A practical synthesis of the chronic renal disease agent, 4,5-dihydro-3H-1,4,8b-triazaacenaphthylen-3-one derivatives, using regioselective chlorination of ethyl 5-methylimidazo[1,2-a]pyridine-3-carboxylate with N-chlorosuccinimide

Article abstract of DOI:10.1016/S0040-4020(00)00709-2

A convenient synthesis of the chronic renal disease agent, trifluoro-N-[4-(3-oxo-3,5-dihydro-4H-1,4,8b-triazaacenaphthylen-4-yl)butyl]me thanesulfonamide (1a), for large scale has been developed via ethyl 5-(chloromethyl)imidazo[1,2-a]pyridine-3-carboxylate (3), which was given by the regioselective chlorination of ethyl 5-methylimidazo[1,2-a]pyridine-3-carboxylate (6) with N-chlorosuccinimide (NCS) using AcOEt as a solvent in 83% yield. The condensation of 3 and primary amines gave 4,5-dihydro-3H-1,4,8b-triazaacenaphthylen-3-one derivatives (1) in good yields. The present synthesis of 1a was accomplished in five steps from 2-amino-6-methylpyridine (4) without requiring a chromatographic method. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00709-2

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 7915±7921
A Practical Synthesis of the Chronic Renal Disease Agent,
4,5-Dihydro-3H-1,4,8b-triazaacenaphthylen-3-one Derivatives,
Using Regioselective Chlorination of
Ethyl 5-methylimidazo[1,2-a]pyridine-3-carboxylate
with N-Chlorosuccinimide
b
b
b
Tomomi Ikemoto,a, Tetsuji Kawamoto, Kiminori Tomimatsu, Muneo Takatani and
*
Mitsuhiro Wakimasub
aChemical Development Research Division, Takeda Chemical Industries Ltd, 2-17-85 Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan
bPharmaceutical Research Division, Takeda Chemical Industries Ltd, 2-17-85 Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan
Received 30 June 2000; accepted 9 August 2000
AbstractÐA convenient synthesis of the chronic renal disease agent, tri¯uoro-N-[4-(3-oxo-3,5-dihydro-4H-1,4,8b-triazaacenaphthylen-4-
yl)butyl]methanesulfonamide (1a), for large scale has been developed via ethyl 5-(chloromethyl)imidazo[1,2-a]pyridine-3-carboxylate (3),
which was given by the regioselective chlorination of ethyl 5-methylimidazo[1,2-a]pyridine-3-carboxylate (6) with N-chlorosuccinimide
(NCS) using AcOEt as a solvent in 83% yield. The condensation of 3 and primary amines gave 4,5-dihydro-3H-1,4,8b-triazaacenaphthylen-
3-one derivatives (1) in good yields. The present synthesis of 1a was accomplished in ®ve steps from 2-amino-6-methylpyridine (4) without
requiring a chromatographic method. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
Tri¯uoro-N-[4-(3-oxo-3,5-dihydro-4H-1,4,8b-triazaacenaph-
thylen-4-yl)butyl]methanesulfonamide (1a) is an agent for
chronic renal disease.1a It was shown to have potent platelet
derived growth factor (PDGF) inhibitory activity and to
inhibit the reduction in GFR in 5/6 nephrectomized rats
and spontaneously hypercholesterolemic (SHC) rats. In
the ®rst synthesis of 1a, the deprotection of the Boc group
of 5-(N-Boc-aminomethyl)imidazo[1,2-a]pyridines (2)
trichloroacetylated at the 3-position with hydrogenchloride
successively effected the intramolecular coupling to
produce the desired 1a. One problem during the develop-
ment of 1a in clinical evaluations was the availability of
large amounts of the raw drug substance, because the
reported synthesis1 required 12 steps to give 1a in 6% over-
all yield via 2. In particular, this method required repeated
chromatographic puri®cations. Hence, an ef®cient synthesis
of 1a for large scale without chromatography was required.
Our retrosynthetic analysis of 1a is depicted in Scheme 1.
Kurata et al. have reported2 that the treatment of ethyl
Keywords: 4,5-dihydro-3H-1,4,8b-triazaacenaphthylen-3-one derivative;
regioselective chlorination; ethyl 5-methylimidazo[1,2-a]pyridine-3-
carboxylate; N-chlorosuccinimide.
* Corresponding author. Tel.: 16-6300-6840; fax: 16-6300-6251; e-mail:
lkemoto_tomomi@takeda.co.jp
Scheme 1.
