Protecting group free synthesis of 6-substituted naphthols and binols

Article abstract of DOI:10.1021/jo1025892

A straightforward route for the preparation of 6-substituted naphthols and 6,6′-disubstituted binols (binol = 2,2′-dihydroxy-1,1′- binaphthyl) is presented. The synthesis has been accomplished by a one-step procedure starting from 6-bromo derivatives via direct lithiation with n-BuLi, followed by the addition of several electrophiles. This C-C functionalization has been successfully achieved with iodomethane, 3-methoxybenzaldehyde, benzophenone, methyl-2-methylbenzoate, methylbenzoate, dimethyl carbonate, ethyl 2-chloro-2-oxoacetate, and 2,2-dimethyloxirane (E). This reactivity offers a useful protecting group free synthetic protocol, toward chiral disubstituted 6,6′-binols with configuration retention of the binol moiety.

Full text of DOI:10.1021/jo1025892

NOTE
pubs.acs.org/joc
Protecting Group Free Synthesis of 6-Substituted Naphthols
and Binols
Daniela Verga,* Claudia Percivalle, Filippo Doria, Alessio Porta, and Mauro Freccero*
Dipartimento di Chimica Organica, Universitꢀa di Pavia, V.le Taramelli 10, 27100 Pavia, Italy
S Supporting Information
b
ABSTRACT: A straightforward route for the preparation of 6-substituted
naphthols and 6,60-disubstituted binols (binol=2,20-dihydroxy-1,10-binaphthyl)
is presented. The synthesis has been accomplished by a one-step procedure
starting from 6-bromo derivatives via direct lithiation with n-BuLi, followed by the
addition of several electrophiles. This C-C functionalization has been success-
fully achieved with iodomethane, 3-methoxybenzaldehyde, benzophenone, meth-
yl-2-methylbenzoate, methylbenzoate, dimethyl carbonate, ethyl 2-chloro-2-
oxoacetate, and 2,2-dimethyloxirane (E). This reactivity offers a useful protecting
group free synthetic protocol, toward chiral disubstituted 6,60-binols with config-
uration retention of the binol moiety.
he functionalization of 2-naphthols and binols has been
investigated for several years. Such an interest is due to the
which the above literature points away from this possibility. In a
very recent example, 2-naphthol and binol derivatives, exploited
as mono- and bis-alkylating agents of DNA, have been synthe-
sized by our group through an efficient reductive amination
protocol, starting from the aldehyde 1 and 2 (Scheme 1). The
above have been prepared by a protecting group free lithiation.19
Our interest in binol derivatives, including binol amino acid
(Binolams) and bis-hydroxymethyl binols, as DNA cross-linking
agents,19 further prompted us to develop a more general and
straightforward synthetic pathway to achieve binol functionaliza-
tion with configuration retention of the starting material. In
this report, we describe the synthesis of both C-6-substituted
2-naphthols and binol analogues.
At the beginning, the synthetic protocol was explored for
naphthol derivatives, which were used as a prototype system.
Starting from 6-bromo-2-naphthol (3), the synthesis of all
compounds proceed by lithiation at C-6, followed by addition/
substitution reaction in the presence of several electrophiles,
including iodomethane, 3-methoxybenzaldehyde, benzophenone,
methyl 2-methylbenzoate, dimethylcarbonate, ethyl 2-chloro-2-
oxoacetate, and 2,2-dimethyloxirane.
The nature of the electrophile biased the synthetic procedure
applied for the preparation of the functionalized naphthols.
Compound 3 was lithiated in dry THF at -78 °C using an
excess of n-BuLi. At least 2.0 equiv of n-BuLi was required.
