Convenient synthesis of 2-alkylamino-6-carboxy-5,7-diarylcyclopenteno[1,2- b]pyridines via direct acylamination with imidoyl chlorides

Article abstract of DOI:10.1016/j.tet.2005.02.003

A robust synthetic method for 2-alkylamino-6-carboxy-5,7- diarylcyclopenteno[1,2-b]pyridines via acylamination at the alpha position of the functionalized pyridine system has been developed. The key step in this method was achieved by treatment of the corresponding pyridine N-oxides with 2.5 equiv of imidoyl chlorides in the presence of triethylamine, thus producing the desired 2-acylaminopyridines in good yields (74-96%).

Full text of DOI:10.1016/j.tet.2005.02.003

Tetrahedron 61 (2005) 3473–3481
Convenient synthesis of
2-alkylamino-6-carboxy-5,7-diarylcyclopenteno[1,2-b]pyridines
via direct acylamination with imidoyl chlorides
*
Hirobumi Takahashi, Takehiro Fukami, Hisaki Kojima, Takeru Yamakawa,
Hiroyuki Takahashi, Toshihiro Sakamoto, Teruyuki Nishimura, Masayuki Nakamura,
Takashi Yosizumi, Kenji Niiyama, Norikazu Ohtake and Takashi Hayama
Tsukuba Research Institute, Banyu Pharmaceutical Co. Ltd, Okubo-3, Tsukuba 300-2611, Ibaraki, Japan
Received 27 December 2004; revised 1 February 2005; accepted 2 February 2005
Abstract—A robust synthetic method for 2-alkylamino-6-carboxy-5,7-diarylcyclopenteno[1,2-b]pyridines via acylamination at the alpha
position of the functionalized pyridine system has been developed. The key step in this method was achieved by treatment of the
corresponding pyridine N-oxides with 2.5 equiv of imidoyl chlorides in the presence of triethylamine, thus producing the desired
2-acylaminopyridines in good yields (74–96%).
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Scheme 1). Therefore, the development of a efficient and
convenient alternative method for this highly functionalized
2-alkylaminocyclopentenopyridine system is necessary.
Endothelin-1 (ET-1)1 and its closely related isopeptides
(ET-2, ET-3) have been identified as potent vasoconstrictor
peptides. The endothelins exert diverse biological actions
through distinct cell surface G-protein coupled receptors
(GPCR) termed ETA and ETB.2 Elevated levels of
endothelins have been observed in numerous disease states
including hypertension, congestive heart failure and renal
diseases.3 Therefore, non-peptide endothelin receptor
antagonists are currently being evaluated by a number of
pharmaceutical companies as potential therapeutic agents
for the treatment of these disease states.
Previously, we reported that potent and selective ETA
antagonists (1 and 2) were identified in a series of
6-carboxy-5,7-diarylcyclopenteno[1,2-b]pyridines.4,5 It is
of significant interest to further clarify the structure–activity
relationships (SARs) of the alkylamino group (Fig. 1, R1) at
the 2-position of the pyridine ring and the substituent
(Fig. 1, R2) at the 20-position of the 7-(4-methoxyphenyl)
ring. However, incorporation of the alkylamino group by the
previous synthetic method is tedious and the subsequent
functionalization on the 7-aryl ring was limited (Route A in
Figure 1.
A number of substituents (Fig. 1, R2) are easily incorporated
in the 7-aryl ring at an early stage in the synthesis,4
therefore, route B is more available than route A in terms of
the synthesis of 2-alkylamino-6-carboxy-5,7-diarylcyclo-
penteno[1,2-b]pyridine derivatives. However, the incorpor-
ation of the alkylamino group (Fig. 1, R1) is a crucial step in
this route. A previous work introduced an alkylamino group
at the 2-position of a pyridine ring by reacting a readily
available pyridine N-oxide with an imidoyl chloride.6 This
reaction is thought to be applicable to our highly
functionalized pyridine system. Unfortunately, the reaction
Keywords: Acylamination; Imidoyl chloride; Cyclopenteno[1,2-b]pyri-
dines; ETA antagonist.
* Corresponding author. Tel.: C81 29 877 2220; fax: C81 29 877 2027;
e-mail: hirobumi_takahashi@merck.com
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.02.003

3474
H. Takahashi et al. / Tetrahedron 61 (2005) 3473–3481
Scheme 1. Possible synthetic route for compound 3.
of the pyridine N-oxide 5 with one equivalent of
N-isopropylbenzimidoyl chloride afforded the desired
compound 6a in a very low yield (4.5%). Optimization of
the detailed reaction conditions is necessary in order to
apply this reaction to the current system.
2. Results and discussion
The optimized acylamination reaction conditions utilizing
pyridine N-oxide 5 and N-isopropylbenzimidoyl chloride
are shown in Table 1. Pyridine N-oxide 5 was readily
prepared from 4 by treatment with m-CPBA at 0 8C under a
nitrogen atmosphere. The initial conditions (entry 1)
afforded the desired amide 6a in a 4.5% yield.6 Under
these conditions, half of the starting material N-oxide 5 was
recovered together with by-products. The structure of the
major by-product was estimated by Mass spectral analysis
Herein, we describe the results of the optimization of the
direct acylamination at the 2-position of functionalized
pyridine derivatives with an imidoyl chloride, as well as a
flexible and convenient synthesis of 2-alkylamino-6-
carboxy-5,7-diarylcyclopenteno[1,2-b]pyridine derivatives.
Table 1. Acylamination of N-oxide 5 with N-isopropylbenzimidoyl chloride
Entry
Imidoyl chloride
(equiv)
Solvent
Additive
Temp. ( 8C)
Results
6a
7a
5
1
2
3
4
5
6
7
8
1
1
10
5
5
5
5
5
5
ClCH2CH2Cl
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
Toluene
THF
None
None
None
100
60
60
60
60
60
60
60
60
60
60
60
4.5%
10%
13%
17%
26%
69%
10%
—
96%
1.4%
16%
94%
22%
15%
21%
13%
27%
6.1%
42%
63%
40%
44%
24%
14%
19%
79%
—
K2CO3 (10 equiv)
Cs2CO3 (10 equiv)
CsF (10 equiv)
Ag2O (10 equiv)
DBU (10 equiv)
Et3N (10 equiv)
Et3N (10 equiv)
Et3N (10 equiv)
Et3N (5 equiv)
b
—
b
—
—
9
10
11
12
5
5
2.5
1.2%b
75%
39%
—
b
—
—
CHCl3
a Total yield of 7, 8, 9 and 10.7
b 4 was isolated as a byproduct

H. Takahashi et al. / Tetrahedron 61 (2005) 3473–3481
3475
Among the inorganic bases tested, cesium fluoride (CsF)
was found to dramatically enhance the desired reaction
pathway resulting in a 69% yield of the 2-acylaminated
pyridine (6a), however the starting material was still
recovered (14%). In evaluating the organic bases, unfortu-
nately, DBU was reacted with the imidoyl chloride to
produce an ammonium salt rapidly; resulting in a 79%
recovery of the starting material (entry 8). In contrast, Et3N
worked very well affording 6a in an excellent yield (96%,
entry 9). With regard to a solvent, chloroform is the best
choice for this reaction. Using toluene or tetrahydrofuran
instead of chloroform, Et3N did not work well and a
considerable amount of the starting material was recovered
(entries 10 and 11). Further experiments around these
conditions revealed that 2.5 equiv of imidoyl chlorides in
the presence of 5 equiv of Et3N (entry 12) afforded the
product 6a in 94% yield. These conditions were determined
to be the optimal conditions.
