Optically Active 1-Deuterio-1-phenylethane – Preparation and Proof of Enantiopurity

Article abstract of DOI:10.1002/ejoc.201900121

Enantiopure (S)-(1-²H)ethylbenzene was prepared in two steps from optically active (S)-1-phenylethanol via (R)-(1-chloroethyl)benzene (two inversions of configuration). Since the value for the specific rotation [α] is very low for the enantiomers of (1-²H)ethylbenzene, the enantiopurity of the synthetic product could not be determined with certainty by polarimetry. Therefore, bis-sulfonamides were prepared by twofold chlorosulfonation (para and ortho) of (S)-(1-²H)ethylbenzene and subsequent amidation with (R)- and (S)-α-phenethylamine. For both diastereoisomers, the (R,R,S)- and the (S,S,S)-sulfonamides, 92 % de was determined by ¹H NMR spectroscopy. Therefore, it could be concluded, that (S)-(1-²H)ethylbenzene had been obtained with 92 % ee.

Full text of DOI:10.1002/ejoc.201900121

A Journal of
Accepted Article
Title: Optically Active 1-Deuterio-1-phenylethane – Preparation and
Proof of Enantiopurity
Authors: Julian Küppers, Ralf Rabus, Heinz Wilkes, and Jens
Christoffers
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900121
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European Journal of Organic Chemistry
10.1002/ejoc.201900121
Optically Active 1-Deuterio-1-phenylethane –
Preparation and Proof of Enantiopurity
[
a]
[b]
[b]
[a]
Julian Küppers, Ralf Rabus, Heinz Wilkes, Jens Christoffers*
[
a]
J. Küppers, Prof. Dr. J. Christoffers
Institut für Chemie, Carl von Ossietzky Universität Oldenburg, 26111 Oldenburg
Germany)
(
E-Mail: jens.christoffers@uol.de
Homepage: https://uol.de/oc-christoffers/
[
b]
Prof. Dr. R. Rabus, Prof. Dr. H. Wilkes
Institut für Chemie und Biologie des Meeres (ICBM), Carl von Ossietzky Universität
Oldenburg, 26111 Oldenburg (Germany)
2
Abstract: Enantiopure (S)-(1- H)ethylbenzene was prepared in two steps from
optically active (S)-1-phenylethanol via (R)-(1-chloroethyl)benzene (two inversions of
configuration). Since the value for the specific rotation [α] is very low for the
2
enantiomers of (1- H)ethylbenzene, the enantiopurity of the synthetic product could
not be determined with certainty by polarimetry. Therefore, bissulfonamides were
2
prepared by twofold chlorosulfonation (para and ortho) of (S)-(1- H)ethylbenzene and
subsequent amidation with (R)- and (S)-α-phenethylamine. For both
diastereoisomers, the (R,R,S)- and the (S,S,S)-sulfonamides, 92% de was
1
determined by H NMR spectroscopy. Therefore, it could be concluded, that (S)-(1-
2
H)ethylbenzene had been obtained with 92% ee.
Key Topic: Stereospecific deuteration
2
Graphical Abstract: Optically active (S)-(1- H)ethylbenzene was prepared from (S)-
1
-phenylethanol via the chloro compound. Its optical purity was determined by NMR
spectroscopy after derivatization to a sulfonamide with (R)-α-phenethylamine.
1
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European Journal of Organic Chemistry
10.1002/ejoc.201900121
Cl
D
D
Me
Me
Me
O
O
S
S
O
O
9
5% ee
92% ee
92% de
HN
Ph HN
Ph
Me
Me
Keywords: chirality, deuteration, hydrocarbons, NMR spectroscopy, sulfonamides
Introduction
2
Optically active 1-deuterio-1-phenylethane [(1- H)ethylbenzene, 3a] was used in se-
veral mechanistic studies on the stereoselective α-hydroxylation of ethylbenzene (3b)
[
1]
[2]
by either chiral metal complexes or microorganisms like fungi. The title compound
3
a was first prepared by Eliel in 1949 by reduction of α-chloroethylbenzene (2a) with
[
3]
LiAlD (Scheme 1). The author started from (R)-1-phenylethanol (1), which was first
4
converted with SOCl to (S)-(–)-2a, before reduction with LiAlD furnished hydro-
2
4
carbon (R)-(–)-3a (Scheme 1). Interestingly, the only tool for determination of enan-
25
D
tiopurity was at that time measurement of the specific rotation (α = –0.51°, neat, l =
2
dm). After Friedel-Crafts acetylation the respective ketone was transformed to its
crystalline oxime, which showed after multiple recrystallizations no change of its
specific rotation. Therefore, quantitative enantiopurity also for the starting material 3a
was assumed. It was furthermore assumed, that both of the two steps proceeded
with inversion of configuration, thus, overall retention of configuration was proposed.
[
4]
The latter assumption was actually based on investigations by Trevoy and Brown.
The latest report (in the year 2010) on the preparation of both enantiomers of
compound 3a also started from phenylethanols 1, but went via the respective bromo
[
5]
compounds 2b as intermediate products. Both enantiomers of intermediate product
b were obtained with 86% ee. Also in this publication it was assumed, that the
2
compounds 3a had "the same ee values, since the configuration cannot be changed
during deuteration".
