Synthetic studies on bradykinin antagonist martinellines: Construction of a pyrrolo[3,2-c]quinoline skeleton using silicon-tether RCM reaction and allylic amination

Article abstract of DOI:10.1016/j.tet.2004.08.014

The pyrrolo[3,2-c]quinoline consisting of a core structure of martinellines, the first naturally occurring heterocycle, was prepared through silicon-tether ring-closing metathesis reaction and intramolecular allylic amination as key steps. Graphical Abstr

Full text of DOI:10.1016/j.tet.2004.08.014

Tetrahedron 60 (2004) 9381–9390
Synthetic studies on bradykinin antagonist martinellines:
construction of a pyrrolo[3,2-c]quinoline skeleton using
silicon-tether RCM reaction and allylic amination
b
b,
Osamu Hara,a, Kazuhiko Sugimoto and Yasumasa Hamada
*
*
aFaculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 460-8503, Japan
bGraduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Received 16 June 2004; revised 6 August 2004; accepted 9 August 2004
Abstract—The pyrrolo[3,2-c]quinoline consisting of a core structure of martinellines, the first naturally occurring heterocycle, was prepared
through silicon-tether ring-closing metathesis reaction and intramolecular allylic amination as key steps.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
tether ring-closing metathesis (RCM) reaction as key
reactions. As shown in Scheme 1, pyrroloquinoline 4
would be constructed from tetrahydroquinolinone 5, which
could be synthesized from allyl acetate 6 by using the
intramolecular cyclization developed by us (Fig. 1).
Heterocycles constitute the core structures of numerous
biologically active natural products and have occupied a
very important position as lead compounds of medicines.
Recently, we have been interested in the unique structure
and biological activities of martinelline (1) and martinellic
acid (2), novel bradykinin antagonists, isolated from
Martinella equitosensis by Witherup et al. in 1995.1
Especially, the pyrrolo[3,2-c]quinoline ring (3), which is
the structural nucleus of the martinellines and the first
naturally occurring ring, has attracted wide attention as a
synthetic target. Many research groups have reported not
only the synthesis of the core heterocycle but also the
synthesis of martinellines.2,3 We have already demonstrated
an asymmetric construction of the tetrahydroquinoline
skeleton via asymmetric allylic substitution reaction using
our developed chiral ligand, 9-PBN.4,5 We describe here a
new method for construction of the pyrroloquinoline
skeleton using the allylic substitution reaction and silicon-
2. Results and discussion
In the synthesis of the tetrahydroquinoline ring, we first
attempted the preparation of the substrate 6 by introduction
of the C4 unit to aldehyde 7 using methyl 4-bromocrotonate
or crotyl reagents. The regioselective introduction using
metal reagents with the allyl unit proved difficult. For
example, the vinylogous Reformatsky reaction of aldehyde
7b with methyl 4-bromocrotonate in the presence of zinc
and iodine non-regioselectively proceeded to produce an
equal mixture of regioisomers 9 and 10.4 Alkylation using
the crotyl metal type reagent occurred not at the desired a
position but at the undesired g position of the crotyl unit via
Scheme 1.
Keywords: Pyrrolo[3,2-c]quinoline; Silicon-tether ring-closing metathesis; Intramolecular allylic amination; Martinelline; Cross-metathesis.
* Corresponding authors. Tel./fax: C81-43-2902987; e-mail: hamada@p.chiba-u.ac.jp
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.08.014

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O. Hara et al. / Tetrahedron 60 (2004) 9381–9390
Figure 1.
SN 20 reaction. Although it appeared difficult to change the
regioselectivity from g to a position, this problem was
partly solved by use of the Thomas procedure.6 Acetoxy-
crotylstannane 11 was pretreated with stannic chloride in
methylene chloride at K78 8C for 5 min and then aldehyde
7a was added. The reaction proceeded regioselectively to
afford an E/Z mixture of a-product 6a in 81% yield with a
small amount of g-product 12 (Scheme 2). However, we did
not pursue this approach since preparation of the starting
stannane 11 was difficult for large-scale production.
Recently, olefin metathesis reaction has become a powerful
tool for construction of an olefin unit, and has been
successfully used for synthesis of many biologically active
substances so far. We thought that the olefin metathesis
reaction would be able to produce the precursor 6 without
contamination of the regioisomer using a cross-metathesis
reaction7 or a RCM reaction8 (Fig. 2).
homoallylic alcohol 13 and allylic acetate. The aldehyde 7
prepared from readily available 5-hydroxyanthranilalde-
hyde was converted to homoallyl alcohol 13 by reaction
with allyl Grignard reagent. The cross-metathesis reactions
between the olefin 13 and the donor olefins, allyl acetate and
crotyl acetate, are summarized in Table 1. The mixture of
olefin 13c and allyl acetate was treated with 10 mol% of
Grubbs reagent 16 to afford cross product 6c in 15% yield
(run 3). The thus-obtained compound 6c was a mixture of E
and Z olefins in the ratio of 4:1–6:1 (run 3). Since an attempt
using an increasing amount of the catalyst and the allyl
acetate failed to improve the chemical yield, crotyl acetate
was used in place of the allyl acetate. The reaction was
similarly carried out in the presence of 10 mol% of the
catalyst and 5 equiv of crotyl acetate to give the desired
compound in 28% yield (run 4). In this case the substrate
disappeared on tlc and a large amount of a side product with
the dimeric structure of 13c generated in 57% yield. An
attempt to prevent the production of this dimeric product
First, the cross-metathesis reaction was examined between
Scheme 2.

O. Hara et al. / Tetrahedron 60 (2004) 9381–9390
9383
Figure 2.
failed. Next, the influence of the protecting group at the
benzylic alcohol was examined because the adjacent
functional groups of olefin are known to often prevent the
catalytic cycle of olefin metathesis reaction by strong
coordination to the ruthenium atom as a ligand. The olefin
13b bearing a free hydroxy group was reacted with the
allylic acetate in the presence of the Grubbs catalyst and the
improvement of chemical yield to 42% was observed
without recovery of 13b (run 2). The change of the
protecting group on the aromatic ring had no effect on the
chemical yield (run 1). As the cross-metathesis gave us
unsatisfactory results, we decided to carry out the chain
extension of 13 by the RCM reaction. The RCM reaction
has been used for the formation of a variety of cyclic
compounds including not only macrocyclic compounds but
also medium-ring ones. For the silicon-tether RCM
reaction,9 we needed a substrate with the allyl silyl moiety
at the benzylic position. The new silicon compound was
prepared from commercially available dichlorodiphenyl-
silane. Dichlorodiphenylsilane was treated with allyl
alcohol in the presence of triethylamine in methylene
chloride at room temperature to give the desired allyloxy-
chlorodiphenylsilane 17 in 87% yield after distillation under
reduced pressure. This compound, however, was very
sensitive to moisture and therefore was immediately used
for next reaction. Introduction of the silane residue to the
hydroxyl group was performed under the general condition.
The silane 17 was easily reacted with alcohol 13a in
methylene chloride at room temperature for 5 min to give
the precursor 14 for the RCM reaction in 97% yield. The
RCM reaction of 14 was carried out with 5 mol% of Grubbs
reagent 16 in 0.07 M solution to form the cyclic silyl ether
15 with the eight-membered ring in 40% yield. As the
starting material was completely consumed in this reaction,
we thought that this low yield might be due to polymeriz-
ation of the substrate. When the concentration of 14 was
diluted to 0.01 M solution, the reaction smoothly took place
at reflux for 5 h to afford the desired product 15 in 86%
yield. Removal of the silicon-tether from 15 with tetran-
butylammonium fluoride (TBAF) gave diol 18 in 84% yield.
