Synthesis of 3-aryl-4-methyl-1,2-benzenedisulfonimides, new chiral Bronsted acids. A combined experimental and theoretical study

Article abstract of DOI:10.1016/j.tet.2011.05.127

We have recently reported the use, in catalytic amounts, of 1,2-benzenedisulfonimide as a safe Bronsted acid in some acid-catalyzed organic reactions. With the design of new and chiral acid organocatalysts with the structure of 1,2-benzenedisulfonimide in

Full text of DOI:10.1016/j.tet.2011.05.127

Tetrahedron 67 (2011) 5789e5797
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Tetrahedron
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Synthesis of 3-aryl-4-methyl-1,2-benzenedisulfonimides, new chiral Brønsted
acids. A combined experimental and theoretical study
,
Margherita Barbero a, Stefano Bazzi a, Silvano Cadamuro a, Lorenzo Di Bari b, Stefano Dughera a
*
,
,
b
a
Giovanni Ghigo a , Daniele Padula , Silvia Tabasso
*
a
ꢀ
Dipartimento di Chimica Generale e Chimica Organica, Universita di Torino, C.so Massimo d’Azeglio 48, 10125 Torino, Italy
b
ꢀ
Dipartimento di Chimica e Chimica Industriale, Universita di Pisa, Via Risorgimento 35, 56126 Pisa, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
We have recently reported the use, in catalytic amounts, of 1,2-benzenedisulfonimide as a safe Brønsted
acid in some acid-catalyzed organic reactions. With the design of new and chiral acid organocatalysts
with the structure of 1,2-benzenedisulfonimide in mind, we herein propose a synthesis of 1,2-
benzenedisulfonimide derivatives bearing an aryl group in the 3-position with good overall yields. The
chirality of these compounds is due to the hindered rotation of the aryl group (atropisomerism). We
resolved the atropisomers of one of these compounds.
Received 18 January 2011
Received in revised form 12 May 2011
Accepted 31 May 2011
Available online 13 June 2011
Keywords:
Atropisomerism
Ó 2011 Elsevier Ltd. All rights reserved.
Brønsted acids
Density functional calculations
3-Arylanthranilic acids
Sulfonimides
1. Introduction
O
S
O
Organocatalysis has become a highly dynamic area in chemical
research.1 Recently, List2 introduced a system of classification of
catalysts based on their action mechanism; thus, there are essen-
tially four categories of organocatalysts: Lewis acids, Lewis bases,
Brønsted bases and Brønsted acids. Of these, Brønsted acids emerge
as powerful catalysts that present a range of benefits including:
a lack of sensitivity to moisture and oxygen, ready availability, a low
cost and low toxicity. This combination confers large direct
benefits in many synthetic protocols when compared with metal
catalysts.1,2
NH
O
S
O
1
Fig. 1. 1,2-Benzenedisulfonimide.
In general, all synthetic methods require mild reaction condi-
tions, short reaction times, good selectivity and the absence or
minimal formation of by-products are observed. Moreover, it is
worthwhile to highlight the further valuable aspect of all the above
reactions. This is the fact that 1 can easily and almost completely be
recovered from the reaction mixtures, in good to high yield, due to
its complete solubility in water. This permits its reuse in catalytic
amounts in other reactions, immediately or after a fast purification
run on a cation-exchange resin, without the loss of catalytic
activity. This obviously has economic and ecological advantages.
The results and advantages of the use of 1 are very promising in
view of the applications of this catalyst in the field of asymmetric
catalysis. Of course, structural modifications are needed so that 1
becomes chiral, while leaving the acidic function responsible of the
catalytic activity unaffected.
We have recently reported the use of 1,2-benzenedisulfonimide
(1, Fig. 1) in catalytic amounts as a safe, nonvolatile and non-
corrosive Brønsted acid in some acid-catalyzed organic reactions,
such as etherification,3 esterification,3,4 acetalization,3 the Ritter
reaction,5 the Nazarov electrocyclization,6 the disproportionation
of dialkyl diarylmethyl ethers,7 the HosomieSakurai reaction,8 the
9
Friedlander annulation, the PicteteSpengler reaction10 and the
€
MukaiyamaeAldol reaction.11
* Corresponding authors. Tel.: þ39 11 6707645; fax: þ39 11 6707642 (S.D.); tel.:
þ39 11 6707872; fax: þ39 11 6707591 (G.G.); e-mail addresses: stefano.dughera@
unito.it (S. Dughera), giovanni.ghigo@unito.it (G. Ghigo).
In this view, it was decided to bind a hindered aryl group to the
3-position of the aromatic ring of 1 in order to prevent the free
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.127

5790
M. Barbero et al. / Tetrahedron 67 (2011) 5789e5797
rotation around the aryl-aryl bond and therefore generate atropi-
somerism12a (Fig. 2). In this paper we describe the synthesis of two
hindered derivatives.
a 5% aqueous solution of NaHCO3 caused its total decomposition
after 2 h (see Experimental section). Owing to these changes, we
obtained good yields of 4aef, as reported in Table 1 (method A:
entries 1e4, 6, 7).
O
O
However, under these conditions it was impossible to obtain
hindered 7-arylisatins 4gej (Table 1, method A: entries 9, 11, 13 and
15). In fact the preparation of hindered biaryls via a Suzuki coupling
has historically proven to be very difficult.22 Nevertheless, the re-
cent literature shows that Suzuki reactions performed with hin-
dered aryl boronic acids proceed in excellent yield with the use of
2-dicyclohexylphosphino-20,60-dimethoxybiphenyl (SPhos) as a li-
gand.22 On these grounds, performing the reactions in the presence
of 10 mol % of Sphos we obtained the hindered isatins 4g,i,j in good
yields (Table 1, method B: entries 10, 14 and 16) with the only ex-
ception of 4h (Table 1, method B: entry 12). It can also be seen that
the use of Sphos was unnecessary in the reactions carried out with
less hindered aryl boronic acids (Table 1, method B: entries 5 and 8).
Finally 3-arylanthranilic acids 5aeg,i,j were easily obtained. The
yields are reported in Table 2.
S
atropisomerism
NH
S
R
R
O
O
Fig. 2. Chiral derivatives of 1,2-benzenedisulfonimide.
To obtain these chiral derivatives, the rotational barrier of the
chirality axis should be high enough to assure an atropisomer long
life time. The role of common substituents in defining this barrier
for biphenyls has already been well established.12b By contrast, the
use of a rigid sulfonimide group is unknown. Therefore, the rota-
tional barriers for a series of 1,2-benzenedisulfonimides derivatives
and precursors have been calculated by the DFT method.
It must be stressed that, recently, three different research groups
have identified a disulfonimide functional group as a powerful motif
for asymmetric catalysis. In particular, Giernoth13 describes the
synthesis of BINBAM, namely (R)-2,20-binaphthyldisulfonimide;
List14a the synthesis of (R)-3,30-bis[3,5-bis(trifluoromethyl)phenyl]-
1,10-binaphthyl-2,20-disulfonimide (and other similar chiral deriva-
tives14b,c), which is a highly active catalyst of the MukaiyamaeAldol
reaction with very good enantioselectivity and Lee15 the synthesis of
several 3,30-diaryl derivatives of (R)-2,20-binaphthyldisulfonimide.
Furthermore, we have, very recently, proposed an alternative and
convenient route to prepare (R)-2,20-binaphthyldisulfonimide.16
It must be stressed that anthranilic acids and their derivatives
are widely utilized in the synthesis of heterocyclic natural products
and biologically active molecules; they are also important in-
termediates in the preparation of quinazolines, quinolines or drugs,
which are useful in the treatment of cancer.23
2.2. Theoretical studies
Discovering a method to prepare the compounds 5 is the first
important synthetic result in this work. However, our main goal is
to synthesize 3-aryl substituted 1,2-benzendisulfonimides
6
endowed with a chiral element due to atropisomerism. Instead of
synthesizing several sulfonimides 6 and then verifying their chiral
stability, we decided to take advantage of theoretical methods to
perform a screening of 6 based on a calculated barrier. The com-
putational method was first tested by calculating the rotational free
energy barrier for binaphthyl whose experimental value (in ben-
2. Results and discussion
2.1. Preparation of anthranilic acids 5
zene) is 24.3 kcal molꢀ1 24
.
