Deprotonation of pyridine carboxamides using lithium magnesiates bases

Article abstract of DOI:10.1016/j.tet.2008.01.064

Regioselective deprotonation of N-methyl- and tert-butylpyridine carboxamides using lithium magnesiates bases was achieved at room temperature avoiding nucleophilic addition on the pyridine molecule and auto-condensation of the arylmetal intermediates on

Full text of DOI:10.1016/j.tet.2008.01.064

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 3236e3245
www.elsevier.com/locate/tet
Deprotonation of pyridine carboxamides using lithium magnesiates bases
´
Hac¸an Hawad, Omar Bayh, Christophe Hoarau, Francois Trecourt, Guy Queguiner,
´
*
Francis Marsais
Laboratoire de Chimie Organique Fine et He´te´rocyclique, UMR 6014-CNRS, INSA et Universite´ de Rouen, IRCOF-INSA de Rouen,
BP 08 76131 Mont-Saint-Aignan Ce´dex, France
Received 30 November 2007; received in revised form 11 January 2008; accepted 14 January 2008
Available online 19 January 2008
Abstract
Regioselective deprotonation of N-methyl- and tert-butylpyridine carboxamides using lithium magnesiates bases was achieved at room
temperature avoiding nucleophilic addition on the pyridine molecule and auto-condensation of the arylmetal intermediates on the amide group
was described. The hydrogenemagnesium exchange was evidenced using 1H NMR spectroscopy at room temperature and the reactivity of the
lithium 2-, 3- and 4-carboxamidopyridinylmagnesiates complexes towards electrophiles and in cross-coupling reactions was studied.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Pyridine carboxamides; Magnesiation; Magnesiate base
1. Introduction
of aromatics flanked with high electrophilic functions such as
esters of benzene and thiophene.3 More recently, lithium
triisobutyl(tetramethylpiperidino)aluminate (tBu3AlTMPLi)
has been designed for the generation of aryl and heteroaryl-
aluminate complexes mainly at room temperature.3 Mulvey
and co-workers reported in 1999 the preparation of a mixed-
metal sodiumemagnesium macrocyclic amide, which has
been used for the site selective dideprotonation of benzene
and toluene.4 Richey and co-workers observed in 2004 that
treatment of benzene halides with magnesiates partially re-
sulted in benzyne formation.5 Since 2001, our group has
been interested in deprotonation of heteroaromatics using lith-
ium magnesiates as deprotonative agent. We recently disclosed
the deprotonation of chloro and fluoropyridines, thiophene,
oxazole and benzoxazole derivatives.6 In this paper, we wish
to report on the deprotonation of N-methyl- and N-tert-butyl-
pyridine carboxamides with lithium magnesiates as deprotona-
tive agents. The hydrogenemagnesium exchange was
Directed ortho-metallation (DoM) is one of the most
important reaction for functionalization of heterocycles.1 Lithi-
ation using alkyllithium and lithium amides has been exten-
sively and mainly developed since lithiated species display
a high reactivity towards many electrophilic functions. Never-
theless, lithiation often requires low-temperature conditions
and the lithiated species can be hardly involved in cross-
coupling reactions. Direct magnesiation at higher temperature
using Grignard and Hauser bases has been first explored but
due to the weak reactivity of these bases the scope of this
method is rather narrow until now. Since the past decade,
the zinc, magnesium and aluminium ate complexes appeared
as new emerging deprotonating agents for chemo and regiose-
lective generation of aryl and heteroarylmetal complexes.2
Kondo and co-workers reported in 1999 the first use of lithium
di(tert-butyl)(tetramethylpiperidino)zincate (tBu2ZnTMPLi)
for regio and chemoselective zincatation at room temperature
1
evidenced using H NMR spectroscopy and the reaction of
the resulting lithium 2-, 3- and 4-carboxamidopyridinylmag-
nesiate complexes with electrophiles and in cross-coupling
reactions was later checked.
* Corresponding author. Tel.: þ33 02 35 52 24 75; fax: þ33 02 35 52 29 62.
E-mail address: francis.marsais@insa-rouen.fr (F. Marsais).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.064

H. Hawad et al. / Tetrahedron 64 (2008) 3236e3245
3237
2. Results and discussions
in THF. Mulzer and co-workers reported the first magne-
siation of N-tert-butylpicolinamide (2) using Hauser’s base
TMPMgCl but a higher temperature (65 ꢁC) and a large excess
of base (6 equiv) was needed to ensure an efficient deproto-
nation.8 Thus, we describe here an improved method of
picolinamide magnesiation at room temperature. We further
investigated the magnesiation of 4-chloro-N-tert-butylpicolin-
amide (3). A quantitative regioselective incorporation of deu-
terium between the two ortho-directing groups was observed
by treating 3 with 1 equiv of Bu3MgLi followed by quenching
the lithium magnesiate intermediate with D2O (Table 1, entry
5). Furthermore, I2 and 3,4,5-trimethoxybenzaldehyde were
successfully reacted to give the C3 substituted products 3b
and 3c in 64 and 50% yields (Table 1, entries 6 and 7).
2.1. Deprotonation of N-alkylpicolinamides with lithium
magnesiate bases
Deprotonation of N-methyl and N-tert-butylpicolinamides
(1 and 2) was first attempted with lithium tributyl magnesiate
(Bu3MgLi) as deprotonative agent at room temperature
(Table 1). The reaction was carried out using 1 equiv of Bu3-
MgLi in THF for 2 h. The lithium magnesiate intermediate
was reacted with D2O affording the C3 deuterated compounds
1a and 2a in 40 and 95% yields, respectively (Table 1, entries
1 and 2).
The use of 2/3 equivof Bu3MgLi corresponding to astoichio-
metric amount of base only led to poor or medium deuterium
incorporation, 10 and 65% of 1a and 2a, respectively, from 1
and 2. Furthermore, the use of 1 equiv of Bu3MgLi and a longer
4 h metallation time did not improve the deuterium incorpora-
tion since 1a was obtained in only 39% yield after D2O quench-
ing. N-tert-Butylamide appeared to be a better DoM group than
N-methylamide as already described for lithiation. Thus,
Epsztajn and co-workers demonstrated that N-methyl picolin-
amide (1)7 reacted in THF at ꢀ78 ꢁC with n-BuLi (2 equiv) to
give a low 32% conversion of N- and C3-dilithiated picoline am-
ide. In contrast, N-tert-butylpicolinamide (2) was lithiated by
Mulzer and co-workers8 with n-BuLi (2 equiv) at ꢀ78 ꢁC and
allowed to react at ꢀ18 ꢁC with N-formylpiperidine (NFMP)
to give the corresponding C3 formylpicolinamide in modest
48 and 60% yields operating in THF or Et2O, respectively.
The lithium magnesiate intermediate obtained by treating 2
with Bu3MgLi was reacted with I2 and 3,4,5-trimethoxybenz-
aldehyde to afford the corresponding C3 substituted
compounds 2b and 2c in 55 and 82% yields (Table 1, entries
3 and 4). Unfortunately the efficiency of the hydrogenemag-
nesium exchange could not be directly checked by recording
2.2. Deprotonation of N-alkylnicotinamides with lithium
magnesiates bases
It is well known that alkyllithiums could not be used for de-
protonation of nicotinamides due to competitive 1,4-addition
and lithiation could only be achieved using lithium amides.9
Similarly, we previously reported that treatment of N-tert-
butylnicotinamide (6) with MgBu2 or the more steric hindered
iPrMgCl exclusively led to 1,4-nucleophilic addition on the
pyridine nucleus.10 Mulzer and co-workers have employed
this latter process to prepare 4-arylnicotinamides by nucleo-
philic addition of arylmagnesium bromide to N-methyl and
N-tert-butylnicotinamides (4 and 6).9e Mulzer also reported
the unique example of deprotonation of N,N-diethylnicotin-
amide using Hauser’s base TMPMgCl.8
Deprotonation of N-methylnicotinamide (4) with 1 equiv of
Bu3MgLi in THF at room temperature for 2 h (Table 2, entry
1) followed by trapping the lithium magnesiate intermediate
with I2 afforded exclusively 4-butyl N-methylnicotinamide
(5) in quantitative amounts. We then turned to the use of
mixed lithium magnesiate bases such as lithium alkylamido-
magnesiates Bu2TMPMgLi, BuTMP2MgLi and BuTMP3-
MgLi2 and lithium tri(amido)magnesiate TMP3MgLi.
