, 2118, 1736, 1276 cmꢁ1
L
-leucine-
a]
24 + 204° (c 0.10 M in acetone); IR
D
D-menthyl ester hydro-
4.3.4.4.
Methyl
(2S)-(-)-2-isothiocyanato-4-methylpentanoate
;
1H NMR (300 MHz,
4b. [33], [a]D ꢁ 18.0° (c 0.016 M in CHCl3).
CDCl3): dH 0.75 (d, J 7.0 Hz, 3H), 0.87 (m, 1H), 0.91 (d, J 7.1 Hz,
3H), 0.91 (d, J 6.5 Hz, 3H), 0.94 (d, J 4.1 Hz, 3H), 0.95 (d, J 6.4 Hz,
3H), 1.08 (m, 1H), 1.46 (m, 3H), 1.68 (m, 3H), 1.86 (m, 3H), 2.04
(m, 1H), 4.22 (m, 1H), 4.74 (dt, J 4.4 and 10.9 Hz, 1H) ppm. 13C
NMR (75 MHz, CDCl3): dC 16.1, 20.9, 21.3, 22.1, 22.9, 23.3, 25.3,
26.3, 31.6, 34.2, 40.7, 42.1, 47.0, 58.5, 76.7, 136.9, 168.6 ppm; Anal.
Calcd. for C17H29NO2S: C, 65.56; H, 9.38; N, 4.50. Found: C, 65.61;
H, 9.26; N, 4.57.
4.3.4.5. Dimethyl (2S)-(-)-2-isothiocyanato pentanedioate 5b. [34].
D ꢁ 18.8° (c 0.010 M in CHCl3).
[a]
4.3.5. Representative synthesis of endo-(1S)-bornyl (2S)-2-
isothiocyanatopropanoate 6
A mixture of L-alanine endo-(1S)-bornyl ester hydrochloride
(7.09 g; 27.1 mmol) [10], chloroform (60 mL), and water (40 mL)

_
O. Michalski, D. Ciez / Journal of Molecular Structure 1037 (2013) 225–235
234
4.3.8. Representative two-step synthesis of (2S)-2-methylbutyl (2S)-2-
isothiocyanatopropanoate 9b
Representative two-step synthesis of (2S)-2-methylbutyl (2S)-
2-isothiocyanatopropanoate 9b via protected (2S)-2-methylbutyl
(2S)-[(2-tert-butoxycarbonyl)amino] propanoate 9a.
reactants were stirred for 30 h at room temperature. Next the
solvent was evaporated, ethyl acetate (75 mL) was added to
the flask and precipitate DCU was separated by filtration. The fil-
trate containing diester was washed with 5% HCl (25 mL) and
brine (20 mL), dried over Na2SO4 and evaporated. The crude
product – 1,2,5,6-di-O-cyclohexylideno-D-mannitol-3,4-di-O-[(2S)
-2-(N-tert-butyloxycarbonyl)aminopropanoate] – was purified on
column chromatography (SiO2; eluent: CHCl3 – MeOH 10:1; Rf on
4.3.8.1. Synthesis of intermediate (2S)-2-methylbutyl (2S)-[(2-tert-
butoxycarbonyl)amino] propanoate 9a. A 100 mL Erlenmeyer flask
was charged with DCM (50 mL), N-Boc-L-AlaOH (2.00 g;
10.6 mmol) and DCC (2.18 g; 10.6 mmol). Reactants were stirred
at room temperature for 30 min and (2S)-(-)-2-methyl-1-butanol
(1.20 mL; 0.983 g; 11.1 mmol) and DMAP (0.123 g; 1.01 mmol)
were added. The reaction mixture was stirred overnight and next
evaporated under reduced pressure. The remainder was dissolved
in ethyl acetate (80 mL), DCU was filtered off and the organic solu-
tion was washed with 5% HCl aq (36 mL) and brine (30 mL). Organ-
ic layer was dried using anhydrous MgSO4. Evaporation of the
solvent gave a crude product which was purified on column chro-
TLC 0.88) to give pure diester 10a (1.965 g, 57%); [a]
