Development of novel reactions using hypervalent iodine(III) reagents: Total synthesis of sulfur-containing pyrroloiminoquinone marine product, (±)-makaluvamine F

Article abstract of DOI:10.1055/s-1999-3462

Novel and efficient intramolecular nucleophilic substitution reactions of phenol ethers using activated hypervalent iodine species have been developed and their application to the total synthesis of strongly cytotoxic makaluvamine F (1), a member of sulfur-containing pyrroloiminoquinone marine products, is described.

Full text of DOI:10.1055/s-1999-3462

FEATURE ARTICLE
885
Development of Novel Reactions Using Hypervalent Iodine(III) Reagents:
Total Synthesis of Sulfur-Containing Pyrroloiminoquinone Marine Product,
(±)-Makaluvamine F
Yasuyuki Kita,* Masahiro Egi, Takeshi Takada, Hirofumi Tohma
Graduate School of Pharmaceutical Sciences, Osaka University, 1–6 Yamada-oka, Suita, Osaka 565–0871, Japan
Fax +81(6)68798229; E-mail: kita@phs.osaka-u.ac.jp
Received 3 December 1998
involves the reactions of phenols, in which the phenolic
Abstract: Novel and efficient intramolecular nucleophilic substitu-
oxygen reacts with the iodine center of the hypervalent io-
dine reagent. In most cases, hypervalent iodine(III) in-
tion reactions of phenol ethers using activated hypervalent iodine
species have been developed and their application to the total syn-
duced phenolic oxidations proceed via Type I reaction
pathway. Successfully utilizing this pathway, we have ac-
complished the total syntheses of biologically active nat-
ural products such as marine anti-cancer alkaloid,
discorhabdin C12 (equation 1) and a variety of Amarylli-
daceae alkaloid derivatives13a,b (equations 2, 3).
thesis of strongly cytotoxic makaluvamine F (1), a member of sul-
fur-containing pyrroloiminoquinone marine products, is described.
Key words: hypervalent iodine reagents, phenol ethers, cation rad-
ical, makaluvamine F, N,S-acetal
Introduction and Background
Hypervalent iodine(III) reagents are now extensively used
in organic synthesis.1 In particular, phenyliodine(III) diac-
etate (PIDA) and phenyliodine(III) bis(trifluoroacetate)
(PIFA) have received a great deal of attention due to their
reactivities similar to that of heavy metal reagents or an-
odic oxidation, low toxicity, ready availability and easy
handling. The reaction of phenols themselves with hyper-
valent iodine(III) reagents leads to resinous products,1a,1b,2
while that of some phenols bearing an electron-withdraw-
ing group on the para site, leads to p-benzoquinones.2
Phenols bearing electron-withdrawing o-nitro and o,p-
dinitro groups react with PIDA to give the corresponding
iodonium salts and related species.3 On the other hand,
some para-substituted phenols react with nucleophiles
(alcohols,4 alkenes,5 amides,6 carboxylic acids,7 oximes,8
fluoride ion,9 water10 and electron-rich aromatic rings11)
in the presence of PIDA or PIFA to give the cross-conju-
gated cyclohexadienone either by an inter- or intramolec-
ular reaction pathway (type I reaction, Scheme 1). Type I
Equation 1
In contrast to Type I pathway, reactions of phenol ethers
with hypervalent iodine reagents have been limited and
have yielded mostly iodonium salts. It is well known that
iodonium salts14 are obtained by the reaction of unsubsti-
tuted or meta-substituted phenol ethers with hypervalent
iodine reagents. However, in the case of para-substituted
phenol ethers with PIFA, no iodonium salts were ob-
tained. We found that the reaction of p-substituted phenol
ethers with some nucleophiles in the presence of PIFA in
Scheme 1
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886
Y. Kita et al.
FEATURE ARTICLE
Equation 2
polar and poorly nucleophilic solvents such as 2,2,2-tri-
fluoroethanol (CF3CH2OH) and 1,1,1,3,3,3-hexafluoro-2-
propanol ((CF3)2CHOH) caused nucleophilic substitution
reactions. Thus, we explored a novel and straightforward
nucleophilic substitution reaction of p-substituted phenol
Equation 3
– 15,16
ethers with various nucleophiles (N3 ,
AcO–,16 b-di-
carbonyl compounds,16 ArS–,17,18 and SCN–18) using PIFA
in CF3CH2OH or (CF3)2CHOH (type II reaction, Scheme
1). Type II involves the reactions of phenol ethers, where-
in the aromatic ring reacts with the hypervalent iodine re- 5),19,20 quinone imine derivatives (equation 6),21,22 and
agent and generates a cation radical intermediate [ArH+◊] sulfur-containing heterocycles (equation 7).23
(equation 4).16
In this paper we report a full account of the total synthesis
Very recently, we have reported successful applications of of potent cytotoxic makaluvamine F (1) using our newly
the intramolecular Type II reaction using the activated hy- developed hypervalent iodine induced reactions.
pervalent iodine reagents such as PIFA–BF3◊Et2O and
PIFA–Me3SiOTf to obtain biaryl compounds (equation
Biographical Sketches
Yasuyuki Kita was born in ty. After two years (1975– Award for Divisional Scien-
1945 in Osaka, Japan. He 1977) of postdoctoral work tific Contributions in 1997.
received his Ph.D. (1972) in with Professor George He is the coauthor of about
chemistry from Osaka Uni- Büchi at MIT, he returned to 290 scientific publications.
versity under the direction Osaka University where he His current research inter-
of Professor Yasumitsu is a professor of chemistry. ests include the develop-
Tamura and subsequently He was awarded the Phar- ment of new synthetic
has been a member of the maceutical Society of Japan methodologies and the syn-
faculty of the Pharmaceuti- (PSJ) Award for Young Sci- thesis of biologically active
cal Sciences of the Universi- entists in 1986 and the PSJ natural products.
Hirofumi Tohma was born Scientists (1992–1993) and interests include the devel-
in 1965 in Osaka, Japan. He then joined the group of opment of new methodolo-
received his Ph.D. (1993) Professor
Richard
R. gies utilizing hypervalent
from Osaka University un- Schrock at MIT as a post- elements in organic synthe-
der the direction of Profes- doctoral fellow of JSPS sis.
sor Yasuyuki Kita. He has (1993–1994). He became a
been granted a Fellowship member of the faculty at Os-
of the Japan Society for the aka University in 1994 and
Promotion of Scieneces currently is an assistant pro-
(JSPS) for Japanese Junior fessor. His current research
Synthesis 1999, No. 5, 885–897 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Development of Novel Reactions Using Hypervalent Iodine(III) Reagents
887
Results and Discussion
Makaluvamines,24 new members of marine alkaloids were
isolated from the Fijian sponge Zyzzya cf. marsailis (A–F)
and the Indonesian sponge Histodermella sp. (G). Among
them, 1 exhibits the most potent biological activity (e.g.
cytotoxicity towards the human colon tumor cell line
HCT-116 (IC50 =0.17 mM) and inhibition of topoi-
somerase II)24,25 and has an essential a-aminodihydro-
benzothiophene skeleton which is a labile N,S-acetal
structure present in all sulfur-containing discorhabdins26
(Figure 1). Synthetic studies towards makaluvamines and
discorhabdins have been carried out by several groups.
However, in most cases these efforts have been devoted
only towards the diverse preparation of the pyrroloimino-
quinone unit.
Equation 4
Figure 1
Equation 5
To our knowledge, the total syntheses of sulfur-containing
discorhabdins and 1 have not yet been reported in spite of
their potent cytotoxicity and their unique structure. In our
efforts towards the synthesis of discorhabdin alkaloids,
we have succeeded in the total synthesis of discorhabdin
C using PIFA mediated spirocyclization reaction12 (equa-
tion 1). Thus, the remaining challenge for total syntheses
of these targets (the sulfur-containing family) is the con-
struction of the labile and highly strained N, S-acetal skel-
etons. Our synthetic strategy for the total synthesis of 1 is
shown in Scheme 2.
