Intramolecular capture of pummerer reaction intermediates by an aromatic nucleophile: Selective construction of 1,4-benzothiazine and indole ring systems

Article abstract of DOI:10.1248/cpb.49.1132

The simple alkyl sulfoxide 6 carrying two aromatic nucleophiles, when treated with trifluoroacetic anhydride at room temperature (Pummerer reaction conditions), underwent an intramolecular aromatic sulfenylation of the 6-exo-tet process in an exclusive ma

Full text of DOI:10.1248/cpb.49.1132

1132
Chem. Pharm. Bull. 49(9) 1132—1137 (2001)
Vol. 49, No. 9
Intramolecular Capture of Pummerer Reaction Intermediates by an
Aromatic Nucleophile: Selective Construction of 1,4-Benzothiazine
and Indole Ring Systems
Yoshie HORIGUCHI, Akihiro SONOBE, Toshiaki SAITOH, Jun TODA, and Takehiro SANO*
Showa Pharmaceutical University, 3–3165 Higashi-tamagawagakuen, Machida, Tokyo 194–8543, Japan.
Received March 26, 2001; accepted June 5, 2001.
The simple alkyl sulfoxide 6 carrying two aromatic nucleophiles, when treated with trifluoroacetic anhy-
dride at room temperature (Pummerer reaction conditions), underwent an intramolecular aromatic sulfenyla-
tion of the 6-exo-tet process in an exclusive manner to yield two regioisomeric 1,4-benzothiazine derivatives, 8
and 9. On the other hand, a similar reaction of the a-acyl sulfoxide 7, possessing identical aromatic nucleophiles,
caused an intramolecular aromatic alkylation of the 5-exo-trig process to produce the 3-oxo-indole derivative 14
in a quantitative yield. These results demonstrate that the construction of 1,4-benzothiazine and indole ring sys-
tems can be achieved in a selective manner by proper choice of the sulfoxide side chain.
Key words Pummerer reaction; sulfoxide; cyclization; sulfenylation; 1,4-benzothiazine; indole
exclusive manner.7b,g) Before our findings, Bates et al. had
The Pummerer reaction proceeds from sulfoxide to a prod-
reported that a sulfoxide possessing a highly electron rich
pyrrole as the nucleophile exclusively underwent intramolec-
ular sulfenylation, when the side chain of an alkyl aryl sul-
foxide was a simple alkyl,2,8) while the reaction of a sulfoxide
whose alkyl side chain contained an electron-withdrawing
group on the a-carbon, induced aromatic intramolecular
alkylation in an exclusive manner.9) These facts suggest that
the reaction path can be diverted in one direction or the other
by the proper choice of either a sulfoxide side chain or nucle-
ophilic aromatic moiety.
In this paper we treat the Pummerer reactions of two dif-
ferent types of sulfoxides, a simple alkyl sulfoxide (A) and
an a-acyl sulfoxide (B) carrying two identical aromatic nu-
cleophiles, with the expectation that the reactions should dis-
close what chemical properties of the sulfoxide side chains
can control two different cyclization reactions. At the same
time, the sulfoxides, because of having two aromatic nuclei
of similar nucleophilicity, could conceivably cause two ad-
ditional cyclizations, as shown in Chart 2: 1) Aromatic
sulfenylation to benzothiazine, 2) aromatic sulfenylation to
benzothiazepine, 3) aromatic alkylation to indole, and 4) aro-
matic alkylation to isoquinoline. Thus, this investigation may
reveal the preference of the ring size formed by each cycliza-
tion.
uct via a sulfonium ion (II) which reacts with a nucleophile
at the carbon (alkylation).1) In the interrupted Pummerer re-
action,2) an acylated sulfoxide intermediate (I) undergoes re-
action with the nucleophile at the sulfur (sulfenylation), lead-
ing to unexpected products under Pummerer reaction condi-
tions.
The finding that the sulfonium ions may serve as elec-
trophiles in electrophilic substitution has generally extended
to the synthetic range of the Pummerer reaction.1) Thus, both
intra-3) and intermolecular4) versions of the process have
been used to prepare a wide range of compounds. Recently,
Padwa et al. emphasized in their review5) that a-acyl sulfo-
nium ions generated from a-acyl sulfoxides are highly reac-
tive and can trap various nucleophiles involving carbon p-
bonds. In particular, they describe that the aromatic cycliza-
tion reactions in which an aromatic nuclei acts as the carbon
nucleophile are useful to construct various complex poly-
cyclic ring systems. More recently, we have demonstrated
that simple alkyl sulfonium ions not having an a-acyl func-
tion are also able to induce aromatic cyclization under mild
reaction conditions.6) This approach provides a highly effec-
tive and convenient technique for preparing a variety of aro-
matic condensed N-heterocyles.6,7)
During the course of the investigations, we observed that
alkyl sulfoxides, if the aromatic nucleophile is highly elec-
tron-rich, predominantly undergo intramolecular sulfenyla-
tion (interrupted Pummerer reaction), while if the aromatic
nucleophile is not highly electron-rich, the sulfoxides un-
dergo intramolecular alkylation (Pummerer reaction) in an
Results and Discussion
The alkyl sulfoxide 6 and the a-acyl sulfoxide 7 were pre-
pared from m-anisidine 1 and piperonal 2 in excellent overall
yields, as follows. Condensation of 1 with 2 in titanium
Chart 1
To whom correspondence should be addressed. e-mail: t-sano@ac.shoyaku.ac.jp
© 2001 Pharmaceutical Society of Japan

September 2001
1133
tetraisopropoxide followed by sodium borohydride reduction tive mass spectrum, which corresponds to the formula
of the resulting imine gave the secondary amine 3. This C25H22F3NO5S, containing the trifluoroacetate moiety. This
amine was condensed with 2-phenylsulfanylacetyl chloride showed that both 8 and 9 are aromatic sulfenylation products.
