Synthesis of BINOL derived phosphorodithioic acids as new chiral Br?nsted acids and an improved synthesis of 3,3′-disubstituted H8-BINOL derivatives

Article abstract of DOI:10.1016/j.tet.2009.10.068

Original phosphorodithioic acid diesters were prepared according to an improved synthesis of 3,3′-disubstituted H₈-BINOL derivatives. In preliminary experiments, these new Br?nsted acids were tested as organocatalysts in three reactions. They promoted the Nazarov cyclisation with mixed selectivities, the Mannich reaction with good enantioselectivity and they catalyzed efficiently the alkylation of N-acyliminium with enol silyl ether.

Full text of DOI:10.1016/j.tet.2009.10.068

Tetrahedron 65 (2009) 10617–10622
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Synthesis of BINOL derived phosphorodithioic acids as new chiral Brønsted acids
and an improved synthesis of 3,30-disubstituted H8-BINOL derivatives
Guillaume Pousse a, Alice Devineau b, Vincent Dalla b, Luke Humphreys c, Marie-Claire Lasne a,
a
a,
*
´ ˆ
Jacques Rouden , Jerome Blanchet
a
´
´
´
Laboratoire de Chimie Moleculaire et Thio-organique, ENSICAEN, Universite de Caen Basse-Normandie, CNRS, 6 boulevard du Marechal Juin, 14050 Caen, France
b Unite´ de Recherche en Chimie Organique et Macromole´culaire, Faculte´ des Sciences et Techniques de l’Universite´ du Havre, 25 rue Philippe Lebon, BP 540,
76058 Le Havre Cedex, France
c Synthetic chemistry, Glaxosmithkline, Medecines Research Centre, Stevenage SG1 2NY, UK
a r t i c l e i n f o
a b s t r a c t
Original phosphorodithioic acid diesters were prepared according to an improved synthesis of 3,30-di-
substituted H8-BINOL derivatives. In preliminary experiments, these new Brønsted acids were tested as
organocatalysts in three reactions. They promoted the Nazarov cyclisation with mixed selectivities, the
Mannich reaction with good enantioselectivity and they catalyzed efficiently the alkylation of N-acyli-
minium with enol silyl ether.
Article history:
Received 31 August 2009
Received in revised form 13 October 2009
Accepted 19 October 2009
Available online 23 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Enantioselective organocatalysis
Brønsted acids
BINOL
Nazarov
Mannich
1. Introduction
a structurally simpler and synthetically cheaper alternative to
Yamamoto’s N-triflylphosphoramide catalysts.2d
The recent emergence of organocatalysis has received a lot of
attention because it opens new perspectives for the mild catalysis
of important reactions with lower environmental impact. Note-
worthy is the design and development of new chiral Brønsted acids.
Since the seminal work of Terada and Akiyama in 2004,1 many
applications of these acids have been reported.2 In our recent in-
terest to discover new organic Brønsted acids for the catalysis of the
Nazarov reaction,3 we were interested in the development of new
derivatives of chiral H8-BINOL phosphoric acid diester as enantio-
selective organocatalysts.
R
O
P
X
S
P
S
P
O
O
RO
RO
RO
RO
RO
RO
P
>
>
XH
O
S
O
Relative stability
R
1 X = O
2
X = S
Preliminary results have shown that BINOL phosphoric acid
diesters 1 display low activity as organocatalysts for the Nazarov
cyclisation,4 most likely due to an inadequate acidity. Recognizing
that sulfur atom would better accommodate a negative charge
owing to its d orbitals leading to a more stabilized phosphoro-
dithioate anion than its oxygen analog,5 we reasoned that, phos-
phorodithioic acids 2 would be more acidic candidates to be tested
(Fig. 1). In addition, this catalyst class may be considered as
Figure 1. Order of stability of the conjugated bases.
2. Results and discussion
In order to prepare the catalyst candidates, we re-evaluated the
general introduction of substituents in the 3,30 position of H8-
BINOL backbones. The usual synthetic approaches involve regio-
selective ortho metalation of suitably protected H8-BINOL followed
by Suzuki–Miyaura coupling to set up bulky aromatic stereo-
differentiating groups.6 This strategy requires a lengthy protecting–
deprotecting sequence and the use of expensive ligand/palladium
* Corresponding author. Tel.: þ33 2 31 45 28 91.
E-mail address: jerome.blanchet@ensicaen.fr (J. Blanchet).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.10.068

10618
G. Pousse et al. / Tetrahedron 65 (2009) 10617–10622
Table 1
catalytic systems for the cross–coupling reaction. Therefore, a more
efficient approach to these structures is highly desired, notably
when bulk quantities are required.