2
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European Journal of Organic Chemistry
10.1002/ejoc.201900121
OH
(a)
X
LiAlD4
D
Ph
Me
R)-1
Ph
(S)-2a (X = Cl),
S)-2b (X = Br)
Me
Ph
Me
(
(R)-3a
(
(
b)
D
D
(
c)
Me
Me
N
O
HO
Me
Me
4
(85%)
5 (72%)
2
Scheme 1. Literature known preparation of optically active (1- H)ethylbenzene (3a)
from 1-phenylethanol (1) and further derivatization to crystalline oxime 4. Reagents:
(
a) SOCl for X = Cl or POBr for X = Br; (b) AcCl, AlCl ; (c) NaOAc, HO-NH ∙ HCl.
2 3 3 2
The second route to enantiopure compound 3a was published by Elsenbaumer and
[
6]
Mosher in 1979, who started from methyl (R)-mandelate (6), which was first trans-
formed with one inversion of configuration to chloroester 8 via the orthoester 7 (this
compound was an optically active mixture of two epimers at the orthoester moiety,
Scheme 2). Three further steps including another inversion gave hydrocarbon (S)-
(+)-3a. The key advantage of this route is that it proceeds via the primary alcohol 9,
which was recrystallized after transformation into its 3,5-dinitrobenzoate. Therefore,
quantitative enantiopurity of compound 9 was assumed. For this reason, this method
is actually referred to by most authors who subsequently used either (R)-(–)-3a or
(S)-(+)-3a in their investigations, although herein the determination of enantiopurity
20
D
also relied on the optical rotation (α
= +0.71°, neat, l = 1 dm).
Me
OMe
OH
CO Me
(a), (b)
O
TMSCl
Cl
O
OAc
Ph
Ph
Ph
2
(
R)-6
(R)-7
(S)-8
1
. LiAlD4 2. H O
2
D
(c), (d)
D
OH
Ph
Me
Ph
(
S)-3a
(R)-9
2
Scheme 2. Modified preparation of optically active (1- H)ethylbenzene (3a) from
methyl mandelate (6). Reagents: (a) LiAlH , (b) MeC(OMe) , (c) TosCl, pyridine, (d)
4
3
3
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European Journal of Organic Chemistry
10.1002/ejoc.201900121
LiAlH4.
To the best of our knowledge, the only determination of the optical purity of com-
[
7]
pound 3a by a method different from optical rotation was published by Flood et al.,
20
D
who used (R)-3a [with 80% ee according to [α]
= –0.65° (neat)] as intermediate
product for the preparation of 8-(α-deuterioethyl)quinoline. The enantiopurity of this
final product was determined to be 40% ee using an optically active, paramagnetic
NMR shift reagent.
Elucidation of the stereochemistry of hydrocarbon-transforming enzyme reactions
could provide valuable insights into the reaction mechanism as previously demon-
[
8]
strated for anaerobic transformation of n-hexane. It has been shown, that the deni-
trifying betaproteobacterium Aromatoleum aromaticum EbN1 employs an intriguing
Mo-containing, multisubunit enzyme (ethylbenzene dehydrogenase) to anaerobically
[
9]
(
in the absence of O ) hydroxylate the methylene carbon atom of ethylbenzene.
2
Furthermore, stereospecific formation of (S)-1-phenylethanol by ethylbenzene de-
[
10]
hydrogenase has been demonstrated.
Current perception of the reaction mechanism involves the formation of an interme-
[
11]
diate carbocation. However, it is unclear whether the reaction proceeds with reten-
tion, inversion or racemization at the methylene group of ethylbenzene. In particular,
racemization would hint at the occurrence of a free carbenium ion in the transition
2
state. We envisioned enantiopure (1- H)ethylbenzene (3a) to be a perfect substrate
for investigations aiming at discriminating these mechanistic possibilities.
Anyhow, after a literature survey we had doubts on the enantiopurity of (R)-3a and
(S)-3a as reported in the literature so far, since the determination of optical rotations
is known to be often associated with large errors, in particular, if the absolute values
[
6]
are relatively low, like it is the case for compounds 3a. Furthermore, standard cu-
vettes require an amount of at least 7 mL of sample volume and, so far, the optical
rotation was determined in a neat sample. Therefore, the objective of this study is the
development of a reliable method to establish the enantiopurity based on NMR
spectroscopy of diastereoisomeric derivatives.
4
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European Journal of Organic Chemistry
10.1002/ejoc.201900121
Results and Discussion
A chiral derivative of ethylbenzene (3b) would be the ideal tool for measuring the en-
2
1
antiopurity of (1- H)ethylbenzene (3a), e.g. by H NMR spectroscopy. After some un-
successful experimentation with Friedel-Crafts acylation reactions with optically ac-
tive acid chlorides we decided to prepare the sulfonylchloride from ethylbenzene and
react it with optically active amines. Indeed, the 4-ethylbenzenesulfonylchloride could
be obtained with chlorosulfonic acid (full conversion within 3 h at ambient tempera-
ture) and it was subsequently converted with α-phenethylamine. However, since the
para-product was formed, the methylene protons, although formally diastereotopic,
appear still as a quartet in the proton NMR spectrum. For this reason, we aimed at
double chlorosulfonation of ethylbenzene (3b) although due to the deactivating effect
of the first (para) sulfonyl group, the second, ortho-substitution required rather harsh
conditions (150°C for 19 h) and the yield was low (46% of compound 10b, Scheme
3
). The pains and drawbacks of double and threefold sulfonations of benzene deriva-
[12]
tives have been experienced in the literature. Anyhow, compound 10b was conver-
ted with two equiv. of (R)-α-phenethylamine in the presence of pyridine to furnish bis-
1
sulfonamide 11b in 56% yield. Upon inspection of the H NMR spectrum the diaste-
reotopic methylene protons indeed appeared as the AM-part of an AMX spin system
3
with sufficient baseline resolution (Figure 1A, δ = 0.12 ppm).