to afford the amide 4. Treatment of 4 with aluminum hydride Furthermore, the behaviors in the mass spectra and the chro-
selectively reduced the amide carbonyl to give the tertiary matography strongly suggested that they are sulfurane deriv-
amine 5 in good yield. Oxidation of 5 and 4 with sodium atives with an O–S covalent bond, not a sulfonium salt.10,11)
metaperiodate in aqueous acetone afforded 6 and 7, respec- The structures of these products were established by spectro-
tively.
scopic means. The assignments of NMR spectra (Fig. 1) in-
Treatment of the alkyl sulfoxide 6 with trifluoroacetic an- dicated that 8 and 9 are regioisomeric compounds possessing
hydride (TFAA) in tetrahydrofuran (THF) at room tempera- a 1,4-benzothiazine ring system formed by the sulfenylation
ture (r.t.) gave two products, 8 and 9, in yields of 54% and path (1) shown in Chart 2.
40%, respectively. The products were readily separated in a
The correctness of this assignment to these products was
pure form by column chromatography over silica gel. They confirmed chemically. The treatment of 8 with sodium
showed the same molecular peak at m/z 505 in their respec- methoxide in methanol at r.t. produced an aniline derivative
10 carrying SPh group in a quantitative yield. Similar treat-
ment of 9 with sodium methoxide gave another aniline deriv-
ative, 11. The NMR spectra clearly indicated that they are re-
gioisomeric to each other. The formation of the aniline deriv-
atives can be rationalized in terms of the fission of the thi-
azine ring by a base catalyzed E2 elimination reaction, fol-
lowed by hydrolysis of the immonium salt 13 derived from
the enamine 12, as shown in Chart 4. The results confirmed
that the Pummerer reaction of 6 induces a sulfenylation path
(1) in an exclusive manner.
On the other hand, the a-acyl sulfoxide 7, when similarly
treated with TFAA as described above, gave 14 in 99% yield.
The structure of this product was established by spectro-
scopic means. The assignment of the aromatic protons of the
1H-NMR spectra using heteronuclear multiple bond correla-
tion (HMBC), as shown in Fig. 2, indicated that the product
has a 2-oxo-indole skeleton rather than the 3-oxo-isoquino-
line one.
This assigned structure was also confirmed by chemical
transformations to several indole derivatives. Reaction of 14
with NiCl2–NaBH4 caused the reductive desulfurization of
the PhS group, to give the 2-oxo-2,3-dihydroindole 15 in
86% yield. Reduction of 14 with aluminum hydride gave the
indole 16 as a major product (86%), and 2,3-dihydroindole
17 as a minor one (14%). Oxidation of 14 with NaIO4 caused
Chart 2
concomitant desulfurylation to give the isatin derivative 18
Chart 3

1134
Vol. 49, No. 9
Fig. 1
Fig. 2
Chart 4
Chart 5

September 2001
1135
Chart 6
Experimental
(42%). Thus, the Pummerer reaction of 7 induced an alkyla-
tion path (3) in an exclusive manner.
The formation mechanism of the products is proposed as
shown in Chart 6. The process begins in a normal Pummerer
General Procedures Melting points were taken on a Yanagimoto SP-
M1 hot-stage melting point apparatus. Thin layer chromatography (TLC)
was performed on Merck precoated Silica gel 60 F254 plates (Merck). Col-
umn chromatography was carried out with silica gel (Wakogel C-200).
reaction with activation of the sulfoxide oxygen. Attack by Medium pressure liquid chromatography (MPLC) was performed on a Ku-
sano CIG prepacked column. IR spectra were obtained as KBr disks with a
the neighboring electron-rich aromatic ring on the sulfur of
the acylated sulfoxide species, 19a, forms a benzothiazine
HORIBA FT-710 spectrometer and are given in cmϪ1. NMR spectra were
measured on a JEOL JNM-EX90 (1H-NMR 90 MHz, 13C-NMR 22.5 MHz)
nucleus as the sulfurane trifluoroacetates 8 and 9. On the other
hand, the formation of 2-oxo-dihydroindole 14 can be ratio-
nalized by the generally accepted mechanism of the Pum-
merer reaction. This process involves a nucleophilic attack of
the aromatic ring on the cationic carbon of the sulfonium ion
21b, which is formed via the sulfur ylide species 20b that is
produced by the abstraction of the sulfinyl a -hydrogen.
The results demonstrated that the reaction path depends on
the difference in acidity of the proton attached to the sulfinyl
a-carbon. In the simple alkyl sulfoxide 6, the process of the
conversion of 19a to the corresponding ylide 20a may be re-
tarded, since the a-proton, because of the absence of an elec-
tron-withdrawing group, is not acidic enough to be ab-
stracted by a weak basic anion species such as trifluoroac-
etate. This prohibits the aromatic alkylation path through the
sulfonium ion 21a; instead, the substitution reaction on the
or JEOL JNM-AL 300 (1H-NMR 300 MHz, 13C-NMR 75.0 MHz) spectrom-
eter in CDCl3 with tetramethylsilane as an internal standard, and the chemi-
cal shifts are given in d values. Low-resolution MS spectra (LR-MS) and
high-resolution MS spectra (HR-MS) were determined on a JEOL JMS-
HX110 A or JMS-D300 spectrometer at 70 eV with a direct inlet system.