Acid-catalyzed acetylation of 18 with acetic anhydride
furnished allyl acetate 6d (Scheme 3).
With the substrates for cyclization in hand, we next
investigated intramolecular allylic substitution reaction of
6 for construction of the tetrahydroquinoline ring (Table 2).
The allyl ester 6c bearing a hinder TBS group and E
geometry on the side chain was treated with bis(benzylidene)
Table 1. Cross-metathesis reaction between homoallylic alcohol 13 and allyl acetate
Run
Compounds
R3
Ru (mol%)
Time
(h)
Yielda
1
2
3
4
13a
13b
13c
13c
H
H
H
CH3
10
10
10
10
44
23
45
20
38% (56%)
42%
15% (85%)
28%
a
The product was obtained as a mixture of E and Z olefins in a ratio of 4:1–6:1. The parentheses are yields based on consumed starting material.

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O. Hara et al. / Tetrahedron 60 (2004) 9381–9390
Scheme 3.
palladium (Pd(dba)2) and trin-butylphosphine (Bu3P) in THF
at room temperature to obtain the desired tetrahydroquinoline
19c with cis relationship as a single product in 92% yield
(run 1). Even if a mixture of E and Z olefins was used in
this reaction, the reaction proceeded in a similar manner to
afford the 2,4-cis product in excellent yield (run 2). The
relative stereochemistry of 19c was judged by the coupling
constant of the 1H NMR spectrum. The values of the
coupling constants between the C-3 axial proton and the
adjacent protons are 11.4 and 11.8 Hz, which show that
both the C-4 proton and the C-2 proton are placed on the
pseudo-axial position. On the other hand, compounds 6a
and 6d bearing hydroxyl and acetoxy groups at the
benzylic position gave a mixture of cis and trans
diastereomers, respectively, under similar conditions.
The observed outcome shows that the hydroxyl and
acetoxy substituents adjacent to the p-allyl palladium
complex affect the stereoselectivity of the cyclization.
With this satisfactory result, the asymmetric cyclization
of 6c using (K)-9-PBN in place of Bu3P was carried out
in the presence of lithium acetate and bis(trimethylsilyl)
acetamide (BSA). The reaction somewhat sluggishly
proceeded in a reagent-controlled manner and provided a
mixture of cis-19c and trans-19c with 60%ee each in the
ratio of 68:32 (run 3).
With the tetrahydroquinoline available in large quantities,
we then focused our attention on introduction of the pyrrole
ring. First, the a-alkylation of tetrahydroquinolone 20 was
extensively investigated (Scheme 4). However, we were
unable to obtain the corresponding C-alkylated product
except O-alkylated product 21 which was produced by
O-alkylation of the lithium enolate derived from 20 and
lithium diisopropylamide (LDA). After many efforts we
found a two-step approach including the Mannich reaction
and 1,4-conjugate addition. Tetrahydroquinolone 20 was
treated with paraformaldehyde in the presence of N-methyl-
aniline trifluoroacetate (TFA$PhNHMe) at reflux for 33 h to
provide the exo-methylene product in 85% yield. For the
introduction of the C1 unit, 1,4-conjugate addition of the
Table 2. Preparation of tetrahydroquinolines using palladium-catalyzed cyclization
Run
Compound
R1
R2
Geometry
E only
Mixture of E and Z
E only
Mixture of E and Z
Z only
E only
Time (h)
20
Yield (%)
92
Ratio of cis:trans
1
2
6c
6c
6c
6a
6d
6e
TBS
TBS
TBS
Bn
Bn
Bn
TBS
TBS
TBS
H
Ac
E only
Only cis
Only cis
68:32
3:1
3:1
3a
4b
5
35
17
44
16
42
96
96
96
6
Only cis
a
This reaction was carried out with the combination of Pd(dba)2 and (K)-9-PBN in the presence of LiOAc ans BSA.
This reaction was carried out in the presence of AcOH.
b

O. Hara et al. / Tetrahedron 60 (2004) 9381–9390
9385
Scheme 4.
nitrile group was examined. The 1,4-conjugate addition
reaction cleanly proceeded by the treatment of potassium
cyanide (KCN) in the presence of acetic acid at room
temperature to afford trans 2,3-disubstituted tetrahydro-
quinolone 22 as the sole product in 71% yield.
by palladium and silicon-tether RCM reaction. Further
investigation directed towards total synthesis of martinel-
lines is underway in our laboratories.
For the construction of pyrroloquinoline, the reduction of
nitrile of 22 with lithium aluminum hydride followed by
oxidation of benzylic alcohol with manganese dioxide
gave an imino product in only poor yield. The resulting
imine was reduced with sodium cyanoborohydride
(NaBH3CN) at room temperature and then treatment
with di-t-butyl dicarbonate (Boc2O) gave pyrroloquino-
line 25 in quantitative yield (Scheme 4). As conversion of
the nitrile to the corresponding amine was disappointing,
the catalytic hydrogenation was employed for the
improvement of yields. Among Rh/Al2O3, PtO2, and
Raney Ni selected as catalysts for the hydrogenation,
Raney Ni gave the best result. Finally, the synthesis of
pyrroloquinoline was achieved in a two-step manner: (1)
the reduction of nitrile with Raney Ni under hydrogen
atmosphere and (2) reduction of the resulting cyclic imine
with NaBH3CN. Pyrroloquinoline 23a and its deprotected
product 23b were obtained in 58 and 28% yields,
respectively. The relative stereochemistry of pyrroloqui-
noline showed the C3–4 cis relationship, which was
confirmed by the NOE experiment.
4. Experimental
4.1. General
Melting points were measured with a SIBATA NEL-270
melting point apparatus. Infrared spectra were recorded
on a JASCO FT/IR-230 Fourier transform infrared
spectrophotometer. Optical rotations were measured on
a JASCO DIOP-14 polarimeter. 1H NMR spectra were
recorded on a JEOL JNM-GSX 400A (400 MHz), JNM
GSX500A (500 MHz), or JNM ECP400 (400 MHz)
spectrometer. Chemical shifts are recorded in ppm from
tetramethylsilane or chloroform as the internal standard.
Analytical thin layer chromatography was performed on
Merck Art. 5715, Kieselgel 60F254/0.25 mm thickness
plates. Mass spectra were obtained on a JEOL HX-110A
spectrometer. Column chromatography was performed
with silica gel BW-820MH (Fuji Davision Co.). Solvents
for reaction were reagent grade and distilled from the
indicated drying agent: tetrahydrofuran (THF), benzene:
sodium/benzophenone ketyl; diethyl ether (Et2O): lithium
aluminum hydride (LiAlH4); acetonitrile, dichloro-
methane (CH2Cl2), diisopropylamine, dimethylformamide
(DMF), n-hexane, toluene, dichloroethane (C2H4Cl2):
calcium hydride; methanol (MeOH): iodine/magnesium.
3. Conclusion
˚
Dimethylsulfoxide (DMSO) was dried over 4 A molecular
sieves. All other commercially available reagents were
used as received.
In summary we have established a new access to
pyrroloquinolines bearing the martinelline core structure
using key reactions, allylic substitution reaction catalyzed

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O. Hara et al. / Tetrahedron 60 (2004) 9381–9390
4.2. Methyl 2-amino-5-hydroxybenzoate
10.0 (1H, s); 13C NMR (100 MHz, CDCl3) d 21.4, 52.4,
70.4, 115.9, 118.0, 121.6, 122.4, 127.2, 127.5, 128.1, 129.4,
133.6, 136.2, 143.6, 154.5, 167.6. Anal. Calcd for
C22H21NO5S: C, 64.22; H, 5.14; N, 3.40. Found: C, 64.11;
H, 4.99; N, 3.28.