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00709-2

7916
T. Ikemoto et al. / Tetrahedron 56 (2000) 7915±7921
Table 1. Chlorination of 6 with NCS in various solvents
Results and Discussion
Regioselective chlorination of 6 to 3
The yields of 5 were generally lower,6 but the potassium salt
of 5 (5´K) could be synthesized in 88% yield by an
improved method whereby a mixture of ethyl chloroacetate
and ethyl formate reacted with potassium t-butoxide in
diisopropyl ether (IPE). Subsequently, the neutralization
of 5´K with H2SO4 in ethanol, followed by the addition of
4, yielded 6 in 60% yield. We examined the reactions of 6
with NCS in a variety of solvents, as shown in Table 1. At
®rst, the reaction of 6 with NCS (1.2 equiv.) and a catalyzed
AIBN in re¯uxing carbon tetrachloride could give a mixture
of chloromethyl derivatives, such as 3 and ethyl 5-(dichlor-
omethyl)imidazo[1,2-a]pyridine-3-carboxylate (9), but
could not give the usual apparent nucleophilic substituents
at the 2-position (10 and 11), as shown in Fig. 1. Moreover,
the reactions of 6 with NCS in ethyl acetate or tetrahydro-
furan gave 3 regioselectively in 83 and 76% yield, respec-
tively, together with 9 and ethyl 5-methyl-2-oxo-2,3-
Entry
Solvent
Conditions
Product yields (%)a
6
3
9
12
b
1
2
3
4
5
6
CCl4
Re¯ux,7 h
rt,24 h
rt,4 h
rt,4 h
rt,4 h
rt,4 h
26
ND
3
ND
ND
ND
55
83
76
1
4
1
4
18
5
NDc
2
6
ND
7
AcOEt
THF
DMF
MeCN
AcOH
5
1
ND
83
a Determined by HPLC.
b Addition of AIBN.
c NDˆNot detected.
5-bromomethyl-2-(methylthio)imidazo[1,2-a]pyridine-3-
carboxylate with primary amines gave 4,5-dihydro-2-
methylthio-4-substituted-3H-1,4,8b-triazaacenaphthylen-3-
one derivatives. Namely, ethyl 5-(halomethyl)imidazo[1,2-
a]pyridine-3-carboxylate was regarded as a synthetic inter-
mediate of 1a. In a previous report,3 5-(chloromethyl)imi-
dazo[1,2-a]pyridine-3-carboxylate (3) was prepared from 2-
amino-6-methylpyridine (4), that is, bromination of 2-methyl-
6-pivaloylaminopyridine with N-bromosuccinimide (NBS)
in the presence of 2,20-azobis-isobutyronitrile (AIBN),
followed by treatment with acid, reaction with ethyl 2-chloro-
3-oxopropanoate (5), and chlorination using thionyl chloride.
However, the reported preparation suffered from poor avail-
ability of 1a and the use of expensive reagents. Hence, we
planned the regioselective chlorination of ethyl 5-methyl-
imidazo[1,2-a]pyridine-3-carboxylate (6). Although many
imidazo[1,2-a]pyridines4 having useful biological activities
and as a biochemical ¯uorescent marker were derived from
the substituents at the 3-position, there were few reports5
regarding electrophilic reactions of imidazo[1,2-a]pyridine
blocked at the 3-position. Halogenation was only reported
by Hand and Paudler5 that treatments of 3-methylimi-
dazo[1,2-a]pyridine (7) or 3-bromo-7-methylimidazo[1,2-
a]pyridine (8) with NBS in chloroform gave the apparent
nucleophilic and the succinimide substituents at the
2-position, respectively. However, we thought that the
desired reaction should occur because the methyl group of
6 was activated by the ester group at the 5-position. In this
paper, we describe the regioselective chlorination of 6 with
N-chlorosuccinimide (NCS) to 3, and the convenient
synthesis of 1a using 3.
dihydroimidazo[1,2-a]pyridine-3-carboxylate
(12)
as
minor products. On the other hand, the chlorination of 6
with NCS in acetic acid as a solvent afforded different
regioselectivity to give 12 in 83% yield (Scheme 2).
The thermostability of 3 was examined for large-scale
operation. The residue of 3 was 58% when 3 as an oil was
kept for one week at 258C, while the sulfuric acid salt
(3´H2SO4) of 3 as a crystalline powder entirely remained.
