Reactions of a series of 1-aminobenzimidazoles and 1-amino-3- methylbenzimidazolium chlorides with 2,4-pentanedione

Article abstract of DOI:10.1016/S0968-0896(99)00254-0

Reactions of a series of 1-aminobenzimidazoles and 1-amino-3- methylbenzimidazolium chlorides with 2,4-pentanedione were carried out and pyridazino[1,6-a]benzimidazoles and 2-pyrazolylanilines were generated. The product ratios of these compounds remarkably depended on the reaction conditions and on the electronic character of the substituent at the benzene moiety. The possible mechanisms involved in these reactions are discussed. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0968-0896(99)00254-0

Bioorganic & Medicinal Chemistry 8 (2000) 37±42
Reactions of a Series of 1-Aminobenzimidazoles and 1-Amino-3-
methylbenzimidazolium Chlorides with 2,4-Pentanedione
Toyo Kaiya, Shinsuke Aoyama and Kohfuku Kohda*
Faculty of Pharmaceutical Sciences, Nagoya City University, Tanabedori, Mizuho-ku, Nagoya 467-8603, Japan
Received 14 June 1999; accepted 19 August 1999
AbstractÐReactions of a series of 1-aminobenzimidazoles and 1-amino-3-methylbenzimidazolium chlorides with 2,4-pentanedione
were carried out and pyridazino[1,6-a]benzimidazoles and 2-pyrazolylanilines were generated. The product ratios of these com-
pounds remarkably depended on the reaction conditions and on the electronic character of the substituent at the benzene moiety.
The possible mechanisms involved in these reactions are discussed. # 2000 Elsevier Science Ltd. All rights reserved.
Introduction
Products were then separated and identi®ed (Scheme 2
and Table 1). From compounds 1a,b, pyridazino[1,6-
a]benzimidazoles (3a,b) were obtained in yields of 78
and 97%, respectively, as already reported.9 Compound
1c has an electron-withdrawing substituent at the
benzene moiety, and when it was allowed to react with
2,4-pentanedione, no product corresponding to com-
pound 3 was produced, although 2-pyrazolylaniline (4c)
was obtained in a low yield of 17%. In this case, the
starting material, 1c, remained, indicating that the
reaction had proceeded slower than with 1a,b. The
structures of compounds 3a,b and 4c were determined
from spectroscopic data (details of 4c will be described
later). Assignments of 1H and 13C NMR signals of these
compounds were carried out by means of HMBC
correlations. In the reaction of 1 with 2,4-pentanedione
in the presence of a catalytic amount of ZnCl2, com-
pound 1a a€orded a quantitative yield of 3a, however,
compound 1b gave 3b and 5b, each in a 27% yield.
In order to elucidate the chemical carcinogenesis of
arylaminating carcinogens, we have examined electro-
philic amination of nucleic acid components.1 To
date, we have generated all isomers of ring-nitrogen
mono-aminated bases and nucleosides of nucleic acid
components.2±6 As a model for the imidazole moiety of
purines, we also examined electrophilic amination of a
series of benzimidazole derivatives.7 In a report on the
utilization of N-aminated derivatives, we previously
described the formation of pyridazinopurine derivatives,
new tricyclic compounds, by the reaction of 7- or 9-
aminoadenine derivatives with 2,4-pentanedione8
(Scheme 1). In the case of 7-aminoadenines, 5-pyra-
zolylpyrimidines were also obtained as by-products.
This study was carried out to elucidate the reaction
mechanisms responsible for formation of these products
using a series of 1-aminobenzimidazole and 1-amino-3-
methylbenzimidazolium chloride derivatives.
Compound 5b will be formed from compound 4b by
further reaction of its amino group with 2,4-pentane-
dione to form a Schi€ base. In the case of 1c, the start-
ing material was completely consumed and the reaction
gave several products, however, only one product, 5c,
was identi®ed with a very low yield (details of the
structure will be described later). These results suggested
that the types and ratios of the products remarkably
depended on the substituent at the benzene moiety and
on the presence or absence of a Lewis acid. With respect
to the reaction of 1c, we used a 1:1 mixture of 1-amino-
5-nitrobenzimidazole and 1-amino-6-nitrobenzimid-
azole because of the diculty in separating these two
isomers. It was interesting that compound 1c gave only
Results and Discussion
Reactions of 1-aminobenzimidazoles (1) with
2,4-pentanedione
Each 1-aminobenzimidazole (1a±c) was dissolved in a
large excess of 2,4-pentanedione and re¯uxed for 4 h.