As reported in the literature,17,18 1 was easily prepared starting
from anthranilic acid.
In the light of this, our first synthetic goal was the preparation of
3-arylanthranilic acids.
The calculated value, obtained as described in the Theoretical
methods section, is 26.7 kcal molꢀ1, which is in reasonable agreement
with the experimental data. Therefore, the conformational free energy
barriers in water at room temperature have been calculated for some
selected 6taking into account the fundamental role of steric hindrance.
Results are collected in Table 3. Only the values of the lower barrier are
reported (see note25 and Supplementary data for more details).
Comparing the isomers 6c and 6e, it is worthwhile noting that
the methyl group is far more effective in increasing the rotational
barrier (from 26 to 40 kcal molꢀ1) when it is found in position 4 of
the benzenedisulfonimide ring instead of position 8 of the naphthyl
ring. A similar remarkable effect is also observed when the methyl
group is added in position 4 of the benzenedisulfonimide in passing
from 6a to 6c. Indeed, the rotational barrier rises from 19 to
40 kcal molꢀ1.The steric effect is also evident from the great dis-
torsion from planarity in the transition structures as shown, as an
example, for 6c in Fig. 3.
It is evident from the data that 6c and 6d are the best candidates
for the synthesis; in fact, for them, the rotational free energy barrier
between the two atropisomers has been calculated to be about
40 kcal molꢀ1 (25 ꢁC). This corresponds to a life time for racemi-
zation of 108 years, which is significantly longer than the arbitrary
threshold of 1000 s, considered by Oki26 the minimum requirement
for chemical separation of atropisomers.
In the literature19 a synthesis of 3-arylanthranilic acid is de-
scribed. The process starts from 2-iodoaniline, passes through in-
termediates 7-iodoisatin 2 and 7-arylisatins 4; the aryl group is
inserted on isatin ring using the Suzuki protocol,20 in the presence of
NaHCO3 as a base. Finally, 3-arylanthranilic acids 5 are easily
obtained via the oxidative cleavage of 7-arylisatins 4 in a 5%
sodium hydroxide and 30% hydrogen peroxide aqueous solutions
(Scheme 1). We modified and improved this procedure using CsF in
place of NaHCO3 and palladium acetate as pre-catalyst in place of
Pd(PPh3)4 (Table 1).
O
O
NaHCO3, Pd(PPh3)4
DME,reflux
Ar B(OH)2
+
O
O
N
N
Y
H
H
3
2
4
I
Ar
COOH
30% H2O2
5% NaOH
Y
NH2
Ar
5
Scheme 1. Synthesis of 3-arylanthranilic acids.
2.3. Preparation of sulfonimides 6c and 6d
The isatins are sensitive to alkaline environments. The Pfitzinger
quinoline synthesis,21 where the reaction of isatin with a base gives
a keto-acid, is well-known. In fact, heating 2a in the presence of
The starting 3-arylanthranilic acids 5 were firstly diazotized
with 3-methylbutyl nitrite to form the internal diazonium salt,

M. Barbero et al. / Tetrahedron 67 (2011) 5789e5797
5791
Table 1
Synthesis of 7-arylisatines 4aej
O
O
H
CsF, Pd(OAc)2
O
+
Ar B(OH)2
O
(Sphos), DME,reflux
N
N
Y
Y
H
2
3
X
4
Ar
2
a
b
X
Y
3 Ar
4 Ar
Y
H
H
H
H
4
f
Ar
Y
I
H
a Ph
a
b
c
d
e
Ph
1-naphthyl
H
Br
Me
b 4-MeOC6H4
c 4-ClC6H4
4-MeOC6H4
4-ClC6H4
g
h
i
2-EtO-1-naphthyl H
2,6-Me2C6H3
2-MeC6H4
H
Me
Me
d 2-MeC6H4
2-MeC6H4
2-i-PrOC6H4
e
2-i-PrOC6H4
H
j
1-naphthyl
f 1-naphthyl
g 2-EtO-1-naphthyl
h 2,6-Me2C6H3
Entry
Reactants
Products and yieldsa (%)
Methodb
Time (h)
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
3a
3b
3c
3d
3d
3e
3f
4a, 81
4b, 82
4c, 92
4d, 62
4d, 63
4e, 71
4f, 82
A
A
A
A
B
A
A
B
A
B
A
B
A
B
A
B
3
4
3
2.5
3
1
1.5
2
6
3
6
6
6
1
6
3
3f
4f, 81
9
3g
3g
3h
3h
3d
3d
3f
4g, dc
4g, 78
4h, dc
4h, tracesc,d
4i, dc
4i, 76
10
11
12
13
14
15
16
4j, dc
4j, 82
3f
a
Yields refer to the pure and isolated products.
Sphos was added as a ligand in the reactions carried out with the method B.
b
c
After 6 h, we observed the total decomposition of 2a or 2b.
d
On the GCeMS analysis of the crude residue traces of 4h were detected, MS (m/z, EI)¼251(Mþ).
Table 2
Synthesis of 3-arylanthranilic acids 5aej
Table 3
Calculated rotational free energy barriers (in kcal molꢀ1) and life times of selected 3-
O
aryl substituted 1,2-benzenedisulfonimides 6
COOH
30% H2O2
O
S
O
O
N
Y
NH2
Y
5% NaOH
NH
O
H
4
Ar
Ar
5
S
Me
O
4,5 Ar
Y
H
H
H
H
H
4,5 Ar
Y
Ar
a
b
c
d
e
Ph
f
g
h
i
1-naphthyl
H
6 a-e
4-MeOC6H4
4-ClC6H4
2-EtO-1-naphthyl
2,6-Me2C6H3
2-MeC6H4
H
H
6
a
b
c
d
e
Ar
Y
2-MeC6H4
2-i-PrOC6H4
Me
Me
2-MeC6H4
1-naphthyl
2-MeC6H4
1-naphthyl
H
H
Me
Me
H
j
1-naphthyl
Entry
Reactants
Products and yieldsa (%)
8-Me-1-naphthyl
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4i
4j
5a, 82
5b, 66
5c, 67
5d, 72
5e, 85
5f, 89
5g, 80
5i, 87
5j, 87
3-Aryl-1,2-benzenedisulfonimides 6
DGatt Life time Optical purity (% after 24 h)
6a
6b
6c
6d
6e
19.4 26 s
0
1
21.9 29 min
39.5 108 year 100
39.6 108 year 100
26.2 710 h
94
a
Yields refer to the pure and isolated products.
oxidative chlorination of these intermediates with chlorineewater
furnished 1,2-benzenedisulfonyl chlorides 8.17b These were then
reacted with ammonia. The resulting ammonium salts were passed
through a cation-exchange resin column to give 6 (Scheme 2).18 The
yields of these reactions are reported in Table 4.
which upon heating, tended to decompose losing nitrogen and
carbon dioxide to give rise to the intermediate benzyne, which in
the presence of carbon disulfide and 3-methylbutan-1-ol provided
2-(3-methylbutoxy)-1,3-benzodithioles 7.17a The subsequent

5792
M. Barbero et al. / Tetrahedron 67 (2011) 5789e5797
O
O
SO2Cl
Me
Me
S
S
H2N
N
DMAP
SO2Cl
Me
+
Me
Me
CH2Cl2
O
O
Me
(RS)-8a
(S)- 9
(RS)- and (SS)-10
O
O
O
NH
O
S
S
MeONa
(RS)-10a
Me
Me
HPLC
separation
(SS)-10b
(R)-(-)-6ca
Scheme 3. Separation of atropisomers of 6c.
Fig. 3. Rotational transition structure for 6c.
COOH
S
S
i-C5H11ONO, CS2
i-C5H11OH
Cl2
Oi-C5H11
t-BuOH, H2O, CH2Cl2
Me
NH2
Me
Ar
Ar
5i: Ar = 2-MeC6H4
5j: Ar = 1-naphthyl
7a: Ar = 2-MeC6H4
7b: Ar = 1-naphthyl
O
S
O
SO2Cl
SO2Cl
1. NH3; PhMe, EtOH
2. Dowex
NH
O
S
Me
Ar
Me
O
Ar
8a: Ar = 2-MeC6H4
8b: Ar = 1-naphthyl
6c: Ar = 2-MeC6H4
6d: Ar = 1-naphthyl
Scheme 2. Synthesis of 3-aryl-1,2-benzenedisulfonimides 6.