The structure of product (13) isolated by HPLC (column;
SEP-PAK; Waters, mobile phase; acetonitrile±water) was
1
determined by LC-MS, H NMR analysis, and elemental
analysis. Therefore, shorter reaction time was required to
avoid the production of 13 for practical preparation. We
examined the in¯uence of various acids on the reaction of
6 and NCS in THF, as shown in Table 2, because it has been
reported7 that NCS would give the protonated species in the
presence of a stronger acid, that is, the elimination ability of
a protonated succinimide group was higher than that of a
succinimide group. As a result, the rates of the reactions to
chloromethyl derivatives were higher by the addition of a
catalystic amount (0.2 equiv.) of a stronger acid, such as
methanesulfonic acid, hydrogenchloride, and tri¯uoroacetic
acid (entry 3, 4, 5). The addition of equimolecular metha-
nesulfonic acid or hydrogenchloride accelerated the reac-
tion rates; however, re¯uxing condition was required
because the powder salts of 6 were precipitated. From
these results, it was considered that the addition of
0.2 equiv. tri¯uoroacetic acid was the optimized condition.
Although the reaction of 6 with NCS in AcOEt at room
Figure 1.

T. Ikemoto et al. / Tetrahedron 56 (2000) 7915±7921
7917
temperature required longer time (24 h) in the absence of
acid, the addition of 0.2 equiv. tri¯uoroacetic acid shortened
the reaction time (2 h) to give 3´H2SO4 in 50% isolated
yield. On the other hand, the addition of acetic acid (0.2
and 1.0 equiv.) did not affect the regioselectvity of 6 to
give the chloromethyl derivatives (entry 6, 10) (Scheme 3).
Synthesis of 1
The coupling of 3´H2SO4 and the primary amine 14´HCl8
(1 equiv.) using triethylamine (4 equiv.) as a base in DMF
for 3 h at 708C under nitrogen atmosphere gave 15 in 24%
yield accompanied with a by-product. This by-product was
thought to be the oxidation product (19) of 15, because
imide 20´HCl was recovered from the mother solution in
the next step, as shown in Fig. 2. Optimization of the
coupling reaction was examined as shown in Table 3. As
a result, the neutralization of 3´H2SO4 and 14´HCl
(1 equiv.) with 28% NaOMe in MeOH (2 equiv.) in DMF,
followed by the addition of sodium iodide (1 equiv.) and
triethylamine (1 equiv.) at 408C was carried out under
nitrogen atmosphere to give the desired 15 in 80% yield
(75% isolated yield). Moreover, alkylamines or benzyl-
amines also afforded the desired 1 in good yields when the
coupling reactions of 3 and various amines were examined, as
shown in Table 4. Aniline did not effect the intramolecular
Scheme 2.
Table 2. The reaction of 6 with NCS (1.2 equiv.) in THF
Entry
Additive (eq)
Conditions
Yields (%)a
6
3
9
12
1
2
±
±
rt, 4 h
3
NDb
ND
2
1
4
2
1
ND
14
76
66
56
56
67
74
52
22
22
59
4
15
20
23
4
6
2
11
5
12
3
8
17
15
5
Re¯ux, 1 h
rt, 2 h
rt, 2 h
rt, 2 h
rt, 4 h
Re¯ux, 1 h
Re¯ux, 1 h
rt, 3 h
3
4
5
MeSO3H (0.2)
HCl±IPE (0.2)
TFA (0.2)
6
7
8
9
10
AcOH (0.2)
MeSO3H (1.0)
HCl±IPE (1.0)
TFA (1.0)
3
18
ND
49
3
AcOH (1.0)
rt, 4 h
a Yields were determined by HPLC.
b NDˆNot detected.
Figure 2.
Table 3. The condensation of 3 and 14´HCl
Entry Additives
Solvent Conditions
Yields (%)a
15
3
1
2
3
4
5
6
NEt3
NaI, NEt3
NaI, NEt3
DBU, NaI, NEt3
NaOMe, NaI, NEt3
DMF
DMF
EtOH
DMF
DMF
708C, 3 h
708C, 1 h
758C, 3 h
408C, 5 h
408C, 1.5 h
408C, 1.5 h
24
34
52
60
80
70
5
NDb
ND
2
1
1
NaOMe, NaI, K2CO3 DMF
a Yields were determined by HPLC.
b NDˆNot detected.
