Reductive opening of 2,7-dihydrodinaphthoxepine and thiepine: Easy regioselective preparation of 2,2′-difunctionalised binaphthyls

Article abstract of DOI:10.1016/j.tetlet.2004.10.041

The lithiation of 2,7-dihydrodinaphthoheteroepines (5) with 2.2 equiv of lithium naphthalenide in THF at -78°C gives dianionic intermediates 8, which by reaction with different electrophiles [H₂O, D₂O, ^tBuCHO, Me₂CO, Et₂CO, (CH₂) ₄CO, (CH₂)₅CO] at the same temperature, followed by hydrolysis, leads to unsymmetrically 2,2′-disubstituted binaphthyls 6. When the lithiation is performed with an excess of lithium in the presence of a catalytic amount of 4,4′-di-tert-butylbiphenyl (DTBB, 10 mol %), a double reductive cleavage takes place to give dianionic intermediate 9, which by reaction with different electrophiles [H₂O, Me ₂CO, Et₂CO, (CH₂)₄CO, (CH ₂)₅CO], followed by hydrolysis with water, yields symmetrically 2,2′-disubstituted binaphthyls 7. In the case of starting from (R)-5a, the reductive opening by treatment with 2.2 equiv of lithium naphthalenide followed by reaction with H₂O or (CH₂) ₅CO as electrophiles and final hydrolysis, leads to enantiomerically pure compounds (R)-6aa and (R)-6af, respectively.

Full text of DOI:10.1016/j.tetlet.2004.10.041

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8983–8986
Reductive opening of 2,7-dihydrodinaphthoxepine and thiepine: easy
regioselective preparation of 2,20-difunctionalised binaphthyls
*
Francisco Foubelo, Benjamın Moreno and Miguel Yus
´
´ ´
Departamento de Quımica Organica, Facultad de Ciencias and Instituto, de Sıntesis Organica (ISO),
Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
´
´
Received 24 September 2004;revised 8 October 2004;accepted 8 October 2004
Available online 22 October 2004
ˆ
Dedicated to Professor Jean-Pierre Genet on occasion of his 60th birthday
Abstract—The lithiation of 2,7-dihydrodinaphthoheteroepines (5) with 2.2equiv of lithium naphthalenide in THF at À78ꢀC gives
dianionic intermediates 8, which by reaction with different electrophiles [H2O, D2O, tBuCHO, Me2CO, Et2CO, (CH2)4CO,
(CH2)5CO] at the same temperature, followed by hydrolysis, leads to unsymmetrically 2,20-disubstituted binaphthyls 6. When the
lithiation is performed with an excess of lithium in the presence of a catalytic amount of 4,40-di-tert-butylbiphenyl (DTBB,
10mol%), a double reductive cleavage takes place to give dianionic intermediate 9, which by reaction with different electrophiles
[H2O, Me2CO, Et2CO, (CH2)4CO, (CH2)5CO], followed by hydrolysis with water, yields symmetrically 2,20-disubstituted binaphth-
yls 7. In the case of starting from (R)-5a, the reductive opening by treatment with 2.2equiv of lithium naphthalenide followed by
reaction with H2O or (CH2)5CO as electrophiles and final hydrolysis, leads to enantiomerically pure compounds (R)-6aa and (R)-
6af, respectively.
ꢁ 2004 Elsevier Ltd. All rights reserved.
Asymmetric synthesis1 deals with the development of
stereodifferentiating reactions in which the source of
the information of the stereochemical course can be pre-
sent in a stoichiometric (chiral auxiliary) or a catalytic
(chiral catalyst) amount, the enantioselective catalysis2
with transition metals in the presence of a chiral ligand
being probably one of the most popular research areas
in organic chemistry in the last decades. Among chiral
ligands, those containing a 1,10-binaphthyl moiety3 have
played a central role in this field and when substituents
are introduced into the 2,20-positions the atropoisomers
become configurationally stable and for that reason eas-
ily resolvable.4 Apart from the interest in the design of
binaphthyls for asymmetric synthesis, they can be used
in materials science because of the unique properties de-
rived from their rigidity, chirality and conjugation.5 On
the other hand, functionalised organolithium com-
pounds6 have found a great applicability in organic syn-
thesis because, their reaction with electrophiles yields
polyfunctionalised molecules in a single process. These
organolithium compounds can be prepared through a
wide range of methodologies,7 the reductive opening
of some heterocycles8 are of special interest due to the
accessibility of the starting materials, in many cases in
enantiomerically pure form when stereogenic elements
are present in their structures. Lithium metal is the lithi-
ating reagent in these electron transfer processes9 either
alone or in the presence of an arene in a stoichiometric
or catalytic amount.10 The reductive opening lithiation
takes place only in the case of strained heterocycles
(three and four membered-ring heterocycles) and those
with activated bonds,8 for instance, compounds with
allylic and benzylic carbon–heteroatom bonds11 as well
as aryl ethers and thioethers. It has been reported that
the reductive opening of different 2,7-dihydrodibenzo-
heteroepines 112,13 by means of excess of lithium in the
presence of a catalytic amount of 4,40-di-tert-butylbi-
phenyl (DTBB) allows the generation of the correspond-
ing functionalised organolithium intermediates 2, which
can be trapped with different electrophiles to yield com-
pounds 3 (Chart 1). In the case of dihydrodibenzothi-
epine 1c, a tandem double sequential lithiation reaction
with electrophiles allows the introduction of two equal
or different electrophiles at the benzylic positions to give
2,20-disubstituted biphenyls 413 (Chart 1). With these
Keywords: Reductive ring opening;Dinaphthoheteroepines;DTBB-
catalysed
lithiation;Electrophilic
substitution;Substituted
binaphthyls.
*
Corresponding author. Tel.: +34 965 909672;fax: +34 965 903549;
e-mail: foubelo@ua.es
0040-4039/$ - see front matter ꢁ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.041

