Controlling chemoselectivity in reactions of unprotected naphthalene-1-carboxylic acid with strong bases

Article abstract of DOI:10.1246/cl.2005.446

Whereas treatment of unprotected naphthalene-1-carboxylic acid with alkyllithiums (RLi) affords 1,4-addition products, the reaction with LTMP/Me₃SiCl under in situ quench conditions provides the arylsilane arising out from the substitution of l

Full text of DOI:10.1246/cl.2005.446

4
46
Chemistry Letters Vol.34, No.3 (2005)
Controlling Chemoselectivity in Reactions of Unprotected Naphthalene-1-carboxylic Acid
with Strong Bases
ꢀ
David Tilly, Anne-Sophie Castanet, and Jacques Mortier
Universit e´ du Maine and CNRS, Unit e´ de Chimie Organique Mol e´ culaire et Macromol e´ culaire (UMR 6011),
Facult e´ des Sciences, Avenue Olivier Messiaen, 72085 Le Mans Cedex 9, France
(Received January 7, 2005; CL-050036)
Whereas treatment of unprotected naphthalene-1-carboxylic
theoretical, but also of practical interest to test conditions for se-
lective lithiation in ortho- or peri-position to the carboxylate,
since the amide counterpart (CONR2) is recalcitrant to hydroly-
sis. There is also a real lack of methods for transformation of
this group to other useful functionalities.
acid with alkyllithiums (RLi) affords 1,4-addition products, the
reaction with LTMP/Me3SiCl under in situ quench conditions
provides the arylsilane arising out from the substitution of lithi-
um 2-lithionaphthalene carboxylate with Me3SiCl. With the
Lochmann–Schlosser superbase (n-BuLi/t-BuOK), metalation
occurs preferentially in the position adjacent to CO2Li although
the peri and ortho, peri-dilithiated species are also formed.
1
6,17
Acid 1 did not react upon treatment with LDA or LTMP
(2.2 equiv.) in THF followed by a D2O quench in the interval
ꢂ
ꢂ
of temperature ꢁ78 C ! 0 C [External quench (EQ)]. When
LTMP and chlorotrimethylsilane were premixed prior to the ad-
1
8
dition of 1 [in situ quench (ISQ) technique], 2-(trimethylsilyl)-
naphthalene-1-carboxylic acid (4) was isolated in 65% yield.
Naphthalenes may undergo nucleophilic attack by organo-
1
lithium compounds, though dearomatisation of a naphthalene
ring requires additional activation by an electron-withdrawing
E
CO2H
H
2
3
substituent. Naphthalenimines, naphthyloxazolines and very
bulky 2,6-di-tert-butylphenyl esters of naphthalenecarboxylic
R
4
acids all accept nucleophiles, losing aromaticity in one ring thus
2
providing valuable synthetic intermediates. The substituent
withdraws sufficient electron density to allow dearomatising nu-
cleophilic attack to take place.
We have reported that naphthalene-1-carboxylic acid (1) un-
dergoes predominantly conjugate addition with alkyllithiums
1
) RLi, −78 °C, THF
2) EX
CO2H
ꢂ
(
1
RLi) at low temperature (ꢁ78 C) in THF and leads to various
1
) LTMP
1
←
,1,2-trisubstituted-1,2-dihydronaphthalenes 2 after quenching
−78 °C 0 °C
THF (EQ)
) D2O+
LTMP (ISQ)
5
,6
with electrophiles (EX) (Scheme 1). Entry of the electrophile
proceeds exclusively from the more accessible opposite face to
that carrying the alkyl group.
2
3
) H3O
CO2H
D
CO2Li
Li
CO2H
SiMe3
Ortho- and peri-lithiations of naphthalenecarboxylic acid
7
3
Me SiCl
derivatives have received so far less attention. The best peri-
lithiation-directing groups are those which coordinate to the in-
coming organolithium but do not acidify nearby protons, thereby
disfavoring directed ortho-lithiation. Typical peri-lithiation sub-
strates are therefore naphthalenes bearing electron-rich oxygen
or nitrogen-based substituents (e.g. OMe, NMe2, or CH2NMe2).7
With the electron withdrawing tertiary amide substituent CO-
NR2—only group able to direct metalation in its adjacent posi-
tion in the naphthalene series—, the ortho-substituted product
(
0%)
4 (65%)
3
ISQ: In situ quench technique
←
1
2
) LTMP, Me3SiCl, −78 °C 0 °C, THF
) H3O+
EQ: External quench technique
Scheme 1.
Chlorotrimethylsilane is known to react slowly with bulky
7
,8
becomes kinetically and thermodynamically favored.
