Behaviour of N-pyridylbenzamides versus benzanilides in the ortho-directed lithiation of masked aromatic carboxylic acids

Article abstract of DOI:10.1002/ejoc.200400156

The reaction of N-pyridylbenzamides 1-3 with n-butyllithium or sec-butyllithium has been examined. The perfect selectivity that has been observed until now in the lithiation of anilides, a reaction used for ortho-functionalisation of masked aromatic carboxylic acids, has been broken; our results indicate that the pyridine ring at the position ortho to the directed metallation group is more susceptible to lithiation than the homoaromatic ring itself. This was proved in an intermolecular comparative study of benz-, picolin- and isonicotinanilides 14-16, and N-cumylbenzamide (17). Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400156

FULL PAPER
Behaviour of N-Pyridylbenzamides versus Benzanilides in the ortho-Directed
Lithiation of Masked Aromatic Carboxylic Acids[‡]
[a]
[a]
[a]
´´
´
Andrzej Jozwiak,* Jacek Z. Brzezinski, Mieczysław W. Płotka,
[a]
[a]
[a]
´
Aleksandra K. Szczesniak, Zbigniew Malinowski, and Jan Epsztajn*
Keywords: N-Pyridylbenzamides / ortho-Lithiation / Benzanilides / Silylated derivatives
The reaction of N-pyridylbenzamides 1−3 with n-butylli-
the directed metallation group is more susceptible to
thium or sec-butyllithium has been examined. The perfect lithiation than the homoaromatic ring itself. This was proved
selectivity that has been observed until now in the lithiation
of anilides, a reaction used for ortho-functionalisation of
masked aromatic carboxylic acids, has been broken; our re-
sults indicate that the pyridine ring at the position ortho to
in an intermolecular comparative study of benz-, picolin- and
isonicotinanilides 14−16, and N-cumylbenzamide (17).
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
mide was subjected to a reaction with n-butyllithium
(nBuLi) in THF, and subsequently with DMF, but this re-
sulted in an intractable mixture. This is astonishing given
the known reaction of arylanilides. In general, it is possible
to conclude, from the hierarchy of ortho-directed metall-
ation groups (o-DMGs), that the anilide functionality in C
could direct the lithiation process at the one of two com-
petitive positions a and b. However, until now, no examples
of lithiation at the b position of the anilides have been
observed.[10Ϫ14] The observed behaviour of N-(pyrid-4-yl)-
benzamide in the reaction with nBuLi suggests that in the
case of anilides, in which the N-aryl ring is replaced by an
N-pyridyl one, the presence of the N-pyridyl moiety could
cause a change in the course of the reaction.
Recently, it has been demonstrated that the 3-hydroxy-N-
(pyrid-4-yl)-2,3-dihydroisoindol-1-ones B could be con-
venient precursors in the preparation of N-(pyridyl)isoindo-
lines A and their derivatives. These compounds show ac-
tivity as selective serotonin reuptake inhibitors.[1,2] This
prompted us to seek more insight into the possibility of
preparing compounds of structure B.
While trying to obtain more insight into this process, we
investigated the reaction of N-pyridylbenzamides 1Ϫ3 with
nBuLi or sBuLi, and we are reporting the results here. We
have determined all the products and their yields.
The reported methods for the preparation of this skeleton
generally require multiple reaction steps, and are unsatisfac-
tory, both in yield and generality.[3,4] The most attractive
route reported to date, for the preparation of N-aryl-3-
hydroxyisoindolin-1-ones is the transformation of second-
ary aromatic carboxanilides of structure C, by ortho-lithi-
ation and subsequent reaction of the dilithiated (C-ortho,N-)
species with N,N-dimethylformamide (DMF).[5Ϫ9]
Therefore, with the aim of developing a methodology for
the synthesis of the required systems, N-(pyrid-4-yl)benza-
Results and Discussion
[‡]
Application of Organolithium and Related Reagents in
Synthesis, 30. Part 29: A. Bieniek, J. Epsztajn, K. K.
The detailed results of the reaction of nBuLi or sBuLi
with N-pyridylbenzamides 1Ϫ3 are reported in Table 1. All
reactions were carried out in THF with 2 equiv. of nBuLi
or sBuLi, and then, before addition of an electrophile, the
reaction mixtures were cooled to Ϫ78 °C. As a way for de-
termining the reaction of the benzamides 1Ϫ3 with lithiat-
Kulikiewicz, Monatsh. Chem. 2004, 135, 69Ϫ77.
[a]
Department of Organic Chemistry, Institute of Chemistry,
´ ´
University of Łodz,
´ ´
Nrutowicza 68, 90-136 Łodz, Poland
Fax: (internat.) ϩ 48-42-678-6583
E-mail: epsztajn@uni.lodz.pl
ajozwiak@uni.lodz.pl
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DOI: 10.1002/ejoc.200400156
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ortho-Directed Lithiation of Masked Aromatic Carboxylic Acids
FULL PAPER
Table 1. Reaction of the N-pyridylbenzamides 1Ϫ3 in the lithiation/silylation process
Benzamides
RLi
Products (yields [%])
Ketones 4 or adduct 10
Overall yields [%]
Silylated products
Recovered benzamides
1
1
3
3
2
nBuLi
sBuLi
nBuLi
sBuLi
nBuLi
4a (50)
4b (25)
4a (22)
4b (16)
10 (12)
5 (1), 6 (16)
1 (26)
1 (16)
3 (10)
3 (10)
2 (21)
93
93
92
78
77
5 (8), 6 (44)
7 (14), 8 (14), 9 (32)
7 (7), 8 (2), 9 (43)
11 (5), 12 (6), 13 (33)
ing agents, the silylation process was selected, since in these
Independently of which lithiating agent (nBuLi or sBuLi)
cases, the products were readily separated and could be was employed for the lithiation/silylation process of amides
characterised unambiguously. An examination of the data 1 and 3, the main products appeared to be compounds 6 or
reveals that the reacting benzamides may be divided into 9, resulting from substitution at position 3 of the pyridine
two groups. The first group comprises benzamides derived ring. This suggests that position 3 of the pyridine moiety
from 2- and 4-aminopyridines 1 and 3. The second one con- is more susceptible towards the lithiation process than the
sists of the benzamide derived from 3-aminopyridine 2.
homoaromatic ring itself.
The ketones 4a and 4b could be simply derived from a
nucleophilic acyl substitution reaction of the starting
benzamides 1 and 3 with nBuLi and sBuLi.
N-(Pyrid-2-yl)- and N-(Pyrid-4-yl)benzamides 1 and 3
Benzamides 1 and 3 reacted with nBuLi or sBuLi, and
subsequent treatment of the lithiated derivatives with chloro-
trimethylsilane (TMSCl) gave the corresponding silylated
products 5Ϫ9, along with a large amount of valerophenone
(4a) or s-butyl phenyl ketone (4b), together with some
amount of recovered starting amide (see Table 1). The
double ortho-lithiation/silylation process gave a consider-
able amount of the disilylated compound 8 from benzamide
3, especially in its reaction with nBuLi. The results pre-
sented in Schemes 1 and 2 show that the cases of the reac-
tion of benzamides 1 and 3 with nBuLi or sBuLi indicate
that the perfect selectivity for path a in the lithiation of
anilides C that has been known until now has been
broken.[15Ϫ20]
N-(Pyrid-3-yl)benzamide (2)
Subjection of benzamide 2 to the lithiation/silylation pro-
cess resulted in the corresponding silylated products 11Ϫ13,
accompanied by a considerable amount of compound 10
and some amount of the starting amide (Table 1). One of
the silylated products in this mixture (Scheme 3), namely
compound 11, is probably formed as the result of the fol-
lowing reaction sequence: firstly, addition of nBuLi across
the pyridine ring, and then ortho-lithiation of the anilide
functionality. However, the reverse sequence cannot be ex-
cluded. Compounds 10 and 11 were formed by aromatis-
ation of the unstable 1,4-dihydro adduct of nBuLi across
the pyridine ring. Formation of adducts 10 and 11 is in
agreement with the behaviour of 3-(pivaloylamino)pyridine
in its reaction with nBuLi.[21Ϫ22] The fact that silylated am-
ide 13, resulting from substitution at C-4 of the pyridine
nucleus, appeared to be the main product is additional evi-
dence for the higher susceptibility of heteroaromatic species
than homoaromatic ones to the lithiation process.
