Synthesis and metallation of 2-(pyridyl)benzoic acids and ethyl 2-(pyridyl)benzoates: A new route to azafluorenones

Article abstract of DOI:10.1016/S0040-4020(03)00761-0

The ring deprotonation of 2-(2- and 4-pyridyl)benzoic acids using lithium dialkylamides in THF at rt, and the in situ cyclization afforded 4- and 2-azafluorenones, respectively. 1-Azafluorenone was obtained from ethyl 2-(3-pyridyl)benzoate using a similar protocol.

Full text of DOI:10.1016/S0040-4020(03)00761-0

Tetrahedron 59 (2003) 4973–4977
Synthesis and metallation of 2-(pyridyl)benzoic acids and ethyl
2-(pyridyl)benzoates: a new route to azafluorenones
*
Anne-Sophie Rebstock, Florence Mongin, Franc¸ois Trecourt and Guy Queguiner
´
´
´ ´
Laboratoire de Chimie Organique Fine et Heterocyclique, UMR 6014, IRCOF, Place E. Blondel, BP 08,
´
76131 Mont-Saint-Aignan Cedex, France
Received 9 April 2003; revised 7 May 2003; accepted 8 May 2003
Abstract—The ring deprotonation of 2-(2- and 4-pyridyl)benzoic acids using lithium dialkylamides in THF at rt, and the in situ cyclization
afforded 4- and 2-azafluorenones, respectively. 1-Azafluorenone was obtained from ethyl 2-(3-pyridyl)benzoate using a similar
protocol. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
The behavior of the corresponding ethyl esters was also
investigated.
The directed ortho-metallation plays an important role in
the modern organic synthesis.1 Despite the maturity gained
by the method since long, the way a substituent acts in its
vicinity is not completely understood.
2. Results and discussion
For this purpose, all the 2-(pyridyl)benzoic acids (2a and c)
were synthesized.
A heteroatom-containing unit (known as the directed
metallation group, DMG) coordinates the base and, by
amplifying this interaction at the transition state, lowers the
energy of activation for the deprotonation process; it also
stabilizes the ‘metallated’ derivative. However, while an
electron-donating substituent only facilitates the deprotona-
tion at nearby sites (not necessarily at the ortho position)
through coordination to the Lewis acidic metal, an electron-
withdrawing substituent too acidifies the ring hydrogens in
its environment (mostly at the ortho position).2
First, the (2-methylphenyl)pyridines 1a–c were easily
prepared by cross-coupling reactions between 2-methyl-
phenylmagnesium chloride and the required chloro-
pyridines under nickel catalysis.7 Next, oxidation of the
compounds 1a and b was performed using a published
procedure,8 to furnish the corresponding benzoic acids 2a
and b (Scheme 1, Table 1).
From all the directing groups, the carboxylic acid and
derived functions stand out as particularly useful for
subsequent elaborations. In the p-deficient aza-aromatic
series, lithium pyridinecarboxylates, pyridineoxazolines
and pyridinecarboxamides have been deprotonated at ring
positions adjacent to the DMG.3 Moreover, studies concern
the deprotonation of a pyridine ring followed by in situ
condensation with remote N,N-dialkylcarboxamide
groups2d,4 or ester function.5
Because of our interest in the lithiation of unprotected
azinecarboxylic acids,6 we decided to synthesize
2-(pyridyl)benzoic acids and to study their metallation.
Keywords: metallation; pyridines; carboxylic acids; esters.
*
Corresponding author. Tel.: þ33-2-35-52-24-82; fax: þ33-2-35-52-29-
62; e-mail: florence.mongin@insa-rouen.fr
Scheme 1.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00761-0

4974
A.-S. Rebstock et al. / Tetrahedron 59 (2003) 4973–4977
Table 1. Synthesis of the 2-(pyridyl)benzoic acids 2a and b
Entry
Chloropyridine
Product, yield (%)a
1a, 88
2a, 65
1
2
1b, 92
2b, 56
3
1c, 50
a
Isolated yields based on the starting chloropyridine.