To a stirred solution of precooled (K15 8C) methanol
(300 mL) was added dropwise thionyl chloride (26 mL,
204 mmol) over 20 min at the temperature maintaining at
below K10 8C and the mixture was stirred at K10 8C for
20 min. 5-Hydroxyanthranilic acid (9 g, 58 mmol) was
added to the mixture. The reaction mixture was stirred at
room temperature for 2 days and heated to reflux for 4 h.
After cooling, the reaction mixture was concentrated in
vacuo and the residue was treated with saturated aqueous
sodium hydrogen carbonate. The whole was extracted with
ethyl acetate. The organic layer was washed with saturated
brine, dried over magnesium sulfate, and concentrated in
vacuo to give methyl 2-amino-5-hydroxybenzoate (8.6 g,
88%) as dark violet crystals: mp 160–162 8C; IR nKmBaxr 3380,
4.2.3.
N-(4-Benzyloxy-2-hydroxymethylphenyl)-4-
methylbenzenesulfonamide. To a stirred suspension of
LiBH4 (1.447 g, 66.4 mmol) in THF (30 mL) at 0 8C was
added dropwise a solution of 8a (18.13 g, 44 mmol) in THF
(50 mL) over 20 min and the reaction mixture was heated to
reflux for 20 h. The reaction mixture was cooled to room
temperature, poured into ice-10% citric acid, and extracted
with ethyl acetate. The organic layer was washed with water
and saturated brine, dried over magnesium sulfate, and
concentrated in vacuo. The residue was crystallized from
1
3300, 1710 cmK1; H NMR (CDCl3) d 3.86 (3H, s), 6.60
ethyl acetate/n-hexane to give the title compound (17.12 g,
KBr
max
(1H, d, JZ8.8 Hz), 6.89 (1H, dd, JZ8.8, 2.9 Hz), 7.33 (1H,
d, JZ2.9 Hz). The solids were used for the next reaction
without further purification.
quant.) as colorless solids: mp 102–104 8C; IR n
3423,
3091, 1499, 1028 cmK1; H NMR (CDCl3) d 2.40 (3H, s),
4.30 (2H, s), 5.02 (2H, s), 6.80 (1H, d, JZ2.8 Hz), 6.83 (1H,
dd, JZ3.1, 8.55 Hz), 7.16 (1H, d, JZ8.6 Hz), 7.22 (2H, d,
JZ8.2 Hz), 7.30–7.39 (5H, m), 7.58 (2H, d, JZ8.2 Hz); 13C
NMR (100 MHz, CDCl3) d 21.5, 63.2, 70.2, 114.7, 115.6,
127.1, 127.3, 127.4, 128.1, 128.2, 128.6, 129.5, 136.0,
136.5, 136.6, 143.7, 157.6. MS: m/z 383 (MC). HRMS
Calcd for C21H21NO4S: 383.1193 (MC). Found: 383.1188.
1
4.2.1. Methyl 5-hydroxy-2-(4-methylbenzenesulfonyl-
amino)benzoate. To a stirred solution of the crude methyl
2-amino-5-hydroxybenzoate (8.6 g, 51.4 mmol) in pyridine
(40 mL) at 0 8C was added p-toluenesulfonyl chloride
(TsCl, 10.3 g, 54 mmol) and the reaction mixture was
stirred at room temperature for 5 h. The excess TsCl was
destroyed by addition of water (2 mL) and stirred for
30 min. The reaction mixture was diluted with ethyl acetate
and washed with 1 N HCl, water, and saturated brine. The
organic layer was dried over magnesium sulfate and
concentrated in vacuo to give methyl 5-hydroxy-2-(toluene-
sulfonylamino)benzoate (16 g, 97%) as dark crystals which
were used for next reaction without purification. The ana-
lytical sample was obtained by purification using column
4.2.4. N-(4-Benzyloxy-2-formylphenyl)-4-methylben-
zenesulfonamide (7a). To a stirred solution of N-(4-
benzyloxy-2-hydroxymethylphenyl)-4-methylbenzenesul-
fonamide (2 g, 5.21 mmol) in CH2Cl2 (25 mL) at room
temperature was added pyridinium dichromate (2.35 g,
6.25 mmol) under argon atomsphere and the reaction
mixture was stirred at room temperature for 3 h. Magnesium
sulfate was added to the reaction mixture and the insoluble
material was filtered through silica gel. The filtrate was
concentrated in vacuo. The residue was crystallized from
chromatography (silica gel, n-hexane/ethyl acetateZ2/1) to
KBr
max
give brown solids: mp 106–113 8C; IR n
3394, 1693,
1405 cmK1; 1H NMR (CDCl3) d 2.46 (3H, s), 3.86 (3H, s),
4.79 (1H, brs), 7.17–7.71 (7H, m), 9.95 (1H, s); 13C NMR
(100 MHz, CDCl3) d 21.4, 52.4, 116.9, 118.4, 121.8, 122.8,
127.2, 129.4, 133.1, 135.9, 143.7, 151.7, 167.5. MS: m/z 321
(MC). HRMS Calcd for C15H15NO5S: 321.0671 (MC).
Found: 321.0684.
ethyl acetate/n-hexane to give aldehyde 7a (1.58 g, 80%) as
KBr
yellow solids: mp 121–123 8C; IR n
3151, 1661, 1497,
max
1388, 1151 cmK1; H NMR (CDCl3) d 2.35 (3H, s), 5.04
(2H, s), 7.11 (1H, d, JZ3.2 Hz), 7.16 (1H, dd, JZ3.2,
9.0 Hz), 7.20 (2H, d, JZ8.5 Hz), 7.28–7.39 (5H, m), 7.67
(1H, d, JZ9.0 Hz), 7.68 (2H, d, JZ8.3 Hz), 9.72 (1H, s);
13C NMR (100 MHz, CDCl3) d 21..5, 70.6, 20.5, 120.8,
122.9, 123.3, 127.1, 127.4, 128.3, 128.7, 129.6, 133.1,
136.0, 136.3, 143.9, 154.7, 194.4. MS: m/z 381 (MC). Anal.
Calcd for C21H19NO4S: C, 66.12; H, 5.02; N, 3.67. Found:
C, 65.97; H, 4.90; N, 3.55.
1
4.2.2. Methyl 5-benzyloxy-2-(4-methylbenzenesulfonyla-
mino)benzoate (8a). To a stirred suspension of NaH
(60% oil dispersion, 5.22 g, 131 mmol) in DMF (300 mL)
at K20 8C was added methyl 5-hydroxy-2-(toluenesulfonyl-
amino)benzoate (20.0 g, 62.2 mmol) and the reaction
mixture was stirred at K20 8C for 30 min under argon
atmosphere. Benzyl bromide (8.1 mL, 68.4 mmol) was
added dropwise to the reaction mixture at 0 8C and the
reaction mixture was stirred for 15 h. The reaction mixture
was queuched with H2O at 0 8C and extracted with ethyl
acetate /n-hexane (8/1). The organic layer was washed with
water and saturated brine, dried over sodium sulfate, and
concentrated in vacuo. The residue was crystallized from
4.2.5. 5-[5-(tert-Butyldimethylsiloxy)-2-(4-methylben-
zenesulfonylamino)phenyl]-5-hydroxypent-2-enoic acid
methyl ester (9) and 2-{[5-(tert-butyldimethylsiloxy)-2-
(4-methylbenzenesulfonylamino)-phenyl]-hydroxymethyl}
but-3-enoic acid methyl ester (10). A mixture of 7b
(4.31 g, 10.7 mmol), methyl 3-bromocrotonate (0.6 mL),
and activated zinc (1.89 g, 28.9 mmol) in ether (5 mL) and
benzene (5 mL) was heated nearly to the boiling point under
argon atmosphere. Iodine (254 mg, 1.07 mmol) was added.