23 + 42.9° (c
D
0.003 M in CHCl3); 1H NMR (300 MHz, CDCl3): dH 1.38 (t, J
7.25 Hz, 6H), 1.43 (s, 18H), 4.19 (m, 2H), 4.32 (m, 2H), 5.30 (m,
2H) ppm; 13C NMR (75 MHz, CDCl3) dC 18.2, 23.7, 23.9, 25.1,
28.3, 34.6, 36.1, 49.3, 65.6, 72.5, 73.5, 79.9, 110.1, 155.2,
172.2 ppm; Anal. Calcd. for C34H56N2O12: C, 59.63; H, 8.24; N,
4.09. Found: C, 59.78; H, 8.45; N, 3.92.
4.3.9.2. Deprotection of diester 10a to (+) 1,2,5,6-di-O-cyclohexylide-
no-D-mannitol-3,4-di-O-[(2S)-2-aminopropanoate] dihydrochloride
10b. Round-bottomed 100 mL flask placed on a magnetic stirrer
and equipped with argon inlet was charged with 1,2,5,6-di-
O-cyclohexylideno-D-mannitol-3,4-di-O-[(2S)-2-(N-tert-butyloxy-
carbonyl)aminopropanoate] 10a (0.606 g; 0.885 mmol) and 4 N
HCl in dioxane (20 mL). The reactants were stirred under argon
at room temperature for 2 h and after the deprotection was com-
pleted, dioxane was evaporated under reduced pressure (tempera-
ture should not exceed 55 °C) and remainder was dried for 3 h over
CaCl2 at room temperature. Next anhydrous diethyl ether (5 mL)
was added and the obtained suspension was cooled to ꢁ20 °C, fil-
tered off and the solid product was dried under vacuum. The ob-
tained 1,2,5,6-di-O-cyclohexylideno-D-mannitol-3,4-di-O-[(2S)-2-
aminopropanoate] dihydrochloride 10b (0.303 g, 61%) was pure
enough to be transformed into 2-isothiocyanate ester 10c;
matography (SiO2; eluent CHCl3 – MeOH 30:1) to give pure 9a as a
23
colorless oil (1.96 g, 72%); [
a]
ꢁ 4.1° (c 0.011 M in CHCl3). IR
D
(ATR): 3361, 2967, 2935, 1712, 1248 cmꢁ1
;
1H NMR (300 MHz,
CDCl3): dH 0.89 (t, J 7.4 Hz, 3H), 0.91 (d, J 6.8 Hz, 3H), 1.18 (m,
1H), 1.37 (d, J 7.2 Hz, 3H), 1.41 (m, 1H), 1.43 (s, 9H), 1.70 (m,
1H), 3.94 (dd, J 6.6 and 10.8 Hz, 1H), 3.98 (dd, J 6.1 and 10.8 Hz,
1H), 4.30 (m, 1H), 5.05 (br s, 1H) ppm; 13C NMR (75 MHz, CDCl3):
dC 11.2, 16.3, 18.8, 25.9, 28.3, 34.1, 49.3, 69.8, 79.7, 155.1,
173.4 ppm; Anal. Calcd. for C13H25NO4: C, 60.21; H, 9.72; N, 5.40.
Found: C, 60.15; H, 9.75; N, 5.51.
4.3.8.2. Transformation of intermediate 9a to (2S)-2-methylbutyl (2S)-
2-isothiocyanatopropanoate
9b. Three-necked
100 mL
flask
equipped with argon inlet and protected from the moisture was
placed on a magnetic stirrer and (2S)-2-methylbutyl (2S)-[(2-
tert-butoxycarbonyl)amino] propanoate 9a (1.76 g; 6.80 mmol)
dissolved in DCM (55 mL) was added. Next TFA (12.4 mL;
19.03 g; 167 mmol) was added and the reaction mixture was stir-
red under argon at room temperature for 2.5 h. After the deprotec-
tion was completed, DCM and TFA were evaporated at 45 °C under
reduced pressure and the residue was transferred into Erlenmeyer
250 mL flask and dissolved in CHCl3 (40 mL). Next thiophosgene
(0.52 mL; 0.786 g; 6.80 mmol) was added dropwise to the flask, so-
dium hydrogen carbonate (1.71 g; 20.4 mmol) and water (60 mL)
were added and reactants were intensively stirred for 1 h. Lower
organic layer was separated, dried with anhydrous MgSO4 and sol-
vent was evaporated giving a crude oily product. Purification was
carried out by distillation under reduced pressure (124–126 °C at
9 mmHg) to furnish pure 9b as the yellowish oil (0.750 g, 55%);
[a]
23 + 41.2° (c 0.002 M in CHCl3); 1H NMR (300 MHz, CDCl3): dH
D
1.44 (d, J 6.31 Hz, 6H), 1.74 (m, 4H), 1.51 (m, 16H), 3.73 (m, 2H),
3.97 (m, 2H), 4.10 (m, 2H), 4.27 (m, 2H), 5.36 (m, 2H) ppm; 13C
NMR (75 MHz, CDCl3): dC 15.6, 23.5, 24.4, 26.3, 41.2, 47.9, 66.3,
69.2, 72.5, 109.1, 170.4 ppm; Anal. Calcd. for C24H42Cl2N2O8: C,
51.71; H, 7.59; N, 5.02. Found: C, 51.48; H, 7.89; N, 4.88.
