Reaction of magnesiated bases on substituted pyridines: Deprotonation or 1,4-addition?

Article abstract of DOI:10.1039/b007270m

N-(tert-Butyl)pyridine-2-carboxamide (1), N-phenylpyridine-2-carboxamide (7) and 2,2-dimethyl-N-(2-pyridyl)-propanamide (18) are readily deprotonated at C3 with a stoichiometric amount of PrⁱMgCl or Bu₂Mg in THF under reflux. Subsequ

Full text of DOI:10.1039/b007270m

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Reaction of magnesiated bases on substituted pyridines:
deprotonation or 1,4-addition?
Véronique Bonnet, Florence Mongin, François Trécourt and Guy Quéguiner*
1
Laboratoire de Chimie Organique Fine et Hétérocyclique, IRCOF, UMR 6014,
Place E. Blondel, BP 08, 76131 Mont-Saint-Aignan, France
Received (in Cambridge, UK) 7th September 2000, Accepted 22nd September 2000
First published as an Advance Article on the web 20th November 2000
N-(tert-Butyl)pyridine-2-carboxamide (1), N-phenylpyridine-2-carboxamide (7) and 2,2-dimethyl-N-(2-pyridyl)-
propanamide (18) are readily deprotonated at C3 with a stoichiometric amount of PriMgCl or Bu2Mg in THF under
reflux. Subsequent trapping with various electrophiles (deuterated water, aldehydes, iodine and dimethyl disulfide)
gives 2,3-disubstituted pyridines carrying a useful carboxylic acid- or amino-derived function at C2. When N-
(tert-butyl)pyridine-3-carboxamide (12) and 2,2-dimethyl-N-(3-pyridyl)propanamide (22) are subjected to the
same reaction conditions, 1,4-addition to the pyridine ring occurs, giving 4-alkyl derivatives. Starting from
N-(tert-butyl)pyridine-4-carboxamide (15), 1,2-addition and deprotonation reactions occur simultaneously.
Table 1 Functionalization of pyridine 1
Introduction
The current abundant literature devoted to the lithiation of
azines1,2 shows that such a reaction plays an important role in
the synthesis of natural products and pharmaceuticals, and in
the elaboration of building blocks for material science and
supramolecular chemistry. This methodology often requires
low temperatures which are not easy to realize on an industrial
scale. A survey of the literature revealed that some benzenes3,4
and pi-electron rich aromatic rings5,6 could be deprotonated
at higher temperatures with alkylmagnesium halides, Hauser
bases (R2NMgX) or magnesium diamides. In the case of
substrates more prone to nucleophilic addition, metallation has
only been effected with Hauser bases. Indeed, deprotonation of
pyridines containing useful carboxylic acid- and amino-derived
functions was accomplished by Mulzer and co-workers with
(2,2,6,6-tetramethylpiperidino)magnesium chloride;7–9 because
of its weaker reactivity when compared to alkylmagnesium
halides, a large excess (6 to 8 equivalents) of expensive base,
which is not available commercially, in general has to be used to
ensure good yields.
Run
Electrophile, E
Product, yielda(%)
1
2
3
4
5
D2O, D
2, 97b
3, 42
4, 25
5, 37
6, 69
PhCHO, CH(OH)Ph
PriCHO, CH(OH)Pri
ButCHO, CH(OH)But
I2, I
a Isolated yields based on 1. b 100% deuterium incorporation was
observed from the 1H NMR spectra integration values.
Table 2 Functionalization of pyridine 7
In this paper, we report to what extent a stoichiometric
amount of commercial dibutylmagnesium, alkylmagnesium
halide or phenylmagnesium halide can deprotonate such
pyridine derivatives.
Run
Electrophile, E
Product, yielda(%)
Results and discussion
N-Substituted pyridinecarboxamides
1
2
3
4
D2O, D
8, 60b
9, 58
10, 15
11, 22
PhCHO, CH(OH)Ph
PriCHO, CH(OH)Pri
MeSSMe, SMe
N-(tert-Butyl)pyridine-2-carboxamide (1) was exposed to vari-
ous bases such as Bu2Mg, PriMgCl, BuMgCl, ButMgCl and
PhMgBr in THF. All these bases, when used in THF under
reflux, were found to be effective in deprotonating 1 at C3 since
deuteriolysis after two hours afforded 3-deuterated compound
2 in 92, 97 (run 1, Table 1), 78, 77 and 49% yield, respectively.
Thus, a stoichiometric amount of PriMgCl or Bu2Mg is enough
to obtain an almost complete deprotonation at C3. Note
that no reaction was observed at rt. Quenching the pyridine
Grignard derivative with aldehydes (runs 2–4, Table 1) and
iodine (run 5, Table 1) respectively gave the alcohols 3–5 and the
iodopyridine 6 in moderate to good yields. The yields obtained
largely depend on the trapping step with the electrophiles, since
a Isolated yields based on 7. b 98% deuterium incorporation was
observed from the 1H NMR spectra integration values.
starting material 1 is the only product recovered beside the
desired compound (Table 1).