The organic extract from each reaction mixture was washed with brine, dried
over anhydrous Na2SO4 or MgSO4 before concentration in vacuo.
N-(3,4-Methylenedioxyphenyl)methyl-3-methoxyaminobenzene (3)
A mixture of 1 (10.0 g, 66.7 mmol), 2 (10.0 g, 81.3 mmol) and titanium
tetraisopropoxide (28.0 g, 98.6 mmol) was heated at 80 °C for 3 h. After
cooling, the reaction mixture was diluted with MeOH (100 ml). To this solu-
tion, NaBH4 (2.5 g, 65.8 mmol) was added in small portions under ice-cool-
ing. The reaction mixture was stirred at r.t. for 1 h and concentrated in
vacuo. Water (ca. 40 ml) was added to the residue, and the mixture was di-
luted with MeOH (ca. 500 ml). After removal of precipitated inorganic ma-
terials by filtration, the filtrate was concentrated in vacuo. The residue was
dissolved in water and extracted with CHCl3. Column chromatography of
the product with hexane/ethyl acetate (9 : 1) gave 3 (1.7 g, 99%) as colorless
needles, mp 49—51 °C, crystallized from Et2O–hexane. IR: 3422, 1618,
1
sulfur atom of 19a proceeds if the aromatic ring is highly nu- 1589, 1520. H-NMR (90 MHz): 3.74 (3H, s, MeO), 4.00 (1H, br s, NH),
cleophilic.
4.20 (2H, s, ArCH2N–), 5.92 (2H, s, OCH2O), 6.1—7.2 (7H, m, ArH). 13C-
NMR (22.5 MHz): 48.0 (t), 54.9 (q), 98.8 (d), 108.8 (t), 102.6 (d), 105.9 (d),
107.9 (d), 108.1 (d), 120.4 (d), 129.8 (d), 133.2 (s), 146.6 (s), 147.8 (s),
The a-proton of the a-acyl sulfoxide 7 is apparently more
acidic than that of the simple alkyl sulfoxide 6. This facili-
tates the formation of the sulfonium ion 21b through the
ylide 20b that is formed by the abstraction of the a-proton
by an anion species, thus inducing the aromatic alkylation in
an exclusive manner.
149.4 (s), 160.7 (s). LR-MS m/z: 257 (Mϩ), 135 (base peak). Anal. Calcd for
C15H15NO3: C, 70.02; H, 5.88; N, 5.44. Found: C, 70.02; H, 5.94; N, 5.34.
N-(3-Methoxyphenyl)-N-(3,4-methylenedioxyphenyl)methyl-2-phenyl-
sulfanylacetamide (4) A solution of 2-phenylsulfanylacetic acid (14.7 g,
87.5 mmol) in oxalyl chloride (37.0 ml, 437 mmol) was stirred at r.t. for 1 h.
Removal of excess oxalyl chloride by repeated evaporation under reduced
pressure gave an oily material. To a solution of this chloride in benzene
(200 ml) a solution of the amine 3 (15.0 g, 58.4 mmol) and Et3N (8.8 g,
87.1 mmol) in benzene (200 ml) was slowly added under ice-cooling, and the
mixture was stirred at r.t. for 20 h. After removal of precipitated materials by
filtration, the filtrate was concentrated in vacuo. The residue was extracted
with CHCl3 then washed with 5% HCl, 5% NaOH, and brine. The residual
oil was chromatographed and eluted with ethyl acetate/hexane (1 : 4) to give
4 (22.6 g, 95%) as colorless prisms, mp 85—87 °C, crystallized from ethyl
acetate–hexane. IR: 1633, 1603, 1489. 1H-NMR (90 MHz): 3.52 (2H, s,
–CH2S–), 3.72 (3H, s, MeO), 4.76 (2H, s, ArCH2N–), 5.92 (2H, s, OCH2O),
6.4—7.4 (12H, m, ArH, PhH). 13C-NMR (22.5 MHz): 37.4 (t), 53.1 (t), 55.3
(q), 100.9 (t), 107.9 (d), 109.4 (d), 113.9 (d), 114.1 (d), 120.5 (d), 122.3 (d),
126.7 (d), 128.8 (dϫ2), 130.2 (d), 130.3 (dϫ2), 130.9 (s), 135.5 (s), 142.6
The results also demonstrated that the reaction path greatly
depended on the ring size formed by each cyclization; in the
aromatic alkylation reaction, the process of 5-exo-trig was fa-
vored over that of 6-exo-trig, and in the aromatic sulfenyla-
tion reaction the process of 6-exo-tet was favored over that of
7-exo-tet. This observed preference coincided well with the
Baldwin rule.12)
In summary, the interrupted Pummerer reaction of the
simple alkyl sulfoxide 6 provided a method for constructing
the benzothiazine ring system. On the other hand, the Pum-
merer reaction of the a-acyl sulfoxide 7, as already reported
by Y. Tamura et al. in the reactions of similar a-acyl sulfox- (s), 146.9 (s), 147.6 (s), 160.3 (s), 168.3 (s). LR-MS m/z: 407 (Mϩ), 135
ides,13) provided a method for preparing the 2-oxoindole ring
(base peak). Anal. Calcd for C23H21NO4S: C, 67.79; H, 5.19; N, 3.44. Found:
C, 67.79; H, 5.29; N, 3.28.