Equation 6
Equation 7
Scheme 2
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888
Y. Kita et al.
FEATURE ARTICLE
f) protected by electron-withdrawing groups with PIFA–
Synthesis of Pyrroloiminoquinones
Me3SiOTf in the presence of H2O. We found that the cor-
The pyrroloiminoquinone system is an essential compo- responding pyrroloiminoquinones (10a,b) or N-deprotect-
nent of a number of recently isolated marine alkaloids. ed pyrroloiminoquinone (2) could be obtained in
Because of their potent biological activities and their moderate yields when the indoles protected with electron-
highly fused structures, pyrroloiminoquinone alkaloids withdrawing groups such as acetyl, benzoyl, tosyl or ben-
have been challenging targets for synthetic chemists for zyloxycarbonyl groups, were treated with PIFA–
years. So far several groups, including ours, have reported Me3SiOTf in (CF3)2CHOH–H2O (50:1).
diverse approaches for their syntheses: (i) intramolecular
imine formation between the indoloquinone and the ter-
minal amino group of the sidechain,12,27 (ii) intramolecu-
lar coupling reaction between the 4-amino group of the
indole and the terminal activated ester group or leaving
Synthesis of a-Azidodihydrobenzothiophene Deriva-
tives
group of the sidechain,28 (iii) formation of pyrrole ring In order to construct the N,S-acetal skeleton, first, it was
from 5-amino-4-formyltetrahydroquinoline,29 (iv) tandem essential to develop an efficient route for the synthesis of
formation of both nitrogen containing rings30 and (v) the starting dihydrobenzothiophene bearing hydroxy
aryne-mediated cyclization of 4-chloro-6-methox- groups. In our previous reports, direct sulfenylation of
ytryptamine derivatives.31
phenol ethers using PIFA and arylthiols has been de-
scribed.17,18 Attempts to apply this methodology to in-
tramolecular reactions were in vain. The reaction of the
phenol ether bearing an alkanethiol sidechain with PIFA
in (CF3)2CHOH gave a complex mixture, which could be
due to the high reactivity of the SH group towards PIFA.35
As a result, the starting dihydrobenzothiophenes were pre-
pared from phenol ethers (11) bearing an alkyl sulfide
sidechain via the intramolecular Type II pathway using
PIFA–BF3◊Et2O followed by the treatment of aq
MeNH2.23 This reaction proceeds chemoselectively to
give only 14a, while sulfoxide (12)36 and/or Pummerer-
type product (13)37 were obtained mainly when using
PIFA in CH2Cl2, CH3CN, or MeOH. This implies that the
oxidation of the sulfur atom occurs prior to that of the
electron rich aromatic ring under these ionic reaction con-
ditions (Scheme 4). This reaction has been applied to a va-
riety of alkoxy substituted phenol ethers (11a–f) to give
the corresponding dihydrobenzothiophenes (14a–d), hy-
drobenzothiopyrans (14e,f) in good to excellent yields
(Table 1).
We have developed a facile and direct preparation of
quinone imine derivatives,12,21,22,27a and very recently we
have communicated the synthesis of pyrroloiminoquino-
nes from the indole bearing an alkyl azido sidechain.32
The starting substrate was prepared as follows (Scheme
3). The treatment of 6,7-dimethoxyindole (5)33 with ox-
alyl chloride followed by LAH reduction gave 3-(hydrox-
yethyl)indole (6) (95% yield) which was converted to 3-
(azidoethyl)indole (8) via 3-(iodoethyl)indole (7) in 65%
yield. N-Protected 3-(azidoethyl)indoles (9a–f) were
readily prepared from 8 by standard alkylation and acyla-
tion methods. The reaction of 8 with PIFA-Me3SiOTf or
the reactions of 9a (R =Me) and 9b (R =SiPri3) with
PIFA–Me3SiOTf gave complex mixtures probably due to
the side reactions occurring at the 1- or 3-positions of the
indole nucleus. In fact, several groups had already report-
ed that 1-, 2- or 3-substituted indole derivatives were ob-
tained from the reaction of indoles with PIDA.34
Therefore we then examined the reactions of indoles (9c–
Scheme 3
Synthesis 1999, No. 5, 885–897 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Development of Novel Reactions Using Hypervalent Iodine(III) Reagents
889
Scheme 4
Table 1
Scheme 5
nation of PhI =O and Me3SiN3.41 The results are listed in
Table 2. Although the azidation of 5-bromo-6-benzyloxy-
dihydrobenzothiophene (14d) gave only a trace amount of
the expected a-azido compound, debenzylation of 14d
followed by acetylation gave 14i, which upon treatment
with PhI =O and Me3SiN3 gave 15e. A similar sequence
of reactions was carried out to obtain 14h before its con-
version to 15d.
Next, we attempted to synthesize a-azidodihydro-
benzothiophenes, which can serve as an N, S-acetal equiv-
alent, by the introduction of an azido group to dihydroben-
zothiophene derivatives (14). Subsequent to the first
report by Böhme and Morf,38 acyclic a-azido sulfides
have generally been synthesized stepwise, via halogena-
tion followed by azidation of sulfides,39 or via thioket-
als.40 On the other hand, a-azidation of cyclic sulfides,
especially dihydrobenzothiophenes, has never been re-
ported, probably due to readily occurring side reactions
such as aromatization, sulfoxide formation, benzylic oxi-
dation and a-oxidation of the sulfur atom under oxidative
conditions. First, we examined the known stepwise meth-
ods to obtain a-azidodihydrobenzothiophene. The initial
chlorination of 14b by N-chlorosuccinimide (NCS) or
SO2Cl2, however, exclusively gave 5-methoxy-
benzothiophene (16), and oxidation of 14b to the sulfox-
ide (17) followed by Pummerer-type azidation gave a
complex mixture (Scheme 5).
Table 2
Therefore, the need to find a direct and efficient approach
to synthesizing a-azidodihydrobenzothiophene brought
forth the challenge to devise another azidation method.
After considerable efforts, we discovered a novel and di-
rect a-azidation method for cyclic sulfides using a combi-
After hydrolytic deprotection of the 6-acetoxy group, 2-
azido-5-bromo-6-hydroxydihydrobenzothiophene (18)
was finally obtained. The entire route to 18 from commer-
Synthesis 1999, No. 5, 885–897 ISSN 0039-7881 © Thieme Stuttgart · New York

890
Y. Kita et al.
FEATURE ARTICLE
cially available methyl (4-hydroxyphenyl)acetate is out-
lined in Scheme 6.
Summary
Hypervalent iodine(III) induced intramolecular cycliza-
tion reactions of phenol ethers have enabled novel and ef-
ficient preparations of synthetically useful products in
fewer steps under mild conditions and their applications to
the first total synthesis of makaluvamine F have been re-
alized. Hence, hypervalent iodine reagents and their acti-
vated species show promise in replacing the use of highly
toxic heavy metal salts and at the same time, will provide
useful tools for the synthesis of a variety of biologically
significant compounds. Synthetic studies towards more
complicated sulfur-containing discorhabdins and their an-
alogs are now underway.
Experimental Section
Scheme 6
Melting points were determined on a Yanagimoto micro melting
point apparatus and are uncorrected. Infrared (IR) absorption spec-
tra were recorded as KBr pellets on a SHIMADZU FTIR-8100
spectrophotometer. NMR spectra were measured on a JEOL JMN-
EX 270 or JEOL JNM-AL 300 or JEOL JNM-GSX 500. Chemical
shifts are expressed in ppm (d) with TMS as an internal standard.
Mass spectra (MS) were measured on a JEOL JMS-AMII50 or
JEOL JMS-D300 instrument. E. Merck silica gel 60 for column
chromatography and E. Merck precoated TLC plates, silica gel F254
for preparative thin layer chromatography were used. Organic lay-
ers were dried with anhydrous MgSO4 or Na2SO4. PIFA and io-
dosobenzene are commercially available. All reagents were of
reagent grade, unless otherwise stated. In general, reactions were
carried out in anhydrous solvents, unless otherwise mentioned.
