Pd(II) complexes of monodentate deoxycholic acid derived binaphthyl diamido phosphites as chiral catalysts in the asymmetric Suzuki-Miyaura cross-coupling

Article abstract of DOI:10.1016/j.tetasy.2017.09.012

Chiral binaphthyl diamidophosphites derived from deoxycholic acid were synthesized and used as ligands for the preparation of mononuclear Pd(II) complexes, which were employed as catalysts in the asymmetric Suzuki-Miyaura cross-coupling of arylboronic acids with aryl bromides. Among the different reaction parameters, the substrate concentration emerged as being crucial for the outcome of the reaction: the reaction was faster in a concentrated reaction mixture, and could be performed at 0 °C, where the reaction promoted by the Pd-complexes was more enantioselective affording cross-coupling products with ee up to 70%.

Full text of DOI:10.1016/j.tetasy.2017.09.012

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Pd(II) complexes of monodentate deoxycholic acid derived
binaphthyl diamido phosphites as chiral catalysts in the asymmetric
Suzuki-Miyaura cross-coupling
Grazia Iannucci , Vincenzo Passarelli b,c, Alessandro Passera a,d, Anna Iuliano a,
a
⇑
a
Dipartimento di Chimica e Chimica Industriale, Università di Pisa, Via Moruzzi 13, 56124 Pisa, Italy
Centro Universitario de la Defensa, Ctra. Huesca s/n, 50090 Zaragoza, Spain
Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), CSIC—Universidad de Zaragoza, Departamento de Química Inorgánica, Pedro Cerbuna 12, 50009 Zaragoza, Spain
Classe di Scienze Matematiche e Naturali, Scuola Normale Superiore, Piazza dei Cavalieri 7, 56126 Pisa, Italy
b
c
d
a r t i c l e i n f o
a b s t r a c t
Article history:
Chiral binaphthyl diamidophosphites derived from deoxycholic acid were synthesized and used as
ligands for the preparation of mononuclear Pd(II) complexes, which were employed as catalysts in the
asymmetric Suzuki-Miyaura cross-coupling of arylboronic acids with aryl bromides. Among the different
reaction parameters, the substrate concentration emerged as being crucial for the outcome of the reac-
tion: the reaction was faster in a concentrated reaction mixture, and could be performed at 0 °C, where
the reaction promoted by the Pd-complexes was more enantioselective affording cross-coupling products
with ee up to 70%.
Received 2 August 2017
Revised 29 August 2017
Accepted 12 September 2017
Available online xxxx
Ó 2017 Elsevier Ltd. All rights reserved.
1
. Introduction
atoms bonded to the phosphorus (only oxygen, nitrogen and oxy-
gen, carbon and oxygen) allows fine-tuning of the donor–acceptor
Asymmetric catalysis with transition metal complexes is a pow-
erful method to obtain valuable enantiomerically enriched prod-
characteristics of the phosphorus atom, which affect the coordina-
tion properties of the ligand.
1
ucts with different structures:
as
a
matter of fact
Over the last ten years enantiopure diamidophosphites, which
present two P–N bonds embedded in a phospholidine ring and
an exocyclic P–O bond, have emerged as promising phosphorus
ligands. The possibility of changing both nitrogen and oxygen sub-
stituents allows high control on the steric and electronic character-
istics of these ligands. In addition, the presence of two substituted
nitrogen atoms increases the steric hindrance and the electronic
density of the phosphorus atom with respect to phosphites and
phosphoramidites. Chiral diamidophosphites, both mono- and
bidentate, have been used in different enantioselective C–C bond
2
3
enantioselective oxidation, hydrogenation and C–C bond forming
4
reactions can be effectively performed under asymmetric metal
catalysis conditions. In this research area, the enantiomerically
pure ligand and its metal complexes play the main role for the
chemical as well as stereochemical outcome of the reaction. For
this reason, a great deal of synthetic effort has been made with
regards to the design and achievement of enantiopure ligands
and metal complexes leading to efficient and selective organic
transformations. In this field, enantiopure phosphorus ligands have
been successfully used in different metal catalyzed asymmetric
reactions and, among them, monodentate phosphorus ligands with
8
forming reactions, such as Pd-catalyzed allylic substitutions, Pd-
9
10
catalyzed cycloaddition, Pd-catalyzed hydrovinylation, Rh-cat-
5
6
11
P-heteroatom bonds, such as phosphites, phopsphoramidites,
alyzed hydroformylation, Cu and Rh-catalyzed conjugate addi-
tion of organometallic reagents to enones. However, despite the
phosphinites and phosphonites7 represent good alternatives to
the bidentate chiral phosphane ligands. This type of ligands can
be obtained more easily than the bidentate ones, they are more
stable than phosphanes and a great variety of structures are acces-
sible, starting from amines or alcohols with different structural and
stereochemical features. In addition, the convenient choice of the
12
success obtained in different Pd-catalyzed enantioselective reac-
tions, to the best of our knowledge no examples concerning the
use of diamidophosphite ligands in the Pd-catalyzed asymmetric
Suzuki-Miyaura cross-coupling reaction have been reported in
the literature, although this reaction has received a great deal of
attention because of the interest in the biaryl reaction products,
1c
whose structural motif is present in chiral auxiliaries as well as
⇑
Corresponding author.
E-mail address: anna.iuliano@unpi.it (A. Iuliano).
1
3
in bioactive compounds.
Other types of chiral phosphorus
https://doi.org/10.1016/j.tetasy.2017.09.012
957-4166/Ó 2017 Elsevier Ltd. All rights reserved.
0
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2
G. Iannucci et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
ligands have been used with this aim, mainly bidentate ligands,
cholan-24-ate with PCl
3
in the presence of trimethylamine, and
1
4
15
such as bishydrazones
or phosphine–carbene ligands,
and
successive reaction of the crude bis-chlorophosphite with (R)- or
1
6
0
0
bulky monophosphines. Some years ago we demonstrated for
the first time that chiral monophosphites can be used as enantios-
elective Pd-ligand in asymmetric Suzuki-Miyaura cross-coupling
(S)-N-N -dimethyl-1,1 -binaphthalenediamine
(DMBNDA)
(Scheme 1) in boiling toluene, according to our previously
described synthetic procedure.
The preparation and characterization of the new diamido phos-
phites 1a-b are reported in the Experimental Section. The com-
plexes 2a-b of general formula PdCl
reacting two equivalents of ligand with PdCl
at room temperature (Scheme 2) for 15 min.
