Directed lithiation of unprotected quinolinecarboxylic acids

Article abstract of DOI:10.1016/S0040-4039(01)02265-1

The lithium salts of quinoline-2-carboxylic acid and 4-methoxyquinoline-2-carboxylic acid undergo deprotonation at C3 when treated with LTMP in THF at -25 and 0°C, respectively. The lithium salts of quinoline-3- and -4-carboxylic acids are more prone to n

Full text of DOI:10.1016/S0040-4039(01)02265-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 767–769
Directed lithiation of unprotected quinolinecarboxylic acids
Anne-Sophie Rebstock, Florence Mongin, Franc¸ois Tre´court and Guy Que´guiner*
Laboratoire de Chimie Organique Fine et He´te´rocyclique, UMR 6014, IRCOF, Place E. Blondel, BP 08,
76131 Mont-Saint-Aignan Ce´dex, France
Received 25 July 2001; accepted 28 November 2001
Abstract—The lithium salts of quinoline-2-carboxylic acid and 4-methoxyquinoline-2-carboxylic acid undergo deprotonation at C3
when treated with LTMP in THF at −25 and 0°C, respectively. The lithium salts of quinoline-3- and -4-carboxylic acids are more
prone to nucleophilic addition; nevertheless, they are deprotonated at C4 and C3, respectively, when treated with LTMP in THF
at −50°C. © 2002 Elsevier Science Ltd. All rights reserved.
Lithiation is an important method for the preparation
of polyfunctional azines (pyridines, quinolines…) since
lithiated derivatives display a high reactivity toward
many electrophilic functions.1 From all the directing
groups, carboxylic acid-derived functions, such as 2-
oxazolino and amide groups, stand out as being partic-
ularly useful for subsequent elaborations.2 Moreover,
deprotonation using ester and amide directing groups
with Hauser bases or magnesium diamides was investi-
gated.3 The protection and deprotection steps required
in these methodologies could be avoided if free car-
boxylic acids could be metalated.
reported; only one example concerns the deprotonation
of a quinoline containing a carboxylic acid-derived
function, N,N-diethylquinoline-4-carboxamide.11
Consequently, we started a study of the metalation of
the lithium salts of commercially available quinoline-
carboxylic acids.
Preliminary experiments showed that BuLi was not
suitable to generate the lithium salts of quinolinecar-
boxylic acids, as used in the case of pyridinecarboxylic
acids.10 Due to its lower LUMO level, quinoline is
more prone to nucleophilic attack and addition of BuLi
to the quinoline ring was concurrently observed. So, we
The lithiation of p-excessive heteroaromatic systems
containing the lithium carboxylate group was studied in
the isothiazole,4 thiophene,5 benzo[b]furan,6 furan,5c,7
and oxazole8 series. Ortho-metalation directed by the
carboxylate group was fully investigated in the benzene
series by Mortier and Bennetau.9 Concerning p-
deficient heteroaromatic systems, our group recently
found conditions for deprotonation of all isomeric
lithium pyridinecarboxylates, avoiding protection and
difficult deprotection steps.10 Compared to lithium 2-
lithiobenzoate, the aza-analogues show good stability
and can be prepared at a higher temperature; extension
of this method to other azinic carboxylic acids seems
thus far accessible.
turned
to
lithium
2,2,6,6-tetramethylpiperidide
(LTMP).
Deprotonation conditions of the lithium salts thus
obtained were found to be identical to those already
described for pyridinecarboxylic acids (LTMP in
THF).10
The metalation of quinaldic acid (1) was achieved with
2 equiv. of LTMP in THF at −25°C, after in situ
formation of the lithium salt with 1 equiv. of LTMP.
Trapping the dilithio derivative with D2O and dry ice
afforded deuterated quinaldic acid 2a12 and quinoline-
2,3-dicarboxylic acid (2b)13 in medium to good yields.
The use of benzaldehyde as an electrophile also allowed
the synthesis of lactone 2c14 after cyclization under
acidic conditions (Scheme 1).
A survey of the literature reveals that metalation of
unprotected quinolinecarboxylic acids has never been
Keywords: lithiation; quinolines; carboxylic acids; neighbouring
group effects.
From 4-methoxyquinaldic acid (3), deprotonation
could be performed at 0°C owing to the substituents
present at both C2 and C4. Quenching the reaction
* Corresponding author. Fax: +33 (0)
2 35 52 29 62; e-mail:
guy.queguiner@insa-rouen.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02265-1