Caution: Reactions involving Me3SiN3 are capable of being vio-
lently explosive.
Total Synthesis of Makaluvamine F
Initial attempts to transform the azido group to the amino
group by catalytic hydrogenation or other reductive meth-
ods under nonacidic conditions proved unsatisfactory (i.e.
2-amino-5-bromo-6-hydroxydihydrobenzothiophene (3)
was found to be quite labile under basic conditions). Fur-
thermore, Wittig type reactions between the phosphine-
imine prepared from 18 and several quinones were also
unsuccessful. Catalytic hydrogenation of 18 followed by
the coupling reaction with 2 in MeOH in the presence of
Me3SiOTf gave 1 only in poor yield. By contrast, the cat-
alytic hydrogenation of 18 using 10% Pd–C in the pres-
ence of 4 equiv. of trifluoroacetic acid (TFA) resulted in
complete reduction to give 3, as a TFA salt in quantitative
yield without any side reactions. The final coupling reac-
tion in MeOH between both synthetic precursors, 3 (TFA
salt) and 2, proceeded in 86% yield to give the TFA salt of
1 whose spectral data were identical to that of the reported
one24,42(Scheme 7).
6,7-Dimethoxy-3-(2-hydroxyethyl)indole (6)
To a solution of 6,7-dimethoxyindole (5) (100 mg, 0.564 mmol) in
Et2O (10 mL) was added dropwise a solution of oxalyl chloride
(0.064 mL, 0.734 mmol) in Et2O (8 mL) under N2 at 0°C, and stirred
for 2 h at 0°C. To the mixture was added EtOH (0.12 mL), and this
was stirred for 3 h. After evaporation, sat. aq NaHCO3 was added,
and the mixture was extracted with EtOAc. The organic layer was
washed with brine, dried, and evaporated in vacuo. The residue was
purified by column chromatography (hexane/EtOAc =5:1) to give
ethyl 6,7-dimethoxyindole-3-glyoxylate (147 mg, 94%) as yellow
crystals; mp 122–124°C (from hexane–EtOAc).
IR (KBr): n = 3220, 2945, 1730, 1635, 1520 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.43 (t, J = 7.2 Hz, 3H,
OCH2CH3), 3.95 (s, 3H, OCH3), 4.02 (s, 3H, OCH3), 4.41 (q, J = 7.2
Hz, 2H, OCH2CH3), 7.03 (d, J = 8.6 Hz, 1H, 5-CH), 8.05 (d, J = 8.6
Hz, 1H, 4-CH), 8.40 (d, J = 3.1 Hz, 1H, 2-CH), 8.88 (br s, 1H, 1-
NH).
13C NMR (75.5 MHz, CDCl3): d = 14.0, 56.9, 61.1, 62.1, 111.0,
114.6, 117.4, 121.8, 130.7, 134.3, 137.0, 148.6, 162.8, 178.1.
HRMS m/z calcd for C14H15NO5 (M+) 277.0950, found 277.0945.
A solution of ethyl 6,7-dimethoxyindole-3-glyoxylate (1.41 g, 5.08
mmol) in THF (25 mL) was added dropwise to a suspension of
LiAlH4 (1.93 g, 50.9 mmol) in THF (80 mL) under N2 at 0°C, and
the mixture was refluxed for 2.5 h. After cooling to 0°C, the mixture
was carefully quenched with EtOAc, MeOH, and H2O. After filtra-
tion through Celite, the filtrate was concentrated in vacuo. The res-
idue was dissolved with EtOAc, and the solution was washed with
Scheme 7
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FEATURE ARTICLE
Development of Novel Reactions Using Hypervalent Iodine(III) Reagents
891
sat. aq NaHCO3, brine, dried, and then evaporated to give pure 6
HRMS m/z calcd for C14H16N4O3 (M+) 288.1222, found 288.1223.
(1.13 g, quant) as a colorless oil.
IR (KBr): n = 3355, 2935, 1630, 1510, 1260 cm–1.
3-(2-Azidoethyl)-1-benzoyl-6,7-dimethoxyindole (9d)
Compound 9d (quant) as a yellow oil.
1H NMR (300 MHz, CDCl3): d = 2.99 (t, J = 6.2 Hz, 2H, 1-CH2),
3.89 (t, J = 6.2 Hz, 2H, 2-CH2), 3.93 (s, 3H, OCH3), 4.00 (s, 3H,
OCH3), 6.86 (d, J = 8.5 Hz, 1H, 5-CH), 6.99 (s, 1H, 2-CH), 7.26 (d,
J = 8.5 Hz, 1H, 4-CH), 8.18 (br s, 1H, 1-NH).
13C NMR (75.5 MHz, CDCl3): d = 28.7, 57.4, 60.8, 62.5, 108.0,
112.4, 113.7, 122.2, 124.2, 130.9, 134.4, 147.1.
IR (KBr): n = 2940, 2105, 1700, 1600, 1505 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.93 (t, J = 7.2 Hz, 2H, 1-CH2),
3.55 (t, J = 7.2 Hz, 2H, 2-CH2), 3.83 (s, 3H, OCH3), 3.92 (s, 3H,
OCH3), 7.01 (d, J = 8.5 Hz, 1H, 5-CH), 7.12 (s, 1H, 2-CH), 7.21 (d,
J = 8.5 Hz, 1H, 4-CH), 7.49 (dd, J = 7.5, 7.2 Hz, 2H, ArH), 7.60 (t,
J = 7.5 Hz, 1H, ArH), 7.83 (d, J = 7.2 Hz, 2H, ArH).
HRMS m/z calcd for C12H15NO3 (M+) 221.1052, found 221.1067.
13C NMR (75.5 MHz, CDCl3): d = 24.8, 50.7, 57.1, 59.9, 110.8,
113.4, 116.7, 126.0, 127.1, 128.5, 129.9, 130.1, 132.8, 134.3, 138.0,
150.9, 167.6.
3-(2-Azidoethyl)-6,7-dimethoxyindole (8)
HRMS m/z calcd for C19H18N4O3 (M+) 350.1379, found 350.1371.
To a solution of 6 (4.70 g, 0.021 mol) in toluene (120 mL) was add-
ed triphenylphosphine (6.69 g, 0.026 mol), imidazole (1.74 g, 0.026
mmol), iodine (6.20 g, 0.024 mol) under N2, and then stirred for
overnight at r.t. After quenching with sat. aq Na2S2O3, sat. aq
NaHCO3, the mixture was extracted with EtOAc. The organic layer
was washed with sat. aq NaHCO3, brine, and dried. After evapora-
tion, the residue was purified by column chromatography (hexane/
EtOAc =5:1) to give 7 (4.75 g, 68%) as a colorless oil.
3-(2-Azidoethyl)-6,7-dimethoxy-1-[(4-methylphenyl)sulfonyl]-
indole (9e)
Compound 9e (89%) as a colorless oil.
IR (KBr): n = 2950, 2100, 1500 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.36 (s, 3H, CH3), 2.95 (t, J = 7.3
Hz, 2H, 1-CH2), 3.59 (t, J = 7.3 Hz, 2H, 2-CH2), 3.83 (s, 3H, OCH3),
3.86 (s, 3H, OCH3), 6.91 (d, J = 8.5 Hz, 1H, 4-CH), 7.13 (d, J = 8.5
Hz, 1H, 5-CH), 7.23 (d, J = 8.5 Hz, 2H, ArH), 7.59 (s, 1H, 2-CH),
7.76 (d, J = 8.5 Hz, 2H, ArH).
13C NMR (67.9 MHz, CDCl3): d = 21.5, 24.7, 50.6, 56.6, 60.5,
109.7, 113.5, 116.3, 125.4, 127.1, 128.6, 129.3, 136.5, 136.6, 143.9,
150.5.
IR (KBr): n = 3400, 2930, 1630, 1575, 1510 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.31 (t, J = 7.3 Hz, 2H, 2-CH2),
3.42 (t, J = 7.3 Hz, 2H, 1-CH2), 3.93 (s, 3H, OCH3), 4.00 (s, 3H,
OCH3), 6.86 (d, J = 8.5 Hz, 1H, 5-CH), 7.00 (d, J = 2.4 Hz, 1H, 2-
CH), 7.21 (d, J = 8.5 Hz, 1H, 4-CH), 8.06 (br s, 1H, 1-NH).