1
8,19
Although the CO2Li group does activate neighboring posi-
tions towards metalation, the effect remains fairly weak.9,10 This
enables regioflexibility as most other electronegative substitu-
ents outperform a competing carboxylate group by their superior
bases such as lithium diisopropylamide (LDA) and LTMP,
20
and with tert-butyllithium and n-butyllithium. Nevertheless,
ꢂ
s-BuLi and s-BuLi:TMEDA destroy Me3SiCl at ꢁ85 C in
1
1
THF. The deprotonation of 1 by LTMP which produces a small
concentration of the trappable aryllithium 3, is sufficiently rapid
to make the process competitive in rate with reaction of the hin-
dered base with Me3SiCl. Deuterium oxide destroys the excess
LTMP under EQ conditions. Although triisopropyl borate is
1
1,12
ortho-directing power.
For instance, whereas 4-fluoro ben-
zoic acid is metalated preferentially in the position adjacent to
the carboxylate by treatment with s-BuLi, s-BuLi/TMEDA or
ꢂ
t-BuLi at ꢃꢁ78 C, a complete reversal in regioselectivity is ob-
ꢂ
13
21
served with LTMP at ꢁ50 C.
known to be an effective in situ-trap in the presence of LTMP,
it did not react under the previous ISQ conditions.
With the n-butyllithium/t-BuOK mixture (LICKOR), initial
results from our laboratories were interesting though not synthet-
ically useful. After much experimental manipulation, the best
We decided to explore metalation conditions using sterically
hindered lithium amides (LDA and LTMP) and the Lochmann–
Schlosser base (n-butyllithium/t-BuOK)14,15 with the intention
of obtaining good chemo- and regiocontrol. It was not only of
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.3 (2005)
447
conditions involved forming the metalated species with LICK-
ꢂ
exchange processes through mechanism-based matching of sub-
11–13,15
OR (4 equiv.) in THF at ꢁ78 C (Scheme 2). The reaction was
stituents and reagents.
Although the yields of 2-substitut-
ꢂ
allowed to warm up to ꢁ50 C, quenched with deuterium oxide
ed naphthalene-1-carboxylic acids are modest, the present meth-
od is direct and does not require protection and deprotection of
the CO2H group. Extensions of the manipulation of carboxylic
functional group are ongoing in our laboratories and will be re-
ported upon in due course.
(
10 equiv.), and acidified at rt with 6 M HCl until pH reached 1.
The deuterated products 2D-1, 8D-1 and 2D, 8D-1 were formed
in a 43:14:9 ratio, via the intermediacy of the organometallic
species 3, 5, and 6 (M = Li or K) resulting from the metalation
of the substrate in ortho, peri, and ortho-peri positions, respec-
tively.22 The nature of the cations M involved in these species
is not known with certainty. Both the structure of bases in solu-
tion as well as the nature of the actual reactive species have been
References and Notes
1
2
3
4
5
6
7
J. A. Dixon, D. H. Fishman, and R. S. Dudinyak, Tetrahedron
Lett., 5, 613 (1964).
M. Shindo, K. Koga, and K. Tomioka, J. Org. Chem., 63, 9351
2
3
the objects of controversial discussions. To the best of our
knowledge, aromatic dianionic carboxylates of the type 6 have
never been reported so far.
(
1998).
L. F. S. V. Kolotuchin and A. I. Meyers, J. Org. Chem., 65,
018 (2000), and references cited therein.
M. Shindo, K. Koga, Y. Asano, and K. Tomioka, Tetrahedron,
5, 4955 (1999).
3
CO2M
M
D
CO2M
M
CO2M
5
M
M
1
) n-BuLi/t-BuOK (4 equiv)
+
+
B. Plunian, M. Vaultier, and J. Mortier, J. Chem. Soc., Chem.
Commun., 1998, 81.
B. Plunian, J. Mortier, M. Vaultier, and L. Toupet, J. Org.
Chem., 61, 5206 (1996).
J. Clayden, C. S. Frampton, C. McCarthy, and N. Westlund,
Tetrahedron, 55, 14161 (1999), and references cited therein.
Review: N. S. Narasimhan and R. S. Mali, Synthesis, 1983, 957.
J. Mortier, J. Moyroud, B. Bennetau, and P. A. Cain, J. Org.
Chem., 59, 4042 (1994); Review: J. Mortier and M. Vaultier,
in ‘‘Recent Research Developments in Organic Chemistry,’’
Transworld Research Network, Trivandrum (1998), Vol. 2,
p 269.