Et
(a)
6%
Et
4
ClO2S
SO Cl
2
3
b
10b
b) 56%
Et
SO NH
(
Me
Ph
Ph
NHO2S
2
Me
(
R,R)-11b
Scheme 3. Twofold chlorosulfonation of ethylbenzene (3b) and conversion to bis-sul-
fonamide 11b. Reagents and conditions: (a) 6 equiv. ClSO H, –7823°C, 3 h;
3
1
50°C, 19 h; (b) 2.4 equiv. (R)-PhCH(NH )Me, 4 equiv. pyridine, CH Cl , 40°C, 20 h.
2
2
2
5
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European Journal of Organic Chemistry
10.1002/ejoc.201900121
2
We then turned to the preparation of bis-sulfonamide 11a from racemic (1- H)ethyl-
benzene (3a) and, therefore, started with racemic alcohol 1, which was converted to
chloro compound 2a (Scheme 4). This intermediate was investigated by GLC on a
chiral phase and, fortunately, baseline resolution of both enantiomers of compound
2
a was achieved. It was then reduced with LiAlD under formation of racemic hydro-
4
carbon 3a. The latter material was further transformed using the conditions esta-
1
blished before into bis-sulfonamide 11a, which was obtained according to H NMR
spectroscopy as a mixture of two diastereoisomers (ratio 1 : 1). In particular, the pro-
tons at the CHD α-carbon atom were detected as two distinguished multiplets, one
2
1
2
for each diastereoisomer, which appear as quartets broadened by the J( H, H)
coupling at δ = 2.83 and 2.90 ppm (Figure 1B).
OH
Me
Cl
D
(
a)
(b)
Me
Me
8
0%
82%
rac-1
rac-2a
rac-3a
(
c) 63%
D
D
(
d)
Me
Me
SO Cl
Me
Ph
Ph
3
9%
NHO2S
SO NH
ClO2S
2
2
Me
(
1R,3R,4R*)-11a
rac-10a
2
Scheme 4. Preparation of racemic (1- H)ethylbenzene (3a) and conversion to bis-sul-
fonamide 11a (two diastereoisomers, dr 1:1). Reagents and conditions: (a) 1.1 equiv.
SOCl , Et O, 23°C, 20 min; (b) 2.0 equiv. LiAlD , THF, 75°C, 20 h; (c) 6 equiv.
2
2
4
ClSO H, CH Cl , –7823°C, 3 h; 95°C, 16 h; (d) 3.0 equiv. (R)-PhCH(NH )Me, 3.2
3
2
2
2
equiv. pyridine, CH Cl , 40°C, 20 h.
2
2
With this preliminary result in the racemic series we turned to the preparation of en-
antiopure hydrocarbon 3a and therefore started with (S)-phenylethanol (1) (Scheme
5
). For the preparation of optically active (1-chloroethyl)benzene (2a) we relied on a
recent report by Huy et al., who developed excellent reaction conditions for the ste-
reoselective nucleophilic displacement of a secondary alcohol function to the respec-
[
13]
tive chloro compound with inversion of configuration.
Compound (R)-2a could be
obtained with 77% yield and 95% ee, as was established by GLC on a chiral phase.
Reduction with LiAlD gave the title compound (S)-3a. The optical rotation was mea-
4
6
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European Journal of Organic Chemistry
10.1002/ejoc.201900121
–1
sured in pentane solution (c = 1 g L ) to be zero, which actually points out the pro-
blems associated with the determination of enantiopurity by this method. Anyhow,
further transformation to bis-sulfonamide (1R,3R,4S)-11a with (R)-phenethylamine
1
gave a material, which was a single diastereoisomer according to H NMR spectro-
scopy (Figure 1C). Only minor residual signals of the diastereoisomer are observed
at 2.83 ppm. In order to access this other diastereoisomer 11a for comparative NMR
investigations, we also prepared compound (S,S,S)-11a from (S)-phenethylamine. Fi-
1
gure 1D shows its H NMR spectrum. Now only residual signals at 2.90 ppm are ob-
served. Since the integration of the respective multiplets could not be executed with
1
high accuracy, we have acquired proton decoupled H NMR spectra of all four iso-
mers by irradiation of the methyl protons at 1.2 ppm. Figures 2A–2D show the
2
respective spectra. For the protio-compound (R,R)-11b an AB-system with J = 15
Hz was obtained (Figure 2A). The epimeric mixture of (1R,3R,4R*)-11a shows two
singlets at 2.90 and 2.84 ppm with equal integrals (Figure 2B). Finally, the spectra of
the two diastereomerically and optically pure isomers (1R,3R,4S)-11a (Figure 2C)
and (S,S,S)-11a (Figure 2D) show the same singlets with of course significantly diffe-
rent integrals (1.00 vs. 0.04 and 0.04 vs. 1.00, resp.). From this ratio the enantiopurity
of compound (S)-3a was determined to be 92% ee. Please remind that the optical ro-
–1
tation of this material was determined to be zero (at c = 1 g L in pentane).