Scheme 2. Identification of side products.
Scheme 3. Proposed reaction mechanism.
to be 7 in the reaction mixture. However, compound 7 was
labile and easily changed by usual work-up and following
isolation using silica-gel column chromatography to a
mixture of 7, 8, 9 and 10 (Scheme 2).7 Lower reaction
temperature with one equivalent of imidoyl chloride (entry
2) or with an excess of imidoyl chloride (entry 3) resulted in
an improved yield of 6a, however, a considerable amount of
the starting material and by-products still recovered.
In an effort to examine the applicability of these reaction
conditions, pyridine N-oxide 5 was reacted with other
imidoyl chlorides (Table 2). As expected, the reaction
conditions were well tolerated, and the corresponding
2-benzoylaminopyridines (6a–6d) were obtained in good
to excellent yields.
The previously described encouraging results prompted the
Table 2. Acylamination with various imidoyl chlorides
Based on these results, we speculated that the formation of
intermediate 11 may be a critical step in this reaction.
Further, two reaction pathways were expected to exist for
this reaction (Scheme 3). In this reaction, additive(s) are
thought to facilitate the formation of the intermediate and
the subsequent desired reaction steps, while formation of the
by-product 7 can be controlled to trap chloride ions.
Moreover, it was reported that addition of a base, such as
DBU or triethylamine (Et3N), increased the yields of
2-acylaminated pyridines in this type of reaction.6f How-
ever, simple pyridine substrates were used in the optimiz-
ation of this reaction. Thus, we reexamined the effect of
several additional bases in order to accelerate the desired
reaction pathway in this highly functionalized pyridine
system.
Entry
1
Imidoyl chloride
Product
Yield (%)
94
RZiso-Pr
6a
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
2
3
4
RZn-Pr
6b
6c
6d
93
96
74
RZBenzyl
RZPhenyl

3476
H. Takahashi et al. / Tetrahedron 61 (2005) 3473–3481
Scheme 4. Synthetic route for 3. Reaction conditions: (a) Methyl Methacrylate, PdCl2(PPh3)2, NaHCO3, DMF, 130 8C; (b) 10% Pd-C, HCOONH4, EtOH,
80 8C (13a, 37%; 13b, 28% 2 steps); (c) m-CPBA, CHCl3, 6 8C (14a, 96%; 14b, 83%); (d) N-isopropylbenzimidoyl chloride, Et3N, CHCl3, 60 8C (15a, 72%;
15b, 74%); (e) TFA, r.t. (f) NaOH, aq-MeOH, 100 8C (3a, 74%; 3b, 67% 2 steps).
synthesis of 3 by route B (Scheme 4). The Heck reaction of
triflate 12 with methyl methacrylate [PdCl2(PPh3)2,
NaHCO3, DMF, 130 8C] followed by subsequent hydro-
genation of the resultant olefin afforded a mixture of
diastereomers (13a and 13b) in a moderate yield.5 The
diastereomers were easily separated by silica gel column
chromatography. Pyridine N-oxide 14a was treated with
N-isopropylbenzimidoyl chloride (2.5 equiv) in the
presence of Et3N (5.0 equiv) at 60 8C and afforded
2-acylaminated pyridine 15a in a 72% yield. The stepwise
deprotection of the protecting groups (tert-butyl ester,
methyl ester, benzamide) on 15a was achieved by treatment
with trifluoroacetic acid (TFA), followed by basic
hydrolysis (NaOH) to afford the target compound 3a. The
transformation of 13b to 3b was successfully achieved in a
manner similar to that described above.
Silica gel column chromatography was carried out on
Wako gel C-300 (Wako Pure Chemical Industries Ltd,
Osaka, Japan.
4.1.1. (5RS,6SR,7SR)-7-(2-Benzyloxy-4-methoxyphenyl)-
6-tert-butoxycarbonyl-5-(3,4-methylenedioxyphenyl)-
cyclopenteno[1,2-b]pyridine N-oxide (5). To a solution of
(5RS,6SR,7SR)-7-(2-Benzyloxy-4-methoxyphenyl)-6-tert-
butoxycarbonyl-5-(3,4-methylenedioxyphenyl)cyclo-
penteno[1,2-b]pyridine 4 (5.29 g, 9.59 mmol) in CHCl3
(50 ml) was added m-CPBA (3.33 g, 19.2 mmol) at 0 8C and
the mixture was stirred for 15 h at cold-room temperature
(6 8C) under N2. The reaction was quenched with 1 M
Na2S2O3 solution while stirring at 6 8C for 30 min and
subsequently extracted using EtOAc. The organic layer was
washed with saturated NaHCO3 solution, water and brine,
dried over Na2SO4 and then concentrated. The residue was
purified by silica gel column chromatography (CHCl3–
MeOHZ100:0 to 30:1) to give 5 as a pale brown amorphous
solid (2.89 g, 53%). 1H NMR (CDCl3) d 7.99 (d, JZ6.6 Hz,
1H), 7.25–7.19 (m, 4H), 7.15–6.96 (m, 3H), 6.62 (d, JZ
7.3 Hz, 1H), 6.55 (d, JZ8.1 Hz, 1H), 6.50–6.43 (m, 2H),
6.38–6.24 (m, 2H), 5.90 (q, JZ1.7 Hz, 2H), 4.98–4.68 (m,
3H), 4.38 (d, JZ8.8 Hz, 1H), 3.76 (s, 3H), 3.27 (t, JZ
9.5 Hz, 1H), 1.33 (s, 9H). HRMS calcd for C34H34NO7
(MC1) 568.2335, found 568.2331.
3. Conclusions
A novel synthetic method for 2-alkylamino-6-carboxy-5,7-
diarylcyclopenteno[1,2-b]pyridines via a key acylamination
of the corresponding N-oxides with imidoyl chlorides has
been developed. This mild acylamination is thought to be
applicable to the other highly functionalized pyridine
derivatives.8
4.1.2. Preparation of N-isopropylbenzimidoyl chloride.
A solution of isopropylamine (35.0 ml, 410 mmol) and Et3N
(69.0 ml, 490 mmol) in THF (200 ml) was cooled in an ice
bath and benzoyl chloride was added to the solution. After
the mixture was stirred at the same temperature for 3 h, the
mixture was diluted with water and extracted with EtOAc.
The organic layer was washed with 2 N HCl, water,
saturated NaHCO3 solution and brine, and subsequently
dried over Na2SO4 and concentrated to give benzisopropyl-
amide as a white solid (51.9 g, 78%). A mixture of
benzisopropylamide (6.09 g, 36.8 mmol) and thionyl
chloride (4.50 ml, 61.7 mmol) was stirred at 90 8C under a
N2 atmosphere. After 2.5 h, thionyl chloride was removed
in vacuo and distilled under reduced pressure to give
N-isopropylbenzimidoyl chloride as a colorless liquid
(6.08 g, 91% yield). Bp 82–83 8C/5 mmHg. (lit.,9 52–
54 8C/1 mmHg). dZ1.15 (1.15 g/1.0 ml). 1H NMR
(CDCl3) d 7.97–7.94 (m, 2H), 7.47–7.34 (m, 3H), 4.14
(sept, JZ6.2 Hz, 1H), 1.27 (d, JZ6.2 Hz, 6H).
4. Experimental
4.1. General
All reagents and solvents were of commercial quality and
used without further purification unless otherwise noted.
Melting points were determined using a Yanaco MP
micromelting point apparatus (Yanaco New Science Inc.