Scheme 1
Scheme 2
Scheme 3
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FULL PAPER
Competitive Study of the Lithiation of Anilides 14؊16 and
N-Cumylbenzamide (17)
small improvement was observed for anilide 14. Increasing
the temperature of the lithiation to 0 °C enhanced the pro-
cess for amides 14 and 17 to 80% and 73%, respectively. We
then found out that the replacement of nBuLi by sBuLi
gave perfect results; complete lithiation was observed in
both cases.
The suggestion that the pyridine moiety is much more
prone to lithiation than the benzene ring itself inspired us
to undertake a competitive study of anilides C into the sus-
ceptibility of the benzene versus the pyridine rings towards
lithiation, as well as of the generality of anilides to act as
o-DMGs. Recently, Snieckus and co-workers have described
that the N-cumylbenzamide is a very effective o-DMG, and
suggested that it could play a central role in synthetic aro-
matic chemistry.[23Ϫ24] However, they have not shown any
comparative studies, or even discussion, of the N-cumyl
group relative to the anilide functionality, whose signifi-
cance as an o-DMG is widely documented.[15Ϫ20] Therefore,
we decided to extend the competitive study of amides C to
include N-cumylbenzamide (17), in order to fill this gap.
On the other hand, picolinanilide (15) and isonicotinanil-
ide (16) gave a perfect lithiation at position 3 of the pyridine
ring when treated with nBuLi, irrespective of the reaction
conditions. In the case of picolinanilide (15), it appeared
that if the process was carried out at 0 °C, generation of the
lithiated species was accompanied by formation of the ke-
tone 18 (ca. 8%) and a trace amount of the nBuLi adduct
across the pyridine ring 19. These compounds were isolated
1
from the testing mixture and characterised by H and 13C
NMR spectroscopy (Table 2).
In order to gain more insight into the susceptibility of
the tested amides 14Ϫ17 towards the lithiation process, an-
ilide 14 was selected as a reference compound, as it is the
most frequently used of the secondary amides as an o-
DMG.[5Ϫ9,15Ϫ20] Thus, intermolecular competition reac-
tions were carried out for the following pairs: 14/15, 14/16,
and 14/17. Detailed results are reported in Table 3. The data
prove that picolinanilide (15) and isonicotinanilide (16) ap-
pear to be the most receptive to lithiation of the amides
tested. Moreover, it has been shown that in these cases, the
lithiation process is independent of the reaction conditions,
as well as the lithiating agents used.
Table 3. Intermolecular competitive lithiation of equimolar mix-
tures of amides 14/15, 14/16, 14/17
Extent of the lithiation [%][a,b]
nBuLi
To this end, benz-, picolin- and isonicotinanilides 14Ϫ16
and N-cumylbenzamide (17) were subjected to a reaction
with nBuLi or sBuLi in THF, and quenched with deuter-
ated methanol (MeOD). The detailed results are reported
in Table 2. At first, it appeared that treatment of the anilide
14 and the N-cumylamide 17 with nBuLi at Ϫ78 °C for
2 h resulted in no lithiation. If an equimolecular amount of
sBuLi
14/15
14/16
14/17
0:100
0:100
39:60
0:100
0:100
45:45
[a] For typical procedures see Exp. Sect. [b] The process was followed
by deuteration (MeOD) and reported data were derived from 1H
TMEDA relative to the lithiation agent was added, only a NMR spectra.
Table 2. Lithiation of amides 14Ϫ17
Amide
Lithiating reagent[a]
Temp. [°C]
D incorporation for the isolated amide [%][b]
14
nBuLi
nBuLi[c]
nBuLi
sBuLi[c]
nBuLi
nBuLi
nBuLi
nBuLi
nBuLi
nBuLi[c]
nBuLi
sBuLi[c]
Ϫ78
Ϫ78
0
Ϫ78
Ϫ78
0
Ϫ78
0
Ϫ78
Ϫ78
0
0
19
80
100
100
100[d]
96
94
0
0
73
15
16
17
Ϫ78
100
[a]
The ratio of amide/lithiated reagents was 1:2 in all cases. [b] Reported data were identified by 1H NMR spectroscopy utilising the peak
[c]
[d]
areas of the hydrogen atoms ortho to the carbamoyl group. The lithiation was carried out in the presence of TMEDA. The isolated
amide 16 was accompanied by ketone 18 (8%) and a trace of adduct 19.
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ortho-Directed Lithiation of Masked Aromatic Carboxylic Acids
FULL PAPER
hexane (3:1) (yield 66%), m.p. 82Ϫ84 °C (ref.[26] m.p. 81Ϫ83 °C).
1H NMR {200 MHz, [D6]DMSO, reference TMS (δ ϭ 0 ppm)}:
δ ϭ 7.14Ϫ7.18 [m, 1 H, Py(5)-H], 7.48Ϫ7.62 [m, 3 H, Ph(3,4,5)-
H], 7.81Ϫ7.86 [m, 1 H, Py(4)-H], 8.01Ϫ8.05 [m, 2 H, Ph(2,6)-H],
The competition reaction between the anilide 14 and N-
cumylbenzamide (17) indicated that there is practically no
difference between the activity as o-DMGs of their func-
tional groups. Therefore, the similar abilities of these func-
tionalities to act as o-DMGs, along with the simplicity of
preparation of the anilide group and the ease of its hydroly-
sis into a carboxylic functionality, mean that the anilide
should be considered the group of choice for ortho-directed
metallation of masked aromatic carboxylic acids.
3
8.20 (d,1 H, JH,H ϭ 7.5 Hz, Py(3)-H], 8.37Ϫ8,39 [m, 1 H, Py(6)-
H], 10.78 (s, 1 H, NH) ppm. 13C NMR {[D6]DMSO, reference
TMS (δ ϭ 0 ppm)}: δ ϭ 114.9, 120.0, 128.2, 128.6, 132.1, 134.3,
138.3, 148.1, 152.4, 166.2 (CO) ppm.