1
←
THF, 3 h, −78 °C
M = Li or K)
−50 °C
(
3
CO2H
CO2H
D
CO2H
2
) D2O (10 equiv)
50 °C
−
D
D
+
+
3
) H3O+ (rt)
8
9
2D-1
8D-1
43:14:9)
2D,8D-1
(
Scheme 2.
With these optimized conditions in hand, we proceeded to
1
1
1
0 C. G. Hartung and V. Snieckus, ‘‘Modern Arene Chemistry,’’
ed. by D. Astruc, Wiley-VCH, New York (2002), p 330.
1 F. Gohier, A.-S. Castanet, and J. Mortier, Org. Lett., 5, 1919
evaluate the scope of the process. Since the separation of the ma-
jor ortho-substituted products was readily accomplished by frac-
tional recrystallization, the reported method provides an easy ac-
cess to very simple 2-substituted naphthalene-1-carboxylic acids
(2003).
2 F. Gohier and J. Mortier, J. Org. Chem., 68, 2030 (2003).
(
Table 1).24
13 F. Gohier, A.-S. Castanet, and J. Mortier, J. Org. Chem., 70,
2005), in press.
(
Table 1. Synthesis of 2-substituted naphthalene-1-carboxylic
acids (7a–f)
1
1
4 L. Lochmann, Eur. J. Inorg. Chem., 2000, 1115.
5 F. Mongin, R. Maggi, and M. Schlosser, Chimia, 50, 650
(1996).
CO2H
CO2H
1
) n-BuLi/t-BuOK (4 equiv)
←
E
16 M. Watanabe and V. Snieckus, J. Am. Chem. Soc., 102, 1457
1980); V. Snieckus, Chem. Rev., 90, 879 (1990).
17 S. O. De Silva, J. N. Reed, R. J. Billedeau, X. Wang, D. J.
THF, −78 °C
−50°C
(
2
3
) EX
) H3O+
Norris, and V. Snieckus, Tetrahedron, 48, 4863 (1992).
1
7a-f
1
8 T. D. Krizan and J. C. Martin, J. Am. Chem. Soc., 105, 6155
1983).
19 Dimethyl sulfate and n-butyllithium are also mutually
ꢂ
Entry
EX
E
Product/%a
mp/ C
(
1
2
3
4
5
6
MeI
EtI
C2Cl6
Me
Et
Cl
Br
I
MeS
7a (48)
7b (38)
7c (29)
7d (32)
7e (30)
7f (34)
125–127
118–119
148–150
136–139
185–187
105–109
ꢂ
compatible in THF at ꢁ78 C: G. C. Nwokogu and H. Hart,
Tetrahedron Lett., 24, 5725 (1983).
0 R. Taylor, Tetrahedron Lett., 16, 435 (1975).
2
2
2
C2Br2Cl4
I2
1 S. Caron and J. M. Hawkins, J. Org. Chem., 63, 2054 (1998).
1
2 Isotope ratios were determined by H NMR and FIMS. The
error is taken to be ꢄ5%.
Me2S2
aIsolated (recrystallized) yields.
2
2
3 W. Bauer and L. Lochmann, J. Am. Chem. Soc., 114, 7482
(1992).
4 General procedure: To a stirred solution of naphthalene-1-
carboxylic acid (1) (300 mg, 1.74 mmol) in anhydrous THF
Reaction with iodomethane and iodoethane gave the antici-
pated products (Entries 1 and 2). Quenching with such electro-
philes as hexachloroethane, 1,2-dibromotetrachloroethane, and
iodine provided the ortho-halogenated benzoic acids 7c–e (En-
tries 3–5). Addition of dimethyl disulfide afforded the methylsul-
fenylated derivative 7f (Entry 6). In each entry, the ortho, peri,
and ortho-peri product distribution was similar to that observed
with D2O (Scheme 2).
ꢂ
ꢂ
(
15 mL) at ꢁ78 C, was added the precooled (ꢁ78 C) THF so-
lution (10 mL) of the LiCKOR base (6.96 mmol, 4 equiv.). The
ꢂ
reaction mixture was allowed to warm up to ꢁ50 C and stirred
at this temperature for 3 h. The electrophile (6–10 equiv.) in
THF (8 mL) was then added. The reaction mixture was allowed
to warm to room temperature over a period of 2 h. Acidification
and standard workup led to a residue which was purified by
chromatography on silicagel using cyclohexane/ethyl acetate
(90:10) followed by recrystallization (heptane/ethyl acetate).
The results reported in this letter corroborate the recent con-
cept of how to achieve chemo or regiocontrol in hydrogen/metal
Published on the web (Advance View) February 23, 2005; DOI 10.1246/cl.2005.446