Kyoto, Japan) and were not corrected. H NMR and 13C
1
NMR spectra were obtained on a Varian MERCURYvx 400
(Varian, Inc. CA, USA) or JEOL JNM-AL 400 (JEOL Ltd.
Tokyo, Japan) instrument at 400 MHz. Chemical shifts were
reported in parts per million as d units relative to
tetramethylsilane as an internal standard. Mass spec-
trometry was performed using micromass Q-Tof 2 (Waters
Co. MA, USA) (ESI positive). Analytical and Preparative
TLC were preformed using E-Merck Kieselgel F254 pre-
coated plates (Merck KGaA. Darmstadt, Germany).

H. Takahashi et al. / Tetrahedron 61 (2005) 3473–3481
3477
4.1.3. Reaction of (5RS,6SR,7SR)-7-(2-Benzyloxy-4-
methoxyphenyl)-6-tert-butoxycarbonyl-5-(3,4-methyl-
enedioxyphenyl)cyclopenteno[1,2-b]pyridine N-oxide (5)
with N-isopropylbenzimidoyl chloride (Table 1). In cases
in which inorganic bases were employed as additives, the
bases were used before being dried under heat. In cases in
which organic bases were used as additives, bases were
dried over NaOH. Imidoyl chloride (1, 2.5, 5 or 10 equiv)
was added to a mixture of 5 (170 mg, 0.30 mmol) and
additive (none, 5 or 10 equiv) in either ClCH2CH2Cl or
CHCl3 (1.0 ml) and stirred in oil bath at a prescribed
temperature under an Ar atmosphere overnight. After
cooling the reaction mixture, saturated NaHCO3 solution
was added to the mixture and extracted using EtOAc. The
organic layer was washed with brine, dried over Na2SO4 and
concentrated. The residue was purified by silica gel column
chromatography (Hexane–EtOAc–MeOH as eluent) and if
needed, further isolation was performed by preparative TLC
(CDCl3) d 8.46 (dd, JZ5.1, 1.5 Hz, 1H), 7.50 (dd, JZ7.3,
1.5 Hz, 1H), 7.34 (br s, 1H), 7.24–7.19 (m, 5H), 7.11–7.05
(m, 1H), 7.07 (dd, JZ7.3, 5.1 Hz, 1H), 6.94–6.82 (m, 1H),
6.67–6.63 (m, 2H), 5.88 (s, 2H), 5.05 (s, 2H), 4.39 (br s,
1H), 3.84 (s, 3H), 1.17 (s, 9H). HRMS calcd for C34H32NO7
(MC1) 566.2179, found 566.2176. 10. 1H NMR (CDCl3) d
8.39 (dd, JZ5.1, 1.5 Hz, 1H), 8.01 (d, JZ8.8 Hz, 1H), 7.22
(d, JZ7.3 Hz, 1H), 7.19–7.12 (m, 3H), 7.07 (dd, JZ7.3,
5.1 Hz, 1H), 6.85–6.81 (m, 2H), 6.73 (d, JZ8.1 Hz, 1H),
6.65 (dd, JZ8.8, 2.2 Hz, 1H), 6.43 (dd, JZ8.1, 1.5 Hz, 1H),
6.39 (d, JZ1.5 Hz, 1H), 6.36 (d, JZ2.2 Hz, 1H), 5.98 (br s,
2H), 4.66 (d, JZ11.0 Hz, 1H), 4.57 (d, JZ11.0 Hz, 1H),
4.20 (s, 1H), 3.78 (s, 3H), 1.24 (s, 9H). HRMS calcd for
C34H32NO7 (MC1) 566.2179, found 566.2182.
4.1.4. Determination of 8 (Scheme 5). To a solution of 8
(32.0 mg, 0.0552 mmol) in MeOH (0.50 ml) was added
10% Na2SO3 solution (0.50 ml). After stirring at room
temperature for 0.5 h, the mixture was diluted using water
and extracted using EtOAc. The organic layer was washed
with brine, dried over Na2SO4 and then concentrated in
vacuo. The residue was purified by silica gel column
chromatography (Hexane–EtOAcZ10:0 to 3:1) to yield 9 as
a white amorphous solid (14.0 mg, 64%).
1
(CHCl3–MeOH as eluent). 6a. H NMR (CDCl3) d 7.27–
7.19 (m, 6H), 7.17–7.11 (m, 2H), 7.08–7.04 (m, 2H), 6.97
(d, JZ8.2 Hz, 1H), 6.94 (dd, JZ7.8, 1.2 Hz, 1H), 6.57–6.53
(m, 2H), 6.53 (d, JZ2.3 Hz, 1H), 6.49 (dd, JZ8.4, 2.3 Hz,
1H), 6.39–6.35 (m, 2H), 5.89 (br s, 2H), 5.01–4.91 (m, 1H),
4.94 (d, JZ11.3 Hz, 1H), 4.90 (d, JZ11.3 Hz, 1H), 4.82 (d,
JZ10.0 Hz, 1H), 4.40 (d, JZ10.0 Hz, 1H), 3.82 (s, 3H),
3.40 (t, JZ10.0 Hz, 1H), 1.28 (s, 9H), 1.25 (d, JZ6.8 Hz,
3H), 1.15 (d, JZ6.8 Hz, 3H). The configuration of 6a were
determined by NOE experiments.7 NOEs were observed
between d 3.40 (Ha) and d 6.36 (Hd), d 3.40 (Ha) and d 6.37
(He), d 4.40 (Hb) and d 4.82 (Hc), d 4.40 (Hb) and d 6.36
(Hd), d 4.40 (Hb) and d 6.37 (He), d 4.82(Hc) and d 6.97 (Hf).
Scheme 5. Conversion of 8 to 9.
4.1.5. Preparations of imidoyl chlorides (Table 2). All
imidoyl chlorides were prepared from the corresponding
amines by a procedure similar to that described for the
preparation of N-isopropylbenzimidoyl chloride. N-n-
propylbenzimidoyl chloride. Colorless liquid. Bp 72–
13C NMR (CDCl3) d 20.6, 21.5, 28.1, 48.9, 51.1, 51.2, 55.4,
61.29, 70.0, 80.7, 99.8, 100.8, 104.5, 108.1, 108.4, 121.3,
121.5, 122.6, 127.1, 127.5, 127.7, 128.2, 128.3, 129.1,
131.4, 133.0, 135.4, 135.9, 136.3, 137.2, 146.3, 147.5,
153.8, 157.3, 159.7, 164.1, 170.0, 172.4. HRMS calcd for
C44H45N2O7 (MC1) 713.3227, found 713.3232. Anal.
Calcd for C44H44N2O7: C, 74.14; H, 6.22; N, 3.93. Found
C, 73.93; H, 6.23; N, 3.83.
1
73 8C/1.1 mmHg. H NMR (CDCl3) d 8.03–8.00 (m, 2H),
7.49–7.39 (m, 3H), 3.69 (t, JZ7.0 Hz, 2H), 1.78 (qt, JZ7.4,
7.0 Hz, 2H), 1.04 (t, JZ7.4 Hz, 3H). N-benzylbenzimidoyl
chloride. Colorless liquid. Bp 139–141 8C/1.1 mmHg. H
1
NMR (CDCl3) d 8.10–8.07 (m, 2H), 7.51–7.27 (m, 8H),
4.95 (s, 2H). N-phenylbenzimidoyl chloride. White solid.
Bp 120–129 8C/1.1 mmHg. (lit.6c 100 8C/0.05 mmHg). Mp
1
35–37 8C (lit.6c 34–35 8C). H NMR (CDCl3) d 8.20–8.17
1
Compound 7 (mixture of 2 isomers). H NMR (CDCl3) d
(m, 2H), 7.59–7.40 (m, 5H), 7.25–7.20 (m, 1H), 7.04–7.01
(m, 2H).
