New reactivity of nitropyrimidinone: Ring transformation and N-C transfer reactions

Article abstract of DOI:10.1055/s-2004-817788

Nitropyrimidinone 1 revealed new reactivity upon treatment with active methylene compounds 2 under basic conditions. The N1-C2-C3-C4 moiety of 1 combined with two carbon units of 2 affording polyfunctionalized pyridones 4, which was hitherto unknown ring transformation. On the other hand, the N1-C2 moiety of 1 was transferred to the methylene group of 2 giving functionalized enamines 3. It was also possible to modify the amino group in 3a by reactions with primary amines. Enamines 3 reacted with hydrazines, and leading to functionalized pyrazoles 7 quantitatively. The ratios of regioisomeric pyrazoles 7/8 were moderately controlled by use of sterically hindered enamines 3h, 3k and 31. Furthermore, enamine 3a was readily converted to 1,4-diazepines 9 having a functional group at the 6-position.

Full text of DOI:10.1055/s-2004-817788

LETTER
703
New Reactivity of Nitropyrimidinone: Ring Transformation and N-C Transfer
Reactions
R
ingTransformati
a
onand
N
-C
g
Transfer Re
a
actions toshi Nishiwaki,* Kazuo Matsushima, Miki Chatani, Mina Tamura, Masahiro Ariga*
Department of Chemistry, Osaka Kyoiku University, Asahigaoka 4-698-1, Kashiwara, Osaka 582-8582, Japan
Fax +81(729)783399; E-mail: ariga@cc.osaka-kyoiku.ac.jp
Received 9 December 2003
Additionally, another reactivity of 1 is observed in the re-
Abstract: Nitropyrimidinone 1 revealed new reactivity upon treat-
ment with active methylene compounds 2 under basic conditions.
The N1-C2-C3-C4 moiety of 1 combined with two carbon units of
2 affording polyfunctionalized pyridones 4, which was hitherto un-
action with primary amines, and nitroenamines having a
carbamoyl group are easily prepared.5 In this reaction, the
N3-C4-C5-C6 moiety is attached to amines with loss of
known ring transformation. On the other hand, the N1-C2 moiety of the N1-C2 moiety. This result prompted us to develop two
1 was transferred to the methylene group of 2 giving functionalized
novel reactivity of nitropyrimidinone 1. We considered
enamines 3. It was also possible to modify the amino group in 3a by
that pyrimidinone 1 behaves as the reagent introducing an
reactions with primary amines. Enamines 3 reacted with hydra-
N-C unit when 1 is allowed to react with other nucleo-
zines, and leading to functionalized pyrazoles 7 quantitatively. The
philes than amines. Furthermore, pyrimidinone 1 is ex-
ratios of regioisomeric pyrazoles 7/8 were moderately controlled by
pected to be a synthetic equivalent of dipolar a-
nitroacrylamide causing the ring transformation in the
different mode from described above.
use of sterically hindered enamines 3h, 3k and 3l. Furthermore,
enamine 3a was readily converted to 1,4-diazepines 9 having a
functional group at the 6-position.
Key words: diazepine, functionalized enamine, nitropyrimidinone,
pyrazole, pyridone
Table 1 Reactions of Pyrimidinone 1 with Active Methylene Com-
pounds Leading to Enamines 3 and Polyfunctionalized Pyridones 4
Easily available 3-methyl-5-nitropyrimidin-4(3H)-one
(1)1 has been shown as an excellent precursor for various
kinds of polyfunctionalized heterocyclic compounds. Py-
rimidinone 1 behaves as the synthetic equivalent of acti-
vated diformylamine when the ring transformation occurs
at the 2- and the 6-positions of 1 accompanied by elimina-
tion of the N3-C4-C5 moiety as nitroacetamide. Pyrimid-
inone 1 actually reacted with bidentate nucleophiles to
afford 4,5-disubstituted pyrimidines,2 3,5-difunctional-
ized 4-pyridones3 and 4-aminopyridines.4 Pyrimidinone 1
also acts as the synthetic equivalent of a-nitroformylace-
tic acid affording 5,6-disubstituted 3-nitro-2-pyridones2a
as a result of the ring transformation occurring at the
4- and the 6-positions together with elimination of the N1-
C2-N3 moiety (Scheme 1).