The Pd(II) complexes were obtained as yellow solids in almost
quantitative yield. They are stable at room temperature under inert
atmosphere and soluble in common organic solvents. They were
1
8h
1
7
reactions. These ligands were biaryl phosphites of deoxycholic
acid and the success in the Suzuki-Miyaura reactions was linked
to the bulkiness of the phosphites, which allow a monosubstituted
catalytic Pd-complex to form in the reaction environment, believed
crucial for the outcome of the reaction. Following our interest in
deoxycholic acid derived chiral ligands to be used in asymmetric
L
2 2
were prepared by
(PhCN) in toluene
2
2
1
8
catalysis, we envisaged that monodentate diamidophosphites
with a binaphthyl diazaphospholidine moiety linked to the steroi-
dal scaffold of deoxycholic acid could be interesting ligands for Pd-
catalyzed asymmetric Suzuki-Miyaura cross-coupling reactions,
aimed at obtaining optically active biaryl derivatives. Herein we
describe the synthesis and characterization of the ligands 1a-b
1
31
13
fully characterized in solution by multinuclear ( H, P and C)
NMR spectroscopy: bidimensional H– C HMBC, 1H–13C-HSQC,
1
13
1
1
1
1
H– H NOESY and H– H COSY experiments were necessary to
assign the majority of the signals.
and their disubstituted mononuclear Pd(II)-complexes (PdCl
a-b (Fig. 1), as well as the use of these Pd-complexes as catalytic
precursors for the asymmetric Suzuki-Miyaura cross-coupling reaction.
L
2 2
)
The coordination of the ligand to the Pd center shifts the 31P sig-
nal at higher fields in both the complexes (117.1 ppm for 2a and
2
3
1
115.8 ppm for 2b) with respect to the P signal in the correspond-
ing ligands (168.8 ppm for 1a and 159.4 ppm for 1b), probably
because of the low
r-donor character of the ligands, as observed
CH
3
CH
3
for other types of Pd(II) complexes with diamido phosphite
N
N
N
N
8e
ligands. Table 1 collects the signals of protons that are shifted
R+
R+
P
P
because of the coordination of the ligand to the metal center: the
different extent of the shift for corresponding protons of the two
diastereomeric complexes is most likely the result of different
arrangements of the ligands in the two complexes.
CH
3
CH
3
1
b
1a
As far as the binaphthyl moiety is concerned, the coordination
0
0
affects mainly the protons a, b and a , b , which are closer to the P
atom. The extent of the shift upon coordination is higher for a
than for b in both the complexes, most probably due to the
higher distance of b from P, and hence from Pd. The coordination
affects in different way the protons a and b of the two com-
plexes: a low shift is observed for these protons when comparing
3
H C
*R
CH
3Cl
Pd
Cl
N
N
P
P
N
N
0
0
R*
3
H C
CH
3
1
a and 2a, whereas a shift comparable to that of protons a and b
2a (aS); 2b (aR)
is detected when comparing 1b and 2b. Other significant differ-
ences were found for protons of the cholestanic backbone, which
could be the result of conformational differences between the
two complexes. The higher shifts observed for protons 1, 2 and
O
O
OCH
3
R*
=
5
in passing from 1a to 2a can suggest the proximity of the Pd
center to the A ring of the steroidal skeleton in 2a, whereas the
higher shifts of protons 12, 8 and 11 in going from 1b to 2b
indicate that in complex 2b, Pd is closer to the C ring of the
cholestanic moiety.
CH
3
COO
Figure 1. Structure of ligands and Pd(II) complexes.
2
2
. Results and discussion
2.2. Asymmetric Suzuki-Miyaura cross-coupling
.1. Synthesis and characterization of ligands and complexes
The reaction between 1-bromo-2-methoxynaphthalene 3a with
ortho-tolylboronic acid 4a (Scheme 3) promoted by the chiral Pd(II)
complexes 2a-b was chosen as the model system for screening the
reaction conditions (Table 2).
The diamido phosphites 1a-b were synthesized in two consec-
utive steps by reacting methyl 3-acetyloxy-12-hydroxydeoxy-
O
OH
N
P
OCH
3
O
N
O
1
. PCl , CH
3
2
Cl
2
OCH3
2
. (R)- or (S)-DMBNDA,
3
3
H COCO
Et N, toluene, reflux
3
H COCO
1a (aS); 1b (aR)
Scheme 1. Synthesis of ligands 1a and 1b.
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G. Iannucci et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
Cl
Pd
L*
Cl
N
P
N
P
O
O
N
O
N
O
PdCl
2 2
(PhCN) (0.5 eq.)
OCH
3
OCH
3
toluene, rt
H
3
COCO
3
H COCO
L*: 1a (aS); 1b (aR)
2a (aS); 2b (aR)
Scheme 2. Synthesis of Pd (II)-complexes 2a and 2b.
Table 1
Chemical shift (ppm) for relevant protons in ligands and complexes
d'
f
c'
e'
l'
b'
e
l
f'
a'
g'
d
c
g
h'
h
Me'
N
P
21
b
N
22
O
a
O
1
9
2
0
Me
23
24
1
1
12
OCH
3
1
8
1
17
3
1
9
16
2
14
1
0
8
7
15
3
3
H COCO
5
4
6
Protons
d
H
1a
d
H
2a
d
H
1b
H
d 2b
a
7.50
7.72
7.41
7.76
8.44
8.04
7.53
7.64
7.66
7.95
7.78
7.80
8.15
8.28
8.58
8.07
b
0
a
0
b
1
2
3
4
5
8
1.90, 1.01
1.70, 1.42
4.72
1.85, 1.69
1.17
0.04, ꢀ0.20
1.72, 0.89
1.89, 1.74
4.91
1.77, 1.55
1.22
1.15, 1.68
1.86, 2.11
4.94
1.52, 1.67
1.13
a
a
a
0.98, 0.67
4.56
1.61, 1.39
a
0.88
1.45
1.38
2.16
1.30
1
1
1
1
1
2
1
2
4
7
8
1
1.69, 1.33
4.28
1.72
1.94
0.82
0.76, 0.70
4.78
1.64
3.01
0.47
2.13, 1.35
4.35
1.67
1.95
0.82
1.74, 3.51
6.16
1.43
2.08
0.54
0.98
1.57
1.00
1.64
NMe
NMe
2.92
2.89
3.99
3.67
2.83
3.03
3.58
3.53
0
a
These signals can be attributed both to protons 2 and 4.
Although most of the Suzuki-Miyaura cross-coupling reactions
yield and reaction rate, both at 40 °C and at rt, but the enantiose-
lectivity was much better: the cross-coupling product was
obtained with 22% ee at 40 °C (entry 3) and with 25% ee. at rt.
