N-(6-Methyl-2-pyridyl)acrylamide: a case of amide hydrolysis without the assistance of acid or base in the synthesis of water-driven H-bonded polymeric chains

Article abstract of DOI:10.1016/j.tetlet.2007.07.016

Amide hydrolysis of N-(6-methyl-2-pyridyl)acrylamide without the assistance of either acid or base produces the aminopyridinium carboxylate salt at low or room temperature. The carboxylate ion and the free amine functionalities are cooperatively involved in hydrogen bonding with lattice water to form a new hydrogen-bonded polymeric chain.

Full text of DOI:10.1016/j.tetlet.2007.07.016

Tetrahedron Letters 48 (2007) 6308–6311
N-(6-Methyl-2-pyridyl)acrylamide: a case of amide
hydrolysis without the assistance of acid or base in the synthesis
of water-driven H-bonded polymeric chains
a,
a
b
*
Kumaresh Ghosh, Tanushree Sen and Roland Fr o¨ hlich
a
Department of Chemistry, University of Kalyani, Kalyani, Nadia 741235, India
Organisch-Chemisches Institut, Universit a¨ t M u¨ nster, Corrensstraße 40, D-48149 M u¨ nster, Germany
b
Received 12 May 2007; revised 22 June 2007; accepted 5 July 2007
Abstract—Amide hydrolysis of N-(6-methyl-2-pyridyl)acrylamide without the assistance of either acid or base produces the
aminopyridinium carboxylate salt at low or room temperature. The carboxylate ion and the free amine functionalities are cooper-
atively involved in hydrogen bonding with lattice water to form a new hydrogen-bonded polymeric chain.
Ó 2007 Elsevier Ltd. All rights reserved.
Substituted pyridine is a versatile motif in the context of
the synthesis of various fused heterocycles and also in
hydrogen bonding motifs in the construction of a new
water-driven hydrogen-bonded polymer.
1
the preparation of heteroatom-based supramolecular
2
hosts for various biologically important guests. In the
O
O
O
majority of cases, the pyridine nitrogen was found to
react with an ester carbonyl pendant at the 2-position
to afford substituted 4H-quinolizin-4-ones. Chandler
N
N
H
N
N
N
N
H
3
et al. devised an alternative route for the Skraup reac-
tion for the synthesis of naphthyridine using the same
protocol. In their approach, condensation between 2-
1
2
3
4
H
N
O
O
amino-6-methylpyridine and ethyl acetoacetate with
phosphoric acid, initiates kinetically favored ring forma-
tion onto the ring nitrogen of the pyridine, which on
thermal isomerization at 350 °C leads to the 1,8-naph-
thyridine ring system in moderate yield. This ring
switching strategy has become increasingly important
in the cleavage of lactone or lactam rings situated at
position 2 of the pyridine ring with simultaneous forma-
tion of other heterocyclic systems. Based on the above
and our research on the synthesis of supramolecular
N
N
N
H
4
5
Compound 16 was obtained by reacting 2-amino-6-
methylpyridine with 2-propenoyl chloride in the pres-
ence of Et N in dry CH Cl . Amide 2 was prepared in
two steps as outlined in Scheme 1. Alkylation of 2-ami-
no-6-methylpyridine at the amino group was performed
3
2
2
5
hosts as well as the identification and characterization
7
according to the reported procedure.
of important hydrogen bonding synthons, we report
here cleavage of the amide bond of 2-acryloylamino-6-
methylpyridine 1 with simultaneous regeneration of
Compound 3 was obtained from 2-amino-6-methylpyri-
dine via reaction with butyryl chloride in the presence of
Et N in dry CH Cl . Under similar conditions, com-
3
2
2
pounds 4 and 5 were obtained by reacting 2-propenoyl
chloride with 2- and 3-aminopyridine, respectively. All
the compounds were characterized by conventional
Keywords: Hydrogen bonding synthon; Amide cleavage; Hydrogen-
bonded polymeric chain; Lattice water; 2-Amino-6-methylpyridine.
1
*
Corresponding author. Tel.: +91 33 25828750; fax: +91 33
5828282; e-mail: ghosh_k2003@yahoo.co.in
methods. Interestingly, the characterization of 1 by H
2
NMR (in CDCl ) adequately supported its structural
3
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.016