As reported by Lee15 the reaction between 8a and (S)-1-
phenylethylamine (9; ee ꢂ99%), performed in the presence of
DMAP, furnished the diastereomeric derivatives of 10. It must be
stressed that performing the same reaction starting from 8b we
obtained only a small amount of diastereomeric derivatives and
was impossible to separate them from several by-products. We
could not separate compounds 10 by silica gel column chroma-
tography; however, their separation was possible by semi-pre-
parative chiral HPLC. Two fractions containing the separated
diastereomers 10a and 10b were collected and subsequently they
were reinjected into the same column to check that they were
diastereomerically pure.
These compounds provided the electronic Circular Dichroism
(ECD) spectra of Fig. 4, which are almost a mirror image, in spite of
the fact that one deals with a pair of diastereomers. Apparently, the
biaryl moiety plays a major role in determining this chiroptical
property and it is only weakly coupled with the phenyl group at-
tached to the chiral carbon atom. The presence of several flexible
moieties made the quantitative analysis of ECD spectra of (RS)-10
and (SS)-10 by computational methods particularly involved and it
will be the subject of a future report. A conformational analysis at
MM level on both diastereomers revealed a large manifold of
structures, differing for the 5-member ring conformation and the
rotation of the single bonds in the amine moiety, together with
a broad distribution of the dihedral angle between the two ben-
zenes around 90ꢁ. This made the system hardly amenable to
a complete analysis and we decided to dissect the amine moiety
Table 4
Synthetic sequence for 3-aryl-1,2-benzenedisulfonimides 6
Entry
Reactant
Products and
yieldsa (%)
Products and
yieldsa (%)
Products and
yieldsa (%)
1
2
5i
5j
7a, 79
7b, 62
8a, 74
8b, 83
6c, 74
6d, 78
a
Yields refer to the pure and isolated products.
Analyzing the 1H and 13C NMR spectra of compounds 7a and 7b,
which have a stereogenic carbon atom, it was possible to clearly see
the presence of two diastereoisomers (and it can be inferred the
presence of two pairs of enantiomers). The barriers for 7a and 7b are
possibly around 40 kcal molꢀ1, which when compared with those of
6c and 6d, should correspond to very long life times under any con-
ditions. In fact, for 7a and 7b the two diastereoisomers were clearly
detected on GC and GCeMS analyses as well. All this experimentally
confirmed that the hindered aryl group prevents the free
rotation around inter-ring CC bond, producing atropisomerism.
2.4. Resolution of atropisomers of 6c
Having obtained the chiral compounds 6c and 6d, our next goal
was to separate their atropisomers. Firstly, we planned to react
them with cinchonidine or cinchonine, in order to try to separate
the resulting diastereomeric salts. Unfortunately, these attempts
failed completely. Because of this, we decided to follow the route
described in the Scheme 3.

M. Barbero et al. / Tetrahedron 67 (2011) 5789e5797
5793
4. Experimental section
4.1. General
Analytical grade reagents and solvents were used and reactions
were monitored, where possible, by GC, GCeMS and TLC. Column
chromatography and TLC were performed on Merck silica gel 60
(70e230 mesh ASTM) and GF254, respectively. Petroleum ether (PE)
refers to the fraction boiling in the range 40e70 ꢁC. Room tem-
perature is 20e25 ꢁC. Mass spectra were recorded on an HP 5989B
mass selective detector connected to an HP 5890 GC, cross-linked
methyl silicone capillary column. 1H NMR and 13C NMR spectra
were recorded on a Brucker Avance 200 spectrometer at 200 and
50 MHz, respectively. HPLC separations were performed on HPLC
Waters 1525. For the determination of optical rotations a Jasco P-
2000 polarimeter was used. CD spectra were recorded with a Jasco
J-710 spectropolarimeter with the following measurement pa-
rameters: scan speed, 50 nm/min; bandwidth, 1 nm; response, 1 s;
16 accumulations.
7-Iodoisatin (2a)19a and 2-bromo-3-methylaniline28 were pre-
pared as reported in the literature. All the other reagents were
purchased by SigmaeAldrich. Structures and purity of all the
products obtained in this work were confirmed by their spectral
(NMR and MS) data. Satisfactory microanalyses were obtained for
all the new compounds.
Fig. 4. Experimental and calculated electronic circular dichroism spectra for com-
pounds 10a and 10b. The thin continuous and broken lines represent the first and the
second eluted compounds, respectively. The bold continuous line represents the cal-
culated Electronic Circular Dichroism spectrum for the N-methyl derivative of com-
pound (R)-6ca (for computational details see Section 4.9).
7-Bromo-6-methylisatin (2b) was prepared, starting from 2-
bromo-3-methylaniline (1.86 g, 10 mmol), as described in the lit-
erature19a for the synthesis of 2a; pale brown solid; 1.82 g (yield
and to formally substitute it with a methyl group, i.e., to limit our
calculation to the N-methyl derivative of 6c, Me6c. This choice
appears justified by the fact that, as noted above, in this case the
observed ECD appear dominated by axial chirality and they respond
to the amine chiral centre only to a minor extent. Our model
compound, (aR)-Me6c, displays two conformational minima cor-
responding to two different orientations of the methyl group, fol-
lowing inversion of the 5-member ring and a large manifold
associated to the dihedral angle between the two benzene groups.
Accordingly, we built 18 conformers of (aR)-Me6c, and optimized
them by DFT, thereby calculating the Boltzmann averaged ECD
spectrum by TDDFT as specified in Section 4.7 and shown Fig. 4. In
spite of the approximation there is a fairly good agreement be-
tween this calculated spectrum and the experimental one relative
to the first eluted diastereomer 10a, which can then be assigned the
(aR,S)-configuration. The only serious point of disagreement be-
tween the two spectra consists in the fact that we calculate a neg-
ative Cotton effect at about 240 nm, which is flanked by two
positive ones at 260 and 230 nm. As we shall discuss in detail in
a forthcoming publication, this may be due to our conformational
average.
76%); mp 212 ꢁC (EtOH); IR (CHCl3)
n
(cmꢀ1): 3419, 3026, 1766,
1743, 1618, 806; 1H NMR (200 MHz, CDCl3):
d 8.12 (br s, 1H), 7.41
(d, 1H, J¼7.2 Hz), 6.97 (d, 1H, J¼7.2 Hz), 2.42 (s, 3H); 13C NMR
(50 MHz, CDCl3):
d 181.9, 159.0, 149.7, 148.4, 125.5, 123.9, 117.3,
108.0, 23.5; MS (m/z, EI)¼239 (Mþ); calcd for C9H6BrNO2: C
45.03%; H 2.52%; Br 33.29%; N 5.83%; found: C 45.07%; H 2.58%; Br
33.30%; N 5.87%.
4.2. 7-Arylisatins 4. General procedures
Method A: Boronic acid 3 (2.4 mmol) and then CsF (2.5 mmol,
0.38 g) dissolved in H2O (5 mL) were added to a stirring mixture
of 7-iodoisatin (2a, 2 mmol, 0.54 g) or 7-bromo-8-methylisatin
(2b, 2 mmol, 0.48 g) and Pd(OAc)2 (0.2 mmol; 24 mg) in DME
(6 mL), first. The mixture was stirred at reflux until the disap-
pearance of 2a or 2b, monitoring the reactions by TLC
(CH2Cl2eEtOAc, 9.8:0.2), GC and GCeMS. Then, the reaction
mixture was poured into CH2Cl2eH2O (100 ml, 1:1). The aqueous
layer was separated and extracted with CH2Cl2 (2ꢃ50 mL).
The combined organic extracts were washed with H2O
(2ꢃ50 mL), dried over Na2SO4 and evaporated under reduced
pressure. The crude residue, purified in a chromatography col-
umn (CH2Cl2eEtOAc, 98:2), afforded pure 4.
