Studies on the 4-benzoylpyridine-3-carboxamide entity as a fragment model of the Isoniazid-NAD adduct

Article abstract of DOI:10.1039/b415439h

An ortho-metallatkm-electrophilic substitution sequence was employed as a key step to build the 4-benzoylpyridine framework. It was found that 4-benzoylpyridine-3-carboxamide and an N-pyridyl alkylated derivative both exist in a unique cyclized hemiamidal

Full text of DOI:10.1039/b415439h

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A R T I C L E
Studies on the 4-benzoylpyridine-3-carboxamide entity as a fragment
model of the Isoniazid–NAD adduct
Sylvain Broussy,a Vania Bernardes-Ge´nisson,a Heinz Gornitzka,b Jean Bernadou*a and
Bernard Meuniera
a Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne, 31077,
Toulouse cedex 4, France. E-mail: bernadou@lcc-toulouse.fr; Fax: 33 (0)5 61 55 30 03;
Tel: 33 (0)5 61 33 31 17
b Laboratoire d’He´te´rochimie Fondamentale et Applique´e (UMR 5069), Universite´ Paul
Sabatier, 118 route de Narbonne, 31062, Toulouse cedex 04, France
Received 6th October 2004, Accepted 3rd December 2004
First published as an Advance Article on the web 13th January 2005
An ortho-metallation–electrophilic substitution sequence was employed as a key step to build the 4-benzoylpyridine
framework. It was found that 4-benzoylpyridine-3-carboxamide and an N-pyridyl alkylated derivative both exist in a
unique cyclized hemiamidal structure, not in the usually expected keto-amide open form. These structures represent
fragment models of the Isoniazid–NAD adducts involved in the mechanism of action of the antituberculous drug
Isoniazid.
and C-7 leading to four diastereoisomers) along with the open
Introduction
keto-amide structures 2 as minor compounds (two epimers, 4S
Isoniazid (INH) (1; Fig. 1) is one of the most common and ef-
and 4R).7,8 It is interesting to note that these adducts have been
ficient drugs used in treatment of tuberculosis.1 After activation
shown, when tested as a purified pool, to be effective inhibitors of
InhA. Recently, Rawat et al. have reported that the analogue of
by the catalase-peroxydase KatG,2 it inhibits long-chain enoyl
acyl carrier protein reductase (InhA), an enzyme involved in the
the INH–NAD adduct derived from benzoic hydrazide (BH–
biosynthesis of mycolic acids which are an integral part of the
6b
NAD 4; Fig. 1) is also a tight-binding inhibitor of InhA.
mycobacterial cell wall.3 Data from X-ray crystallography4 and
Concerning the oxidized adduct 5, preliminary NMR results
mass spectrometry5 reveal that the mechanism of the inhibition
support its existence as two diastereoisomeric cyclic adducts
involves a covalent attachment of the activated form of the drug
(isonicotinoyl radical) with the nicotinamide ring of NAD(H)
(form 6).8
In connection with our research program on the synthesis of
(nicotinamide adenine dinucleotide), thereby modifying the
simplified models of INH–NAD adducts, we were interested in
nature of the coenzyme and its interaction with the target
enzyme InhA. Recent studies have suggested that the 1,4-
the preparation of the 4-benzoylpyridine-3-carboxamide core 14
(Scheme 1). This compound, which represents a fragment model
dihydropyridine INH–NAD adduct(s) and oxidized analogue(s)
and a synthetic precursor of simplified analogues of the INH–
(of a pyridinium type) exhibit the keto-carboxamide structures
NAD adduct, would be useful to understand more about the
4–6a,b
2 and 5, respectively (Fig. 1).
On the other hand, our
different structures of the INH–NAD inhibitors and also for fur-
ther design and access to potential antituberculous compounds.
group has reported that the biomimetic activation of INH with
manganese(III) pyrophosphate in the presence of the coenzyme
NAD+ results mainly in the formation of cyclized hemiamidal
dihydropyridines 3 (with creation of two new chiral carbons C-4
Results and discussion
The preparation of functionalized 3,4-disubstituted pyri-
dines in which both substituents are carbon atoms by an
ortho-metallation–electrophilic substitution sequence is a well-
established strategy in organic synthesis.9 However, to our
knowledge, this route has not yet been explored for the synthesis
of 4-benzoylpyridine-3-carboxamide 14. Therefore, we decided
to adapt two previous procedures10,11 to realize the first synthesis
of this molecule.