13C NMR (67.9 MHz, CDCl3): d = 6.0, 30.5, 57.5, 60.9, 108.4,
113.3, 115.8, 121.5, 123.5, 130.8, 134.6, 147.2.
HRMS m/z calcd for C19H20N4O4S (M+) 400.1205, found 400.1205.
FABMS m/z calcd for C12H14INO2 (M+) 331.0069, found 331.0044.
Phenylmethyl 3-(2-Azidoethyl)-6,7-dimethoxyindole-1-carbox-
ylate (9f)
Compound 9f (96%) as a colorless oil.
IR (KBr): n = 2940, 2100, 1760, 1500, 1265 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.90 (t, J = 7.2 Hz, 2H, 1-CH2),
3.55 (t, J = 7.2 Hz, 2H, 2-CH2), 3.92 (s, 3H, OCH3), 3.93 (s, 3H,
OCH3), 5.43 (s, 2H, OCH2Ph), 6.98 (d, J = 8.5 Hz, 1H, 5-CH), 7.16
(d, J = 8.5 Hz, 1H, 4-CH), 7.34–7.52 (m, 6H, 2-CH and ArH).
NaN3 (352 mg, 4.87 mmol) was added to a solution of 7 (1.01 g,
3.05 mmol) in DMF (50 mL) under N2 at r.t.. The mixture was
stirred for 5 h, quenched with H2O, and then extracted with Et2O.
The organic layer was washed with H2O, brine, dried, and evaporat-
ed. The residue was purified by column chromatography (CH2Cl2)
to give 8 (751 mg, quant) as a brown oil.
IR (KBr): n = 3350, 2935, 2100, 1510 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.01 (t, J = 7.3 Hz, 2H, 1-CH2),
3.55 (t, J = 7.3 Hz, 2H, 2-CH2), 3.93 (s, 3H, OCH3), 4.00 (s, 3H,
OCH3), 6.86 (d, J = 8.5 Hz, 1H, 5-CH), 6.99 (d, J = 1.8 Hz, 1H, 2-
CH), 7.22 (d, J = 8.5 Hz, 1H, 4-CH), 8.07 (br s, 1H, 1-NH).
13C NMR (67.9 MHz, CDCl3): d = 25.2, 51.6, 57.5, 60.9, 108.4,
112.7, 113.4, 121.8, 123.9, 130.9, 134.6, 147.2.
13C NMR (67.9 MHz, CDCl3): d = 24.6, 50.6, 57.1, 61.2, 68.8,
110.3, 113.4, 116.9, 124.7, 127.2, 128.3, 128.4, 128.5, 128.9, 135.1,
137.9, 150.0, 151.5.
HRMS m/z calcd for C20H20N4O4 (M+) 380.1484, found 380.1482.
Pyrroloiminoquinones (2, 10a,b); General Procedure
To a stirred solution of 9 (0.20 mmol) in (CF3)2CHOH/H2O (10 mL:
0.20 mL) was added dropwise trimethylsilyl trifluoromethane-
sulfonate (0.500 mmol) at 0°C under N2, and added PIFA (0.24
mmol). After stirring for 1.5 h at 0°C, the mixture was quenched
with sat. aq NaHCO3, and evaporated. The residue was extracted
with CH2Cl2, and the organic layer was washed with brine, dried,
and evaporated in vacuo. The residue was purified by column chro-
matography to give 2 or 10a,b.
HRMS m/z calcd for C12H14N4O2 (M+) 246.1117, found 246.1121
N-Protection of 8: To a stirred suspension of potassium t-butoxide
(1.0 mmol) in THF (1.25 mL) was added dropwise a solution of 8
(0.50 mmol) in THF (5.0 mL) under N2 at 0°C and stirred at 0°C for
1 h. After adding acetyl chloride (benzoyl chloride, p-toluenesulfo-
nyl chloride or benzyl chloroformate) (1.2 mmol) at 0°C, the mix-
ture was stirred for overnight at r.t.. The mixture was quenched with
H2O, and extracted with CH2Cl2. The organic layer was washed
with brine, dried, and evaporated. The residue was purified by col-
umn chromatography to give 9.
7-Methoxy-2,4-dihydropyrrolo[4,3,2-de]quinolin-8(1H)-one (2)
Compound 2 (51% from 9c; 47% from 9d) as an unstable yellow
solid.
IR (KBr): n = 2850, 1670, 1625, 1560 cm–1.
1-Acetyl-3-(2-azidoethyl)-6,7-dimethoxyindole (9c)
Compound 9c (91%) as a colorless oil.
1H NMR (300 MHz, CDCl3): d = 2.78 (t, J = 7.9 Hz, 2H, 3-CH2),
3.84 (s, 3H, OCH3), 4.16 (t, J = 7.9 Hz, 2H, 4-CH2), 6.10 (s, 1H, 6-
CH), 6.87 (s, 1H, 2-CH).
13C NMR (67.9 MHz, CDCl3): d = 18.3, 50.4, 56.5, 105.5, 117.0,
121.3, 122.9, 123.7, 156.7, 158.5, 170.9.
IR (KBr): n = 2940, 2105, 1715, 1495 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.67 (s, 3H, AcN), 2.93 (t, J = 7.0
Hz, 2H, 1-CH2), 3.58 (t, J = 7.0 Hz, 2H, 2-CH2), 3.90 (s, 3H, OCH3),
3.95 (s, 3H, OCH3), 6.99 (d, J = 8.5 Hz, 1H, 5-CH), 7.18 (d, J = 8.5
Hz, 1H, 4-CH), 7.40 (s, 1H, 2-CH).
13C NMR (75.5 MHz, CDCl3): d = 24.6, 25.3, 50.5, 56.9, 60.7,
110.2, 113.6, 117.4, 124.5, 127.6, 128.8, 137.7, 151.2, 168.8.
HRMS m/z calcd for C11H10N2O2 (M+) 202.0742, found 202.0744.
Synthesis 1999, No. 5, 885–897 ISSN 0039-7881 © Thieme Stuttgart · New York

892
Y. Kita et al.
FEATURE ARTICLE
7-Methoxy-1-[(4-methylphenyl)sulfonyl]-3,4-dihydropyrro-
lo[4,3,2-de]quinolin-8(1H)-one (10a)
6-CH), 6.66 (s, 1H, 2-CH), 6.76 (d, J = 8.5 Hz, 1H, 5-CH), 7.18–
7.33 (m, 5H, SCH2Ph).
Compound 10a (61%) as an unstable yellow solid.
IR (KBr): n = 1670, 1620, 1595, 1580, 1535 cm–1.
Anal. Calcd for C19H24O2S: C, 72.11; H, 7.64; S, 10.13. Found: C,
71.83; H, 7.69; S, 10.32.
1H NMR (270 MHz, CDCl3): d = 2.40 (s, 3H, CH3), 2.78 (t, J = 7.6
Hz, 2H, 3-CH2), 3.78 (s, 3H, 7-OCH3), 4.18 (t, J = 7.6 Hz, 2H, 4-
CH2), 6.09 (s, 1H, 6-CH), 7.31 (d, J = 8.2 Hz, 2H, ArH), 7.51 (s, 1H,
2-CH), 8.08 (d, J = 8.2 Hz, 2H, ArH).
Benzyl 3-(3,4,5-Trimethoxyphenyl)propyl Sulfide (11f)
A colorless oil.
IR (KBr): n = 2940, 1590, 1510 cm–1.
1H NMR (270 MHz, CDCl3): d = 1.86 (tt, J = 7.6, 7.3 Hz, 2H, 2-
CH2), 2.44 (t, J = 7.3 Hz, 2H, 1-CH2), 2.62 (t, J = 7.6 Hz, 2H, 3-
CH2), 3.71 (s, 2H, SCH2Ph), 3.82 (s, 3H, OCH3), 3.83 (s, 6H,
OCH3), 6.36 (s, 2H, 2-CH and 6-CH), 7.18–7.36 (m, 5H, SCH2Ph).