R1
R2
R3
Yield (%) Yield (%)
of 3
70
0
of 4
MeCO
OEt
Me
aa
0
b
67
0
PhCO
MeCO
PhCO
COOEt
CN
OEt
Me
Ph
ba
41
0
b
84
0
Me
Ph
ca
38
0
b
0
Me
da
12
0
0
b
0
OEt
OEt
OH
NH2
ea
41
0
78
31
70
67
b
fa
47
0
b
a Base: NaOEt, time: 4 h.
Scheme 1
b Base: piperidine, time: 24 h.
SYNLETT 2004, No. 4, pp 0703–0707
0
9.
0
3.
2
0
0
4
Advanced online publication: 17.02.2004
DOI: 10.1055/s-2004-817788; Art ID: U27603ST
© Georg Thieme Verlag Stuttgart · New York

704
N. Nishiwaki et al.
LETTER
To a solution of pyrimidinone 1 (3 mmol) in ethanol (40 ed to give corresponding enamines 3g and 3h. Sterically
mL), were added a solution of ethyl 3-oxobutanoate (2a, hindered alkyl groups such as tert-butyl and adamantyl
3 mmol) and sodium ethoxide (3 mmol) in ethanol (20 groups could be also introduced though elevated temper-
mL) under reflux over 1 hour, and the resultant mixture ature was necessary for effective conversion (Table 2).
was heated at 80 °C for 4 hours. After quenching the reac-
Table 2 Modification of the Amino Group of Enamine 3a
tion with 1 M hydrochloric acid, the solvent was removed
under reduced pressure. The residue was treated with col-
umn chromatography on silica gel to afford functionalized
enamine 3a in 38% yield.6 When two equivalents of sodi-
um enolate were used, the yield of 3a was improved to
70%. Pyrimidinone 1 similarly reacted with other active
methylene compounds 2b–f leading to corresponding
enamines 3b–f in moderate yields (Table 1). In cases of 2e
and 2f, ring transformed products 4e and 4f were addition-
ally isolated, however 4a–d were not detected in reactions
using 2a–d. Since pyridones 4a–d are electron-deficient
as well as pyrimidinone 1, further reactions such as ring
transformation or decomposition might proceed under the
present conditions. When less basic piperidine was em-
ployed instead of sodium ethoxide, it was achieved to iso-
late pyridones 4a and 4b derived from keto esters 2a and
2b (Scheme 2).7,8
R4
Temp
(°C)
Yield (%)a
Recovery
(%) of 3aa
p-MeOC6H4
p-MeOC6H4
p-NO2C6H4
Pr
3g
r.t.
80
77
23
0
Quant. (86)c
15
3h
3i
120b
r.t.
r.t.
80
85
0
Quant. (87)c
85
t-Bu
3j
15
0
t-Bu
Quant. (93)c
Quant. (70)c
Adamantyl
3k
80
0
a Determined by 1H NMR.
b In a sealed tube.
c Isolated yield.
Since the aminomethylene group is regarded as a synthet-
ic equivalent of a formyl group as well as ethoxymethyl-
ene and (dimethylamino)methylene groups, enamines 3
can be used for preparation of functionalized heterocyclic
compounds by condensation with bidentate nucleophiles.
When enol ether 59 and enamine 610 are allowed to react
with methylhydrazine at 0 °C, both two regioisomeric
pyrazoles 7a and 8a were produced in 90/10 and 77/23 ra-
tios, respectively.11 On the other hand, enamine 3a
(R4 = H) afforded pyrazole 7a exclusively even at room
temperature due to less steric hindrance. As shown in
Table 3, the increased bulkiness on the amino group
showed one possibility to control the regioselectivity in
the condensation of 3 with substituted hydrazines. The
ratio of 8a in the reaction mixture was improved up to
35% when enamine 3k was employed (Scheme 3).