N-(Pyrid-3-yl)benzamide (2): Amide 2 was prepared from 3-amino-
pyridine and benzoyl chloride in pyridine.[25] It was purified by
recrystallisation from benzene (yield 72%), m.p. 123Ϫ124 °C
(ref.[25] m.p. 118 °C). 1H NMR {200 MHz, [D6]DMSO, reference
Conclusion
3
3
TMS (δ ϭ 0 ppm)}: δ ϭ 7.41 [dd, JH,H ϭ 8.3, JH,H ϭ 4.6 Hz, 1
H, Py(5)-H], 7.49Ϫ7.70 [m, 3 H, Ph(3,4,5)-H], 7.95Ϫ8.06 [m, 2 H,
The results presented here indicate that replacement of
the aniline in the benzanilides C for aminopyridines caused
the breaking of the perfect selectivity of the ortho-lithiation
reaction for masked aromatic carboxylic acids that has been
known until now. In addition, the competitive study of anil-
3
4
Ph(2,6)-H], 8.22 [dd, JH,H ϭ 8.4, JH,H ϭ 1.6 Hz, 1 H, Py(4)-H],
3
4
8.33 [d, JH,H ϭ 4.7 Hz, 1 H, Py(6)-H], 8.97 [d, JH,H ϭ 1.6 Hz, 1
H, Py(2)-H], 10.49 (s, 1 H, NH; signal disappeared after addition
of D2O) ppm. 13C NMR {[D6]DMSO, reference TMS (δ ϭ
0 ppm)}: δ ϭ 123.4, 127.2, 127.7, 128.4, 131.8, 134.3, 135.8, 141.9,
ides 14Ϫ16, and N-cumylbenzamide (17) showed that posi- 144.5, 165.9 (CO) ppm.
tion 3 of the pyridine moiety is more susceptible to lithi-
N-(Pyrid-4-yl)benzamide (3): Compound 3 was prepared from 4-
ation than the homoaromatic ring itself. Moreover, the re-
sult of the competitive lithiation of the benzanilide (14) and
N-cumylbenzamide (17) indicates that the anilide func-
tionality should be recognised as an important o-DMG for
the ortho-lithiation of aromatic carboxylic acids.
aminopyridine and benzoyl chloride in the presence of triethyl-
amine.[27] It was purified by crystallisation from ethanol (yield
45%), m.p. 210Ϫ211 °C (ref.[25] m.p. 202 °C). 1H NMR {200 MHz,
[D6]DMSO, reference TMS (δ ϭ 0 ppm)}: δ ϭ 7.48Ϫ7.72 [m, 3 H,
Ph(3,4,5)-H], 7.75Ϫ7.85 [m, 2 H, Py(3,5)-H], 7.91Ϫ8.04 [m, 2 H,
Ph(2,6)-H], 8.43Ϫ8.55 [m, 2 H, Py(2,6)-H], 10.61 (s, 1 H, NH) ppm.
13C NMR {[D6]DMSO, reference TMS (δ ϭ 0 ppm)}: δ ϭ 113.9,
127.8, 128.4, 132.1, 134.2, 145.9, 150.3, 166.5 (CO) ppm.
Experimental Section
N-Phenylbenzamide (14): Compound 14 was obtained from benzoyl
chloride and aniline according to a known procedure.[28] 1H NMR
{500 MHz, [D6]DMSO, reference [D6]DMSO (δ ϭ 2.49 ppm)}: δ ϭ
General: Melting points were determined with a Boetius hot stage
apparatus and are uncorrected. Yields are given on chromatograph-
1
ically pure products and are not optimised. H NMR spectra were
3
3
7.09 [t, JH,H ϭ 7.3 Hz, 1 H, Ph2(4)-H], 7.34 [t, JH,H ϭ 7.7 Hz, 2
recorded at 200 MHz with a Varian Gemini 200 BB or at 500 MHz
with a Bruker Avance DRX500 spectrometer. 13C NMR spectra
were recorded at 50 MHz with a Varian Gemini 200 BB spec-
trometer. IR spectra were recorded with a Nexus FT-IR spec-
trometer (Thermo Nicolet). HRMS data were recorded by using
chemical ionisation with a Finnigan MAT 95 spectrometer. TLC
was carried out on Merck silica gel plates (Kiselgel 60 F254, layer
thickness 0.2 mm) and visualised using a UV lamp at 254 nm and
in an iodine chamber. Column chromatography separations and
purifications were performed on silica gel 60 (0.063Ϫ0.100 mm)
from Merck, using 30 g of silica gel per 1 g of the material to be
separated or purified. All reagents and commercially available ma-
terials were used without purification unless otherwise stated. n-
Butyllithium (1.6  solution in hexane) and sec-butyllithium (1.4
3
H, Ph2(3,5)-H], 7.52 [t, JH,H ϭ 7.4 Hz, 2 H, Ph1(3,5)-H],
3
7.56Ϫ7.61 [m, 1 H, Ph1(4)-H], 7.77 [d, JH,H ϭ 8.2 Hz, 2 H,
4
3
Ph2(2,6)-H], 7.94 [dd, JH,H ϭ 1.2 Hz, JH,H ϭ 8.3 Hz, 2 H,
Ph1(2,6)-H], 10.25 (s, 1 H, NH) ppm. 13C NMR {[D6]DMSO, refer-
ence [D6]DMSO (δ ϭ 39.5 ppm)}: δ ϭ 120.3, 123.6, 127.6, 128.3,
128.5, 131.5, 135.0, 139.1, 165.5 (CO) ppm.
N-Phenylpyridine-2-carboxamide (15): 15 was prepared from 2-pyri-
dinecarboxylic acid according to a procedure given by Brunner.[29]
Compound 15 was purified by crystallisation from hexane (yield
76%), m.p. 74Ϫ76 °C (ref.[29] m.p. 75 °C). 1H NMR {500 MHz,
[D6]DMSO, reference [D6]DMSO (δ ϭ 2.49 ppm)}: δ ϭ 7.10 [t,
3JH,H ϭ 7.3 Hz, 1 H, Ph(4)-H], 7.32Ϫ7.37 [m, 2 H, Ph(3,5)-H],
7.63Ϫ7.68 [m, 1 H, Py(5)-H], 7.90 [d, 3JH,H ϭ 7.7 Hz, 2 H, Ph(2,6)-
4
3
 solution in cyclohexane) were obtained from Aldrich and were H], 8.06 [dd, JH,H ϭ 1.7 Hz, JH,H ϭ 7.7 Hz, 1 H, Py(4)-H],
3
titrated before use. Benzoyl chloride (pure) and 3-aminopyridine
(pure) were obtained from POCh. N,N,NЈ,NЈ-Tetramethylethylen-
8.09Ϫ8.17 [m, 1 H, Py(3)-H], 8.73 [d, JH,H ϭ 4.3 Hz, 2 H, Py(6)-
H], 10.62 (s, 1 H, NH) ppm. 13C NMR {[D6]DMSO, reference
ediamine (TMEDA) (99%) from Aldrich was distilled before use [D6]DMSO (δ ϭ 39.5 ppm)}: δ ϭ 120.2, 122.3, 123.8, 126.8, 128.6,
and stored over potassium hydroxide pellets. Chlorotrimethylsilane
(TMSCl) was obtained from Fluka. [D1]Methanol (99.8%) was ob-
tained from IBJ Swierk and used as received. Tetrahydrofuran
(THF) (pure) was obtained from POCh and freshly distilled from
sodium benzophenone ketyl. Pyridine (pure) was obtained from
Ubichem Ltd.
138.0, 138.3, 148.2, 149.8, 162.3 (CO) ppm.
N-Phenylpyridine-4-carboxamide (16): Compound 16 was obtained
from 4-pyridinecarbonyl chloride and aniline in pyridine according
to a procedure given by Park.[30] 1H NMR {500 MHz, [D6]DMSO,
reference [D6]DMSO (δ ϭ 2.49 ppm)}: δ ϭ 7.13 [t, 3JH,H ϭ 7.3 Hz,
3
1 H, Ph(4)-H], 7.37 [t, JH,H ϭ 7.7 Hz, 2 H, Ph(3,5)-H], 7.77 [d,
Amides 1؊3, 14؊17: These compounds were obtained according
to known procedures. N-(Pyrid-2-yl)benzamide (1) was obtained
3JH,H ϭ 7.9 Hz, 2 H, Ph(2,6)-H], 7.85 [dd, 4JH,H ϭ 1.4 Hz, 3JH,H ϭ
4.4 Hz, 2 H, Py(3,5)-H], 8.75 [dd, 4JH,H ϭ 1.4 Hz, JH,H ϭ 4.4 Hz,
3
from 2-aminopyridine and benzoyl chloride in pyridine according 2 H, Py(2,6)-H], 10.49 (s, 1 H, NH) ppm. 13C NMR {[D6]DMSO,
to the procedure given by Pentimalli for N-(pyrid-3-yl)benzamide
reference [D6]DMSO (δ ϭ 39.5 ppm)}: δ ϭ 120.4, 121.5, 124.1,
128.7, 138.5, 141.9, 150.2, 163.9 (CO) ppm.