These results point out the matched relationship between the
(R)-absolute configuration of the biaryldiamido phosphite moiety
and the stereochemistry of the cholestanic backbone. In addition,
unlike that observed with the analogous binaphthyl phosphites,
the absolute configuration of the product depends on the absolute
configuration of the binaphthyl moiety of the ligand: the opposite
prevailing enantiomer is obtained when using 2a instead of 2b
(entries 1 and 3). This result indicates a different asymmetric
induction mechanism for the catalytic precursors 2a-b with
respect to those obtained from the analogous phosphites.17 Having
established that 2b gave the better enantioselectivities, optimiza-
tion of the reaction conditions was carried out using this catalytic
are carried out in organic solvent–water medium, both biphasic
and homogeneous, dry solvents were used because of the water
sensitivity of the Pd-complexes.
Dry reaction conditions affected the solubility of the bases,
therefore the use of bases with some solubility in organic solvents,
such as CsF or Cs CO , was mandatory: nevertheless the reaction
2 3
mixtures were always suspensions.
At first the reaction was performed in toluene at 40 °C with 5%
catalyst loading, using the complex 2a, two equivalents of Cs CO ,
2 3
with an aryl bromide concentration of 0.02 M (entry 1): the reac-
tion was complete in 14 h but the product was obtained with only
% ee. Lowering the temperature slowed down the reaction rate,
and did not improve the enantioselectivity (entry 2). The use of
the diastereomeric complex 2b gave the same results in terms of
6
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4
G. Iannucci et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Br
B(OH)
2
R
R'
R
+
R'
4
4
4
a: R=Me
3
a: R=OMe
b: R=Me
Br
b: R=CHO
c: R=OMe
3
5a: R=OMe, R'=Me
Me
5
5
5
5
b: R=OMe, R'=CHO
c: R=Me, R'=OMe
d: R=OMe, R'=OMe
e: R=Me, R'=Me
8
a
R'
Br
R'
B(OH)2
R
R
+
R
R"
R'
6a: R=OMe, R'=H
3
3
3
a: R=OMe, R'=H
b: R=Me, R'=H
c: R=H, R'=Me
6b
:
R=R'=H
7a: R=H, R'= R"=Me
6
c: R=H, R'= Me
7b: R=H, R'=Me, R"OMe
7
c: R=OMe, R'=R"=H
Scheme 3. Asymmetric Suzuki-Miyaura biaryl coupling.
Table 2
Asymmetric Suzuki-Miyaura cross-coupling of 3a and 4aa
Run
Pd complex
Base
Solvent
Conc (M)
T (°C)
t (h)
Yield %b
ee %c
ACd
1
2
3
4
5
6
7
8
9
2a
2a
2b
2b
2b
2b
2b
2b
2b
2b
Cs
Cs
Cs
Cs
CsF
CsF
2
2
2
2
CO
CO
CO
CO
3
3
3
3
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DME
THF
Toluene
Toluene
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.1
40
rt
40
rt
40
rt
rt
rt
rt
0
14
48
14
48
14
48
40
40
16
48
96
96
96
96
95
94
93
94
95
94
6
7
(ꢀ)
(ꢀ)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
22
25
22
27
24
22
25
36
Cs
2
Cs
2
Cs
2
Cs
2
CO
CO
CO
CO
3
3
3
3
1
0
0.1
a
b
c
The reactions were stopped at complete conversion of the substrate or when it did not proceed further.
NMR yield.
Enantiomeric excess (ee) determined by enantioselective HPLC (Chiralcel OJ, hexane/2-propanol 99/1, 1.0 mL/min, T = 25°C, k = 230 nm).
d
Sign of the specific rotation of the sample.
precursor. Changing the base from Cs
2
CO
3
to CsF did not affect the
as a consequence of the lower temperature the reaction slowed
down and longer reaction times were required in order to obtain
satisfactory yields of the products. At low temperatures, the aryl-
boronic acids and the aryl bromides were less soluble, leading in
some cases to low yields of the products (entries 5, 7, 12 and 14).
It was difficult to find a dependence of the outcome of the reac-
tion only on the structural characteristics of the aryl bromide, as
well as only on those of the aryl boronic acid: as a matter of fact,
both reaction rate and enantioselectivity seem dependent on the
combination aryl bromide—arylboronic acid. The 2-tolyl boronic
acid 4a gave a significantly lower reaction rate when coupled with
3b (entry 9) than with 3a (entry 2), but 3a gave faster reactions
when coupled with 4b, 4c and 6b (entries 3, 4 and 11) than with
6c (entries 13 and 14). The reaction between 3a and 6b, the aryl
boronic acid devoid of substituent, was the fastest one, giving the
product in 95% yield at 0 °C in only 24 hours of reaction (entry
11), suggesting that the steric hindrance near the boronic group
can reasonably account for the reaction rate. At the same time, dif-
ferent enantioselectivities of the reaction were observed using the
same aryl bromide (entries 1, 3, 4, 13) or the same aryl boronic acid
(entries 2 and 9 or 5 and 7). The presence of a methoxy group near
to the boronic moiety increases the enantioselectivity when the
cross-coupling involves a 2-methyl substituted aryl bromide
yield or the enantioselectivity of the reaction to significant extent
both at 40 °C and rt (entries 5 and 6). Similar results were obtained
by changing the reaction solvent. The use of ether solvents, such as
tetrahydrofuran or dimethoxyethane, gave the cross-coupling pro-
duct in good yields in shorter reaction times (entries 7 and 8). It is
conceivable that a coordinating solvent, THF or DME, can displace
one ligand of the complex, giving rise to a monoligated species,
which is slightly more active than the original complex,17 but not
more enantioselective. This species is less hindered and this can
justify the higher reaction rate observed in coordinating solvents.
Increasing the substrate concentration, in toluene as a solvent,
had no influence on the enantioselectivity of the reaction (entries
4
and 9), but a higher reaction rate was observed, which gave com-
plete conversion of the substrate at rt in only 16 h (entry 9). The
increased rate allowed for the reaction to be carried out at lower
temperature (entry 10), thus reaching the highest ee value of the
product.
The optimized reaction conditions were used to screen different
aryl bromides and different arylboronic acids in the reaction: the
results are shown in Table 3.