Keywords: N-aminobenzimidazole; 2,4-pentanedione; pyridazino-
benzimidazole; chemical carcinogenesis.
*Corresponding author. Tel.: +81-52-836-3796; fax: +81-52-834-
9309; e-mail: kohda@phar.nagoya-cu.ac.jp
0968-0896/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(99)00254-0

38
T. Kaiya et al. / Bioorg. Med. Chem. 8 (2000) 37±42
Scheme 1. Reactions of N-aminoadenines with 2,4-pentanedione.
Scheme 2. Reactions of 1-aminobenzimidazole derivatives with 2,4-pentanedione.
the 4-nitro derivative of 4 (R1ˆNO2, R2ˆH) when 1c
was allowed to react with 2,4-pentanedione in the
absence of a Lewis acid, whereas in the presence of
ZnCl2, the reaction gave only the 5-nitro derivative of 5
(R1ˆH, R2ˆNO2). These results indicated that the
reactivity of 1-amino-5-nitrobenzimidazole and 1-
amino-6-nitrobenzimidazole toward 2,4-pentanedione
was altered by the presence of ZnCl2. The e€ect of
another Lewis acid, AlCl3, on the reaction of 1b was
also examined, and results showed that the yield of 5b
was lower than with ZnCl2 (Table 1). With respect to
material had been totally consumed and product 3b was
the major product along with a smaller amount of 2b. In
the presence of ZnCl2, the reaction mixture contained
no starting material after 30 min, and product 2b was
the major product with smaller amounts of products 3b
and 5b. After 2 h, a decreased amount of product 2b and
an increased amount of products 3b and 5b were noted.
No product corresponding to compound
4 was
observed, suggesting that the amino group of product 4,
once formed, was converted to Schi€ base 5 very
quickly by further reaction with 1,2-pentanedione.
1
the tautomeric structures of 5b,c, the H NMR spectra
showed that they are in the enol form as is 2b, as shown
in Scheme 2.
These results strongly suggested that the Schi€ base
product 2b is the ®rst to yield products 3b and 5b. For
further con®rmation of the reaction pathway, com-
pound 2b was obtained as an oil from the reaction mix-
ture in which 1b and 2,4-pentanedione were re¯uxed for
30 min (Table 1). Compound 2b was then allowed to
react with 2,4-pentanedione in the presence or absence
of ZnCl2, and product analyses were carried out using
HPLC. In the absence of ZnCl2, a decreased amount of
2b and an increased amount of 3b were obtained after
30 min, but after 2 h, only compound 3b was observed.
In the presence of ZnCl2, products 3b and 5b appeared
after 30 min with a decreased amount of 2b, and after
HPLC study of reaction pathways
The reaction pathway of 1b with 2,4-pentanedione was
examined using HPLC. Compound 1b was allowed to
react with 2,4-pentanedione under the same reaction
conditions described above. Identi®cation and quanti®-
cation of products 1b, 2b, 3b and 5b were carried out at
the appropriate times. In the absence of a Lewis acid,
the reaction mixture after 30 min contained starting
material 1b and products 2b and 3b. After 2 h, the starting

T. Kaiya et al. / Bioorg. Med. Chem. 8 (2000) 37±42
39
Table 1. Reactions of 1-aminoobenzimidazoles (1) with 2,4-pentane-
dione and yields of productsa
were similar to those obtained with 1c, as shown in
Table 1. Structures of products 8 were determined
1
mainly by means of H and 13C NMR spectroscopies
Starting Lewis Reaction
material acid
Yields of products (%)b
Comments
and HMBC correlation analyses. Unequivocal struc-
tural determination of 8 was carried out with products
8c,d, and the structures of 8a,b were determined by
comparing their spectroscopic data with those of 8c,d.