To obtain acid 2c, another two steps synthesis was
preferred: cross-coupling reaction between 3-pyridyl-
boronic acid9 and ethyl 2-iodobenzoate under Suzuki’s
conditions10 allowed the ester 3a to be obtained, the latter
was then hydrolyzed to give compound 2c (Scheme 2).
Scheme 3.
Interestingly, when exposed to LDA in tetrahydrofuran
(THF) at rt, the acid 2a was deprotonated and the lithio
derivative at the remote pyridine position was converted in
situ to 4-azafluorenone (4). For the acid 2b, the use of
lithium 2,2,6,6-tetramethylpiperidide (LTMP, pKa 37.3
against 35.7 for LDA) and a longer reaction time led to
2-azafluorenone (5) in 67% yield (Scheme 4).
The two other ethyl 2-(pyridyl)benzoates 3a and b were
prepared. Cross-coupling reaction was led from 2-bromo-
pyridine and ethyl 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-
yl)benzoate, as described11 by Vedsø and co-workers for the
syntheses of substituted biphenyls, to give the ester 3a.
Esterification of the carboxylic acid 2b furnished the ester
3b (Scheme 3).
On the other hand, the acid 2c either remained unchanged or
underwent degradation reactions on exposure to the lithium
dialkylamides, depending on the conditions used. This
observation could be interpreted by comparing the
stabilities of the pyridyllithiums formed. The 3-pyridyl-
lithiums obtained from 2a and b react with the carboxylate
group at rt. A more stable 4-pyridyllithium,3 which could
result either from a direct lithiation of 2c at C4, or an
isomerization of a 2-pyridyllithium initially formed, could
be inert towards the function under the conditions used.15
First examples of metallation and subsequent intramolecular
condensation with a remote metal carboxylate unit were
reported by Snieckus0 and co-workers in the triphenyl-
phosphine oxide,12 1,1 -oxybis[benzene]4 and 1,10-sulfonyl-
bis[benzene]4 series using lithium diisopropylamide (LDA).
Studies of Mortier and co-workers showed more recently
that the Schlosser–Lochmann base LICKOR,13 when used
in benzene at 608C, allowed [1,10-biphenyl]-2-carboxylic
acid to be deprotonated, the intermediate at C20 instan-
taneously cyclizing to fluorenone.14 Since the alkyllithiums
are renowned for undergoing a facile nucleophilic addition
to the CvN bond of the azines (low LUMO energy
values),3 we turned to the lithium dialkylamides, which
usually leads to preferential protophilic attack,3 to conduct
experiments on the 2-(pyridyl)benzoic acids 2a–c.
Metallation of pyridine rings with a remote methyl ester
function, followed by condensation to azaanthraquinones,
was reported by Epsztajn and co-workers using LDA.5
Nevertheless, a survey of the literature revealed that LTMP
was capable of deprotonate ethyl benzoate at the ortho
position while LDA was found to react with the function.11
We thus decided to examine the behavior of the ethyl
2-(pyridyl)benzoates 3a–c, carrying out the reaction with
LTMP.
Scheme 2.
Scheme 4.

A.-S. Rebstock et al. / Tetrahedron 59 (2003) 4973–4977
4975
lower than 45 ppm by the modified Karl Fischer method.16
Reactions were carried out under dry N2. Silica gel
(Geduran Si 60, 0.063–0.200 mm) was purchased from
Merck. 2-Methylphenylmagnesium chloride (1.0 M) in
THF, iPrMgCl (2.0 M) in THF, and BuLi (2.5 M) in hexane
were purchased from Aldrich. Ethyl 2-iodobenzoate was
supplied by Lancaster, Ni(acac)2 by Acros, and dppp by
Lancaster. Pd(PPh3)4,17 ethyl 2-(5,5-dimethyl-1,3,2-dioxa-
borinan-2-yl)benzoate,11 and 3-pyridylboronic acid9 were
prepared according to published procedures. Petrol refers to
petroleum ether (bp 40–608C).
Scheme 5.