When the reactions were performed at 0 °C, higher enantioselec-
tivities than at rt were observed (entries 1 and 2, 6 and 7). However,
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G. Iannucci et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
Table 3
Asymmetric Suzuki-Miyaura cross-coupling with complex 2b
a
Run
ArBr
ArB(OH)
2
Ar-Ar
T
t (h)
Yield %b
ee %c
ACd
1
2
3
4
5
6
7
8
9
3a
3a
3a
3a
3a
3b
3b
3b
3b
3c
3a
8a
3a
3a
4a
4a
4b
4c
4c
4c
4c
6c
4a
6a
6b
6a
6c
6c
5a
5a
5b
5d
5d
5c
5c
7a
5e
7b
7c
5a
7b
7b
rt
0 °C
rt
rt
0 °C
rt
0 °C
rt
0 °C
rt
0 °C
0 °C
rt
16
48
24
18
48
48
72
48
72
48
24
18
48
72
95
94
85
90
25
56
35
95
75
94
95
32
25
36
Racemic
10
12
51
70
13
13
52
31
40
17
(+)
(+)
(ꢀ)
(ꢀ)
(ꢀ)
(ꢀ)
(R)
(ꢀ)
(S)
(R)
(+)
(S)
e
e
e
e
10
11
12
13
14
e
e
88 (75 )
e
0 °C
38
19
(S)
a
b
c
All reactions were stopped at complete substrate conversion or when it did not proceed further.
NMR yield.
Enantiomeric excess (ee) determined by enantioselective HPLC (for conditions see experimental).
Sign of the specific rotation of the sample or absolute configuration of the prevailing enantiomer, based on the elution order by comparison with the literature data.
Isolated yield.
d
e
(
entries 7, 12): the highest ee value was obtained when 2-methox-
4. Experimental
4.1. General
yphenyl boronic acid was reacted with 1-bromo-2-methylnaph-
thalene at 0 °C (entry 7). The reaction of 2-bromotoluene with 2-
methoxy-1-naphthyl boronic acid (entry 12), a similar combina-
tion, gave the product with a lower ee, suggesting that also the size
of the aryl moiety of the aryl boronic acid also plays an important
role in determining the extent of the enantioselectivity. The ees of
the products were still satisfactory when the 2-methoxy substi-
tuted aryl boronic acid was coupled with an aryl bromide where
the methyl group was at the 4-position (entry 10), whereas the
opposite combination, where the methoxy group was on the aryl
bromide gave the same product but with very low ee (entries 13
and 14). The presence of a methoxy group both at the 2-position
of the aryl bromide and the arylboronic acid decreased the enan-
tioselectivity of the cross-coupling (entries 4 and 5), as did the
presence of a methyl group at the same position on both the reac-
tants (entry 9). The reaction exhibited a modest enantioselectivity
when the 1-naphthyl boronic acid 6b, devoid of substituent on the
aryl moiety, was coupled with the 2-methoxy-1-bromonaph-
thalene 3a (entry 11). By contrast the presence of a methyl group
at the 4-position of the 1-naphthyl boronic acid (entries 8, 13,
TLC analyses were performed on 60 F254 plates (0.2 mm) and
chromatography purifications were carried out with silica gel
(230–400 mesh) or with neutral alumina (Brockmann I). All reac-
tions involving sensitive compounds were carried out under dry
N , in flame-dried glassware. Toluene was refluxed over sodium-
2
benzophenone and distilled before the use. n-Hexane, THF and
DME were refluxed over potassium-benzophenone and distilled
before the use. Dichloromethane, triethylamine and pyridine were
refluxed over CaH and distilled before the use. PCl was distilled
and dried with freeze–pump–thaw method before the use. Unless
otherwise specified, the other compounds were commercially
available and used as received. Methyl-3-acetyl-deoxycholan-24-
ate was obtained as described previously and matched the
2
3
1
8h
reported characteristics.
1
H, C and 31P NMR spectra were recorded in CDCl3 or ben-
13
zene-d , on a Bruker AV-400 spectrometer (400.16 MHz for 1H)
6
1
13
and the temperature was controlled to ±0.1 °C. H and C NMR
1
4) or a formyl group at the 2-position of the aryl boronic acid
chemical shifts (ppm) are referred to TMS as external standard,
3
1
(
entry 3) decreased the enantioselectivity of the reaction. It should
3 4
P NMR chemical shifts (ppm) are referred to H PO as external
be noted that when the same cross-coupling product was prepared
with the opposite combination of aryl bromide and aryl boronic
acid (entries 2 and 12, 10 and 13), the same absolute configuration
of the prevailing enantiomer was obtained in the presence of quite
different yields (entries 2 and 12) and ees (entries 10 and 13). The
different combination seems to influence the reaction rate or the
extent of asymmetric induction but not its sense, which remains
the same.
standard: the following abbreviations are used: singlet (s), doublet
(d), double of doublets (dd), double double doublet (ddd), double
triplet (dt), triplet of doublets (td), triplet (t), multiplet (m), broad
(br). Enantiomeric excesses were determined by HPLC analysis on
chiral stationary phase, using Chiracel OD-H and OJ as columns
with hexane or hexane/ PrOH mixtures as a mobile phase and UV
detection at 230 or 254 nm. Elemental analyses were obtained
using an Elementar Vario MICRO cube equipment.
i
4
.2. General procedure for the synthesis of diamido phosphites
3
. Conclusions
To a solution of methyl-3-acetyl-deoxycholan-24-ate (0.400 g,
Pd(II) complexes of deoxycholic acid derived binaphthyl dia-
3
0.9 mmol) in dry dichloromethane (5 ml), PCl (0.24 ml, 2.7 mmol)
mido phosphites have proven to work as chiral catalysts in the
asymmetric Suzuki-Miyaura cross-coupling of aryl bromides with
aryl boronic acids. A matched relationship between the stereo-
chemistry of the bile acid and the (R)-absolute configuration of
the binaphthyl diamido phosphite moiety was observed, and com-
plex 2b gave better enantioselectivities. This complex displayed
high activity allowing the reactions to be performed at 0 °C, where
the products were obtained in moderate to very good yields and
with ees up to 70%.
was added under an inert atmosphere, and the reaction mixture
was stirred at room temperature for 24 h. After removing the sol-
vent under reduced pressure, the crude product was dissolved in
0
dry toluene (2.5 ml) and a solution of N,N -dimethyl-binaphtyl-
diamine (0.234 g, 0.75 mmol) and triethylamine (0.38 ml,
2.7 mmol) in dry toluene (2 ml) was added dropwise to this. After
the addition, the reaction mixture was refluxed overnight. The
mixture was cooled to room temperature and, after adding dry
hexane (5 ml), was filtered under an inert atmosphere: the filtrate
Please cite this article in press as: Iannucci, G.; et al. Tetrahedron: Asymmetry (2017), https://doi.org/10.1016/j.tetasy.2017.09.012

6
G. Iannucci et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
was concentrated under vacuum and the crude product was puri-
fied by filtration under an inert atmosphere on a pad of neutral
Al O (3 g in a 2.5 cm diameter column) using dry dichloromethane
2 3
stirring, the solvent was removed under reduced pressure and
the yellow-orange solid was washed with n–hexane (3 ꢁ 4 mL)
then dried under vacuum.
as eluent, obtaining the pure diammido phosphite as a white amor-
phous solid.