768
A.-S. Rebstock et al. / Tetrahedron Letters 43 (2002) 767–769
1) 3 eq. LTMP
E
THF, -25 °C, 30 min.
OH
OH
2) Electrophile
3) H+
N
N
1
O
O
2a: E= D, 57% (100% D)
2b: E= COOH, 75%.
1) 3 eq. LTMP
THF, -25 °C, 30 min.
2) PhCHO
(48%)
3) CH3CO2H, EtOH
reflux
Ph
O
N
O
2c
Scheme 1.
Remark that deprotonation occurred at C4 as previ-
ously observed from nicotinic acid.10
mixture with D2O, dry ice and iodine gave, after subse-
quent acidification, deuterated 4-methoxyquinaldic acid
4a,15 4-methoxyquinoline-2,3-dicarboxylic acid (4b)16
and 3-iodo-4-methoxyquinoline-2-carboxylic acid (4c)17
(Scheme 2).
Concerning the lithium salt of quinoline-4-carboxylic
acid (7), no lithiation was observed using less than 5
equiv. of LTMP at −50°C. A large excess of metalating
agent was required; when 6 equiv. of LTMP were used,
the 3-lithio derivative formed reacted with D2O to
afford compound 821 in a low yield of 35% (Scheme 4).
1
Note that the H NMR spectra obtained after evapora-
tion of the reaction mixtures showed lithium carboxy-
lates of 2a–b and 4b–c as the only quinolinic
compounds; yields mainly depend on the isolation of
the quinolinecarboxylic acids.
The dihedral angle between the hydrogen at C3 and the
carbonyl oxygen could be responsible for the decreased
efficiency of the directing power of the lithium
carboxylate.22
From quinoline-3-carboxylic acid (5), attempts to
obtain deprotonation as the exclusive reaction failed
when LTMP was used at 0 or −25°C,18 due to the easy
addition at C2 and C4 of the 4-lithio derivative to the
lithium salt of compound 5. Nevertheless, this side
reaction could be avoided by working at a lower tem-
perature (−50°C) and the syntheses of compounds 6a19
and 6b,20 in, respectively 59 and 80% yield, were
allowed (Scheme 3).
Note that a lack of reactivity was also observed by
Kelly during the metalation of N,N-diethylquinoline-4-
carboxamide.11
Metalation; typical procedure: BuLi (24 mL of a 2.5 M
solution in hexane, 60 mmol) and, 5 min later,
quinaldic acid (3.5 g, 20 mmol) were added to a solu-
O
O
1) 3 eq. LTMP
THF, 0 °C, 30 min.
E
OH
OH
2) Electrophile
3) H+
N
N
3
O
O
4a: E= D, 70% (85% D)
4b: E= COOH, 60%
4c: E= I, 45%.
Scheme 2.
O
E
N
O
1) 3 eq. LTMP
THF, -50 °C, 30 min.
OH
OH
2) Electrophile
3) H+
N
5
6a: E= D, 74% (80% D)
6b: E= COOH, 80%
Scheme 3.

A.-S. Rebstock et al. / Tetrahedron Letters 43 (2002) 767–769
769
Li
O
O
O
O
OH
OH
H
1) 6 eq. LTMP
THF, -50 °C, 30 min.
D
2) D2O
3) H+
N
N
N
7
8
(50%, 65% D)
Scheme 4.
tion of 2,2,6,6-tetramethylpiperidine (10 mL, 60 mmol)
in THF (100 mL) at −25°C. The mixture was stirred at
this temperature for 30 min and poured onto an excess
of freshly crushed dry ice. After concentration under
reduced pressure, the residue was washed with a cyclo-
hexane/ether (30/70) mixture (500 mL) and dried. It
was then treated with 2.5 M hydrochloric acid until pH
4, washed with dichloromethane (3×50 mL), acidified to
pH 2–3 and stirred for 3 days. Filtration and drying of
the precipitate afforded compound 2b (75% yield).
8. Meyers, A. I.; Lawson, J. P. Tetrahedron Lett. 1981, 22,
3163–3166.
9. (a) Mortier, J.; Moyroud, J.; Bennetau, B.; Cain, P. A. J.
Org. Chem. 1994, 59, 4042–4044; (b) Bennetau, B.; Mor-
tier, J.; Moyroud, J.; Guesnet, J.-L. J. Chem. Soc., Perkin
Trans. 1 1995, 1265–1271; (c) Moyroud, J.; Guesnet,
J.-L.; Bennetau, B.; Mortier, J. Tetrahedron Lett. 1995,
36, 881–884; (d) Moyroud, J.; Guesnet, J.-L.; Bennetau,
B.; Mortier, J. Bull. Soc. Chim. Fr. 1996, 133, 133–141.
10. Mongin, F.; Tre´court, F.; Que´guiner, G. Tetrahedron
Lett. 1999, 40, 5483–5486.
11. Kelly, T. R.; Zhao, Y.; Cavero, M.; Torneiro, M. Org.
Lett. 2000, 2, 3735–3737.
12. Compound 2a 1H NMR (DMSO-d6): 8.54 (s, 1H), 8.17
(d, 1H, J=8.7), 8.08 (d, 1H, J=8.7), 7.86 (t, 1H, J=7.5),
7.77 (t, 1H, J=7.5).
13. Compound 2b mp 270–272°C. Godard, A.; Que´guiner,
G.; Pastour, P. Bull. Soc. Chim. Fr. 1971, 906–912, mp
274°C.
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1
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