N-(3,4-Methylenedioxyphenylmethyl)-N-(2-phenylsulfanylethyl)-3-
system.

1136
Vol. 49, No. 9
methoxyaminobenzene (5) A solution of 4 (2.0 g, 4.91 mmol) in dry 505.1165.
Et2O–THF (1 : 1) (20 ml) was added to a solution of AlH3 in dry Et2O
Reaction of 8 with NaOMe A solution of 8 (50 mg, 0.10 mmol) in 5%
(20 ml), prepared in situ from LiAlH4 (500 mg) and AlCl3 (430 mg) under an NaOMe–MeOH (10 ml) was stirred at r.t. for 1 h. The reaction mixture was
argon atmosphere. The mixture was stirred at r.t. for 30 min. The reaction concentrated in vacuo and extracted with CHCl3. The residue was chro-
mixture was diluted with CHCl3 and passed through a short column of matographed and eluted with ethyl acetate/hexane (1 : 2) to give N-(3,4-
SiO2. The eluate was concentrated in vacuo. The residual oil was chro-
methylenedioxyphenyl)methyl-5-methoxy-2-(phenylsulfanyl)aminobenzene
matographed and eluted with benzene to give 5 (1.6 g, 84%) as a pale yellow (10) (33 mg, 92%) as a pale yellow oil. IR: 1600, 1508, 1488. 1H-NMR
oil. IR: 1610, 1500. UV: 254 (20600), 288 (8800). 1H-NMR (300 MHz): (300 MHz): 3.75 (3H, s, MeO), 4.21 (2H, d, Jϭ5 Hz, ArCH2N–), 5.34 (1H,
3.0—3.2 (2H, m, –NCH2CH2S–), 3.5—3.7 (2H, m, –NCH2CH2S–), 3.71 t, Jϭ5 Hz, NH), 5.90 (2H, s, OCH2O), 6.16 (1H, d, Jϭ3 Hz, C6-H), 6.27
(3H, s, MeO), 4.42 (2H, s, ArCH2N–), 5.92 (2H, s, OCH2O), 6.1—7.4 (12H,
(1H, dd, Jϭ3, 8 Hz, C4-H), 7.0—7.3 (5H, m, PhH), 7.42 (1H, d, Jϭ8 Hz,
m, ArH, PhH). 13C-NMR (75.0 MHz): 30.7 (t), 50.7 (t), 54.5 (t), 55.1 (q), C3-H). 13C-NMR (75.0 MHz): 47.5 (t), 56.1 (q), 99.9 (d), 100.9 (t), 101.2
99.0 (d), 100.9 (t), 101.7 (d), 105.4 (d), 107.2 (d), 108.3 (d), 119.7 (d), 126.5
(s), 104.1 (d), 107.5 (d), 108.2 (d), 120.0 (d), 125.0 (d), 125.9 (dϫ2), 128.8
(dϫ2), 131.8 (d), 133.0 (s), 136.6 (s), 146.6 (s), 147.8 (s), 150.7 (s), 161.6
(d), 129.0 (dϫ2), 129.9 (dϫ2), 130.0 (d), 132.5 (s), 135.4 (s), 146.5 (s),
148.0 (s), 149.1 (s), 160.8 (s). LR-MS m/z: 393 (Mϩ), 135 (base peak). HR- (s). LR-MS: m/z 365 (Mϩ), 135 (base peak). HR-MS m/z (Mϩ): Calcd for
MS m/z (Mϩ): Calcd for C23H23NO3S: 393.1399. Found: 393.1416.
C21H19NO3S: 365.1083. Found: 365.1063.
N-(3,4-Methylenedioxyphenyl)methyl-N-(2-phenylsulfinylethyl)-3-
Reaction of 9 with NaOMe A solution of 9 (50 mg, 0.10 mmol) in 1%
methoxyaminobenzene (6) To a solution of 5 (1.0 g, 2.54 mmol) in ace- NaOMe–MeOH (10 ml) was stirred at r.t. for 2 h. The reaction mixture was
tone (150 ml), a solution of NaIO4 (820 mg, 3.83 mmol) in H2O (15 ml) was concentrated in vacuo and extracted with CHCl3. The residue was chro-
added, and the mixture was heated under reflux for 20 h. After removal of matographed and eluted with ethyl acetate/hexane (1 : 2) to give N-(3,4-
the inorganic precipitate, the filtrate was concentrated in vacuo and extracted methylenedioxyphenyl)methyl-3-methoxy-2-(phenylsulfanyl)aminobenzene
with CHCl3. The residual oil was chromatographed and eluted with ethyl ac- (11) (34 mg, 94%) as a pale yellow oil. IR: 1589, 1502, 1488. 1H-NMR
etate/hexane (1 : 3) to give 6 (848 mg, 82%) as a brownish yellow gum. IR:
1610, 1500. H-NMR (300 MHz): 2.8—3.2 (2H, m, –NCH2CH2S–), 3.6—
(300 MHz): 3.81 (3H, s, MeO), 4.25 (2H, d, Jϭ6 Hz, ArCH2N–), 5.61 (1H,
t, Jϭ6 Hz, NH), 5.91 (2H, s, OCH2O), 6.30 (1H, dd, Jϭ1, 8 Hz, C4-H), 6.34
1
4.0 (2H, m, –NCH2CH2S–), 3.73 (3H, s, MeO), 4.40 (1H, d, Jϭ17 Hz, (1H, dd, Jϭ1, 8 Hz, C6-H), 6.6—6.7 (3H, m, ArH), 7.0—7.3 (6H, m, C5-H,
ArCH2N–), 4.47 (1H, d, Jϭ17 Hz, ArCH2N–), 5.92 (2H, s, OCH2O), 6.2— PhH). 13C-NMR (75.0 MHz): 47.3 (t), 55.1 (q), 97.2 (d), 100.9 (t), 102.3 (d),
7.1 (7H, m, ArH), 7.4—7.6 (5H, m, PhH). 13C-NMR (75.0 MHz): 43.9 (t), 105.5 (s), 107.5 (d), 108.2 (d), 120.1 (d), 125.1 (d), 125.8 (dϫ2), 128.9
53.8 (t), 54.7 (t), 55.1 (q), 99.5 (d), 100.9 (t), 102.2 (d), 105.8 (d), 107.1 (d), (dϫ2), 132.7 (s), 137.7 (s), 138.9 (d), 146.6 (s), 147.9 (s), 150.3 (s), 162.6
108.3 (d), 119.7 (d), 123.8 (dϫ2), 129.3 (dϫ2), 130.1 (d), 131.0 (d), 132.1 (s). LR-MS: m/z 365 (Mϩ), 149 (base peak). HR-MS m/z (Mϩ): Calcd for
(s), 143.3 (s), 146.6 (s), 147.9 (s), 148.8 (s), 160.9 (s). LR-MS m/z: 409
C21H19NO3S: 365.1085. Found: 365.1085.