4.3.1. PdCl
50 mg (0.48 mmol, 96%) [
(400 MHz, 298 K, C ), d: 8.44 (d,
2 2
(1a) , 2a
3
1
1
8
a]
D
= ꢀ211 (c 0.89, CH
2 2
Cl ). H NMR
3
4
.2.1. Methyl-3a-acetyl-12a-[(S)-N,N-dimethylbinaphthyl]diaza-
6
D
6
J
HH = 9.0 Hz, 1H, a), 8.04 (d,
3
3
0
phospholidine-5b-cholan-24-ate, 1a
J
J
J
J
J
J
HH = 9.0 Hz, 1H, b), 7.66 (d,
HH = 8.9 Hz, 1H, b ), 7.53 (d,
J
J
HH = 8.2 Hz, 1H, f ), 7.64 (d,
HH = 8.9 Hz, 1H, a ), 7.51 (d,
1
3
3
3
3
3
0
3
0
0
.382 g (0.48 mmol, 55 %); H NMR (400 MHz, 298 K, C
6
D
6
), d:
3
0
3
0
HH = 7.9 Hz, 1H, c), 7.21 (d, 3JHH = 8.4 Hz, 1H, c ), 7.15 (dd,
HH = 8.2, 7.2 Hz, 1H, e ), 7.07 (d, 3JHH = 8.8 Hz, 1H, f), 6.95 (dd,
HH = 7.9, 6.9 Hz, 1H, d), 6.84 (dd, 3JHH = 8.4, 7.2, 1H, d ), 6.73 (dd,
HH = 8.8, 6.9 Hz, 1H, e), 4.78 (m, 1H, 12), 4.56 (m, 1H, 3), 3.99 (t,
0
7
.78 (d,
J
HH = 8.1 Hz, c ), 7.76 (d,
JHH = 8.5 Hz, b ), 7.72 (d,
3
3
0
J
J
J
HH = 8.5 Hz, 1H, b), 7.68 (d,
J
HH = 8.1 Hz, 1H, c), 7.50 (d,
3
3
HH = 8.8 Hz, 1H, a),7.41 (d, 3JHH = 8.5 Hz, 1H, a ), 7.36 (dd,
0
0
4
0
3
4
HH = 8.8 Hz, JHH = 0.9 Hz, f ), 7.29 (dd, JHH = 8.9 Hz, JHH = 0.8 Hz,
3
HH = 8.1, 6.9 Hz, 4
0
3JHP = 6.2 Hz, 3H, NMe), 3.67 (t,
3
0
1
H, f), 7.19 (ddd,
J
J
HH = 0.9 Hz, d ), 7.15 (ddd,
J
HP = 5.9 Hz, 3H, NMe ), 3.43 (s,
3
HH = 8.1, 6.8 Hz, 4JHH = 0.8 Hz, d), 6.93 (ddd,
3
3
J
J
HH = 8.9, 6.8 Hz,
HH = 1.2 Hz, e ),
HH = 2.6 Hz, 1H, 12), 3.40
3H, OCH
3
), 3.01 (q,
J
HH = 9.6 Hz, 1H, 17), 2.60 (m, 1H, 23), 2.44
4
3
4
0
3
J
HH = 1.2 Hz, e), 6.91 (ddd,
.72 (m, 1H, 3), 4.28 (dt,
s, 3H, OCH
J
HH = 8.8, 6.9 Hz,
J
(m, 1H, 23), 2.07–0.62 (m, 27H), 1.57 (d, JHH = 6.3 Hz, 21), 0.58
(s, 3H, 19), 0.47 (s, 3H, 18), 0.04 (td, JHH = 14.4 Hz, JHH = 2.8 Hz,
3
3
2
3
4
(
J
HP = 7.8 Hz,
J
3
3
2
13
1
3
), 2.92 (d, JHP = 9.1 Hz, 3H, NMe), 2.89 (d, JHP = 13.2 -
Hz, 3H, NMe ), 2.24 (m, 1H, 23), 2.14 (m, 1H, 23), 1.96–1.78 (m, 6H,
, 2/4, 8/9, 16, 17, 22), 1.76–1.56 (5H, 2 , 4 , 11, 6/7, 14), 1.51 (s, 3H,
1H, 1), -0.20 (d,
298 K, C
J
HH = 14.4 Hz, 1H, 1). C{ H} NMR (100 MHz,
0
0
6
D
6
), d: 174.0 (24), 169.4 (C@O), 133.7 (g), 133.5 (g ),
131.8 (h), 131.7 (h ), 129.6 (b), 128.6 (b , c, c ), 127.6 (f ), 127.3
(f), 126.6 (d ), 126.4 (e), 126.0 (e ), 124.8 (d), 123.2 (a ), 122.2 (a),
JcP = 6.8 Hz, 12), 73.8 (3), 51.1 (OCH ), 47.5 (14), 46.4
3
(17), 41.7 (5), 40.8 (t, JCP = 10.6 Hz, NMe ), 38.2 (t, JCP = 5.8 Hz,
0
0
0
0
0
0
1
3
0
0
0
HCH
.63 (s, 3H, 19), 0.82 (s, 3H, 18); C{ H} NMR (100 MHz, 298 K,
), d: 173.9 (24), 169.5 (C@O), 145.8 (d, JCP = 7.5 Hz, h/i),
2
(C@O)), 1.49–1.00 (m, 12H), 0.98 (d,
J
HH = 6.7 Hz, 3H, 21),
13
1
2
0
82.8 (t,
2
0
2
C
1
1
1
1
(
3
(
2
6
D
6
5
0
0
0
0
43.2 (d,
J
CP = 6.4 Hz, h /i ), 133.8 (m), 133.4 (m ), 132.0 (g ),
NMe), 36.0 (8/9), 35.9 (20), 34.9 (9/8), 34.2 (1), 32.6 (4), 32.2
(23), 31.7 (22), 27.43 (16), 27.37 (6/7), 26.3 (7/6), 25.8 (2), 24.2
0
0
31.6 (g), 129.3 (b), 128.52(b ), 128.46 (b ), 128.4 (c), 128.3 (d),
0
0
0
0
27.9 (f ), 127.3 (f), 126.2 (e), 126.1 (e ), 125.1 (d ), 124.2 (a ),
(15), 23.0 (11), 22.6 (18), 21.2 (CH
3
(C@O)), 18.9 (21), 12.8 (19).