(2).[25] Compound 1 was purified by crystallisation from benzene/
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FULL PAPER
N-(1-Methyl-1-phenylethyl)benzamide (17): Amide 17 was obtained ν˜max. ϭ 1656 (CO) cmϪ1. C15H18N2OSi (270.41): calcd. C 66.63, H
from (1-methyl-1-phenylethyl)amine (this amine was prepared by 6.71, N 10.36, O 5.91, Si 10.39; found C 66.6, H 6.7, N 10.4.
treatment of 2-bromo-2-phenylpropane with liquid ammonia) and
benzoyl chloride in the presence of triethylamine.[31] It was purified
by crystallisation from hexane/ethyl acetate (1:2) (yield 66%), m.p.
168Ϫ170 °C (ref.[32] m.p. 168Ϫ169 °C). 1H NMR {500 MHz,
[D6]DMSO, reference [D6]DMSO (δ ϭ 2.49 ppm)}: δ ϭ 1.65 (s, 6
Reaction of N-(Pyrid-2-yl)benzamide (1) with sec-Butyllithium and
then with Chlorotrimethylsilane: sec-Butyllithium (20 mmol) was
added to a stirred solution of the amide 1 (1.98 g, 10 mmol) and
TMEDA (20 mmol) in THF (70 mL) at Ϫ78 °C. The solution was
kept at Ϫ78 °C for 2 h, and chlorotrimethylsilane (20 mmol) was
added. Stirring at Ϫ78 °C was continued for another 0.5 h, then
the reaction mixture was warmed up to room temperature and
water (20 mL) was added. The mixture was adjusted to pH ഠ 5
with hydrochloric acid (2.0  solution in water) and the organic
layer was separated. The water layer was extracted with CHCl3 (3
ϫ 15 mL). The combined organic solutions were dried with mag-
nesium sulfate. Analysis (TLC; CHCl3/acetone, 8:1) of the organic
solution indicated the presence of at least four compounds (Rf ϭ
0.70, 0.45, 0.32, and 0.11), which were separated by column chro-
matography. The first eluted fraction (Rf ϭ 0.70) was identified as
ketone 4b (0.41 g, yield 25%). It was purified by kugelrohr distil-
lation (oil bath 130 °C, 5.0 Torr; ref.[34] b.p. 110Ϫ112 °C/9.5 Torr).
1H NMR [200 MHz, CDCl3, reference TMS (δ ϭ 0 ppm)]: δ ϭ
3
H, Me), 7.15 [t, JH,H ϭ 7.5 Hz, 1 H, Ph2(4)-H], 7.23Ϫ7.30 [m, 2
3
H, Ph2(3,5)-H], 7.36 [d, JH,H ϭ 7.6 Hz, 2 H, Ph2(2,6)-H],
7.41Ϫ7.46 [m, 2 H, Ph1(3,5)-H], 7.47Ϫ7.52 [m, 1 H, Ph1(4)-H], 7.83
3
[d, JH,H ϭ 7.8 Hz, 2 H, Ph1(2,6)-H], 8.42 (s, 1 H, NH) ppm. 13C
NMR {[D6]DMSO, reference [D6]DMSO (δ ϭ 39.5 ppm)}: δ ϭ
29.6, 55.3, 124.6, 125.6, 127.4, 127.8, 128.0, 130.9, 135.4, 148.0,
165.8 (CO) ppm.
Reaction of N-(Pyrid-2-yl)benzamide (1) with n-Butyllithium and
then with Chlorotrimethylsilane: n-Butyllithium (20 mmol) was ad-
ded to a stirred solution of the amide 1 (1.98 g, 10 mmol) and
TMEDA (20 mmol) in THF (100 mL) at Ϫ78 °C. The solution was
kept at Ϫ78 °C for 0.5 h, then warmed up to 0 °C and kept at this
temperature for 0.1 h. The mixture was then cooled to Ϫ78 °C, and
chlorotrimethylsilane (20 mmol) was added. Stirring at Ϫ78 °C was
continued for another 0.25 h, then the reaction mixture was
warmed up to room temperature and water (20 mL) was added.
The mixture was adjusted to pH ഠ 5 with hydrochloric acid (2.0 
solution in water) and the organic layer was separated. The water
layer was extracted with CHCl3 (3 ϫ 15 mL). The combined or-
ganic solutions were dried with magnesium sulfate. Analysis (TLC;
CHCl3/acetone, 6:1) of the organic solution indicated the presence
of at least four compounds (Rf ϭ 0.88, 0.77, 0.65, 0.40), which were
separated by column chromatography. The first eluted fraction
3
0.92 (t, JH,H ϭ 7.4 Hz, 3 H, Me), 1.19 (d,3JH,H ϭ 6.9 Hz, 3 H,
Me), 1.39Ϫ1.60 (m, 1 H, CH2), 1.74Ϫ1.95 (m, 1 H, CH2),
3.32Ϫ3.49 (m, 1 H, CH), 7.41Ϫ7.59 [m, 3 H, Ph(3,4,5)-H],
7.92Ϫ7.99 [m, 2 H, Ph(2,6)-H] ppm. 13C NMR [CDCl3, reference
TMS (δ ϭ 0 ppm)]: δ ϭ 11.7, 16.7, 26.6, 42.1, 128.1, 128.5, 132.7,
136.7, 204.3 (CO) ppm. IR (film): ν˜max. ϭ 1684 (CO) cmϪ1. The
second, third and fourth fractions were identical to those upon the
reaction of amide 1 with nBuLi and TMSCl (for differences in yield
see Table 1).