Table 4. Reactions of 3 with amines (RNH2)
Entry
R
Conditions
Isolated yield (%)
1a
2
3
4
TfNH(CH2)4
Me
n-Bu
Re¯ux, 4 h
408C, 3 h
408C, 2 h
408C, 3 h
408C, 3 h
408C, 3 h
908C, 3 h
1a, 77
1b, 70
1c, 88
1d, 83
1e, 81
1f, 78
1g, 70
PhCH2
5
4-ClC6H4CH2
4-MeOC6H4CH2
Ph
6
7b
a EtOH was used as a solvent.
b K2CO3 (2 equiv.) was used as a base.
Scheme 3.

7918
T. Ikemoto et al. / Tetrahedron 56 (2000) 7915±7921
Table 5. Calculations of HOMO for 6
N(1)
C(2)
C(3)
N(4)
C(5)
C(6)
C(7)
C(8)
C(9)
Me
6a
6b
6c
6d
6e
0.153
0.002
0.065
0.022
0.001
0.007
0.022
0.054
0.151
0.164
0.292
0.001
0.032
0.194
0.114
0.001
0.184
0.142
0.078
0.104
0.151
0.045
0.024
0.026
0.075
0.053
0.120
0.142
0.011
0.046
0.100
0.052
0.028
0.134
0.063
0.138
0.152
0.218
0.066
0.021
0.034
0.074
0.032
0.087
0.147
0.006
0.319
0.253
0.087
0.204
amidation to get ethyl 5-(phenylaminomethyl)imidazo[1,2-
a]pyridine-3-carboxylate. Aniline derivative (1g) was
obtained by the reaction using potassium carbonate
(2 equiv.) instead of triethylamine at 908C. The reaction of
3 and N-(4-aminobutyl)(tri¯uoro)methanesulfonamine (18,
1 equiv.) preparated from 14´HCl gave 1a in 77% yield
(route B). The hydrogenation of 15 in MeOH at 508C for
2 h gave 16´HCl. Compound 1a was given by the treatment
of 16´HCl with triethylamine and N-phenyltri¯uoromethane-
sulfonimide in 72% yield (from 15, route A).
calculated the frontier p-electron densitiy of ®ve tautomers
of 6 using the AM1 method developed by Dewar.10 These
calculations showed that the highest-occupied molecular
orbital (HOMO) of 6 was at the 3-position (6a and 6d)
and the carbon of the methyl group (6b, 6c and 6e), as
shown in Table 5. These data suggest, therefore, that
electrophilic attack would occur at these positions (the 3-
position or methyl group or both). The mechanism of forma-
tion of 3 and 12 from 6 was thought to be, as shown in
Scheme 4. Namely, the carbon at the 3-position attacked
NCS (or AcOCl)11 to give the cationic intermediate 21
and the successive 1,4-chlorine shift produced the chloro-
methyl derivatives, while Hand and Paudler5 have deduced
that the bromonations of 7 or 8 with NBS passed through the
1-bromoimidazo[1,2-a]pyridium by the calculation.
Another possible explanation might be that the carbon of
the methyl group at the 5-position directly attacked NCS to
give the chloromethyl derivatives. In the case of acetic acid
as a solvent, acetic acid (quenching water) nucleophilically
substituted the intermediate 21 at the 2-position to form the
cation 22 leading to 12. These mechanisms are worthy of
further study.
Reaction mechanism of 6 to 3 or 12
Different results attained by the treatment of 6 with NCS
were of interest in connection with the reaction mechanism.
The different regioselectivity of 8-hydroxyimidazo[1,2-
a]pyridine was interpreted by various MO calculations9
using the MNDO method. In order to interpret the regio-
selective chlorination of 6 with NCS due to solvents, we
Conclusion
A practical preparation of an agent for chronic renal disease,
1a has been developed on large scale. The reaction of 6 with
NCS afforded the unusual results to give regioselectively 3.
The coupling of 3 and the primary amines successively
produced the 4,5-dihydro-4-substituted-3H-1,4,8b-triaza-
acenaphthylen-3-one derivatives. Our synthesis of 1a was
accomplished in ®ve steps from 2-amino-6-methylpyridine
(4) without requiring chromatographic puri®cation.
Experimental
Melting points were recorded on a Yanagimoto micro melt-
ing apparatus and were uncorrected. IR spectra were
1
recorded on a Horiba FT-210 spectrophotometer. H and
13C NMR spectra were recorded on a Bruker DPX-300
spectrometer using tetramethylsilane as an internal
standard. Column chromatography was performed with a
Wakogel C-200 (75±150 mm). HPLC was performed on a
YMC-Pack ODS-A302 column (6i.d.£150 mm) with
0.05 M KH2PO4 aqueous solution±MeCN (55:45) at
258C. Detection was effected with a Shimadzu SPD-10A
Scheme 4.