OH
Me
Cl
D
(
a)
(b)
Me
Me
7
7%
73%
9
5% ee
(S)-1
(R)-2a
(S)-3a
(
c) 85%
D
D
(d)
Me
Me
SO Cl
Me
Ph
Ph
NHO2S
SO NH
ClO2S
2
2
Me
(
1R,3R,4S)-11a, 42%
(S)-10a
(
S,S,S)-11a, 49%
2
Scheme 5. Preparation of optically active (1- H)ethylbenzene (3a) and conversion to
bis-sulfonamide 11a (two diastereoisomers). Reagents and conditions: (a) 1.5 equiv.
PhCOCl, 0.2 equiv. 1-formylpyrrolidine, 23°C, 24 h; (b) 2.0 equiv. LiAlD , THF, 75°C,
4
2
0 h; (c) 6 equiv. ClSO H, –7823°C, 3 h; 95°C, 16 h; (d) 3.0 equiv. (R)-
3
PhCH(NH )Me or (S)-PhCH(NH )Me, 3.2 equiv. pyridine, CH Cl , 40°C, 20 h.
2
2
2
2
7
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European Journal of Organic Chemistry
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8
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European Journal of Organic Chemistry
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1
Figure 1. Methylene region of the H NMR-spectra (500 MHz, CDCl ) of compounds
3
(R,R)-11b (A), (1R,3R,4R*)-11a (B), (1R,3R,4S)-11a (C) and (S,S,S)-11a (D).
9
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European Journal of Organic Chemistry
10.1002/ejoc.201900121
1
Figure 2. Methylene region of the H NMR-spectra (500 MHz, CDCl ) with proton de-
3
1
0
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European Journal of Organic Chemistry
10.1002/ejoc.201900121
coupling by irradiation of the methyl group at 1.2 ppm of compounds (R,R)-11b (A),
(1R,3R,4R*)-11a (B), (1R,3R,4S)-11a (C) and (S,S,S)-11a (D).
Conclusion
2
Optically active (1- H)ethylbenzene (3a) was reported to be a useful substrate for
mechanistic investigations in metal catalysis and bioorganic chemistry. It's prepara-
tion from optically active 1-phenylethanol (1) by twofold nucleophilic displacement via
α-chloro- or bromoethylbenzene (2a or 2b) was reported before in the literature.
However, the determination of the enantiopurity of the title compound 3a was so far
relying on the optical rotation. This methodology is generally associated with
relatively large uncertainty. Even worse in this case is the very low [α] for compound
3
a with the necessity to obtain the value of α in a neat sample, i.e. without dilution by
solvent. Since we were aiming to prepare compound 3a in optically pure form for me-
chanistic investigations, we report herein a method for the determination of enantio-
purity by NMR-spectroscopy of a derivative with additional stereocenters. First of all,
[
13]
we followed a recently published protocol
for the stereospecific preparation of α-
chloroethylbenzene (R)-2a from (S)-1-phenylethanol (1) (77% yield). Enantiopurity of
compound 2a was determined by GLC on a chiral phase to be 95% ee. We then sub-
mitted this intermediate product 2a to S 2 reaction with LiAlD and indeed obtained
N
4
title compound (S)-3a in 73% yield, however, no optical rotation could be detected in
pentane solution. We then submitted this product to twofold chlorosulfonation with
ClSO H (85% yield) and converted this intermediate with (R)- and (S)-α-phenethyl-
3
amine and obtained two diastereoisomeric bissulfonamides (1R,3R,4S)- and (S,S,S)-
1
1
1a. The diastereomeric ratio of both compounds was determined by H NMR spec-
troscopy to be 25:1 in both cases (i.e. 92% de), therefore, it could be concluded, that
2
(
1- H)ethylbenzene (S)-3a had an enantiopurity of 92% ee. Consequently, the nu-
cleophilic substitution from chloro compound 2a (95% ee) to product 3a (92% ee)
was proceeding with almost full inversion of configuration.
1
1
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European Journal of Organic Chemistry
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Experimental Section
General. All synthetic transformations were performed under inert conditions (nitro-
gen atmosphere, exclusion of air and moisture). Preparative column chromatography
was carried out using Merck SiO (35–70 µm, type 60 A) with hexanes, n-pentane,
2
tert-butylmethylether (MTBE), and diethyl ether as eluents. TLC was performed on
1
2
13
aluminum plates coated with SiO F . H, H and C NMR spectra were recorded
2
254
on Bruker Avance DRX 500 and 300 instruments. Multiplicities of carbon signals
were determined with DEPT experiments. HRMS spectra of products were obtained
with Waters Q-TOF Premier (ESI) or Thermo Scientific DFS (EI) spectrometers. IR
spectra were recorded on a Bruker Tensor 27 spectrometer equipped with a diamond
ATR unit. Optical rotations were determined with a with a Perkin Elmer polarimeter
3
43. GLC analyses were performed on a Focus GC (Thermo-Fisher) on a chiral Lipo-
dex E capillary column (Macherey-Nagel, 25 m, 0.25 mm) with H as carrier gas. All
2
starting materials were commercially available.
rac-(1-Chloroethyl)benzene (rac-2a). At 0°C (ice-water bath), SOCl (13.2 mmol,
2
1
.57 g, 1.1 eq) was added to a solution of 1-phenylethanol (rac-1) (12.0 mmol, 1.47
g, 1.0 eq) in abs. Et O (6 mL) and the mixture was stirred at ambient temperature for
2
2
0 min. The organic layer was washed with saturated aqueous NaHCO solution and
3
brine (each 10 mL), dried over MgSO , filtered and the solvent was evaporated. The
4
residue was chromatographed (SiO , n-pentane, R = 0.50) to yield compound rac-2a
2
f
1
(
1.35 g, 9.60 mmol, 80%) as a colorless oil. H NMR (300 MHz, CDCl ): δ = 1.86 (d, J
3
=
6.9 Hz, 3H), 5.11 (q, J = 6.9 Hz, 1H), 7.28–7.40 (m, 3H), 7.40–7.46 (m, 2H) ppm.
[
13]
All other data were in accordance with the literature.