), d: 117.1. Anal. Calcd. for C98
2 4 10 2
H122Cl N O P Pd: C, 67.06; H, 7.01; N, 3.19. Found: C, 66.98; H,
2
31
1
22.2 (a), 77.0 (d,
J
CP = 7.1 Hz, 12), 73.8 (3), 50.9 (OCH
3
), 48.4
CP = 44.9 Hz, NMe ), 36.3 (20),
CP = 23.2 Hz, NMe), 35.9 (8/9), 35.2 (1), 34.2 (8/9), 32.5
P{ H} NMR (161 MHz, 298 K, C
6
D
6
-
2
0
14), 46.2 (17), 42.0 (5), 38.1 (d,
J
2
6.1 (d,
2/4), 31.3 (22), 31.1 (23), 27.9 (16), 27.8 (d,
7.5 (2/4), 27.3 (15), 26.9 (6/7), 24.4 (6/7), 23.2 (18), 21.0 (s, Me
J
6.99; N, 3.18.
5
JCP = 5.2 Hz, 11),
4.3.2. PdCl
810 mg (0.46 mmol, 92%). [
(400 MHz, 298 K, C ), d: 8.58 (d,
2 2
(1b) , 2b
6
31
1
25
). 1H NMR
HH = 8.8 Hz, 1H, a ), 8.28 (d,
(
(
C@O)), 18.2 (d,
161 MHz, 298 K, C
J
D
CP = 9.6 Hz, 21), 12.9 (19);
), d: 168.8. Anal. Calcd. For C49
P{ H} NMR
P:
a]
D
= +273 (c 1, CH
2
Cl
2
3
0
6
6
H
61
N
2
O
5
6
D
6
J
3
3
C, 74.59; H, 7.79; N, 3.55. Found: C, 74.71; H, 7.76; N, 3.54.
J
HH = 8.7 Hz, 1H, b), 8.15 (d,
JHH = 8.7 Hz, 1H, a), 8.07 (d,
3JHH = 8.8 Hz, 1H, b ), 7.91 (d, br.s., 1H, c ), 7.68 (d,
0
0
3
J
HH = 8.2 Hz,
HH = 8.8 Hz, 1H, f ),
3
3
0
4
.2.2. Methyl-3a-acetyl-12a-[(R)-N,N-dimethylbinaphthyl]diaza-
1H, c), 7.30 (d,
J
HH = 8.3 Hz, 1H, f), 7.27 (d,
J
3
0
3
phospholidine-5b-cholan-24-ate, 1b
7.18 (t,
d), 6.91 (t,
1H, e), 6.16 (br.s., 1H, 12), 4.94 (m, 1H, 3), 3.58 (t, JHP = 4.6 Hz,
JHH = 7.4 Hz, 1H, d ), 7.07 (ddd, JHH = 8.2, 6.9, 1.0 Hz, 1H,
25
1
3
0
3
0
.313 g (0.40 mmol, 45 %). [
a
]
D
= ꢀ198 (c 0.1, CH
2
Cl
2
); H NMR
JHH = 7.4, Hz 1H, e ), 6.83 (ddd, JHH = 8.3, 6.9, 1.2 Hz,
3
3
(
4
1
6
400 MHz, 298 K, C ), d: 7.95 (d, JHH = 8.6 Hz, b), 7.80–7.68 (m,
H, a , b , c, c ), 7.66 (d,
H, f), 7.40 (d,
.87 (m, 2H, e, e ), 4.91 (m, 1H, 3), 4.35 (br s, 1H, 12), 3.40 (s, 3H,
OCH
H, NMe), 2.23 (m, 2H, 23,23 ), 2.18–2.06 (m, 3H, 8,6,11), 2.01–
.59 (m, 9H, 1,17,9,2,2 ,22,4,7,14), 1.81 (s, 3H, CH
6
D
6
0
0
0
3
3
3
0
J
HH = 8.6 Hz, a), 7.43 (d,
J
HH = 8.7 Hz,
3H, NMe), 3.51 (t,
J
HP = 6.0 Hz, 3H, NMe ), 3.46 (s, 3H, OCH
3
),
3
0
0
0
J
HH = 8.5 Hz, f ), 7.20–7.10 (m, 2H, d, d ), 6.99–
3.51 (m, 1H, 11), 2.51 (m, 1H, 23), 2.32 (m, 1H, 23 ), 2.20–1.79
0
0
0
(m, 6H, 22,22 ,17,2,2 ,9), 1.76 (s, 3H, CH
3
C@O), 1.75–1.61 (m, 3H,
3
0
3
0
3
3
), 3.03 (d,
J
HP = 7.6 Hz, 3H, NMe ), 2.83 (d,
J
HP = 12.5 Hz,
1,4,11 ), 1.64 (d, 1H,
4 ,1 ,5,6,8, 14,15,16,16 ,20), 0.90–0.78 (m, 4H, 7,7 ,15 ,6 ) 0.69 (s,
3H, 19), 0.54 (s, 3H, 18).
C{ H} NMR (100 MHz, 298 K, C
(C@O), 143.1 (i/i ), 142.8 (i/i ), 133.8 133.3, 133.2, 133.1 (g/g /h/
h ), 129.5, 129.4 (l/l ), 129.2 (b ), 129.1 (b), 129.0 (a ), 128.6 (c),
128.5 (c ), 127.9 (f), 127.7 (a), 127.5 (f ), 126.4 (e), 126.2 (e ),
126.1 (d), 125.5 (d ), 81.2 (12), 74.6 (3), 51.2 (OCH
JHH = 4.0 Hz, 21), 1.61–1.01 (m, 10H,
0
0
0
0
0
0
0
3
1
0
3
0
C@O), 1.60–
0
0
0
0
0
0
0
13
1
0
.86 (m, 11H, 4 ,15,15 ,20,16,16 ,5,22 , 11 ,1 ,7 ,6 ), 1.00 (d,
6
D
6
), d: 174.2 (24), 170.2
3
13
1
0
0
0
J
HH = 6.5 Hz, 3H, 21), 0.82 (s, 3H, 18), 0.62 (s, 3H, 19). C{ H}
0
0
0
0
NMR (100 MHz, 298 K, C
6
D
6
), d: 173.5 (24), 169.7 (C@O), 145.4
0
5
0
0
0
0
(
d, JCP = 7.3 Hz, ì ), 143.0 (d,
J
CP = 6.7 Hz, i), 133.5 (g ), 133.1 (g),
0
0
0
0
1
1
1
1
3
31.8 (l ), 131.7 (l), 131.3 (h), 131.0 (h ), 129.1 (b ), 128.3 (b),
3
), 47.2 (17),
0
0
0
0
28.1 (c), 128.0 (c ), 127.5 (f), 127.1 (f ), 125.9 (e), 125.8 (e ),
47.2 (13), 46.7 (14), 42.7 (NMe ), 42.4 (5), 40.3(NMe), 37.7 (20),
36.8 (8), 35.5 (9), 33.6 (4), 32.8 (23), 32.0 (10), 31.1 (22), 30.4
(11), 29.1 (1), 28.6 (2), 28.2 (16), 26.8 (15), 24.8 (6), 23.2 (18),
0
0
2
24.8 (d), 124.7 (a), 124.5 (d ), 123.7 (a ), 77.5 (d,
JCP = 14 Hz,
2), 73.8 (3), 50.7 (OCH ), 47.9 (14), 47.1 (13), 46.2 (17), 41.6 (5),
3
2
2
31
1
8.0 (d,
J
CP = 43.0 Hz, NMe), 36.0 (20), 35.8 (d,
J
CP = 20.0 Hz,
22.6 (18), 21.2 (CH
(161 MHz, 298 K, C
Pd: C, 67.06; H, 7.01; N, 3.19. Found: C, 67.12; H, 7.02; N, 3.18.