T. Ikemoto et al. / Tetrahedron 56 (2000) 7915±7921
7919
spectrophotometric detector at 254 nm. Elemental analyses
and mass spectra were analyzed by Takeda Analytical
Research Laboratories Ltd.
4.17 (q, Jˆ7.1, 2H), 4.43 (q, Jˆ7.1, 2H), 5.51 (s, 2H), 7.05
(s, 2H), 7.60 (dd, Jˆ7.1, 8.8, 1H), 7.84 (d, Jˆ8.8, 1H), 7.86
(d, Jˆ7.1, 1H), 7.97 (d, Jˆ6.6, 1H), 8.12 (s, 1H), 8.24 (dd,
Jˆ6.6, 6.9, 1H), 8.34 (s, 1H), 8.86 (d, Jˆ9.1, 1H).
Ethyl 5-methylimidazo[1,2-a]pyridine-3-carboxylate sul-
furic acid salt (6´H2SO4). A mixture of ethyl formate
(334 g, 4.5 mol) and ethyl chloroacetate (552 g, 4.5 mol)
was added to a suspension of potassium t-butoxide (505 g,
4.5 mol) and IPE (5 L) at 08C, and the whole was stirred for
24 h at room temperature. The resulting precipitates were
collected by ®ltration to give ethyl 2-chloro-3-oxopropano-
ate potassium salt (5´K, 761 g, 88%) as an orange solid.
Benzyl 4-(3-oxo-3,5-dihydro-4H-1,4,8b-triazaacenaph-
thylen-4-yl)butylcarbamate (15). After 28% NaOMe in
MeOH (2.32 L, 12.0 mol) was added to a suspension of
3´H2SO4 (1.35 kg, 4.0 mol), benzyl 4-aminobutylcarbamate
hydrogenchloride (14´HCl, 1.04 kg, 4.0 mol) and DMF
(6 L), triethylamine (560 mL) and NaI (600 g) was added.
The reaction mixture was stirred at 408C for 1 h. After cool-
ing, water was poured into the reaction mixture, and
extracted with AcOEt (14 L). The AcOEt extract was
washed with water and concentrated in vacuo. The residue
was triturated with AcOEt (2.4 L), collected by ®ltration,
washed with IPE, and dried at room temperature to give 15
(1.13 kg, 75%) as a white solid; mp 108±1108C. Anal.
Calcd for C21H22N4O3: C, 66.65; H, 5.86; N, 14.81.
To a solution of concentrated H2SO4 (80 mL, 1.6 mol) and
EtOH (1.5 L) at 08C were added 5´K (596 g, 3.1 mol) and
2-amino-6-methylpyridine (4, 108 g, 1.0 mol), and the
whole was re¯uxed for 5 h. After cooling and concentration,
AcOEt (1 L) was poured into the residue and extracted with
water. The aqueous layer was neutralized with 2N-NaOH
solution and extracted with AcOEt (1 L). The AcOEt extract
was washed with water and concentrated in vacuo. EtOH
was poured into the residue, and concentrated H2SO4
(51 mL) was added at 08C. The resulting precipitates were
collected by ®ltration, washed with IPE, and dried at room
temperature to give 6´H2SO4 (194 g, 60% from 4) as a white
solid; mp 125±1268C. Anal. Calcd for C11H14N2O6S: C,
43.70; H, 4.67; N, 9.27; S, 10.61. Found: C, 43.47; H,
1
Found: C, 66.61; H, 6.02; N, 14.78. H NMR (CDCl3): d
1.59±1.73 (m, 4H), 3.26 (m, 2H), 3.57 (m, 2H), 4.96 (s, 2H),
5.09 (s, 2H), 6.70 (d, Jˆ6.9, 1H), 7.24±7.34 (m, 7H), 7.49
(d, Jˆ9.1, 1H), 8.15 (s, 1H). IR (Nujol, cm21):1709, 1660,
1537.
The following compounds were prepared in a manner
similar to that for 15:
1
4.75; N, 9.16; S, 10.89. H NMR (D2O): d 1.23 (t, Jˆ7.1,
3H), 2.62 (s, 3H), 4.28 (d, Jˆ7.1, 2H), 7.16 (d, Jˆ7.3, 1H),
7.68 (d, Jˆ8.9, 1H), 7.80 (dd, Jˆ7.3, 8.9, 1H), 8.40 (s, 1H).