With N-phenylpyridine-2-carboxamide (7), PriMgCl and
Bu2Mg were effectively tested under the same conditions. In
the case of Bu2Mg, quenching the intermediate with D2O
(run 1, Table 2), aldehydes (runs 2–3, Table 2) and dimethyl
disulfide (run 4, Table 2) respectively afforded the deuterated
compound 8, the desired alcohols 9–10 and the sulfide 11.
DOI: 10.1039/b007270m
J. Chem. Soc., Perkin Trans. 1, 2000, 4245–4249
This journal is © The Royal Society of Chemistry 2000
4245

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Table 3 Functionalization of pyridine 12
Table 5 Functionalization of pyridine 18
Product, yielda(%)
Run
Electrophile, E
Product, yielda(%)
Run
Base, R
19, 97b
20, 45
21, 66
1
2
PriMgCl, Pri
Bu2Mg, Bu
13, 70
14, 51
1
2
3
D2O, D
PhCHO, CH(OH)Ph
I2, I
a Isolated yields based on 12.
a Isolated yields based on 18. b 98% deuterium incorporation was
observed from the 1H NMR spectra integration values.
Table 4 Functionalization of pyridine 15
Table 6 Functionalization of pyridine 22
Product,
Yield of
16(%)
Product 17,
yielda(%)
Run
Electrophile
E, yielda(%)
Run
Base, R
17a, D, 23b
17b, I, 22
1
2
PriMgCl, Pri
Bu2Mg, Bu
23, 68
24, 50
1
2
D2O
I2
60
59
a Isolated yields based on 22.
a Isolated yields based on 15. b 83% deuterium incorporation was
observed from the 1H NMR spectra integration values.
alkylpyridines 23, 24 (Table 6). Similar addition of BuLi to
22 has been previously reported by Turner.13
With isobutyraldehyde as the electrophile (run 3, Table 2), the
main limitation is the abstraction of its enolizable proton by the
magnesiated pyridine formed (Table 2).
N-(tert-Butyl)pyridine-3- and -4-carboxamides (12 and 15)
were exposed to PriMgCl, Bu2Mg and 2-mesitylmagnesium
bromide under the same reaction conditions. No reaction was
observed using 2-mesitylmagnesium bromide.
With pyridine-3-carboxamide 12, 1,4-addition of the base
to the substrate was the only reaction observed when Pri-
MgCl (run 1, Table 3) and Bu2Mg (run 2, Table 3) were used.
Dihydropyridines are present in the crude product mixture
but oxidation rapidly occurs during the work-up procedure
(Table 3).
The reaction proceeds analogously to the previously reported
1,4-addition reaction of magnesiated bases such as EtMgBr and
PhMgBr to N,N-di-tert-butylpyridine-2,5-dicarboxamide.10
In the case of pyridine-4-carboxamide 15, deprotonation
reaction at C3 was observed together with the 1,2-addition
reaction of the base to the substrate when Bu2Mg was used
in THF under reflux. Aromatization of the dihydropyridine
intermediates is likewise observed during the work-up pro-
cedure (Table 4).
Note that 2,2-dimethyl-N-(4-pyridyl)propanamide13 did not
react at all when treated with PriMgCl or Bu2Mg under the
same reaction conditions.
During lithiation, deprotonation of 2,2-dimethyl-N-pyridyl-
propanamides is effected at higher temperatures than deproton-
ation of N-substituted pyridinecarboxamides, so nucleophilic
addition of the base to the substrate occurs concurrently.13,14
In our case, weaker reactivity of magnesiated bases compared
to the lithiated bases did not allow deprotonation in the cases
of 22 and 2,2-dimethyl-N-(4-pyridyl)propanamide.
Conclusion
This work describes the first pyridine deprotonation using an
alkylmagnesium halide (PriMgCl) and a dialkylmagnesium
(Bu2Mg). The method gives good results when the carboxylic
acid- or amino-derived functional group is present at C2,
allowing a range of groups to be introduced at C3. The effective-
ness of these reagents in promoting deprotonation avoids the
use of a large excess (in general 6 to 8 equivalents) of (2,2,6,6-
tetramethylpiperidino)magnesium chloride, which is a rather
expensive base which is not available commercially.
Compared to the lithiation reaction which often requires low
to very low temperatures, this magnesiation method proceeds
under reflux.
Interestingly, the magnesiated pyridines, which are more
stable than their corresponding lithio derivatives, could also be
involved in coupling reactions.