After a few minute the exothermic reaction began and an
additional methyl 3-bromocrotonate (2.8 mL) was slowly
added. The reaction mixture was heated to reflux for 3.5 h
during which time additional activated zincs (450 mg) were
added three times in every 1 h. The completion of the
ethyl acetate/n-hexane to give the title compound 8a
(23.9 g, 93.3%) as colorless solids: mp 94–96 8C; IR n
KBr
max
1
3160, 1685, 1505, 1288, 1163 cmK1; H NMR (CDCl3) d
2.36 (3H, s), 3.81 (3H, s), 5.00 (2H, s), 7.11 (1H, dd, JZ2.9,
9.0 Hz), 7.18 (2H, d, JZ8.5 Hz), 7.33–7.38 (5H, m), 7.44
(1H, d, JZ2.7 Hz), 7.62 (1H, s), 7.65 (2H, d, JZ9.5 Hz),

O. Hara et al. / Tetrahedron 60 (2004) 9381–9390
9387
reaction was judged according to tlc analysis. The mixture
was cooled to 23 8C and diluted with ethyl acetate (300 mL)
and the partly insoluble product was dissolved by addition
of acetic acid. The clear solution was decanted for removal
of an excess of zinc metal, washed with water, saturated
sodium hydrogen carbonate, water, and saturated brine, and
dried over magnesium sulfate. Filtration of the mixture
followed by concentration of the filtrate gave the crude
product (6.48 g) which was purified by column chromato-
graphy (silica gel, n-hexane/ethyl acetateZ2/1) to give
g-product 9 (2.60 g, 48.3%) as yellow crystals together with
degassed again by three freeze-thaw cycles. The reaction
mixture was heated to reflux for 44 h. The reaction mixture
was quenched with 1 M HCl and extracted with ethyl
acetate. The organic layer was washed with water and
saturated brine, dried over sodium sulfate, and concen-
trated in vacuo. The residue was purified by column
chromatography (silica gel, n-hexane/ethyl acetateZ3/2 to
1/1) to give the title compound 6a (577 mg, 38%, E/ZZ6:1)
as a dark oil and the starting material (726 mg, 56%) as a
yellow oil. 6a: IR nnmeaaxt 2929, 3482, 3255, 3031, 2925, 1733,
1
1498, 1236, 1159 cmK1; H NMR (CDCl3) d 2.04 (3H, s),
a-product 10 (2.55 g, 47.3%) as a slightly yellow oil. 9: mp
72–75 8C; IR n
2.17–2.24 (1H, m), 2.33–2.36 (1H, m), 2.39 (3H, s), 2.71
(1H, s), 4.46 (2H, d, JZ5.2 Hz), 4.76 (1H, t, JZ6.9 Hz),
5.00 (2H, s), 5.47–5.60 (2H, m), 6.75 (1H, dd, JZ2.9,
8.9 Hz), 6.83 (1H, d, JZ3.0 Hz), 7.03 (1H, d, JZ8.9 Hz),
7.31–7.36 (5H, m), 7.37 (2H, d, JZ6.7 Hz), 7.48 (1H, s),
7.60 (2H, d, JZ8.2 Hz); 13C NMR (100 MHz, CDCl3) d
21.0, 21.5, 39.8, 64.7, 70.2, 71.1, 113.8, 114.4, 126.5, 127.3,
127.4, 127.5, 127.7, 128.1, 128.6, 129.6, 130.8, 136.5,
136.7, 138.4, 143.7, 157.0. MS: m/z 495 (MC). HRMS
Calcd for C27H29NO6S: 495.1716 (MC). Found: 495.1703.
3410, 3136, 1716 cmK1 1H NMR
;
neat
max
(CDCl3) d 0.15 (6H, s), 0.95 (9H, s), 2.39 (3H, s), 2.37
(3H, s), 2.32–2.38 (1H, m), 2.46–2.52 (1H, m), 3.71 (3H, s),
4.83 (1H, td, JZ7.0, 2.2 Hz), 5.72 (1H, d, JZ15.7 Hz),
6.63–6.68 (2H, m), 6.76 (1H, dt, JZ15.7, 7.1 Hz), 7.00 (1H,
d, JZ8.5 Hz), 7.23 (1H, d, JZ8.2 Hz), 7.30 (1H, s), 7.59
(1H, d, JZ8.2 Hz); 13C NMR (100 MH, CDCl3) d K4.5,
18.2, 21.5, 25.6, 39.4, 51.5, 70.6, 119.0, 120.0, 127.3, 127.7,
129.6, 136.4, 137.9, 143.9, 166.5. HRMS Calcd for
C24H25NO4S: 505.1954 (MC). Found: 505.1965. 10: IR
neat
max
1
n
3462, 3273, 2954, 1734 cmK1; H NMR (CDCl3) d
4.2.8. Allyloxychlorodiphenylsilane (17). To a stirred
solution of dichlorodiphenylsilane (8.3 mL, 39.9 mmol) in
CH2Cl2 (200 mL) at 0 8C was added Et3N (6.6 mL,
47.5 mmol) and allyl alcohol (2.6 mL, 38.2 mmol) and the
reaction mixture was stirred at room temperature. After
24 h, the reaction mixture was concentrated in vacuo. The
residue was distilled under reduced pressure to give
0.14 (6H, s), 0.94 (9H, s), 1.66 (1H, brs), 2.38 (3H, s), 3.33–
3.34 (1H, m), 4.69 (1H, d, JZ17.1 Hz), 4.83 (1H, d, JZ
8.1 Hz), 4.94 (1H, d, JZ10.3 Hz), 5.33–5.39 (1H, m), 6.52
(1H, d, JZ2.9 Hz), 6.66 (1H, dd, JZ8.8, 2.92 Hz), 7.18
(1H, d, JZ8.8 Hz), 7.23 (2H, d, JZ8.1 Hz), 7.66 (2H, d,
JZ8.1 Hz). HRMS Calcd for C24H25NO4S: 505.1954
(MC). Found: 505.1958.
allyloxychlorodiphenylsilane 17 (7.826 g, 87.0%) as a
neat
max
colorless oil: bp 130 8C (4 mmHg); IR n
3071, 2864,
4.2.6. N-[4-Benzyloxy-2-(1-hydroxybut-3-enyl)phenyl]-
4-methylbenzenesulfonamide (13a). To a stirred solution
of allylmagnesiumbromide (72.7 mL, 43.6 mmol, 0.6 M) in
ether at K20 8C was added dropwise a solution of 7a
(7.922 g, 20.8 mmol) in ether (80 mL) in THF (80 mL)
under argon atomsphere and the reaction mixture was stirred
at K10 8C for 2 h. The reaction mixture was quenched with
saturated NH4Cl at 0 8C and extracted with ethyl acetate.