HRMS m/z calcd for C18H16N2O4S (M+) 356.0831, found 356.0825.
Phenylmethyl 7-Methoxy-8-oxo-4,8-dihydropyrrolo[4,3,2-
de]quinoline-1(3H)-carboxylate (10b)
Compound 10b (47%) as an unstable yellow solid.
IR (KBr): n = 1775, 1740, 1670, 1620, 1580 cm–1.
Anal. Calcd for C19H24O3S: C, 68.64; H, 7.28; S, 9.64. Found: C,
68.47; H, 7.31; S, 9.61.
1H NMR (300 MHz, CDCl3): d = 2.74 (t, J = 7.5 Hz, 2H, 3-CH2),
3.84 (s, 3H, 7-OCH3), 4.16 (t, J = 7.5 Hz, 2H, 4-CH2), 5.44 (s, 2H,
OCH2Ph), 6.14 (s, 1H, 6-CH), 7.30–7.45 (m, 4H, 2-CH and ArH),
7.52–7.55 (m, 2H, ArH).
FABMS m/z calcd for C19H16N2O4Na (M+Na)+ 359.1008, found
359.0996.
Benzyl 2-(3,4-Dimethoxyphenyl)ethyl Sulfoxide (12)
A white powder; mp 99–101°C (from EtOAc).
IR (KBr): n = 2905, 1590, 1515 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.82 (t, J = 7.3 Hz, 2H, CH2CH2S),
2.93–3.10 (m, 2H, CH2CH2S), 3.84 (s, 6H, OCH3), 3.95, 4.05 (ABq,
J = 12.8 Hz, 2H, PhCH2), 6.70 (s, 1H, 2-CH), 6.72 (d, J = 7.9 Hz,
1H, ArH), 6.79 (d, J = 7.9 Hz, 1H, ArH), 7.28 (s, 2H, ArH), 7.36 (d,
J = 7.0 Hz, 3H, ArH).
Preparation of Phenol Ethers Bearing a Benzylsulfide
Sidechain (11)
Compound 11 was prepared from methyl (MeO)nphenylacetate or
methyl (MeO)nphenylpropionate in 3 steps; LiAlH4 reduction in
THF, then iodination by I2, imidazole and PPh3, followed by the re-
action with benzyl thioacetate or Na/benzylthiol in EtOH.
Anal. Calcd for C17H20O3S: C, 67.08; H, 6.62; S, 10.53. Found: C,
66.96; H, 6.47; S, 10.47.
2-(3,4-Dimethoxyphenyl)ethyl Methoxyphenylmethyl Sulfide
(13)
A colorless oil.
IR (KBr): n = 2935, 1590, 1515 cm–1.
Benzyl 2-(3,4-Dimethoxyphenyl)ethyl Sulfide (11a)
A colorless oil.
IR (KBr): n = 2910, 1590, 1515 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.58–2.82 (m, 4H, -CH2 and 2-
CH2), 3.44 (s, 3H, OCH3), 3.85 (s, 6H, OCH3), 5.47 (s, 1H, SCHPh),
6.63 (s, 1H, 2-CH), 6.66 (d, J = 8.0 Hz, 1H, ArH), 6.77 (d, J = 8.0
Hz, 1H, ArH), 7.27 (t, J = 6.5 Hz, 1H, ArH), 7.35 (t, J = 6.5 Hz, 2H,
ArH), 7.44 (d, J = 6.5 Hz, 2H, ArH).
1H NMR (270 MHz, CDCl3): d = 2.60–2.67 (m, 2H, 1-CH2), 2.74–
2.82 (m, 2H, 2-CH2), 3.72 (s, 2H, SCH2Ph), 3.85 (s, 6H, OCH3),
6.65 (d, 1H, J = 2.0 Hz, 2-CH), 6.68 (dd, 1H, J = 8.3, 2.0 Hz, 6-CH),
6.78 (d, 1H, J = 8.3 Hz, 5-CH), 7.19–7.38 (m, 5H, ArH).
Anal. Calcd for C18H22O3S: C, 67.89; H, 6.96; S, 10.07. Found: C,
67.84; H, 6.97; S, 10.14.
Anal. Calcd for C17H20O2S: C, 70.80; H, 6.99; S, 11.12. Found: C,
70.66; H, 7.01; S, 11.19.
Benzyl 2-(3-Methoxyphenyl)ethyl Sulfide (11b)
A colorless oil.
IR (KBr): n = 2915, 1600, 1495 cm–1.
1H NMR (270 MHz, CDCl3): d = 2.61–2.69 (m, 2H, 1-CH2), 2.76–
2.84 (m, 2H, 2-CH2), 3.72 (s, 2H, SCH2Ph), 3.78 (s, 3H, OCH3),
6.69 (d, J = 2.5 Hz, 1H, ArH), 6.74 (dd, J = 8.0, 2.5 Hz, 2H, ArH),
7.18 (d, J = 8.0 Hz, 1H, ArH), 7.21–7.33 (m, 5H, SCH2Ph).
Dihydrobenzothiophene Derivatives; General Procedure
To a stirred solution of 11 (0.100 mmol) in CH2Cl2 (3 mL) was add-
ed dropwise a solution of PIFA (0.120 mmol) and BF3•Et2O (0.240
mmol) in CH2Cl2 (2 mL) at –78°C under N2. The mixture was stirred
for 30 min at –78°C, then 40% aq MeNH2 (2 mL) was added, and
the mixture was stirred at r.t. for 30 min. The resulting solution was
acidified by 10% HCl, and extracted with CH2Cl2 (10 mL x 3). The
organic layer was washed with H2O and brine, dried, and evaporat-
ed. The residue was purified by column chromatography on silica
gel to give 14.
Anal. Calcd for C16H18OS: C, 74.38; H, 7.02; S, 12.41. Found: C,
74.54; H, 7.09; S, 12.44.
Benzyl 2-(3,4,5-Trimethoxyphenyl)ethyl Sulfide (11c)
A colorless oil.
IR (KBr): n = 2940, 1590, 1510 cm–1.
1H NMR (270 MHz, CDCl3): d = 2.61–2.68 (m, 2H, 1-CH2), 2.72–
2.80 (m, 2H, 2-CH2), 3.73 (s, 2H, SCH2Ph), 3.81 (s, 3H, OCH3),
3.83 (s, 6H, OCH3), 6.34 (s, 2H, 2-CH and 6-CH), 7.20–7.38 (m,
5H, SCH2Ph).
5,6-Dimethoxy-2,3-dihydrobenzothiophene (14a)
Compound 14a (98%) as colorless crystals; mp 76–77°C (from
Et2O).
IR (KBr): n = 2935, 1600, 1495 cm–1.
1H NMR (270 MHz, CDCl3): d = 3.22 (t, J = 7.5 Hz, 2H, 3-CH2),
3.38 (t, J = 7.5 Hz, 2H, 2-CH2), 3.83 (s, 3H, OCH3), 3.84 (s, 3H,
OCH3), 6.76 (s, 1H, ArH), 6.77 (s, 1H, ArH).
Anal. Calcd for C18H22O3S: C, 67.89; H, 6.96; S, 10.07. Found: C,
67.83; H, 6.88; S, 10.17.
Anal. Calcd for C10H12O2S: C, 61.20; H, 6.16; S, 16.34. Found: C,
61.12; H, 6.09; S, 16.29.
Benzyl 3-(3,4-Dimethoxyphenyl)-1-methylpropyl Sulfide (11e)
A colorless oil.
IR (KBr): n = 2930, 1590, 1515 cm–1.
1H NMR (270 MHz, CDCl3): d = 1.31 (d, J = 6.5 Hz, 3H, SCHCH3),
1.67–1.92 (m, 2H, 2-CH2), 2.59–2.71 (m, 3H, 3-CH2 and 1-CH),
3.73 (s, 2H, SCH2Ph), 3.85 (s, 6H, OCH3), 6.65 (d, J = 8.5 Hz, 1H,
5-Methoxy-2,3-dihydrobenzothiophene (14b)
Compound 14b (98%) as a colorless oil.