Scheme 2 A plausible mechanism for the ring opening reaction of 1
The present reaction is initiated with addition of the eno-
late at the 2- and the 6-positions of pyrimidinone 1. The
following ring opening reaction divides the pyrimidinone
ring, and these two components furnished 3 and 4, respec-
tively. As another possibility, the ring opening reaction
might occur after addition of first molecule of enolate at
the 6-position, and the methaneimidoyl group on the ni-
trogen is eliminated by the attack of second enolate, which
leads to same products 3 and 4.
Scheme 3
Reactions of enamine 3a with other hydrazines similarly
underwent to furnish corresponding pyrazoles 7l–p as a
single regioisomer in high yields (Table 4).12 Sterically
hindered hydrazines besides aromatic and functionalized
hydrazines were applicable to the present reaction. Ena-
mines 3b and 3d were quantitatively converted to
pyrazoles upon treatment with methylhydrazine at room
temperature. In the case of 3d derived from diketone, two
Modification on the amino group of enamine 3a was eas-
ily performed. To a solution of 3a in ethanol, propylamine
was added, and the solution was stirred at room tempera-
ture for 1 day. The 1H NMR of the reaction mixture after
concentration showed signals for only modified enamine
3i. Reactions of 3a with aromatic amines readily proceed-
Synlett 2004, No. 4, 703–707 © Thieme Stuttgart · New York

LETTER
Ring Transformation and N-C Transfer Reactions
705
Table 3 Steric Effects on the Ratio of 7a/8aa
Enamine
Temp (°C) Total yield Ratio of
Recovery
(%)b
Quant.c
Quant.
25
7a/8ab
100:0
87:13
70:30
70:30
65:35
(%) of 3b
3a
3g
3j
r.t.
r.t.
r.t.
80
80
0
0
Scheme 4
75
18
65
82
Synthesis of 1,4-diazepine having an ethoxycarbonyl
group was studied by using 1,2-diamines as bidentate nu-
cleophiles. To a solution of enamine 3a (1 mmol) in etha-
nol (20 mL), a solution of N-ethyl-1,2-diaminoethane (1.1
mmol) in ethanol (20 mL) was added at room temperature
over 1 hour, and the mixture was stirred for 1 day (Method
A, Table 5). Although consumption of 3a was confirmed
with TLC, residual product after evaporation was not di-
azepine 9q. In the 1H NMR a doublet having a large cou-
pling constant was observed, which was characteristic
feature for enamines substituted with an electron-with-
drawing group at the b-position, thus the product was as-
signed as enamine 3q.14 Heating a solution of 3q in
ethanol under reflux for 3 days realized the ring closure to
afford diazepine 9q15 in 80% yield (Scheme 5).
3k
35
a In EtOH, time: 24 h.
b Determined by 1H NMR.
c Pyrazole 7a was isolated in 98% yield.
Table 4 Reactions of 3a with Substituted Hydrazines R5NHNH2
R5
Temp (°C) Yield (%)
Recovery
of 7a
(%) of 3aa
H
r.t.
r.t.
80
r.t.
80
Quant. (97)b
37
l
0
63
0
t-Bu
t-Bu
Ph
m
Quant. (88) b
78
n
22
0
Ph
Quant. (71)b
80 (65)b
p-NO2C6H4 80
o
20
0
CH2COOEt r.t.
Quant. (45)b
p
a Determined by 1H NMR.
b Isolated yield.
kinds of pyrazoles 7d and 7d¢ were obtained in a 1/1 ratio.
Amino derivative 7f13 was also prepared from 3f in 60%
yield at room temperature, and in a quantitative yield at 80
°C (Figure 1).