Actually, the best results were achieved using a molar ratio
3/n-BuLi = 1:4.4. After 5 h, the solution color turned from pale
yellow to bright yellow due to the generation of the C-lithiated
intermediate, and an excess of iodomethane was added. The
solution was stirred for 45 min, keeping the temperature below
-50 °C. Subsequent hydrolysis afforded the methylated product
T
great versatility of binaphthyl derivatives, which has found a wide
array of applications in many different areas of chemistry.1 Due to
their axial chirality with C2 symmetry, and exhibiting a stable
configuration in a broad range of conditions, binol derivatives
have become important molecules in several fields, including
asymmetric catalysis,2 chiral supramolecular recognition,3 crystal
engineering,4 electro-optic materials,5 molecular electronics,6
and DNA alkylation.7 The binol core has been conveniently
functionalized at both the 4,40 and 3,30 positions.1,3-8 Further-
more, the access to the 6,60 carbons has seldom been
documented.9 Recently, the functionalization at the C-6 position
of 2-naphthol and binol has been carried out by a carbon halogen
cleavage process, activated by photoexcitation of 6-bromo-2-
naphthol10 and 6,60-dibromobinol.11 With the exception of this
example, all of the synthetic pathways for this type of functiona-
lization require a protecting group strategy and a sequential
lithiation reaction, resulting in multistep synthetic protocols. In
this work, a free protecting group synthetic protocol has been
exploited for the direct lithiation of 6-bromo-2-naphthol and the
binol analogue, following a similar strategy described by Posner
and co-workers.12 They paved the route for the development of a
general direct lithiation of unprotected phenols, showing the
active role of lithium phenoxide as an ortho-directing moiety.
More recently, direct lithiation has been exploited on several
hydric and polyhydric aromatic compounds (monohydroxy
polycyclic aromatics, naphthols,13 o-hydroxybenzylamines,14
and arenethiol15). Similar results have been achieved by direct
lithiation of halo-substituted hydric derivatives, such as bromoar-
ylalkonic acids and amides,16 dihydric phenols,17 and salicylic
acids,18 functionalized by lithium-halogen exchange reactions.
Our group applied the latter synthetic strategy for the functio-
nalization of both 2-naphthol and binol bromo derivatives, for
Received: December 29, 2010
Published: March 08, 2011
r
2011 American Chemical Society
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|

The Journal of Organic Chemistry
NOTE
Scheme 1. Carbaldehydes 1 and 2 Used as Starting Materials
in the Synthesis of Naphthol and Binol Amino Acids as
Triggerable Photoalkylating Agents
aqueous workup (Table 1). These reactions required an excess
of the electrophile, with best yields achieved using a molar ratio
3/electrophiles = 1:5. The 2,2-dimethyloxirane, being less reac-
tive as electrophile, required different reaction conditions for the
synthesis of 4g. In fact, the reaction of 3 in the presence of n-BuLi
in THF and subsequent addition of 2,2-dimethyloxirane did not
proceed with temperature ranging from -78 to 0 °C, even after a
longer reaction time. A clean reaction took place in the presence
of 2,2-dimethyloxirane with the addition of BF3 Et2O at -
3
78 °C21 to give the corresponding product 4g in fairly good yield
(Table 1).
The best conversions (>65%) have been achieved for the most
reactive and monofunctional electrophiles such as alkyl halides,
aldehydes, and ketones. The lowest yields (40-50%) are typical
for the reaction with esters and acyl halides, where 2-naphthol
(5) has always been recovered as byproduct.
Table 1. Reactivity of 6-Bromo-2-naphthol (3) in the Pre-
sence of the Listed Electrophiles (E)
6,60-Dibromobinol (6) is a much more interesting reactant
than 3 because it is widely used as a precursor in the synthesis of
both 6,60-disubstituted chiral ligands19,20 and helicates with
different cavity sizes and chemical properties.1,2 These important
applications prompted us to explore the bisfunctionalization of
the binol at the C-6 and C-60 by direct lithiation. The application
of our protecting group free protocol can reduce the reaction step
number from four to two. In fact, it has already been shown that
the compound 219 can be prepared in fairly good yield through a
four-step synthesis, including protection/deprotection of both
the binol hydroxyl moieties.22 The reactivity of 6 in the presence
of electrophiles has been investigated for the synthesis of 6,60-
bisfunctionalized binols as described in Table 2. Therefore, the
very same protocol optimized for the functionalization of 3 was
applied. The synthetic protocol was tested in the presence of
several electrophiles, such as iodomethane, benzophenone,
methylbenzoate, dimethylcarbonate, ethyl 2-chloro-2-oxoace-
tate, and 2,2-dimethyloxirane.