1
the H NMR spectra of lithium N-tert-butyl-2-carboxamido-
pyridinylmagnesiate complex, which appears to be insoluble
Table 1
C3 substitution of N-methyl and N-tert-butylpicolinamides (1e3)
Table 2
Assays of deprotonation of N-methylnicotinamide (4) using lithium magne-
siate bases
R2
R2
1. Bu3MgLi (1equiv.),
2h, r.t., THF
2.Electrophile
E
NHR1
NHR1
D
N
O
O
Bu
N
O
N
N
1. Base (1 equiv.)
2h, r.t., THF
NHMe
NHMe
O
O
NHMe
+
R1= Me, R2=H
R1=tBu, R2 =H
R1=tBu, R2 =Cl
1
2
3
2 D2O
N
4
4a-c
5
Entry Base
Electrophile, E
4-Substituted
nicotinamidea (%)
5a (%)
Entry
1
R1
R2
H
Electrophile, E
D2O, D
Product
Yielda
40
CH3
1a
1
2
3
4
5
Bu3MgLi
D2O, D
d
d
100
48
Bu2TMPMgLi
BuTMP2MgLi
BuTMP3MgLi2
TMP3MgLi
2
3
4
5
6
7
a
H
D2O, D
I2, I
2a
2b
2c
3a
3b
3c
95
55
82
80
61
4a
4a
4a
d
d
d
H
H
ArCHO, CH(OH)Ar
D2O, D
I2, I
ArCHO,b CH(OH)Ar
82
tBu
Cl
Cl
Cl
100
64
6
7
BuTMP2MgLi I2, I
78
4b
4c
d
d
BuTMP2MgLi ArCHO,b Ar(CH)OH 62
50
a
Yield of isolated products.
ArCHO¼3,4,5-trimethoxybenzaldehyde.
Yield of isolated product.
ArCHO¼3,4,5-trimethoxybenzaldehyde.
b
b

3238
H. Hawad et al. / Tetrahedron 64 (2008) 3236e3245
Comparative results depicted in Table 2 (entries 2e5) showed
that the best deuterium incorporation was obtained using the
BuTMP2MgLi as base. Quenching with D2O gave the C4
deuterio compound 4a in 82% yield (Table 2, entry 3). The
lithium N-methyl-3-carboxamidopyridinylmagnesiate com-
plex was then trapped by I2 and 3,4,5-trimethoxybenzaldehyde
to provide the corresponding 4-substituted compounds 4b and
4c in good yields (Table 2, entries 6 and 7). Treatment of
N-tert-butylnicotinamide (6) with BuTMP2MgLi was further
Moreover, the use of I2 as electrophile led to the dimeric
side-product 12 in 33% yield (entry 7). This could be avoided
by replacing BuTMP2MgLi by BuTMP3MgLi2. The employ-
ment of BuTMP3MgLi2 gave similar results than the use of
BuTMP2MgLi for deuterium and halogen incorporation at
C4 position of 7 (Table 3, entries 7 and 8) but surprisingly
the novel lithium 6-chloro-N-tert-butylnicotinylmagnesiate
complex formed by treatment of 7 with BuTMP3MgLi2 re-
vealed to be unreactive towards 4-chlorobenzaldehyde even
using an excess (Table 3, entry 9).
1
investigated and we recorded the H NMR spectrum of the
resulting lithium magnesiate complex where the complete
disappearance of the H4 signal of the starting material was
clearly observed. Surprisingly, an important shielding of H6
2.3. Deprotonation of N-alkylisonicotinamides with lithium
magnesiates bases
1
at the meta position of magnesium atom was noticed in H
NMR spectra (8.02 ppm instead of 8.72 ppm for the starting
material) (Scheme 1).
Epsztajn and co-workers first demonstrated that N-methyl-
isonicotinamide (8) reacted in THF with 2 equiv of n-BuLi
to give the corresponding lithiated amide with poor 30%
yield.7 We recently reported that N-tert-butylisonicotinamide
(10) reacts with Bu2Mg in THF under reflux to give
after quenching with D2O a low deuterium incorporation at
C3 position. The 1,2-butyl addition product was mainly
formed.10
Deprotonation of N-methylisonicotinamide (8) was suc-
cessfully achieved using 1 equiv of Bu3MgLi base at room
temperature for 2 h (Table 4). Quenching the lithium magnesi-
ate intermediate with D2O, I2 and C2Cl6 afforded the C3
monosubstituted N-methylisonicotinamides 8aec and the
3,4-disubstituted N-methylisonicotinamides 9aec were also
formed in moderate yields (Table 4, entries 1e3). Increase
of the steric hindrance on the amide function allowed to avoid
the second metallation. Treatment of 10 with 1 equiv of
Bu3MgLi at room temperature in THF for 2 h led to clean hy-
drogenemagnesium exchange as showed in the 1H NMR
spectra of the lithium N-tert-butyl-4-carboxamidopyridinyl-
magnesiate complex (Scheme 2). As previously observed an
It appeared then that the structure of the lithium N-tert-butyl-
3-carboxamidomagnesiate complex is different from the one
proposed in Scheme 1 using the dual basicity of BuTMP2-
MgLi,11 i.e., first the deprotonation of the secondary amide
function with the butyl group of BuTMP2MgLi followed by
a second deprotonation of the pyridine molecule with a TMP
group (Scheme 1). Actually, we suspected the existence of
aggregates in which the pyridine nitrogen atom would interfere
as metal ligand. High field NMR studies are currently under-
taken to bring more precise structural informations.
The lithium N-tert-butyl-3-carboxamidopyridinylmagne-
siate complex was then reacted with various electrophiles to
give the corresponding 4-substituted nicotinamides 6aee in
54e64% yields (Table 3, entries 1e5). 6-Chloro-N-tert-butyl-
nicotinamide (7) was further treated with 1 equiv of BuTMP2-
MgLi before quenching the lithium magnesiate intermediate
with D2O, I2, C2Cl6 and 4-chlorobenzaldehyde to afford
the corresponding 4-substituted-6-chloro-N-tert-butylnicotin-
amides 7aed in moderate yields (Table 3, entries 6e9).
TMP
Li
TMP
Mg
Li
Mg
N
O
O
TMP
4
BuTMP2MgLi
(1 equiv)
O
5
6
5
6
4
N
N
H
5
6
N
2
2
-TMPH
-BuH
N
2
N
H2
H5
H4
H6
NH
H6
H5
H2
Scheme 1. 1H NMR spectra of lithium N-tert-butyl-3-carboxamidopyridinylmagnesiate.

H. Hawad et al. / Tetrahedron 64 (2008) 3236e3245
3239
Table 3
C4 substitution of N-methylnicotinamide (6) and 6-chloro-N-methylnicotinamide (7)
N
N
Cl
O
E
N
O
O
t
BuNH
1. Bu(TMP)2MgLi (1 equiv.)
NHtBu
1h, r.t., THF
NHtBu
O
NH tBu
2.Electrophile
R
R
N
Cl
6a-6e
7a-7d
R= H 6
R= Cl 7
12
Entry
R
Electrophile, E
Product
Yielda
1
2
3
4
5
H
H
H
H
H
D2O
I2, I
6a
6b
6c
6d
6e
64
55
54
60
60
C2Cl6, Cl
TMSCl, TMS
ArCHO, CH(OH)Ar
6
7
8
9
a
Cl
Cl
Cl
Cl
D2O, D
I2, I
C2Cl6, Cl
ArCHO,e CH(OH)Ar
7a
7b
7c
7d
58 (68)c
45b (55)c,d
54 (50)c
50 (0)c
Isolated yields.
b
c
d
e
Dimmer compound 12 was formed in 33% isolated yield.
Isolated yield using BuTMP3MgLi2.
Compound 12 was not formed.
ArCHO¼4-chlorobenzaldehyde.
important shielding of the H-6 proton was observed
(8.28 ppm instead of 8.73 ppm for the starting isonicotin-
amide). Actually, we suspected the existence of aggregates
in which the pyridine nitrogen atom would interfere as metal
ligand, thus changing the magnetic environment of the H-6
proton. High field NMR studies and quantum computations
are currently undertaken to bring more precise structural
informations.