The ester 3c could be easily deprotonated at C20 using
LTMP in THF at 08C, and converted in situ to
1-azafluorenone (6) (Scheme 5).
The kinetic lithio derivative formed at C20 (chelation of the
lithium atom of the base by both the ester function and the
ring nitrogen) is intercepted through cyclization before
isomerization to a more stable lithio derivative at C40 (no
more electronic repulsion between the carbanion and the
lone pair of the azine nitrogen).3
Unless otherwise noted, the aqueous solution was extracted
several times with CH2Cl2 after the reaction. The organic
layer was dried over MgSO4, the solvents were evaporated
under reduced pressure, and the crude compound was
chromatographed on a silica gel column (eluent is given in
the product description).
4.2. General procedure 1: preparation of 2-, 3- and 4-(2-
methylphenyl)pyridines (1a–c)
Unlike the ester 3c, when the isomers 3a and b were
involved in a reaction using the same base, they either
remained unchanged or underwent degradation reactions at
higher temperatures. The difficulty of the ester function to
compete with the pyridine nitrogen in chelating the lithium
atom of the base could be responsible for the result
observed.
Ni(acac)2 (13 mg, 50 mmol), dppp (21 mg, 50 mmol) and,
10 min later, the halo derivative (1.0 mmol) were added to
THF (3 mL). 2-Methylphenylmagnesium chloride
(1.2 mmol) was added dropwise at rt. After stirring for
18 h at rt, the mixture was quenched with an aqueous
saturated NH4Cl solution (5 mL).
3. Conclusion
4.2.1. 2-(2-Methylphenyl)pyridine (1a). The general
procedure 1, starting from 2-chloropyridine (95 mL), gave
1a (eluent: CH2Cl2) as a pale yellow oil. Yield: 88%. The
spectral data are in accordance with those described.18
We have described syntheses of 1-, 2- and 4-azafluorenones,
using as the key step the tandem metallation—in situ
cyclization of ethyl 2-(3-pyridyl)benzoate, 2-(4-pyridyl)-
benzoic acid and 2-(2-pyridyl)benzoic acid, respectively.
4.2.2. 4-(2-Methylphenyl)pyridine (1b). The general
procedure 1, starting from 4-chloropyridinium chloride
(0.15 g), and using 2-methylphenylmagnesium chloride
(2.4 mmol), gave 1b (eluent: CH2Cl2) as a colorless oil.
Yield: 92%. The 1H NMR data are in accordance with those
of the literature;19 13C NMR (CDCl3) d 20.6 (Me), 124.6
Whereas the ethyl ester function seems to behave mostly as
an in situ trap, the lithium carboxylate could both chelate the
Lewis acidic metal of the base and stabilize the lithio
derivative formed.
0
(C3,5), 126.5 (C4 ), 128.8 (C6 ), 129.6 (C5 ), 131.0 (C3 ),
0
0
0
The azafluorenones are common skeletons in natural
products and molecules of pharmacological interest. We
provide a regiospecific method for building these structures
under mild anionic conditions thus superceding classical
methods requiring harsh conditions that are of limited
scope.
0
0
135.4 (C1 ), 139.5 (C2 ), 150.0 (C2,6), 150.2 (C4); IR (KBr) n
3401, 3063, 3023, 1595, 1542, 1480, 1409, 830, 762, 747,
726, 618 cm21; mass (CI): m/z 170 (100%, MþHþ).
4.2.3. 3-(2-Methylphenyl)pyridine (1c).20 The general
procedure 1, starting from 3-chloropyridine (95 mL), gave
1c (eluent: petrol/AcOEt 95:5) as a colorless oil. Yield:
50%. The spectral data are in accordance with those
described;19,20 IR (KBr) n 3369, 3021, 2953, 2924, 1588,
4. Experimental
4.1. General
1562 cm21
.
4.3. Preparation of 2-(2-, 3- and 4-pyridyl)benzoic acids
(2a–c)
Melting points were measured on a Kofler apparatus. NMR
spectra were recorded in CDCl3 or DMSO-d6 with a Bruker
AM 300 spectrometer (1H at 300 MHz and 13C at 75 MHz).