As described above, compound 6 was dissolved in anhydrous
THF and the solution purged with argon and cooled to -78 °C.
To the vigorously stirred solution was added n-BuLi in hexane. A
high excess of n-BuLi was required for the reaction. The higher
reaction yields were achieved using a 6/n-BuLi = 1:8 molar ratio.
The color change of the reaction is very helpful, clearly indicating
the end of the lithiation process. In fact, at the beginning, the
solution became bright yellow and the lithium phenolate pre-
cipitated. The bis-lithiation at both the positions 6 and 60
increased the solubility in THF, and after 5.5-6 h at -78 °C,
a clear brownish-orange solution was obtained. The electrophile
was added in the same way as described for compound 3, with the
molar ratio 6/electrophiles = 1:8.8. After stirring at -50 °C, the
solution was warmed to 0°C, and the products were recovered
after workup in HCl/ice.
The reaction has been optimized with different electrophiles
in order to improve the reaction yields of the bifunctional
products (Table 2). The 6,60-bis-substituted binols (7a, 7c-e,
and 7g) obtained from this synthetic procedure are listed in
Table 2. The reaction carried out in presence of ethyl 2-chloro-2-
oxoacetate gave a complex reaction mixture, and no further
isolation of the resulting products was performed.
Reaction conditions: 1 mmol of 3 reacts with 4.4 mmol of n-
BuLi and 5 mmol of electrophile. After adding the electrophile,
the temperature was kept under -50 °C and stirred for different
times: a 45 min; b 1.5 h; c 2 h. d The reaction was carried out in
presence of BF3 2Et2O (7.5 mmol, for 5 mmol electrophile),
3
which was added after the electrophile and stirred for 2 h.
4a in a good yield (Table 1). A very similar procedure was
followed for compounds 4b and 4c, shortening the reaction time,
in the presence of the electrophile, to 1.5 h. The naphthols 4d-f
were synthesized following a slightly different procedure, as the
resulting compounds could react further with a second equiva-
lent of the lithiated naphthol. For this reason, the lithiated species
was added to a solution of the electrophile in THF at -78 °C and
stirred for 1.5 h below -40 °C. 4d-f were obtained after
As displayed in Table 2, the higher yields were obtained for the
monofunctional electrophiles. Lower yields were achieved for
methyl benzoate and dimethyl carbonate, from which binol 8 was
formed in a sizable amount (∼25% yields) as byproduct. Longer
reaction time (2 h) and higher temperatures (-40 °C) were
required.
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NOTE
Table 2. Reactivity of 6,60-Dibromobinol (6) in the Presence
of the Listed Electrophiles (E)
Table 3. Reaction Yields and Temperature, Together with
Retention Times and Enantiomeric Excess (ee), Measured by
Chiral HPLCa
adduct
yield (%)
T (°C)
tr (min)
ee %
(S)-7a
(S)-7c
(R)-7e
84
67
32
-50
-50
-40
9.7
10.9
17.4
99.7b
97.0c
88.4c
a Concentration of 6 = 1 ꢀ 10-3 M in IPA (isopropyl alcohol).
b CHIRALCEL OD-H column: n-heptane/IPA 90:10. c Kromasil
KR100-5CHI-DMB column: n-heptane/IPA 80:20.
above -50 °C but was not significantly affected by the reac-
tion time. Indeed, the slight reduction of the reaction ee using
reactive electrophiles affording products such as (S)-7c has to
be mainly ascribed to the bromination reaction of the chiral
binol rather than to the lithiation step (Supporting Information
Figure S1).
In conclusion, we have described the alkylation and acylation
of 6-bromo-2-naphthol and 6,60-dibromobinol, through the
generation of mono- and bis-lithiated intermediates and further
“one-pot” functionalization following a protecting group free
protocol. The above offers a straightforward and general strategy
for the synthesis of 6,60-disubstituted binols as chiral DNA cross-
linking agents since it has been shown that chirality of the binol
moiety is preserved.