The organic layer was washed with water and saturated
brine, dried over magnesium sulfate, and concentrated in
vacuo. The residue was purified by column chromatography
1646, 1590, 1428, 1125 cmK1; H NMR (CDCl3) d 4.33
(1H, d, JZ4.9 Hz), 4.39 (1H, d, JZ4.9 Hz), 5.13 (1H, t, JZ
10.5 Hz), 5.32 (1H, d, JZ15.3 Hz), 5.92–5.99 (1H, m),
7.34–7.72 (10H, m).
1
4.2.9. N-[4-Benzyloxy-2-(1-(allyloxydiphenylsilyloxy)-
but-3-enyl)phenyl]-4-methylbenzenesulfonamide (14).
To a stirred solution of 13a (989 mg, 2.35 mmol) and
Et3N (0.68 mL, 4.90 mmol) in CH2Cl2 (10 mL) at room
temperature was added dropwise allyloxychlorodiphenly-
silane (1.267 g, 4.61 mol) in CH2Cl2 (2 mL) under argon
atmosphere and the reaction mixture was stirred at room
temperature. After 5 min, the reaction mixture was
quenched with saturated sodium hydrogen carbonate and
extracted with ethyl acetate. The organic layer was washed
with water and saturated brine, dried over sodium sulfate,
and concentrated in vacuo. The residue was purified by
column chromatography (silica gel, n-hexane/ethyl acet-
(silica gel, n-hexane/ethyl acetateZ2/1) to give the title
compound 13a (8.76 g, 100%) as a colorless oil: IR n
max
neat
1
3464, 2922, 1499, 1159 cmK1; H NMR (CDCl3) d 2.19–
2.30 (2H, m), 2.37 (3H, s), 2.71 (1H, d, JZ2.9 Hz), 4.61–
4.64 (1H, m), 4.99 (2H, s), 4.99 (1H, dd, JZ1.5, 17.1 Hz),
5.05 (1H, d, JZ10.1 Hz), 5.55–5.63 (2H, m), 6.77 (1H, dd,
JZ3.1, 11.0 Hz), 7.78 (1H, s), 7.17 (1H, d, JZ9.1 Hz), 7.21
(2H, d, JZ7.9 Hz), 7.30–7.36 (5H, m), 7.37 (2H, d, JZ
6.7 Hz), 7.59 (1H, s); 13C NMR (100 MHz, CDCl3) d 21.4,
41.1, 70.2, 71.4, 114.0, 114.2, 118.8, 125.9, 127.2, 127.4,
127.8, 128.0, 128.5, 129.5, 133.8, 136.5, 136.7, 137.0,
143.6, 156.6. MS: m/z 423 (MC). HRMS Calcd for
C24H25NO4S: 423.1504 (MC). Found: 423.1476.
ateZ6/1 to 2/1) to give the title compound 14 (1.505 g,
neat
max
97.4%) as a yellow oil: IR n
3277, 3070, 2919, 1500,
1428, 1161, 1125 cmK1; H NMR (CDCl3) d 1.24–1.52
(1H, m), 2.28–2.36 (1H, m), 2.33 (3H, s), 3.94–3.96 (2H,
m), 4.68 (1H, t, JZ6.9 Hz), 4.71 (1H, d, JZ12.5 Hz), 4.83
(1H, d, JZ9.5 Hz), 4.92 (2H, s), 5.05 (1H, d, JZ9.9 Hz),
5.19 (1H, d, JZ17.0 Hz), 5.21–5.32 (1H, m), 5.72–5.83
(1H, m), 6.52 (1H, d, JZ2.9 Hz), 6.78 (1H, dd, JZ2.7,
8.8 Hz), 7.12 (2H, d, JZ8.05 Hz), 7.30–7.64 (17H, m), 7.81
(1H, s); 13C NMR (100 MHz, CDCl3) d 21.4, 41.7, 64.0,
70.1, 74.6, 114.4, 114.7, 114.8, 117.6, 124.2, 127.0, 127.4,
127.8, 127.8, 127.9, 128.0, 128.5, 129.5, 130.2, 130.4,
130.6, 130.7, 133.7, 134.3, 134.8, 134.9, 135.9, 137.0,
1
4.2.7. 5-[5-Benzyloxy-2-(4-methylbenzenesulfonylamino)
phenyl]-5-hydroxypent-2-enyl acetate (6a). A stirred
solution of 13a (1.284 g, 3 mmol) and allylacetate
(1.6 mL, 14.8 mmol) in CH2Cl2 (40 mL) was degassed by
three freeze-thaw cycles under argon atmosphere. Grubbs
reagent 16 (271 mg, 0.315 mmol) was added to the reaction
mixture at room temperature and the reaction mixture was

9388
O. Hara et al. / Tetrahedron 60 (2004) 9381–9390
143.4, 155.6. MS: m/z 661 (MC). HRMS Calcd for
113.8, 115.4, 126.7, 127.1, 127.5, 128.1, 128.6, 128.8,
129.2, 129.6, 135.5, 136.3, 137.0, 143.5, 157.6, 170.8,
171.4. MS: m/z 537 (MC). HRMS Calcd for C37H35NO5Si:
537.1821 (MC). Found: 537.1803.
C39H39NO5SSi: 661.2318 (MC). Found: 661.2338.
4.2.10. N-[4-Benzyloxy-2-(2,2-diphenyl-5,8-dihydro-4H-
[1,3,2]dioxasilocin-4-yl)phenyl]-4-methylbenzenesulfon-
amide (15). A stirred solution of 14 (39 mg, 0.059 mmol) in
CH2Cl2 (5.8 mL) was degassed by three freeze-thaw cycles
under argon atmosphere and Grubbs reagent 16 (2.4 mg,
0.0029 mmol) was added to the reaction mixture at room
temperature. The reaction mixture was degassed again by
three freeze-thaw cycles and heated to reflux. After 5 h, the
reaction mixture was queuched with 1 M HCl, and extracted
with ethyl acetate. The organic layer was washed with water
and saturated brine, dried over sodium sulfate, and
concentrated in vacuo. The residue was purified by column
chromatography (silica gel, n-hexane/ethyl acetateZ3/1) to
give 15 (32 mg, 85.7%) as a yellow oil: IR nnmeaaxt 3273, 1497,
4.2.12. 6-Benzyloxy-1-(4-methylbenzenesulfonyl)-2-
vinyl-1,2,3,4-tetrahydroquinolin-4-ol (19a). To a stirred
solution of Pd(dba)2 (197 mg, 0.34 mmol) in THF (35 mL)
was added trin-buthylphosphine (0.17 mL, 0.68 mmol) at
0 8C under argon atmosphere and the reaction mixture was
degassed by three freeze-thaw cycles and stirred at 0 8C for
30 min. Allyl acetate 6a (1.706 g, 3.4 mmol) in THF
(10 mL) and AcOH (0.21 mL, 3.7 mmol) were added to
the reaction mixture at 0 8C. The reaction mixture was
degassed again by three freeze-thaw cycles, warmed to
room temperature, and stirred for 17 h. The reaction mixture
was quenched with saturated aqueous NH4Cl and extracted
with ethyl acetate. The organic layer was washed with water
and saturated brine, dried over sodium sulfate, and
concentrated in vacuo. The residue was purified by column
chromatography (silica gel, n-hexane/ethyl acetateZ3/2) to
give cyclized product 19a (1.428 g, 95.7%, cis/transZ3:1)
as a colorless oil. Major product: IR nnmeaaxt 3504, 3032, 1606,
1
1160, 1125 cmK1; H NMR (CDCl3) d 2.34 (3H, s), 2.53–
2.58 (1H, m), 2.66–2.73 (1H, m), 4.47 (1H, dd, JZ4.4,
14.9 Hz), 4.58 (1H, dd, JZ5.6, 14.6 Hz), 4.83 (1H, dd, JZ
3.2, 7.3 Hz), 4.88 (2H, s), 5.50 (1H, dd, JZ8.5, 19.3 Hz),
5.88 (1H, dt, JZ5.6, 11.2 Hz), 6.70 (1H, d, JZ2.7 Hz), 6.74
(1H, dd, JZ2.7, 8.8 Hz), 7.13 (2H, d, JZ8.3 Hz), 7.20–7.66
(17H, m); 13C NMR (100 MHz, CDCl3) d 21.4, 34.7, 61.5,
70.1, 73.2, 113.5, 114.1, 125.0, 127.1, 127.4, 127.6, 127.7,
127.7, 127.9, 128.0, 128.5, 129.4, 130.2, 130.5, 132.6,
134.3, 134.4, 134.5, 134.7, 136.6, 136.7, 136.9, 143.4,
156.2. MS: m/z 633 (MC). HRMS Calcd for C37H35NO5Si:
633.2006 (MC). Found: 633.1992.