Ligandless Suzuki coupling using 3,30-diiodo-H8-BINOL 3ba
I
Ar
Pd/C, ArB(OH)2
While it is well know that Suzuki–Miyaura coupling accom-
modates protection-free phenols,7 it is only recently that a suc-
cessful application involving dibromo H8-BINOL 3a has been
reported.8 One key feature of the methodology is the use of the
bulky and electron-rich n-butyl-di-1-adamantylphosphine 4 to
generate biaryl products with high yields (Fig. 2). However, the
glove-box required for the manipulation of such air-sensitive
phosphine and therefore rigorously oxygen-free reaction condi-
tions associated with the expensive cost of the latter render this
method less attractive when larger reaction scale is required.
K2CO3
OH
OH
OH
OH
dioxane/H2O
95 °C
I
Ar
3b
7a-m
Entry
Ar
Product
Yieldb (%)
0c,d
0d
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
7a
7a
7a
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
87
92e
88
70
98
93
94
97
81
94
72
32
X
4-MeO-C6H4
3,5-CF3-C6H3
1-naphtyl
4-Cl-C6H4
9-phenanthryl
4-tBu-C6H4
4-F-C6H4
2,5-MeO-C6H3
2-iPr-C6H4
4-vinyl-C6H4
OH
OH
PCy2
OMe
P
MeO
9
10
11
12
13
14
X
3a
4
5
X = Br
3b X = I
Figure 2. Substrates and ligands used in Suzuki–Miyaura reactions.
a
Reaction conditions ArB(OH)2 (4 equiv), Pd/C (5 mol %), K2CO3 (5 equiv), di-
oxane, water, 7–8 h, 95 ꢀC.
Therefore we envisioned ligandless conditions for the Suzuki–
Miyaura cross coupling. We directed our efforts toward conditions
involving an inexpensive and reusable catalyst, such as hetero-
geneous palladium on charcoal.9 Several attempts to use dibromo
derivative 3a as substrate for the coupling reaction were un-
expectedly not successful, even under forced conditions (Pd/C
5 mol %, K2CO3, dioxane/water, 120 ꢀC, 10 h) only very low conver-
sion was observed. In order to facilitate the oxidative insertion of
the palladium in the carbon–halogen bond, we sought to use diiodo
analog 3b, which is readily prepared in two steps from (R)-BINOL 6
and isolated in 92% yield (Scheme 1).
b
Isolated yield.
Run only in water.
Run at room temperature.
Run with 1 mol % Pd/C.
c
d
e
In order to solve the problem associated with the use of highly
hindered boronic acids we developed a second set of reaction
conditions involving air-stable S-Phos 5, which can be easily re-
covered once the reaction is complete.11
Under carefully optimized conditions, higher yields than those
previously reported by Beller8 were achieved with various aryl
boronic acids (Table 2) using small amount of catalyst and ligand.
Satisfyingly, mesityl boronic acid delivered a 64% yield (Table 2,
entries 5). Also noteworthy was the yield of 7k (Ar¼4-vinyl-C6H4,
Table 2, entry 4), which was substantially improved to 78%. Test
experiments showed that the dibromo derivative 3a was also
a good substrate, although higher ligand loading (20 mol %) was
necessary to achieve high yields (data not shown).
I
1. PtO2, AcOH, H2
2. I2, morpholine
CH2Cl2, r.t.
OH
OH
OH
OH
90% over 2 steps
I
6
3b
Scheme 1. Synthesis of the 3,30-diiodo H8-BINOL 3b.
Table 2
Synthesis of 3,30-H8-BINOL derivatives using ligand 5a
I
Ar
Initial attempts at using room temperature aqueous condi-
tions10 failed to afford the desired product 7, even when dioxane
was used as co-solvent (Table 1, entries 1–2). However, upon
warming the reaction at 95 ꢀC, the bis-arylated products 7 were
isolated in 72–97% yield (Table 1, entries 3–12). By comparison with
the previous coupling of simple iodophenols at room temperature
in water,10 this result is likely the consequence of an increased
solubility of the reactants.
Optimized conditions afforded high yields under aerobic con-
ditions regardless of whether electron rich or electron poor aryl
boronic acids were used (Table 1, comparison of entries 6 and 11
with entries 5 and 12). Even very low loading of catalyst (1 mol %)
deliver excellent yield (Table 1, entry 4). Sterically hindered 2-iso-
propylbenzene boronic acid gave 2j with good yield (72%). Sur-
prisingly the coupling reaction with styrene boronic acid produced
7k in a low 32% yield (Table 1, entries 14), even though complete
conversion was observed by TLC monitoring. No side-product
arising from an unwanted Heck reaction was identified. The more
congested mesityl boronic acid failed to give any conversion, even
after prolonged reaction time or increased warming.