Scheme 5
Table 5 Reaction of Enamine 3a with Diamine (Method A)
Pyrazoles could be directly prepared from pyrimidinone 1
without isolation of intermediate enamines 3. To an etha-
nol solution of the reaction mixture including enamine 3a,
methylhydrazine was added and the mixture was stirred at
room temperature for 1 day. After removal of the solvent,
pyrazole 7a was obtained upon treatment of the residue by
column chromatography (Scheme 4). The present method
was especially effective for diketone 2c since it was some-
what troublesome to isolate enamine 3c.
R6
Solvent R7
(mL)
Yield (%) Yield (%)
of 3a
Quant.
Quant.
49
of 9a
Et
H
H
40
40
Et
q
r
0
CH=CAcCOOEt
CH=CAcCOOEt
0
200
51
a Determined by 1H NMR.
In the case of unsubstituted diamine, double substitution
exclusively proceeded to afford 3r16 under the same con-
ditions. Dilution and slow addition of a diamine solution
enabled the intramolecular cyclization giving diazepine
9r in 51% yield. Furthermore, quantitative conversion
from 3a to 9r was successful when a solution of 3a was
slowly added to a diamine solution under reflux (Method
B, Table 6).
Figure 1
Synlett 2004, No. 4, 703–707 © Thieme Stuttgart · New York

706
N. Nishiwaki et al.
LETTER
Table 6 Reaction of Enamine 3a with Diamine (Method B)
References
R8
H
Solvent (mL)
200
Yield (%) of 3a Yield (%) of 9a
(1) Pyrimidinone 1 is readily prepared from 2-thiouracil by
reduction, methylation and nitration2b in 43% overall yield.
(2) (a) Nishiwaki, N.; Adachi, T.; Matsuo, K.; Wang, H.-P.;
Matsunaga, T.; Tohda, Y.; Ariga, M. J. Chem. Soc., Perkin
Trans. 1 2000, 27. (b) Nishiwaki, N.; Matsunaga, T.; Tohda,
Y.; Ariga, M. Heterocycles 1994, 38, 249.
(3) Nishiwaki, N.; Tohda, Y.; Ariga, M. Synthesis 1997, 1277.
(4) Nishiwaki, N.; Azuma, M.; Tamura, M.; Hori, K.; Tohda,
Y.; Ariga, M. Chem. Commun. 2002, 2170.
r
s
0
52
27
Quant.
48
Me
Me
200
1200
73
a Determined by 1H NMR.
(5) Nishiwaki, N.; Mizukawa, Y.; Terai, R.; Tohda, Y.; Ariga,
M. Arkivoc 2000, 1, 103.
(6) Kiyama, R.; Fuji, M.; Hara, M.; Fujimoto, M.; Kawabata, T.;
Nakamura, M.; Fujishita, T. Chem. Pharm. Bull. 1995, 43,
450.
This reaction was highly sensitive to a steric factor, and
1,2-diaminopropane afforded double substituted enamine
3s in a considerable yield due to the prevention of cycliza-
tion by a methyl group. Using a more diluted solution im-
proved the yield of diazepine 9s to 73%.
(7) Typical Procedure: To a solution of pyrimidinone 1 (155
mg, 1 mmol), in EtOH (20 mL), were added 2a (253 mL, 2.0
mmol) and piperidine (198 mL, 2.0 mmol), and the mixture
was heated under reflux for 1 d. After removal of the solvent,
the residue was extracted with benzene (20 mL × 3), and the
extract was concentrated. The residual red oil was treated
with column chromatography on silica gel to afford 4a5
(eluted with chloroform/EtOAc = 7:1, 162 mg, 0.67 mmol,
67%).