Finally, the reaction of the first separated diastereoisomer (RS)-
10a with sodium methoxide27 afforded the atropisomers (R)-(ꢀ)
6ca. Because the starting material (RS)-10a resulted diaster-
eomerically pure (see above) and on account of the high enantio-
meric purity (ee: ꢂ99%) of the amine we used for this resolution,
we can put forward that the atropisomer (R)-(ꢀ)6ca we obtained
are highly enantiopure (ee ꢂ99%) although this was not further
checked.
Method B: The only difference in comparison with method A
consisted in the use of 2-dicyclohexylphosphino-20,60-dimethox-
ybiphenyl (Sphos) as a ligand (0.4 mmol; 0.16 g).
In a collateral proof, using NaHCO3 (4.0 mmol, 0.34 g) dis-
solved in H2O (60 mL, as reported in the literature18) instead of
CsF, we obtained 4a in lower yield (0.24 g, 50%). In another col-
lateral proof, heating at reflux 2a (2 mmol, 0.54 g) dissolved in
DME (60 mL) in the presence of NaHCO3 (4.0 mmol, 0.34 g) dis-
solved in 60 mL of H2O after 2 h we observed the total de-
composition of 4a.
3. Conclusions
Our previous research showed that the potential applications of
1,2-benzenedisulfonimide 1 as a safe, noncorrosive, nonvolatile,
recoverable and recyclable strong Brønsted acid-organocatalyst are
in theory unlimited. For these reasons, to have synthesized the
chiral compounds 6c and 6d and to have separated one of the
atropisomers of 6c could be very interesting indeed, since they
should maintain the same attractive features of 1 in the field of
asymmetric catalysis.
4.2.1. 7-Phenylisatin (4a). Orange solid; 0.39 g (yield 81%); mp
185 ꢁC (EtOH; lit.19a 185e186); Rf¼0.59. 1H NMR (200 MHz, CDCl3):
d
7.85 (br s, 1H), 7.59e7.33 (m, 7H), 7.22e7.11 (m, 1H); 1H NMR data

5794
M. Barbero et al. / Tetrahedron 67 (2011) 5789e5797
identical to that reported in the literature;19a MS (m/z, EI)¼223
d
7.47 (d, J¼7.6 Hz, 1H), 7.34e7.24 (m, 3H), 7.06e6.93 (m, 3H), 2.06
(Mþ).
(s, 3H), 2.04 (s, 3H); 13C NMR (50 MHz, CDCl3, 25 ꢁC):
d
182.4,
159.1, 148.8, 147.2, 136.3, 132.5, 130.8, 129.2, 128.9, 126.7, 125.4,
125.1, 124.3, 115.8, 20.7, 19.2; MS (m/z, EI)¼251(Mþ); calcd for
C16H13NO2: C 76.48%; H 5.21%; N 5.57%; found: C 76.47%; H 5.27%;
N 5.56%.
4.2.2. 7-(4-Methoxyphenyl)isatin (4b). Orange solid; 0.42 g (yield
82%); mp 240 ꢁC (EtOH; lit.19a>200); Rf¼0.40. 1H NMR (200 MHz,
CDCl3):
d
7.66 (br s, 1H), 7.55e7.46 (m, 2H), 7.29 (d, J¼8.6 Hz, 2H),
7.25e7.21 (m, 1H), 7.09 (d, J¼8.6 Hz, 2H), 3.82 (s, 3H); 1H NMR data
identical to that reported in the literature;19a MS (m/z, EI)¼253
(Mþ).
4.2.10. 6-Methyl-7-(1-naphthyl)isatin (4j). Orange solid; 0.47
g
(yield 82%); mp 215e216 ꢁC (EtOH); Rf¼0.47. IR (CHCl3)
n
(cmꢀ1):
3419, 3027, 1758, 1754, 1618, 1600, 1428, 1316, 1229, 1212, 790, 775,
4.2.3. 7-(4-Chlorophenyl)isatin (4c). Orange solid; 0.47 g (yield
707, 667; 1H NMR (200 MHz, CDCl3):
d
7.93 (d, J¼3.6 Hz,1H), 7.89 (d,
92%); mp 238e239 ꢁC (EtOH); Rf¼0.53. IR (CHCl3)
n
(cmꢀ1): 3424,
J¼3.6 Hz, 1H), 7.58e7.36 (m, 5H), 7.31 (d, J¼7.6 Hz, 1H), 7.07 (d,
3036, 1750, 1743, 1608, 1210, 825; 1H NMR (200 MHz, CDCl3):
d 7.75
J¼7.6 Hz, 1H), 6.90 (br s, 1H), 2.04 (s, 3H); 13C NMR (50 MHz, CDCl3):
(br s, 1H), 7.59e7.42 (m, 4H), 7.33e7.25 (m, 2H), 7.11e7.05 (m, 1H);
d 182.4, 158.9, 149.7, 148.0, 133.8, 130.8, 130.5, 129.3, 128.7, 127.3,
13C NMR (50 MHz, CD3COCD3):
d
183.8, 159.0, 147.4, 138.2, 134.4,
127.1, 126.6, 125.6, 125.2, 124.7, 124.3, 124.0, 115.9, 20.9; MS (m/z,
EI)¼287 (Mþ); calcd for C19H13NO2: C 79.43%; H 4.56%; N 4.87%;
found: C 79.38%; H 4.53%; N 4.82%.
133.5,130.0, 129.0, 124.9,123.7,123.2, 118.6; MS (m/z, EI)¼259 (Mþ),
257 (Mþ); calcd for C14H8ClNO2: C 65.26%; H 3.13%; Cl 13.76%; N
5.44%; found: C 65.27%; H 3.18%; Cl 13.70%; N 5.47%.
4.3. 3-Arylanthranilic acids 5. General procedure
4.2.4. 7-(2-Tolyl)isatin (4d). Orange solid; 0.29 g (yield 62%); mp
145e146 ꢁC (EtOH); Rf¼0.60. IR (CHCl3)
n
(cmꢀ1): 3422, 3034, 1748,
As reported in the literature,19a 30% hydrogen peroxide aqueous
solution (10 mL) was added dropwise to a stirred suspension of 7-
arylisatin 4 (2 mmol) in a 5% aqueous NaOH solution (10 mL). The
reaction mixture was stirred at 50 ꢁC for 30 min and then was taken
to room temperature, stirring for other 30 min. The reaction mix-
ture was filtered, and the resulting solution was acidified with 1M
HCl until pH 3e4; the precipitated solid, 5 virtually pure, was col-
lected by filtration on a Buchner funnel.
1743, 1606, 1212, 789; 1H NMR (200 MHz, CDCl3,):
d 7.64e7.60 (m,
1H), 7.48 (br s, 1H), 7.47e7.44 (m, 1H), 7.37e7.27 (m, 3H), 7.23e7.18
(m, 2H), 2.23 (s, 3H); 13C NMR (50 MHz, CDCl3):
d
183.1, 158.7, 146.8,
139.2, 136.2, 133.9, 131.0, 129.4, 129.1, 126.6, 126.1, 124.5, 123.7, 118.1,
19.7; MS (m/z, EI)¼237 (Mþ); calcd for C15H11NO2: C 75.94%; H
4.67%; N 5.90%; found: C 75.97%; H 4.68%; N 5.87%.
4.2.5. 7-(2-Isopropoxyphenyl)isatin (4e). Orange solid; 0.40 g (yield
71%); mp 120e121 ꢁC (EtOH); Rf¼0.41. IR (CHCl3)
n
(cmꢀ1): 3423,
4.3.1. 3-Phenylanthranilic acid (5a). White solid; 0.35 g (yield 82%);
3035, 1747, 1743, 1607, 1225, 1212, 785; 1H NMR (200 MHz, CDCl3):
mp 146 ꢁC (EtOH; lit.19a 146 ꢁC). 1H NMR (200 MHz, CDCl3):
d
7.76 (br s, 1H), 7.57e7.47 (m, 2H), 7.39e7.33 (m, 1H), 7.30e7.29 (m,
d 7.94e7.89 (m, 1H), 7.49e7.38 (m, 5H), 7.23e7.19 (m, 1H),
1H), 7.25e7.24 (m,1H), 7.21e6.98 (m, 2H), 4.52 (septuplet, J¼6.2 Hz,
6.73e6.65 (m, 1H); 1H NMR data identical to that reported in the
1H), 1.20 (d, J¼6.2 Hz, 3H), 1.18 (d, J¼6.2 Hz, 3H); 13C NMR (50 MHz,
literature.19a
CDCl3):
d 184.0, 159.1, 154.4, 147.8, 140.1, 131.5, 130.5, 125.5, 124.3,
123.8, 121.9, 118.2, 115.0, 71.7, 22.14; MS (m/z, EI)¼281 (Mþ); calcd
for C17H15NO3: C 72.58%; H 5.37%; N 4.98%; found: C 72.61%; H
5.42%; N 5.00%.