Our results can be compared to those observed by Epsztajn
and co-workers during the reaction of N-phenylpyridine-
carboxamides with BuLi.11,12 When treated with BuLi, N-
phenylpyridine-2- and -4-carboxamides are deprotonated at
C3 while 1,4-addition was the only reaction observed in the case
of N-phenylpyridine-3-carboxamide.
2,2-Dimethyl-N-pyridylpropanamides
Clean deprotonation of 2,2-dimethyl-N-(2-pyridyl)propan-
amide (18) at C3 has likewise been performed with Bu2Mg
(run 1, Table 5). Alcohol 20 and iodopyridine 21 were syn-
thesized by trapping with benzaldehyde (run 2, Table 5) and
iodine (run 3, Table 5) respectively.
Experimental
General
Melting points were measured on a Kofler apparatus. NMR
spectra were recorded in CDCl3 on a Bruker AM 300 spectro-
meter (1H at 300 MHz and 13C decoupled spectra at 75 MHz)
with residual protic solvent as the internal reference. Chemical
2,2-Dimethyl-N-(3-pyridyl)propanamide 22 is much more
prone to nucleophilic addition of the base leading to 4-
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shifts are quoted in ppm and coupling constants in Hz. IR
spectra were taken on a Perkin-Elmer FT IR 205 spectrometer,
and main IR absorptions are given in cmϪ1. Elemental analyses
were performed on a Carlo Erba 1106 apparatus.
THF was distilled from benzophenone–Na. Reactions were
carried out under dry N2. Silica gel (Geduran Si 60, 0.063–
0.200 mm) was purchased from Merck. PriMgCl (2 mol dmϪ3
in THF), BuMgCl (2 mol dmϪ3 in THF), PhMgBr (1 mol dmϪ3
in THF), ButMgCl (1 mol dmϪ3 in THF), 2-mesitylmagnesium
bromide (1 mol dmϪ3 in THF), and Bu2Mg (1 mol dmϪ3 in
heptane) were purchased from Aldrich in Sure/Seal bottles.
Petrol refers to petroleum ether (bp 40–60 ЊC).
Action of the magnesiated bases and condensation with
electrophiles
The magnesiated base (10 mmol) was added to the pyridine
substrate (5 mmol) in THF (15 cm3) at 0 ЊC. After 2 h under
THF reflux, the mixture was cooled to rt and, when necessary,
the electrophile (10 mmol, or 20 mmol when Bu2Mg was used)
was added. The mixture was stirred at rt for 15 h before
hydrolysis with water (20 cm3).
N-(tert-Butyl)-3-deuteriopyridine-2-carboxamide 2. Com-
pound 2 was obtained from 1 using PriMgCl and after trapping
with D2O. Column chromatography on silica gel (DCM)
afforded 2 (0.87 g, 97%, 100% d). The characteristics of this
product were found to be identical to those described for 1
Note: unless otherwise specified ‘work-upЈ refers to extrac-
tion with diethyl ether (20 cm3) and DCM (2 × 20 cm3),
followed by drying (MgSO4) and removal of the solvent in
vacuo.
1
except for H and 13C NMR spectra where the 3-H and 3-C
signals respectively had disappeared.
Starting materials
N-(tert-Butyl)-3-[hydroxy(phenyl)methyl]pyridine-2-carb-
oxamide 3. Compound 3 was obtained from 1 using PriMgCl
and then trapping with PhCHO. Column chromatography
on silica gel (1:1 DCM–Et2O) afforded 3 (0.60 g, 42%) as a
white powder; mp 69–70 ЊC (Found: C, 72.0; H, 7.0; N, 9.8.
C17H20N2O2 requires: C, 71.8; H, 7.1; N, 9.85%); νmax/cmϪ1
(KBr) 3361, 2968, 1652, 1520, 1453, 1221, 1038; δH 8.34 (1 H,
dd, J 4.7 and 0.8, 6-H), 7.89 (1 H, s, NH), 7.44 (1 H, dd, J 7.0
and 0.8, 4-H), 7.2 (5 H, m, Ph), 6.54 (1 H, dd, J 7.0 and 4.7,
5-H), 6.09 (1 H, d, J 7.0, OH), 4.53 (1 H, d, J 7.0, CH(OH)Ph),
1.29 (9 H, s, But); δC 165.0 (CO), 148.6 (2-C), 145.5 (6-C), 141.1
(1Ј-C), 139.7 (3-C), 137.6 (4-C), 127.4 (3Ј-C and 5Ј-C), 126.3
(4Ј-C), 125.6 (2Ј-C and 6Ј-C), 124.6 (5-C), 72.2 (CH(OH)Ph),
50.3 (CMe3), 27.4 (CMe3).