IR (KBr): n = 2935, 1575, 1475 cm–1.
1H NMR (270 MHz, CDCl3): d = 3.24 (t, J = 7.0 Hz, 2H, 3-CH2),
3.36 (t, J = 7.0 Hz, 2H, 2-CH2), 3.76 (s, 3H, OCH3), 6.69 (dd, J =
Synthesis 1999, No. 5, 885–897 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Development of Novel Reactions Using Hypervalent Iodine(III) Reagents
893
8.2, 2.5 Hz, 1H, 6-CH), 6.78 (d, J = 2.5 Hz, 1H, 4-CH), 7.09 (d, J =
8.2 Hz, 1H, 7-CH).
a-Azidation of 14; General Procedure
To a stirred solution of 14 in CH3CN, Me3SiN3 (4.0 equiv) was add-
ed dropwise at –40°C under N2. Iodosobenzene (2.0 equiv) was
added to the mixture, which was then slowly warmed to –25°C with
stirring for 1–2 h. Evaporation of solvent followed by preparative
TLC or column chromatography gave 15.
Anal. Calcd for C9H10OS: C, 65.03; H, 6.06; S, 19.29. Found: C,
65.30; H, 6.20; S, 19.13.
5,6,7-Trimethoxy-2,3-dihydrobenzothiophene (14c)
Compound 14c (96%) as colorless crystals; mp 68–69°C (from
Et2O).
IR (KBr): n = 2940, 1575, 1480 cm–1.
1H NMR (270 MHz, CDCl3): d = 3.19–3.27 (m, 2H, 3-CH2), 3.30–
3.37 (m, 2H, 2-CH2), 3.82 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 3.91
(s, 3H, OCH3), 6.59 (s, 1H, 4-CH).
2-Azido-5-methoxy-2,3-dihydrobenzothiophene (15a)
Compound 15a (63%) as a colorless oil.
IR (KBr): n = 2935, 2110, 1595, 1475 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.25 (d, J = 16.2 Hz, 1H, 3-CH),
3.48 (dd, J = 16.2, 6.0 Hz, 1H, 3-CH), 3.78 (s, 3H, 5-OCH3), 5.38 (
d, J = 6.0 Hz, 1H, 2-CH), 6.78 (dd, J = 8.5, 2.6 Hz, 1H, 6-CH), 6.85
(s, 1H, 4-CH), 7.16 (d, J = 8.5 Hz, 1H, 7-CH).
13C NMR (67.9 MHz, CDCl3): d = 44.1, 55.5, 71.0, 111.4, 113.7,
122.9, 128.8, 138.5, 158.1.
Anal. Calcd for C11H14O3S: C, 58.39; H, 6.24; S, 14.17. Found: C,
58.26; H, 6.11; S, 14.13.
6-Benzyloxy-5-bromo-2,3-dihydrobenzothiophene (14d)
Compound 14d (66%) as colorless crystals; mp 77 °C (from Et2O).
IR (KBr): n = 2940, 1590, 1480 cm–1.
Anal. Calcd for C9H9N3OS: C, 52.16; H, 4.38; N, 20.27; S, 15.47.
Found: C, 52.23; H, 4.43; N, 20.21; S, 15.23.
1H NMR (500 MHz, CDCl3): d = 3.21 (t, J = 7.9 Hz, 2H, 3-CH2),
3.37 (t, J = 7.9 Hz, 2H, 2-CH2), 5.10 (s, 2H, OCH2Ph), 6.82 (s, 1H,
7-CH), 7.33 (s, 1H, 4-CH), 7.32–7.47 (m, 5H, ArH).
13C NMR (67.9 MHz, CDCl3): d = 34.2, 35.2, 71.0, 107.5, 107.9,
127.0, 127.9, 128.5(x2), 133.8, 136.4, 142.2, 154.3.
2-Azido-5,6,7-trimethoxy-2,3-dihydrobenzothiophene (15b)
Compound 15b (42%) as a colorless oil.
IR (KBr): n = 2935, 2110, 1580, 1480 cm–1.
1H NMR (270 MHz, CDCl3): d = 3.23 (d, J = 16.2 Hz, 1H, 3-CH),
3.47 (dd, J = 16.2, 5.9 Hz, 1H, 3-CH), 3.83 (s, 3H, OCH3), 3.86 (s,
3H, OCH3), 3.94 (s, 3H, OCH3), 5.35 (d, J = 5.9 Hz, 1H, 2-CH),
6.63 (s, 1H, 4-CH).
Anal. Calcd for C15H13BrOS: C, 56.09; H, 4.08. Found: C, 55.96; H,
4.07.
HRMS m/z calcd for C11H13N3O3S (M+) 267.0677, found 267.0685.
6,7-Dimethoxy-2-methyl-3,4-dihydrobenzothiopyran (14e)
Compound 14e (93%) as colorless crystals; mp 87–88°C (from hex-
ane–Et2O).
IR (KBr): n = 2930, 1605, 1510 cm–1.
1H NMR (270 MHz, CDCl3): d = 1.36 (d, J = 6.6 Hz, SCHCH3),
1.67–1.82 (m, 1H, 3-CH2), 2.12–2.23 (m, 1H, 3-CH2), 2.76–2.83
(m, 2H, 4-CH2), 3.29–3.42 (m, 1H, SCHCH3), 3.82 (s, 6H, OCH3),
6.56 (s, 1H, ArH), 6.58 (s, 1H, ArH).
2-Azido-2,3-dihydrobenzothiophene (15c)
Compound 15c (69%) as a colorless oil.
IR (KBr): n = 3065, 2105, 1590, 1460 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.30 (d, J = 16.0 Hz, 1H, 3-CH),
3.50 (dd, J = 16.0 , 6.2 Hz, 1H, 3-CH), 5.37 (d, J = 6.2 Hz, 1H, 2-
CH), 7.10 (t, J = 7.3 Hz, 1H, ArH), 7.15–7.30 (m, 3H, ArH).
13C NMR (75.5 MHz, CDCl3): d = 43.8, 70.3, 122.5, 124.9, 125.2,
128.0, 136.9, 138.0.
HRMS m/z calcd for C8H7N3S (M+) 177.0361, found 177.0392.
Anal. Calcd for C12H16O2S: C, 64.25; H, 7.19; S, 14.29. Found: C,
64.22; H, 7.06; S, 14.08.
6,7,8-Trimethoxy-3,4-dihydrobenzothiopyran (14f)
Compound 14f (81%) as colorless crystals; mp 65–66°C (from
Et2O).
6-Acetoxy-2-azido-2,3-dihydrobenzothiophene (15d)
Compound 15d (70%) as a colorless oil.
IR (KBr): n = 2935, 1565, 1485 cm–1.
IR (KBr): n = 2110, 1760, 1600 cm–1.
1H NMR (270 MHz, CDCl3): d = 2.07 (qu, J = 5.9 Hz, 2H, 3-CH2),
2.75 (t, J = 5.9 Hz, 2H, 4-CH2), 2.93–2.98 (m, 2H, 2-CH2), 3.81 (s,
3H, OCH3), 3.84 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 6.40 (s, 1H, 5-
CH).
1H NMR (300 MHz, CDCl3): d = 2.29 (s, 3H, AcO), 3.27 (d, J =
16.2 Hz, 1H, 3-CH), 3.47 (dd, J = 16.2 Hz, 1H, 3-CH), 5.42 (d, J =
5.5 Hz, 1H, 2-CH), 6.82 (dd, J = 8.2, 1.8 Hz, 1H, 5-CH), 7.02 (d, J
= 1.8 Hz, 1H, 7-CH), 7.24 (d, J = 8.2 Hz, 1H, 4-CH).
Anal. Calcd for C12H16O3S: C, 59.98; H, 6.71; S, 13.34. Found: C,
59.83; H, 6.62; S, 13.31.