IR (Nujol, cm21): 1732, 1655, 1552, 1531.
4-Methyl-3,5-dihydro-4H-1,4,8b-triazaacenaphthylen-3-one
(1b): A white solid, mp 171±1728C. Anal. Calcd for
C10H9N3O: C, 64.16; H, 4.85; N, 22.45. Found: C, 64.18;
H, 4.54; N, 22.49. 1H NMR (CDCl3): d 3.13 (s, 3H), 5.00 (s,
2H), 6.72 (d, Jˆ7.0, 1H), 7.31 (dd, Jˆ7.0, 9.1, 1H), 7.52 (d,
Jˆ9.1, 1H), 8.17 (s, 1H). IR (KBr, cm21):1631, 1556, 1538,
1313, 1151.
Ethyl 5-(chloromethyl)imidazo[1,2-a]pyridine-3-carboxyl-
ate sulfuric acid salt (3´H2SO4). After a suspension of
6´H2SO4 (2.50 kg, 8.3 mol) and AcOEt (25 L) was neutra-
lized with 8N-NaOH, the AcOEt extract was concentrated.
AcOEt (25 L) was poured into the residue, successively
NCS (1.33 kg, 10.0 mol) and TFA (64.4 mL, 0.8 mol)
were added. After the reaction mixture was stirred at 308C
for 2 h, 1N-HCl solution (10 L) was poured into the reaction
mixture. The aqueous layer was neutralized with 30%
NaOH solution (4.5 L) and extracted with IPE (50 L). The
IPE extract was washed with water and concentrated in
vacuo. MeCN (14 L) was poured into the residue, and
concentrated H2SO4 (394 mL, 6.0 mol) was added at 08C.
The resulting precipitates were collected by ®ltration,
washed with IPE, and dried at room temperature to give
3´H2SO4 (1.40 kg, 50%) as a white solid; mp 155±1578C.
Anal. Calcd for C11H13N2O6SCl: C, 39.33; H, 3.89; N, 8.32;
S, 9.52; Cl, 10.53. Found: C, 38.97; H, 3.92; N, 8.16; S,
9.59; Cl, 10.60. 1H NMR (D2O): d 1.41 (t, Jˆ7.2, 3H), 4.49
(d, Jˆ7.1, 2H), 5.41 (s, 2H), 7.70 (d, Jˆ5.4, 1H), 8.04±8.08
(m, 2H), 8.66 (s, 1H). IR (Nujol, cm21): 1731, 1651, 1550,
1529.
4-Butyl-3,5-dihydro-4H-1,4,8b-triazaacenaphthylen-3-one
(1c): A light brown oil. EI-MS: 229 (M1). 1H NMR
(CDCl3): d 0.98 (t, Jˆ7.3, 3H), 1.42 (m, 2H), 1.65 (m,
2H), 3.58 (t, Jˆ7.4, 2H), 5.00 (s, 2H), 6.73 (d, Jˆ7.0,
1H), 7.31 (dd, Jˆ7.0, 9.0, 1H), 7.52 (d, Jˆ9.0, 1H), 8.17
(s, 1H). IR (neat, cm21):1637, 1536, 1465, 1336, 1301,
1213, 1153.
4-Benzyl-3,5-dihydro-4H-1,4,8b-triazaacenaphthylen-3-one
(1d): A white solid, mp 141±1428C. Anal. Calcd for
C16H13N3O: C, 72.99; H, 4.98; N, 15.96. Found: C, 72.85;
H, 4.84; N, 15.98. 1H NMR (CDCl3): d 4.79 (s, 2H), 4.86 (s,
2H), 6.65 (d, Jˆ7.0, 1H), 7.24±7.38 (m, 6H), 7.51 (d,
Jˆ9.1, 1H), 8.24 (s, 1H). IR (KBr, cm21):1650, 1535, 707.
4-(4-Chlorobenzyl)-3,5-dihydro-4H-1,4,8b-triazaacenaph-
thylen-3-one (1e): A white solid, mp 161±1638C. Anal.