(Rf ϭ 0.88) appeared to be valerophenone (4a) (0.80 g, yield 49%). Reaction of N-(Pyrid-4-yl)benzamide (3) with n-Butyllithium and
It was purified by kugelrohr distillation (oil bath 130 °C/2.0 Torr ; then with Chlorotrimethylsilane: n-Butyllithium (20 mmol) was ad-
ref.[33] b.p. 82Ϫ86 °C/0.5 Torr). 1H NMR [200 MHz, CDCl3, refer- ded to a stirred solution of the amide 3 (1.98 g, 10 mmol) and
3
ence TMS (δ ϭ 0 ppm)]: δ ϭ 0.92 (t, JH,H ϭ 7.2 Hz, 3 H, Me), TMEDA (20 mmol) in THF (100 mL) at Ϫ78 °C under argon. The
1.31Ϫ1.49 (m, 2 H, CH2), 1.62Ϫ1.85 (m, 2 H, CH2), 2.96 (t, solution was kept at Ϫ78 °C for 0.5 h, then allowed to warm to 0
3JH,H ϭ 7.0 Hz, 2 H, CH2), 7.41Ϫ7.59 [m, 3 H, Ph(3,4,5)-H], °C and kept at this temperature for 6 min. The mixture was cooled
7.91Ϫ8.01 [m, 2 H, Ph(2,6)-H] ppm. 13C NMR [CDCl3, reference to Ϫ78 °C and chlorotrimethylsilane (20 mmol) was added. After
TMS (δ ϭ 0 ppm)]: δ ϭ 13.9, 22.4, 26.4, 38.2, 127.9, 128.5, 132.7, 0.25 h at Ϫ78 °C, the reaction mixture was warmed to room tem-
136.9, 200.4 (CO) ppm. IR (film): ν˜max. ϭ 1686 (CO) cmϪ1. The perature, and water (10 mL) was added. The mixture was adjusted
second eluted fraction (Rf ϭ 0.77) was identified as N-(pyrid-2- to pH ഠ 5 with hydrochloric acid (2.0  solution in water) and the
yl)-2-(trimethylsilyl)benzamide (5) (0.22 g, yield 7%). The analytical organic layer was separated. The water layer was extracted with
sample was obtained after recrystallisation from hexane, m.p. CHCl3/THF (1:1) (3 ϫ 15 mL). The analysis (TLC; ethyl acetate)
111Ϫ114 °C. 1H NMR {200 MHz, [D6]DMSO, reference of the combined organic solutions indicated the presence of at least
[D6]DMSO (δ ϭ 2.49 ppm)}: δ ϭ 0.26 (s, 9 H, SiMe3), 7.12Ϫ7.18 five compounds (Rf ϭ 0.76, 0.48, 0.35, 0.24 and 0.16), which were
[m, 1 H, Py(5)-H], 7.42Ϫ7.56 (m, 4 H, Ph-H), 7.78Ϫ7.92 [m, 1 H, separated by the column chromatography. The first eluted fraction
3
Py(4)-H], 8.19 [d, JH,H ϭ 8.3 Hz, 1 H, Py(3)-H], 8.31Ϫ8.40 [m, 1 (Rf ϭ 0.76) turned out to be valerophenone (4a) (0.36 g, yield 22%).
H, Py(6)-H], 10.86 (s, 1 H, NH) ppm. 13C NMR {[D6]DMSO, ref- The second eluted fraction (Rf ϭ 0.48) was identified as 2-(trimeth-
erence [D6]DMSO (δ ϭ 39.5 ppm)}: δ ϭ 0.0, 114.4, 119.9, 127.4, ylsilyl)-N-[3-(trimethylsilyl)pyrid-4-yl]benzamide (8) (0.48 g; yield
128.8, 129.7, 134.9, 139.0, 139.3, 142.0, 148.2 152.3, 169.8 (CO) 14%). An analytical sample was obtained after recrystallisation
ppm. IR (KBr): ν˜max. ϭ 1683 (CO) cmϪ1. C15H18N2OSi (270.41): from hexane, m.p. 71Ϫ72 °C. 1H NMR {200 MHz, [D6]DMSO,
calcd. C 66.63, H 6.71, N 10.36, O 5.91, Si 10.39; found C 66.9, H reference [D6]DMSO (δ ϭ 2.49 ppm)}: δ ϭ 0.32 and 0.26 ppm (2
3
6.8, N 10.4. The third eluted fraction (Rf ϭ 0.65) turned out to be overlapping s, 18 H, SiMe3), 7.34 [d, JH,H ϭ 5.5 Hz, 1 H, Py(5)-
starting amide 1 (0.52 g, yield 26%). The fourth eluted fraction H], 7.42Ϫ7.84 (m, 4 H, Ph-H), 8.58 [d,3JH.H ϭ 5.5 Hz, 1 H, Py(6)-
(Rf ϭ 0.40) was identified as N-[3-(trimethylsilyl)pyrid-2-yl]benza- H], 8.66 [s, 1 H, Py(2)-H], 10.00 (s, 1 H, NH) ppm. 13C NMR
mide (6) (0.43 g, yield 16%). An analytical sample was obtained {[D6]DMSO, reference [D6]DMSO (δ ϭ 39.5 ppm)}: δ ϭ Ϫ0.2, 0.6,
after recrystallisation from diisopropyl ether, m.p. 105Ϫ108 °C. 1H 120.7, 126.8, 129.0, 129.9, 130.2, 135.3, 140.0, 140.7, 150.1, 150.8,
NMR {200 MHz, [D6]DMSO, reference [D6]DMSO (δ
ϭ
155.7, 169.1 (CO) ppm. IR (KBr): ν˜max. ϭ 1690.3 (CO) cmϪ1
.
2.49 ppm)}: δ ϭ 0.23 (s, 9 H, SiMe3), 7.35 [dd, 3JH,H ϭ 7.4, 4.8 Hz, C18H26N2OSi2 (342.59): calcd. C 63.10, H 7.65, N 8.18, O 4.67, Si
1 H, Py(5)-H], 7.49Ϫ7.61 [m, 3 H, Ph(2,6)-H, Py(4)-H], 7.96Ϫ8.01 16.40; found C 63.2, H 7.7, N 8.2. The third eluted fraction (Rf ϭ
3
[m, 3 H, Ph(3,4,5)-H], 8.52 [dd, JH,H ϭ 4.6, 1.6 Hz, 1 H, Py(6)- 0.35) was identified as N-[3-(trimethylsilyl)pyrid-4-yl]benzamide (9)
H], 10.50 (s, 1 H, NH) ppm. 13C NMR {[D6]DMSO, reference (0.86 g; yield 32%). An analytical sample was obtained after recrys-
[D6]DMSO (δ ϭ 39.5 ppm)}: δ ϭ 0.0, 122.3, 127.8, 128.7, 131.9, tallisation from diisopropyl ether, m.p. 141Ϫ142 °C. 1H NMR
132.7, 134.3, 144.7, 149.6, 155.1, 167.0 (CO) ppm. IR (KBr): {200 MHz, [D6]DMSO, reference [D6]DMSO (δ ϭ 2.49 ppm)}: δ ϭ
3258
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3254Ϫ3261

ortho-Directed Lithiation of Masked Aromatic Carboxylic Acids
FULL PAPER
3
0.28 (s, 9 H, SiMe3), 7.32 [d, JH,H ϭ 5.2 Hz, 1 H, Py(5)-H], tra, appeared to be undefined, complex mixtures, and no further
7.43Ϫ7.65 [m, 3 H, Ph(3,4,5)-H], 7.84Ϫ8.30 [m, 2 H, Ph(2,6)-H], attempts of their identification were undertaken. The third eluted
8.58 [d, 3JH,H ϭ 5.2 Hz, 1 H, Py(6)-H], 8.66 [s, 1 H, Py(2)-H], 10.08 fraction (Rf ϭ 0.44 in ethyl acetate) was a yellow, viscous liquid,
(s, 1 H, NH) ppm. 13C NMR {[D6]DMSO, reference [D6]DMSO and was identified as N-(4-butylpyrid-3-yl)-2-(trimethylsilyl)benz-
(δ ϭ 39.5 ppm)}: δ ϭ Ϫ0.3, 122.1, 127.6, 128.6, 131.1, 132.0, 133.8, amide (11) (0.15 g, 5%). An analytical sample was obtained as a
150.3, 150.8, 155.5, 166.0 (CO) ppm. IR (KBr): ν˜max. ϭ 1644 (CO) colourless, viscous liquid after repeated column chromatography
cmϪ1. C15H18N2OSi (270.41): calcd. C 66.63, H 6.71, N 10.36, O on silica gel using ethyl acetate/hexane (1:1) as eluent. 1H NMR
5.91, Si 10.39; found C 66.5, H 6.4, N 10.4. The fourth eluted {200 MHz, [D6]DMSO, reference [D6]DMSO (δ ϭ 2.49 ppm)}: δ ϭ
3
fraction (Rf ϭ 0.24) was identified as N-(pyrid-4-yl)-2-(trimethyl- 0.26 (s, 9 H, SiMe3), 0.87 (t, JH,H ϭ 7.2 Hz, 3 H, CH2CH3),
silyl)benzamide (7) (0.38 g; yield 14%). An analytical sample was 1.17Ϫ1.44 (m, 2 H, CH2), 1.44Ϫ1.67 (m, 2 H, CH2), 2.65 (t,
3
obtained after recrystallisation from diisopropyl ether, m.p. 3JH,H ϭ 7.5 Hz, 2 H, PyCH2), 7.32 [d, JH,H ϭ 5.0 Hz, 1 H, Py(5)-
136Ϫ137 °C. 1H NMR {200 MHz, [D6]DMSO, reference H], 7.43Ϫ7.60 (m, 2 H, Ph-H), 7.60Ϫ7.71 (m, 1 H, Ph-H),
[D6]DMSO (δ ϭ 2.49 ppm)}: δ ϭ 0.26 (s, 9 H, SiMe3), 7.44Ϫ7.86 7.71Ϫ7.83 (m, 1 H, Ph-H), 8.35 [d, 1 H, Py(6)-H], 8.46 [s, 1 H,
[m, 6 H, Ph-H, Py(3,5)-H], 8.42Ϫ8.56 [m, 2 H, Py(2,6)-H], 10.75 Py(2)-H], 10.12 (s, 1 H, NH) ppm. 13C NMR {[D6]DMSO, refer-
(s, 1 H, NH) ppm. 13C NMR {[D6]DMSO, reference [D6]DMSO ence [D6]DMSO (δ ϭ 39.5 ppm)}: δ ϭ 0.4 (SiMe3), 13.8, 22.1, 29.8,
δ ϭ 39.5 ppm)}: δ ϭ 0.1, 113.6, 126.9, 128.8, 129.7, 134.9, 138.6, 30.7 (PyCH2), 124.2, 127.2, 128.9, 129.9, 132.9, 135.1, 139.5, 141.4,
142.1, 145.8, 150.4, 170.1 (CO) ppm. IR (KBr): ν˜max. ϭ 1684 cmϪ1 146.9, 148.0, 169.5 (CO) ppm. IR (film): ν˜max. ϭ 1668 (CO) cmϪ1
.