13C NMR (75.5 MHz, CDCl3): d = 21.1, 43.1, 71.0, 116.0, 118.4,
125.3, 134.5, 139.5, 150.5, 169.4.
6-Acetoxy-2,3-dihydrobenzothiophene (14h)
HRMS m/z calcd for C10H9N3O2S (M+) 235.0415, found 235.0417.
Compound 14h was prepared from 14d by the treatment with
BF3◊Et2O in ethanethiol followed by acetylation. Compound 14h as
colorless crystals; mp 51–52°C (from hexane–Et2O).
IR (KBr): n = 2950, 1765, 1600 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.28 (s, 3H, AcO), 3.25 (t, J = 7.5
Hz, 2H, 3-CH2), 3.38 (t, J = 7.5 Hz, 2H, 2-CH2), 6.70 (dd, J = 8.1,
2.0 Hz, 1H, 5-CH), 6.92 (d, J = 2.0 Hz, 1H, 7-CH), 7.15 (d, J = 8.1
Hz, 1H, 4-CH).
13C NMR (75.5 MHz, CDCl3): d = 20.8, 33.8, 35.3, 115.3, 117.0,
124.4, 137.4, 143.0, 149.8, 169.3.
HRMS m/z calcd for C10H10O2S (M+) 194.0401, found 194.0399.
6-Acetoxy-2-azido-5-bromo-2,3-dihydrobenzothiophene (15e)
Recovered 14i (40%) and 15e (28%) as a colorless oil.
IR (KBr): n = 2110, 1770, 1465 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.35 (s, 3H, AcO), 3.25 (d, J =
15.8 Hz, 1H, 3-CH), 3.47 (dd, J = 15.8, 5.1 Hz, 1H, 3-CH), 5.44 (d,
J = 5.1 Hz, 1H, 2-CH), 7.05 (s, 1H, 7-CH), 7.46 (s, 1H, 4-CH).
13C NMR (75 MHz, CDCl3): d = 20.8, 43.0, 71.2, 112.4, 117.7,
129.0, 136.6, 139.1, 147.9, 168.5.
HRMS m/z calcd for C10H8N3O2SBr (M+) 312.9520, found
312.9552.
5-Methoxybenzothiophene (16)
Pale yellow glassy crystals; mp 39–43°C (from hexane–Et2O).
IR (KBr): n = 2950, 1605, 1505 cm–1.
Synthesis 1999, No. 5, 885–897 ISSN 0039-7881 © Thieme Stuttgart · New York

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Y. Kita et al.
FEATURE ARTICLE
1H NMR (300 MHz, CDCl3): d = 3.87 (s, 3H, OCH3), 6.99 (dd, J =
8.8, 2.4 Hz, 1H, 6-CH), 7.20–7.30 (m, 2H, 3-CH and 4-CH), 7.44
(d, J = 5.5 Hz, 1H, 2-CH), 7.73 (d, J = 8.8 Hz, 1H, 7-CH).
13C NMR (75.5 MHz, CDCl3): d = 55.5, 105.5, 114.6, 123.0, 123.6,
127.5, 132.1, 140.6, 157.4.
NaHCO3, brine, dried, and evaporated to give pure 2-(4-benzyloxy-
3-bromophenyl)-1-ethanol (27.9 g, 92%) as a colorless oil.
IR (KBr): n = 3370, 2880, 1495 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.79 (t, J = 6.4 Hz, 2H, 2-CH2),
3.83 (dt, J = 6.4, 6.3 Hz, 2H, 1-CH2), 5.15 (s, 2H, OCH2Ph), 6.88
(d, J = 8.4 Hz, 1H, 5-CH), 7.09 (d, J = 8.4 Hz, 1H, 6-CH), 7.28–7.50
(m, 6H, 2-CH and ArH).
13C NMR (75.5 MHz, CDCl3): d = 37.8, 63.5, 70.9, 112.5, 113.9,
127.0, 127.9, 128.5, 128.9, 132.5, 133.7, 136.5, 153.6.
HRMS m/z calcd for C15H15BrO2 (M+) 306.0255, found 306.0249.
HRMS m/z calcd for C9H8OS (M+) 164.0296, found 164.0306.
5-Methoxy-2,3-dihydro-1-benzothiophene 1-Oxide (17)
A colorless oil.
IR (KBr): n = 3500, 1595, 1480, 1270 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.22–3.37 (m, 3H, 2-CH and 3-
CH2), 3.81-3.92 (m, 1H, 2-CH), 3.85 (s, 3H, OCH3), 6.92 (d, J = 7.3
Hz, 1H, 6-CH), 6.93 (s, 1H, 4-CH), 7.74 (d, J = 7.3 Hz, 1H, 7-CH).
13C NMR (67.9 MHz, CDCl3): d = 31.7, 53.2, 55.6, 110.6, 114.6,
128.1, 136.8, 146.4, 163.2.
HRMS m/z calcd for C9H10O2S (M+) 182.0401, found 182.0402.
Benzyl 2-(4-Benzyloxy-3-bromophenyl)ethyl Sulfide (11d)
To a stirred solution of 2-(4-benzyloxy-3-bromophenyl)-1-ethanol
(1.68 g, 5.47 mmol) in toluene (40 mL) was added Ph3P (1.72 g,
6.56 mmol), imidazole (447 mg, 6.57 mmol), iodine (1.60 g, 6.30
mmol) under N2, and then stirred for overnight at r.t. After quench-
ing with sat. aq Na2S2O3 and sat. aq NaHCO3, the mixture was ex-
tracted with EtOAc. The organic layer was washed with sat. aq
NaHCO3, brine, dried, and evaporated. The residue was purified by
column chromatography (hexane/Et2O =20:1) to give 2-(4-benzy-
loxy-3-bromophenyl)-1-iodoethane (1.48 g, 65%) as a colorless oil.
Total Synthesis of Makaluvamine F
Methyl 3-Bromo-4-hydroxyphenylacetate
To a stirred solution of methyl 4-hydroxyphenylacetate (1.13 g,
6.80 mmol) in HOAc (20 mL) was added Br2 (0.380 mL, 7.38
mmol) in HOAc (15 mL) over 15 min. The mixture was stirred for
30 min, then evaporated. The residue was purified by column chro-
matography (hexane/EtOAc = 5:1) to give methyl 3-bromo-4-hy-
droxyphenylacetate (1.43 g, 86%) as a colorless oil.
IR (KBr): n = 3033, 1495, 1255 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.08 (t, J = 7.7 Hz, 2H, CH2CH2I),
3.29 (t, J = 7.7 Hz, 2H, CH2CH2I), 5.14 (s, 2H, OCH2Ph), 6.87 (d, J
= 8.4 Hz, 1H, 5-CH), 7.05 (dd, J = 8.4, 2.2 Hz, 1H, 6-CH), 7.28–
7.53 (m, 6H, 2-CH and ArH).
IR (KBr): n = 3440, 1740, 1495 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.54 (s, 2H, PhCH2), 3.70 (s, 3H,
CO2CH3), 5.48 (s, 1H, 4-OH), 6.97 (d, J = 8.0 Hz, 1H, 5-CH), 7.13
(dd, J = 8.0, 2.2 Hz, 1H, 6-CH), 7.40 (d, J = 2.2 Hz, 1H, 2-CH).
13C NMR (75.5 MHz, CDCl3): d = 39.7, 52.2, 110.0, 116.1, 127.3,
130.0, 132.7, 151.5, 172.0.
13C NMR (75.5 MHz, CDCl3): d = 5.6, 38.9, 70.7, 112.4, 113.7,
126.9, 127.9, 128.2, 128.5, 133.1, 134.4, 136.4, 153.8.
Anal. Calcd for C15H14BrIO: C, 43.20; H, 3.38. Found: C, 43.32; H,
3.40.
To a stirred solution of 2-(4-benzyloxy-3-bromophenyl)-1-iodoet-
hane (5.00 g, 0.012 mol) in MeOH (50 mL) was added NaOH (575
mg, 0.014 mol) in MeOH (10 mL) under N2, and was added drop-
wise a solution of benzyl thioacetate43 (2.39 mg, 0.014 mmol) in
MeOH (10 mL), and the resulting mixture was stirred for overnight.