The N-tert-butyl-4-carboxamidopyridinylmagnesiate com-
plex was then quenched with electrophiles affording the
C3-monsubstituted products 10aef in goods yields (Table 4,
entries 4e9). We further investigated the magnesiation of
2-chloro-N-tert-butylisonicotinamide (11) using 1 equiv of
Bu3MgLi. Trapping the lithium magnesiate intermediate
with D2O and I2 afforded the expected C3 deuterated and
iodo products 11a and b in poor 42 and 39% yields,
Table 4
Assays of magnesiation of N-methyl and N-tert-butylisonicotinamides (8e11) using Bu3MgLi base
NHR1
NHR1
O
O
NHR1
E
O
1. Bu 3MgLi (1 equiv.)
2h, r.t., THF
E
E
+
2.Electrophile
R2
R2
N
N
R2
N
R =Me,R2=H
8
1
t
R = Bu, R2=H 10
1
t
R = Bu, R2=Cl 11
1
Entry
R1
R2
H
Electrophile, E
Monosubstituted (%)a
Product
Disubstituted (%)a
Product
1
2
3
D2O, D
I2, I
C2Cl6, Cl
62
57
44
8a
8b
8c
20
15
16
9a
9b
9c
Me
4
D2O, D
I2, I
Br2, Br
100
66
10a
10b
10c
10d
10e
10f
d
d
5
6
H
43
62
7
tBu
C2Cl6, Cl
TMSCl, TMS
ArCHO,b CH(OH)Ar
D2O, D
d
d
d
d
d
8
94
75
42 (80)c
39 (66)c
9
10
11
a
Cl
11a
11b
I2, I
Yield of isolated products.
ArCHO¼3,4,5-trimethoxybenzaldehyde.
b
c
Bu3MgLi was replaced by Bu4MgLi2.

3240
H. Hawad et al. / Tetrahedron 64 (2008) 3236e3245
Li
Li
Bu
H
N
N
O
N
Mg
O
O
Bu
Bu
Mg
5
6
Bu3MgLi (1 equiv)
2h, r.t, THF
5
6
3
5
3
2
6
2
N
2
N
N
Scheme 2. 1H NMR spectra of lithium N-tert-butyl-4-carboxamidopyridinylmagnesiate.
respectively (Table 4, entries 10 and 11). Nevertheless, the use
of the higher order dilithium tetrabutylmagnesiate Bu4MgLi2
allowed an excellent incorporation of deuterium and iodide
at C3 position of 11 (Table 4, entry 10e11).
Ni(acac)2 and PPh3, were used.6 The results are depicted in
Table 5. Surprisingly, only N-tert-butylisonicotinamide (10)
could be coupled with 2-chloropyridine in modest 47% yield
under nickel catalysis (Table 5, entry 6).
3. Conclusion
2.4. First attempts at cross-coupling for lithium carbox-
amidopyridinylmagnesiate complexes with arylhalides
This present work described the first systematic study of
regioselective deprotonation of N-methyl- and tert-butylpico-
line, nicotine and isonicotinamide using lithium alkyl- and
amidomagnesiate bases at room temperature. The use of
magnesiates allows the regioselective ortho-magnesiation
avoiding nucleophilic addition on the pyridine nucleus and
auto-condensation of the arylmetal intermediates on the
amide group. The lithium tri- and tetrabutylmagnesiates
Bu3MgLi and Bu4MgLi2 were specifically designed for
magnesiation of N-alkylisonicotinamide and picolinamide at
C3 whereas the mixed lithium alkylamidomagnesiate
BuTMP2MgLi was selected for magnesiation of the N-alkyl-
nicotinamide to avoid 1,4-addition of a butyl group. The
optimized magnesiation conditions were successfully ex-
tended to chlorocarboxamidopyridines. We also demonstrated
that the new lithium carboxamidopyridinylmagnesiate com-
plexes display a good reactivity towards electrophiles. A pre-
liminary study on the reactivity of the latter in cross-coupling
reactions with 2-halopyridine was achieved. It revealed that
only N-tert-butylisonicotinamide (10) could be coupled with
2-chloropyridine under nickel catalysis in modest 47% yield.
A broad screening of catalytic systems is being currently
undertaken. These first results clearly showed that the reac-
tivity of the lithium carboxamidopyridinylmagnesiates seems
to be highly dependent on the structure of the complex. Fur-
As last part of this study, the pyridine lithium magnesiate
complexes obtained by deprotonation of N-tert-butylpicolina-
mide (2) and N-tert-butylisonicotinamide (10) with Bu3MgLi
base and N-tert-butylnicotinamide (6) with BuTMP2MgLi
under optimized conditions as described beforehand were
engaged in palladium cross-coupling reactions with 2-bromo
and 2-chloropyridine. Two catalyst systems previously
designed by the laboratory, PdCl2dppf (5 mol %), and
Table 5
Assays of magnesiation of N-tert-butylpyridine carboxamides 2, 6 and 10 fol-
lowed by in situ catalyzed cross-coupling reactions with 2-halopyridines
H
O
H
N
N
1. Base (1 equiv.),
2h, r.t., THF
O
2.Catalyst
, 18h, Δ
N
N
N
(3 equiv)
2, 6, 10
13,14,15
N
X
Entry Substrate Base
X
Catalyst
Product Yielda (%)
1
2
3
2
Bu3MgLi
BuTMP2MgLi
Bu3MgLi
Br PdCl2(dppf)
(5 mol %)
13
14
15
d
d
d
6
10
4
5
6
2
Bu3MgLi
BuTMP2MgLi
Bu3MgLi
Cl Ni(acac)2, PPh3 13
d
d
47
1
6
10
(5 mol %)
14
15
thermore, an important shielding in H NMR spectroscopy
of one proton ortho to the pyridine nitrogen could be ob-
served in the case of nicotine and isonicotinamides. These
a
Yield of isolated product.

H. Hawad et al. / Tetrahedron 64 (2008) 3236e3245
3241
observations may be related to a particular interaction be-
tween metal and pyridine nitrogen. More advanced NMR
studies are currently done.
NMR (75 MHz, CDCl3) d ppm 163.9, 152.7, 150.8, 146.4,
122.2, 120.1, 52.8, 29.0. Anal. Calcd for C10H13ClN2O: C,
56.47; H, 6.16; N, 13.17. Found: C, 56.34; H, 6.68; N, 13.07.
4. Experimental section
4.2.2. Preparation of 4-chloro N-(tert-butyl)picolinamide (3)
Thionyl chloride (30 ml) was added to picolinic acid
(40 mmol) and sodium bromide (0.4 g, 4 mmol) at room tem-
perature under N2. The resulting mixture was stirred at reflux
for 24 h. After evaporation of thionyl chloride under reduced
pressure, the crude product was dissolved in CH2Cl2 (30 ml)
and the resulting solution was cooled at 0 ꢁC before dropwise
addition of tert-butylamine (80 mmol). After stirring 20 h at
room temperature, aq K2CO3 (2 M, 40 ml) was added and
the separated aqueous layer was extracted with CH2Cl2. The
combined organic phases were dried (MgSO4) and evaporated
under reduced pressure to give crude 3.
4.1. General
Tetrahydrofuran (THF) and diethyl ether (Et2O) were
pre-dried with pellets of KOH and distilled over sodium
benzophenone ketyl under Ar before use. CH2Cl2, NEt3 and
toluene were distilled from CaH2. Methanol and ethanol
were distilled from magnesium turning. Dimethylacetamide
˚
was stored over 4 A molecular sieves before distillation. Flash
chromatographic separations were done on Merck silica gel
(70e230 mesh). The melting points were measured on a Kofler
1
melting point apparatus and were not corrected. The H and
13C NMR spectra were recorded on a Bruker Avance-300
spectrometer operating at 300 MHz. Infrared spectra were
recorded on a PerkineElmer FTIR 1650 spectrophotometer.
Elemental analyses were carried out on a Carlo Erba 1160.
Commercially available starting materials were used without
further purification.
4.2.2.1. N-(tert-Butyl)-4-chloropyridine-2-carboxamide (3). Col-
umn chromatography on silica gel (CH2Cl2) afforded 3 (6.0 g,
1
26.8 mmol, 70%) as a solid. Mp <44 ꢁC. H NMR (300 MHz,
CDCl3) d ppm 8.32 (d, J¼5.1 Hz, 1H), 8.07 (d, J¼2.1 Hz, 1H),
7.83 (s, 1H), 7.30 (dd, J¼5.1, 2.1 Hz, 1H), 1.39 (s, 9H). 13C
NMR (75 MHz, CDCl3) d ppm 162.4, 152.6, 149.0, 146.1,
126.3, 122.6, 51.4, 29.0. Anal. Calcd for C10H13ClN2O: C,
56.47; H, 6.16; N, 13.17. Found: C, 55.94; H, 6.32; N, 13.35.