N-Substituted pyridinecarboxamides were prepared from the
corresponding ethyl pyridinecarboxylates, using a procedure
described in the literature.9,15 To a solution of tert-butylamine
(25 mmol, 1.8 g, 2.6 cm3) or aniline (25 mmol, 2.3 g, 2.3 cm3) in
dry toluene (100 cm3) was added dropwise BuMgCl (25 mmol)
and the resulting mixture was heated under reflux for 10 min.
The required ethyl pyridinecarboxylate (7.3 mmol, 1.1 g,
1.1 cm3) in THF (30 cm3) was added dropwise and the resulting
mixture was refluxed for an additional 2 h. The solution was
poured into cooled 10% aqueous NH3.
N-(tert-Butyl)pyridine-2-carboxamide 1.7 Column chroma-
tography on silica gel (DCM) afforded 1 (1.1 g, 87%) as a pale
yellow oil (Found: C, 67.7; H, 8.0; N, 15.9. C10H14N2O requires:
C, 67.4; H, 7.9; N, 15.7%); νmax/cmϪ1 (neat) 3375, 2966, 2931,
1679, 1518, 1463, 1288; δH 8.21 (1 H, d, J 4.8, 6-H), 7.86 (1 H,
d, J 8.0, 3-H), 7.72 (1 H, s, NH), 7.51 (1 H, m, 4-H), 7.05 (1 H,
m, 5-H), 1.05 (9 H, s, But); δC 161.8 (CO), 149.3 (2-C), 146.7
(6-C), 136.0 (4-C), 125.3 (3-C), 120.4 (5-C), 50.7 (CMe3), 28.9
(CMe3).
N-(tert-Butyl)-3-(ꢀ-hydroxy-ꢁ-methylpropyl)pyridine-2-carb-
oxamide 4. Compound 4 was obtained from 1 using PriMgCl
and then trapping with PriCHO. Column chromatography
on silica gel (1:1 DCM–Et2O) afforded 4 (0.31 g, 25%) as a
white powder; mp 78–79 ЊC (Found: C, 67.4; H, 8.8; N, 11.0.
C14H22N2O2 requires: C, 67.2; H, 8.9; N, 11.2%); νmax/cmϪ1
(KBr) 3402, 2966, 1658, 1520, 1374, 1364, 1222, 1035; δH 8.40
(1 H, dd, J 4.8 and 0.9, 6-H), 8.22 (1 H, s, NH), 7.66 (1 H, dd,
J 7.0 and 0.9, 4-H), 7.26 (1 H, dd, J 7.0 and 4.8, 5-H), 6.18 (1 H,
s, OH), 4.32 (1 H, m, CH(OH)Pri), 2.10 (1 H, m, CHMe2), 1.38
(9 H, s, But), 1.02 (6 H, 2d, J 6.6, CHMe2); δC 164.4 (CO), 146.8
(2-C), 145.2 (6-C), 139.8 (3-C), 138.5 (4-C), 124.4 (5-C), 79.9
(CH(OH)Pri), 52.4 (CMe3), 32.5 (CHMe2), 27.5 (CMe3), 19.4
and 18.6 (CHMe2).
N-(tert-Butyl)pyridine-3-carboxamide 12. Washing with
petrol (20 cm3) afforded 12 (1.0 g, 78%) as a white powder;
mp 88–90 ЊC (lit.,16,17 85–86 ЊC) (Found: C, 67.1; H, 7.9; N,
15.7. C10H14N2O requires: C, 67.4; H, 7.9; N, 15.7%); νmax/cmϪ1
(KBr) 3358, 2981, 2961, 1639, 1545, 1313, 1220, 1022; δH 8.84
(1 H, s, 2-H), 8.63 (1 H, dd, J 4.9 and 0.9, 6-H), 7.99 (1 H, dd,
J 7.9 and 0.9, 4-H), 7.29 (1 H, dd, J 7.9 and 4.9, 5-H), 5.93 (1 H,
s, NH), 1.42 (9 H, s, But); δC 165.3 (CO), 153.4 (6-C), 148.5
(2-C), 136.4 (4-C), 131.9 (3-C), 124.3 (5-C), 52.4 (CMe3), 29.7
(CMe3).
N-(tert-Butyl)-3-(ꢀ-hydroxy-ꢁ,ꢁ-dimethylpropyl)pyridine-2-
carboxamide 5. Compound 5 was obtained from 1 using
PriMgCl and then trapping with ButCHO. Column chroma-
tography on silica gel (1:1 DCM–Et2O) afforded 5 (0.49 g,
37%) as a pale yellow oil (Found: C, 68.2; H, 9.0; N, 10.4.