GLC (Lipodex E, 5 min at
–
1
–1
5
4
0°C, then 1 K min to 90°C, then 10 K min to 180°C): t (R) = 37.51 min, t (S) =
R
R
–1
0.52 min. C H Cl (140.61 g mol ).
8
9
[
13]
(
R)-(1-Chloroethyl)benzene [(R)-2a]. Following the procedure of Huy et al., ben-
zoyl chloride (30.0 mmol, 4.22 g, 1.5 eq) was added at 0°C (ice-water bath) to a solu-
tion of 1-phenylethanol (S)-1 (20.0 mmol, 2.44 g, 1.0 eq) and 1-formylpyrrolidine (4.0
mmol, 0.40 g, 0.2 eq) over a period of 5 min and the mixture was stirred for 2 h at
0
2
°C and finally for 24 h at ambient temperature. Ethanolamine (40.0 mmol, 2.44 g,
.0 eq) was added at ambient temperature and the mixture was stirred for 30 min at
1
2
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European Journal of Organic Chemistry
10.1002/ejoc.201900121
ambient temperature. It was then diluted with Et O (60 mL), and at 0°C (ice-water
2
bath), saturated aqueous NaHCO (20 mL) and water (10 mL) were added and the
3
mixture was stirred for 5 min at 0°C. The layers were separated and the organic layer
was washed with saturated aqueous NaHCO (20 mL), dried over MgSO , filtered
3
4
and the solvent was evaporated (40°C, 100 mbar, 2 min). The residue was chromato-
graphed (21.1 g SiO , n-pentane/Et O 200:1, R = 0.66) to yield compound (R)-2a
2
2
f
(2.16 g, 15.4 mmol, 77%, 95% ee) as a colorless oil. All data were in accordance with
–1
–
the racemate. GLC (Lipodex E, 5 min at 50°C, then 1 K min to 90°C, then 10 K min
1
20
to 180°C): t (R) = 37.34 min (major), t (S) = 40.91 min (minor), 95% ee. [α]
D
=
R
R
–1
[13]
20
–1
+
113.15° (CH Cl , 0.9 g L ). {lit.
[α]D = +108.0 (CDCl , 8.8 g L ). C H Cl
3 8 9
2
2
–1
(
140.61 g mol ).
2
rac-(1- H)Ethylbenzene (rac-3a). At 0°C (ice-water bath), LiAlD (5.3 mmol, 0.22 g,
4
2
.0 eq) was added to a solution of rac-2a (2.6 mmol, 0.37 g, 1.0 eq) in abs. THF (20
mL) and the mixture was stirred for 20 h at 75°C. At 0°C (ice-water bath), it was dilu-
ted with ice-cold water (10 mL) and extracted with n-pentane (3  10 mL). The com-
bined organic layers were washed with phosphoric acid (85%), water, saturated
aqueous NaHCO solution, again water and brine (each 30 mL), dried over MgSO ,
3
4
filtered and the solvent was evaporated (50°C, 950 mbar) to yield rac-3a (0.23 g,
1
2
.15 mmol, 82%) as a colorless oil. H NMR (300 MHz, CDCl ): δ = 1.27 (dt, J = 7.6
3
Hz, J = 1.1 Hz, 3H), 2.67 (qt, J = 7.6 Hz, J = 2.0 Hz, 1H), 7.16–7.26 (m, 3H), 7.27–
2
7
.36 (m, 2H) ppm. H NMR (77 MHz, CDCl ): δ = 2.74 (s, 1D) ppm. All other data
3
[
5]
–1
were in accordance with the literature. C H D (107.07 g mol ).
8
9
2
(
S)-(1- H)Ethylbenzene [(S)-3a]. Following the procedure for rac-3a, the product (S)-
a (1.19 g, 11.1 mmol, 73%) was obtained as a colorless oil from (R)-2a (2.15 g, 15.3
mmol) and LiAlD (1.28 g, 30.5 mmol). All data were in accordance with the race-
3
4
20
–1
–1
mate. [α]D = ±0.00° (n-pentane, 1.0 g L ). C H D (107.07 g mol ).