Mass spectra were recorded with a Jeol JMS-AX500
spectrometer, and the molecular peak is given. IR spectra
were taken on a Perkin–Elmer FT IR 205 spectrometer, and
main IR absorptions are given in cm21. Elemental analyses
were performed on a Carlo Erba 1106 apparatus.
4.3.1. 2-(2-Pyridyl)benzoic acid (2a). The title compound
was prepared according to a described procedure.8 Yield:
65%; mp 200–2028C (lit.8 2028C). The 1H NMR data are in
accordance with those of the literature;8 13C NMR (DMSO-
0
0
d6) d 122.6 (C3 ), 123.1 (C5 ), 128.6 (C4), 129.3 (C5), 130.1
0
(C3), 130.9 (C6), 133.5 (C1), 136.9 (C4 ), 140.3 (C2), 149.1
0
0
(C6 ), 158.3 (C2 ), 170.1 (CO); IR (KBr) n 3085, 2772, 2452,
1689, 1599, 1564 cm21
Starting materials. THF was distilled from benzophenone/
Na. The water content of the solvents was estimated to be
.

4976
A.-S. Rebstock et al. / Tetrahedron 59 (2003) 4973–4977
4.3.2. 2-(4-Pyridyl)benzoic acid (2b).21 A mixture of 1b
(1.7 g, 10 mmol) and water (20 mL) was heated under reflux
with KMnO4 (1.8 g, 11 mmol). After removal of the
coloration, and addition of KMnO4 (1.5 g, 9.5 mmol) and
water (10 mL), reflux was pursued similarly. After filtration
over celitew, the aqueous phase was washed with Et2O and
then acidified to pH 5 using a 3 M aqueous solution of
hydrochloric acid. Compound 2b was recovered by filtration
and drying under vacuum. Yield: 56%; mp 1808C; 1H NMR
reflux for 2 h. After removal of the excess of SOCl2, EtOH
(40 mL) was introduced dropwise at 08C. After 12 h at rt,
EtOH was evaporated and water (10 mL) was added. Yield
(eluent: CH2Cl2/Et2O 80:20): 92%; mp 678C; 1H NMR
(CDCl3) d 0.97 (t, 3H, J¼7.1 Hz, Me), 4.05 (q, 2H,
0
0
J¼7.1 Hz, CH2), 7.18 (d, 2H, J¼5.7 Hz, H3 ,5 ), 7.25 (dd,
1H, J¼7.6, 1.5 Hz, H3), 7.42 (td, 1H, J¼7.5, 1.1 Hz, H4),
7.48 (td, 1H, J¼7.5, 1.5 Hz, H5), 7.86 (dd, 1H, J¼7.5,
1.1 Hz, H6), 8.56 (d, 2H, J¼5.7 Hz, H2 ,6 ); 13C NMR
(CDCl3) d 12.6 (Me), 60.1 (CH2), 122.5 (C5), 127.3 (C3),
0
0
0
0
(DMSO-d6) d 7.40 (d, 2H, J¼6.0 Hz, H3 ,5 ), 7.47 (d, 1H,
J¼7.5 Hz, H3), 7.61 (t, 1H, J¼7.5 Hz, H5), 7.70 (t, 1H,
J¼7.5 Hz, H4), 7.90 (d, 1H, J¼7.5 Hz, H6), 8.64 (d, 2H,
0
129.2 (C4), 129.3 (C3 ,5 ), 129.6 (C2), 130.6 (C6), 138.9 (C1),
0
0
0
0
148.3 (C2 ,6 ), 148.6 (C4 ), 166.7 (CO); IR (KBr) n 3035,
2977, 2903, 1702, 1598, 1300, 1138, 834, 766, 710 cm21
J¼6.0 Hz, H2 ,6 ); 13C NMR (DMSO-d6) d 123.8 (C3 ,5 ),
.