Pd2dba3, ArB(OH)2
5, K3PO4
OH
OH
OH
OH
toluene, 100 °C
I
Ar
3b
7a-m
Entry
Ar
Ph
Product
Yieldb (%)
1
2
3
4
5
7a
7d
7f
7k
7l
97
88
88
78
64
1-naphtyl
9-phenanthryl
4-vinyl-C6H4
2,4,6-Me-C6H2
a
Reaction conditions ArB(OH)2 (4 equiv), Pd2(dba)3 (2 mol %), 5 (4 mol %), K3PO4
(5 equiv), toluene, 3–18 h, 100 ꢀC.
b
Isolated yield.
Having revisited the synthesis of H8-BINOL derivatives, we next
prepared a series of phosphorodithioic acid diesters by the treat-
ment of the biphenols with P4S10 at 140 ꢀC in toluene.12 High yields

G. Pousse et al. / Tetrahedron 65 (2009) 10617–10622
10619
MeO
OMe
were obtained with less hindered derivatives (Table 3, entries 1–4),
whereas increased steric hindrance of the substrate gave lower
amounts of the corresponding dithioic acids.
2c (5 mol %),
O
toluene, 0 °C, 72 h
N
O
HN
92 %
Table 3
Preparation of phosphorodithioic acid diesters
NO2
NO2
R
P4S10 0.7 equiv.
toluene, 140 °C
24 h
R
10
11
syn/anti 30/70
ee anti 63 %
S
OH
OH
O
O
P
SH
Scheme 2. Mannich reaction.
R
R
Despite those puzzling results in terms of selectivity for the
Nazarov and the Mannich reactions, we examined another reaction
in which these new catalysts might offer interesting complemen-
tary or additional reactivity to the known phosphoric acid diesters.
In particular we tested the alkylation of hemiaminal 12 with silyl
enol ether 13 derived from acetophenone. This reaction is known to
be easily triggered by a strong Brønsted acid (2 mol %), such as
triflimide (Tf2NH).14 Several attempts to define suitable conditions
to carry out the reaction using BINOL phosphoric acid rac-1a as
catalyst were unsuccessful. As expected, the stronger phosphor-
odithioic acid rac-2a gave a quantitative yield of the substituted
pyrrolidine 14 after only 2 h (Scheme 3).
1a, 7a-f
2a-f 46-82 %
Entry
R
Product
Yielda (%)
1
2
3
4
5
6
H
Br
Ph
2a
2b
2c
2d
2e
2f
79
70
82
71
54
46
3,5-CF3-C6H3
9-phenanthryl
1-Naphthyl
a
Isolated yield.
Due to the high temperature used for their preparation (140 ꢀC),
one may question the configurational stability of the BINOL phos-
phorodithioic acid diesters. The absence of racemization during the
process was ascertained by reducing 2c with lithium aluminum
hydride to yield 7a in ee higher than 99% (measured by chiral
HPLC).
As expected, phosphorodithioic acids diesters displayed an im-
proved activity for the Nazarov cyclization of a model substrate 8
compared to the phosphoric acid counterparts.
OSiMe3
O
13
Ph
Ph
OMe
N
Cbz
rac-1a, 20 h, trace
rac-2a, 2h, 100%
N
Cbz
1a 2a
or
2 mol %
CH3CN, 20 °C
12
14
Scheme 3. N-Acyliminium alkylation reaction.
To illustrate this point, 2d afforded 9 with a 83% yield in 1.5 h at
room temperature in CHCl3 while reactions using corresponding
phosphoric acids (Table 4) typically require 60 ꢀC in toluene (60–
70% yield).2n
3. Conclusion
In conclusion we have reported a convenient method to access
3,30-disubstituted H8-BINOL derivatives with an inexpensive Pd
source and under aerobic conditions. We have also improved the
previously reported yields when mesityl boronic acid is used in the
cross coupling step. The phosphorodithioic acid diesters synthe-
sized using this method were efficiently tested for three reactions,
and thus constitute a new class of organocatalysts. While these
catalysts displayed good diastereoselectivity but no useful enan-
tioselectivity for the Nazarov cyclization, interesting reactivity was
found for the alkylation of N-acyliminium ion precursor with enol
silyl ether 13 and for a Mannich reaction involving cyclohexa-
none.15 We are currently exploring the scope and limitations of this
reaction with various substrates catalyzed by a series of chiral
phosphorodithioic acids. The full study will be reported in due
course.
