Synthesis of a new chiral sulfonic acid

Article abstract of DOI:10.1055/s-0031-1290753

A convenient route to an original chiral sulfonic acid is disclosed. The synthesis is based on an optimized and regioselective direct bis-orthoarylation of a commercially available phenol, followed by a Newman-Kwart rearrangement. Resolution by preparative chiral HPLC and oxidative cleavage give the targeted Brnsted acid in >99% ee. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290753

See discussions, stats, and author profiles for this publication at: http://www.researchgate.net/publication/232707292
Synthesis of a New Chiral Sulfonic Acid A New
Chiral Sulfonic Acid
ARTICLE in SYNTHESIS · MARCH 2012
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PAPER
▌1349
paper
Synthesis of a New Chiral Sulfonic Acid
A New Chiral Sulfonic Acid
Joydeb Das, Fabien Le Cavelier, Jacques Rouden, Jérôme Blanchet*
Laboratoire de Chimie Moléculaire et Thio-organique, ENSICAEN, Université de Caen, UMR CNRS 6507, INC3M FR 3038, 6 boulevard du
Maréchal Juin, 14050 Caen, France
Fax +33(2)31452877; E-Mail: jerome.blanchet@ensicaen.fr
Received: 12.01.2012; Accepted after revision: 17.02.2012
Abstract: A convenient route to an original chiral sulfonic acid is
OH
SO3H
disclosed. The synthesis is based on an optimized and regioselective
direct bis-orthoarylation of a commercially available phenol, fol-
lowed by a Newman–Kwart rearrangement. Resolution by prepara-
tive chiral HPLC and oxidative cleavage give the targeted Brønsted
acid in >99% ee.
1
2
Key words: Brønsted acid, sulfonic acid, Pinhey–Barton reaction,
Newman–Kwart rearrangement, synthesis
Figure 1 Structure of phenol 1
the starting material and relied on a Newman–Kwart rear-
rangement of an O-aryl thiocarbamate to introduce the
sulfur moiety.7 Initially, it was thought to introduce aryl
ortho-substituents by using a suitably halogenated thio-
carbamate. Accordingly, the S-aryl thiocarbamate 4 was
easily synthesized from 3,5-dimethylphenol (3) (Scheme
1), but its regioselective 2,6-dibromination proved to be
unsuccessful.
The research field dedicated to chiral Brønsted acid catal-
ysis has grown enormously during the last few years.
BINOL derived chiral phosphoric acids have emerged as
effective catalysts for various enantioselective transfor-
mations.1 Even if numerous applications have appeared,
the uses of these Brønsted acids are generally restricted to
the electrophilic activation of imines with a proper basic
character. As a consequence, many efforts are devoted to
improve the acidity of the catalyst in order to widen the
scope of activation to functionalities such as carbonyl, hy-
droxy, or double bonds.2 Mostly, modifications of the
phosphoric acid moiety by the appropriate introduction of
electron-withdrawing group (triflyl) or substitution of ox-
ygen atoms with more stabilizing ones (sulfur or seleni-
um) are reported.3 Interestingly, the design of chiral
strong sulfonic acids has been less investigated. For ex-
ample, the bis-sulfonic acids based on a chiral binaphthyl
backbone (BINSA) have failed to deliver any useful selec-
tivity.4 However, DFT calculations have shown that sul-
fonic acids behaved as bifunctional catalysts similarly to
phosphoric acids.5 In this context, there is still a need for
new chiral sulfonic acids with suitable chiral environment
and appropriate acidity to activate a broad range of func-
tionalities.
OH
SCONMe2
a, b
3
4
OCSNMe2
Br
c, d
Br
5
Scheme 1 Unsuccessful attempts for the preparation of 2. Reagents
and conditions: a) ClCSNMe2, K2CO3, acetone, 65 °C; b) neat, 250
°C, 66% from 3; c) Br2, t-BuNH2, toluene, –78 °C; d) ClCSNMe2,
K2CO3, acetone, 65 °C, 46% from 3.
A few years ago, Yamamoto reported phenol 1 bearing C2
symmetry elements as an efficient chiral auxiliary for al-
dol and Mannich reactions (Figure 1).6 As a consequence,
the sulfonic acid 2 based on this chiral scaffold was envi-
sioned as a candidate for the development of a new cata-
lyst. In this contribution, we report on the synthesis and
the resolution of this new Brønsted acid.