1487 cmK1 1H NMR (CDCl3) d 1.60 (1H, dt, JZ8.0,
;
16.0 Hz), 2.14 (1H, ddd, JZ4.7, 7.0, 13.3 Hz), 2.37 (3H, s),
3.64–3.76 (1H, m), 4.76–4.81 (1H, m), 5.11 (2H, ABq, JZ
11.6 Hz), 5.12 (1H, d, JZ10.5 Hz), 5.32 (1H, dq, JZ1.1,
17.0 Hz), 5.87 (1H, ddd. JZ4.8, 10.4, 17.0 Hz), 6.93 (1H, d,
JZ3.0, 8.9 Hz), 6.98 (1H, d, JZ2.2 Hz), 7.15 (2H, d, JZ
7.9 Hz), 7.33–7.44 (7H, m), 7.66 (1H, d, JZ8.7 Hz); 13C
NMR (100 MHz, CDCl3) d 21.5, 38.8, 55.3, 64.7, 70.2,
76.7, 77.0, 77.3, 110.9, 114.4, 115.5, 126.7, 127.0, 127.5,
128.0, 128.5, 129.6, 135.8, 136.7, 138.0, 138.1, 143.7,
157.0. MS: m/z 435 (MC). HRMS Calcd for C25H25O4NS:
435.1504. Found: 435.1490.
4.2.11. (Z)-1,5-Diacetoxy-5-[5-benzyloxy-2-(4-methyl-
benzenesulfonylamino)phenyl]-2-pentene (6d). To a stirred
solution of 15 (709 mg, 1.11 mmol) in THF (7.4 mL) at room
temperature was added dropwise TBAF (2.6 mL, 2.6 mmol)
underargonatmosphere andthereactionmixturewasstirredat
room temperature for 5 h. The reaction mixture was quenched
with1 M potassium hydrogen sulfate, and extracted with ethyl
acetate. The organic layer was washed with water and
saturated brine, dried over sodium sulfate, and concentrated
invacuo. The residue was purified bycolumnchromatography
(silica gel, n-hexane/ethyl acetateZ1/2) to give 18 (427 mg,
84.3%) as a dark oil which was used for the next reaction
without further purification.
4.2.13. 4,6-(Di-tert-butyldimethylsiloxy)-1-(4-methylben-
zenesulfonyl)-2-vinyl-1,2,3,4-tetrahydroquinoline (19c).
To a stirred solution of Pd(dba)2 (1 mg, 0.0018 mmol) in
THF (1 mL) was added trin-buthylphosphine (0.7 mL,
0.0036 mmol) at K15 8C under argon atmosphere and the
reaction mixture was degassed by three freeze-thaw cycles
and stirred at K15 8C for 30 min. 6c (22.2 mg, 0.035 mmol)
in THF (1 mL) was added to the reaction mixture at K15 8C.
The reaction mixture was degassed again by three freeze-thaw
cycles, warmed to room temperature, and stirred for 12 h.
After the reaction was completed, the reaction mixture was
quenched with saturated aqueous NH4Cl and extracted with
ethyl acetate. The organic layer was washed with water and
saturated brine, dried over magnesium sulfate, and concen-
trated in vacuo. The residue was purified by column
chromatography (silica gel, n-hexane/ethyl acetateZ12/1) to
give 19c (18.5 mg, 92%) as yellow crystals: mp 78–80 8C; IR
nnmeaaxt 3448, 2952, 1485 cmK1; 1H NMR (CDCl3) dK0.16 (6H,
s), 0.19 (6H, s), 0.84 (9H, s), 0.98 (9H, s), 1.42 (1H, dt, JZ
11.4, 11.8 Hz), 2.19 (1H, ddd, JZ4.3, 8.0, 12.5 Hz), 2.37 (3H,
s), 3.19 (1H, dd, JZ11.6, 4.3 Hz), 4.56–4.62 (1H, m), 5.14
(1H, dd, JZ11.5, 1.0 Hz), 5.35 (1H, dd, JZ1.0, 17.1 Hz),
5.83–5.88 (1H, m), 6.73 (1H, d, JZ2.7 Hz), 6.76 (1H, dd, JZ
2.7, 8.5 Hz), 7.15 (2H, d, JZ8.0 Hz), 7.31 (2H, d, JZ8.0 Hz),
7.33–7.44 (2H, m), 7.51 (1H, d, JZ8.5 Hz); 13C NMR
(100 MHz, CDCl3) d K5.4, K4.5, K4.4, 18.0, 18.3, 21.5,
25.6, 25.7, 41.3, 56.1, 65.5, 114.5, 114.8, 119.1, 126.6, 127.0,
To a stirred solution of the above diol 18 (335 mg,
0.74 mmol) and p-toluenesulfonic acid (295 mg,
1.55 mmol) in methylene chloride (5 mL) at 0 8C was
added dropwise acetic anhydride (0.20 mL, 2.13 mmol) and
the reaction mixture was stirred at 0 8C for 3 h. The reaction
mixture was quenched with water and extracted with ethyl
acetate. The organic layer was washed with water and
saturated brine, dried over sodium sulfate, and concentrated
in vacuo. The residue was purified by column chromato-
graphy (silica gel, n-hexane/ethyl acetateZ2/1) to give 6d
neat
max
(385 mg, 97%) as a yellow oil: IR n
3255, 2923, 1735,
1498, 1236, 1162 cmK1; H NMR (CDCl3) d 1.83–1.87
(1H, m), 1.95 (3H, s), 2.06 (3H, s), 2.38 (3H, s), 2.67 (1H, dt,
JZ8.1, 14.8 Hz), 4.55 (2H, d, JZ7.1 Hz), 5.03 (2H, s),
5.07–5.14 (1H, m), 5.29 (1H, dd, JZ4.4, 9.5 Hz), 5.54 (1H,
dt, JZ6.8, 10.9 Hz), 6.92 (1H, d, JZ2.9 Hz), 7.23 (1H, d,
JZ8.1 Hz), 7.29 (2H, dd, JZ1.2, 7.8 Hz), 7.32–7.43 (7H,
m), 7.61 (1H, s), 7.61 (2H, d, JZ8.3 Hz); 13C NMR
(100 MHz, CDCl3) d 20.8, 20.9, 21.4, 32.2, 60.1, 70.2, 70.4,
1

O. Hara et al. / Tetrahedron 60 (2004) 9381–9390
9389
129.5, 135.7, 138.6, 141.5, 143.5, 154.3. MS (FAB): m/z 575
(MCHC). Anal. CalcdforC30H47NO4SSi2: C, 62.78;H, 8.25;
N, 2.44. Found: C, 62.49; H, 8.38; N, 2.33.