’ EXPERIMENTAL SECTION
Reaction conditions: 1 mmol of 6 reacts with 8 mmol of n-
BuLi and 8.8 mmol of electrophile. After adding the electrophile,
the temperature was kept under -50 °C and stirred for different
323 and 624 have been synthesized via standard published procedures.
The substituted naphthols, 4a,25 4c,26 and 4e,27 together with the binol
7a28 are known products.
a
times: 45 min; b 1.5 h; c 2 h. d The reaction was carried out in the
6-(Hydroxy(3-methoxyphenyl)methyl)naphthalen-2-ol
(4b). 3 (0.200 g, 9.06 ꢀ 10-4 mol) was dissolved in 10.8 mL of dry THF
under argon. The stirred solution was cooled to -78 °C, and 2.50 mL of
n-BuLi in n-hexane (1.6 M) (3.98 ꢀ 10-3 mol) was added at such a rate
to keep the temperature at -70 °C. Temperature was measured using an
internal probe in the reaction flask. After 5 h, 3-methoxybenzaldehyde
(0.617 g, 0.552 mL, 4.53 ꢀ 10-3 mol) was added, keeping the
temperature below -50 °C. The solution was stirred at -50 °C for
1.5 h. The reaction mixture was poured into HCl/ice under vigorous
stirring and allowed to reach room temperature overnight. The reaction
mixture was extracted three times with CH2Cl2, and the combined
organic phases were washed twice with water and dried over MgSO4.
The solvent was removed under reduced pressure, and the crude was
purified by column chromatography cyclohexane/ethyl acetate = 7/3 to
give 0.170 g of 4b (67%, yield): white solid, mp 168-169 °C; 1H NMR
(DMSO) δ 3.72 (s, 3H), 5.76 (d, J = 3.8 Hz, 1H), 5.91 (d, J = 3.8 Hz,
1H), 6.77 (dd, J = 8.1, 1.6 Hz, 1H), 6.96 (d, J = 7.7 Hz, 1H), 7.00 (d, J =
1.1 Hz, 1H), 7.05-7.07 (m, 1H), 7.18-7.23 (m, 1H), 7.35 (d, J = 8.6
Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.77 (s, 1H);
13C NMR (DMSO) δ 21.4, 109.3, 117.6, 126.1, 126.4, 126.6, 128.7,
129.0, 132.6, 133.0, 152.6. Anal. Calcd for C18H16O3: C, 77.12; H, 5.75;
O, 17.12. Found: C, 77.09; H, 5.77.
presence of BF3 2Et2O (13.2 mmol, for 8.8 mmol electrophile)
3e
stirring for 2 h. The reaction was carried out on enantiopure
binol 6 and the preservation of the chirality evaluated by HPLC
chromatography, using a chiral column.
The reactivity pattern appeared to be fairly similar to that of
6-bromo-2-naphthol (3). The main difference was the formation
of sloppy reaction mixtures with polyfunctional electrophiles
such as 2-chloro-2-oxoacetate.
To evaluate the potential application of our functionaliza-
tion protocol for synthetic purposes, we had to clarify if the
chirality of the binol moiety was preserved in the lithiation
process. Therefore, we decided to investigate the lithiation
of both (S)- and (R)-6 following the same procedure des-
cribed above. The subsequent alkylation/acylation of the
resulting lithiated binol by iodomethane, benzophenone,
and dimethylcarbonate afforded the chiral adducts (S)-7a,
(S)-7c, and (R)-7e, respectively, with retention of the binol
moiety configuration (Table 3). The structural and config-
uration assignment of (S)-7a, (S)-7c, and (R)-7e has been
achieved by chiral HPLC chromatography, comparing the
retention time of the resulting chiral products to those of
the racemic adducts arising from the same reaction carried
out on the racemic reactant 6 (Supporting Information
Figures S2-S4).