3
(C@O)), 18.8 (21), 13.1 (19). P{ H} NMR
0
NMe ), 35.1 (1), 34.3 (10), 33.3 (9), 32.3 (4), 31.1 (23), 30.9 (22),
2
2
6
D
6
), d: 115.8. Anal. Calcd. for C98H122Cl N O -
2 4 10
9.8 (8), 27.8 (7), 27.0 (2), 26.8 (6), 26.4 (d, 5
6.3 (16), 24.0 (15), 22.7 (18), 20.8 (Me(C@O)), 17.4 (21), 12.4
JCP = 12.0 Hz, 11),
P
2
3
1
1
(
19). P{ H} NMR (161 MHz, 298 K, C
6
D
6
), d: 159.4. Anal. Calcd.
4.4. General procedure for Suzuki-Miyaura cross coupling
reaction
for C49 P: C, 74.59; H, 7.79; N, 3.55. Found: C, 74.50; H,
61 2 5
H N O
7
.81; N, 3.56.
2 2
.3. General procedure for the synthesis of complexes PdCl L
A flame dried Schlenk was charged under an inert atmosphere
with aryl bromide (0.5 mmol), aryl boronic acid (0.75 mmol) and
4
2
b (0.025 mmol, 5 mol %) dissolved in dry toluene (5 ml), then Cs
CO (1.25 mmol) was added. The mixture was stirred at room tem-
perature or 0 °C until TLC analysis (hexane–CH Cl 8:2) showed
complete substrate conversion or when it did not proceed further.
2
-
A solution of the ligand (0.5 mmol) in dry toluene (8 mL) was
added to a red solution of PdCl (PhCN) (0.25 mmol) in dry toluene
20 mL), which turned from red to yellow-orange. After 15 min
3
2
2
2
2
(
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G. Iannucci et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
7
The reaction was quenched with NH
diethyl ether (3 ꢁ 10 mL) and the organic phase was dried over
anhydrous Na SO . After removing the solvent at reduced pressure,
the crude product was directly analysed by H NMR and, if neces-
sary, purified by column chromatography (SiO ; hexane–CH Cl
:2). The ee of the biaryl products were determined by HPLC on
a chiral stationary phase.
4
Cl solution, extracted with
{1H} NMR (100 MHz, 298 K, CDCl
132.6, 132.0, 130.0, 128.6, 127.8, 127.4, 127.1, 126.0, 125.9,
125.7, 124.8, 20.3, 19.5. HPLC (Chiracel OJ, hexane, 0.5 ml/min,
3
), d: 139.2, 137.5, 136.8, 133.1,
2
4
1
1 2
T = 25 °C, 254 nm): t = 12.5 min (major), t = 19.5 min (minor).
2
2
2
0
0
14
8
4.4.6. (R)-2,4 -Dimethyl-1,1 -binaphthyl, 7a
From 1-bromo-2-methylnaphthalene and 4-methyl-1-naph-
thaleneboronic acid, after 48 h at rt. H NMR (400 MHz, 298 K,
1
4
.4.1. (+)-2-Methoxy-1-(2-methylphenyl)-naphthalene, 19 5a
From ortho-tolylboronic acid and 1-bromo-2-methoxynaph-
thalene after 16 h at RT. 1H NMR (400 MHz, 298 K, CDCl
), d:
.90 (d, 1H, JHH = 9.2 Hz), 7.86–7.81 (m, 1H), 7.36–7.20 (m, 7H),
3
CDCl ), d: 8.10 (d, 1H, JHH = 9.3 Hz), 7.89 (d, 1H, JHH = 8.1 Hz), 7.87
(d, 1H, JHH = 8.4 Hz), 7.57–7.15 (m, 9H), 2.83 (s, 3H), 2.13 (s, 3H).
13
1
3
3
C{ H} NMR (100 MHz, 298 K, CDCl ), d: 136.5, 135.9, 134.6,
7
7
134.0, 133.8, 133.0, 132.8, 132.2, 128.7, 127.9, 127.6, 126.8,
126.6, 126.5, 126.0, 125.9, 125.8, 124.9, 124.6, 20.7, 19.7. HPLC
(Chiracel OJ, hexane/2-propanol 90:10, 1.0 mL/min, T = 25 °C,
.17 (d, 1H, JHH = 5.0 Hz), 3.83 (s, 3H), 1.98 (s, 3H). 13C{ H} NMR
1
(
100 MHz, 298 K, CDCl
3
), d: 153.6, 137.6, 136.1, 133.4, 130.8,
1
1
1
29.8, 128.9, 127.8. 127.5, 126.3, 125.6, 125.0, 124.5, 123.4,
13.6, 56.5, 19.7. HPLC: (Chiracel OJ, hexane/2-propanol 99:1,
k = 230 nm): t
1
= 4.7 min (major) and t
2
= 15.3 min (minor).
0
0
14
.0 mL/min,
T = 25 °C,
k = 230 nm):
t
1
= 8.4 min
(major),
4.4.7. (S)-2-Methoxy-4 -methyl-1,1 -binaphthyl, 7b
0
t
2
= 11.5 min (minor).
From 1-bromo-4 -methylnaphthalene and 2-methoxy-1-naph-
thaleneboronic acid, after 48 h at rt.