4.3.2. 3-(4-Methoxyphenyl)anthranilic acid (5b). White solid;
0.32 g (yield 66%); mp 214 ꢁC (EtOH; lit.19a 158 ꢁC). 1H NMR
(200 MHz, CDCl3):
d
7.84e7.76 (m, 1H), 7.29 (d, J¼8.6 Hz, 2H),
7.13e7.09 (m, 1H), 6.99 (d, J¼8.6 Hz, 2H), 6.63e6.56 (m, 1H), 3.78 (s,
4.2.6. 7-(1-Naphthyl)isatin (4f). Orange solid; 0.45 g (yield 82%);
3H); 1H NMR data identical to that reported in the literature.19a
mp 224e225 ꢁC (EtOH); Rf¼0.44. IR (CHCl3)
n
(cmꢀ1): 3422, 3033,
1748, 1742, 1609, 1225, 1212, 785, 771, 680; 1H NMR (200 MHz,
4.3.3. 3-(4-Chlorophenyl)anthranilic acid (5c). White solid; 0.33 g
CDCl3):
d
7.99e7.95 (m, 2H), 7.75e7.43 (m, 7H), 7.38e7.24 (m, 2H);
183.2, 158.6, 147.5, 140.1, 134.1, 132.2,
(yield 67%); mp 187e188 ꢁC (EtOH). IR (CHCl3) (cmꢀ1): 3501, 3376,
n
13C NMR (50 MHz, CDCl3):
d
3017, 1668, 1607, 1566, 1447, 1235, 1209, 840; 1H NMR (200 MHz,
CDCl3):
7.93 (dd, J1¼8.0 Hz, J2¼1.6 Hz, 1H), 7.40 (d, J¼8.6 Hz, 2H),
130.8,129.7,129.1,127.7,127.6,126.9,125.9,125.0,124.9,124.8,124.1,
118.3; MS (m/z, EI)¼273 (Mþ); calcd for C18H11NO2: C 79.11%; H
4.06%; N 5.13%; found: C 79.15%; H 4.08%; N 5.16%.
d
7.30 (d, J¼8.6 Hz, 2H), 7.17 (dd, J1¼8.0 Hz, J2¼1.6 Hz, 1H), 6.68 (t,
J¼7.6 Hz, 1H); 13C NMR (50 MHz, CDCl3):
d 173.7, 148.4, 136.4, 135.8,
133.6. 131.9, 130.5, 129.2, 127.4, 115.8, 109.4; calcd for C13H10ClNO2:
C 63.04%; H 4.07%; Cl 14.31%; N 5.66%; found: C 63.00%; H 4.04%; Cl
14.35%; N 5.67%.
4.2.7. 7-(2-Ethoxy-1-naphthyl)isatin (4g). Orange solid; 0.50
g
(yield 78%); mp 152e153 ꢁC (EtOH); Rf¼0.35. IR (CHCl3)
n
(cmꢀ1):
3422, 3027, 1752, 1743, 1605, 1224, 795, 772, 678; 1H NMR
(200 MHz, CDCl3):
d
7.90 (d, J¼9.0 Hz, 1H), 7.84e7.80 (m, 1H), 7.63
4.3.4. 3-(2-Tolyl)anthranilic acid (5d). White solid; 0.32 g (yield
(d, J¼7.4 Hz, 1H), 7.52 (dd J1¼7.6 Hz, J2¼1.2 Hz, 1H), 7.44e7.29 (m,
72%); mp 137e138 ꢁC (EtOH). IR (CHCl3) (cmꢀ1): 3505, 3373, 3012,
n
4H), 7.22e7.15 (m, 2H), 4.14e4.05 (m, 2H), 1.24 (t, J¼7.0 Hz, 3H);
1667, 1605, 1566, 1445, 1233, 1211, 798; 1H NMR (200 MHz, CDCl3,
13C NMR (50 MHz):
d
183.2, 158.5, 153.3, 148.2, 141.3, 132.4, 131.0,
25 ꢁC):
d
8.00 (dd, J1¼8.0 Hz, J2¼1.6 Hz, 1H), 7.35e7.17 (m, 5H), 6.74
129.0, 128.3, 127.4, 124.4, 124.1, 123.7, 123.3, 120.8, 118.1, 116.4,
114.1, 64.8, 14.8; MS (m/z, EI)¼317 (Mþ); calcd for C20H15NO3
(317.34): C 75.70%; H 4.76%; N 4.41%; found: C 75.77%; H 4.78%; N
4.45%.
(t, J¼7.6 Hz, 1H), 2.17 (s, 3H); 13C NMR (50 MHz, CDCl3):
d 173.8,
148.7, 137.3, 137.2, 135.7, 131.5, 130.5, 130.2, 128.6, 128.2, 126.5, 115.7.
109.1, 19.5; calcd for C14H13NO2: C 73.99%; H 5.77%; N 6.16%; found:
C 74.02%; H 5.78%; N 6.19%.
4.2.8. 7-(2,6-Xylyl)isatin (4h). Only few traces detected on GCeMS
analysis (see Table 1, entry 12); MS (m/z, EI)¼251 (Mþ).
4.3.5. 3-(2-Isopropoxyphenyl)anthranilic acid (5e). White solid;
0.46 g (yield 85%); mp 151 ꢁC (EtOH). IR (CHCl3)
n
(cmꢀ1): 3504,
3374, 3022, 1669, 1605, 1564, 1444, 1235, 1214, 1178, 1160, 791; 1H
NMR (200 MHz, CDCl3):
4.2.9. 6-Methyl-7-(2-tolyl)isatin (4i). Orange solid; 0.38 g (yield
d
7.93 (dd, J1¼8.0 Hz, J2¼1.6 Hz, 1H),
76%); mp 207 ꢁC (EtOH); Rf¼0.61. IR (CHCl3)
n
(cmꢀ1): 3422, 3030,
7.33e7.18 (m, 3H), 6.99 (t, J¼7.0 Hz, 2H), 6.67 (t, J¼7.6 Hz, 1H), 4.36
(septuplet, J¼6.2 Hz, 1H), 1.16 (d, J¼6.2 Hz, 3H), 1.13 (d, J¼6.2, 3H);
1765, 1750, 1610, 1602, 1212, 785; 1H NMR (200 MHz, CDCl3):

M. Barbero et al. / Tetrahedron 67 (2011) 5789e5797
5795
13C NMR (50 MHz, CDCl3):
129.5, 128.8, 126.7, 121.7, 115.9, 115.7, 109.5, 71.6, 22.2; calcd for
C16H17NO3: C 70.83%; H 6.32%; N 5.16%; found: C 70.87%; H 6.38%; N
5.18%.
d
74.4, 155.7, 149.6, 137.0, 132.2, 131.6,
analyses. The diastereomers ratio was determined by 1H NMR
analysis. In particular, the ratio was deduced by comparing the
integration area of the signal centred at 6.69 ppm (pertinent to the
H of the C bound to two S) of one diastereomer, with the signal
centred at 6.68 ppm of the other diastereomer.