Table 4
Nazarov cyclisations
2a-f
10 mol %
O
O
CHCl3 or toluene
20 °C, 1-48h
O
O
Ph
Ph
8
9
Entry
Catalyst
Solvent
Yielda (%)
syn/antib
ee (%) (syn, anti)c
1
2
3
4
5
6
7
2a
2b
2c
2c
2d
2e
2f
CHCl3
CHCl3
CHCl3
Toluene
CHCl3
CHCl3
CHCl3
74
85
93
60
83
87
70
3:1
3:1
9:1
<5:1
9:1
9:1
4, 4
5, 10
2, 10
4, 20
10, 18
2, 5
6:1
9, 1
a
Isolated yield.
Determined by 1H NMR.
Determined by HPLC: Daicel OJ-H column 4.6 mmꢁ250 mm, 1 mL/min, 90% n-
4. Experimentals
b
c
4.1. General remarks
heptane 10% propan-2-ol, 20 ꢀC.
Commercially available compounds were used without further
purification. Solvents (THF, CH2Cl2, MeCN, Et2O, DMF, toluene) were
dried and purified from Pure-SolvÔ 400 Solvent Purification Sys-
tem. Melting points were determined on an Electrothermal digital
apparatus IA9100 series and are uncorrected. 1H NMR, 13C NMR,
and 19F, and 31P NMR spectra were recorded on a Bruker Avance
DPX 500 or Bruker Avance DPX 400 spectrometers. Chemical shifts
are reported in parts per million (d) relative to TMS or to solvent as
the internal standard. Thin layer chromatography was performed
on silica gel 60 F-254 plates (0.1 mm, Merck). Detection was
While the enantioselectivity was much lower than those
reported using BINOL N-triflyl phosphoramides,2n higher diaster-
eoselectivity was obtained (syn/anti 9:1 compared to 6:1). In an
attempt to achieve interesting selectivity, phosphorodithioic acid
diesters were tested for the Mannich reaction13 between cyclo-
hexanone and an electron poor aldimine 10 (Scheme 2).
Gratifyingly, amongst the various catalysts tested 2a–f, 2c
afforded the Mannich adduct 11 in 92% yield with a 63% ee for the
major anti product.

10620
G. Pousse et al. / Tetrahedron 65 (2009) 10617–10622
accomplished by irradiation with a UV lamp or staining with
KMnO4. Chromatographic separations were achieved on silica gel
(m, 4H), 2.59–2.42 (m, 2H), 2.42–2.29 (m, 2H), 1.84–1.73 (m, 8H).
13C NMR (100.6 MHz, DMSO, 110 ꢀC)
150.4 (C), 138.2 (C), 137.2 (C),
d
columns (Kieselgel 60, 40–63
m
m, Merck). Analytical high perfor-
134.4 (2C, C), 133.2 (CH), 131.9 (C), 129.1 (CH), 128.7 (C), 128.4 (CH),
128.0 (CH), 126.3 (CH), 126.2 (3C, CH), 124.3 (C), 29.7 (CH2), 27.7
(CH2), 23.8 (CH2), 23.6 (CH2). IR (neat, cmꢂ1): 3524, 2923, 2851,
1609, 1448, 1233, 801, 776. HRMS calcd for (MþH)þ C40H35O2:
547.2637 found: 547.2628.
mance liquid chromatographies (HPLC) were carried out with
a Waters instrument [detector M996 (200–400 nm) and pump
600]. The conditions are precised for each compound. Mass spectra
and high resolution mass spectra (HRMS) were obtained on a Wa-
ters-Micromass Q-Tof micro instrument. IR spectra were recorded
on a Perkin–Elmer 16 PC FTIR spectrometer. Optical rotations were
measured, at room temperature, on a Perkin–Elmer 241 LC polar-
4.5. (R)-3,30-Bis(2,5-dimethoxyphenyl)-5,50,6,60,7,70,8,80-
octahydro-1,10-binaphthyl-2,20-diol 7i
imeter in a 10 cm cell. [
a]
values are given in units of 10ꢂ1 deg
D
cm2 gꢂ1
.
Prepared according to the general procedure from 3b as a col-
orless solid (94% yield). Mp: 117 ꢀC (CHCl3). [
a
]D: ꢂ0.5 (c 1.0, CHCl3).