C15H24N2O2 requires: C, 68.15; H, 9.15; N, 10.6%); νmax/cmϪ1
(neat) 3459, 3321, 2961, 1661, 1520, 1364, 1223, 1044, 1011;
δH 8.40 (1 H, dd, J 4.7 and 0.8, 6-H), 8.10 (1 H, s, NH), 7.80
(1 H, dd, J 6.9 and 0.8, 4-H), 7.32 (1 H, dd, J 6.9 and 4.7, 5-H),
6.12 (1 H, s, OH), 5.00 (1 H, s, CH(OH)But), 1.36 (9 H,
s, NHBut), 0.79 (9 H, s, CH(OH)But); δC 166.8 (CO), 149.3
(2-C), 146.3 (6-C), 140.7 (4-C), 139.4 (3-C), 125.1 (5-C), 80.9
(CH(OH)But), 51.5 (NHCMe3), 38.0 (CH(OH)CMe3), 28.9
(NHCMe3), 26.7 (CH(OH)CMe3).
N-(tert-Butyl)pyridine-4-carboxamide 15.18 Recrystallization
from petrol afforded 15 (0.99 g, 76%) as a white powder;
mp 117–118 ЊC (Found: C, 67.2; H, 7.9; N, 15.5. C10H14N2O
requires: C, 67.4; H, 7.9; N, 15.7%); νmax/cmϪ1 (KBr) 3283, 2979,
2963, 1638, 1546, 1320, 1215; δH 8.64 (2 H, dd, J 4.5 and 1.5,
2-H and 6-H), 7.49 (2 H, dd, J 4.5 and 1.5, 3-H and 5-H),
5.94 (1 H, s, NH), 1.41 (9 H, s, But); δC 162.8 (CO), 150.9 (2-C
and 6-C), 143.3 (4-C), 121.1 (3-C and 5-C), 52.5 (CMe3), 29.1
(CMe3).
N-Phenylpyridine-2-carboxamide 7. Recrystallization from
petrol afforded 7 (1.1 g, 75%) as a white powder; mp 72–74 ЊC
(lit.,19 76 ЊC); the spectroscopic data are in accordance with
those of the literature.20
2,2-Dimethyl-N-pyridylpropanamides were prepared using
the procedure described in the literature.13 2,2-Dimethyl-N-
(2-pyridyl)propanamide (18) and 2,2-dimethyl-N-(3-pyridyl)-
propanamide (22) were found to be identical to authentic
samples.13
N-(tert-Butyl)-3-iodopyridine-2-carboxamide 6. Compound 6
was obtained from 1 using PriMgCl and then trapping with
I2. Column chromatography on silica gel (9:1 DCM–Et2O)
afforded 6 (1.0 g, 69%) as a yellow powder; mp 93–94 ЊC
(Found: C, 39.3; H, 4.6; N, 9.2. C10H13IN2O requires: C, 39.5;
H, 4.3; N, 9.2%); νmax/cmϪ1 (KBr) 3372, 3054, 2966, 1681, 1519,
1222, 1014; δH 8.39 (1 H, dd, J 4.4 and 1.5, 6-H), 8.23 (1 H, dd,
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J 7.7 and 1.5, 4-H), 7.40 (1 H, s, NH), 6.97 (1 H, dd, J 7.7 and
4.4, 5-H), 1.39 (9 H, s, But); δC 162.5 (CO), 150.9 (6-C), 149.2
(2-C), 147.3 (4-C), 126.3 (5-C), 87.5 (3-C), 51.6 (CMe3), 29.1
(CMe3).
51%) as a pale yellow oil (Found: C, 71.5; H, 9.8; N, 11.7.
C14H22N2O requires: C, 71.8; H, 9.5; N, 11.95%); νmax/cmϪ1
(KBr) 3358, 2982, 2962, 1639, 1462, 1313; δH 8.48 (1 H, s, 2-H),
8.46 (1 H, d, J 4.8, 6-H), 7.20 (1 H, d, J 4.8, 5-H), 5.69 (1 H, s,
NH), 3.08 (2 H, m, CH2CH2CH2Me), 1.6 (4 H, m, CH2CH2-
CH2Me), 1.45 (9 H, s, But), 1.21 (3 H, t, J 7.8, CH2CH2-
CH2Me); δC 166.3 (CO), 154.3 (6-C), 148.6 (2-C), 145.6 (4-C),
132.9 (3-C), 123.8 (5-C), 51.5 (CMe3), 35.6 (CH2CH2CH2Me),
30.5 (CH2CH2CH2Me), 27.9 (CMe3), 20.7 (CH2CH2CH2Me),
12.8 (CH2CH2CH2Me).
N-Phenyl-3-deuteriopyridine-2-carboxamide 8.11,12 Com-
pound 8 was obtained from 7 using Bu2Mg and then trapping
with D2O. Column chromatography on silica gel (4:1 DCM–
Et2O) afforded 8 (0.60 g, 60%, 98% d). The characteristics of
this product were found to be identical to those described for
1
7 except for H and 13C NMR spectra where the 3-H and 3-C
signals respectively had disappeared.