Then, an electrophilic bromination was carried out earlier
in the synthesis, and O-aryl thiocarbamate 5 was prepared
in two steps from phenol 3 (Scheme 1).6b Unfortunately,
no conversion was observed for the Suzuki–Miyaura cou-
pling of 5 with 2-isopropylbenzeneboronic acid, probably
due to the increased steric hindrance developed by the
bulky thiocarbamate group.
Several strategies were investigated for the synthesis of
the sulfonic acid 2. All synthetic approaches shared the
cheap commercially available 3,5-dimethylphenol (3) as
As the late introduction of aryl substituents was ineffec-
tive, the biarylphenol 1 was prepared from phenol 3 fol-
lowing two methods (Scheme 2). According to reaction
conditions developed previously,3b the Suzuki–Miyaura
coupling of dibromophenol 6 with 2-isopropylbenzenebo-
ronic acid afforded an excellent 91% yield of an insepara-
ble 5:1 mixture of racemic and meso-phenol 1.
SYNTHESIS 2012, 44, 1349–1352
Advanced online publication: 28.03.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1290753; Art ID: SS-2012-Z0039-OP
© Georg Thieme Verlag Stuttgart · New York

1350
J. Das et al.
PAPER
tive configuration of 9 was undoubtedly determined by X-
ray diffraction study of a single crystal (Figure 2). Then,
racemic acid 2 was easily obtained through the oxidative
cleavage of 8 with hydrogen peroxide in formic acid.12
OH
OH
a
Br
Br
6
1
rac/meso 5:1
b
1
3
rac/meso > 99:1
Scheme 2 Regioselective bis-orthoarylation of phenol 3. Reagents
and conditions: a) Pd(dba)2, S-Phos, 2-(i-Pr)C6H4B(OH)2, K3PO4, tol-
uene, 100 °C, 20 h, 91%; b) 2-(i-Pr)C6H4Pb(OAc)3, DABCO, toluene,
r.t., 82%.
The second strategy involved a Pinhey–Barton arylation
using (2-isopropyl)phenyllead triacetate in the presence
of DABCO. This reaction afforded stereoselectively the
racemic phenol 1 in 82% yield (Scheme 2).8 The required
2-isopropylphenyllead(IV) triacetate was easily prepared
on large scale through a mercury-catalyzed boron–lead
exchange.9 Finally, racemic phenol 1 was treated with di-
methylaminothiocarbamoyl chloride under vigorous con-
ditions to afford the O-aryl thiocarbamate 7 in 75% yield
(Scheme 3).
The Newman–Kwart rearrangement7 of 7 was carried out
under microwave irradiation at different temperatures.10
The formation of a 1:1 mixture of easily separable rac-8
and meso-9 S-aryl thiocarbamates was systematically ob-
served (Scheme 3). When the conversion was incomplete,
Figure 2 X-ray diffraction structure of meso-thiocarbamate 9
The resolution of sulfonic acid 2 was attempted following
several approaches. In the presence of chiral α-methyl-
benzylamine, no suitable crystallization was observed.
Derivatization of the corresponding sulfonyl chloride to
sulfonate or sulfonamide diastereomers failed due to lack
of reactivity, even in the presence of lithium (R)-2-ethyl-
phenylamide. These unsuccessful results suggested a very
high steric hindrance around the sulfur moiety. Finally,
the resolution of S-aryl thiocarbamates 8 was achieved by
preparative chiral HPLC.13 Using simple conditions [Daicel
Chiralpak® IA, n-heptane–i-PrOH (98:2), 20 °C, 1 mL/min]
both enantiomers of 8 were obtained in enantiopure form
in gram quantities. The (–)-S-thiocarbamate 8 was oxi-
1
isomerization of racemic 7 was observed by H NMR
spectroscopy, thus suggesting that the latter occurred prior
to the rearrangement. Attempts to decrease the tempera-
ture in order to avoid the formation of meso-isomer 9 us-
ing the recently published Pd-catalyzed rearrangement11
were unsuccessful.
After optimization, the sulfonic acid precursor 8 was iso-
lated in 45% yield (Scheme 3). The moderate yield of the
reaction could be improved by equilibrating the isolated
meso-9 at 285 °C under microwave irradiation. The rela-
Me2N
S
a
O
1
7
Me2N
S
Me2N
O
S
O
b
+
7
9
8
Scheme 3 Newman–Kwart rearrangement. Reagents and conditions: a) ClCSNMe2, NaH, THF, 70 °C, 75%; b) neat, MW 220 °C, 45%.