temperature was added 20 (25 mg, 0.057 mmol) in 1,4-
dioxane (0.5 mL) under argon atmosphere and the reaction
mixture was stirred at reflux for 8 h. A second portion of
paraformaldehyde (5.5 mg, 0.18 mmol) and TFA$PhNHMe
(38 mg, 0.17 mmol) was added again to the reaction
mixture. After stirring the mixture for 25 h, the reaction
mixture was quenched with saturated aqueous NaHCO3 and
extracted with ethyl acetate. The organic layer was washed
with water and saturated brine, dried over sodium sulfate,
and concentrated in vacuo. The residue was purified by
column chromatography (silica gel, n-hexane/ethyl acet-
4.2.14. 6-Benzyloxy-4-(tert-butyldimethylsiloxy)-1-(4-
methylbenzenesulfonyl)-2-vinyl-1,2,3,4-tetrahydroqui-
noline (19e). To a stirred solution of Pd(dba)2 (127 mg,
0.22 mmol) in THF(15 mL) was added trin-buthylphos-
phine (0.11 mL, 0.44 mmol) at 0 8C under argon atmosphere
and the reaction mixture was degassed by three freeze-thaw
cycles and stirred at 0 8C for 30 min. 6e (1.357 g
2.22 mmol) in THF (7 mL) was added to the reaction
mixture at 0 8C. The reaction mixture was degassed again by
three freeze-thaw cycles, warmed to room temperature, and
stirred for 16 h. The reaction mixture was quenched with
saturated aqueous NH4Cl and extracted with ethyl acetate.
The organic layer was washed with water and saturated
brine, dried over sodium sulfate, and concentrated in vacuo.
The residue was purified by column chromatography (silica
gel, n-hexane/ethyl acetateZ10/1 to 3/1) to give the title
compound 19e (1.169 g, 95.6%) as a yellow oil: IR nmax
ateZ6/1) to give the title compound (21.7 mg, 84.7%) as
KBr
max
yellow solids; mp 104–106 8C; IR n
3088, 3032, 2924,
1680, 1602, 1485, 1166 cmK1; H NMR (CDCl3) d 2.33
(3H, s), 5.03 (1H, dd, JZ2.2, 17.3 Hz), 5.08 (2H, ABq),
5.12 (1H, dd, JZ2.2, 10.5 Hz), 5.33 (1H, s), 5.68 (1H, br),
5.85 (1H, ddd, JZ3.4, 10.3, 17.3 Hz), 6.11 (1H, s), 7.07
(2H, d, JZ8.0 Hz), 7.24 (2H, d, JZ8.3 Hz), 7.25 (1H, dd,
JZ3.1, 8.8 Hz), 7.35–7.44 (6H, m), 7.74 (1H, d, JZ
9.0 Hz); 13C NMR (100 MHz, CDCl3) d 21.5, 62.4, 70.3,
110.9, 118.6, 122.8, 125.5, 127.6, 127.8, 128.2, 128.6,
129.0, 129.4, 129.7, 133.3, 134.2, 136.1, 136.2, 138.6,
144.2, 157.5, 181.6. MS: m/z 445 (MC). HRMS Calcd for
C26H24NO4S: 446.1426 (MCHC). Found: 446.1416.
1
2952, 2927, 2856, 1486, 1353, 1159 cmK1 1H NMR
;
(CDCl3) d K0.009 (6H, s), 0.838 (9H, s), 1.43 (1H, dt,
JZ11.5, 12.9 Hz), 2.19 (1H, ddd, JZ4.2, 8.1, 12.4 Hz),
2.36 (3H, s), 3.25 (1H, dd, JZ3.9, 11.2 Hz), 4.57–4.63 (1H,
m), 5.06 (2H,s), 5.12 (1H, d, JZ10.2 Hz), 5.34 (1H, d, JZ
17.1 Hz), 5.85 (1H, ddd, JZ5.4, 10.2, 16.8 Hz), 6.86 (1H, d,
JZ2.9 Hz), 6.91 (1H, dd, JZ2.63, 8.53 Hz), 7.16 (2H, d,
JZ7.8 Hz), 7.31–7.49 (7H, m), 7.56 (1H, d, JZ8.78 Hz);
13C NMR (100 MHz, CDCl3) d K5.46, K5.41, 17.9, 21.3,
25.5, 41.1, 55.8, 65.5, 69.9, 108.9, 113.7, 114.7, 126.1,
126.8, 127.3, 127.8, 128.2, 128.2, 128.4, 128.8, 129.4,
135.6, 136.7, 138.4, 141.4, 143.4, 157.2. MS: m/z 549 (MC).
HRMS Calcd for C31H39NO4SSi: 549.2369 (MC). Found:
549.2359.
4.2.17. [6-Benzyloxy-4-oxo-1-(4-methylbenzenesulfonyl)-
2-vinyl-1,2,3,4-tetrahydroquinolin-3-yl]acetonitrile (22).
To a stirred solution of 6-benzyloxy-3-methylene-1-(4-
methylbenzenesulfonyl)-2-vinyl-2,3-dihydro-1H-quinolin-
4-one (147 mg, 0.34 mmol) in ethanol (10 mL) at room
temperature was added KCN (43.8 mg, 0.673 mmol) in
water (0.4 mL) and acetic acid (0.026 mL, 0.47 mmol).
After stirring the reaction mixture at room temperature for
7 h, the reaction mixture was concentrated in vacuo. The
residue was diluted with ethyl acetate, washed with water
and saturated brine, dried over sodium sulfate, and
concentrated in vacuo. The residue was purified by column
chromatography (silica gel, n-hexane/ethyl acetateZ7/2) to
give 22 (110 mg, 70.5%) as a brown oil: IR nnmeaaxt 2924, 2250,
1690, 1488, 1164 cmK1; 1H NMR (CDCl3) d 2.17 (1H, dd,
JZ10.7, 17.4 Hz), 2.42 (3H, s), 2.70 (1H, ddd, JZ4.2, 10.0,
16.5 Hz), 2.97 (1H, dd, JZ4.39, 17.3 Hz), 5.03 (1H, dd, JZ
2.7, 10.2 Hz), 5.07 (2H, s), 5.30–5.36 (2H, m), 5.54–5.62
(1H, m), 7.30 (2H, d, JZ8.3 Hz), 7.34–7.48 (7H, m), 7.65
(2H, d, JZ8.31 Hz), 7.84 (1H, d, JZ9.1 Hz); 13C NMR
(100 MHz, CDCl3) d 14.7, 21.5, 44.7, 61.6, 70.3, 110.5,
117.1, 123.0, 123.9, 124.6, 126.8, 127.0, 127.5, 128.2,
128.3, 128.6, 130.3, 133.7, 135.9, 136.5, 144.8, 156.3,
190.3. MS: m/z 472 (MC). HRMS Calcd for C27H24N2O4S:
472.1457 (MC). Found: 472.1447.
4.2.15. 6-Benzyloxy-1-(4-methylbenzenesulfonyl)-2-
vinyl-2,3-dihydro-1H-quinolin-4-one (20). To a stirred
solution of 19a (64 mg, 0.15 mmol) in CH2Cl2 (1 mL) at
room temperature was added pyridinium dichromate
(66.3 mg, 0.176 mmol) under argon atmosphere and the
reaction mixture was stirred at room temperature. After
15 h, magnesium sulfate was added to the reaction mixture
and the insoluble material was filtered through silica gel.