4.2. Starting materials
N-Methyl and (tert-butyl)pyridine carboxamides 1, 2, 4, 6,
8 and 10 were prepared from a procedure described in the
literature.6,7,12,13
4.3. General procedure of deprotonation using lithium
tributyl magnesiate (Bu3MgLi) and condensation with
D2O as external quench
4.2.1. Preparation of 6-chloro N-(tert-butyl)nicotinamide
(7) and 2-chloro N-(tert-butyl)isonicotinamide (11)
To a solution of MgBr2 (2.0 mmol) in THF (3 ml) at
ꢀ10 ꢁC was added BuLi (6 mmol). After stirring for 1 h at
room temperature, the required pyridocarbaxamides 1e4, 8,
10 and 11 were added (2 mmol). After 2 h at room tempera-
ture, D2O (8 mmol) was added and the mixture stirred for
2 h at room temperature before addition of satd aq NH4Cl
(1 ml). The product was extracted with CH2Cl2, the combined
organic phases dried (MgSO4) and evaporated under reduced
pressure. Column chromatography on silica gel (CH2Cl2/
Et2O 1:1) afforded the deuteriopyridine carboxamides 1a,
2a, 3a, 10a and 11a in yields indicated in Tables 1e4 except
from compound 4 for which the product of 1,4-butyl addition
5 was only obtained and except from compound 8 for which
a mixture of C3 monodeuterated compound 8a and C-3,5-di-
deuterated compound 9b was obtained (see Table 4).
6-Chloronicotinic acid or 2-chloroisonicotinic acid
(65 mmol) and thionyl chloride (30 ml) were heated under
reflux for 2 h under N2. After evaporation of thionyl chloride
under reduced pressure, the crude acyl chloride was dissolved
in CH2Cl2 (100 ml) and the resulted solution was cooled at
0 ꢁC before addition of tert-butylamine (130 mmol). After stir-
ring 20 h at room temperature, the product was extracted with
EtOAc. The combined organic phases were dried (MgSO4)
and evaporated under reduced pressure to give crude 7 and 11.
4.2.1.1. N-(tert-Butyl)-6-chloropyridine-3-carboxamide (7). Col-
umn chromatography on silica gel (CH2Cl2) afforded 7 (12 g,
57.2 mmol, 88%) as a white solid. Mp 108e109 ꢁC. 1H NMR
(300 MHz, CDCl3) d ppm 8.61 (d, J¼2.4 Hz, 1H), 7.96 (dd,
J¼8.3, 2.4 Hz, 1H), 7.33 (d, J¼8.3 Hz, 1H), 5.81 (s, 1H),
1.41 (s, 9H). 13C NMR (75 MHz, CDCl3) d ppm 163.4,
154.1, 148.2, 138.1, 130.8, 124.6, 52.7, 29.1. Anal. Calcd
for C10H13ClN2O: C, 56.47; H, 6.16; N, 13.17. Found: C,
56.38; H, 6.08; N, 13.15.
4.3.1. 4-Butyl-N-(tert-butyl)pyridine-3-carboxamide (5)
Column chromatography on silica gel (CH2Cl2) afforded 5
from 4 (284 mg, 1.48 mmol, 74%) as a brown solid. Mp 61e
1
62 ꢁC. H NMR (300 MHz, CDCl3) d ppm 8.46 (s, 1H), 8.44
(d, J¼5.1 Hz, 1H), 7.11 (d, J¼5.1 Hz, 1H), 5.85 (m, 1H), 2.96
(d, J¼4.9 Hz, 1H), 2.73 (t, J¼7.9 Hz, 2H), 1.52 (m, 2H), 1.30
(m, 2H), 0.86 (t, J¼7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3)
d ppm 168.7, 150.9, 150.1, 147.5, 133.0, 124.9, 32.7, 32.4,
26.8, 22.7, 14.1. Anal. Calcd for C11H16N2O: C, 68.72; H,
8.39; N, 14.57. Found: C, 68.22; H, 8.46; N, 14.38.
4.2.1.2. N-(tert-Butyl)-2-chloropyridine-4-carboxamide (11)14. Col-
umn chromatography on silica gel (CH2Cl2) afforded 11 (7.7 g,
1
36.4 mmol, 56%) as a white solid. Mp 97e98 ꢁC. H NMR
(300 MHz, CDCl3) d ppm 8.46 (d, J¼5.1 Hz, 1H), 7.57 (s,
1H), 7.47 (d, J¼5.1 Hz, 1H), 6.00 (s, 1H), 1.46 (s, 9H). 13C

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H. Hawad et al. / Tetrahedron 64 (2008) 3236e3245
4.4. Deprotonation of N-(tert-butyl)picolinamide and
isonicotinamide (2, 3, 10 and 11) using lithium
tributyl magnesiate (Bu3MgLi) and condensation with
electrophiles
4.4.4. N-(tert-Butyl)-4-chloro-3-[(hydroxy)(3,4,5-trimethoxy-
phenyl)methyl]pyridine-2-carboxamide (3c)
Compound 3c was obtained from 3 by trapping the magnesi-
ate intermediate with 3,4,5-trimethoxybenzaldehyde (6 mmol).
Column chromatography on silica gel (CH2Cl2/Et2O 9:1)
afforded 3c (409 mg, 1.0 mmol, 50%) as a yellow solid. Mp
111e112 ꢁC. 1H NMR (300 MHz, CDCl3) d ppm 8.31 (d,
J¼5.1 Hz, 1H), 7.47 (d, J¼5.1 Hz, 1H), 7.38 (s, 1H), 7.34 (d,
J¼11.7 Hz, 1H), 6.42 (d, J¼11.7 Hz, 1H), 6.37 (s, 2H), 3.72
(s, 3H), 3.71 (s, 6H), 1.19 (s, 9H). 13C NMR (75 MHz,
CDCl3) d ppm 166.4, 153.1, 152.9, 147.4, 146.4, 139.0, 138.8,
137.1, 127.2, 103.7, 70.5, 61.1, 56.5, 52.0, 28.5. Anal. Calcd
for C20H25ClN2O5: C, 58.75; H, 6.16; N, 6.85. Found: C,
58.45; H, 6.27; N, 6.77.
To a solution of MgBr2 (2.0 mmol) in THF (3 ml) at
ꢀ10 ꢁC was added BuLi (6 mmol). After stirring for 1 h at
room temperature, the required N-tert-butylpyridine 2- and
4-carboxamides (2, 3, 10 and 11) were added (2 mmol). After
2 h at room temperature, the electrophile was added and the
mixture was stirred for 2 h at room temperature before addi-
tion of satd aq NH4Cl (1 ml). The product was extracted
with CH2Cl2, the combined organic phases dried (MgSO4)
and evaporated under reduced pressure to give crude 2be2c,
3be3c, 10be10f and 11b.
4.4.5. N-(tert-Butyl)-3-iodopyridine-4-carboxamide (10b)
Compound 10b was obtained from 10 by trapping the mag-
nesiate intermediate with I2 (6 mmol). Column chromatography
on silica gel (CH2Cl2/Et2O 7:3) afforded 10b (401 mg,
1.32 mmol, 66%) as a white solid. Mp 161e162 ꢁC. 1H NMR
(300 MHz, CDCl3) d ppm 8.89 (s, 1H), 8.50 (d, J¼4.9 Hz,
1H), 7.25 (d, J¼4.9 Hz, 1H), 5.50 (s, 1H), 1.43 (s, 9H). 13C
NMR (75 MHz, CDCl3) d ppm 166.8, 157.8, 150.0, 149.0,
122.7, 92.3, 52.9, 28.9. Anal. Calcd for C10H13IN2O: C,
39.49; H, 4.31; N, 9.21. Found: C, 39.52; H, 4.03; N, 9.31.
4.4.1. N-(tert-Butyl)-3-iodopyridine-2-carboxamide (2b)
Compound 2b was obtained from 2 by trapping the mag-
nesiate intermediate with I2 (6 mmol). Column chromatogra-
phy on silica gel (CH2Cl2/Et2O 9:1) afforded 2b (334 mg,
1.10 mmol, 55%) as a yellow powder. Mp 93e94 ꢁC. 1H
NMR (300 MHz, CDCl3) d ppm 8.37 (dd, J¼4.5, 1.3 Hz,
1H), 8.22 (dd, J¼7.9, 1.3 Hz, 1H), 7.74 (s, 1H), 6.93 (dd,
J¼7.9, 4.5 Hz, 1H), 1.36 (s, 9H). 13C NMR (75 MHz,
CDCl3) d ppm 164.4, 150.7, 149.6, 147.3, 126.3, 89.0, 51.5,
29.0. Anal. Calcd for C10H13IN2O: C, 39.49; H, 4.31; N,
9.21. Found: C, 39.38; H, 4.62; N, 9.25.
4.4.6. 3-Bromo-N-(tert-butyl)pyridine-4-carboxamide (10c)
Compound 10cwasobtainedfrom10bytrappingthemagnesi-
ate intermediate with 1,2-dibromotetrachloroethane (6 mmol).