4.3.9.3. Synthesis of (+) 1,2,5,6-di-O-cyclohexylideno-D-mannitol-3,4-
di-O-[(2S)-2-isothiocyanatopropanoate] 10c. A suspension of
1,2,5,6-di-O-cyclohexylideno-D-mannitol-3,4-di-O-[(2S)-2-amino-
propanoate] dihydrochloride 10b (0.226 g; 0.405 mmol) in chloro-
form (50 mL) was placed on a magnetic stirrer and cooled to
ꢁ78 °C. Next thiophosgene (0.062 mL; 0.093 g; 0.81 mmol) was
added in one batch and DIEA (0.42 mL; 0.314 g; 2.43 mmol) in
chloroform (3 mL) was dropped to the solution. The reaction mix-
ture was stirred for 5 min. at ꢁ78 °C and 60 min. at room temper-
ature. Next the solvent was evaporated under reduced pressure
(temperature should not exceed 40 °C) and oily product 8 was
purified using column chromatography (SiO2; eluent: CHCl3
– MeOH 30:1; Rf on TLC: 0.48) to give 1,2,5,6-di-O-cyclohexylide-
[a]
24 = +17.8° (c 0.003 M; CHCl3); IR (ATR): 2964, 2935, 2878,
D
2059, 1743, 1458, 1379, 1289, 1198, 1149, 1054 cmꢁ1 1H NMR
;
(300 MHz, CDCl3): dH 0.91 (t, J 7.4 Hz, 3H), 0.95 (d, J 6.8 Hz, 3H),
1.22 (m, 1H), 1.44 (m, 1H), 1.59 (d, J 7.1 Hz, 3H), 1.77 (m, 1H),
4.01 (dd, J 6.6 and 10.5 Hz, 1H), 4.08 (dd, J 5.94 and 10.5 Hz, 1H),
4.33 (q, J 7.1 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3): dC 11.1,
16.3, 19.5, 25.9, 34.0, 54.9, 70.9, 137.3, 169.0 ppm; GC–MS (EI):
m/z 201 (M+), 132, 86, 71; Anal. Calcd. for C9H15NO2S: C, 53.70;
H, 7.51; N, 6.96. Found: C, 53.78; H, 7.65; N, 7.05.
no-D-mannitol-3,4-di-O-[(2S)-2-isothiocyanatopropanoate]
10c
as yellow oil (0.122 g, 54%); [
a]
25 + 41.2° (c 0.012 M in CHCl3);
D
1H NMR (300 MHz, CDCl3): dH 1.58 (m, 20H), 1.62 (d, J 7.08 Hz,
6H), 3.84 (dd, J 5.6 and 8.4 Hz, 2H), 3.98 (dd, J 6.1 and 8.4 Hz,
2H), 4.16 (m, 2H), 4.38 (q, J 7.1 Hz, 2H), 5.37 (d, J 7.1 Hz, 2H)
ppm; 13C NMR (75 MHz, CDCl3): dC 19.5, 23.7, 23.8, 25.0, 26.3,
34.6, 36.2, 54.8, 66.0, 73.3, 73.9, 110.4, 138.1, 167.8 ppm; Anal.
Calcd. for C26H36N2O8S2: C, 54.91; H, 6.38; N, 4.93. Found: C,
54.97; H, 6.30; N, 4.86.
4.3.9. Three step synthesis of 1,2,5,6-di-O-cyclohexylideno-D-
mannitol-3,4-di-O-[(2S)-2-isothiocyanatopropanoate] 10c
4.3.9.1. Preparation of 1,2,5,6-di-O-cyclohexylideno-D-mannitol-3,4-
di-O-[(2S)-2-(N-tert-butyloxycarbonyl)aminopropanoate] 10a. Pro-
tected N-Boc L-alanine (2.270 g, 12 mmol) and DCC (2.47 g;
12 mmol) were dissolved in DCM (75 mL) at 0 °C. The reaction mix-
ture was stirred at 0 °C for 30 min. and next 1,2;5,6-di-O-cyclo-
hexylidene-D-mannitol [35] (1.71 g; 5.00 mmol) and DMAP
(0.14 g) were added to the flask. An ice-bath was removed and
Acknowledgements
This work was supported by the Polish Ministry of Science and
Higher Education (Grant No. N N204 310037) and the research was

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O. Michalski, D. Ciez / Journal of Molecular Structure 1037 (2013) 225–235
235
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