0
0
0
0
128.8 (C5), 130.0 (C2), 130.7 (C3), 131.8 (C4), 131.9 (C1),
Anal. calcd for C14H13NO2 (227.27): C, 73.99; H, 5.77; N,
6.16. Found: C, 73.72; H, 5.62; N, 6.02%.
0
0
0
139.3 (C6), 149.1 (C4 ), 149.5 (C2 ,6 ), 169.1 (CO); IR (KBr)
n 3075, 3050, 2373, 1945, 1686, 1612, 1478, 1413, 1273,
1009, 842, 765, 625 cm21. Anal. calcd for C12H9NO2
(199.21): C, 72.35; H, 4.55; N, 7.03. Found: C, 72.11; H,
4.44; N, 6.93%.
4.4.3. Ethyl 2-(3-pyridyl)benzoate (3c). A degassed
mixture of ethyl 2-iodobenzoate (0.28 g, 1.0 mmol),
Pd(PPh3)4 (58 mg, 50 mmol), dimethoxyethane (8 mL),
3-pyridylboronic acid (0.13 g, 1.1 mmol), NaHCO3
(0.25 g, 3.0 mmol), and water (4 mL) was heated under
reflux for 2 days. The solvents were removed under reduced
pressure and water (10 mL) was added. Yield (eluent:
CH2Cl2/Et2O 95:5): 58%; pale yellow oil. The spectral data
are in accordance with those described;23 13C NMR
4.3.3. 2-(3-Pyridyl)benzoic acid (2c). A mixture of 3c
(0.91 g, 4.0 mmol) and NaOH (0.32 g, 8.0 mmol) in EtOH
was heated under reflux for 18 h. After removal of the
solvent, the residue was dissolved in water (10 mL) and the
pH was adjusted to 6. The precipitate thus obtained was
recovered by filtration and dried under vacuum to give 2c.
Yield: 50%; mp 1808C; 1H NMR (DMSO-d6) d 7.3 (m, 2H,
0
(CDCl3) d 14.1 (Me), 61.4 (CH2), 123.1 (C3 ), 128.4 (C5 ),
0
0
130.8 (C3), 131.1 (C4 ), 131.2 (C5), 132.0 (C4), 136.1 (C6),
0
0
0
H3,5 ), 7.39 (td, 1H, J¼7.5, 0.75 Hz, H5), 7.49 (td, 1H,
137.7 (C1), 139.4 (C2), 148.6 (C6 ), 149.4 (C2 ), 168.1 (CO);
IR (KBr) n 3420, 2982, 1715, 1600, 1410, 1288, 1253, 1131,
1092, 760, 713 cm21. Anal. calcd for C14H13NO2 (227.27):
C, 73.99; H, 5.77; N, 6.16. Found: C, 73.75; H, 6.02; N,
6.24%.
0
J¼7.1, 1.1 Hz, H4), 7.63 (dt, 1H, J¼7.9, 1.9 Hz, H4 ), 7.71
0
(dd, 1H, J¼7.5, 1.1 Hz, H6), 8.39 (d, 1H, J¼1.9 Hz, H2 ),
8.43 (dd, 1H, J¼4.9, 1.1 Hz, H6 ); 13C NMR (DMSO-d6) d
0
0
123.4 (C5 ), 128.3 (C4 ), 130.0 (C3), 131.1 (C5), 131.4 (C4),
0
0
0
0
136.1 (C6), 137.2 (C3 ), 138.2 (C1), 148.4 (C6 ), 148.9 (C2 ),
153.3 (C2), 169.4 (CO); IR (KBr) n 3425, 3067, 2961, 1601,
1290, 1048, 818, 754, 702 cm21. Anal. calcd for C12H9NO2
(199.21): C, 72.35; H, 4.55; N, 7.03. Found: C, 72.09; H,
4.28; N, 6.79%.