8.51 and 8.43 (dd, JZ4.9, 1.5 Hz, 1H), 7.06–7.48 (m, 8H),
6.82–6.44 (m, 5H), 5.98 and 5.87 (br s, 2H), 5.18–4.68 (m,
4H), 3.83 and 3.76 (s, 3H), 1.21 and 1.17 (s, 9H). HRMS
calcd for C34H32NO6 (MC1) 550.2230, found 550.2229. 8.
1H NMR (CDCl3) d 9.44 (s, 1H), 8.47 (dd, JZ4.9, 1.6 Hz,
1H), 7.61 (dd, JZ7.5, 1.6 Hz, 1H), 7.37 (d, JZ9.0 Hz, 1H),
7.23 7.17 (m, 5H), 7.11 (dd, JZ7.5, 4.9 Hz, 1H), 6.98 (d,
JZ1.8 Hz, 1H), 6.85 (dd, JZ8.2, 1.8 Hz, 1H), 6.64 (dd, JZ
7.0, 2.4 Hz, 1H), 6.63 (br s, 1H), 6.56 (d, JZ8.2 Hz, 1H),
5.90 (br s, 2H), 5.00 (d, JZ11.2 Hz, 1H), 4.95 (d, JZ
11.2 Hz, 1H), 3.85 (s, 3H), 1.21 (s, 9H). HRMS calcd for
C34H32NO8 (MC1) 582.2128, found 582.2134. 9. 1H NMR
4.1.6. Reaction of (5RS,6SR,7SR)-7-(2-Benzyloxy-4-
methoxyphenyl)-6-tert-butoxycarbonyl-5-(3,4-methyl-
enedioxyphenyl)cyclopenteno[1,2-b]pyridine N-oxide (5)
with various imidoyl chlorides (Table 2). Imidoyl chloride
(0.75 mmol) was added to a mixture of 5 (170 mg,
0.30 mmol) and Et3N (0.21 ml, 1.50 mmol) in CHCl3
(1.0 ml) and stirred in oil bath (60 8C) under an Ar
atmosphere overnight. After cooling the reaction mixture,
saturated NaHCO3 solution was added to the mixture and

3478
H. Takahashi et al. / Tetrahedron 61 (2005) 3473–3481
extracted using EtOAc. The organic layer was washed with
brine, dried over Na2SO4 and then concentrated. The
residue was purified by silica gel column chromatography
(Hexane–EtOAc as eluent) to give 6b–6d. 6b. white
dried over Na2SO4 and then concentrated. The residue was
purified by silica gel column chromatography (hexane–
EtOAcZ4:1 to 3:2) to give mixture of endo and exo olefins
(1:5 by 1H NMR) as a pale brown amorphous solid (9.48 g,
quant). This solid was used in the subsequent reaction
without further separation. Pure samples of each exo and
endo olefins were isolated by further separation with silica
gel column chromatography (hexane–EtOAcZ3:1 to 2:1).
The exo olefin. white amorphous solid. 1H NMR (CDCl3) d
8.42 (d, JZ4.9 Hz, 1H), 7.27 (d, JZ7.6 Hz, 1H), 7.08 (dd,
JZ7.6, 4.9 Hz, 1H), 7.04–6.63 (m, 6H), 6.26 (d, JZ1.1 Hz,
1H), 5.95 (br s, 2H), 5.46 (br s, 1H), 4.79 (d, JZ10.2 Hz,
1H), 4.51 (d, JZ10.2 Hz, 1H), 4.00–3.40 (m, 2H), 3.77 (s,
3H), 3.74 (s, 3H), 3.21 (t, JZ10.2 Hz, 1H), 1.35 (s, 9H).
HRMS calcd for C32H34NO7 (MC1) 544.2335, found
544.2327. The endo olefin. Pale brown amorphous solid. 1H
NMR (CDCl3) d 8.42 (d, JZ4.9 Hz, 1H), 7.49 (s, 1H), 7.28
(d, JZ7.6 Hz, 1H), 7.16–6.67 (m, 6H), 7.10 (dd, JZ7.6,
4.9 Hz, 1H), 5.97 (br s, 2H), 4.75 (d, JZ10.4 Hz, 1H), 4.53
(d, JZ10.4 Hz, 1H), 3.80 (s, 3H), 3.73 (s, 3H), 3.19 (t, JZ
10.4 Hz, 1H), 1.92 (d, JZ1.3 Hz, 3H), 1.32 (s, 9H). HRMS
calcd for C32H34NO7 (MC1) 544.2335, found 544.2330.
1
amorphous solid (201 mg, 93% yield). H NMR (CDCl3)
d 7.32–7.15 (m, 8H), 7.07 (d, JZ8.2 Hz, 1H), 6.99–6.95 (m,
2H), 6.90 (dd, JZ8.0, 1.2 Hz, 1H), 6.56–6.48 (m, 4H), 6.35
(d, JZ1.7 Hz, 1H), 6.31 (dd, JZ7.9, 1.7 Hz, 1H), 5.89 (br s,
2H), 4.92 (d, JZ11.4 Hz, 1H), 4.85 (d, JZ11.4 Hz, 1H),
4.75 (d, JZ10.1 Hz, 1H), 4.39 (d, JZ10.1 Hz, 1H), 3.98–
3.84 (m, 1H), 3.82 (s, 3H), 3.42 (t, JZ10.1 Hz, 1H), 1.71–
1.45 (m, 2H), 1.29 (s, 9H), 0.79 (t, JZ7.4 Hz, 3H). 13C
NMR (CDCl3) d 11.4, 21.2, 28.1, 50.4, 51.3, 51.9, 55.4,
61.2, 70.0, 80.8, 100.0, 100.9, 104.5, 108.2, 108.6, 120.7,
121.1, 121.7, 127.3, 127.9, 128.0, 128.5, 128.6, 129.8,
132.1, 133.4, 135.4, 135.7, 136.4, 136.7, 146.5, 147.7,
155.6, 157.6, 160.2, 164.5, 170.5, 172.8. HRMS calcd for
C44H45N2O7 (MC1) 713.3227, found 713.3226. Anal.
Calcd for C44H44N2O7: C, 74.14; H, 6.22; N, 3.93. Found
C, 74.05; H, 6.38; N, 3.75. 6c. White amorphous solid
1
(219 mg, 96% yield). H NMR (CDCl3) d 7.37–7.05 (m,
14H), 6.76 (d, JZ8.0 Hz, 1H), 6.74–6.68 (m, 2H), 6.57–
6.52 (m, 2H), 6.48–6.41 (m, 2H), 6.25 (d, JZ1.4 Hz, 1H),
6.15 (dd, JZ7.9, 1.4 Hz, 1H), 5.86 (s, 2H), 5.23 (s, 2H),
4.77 (d, JZ11.0 Hz, 1H), 4.71 (d, JZ10.2 Hz, 1H), 4.67 (d,
JZ11.0 Hz, 1H), 4.34 (d, JZ10.2 Hz, 1H), 3.85 (s, 3H),
3.41 (t, JZ10.2 Hz, 1H), 1.29 (s, 9H). 13C NMR (CDCl3) d
28.1, 51.3, 51.7, 52.1, 55.5, 60.9, 70.0, 80.8, 100.0, 100.9,
104.4, 108.3, 108.7, 120.5, 121.1, 121.6, 127.1, 127.6,
127.9, 128.0, 128.3, 128.7, 130.2, 132.2, 133.1 135.1, 135.6,
136.2, 136.2, 138.0, 146.4, 147.6, 155.2, 157.7, 160.3,
164.4, 171.0, 172.9. HRMS calcd for C48H45N2O7 (MC1)
761.3227, found 761.3214. Anal. Calcd for C48H44N2O7: C,
75.77; H, 5.83; N, 3.68. Found C, 75.75; H, 5.96; N, 3.55.