4.2. (R)-3,30-Diiodo-octahydrobinaphtol 3b
1H NMR (400 MHz, CDCl3)
d
(ppm) 7.10 (s, 2H), 7.02 (d, J¼28 Hz,
2H), 6.97–6.94 (m, 2H), 6.91–6.88 (m, 2H), 5.97 (s, 2H), 3.84 (s, 6H),
3.80 (s, 6H), 2.88–2.83 (m, 4H), 2.59–2.49 (m, 2H), 2.36–2.27 (m,
To a solution of (R)-5,50,6,60,7,70,8,80-octahydro-1,10-binaphthyl-
2,20-diol16 (2 g, 6.8 mmol) in CH2Cl2 (60 mL) were added succes-
sively at room temperature, morpholine (3.6 mL, 41 mmol, 6 equiv)
and I2 (3.45 g, 13.6 mmol, 2 equiv). The mixture was stirred at this
temperature for 5 h and turned progressively red. Then CH2Cl2
(50 mL) and HCl (1 N, 50 mL) were added. The aqueous layer was
extracted with CH2Cl2 and the combined organic layers were
washed successively with a saturated sodium thiosulfate solution
(3ꢁ50 mL) and brine, then dried over MgSO4 and concentrated to
afford 3b as a colorless solid (3.36 g, 91%), which can be used
2H), 1.86–1.73 (m, 8H). 13C NMR (100.6 MHz, CDCl3)
d 154.4 (C),
150.1 (C), 148.7 (C), 136.9 (C), 131.3 (CH), 129.6 (C), 129.0 (C), 124.1
(C), 123.6 (C), 117.4 (CH), 113.8 (CH), 112.9 (CH), 56.9 (CH3), 55.8
(CH3), 29.4 (CH2), 27.2 (CH2), 23.3 (CH2), 23.2 (CH2). IR (neat, cmꢂ1):
3302, 2923, 2853, 1609, 1584, 1497, 1455, 1272, 1217, 1048, 1012,
868, 733. HRMS calcd for (MþH)þ C36H39O6: 567.2747 found:
567.2725.
4.6. (R)-3,30-Bis(2-isopropylphenyl)-5,50,6,60,7,70,8,80-
octahydro-1,10-binaphthyl-2,20-diol 7j
without any purification. Mp: 214 ꢀC. [
NMR (400 MHz, CDCl3)
a]
ꢂ24 (c 1.0, CHCl3); 1H
D
d
7.51 (s, 2H), 4.97 (s, 2H), 2.78–2.70 (m,
4H), 2.31–2.22 (m, 2H), 2.15–2.05 (m, 2H), 1.76–1.65 (m, 8H); 13C
NMR (100.6 MHz, CDCl3) 149.8,139.3,137.8,132.5,120.7, 81.1, 28.9,
Prepared according to the general procedure from 3b as col-
d
orless foam (72% yield). Mp: 90 ꢀC (CHCl3). [
a
]D: þ0.5 (c 1.0,
27.0, 22.8, 22.7; IR (neat) 3446, 2923, 2857, 1458, 1396, 1307, 1151,
1013, 873 cmꢂ1. HRMS (ESI) calcd for C20H19I2O2 544.9475, found
544.9473.
CHCl3). 1H NMR (400 MHz, DMF, 110 ꢀC)
d
(ppm) 7.45–7.43 (m, 2H),
0
7.39–7.36 (m, 2H), 7.26–7.20 (m, 4H), 6.89 (s, 2H, H4,4 ), 3.15–3.09
(m, 2H, 2ꢁCH), 2.83–2.80 (m, 4H), 2.57–2.50 (m, 2H), 2.35–2.29
(m, 2H), 1.83–1.75 (m, 8H), 1.28–1.17 (m, 12H, 4ꢁCH3). 13C NMR
4.3. General procedure for the ligandless Suzuki–Miyaura
cross coupling
(100.6 MHz, DMF, 110 ꢀC)
d 149.6 (C), 148.1 (C), 138.1 (C), 136.4 (C),
130.9 (CH), 130.7 (CH), 128.7 (C), 127.7 (CH), 127.1 (C), 125.4 (CH),
125.3 (CH), 123.0 (C), 30.2 (CH2), 29.2 (CH), 27.1 (CH3), 26.9 (CH2),
23.4 (CH2), 23.2 (CH3). IR (neat, cmꢂ1): 3528, 2926, 2863, 1610,
1437, 1232, 1135, 757. HRMS calcd for (MþH)þ C36H43O2: 531.3263
found: 531.3244.