Column chromatography on silica gel (CH2Cl2/Et2O 1:1) af-
forded 10c (221 mg, 0.86 mmol, 43%) as a yellow solid. Mp
139e140 ꢁC. 1H NMR (300 MHz, CDCl3) d ppm 8.69 (s, 1H),
8.50 (d, J¼4.7 Hz, 1H), 7.35 (d, J¼4.7 Hz, 1H), 5.72 (s, 1H),
1.42 (s, 9H). 13C NMR (75 MHz, CDCl3) d ppm 165.0, 152.6,
148.7, 145.9, 123.3, 117.6, 53.0, 29.0. Anal. Calcd for
C10H13BrN2O: C, 46.71; H, 5.10; N, 10.89. Found: C, 47.11; H,
4.95; N, 10.68.
4.4.2. N-(tert-Butyl)-3-[(hydroxy)(3,4,5-trimethoxyphenyl)-
methyl]pyridine-2-carboxamide (2c)
Compound 2c was obtained from 2 by trapping the magnesi-
ate intermediate with 3,4,5-trimethoxybenzaldehyde (6 mmol).
Column chromatography on silica gel (CH2Cl2/Et2O 9:1)
afforded 2c (614 mg, 1.64 mmol, 82%) as a yellow solid. Mp
1
<50 ꢁC. H NMR (300 MHz, CDCl3) d ppm 8.38 (dd, J¼4.5,
1.3 Hz, 1H), 8.02 (s, 1H), 7.38 (dd, J¼7.9, 1.3 Hz, 1H), 7.27
(dd, J¼7.9, 4.5 Hz, 1H), 6.52 (s, 2H), 6.10 (s, 1H), 3.78 (s,
3H), 3.75 (s, 6H), 1.39 (s, 9H). 13C NMR (75 MHz, CDCl3)
d ppm 166.4, 153.4, 149.2, 147.0, 141.2, 138.8, 138.1, 126.2,
104.2, 73.2, 61.2, 56.4, 51.7, 28.9. Anal. Calcd for
C20H26N2O5: C, 64.15; H, 7.00; N, 7.48. Found: C, 63.93; H,
7.18; N, 7.26.
4.4.7. N-(tert-Butyl)-3-chloropyridine-4-carboxamide (10d)
Compound 10d was obtained from 10 by trapping the mag-
nesiate intermediate with C2Cl6 (6 mmol). Column chromatog-
raphy on silica gel (CH2Cl2/Et2O 1:1) afforded 10d (269 mg,
1.24 mmol, 62%) as a white solid. Mp 136e137 ꢁC. 1H NMR
(300 MHz, CDCl3) d ppm 8.57 (s, 1H), 8.49 (d, J¼4.8 Hz,
1H), 7.45 (d, J¼4.8 Hz, 1H), 5.90 (s, 1H), 1.42 (s, 9H). 13C
NMR (75 MHz, CDCl3) d ppm 164.0, 150.2, 148.1, 143.5,
128.1, 123.2, 52.9, 28.9. Anal. Calcd for C10H13ClN2O: C,
56.47; H, 6.16; N, 13.17. Found: C, 56.67; H, 6.06; N, 13.18.
4.4.3. N-(tert-Butyl)-4-chloro-3-iodopyridine-2-
carboxamide (3b)
Compound 3b was obtained from 3 by trapping the mag-
nesiate intermediate with I2 (6 mmol). Column chromatog-
raphy on silica gel (CH2Cl2/Et2O 7:3) afforded 3b
(433 mg, 1.28 mmol, 64%) as a yellow solid. Mp 142e
143 ꢁC. 1H NMR (300 MHz, CDCl3) d ppm 8.19 (d,
J¼5.1 Hz, 1H), 7.33 (d, J¼5.1, 1H), 7.16 (s, 1H), 1.36
(s, 9H). 13C NMR (75 MHz, CDCl3) d ppm 164.3, 155.7,
151.8, 148.0, 125.6, 95.2, 52.0, 28.9. Anal. Calcd for
C10H12ClIN2O: C, 35.48; H, 3.57; N, 8.27. Found: C,
35.32; H, 3.64; N, 8.24.
4.4.8. N-(tert-Butyl)-3-(trimethylsilyl)pyridine-4-
carboxamide (10e)
Compound 10e was obtained from 10 by trapping the mag-
nesiate intermediate with TMSCl (6 mmol). Column chroma-
tography on silica gel (CH2Cl2/Et2O 7:3) afforded 10e
(470 mg, 1.88 mmol, 94%) as a brown solid. Mp 104e
105 ꢁC. 1H NMR (300 MHz, CDCl3) d ppm 8.71 (s, 1H),
8.55 (d, J¼4.9 Hz, 1H), 7.16 (d, J¼4.9 Hz, 1H), 5.64 (s, 1H),

H. Hawad et al. / Tetrahedron 64 (2008) 3236e3245
3243
1.41 (s, 9H), 0.30 (s, 9H). 13C NMR (75 MHz, CDCl3) d ppm
168.9, 155.3, 150.8, 150.0, 132.9, 120.9, 52.2, 28.8, 0.0. Anal.
Calcd for C13H22N2OSi: C, 62.35; H, 8.86; N, 11.19. Found: C,
61.72; H, 9.17; N, 10.95.
4.5.2. N-Methyl-3,5-diiodopyridine-4-carboxamide (9b)
White solid (117 mg, 0.30 mmol, 15%). Mp 129e130 ꢁC. 1H
NMR (300 MHz, CDCl3) d ppm 8.75 (s, 2H), 5.65 (s, 1H), 3.00
(d, J¼4.9 Hz, 1H). 13C NMR (75 MHz, CDCl3) d ppm 167.2,
155.1, 153.0, 90.7, 25.6. Anal. Calcd for C7H6I2N2O: C,
21.67; H, 1.56; N, 7.22. Found: C, 21.53; H, 1.61; N, 7.36.
4.4.9. N-(tert-Butyl)-3-[(hydroxy)(3,4,5-trimethoxyphenyl)-
methyl]pyridine-4-carboxamide (10f)
4.5.3. N-Methyl-3-chloropyridine-4-carboxamide (8c)
Brown solid (150 mg, 0.86 mmol, 44%). Mp 76e77 ꢁC. 1H
NMR (300 MHz, CDCl3) d ppm 8.50 (s, 1H), 8.42 (d,
J¼5.1 Hz, 1H), 7.44 (d, J¼5.1 Hz, 1H), 6.12 (m, 1H), 2.90 (d,
J¼4.9 Hz, 1H). 13C NMR (75 MHz, CDCl3) d ppm 165.4,
150.5, 148.4, 142.3, 128.3, 123.6, 27.1. Anal. Calcd for
C7H7ClN2O: C, 49.28; H, 4.14; N, 16.42. Found: C, 49.71; H,
4.29; N, 15.89.
Compound10f wasobtainedfrom10bytrappingthemagnesi-
ate intermediate with 3,4,5-trimethoxybenzaldehyde (6 mmol).
Column chromatography on silica gel (EtOAc/CH2Cl2 8:2)
afforded 10f (562 mg, 1.50 mmol, 75%) as an orange solid. Mp
1
62e63 ꢁC. H NMR (300 MHz, CDCl3) d ppm 8.51 (m, 2H),
7.23 (d, J¼4.9 Hz, 1H), 6.44 (s, 2H), 594 (s, 1H), 5.76 (s, 1H),
5.43 (s, 1H), 3.74 (s, 3H), 3.72 (s, 6H), 1.19 (s, 9H). 13C NMR
(75 MHz, CDCl3) d ppm 167.5, 153.2, 150.2, 149.3, 144.3,
138.2, 137.1, 136.5, 122.6, 103.9, 72.3, 60.9, 56.3, 52.4, 28.5.
Anal. Calcd for C20H26N2O5: C, 64.16; H, 7.00; N, 7.48. Found:
C, 62.56; H, 6.82; N, 6.76.