(CO). C15H18N2OSi (270.41): calcd. C 66.63, H 6.71, N 10.36, O HRMS for C19H27N2OSi: calcd. [M ϩ 1]ϩ: 327.189267, found
5.91, Si 10.39; found C 66.7, H 6.8, N 10.4. The fifth fraction eluted 327.188800. The fourth eluted fraction (Rf ϭ 0.31 in ethyl acetate)
(Rf ϭ 0.16) proved to be starting N-(pyrid-4-yl)benzamide (3) was a yellow, viscous liquid, and was identified as N-(pyrid-3-yl)-
(0.20 g; 10%).
2-(trimethylsilyl)benzamide (12) (0.14 g, 5%). An analytical sample
was obtained as a colourless solid after repeated column chroma-
tography on silica gel using ethyl acetate/hexane (1:1) as eluent and
subsequent recrystallisation from benzene/hexane (1:4); m.p.
88Ϫ92 °C. 1H NMR {200 MHz, [D6]DMSO, reference [D6]DMSO
Reaction of N-(Pyrid-4-yl)benzamide (3) with sec-Butyllithium and
then with Chlorotrimethylsilane: The reaction was carried out ac-
cording to the procedure given for N-(pyrid-2-yl)benzamide (1)
with sec-butyllithium and then chlorotrimethylsilane. The analysis
(TLC; ethyl acetate) of the combined organic solution indicated the
presence of at least five compounds (Rf ϭ 0.70, 0.48, 0.35, 0.24 and
0.16), which were separated by the column chromatography. The
first eluted fraction was identified as ketone 4b (0.26 g, yield 16%).
The second, third, fourth and fifth fractions were identical to those
upon the reaction of amide 1 with nBuLi and TMSCl (for differ-
ences in yield see Table 1).
3
(δ ϭ 2.49 ppm)}: δ ϭ 0.25 (s, 9 H, SiMe3), 7.39 [dd, JH,H ϭ 4.7,
3JH,H ϭ 8.3 Hz, 1 H, Py(5)-H], 7.45Ϫ7.59 (m, 2 H, Ph-H),
7.59Ϫ7.73 (m, 2 H, Ph-H), 8.13Ϫ8.25 [m, 1 H, Py(4)-H], 8.30 [d,
3JH,H ϭ 3.9 Hz, 1 H, Py(6)-H], 8.88 [s, 1 H, Py(2)-H], 10.60 (s, 1
H, NH) ppm. 13C NMR {[D6]DMSO, reference [D6]DMSO (δ ϭ
39.5 ppm)}: δ ϭ 0.1 (SiMe3), 123.7, 126.6, 126.9, 128.8, 129.6,
134.9, 135.9, 138.6, 141.4, 142.2, 144.5, 169.6 (CO) ppm. IR
(CHCl3): ν˜max. ϭ 1684 (CO) cmϪ1. HRMS for C15H19N2OSi: calcd.
[M ϩ 1]ϩ: 271.126667, found 271.126500. The fifth eluted fraction
(Rf ϭ 0.27 in ethyl acetate) was a tan solid, and was identified
as N-(pyrid-3-yl)-4-(trimethylsilyl)benzamide (13) (0.88 g, 33%). An
analytical sample was obtained as a colourless solid after recrystal-
lisation from ethyl acetate/hexane (1:1); m.p. 152Ϫ154 °C. 1H
Reaction of N-(Pyrid-3-yl)benzamide (2) with n-Butyllithium and
then with Chlorotrimethylsilane: n-Butyllithium (20.0 mmol) was
added to a stirred THF (100 mL) solution of amide 2 (1.98 g,
10.0 mmol) and TMEDA (20.0 mmol) at Ϫ78 °C. The resulting
solution was stirred at Ϫ78 °C for 0.5 h and then allowed to warm
up to 0 °C. After subsequent cooling to Ϫ78 °C, chlorotrimethylsil-
ane (2.54 mL, 20.0 mmol) was added, and stirring at this tempera-
ture was continued for another 0.25 h. The resulting mixture was
allowed to reach room temperature and water (10 mL) was added.
The mixture was adjusted to pH ഠ 5 with 2.0  aqueous solution
of hydrochloric acid, the layers were separated and the organic
layer was dried with anhydrous magnesium sulfate. The analysis
(TLC; ethyl acetate) of the organic solution indicated the presence
of at least six compounds (Rf ϭ 0.75, 0.54, 0.44, 0.31, 0.27 and
0.20). All volatile materials were distilled off under reduced press-
ure, and 3.19 g of a brown, very viscous liquid was obtained. This
liquid was dissolved in acetone (50 mL) and a saturated solution
of potassium permanganate in acetone was added dropwise with
stirring at room temperature until a permanent purple colour of
the reaction mixture was obtained. The mixture was decolourised
with propan-2-ol, the separated manganese(IV) oxide was filtered
off and washed with acetone (5 ϫ 5 mL). The TLC plate (ethyl
acetate) of the acetone solution looked the same as the TLC plate
of the organic solution directly after reaction. Acetone was distilled
off under reduced pressure, and a brown, very viscous liquid was
obtained, and was separated by the column chromatography, using
ethyl acetate/hexane (1:1) as eluent. After chromatography, six frac-
tions were collected. The first and second eluted fractions (Rf ϭ
0.75 and 0.54 in ethyl acetate) were yellow, viscous liquids (0.10 g
and 0.31 g), which, according to the 1H NMR and 13C NMR spec-
NMR {200 MHz, [D6]DMSO, reference [D6]DMSO (δ
ϭ
2.49 ppm)}: δ ϭ 0.24 (s, 9 H, SiMe3), 7.45Ϫ7.68 [m, 4 H, Ph(3,4,5)-
H, Py(5)-H], 7.94Ϫ8.07 [m, 2 H, Ph(2,6)-H], 8.39 [s, 1 H, Py(2)-H],
3
8.48 [d, JH,H ϭ 4.8 Hz, 1 H, Py(6)-H], 10.18 (s, 1 H, NH) ppm.