N-(tert-Butyl)-2-butylpyridine-4-carboxamide 16. Compound
16 was obtained from 15 using Bu2Mg. Column chroma-
tography on silica gel (1:1 DCM–Et2O) afforded 16 (0.70 g,
60%) as a colorless viscous oil (Found: C, 72.1; H, 9.3; N, 11.6.
C14H22N2O requires: C, 71.8; H, 9.5; N, 11.95%); νmax/cmϪ1
(KBr) 3284, 2978, 2962, 1639, 1546, 1461, 1319; δH 8.51 (1 H,
d, J 4.5, 6-H), 7.38 (1 H, d, J 0.6, 3-H), 6.11 (1 H, s, NH), 7.26
(1 H, dd, J 4.5 and 0.6, 5-H), 2.66 (2 H, m, CH2CH2CH2Me),
1.5 (4 H, m, CH2CH2CH2Me), 1.26 (9 H, s, But), 0.88 (3 H, t,
J 7.5, CH2CH2CH2Me); m/z (CI) 235 (100%, M ϩ Hϩ).
N-Phenyl-3-[hydroxy(phenyl)methyl]pyridine-2-carboxamide
9. Compound 9 was obtained from 7 using Bu2Mg and then
trapping with PhCHO. Column chromatography on silica gel
(1:1 DCM–Et2O) afforded 9 (0.88 g, 58%) as a white powder;
mp 96–97 ЊC (Found: C, 75.2; H, 5.2; N, 9.4. C19H16N2O2
requires: C, 75.0; H, 5.3; N, 9.2%); νmax/cmϪ1 (KBr) 3335, 2956,
2924, 2853, 1671, 1458, 1260; δH 10.3 (1 H, s, NH), 8.49 (1 H, m,
6-H), 7.68 (5 H, m, Ph), 7.56 (1 H, m, 4-H), 7.32 (5 H, m, Ph),
7.11 (1 H, m, 5-H), 6.45 (1 H, s, OH), 5.73 (1 H, s, CH(OH)Ph);
δC 164.4 (CO), 147.4 (2-C), 147.0 (6-C), 142.2 (3-C), 142.1
(1Љ-C), 139.2 (4-C), 137.6 (1Ј-C), 129.4 (3Ј-C and 5Ј-C), 128.7
(3Љ-C and 5Љ-C), 127.7 (4Љ-C), 127.2 (2Љ-C and 6Љ-C), 125.1
(5-C), 120.5 (4Ј-C), 120.6 (2Ј-C and 6Ј-C), 72.9 (CH(OH)Ph).
N-(tert-Butyl)-3-deuteriopyridine-4-carboxamide 17a. Com-
pound 17a was obtained from 15 using Bu2Mg and then
trapping with D2O. Column chromatography on silica gel
(4:1 DCM–Et2O) afforded 17a (0.20 g, 23%, 83% d). The
characteristics of this product were found to be identical to
1
N-Phenyl-3-(ꢀ-hydroxy-ꢁ-methylpropyl)pyridine-2-carb-
oxamide 10. Compound 10 was obtained from 7 using Bu2Mg
and then trapping with PriCHO. Column chromatography
on silica gel (1:1 DCM–Et2O) afforded 10 (0.20 g, 15%) as
a yellow powder; mp 78–79 ЊC (Found: C, 70.9; H, 6.6; N, 10.7.
C16H18N2O2 requires: C, 71.1; H, 6.7; N, 10.4%); νmax/cmϪ1
(KBr) 3448, 2966, 1729, 1469, 1387, 1262, 1160; δH 9.00 (1 H,
s, NH), 8.41 (1 H, m, 6-H), 7.64 (1 H, m, 4-H), 7.37 (5 H, m,
Ph), 7.15 (1 H, m, 5-H), 5.90 (1 H, s, OH), 4.32 (1 H, m,
CH(OH)Pri), 1.86 (1 H, m, CHMe2), 1.14 (6 H, d, J 6.5,
CHMe2); δC 165.1 (CO), 147.0 (2-C), 146.0 (6-C), 141.1 (3-C),
138.9 (4-C), 134.5 (1Ј-C), 128.5 (3Ј-C and 5Ј-C), 126.3 (5-C),
124.3 (4Ј-C), 120.5 (2Ј-C and 6Ј-C), 72.0 (CH(OH)Pri), 32.0
(CHMe2), 15.2 (CHMe2).
those described for 15 except for H and 13C NMR spectra
where the 3-H and 3-C signals respectively had disappeared.