(8) Pyridone 4f: Colorless needles (recrystallized from EtOH);
mp 253–255 °C. 1H NMR (400 MHz, DMSO-d6): d = 1.32
(t, J = 7.1 Hz, 3 H), 3.37 (s, 3 H), 4.29 (q, J = 7.1 Hz, 2 H),
8.72 (brs, 1 H), 8.84 (s, 1 H), 9.28 (brs, 1 H). 13C NMR (100
MHz, DMSO-d6): d = 14.0 (q), 28.9 (q), 60.8 (t), 89.3 (s),
123.4 (s), 140.0 (d), 153.7 (s), 156.9 (s), 165.2 (s). Anal.
Calcd for C9H11N2O5: C, 44.82; H, 4.60; N, 17.42. Found: C,
44.70; H, 4.50; N, 17.41.
(9) (a) Milata, V. Aldrichimica Acta 2001, 34, 20.
(b) Takamura, S.; Yoshimiya, T.; Kameyama, S.; Nishida,
A.; Yamamoto, H.; Noguchi, M. Synthesis 2000, 637.
(10) (a) Gabutt, C. D.; Hepworth, J. D.; Heron, B. M.; Pugh, S. L.
J. Chem. Soc., Perkin Trans. 1 2002, 2799. (b) Juki, L.;
Svete, J.; Stanovnik, B. J. Heterocycl. Chem. 2001, 38, 869.
(11) Menozzi, G.; Mosti, L.; Schenone, P. J. Heterocycl. Chem.
1987, 24, 1669.
In summary, nitropyrimidinone 1 revealed new reactivity
with cleavage of both N1-C6 and C2-N3 bonds. The N3-
C4-C5-C6 moiety behaves as the synthetic equivalent of
dipolar a-nitroacrylamide to cause new-type ring transfor-
mation, and the N1-C2 moiety is used for introducing
agent of an aminomethylene group. When pyrimidinone 1
was treated with active methylene compounds under basic
conditions, polyfunctionalized pyridones 4 and enamines
3 were readily prepared. The latter compounds were ef-
fectively converted to pyrazoles 7/8 and 1,4-diazepines 9
having a functional group (Scheme 6). All of the reactions
required only simple experimental manipulations, and no
by-product was formed in the ring construction reactions.
Hence, these reactions will provide a new methodology
for the preparation of functionalized heterocyclic com-
pounds.
(12) Pyrazoles having an ethoxycarbonyl group are widely used
for synthetic intermediates of agrochemicals such as
insecticides, fungicides, herbicides and so on, see:
(a) Kitajima, T.; Tomiya, K.; Kodaka, K. Jpn. Kokai Tokkyo
Koho, JP 2000212166, 2000; Chem. Abstr., 2000, 133,
120326. (b) Okimura, N.; Tanaka, T.; Fukuchi, T.; Okada, I.
Jpn. Kokai Tokkyo Koho, JP 04021671, 1992; Chem. Abstr.,
1992, 117, 2830. (c) Ishii, T.; Kuwazuka, T.; Shimotori, H.;
Tanaka, Y.; Ishikawa, K. Jpn. Kokai Tokkyo Koho, JP
01106866, 1989; Chem. Abstr., 1989, 111, 194759. (d) The
NOESY spectrum of 7o showed correlation between the
phenyl group and the methyl one that was derived from the
acetyl group of 3a.
(13) Kopp, M.; Lancelot, J.-C.; Dallemagne, P.; Rault, S.