A quantity of 6.5 g of 10% Pd–C and 20.2 g HCOONH4 was
added to a suspension of the olefin (9.48 g, 16.9 mmol) in
EtOH (160 ml). After the mixture was heated with stirring at
80 8C for 24 h, insoluble materials were filtered off using a
Celite pad and the Celite pad was washed with EtOAc and
MeOH. After the combined filtrate was concentrated, the
residue was diluted with EtOAc and water and the organic
layer was separated. The organic layer was washed with
saturated NaHCO3 solution and brine, dried over Na2SO4
and then concentrated. The residue was purified by silica gel
column chromatography (hexane–EtOAcZ9:1 to 2:1) to
give the more polar diastereomer 13a as a colorless oil
(3.44 g, 37%) and the less polar diastereomer 13b as a white
amorphous solid (2.54 g, 28%).
1
6d. White amorphous solid (167 mg, 74% yield). H NMR
(CDCl3) d 7.45–7.41 (m, 2H), 7.31–7.09 (m, 12H), 7.00 (dd,
JZ8.0, 0.8 Hz, 1H), 6.90–6.85 (m, 3H), 6.52 (d, JZ8.0 Hz,
1H), 6.44 (d, JZ2.4 Hz, 1H), 6.40 (dd, JZ8.2, 2.4 Hz, 1H),
6.33 (d, JZ1.7 Hz, 1H), 6.26 (dd, JZ8.0, 1.7 Hz, 1H), 5.89
(d, JZ1.4 Hz, 1H), 5.89 (d, JZ1.4 Hz, 1H), 4.75 (d, JZ
11.2 Hz, 1H), 4.64 (d, JZ10.0 Hz, 1H), 4.63 (d, JZ
11.2 Hz, 1H), 4.38 (d, JZ10.0 Hz, 1H), 3.80 (s, 3H), 3.33 (t,
JZ10.0 Hz, 1H), 1.27 (s, 9H). 13C NMR (CDCl3) d 28.1,
51.3, 51.8, 55.4, 61.3, 70.0, 80.7, 99.9, 100.9, 104.5, 108.3,
108.7, 120.1, 121.1, 121.7, 126.7, 127.7, 127.8, 127.9,
128.4, 129.0, 129.0, 130.1, 131.8, 134.2, 135.8, 136.1,
136.4, 136.5, 142.9, 146.5, 147.7, 155.9, 157.6, 160.0,
164.6, 170.9, 172.7. HRMS calcd for C47H43N2O7 (MC1)
747.3070, found 747.3078. Anal. Calcd for C47H42N2O7: C,
75.58; H, 5.67; N, 3.75. Found C, 75.26; H, 5.71; N, 3.61.
1
4.1.8. More polar diastereomer 13a. H NMR (CDCl3) d
8.43 (d, JZ5.0 Hz, 1H), 7.29 (d, JZ7.6 Hz, 1H), 7.09 (dd,
JZ7.6, 5.0 Hz, 1H), 6.92–6.65 (m, 6H), 6.37 (s, 1H), 5.97
(br s, 2H), 4.91 (d, JZ10.1 Hz, 1H), 4.53 (d, JZ10.1 Hz,
1H), 3.76 (s, 3H), 3.66 (s, 3H), 3.20 (t, JZ10.1 Hz, 1H),
3.19–2.79 (m, 3H), 1.34 (s, 9H), 1.22 (d, JZ6.6 Hz, 3H).
13C NMR (CDCl3) d 17.1, 27.9, 36.5, 41.2, 49.5, 51.5, 51.9,
55.0, 64.4, 81.0, 100.8, 108.1, 108.1, 112.6, 115.0, 121.6,
121.7, 129.4, 132.0, 132.3, 135.5, 137.6, 139.6, 146.4,
147.7, 149.2, 157.7, 164.6, 172.1, 176.3. HRMS calcd for
C32H36NO7 (MC1) 546.24292, found 546.2488.
1
4.1.9. Less polar diastereomer 13b. H NMR (CDCl3) d
4.1.7. (5RS,6SR,7SR)-6-tert-Butoxycarbonyl-7-[2-(2-
methoxycarbonylpropyl)-4-methoxyphenyl]-5-(3,4-
methylenedioxyphenyl)cyclopenteno[1,2-b]pyridine
(13a, 13b). A mixture of PdCl2(PPh3)2 (2.37 g, 3.37 mmol),
NaHCO3 (5.66 g, 67.4 mmol), methyl methacrylate (90 ml,
841 mmol) and 125 (9.99 g, 16.9 mmol) in DMF (240 ml)
was heated with stirring at 130 8C for 15 h under a N2
atmosphere. After cooling to room temperature, the reaction
mixture was diluted with EtOAc (200 ml). Insoluble
materials were filtered off using Celite pad and the Celite
pad was washed with EtOAc. The combined filtrate was
washed with saturated NaHCO3 solution, water and brine,
8.41 (d, JZ4.9 Hz, 1H), 7.29 (d, JZ7.6 Hz, 1H), 7.08 (dd,
JZ7.6, 4.9 Hz, 1H), 6.94–6.86 (m, 1H), 6.80 (d, JZ7.9 Hz,
1H), 6.79–6.67 (m, 4H), 5.97 (br s, 2H), 4.94 (d, JZ9.7 Hz,
1H), 4.55 (d, JZ9.7 Hz, 1H), 3.77 (s, 3H), 3.63 (s, 3H),
3.48–3.24 (m, 1H), 3.24 (t, JZ9.7 Hz, 1H), 2.95–2.50 (m,
2H), 1.34 (s, 9H), 1.28–1.15 (m, 3H). 13C NMR (CDCl3) d
17.1, 28.1, 37.3, 41.0, 49.1, 51.7, 52.0, 55.2, 64.6, 81.1,
101.0, 108.2, 108.3, 112.7, 115.6, 121.8, 129.6, 132.2,
132.4, 135.8, 137.7, 139.6, 146.6, 147.9, 149.4, 157.7,
164.9, 172.2, 176.5. HRMS calcd for C32H36NO7 (MC1)
546.2492, found 546.2485.