N-(tert-Butyl)-3-iodopyridine-4-carboxamide 17b. Com-
pound 17b was obtained from 15 using Bu2Mg and then
trapping with I2. Column chromatography on silica gel (7:3
DCM–Et2O) afforded 17b (0.33 g, 22%) as a white powder;
mp 161–162 ЊC (Found: C, 39.5; H, 4.0; N, 9.3. C10H13IN2O
requires: C, 39.5; H, 4.3; N, 9.2%); νmax/cmϪ1 (KBr) 3224, 2966,
2930, 1649, 1458, 1365, 1341, 1227; δH 8.86 (1 H, s, 2-H), 8.48
(1 H, d, J 4.9, 6-H), 7.23 (1 H, d, J 4.9, 5-H), 5.63 (1 H, s, NH),
1.42 (9 H, s, But); δC 166.7 (CO), 159.5 (2-C), 150.8 (6-C), 149.5
(4-C), 123.2 (5-C), 99.7 (3-C), 52.6 (CMe3), 29.1 (CMe3).
2,2-Dimethyl-N-(3-deuterio-2-pyridyl)propanamide
19.13
N-Phenyl-3-(methylthio)pyridine-2-carboxamide 11. Com-
pound 11 was obtained from 7 using Bu2Mg and then trapping
with dimethyl disulfide. Column chromatography on silica
gel (9:1 petrol-Et2O) afforded 11 (0.27 g, 22%) as a yellow
powder; mp 96–98 ЊC (Found: C, 63.8; H, 4.9; N, 11.4; S,
13.0. C13H12N2OS requires: C, 63.9; H, 4.95; N, 11.5; S, 13.1%);
νmax/cmϪ1 (KBr) 3328, 3046, 2916, 1681, 1679, 1529, 1441;
δH 10.1 (1 H, s, NH), 8.30 (1 H, d, J 4.7, 6-H), 7.4 (7 H, m, 4-H,
5-H and Ph), 2.36 (3 H, s, Me); δC 165.7 (CO), 147.2 (2-C),
142.6 (6-C), 135.0 (3-C), 133.2 (4-C), 132.9 (1Ј-C), 129.3 (3Ј-C
and 5Ј-C), 126.3 (4Ј-C), 124.7 (5-C), 119.9 (2Ј-C and 6Ј-C),
15.3 (Me).
Compound 19 was obtained from 18 using Bu2Mg and then
trapping with D2O. Column chromatography on silica gel
(3:2 AcOEt–petrol) afforded 19 (0.87 g, 97%, 98% d). The
characteristics of this product were found to be identical to
1
those described for 18 except for H and 13C NMR spectra
where the 3-H and 3-C signals respectively had disappeared.
2,2-Dimethyl-N-(3-(hydroxy(phenyl)methyl)-2-pyridyl)propan-
amide 20. Compound 20 was obtained from 18 using Bu2Mg
and then trapping with PhCHO. Column chromatography
on silica gel (AcOEt) afforded 20 (0.64 g, 45%) as a white
powder; mp 115–117 ЊC (lit.,13 114–117 ЊC); δC 167.3 (CO),
150.9 (2-C), 148.1 (6-C), 139.2 (1Ј-C), 137.7 (4-C), 133.1 (5-C),
132.2 (3-C), 127.7 (3Ј-C and 5Ј-C), 126.4 (2Ј-C and 6Ј-C), 125.6
(4Ј-C), 71.8 (CH(OH)Ph), 51.2 (CMe3), 29.3 (CMe3).
N-(tert-Butyl)-4-isopropylpyridine-3-carboxamide 13. Com-
pound 13 was obtained from 12 using PriMgCl. Column
chromatography on silica gel (7:3 DCM–Et2O) afforded 13
(0.77 g, 70%) as a white powder; mp 112–113 ЊC (Found:
C, 70.6; H, 9.4; N, 12.8. C13H20N2O requires: C, 70.9; H, 9.15;
N, 12.7%); νmax/cmϪ1 (KBr) 3264, 2972, 1633, 1364, 1328, 1224;
δH 8.41 (1 H, d, J 4.7, 6-H), 8.36 (1 H, s, 2-H), 7.15 (1 H, d,
J 4.7, 5-H), 5.79 (1 H, s, NH), 3.30 (1 H, m, CHMe2), 1.40 (9 H,
s, But), 1.18 (6 H, d, J 6.6, CHMe2); δC 165.3 (CO), 156.1 (4-C),
151.0 (6-C), 149.0 (2-C), 130.2 (3-C), 121.4 (5-C), 52.6 (CMe3),
29.9 (CHMe2), 29.2 (CMe3), 23.6 (CHMe2).