K. Ghosh et al. / Tetrahedron Letters 48 (2007) 6308–6311
COCl, Et N
RBr, K CO , cat. KI
6309
COCl, Et N
3
3
2
3
O
1
dry CH Cl
dry acetone
NH2
dry CH Cl
2 2
2
2
N
N
NHR
N
N
R
2: R = n-butyl,
Scheme 1. Syntheses of compounds 1 and 2.
features. However, on storing in the absence of solvent
(26 °C). The low temperature favors the conversion pos-
sibly due to the insoluble nature of 1a that separates as a
solid from the starting material, which is gummy in nat-
ure. The reaction is reversible and the kinetically favored
product 1a is fully converted to the thermodynamically
stable amide 1 on heating in boiling xylene for 1–2 h.
Reformation of amide 1 in boiling xylene is presumably
ascribed to the azeotropic loss of water. The conversion
of 1a into 1 is also feasible in solution phase. In dry ethyl
acetate, 1a was completely converted to 1 at room tem-
perature after 2 h. In dry CHCl , CH OH, and THF the
same conversion was only 20%, 10%, and 50% complete,
respectively, after one day. Methanol, a polar H-bond
donor solvent, stabilizes 1a by solvating the carboxylate
ion as well as the amine group through H-bonding and
makes the conversion of 1 to 1a less facile. The free
amine salt 1a was very labile such that we could not
form an amide with butyryl chloride; instead we isolated
in a freezer for a couple of days, compound 1 produced
6
a white, chloroform insoluble solid 1a, which exhibited
1
a different H NMR spectrum (in DMSO-d ). Careful
6
1
analysis of the H NMR spectrum of the newly formed
solid revealed the disappearance of the vinylic protons
(
d 6.45, 6.25, and 5.77 ppm) with the appearance of
new signals centered at d 4.26 and 2.33 ppm. Also, FTIR
analysis showed significant changes in the carbonyl
À1
stretching frequencies (1676 cm
1
in 1 changed to
À1
À1
668 cm in 1a). The amide NH stretch at 3270 cm
3
3
À1
in 1, appeared as two peaks (3408 and 3290 cm ) in
the chloroform insoluble solid. This indicated the pres-
ence of a free amine functionality in the newly formed
solid. Mass analysis showed a peak at m/z 181.2
(
M+H) instead of m/z 162 for 1. A single crystal of this
solid was prepared from chloroform/methanol and anal-
8
ysis confirmed structure 1a.
1
as the sole product. The presence of an electron-donat-
ing methyl group in 1 promotes the amide cleavage pos-
sibly by increasing the donor capacity of the pyridine
ring nitrogen in the Michael type addition reaction in
Scheme 2. This was established by reacting compound
N
O
NH2
+
4
, which under similar conditions was stable, although
9
b
Szafran et al. had reported the nucleophilic reaction
of 2-aminopyridine itself with 3-bromopropionic acid
to afford 3-(2-aminopyridinium)propionate. Compound
-
O
1
a
5
was also stable under similar conditions. In addition,
this conversion was not observed with derivatives 2
and 3 suggesting the kinetic inertness of the 3° and sat-
urated 2° amides, respectively. Compound 1a crystal-
lized in the triclinic system with one water molecule in
the asymmetric unit and is interesting in the context of
the synthesis of new hydrogen bonding synthons in
supramolecular chemistry. During the rearrangement
of 1 as shown in Scheme 2, the hydrogen-bonding pat-
tern (AD; A = H-bond acceptor; D = H-bond donor)
was altered to an AADD pattern in 1a (Fig. 1).
This finding is interesting and to the best of our knowl-
edge, is unknown in the literature. The generation of 1a
can be explained by invoking the following suggested
mechanism where the pyridine amide proton on tauto-
8
meric shift presumably initiates the reaction. Michael
type addition of the pyridine nitrogen to the pendant
group at C-2 of pyridine gives the cyclic imine 6, which
on hydrolysis in the presence of atmospheric water, pro-
duces 1a. In this regard, cleavage of amide linkage fol-
lowed by intermolecular alkylation on the pyridyl ring
nitrogen to afford 1a cannot be excluded. Compound
This hydrogen bond alteration particularly, has a pro-
found role in the synthesis of supramolecules of great
1
, in absence of solvent, was found to undergo complete
conversion to 1a after 35 days in a freezer at 5 °C. The
same conversion was 10% complete on keeping for 35
days in the open atmosphere at room temperature
interest. Figure 2 shows the ORTEP plot of 1aÆH O
with atom numbering scheme. In the unit cell, two
charged pyridyl rings with carboxylate ions are aligned
2
H O
H O
2
2
1a
N
N
N
H
N
N
N
N
N
N
NH
OH
N
NH
+
+
+
OH
OH
O
OH
O
6
Scheme 2. Probable mechanism of the rearrangement.