Pummerer Reaction of 7 TFAA (0.17 ml, 1.21 mmol) was added to a
(Mϩ), 135 (base peak).
N-(3-Methoxyphenyl)-N-(3,4-methylenedioxyphenyl)methyl-2-phenyl- solution of 7 (100 mg, 0.24 mmol) in benzene (10 ml) at r.t. under an argon
sulfinylacetamide (7) A solution of 4 (10 g, 24.6 mmol) and NaIO4 (7.9 g, atmosphere, and the mixture was stirred for 1 h. After removal of the solvent
36.9 mmol) in MeOH (150 ml) and H2O (50 ml) was heated under reflux for in vacuo, the residual oil was chromatographed and eluted with ethyl ac-
2 h. After removal of inorganic precipitates by filtration, the filtrate was con- etate/hexane (1 : 5) to give 6-methoxy-1-(3,4-methylenedioxyphenyl)methyl--
centrated in vacuo. The residue was extracted with CHCl3 and washed with 2-oxo-3-phenylsulfanyl-2,3-dihydroindole (14) (97 mg, 99%) as colorless
brine. The product was chromatographed and eluted with ethyl acetate/ needles crystallized from CHCl3–Et2O, mp 116—117 °C. IR: 1719, 1626,
hexane (2 : 3) to give 7 (10 g, 99%) as a brownish yellow gum. IR: 1651, 1504. UV: 285 (7700). 1H-NMR (500 MHz): 3.72 (3H, s, MeO), 4.49 (1H, d,
1
1603, 1491, 1040. UV: 281 (6800). H-NMR (90 MHz): 3.48 (1H, d, Jϭ14 Jϭ16 Hz, ArCH2N–), 4.59 (1H, d, Jϭ16 Hz, ArCH2N–), 4.59 (1H, d,
Hz, –CH2S–), 3.87 (1H, d, Jϭ14 Hz, –CH2S–), 3.78 (3H, s, MeO), 4.58 Jϭ1 Hz, C3-H), 5.91 (2H, s, OCH2O), 6.15 (1H, d, Jϭ2 Hz, C7-H), 6.46
(H, d, Jϭ14 Hz, ArCH2N–), 4.80 (H, d, Jϭ14 Hz, ArCH2N–), 5.93 (2H,
(1H, br s, C2Љ-H), 6.47 (1H, br d, Jϭ7 Hz, C6Љ-H), 6.55 (1H, dd, Jϭ2, 8 Hz,
s, OCH2O), 6.2—7.7 (12H, m, ArH, PhH). LR-MS m/z: 423 (Mϩ), 135 C5-H), 6.64 (1H, d, Jϭ7 Hz, C5Љ-H), 7.1—7.4 (5H, m, PhH), 7.32 (1H, dd,
(base peak). HR-MS m/z (Mϩ): Calcd for C23H21NO5S: 423.1140. Found:
Jϭ1, 8 Hz, C4-H). 13C-NMR (125 MHz): 43.9 (t), 48.9 (d), 55.4 (q), 97.3
423.1155.
(d), 101.1 (t), 106.5 (d), 107.7 (d), 108.3 (d), 117.9 (s), 120.5 (d), 126.0 (d),
Pummerer Reaction of 6 TFAA (0.17 ml, 1.21 mmol) was added to a 128.8 (dϫ3), 129.1 (s), 130.8 (s), 134.4 (dϫ2), 144.3 (s), 147.0 (s), 148.0
solution of 6 (100 mg, 0.24 mmol) in THF (10 ml) at r.t. under an argon at- (s), 160.6 (s), 174.8 (s). LR-MS: m/z 405 (Mϩ), 135 (base peak). Anal.
mosphere, and the mixture was stirred for 1 h. The reaction mixture was Calcd for C23H19NO4S: C, 68.13; H, 4.72; N, 3.45. Found: C, 67.91; H, 4.81;
concentrated in vacuo. The residual oil was chromatographed and eluted N, 3.17.
with CHCl3/MeOH (5 : 1) to give 8 (66 mg, 54%) as a colorless gum and 9
6-Methoxy-1-(3,4-methylenedioxyphenyl)methyl-2-oxo-2,3-dihydroin-
(49 mg, 40%) as colorless prisms, crystallized from ethyl acetate/hexane, mp dole (15) To a stirred solution of 14 (300 mg, 0.74 mmol) and NiCl2·6H2O
135—137 °C.