The filtrate was concentrated in vacuo. The residue was
purified by column chromatography (silica gel, n-hexane/
ethyl acetateZ3/1) to give quinolone 20 (62 mg, 97.3%) as
brown solids: mp 92–96 8C; IR nKmBaxr 3032, 1691, 1605 cmK1
;
1H NMR (CDCl3) d 2.37–2.43 (1H, m), 2.39 (3H, s), 2.53
(1H, dd, JZ1.8, 17.9 Hz), 5.06 (2H, s), 5.13 (1H, ddd, JZ
2.2, 6.8 Hz), 5.16 (1H, d, JZ2.0 Hz), 5.26–5.29 (1H, m),
5.78 (1H, dd, JZ4.2, 10.7, 17.3 Hz), 7.82 (1H, d, JZ
9.0 Hz), 7.21–7.52 (11H, m); 13C NMR (100 MHz, CDCl3)
d 21.5, 391, 56.8, 70.3, 76.7, 77.0, 77.3, 110.1, 118.4, 123.1,
126.7, 126.9, 127.5, 127.9, 128.1, 128.5, 130.0, 133.5,
135.3, 136.1, 136.4, 144.4, 156.5, 191.8. MS: m/z 434 (MC).
HRMS Calcd for C25H24O4NS: 434.1426. Found: 434.1434.
4.2.18. 8-Benzyloxy-4-ethyl-5-(4-methylbenzenesulfonyl)-
2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline (23a)
and 8-hydroxy-4-ethyl-5-(4-methylbenzenesulfonyl)-
2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline
(23b). To a stirred solution of 22 (9 mg, 0.019 mmol) in
ethanol (2 mL) at room temperature was added Raney Ni
(300 mg) and the reaction mixture was stirred under
hydrogen atmosphere. After 48 h, the reaction mixture
was filtered through celite and concentrated in vacuo to
afford the crude cyclic imine (11 mg). The crude imine was
dissolved in MeOH (2 mL) and sodium cyanoborohydride
(3 mg, 0.048 mmol) was added at room temperature under
4.2.16. 6-Benzyloxy-3-methylene-1-(4-methylbenzene-
sulfonyl)-2-vinyl-2,3-dihydro-1H-quinolin-4-one. To a
stirred mixture of paraformaldehyde (7 mg, 0.23 mmol)
and N-methylaniline trifluoroacetate (TFA$PhNHMe,
19 mg, 0.086 mmol) in 1,4-dioxane (0.5 mL) at room

9390
O. Hara et al. / Tetrahedron 60 (2004) 9381–9390
4, 2913–2916. (e) Xia, C.; Heng, L.; Ma, D. Tetrahedron Lett.
2002, 43, 9405–9409. (f) Ma, D.; Xia, C.; Jiang, J.; Zhang, J.;
Tang, W. J. Org. Chem. 2003, 68, 442–451.
argon atmosphere. The reaction mixture was acidified to pH
4 with 2 N HCl. After stirring the mixture for 3 h, the
reaction mixture was concentrated in vacuo, quenched with
0.1 N KOH, and extracted with ether. The organic layer was
washed with water and saturated brine, dried over sodium
sulfate, and concentrated in vacuo. The residue was purified
by column chromatography (silica gel, CHCl3/MeOHZ20/1
containing 1% triethylamine) to give pyrroloquinoline 23a
(5 mg, 56.7%) as a colorless oil and debenzylated
pyrroloquinoline 23b (2 mg, 28.2%) as a colorless oil.
3. (a) Ho, T. C. T.; Jones, K. Tetrahedron 1997, 53, 8287–8294.
(b) Gurjar, M. K.; Pal, S.; Rama Rao, A. V. Heterocycles 1997,
45, 231–234. (c) Kim, S. S.; Cheon, H. G.; Kang, S. K.; Yum,
E. K.; Choi, J. K. Heterocycles 1998, 48, 221–226. (d) Hadden,
M.; Stevenson, P. J. Tetrahedron Lett. 1999, 40, 1215–1218.
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A. J. Chem. Commun. 1999, 651–652. (f) Lovely, C. J.;
Mahmud, H. Tetrahedron Lett. 1999, 40, 2079–2082.
(g) Snider, B. B.; Ahn, Y.; Foxman, B. M. Tetrahedron Lett.
1999, 40, 3339–3342. (h) Frank, K. E.; Aube, J. J. Org. Chem.
2000, 65, 655–666. (i) Nieman, J. A.; Ennis, M. D. Org. Lett.
2000, 2, 1395–1397. (j) Nyerges, M.; Fejes, I.; Toke, L.
Tetrahedron Lett. 2000, 41, 7951–7954. (k) Mahmud, H.;
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(l) Hadden, M.; Nieuwenhuyzen, M.; Potts, D.; Stevenson,
P. J.; Thompson, N. Tetrahedron 2001, 57, 5615–5624.
(m) Hadden, M.; Nieuwenhuyzen, M.; Osborne, D.;
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Dias, H. V. R.; Lovely, C. J. Tetrahedron Lett. 2002, 43,
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Hurvois, J.; Moinet, C. Synlett 2002, 1500–1504. (q) Nyerges,
M.; Fejes, I.; Toke, L. Synthesis 2002, 1823–1828.
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97–100.
2926, 1491, 1162 cmK1; H NMR (CDCl3) d
neat
1
23a: IR n
max
0.88–0.96 (3H, m), 1.25–1.31 (1H, m), 1.37–1.47 (1H, m),
1.85–1.88 (1H, m), 2.33–2.41 (1H, m), 2.37 (3H, s), 2.75
(1H, dt, JZ5.3, 10.7 Hz), 2.95–3.04 (1H, m), 3.29 (1H, d,
JZ8.1 Hz), 4.24–4.30 (1H, m), 5.04 (2H, s), 6.92 (1H, dd,
JZ2.4, 8.8 Hz), 7.06 (1H, br), 7.15 (2H, d, JZ9.0 Hz),
7.31–7.46 (6H, m), 7.62 (2H, d, JZ9.0 Hz). MS: m/z 462
(MC). HRMS (FAB, NBA) Calcd for C27H30N2O3S:
463.2065 (MCHC). Found: 463.2070. 23b: 1H NMR
(CDCl3) d 0.81–0.94 (3H, m). 1.25–1.35 (1H, m), 1.45–
1.53 (1H, m), 1.70–1.80 (1H, m), 1.95–2.04 (1H, m), 2.37
(3H, s), 2.91–3.01 (1H, m), 3.13–3.20 (1H, m), 3.66 (1H, d,
JZ8.5 Hz), 4.21–4.24 (1H, m), 6.79 (1H, dd, JZ2.7,
9.0 Hz), 7.10 (1H, br), 7.14 (2H, d, JZ8.1 Hz), 7.38 (2H, d,
JZ8.3 Hz), 7.55 (1H, d, JZ8.8 Hz). MS: m/z 372 (MC).
HRMS (FBA, NBA) Calcd for C20H25N2O3S: 373.1586
(MCHC). Found: 373.1594.
Acknowledgements
5. (a) Hamada, Y.; Seto, N.; Ohmori, H.; Hatano, K. Tetrahedron
Lett. 1996, 37, 7565–7568. (b) Hamada, Y.; Seto, N.;
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This work was financially supported in part by a Grant-in-
Aid for Scientific Research (C) from the Ministry of
Education, Culture, Sports, Science, and Technology,
Japan.
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