6310
K. Ghosh et al. / Tetrahedron Letters 48 (2007) 6308–6311
molecular packing (Fig. 3) indicates that the water mol-
ecules are associated by O–HÁ Á ÁO (O1–H1AÁ Á ÁO12:
O
H
˚
˚
˚
N
O
N
H
0.89 A, 1.94 A, 177° and O1–H1BÁ Á ÁO13#: 0.94 A,
+
D
N
N
H
˚
˚
˚
1
1
.85 A, 160°) and N–HÁ Á ÁO (H8–H8AÁ Á ÁO1#: 0.91 A,
.98 A, 171°) hydrogen bonds and adopts a trigonal pla-
D
A
A
nar arrangement. These two different types of hydrogen
bonds (O–HÁ Á ÁO and N–HÁ Á ÁO) result in self-assemblies
into ladder-like chains that consist of two different alter-
nate 12-membered rings. Both rings adopt a favorable
chair-like arrangement with two water molecules at
opposite ends of the chair. These cooperative interac-
tions help not only to form a hydrogen-bonded polymer
but also to stabilize the whole structure.
-
O
A
D
1
1a
Figure 1. Hydrogen bonding groups in 1 and 1a (A = hydrogen bond
acceptor, D = hydrogen bond donor).
In summary, we have identified the lability of the amide
linkage of N-(6-methyl-2-pyridyl)acrylamide, which
undergoes clean hydrolysis without the assistance of
acid or base to produce 3-(2-amino-6-methylpyridi-
nium)propionate monohydrate 1a, which forms hydro-
gen-bonded polymeric chains. This observation forms
the basis of the synthesis of new hydrogen-bonding syn-
thons in supramolecular chemistry. Further work is in
progress in our laboratory.
C4
C5
C6
C3
C2
C7
N8
N1
C9
C10
Acknowledgments
We thank DST (SR/FTP/CS-18/2004), Government of
India, for financial support. T.S. thanks CSIR, Govt.
of India for a fellowship.
C11
O12
O1
O13
Figure 2. SCHAKAL plot of 1aÆH O.
References and notes
2
1
. (a) Ma, Y.; Kolotuchin, S. V.; Zimmerman, S. C. J. Am.
Chem. Soc. 2002, 124, 13757–13769; (b) Bernstein, J.;
Stearns, B.; Shaw, E.; Lott, W. A. J. Am. Chem. Soc. 1947,
69, 1151–1158; (c) Fenlon, E. E.; Murray, T. Z.; Baloga, M.
in opposite directions with a distance of separation of
˚
.860 A to avoid electrostatic repulsion.
3
Figure 3. Two different views of the ladder-like chains through hydrogen bonding in 1a.
In the present case, the free amine and the carboxylate
ion are intramolecularly hydrogen bonded forming an
H.; Zimmerman, S. C. J. Org. Chem. 1993, 58, 6625–6628,
and references cited therein.
. (a) Bielawski, C.; Chen, Y.-S.; Zhang, P. Chem. Commun.
2
3
4
8
-membered ring being suggested as optimal for hydro-
1
998, 1313–1314; (b) Archer, E. A.; Gong, H.; Krische, M.
gen bonding in a cyclic array. The heavy atom separation
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. (a) Stanovnik, B.; Svete, J. Chem. Rev. 2004, 104, 2433–
is consistent with a strong bond, and the N–HÁ Á ÁO angle
˚
˚
is not far off linear (N8–H8BÁ Á ÁO12: 0.91 A, 1.85 A,
2
480; (b) Kolar, P.; Petrie, A.; Tisler, M. J. Heterocycl.
1
68°). The AADD hydrogen bonding groups have con-
Chem. 1997, 34, 1067–1098.
. Chandler, C. J.; Deady, L. W.; Reiss, J. A.; Tzimos, V. J.
Heterocycl. Chem 1982, 19, 1017–1019.
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verged into bifunctional AD groups, which on H-bond
linking with lattice water gives a water-driven H-bonded
polymer. In a layer, each single chain, which arises due to
C5–HÁ Á ÁO13 hydrogen bonds, is further connected to the
adjacent chain through water. Close examination of the
2
365–2369.