1
4
.4.2. 2-Methoxy-1-(2-formylphenyl)-naphthalene,17 5b
From 1-bromo-2-methoxynaphthalene and 2-formylphenyl-
3
H NMR (400 MHz, 298 K, CDCl ), d: 7.92 (d, 1H, JHH = 9.2 Hz),
7.86 (m, 1H), 7.41–7.26 (m, 9H), 7.21 (m, 1H), 3.80 (s, 3H), 2.85
1
13
1
boronic acid after 24 h at rt. H NMR (400 MHz, 298 K, CDCl
3
), d:
.64 (s, 1H), 8.15 (dd, 1H, JHH = 7.5, 3.9 Hz), 7.99 (d, 1H, JHH = 9 Hz),
.74 (t, 1H, JHH = 7.5 Hz), 7.66 (dd, 1H, JHH = 9.6 Hz, 3.3 Hz) 7.59 (t,
3
(s, 3H). C{ H} NMR (100 MHz, 298 K, CDCl ), d: 154.8, 134.6,
9
7
1
134.0, 133.1, 133.0, 132.9, 129.5, 128.2, 127.9, 126.9, 126.6,
126.5, 125.8, 125.7, 125.6, 124.5, 123.7, 114.0, 56.9, 19.8. HPLC
(Chiracel OJ, hexane/2-propanol 90:10, 1.0 mL/min, T = 30 °C,
13
1
H, JHH = 6.9 Hz), 7.41–7.33 (m, 5H), 3.84 (s, 3H). C{ H} NMR
), d: 192.8, 154.4, 140.6, 135.3, 134.1,
(
100 MHz, 298 K, CDCl
3
k = 227 nm): t
1
2
= 7.2 min (major) and t = 29.3 min (minor).
1
1
1
33.9, 132.6, 130.6, 129.2, 128.3, 128.2, 127.2, 125.1, 124.1,
20.3, 113.0, 56.6. HPLC (Chiralcel OJ, hexane/2-propanol 99:1
0
14
4.4.8. (R)-2-Methoxy-1,1 -binaphthyl, 7c
.0 mL/min, T = 25 °C, k = 230 nm):
t
1
= 20.1 min (major),
From
thaleneboronic acid after 24 h at 0 °C. H NMR (400 MHz, 298 K,
CDCl ), d: 8.01–7.90 (m, 3H), 7.87 (d, 1H, JHH = 8.1 Hz), 7.62 (t,
1H, JHH = 6 Hz), 7.48–7.41 (m, 3H), 7.35–7.13 (m, 5H), 3.75 (s,
1-bromo-2-methoxynaphthalene
and
1-naph-
1
t
2
= 26.9 min (minor).
3
4
.4.3. (ꢀ) 2-Methyl-1-(2-methoxyphenyl)-naphthalene, 5c
1
3
1
From 1-bromo-2-methylnaphthalene and 2-methoxyphenyl
3H).
3
C{ H} NMR (100 MHz, 298 K, CDCl ), d: 154.8, 134.7,
boronic acid, after 48 h at rt, the reaction mixture was purified giv-
ing 70 mg (0.28 mmol, 56%) of 2-methyl-1-(2-methoxyphenyl)-
134.4, 133.8, 133.1, 129.6, 129.2, 128.6, 128.4, 127.9, 127.8,
126.5, 126.3, 126.0, 125.8, 125.7, 125.6, 123.7, 123.4, 114.0, 56.9.
HPLC (Chiracel OJ, hexane/2-propanol 95:5, 1.0 mL/min, T = 25 °C,
2
5
1
naphthalene. [
NMR (400 MHz, 298 K, CDCl
a
]
D
= ꢀ3 (c 1, CHCl
), d: 7.89 (d, 1H, JHH = 8.0 Hz), 7.84
d, 1H, JHH = 8.0 Hz), 7.52–7.33 (m, 5H), 7.24–7.08 (m, 3H), 3.73
3
) for a sample with 51% ee. H
3
1 2
k = 230 nm): t = 10.2 min (major) and t = 15.7 min (minor).
(
(
1
1
13
1
s, 3H), 2.29 (s, 3H). C{ H} NMR (100 MHz, 298 K, CDCl
3
), d:
57.4, 134.7, 133.9, 132.9, 132.0, 131.8, 128.8, 128.5, 128.3,
27.8, 127.2, 125.9, 125.7, 124.6, 120.7, 111.2, 55.5, 20.6. HPLC
Acknowledgements
This work was supported by University of Pisa. Financial sup-
port from the Ministerio de Economía Competitividad
MINECO/FEDER) of Spain (Projects CTQ2013-42532-P and
(
Chiracel OJ, hexane:2-propanol 99.5:0.5, 0.7 ml/min, 230 nm)
= 10.0 min (major), = 14.1 min (minor). Anal. Calcd. for
16O: C, 87.06; H, 6.49. Found: C, 86.98; H, 6.48.
y
t
1
t
2
(
C
18
H
CTQ2016-75884-P) and Diputación General de Aragón (DGA/FSE
E07) is gratefully acknowledged.
1
7
4
.4.4. (ꢀ) 2-Methoxy-1-(2-methoxyphenyl)-naphthalene, 5d
From 1-bromo-2-methoxynaphthalene and 2-methoxyphenyl-
A. Supplementary data
boronic acid after 48 h at 0 °C, the reaction mixture was purified
by column chromatography giving 33 mg (0.125 mmol, 25%) of
Supplementary data (NMR spectra and 2D maps of all new com-
pounds and HPLC chromatograms) associated with this article can
be found, in the online version, at http://dx.doi.org/10.1016/j.
tetasy.2017.09.012.
2
-methoxy-1-(2-methoxyphenyl)-naphthalene as a white solid.
1
H NMR (400 MHz, 298 K, CDCl
3
), d: 7.88 (d, 1H, JHH = 9.0 Hz),
7
1
.80 (m, 1H), 7.45–7.28 (m, 5H), 7.21 (dd, 1H, JHH = 7.2 Hz,
.8 Hz), 7.07 (m, 2H), 3.84 (s, 3H), 3.70 (s, 3H). 13C{ H} NMR
1
(
100 MHz, 298 K, CDCl
3
), d: 157.9, 154.4, 133.8, 132.5, 129.2,
1
1
9
28.9, 127.9, 126.2, 125.6, 125.4, 123.5, 122.4, 120.7, 114.4,
11.5, 108.0, 57.2, 55.9. HPLC (Chiralcel OJ, hexane/2-propanol
9:1 1.0 mL/min, T = 25 °C, k = 230 nm): t = 16.4 min (minor),
1
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