4.5. Preparation of 1-, 2- and 4-azafluorenones (4–6)
4.5.1. 5H-Indeno(1,2-b(pyridin-5-one (4,4-azafluore-
none). To a solution of 2a (0.10 g, 0.50 mmol) in THF
(3 mL) at 08C was added a solution of LDA (obtained by
adding BuLi (1.5 mmol) to a solution of diisopropylamine
(0.22 mL, 1.6 mmol) in THF (2 mL) at 08C(. The mixture
was stirred at rt for 2 h before hydrolysis with water (2 mL).
Yield (eluent: CH2Cl2/Et2O 90:10): 52%; mp 139–1408C
4.4. Preparation of ethyl 2-(2-, 3- and 4-pyridyl)benzo-
ates (3a–c)
4.4.1. Ethyl 2-(2-pyridyl)benzoate (3a).22 A degassed
mixture of 2-bromopyridine (0.11 mL, 1.2 mmol),
Pd(PPh3)4 (35 mg, 30 mmol), dioxane (10 mL), ethyl
2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzoate (0.26 g,
1.0 mmol), and K3PO4·3H2O (0.53 g, 2.0 mmol) was heated
at 1008C for 18 h. The solvents were removed under reduced
pressure and water (10 mL) was added. Yield (eluent:
CH2Cl2/Et2O 95:5): 65%; pale yellow oil; 1H NMR
(CDCl3) d 0.97 (t, 3H, J¼7.1 Hz, Me), 4.05 (q, 2H,
1
(lit.24 138–1408C). The H NMR data are in accordance
with those of the literature;24 13C NMR (CDCl3) d 121.4
(C3), 123.7 (C9), 124.6 (C4), 131.4 (C7), 131.8 (C6), 135.2
(Cc), 135.8 (C8), 143.9 (Ca), 154.5 (C2), 155.7 (Cb), 165.5
(Cd), 192.2 (CO); IR (KBr) n 3065, 2984, 1836, 1715, 1592,
1405, 1259, 1092, 1021, 743 cm21
.
4.5.2. 9H-Indeno(2,1-c(pyridin-9-one (5,2-azafluore-
none). To a solution of 2b (0.10 g, 0.50 mmol) in THF
(3 mL) at 08C was added a solution of LTMP (obtained by
adding BuLi (1.5 mmol) to a solution of 2,2,6,6-tetra-
methylpiperidine (0.27 mL, 1.6 mmol) in THF (2 mL) at
08C(. The mixture was stirred at rt for 18 h before hydrolysis
with water (2 mL). Yield (eluent: CH2Cl2/Et2O 90:10):
67%; mp 1578C (lit.25 156–1578C). The spectral data are in
accordance with those described;25 13C NMR (CDCl3) d
115.8 (C4), 122.3 (C5), 125.1 (C8), 128.7 (Ca), 131.9 (C7),
134.3 (Cb), 135.4 (C6), 142.2 (Cd), 145.5 (C1), 152.2 (Cc),
156.2 (C3), 193.0 (CO). Anal. calcd for C12H7NO (181.20):
C, 79.55; H, 3.89; N, 7.73. Found: C, 79.27; H, 4.12; N,
7.64%.
0
J¼7.1 Hz, CH2), 7.17 (dd, 1H, J¼7.1, 5.6 Hz, H5 ), 7.4 (m,
0
0
2H, H4,3 ), 7.5 (m, 2H, H6,4 ), 7.65 (td, 1H, J¼7.5, 1.5 Hz,
H5), 7.75 (d, 1H, J¼7.1 Hz, H3), 8.55 (d, 1H, J¼4.9 Hz,
H6 ); 13C NMR (CDCl3) d 14.2 (Me), 61.3 (CH2), 122.4
0
0
0
(C3 ), 123.2 (C5 ), 128.7 (C5), 130.1 (C3), 130.1 (C4), 131.5
0
(C6), 132.2 (C1), 136.6 (C4 ), 141.4 (C2), 149.4 (C6 ), 159.2
0
0
(C2 ), 169.2 (CO); IR (KBr) n 3423, 3068, 2983, 2898,
1725, 1588 cm21. Anal. calcd for C14H13NO2 (227.27):
C, 73.99; H, 5.77; N, 6.16. Found: C, 74.01; H, 5.73; N,
6.17%.