Because tertiary amides are extremely powerful ortho-
directing groups,12 the starting nicotinic acid 7 was converted
to N,N-diisopropylnicotinamide 8 via the intermediate acid
chloride (Scheme 1).13 When 8 was treated with LDA in THF
at −78 ◦C followed by addition of N,N-dimethylbenzamide,
a useful benzoylation agent, the condensation product 9 was
obtained regioselectively in a very good yield.14 Although
tertiary carboxamide can be seen as a masked carboxylic acid,
all attempts to realize its hydrolysis to obtain directly 12 failed.
So, in order to overcome this obstacle, the keto-amide 9 was first
reduced by action of NaBH4 to give the alcohol-carboxamide
10. By treatment with formic acid, 10 was then cyclized to the
lactone 11 with loss of diisopropyl amine. In our hands, the use
of other acid catalysts such as p-toluenesulfonic acid decreased
the yield of this transformation. Subsequently, the unstable
Fig. 1 Isoniazid (INH) and proposed structures for Isoniazid–NAD
and benzoic hydrazide–NAD adducts.
6 6 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 6 6 6 – 6 6 9
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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Scheme 1 Reagents and conditions: a) SOCl2, b) (iPr)2NH, c) LDA, THF, C6H5CON(CH3)2, d) NaBH4, ethanol, e) HCOOH, reflux, f) Na2CO3,
MeOH–H2O, then conc. HCl, g) MnO2, acetone, h) SOCl2, i) aq. NH4OH, j) BrCH2COOEt, THF.
lactone 11 was opened in a basic medium (Na2CO3) to give,
after acidification, the corresponding hydroxy-acid derivative,
which upon air oxidation slowly afforded 4-benzoylnicotinic
acid 12. To accelerate this last transformation, a manganese
dioxide oxidation reaction was performed. It is interesting to
note that the keto-acid intermediate 12 exists exclusively in
the uncyclized form (13C NMR: ketone CO at 195.4 ppm and
carboxylic acid CO at 166.4 ppm). Finally, to convert the acid
12 into the amide 14, the classical reaction of ammonia with
the corresponding acid chloride was employed. In fact, when 12
was treated with SOCl2, the cyclized structure 13 was obtained15
In order to verify whether this tendency to ring closure can
also be found in the pyridinium analogue, the hemiamidal 16 was
alkylated with ethyl bromoacetate. The resulting product showed
spectroscopic data (13C NMR, IR) in favour of the cyclized
structure 17. No equilibrium between the ring-chain isomers
could be observed.
Conclusion
In conclusion, the elaboration of the 4-benzoylpyridine frame-
work using nicotinic acid as a starting material is possible
using an ortho-metallation–electrophilic substitution sequence.
However, the target compound 14 was shown to exist exclusively
in a hemiamidal structure that results from cyclization involving
the 3-carboxamide group and the ketone function. Furthermore,
quaternization of the pyridine nitrogen did not affect this
cyclized structure and provided the pyridinium derivative 17 in a
cyclized form. In light of these observations, the question of the
exact structures of the parent reduced and oxidized INH–NAD
adducts (opened or cyclized structures), which are the inhibitors
resulting of Isoniazid activation, should be reconsidered. In
addition, compounds 16 and 17 may be useful as synthetic
precursors of simplified analogues of the INH–NAD adducts
with potential interest as antituberculous drugs.
(IR: m O 1803 cm−1). This intermediate possesses two different
=
C
electrophilic centres able to react with ammonia:16 the carbonyl
carbon atom (acylation of the amine with opening of the ring),
which gives the desired product 14, or the halogenated carbon
atom (alkylation of the amine) to give the lactone 15. The
reaction of ammonia with 13 gave exclusively 16. This result
suggests that this compound arises from the attack of ammonia
upon the carbonyl group of 13 to give the open intermediate
14 which instantaneously isomerizes to afford the cyclized
hemiamidal 16. No trace of the open isomer 14 could be isolated
or detected. The structure of 16 was unambiguously confirmed
by 13C NMR (tetrahedral carbon C-7 at 88.5 ppm) and X-ray
structural analysis (Fig. 2). These experiences confirm that the
formation of the open structure 14 is less favourable than the
corresponding cyclized hemiamidal compound 16, in which a
5-membered ring is constructed. The overall yield of 16 from 8
was 15%.