Unequivocal structural determination of product 7 was
not successful because 7 is a quaternary ammonium salt
and its puri®cation and crystallization could not be
achieved. However, there is strong evidence for the
structure of 7 in that the UV spectrum of 7c in H2O
(lmax 236 and 309 nm) was quite similar to that of 3b in
acidic media (the protonation site may be at N5 and the
lmax were 235 and 308 nm). Moreover, spots of both 3
and 7 on TLC ¯uoresced a light blue and purplish blue
color, respectively, when exposed to UV light.
time (h)
2
3
4
5
1a
1b
1cc
None
None
None
4
4
4
78
97
f
17d
1a
1b
1cc
ZnCl2
ZnCl2
ZnCl2
4
4
4
100
27
27
g
f
6e
1b
1b
None
AlCl3
0.5
4
23
5
25
5
2b
2b
None
ZnCl2
4
4
88
18
21
aA solution of 1 or 2 (0.5 mmol) in 1,2-pentanedione (10 mL) was
re¯uxed for 0.5 or 4 h in the presence or absence of a Lewis acid (10 mg).
bIsolation yield.
cA 1:1 mixture (R1ˆNO2, R2ˆH and R1ˆH, R2ˆNO2) was used
Proposed reaction mechanisms
(Scheme 2).
dR1ˆNO2, R2ˆH.
In the reaction of 1-aminobenzimidazoles (1) with 2,4-
pentanedione, the initial step of the reaction is the
formation of Schi€ base product 2 (Scheme 3). Products
3 and 4 will be formed by cyclization at C2 and C30 and
subsequent aromatization, and by cyclization at C2 and
C20 and subsequent C2±N3 bond cleavage of the imi-
dazole ring, respectively. Product 5 is formed by the
further reaction of 4 with 2,4-pentanedione. When the
electron density of the imidazole moiety is decreased by
the introduction of an electron-withdrawing substituent
at the benzene moiety (compound 1c) or by the presence
eR1ˆH, R2ˆNO2.
fStarting material remained.
gUnidenti®ed products were included.
2 h, products 3b and 5b predominated with only a trace
amount of 2b remaining.
Reactions of 1-amino-3-methylbenzimidazolium chlorides
(6) with 2,4-pentanedione
Similar reactions were carried out with 2,4-pentane-
dione and compounds 6, the quaternary salts of 1
(Table 2). Since these reactions did not proceed well
without ZnCl2, this Lewis acid was included in the
reactions. Four derivatives of 1-amino-3-methylbenzi-
midazolium chlorides (6a±d) were employed. Although
the yields of products were low, 2,4,5-trimethylpyr-
idazino[1,6-a]benzimidazolium chlorides (7a±c) and 2-
(4-acetyl-3-methylpyrazol-1-yl)-N-methylanilines (8a±c)
were obtained from 6a±c. In contrast, compound 6d,
which has an electron-withdrawing substituent at the
benzene moiety, produced 8d and no 7d. These results
of a Lewis acid, the reaction pathway forming
compound 4 or 5 is favored. Similarly, in the reaction
of 1-amino-3-methylbenzimidazolium chlorides 6 with
2,4-pentanedione, a Schi€ base is formed initially and
its cyclization at C2 and C20 gives 8 (Scheme 4). For
formation of 7, the carbanion at C2 may attack the
carbonyl carbon of the side chain to form 7, although
we have no evidence supporting the participation of the
carbanion in this reaction as yet. Formation of similar
types of cationic tricyclic system using other proce-
dures10 and description of similar types of reaction
mechanisms11 have been reported by others.
Table 2. Reactions of 1-amino-3-methylbenzimidazolium chlorides (6) with 2,4-pentanedione and yields of products
R1
R2
Isolation yields (%)
a:
b:
c:
d:
CH3
CH3
H
CH3
H
H
NO2
7
a
8
17
14
34
5
None
H
aA product was formed but not isolated.

40
T. Kaiya et al. / Bioorg. Med. Chem. 8 (2000) 37±42
Scheme 3. Proposed reaction mechanisms.
Scheme 4. Proposed reaction mechanisms.
Experimental
benzimidazolium chloride derivatives14 were also pre-
pared as previously described.