2,2-Dimethyl-N-(3-iodo-2-pyridyl)propanamide 21. Com-
pound 21 was obtained from 18 using Bu2Mg and then trapping
with I2. Column chromatography on silica gel (1:1 AcOEt–
petrol) afforded 21 (1.0 g, 66%) as a white powder; mp 148–
149 ЊC (lit.,21 148 ЊC); δC 177.0 (CO), 152.4 (2-C), 148.7 (6-C),
148.3 (4-C), 122.1 (5-C), 88.2 (3-C), 50.2 (CMe3), 27.9 (CMe3).
2,2-Dimethyl-N-(4-isopropyl-3-pyridyl)propanamide
23.
Compound 23 was obtained from 22 using PriMgCl. Column
chromatography on silica gel (4:1 AcOEt–petrol) afforded 23
(0.75 g, 68%) as a white powder; mp 104–105 ЊC (Found:
C, 70.6; H, 9.4; N, 12.4. C13H20N2O requires: C, 70.9; H, 9.15;
N-(tert-Butyl)-4-butylpyridine-3-carboxamide 14. Compound
14 was obtained from 12 using Bu2Mg. Column chroma-
tography on silica gel (7:3 DCM–Et2O) afforded 14 (0.60 g,
4248
J. Chem. Soc., Perkin Trans. 1, 2000, 4245–4249

View Article Online
N, 12.7%); νmax/cmϪ1 (KBr) 3318, 2965, 2871, 1649, 1510, 1408;
δH 8.58 (1 H, s, 2-H), 8.27 (1 H, d, J 4.7, 6-H), 7.86 (1 H, s, NH),
7.15 (1 H, d, J 4.7, 5-H), 2.97 (1 H, m, CHMe2), 1.22 (9 H, s,
But), 1.10 (6 H, d, J 6.6, CHMe2); δC 176.9 (CO), 144.9 (6-C),
142.7 (2-C), 136.8 (4-C), 127.9 (3-C), 123.1 (5-C), 39.6 (CMe3),
31.3 (CHMe2), 28.4 (CMe3), 26.2 (CHMe2).
6 P. D. Rao, B. J. Littler, G. R. Geier III and J. S. Lindsey, J. Org.
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7 W. Schlecker, A. Huth, E. Ottow and J. Mulzer, J. Org. Chem., 1995,
60, 8414.
8 W. Schlecker, A. Huth, E. Ottow and J. Mulzer, Liebigs Ann. Chem.,
1995, 1441.
9 W. Schlecker, A. Huth, E. Ottow and J. Mulzer, Synthesis, 1995,
1225.
10 W. Schlecker, A. Huth, E. Ottow and J. Mulzer, Tetrahedron, 1995,
51, 9531.
11 J. Epsztajn, A. Bieniek, J. Z. Brzezinski and A. Jozwiak, Tetrahedron
Lett., 1983, 24, 4735.
12 J. Epsztajn, A. Bieniek and M. W. Plotka, J. Chem. Res. (S), 1986,
20; J. Epsztajn, A. Bieniek and M. W. Plotta, J. Chem. Res. (M),
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13 J. A. Turner, J. Org. Chem., 1983, 48, 3401.
14 T. Güngör, F. Marsais and G. Quéguiner, Synthesis, 1982, 499.
15 R. P. Houghton and C. S. Williams, Tetrahedron Lett., 1967, 3929.
16 N. L. Wendler, D. Taub and C. H. Kuo (Merck and Co., Inc.) USP 3
450 706/1969; N. L. Wendler, D. Taub and C. H. Kuo (Merck and
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2,2-Dimethyl-N-(4-butyl-3-pyridyl)propanamide 24. Com-
pound 24 was obtained from 22 using Bu2Mg. Column
chromatography on silica gel (1:1 AcOEt–petrol) afforded 24
(0.59 g, 50%) as a colorless oil (Found: C, 71.5; H, 9.8; N, 11.9.
C14H22N2O requires: C, 71.8; H, 9.5; N, 11.95%); νmax/cmϪ1
(KBr) 3172, 3046, 2896, 1680, 1476, 1365, 1164; δH 7.95 (1 H,
s, 2-H), 7.89 (1 H, d, J 4.9, 6-H), 7.53 (1 H, s, NH), 6.88 (1 H,
d, J 4.9, 5-H), 2.55 (2 H, m, CH2CH2CH2Me), 2.44 (2 H, m,
CH2CH2CH2Me), 1.48 (2 H, m, CH2CH2CH2Me), 1.18 (9 H, s,
But), 1.04 (3 H, t, J 8.2, CH2CH2CH2Me); m/z (CI) 235 (100%,
M ϩ Hϩ).
17 N. L. Wendler, D. Taub and C. H. Kuo (Merck and Co., Inc.) USP 3
578 670/1971; N. L. Wendler, D. Taub and C. H. Kuo (Merck and
Co., Inc.) Chem. Abstr., 1971, 75, 48918f.
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