(1.2 g, 5.04 mmol) in MeOH–THF (3 : 1) (15 ml) was added NaBH4 (600
mg, 15.8 mmol) by portions at 0 °C, and stirring was continued at r.t. for
1-Trifluoroacetoxy-6-methoxy-4-(3,4-methylenedioxyphenyl)methyl-1-
phenyl-1,2,3,4-tetrahydro-1,4-benzothiazine (8): IR: 1685, 1604, 1504. UV: 30 min. The reaction mixture was filtered and the filtrate was concentrated
1
233 (31900), 286 (6400), 317 (4100). H-NMR (300 MHz): 3.1—3.9 (4H, in vacuo. The residue was extracted with CHCl3. The product was chro-
m, C2-H, C3-H), 3.80 (3H, s, MeO), 4.48 (1H, d, Jϭ16 Hz, ArCH2N–), 4.54 matographed and elued with ethyl acetate/hexane (2 : 3) to give (15)
(1H, d, Jϭ16 Hz, ArCH2N–), 5.95 (1H, d, Jϭ2 Hz, OCH2O), 5.95 (1H, d, (189 mg, 86%) as colorless needles crystallized from CHCl3–Et2O, mp
1
Jϭ2 Hz, OCH2O), 6.45 (1H, d, Jϭ2 Hz, C5-H), 6.49 (1H, dd, Jϭ2, 9 Hz,
118—120 °C. IR: 1709, 1628, 1504. UV: 286 (7100). H-NMR (500 MHz):
C7-H), 6.56 (1H, d, Jϭ2 Hz, C2Љ-H), 6.61 (1H, dd, Jϭ2, 8 Hz, C6Љ-H), 6.75 3.53 (2H, s, C3-H), 3.75 (3H, s, MeO), 4.78 (2H, s, ArCH2N–), 5.92 (2H, s,
(1H, d, Jϭ8 Hz, C5Љ-H), 7.35 (1H, d, Jϭ9 Hz, C8-H), 7.5—7.7 (5H, m, OCH2O), 6.34 (1H, d, Jϭ2 Hz, C7-H), 6.51 (1H, dd, Jϭ2, 8 Hz, C5-H), 6.74
PhH). 13C-NMR (75.0 MHz): 36.5 (t), 41.3 (t), 55.6 (q), 55.8 (t), 86.4 (s), (1H, d, Jϭ8 Hz, C5Љ-H), 6.79 (1H, br s, C2Љ-H), 6.79 (1H, br d, Jϭ8 Hz,
99.7 (d), 101.3 (t), 106.0 (d), 106.7 (d), 108.7 (d), 119.8 (d), 127.8 (s), 128.8
C6Љ-H), 7.12 (1H, d, Jϭ8 Hz, C4-H). 13C-NMR (125 MHz): 35.1 (t), 43.6
(dϫ2), 129.0 (s), 130.9 (dϫ2), 133.0 (d), 136.0 (d), 147.2 (s), 147.4 (s),
(t), 55.5 (q), 97.4 (d), 101.1 (t), 106.0 (d), 107.9 (d), 108.3 (d), 116.3 (s),
148.4 (s), 166.2 (s). LR-MS m/z: 505 (Mϩ), 135 (base peak). HR-MS m/z 120.8 (d), 124.8 (d), 129.7 (s), 145.4 (s), 147.1 (s), 148.1 (s), 159.8 (s),
(Mϩ): Calcd for C25H22F3NO5S: 505.1171 Found: 505.1160.
1-Trifluoroacetoxy-8-methoxy-4-(3,4-methylenedioxyphenyl)methyl-1-
175.9 (s). LR-MS: m/z 297 (Mϩ), 135 (base peak). Anal. Calcd for
C17H15NO4: C, 68.68; H, 5.09; N, 4.71. Found: C, 68.57; H, 5.20; N, 4.65.
Reduction of 14 with AlH3 A solution of 14 (100 mg, 0.25 mmol) in
phenyl-1,2,3,4-tetrahydro-1,4-benzothiazine (9): IR: 1683, 1506. UV: 287
1
(3300), 332 (4500). H-NMR (300 MHz, CD3OD): 3.4—4.9 (4H, m, C2-H, dry Et2O–THF (1 : 1) (10 ml) was added to a solution of AlH3 in dry Et2O
C3-H), 3.81 (3H, s, MeO), 4.52 (1H, d, Jϭ17 Hz, ArCH2N–), 4.62 (1H, d,
(10 ml) prepared in situ from LiAlH4 (86 mg) and AlCl3 (100 mg) under an
Jϭ17 Hz, ArCH2N–), 5.93 (2H, s, OCH2O), 6.38 (1H, d, Jϭ8 Hz, C7-H), argon atmosphere. The mixture was stirred at r.t. for 30 min. The reaction
6.60—6.63 (3H, m, ArH), 6.73 (1H, d, Jϭ8 Hz, C5-H), 7.43 (1H, t, Jϭ8 Hz, mixture was diluted with CHCl3. The extract was washed with 5% NH4OH
C6-H), 7.5—7.8 (5H, m, PhH). 13C-NMR (75.0 MHz, CD3OD): 35.8 (t), and brine. The residual oil was chromatographed and eluted with ethyl ac-
41.0 (t), 56.2 (t), 56.9 (q), 85.1 (s), 99.4 (d), 101.2 (t), 106.8 (d), 107.6 (d),
etate/hexane (1 : 4) to give 16 (59 mg, 86%) as a colorless oil and 17 (10 mg,
108.6 (d), 119.8 (d), 127.8 (s), 128.8 (dϫ2), 129.5 (s), 130.7 (dϫ2), 132.9 14%) as a pale yellow oil.