8984
F. Foubelo et al. / Tetrahedron Letters 45 (2004) 8983–8986
YLi
Li
YH
E
E2
E1
Y
1a: Y = O
2a: Y = O
3a: Y = O
4
1b: Y = NMe
1c: Y = S
2b: Y = NMe
2c: Y = S
3b: Y = NMe
3c: Y = S
Chart 1.
antecedents in mind, we considered out of interest to
study the reductive opening of different dinaphthohete-
roepines 5 in order to prepare unsymmetrical and sym-
metrical 2,20-disubstituted-1,10-binaphthyls 6 and 7,
respectively.
of lithium metal in the presence of a catalytic amount
of DTBB (10mol%) as the lithiating reagent and after
addition of the corresponding electrophile under the
same reaction conditions (Method B),19 it was not pos-
sible to obtain the expected functionalised binaphthyls 6
in reasonable yields, even after short reaction times. In-
stead of that, a significant amount of the symmetrical
2,20-disubstituted derivatives 7 were obtained as reac-
tion products. The yield of these reactions was improved
when 2.2equiv of the corresponding electrophile [H2O,
Me2CO, Et2CO, (CH2)4CO, (CH2)5CO] were added
(Scheme 1, Table 1, entries 11–16). These results indi-
cated that, after the reductive opening of compounds 5
to give dianionic intermediate 8 (Chart 2), a second
reductive cleavage of the remaining benzylic carbon–
heteroatom bond took place in the highly reductive
reaction medium to give the dilithium derivative 920
(Chart 2).
Starting materials 5 were prepared from commercially
available 1-bromo-2-methylnaphthalene in only three
steps and in around 40% overall yield in both cases.
First, aryl–aryl coupling of the mentioned bromoarene
with its Grignard reagent in the presence of a catalytic
amount of bis[triphenylphosphine]dichloronickel to give
2,20-dimethyl-1,10-binaphthyl (7a).14 After that, radical
benzylic bromination with N-bromosuccinimide in the
presence of AIBN15 gave 2,20-bis(bromomethyl)-1,10-
binaphthyl. Finally, double nucleophilic substitution
by treatment with a 5M NaOH aqueous solution in
dioxane in the presence of 2,6-lutidine16 and with so-
dium sulfide nonahydrate17 afforded compounds 5a
and 5b, respectively.
Since both enantiomers of the starting materials 5 can be
accessible through already described procedures, this
methodology could be applied to the synthesis of 2,20-
disubstituted-1,10-binaphthyls in an enantiomerically
pure form. Thus, heterocycle (R)-5a was obtained
through the methodology described above for the race-
mic heterocycles, starting from (R)-2,20-dimethyl-1,10-
binaphthyl [prepared from commercially available
(R)-BINOL (>99% ee) by transforming it into the corre-
sponding bistriflate and performing a bis(triphenyl-
The reaction of 2,7-dihydrodinaphthoheteroepines 5
with 2.2equiv of lithium naphthalenide in THF at
À78ꢀC for 1h (method A)18 followed by addition of dif-
ferent electrophiles [H2O, D2O, tBuCHO, Me2CO,
Et2CO, (CH2)4CO, (CH2)5CO] at the same temperature
gave, after hydrolysis with water in the case of the oxy-
gen derivative 5a or a 3M HCl aqueous solution for the
sulfur derivative 5b, the corresponding hydroxyl or sulf-
anyl functionalised binaphthyl derivatives 6 in good to
moderate yields (Scheme 1, Table 1, entries 1–10). When
pivalaldehyde was used as electrophile, a 1:1 mixture of
diastereomers was obtained (Table 1, entry 3) and sepa-
rated by column chromatography.
phosphine)dichloronickel-catalysed
coupling
with
methylmagnesium bromide]. Reductive lithiation of
(R)-5a with lithium naphthalenide (Method A) followed
by reaction with H2O and cyclohexanone as electro-
philes and final hydrolysis with water gave compounds
(R)-6aa21a and (R)-6af21b in 80% and 49% yield, respec-
tively (Scheme 2).
Regarding the mechanism of this process, it is assumed
that the functionalised organolithium compound 8
(Chart 2) is formed after reductive ring opening of the
starting heterocycles 5. In the case of using an excess
In conclusion, we report here that the reductive opening
lithiation of 2,7-dihydrodinaphthoheteroepines 5 at
YH
i-iii
E
iv,ii,iii
[Method B]
Y
[Method A]
E
E
6
5a: Y = O
5b: Y = S
7
Scheme 1. Reagents and conditions: (i) LiC10H8 (2.2equiv), THF, À78ꢀC, 1h;(ii) E + = H2O, D2O, tBuCHO, Me2CO, Et2CO, (CH2)4CO,
(CH2)5CO, À78ꢀC, 15min;(iii) H 2O for Y = O or 3M HCl for Y = S, À78 to 20ꢀC;(iv) Li, DTBB (10mol%), THF, À78ꢀC, 1h.