6-(2-Hydroxy-2-methylpropyl)naphthalen-2-ol (4g). 3
(0.200 g, 9.06 ꢀ 10-4 mol) was dissolved in 10.8 mL of dry THF
under argon. The solution vigorously stirred was cooled to -78 °C, and
2.50 mL of n-BuLi in n-hexane (1.6 M) (3.98 ꢀ 10-3 mol) was added,
keeping the temperature below -70 °C. After 5 h of stirring at this
temperature, 2,2-dimethyloxirane (0.327 g, 0.400 mL, 4.53 ꢀ 10-3 mol3
mol) was added, keeping the temperature at -50 °C. After stirring for 30
The enantiomeric excess of the products (ee) was affected by
the nature of the electrophile since, with the less reactive ones,
a higher reaction temperature was required. In more detail,
product ee was lowered by the rising of the reaction temperature
min, BF3 2Et2O (0.964 g, 0.839 mL, 6.80 ꢀ 10-3 mol) was added very
3
slowly to the solution. After stirring for an additional 1.5 h at this
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NOTE
temperature, the reaction mixture was poured into HCl/ice (pH < 1)
under vigorous stirring. The mixture was allowed to reach room
temperature overnight and extracted three times with CH2Cl2. The
combined organic phases were washed twice with water and dried over
MgSO4. Then, the solvent was removed under reduced pressure to give
the crude as oil, which was purified by column chromatography
(cyclohexane/ethyl acetate = 7/3) to give 0.118 g of 4g (60% yield):
white solid, mp 117-119 °C; 1H NMR (CDCl3) δ 1.31 (s, 6H), 1.58 (s,
1H), 2.93 (s, 2H), 5.50 (br s, 1H), 7.09-7.14 (m, 2H), 7.33 (d, J = 9.4
Hz, 1H), 7.61-7.64 (m, 2H), 7.70 (d, J = 8.7 Hz, 1H); 13C NMR
(CDCl3) δ 29.1, 49.5, 71.3, 109.2, 118.0, 126.1, 128.6, 129.4, 129.5,
132.6, 133.3, 153.3. Anal. Calcd for C14H16O2: C, 77.75; H, 7.46; O,
14.80. Found: C, 77.71; H, 7.50.
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(2,20-Dihydroxy-1,10-binaphthyl-6,60-diyl)bis(phenyl metha-
none) (7d). A 0.200 g sample of 6 (4.66 ꢀ 10-4 mol) was dissolved
in 5.59 mL of dry THF under argon. After cooling at -78 °C,
2.33 mL of n-BuLi in n-hexane (1.6 M) (3.73 ꢀ 10-3 mol) was added at
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into HCl/ice (pH < 1) under vigorous stirring. The solution was allowed
to reach room temperature overnight and extracted twice with CH2Cl2.
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MgSO4, and the solvent was removed under reduced pressure to give an
oily residue. The crude was purified by column chromatography
(cyclohexane/ethyl acetate = 8/2) to give 0.104 g of 7d (45% yield)
as colorless oil: 1H NMR (acetone-d6) δ 7.26 (d, J = 8.8 Hz, 2H), 7.50
(d, J = 8.9 Hz, 2H), 7.56-7.61 (m, 4H), 7.67 (d, J = 7.3 Hz, 2H), 7.74
(dd, J = 8.8, 1.7 Hz, 2H), 7.84-7.86 (m, 4H), 8.14 (d, J = 8.9 Hz, 2H),
8.37 (d, J = 1.7 Hz, 2H); 13C NMR (acetone-d6) δ 115.6, 120.9, 126.0,
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’ ASSOCIATED CONTENT
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Supporting Information. General experimental meth-
b
ods, synthetic procedure for naphthols 4a, 4c, 4d, 4e, and 4f,
and binols 7a, 7c, 7e, and 7g and compound 4a, 4c, 4d, 4e, 4f, 7a,
7c, 7e, and 7g characterization data. 1H NMR and 13C NMR for
the adducts 4a, 4b, 4c, 4d, 4e, 4f, 4g, 7a, 7c, 7d, 7e, and 7g. This
material is available free of charge via the Internet at http://pubs.
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’ AUTHOR INFORMATION
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Corresponding Author
*E-mail: danielaverga@gmail.com, mauro.freccero@unipv.it.
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’ ACKNOWLEDGMENT
We gratefully acknowledge funding from Italian Ministry of
University and Research (MIUR, Project RBID082ATK_003)
and the University of Pavia.
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