(d), 136.2 (d), 147.2 (sϫ2), 148.3 (s), 159.7 (s). LR-MS m/z: 505 (Mϩ), 135
6-Methoxy-1-(3,4-methylenedioxyphenyl)methylindole (16): IR: 1623,
(base peak). HR-MS m/z (Mϩ): Calcd for C25H22F3NO5S: 505.1171. Found: 1490. UV: 289 (9400). 1H-NMR (300 MHz): 3.81 (3H, s, MeO), 5.15 (2H, s,

September 2001
1137
Shindo H., Uenishi J., Ishibashi H., Tetrahedron Lett., 22, 81—84
(1981); d) Kataoka T., Tomoto A., Shimizu H., Hori M., J. Chem.
Soc., Perkin Trans. 1, 1983, 2913—2919.
ArCH2N–), 5.91 (2H, s, OCH2O), 6.46 (1H, d, Jϭ3 Hz, C3-H), 6.58 (1H, d,
Jϭ1 Hz, C2Љ-H), 6.63 (1H, br dd, Jϭ1, 8 Hz, C6Љ-H), 6.73 (1H, d, Jϭ8 Hz,
C5Љ-H), 6.74 (1H, br s, C7-H), 6.78 (1H, dd, Jϭ2, 9 Hz, C5-H), 6.99 (1H, d,
Jϭ3 Hz, C2-H), 7.50 (1H, d, Jϭ9 Hz, C4-H). 13C-NMR (75.0 MHz): 49.9
(t), 55.7 (q), 93.5 (d), 101.1 (t), 101.6 (d), 107.4 (d), 108.3 (d), 109.3 (d),
120.2 (d), 121.5 (d), 123.1 (s), 127.1 (d), 131.3 (s), 137.0 (s), 147.1 (s),
148.1 (s), 156.3 (s). LR-MS: m/z 281 (Mϩ), 135 (base peak). HR-MS m/z
(Mϩ): Calcd for C17H15NO3: 281.1051. Found: 281.1056.
6-Methoxy-1-(3,4-methylenedioxyphenyl)methyl-2,3-dihydroindole (17):
IR: 1620, 1498. UV: 252 (9200), 290 (7200). 1H-NMR (300 MHz): 2.89
(2H, t, Jϭ8 Hz, C3-H), 3.30 (2H, t, Jϭ8 Hz, C2-H), 3.75 (3H, s, MeO), 4.13
(2H, s, ArCH2N–), 5.94 (2H, s, OCH2O), 6.10 (1H, d, Jϭ2 Hz, C7-H), 6.18
(1H, dd, Jϭ2, 8 Hz, C5-H), 6.7—6.9 (3H, m, ArH), 6.96 (1H, d, Jϭ8 Hz,
C4-H). 13C-NMR (75.0 MHz): 27.7 (t), 53.1 (t), 53.9 (t), 55.4 (q), 94.8 (d),
100.9 (t), 101.4 (d), 108.1 (d), 108.4 (d), 120.9 (d), 122.4 (s), 124.4 (d),
132.2 (s), 146.7 (s), 147.8 (s), 153.7 (s), 160.1 (s). LR-MS: m/z 283 (Mϩ),
135 (base peak). HR-MS m/z (Mϩ): Calcd for C17H17NO3: 283.1209. Found:
283.1212.
4) a) Bates D. K., J. Org. Chem., 42, 3453—3453 (1977); b) Tamura Y.,
Choi H. D., Maeda H., Ishibashi H., Tetrahedron Lett., 22, 1343—
1344 (1981); c) Ishibashi H., Miki Y., Ikeda Y., Kiriyama A., Ikeda
M., Chem. Pharm. Bull., 37, 3396—3398 (1989).
5) Padwa A, Gunn D. E., Jr., Osterhout M. H., Synthesis, 1997, 1353—
1377.
6) Shinohara T., Toda J., Sano T., Chem. Pharm. Bull., 45, 813—819
(1997).
7) a) Shinohara T., Takeda A., Toda J., Terasawa N., Sano T., Heterocy-
cles, 46, 555—565 (1997); b) Shinohara T., Takeda A., Toda J., Ueda
Y., Kohno M., Sano, T., Chem. Pharm. Bull., 46, 918—927 (1998); c)
Shinohara T., Takeda A., Toda J., Sano T., ibid., 46, 430—433 (1998);
d) Toda J., Niimura Y., Takeda K., Sano T., Tsuda Y., ibid., 46, 906—
912 (1998); e) Toda J., Niimura Y., Sano T., Tsuda Y., Heterocycles,
48, 1599—1607 (1998); f ) Shinohara T., Takeda A., Toda J., Sano T.,
ibid., 48, 981—992 (1998); g) Toda J., Sakagami M., Sano T., Chem.