H. Takahashi et al. / Tetrahedron 61 (2005) 3473–3481
3479
4.1.10. (5RS,6SR,7SR)-6-tert-Butoxycarbonyl-7-[2-(2-
methoxycarbonylpropyl)-4-methoxyphenyl]-5-(3,4-
methylenedioxyphenyl)cyclopenteno[1,2-b]pyridine
N-oxide (14a). To a solution of 13a (3.63 g, 6.65 mmol) in
CHCl3 (50 ml) was added m-CPBA (2.47 g, 14.3 mmol) at
0 8C and the mixture was stirred for 15 h at cold room
temperature (6 8C) under a N2 atmosphere. The reaction was
quenched with 1 M Na2S2O3 solution, stirred at 6 8C for
30 min and then extracted with EtOAc. The organic layer
was washed with saturated NaHCO3 solution, water and
brine, dried over Na2SO4 and then concentrated. The
residue was purified by silica gel column chromatography
(CHCl3–MeOHZ30:1) to give 14a as a pale brown
to that described for the preparation of 15a. White
amorphous solid (74% yield). H NMR (CDCl3) d 7.25–
1
7.12 (m, 5H), 7.01 (dd, JZ7.7, 1.1 Hz, 1H), 6.79–6.69 (m,
4H), 6.64 (dd, JZ7.8, 2.0 Hz, 1H), 6.58–6.51 (m, 2H), 5.96
(br s, 2H), 4.96 (septet, JZ6.8 Hz, 1H), 4.90 (d, JZ9.8 Hz,
1H), 4.49 (d, JZ9.8 Hz, 1H), 3.82 (s, 3H), 3.68 (s, 3H),
3.52–3.43 (m, 1H), 3.21 (t, JZ9.8 Hz, 1H), 2.99–2.89 (m,
1H), 2.63–2.53 (m, 1H), 1.34 (s, 9H), 1.18 (d, JZ7.0 Hz,
3H), 1.12 (d, JZ7.0 Hz, 3H), 1.10 (d, JZ7.0 Hz, 3H). 13C
NMR (CDCl3) d 16.4, 20.7, 21.2, 28.0, 37.4, 40.6, 48.2,
48.8, 51.0, 51.7, 55.3, 64.3, 81.3, 101.1, 108.2, 108.4, 112.8,
115.7, 121.8, 123.4, 127.6, 128.4, 129.3, 129.4, 132.9,
133.7, 136.1, 136.2, 137.4, 139.6, 146.8, 148.0, 154.4,
157.7, 164.7, 170.2, 172.3, 176.8. HRMS calcd for
C42H47N2O8 (MC1) 707.3332, found 707.3329. Anal.
Calcd for C42H46N2O8: C, 71.37; H, 6.56; N, 3.96. Found
C, 71.15 H, 6.57; N, 3.83.
1
amorphous solid (3.58 g, 96%). H NMR (CDCl3) d 8.02
(d, JZ6.2 Hz, 1H), 7.14 (dd, JZ7.7, 7.0 Hz, 1H), 6.92 (d,
JZ7.7 Hz, 1H), 6.82–6.60 (m, 6H), 5.96 (br s, 2H), 5.05 (d,
JZ7.0 Hz, 1H), 4.56 (d, JZ7.7 Hz, 1H), 3.73 (s, 3H), 3.64
(s, 3H), 3.40–2.98 (m, 4H), 1.42 (s, 9H), 1.31 (d, JZ7.0 Hz,
3H). HRMS calcd for C32H36NO8 (MC1) 562.2441, found
562.2444.
4.1.14. (5RS,6SR,7SR)-7-[2-(2-Carboxypropyl)-4-meth-
oxyphenyl]-5-(3,4-methylenedioxyphenyl)-2-iso-propyl-
aminocyclopenteno[1,2-b]pyridine-6-carboxylic acid
(3a). Compound 15a (3.40 g, 4.81 mmol) were dissolved
with TFA (50 ml) and stirred for 4 h at room temperature.
After TFA was removed in vacuo, water was added to the
residue and the compound was extracted with EtOAc. The
organic layer was washed with brine, dried over Na2SO4 and
then concentrated. The residue was purified by silica gel
column chromatography (CHCl3 to CHCl3–MeOHZ10:1)
to yield the monoester as a white amorphous solid (2.94 g,
94%). 1H NMR (CDCl3) d 7.25–7.09 (m, 5H), 7.01 (d, JZ
7.9 Hz, 1H), 6.76–6.53 (m, 7H), 5.94 (br s, 2H), 4.95 (septet,
JZ6.8 Hz, 1H), 4.93 (d, JZ9.6 Hz, 1H), 4.52 (d, JZ
9.6 Hz, 1H), 3.79 (s, 3H), 3.61 (s, 3H), 3.28 (t, JZ9.6 Hz,
1H), 3.09–2.78 (m, 3H), 1.22 (d, JZ6.8 Hz, 3H), 1.12 (d,
JZ6.8 Hz, 3H), 1.11 (d, JZ6.8 Hz, 3H). HRMS calcd for
C38H39N2O8 (MC1) 651.2706, found 651.2699. A quantity
of 50 ml (200 mmol) of 4 M NaOH solution was added to a
solution of monoester (2.94 g, 4.52 mmol) in MeOH (70 ml)
and the mixture was stirred under reflux overnight. After
cooling to room temperature, 4 N HCl was added drop-wise
to the mixture until it reached pH 2–3. The mixture was then
extracted with EtOAc and the organic layer was washed
with brine, dried over Na2SO4 and then concentrated. The
residue was purified by silica gel column chromatography
(hexane–EtOAcZ1:2 to CHCl3–MeOHZ10:1) to give 3a
4.1.11. A diastereomer of 14a (14b). Compound 14b was
prepared from 13b (starting material) in a similar procedure
to that described for the preparation of 14a. White
1
amorphous solid (83% yield); H NMR (CDCl3) d 8.01 (d,
JZ6.4 Hz, 1H), 7.15 (t, JZ7.1 Hz, 1H), 6.94 (d, JZ7.9 Hz,
1H), 6.80–6.66 (m, 6H), 5.96 (s, 2H), 5.09 (d, JZ7.3 Hz,
1H), 4.61 (d, JZ8.2 Hz, 1H), 3.73 (s, 3H), 3.65 (s, 3H), 3.52
(dd, JZ13.9, 4.6 Hz, 1H), 3.40–3.29 (m, 1H), 3.15 (dd, JZ
8.2, 7.3 Hz, 1H), 2.64 (dd, JZ13.9, 10.4 Hz, 1H), 1.42 (s,
9H), 1.20 (d, JZ6.8 Hz, 3H). HRMS calcd for C32H36NO8
(MC1) 562.2441, found 562.2441.
4.1.12. (5RS,6SR,7SR)-2-(1-Benzoyl-1-iso-propylamino)-
6-tert-butoxycarbonyl-7-[2-(2-methoxycarbonylpropyl)-
4-methoxyphenyl]-5-(3,4-methylenedioxyphenyl)cyclo-
penteno[1,2-b]pyridine (15a). To a solution of 14a (3.40 g,
6.05 mmol) and Et3N (2.7 ml, 19.4 mmol) in CHCl3 (30 ml)
was added N-isopropylbenzoylimidoyl chloride (2.97 ml,
18.9 mmol) at room temperature. After stirring overnight at
60 8C under N2, the mixture was cooled to room temperature
and diluted with saturated NaHCO3 solution. The mixture
was extracted with ethyl acetate and the organic layer was
washed with brine, dried over Na2SO4 and then concen-
trated. The residue was purified by silica gel column
chromatography (hexane–EtOAcZ10:0 to 4:1) to give 15a
1
as a white solid (1.79 g, 74%). Mp 158–160 8C. H NMR
(acetone-d6) d 7.08 (d, JZ8.5 Hz, 1H), 7.05 (d, JZ8.3 Hz,
1H), 6.88–6.72 (m, 5H), 6.38 (d, JZ8.5 Hz, 1H), 6.00 (s,
2H), 5.20 (br s, 1H), 4.90 (d, JZ9.5 Hz, 1H), 4.47 (d, JZ
8.9 Hz, 1H), 3.87–3.75 (m, 1H), 3.75 (s, 3H), 3.29 (dd, JZ
9.5, 8.9 Hz, 1H), 3.17–3.10 (m, 1H), 3.00–2.80 (m, 2H),
1.22 (d, JZ6.5 Hz, 3H), 1.13 (d, JZ6.3 Hz, 3H), 1.10 (d,
JZ6.3 Hz, 3H). 13C NMR (acetone-d6) d 17.8, 22.8, 22.9,
38.6, 42.6, 43.4, 50.3, 52.0, 55.2, 63.7, 101.8, 106.8, 108.7,
108.9, 113.3, 115.8, 122.2, 125.7, 130.3, 133.8, 135.0,
138.4, 140.7, 147.2, 148.6, 158.6, 159.6, 162.8, 174.9,
176.7. HRMS calcd for C30H33N2O7 (MC1) 533.2288,
found 533.2282. Anal. Calcd for C30H32N2O7$0.5 H2O: C,
66.53; H, 6.14; N, 5.17. Found C, 66.55 H, 6.28; N, 5.01.