4.4.2. Ethyl 2-(4-pyridyl)benzoate (3b). A mixture of 2b
(2.4 g, 12 mmol) and SOCl2 (30 mL) was heated under

A.-S. Rebstock et al. / Tetrahedron 59 (2003) 4973–4977
4977
¨
V. P. W.; Weskamp, T.; Gstottmayr, C. W. K.; Herrmann,
4.5.3. 9H-Indeno(2,1-b(pyridin-9-one (6,1-azafluore-
none). To a solution of 3c (0.10 g, 0.44 mmol) in THF
(3 mL) at 08C was added a solution of LTMP (obtained by
adding BuLi (1.3 mmol) to a solution of 2,2,6,6-tetra-
methylpiperidine (0.24 mL, 1.4 mmol) in THF (2 mL) at
08C). The mixture was stirred at 08C for 2 h before
hydrolysis with water (2 mL). Yield (eluent: CH2Cl2/Et2O
95:5): 70%; mp 125–1278C (lit.25 126–1278C). The IR data
are in accordance with those described;25 1H NMR (CDCl3)
d 7.25 (dd, 1H, J¼7.5, 4.9 Hz, H3), 7.3 (m, 1H, H7), 7.47 (m,
2H, H5,6), 7.67 (d, 1H, J¼7.2 Hz, H8), 7.77 (dd, 1H, J¼7.5,
1.1 Hz, H4), 8.51 (dd, 1H, J¼4.9, 1.1 Hz, H2); 13C NMR
(CDCl3) d 120.1 (C5), 123.9 (C3), 126.1 (C7), 126.8 (C8),
129.1 (C4), 131.4 (Cb), 134.5 (C6), 140.0 (Cc), 140.6 (Cd),
149.4 (C2), 152.2 (Ca), 191.5 (CO); mass (EI): m/z 181.
W. A. Angew. Chem. Int. Ed. 2000, 39, 1602–1604.
´
(c) Bonnet, V.; Mongin, F.; Trecourt, F.; Breton, G.; Marsais,
´
F.; Knochel, P.; Queguiner, G. Synlett 2002, 1008–1010.
8. Timari, G.; Hajos, G.; Batori, S.; Messner, A. Chem. Ber.
1992, 125, 929–932.
9. Cai, D.; Larsen, R. D.; Reider, P. J. Tetrahedron Lett. 2002, 43,
4285–4287.
10. (a) Collot, V.; Dallemagne, P.; Bovy, P. R.; Rault, S.
Tetrahedron 1999, 55, 6917–6922. Concerning Suzuki
cross-coupling reactions, see: (b) Miyaura, N.; Suzuki, A.
Chem. Rev. 1995, 95, 2457–2483. (c) Stanforth, S. P.
Tetrahedron 1998, 54, 263–303. (d) Suzuki, A.
J. Organomet. Chem. 1999, 576, 147–168. (e) Kotha, S.;
Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633–9695.
(f) Suzuki, A. In Metal-catalyzed Cross-coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH, 1998; pp 49–97.
11. Kristensen, J.; Lysen, M.; Vedso, P.; Begtrup, M. Org. Lett.
2001, 3, 1435–1437.
References
1. The concept emerged from the systematic studies of Gilman,
Wittig and Hauser, and found numerous disciples, notably
Gschwend and Snieckus: (a) Gilman, H.; Bebb, R. L. J. Am.
Chem. Soc. 1939, 61, 109–112. (b) Wittig, G.; Fuhrmann, G.
Chem. Ber. 1940, 73B, 1197–1218. (c) Hauser, C. R.;
Puterbaugh, W. H. J. Org. Chem. 1964, 29, 853–856.
(d) Gschwend, H. W.; Rodriguez, H. R. Org. React. 1979,
26, 1–360. (e) Snieckus, V. Chem. Rev. 1990, 90, 879–933.