Pharm. Bull., 47, 1269—1275 (1999); h) Toda J., Matsumoto S.,
Saitoh T., Sano T., ibid., 48, 91—98 (2000); i) Toda J., Ichikawa T.,
Saithoh T., Horiguchi Y., Sano T., Heterocycles, 53, 2009—2018
(2000); j) Toda J., Sonobe A., Ichikawa T., Saitoh T., Horiguchi Y.,
Sano T., ARKIVOC, 1, 165—180 (2000); k) Toda J., Sakagami M.,
Goan Y., Simakata M., Saitoh T., Horiguchi Y., Sano T., Chem.
Pharm. Bull., 48, 1854—1861 (2000).
8) a) Tafel K. A., Bates D. K. J. Org. Chem., 57, 3676—3680 (1992); b)
Bates D. K., Tafel K. A., ibid., 59, 8076—8080 (1994); c) Picard J. A.,
Chen S., Bates D. K. Heterocycles, 38, 1775—1789 (1994).
9) a) Bates D. K., Winter R. T., Sell B. A., J. Heterocycl. Chem., 23,
695—699 (1986); b) Bates D. K., Sell B. A., Picard J. A. Tetrahedron
Lett., 28. 3535—3538 (1987); c) Wang H-M., Lin M.-C, Chen L-C.,
Heterocycles, 38, 1519—1526 (1994).
10) It has been reported that a stable sulfurane can be derived from nucle-
ophilic attack on a sulfoxide sulfur atom. [Adzima L. J., Chiang C. C.,
Paul I. C., Martin J. C., J. Am. Chem. Soc., 100, 953—959 (1978)].
11) Typical papers dealing with stable sulfuranes are listed. [Korp J. D.,
Bernal I., Harris M. M., Patel P. K., Tetrahedron Lett., 1979, 4099—
4100 (1979); Ogawa S., Matsunaga Y., Sato S., Ida I., Furukawa N., J.
Chem. Soc., Chem. Commun. 1992, 1141—1142; Fowler J. E., Schae-
fer H. F., J. Am. Chem. Soc., 116, 9596—9601 (1994); Sato S., Fu-
rukawa N., Tetrahedron Lett., 36, 2803—2806 (1995)].
Oxidation of 14 with NaIO4 To a solution of 14 (0.1 g, 0.25 mmol) in
acetone (10 ml) was added a solution of NaIO4 (53 mg, 0.25 mmol) in H2O
(5 ml), and the mixture was stirred at r.t. for 18 h. After removal of the pre-
cipitated inorganic materials by filtration, the filtrate was concentrated in
vacuo. The residue was extracted with CHCl3. The product was chro-
matographed and eluted with ethyl acetate/hexane (1 : 4) to give 6-methoxy-
1-(3,4-methylenedioxyphenyl)methyl-2,3-dioxo-2,3-dihydroindole (18) (32
mg, 42%) as reddish yellow crystals crystallized from CHCl3–Et2O, mp
179—182 °C. IR: 1736, 1717, 1626. UV: 263 (20300), 292 (6100), 312
1
(6700). H-NMR (300 MHz): 3.85 (3H, s, MeO), 4.79 (2H, s, ArCH2N–),
5.94 (2H, s, OCH2O), 6.29 (1H, d, Jϭ2 Hz, C7-H), 6.53 (1H, dd, Jϭ2, 8 Hz,
C5-H), 6.7—6.9 (3H, m, ArH), 7.58 (1H, d, Jϭ8 Hz, C4-H). 13C-NMR
(75.0 MHz): 43.7 (t), 56.0 (q), 98.3 (d), 101.2 (t), 107.7 (d), 107.8 (d), 108.4
(d), 111.3 (s), 120.9 (d), 128.0 (d), 128.4 (s), 147.4 (s), 148.2 (s), 153.0 (s),
160.0 (s), 168.0 (s), 180.5 (s). LR-MS: m/z 311 (Mϩ), 176 (base peak). HR-
MS m/z (Mϩ): Calcd for C17H13NO5: 311.0794. Found: 311.0809. Anal.
Calcd for C17H13NO5: C, 65.59; H, 4.21; N, 4.50. Found: C, 65.40; H, 4.33;
N, 4.37.
Acknowledgements This work was supported by a Grant-in-Aid for
Scientific Research (No. 11672115) from the Ministry of Education, Sci-
ence, Sports and Culture of Japan.
References and Notes
12) Baldwin J. E., J. Chem. Soc., Chem. Commum., 1976, 734—735;
Baldwin J. E., Culting J., Dupont W., Kruse L., Silberman L., Thomas
R. C., ibid., 1976, 736—738; Baldwin J. E., Thomas R. C., Kruse L.
I., Silberman L., J. Org. Chem., 42, 3846—3852 (1977).
13) Tamura Y., Uenishi J. I., Maeda H., Choi H. D., Ishibashi H.,
Synthesis, 1981, 534—537.
1) Kennedy M., McKervey M., “Comprehensive Organic Chemistry,Љ
Vol. 7, ed. by Trost B., Fleming I., Pergamon, Oxford, 1991, pp. 193—
216.
2) Bates D. K.,Winters R. T., Picard J. A., J. Org. Chem., 57, 3094—3097
(1992).
3) a) Oikawa Y., Yonemitsu O., Tetrahedron Lett., 1972, 3393—3396; b)
Idem, Tetrahedron, 30, 2653—2660 (1974); c) Tamura Y., Choi H.-D.,