4.3.6. 3-(1-Naphthyl)anthranilic acid (5f). White solid; 0.47 g (yield
1H NMR (200 MHz, CDCl3):
d 7.35e7.22 (m, 4H), 7.07e7.03 (m,
89%); mp 195 ꢁC (EtOH). IR (CHCl3)
n
(cmꢀ1): 3502, 3376, 3026,
2H), 6.69 (s, 1H), 6.68 (s,1H), 3.48e3.44 (m, 2H), 2.15 (s, 3H), 2.06 (s,
3H), 1.98 (s, 3H), 1.75e1.22 (m, 1H), 1.47e1.41 (s, 2H), 0.90 (d,
J¼6.2 Hz, 6H), 0.88 (d, J¼6.2 Hz, 6H); 13C NMR (50 MHz, CDCl3):
2400, 1670, 1606, 1563, 1448, 1231, 929, 803, 708, 675; 1H NMR
(200 MHz, CDCl3):
8.08 (dd, J1¼8.0 Hz, J2¼1.6 Hz, 1H), 7.94 (d,
d
J¼8.0 Hz, 2H), 7.64e7.35 (m, 5H), 7.30 (d, J¼8.0 Hz, 1H), 6.80 (t,
d 140.0, 139.9, 137.4, 137.3, 135.7, 135.4, 135.3, 135.1, 133.1, 133.0,
J¼7.6 Hz, 1H); 13C NMR (50 MHz, CDCl3):
d
173.9, 149.2, 136.7, 135.8,
130.2, 128.5, 128.00, 127.9, 127.0, 126.2, 120.2, 120.1, 89.3, 89.1, 62.0,
61.8, 37.7, 37.6, 24.8, 24.7, 22.5, 22.4, 22.3 19.3, 19.2.
The two diastereomers were separated (0.30 g) by column
chromatography (hexane/Et2O 98:2).
134.0, 132.1, 131.8, 128.6, 128.5, 128.0, 127.2, 126.7, 126.4, 126.0,
125.9. 116.0; calcd for C17H13NO2: C 77.55%; H 4.98%; N 5.32%;
found: C 77.58%; H 4.98%; N 5.35%.
Diastereomer 1: viscous pale yellow oil; 0.16 g; Rf¼0.78. IR
4.3.7. 3-(2-Ethoxy-1-naphthyl)anthranilic acid (5g). White solid;
(CHCl3) n
(cmꢀ1): 3150, 2954, 2251, 1812, 1790, 1643, 1462, 1380,
0.49 g (yield 80%); mp 159e160 ꢁC (EtOH). IR (CHCl3)
n
(cmꢀ1):
1200, 1090, 812; 1H NMR (200 MHz, CDCl3):
d 7.33e7.20 (m, 4H),
3501, 3380, 3015, 1668, 1607, 1561, 1448, 1237, 1211, 810, 772, 665;
7.08e7.04 (m, 2H), 6.68 (s, 1H), 3.47e3.42 (m, 2H), 2.15 (s, 3H), 1.97
(s, 3H), 1.70e1.21 (m, 1H), 1.46e1.41 (s, 2H), 0.91 (d, J¼6.2 Hz, 6H);
1H NMR (200 MHz, CDCl3):
d
8.02e7.99 (m, 1H), 7.88e7.76 (m, 2H),
7.40e7.28 (m, 4H), 7.22e7.19 (m, 1H), 6.73 (t, J¼7.6 Hz, 1H), 4.07
13C NMR (50 MHz, CDCl3):
d 140.0, 137.5, 135.8, 135.3, 135.0, 133.2,
(q, J¼7.0 Hz, 2H), 1.20 (t, J¼7.0 Hz, 3H); 13C NMR (50 MHz, CDCl3
130.2, 128.6, 128.1, 126.9, 126.3, 120.1, 89.3, 62.0, 37.7, 24.8, 22.4,
22.2, 19.2; MS (m/z, EI)¼344 (Mþ); calcd for C20H24OS2: C 69.72%; H
7.02%; S 18.61%; found: C 69.77%; H 6.98%; S 18.61%.
25 ꢁC):
d 173.8, 153.9, 149.4, 137.4, 133.2, 131.5, 129.8, 129.2, 128.3,
127.8, 126.7, 124.7, 123.8, 123.0, 120.7, 115.6, 109.4, 65.2, 14.9;
calcd for C19H17NO3: C 74.25%; H 5.58%; N 4.56%; found: C 74.26%; H
5.55%; N 4.59%.
Diastereomer 2: waxy solid: 0.14 g; Rf¼0.72. IR (CHCl3)
3148, 2952, 2250, 1812, 1790, 1642, 1461, 1380, 1202, 1091, 812; 1H
NMR (200 MHz, CDCl3): 7.33e7.21 (m, 4H), 7.08e7.04 (m, 2H),
n
(cmꢀ1):
d
4.3.8. 4-Methyl-3-(2-tolyl)anthranilic acid (5i). White solid; 0.42 g
6.66 (s, 1H), 3.47e3.43 (m, 2H), 2.07 (s, 3H), 1.97 (s, 3H), 1.73e1.21
(yield 87%); mp 191 ꢁC (EtOH). IR (CHCl3) (cmꢀ1): 3500, 3377, 3025,
n
(m, 1H), 1.46e1.40 (s, 2H), 0.88 (d, J¼6.2 Hz, 6H); 13C NMR (50 MHz,
1664, 1601, 1552, 1449, 1238, 1203, 804; 1H NMR (200 MHz, CDCl3):
CDCl3): d 139.9, 137.4, 135.8, 135.3, 134.9, 133.0, 130.2, 128.5, 128.0,
d
7.82 (d, J¼8.2 Hz,1H), 7.28e7.22 (m, 3H), 7.05e7.01 (m,1H), 6.57 (d,
127.0, 126.2, 120.0, 89.1, 61.9, 37.6, 24.7, 22.3, 22.2, 19.2; MS (m/z,
EI)¼344 (Mþ); calcd for C20H24OS2: C 69.72%; H 7.02%; S 18.61%;
found: C 69.71%; H 7.03%; S 18.60%.
J¼8.2 Hz, 1H), 2.00 (s, 3H), 1.87 (s, 3H) ppm; 13C NMR (50 MHz,
CDCl3):
d 173.2, 148.7, 143.5, 137.1, 135.9, 130.7, 130.6, 129.9, 128.0,
127.2, 126.8, 117.9, 106.7, 20.6, 18.9; calcd for C15H15NO2 (241.29): C
74.67%; H 6.27%; N 5.80%; found: C 74.68%; H 6.31%; N 5.77%.
4.4.2. 5-Methyl-4-(1-naphthyl)-2-(3-methylbutoxy)-1,3-
benzodithiole (7b). Pale yellow waxy solid as a mixture (1:1) of two
diastereomer 0.47 g (yield: 62%). Having different retention times,
the two diastereomer were clearly detected by GC analyses. The
diastereomers ratio was determined by 1H NMR analysis. In par-
ticular, the ratio was deduced by comparing the integration area of
the signal centred at 6.61 ppm (pertinent to the H of the C bound to
two S) of one diastereomer, with the signal centred at 6.58 ppm of
the other diastereomer.
4.3.9. 4-Methyl-3-(1-naphthyl)anthranilic acid (5j). White solid;
0.48 g (yield 87%); mp 197e198 ꢁC (EtOH). IR (CHCl3)
n
(cmꢀ1):
3500, 3380, 3015, 1666, 1601, 1222, 1215, 790, 701, 670; 1H NMR
(200 MHz, CDCl3):
d
7.89 (d, J¼8.2 Hz, 1H), 7.85 (d, J¼8.2 Hz, 1H),
7.57e7.29 (m, 6H), 6.62 (d, J¼8.2 Hz, 1H), 1.82 (s, 3H) ppm; 13C NMR
(CDCl3, 50 MHz, 25 ꢁC):
d 173.3, 149.4, 144.6, 134.3, 133.9, 131.5,
131.2, 128.3, 128.0, 127.8, 126.5, 126.1, 126.0, 125.6, 124.8, 117.9, 107.1,
20.7 ppm; calcd for C18H15NO2: C 77.96%; H 5.45%; N 5.05%; found:
C 77.97%; H 5.42%; N 5.07%.
IR (CHCl3)
1382, 1210, 1096, 804, 705, 688; 1H NMR (200 MHz, CDCl3):
7.91e7.86 (m, 2H), 7.54e7.28 (m, 6H), 7.11e7.06 (m, 1H), 6.61 (s,
n
(cmꢀ1): 3156, 2957, 2255, 1817, 1794, 1644, 1466,
d
4.4. 4-Aryl-5-Methyl-2-(3-methylbutoxy)-1,3-benzodithioles 7.