Experimental
Materials and methods
Melting points were determined on an Electrothermal 9300
capillary melting point apparatus and are not corrected. 1H
NMR spectra were recorded on an AC Bruker spectrometer at
250 and 300 MHz using CDCl3 or d6-DMSO as the solvent. For
1H NMR the residual proton signal of the deuteriated solvent
was used as an internal reference: CDCl3 d = 7.29 ppm and d6-
DMSO d = 2.50 ppm. 13C NMR spectra were recorded on an AC
Bruker spectrometer at 63 and 75 MHz. Infra-red spectra were
recorded on a Perkin–Elmer spectrometer GX FT-IR. Mass
spectra (EI and CI) were obtained on a MS-Nermag R10–10
spectrometer. For MS-ESI, in the positive mode, a Perkin–Elmer
SCIEX API 365 spectrometer was used. Elemental analysis were
performed in the “Laboratoire de Chimie de Coordination du
CNRS”. Column chromatography was performed on silica gel
Fig. 2 X-Ray structure of compound 16.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 6 6 6 – 6 6 9
6 6 7

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(Acros 0.035–0.070 mm). All reagents were obtained from com-
mercial suppliers and were used without purification. Anhydrous
solvents were freshly distilled before use. THF was dried over
sodium in the presence of benzophenone.
J = 5.1 Hz, H5-Py), 7.30–7.38 (m, 5H, H-phenyl), 6.42 (s, 1H,
CHO). 13C NMR (75 MHz, CDCl3) d 169.0 (C), 158.1 (C), 154.1
(CH), 148.4 (CH), 135.1 (C), 130.2 (CH), 129.6 (2 × CH), 137.2
(2 × CH), 122.2 (C), 118.8 (CH), 82.7 (CH).
4-Benzoylnicotinic acid10 (12). To a solution of 11 (0.252 g,
1.20 mmol) in MeOH–H2O (60 : 40) (25 cm3), was added Na2CO3
(0.120 g). The reaction mixture was stirred at room temperature
for 2 h, acidified with concentrated hydrochloric acid to pH 1,
and then concentrated in vacuo. The residue was dissolved in
acetone (40 cm3) and MnO2 (0.520 g, 6.00 mmol) was added.
The mixture was stirred at room temperature for 24 h and
then filtered through Celite (eluant: ethyl acetate) to remove
MnO2. The filtrate was concentrated in vacuo, diluted with ethyl
acetate and washed with water. The aqueous phase (pH adjusted
to 7) was extracted 4 times with ethyl acetate, the combined
organic extracts were dried over MgSO4 and concentrated by
rotary evaporation. The solid obtained was purified by washing
with dichloromethane to afford after drying 0.120 g (44%) of
4-Benzoyl-N,N-diisopropylnicotinamide (9). To a solution of
N,N-diisopropyl◦nicotinamide 8 (1.24 g, 6.00 mmol) in THF
(100 cm3) at −80 C, lithium diisopropylamide (6 cm3, 10.8 mmol
in heptane–THF–ethylbenzene 4 : 8 : 3) was added dropwise.
After 15 min stirring, a solution of N,N-dimethylbenzamide
(894 mg, 6 mmol) in THF (10 cm3) was added dropwise at −80 ◦C
and the mixture was allowed to warm to room temperature (3 h).
Water was added (50 cm3) and the product was extracted with
diethyl ether (3 × 100 cm3). The combined organic extracts were
washed with brine, dried over Na2SO4 and concentrated in vacuo.