1H and 13C NMR spectra were recorded on JEOL EX
270, GSX 400 and ALPHA 500 spectrometers, and
chemical shifts are expressed in parts per million down-
®eld from internal tetramethylsilane. Mass spectra were
obtained with JEOL AX 505HA and SX 102A spectro-
meters. UV spectra were recorded on a Shimadzu UV-
2100 spectrophotometer and pKa values were estimated
from pH-dependent UV spectral changes. HPLC ana-
lyses were carried out using a Shimadzu LC-10AD
apparatus equipped with a photodiode array UV detec-
tor SPD-M6A. A Merck LiChrospher 100RP-18(e)
column (4Â250 mm) was used and eluted with a solvent
system of 1/15 M phosphate bu€er (pH 6.8)±MeOH (a
linear gradient of 20% MeOH at 0 min to 70% MeOH
at 40 min at a ¯ow rate of 0.8 mL/min). Melting points
(Mp) were measured with a Yanagimoto micro-melting
point apparatus and are uncorrected. Preparative thin-
layer chromatography (PLC) was carried out with
Merck silica gel 60 PF254 plates. 1-Aminobenzimida-
zole12 and 1-amino-5,6-dimethylbenzimidazole13 were
prepared as previously reported. 1-Amino-3-methyl-
Preparation of a 1:1 mixture of 1-amino-5-nitrobenzimi-
dazole and 1-amino-6-nitrobenzimidazole (1c). 5-Nitro-
benzimidazole (82 mg, 0.5 mmol) was dissolved in 5 mL
of water containing KOH (84 mg, 1.5 mmol). Then,
5 mL of water containing hydroxylamine-O-sulfonic
acid (170 mg, 1.5 mmol) and NaHCO3 (126 mg,
1.5 mmol) were added to this solution, and the mixture
was heated at 60 ꢀC for 2 h. The reaction mixture was
then neutralized with acetic acid and the solvent was
removed by evaporation to dryness. Products were
extracted from the residue with MeOH and separated
by repeated PLC (silica gel, CHCl3:MeOH=85:15).
Colorless crystals of a 1:1 mixture of 1-amino-5-nito-
benzimidazole (5-NO2) and 1-amino-6-nitobenzimida-
zole (6-NO2) were obtained in a 44 mg (49%) yield. The
extent of recovery of the starting material was 28 mg
1
(34%). H NMR (CDCl3) (pairs of signals having the
same heights were observed) d 4.99 and 5.02 (each s,
each 2H, NH2 of 5-NO2 and 6-NO2), 7.57 and 7.84
(each d, each 1H, each J=9.0 Hz, 7-H of 5-NO2, 4-H of

T. Kaiya et al. / Bioorg. Med. Chem. 8 (2000) 37±42
41
6-NO2), 8.15 and 8.22 (each s, each 1H, 2-H of 5-NO2
and 6-NO2), 8.22 and 8.29 (each dd, each 1H, each
J=2.2, 9.0 Hz, 6-H of 5-NO2, 5-H of 6-NO2), 8.46 and
8.70 (each d, each 1H, each J=2.2 Hz, 4-H of 5-NO2, 7-H
of 6-NO2); MS m/z 178 (M+). HRMS m/z M+ calcd for
C7H6N4O2: 178.0491; found: 178.0491.
125.7 (d, 4-C), 127.9 and 128.2 (each d, 3- and 6-C),
128.5 (d, 5-C), 131.2 (s, 2-C), 135.1 (d, 500-C), 135.7 (s, 1-
C), 151.8 (s, 300-C), 160.6 (s, 10-C), 192.7 (s, COCH3),
197.0 (s, 30-C); MS m/z 297 (M+), 282 (M+ CH3), 254
(M+ COCH3), 240 (M+ CH=C(OH)-CH3). Anal.
calcd for C17H19N3O2: C, 68.67; H, 6.44; N, 14.13.
Found: C, 68.54; H, 6.42; N, 14.15.
General procedure for the reactions of 1-aminobenzimi-
dazoles (1) with 2,4-pentanedione
2-(4-Acetyl-3-methylpyrazol-1-yl)-N-(3-hydroxy-1-methyl-
2-butenylidene)-5-nitroaniline (5c). Recrystallization
from MeOH gave a yellow ¯occuli. Mp 200±202 ꢀC; H
1
Each 1-aminobenzimidazole derivative (1a±c, 0.5 mmol)
was dissolved in 2,4-pentanedione (10 mL) and the
solution was re¯uxed for 4 h in the presence or absence
of ZnCl2 (10 mg). After the reaction, 2,4-pentanedione
was removed by evaporation and the residues were
subjected to PLC (silica gel, CHCl3:MeOH=95:5).