1
as a pale brown amorphous solid (3.20 g, 72% yield). H
NMR (CDCl3) d 7.27–7.12 (m, 5H), 7.02–6.97 (m, 1H),
6.79–6.48 (m, 7H), 5.94 (br s, 2H), 4.98 (sept, JZ6.8 Hz,
1H), 4.89 (d, JZ9.8 Hz, 1H), 4.46 (d, JZ9.8 Hz, 1H), 3.81
(s, 3H), 3.67 (s, 3H), 3.14 (t, JZ9.8 Hz, 1H), 3.07–2.96 (m,
2H), 2.92–2.82 (m, 1H), 1.34 (s, 9H), 1.25 (d, JZ7.0 Hz,
3H), 1.13 (d, JZ7.0 Hz, 6H). 13C NMR (CDCl3) d 17.0,
20.8, 21.1, 28.0, 36.6, 41.8, 48.2, 49.0, 51.3, 51.7, 55.2,
64.7, 81.3, 101.1, 108.1, 108.3, 113.0, 114.4, 121.8, 123.5,
127.6, 128.4, 129.2, 129.4, 133.0, 133.6, 135.9, 136.3,
137.5, 140.0, 146.8, 148.0, 154.3, 158.0, 164.6, 170.2,
172.4, 176.8. HRMS calcd for C42H47N2O8 (MC1)
707.3332, found 707.3325. Anal. Calcd for C42H46N2O8:
C, 71.37; H, 6.56; N, 3.96. Found C, 71.09 H, 6.59; N, 3.83.
4.1.15. A diastereomer of 3a (3b). A volume of 2 ml of 6 M
NaOH solution (12 mmol) was added to a solution of 15b
(85 mg, 0.120 mmol) in MeOH (4 ml) and the mixture was
4.1.13. A diastereomer of 15a (15b). Compound 15b was
prepared from 14b (starting material) in a similar procedure

3480
H. Takahashi et al. / Tetrahedron 61 (2005) 3473–3481
Yamamori, T. J. Med. Chem. 2002, 45, 2041–2055. (h)
Murugesan, N.; Gu, Z.; Spergel, S.; Young, M.; Chen, P.;
Mathur, A.; Leith, L.; Hermsmeier, M.; Liu, E. C.-K.; Zhang,
R.; Bird, E.; Waldron, T.; Marino, A.; Koplowitz, B.;
Humphreys, W. G.; Chong, S.; Morrison, R. A.; Webb, M. L.;
Moreland, S.; Trippodo, N.; Barrish, J. C. J. Med. Chem. 2003,
46, 125–137. For ETB selective antagonist. (a) Balwierczak,
J. L.; Bruseo, C. W.; Del Grande, D.; Jeng, A. Y.; Savage, P.;
Shetty, S. S. J. Cardiovasc. Pharmacol. 1995, 26(Suppl. 3),
S393–S396. (b) Chan, M. F.; Kois, A.; Verner, E. J.; Raju,
B. G.; Castillo, R. S.; Wu, C.; Okun, I.; Stavros, F. D.; Balaji,
V. N. Bioorg. Med. Chem. 1998, 6, 2301–2316. (c) Liu, G.;
Kozmina, N. S.; Winn, M.; von Geldern, T. W.; Chiou, W. J.;
Dixon, D. B.; Nguyen, B.; Marsh, K. C.; Opgenorth, T. J.
J. Med. Chem. 1999, 42, 3679–3689. (d) Mederski,
W. W. K. R.; Osswald, M.; Dorsch, D.; Christadler, M.;
Schmitges, C.-J.; Wilm, C. Bioorg. Med. Chem. Lett. 1999, 9,
619–622. For ETA/ETB balanced antagonist. (a) Clozel, M.;
Breu, V.; Gray, G. A.; Kalina, B.; Loffler, B.; Burri, K.; Cassal,
J.; Hirth, G.; Muller, M.; Neidhart, W.; Ramuz, H.
J. Pharmacol. Exp. Ther. 1994, 270, 228–235. (b) Elliot,
J. D.; Lago, M. A.; Cousins, R. D.; Gao, A.; Leber, J. D.; Erhard,
K. F.; Nambi, P.; Elshourbagy, N. A.; Kumar, C.; Lee, J. A.;
Bean, J. W.; Debrosse, C. W.; Eggleston, D. S.; Brooks, D. P.;
Feuerstein, G.; Ruffolo, R. R.; Weinstock, J.; Gleason, J. G.;
Peishoff, C. E.; Ohlstein, E. J. Med. Chem. 1994, 37,
1553–1557. (c) Walsh, T. F.; Fitch, K. J.; Chakravarty, P. K.;
Williams, D. L.; Murphy, K. A.; Nolan, N. A.; O’Brien, J. A.;
Lis, E. V.; Pettibone, D. J.; Kivlighn, S. D.; Gabel, R. A.;
Zingaro, G. J.; Krause, S. M.; Siegl, P. K. S.; Clineschmidt, B.
V.; Greenlee, W. J. Abstracts of American Chemical Society
National Meeting, Washington, DC, August 21-25, 1994,
American Chemical Society: Washington, DC, 1994; MEDI
145. (d) Jae, H.-S.; Winn, M.; Dixon, D. B.; Marsh, K. C.;
Nguyen, B.; Opgenorth, T. J.; von Geldern, T. W. J. Med.
stirred under reflux overnight. After cooling to room
temperature, 6 N HCl was added to the mixture until it
reached pH 2–3. Insoluble material was collected by
filtration and the filtrate was extracted using EtOAc. The
organic layer was washed with brine, dried over Na2SO4 and
then concentrated. The residue and the insoluble material
were combined and purified by silica gel column chroma-
tography (CHCl3–MeOHZ10:0 to 9:1) to give 3b as a pale
brown solid (43 mg, 67%). Mp 137–141 8C. 1H NMR
(CD3OD) d 7.33 (d, JZ8.8 Hz, 1H), 6.94 (d, JZ7.8 Hz,
1H), 6.83–6.75 (m, 5H), 6.68 (d, JZ8.8 Hz, 1H), 5.92 (s,
2H), 5.16–5.05 (m, 1H), 4.48 (d, JZ8.4 Hz, 1H), 3.90–3.80
(m, 1H), 3.76 (s, 3H), 3.28–3.20 (m, 1H), 3.14–3.06 (m,
1H), 2.85 (dd, JZ14.6, 7.0 Hz, 1H), 2.73–2.62 (m, 1H),
1.30–1.23 (m, 3H), 1.21 (d, JZ6.3 Hz, 3H), 1.14 (d, JZ
6.3 Hz, 3H). 13C NMR (CD3OD) d 18.3, 22.3, 22.6, 37.5,
43.2, 45.1, 52.8, 55.7, 65.4, 102.4, 109.1, 109.2, 110.6,
114.0, 116.0, 122.4, 127.8, 130.3, 132.6, 137.2, 139.9,
141.8, 148.2, 149.4, 156.0, 156.2, 159.9, 176.1, 180.5.