13C NMR {[D6]DMSO, reference [D6]DMSO (δ ϭ 39.5 ppm)]}:
δ ϭ Ϫ0.9 (SiMe3), 127.6, 128.5, 128.9, 131.8, 133.8, 138.7, 146.7,
147.6, 149.1, 166.7 (CO) ppm. IR (CHCl3): ν˜max. ϭ 1680 (CO)
cmϪ1. C15H18N2OSi (270.41): calcd. C 66.63, H 6.71, N 10.36;
found C 66.59, H 6.70, N 10.48. The sixth eluted fraction (Rf ϭ
0.20 in ethyl acetate) was a yellow, viscous liquid, and appeared to
be a mixture of N-(4-butyl-pyrid-3-yl)benzamide (10) and starting
N-(pyrid-3-yl)benzamide (2) (0.41 g) in a 2.18:1.00 molar ratio
based on the 1H NMR spectrum. On the basis of this ratio, the
yield of product 10 was calculated to be 12% and the yield of reco-
vered starting amide was calculated to be 6%. The mixture was five
times heated under reflux with water (5 mL) for 10Ϫ15 min, and
each time hot water was decanted from the organic liquid. After
that, the residual liquid was dissolved in dichloromethane and dried
with anhydrous magnesium sulfate. The solvent was distilled off
under reduced pressure from the solution, and a yellow, viscous
liquid was obtained which, according to the 1H NMR and 13C
NMR spectra, appeared to be product 10, free of the starting amide
2. An analytical sample of compound 10 was obtained as a colour-
less, viscous liquid after repeated column chromatography on silica
gel, using ethyl acetate/hexane (1:1) as eluent. 1H NMR {200 MHz,
Eur. J. Org. Chem. 2004, 3254Ϫ3261
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3259

´ ´
A. Jozwiak, J. Epsztajn et al.
FULL PAPER
[D6]DMSO, reference [D6]DMSO (δ ϭ 2.49 ppm)}: δ ϭ 0.82 (t,
Competitive Lithiation Tests for Mixture of Amides 14Ϫ17: The
3JH,H ϭ 7.2 Hz, 3 H, Me), 1.10Ϫ1.38 (m, 2 H, CH2), 1.40Ϫ1.64 (m, competitive lithiation tests for the mixtures of amides 14/15, 14/16
3
2 H, CH2), 2.54Ϫ2.70 (m, 2 H, PyCH2), 7.32 [d, JH,H ϭ 4.9 Hz, 1 and 14/17 were carried out as follows: nBuLi or sBuLi (15.5 mmol)
H, Py(5)-H], 7.44Ϫ7.68 [m, 3 H, Ph(3,4,5)-H], 7.89Ϫ8.06 [m, 2 H, was added to the particular equimolecular mixture of amides
3
Ph(2,6)-H], 8.36 [d, JH,H ϭ 4.8 Hz, 1 H, Py(6)-H], 8.43 [s, 1 H, (10.0 mmol) in THF (100 mL), and the general procedure was used,
Py(2)-H], 10.12 (s, 1 H, NH) ppm. 13C NMR {[D6]DMSO, refer-
ence [D6]DMSO (δ ϭ 39.5 ppm)}: δ ϭ 13.7, 21.9, 29.9, 30.6
(PyCH2), 124.1, 127.6, 128.5, 131.8, 134.0, 147.2, 147.5, 148.5,
166.1 (CO) ppm. IR ((film): ν˜max. ϭ 1651 (CO) cmϪ1. HRMS for
C16H18N2O: calcd. [M]ϩ: 254.141913, found 254.142000.
following the periods of time and the temperature of the reactions.
Acknowledgments
This work was supported by Grant in Aid for Scientific Research
´ ´
[No. 505/261 (2002)] from the University of Łodz that is grate-
fully acknowledged.
General Procedure for the Lithiation of the Amides 14؊17: nBuLi
or sBuLi (10 mmol) was added to the anilides 14Ϫ17 (5 mmol)
with or without TMEDA (10 mmol) and stirred in THF (50 mL)
at Ϫ78 °C. In the case when nBuLi was used, two procedures were
applied. The reaction mixture was kept at Ϫ78 °C for 2 h and next
was quenched with MeOD; or the solution was kept at Ϫ78 °C for
0.25 h, warmed to 0 °C, kept at 0 °C for 0.1 h and again cooled to
Ϫ78 °C before quenching with MeOD. When sBuLi was used, the
reaction mixture was kept at Ϫ78 °C for 2 h before adding MeOD.
[1]
K. J. Kapples, G. M. Shutske, J. Heterocycl. Chem. 1997, 34,
1335Ϫ1338.
[2]
R. C. Effland, J. T. Klein, L. L. Martin, G. M. Shutske, K. J.
Kapples, J. D. Tomer IV, US Patent 5,328,920, 1994; see http://
www.uspto.gov/main/patents.htm
[3]
J. D. White, M. E. Mann, Adv. Heterocycl. Chem. 1969, 10,
The
D
content was determined by 1H NMR spectroscopy
113Ϫ147.
(500 MHz, [D6]DMSO) using the following peak areas: For Amide
[4]
R. Bonnett, S. A. North, Adv. Heterocycl. Chem. 1981, 29,
4
3
14: δ ϭ 7.94 [dd, JH,H ϭ 1.2 Hz, JH,H ϭ 8.3 Hz, 2 H, Ph1(2,6)-
341Ϫ399.
H], 7.61Ϫ7.56 [m, 1 H, Ph1(4)-H] ppm. For Amide 15: δ ϭ
8.17Ϫ8.09 [m, 1 H, Py(3)-H], 8.06 [dd, JH,H ϭ 1.7 Hz, JH,H
7.7 Hz, 1 H, Py(4)-H] ppm. For Amide 16: δ ϭ 8.75 [dd, JH,H
[5]
´ ´
´
J. Epsztajn, A. Jozwiak, K. Czech, A. K. Szczesniak, Monatsh.
Chem. 1990, 121, 909Ϫ921.
4
3
ϭ
ϭ
4
[6]
[7]
[8]
[9]
´ ´
´
J. Epsztajn, A. Jozwiak, A. K. Szczesniak, Tetrahedron 1993,
3
4
1.4 Hz, JH,H ϭ 4.4 Hz, 2 H, Py(2,6)-H], 7.85 [dd, JH,H ϭ 1.4 Hz,
49, 929Ϫ938.
3JH,H ϭ 4.4 Hz, 2 H, Py(3,5)-H] ppm. For Amide 17: δ ϭ 7.83 [d,
´ ´
´
J. Epsztajn, A. Jozwiak, A. K. Szczesniak, Synthetic Commun.
1994, 24, 1789Ϫ1798.
J. Epsztajn, R. Grzelak, A. Jozwiak, Synthesis 1996,
3JH,H ϭ 7.8 Hz, 2 H, Ph1(2,6)-H], 7.15 [t, JH,H ϭ 7.5 Hz, 1 H,
3
´ ´
Ph2(4)-H] ppm. In the case of the reaction of N-phenylpyridine-2-
carboxamide (15), on increasing the temperature to 0 °C, analysis
(TLC; diisopropyl ether) showed anilide 15 (Rf ϭ 0.39) and two
additional spots (Rf ϭ 0.48, 0.57). Preparative TLC (diisopropyl
ether) resulted in three fractions. The first one (Rf ϭ 0.57) was a
1212Ϫ1216.