General procedure
1H), 6.58 (s, 1H), 3.44e3.27 (m, 2H), 1.92 (s, 3H), 1.90 (s, 3H)
1.71e1.22 (m, 3H), 0.91e0.87 (m, 6H); 13C NMR (50 MHz, CDCl3):
d
138.2, 134.3, 134.0, 133.7, 133.6, 133.4, 133.2, 130.8, 130.5, 128.4,
3-Methylbutyl nitrite (2.4 mmol, 0.28 g), 3-methylbutan-1-ol
(2 mmol, 0.36 g) and CS2 (16.6 mmol, 1.26 g) were dissolved in
1,2-dichloroethane (30 mL) and heated to reflux at 82 ꢁC.
Anthranilic acid 5 (2 mmol) dissolved in 1,4-dioxane (12 mL) was
added dropwise to the previously prepared mixture. The resulting
mixture was stirred first at reflux for 45 min and then at room
temperature for 1 h. The reaction mixture was poured into
Et2OeH2O (100 mL, 1:1). The aqueous layer was separated and
extracted with Et2O (2ꢃ50 mL). The combined organic extracts
were washed with H2O (2ꢃ50 mL) and saturated solution of
Na2CO3 (50 mL), dried over Na2SO4 and evaporated under reduced
pressure. The crude residue, purified by column chromatography
(PEeEt2O 95:5), afforded the pure title compound 7.
128.2, 128.1, 127.1, 127.0, 126.4, 126.3, 126.0, 125.9, 125.6, 125.5,
125.0, 124.8, 120.6, 89.4, 89.0, 62.3, 61.6, 37.6, 24.8, 24.7, 22.3, 19.4,
19.3; calcd for C23H24OS2: C 72.59%; H 6.36%; S 16.85%; found: C
72.54%; H 6.40%; S 16.86%.
Attempts to separate the two diastereomer by column chro-
matography failed.
4.5. 3-Aryl-4-methyl-1,2-benzenedisulfonyl chlorides 8.
General procedure
4-Aryl-2-(3-methylbutoxy)-1,3-benzodithiole 8 (2 mmol) was
dissolved in tert-butyl alcohol (20 mL), CH2Cl2 (16 mL) and H2O
(3 mL).The resulting mixture was cooled to 0e5 ꢁC. Chlorine was
bubbled through while maintaining the temperature at 0e5 ꢁC and
vigorously stirring the reaction mixture. The reaction was moni-
tored on TLC (PE/EtOAc 7:3). After 1 h, when the spot of 7 dis-
appeared and there was only one other spot, the reaction was
complete. The reaction mixture was poured into CH2Cl2eH2O
4.4.1. 5-Methyl-4-(2-tolyl)-2-(3-methylbutoxy)-1,3-benzodithiole
(7a). Pale yellow waxy solid as a mixture (1:1) of two di-
astereomers; 0.55 g (yield: 79%). Having different retention times,
the two diastereomers were clearly detected by GC and GCeMS

5796
M. Barbero et al. / Tetrahedron 67 (2011) 5789e5797
(100 mL, 1:1) The aqueous layer was separated and extracted with
CH2Cl2 (2ꢃ50 mL). The combined organic extracts were washed
with a 5% NaOH solution (2ꢃ50 mL), dried over Na2SO4 and
evaporated under reduced pressure. The crude residue, purified in
a chromatography column (PEeEtOAc 7:3) afforded the pure title
compound 8.
(PEeEt2O 3:2). After 24 h, the reaction was completed. CH2Cl2 was
removed under a nitrogen flow and the crude residue was purified
in a chromatography column (PEeEt2O 3:2) affording the pure
title compound 10 (waxy solid; 0.32 g, 75%) as a mixture (1:1) of
two diastereomers. The diastereomers ratio was determined by 1H
NMR analysis. In particular, the ratio was deduced by comparing
the integration area of the signal centred at 1.99 ppm (pertinent to
one of the Me group) of one diastereomer, with the signal centred
at 1.97 ppm of the other diastereomer. 1H NMR (200 MHz, CDCl3):
4.5.1. 4-Methyl-3-(2-tolyl)-1,2-benzenedisulfonyl chloride (8a). Pale
brown solid; 0.58 g (yield: 74%); mp 148e149 ꢁC (EtOH); Rf¼0.35. IR
(CHCl3)
(200 MHz, CD3CN):
7.33e7.20 (m, 3H), 7.05 (d, J¼7.2 Hz, 1H), 1.98 (s, 3H), 1.95 (s, 3H);
13C NMR (50 MHz, CDCl3):
149.2, 145.0, 141.5, 140.0, 135.9, 135.5,
n
(cmꢀ1): 3027, 3017, 1380, 1231, 1200, 803; 1H NMR
d
7.79 (d, J¼8.0 Hz, 1H), 7.68 (d, J¼8.0 Hz, 1H), 7.51e7.47 (m, 2H),
d
8.43 (d, J¼8.0 Hz, 1H), 7.92 (d, J¼8.0 Hz, 1H),
7.39e7.09 (m, 7H), 5.27 (q, J¼7.2 Hz, 1H), 2.09 (s, 3H), 1.99 (s, 3H),
1.97 (s, 3H), 1.95 (d, J¼7.2 Hz, 3H), 1.94 (d, J¼7.2 Hz, 3H); 13C NMR
d
(50 MHz, CDCl3): d 145.5, 137.7, 137.3, 136.1, 135.5, 133.9, 133.0,
135.4, 131.7, 130.1, 128.9, 127.6, 125.9, 21.4, 19.9; calcd for
C14H12Cl2O4S2: C 44.34%; H 3.19%; Cl 18.70%; S 16.91%; found: C
44.33%; H 3.22%; Cl 18.65%; S 16.95%.
132.3, 130.2, 129.5, 129.1, 128.5, 128.3, 127.9, 125.9, 120.3, 56.3,
56.2, 19.6, 19.5, 19.1, 19.0.
Compound 10 (38 mg) was chromatographed on a semi-
preparative Chiralpak IC column (
F
10ꢃ250 mm, Daicel, Osaka,
4.5.2. 4-Methyl-3-(1-naphthyl)-1,2-benzenedisulfonyl
(8b). Pale brown solid; 0.58 g (yield: 83%); mp 89e90 ꢁC (EtOH);
Rf¼0.27. IR (CHCl3)
(cmꢀ1): 3030, 3015, 1380, 1231, 1201, 798, 701,
chloride
Japan) employing an isocratic elution with heptaneeCH2Cl2 (1:1) at
a flow rate of 4.7 mL/min. The compounds eluted from the column
were monitored with a photodiode array detector. Compounds 10a
(18.8 mg) and 10b (19.2 mg), eluted as single peaks at 8.9 and
12.8 min, were collected, after removing the solvents under nitro-
gen flow.
n
680; 1H NMR (200 MHz, CDCl3):
d
8.47 (d, J¼8.0 Hz, 1H), 8.33 (d,
J¼8.0 Hz, 1H), 7.85e7.12 (m, 7H), 1.91 (s, 3H); 13C NMR (50 MHz,
CDCl3): d150.0, 142.8, 141.7, 140.9, 136.2, 133.9, 133.3, 132.3, 130.6,
127.8, 127.4, 126.9, 126.7, 125.8, 125.5, 125.1, 21.5; calcd for
C17H12Cl2O4S2: C 49.17%; H 2.91%; Cl 17.07%; S 15.44%; found: C
49.12%; H 2.92%; Cl 17.09%; S 15.49%.
Compound (RS)-10a: waxy solid; [
(CHCl3)
NMR (200 MHz, CDCl3):
a
]
23 ꢀ12.1 (c 0.60, CH2Cl2); IR
D
n
(cmꢀ1): 3025, 1603, 1457, 1349, 1167, 883, 709, 696; 1H
d
(d, J¼8.0 Hz, 1H), 7.68 (d, J¼8.0 Hz, 1H),
7.51e7.46 (m, 2H), 7.39e7.07 (m, 7H), 5.27 (q, J¼7.2 Hz, 1H), 2.09 (s,
3H), 1.98 (s, 3H), 1.95 (d, J¼7.2 Hz); 13C NMR (50 MHz, CDCl3): 145.5,
137.7,137.2,136.1,135.4,133.9,133.0,132.2,130.2, 129.5, 129.1, 128.5,
128.3, 127.9, 125.9, 120.2, 56.1, 19.6, 19.5, 19.0; calcd for
C22H21NO4S2: C 61.81%; H 4.95%; N 3.28%; S 15.00; found: C 61.85%;
H 4.90%; N 3.30%; S 14.98%. By preliminary electronic Circular Di-
chroism analyses, 10a can be assigned to the aR axial chirality and
thus is the RS diastereomer.