J. Heterocycl. Chem. 2001, 38, 1045.
(14) Enamine 3q: Isolated yield 91%. Brown oil. 1H NMR (400
MHz, CDCl3): E-isomer d = 1.11 (t, J = 7.2 Hz, 3 H), 1.30 (t,
J = 7.2 Hz, 3 H), 1.80–2.30 (br, 1 H), 2.49 (s, 3 H), 2.60–
2.80 (m, 2 H), 2.84 (t, J = 5.6 Hz, 2 H), 3.46 (q, J = 7.2 Hz,
2 H), 4.19 (q, J = 7.2 Hz, 2 H), 8.03 (d, J = 13.6 Hz, 1 H),
10.90–11.20 (br, 1 H); Z-isomer d = 1.11 (t, J = 7.2 Hz, 3 H),
1.30 (t, J = 7.2 Hz, 3 H), 1.80–2.30 (br, 1 H), 2.42 (s, 3 H),
2.60–2.80 (m, 2 H), 2.84 (t, J = 5.6 Hz, 2 H), 3.46 (q, J = 7.2
Hz, 2 H), 4.37 (q, J = 7.2 Hz, 2 H), 8.17 (d, J = 14.8 Hz, 1
Scheme 6
H), 9.20–9.40 (br, 1 H), 8.90–9.10 (br, 1 H); E/Z = 9/1. 13
C
NMR (100 MHz, CDCl3): E-isomer d = 14.1 (q), 15.3 (q),
30.9 (q), 43.8 (t), 49.2 (t), 52.0 (t), 59.7 (t), 100.4 (s), 160.3
Synlett 2004, No. 4, 703–707 © Thieme Stuttgart · New York

LETTER
Ring Transformation and N-C Transfer Reactions
707
(d), 167.4 (s), 199.4 (s); Z-isomer d = 14.1 (q), 15.3 (q), 30.9
J = 7.1 Hz, 4 H), 7.94 (d, J = 14.1 Hz, 2 H), 9.12 (brd,
(q), 41.4 (t), 49.2 (t), 52.0 (t), 59.7 (t), 100.3 (s), 160.2 (d),
169.2 (s), 195.7 (s).
J = 14.1 Hz, 2 H); isomer B d = 1.19 (t, J = 7.1 Hz, 6 H), 2.30
(s, 6 H), 3.55 (brs, 4 H), 4.05 (q, J = 7.1 Hz, 4 H), 7.88 (d,
J = 13.2 Hz, 2 H), 10.72 (brd, J = 13.2 Hz, 2 H); A/B = 1/7.
Since NMR spectra suggested both isomers A and B had
symmetrical structures, they were thought to be EE and ZZ
isomers. 13C NMR (100 MHz, DMSO-d6): isomer A d = 13.6
(q), 29.7 (q), 48.9 (t), 58.1 (t), 98.6 (s), 159.5 (d), 165.7 (s),
196.2 (s); isomer B d = 13.6 (q), 29.9 (q), 48.9 (t), 58.0 (t),
98.6 (s), 159.5 (d), 165.7 (s), 196.2 (s). IR (nujol): 1648,
1699 cm–1. MS (FAB): m/z (%) = 341 (100) [M+ + 1]. Anal.
Calcd for C7H11NO3: C, 56.46; H, 7.11; N, 8.23. Found: C,
56.19; H, 7.17; N, 8.23.
(15) Diazepine 9q: Isolated yield 30%. Dark brown oil. 1H NMR
(400 MHz, CDCl3): d = 1.23 (t, J = 7.2 Hz, 3 H), 1.30 (t,
J = 7.2 Hz, 3 H), 2.31 (s, 3 H), 3.31 (q, J = 7.2 Hz, 2 H), 3.44
(t, J = 4.0 Hz, 2 H), 3.80–4.00 (br, 2 H), 4.19 (q, J = 7.2 Hz,
2 H), 7.64 (s, 1 H). 13C NMR (100 MHz, CDCl3): d = 14.1
(q), 14.5 (q), 27.7 (q), 51.2 (t), 53.1 (t), 55.0 (t), 60.0 (t), 97.0
(s), 150.0 (d), 168.6 (s), 169.7 (s).
(16) Enamine 3r: Isolated yield 82%. Colorless needles; mp 203–
204 °C. 1H NMR (400 MHz, DMSO-d6): isomer A d = 1.25
(t, J = 7.1 Hz, 6 H), 2.24 (s, 6 H), 3.55 (brs, 4 H), 4.16 (q,
Synlett 2004, No. 4, 703–707 © Thieme Stuttgart · New York