4.5.4. N-Methyl-3,5-dichloropyridine-4-carboxamide (9c)
Oil (67 mg, 0.33 mmol, 16%). 1H NMR (300 MHz, CDCl3)
d ppm 8.46 (s, 2H), 5.74 (s, 1H), 3.00 (d, J¼4.9 Hz, 1H). 13C
NMR (75 MHz, CDCl3) d ppm 163.2, 147.9, 142.9, 129.4,
26.4. Anal. Calcd for C7H6Cl2N2O: C, 41.00; H, 2.95; N,
13.66. Found: C, 41.21; H, 2.89; N, 13.52.
4.4.10. N-(tert-Butyl)-2-chloro-3-iodopyridine-4-
carboxamide (11b)
Compound 11b was obtained from 11 by trapping the mag-
nesiate intermediate with I2 (6 mmol). Column chromatography
on silica gel (CH2Cl2/Et2O 9:1) afforded 11b (253 mg,
0.78 mmol, 39%) as a brown solid. Mp 176e177 ꢁC. 1H NMR
(300 MHz, CDCl3) d ppm 8.42 (d, J¼4.9 Hz, 1H), 7.18 (d,
J¼4.9 Hz, 1H), 5.54 (s, 1H), 1.56 (s, 9H). 13C NMR (75 MHz,
CDCl3) d ppm 166.8, 156.3, 154.9, 149.4, 120.6, 94.2, 53.3,
29.0. Anal. Calcd for C10H12ClIN2O: C, 35.48; H, 3.57; N,
8.27. Found: C, 38.63; H, 3.49; N, 7.92.
4.6. Deprotonation of N-methyl and (tert-butyl)nicotinamides
(4, 6 and 7) using lithium dibutyl(2,2,6,6-tetramethyl-
piperidino)magnesiate (Bu2TMPMgLi) and condensation
with electrophiles
To a solution of MgBr2 (2.0 mmol) in THF (3 ml) at ꢀ10 ꢁC
were added BuLi (6 mmol) and 2,2,6,6-tetramethylpiperidine
TMPH (2 mmol). After stirring for 1 h at room temperature,
the required N-alkylnicotinamides 4, 6 and 7 was added
(2 mmol). After 2 h at room temperature, the electrophile
(6 mmol) was added and the mixture stirred for 2 h at room tem-
perature before addition of satd aq NH4Cl (1 ml). The product
was extracted with CH2Cl2, the combined organic phases dried
(MgSO4) and evaporated under reduced pressure to give crude
4ae4c, 6ae6e and 7ae7c.
4.5. Deprotonation of N-methylisonicotinamide (8) using
lithium tributyl magnesiate (Bu3MgLi) and condensation
with I2 and C2Cl6
To a solution of MgBr2 (2.0 mmol) in THF (3 ml) at
ꢀ10 ꢁC was added BuLi (6 mmol). After stirring for 1 h at
room temperature, the required N-methyl pyridine-4-carboxa-
mides (8) were added (2 mmol). After 2 h at room tempera-
ture, I2 and C2Cl6 (6 mmol) were added and the mixture
stirred for 2 h at room temperature before addition of satd
aq NH4Cl (1 ml). The product was extracted with CH2Cl2,
the combined organic phases dried (MgSO4) and evaporated
under reduced pressure to give a crude mixture of monosub-
stituted N-methyl pyridine-4-carboxamides 8bec and disub-
stituted N-methyl pyridine-4-carboxamides 9bec, which was
separated by column chromatography on silica gel (CH2Cl2/
Et2O 9:1).
4.6.1. 4-Deuterio-N-methylpyridine-3-carboxamide (4a)
Compound 4a was obtained from 4 by trapping the magnesi-
ate intermediate with D2O (8 mmol). Column chromatography
on silica gel (CH2Cl2/Et2O 9:1) afforded 4a (0.2 g, 1.6 mmol,
1
82%) as a white solid. Mp 102e108 ꢁC. H NMR (300 MHz,
CDCl3) d ppm 8.90 (s, 1H), 8.64 (d, J¼4.9 Hz, 1H), 7.33 (d,
J¼4.9 Hz, 1H), 6.45 (s, 1H), 2.97 (s, 3H). 13C NMR (75 MHz,
CDCl3) d ppm 166.8, 151.9, 148.6, 135.2, 130.6, 123.6, 27.1.
Anal. Calcd for C7H7DN2O: C, 61.30; H, 6.61; N, 20.42. Found:
C, 61.06; H, 5.97; N, 20.10.
4.5.1. N-Methyl-3-iodopyridine-4-carboxamide (8b)
4.6.2. N-Methyl-4-iodopyridine-3-carboxamide (4b)
White solid (302 mg, 1.14 mmol, 57%). Mp 129e130 ꢁC. 1H
NMR (300 MHz, CDCl3) d ppm 8.92 (s, 1H), 8.53 (d, J¼4.7 Hz,
1H), 7.29 (d, J¼4.7 Hz, 1H), 5.77 (m, 1H), 2.98 (d, J¼5.1 Hz,
1H). 13C NMR (75 MHz, CDCl3) d ppm 168.2, 158.2, 149.4,
149.1, 122.9, 92.2, 27.1. Anal. Calcd for C7H7IN2O: C, 32.08;
H, 2.69; N, 10.69. Found: C, 33.36; H, 2.94; N, 10.57.
Compound 4b was obtained from 4 by trapping the magnesi-
ate intermediate with I2 (6 mmol). Column chromatography on
silica gel (CH2Cl2/Et2O 9:1) afforded 4b (0.4 g, 1.6 mmol, 78%)
as yellow oil. 1H NMR (300 MHz, CDCl3) d ppm 8.43 (m, 1H),
8.31 (s, 1H), 8.12 (d, J¼5.3 Hz, 1H), 7.87 (d, J¼5.3 Hz, 1H),
2.68 (d, J¼4.5 Hz, 3H). 13C NMR (75 MHz, CDCl3) d ppm

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H. Hawad et al. / Tetrahedron 64 (2008) 3236e3245
167.7, 150.4, 147.4, 139.2, 134.6, 106.9, 26.4. Anal. Calcd for
C7H7IN2O: C, 32.08; H, 2.69; N, 10.69. Found: C, 31.94; H,
2.85; N, 10.62.
for C13H22N2OSi: C, 62.35; H, 8.86; N, 11.19. Found: C, 62.89;
H, 8.94; N, 10.79.
4.6.8. N-(tert-Butyl)-4-[(hydroxy)(3,4,5-trimethoxyphenyl)-
methyl]pyridine-3-carboxamide (6e)
4.6.3. N-Methyl-4-[(hydroxy)(3,4,5-trimethoxyphenyl)-
methyl]pyridine-3-carboxamide (4c)
Compound6ewas obtained from6 bytrappingthe magnesiate
intermediate with 3,4,5-trimethoxybenzaldehyde (6 mmol). Col-
umn chromatography on silica gel (EtOAc/CH2Cl2 8:2) afforded
6e(0.22 g,0.6 mmol, 60%)asabrownsolid.Mp140e141 ꢁC.1H
NMR d ppm 8.56 (m, 1H), 7.21 (d, J¼5.3 Hz, 1H), 6.45 (s, 2H),
5.46 (d, J¼5.3 Hz, 1H), 3.75 (s, 3H), 3.73 (s, 6H), 1.25 (s, 9H).
13C NMR (75 MHz, CDCl3) d ppm 168.1, 153.5, 151.9, 151.8,
148.4, 137.6, 132.5, 123.8, 104.3, 73.7, 61.2, 56.5, 52.8, 28.8.
Anal. Calcd for C20H26N2O5: C, 64.15; H, 7.00; N, 7.48. Found:
C, 61.73; H, 7.18; N, 6.16.
Compound 4cwas obtainedfrom4 bytrappingthe magnesiate
intermediate with 3,4,5-trimethoxybenzaldehyde (6 mmol). Col-
umn chromatography on silica gel (CH2Cl2/Et2O 9:1) afforded 4c
(0.4 g, 1.2 mmol, 62%)aswhite solid. Mp165e166 ꢁC. 1H NMR
(300 MHz, CDCl3) d ppm 8.50 (s, 1H), 8.46 (d, J¼4.9 Hz, 1H),
7.55 (s, 1H), 7.26 (d, J¼4.9 Hz, 1H), 6.50 (s, 2H), 5.95 (s, 1H),
5.85 (s, 1H), 3.74 (s, 3H), 3.73 (s, 6H), 2.83 (d, J¼4.5 Hz, 1H).
13C NMR (75 MHz, CDCl3) d ppm 169.2, 153.4, 152.7, 151.8,
148.1, 137.4, 131.3, 123.2, 104.0, 72.8, 61.2, 56.4, 27.3. Anal.