The residue was purified by column chromatography (silica gel,
elution with CH2Cl2–MeOH 95 : 5) to give 9 (1.52 g, 82%). IR
1
mmax(KBr)/cm−1 1627 and 1670 (C O). H NMR (300 MHz,
=
CDCl3) d 8.72 (d, 1H, J = 5.1 Hz, H6-Py), 8.65 (d, 1H, J =
0.9 Hz, H2-Py), 7.82 (m, 2H, H-phenyl), 7.61 (m, 1H, H-phenyl),
7.48 (m, 2H, H-phenyl), 7.36 (dd, 1H, J = 5.0 Hz and J = 0.8 Hz,
H5–Py), 3.84 (m, 1H, CH(CH3)2), 3.48 (m, 1H, CH(CH3)2), 1.39
(d, 6H, J = 6.6 Hz, CH3), 1.24 (d, 6H, J = 6.6 Hz, CH3). 13C
NMR (75 MHz, CDCl3) d 195.4 (C), 167.0 (C), 149.6 (CH),
147.3 (CH) 144.9 (C), 136.2 (C), 134.3 (CH), 134.2 (C), 130.7
(2 × CH), 129.0 (2 × CH), 123.0 (CH), 52.1 (CH), 46.5 (CH),
21.0 (CH3), 20.5 (CH3). MS (EI) m/z 310 (M+), 210, 100, 77.
Anal. Calcd. for C19H22N2O2: C 73.52; H 7.14; N 9.02. Found :
C 73.33; H 7.50; N 8.98.
keto-acid 12. Mp 228 ◦C (dec.). IR mmax(KBr)/cm−1 3063, 2446,
1
=
1713 and 1673 (C O), 1596, 1293, 1268. H NMR (250 MHz,
CD3OD) d 9.23 (s, 1H, H2-Py), 8.85 (d, 1H, J = 5.1Hz, H6-Py),
7.49–7.74 (m, 6H, 5 × H-phenyl + H5-Py). NMR 13C (75 MHz,
d6-DMSO) d 195.4 (C), 166.4 (C), 154.2 (CH), 151.7 (CH), 149.5
(C), 136.5 (C), 134.6 (CH), 129.9 (2 × CH), 129.7 (2 × CH), 125.2
(C), 122.4 (CH). MS (EI) m/z 227 (M+), 183 (M+ − COO), 105
(M+ − pyCOOH), 77, 51.
1-Hydroxy-1-phenyl-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-
one (16). A solution of 12 (0.230 g, 1.02 mmol) in SOCl2
(7.5 cm3) was stirred at 60 ◦C for 2.5 h. The reaction
mixture was concentrated, the crude residue was dissolved in
dichloromethane and the solvent removed in vacuo. This last
operation was done twice. The oil obtained (IR mmax 1803 cm−1)
was diluted in acetone (1.5 cm3) and a solution of 28% NH4OH
(5 cm3) was added dropwise. The mixture was stirred at room
temperature for 1.5 h, diluted with water (15 cm3) and extracted
with ethyl acetate. The organic phase was dried over MgSO4,
filtered and concentrated in vacuo. The precipitate, obtained
after addition of dichloromethane, was filtered and washed with
this same solvent to give, after drying, 120 mg (53%) of 16. Mp
223 ◦C. IR mmax(KBr)/cm−1 3157, 1699, 1679, 1612, 1448, 1323,
1066. 1H NMR (250 MHz, d6-DMSO) d 9.50 (s, 1H, NH), 8.87
(s, 1H, H2-Py), 8.71 (d, 1H, J = 5.1 Hz, H6-Py), 7.33–7.52 (m,
6H, 5 × H-phenyl and H5-Py), 7,18 (s, 1H, OH). 13C NMR
(75 MHz, d6-DMSO) d 167.9 (C), 158.4 (C), 153.8 (CH), 145.4
(CH), 141.4 (C), 129.3 (2 × CH), 129.1 (CH), 127.0 (C), 126.4
(2 × CH), 118.7 (CH), 88.1 (C). MS (DCI) m/z 227 (M + H+),
244 (M + NH4+). Anal. Calcd. for C13H10N2O2: C, 69.02; H,
4.46; N, 12.38. Found : C, 69.28; H, 4.16; N, 12.31.
4-[Hydroxy(phenyl)methyl]-N,N-diisopropylnicotinamide (10).