8
9
4
-Ethyl-1,3-benzenedisulfonyldichloride (10b). At –78°C (cooling with dry ice-ace-
tone), ClSO H (56.5 mmol, 6.58 g, 6.0 eq) was added to ethylbenzene (3b) (9.40
3
mmol, 1.00 g, 1.0 eq) and the mixture was stirred for 3 h at 0°C, then 3 h at ambient
temperature and finally for 19 h at 150°C. It was diluted with CH Cl (10 ml) and
2
2
washed with ice-cold water (3  10 mL). The organic layer was dried over MgSO4,
1
3
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European Journal of Organic Chemistry
10.1002/ejoc.201900121
filtered and concentrated by evaporation to yield 4-ethyl-1,3-benzenedisulfonyldichlo-
ride (10b) (1.32 g, 4.35 mmol, 46%) as a dark-yellow oil, which was used further with-
1
out purification. H NMR (300 MHz, CDCl ): δ = 1.44 (t, J = 7.5 Hz, 3H), 3.33 (q, J =
3
7
=
1
.5 Hz, 2H), 7.78 (d, J = 8.3 Hz, 1H), 8.28 (dd, J = 8.3 Hz, J = 2.0 Hz, 1H), 8.71 (d, J
13
1
2.0 Hz, 1H) ppm. C{ H} NMR (125 MHz, CDCl ): δ = 14.66 (CH ), 26.27 (CH ),
3
3
2
27.64 (CH), 132.63 (CH), 133.40 (CH), 142.58 (C), 143.67 (C), 151.94 (C) ppm. IR
(ATR): nu(tilde) = 3095 (w), 3069 (w), 2972 (w), 2939 (w), 1381 (vs), 1172 (vs), 699
–1
.
(m), 657 (s), 610 (m), 586 (m), 577 (vs) cm
HRMS (ESI, neg. mode): calcd.
–
2
+
–
3
00.9168 (for C H Cl O S ); found 300.9171 [M – H ]. C H Cl O S (303.17 g mol
8
7
2
4
8
8
2
4 2
1
).
(R,R)-4-Ethyl-1,3-benzenedisulfonic acid bis(1-phenylethyl)amide [(R,R)-11b].
(R)-(+)-1-Phenylethylamine (3.96 mmol, 480 mg, 2.4 eq) and pyridine (6.60 mmol,
5
22 mg, 4.0 eq) were added to a solution of compound 10b (1.65 mmol, 500 mg, 1.0
eq) in CH Cl (5 mL) at 0°C (ice-water bath). After stirring the mixture at 40°C for 20
2
2
h it was cooled to ambient temperature and diluted with water (5 mL). The aqueous
layer was extracted with CH Cl (3  5 mL) and the combined organic layers were
2
2
washed with saturated aqueous NaHCO solution and brine (each 5 mL). The orga-
3
nic layer was dried over MgSO , filtered and the solvent was evaporated. The residue
4
was chromatographed (SiO , hexanes/MTBE 1:2, R = 0.50) to yield compound
2
f
1
(
R,R)-11b (438 mg, 0.93 mmol, 56%) as a yellow oil. H NMR (500 MHz, CDCl ): δ =
3
1
=
4
7
.22 (t, J = 7.5 Hz, 3H), 1.43 (d, J = 6.9 Hz, 3H), 1.46 (d, J = 6.9 Hz, 3H), 2.85 (dq, J
14.9 Hz, J = 7.5 Hz, 1H), 2.96 (dq, J = 14.9 Hz, J = 7.5 Hz, 1H), 4.41–4.53 (m, 2H),
.74 (d, J = 7.2 Hz, 1H), 4.76 (d, J = 7.1 Hz, 1H), 6.95–7.05 (m, 4H), 7.09–7.20 (m,
13
1
H), 7.63 (dd, J = 8.1 Hz, J = 2.0 Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H) ppm. C{ H} NMR
(
125 MHz, CDCl ): δ = 14.75 (CH ), 23.57 (CH ), 23.65 (CH ), 25.91 (CH ), 53.93
3 3 3 3 2
(
CH), 53.96 (CH), 126.02 (2 CH), 126.10 (2 CH),127.63 (CH), 127.73 (CH), 128.07
CH), 128.54 (2 CH), 128.62 (2 CH), 130.42 (CH), 130.83 (CH), 138.61 (C), 139.10
C), 141.26 (2 C), 147.46 (C) ppm. IR (ATR): nu(tilde) = 3277 (br), 2973 (w), 2929
w), 1454 (m), 1425 (m), 1320 (s), 1147 (vs), 1104 (s), 1083 (s), 1018 (m), 961 (s),
(
(
(
–1
8
73 (m), 842 (m), 762 (s), 698 (vs), 668 (s), 610 (s), 588 (vs) cm . HRMS (ESI, pos.
+
2
+
20
mode): calcd. 495.1383 (for C H N NaO S ); found 495.1384 [M + Na ]. [α]
D
=
24
28
2
4
–
1
–1
+
60.7° (CH Cl , 1 g L ). C H N O S (472.62 g mol ).