Calcd for C16H12N3OCl: C, 64.54; H, 4.06; N, 14.11; Cl,
1
11.91. Found: C, 64.42; H, 4.05; N, 14.10; Cl, 11.80. H
Oil 3 was held for one week at room temperature. The
residue was separated by HPLC (column; SEP-PAK;
Waters; mobile phase; acetonitrile±water (15:85);
detective; 254 nm) to give 13 as a white solid. LC-MS
(EI); 441 (M1), 139 (M1). Anal. Calcd for
C22H22N4O4Cl2´1.5H2O: C, 52.33; H, 5.00; N, 11.10; Cl,
14.04. Found: C, 52.39; H, 4.96; N, 11.10; Cl, 13.80. H
NMR (CDCl3): d 26 (t, Jˆ7.1, 3H), 1.39 (t, Jˆ7.1, 3H),
NMR (CDCl3): d 4.76 (s, 2H), 4.86 (s, 2H), 6.67 (d, Jˆ7.0,
1H), 7.24±7.35 (m, 5H), 7.53 (d, Jˆ9.1, 1H), 8.24 (s, 1H).
IR (KBr, cm21):1643, 1525, 1305, 1199, 781.
4-(4-Methoxybenzyl)-3,5-dihydro-4H-1,4,8b-triazaacenaph-
thylen-3-one (1f): A white solid, mp 138±1398C. Anal.
Calcd for C17H15N3O2: C, 69.61; H, 5.15; N, 14.33. Found:
1
1
C, 69.57; H, 5.34; N, 14.26. H NMR (CDCl3): d 3.80 (s,

7920
T. Ikemoto et al. / Tetrahedron 56 (2000) 7915±7921
3H), 4.73 (s, 2H), 4.84 (s, 2H), 6.65 (d, Jˆ6.9, 1H), 6.89 (dd,
Jˆ6.6, 1.9, 1H), 7.24±7.33 (m, 4H), 7.51 (d, Jˆ9.1, 1H),
8.23 (s, 1H). IR (KBr, cm21):1641, 1540, 1508, 1249, 742.
C13H17N2O4SF3: C, 44.06; H, 4.80; N, 7.90. Found: C,
43.97; H, 4.94; N, 7.78. H NMR (CDCl3): d 1.59 (m,
4H), 3.19±3.23 (m, 2H), 3.28 (m, 2H), 5.09 (s, 2H), 6.24
(brs, 1H), 7.35±7.39 (m, 5H). IR (Nujol, cm21): 3419, 1695,
1545.
1
4-Phenyl-3,5-dihydro-4H-1,4,8b-triazaacenaphthylen-3-one
(1g): A white solid, mp 219±2208C. Anal. Calcd for
C15H11N3O´0.1H2O: C, 71.75; H, 4.50; N, 16.73. Found:
N-(4-Aminobutyl)(tri¯uoro)methanesulfonamine (18).
To a solution of 17 (2.00 g, 5.5 mmol) and MeOH
(20 mL) was added 10% Pd±C (0.20 g), and the suspension
was stirred at room temperature for 2 h under hydrogen
atmosphere. After Pd±C was removed by ®ltration, the
mother solution was concentrated. The residue was tritu-
rated with IPE, collected by ®ltration, washed with IPE,
and dried in vacuo at room temperature to give 18 (1.18 g,
95%) as a white solid; mp 110±1148C. Anal. Calcd for
C5H11N2O2SF3: C, 27.27; H, 5.03; N, 12.72. Found: C,
1
C, 71.86; H, 4.50; N, 16.73. H NMR (CDCl3): d 5.36 (s,
2H), 6.79 (d, Jˆ7.0, 1H), 7.30±7.50 (m, 6H), 7.61 (d,
Jˆ9.1, 1H), 8.30 (s, 1H). IR (KBr, cm21): 1643, 1527,
1502, 1303, 721.
Tri¯uoro-N-[4-(3-oxo-3,5-dihydro-4H-1,4,8b-triazaace-
naphthylen-4-yl)butyl]methanesulfonamide (1a). To a
solution of 15 (960 g, 2.5 mol) and MeOH (10 L) was
added 5% Pd±C (100 g), and the suspension was stirred at
508C for 6 h under hydrogen atmosphere. After cooling and
Pd±C was removed by ®ltration, concentrated HCl
(258 mL, 2.5 mol) was added and concentrated. MeOH
(10 L) and THF (10 L) were added to the residue at
0±58C and stirred for 4 h at the same temperature. The
resulting precipitates were collected by ®ltration, washed
with IPE, and dried at room temperature to give 16´HCl
(710 g, 97%) as a white solid. Concentration of the mother
solution, successively recrystallization from EtOH yielded
20´HCl as a white solid. 20´HCl (18.7 g, 2%); mp. decom-
position (2238C). Anal. Calcd for C13H15N4O2Cl´0.1H2O: C,
52.65; H, 5.17; N, 18.90; Cl, 11.97. Found: C, 52.45; H,
5.19; N, 18.66; Cl, 11.73. 1H NMR (D2O): d 1.72±1.84 (m,
4H), 3.10±3.15 (m, 2H), 4.13±4.17 (m, 2H), 7.96 (dd,
Jˆ7.3, 9.1, 1H), 8.16±8.22 (m, 2H), 8.56 (s, 1H). IR
(Nujol, cm21): 1656, 1627, 1545.