Calcd for C17H20N2O5: C, 61.44; H, 6.07; N, 8.43. Found: C,
58.87; H, 6.48; N, 7.22.
4.6.9. N-(tert-Butyl)-6-chloro-4-deuteriopyridine-3-
carboxamide (7a)
4.6.4. N-(tert-Butyl)-4-deuteriopyridine-3-carboxamide (6a)
Compound 6awasobtainedfrom6bytrappingthemagnesiate
intermediate with D2O (6 mmol). Column chromatography on
silica gel (CH2Cl2/Et2O 9:1) afforded 6a (0.23 g, 1.3 mmol,
Compound7awasobtainedfrom7 bytrappingthe magnesiate
intermediate with D2O (6 mmol). Column chromatography on
silica gel (CH2Cl2/Et2O 7:3) afforded 7a (0.25 g, 1.16 mmol,
1
58%) as a white solid. Mp 108e109 ꢁC. H NMR (300 MHz,
1
64%) as a white solid. Mp 89e90 ꢁC. H NMR (300 MHz,
CDCl3) d ppm 8.55 (s, 1H), 7.27 (s, 1H), 5.74 (s, 1H), 1.35 (s,
9H). 13C NMR (75 MHz, CDCl3) d ppm 164.5, 153.5, 148.6,
137.8, 130.6, 124.1, 52.4, 28.9. Anal. Calcd for C10H12ClDN2O:
C, 56.21; H, 6.60; N, 13.11. Found: C, 56.34; H, 6.61; N, 13.32.
CDCl3) d ppm 8.84 (s, 1H), 8.63 (d, J¼4.9 Hz, 1H), 7.29 (d,
J¼4.9 Hz, 1H), 5.93 (s, 1H), 1.42 (s, 9H). 13C NMR (75 MHz,
CDCl3) d ppm 165.6, 151.6, 148.4, 134.9, 131.8, 123.3, 52.2,
29.0. Anal. Calcd for C10H13DN2O: C, 67.01; H, 8.43; N,
15.63. Found: C, 68.96; H, 8.32; N, 15.79.
4.6.10. N-(tert-Butyl)-6-chloro-4-iodopyridine-3-carbox-
amide (7b) and 4,40-bis N-(tert-butyl)-6-chloro-4-deuterio-
pyridine-3-carboxamide (12)
4.6.5. N-(tert-Butyl)-4-iodopyridine-3-carboxamide (6b)
Compound 6bwas obtainedfrom 6bytrappingthemagnesiate
intermediatewith I2 (6 mmol). Column chromatography on silica
gel (CH2Cl2/Et2O 9:1) afforded 6a (0.33 g, 1.1 mmol, 55%) as an
Trapping the magnesiate intermediate with I2 (6 mmol) gave
a mixture of compounds 7b and 12. Column chromatography on
silica gel (CH2Cl2/Et2O 9:1) afforded separately isolated 7b
(335 mg, 0.9 mmol, 45%) as a yellow solid. Mp 100e101 ꢁC.
1H NMR (300 MHz, CDCl3) d ppm 8.16 (s, 1H), 7.72 (s, 1H),
5.53 (s, 1H), 1.36 (s, 9H). 13C NMR (75 MHz, CDCl3) d ppm
165.8, 151.8, 147.2, 138.2, 134.6, 106.4, 53.0, 28.9. Anal.
Calcd for C10H12ClIN2O: C, 35.47; H, 3.57; N, 8.27. Found:
C, 35.92; H, 3.66; N, 8.14. Compound 12 (0.28 g, 0.66 mmol,
33%) as a yellow solid. Mp 223e224 ꢁC. 1H NMR (300 MHz,
CDCl3) d ppm 8.52 (s, 2H), 7.06 (s, 2H), 6.75 (s, 2H), 1.14
(s, 18H). 13C NMR (75 MHz, CDCl3) d ppm 165.3, 152.6,
148.3, 146.7, 131.4, 123.2, 52.8, 28.6. Anal. Calcd for
C20H24Cl2N4O2: C, 56.74; H, 5.71; N, 13.23. Found: C, 56.79;
H, 5.78; N, 12.69.
1
unstable brown solid. Mp not measured. H NMR (300 MHz,
CDCl3) d ppm 8.37 (s, 1H), 8.05 (d, J¼5.1 Hz, 1H), 7.66 (d,
J¼5.1 Hz, 1H), 5.93 (s, 1H), 1.46 (s, 9H).
4.6.6. N-(tert-Butyl)-4-chloropyridine-3-carboxamide (6c)
Compound 6c was obtained from 6 by trapping the magnesi-
ate intermediatewith C2Cl6 (6 mmol). Column chromatography
on silica gel (CH2Cl2/Et2O 1:1) afforded 6c (0.23 g, 1.1 mmol,
1
54%) as a yellow solid. Mp 117e118 ꢁC. H NMR d ppm
8.72 (s, 1H), 8.45 (d, J¼5.3 Hz, 1H), 7.27 (d, J¼5.3 Hz, 1H),
5.84 (s, 1H), 1.42 (s, 9H). 13C NMR (75 MHz, CDCl3) d ppm
163.9, 151.1, 150.1, 141.0, 132.8, 125.1, 52.8, 29.0. Anal. Calcd
for C10H13ClN2O: C, 56.47; H, 6.16; N, 13.17. Found: C, 56.43;
H, 6.28; N, 12.61.
4.6.11. N-(tert-Butyl)-6-chloro-4-chloropyridine-3-
carboxamide (7c)
4.6.7. N-(tert-Butyl)-4-trimethylsilylpyridine-3-carboxamide
(6d)
Compound 7c was obtained from 7 by trapping the magnesi-
ate intermediate with C2Cl6 (8 mmol). Column chromatography
on silica gel (CH2Cl2/Et2O 9:1) afforded separately isolated 7c
(410 mg, 1.08 mmol, 54%) as oil. 1H NMR (300 MHz, CDCl3)
Compound 6dwas obtainedfrom 6bytrappingthemagnesiate
intermediatewith TMSCl (6 mmol). Column chromatography on
silicagel(CH2Cl2/Et2O 7:3) afforded 6d(0.15 g,0.6 mmol, 60%)
as a yellow solid. Mp 87e88 ꢁC. 1H NMR d ppm 8.54 (s, 1H),
8.52 (d, J¼4.9 Hz, 1H), 7.42 (d, J¼4.9 Hz, 1H), 5.72 (s, 1H),
1.42 (s, 9H), 0.29 (s, 9H). 13C NMR (75 MHz, CDCl3) d ppm
163.0, 150.2, 149.8, 146.9, 139.3, 129.8, 52.3, 29.3. Anal. Calcd
d ppm 8.51 (s, 1H), 7.33 (s, 1H), 5.87 (s, 1H), 1.41 (s, 9H). 13
C
NMR (75 MHz, CDCl3) d ppm 162.9, 152.9, 150.1, 142.9,
131.6, 125.2, 53.1, 29.0. Anal. Calcd for C10H12Cl2N2O: C,
48.60; H, 4.89; N, 11.34. Found: C, 49.03; H, 5.10; N, 10.81.

H. Hawad et al. / Tetrahedron 64 (2008) 3236e3245
3245
4.6.12. N-(tert-Butyl)-4-[(hydroxy)(4-chlorophenyl)methyl]-
pyridine-3-carboxamide (7d)
149.4, 149.0, 143.9, 136.7, 132.5, 123.9, 122.8, 122.0, 51.7,
28.1. Anal. Calcd for C15H17N3O: C, 70.56; H, 6.71; N, 16.46.
Found: C, 70.77; H, 6.63; N, 16.35.
Compound 7d was obtained from 7 by trapping the magnesiate
intermediate with 4-chlorobenzaldehyde (6 mmol). Column chro-
matography on silica gel (EtOAc/CH2Cl2 9:1) afforded 7d(0.35 g,
1.0 mmol, 50%) as a yellow solid. Mp 92e93 ꢁC. 1H NMR d ppm
8.33 (s, 1H), 7.21 (m, 5H), 5.78 (d, J¼7.7 Hz, 1H), 5.63 (s, 1H),
5.28 (s, 1H), 1.21 (s, 9H). 13C NMR (75 MHz, CDCl3) d ppm
165.9, 153.6, 147.2, 138.4, 132.6, 129.8, 127.6, 127.5, 127.2,
126.9, 123.3, 72.0, 51.7, 27.3. Anal. Calcd for C17H18Cl2N2O2:
C, 57.80; H, 5.14; N, 7.93. Found: C, 57.69; H, 5.23; N, 7.97.