NMR (Me2SO-d6) d 2.01 (s, 3H, 30-CH3), 2.08 (s, 3H,
10-CH3), 2.43 (s, 3H, COCH3), 2.45 (s, 3H, 300-CH3),
5.43 (s, 1H, 20-H), 7.74 (d, 1H, J=9.0 Hz, 3-H), 8.26
(dd, 1H, J=2.3, 9.0 Hz, 4-H), 8.43 (d, 1H, J=2.3 Hz,
6-H), 8.96 (s, 1H, 500-H), 12.49 (br s, OH); MS m/z 342
(M+), 327 (M+ CH3), 299 (M+ COCH3), 285
(M+ CH=C(OH)-CH3). HRMS m/z M+ calcd for
C17H18N4O4: 342.1328; found: 342.1328. Anal. calcd
2,4,7,8-Tetramethylpyridazino[1,6-a]benzimidazole (3a).9
1H NMR (CDCl3) d 2.46 and 2.48 (each s, each 3H, 7-
and 8-CH3), 2.59 (s, 3H, 2-CH3), 2.69 (s, 3H, 4-CH3),
6.89 (s, 1H, 3-H), 7.70 (s, 1H, 6-H), 7.87 (s, 1H, 9-H);
13C NMR (CDCl3) d 16.9 (q, 4-CH3), 20.6 and 20.8
(each q, 7- and 8-CH3), 21.5 (q, 2-CH3), 111.4 (d, 9-C),
119.8 (d, 6-C), 121.3 (d, 3-C), 129.3 (s, 5a-C), 132.1 (s, 7-
C), 135.0 (s, 8-C), 136.6 (s, 4a-C), 141.5 and 142.6 (each
s, 4- and 9a-C), 149.4 (s, 2-C); MS m/z 225 (M+).
.
for C17H18N4O4 2/3H2O: C, 57.62; H, 5.50; N, 15.81.
Found: C, 57.32; H, 5.17; N, 15.78.
1-(3-Hydroxy-1-methyl-2-butenylideneamino)benzimidazole
(2b). H NMR (CDCl3) d 1.71 (s, 3H, 10-CH3), 2.19 (s,
1
3H, 30-CH3), 5.38 (s, 1H, 20-CH), 7.34 (m, 3H, 5-, 6-H
and 4- or 7-H), 7.81 (dd, 1H, J=1.8, 6.7 Hz, 7- or 4-H),
7.94 (s, 1H, 2-H), 12.28 (br s, 1H, OH); 13C NMR
(CDCl3) d 17.1 (q, 10-CH3), 29.5 (q, 40-C), 99.2 (d, 20-C),
108.9 and 121.0 (each d, 4- and 7-C), 123.2 and 124.4
(each d, 5 and 6-C), 133.8 and 141.3 (each s, 3a- and
7a-C), 142.8 (d, 2-C), 161.1 (s, 10-C), 198.4 (s, 30-C);
MS m/z 215 (M+), 200 (M+ CH3), 198 (M+ OH).
2,4-Dimethylpyridazino[1,6-a]benzimidazole (3b).9 Recrys-
tallization from CHCl3±hexane gave colorless plates.
Mp 139±141 ꢀC; H NMR (CDCl3) d 2.60 (s, 3H, 2-
1
CH3), 2.70 (s, 3H, 4-CH3), 6.92 (s, 1H, 3-H), 7.42 (t, 1H,
J=7.3 Hz, 7-H), 7.52 (t, 1H, J=7.3 Hz, 8-H), 7.96 (d,
1H, J=7.3 Hz, 6-H), 8.11 (d, 1H, J=7.3 Hz, 9-H); 13C
NMR (CDCl3) d 16.9 (q, 4-CH3), 21.6 (q, 2-CH3), 111.8
(d, 9-C), 120.2 (d, 6-C), 122.2 (d, 3-C), 122.4 (d, 7-C),
125.5 (d, 8-C), 130.8 (s, 5a-C), 136.8 (s, 4a-C), 142.7 (s,
9a-C), 143.3 (s, 4-C), 150.0 (s, 2-C); UV lmax nm, (pH 1)
235, 308, (H2O and pH 12) 243, 316; pKa 4.3; MS m/z
197 (M+). Anal. calcd for C12H11N3: C, 73.03; H, 5.62;
N, 21.30. Found: C, 73.33; H, 5.70; N, 21.16.