1
27.46; H, 5.14; N, 12.74. H NMR (CDCl3): d 1.59±1.67
(m, 4H), 1.74±1.82 (m, 2H), 2.80±2.86 (m, 2H), 3.19±3.25
(m, 2H). IR (Nujol, cm21): 1628, 1543.
Ethyl 5-methyl-2-oxo-2,3-dihydroimidazo[1,2-a]pyridine-
3-carboxylate (12). To a suspension of 6 (2.00 g, 9.8 mmol)
and AcOH (20 mL) was added NCS (1.57 g, 11.8 mmol),
and the whole was stirred for 4 h at room temperature.
Water was poured into the reaction mixture and extracted
with 2-butanol. After the 2-butanol extract was concentrated
in vacuo to give a solid (0.81 g). The residue (300 mg) was
puri®ed by silica gel column chromatography (CH2Cl2±
MeOHˆ4:1) to give 12 (280 mg, 35%) as a white solid;
mp 126±1288C. Anal. Calcd for C11H12N2O3´0.1H2O: C,
59.50; H, 5.63; N, 12.62. Found: C, 59.47; H, 5.50; N,
12.75. 1H NMR (DMSO-d6): d; keto:enolˆ1:1.16; keto
form; 1.23 (t, Jˆ7.3, 3H), 2.34 (s, 3H), 4.27 (q, Jˆ7.3,
2H), 5.77 (s, 1H), 6.82 (d, Jˆ7.3, 1H), 7.01 (d, Jˆ7.3,
1H), 7.84 (dd, Jˆ8.3, 7.3, 1H), enol form; 1.26 (t, Jˆ7.3,
3H), 2.55 (s, 3H), 4.20 (q, Jˆ7.3, 2H), 7.08 (d, Jˆ7.3, 1H),
7.24 (d, Jˆ7.3, 1H), 7.60 (dd, Jˆ8.3, 7.3, 1H), 12.17 (bs,
1H). IR (Nujol, cm21): 1687, 1653, 1554, 1532.
N-Phenyltri¯uoromethanesulfonimide (1.24 kg, 3.5 mol)
was added to a mixture of 16´HCl (604 g, 2.2 mol), triethyl-
amine (783 mL, 5.7 mol) and DMF (6.1 L). After the reac-
tion mixture was stirred at room temperature for 1 h, AcOEt
(5 L) was poured into the reaction mixture and extracted
with 1N HCl (6 L£2). The aqueous layer was neutralized
with 6N NaOH solution and extracted with 2-butanone±
AcOEt (1: 1, 12 L£3). The organic extract was washed
with water and concentrated in vacuo. The residue was
triturated with AcOEt (3 L), collected by ®ltration, washed
with IPE, and dried in vacuo at 408C to give 1a (505 g, 61%)
as a white solid. Compound 1a (90 g, 11%) was recovered
from the mother solution; mp 176±1788C. Anal. Calcd for
C14H15N4O3SF3: C, 44.68; H, 4.02; N, 14.89. Found: C,
Acknowledgements
The authors thank Mr Toshimasa Tanaka for calculations of
6 and Dr Taiichi Okada for helpful discussions.
References
1
44.40; H, 3.97; N, 14.74. H NMR (CDCl3): d 1.63±1.98
(m, 4H), 3.41 (m 2H), 3.63 (m, 2H), 5.02 (s, 2H), 6.74 (d,
Jˆ7.3, 1H), 7.33 (dd, Jˆ7.3, 8.8, 1H), 7.54 (d, Jˆ8.8, 1H),
8.18 (s, 1H). IR (Nujol, cm21): 1641, 1541, 1508.
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7921
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11. This active reagent was suggested by the referee in the case of
the reaction using AcOH as a solvent.