´ ´
J. Epsztajn, A. Jozwiak, P. Kołuda, I. Sadokierska, I. D. Wil-
kowska, Tetrahedron 2000, 56, 4837Ϫ4844.
[10]
[11]
[12]
[13]
P. Beak, V. Snieckus, Acc. Chem. Res. 1982, 10, 306Ϫ312.
N. S. Narasimhan, R. S. Mali, Synthesis 1983, 957Ϫ986.
P. Beak, A. I. Meyers, Acc. Chem. Res. 1986, 19, 356Ϫ363.
N. S. Narasimhan, R. S. Mali, Top. Curr. Chem. 1987, 138,
63Ϫ147.
1
yellow, viscous liquid (36 mg), which, according to the H and 13C
NMR spectra, appeared to be an undefined, complex mixture, and
no further attempts at its identification were undertaken. The se-
cond fraction (Rf ϭ 0.48) was a mixture of 1-(pyridin-2-yl)pentan-
1-one (18) and 6-butyl-N-phenylpyridine-2-carboxamide (19) in a
molar ratio of 2:1. Kugelrohr distillation (oil bath 190 °C, 20 Torr,
ref.[35] b.p. 60/0.4 Torr) gave the ketone 18 (65 mg, 0.4 mmol) (yield
[14]
[15]
V. Snieckus, Chem. Rev. 1990, 90, 879Ϫ933.
´
´ ´
J. Epsztajn, A. Bieniek, J. Z. Brzezinski, A. Jozwiak, Tetra-
hedron Lett. 1983, 24, 4735Ϫ4738.
J. Epsztajn, A. Bieniek, M. W. Płotka, J. Chem. Research (S)
1986, 20Ϫ21; (M), 0442Ϫ0474.
J. Epsztajn, A. Bieniek, J. A. M. W. Płotka, K. Suwald, Tetra-
hedron 1989, 45, 7469Ϫ7476.
J. Epsztajn, A. Bieniek, J. Kowalska, Tetrahedron 1991, 47,
[16]
[17]
[18]
[19]
[20]
1
8%). H NMR [200 MHz, CDCl3, reference TMS (δ ϭ 0.0 ppm)]:
δ ϭ 0.91Ϫ0.99 (m, 3 H, Me), 1.34Ϫ1.52 (m, 2 H, CH2), 1.64Ϫ1.81
(m, 2 H, CH2), 3.17Ϫ3.27 (m, 2 H, CH2), 7.42Ϫ7.51 [m, 1 H, Py(5)-
4
3
H], 7.83 [dd, JH,H ϭ 1.7 Hz, JH,H ϭ 7.7 Hz, 2 H, Py(4)-H], 8.04
1697Ϫ1706.
3
3
J. Epsztajn, A. Bieniek, J. A. Kowalska, Monatsh. Chem. 1996,
127, 701Ϫ715.
J. Epsztajn, Z. Malinowski, J. Brzezinski, M. Karzatka, Syn-
[d, JH,H ϭ 7.9 Hz, 1 H, Py(3)-H], 8.68 [d, JH,H ϭ 4.8 Hz, 1 H,
Py(6)-H] ppm. 13C NMR [CDCl3, reference TMS (δ ϭ 0.0 ppm)]:
δ ϭ 13.9, 22.4, 26.1, 37.4, 121.7, 126.9, 136.8, 148.8, 153.5, 202.1
(CO) ppm. IR (film): ν˜max. ϭ 1699 (CO) cmϪ1. The residue from
the distillation was initially purified by column chromatography
(acetone). The eluate was purified by evaporation of the solvent
and kugelrohr distillation (oil bath 180 °C, 5 Torr) to give 6-butyl-
N-phenylpyridine-2-carboxamide (19) (51 mg, 0.2 mmol, yield 4%).
1H NMR [200 MHz, CDCl3, reference TMS (δ ϭ 0.0 ppm)]: δ ϭ
0.91Ϫ0.99 (m, 3 H, Me), 1.34Ϫ1.52 (m, 2 H, CH2), 1.64Ϫ1.81 (m,
2 H, CH2), 3.17Ϫ3.27 (m, 2 H, CH2), 7.09Ϫ7.19 [m, 1 H, Ph(4)-
H], 7.28Ϫ7.44 [m, 3 H, Ph(3,5), Py(5)-H], 7.73Ϫ7.84 [m, 3 H,
´
thesis 2001, 2085Ϫ2090.
[21]
[22]
[23]
J. A. Turner, J. Org. Chem. 1983, 48, 3401Ϫ3408.
J. A. Turner, J. Org. Chem. 1990, 55, 4744Ϫ4750.
C. Metallionos, S. Nerdinger, V. Snieckus, Org. Lett. 1999, 1,
1183Ϫ1186.
C. G. Hartung, V. Snieckus, in Modern Arene Chemistry (Ed.:
D. Astruc), Wiley-VCH Verlag Gmbh and KGaA, Weinheim,
2002, pp. 330Ϫ367.
L. Pentimalli, Tetrahedron 1960, 9, 194Ϫ201.
E. H. Huntress, H. C. Walter, J. Org. Chem. 1948, 13, 735Ϫ737.
D. B. MacQueen, K. S. Schanze, J. Am. Chem. Soc. 1991,
113, 6108Ϫ6110.
A. I. Vogel, in Elementary Practical Organic Chemistry, Long-
mans, Green and Co. Ltd., London, New York, Toronto, 1959,
pp. 243Ϫ244.
[24]
[25]
[26]
[27]
3
Ph(2,6), Py(4)-H], 8.11 [d, JH,H ϭ 7.7 Hz, 1 H, Py(3)-H], 10.12
[br. s, 1 H, NH] ppm. 13C NMR [CDCl3, reference TMS (δ ϭ
0.0 ppm)]: δ ϭ 13.9, 22.4, 31.6, 37.6, 119.7, 124.2, 125.6, 129.0,
137.7, 137.8, 149.1, 161.2, 162.3 (CO) ppm. IR (film): ν˜max. ϭ 1689
(CO) cmϪ1. The third fraction (Rf ϭ 0.39) was the anilide 15
(729 mg, 4 mmol, yield 80%).
[28]
[29]
H. Brunner, B. Nuber, M. Prommesberger, J. Organomet.
Chem. 1996, 523, 179Ϫ185.
3260
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3254Ϫ3261

ortho-Directed Lithiation of Masked Aromatic Carboxylic Acids
FULL PAPER
P. G. Gassman, G. D. Richmond, J. Org. Chem. 1966, 31,
2355Ϫ2357.
[30]
[33]
[34]
[35]
Y.-T. Park, C.-H. Jung, K.-W. Kim, J. Org. Chem. 1999, 64,
8546Ϫ8556.
[31]
P. C. J. Kamer, R. J. M. Nolte, W. Drenth, J. Am. Chem. Soc.
M. A. Al.-Aseer, S. G. Smith, J. Org. Chem. 1984, 49,
1988, 110, 6818Ϫ6825.
K. Kondo, E. Sekimoto, J. Nakao, Y. Murakami, Tetrahedron
2608Ϫ2613.
[32]
R. J. Sundberg, J. Am. Chem. Soc. 1966, 88, 3781Ϫ3789.
Received March 9, 2004
2000, 56, 5843Ϫ5856.
Eur. J. Org. Chem. 2004, 3254Ϫ3261
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3261