4.3.1. (R)-3,30-Bis(4-tBu-phenyl)-5,50,6,60,7,70,8,80-octahydro-1,10-bi-
naphthyl-2,20-diol 7g. To a solution of (R)-3,30-diiodo-5,50,6,60,7,70,8,80-
octahydro-1,10-binaphthyl-2,20-diol 3b (50 mg, 0.092 mmol) in
dioxane/water (1/1, 2 mL) was added successively at room tempera-
ture, potassium carbonate (49 mg, 0.36 mmol, 4 equiv), palladium on
charcoal 10% (4.5 mg, 0.0046 mmol, 0.05 equiv) and 4-tert-butyl-
phenylboronic acid (66 mg, 0.36 mmol, 4 equiv). The mixture was
stirred at 95 ꢀC for 6 h, then EtOAc (10 mL) and HCl (2 N, 10 mL) were
added. The aqueous layer was extracted with EtOAc and the organic
layers were combined, washed with brine (10 mL), dried over MgSO4
and concentrated. The crude product was purified by flash chroma-
tography (cyclohexane/EtOAc, 95:5) to afford 7g as a colorless solid
4.7. General procedure for the Suzuki–Miyaura coupling with
phosphine 5
A
round bottom flask was charged with (R)-3,30-diiodo-
5,50,6,60,7,70,8,80-octahydro-1,10-binaphthyl-2,20-diol 3b (580 mg,
1.06 mmol), Pd2(dba)3 (19 mg, 0.021 mmol, 0.02 equiv), K3PO4
(1.12 g, 5.3 mmol, 5 equiv), 2,4,6-trimethylphenylboronic acid
(697 mg, 4.25 mmol, 4 equiv), the phosphine
5
(18 mg,
(50 mg, 97%). Mp: 147 ꢀC (CHCl3). [
(400 MHz, CDCl3)
a
]D: ꢂ52.3 (c 1.0, CHCl3). 1H NMR
0.043 mmol, 0.04 equiv) in 10 mL of toluene under an argon at-
mosphere. The mixture was degassed with argon during 2 min, and
then stirred at 100 ꢀC for 18 h. Then EtOAc (30 mL) and HCl (2 N,
30 mL) were added. The aqueous layer was extracted with EtOAc
and the organic layers were combined, washed with brine (30 mL),
dried over MgSO4 and concentrated. The crude product was puri-
fied by flash chromatography (cyclohexane/EtOAc, 98:2) to afford
7l as a colorless solid (360 mg, 64%).
d
(ppm) 7.60–7.55 (m, 4H), 7.50–7.46 (m, 4H), 7.19
(s, 2H), 4.97 (s, 2H), 2.85–2.80 (m, 4H), 2.49–2.39 (m, 2H), 2.33–2.18
(m, 2H), 1.84–1.70 (m, 8H), 1.39 (s, 18H). 13C NMR (100.6 MHz, CDCl3)
d
149.9 (C), 148.2 (C), 136.3 (C), 135.0 (C), 131.6 (CH), 130.1 (C), 128.8
(CH), 125.9 (C), 125.4 (CH), 120.2 (C), 34.6 (C), 31.4 (CH3), 29.3 (CH2),
27.2 (CH2), 23.2 (CH2), 23.1 (CH2). IR (neat, cmꢂ1): 3515, 2926, 1515,
1457, 1393, 1261, 1136, 1021, 834, 803. HRMS calcd for (MþH)þ
C40H47O2: 559.3576 found: 559.3600.
4.8. General procedure for the synthesis of phosphorodithioic
acids
4.4. (R)-3,30-1-Naphtyl-5,50,6,60,7,70,8,80-octahydro-1,10-
binaphthyl-2,20-diol 7d
4.8.1. (R)-5,6,7,8,50,60,70,80-Octahydro-[1,10]binaphthalenyl-2,20-phos-
phorodithioic acid 2a. P4S10 (60.5 mg, 0.27 mmol, 0.6 equiv) was
added to a solution of H8-BINOL 7a (130 mg, 0.44 mmol, 1 equiv) in
dry toluene (5 mL). The mixture was stirred under argon for 20 h at
140 ꢀC. The reaction mixture was evaporated and the residue pu-
rified by flash chromatography (CH2Cl2/MeOH from 100:0 to 90:10)
Prepared according to the general procedure from 3b as a col-
orless solid (86% yield). Mp: 149 ꢀC (CHCl3). [
a
]D: ꢂ31 (c 1.0, CHCl3).