4.6. 3-Aryl-4-methyl-1,2-benzenedisulfonimides 6. General
procedure
3-Aryl-1,2-benzenedisulfonyl chloride 8 (2 mmol) was dissolved
in toluene (8 mL) and EtOH (12 mL). The resulting mixture was
cooled to 0e5 ꢁC. Ammonia was bubbled through while main-
taining the temperature at 0e5 ꢁC and vigorously stirring the re-
action mixture. The reaction was monitored by TLC (PEeEtOAc 7:3).
After 30 min, the reaction was completed. The mixture was first
filtered in order to eliminate NH4Cl and then solvent was evapo-
rated under reduced pressure. The crude residue, dissolved in H2O
and passed through a Dowex (HCReW2) column (H2O), afforded
the pure title compound 6.
Compound (SS)-10b: waxy solid; [
(CHCl3)
NMR (200 MHz, CDCl3):
7.51e7.46 (m, 2H), 7.39e7.07 (m, 7H), 5.27 (q, J¼7.2 Hz, 1H), 2.09 (s,
3H), 1.98 (s, 3H), 1.95 (d, J¼7.2 Hz); 13C NMR (50 MHz, CDCl3): 145.5,
137.7,137.2,136.1,135.4,133.9,133.0,132.2,130.2, 129.5, 129.1, 128.5,
128.3, 127.9, 125.9, 120.2, 56.2, 19.6, 19.5, 19.1; calcd for
C22H21NO4S2: C 61.81%; H 4.95%; N 3.28%; S 15.00; found: C 61.87%;
H 4.93%; N 3.25%; S 15.02%.
a
]
23 ꢀ2.4 (c 0.69, CH2Cl2); IR
D
n
(cmꢀ1): 3025, 1603, 1457, 1349, 1167, 883, 709, 696; 1H
d
(d, J¼8.0 Hz, 1H), 7.68 (d, J¼8.0 Hz, 1H),
4.6.1. 4-Methyl-3-(2-tolyl)-1,2-benzenedisulfonimide
brown waxy solid; 0.48 g (yield: 74%); IR (CHCl3)
(6c). Pale
n
(cmꢀ1): 3432,
3034, 1602, 1460, 1370, 1228, 797; 1H NMR (200 MHz, CDCl3):
d
7.81
(d, J¼8.0 Hz, 1H), 7.72 (d, J¼8.0 Hz, 1H) 7.35e7.10 (m, 5H), 2.12 (s,
3H), 2.00 (s, 3H); 13C NMR (50 MHz, CDCl3):
145.9, 138.3, 136.4,
4.8. Preparation of (R)-(L)-6ca from (RS)-10a
d
136.0, 135.9, 132.2, 130.3, 129.6, 129.0, 126.5, 126.0, 120.8, 19.9, 19.5;
calcd for C14H13NO4S2: C 52.00%; H 4.05%; N 4.33%; S 19.83%; found:
C 52.05%; H 4.00%; N 4.37%; S 19.91%.
Sodium methoxide 0.5 M in MeOH (14 mg, 0.0843 mmol) was
added to a solution of (RS)-10a (36 mg, 0.0843 mmol) in MeOH
(1 mL). The reaction was monitored on TLC (PEeEt2O 3:2). After
24 h, when the spot of (RS)-10a disappeared, the reaction was
complete. MeOH was removed under nitrogen flow; the crude
residue was poured into CH2Cl2eH2O (2 mL, 1:1). The aqueous layer
was separated and passed through a Dowex (HCReW2) column
(H2O), affording pure title compound (R)-(ꢀ)-6ca, (26 mg, 96%
yield) after removing H2O under nitrogen flow.
4.6.2. 4-Methyl-3-(1-naphthyl)-1,2-benzenedisulfonimide (6d). Pale
brown solid; 0.56 g (yield: 78%); mp 134e136 ꢁC (EtOH). IR (CHCl3)
n
(cmꢀ1): 3432, 3032,1602, 1370, 1231, 1228, 804, 704, 679; 1H NMR
(200 MHz, CDCl3):
d
8.36e8.29 (m, 1H), 7.92e7.06 (m, 8H), 2.05 (s,
145.9, 137.7, 136.7, 136.2, 134.9,
3H); 13C NMR (50 MHz, CDCl3):
d
134.0, 133.1, 132.6, 132.1, 131.8, 130.7, 129.8, 127.8, 126.7, 125.5, 121.5,
19.7; calcd for C17H13NO4S2: C 56.81%; H 3.65%; N 3.90%; S 17.84%;
found: C 56.84%; H 3.66%; N 3.70%; S 17.80%.
Compound (R)-(ꢀ)-6ca: pale brown waxy solid; [
a
]
D
22.5 ꢀ14.1 (c
0.18, CH2Cl2); spectral data identical to that reported for 6c.
4.9. Theoretical method
4.7. Synthesis of N-(2-phenylethyl)-1,2-benzenedisulfonimide
(10) and separation of its diastereoisomers 10a and 10b
The theoretical study was performed within the Density Func-
tional Theory (DFT)29 making use of the M05-2x functional.30 All
geometries were fully optimized with the basis set 6e31þG(d)31a,b
and characterized through vibrational frequency analysis.32 Then,
single point energy calculations were performed with the basis set
6-311þ(3df,2p)31c,d including the electrostatic and non electrostatic
DMAP (122 mg, 0.1 mmol) and Et3N (0.20 g, 2.1 mmol) were
added to a solution of 8a (0.38 g, 1 mmol) in CH2Cl2 (100 mL).
Then (S)-1-phenylethylamine (9, 0.12 g, 1.05 mmol; ee ꢂ99%) was
slowly added dropwise. The reaction was monitored by TLC

M. Barbero et al. / Tetrahedron 67 (2011) 5789e5797
5797
solvent effects with the Polarized Continuum Method.33 Finally,
these data were combined with the gas-phase thermal and entropy
corrections. All energy values are reported in the Supplementary
data. Calculations were performed with the Gaussian 03 pro-
gram.34 Fig. 3 was prepared with program Molden.35
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On the N-methyl derivative of compound (R)-6ca a conforma-
tional analysis and subsequent calculation of Electronic CD spec-
trum were performed. A first conformational search was conducted
at Molecular Mechanics (MMFF force field) level by means of the
procedure ‘Systematic’ implemented into Spartan 08.36 8 con-
formers within 2 kcal molꢀ1 above the total minimum were opti-
mized DFT/B3LYP/6-31G(d) with Gaussian.34 On the two lowest
lying structures found above, the dihedral angle between the two
aromatic rings was scanned in 5ꢁ steps and relative energies were
calculated at DFT/CAM-B3LYP/SVP level. The Electronic CD spectra
were calculated at TDDFT/CAM-B3LYP/SVP level. The final spec-
trum was obtained by Boltzmann averaging of 18 structures (eight
dihedral angle steps on two conformers).
16. Barbero, M.; Bazzi, S.; Cadamuro, S.; Dughera, S.; Magistris, C.; Venturello, P.
Synlett 2010, 1803.
17. (a) Nakayama, J. Synthesis 1975, 38; (b) Barbero, M.; Degani, I.; Fochi, R.;
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25. In the stable conformers of compounds 8, the two aromatic rings are roughly
perpendicular with dihedral angles between 90 and 120ꢁ. The conformers
where the two aromatic rings are nearly planar correspond to transition
structures. Because the aromatic ring (Ar in schemes) is substituted with
a methyl or a second ring (Ar¼naphthyl) we have two transition structures:
one (TSanti) with the substituent on the opposite side of the sulphur atom; the
second (TSsyn) with the substituent on the same side.
Acknowledgements
This work was supported by the University of Torino.
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data include MOL files and InChIKeys of the most important com-
pounds described in this article.
ꢁ
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