Synthesis 2012, 44, 1349–1352
© Georg Thieme Verlag Stuttgart · New York

PAPER
A New Chiral Sulfonic Acid
1351
(+)-S-[2,6-Bis(2-isopropylphenyl)-3,5-dimethylphenyl] N,N-Di-
methylthiocarbamate [(+)-8]
dized using in situ generated performic acid to afford the
desired sulfonic acid (–)-2 in 50% yield (Scheme 4).
O-Aryl thiocarbamate 7 (200 mg, 0.46 mmol) was introduced in a
microwave quartz tube and placed in a Discover® microwave oven
at 220 °C for 20 min. 1H NMR spectrum showed complete conver-
sion of the starting material. The crude product was purified by flash
chromatography using cyclohexane–EtOAc (98:2 to 95:5) as eluent
to afford racemic and meso products in a 1.13:1 ratio [rac-8; yield:
90 mg (45%) and meso-9; yield: 80 mg (40%)]. The enantiomers
were separated by preparative chiral HPLC on Daicel Chiralpak IA
using 98% n-heptane, 2% i-PrOH, 1 mL/min, 20 °C, 210.0 nm, t1 =
4.21 min (+), t2 = 4.67 min (–).
H2O2
SO3H
(–)-8
HCO2H
55 °C, 16 h
50%
(–)-2
Yield: 90 mg (45%); colorless solid; mp 57 °C; [α]D20 + 9.7 (c = 1.0,
CHCl3); ee = 100%.
Scheme 4 Oxidation of thiocarbamate into sulfonic acid
IR (neat): 2959, 2924, 2866, 1665, 1444, 1359, 1261 cm–1.
In conclusion, a new chiral sulfonic acid (–)-2 based on a
benzene scaffold was synthesized in 5 steps (overall yield:
5.5%) from the cheap commercially available 3,5-dimeth-
ylphenol (3). This opens new opportunities to investigate
the catalytic activities of this original chiral sulfonic acid
as organocatalyst for several asymmetric transformations.
Several asymmetric chemical reactions are currently un-
der investigation in our laboratory.
1H NMR (400 MHz, CDCl3): δ = 7.36–7.29 (m, 4 H, ArH), 7.23 (s,
1 H, ArH), 7.14 (t, J = 6.8 Hz, 2 H, ArH), 7.03 (br s, 2 H, ArH), 2.70
[br s, 2 H, CH(CH3)2], 2.51 (br s, 6 H, NCH3), 2.02 (s, 6 H, CH3),
1.13–1.08 [br m, J = 6.8 Hz, 12 H, CH(CH3)2].
13C NMR (100.6 MHz, CDCl3): δ = 166.5 (C), 139.1 (C), 136.2 (C),
133.0 (CH), 130.3 (CH), 129.3 (C), 127.5 (CH), 125.3 (CH), 124.8
(CH), 43.6 (CH3), 30.3 (CH), 30.1 (CH), 24.6 (CH3), 23.8 (CH3),
21.2 (CH3).
HRMS (ESI): m/z calcd for C29H36NOS (M + H)+: 446.2518; found:
446.2497.
Commercially available compounds were used without further pu-
rification. Solvents were obtained from a Pure-SolvTM 400 Solvent
Purification System. Melting points were determined on a Electro-
thermal digital apparatus IA9100 series. NMR spectra were record-
ed on a Bruker Avance DPX 500 or DPX 400 spectrometers.
Chemical shifts are relative to TMS or to solvent as the internal
standard. Chromatographic separations were achieved on silica gel
columns (Kieselgel 60, 40–63 μm, Merck). MS and HRMS were
obtained on a Waters-Micromass Q-Tof micro instrument. IR spec-
tra were recorded on a Perkin-Elmer 16 PC FTIR spectrometer. Op-
tical rotations were measured using a Perkin-Elmer 241 LC
polarimeter.
(–)-2,6-Bis(2-isopropylphenyl)-3,5-dimethylphenylsulfonic
Acid [(–)-2]
To a solution of (–)-S-aryl thiocarbamate 8 (335 mg, 0.75 mmol) in
HCO2H (5 mL) was added H2O2 (1.8 mL, 18 mmol, 18 equiv) at r.t.
and the reaction mixture was stirred for 16 h at 55 °C. H2O (5 mL)
was added and the aqueous phase was extracted with CH2Cl2 (3 ×
10 mL). Evaporation of the combined organic layers gave a brown-
ish crude product (300 mg). The crude product was purified by flash
chromatography using CH2Cl2–MeOH (95:5 to 9:1) to afford (–)-2
as a colorless solid (156 mg, 50%); mp 274 °C; [α]D20 –17.2 (c = 1,
CHCl3).