2 2 24 28 2 4 2
1
4
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European Journal of Organic Chemistry
10.1002/ejoc.201900121
2
rac-4-(1- H)Ethyl-1,3-benzenedisulfonyldichloride (rac-10a). At –78°C (cooling
with dry ice-acetone), ClSO H (10.3 mmol, 1.20 g, 6.0 eq) dissolved in abs. CH Cl (1
3
2
2
2
mL) was added to a solution of (1- H)ethylbenzene (rac-3a) (1.72 mmol, 184 mg, 1.0
eq) in abs. CH Cl (2 mL) and the mixture was stirred for 3 h. During that time the
2
2
mixture was allowed to warm up to 0°C and finally it was stirred for 16 h at 95°C. It
was then diluted with CH Cl (5 ml) and overlaid with ice-cold water (5 mL). Without
2
2
mixing them, the layers were separated and aqueous layer was extracted with
CH Cl (3  5 mL). The combined organic layers were dried over MgSO and after fil-
2
2
4
2
tration concentrated by evaporation to yield 4-(1- H)ethyl-1,3-benzenedisulfonyldi-
chloride (rac-10a) (0.33 g, 1.1 mmol, 63%) as a dark-red oil which was used without
1
further purification. H NMR (300 MHz, CDCl ): δ = 1.43 (d, J = 7.4 Hz, 3H), 3.30 (qt,
3
J = 7.4 Hz, J = 2.1 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H), 8.29 (dd, J = 8.3 Hz, J = 2.0 Hz,
1
3
1
1
2
1
H), 8.69 (d, J = 2.0 Hz, 1H) ppm. C{ H} NMR (125 MHz, CDCl ): δ = 14.57 (CH ),
3 3
5.95 (t, J = 20.0 Hz, CHD), 127.57 (CH), 132.64 (CH), 133.47 (CH), 142.49 (C),
43.58 (C), 151.94 (C) ppm. IR (ATR): nu(tilde) = 3090 (w), 3075 (w), 2997 (w), 2979
(
w), 2941 (w), 1375 (s), 1168 (s), 1100 (m), 1051 (m), 1026 (m), 831 (m), 696 (m),
–1
6
76 (m), 653 (m), 606 (m), 572 (s), 560 (vs) cm . HRMS (EI): calcd. 302.9298 (for
+
2
+
–1
C H Cl DO S ); found 302.9304 [M ]. C H DCl O S (304.17 g mol ).
8
7
2
4
8
7
2
4 2
2
(
1R,3R,4R*)-4-(1- H)Ethyl-1,3-benzenedisulfonic acid bis(1-phenylethyl)amide
(1R,2R,4R*)-11a]. Following the procedure for (R,R)-11b, the product (1R,3R,4R*)-
[
1
1a (0.20 g, 0.42 mmol, 39%) was obtained from rac-10a (1.07 mmol, 325 mg), (R)-
+)-1-phenylethylamine (3.21 mmol, 388 mg) and pyridine (3.42 mmol, 270 mg) after
chromatography (SiO , hexanes/MTBE 3:2, R = 0.22) as a colorless solid, mp. 55–
(
2
f
1
7
3
4
4
0°C. H NMR (500 MHz, CDCl ): δ = 1.20 (d, J = 7.6 Hz, 3H), 1.42 (d, J = 6.9 Hz,
3
H), 1.45 (d, J = 6.9 Hz, 3H), 2.83 (q, J = 7.4 Hz, 0.5H), 2.90 (q, J = 7.4 Hz, 0.5H),
.45–4.51 (m, 2H), 5.07 (d, J = 7.2 Hz, 1H), 5.17 (d, J = 7.3 Hz, 1H), 7.02–7.06 (m,
H), 7.10–7.16 (m, 7H), 7.61 (dd, J = 8.1 Hz, J = 1.7 Hz, 1H), 8.11–8.14 (m, 1H)
13
1
ppm. C{ H} NMR (125 MHz, CDCl ): δ = 14.66 (CH ), 23.56 (CH ), 23.64 (CH ),
3
3
3
3
2
1
1
5.62 (t, J = 19.6 Hz, CHD), 53.95 (CH), 53.98 (CH), 126.04 (2 CH), 126.12 (2 CH),
27.64 (CH), 127.74 (CH), 128.08 (CH), 128.56 (2 CH), 128.64 (2 CH), 130.44 (CH),
2
30.88 (CH), 138.73 (C), 139.24 (C), 141.35 (2 C), 147.49 (C) ppm. H NMR (77
MHz, CDCl ): δ = 2.93 (s, 1D) ppm. IR (ATR): nu(tilde) = 3277 (br), 3065 (w), 3029
3
(
w), 2976 (w), 2936 (w), 1320 (s), 1151 (vs), 1118 (m), 1104 (s), 1083 (s), 1062 (m),
1
5
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European Journal of Organic Chemistry
10.1002/ejoc.201900121
–1
1
018 (m), 962 (s), 910 (m), 875 (m), 762 (m), 698 (vs), 666 (s), 609 (s), 594 (s) cm .
+
4 2
HRMS (ESI, pos. mode): calcd. 480.1708 (for C H DLiN O S ); found 480.1703 [M
24
27
2
+
20
–1
–1
+
Li ]. [α]D = +98.33° (CH Cl , 1 g L ). C H DN O S (473.62 g mol ).
2 2 24 27 2 4 2
2
(
S)-4-(1- H)Ethyl-1,3-benzenedisulfonyldichloride [(S)-10a]. Following the proce-
dure for rac-10a, the product (S)-10a (0.63 g, 2.07 mmol, 85%) was obtained as a
dark-red oil from (S)-3a (0.26 g, 2.44 mmol) and ClSO H (1.70 g, 14.6 mmol). All da-
3
20
–1
ta were in accordance with the racemate. [α]D = +0.07° (CH Cl , 1.09 g L ).
2
2
–1
C H DCl O S (304.17 g mol ).