References and notes
1. (a) Epsztajn, J.; Jozwiak, A.; Szczesniak, A. K. Curr. Org. Chem. 2006,
10, 1817e1848; (b) Ila, H.; Baron, O.; Wagner, A. J.; Knochel, P.
Chem. Lett. 2006, 35, 1e7; (c) Schlosser, M. Angew. Chem., Int. Ed.
2005, 44, 376e393; (d) Anctil, E. J. G.; Snieckus, V. The Directed ortho
Metalation-Cross coupling Nexus. Synthetic Methodology for AryleAryl
and AryleHeteroatomeAryl Bonds. In Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed; Diederich, F., de Meijere, A., Eds.; Wiley-VCH: Wein-
heim, 2004; pp 761e813; (e) Clayden, J. Organolithiums: Selectivity for
Synthesis, 1st ed.; Baldwin, J. E., Williams, R. M., Eds.; Elsevier
4.7. Deprotonation of N-(tert-butyl)-6-chloronicotinamide (7)
using dilithium butyltri(2,2,6,6-tetramethylpiperidino)-
magnesiate (BuTMP3MgLi2) and condensation with
electrophiles
´
Science: Oxford, 2002; (f) Mongin, F.; Queguiner, G. Tetrahedron
2001, 57, 4059e4090; (g) Snieckus, V. Chem. Rev. 1990, 90, 879e933.
2. Mulvey, R. E.; Mongin, F.; Uchiyama, M.; Kondo, Y. Angew. Chem., Int.
Ed. 2007, 46, 3802e3824.
To a solution of MgBr2 (2.0 mmol) in THF (3 ml) at ꢀ10 ꢁC
were added nBuLi (8 mmol) and 2,2,6,6-tetramethylpiperidine
TMPH (6 mmol). After stirring for 1 h at room temperature,
N-(tert-butyl)-6-chloronicotinamide (7) was added (2 mmol).
After 2 h at room temperature, D2O, I2 and C2Cl6 (6 mmol)
were added and the mixture stirred for 2 h at room temperature
before addition of satd aq NH4Cl (1 ml). The product was
extracted with CH2Cl2, the combined organic phases dried
(MgSO4) and evaporated under reduced pressure to give crude
7ae7c, which was purified by column chromatography follow-
ing the above procedure to give pure 7a (293 mg, 1.36 mmol,
68%), 7b (410 mg, 1.10 mmol, 55%) and 7c (424 mg,
1 mmol, 50%) with the same characteristic data as described
before.
3. (a) Kondo, Y.; Shilai, M.; Uchiyama, M.; Sakamoto, T. J. Am. Chem. Soc.
1999, 121, 3539e3540; (b) Imahori, T.; Uchiyama, M.; Sakamoto, T.; Kondo,
Y. Chem. Commun. 2001, 2450e2451; (c) Uchiyama, M.; Naka, H.; Matsu-
moto, Y.; Ohwada, T. J. Am. Chem. Soc. 2004, 126, 10526e10527; (d)
Naka, H.; Uchiyama, M.; Matsumoto, Y.; Wheatley, A. E. H.; McPartlin,
M.; Morey, J. V.; Kondo, Y. J. Am. Chem. Soc. 2007, 129, 1921e1930.
4. (a) Armstrong, D. R.; Kennedy, A. R.; Mulvey, R. E.; Rowlings, R. B.
Angew. Chem., Int. Ed. 1999, 38, 131e133; (b) Andrikopoulos, P. C.;
Armstrong, D. R.; Graham, D. V.; Hevia, E.; Kennedy, A. R.; Mulvey,
R. E.; O’Hara, C. T.; Talmard, C. Angew. Chem., Int. Ed. 2005, 44,
3459e3462.
5. Farkas, J.; Stoudt, S. J.; Hanawalt, E. M.; Pajerski, A. D.; Richey, H. G.,
Jr. Organometallics 2004, 23, 423e427.
´
6. (a) Awad, H.; Mongin, F.; Trecourt, F.; Queguiner, G.; Marsais, F.
´
Tetrahedron Lett. 2004, 45, 7873e7877; (b) Bayh, O.; Awad, H.; Mongin,
´
F.; Hoarau, C.; Trecourt, F.; Queguiner, G.; Marsais, F.; Blanco, F.;
Abarca, B.; Ballesteros, R. Tetrahedron 2005, 61, 4779e4784; (c)
´
´
´
Awad, H.; Bayh, O.; Mongin, F.; Trecourt, F.; Queguiner, G.; Marsais,
F.; Blanco, F.; Abarca, B.; Ballesteros, R. Tetrahedron Lett. 2004, 45,
6697e6701; (d) Bayh, O.; Awad, H.; Mongin, F.; Hoarau, C.; Bischoff,
4.8. General procedure for deprotonation of pyridine-
carboxamides 1, 6 and 10 and subsequent cross-coupling
with 2-halogenopyridine
´
´
L.; Trecourt, F.; Queguiner, G.; Marsais, F.; Blanco, F.; Abarca, B.;
Ballesteros, R. J. Org. Chem. 2005, 70, 5190e5196.
7. Epsztajn, J.; Bieniek, A.; Plotka, M. W. J. Chem. Res., Synop. 1986,
20e21.
To a solution of carboxyamidopyridinyl magnesiate interme-
diates resulting from deprotonation of 1, 6 and 10 by following
the general procedures in Sections 4.3 and 4.6 were added
2-bromopyridine (6 mmol) and PdCl2(dppf) (0.3 mmol) or
2-chloropyridine (6 mmol), Ni(acac)2 (0.3 mmol) and triphe-
nylphosphine (0.3 mmol). The resulting solution was refluxed
18 h before addition of satd aq NH4Cl. After filtration through
a short pad of Celite, the product was extracted with CH2Cl2
and the combined organic extracts were dried (MgSO4) and
evaporated in vacuo to give crude products, which was purified
by column chromatography. The starting material was recov-
ered from the reactions between 1, 6, 10 and 2-bromopyridine
under palladium-catalyzed and reactions between 1, 6 and
2-chloropyridine under nickel-catalyzed. A coupling product
was isolated from the reaction of 10 with 2-chloropyridine as
8. Schlecker, W.; Huth, A.; Ottow, E.; Mulzer, J. J. Org. Chem. 1995, 60,
8414e8416.
9. (a) Meyers, A. I.; Gabel, R. A. J. Org. Chem. 1982, 47, 2633e2637; (b)
Hauck, A. E.; Giam, C. S. J. Chem. Soc., Perkin Trans. 1 1984, 2227e
2231; (c) Dubey, S. K.; Knaus, E. E.; Giam, C. S. Heterocycles 1984,
´
22, 1091e1093; (d) Binay, P.; Dupas, G.; Bourguignon, J.; Queguiner,
G. Can. J. Chem. 1987, 65, 648e655; (e) Schlecker, W.; Huth, A.; Ottow,
E.; Mulzer, J. Tetrahedron 1995, 51, 9531e9542.
´
´
10. Bonnet, V.; Mongin, F.; Trecourt, F.; Queguiner, G. J. Chem. Soc., Perkin
Trans. 1 2000, 4245e4249.
11. (a) For precedents of type of dual basicity of mixed alkylamidomagnesiate
base, see: Mulvey, R. E. Organometallics 2006, 25, 1060e1075; (b) For
structural informations on BuTMP2MgNa as its TMEDA adduct see:
Hevia, E.; Gallagher, D. J.; Kennedy, A. R.; Mulvey, R. E.; O’Hara,
C. T.; Talmard, C. Chem. Commun. 2004, 2422e2423.
12. Khalafi-Nezhad, A.; Parhami, A.; Soltani Rad, M. N. S.; Zarea, A.
Tetrahedron Lett. 2005, 46, 6879e6882.
1
a solid: (15, 240 mg, 47%). Mp 65e66 ꢁC. H NMR d ppm
13. Guo, Z.; Dowdy, E. D.; Li, W.-S.; Polniaszek. Tetrahedron Lett. 2001, 42,
1843e1845.
8.77 (s, 1H), 8.70 (m, 2H), 7.82 (t, J¼7.7 Hz, 1H), 7.55 (m,
2H), 7.36 (dd, J¼7.5, 1.7 Hz, 1H), 6.26 (s, 1H, NH), 1.27 (s,
9H). 13C NMR (75 MHz, CDCl3) d ppm 166.5, 154.9, 150.2,
14. Povlova, M. V.; Mikhalev, A. I.; Kon’shin, M. E.; Vasilyuk, M. V.;
Kotegov, V. P. Pharm. Chem. J. 2002, 36, 425e427.