1H NMR (500 MHz, DMSO, 110 ꢀC)
d
(ppm) 7.92 (d, J¼7.5 Hz, 2H),
7.88 (d, J¼8 Hz, 2H), 7.86–7.73 (m, 2H), 7.55 (t, J¼8 Hz, 2H), 7.50–
7.45 (m, 4H), 7.44–7.36 (m, 2H), 6.93 (s, 2H), 6.59 (s, 2H), 2.82–2.74

G. Pousse et al. / Tetrahedron 65 (2009) 10617–10622
10621
to afford 2a (140 mg, 79%) as a colorless solid. Mp: 100 ꢀC (de-
137.8 (m, C), 136.4 (C), 135.3 (m, C), 134.1–134.0 (m, C), 133.3–133.2
(m, CH), 132.7–132.2 (m, CH), 131.2–131.4 (m, C), 131.0–130.8 (m, C),
130.4–130.2 (m, CH), 130.1–129.7 (m, C), 128.9–128.7 (m, 2*CH),
127.9–127.5 (m, C), 126.0–126.7 (m, 3*CH), 122.7–122.8 (m, CH),
122.5–122.6 (m, CH), 29.5–29.4 (m, CH2), 28.1 (m, CH2), 22.8–22.6
composition). [
a
]D: ꢂ209.5 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3)
d
(ppm) 7.20–7.13 (d, 2H, J¼8.3 Hz), 7.11–7.08 (dd, 2H, J¼8.2 Hz and
2 Hz), 2.95–2.75 (m, 4H), 2.72–2.65 (dq, 2H, J¼16.3 Hz and 4.2 Hz),
2.29 (dt, 2H, J¼16.3 Hz and 5.6 Hz), 1.86–1.75 (m, 6H), 1.62–1.52 (m,
2H). 13C NMR (100.6 MHz, CDCl3)
d
(ppm) 146.6 (C), 139.2 (C), 136.7
(m, 2*CH2). 31P NMR (162.0 MHz, CDCl3)
d (ppm) 91.8–91.2 (m, P). IR
(C), 130.3 (CH), 127.3 (C), 119.3 (CH), 29.6 (CH2), 28.3 (CH2), 22.8
(neat, cmꢂ1): 2924, 1448, 1418, 1214, 936, 862, 747, 725. HRMS calcd
(CH2), 22.7 (CH2). 31P NMR (162.0 MHz, CDCl3)
d
(ppm) 95.3. IR
for (MꢂH)ꢂ C48H37O2PS2: 739.1894 found: 739.1901.
(neat, cmꢂꢂ1): 2927, 1464, 1212, 1051, 940, 854, 715, 681. HRMS calcd
4.13. (R)-3,30-Bis-(1-naphtyl)-5,6,7,8,50,60,70,80-octahydro-
[1,10]binaphthalenyl-2,20-phosphorodithioic acid 2f
for (MꢂH) C20H20O2PS2: 387.0642 found: 387.0656.
4.9. (R)-3,30-Dibromo-5,6,7,8,50,60,70,80-octahydro-[1,10]-
binaphthalenyl-2,20-phosphorodithioic acid 2b
Prepared according to the general procedure from 7d as a col-
orless foam (46% yield). Mp: 225 ꢀC (decomposition). [
a
]D: ꢂ174.5
(c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3)
d (ppm) 7.95–7.70 (m, 4H),
Prepared according to the general procedure from 3a as color-
less foam (70% yield). Mp: 130 ꢀC (decomposition). [
a
]D: ꢂ209.1 (c
(ppm) 7.44 (s, 2H), 2.88–
2.78 (m, 4H), 2.62–2.50 (m, 2H), 2.21–2.13 (m, 2H), 1.84–1.72 (m,
6H), 1.62–1.52 (m, 2H). 13C NMR (100.6 MHz, CDCl3)
(ppm) 143.6
7.55–7.35 (m, 10H), 7.18 (s, 1H), 7.12 (s, 1H), 2.94–2.7 (m, 6H), 2.59–
1.0, CHCl3). 1H NMR (400 MHz, CDCl3)
d
2.38 (m, 2H), 1.95–1.65 (m, 8H). 13C NMR (100.6 MHz, CDCl3)
d
(ppm) 144.2–144.1 (m, C), 138.5–138.2 (m, C), 136.8–136.7 (m, C),
d
135.9–135.7 (m, C), 134.5–134.4 (m, C), 133.7–133.5 (m, CH), 133.2–
133.1 (m, CH), 132.4–132.1 (m, C), 131.5–131.2 (m, C), 129.9–129.7
(m, CH), 129.3–129.2 (m, C), 128.9–128.5 (m, 2*CH), 127.9–127.8 (m,
C), 127.2–127.0 (m, CH), 126.5–126.2 (m, CH), 126.1–125.9 (m, CH),
125.6–125.4 (m, CH), 29.8 (m, CH2), 28.5 (m, CH2), 23.1 (m, CH2),
(C), 138.3 (C), 138.0 (C), 134.2 (CH), 128.7 (C), 112.8 (C), 29.4 (CH2),
28.1 (CH2), 22.7 (CH2), 22.5 (CH2). 31P NMR (162.0 MHz, CDCl3)
d
(ppm) 92.7. IR (neat, cmꢂ1): 2931, 1417, 1220, 1012, 949, 869, 699.
HRMS calcd for (MꢂH)ꢂ C20H18Br2O2PS2: 542.8853 found:
23.0 (m, CH2). 31P NMR (162.0 MHz, CDCl3)
d (ppm) 90.9–91.4 (m,
542.8826.
P). IR (neat, cmꢂ1): 2929, 1507, 1395, 1214, 1088, 942, 886, 800, 767,
705. HRMS calcd for (MꢂH)ꢂ. C40H32O2PS2: 639.1581 found:
639.1600.