General procedure for the reactions of 1-amino-3-methyl-
benzimidazolium chlorides (6) with 2,4-pentanedione
Each 1-amino-3-methylbenzimidazolium chloride deri-
vative (6a±d, 0.5 mmol) was dissolved in 2,4-pentane-
dione (10 mL) and the solution was re¯uxed for 4 h in
the presence of ZnCl2 (10 mg). After the reaction, 2,4-
pentanedione was removed by evaporation and the
residues were subjected to PLC (silica gel, CHCl3 then
CHCl3:MeOH=85:15).
2-(4-Acetyl-3-methylpyrazol-1-yl)-4-nitroaniline (4c).
Recrystallization from MeOH gave yellow needles. Mp
218±220 ꢀC; 1H NMR (Me2SO-d6) d 2.44 (s, 3H, 30-CH3),
2.45 (s, 3H, COCH3), 6.96 (d, 1H, J=9.0 Hz, 6-H), 7.03
(br s, 2H, NH2), 8.06 (dd, 1H, J=2.4, 9.0 Hz, 5-H), 8.21
(d, 1H, J=2.4 Hz, 3-H), 8.96 (s, 1H, 50-H); 13C NMR
(Me2SO-d6) d 13.7 (q, CH3), 28.5 (q, COCH3), 115.3 (d,
6-C), 121.0 (s, 40-C), 121.2 (d, 3-C), 122.2 (s, 2-C), 125.1
(d, 5-C), 135.5 (s, 4-C), 136.9 (d, 50-C), 148.9 (s, 1-C),
150.4 (s, 30-C), 192.5 (s, COCH3); MS m/z 260 (M+),
245 (M+ CH3). Anal. calcd for C12H12N4O3: C, 55.38;
H, 4.65; N, 21.53. Found: C, 55.02; H, 4.68; N, 21.20.
2,4,5,7,8-Pentamethylpyridazino[1,6-a]benzimidazolium
1
chloride (7a). H NMR (Me2SO-d6) d 2.51 (s, 3H, 8-
CH3), 2.53 (s, 3H, 7-CH3), 2.71 (s, 3H, 2-CH3), 2.95 (s,
3H, 4-CH3), 4.38 (s, 3H, 5-CH3), 7.90 (s, 1H, 3-H), 8.09
(s, 1H, 6-H), 8.19 (s, 1H, 9-H); 13C NMR (Me2SO-d6) d
18.2 (q, 4-CH3), 19.8 (q, 8-CH3), 20.5 (q, 7-CH3), 20.9
(q, 2-CH3), 33.3 (q, N-CH3), 112.6 (2d, 6- and 9-C),
125.6 (s, 9a-C), 130.2 (d, 3-C), 130.8 (s, 5a-C), 134.0 (s,
4-C), 136.4 (s, 8-C), 138.7 (s, 4a-C), 140.1 (s, 7-C), 155.5
(s, 2-C).
2-(4-Acetyl-3-methylpyrazol-1-yl)-N-(3-hydroxy-1-methyl-
2-butenylidene)aniline (5b). Recrystallization from
2,4,5-Trimethylpyridazino[1,6-a]benzimidazolium chloride
1
MeOH gave brown plates. Mp 161±163 ꢀC; H NMR
(7c). H NMR (Me2SO-d6) d 2.73 (s, 3H, 2-CH3), 2.97
1
(CDCl3) d 1.62 (s, 3H, 10-CH3), 2.09 (s, 3H, 30-CH3),
2.38 (s, 3H, COCH3), 2.55 (s, 3H, 300-CH3), 5.20 (s, 1H,
20-H), 7.29 (m, 1H, 5-H), 7.40 (m, 2H, 3- and 6-H), 7.71
(m, 1H, 4-H), 8.14 (s, 1H, 500-H), 12.30 (br s, OH); 13C
NMR (CDCl3) d 14.0 (q, 300-CH3), 19.2 (q, 10-CH3), 28.5
(q, COCH3), 29.2 (q, 40-C), 98.3 (d, 20-C), 122.3 (s, 400-C),
(s, 3H, 4-CH3), 4.43 (s, 3H, N-CH3), 7.81 (t, 1H,
J=7.9 Hz, 8-H), 7.95 (t, 1H, J=7.9 Hz, 7-H), 7.98 (s,
1H, 3-H), 8.30 (d, 1H, J=7.9 Hz, 9-H), 8.42 (d, 1H,
J=7.9 Hz, 6-H); 13C NMR (Me2SO-d6) d 18.2 (q, 4-
CH3), 20.8 (q, 2-CH3), 33.3 (q, N-CH3), 113.0 (d, 9-C),
113.2 (d, 6-C), 126.2 (d, 8-C), 127.1 (s, 9a-C), 129.7 (d,

42
T. Kaiya et al. / Bioorg. Med. Chem. 8 (2000) 37±42
7-C), 131.0 (d, 3-C), 132.1 (s, 5a-C), 134.0 (s, 4-C), 139.6
(s, 4a-C), 155.7 (s, 2-C). UV lmax nm; (H2O) 236, 309.