To a solution of amide 9 (2.50 g, 8.1 mmol) in ethanol was
added NaBH4 (1.47 g, 39.7 mmol). The reaction mixture was
stirred at room temperature under an argon atmosphere for 1.5 h
and then acetone (20 cm3) and water (50 cm3) were added. The
final mixture was extracted with dichloromethane, the organic
phase was dried over MgSO4, filtered and concentrated in vacuo.
The residue was purified by column chromatography (silica gel,
elution with CH2Cl2–MeOH 98 : 2, 95 : 5) to give the alcohol-
amide 10 as a mixture of two diastereoisomers17 (2.04 g, 81%).
−1
=
IR mmax(KBr)/cm : 3277 (O–H), 2969, 2934, 1621 (C O), 1591,
1
1443, 1028. H NMR (250 MHz, CDCl3) d 8.62 (d, 1H, J =
5,0 Hz, H6-Py), 8.53 (d, 1H, J = 5.1 Hz, H6-Py), 8.41 (s, 1H,
H2-Py), 8.37 (s, 1H, H2-Py), 7.42 (d, 1H, J = 5.0 Hz, H5-Py),
7.21–7.37 (m, 11H, 2 × (5 × H-phenyl) + H5-Py), 6.04 (d, 1H,
J = 3.3 Hz, CHOH), 5.75 (d, 1H, J = 10.0 Hz, CHOH), 5.69
(d, 1H, J = 9.9 Hz, OH), 3.85 (d, 1H, J = 3.4 Hz, OH), 3.23–
3.63 (m, 4H, CH(CH3)2), 1.52 (d, 3H, J = 6.7 Hz, CH(CH3)2),
1.50 (d, 3H, J = 6.7 Hz, CH(CH3)2), 1.42 (d, 3H, J = 6.8 Hz,
CH(CH3)2), 1.28 (d, 3H, J = 6.8 Hz, CH(CH3)2), 1.15 (d, 3H,
J = 6.8 Hz, CH(CH3)2), 1.11 (d, 3H, J = 6.6 Hz, CH(CH3)2),
0.67 (d, 3H, J = 6.6 Hz, CH(CH3)2), 0.45 (d, 3H, J = 6.6 Hz,
CH(CH3)2). 13C NMR (75 MHz, CDCl3) d 169.5 (C), 168.6 (C),
151.4 (2 × C), 150.9 (CH), 150.5 (CH), 147.6 (CH), 146.0 (CH),
142.9 (C), 141.6 (C), 132.6 (C), 132.3 (C), 129.1 (2 × CH), 128.8
(2 × CH), 128.5 (CH), 128.4 (2 × CH), 127.6 (CH), 126.5 (2 ×
CH), 125.2 (CH), 122.3 (CH), 75.7 (CH), 71.9 (CH), 51.8 (CH),
51.7 (CH), 46.8 (CH), 46.7 (CH), 21.1 (CH3), 21.0 (CH3), 20.8
(2 × CH3), 20.7 (CH3), 20.5 (2 × CH3), 20.3 (CH3). MS (EI)
m/z 312 (M+), 269, 210, 106, 84, 49.
Crystal data for compound 16. C13H10N2O2, M 226.23,
˚
˚
monoclinic, P21/c, a = 10.245(2) A, b = 7.160(1) A, c =
◦
3
˚
˚
15.020(3) A, b = 107.943(4) , V = 1048.2(3) A , Z = 4, T =
193(2) K. 5860 reflections (2147 independent, Rint = 0.0343)
were collected at low temperature using an oil-coated shock-
cooled crystal on a Bruker-AXS CCD 1000 diffractometer with
˚
MoKa radiation (k = 0.71073 A). The structure was solved
by direct methods (SHELXS-97)18 and all non-hydrogen atoms
were refined anisotropically using the least-squares method on
−3
F2.19 Largest electron density residue: 0.271 e A , R1 (for
˚
I > 2r(I)) = 0.0411 and wR2 = 0.0962 (all data) with R1 =
ꢀ
ꢀ
ꢀ
1-Phenyl-1,3-dihydrofuro[3,4-c]pyridin-3-one (11). A solu-
tion of 10 (0.413 g, 1.32 mmol) in formic acid (50 cm3) was
heated under reflux for 23 h. The solvent was removed in vacuo
and the residue was dissolved in dichloromethane (25 cm3). The
organic phase was washed with 5% aqueous Na2CO3, and the
aqueous phase was extracted with dichloromethane. The organic
extracts were dried over MgSO4, filtered and concentrated in
vacuo to give 0.275 g (98%) of the unstable lactone 11. 1H NMR
(250 MHz, CDCl3) d 9.23 (d, 1H, J = 1.0 Hz, H2-Py), 8.83
(d, 1H, J = 5.1 Hz, H6-Py), 7.32 (dd, 1H, J = 1.0 Hz and
(
||F0| − |Fc||)/
2 0.5
|F0| and wR2 = { w(F0 − Fc )2/
2
2
ꢀ
w(F0 )2} . CCDC reference number 252382. See http://
www.rsc.org/suppdata/ob/b4/b415439h/ for crystallographic
data in .cif format.