F. Foubelo et al. / Tetrahedron Letters 45 (2004) 8983–8986
Table 1. Preparation of compounds 6 and 7
8985
Entry
Starting material
Method
E+
Producta
E
No.
Y
Yieldb(%)
1
5a
5a
5a
5a
5a
5a
5b
5b
5b
5b
5a
5a
5b
5b
5b
5b
A
A
A
A
A
A
A
A
A
A
B
B
B
B
B
B
H2O
6aa
6ab
6ac
6ad
6ae
6af
6bd
6be
6bf
6bg
7a
O
O
O
O
O
O
S
H
81
68c
48d
38
51
48
64
56
53
36
96
48
52
57
31
38
2
D2O
D
3
tBuCHO
Me2CO
Et2CO
tBuCHOH
Me2COH
Et2COH
(CH2)5COH
Me2COH
Et2COH
(CH2)5COH
(CH2)4COH
H
4
5
6
(CH2)5CO
Me2CO
Et2CO
7
8
S
9
(CH2)5CO
(CH2)4CO
H2O
S
10
11
12
13
14
15
16
S
—
—
—
—
—
—
Me2CO
Me2CO
Et2CO
7d
7d
Me2COH
Me2COH
Et2COH
(CH2)5COH
(CH2)4COH
7e
(CH2)5CO
(CH2)4CO
7f
7g
a Products 6 and 7 were P95% pure (GLC and 300MHz 1H NMR) and were fully characterised by spectroscopic means (IR, 1H, and 13C NMR and
LRMS/HRMS).
b Isolated yield after column chromatography (silica gel, hexane/ethyl acetate) based on the starting material 5.
c
ꢀ70% Deuterium incorporation (13C NMR).
d A ca. 1:1 diastereomeric mixture was obtained and separated by column chromatography (silica gel, hexane/ethyl acetate).
enantiomerically pure dinaphthoheteroepines 5 as start-
ing materials.
YLi
Li
Li
Li
Acknowledgements
´
This work was generously supported by the Direccion
General de Ensen˜anza Superior (DGES) of the current
8
9
´
Spanish Ministerio de Ciencia y Tecnologıa (MCyT;
Chart 2.
grant no. BQU2001-0538) and the Generalitat Valen-
ciana (projects no. GV01-443 and CTIDIB/2002/318).
B.M. thanks the MCyT for a scholarship.
OH
E
i,ii,iii
[Method A]
References and notes
O
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(R)-5a
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Scheme 2. Reagents and conditions: (i) LiC10H8 (2.2equiv), THF,
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when the lithiation was performed with an excess of lith-
ium metal in the presence of a catalytic amount of
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catalytic amount of DTBB (26mg, 0.1mmol) in THF
(3mL) was added dropwise a solution of compound 5
(0.5mmol) in THF (1mL) under argon and the mixture
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