IR (neat): 2960, 2928, 2868, 2790, 2476, 1735, 1625, 1463, 1442,
1384 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.32–7.24 (m, 6 H, ArH), 7.14–
7.06 (m, 3 H, ArH), 6.32 (br s, 1 H, OH), 2.60–2.53 [m, 2 H,
CH(CH3)2], 1.89 (s, 6 H, CH3), 1.12 [d, J = 6.8 Hz, 6 H, CH(CH3)2],
1.08 [d, J = 6.8 Hz, 6 H, CH(CH3)2].
13C NMR (100.6 MHz, CDCl3): δ = 146.9 (C), 139.1 (C), 137.7 (C),
137.4 (C), 136.8 (C), 134.3 (CH), 130.1 (CH), 127.4 (CH), 125.4
(CH), 124.8 (CH), 34.9 (CH), 30.5 (CH), 24.4 (CH3), 23.9 (CH3),
21.3 (CH3).
O-[2,6-Bis(2-isopropylphenyl)-3,5-dimethylphenyl] N,N-Di-
methylthiocarbamate (7)
To a solution of phenol 1 (960 mg, 2.68 mmol, 1 equiv) in anhyd
THF (60 mL) was added NaH (60% oil dispersed, 268 mg, 6.7
mmol, 2.5 equiv) at r.t. The suspension was stirred for 5 min, treated
with ClCSNMe2 (989 mg, 8.04 mmol, 3 equiv), and the mixture was
further stirred for 48 h at 70 °C. H2O (5 mL) was added and the
aqueous phase was extracted with EtOAc (3 × 10 mL). The com-
bined organic layers were evaporated and the residue was washed
with MeCN (1 mL) to afford 7 as a colorless solid (890 mg, 74%);
mp 193 °C.
HRMS (ENI): m/z calcd for C26H29O3S (M – H)+: 421.1837; found:
421.1832.
IR (neat): 2961, 2929, 1526, 1391, 1250, 1160 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.53 (d, J = 7.6 Hz, 1 H, ArH),
7.37 (dd, J = 7.6, 1.2 Hz, 1 H, ArH), 7.32–7.27 (m, 3 H, ArH), 7.18–
7.12 (m, 3 H, ArH), 7.18–7.12 (m, 3 H, ArH), 6.94 (dd, J = 8.2, 1.2
Hz, 1 H, ArH), 3.05–2.98 [m, 1 H, CH(CH3)2], 2.91 (s, 3 H, NCH3),
2.64–2.58 [m, 3 H, CH(CH3)2], 2.48 (s, 3 H, NCH3), 2.12 (s, 3 H,
CH3), 2.03 (s, 3 H, CH3), 1.26 [d, J = 6.8 Hz, 3 H, CH(CH3)2], 1.22
[d, J = 6.8 Hz, 6 H, CH(CH3)2], 1.07 [d, J = 6.8 Hz, 3 H, CH(CH3)2].
13C NMR (100.6 MHz, CDCl3): δ = 186.1 (C),149.7 (C),148.7 (C),
146.8 (C), 137.0 (C), 136.8 (C), 134.9 (C), 134.8 (C), 132.8
(C), 132.8 (C), 131.8 (CH), 131.4 (CH), 129.2 (CH), 127.7 (CH),
126.4 (CH), 124.8 (CH), 124.7 (CH), 124.4 (CH), 42.7 (NCH3),
37.8 (NCH3), 30.4 (CH), 30.0 (CH), 26.7 (CH3), 24.8 (CH3), 24.2
(CH3), 23.6 (CH3), 20.5 (CH3), 20.4 (CH3).
Acknowledgment
We gratefully acknowledge ANR ‘MESORCAT’ for a fellowship
to J.D. (CP2D program), CNRS, Ministère de l’Enseignement Su-
périeur et de la Recherche, Région Basse-Normandie, and the Euro-
pean Union (FEDER funding) for financial support.
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HRMS (ESI): m/z calcd for C29H36NOS (M + H)+: 446.2518; found:
446.2498.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1349–1352

1352
J. Das et al.
PAPER
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Synthesis 2012, 44, 1349–1352
© Georg Thieme Verlag Stuttgart · New York