2. (a) Roberts, J. D.; Curtin, D. Y. J. Am. Chem. Soc. 1946, 68,
1658–1660. (b) Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986,
19, 356–363. (c) Klumpp, G. W. Rec. Trav. Chim. Pays-Bas
1986, 105, 1–21. (d) Fu, J.-m.; Zhao, B.-p.; Sharp, M. J.;
Snieckus, V. J. Org. Chem. 1991, 56, 1683–1685.
12. Gray, M.; Chapell, B. J.; Taylor, N. J.; Snieckus, V. Angew.
Chem. Int. Ed. Engl. 1996, 35, 1558–1560.
13. Concerning LICKOR (BuLi/tBuOK), see: (a) Katsoulos, G.;
Schlosser, M. Tetrahedron Lett. 1993, 34, 6263–6266.
(b) Lochmann, L. Eur. J. Inorg. Chem. 2000, 1115–1126.
14. Unpublished results, see: Tilly, D.; Samanta, S. S.; Faigl, F.;
Mortier, J. Tetrahedron Lett. 2002, 43, 8347–8350.
15. Note that Snieckus and co-workers observed the intra-
molecular cyclization of substituted 4-lithiopyridines bearing
remote N,N-dialkylcarboxamide groups (Refs. 2d,4).
16. Bizot, J. Bull. Soc. Chim. Fr. 1967, 151.
17. Coulson, D. R. Inorg. Synth. 1972, 13, 121.
18. (a) Terashima, M.; Seki, K. I.; Yoshida, C.; Ohkura, K.;
Kanaoka, Y. Chem. Pharm. Bull. 1985, 33, 1009–1015.
(b) Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123,
2719–2724.
´
3. (a) Queguiner, G.; Marsais, F.; Snieckus, V.; Epsztajn, J. Adv.
Heterocycl. Chem. 1991, 52, 187–304, and references cited
´
therein. (b) Mongin, F.; Queguiner, G. Tetrahedron 2001, 57,
4059–4090.
4. Familoni, O. B.; Ionica, I.; Bower, J. F.; Snieckus, V. Synlett
1997, 1081–1083.
19. Srogl, J.; Liu, W.; Marshall, D.; Liebeskind, L. S. J. Am.
Chem. Soc. 1999, 121, 9449–9450.
20. Ishikura, M.; Kamada, M.; Terashima, M. Heterocycles 1984,
22, 265–268.
5. Epsztajn, J.; Jozwiak, A.; Krysiak, J. K.; Lucka, D.
Tetrahedron 1996, 52, 11025–11036.
´ ´
6. (a) Mongin, F.; Trecourt, F.; Queguiner, G. Tetrahedron Lett.
21. Shiao, M. J.; Perng, C. Y.; Shen, C. C. J. Chin. Chem. Soc.
1991, 38, 47–50.
1999, 40, 5483–5486. (b) Rebstock, A.-S.; Mongin, F.;
´ ´
Trecourt, F.; Queguiner, G. Tetrahedron Lett. 2002, 43,
22. Bradsher, C. K.; Voigt, C. F. J. Org. Chem. 1971, 36,
1603–1607.
767–769. (c) Lazaar, J.; Rebstock, A.-S.; Mongin, F.; Godard,
23. Kondo, Y.; Shilai, M.; Uchiyama, M.; Sakamoto, T. J. Am.
Chem. Soc. 1999, 121, 3539–3540.
´
A.; Trecourt, F.; Marsais, F.; Queguiner, G. Tetrahedron 2002,
´
58, 6723–6728.
24. DuPriest, M. T.; Schmidt, C. L.; Kuzmich, D.; Williams, S. B.
J. Org. Chem. 1986, 51, 2021–2023.
7. Concerning Kharasch cross-coupling reactions between aryl-
magnesium halides and aryl chlorides under nickel catalysis,
see: (a) Sengupta, S.; Leite, M.; Raslan, D. S.; Quesnelle, C.;
25. Mayor, C.; Wentrup, C. J. Am. Chem. Soc. 1975, 97,
7467–7480.
¨
Snieckus, V. J. Org. Chem. 1992, 57, 4066–4068. (b) Bohm,