HRMS calcd for C30H33N2O7 (MC1) 533.2288, found
533.2295. Anal. Calcd for C30H32N2O7$0.5 H2CO3: C,
65.00; H, 5.90; N, 4.97. Found C, 64.99 H, 6.04; N, 4.94.
Acknowledgements
We thank Dr. Shigeru Nakajima and Mr. Hirokazu Ohsawa
for analytical support (NMR and Mass spectra). We also
thank Toray Research Center, Inc. for elemental analysis.
References and notes
¨
Chem. 1997, 40, 3217–3227. (e) Amberg, W.; Hergenroder, S.;
1. Yanagisawa, M.; Kurihara, H.; Kimura, S.; Tomobe, Y.;
Kobayashi, M.; Mitsui, Y.; Yazaki, Y.; Goto, K.; Masaki, T.
Nature 1988, 332, 411–415.
Hillen, H.; Jansen, R.; Kettschau, G.; Kling, A.; Klinge, D.;
Raschack, M.; Riechers, H.; Unger, L. J. Med. Chem. 1999, 42,
3026–3032.
2. Hosoda, K.; Nakao, K.; Arai, H.; Nagakawa, O.; Hosoda, K.;
Suga, S.; Nakanishi, S.; Imura, H. FEBS Lett. 1991, 287, 23–26.
3. For ETA selective antagonist. (a) Winn, M.; Geldern, T. W.;
Opgenorth, T. J.; Jae, H.; Tasker, A. S.; Boyd, S. A.; Kester,
J. A.; Mantei, R. A.; Bal, R.; Sorensen, B. K.; Wu-Wong, J. R.;
Chiou, W. J.; Dixon, D. B.; Novosad, E. I.; Hernadez, L.;
Marsh, K. C. J. Med. Chem. 1996, 38, 1039–1048. (b) Wu, C.;
Chan, M. F.; Stavros, F.; Okun, I.; Mong, S.; Keller, K. M.;
Brock, T.; Kogan, T. P.; Dixon, R. A. F. J. Med. Chem. 1997,
40, 1690–1697. (c) Liu, G.; Henry, K. J., Jr.; Szczepankiewicz,
B. G.; Winn, M.; Kozmina, N. S.; Boyd, S. A.; Wasicak, J.; von
Geldern, T. W.; Wu-Wong, J. R.; Chiou, W. J.; Dixon, D. B.;
Nguyen, B.; Marsh, K. C.; Opgenorth, T. J. J. Med. Chem. 1998,
41, 3261–3275. (d) Astles, P. C.; Brown, T. J.; Halley, F.;
Handscombe, C. M.; Harris, N. V.; Majid, T. N.; McCarthy, C.;
McLay, A.; Porter, B.; Roach, A. G.; Sargent, C.; Smith, C.;
Walsh, R. J. A. J. Med. Chem. 2000, 43, 900–910. (e) Wu, C.;
Decker, E. R.; Blok, N.; Li, J.; Bourgoyne, A. R.; Bui, H.;
Keller, K. M.; Knowles, V.; Li, W.; Stavros, F. D.; Holland,
G. W.; Brock, T. A.; Dixon, R. A. F. J. Med. Chem. 2001, 44,
1211–1216. (f) Morimoto, H.; Ohashi, N.; Shimadzu, H.;
Kushiyama, E.; Kawanishi, H.; Hosaka, T.; Kawase, Y.;
Yasuda, K.; Kikkawa, K.; Yamauchi-Kohno, R.; Yamada, K.
J. Med. Chem. 2001, 44, 3369–3377. (g) Ishizuka, N.;
Matsumura, K.; Sakai, K.; Fujimoto, M.; Mihara, S.;
4. Niiyama, K.; Takahashi, H.; Nagase, T.; Kojima, H.; Amano,
Y.; Katsuki, K.; Yamakawa, T.; Ozaki, S.; Ihara, M.; Yano, M.;
Fukuroda, T.; Nishikibe, M.; Ishikawa, K. Bioorg. Med. Chem.
Lett. 2002, 12, 3041–3045.
5. Niiyama, K.; Mase, T.; Takahashi, H.; Naya, A.; Katsuki, K.;
Nagase, T.; Ito, S.; Hayama, T.; Hisaka, A.; Ozaki, S.; Ihara, M.;
Yano, M.; Fukuroda, T.; Noguchi, K.; Nishikibe, M.; Ishikawa,
K. Bioorg. Med. Chem. 2002, 10, 2461–2470.
6. (a) Abramovitch, R. A.; Singer, G. M. J. Am. Chem. Soc. 1969,
91, 5672–5673. (b) Abramovitch, R. A.; Rogers, R. B.
Tetrahedron Lett. 1971, 22, 1951–1954. (c) Abramovitch,
R. A.; Singer, G. M. J. Org. Chem. 1974, 39, 1795–1802. (d)
Abramovitch, R. A.; Rogers, R. B. J. Org. Chem. 1974, 39,
1802–1807. (e) Abramovitch, R. A.; Rogers, R. B.; Singer,
G. M. J. Org. Chem. 1975, 40, 41–47. (f) Abramovitch, R. A.;
Bailey, T. D. J. Heterocycl. Chem. 1975, 12, 1079–1080. (g)
Abramovitch, R. A.; Abramovitch, D. A.; Tomasik, P. J. Chem.
Soc., Chem. Commun. 1979, 21, 956–957. (h) Abramovitch,
R. A.; Pilski, J.; Konitz, A.; Tomasik, P. J. Org. Chem. 1983, 48,
4391–4393. Recently, one pot method for the generation of
imidoyl chloride and in situ reaction with pyridine N-oxide was
described. Manley, P. J.; Bilodeau, M. T. Org. Lett. 2002, 4,
3127–3129.
7. Compound 7 and 9 was synthesized or determined in previous

H. Takahashi et al. / Tetrahedron 61 (2005) 3473–3481
3481
literature. Niiyama, K.; Yoshizumi, T.; Takahashi, H.; Naya, A.;
Ohtake, N.; Fukami, T.; Mase, T.; Hayama, T.; Ishikawa, K.
Bioorg. Med. Chem. 2002, 10, 3437–3444. Compound 10 was
synthesized in the unpublished SAR study of 7-aryl part. The
structure of 8 was elucidated by conversion of 8 to 9 (10%
aqueous Na2SO3 solution, Scheme 5).
M.; Saito, M.; Sawazaki, Y.; Hayama, T.; Nishikibe, M. Bioorg.
Med. Chem. Lett. 2004, 14, 1503–1507. (b) Yoshizumi, T.;
Takahashi, H.; Ohtake, N.; Jona, H.; Sato, Y.; Kishino, H.;
Sakamoto, T.; Ozaki, S.; Takahashi, H.; Shibata, Y.; Ishii, Y.;
Saito, M.; Okada, M.; Okada, M.; Hayama, T.; Nishikibe, M.
Bioorg. Med. Chem. 2004, 12, 2139–3150.
8. (a) Takahashi, H.; Ohtake, N.; Sakamoto, T.; Iino, T.;
Kawanishi, N.; Nakamura, M.; Yoshizumi, T.; Niiyama, K.;
Ozaki, S.; Okada, H.; Kano, A.; Takahashi, H.; Ishii, Y.; Okada,
9. Brindly, J. C.; Caldwell, J. M.; Meakins, G. D.; Plackett, S. J.;
Price J. Chem. Soc., Perkin Trans. 1 1987, 1153–1158.