4.10. (R)-3,30-Diphenyl-5,6,7,8,50,60,70,80-octahydro-
[1,10]binaphthalenyl-2,20-phosphorodithioic acid 2c
Prepared according to the general procedure from 7a as color-
4.14. 2-((4-Methoxyphenylamino) (4-nitrophenyl)methyl)-
cyclohexanone 11
less foam (82% yield). Mp: 170 ꢀC (decomposition). [
a]D: ꢂ226.5 (c
1.0, CHCl3). 1H NMR (400 MHz, CDCl3)
d (ppm) 7.61–7.56 (m, 4H),
To a cold solution (0 ꢀC) of 13 (51 mg, 0.2 mmol, 1 equiv) and
catalyst 2c (5.4 mg, 0.01 mmol, 5 mol %) in 2.5 mL of toluene was
added cyclohexanone (196 mg, 2 mmol, 10 equiv). The reaction was
stirred at 0 ꢀC during 3 days. The crude mixture (anti/syn 70/30 by
NMR) was concentrated and purified by flash chromatography
(cyclohexane/EtOAc, 80:20) to afford 14 as a colorless solid (65 mg,
92%). Enantiomeric excess was determined using Daicel AD-H
chiral HPLC (1 mL minꢂ1, n-heptane 75%, 12.5% MeOH, 12.5% EtOH,
20 ꢀC) to be 63% for the major anti diastereoisomer. Analytical data
was found to be identical as reported previously.14
7.44–7.38 (m, 4H), 7.37–7.32 (m, 2H), 2.98–2.91 (m, 4H), 2.78–2.68
(m, 2H), 2.45–2.38 (m, 2H), 1.91–1.80 (m, 6H), 1.74–1.69(m, 2H). 13C
NMR (100.6 MHz, CDCl3) d (ppm) 143.3 (C),138.1 (C),137.7 (C),136.5
(C), 132.6 (C), 131.5 (CH), 130.2 (CH), 129.9 (C), 128.6 (CH), 127.7
(CH), 29.7 (CH2), 28.2 (CH2), 23.0 (CH2), 22.9 (CH2). 31P NMR
(162.0 MHz, CDCl3)
d
(ppm) 91.3. IR (neat, cmꢂ1): 2925, 1601, 1444,
1409, 1207, 944, 862, 767, 696. HRMS calcd for (MꢂH)ꢂ
C32H28O2PS2: 539.1268 found: 539.1259.
4.11. (R)-3,30-Bis-(3,5-bis-trifluoromethyl-phenyl)-
5,6,7,8,50,60,70,80-octahydro-[1,10]binaphthalenyl-2,20-
phosphorodithioic acid 2d
Acknowledgements
Prepared according to the general procedure from 7c as a col-
We gratefully acknowledge Glaxo-Smith-Kline and CNRS for
orless foam (71% yield). Mp: 140 ꢀC (decomposition). [
a
]D: ꢂ166.8
´
a fellowship to GP, ANR ‘Mesorcat’ (program CP2D), Region Basse-
(c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3)
d (ppm) 8.03 (s, 4H), 7.88
Normandie, Re´gion Haute-Normandie (re´seau CRUNCH) for a fel-
lowship to AD and the European Union (FEDER funding) for fi-
nancial supports.
(s, 2H), 7.29 (s, 2H), 2.98–2.92 (m, 4H), 2.80–2.68 (m, 2H), 2.51–2.40
(m, 2H), 1.97–1.84 (m, 6H), 1.80–1.68 (m, 2H). 13C NMR (100.6 MHz,
CDCl3)
d (ppm) 143.2 (C), 140.2 (C), 139.6 (C), 137.5 (C), 132.1 (C),
131.7 (C), 131.3 (CH), 130.4 (CH), 129.8 (C), 128.5 (C), 125.1 (C), 122.4
Supplementary data
(C), 121.5 (CH), 29.6 (CH2), 28.3 (CH2), 22.8 (CH2), 22.6 (CH2). 31P
NMR (162.0 MHz, CDCl3)
d
1108, 957, 892, 705, 681. HRMS calcd for (MꢂH)ꢂ C32H24F2O2PS2:
d
(ppm) 91.1. 19F NMR (235.3 MHz, CDCl3)
Supplementary data associated with this article (NMR spectra of
new compounds) can be found in the online version, at doi:10.1016/
j.tet.2009.10.068.
(ppm) ꢂ62.7. IR (neat, cmꢂ1): 2937, 1620, 1460, 1388, 1275, 1179,
811.0764 found: 811.0750.
References and notes
4.12. (R)-3,30-Bis-(phenanthryl)-5,6,7,8,50,60,70,80-octahydro-
[1,10]binaphthalenyl-2,20-phosphorodithioic acid 2e
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