COCH3), 2.59 (s, 3H, 30-CH3), 2.97 (s, 3H, N-CH3),
6.44 (br s, 1H, NH), 7.29 (d, 1H, J=8.5 Hz, 3-H), 7.57
(dd, 1H, J=2.4, 8.5 Hz, 4-H), 7.59 (d, 1H, J=2.4 Hz, 6-
H), 8.15 (s, 1H, 50-H); 13C NMR (CDCl3) d 14.3 (q, 30-
CH3), 28.8 (q, COCH3), 30.1 (q, N-CH3), 106.4 (d, 6-C),
110.9 (d, 4-C), 122.2 (s, 40-C), 123.3 (d, 3-C), 128.9 (s, 2-
C), 134.3 (d, 50-C), 143.9 (s, 1-C), 148.4 (s, 5-C), 152.5
(s, 30-C), 192.1 (s, COCH3); MS m/z 274 (M+), 259
(M+ CH3). Anal. calcd for C13H14N4O3: C, 56.93; H,
5.14; N, 20.43. Found: C, 56.83; H, 5.25; N, 20.40.
2-(4-Acetyl-3-methylpyrazol-1-yl)-N,4,5-trimethylaniline
1
(8a). H NMR (CDCl3) d 2.20 (s, 3H, 4-CH3), 2.28 (s,
3H, 5-CH3), 2.45 (s, 3H, COCH3), 2.55 (s, 3H, 30-CH3),
2.84 (s, 3H, N-CH3), 5.20 (br s, 1H, NH), 6.61 (s, 1H, 6-H),
6.93 (s, 1H, 3-H), 8.02 (s, 1H, 50-H); 13C NMR (CDCl3)
d 14.2 (q, 30-CH3), 18.5 (q, 4-CH3), 20.0 (q, 5-CH3), 28.7
(q, COCH3), 30.4 (q, N-CH3), 113.3 (d, 6-C), 121.3 (s,
40-C), 123.2 (s, 2-C), 124.4 (s, 4-C), 125.2 (d, 3-C), 134.6
(d, 50-C), 138.2 (s, 5-C), 141.4 (1-C), 151.7 (s, 30-C),
192.4 (s, COCH3); MS m/z 257 (M+), 242 (M+ CH3),
214 (M+ COCH3).
Acknowledgement
We would like to thank Professor Emeritus Y. Kawazoe
of Nagoya City University for his helpful advice and
encouragement.
2-(4-Acetyl-3-methylpyrazol-1-yl)-N,4-dimethylaniline (8b).
1H NMR (CDCl3) d 2.29 (s, 3H, 4-CH3), 2.46 (s, 3H,
COCH3), 2.56 (s, 3H, 30-CH3), 2.83 (s, 3H, N-CH3),
5.22 (br s, 1H, NH), 6.69 (d, 1H, J=8.3 Hz, 6-H), 6.97
(s, 1H, 3-H), 7.10 (d, 1H, J=8.3 Hz, 5-H), 8.04 (s, 1H,
50-H); 13C NMR (CDCl3) d 14.2 (q, 30-CH3), 20.1 (q, 4-
CH3), 28.7 (q, COCH3), 30.4 (q, N-CH3), 111.9 (d, 6-C),
121.4 (s, 40-C), 124.8 (d, 3-C), 125.3 and 125.9 (each s, 2-
and 4-C), 130.3 (d, 5-C), 134.6 (d, 50-C), 141.3 (1-C),
151.8 (s, 30-C), 192.4 (s, COCH3); MS m/z 243 (M+),
200 (M+ COCH3).
