Facile synthesis of functionalized 4-aminopyridines
Nagatoshi Nishiwaki,* Mayumi Azuma, Mina Tamura, Kazushige Hori, Yasuo Tohda and Masahiro
Ariga*
Department of Chemistry, Osaka Kyoiku University, Asahigaoka 4-698-1, Kashiwara, Osaka 582-8582,
Japan. E-mail: ariga@cc.osaka-kyoiku.ac.jp; Fax: 81-729-78-3399; Tel: 81-729-78-3398
Received (in Cambridge, UK) 7th June 2002, Accepted 9th August 2002
First published as an Advance Article on the web 23rd August 2002
The title compounds are readily available by ring trans-
formation of nitropyrimidinone with active methylene
compounds in the presence of ammonium acetate.
Other oxobutanoates 2b–d also gave the corresponding
aminopyridines 4b–d in good yields (runs 2–4). When the
alkoxy group is sterically hindered, small amounts of pyridones
5
c and 5d are additionally produced. Substrate 2 for this
4
-Aminopyridine-3-carboxylic acid (4-aminonicotinic acid)
reaction does not require an acetyl group, and keto esters 2e,f
similarly react with pyrimidinone 1 giving 4-aminopyridine-
3-carboxylates having a methyl or a methoxy groups at the
5-position (runs 5 and 6). The present reaction is applicable to
b-keto amide 2g and chloroacetone 2h to enable the introduc-
tion of other functional group at the 3-position (runs 7 and 8).
2,4-Pentanedione 2i is less reactive under the same conditions
(run 9). A strong intramolecular hydrogen bond might be a
possible reason for the failure of the reaction with 2i. By
contrast, tricarbonyl compounds 2j,k only furnish difunction-
alized 4-pyridones 5j,k without formation of 3,5-difunction-
alized 4APs 4j,k (runs 10 and 11).
A plausible mechanism for this reaction is proposed in
Scheme 2. This reaction is initiated with nucleophilic addition
of the enol form of 2 to the electron-deficient 6-position of
nitropyrimidinone 1. The ketone carbonyl group in the adduct 6
is converted to the amino group by ammonium salt 3, then the
resultant enamine 7 intramolecularly attacks the 2-position to
afford a bicyclic intermediate 8. The elimination of ni-
troacetamide from 8 leads to 4AP 4. When 2j and 2k are
employed as the substrate, the enolization of 6 easily occurs
rather than conversion to the enamine, thus 4-pyridone 5 is
produced with similar transformation of enol form 9 via bicyclic
intermediate 10. In cases of oxobutanoates 2c and 2d, the
sterically hindered alkoxy group prevents ammonium salt 3
from approaching to the carbonyl group, which causes both ring
transformations to afford small amounts of pyridones 5c,d in
addition to 4APs 4c,d.
and its ester are sometimes found as a partial structure in natural
products,1 and their derivatives behave as NAD analogs.2
4
-Aminopyridines (4APs) having a functional group at the
vicinal position are also excellent precursors for [c]-fused
pyrido compounds such as pyridopyrimidine, imidazopyridine,
pyrazolopyridine and naphthyridine, those are widely used for
3
medicines or their synthetic intermediates. Although some
preparative procedures for functionalized 4APs have been
established, multistep reactions and troublesome experimental
4
manipulations are necessary. Furthermore functionalized 4AP
has high possibility being a key compound for design of new
medicines since 4AP plays an important role in neuroscience.5
Hence, development of a facile preparative method for title
compounds is one of significant projects.
In our course of study on the ring transformation,6
,7
3
-methyl-5-nitropyrimidin-4(3H)-one (1)† is shown to be a
suitable structure for this kind of reaction. The 2- and the
-positions of 1 are electrophilic and the N3–C4–C5 unit is
6
readily eliminated as nitroacetamide. In the present paper, a new
ring transformation yielding functionalized 4APs will be
provided (Scheme 1).
To a solution of pyrimidinone 1 (155 mg, 1 mmol) in
3
methanol (20 cm ), were added ethyl 3-oxobutanoate (2a, 0.25
cm , 2 mmol) and ammonium acetate 3 (154 mg, 2 mmol), then
the mixture was heated under reflux for 3 days. After removal of
the solvent, the residue was treated with column chromatog-
raphy on silica gel to furnish 4-amino-3-ethoxycarbonylpyr-
3
8
idine (4a) and N-methylnitroacetamide in 97 and 82% yields,
On the basis of the mechanism shown in Scheme 2, it seems
to be possible to employ aliphatic ketones instead of active
methylene compounds. Actually, the reaction of pyrimidinone 1
with 2-hexanone 2l under the same conditions gave three types
of ring transformed products. 4-Amino-3-propylpyridine (4l) is
isolated in 23% yield to our expectation, besides 6-butyl-
respectively (Table, run 1). The C2–N1–C6 unit of 1 behaves as
the synthetic equivalent of activated diformylamine to compose
the C2–N1–C6 unit of 4a. Additionally, the carbonyl group of
2
a is converted to the amino group. Since 3-ethoxycarbonyl-
7
4-pyridone 5a, prepared by a different method, is intact under
6
the same conditions, introduction of an amino group is not
performed after the formation of 5a. Ammonium ion 3 also
causes no change on keto ester 2a, which indicates enamine of
3-nitro-2-pyridone 11 and 4-butylpyrimidine 12 (Scheme 3).
Since the pentanoyl group in the adduct intermediate 6A shows
less electrophilicity than the carbonyl group of 6 in Scheme 2,
2a is not the nucleophile in this reaction.
Table 1 Reactions of pyrimidinone 1 with active methylene compounds
Run
R1
R2
4
5
1
2
3
4
5
6
7
8
9
H
H
H
H
Me
MeO
H
H
H
COOEt
a
b
c
d
e
f
g
h
i
97
87
57
81
97
97
31
17
0
0
0
7
12
0
0
0
0
0
COOMe
COOPr
COOPenta
COOMe
COOMe
CONH
Cl
2
COMe
COMe
COOEt
1
1
0
1
COMe
COOEt
j
k
0
0
45
88
a
2
-Pentyl.
Scheme 1 The ring transformation affording 4-aminopyridines 4.
2
170
CHEM. COMMUN., 2002, 2170–2171
This journal is © The Royal Society of Chemistry 2002