5-[(Ethoxycarbonyl)methyl]-1-hydroxy-3-oxo-1-phenyl-1,2-di-
hydro-3H-pyrrolo[3,4-c]pyridinium bromide (17). To
a
refluxing solution of hemiamidal 16 (100 mg, 0.35 mmol) in
THF (10 cm3), ethyl bromoacetate (88 mg, 5.3 mmol) was
added. After 15 h of reaction, the white precipitate was filtered,
6 6 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 6 6 6 – 6 6 9

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washed three times with THF and ether, and dried under
4 D. A. Rozwarski, G. A. Grant, D. H. R. Barton, W. R. Jacobs Jr. and
vacuum to give 100 mg (70%) of 17. IR mmax(KBr)/cm−1 3089,
J. C. Sacchettini, Science, 1998, 279, 98–102.
1755, 1717 (C O), 1653 (C O), 1228, 1215, 1051, 702. 1H
NMR (300 MHz, d6-DMSO) d 10.29 (s, 1H, NH), 9.57 (s,
1H, H2-Py), 9.18 (d, 1H, J = 6 Hz, H6-Py), 8.31 (d, 1H, J =
6 Hz, H5-Py), 7.80 (s, 1H, OH), 7.58 (m, 2H, H-phenyl), 7.44
(m, 3H, H-phenyl), 5.73 (s, 2H, NCH2CO), 4.24 (q, 2H, J =
7 Hz, OCH2CH3), 1.26 (t, 3H, J = 7 Hz, OCH2CH3). 13C NMR
(75 MHz, d6-DMSO d 167.1 (C), 166.5 (C), 163.9 (C), 151.3
(CH), 143.8 (CH), 138.9 (C), 130.6 (C), 130.1 (CH), 129.7 (2 ×
CH), 126.7 (2 × CH), 122.7 (CH), 88.5 (C), 63.3 (CH2), 61.3
(CH2), 14.8 (CH3). MS (EI) m/z 313 (M+). HRMS (FAB+)
found 313.1185, calc. 313.1188.
5 M. Wilming and K. Johnsson, Angew. Chem., Int. Ed., 1999, 38,
=
=
2588–2590.
6 (a) B. Lei, C.-J. Wei and S.-C. Tu, J. Biol. Chem., 2000, 275, 2520–
2526; (b) R. Rawat, A. Whitty and P. Tonge, Proc. Natl. Acad. Sci.
U.S.A., 2003, 100, 13881–13886.
7 M. Nguyen, C. Claparols, J. Bernadou and B. Meunier, Chem-
BioChem, 2001, 2, 877–833; M. Nguyen, A. Que´mard, S. Broussy, J.
Bernadou and B. Meunier, Antimicrob. Agents Chemother., 2002, 46,
2137–2143.
8 S. Broussy, Y. Coppel, M. Nguyen, J. Bernadou and B. Meunier,
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9 V. Snieckus, Chem. Rev., 1990, 90, 879–933.
10 J. Epsztajn, J. Z. Brzezinski and A. J. Jozwiak, J. Chem. Res., 1986,
401–441.
11 J. Epsztajn, A. Bieniek, J. Z. Brzezinski and A. Jozwiak, Tetrahedron
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¨
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 6 6 6 – 6 6 9
6 6 9