8
7
2
4 2
2
(
1R,3R,4S)-4-(1- H)Ethyl-1,3-benzenedisulfonic acid bis(1-phenylethyl)amide
(1R,3R,4S)-11a]. Following the procedure for (R,R)-11b, the product (1R,3R,4S)-
[
1
1a (0.39 g, 0.82 mmol, 42%) was obtained from (S)-10a (1.97 mmol, 600 mg), (R)-
+)-1-phenylethylamine (5.92 mmol, 717 mg) and pyridine (6.30 mmol, 498 mg) after
chromatography (SiO , hexanes/MTBE 2:3, R = 0.57) as a colorless solid. mp. 57–
(
2
f
1
6
3
7
5°C. H NMR (500 MHz, CDCl ): δ = 1.19 (d, J = 7.4 Hz, 3H), 1.42 (d, J = 6.9 Hz,
3
H), 1.45 (d, J = 6.9 Hz, 3H), 2.90 (q, J = 7.4 Hz, 1H), 4.45–4.52 (m, 2H), 5.12 (d, J =
.3 Hz, 1H), 5.23 (d, J = 7.4 Hz, 1H), 7.02–7.06 (m, 4H), 7.10–7.16 (m, 7H), 7.61 (dd,
13
1
J = 8.1 Hz, J = 2.0 Hz, 1H), 8.13 (d, J = 2.0 Hz, 1H) ppm. C{ H} NMR (125 MHz,
CDCl ): δ = 14.69 (CH ), 23.56 (CH ), 23.64 (CH ), 25.61 (t, J = 20.1 Hz, CHD),
3
3
3
3
5
1
1
2
3.92 (CH), 53.96 (CH), 126.02 (2 CH), 126.10 (2 CH),127.62 (CH), 127.71 (CH),
28.06 (CH), 128.53 (2 CH), 128.61 (2 CH), 130.42 (CH), 130.86 (CH), 138.62 (C),
2
39.12 (C), 141.28 (C), 141.49 (2 C), 147.44 (C) ppm. H NMR (77 MHz, CDCl ): δ =
3
.91 (s, 1D) ppm. IR (ATR): nu(tilde) = 3280 (br), 2979 (w), 2931 (w), 2886 (w), 1457
(m), 1428 (m), 1321 (s), 1153 (vs), 1106 (s), 1085 (s), 1063 (m), 1020 (m), 964 (s),
–
1
8
4
76 (m), 764 (m), 700 (vs), 669 (s), 590 (s) 560 (vs) cm . HRMS (EI): calcd.
+
2
+
20
D
73.2548 (for C H DN O S ); found 473.1544 [M ]. [α]
= +116.67° (CH Cl , 1.0
2 2
24
27
2
4
–1
–1
g L ). C H DN O S (473.62 g mol ).
24
27
2
4 2
2
(
S,S,S)-4-(1- H)Ethyl-1,3-benzenedisulfonic
acid
bis(1-phenylethyl)amide
[(S,S,S)-11a]. Following the procedure for (R,R)-11b, the product (S,S,S)-11a (0.30
g, 0.63 mmol, 49%) was obtained from (S)-10a (1.3 mmol, 0.39 mg), (S)-(–)-1-
phenylethylamine (3.83 mmol, 464 mg) and pyridine (3.83 mmol, 303 mg) after chro-
matography (SiO , hexanes/MTBE 2:3, R = 0.48) as a colorless solid, mp. 51–76°C.
2
f
1
6
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201900121
1
H NMR (500 MHz, CDCl ): δ = 1.20 (d, J = 7.4 Hz, 3H), 1.42 (d, J = 6.9 Hz, 3H),
3
1
.45 (d, J = 6.9 Hz, 3H), 2.83 (q, J = 7.4 Hz, 1H), 4.45–4.51 (m, 2H), 5.10 (d, J = 7.3
Hz, 1H), 5.21 (d, J = 7.4 Hz, 1H), 7.01–7.05 (m, 4H), 7.10–7.17 (m, 7H), 7.62 (dd, J =
13
1
8
.1 Hz, J = 2.0 Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H) ppm. C{ H} NMR (125 MHz,
CDCl ): δ = 14.69 (CH ), 23.57 (CH ), 23.65 (CH ), 25.62 (t, J = 19.5 Hz, CHD),
3
3
3
3
5
1
1
3.93 (CH), 53.96 (CH), 126.02 (2 CH), 126.10 (2 CH),127.63 (CH), 127.72 (CH),
28.07 (CH), 128.53 (2 CH), 128.62 (2 CH), 130.42 (CH), 130.86 (CH), 138.62 (C),
2
39.11 (C), 141.27 (2 C), 147.45 (C) ppm. H NMR (77 MHz, CDCl ): δ = 2.96 (s, 1D)
3
ppm. IR (ATR): nu(tilde) = 3294 (br), 2974 (w), 2931 (w), 2886 (w), 1457 (m), 1428
(m), 1321 (s), 1153 (vs), 1106 (s), 1085 (s), 1063 (m), 1020 (m), 964 (s), 876 (m),
–
1
7
4
64 (m), 700 (vs), 669 (s), 590 (s) 560 (vs) cm . HRMS (ESI, pos. mode): calcd.
+
2
+
20
96.1445 (for C H DN NaO S ); found 496.1443 [M + Na ]. [α]
D
= –91.67°
24
27
2
4
–
1
–1
(
CH Cl , 1.0 g L ). C H DN O S (473.62 g mol ).
2 2 24 27 2 4 2
Acknowledgement
This work was generously supported by the Deutsche Forschungsgemeinschaft
GRK2226). MTBE was obtained as a generous gift from Evonik Industries, Marl,
Germany.
(
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