K. Ghosh et al. / Tetrahedron Letters 48 (2007) 6308–6311
. Compound 1 was purified by column chromatography using 8. Crystal data of 1aÆH
6311
6
2
O: C
9
14
H N
2
O
3
, triclinic, space group
˚
1
2
0% EtOAc in pet ether. Compound 1, gummy in nature, H
P À 1 (No. 2), a = 7.377(1), b = 8.423(1), c = 8.498(1) A,
˚
3
NMR (400 MHz, CDCl , d in ppm) 8.46 (1H, s), 8.10 (1H, d,
J = 8 Hz), 7.61 (1H, t, J = 8 Hz), 6.90 (1H, d, J = 8 Hz),
a = 97.81(1), b = 93.24(1), c = 113.22(1)°, V = 477.2(1) A ,
3
À3
T = 223(2) K, Z = 2, qcalcd = 1.379 mg m , k (Cu-Ka) =
˚
6
.45 (1H, d, J = 16.8 Hz), 6.25 (1H, m), 5.77 (1H, d,
1.54178 A, 3901 total reflections of which 1582 were
À1
J = 10.4 Hz), 2.44 (3H, s), FTIR (m cm , KBr) 3270,
independent, 1541 observed [I > 2r (I)]. Structure solution
+
1
676, 1602, 1577, 1455. Mass (ESI) 185.0 (M+Na ), 163.3
and refinement with SHELXS-97 and SHELXL-97, final refine-
+
1
2
(
M+H) , 145.1, 109.2. Compound 1a, mp = 126 °C,
H
ment against F with 144 parameters, hydrogen atoms at
NMR (400 MHz, DMSO-d
6
, d in ppm) 7.63 (1H, t,
N8 and O1 from difference Fourier map and refined free
with isotropic thermal parameters, other calculated and
J = 8 Hz), 6.87 (1H, d, J = 8 Hz), 6.71 (1H, d, J = 8 Hz),
4
NH
.26 (2H, t, J = 4.8 Hz), 2.49 (3H, s), 2.33 (2H, m), free –
1 2
refined riding, R [I > 2r (I)] = 0.037, wR = 0.099. CCDC
611076.
9. (a) Katritzky, A. R.; Ghiviriga, I. J. Chem. Soc., Perkin
Trans. 2 1995, 1651–1653; (b) Szafran, M.; Kowalczyk, I.;
Katrusiak, A. J. Mol. Struct. 2006, 786, 25–32.
À1
2
– was not found, FTIR (m cm , KBr) 3408, 3290, 1668,
+
1
602, 1537, 1455. Mass (ESI) 181.2 (M+H) , 163.2, 109.3.
. Mazik, M.; Radunz, W.; Sicking, W. Org. Lett. 2002, 4,
579–4582.
7
4