References and Notes
1. References cited in ref 14.
2. Huang, G.-F. (Kohda, K.); Maeda, M.; Okamoto, T.;
Kawazoe, Y. Tetrahedron 1975, 31, 1363.
3. Kohda, K.; Baba, K.; Kawazoe, Y. Chem. Pharm. Bull.
1986, 34, 2298.
4. Kohda, K.; Yasuda, M.; Ukai, H.; Baba, K.; Yamagata, Y.;
Kawazoe, Y. Tetrahedron 1989, 45, 6367.
5. Kohda, K.; Kobayashi, I.; Itano, K.; Asano, S.; Kawazoe,
Y. Tetrahedron 1993, 49, 3947.
6. Saga, T.; Kaiya, T.; Kohda, K. Nucleosides Nucleotides
1996, 15, 219.
7. Kaiya, T.; Ohta, M.; Kohda, K. Tetrahedron 1993, 49, 8795.
8. Kaiya, T.; Saga, T.; Yamagata, Y.; Kohda, K. Bioorg. Med.
Chem. Lett. 1998, 8, 2197.
9. Kuz'umenko, V. V.; Komissarov, V. N.; Simonov, A. M.
Khim. Geterotsikl. Soedin. 1983, 386 [C. A. 99, 212479g
(1983)].
10. Pastor, J.; Siro, J. G.; Garcia-Navio, J. L.; Vaquero, J. J.;
Alvarez-Builla, J.; Gago, F.; de Pascual-Teresa, B.; Pastor,
M.; Rodrigo, M. M. J. Org. Chem. 1997, 62, 5476.
11. Wang, M.; Hecht, S. S. Chem. Res. Toxicol. 1997, 10, 772.
12. Somei, M.; Matsubara, M.; Kanda, Y.; Natsume, M.
Chem. Pharm. Bull. 1978, 26, 2522.
13. Kuz'umenko, V. V.; Komissarov, V. N.; Simonov, A. M.
Khim. Geterotsikl. Soedin. 1981, 1497 [C. A. 96, 85465k
(1982)].
14. Kaiya, T.; Aoyama, S.; Kohda, K. Bioorg. Med. Chem.
Lett. 1999, 9, 961.
2-(4-Acetyl-3-methylpyrazol-1-yl)-N-methylaniline (8c).
Recrystallization from MeOH gave light brown nee-
dles. Mp 114±116 ꢀC; H NMR (CDCl3) d 2.46 (s, 3H,
1
COCH3), 2.57 (s, 3H, 30-CH3), 2.86 (s, 3H, N-CH3),
5.44 (br s, 1H, NH), 6.73 (ddd, 1H, J=1.2, 7.3, 7.3 Hz,
4-H), 6.77 (dd, 1H, J=1.2, 7.3 Hz, 3-H), 7.14 (dd, 1H,
J=1.2, 7.3 Hz, 6-H), 7.30 (ddd, 1H, J=1.2, 7.3, 7.3 Hz,
5-H), 8.05 (s, 1H, 50-H); 13C NMR (CDCl3) d 14.2 (q,
30-CH3), 28.7 (q, COCH3), 30.2 (q, N-CH3), 111.8 (d, 3-
C), 116.3 (s, 4-C), 121.5 (s, 40-C), 124.2 (d, 6-C), 125.3
(s, 2-C), 129.8 (d, 5-C), 134.7 (d, 50-C), 143.5 (s, 1-C),
151.9 (s, 30-C), 192.4 (s, COCH3); UV lmax nm, (pH 1)
264, (H2O and pH 12) 239, 300; MS m/z 229 (M+).
HRMS m/z M+ calcd for C13H15N3O: 229.1214; found:
229.1215. Anal. calcd for C13H15N3O: C, 68.10; H, 6.59;
N, 18.33. Found: C, 67.96; H, 6.48; N, 18.09.
2-(4-Acetyl-3-methylpyrazol-1-yl)-N-methyl-5-nitroaniline
(8d). Recrystallization from CHCl3±hexane gave orange
plates. Mp 176±179 ꢀC; 1H NMR (CDCl3) d 2.49 (s, 3H,