The mixture was concentrated in vacuo, quenched with H2O, and
then extracted with CH2Cl2. The organic layer was dried, and evap-
orated. The residue was purified by column chromatography (hex-
ane/EtOAc =20:1) to give 11d (4.85 g, 98%) as a colorless oil.
Anal. Calcd for C9H9BrO3: C, 44.11; H, 3.70; Br, 32.60. Found: C,
44.06; H, 3.85; Br, 32.34.
Ethyl 4-Benzyloxy-3-bromophenylacetate
To a stirred solution of methyl 3-bromo-4-hydroxyphenylacetate
(5.95 g, 0.024 mol) in EtOH (180 mL) was added K2CO3 (10.0 g,
0.072 mol) and benzyl bromide (4.30 mL, 0.036 mol). The suspen-
sion was refluxed for 2 h and was cooled to r.t. and concentrated.
The residue was dissolved in Et2O, and the solution was washed
with H2O, sat. aq NaHCO3, and brine and then evaporated. The res-
idue was purified by column chromatography (from hexane to hex-
ane/EtOAc =3:1) to give ethyl 4-benzyloxy-3-bromophenylacetate
(7.60 g, 90%) as a colorless oil.
IR (KBr): n = 2913, 1603, 1495, 1254 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.61 (t, J = 7.0 Hz, 2H, 2-CH2),
2.73 (t, J = 7.0 Hz, 2H, 1-CH2), 3.69 (s, 2H, SCH2Ph), 5.12 (s, 2H,
OCH2Ph), 6.83 (d, J = 8.5 Hz, 1H, 5-CH), 6.98 (dd, J = 8.5, 2.0 Hz,
1H, 6-CH), 7.23–7.35 (m, 7H, 2-CH and ArH), 7.38 (t, J = 7.3 Hz,
2H, ArH), 7.46 (d, J = 7.3 Hz, 2H, ArH).
13C NMR (67.9 MHz, CDCl3): d = 32.7, 34.7, 36.5, 70.9, 112.4,
113.8, 127.0 (x2), 127.9, 128.3, 128.5 (x2), 128.8, 133.3, 134.5,
136.6, 138.3, 153.5.
IR (KBr): n = 2980, 1730, 1495 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.26 (t, J = 7.2 Hz, 3H, CH2CH3),
3.52 (s, 2H, PhCH2CO2), 4.15 (q, J = 7.2 Hz, 2H, CH2CH3), 5.15 (s,
2H, OCH2Ph), 6.88 (d, J = 8.4 Hz, 1H, 5-CH), 7.15 (dd, J = 8.4, 2.2
Hz, 1H, 6-CH), 7.30–7.51 (m, 6H, 2-CH and ArH).
13C NMR (75.5 MHz, CDCl3): d = 14.1, 40.0, 60.9, 70.7, 112.3,
113.6, 126.9, 127.9 (x2), 128.5, 129.2, 134.0, 136.4, 154.0, 171.3.
Anal. Calcd for C22H21BrOS: C, 63.92; H, 5.12. Found: C, 63.99; H,
5.17.
Anal. Calcd for C17H17BrO3: C, 58.47; H, 4.91; Br, 22.88. Found:
C, 58.43; H, 5.01; Br, 22.69.
6-Acetoxy-5-bromo-2,3-dihydrobenzothiophene (14i)
To a stirred solution of 14d (747 mg, 2.33 mmol) in ethanethiol (13
mL) was added dropwise BF3◊Et2O (0.858 ml, 6.98 mmol) at r.t.,
and the resulting mixture was stirred for 1.5 h. The mixture was
quenched with sat. aq NaHCO3, and then extracted with CH2Cl2.
The organic layer was washed with sat. aq NaHCO3 and brine,
dried, and evaporated. The residue was purified by column chroma-
tography (hexane/EtOAc =6:1) to give 5-bromo-6-hydroxy-2,3-di-
hydrobenzothiophene (222 mg, 41%) as a white solid: mp 71–73°C
(from hexane-Et2O).
2-(4-Benzyloxy-3-bromophenyl)-1-ethanol
To a stirred suspension of LiAlH4 (5.60 g, 0.148 mol) in THF (250
mL) was added dropwise a solution of ethyl 4-benzyloxy-3-bro-
mophenylacetate (34.6 g, 0.099 mol) in THF (60 mL) at 0°C under
N2. The mixture was stirred at r.t. for 3 h. The mixture was carefully
quenched with EtOAc, MeOH, and H2O. After filtration through
Celite, the filtrate was concentrated in vacuo. The residue was dis-
solved in EtOAc, and the solution was washed with sat. aq
IR (KBr): n = 3000, 2945, 1590, 1565, 1475 cm–1.
Synthesis 1999, No. 5, 885–897 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Development of Novel Reactions Using Hypervalent Iodine(III) Reagents
895
1H NMR (500 MHz, CDCl3): d = 3.20 (t, J = 8.0 Hz, 2H, 3-CH2),
3.36 (t, J = 8.0 Hz, 2H, 2-CH2), 5.35 (s, 1H, 6-OH), 6.87 (s, 1H, 7-
CH), 7.23 (s, 1H, 4-CH).
13C NMR (125.7 MHz, CD3OD): d = 19.3, 41.6, 44.6, 64.4, 88.8,
107.3, 110.7, 120.4, 123.3, 125.6, 127.4, 130.1, 130.5, 140.3, 152.5,
155.2, 160.2, 168.4.
13C NMR (67.9 MHz, CDCl3): d = 34.1, 35.1, 105.1, 109.6, 126.9,
UV (MeOH) lmax: 310 (e 10100), 347 nm (16600).
FABMS Calcd for C18H15O2N3BrS (M+H)+; 416.0068. Found
416.0077.
133.8, 143.3, 151.4.
Anal. Calcd for C8H7BrOS: C, 41.58; H, 3.05. Found: C, 41.91; H,
3.08.
To a stirred suspension of 5-bromo-6-hydroxy-2,3-dihydroben-
zothiophene (286 mg, 1.24 mmol) in H2O (15 mL) was added
NaOH (74 mg, 1.85 mmol), and was added acetic anhydride (0.175
mL, 1.85 mmol) and sodium acetate (152 mg, 1.85 mmol). After
stirring for 4.5 h, the resulting mixture was extracted with CH2Cl2.
The organic layer was washed with brine, dried, and evaporated.
The residue was purified by column chromatography over silica gel
(hexane/acetone =9:1) to give 14i (282 mg, 83%) as colorless crys-
tals; mp 48–49°C (from hexane-Et2O).
References
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plement D, Eds., Patai, S.; Rappoport, Z., Wiley: New York,
1983, Chapter 18 and 25.
(e) Varvoglis, A. Synthesis 1984, 709.
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IR (KBr): n = 1770, 1460 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.32 (s, 3H, AcO), 3.25 (t, J = 7.9
Hz, 2H, 3-CH2), 3.39 (t, J = 7.9 Hz, 2H, 2-CH2), 6.95 (s, 1H, 7-CH),
7.36 (s, 1H, 4-CH).
13C NMR (67.9 MHz, CDCl3): d = 20.6, 34.1, 35.3, 110.8, 117.0,
128.1, 139.6, 142.8, 147.2, 168.4.
(i) Ochiai, M. Rev. Heteroatom Chem. 1989, 2, 92.
(j) Moriarty, R. M.; Vaid, R. K. Synthesis 1990, 431.
(k) Moriarty, R. M.; Vaid, R. K.; Koser, G. F. Synlett 1990,
365.
(l) Stang, P. J. Angew. Chem., Int. Ed. Engl. 1992, 31, 274.
(m) Varvoglis, A. The Organic Chemistry of Polycoordinated
Iodine VCH: New York, 1992.
(n) Kita, Y.; Tohma, H.; Yakura, T. Trends in Organic Che-
mistry 1992, 3, 113.
(o) Kita, Y.; Tohma, H. Farumashia 1992, 28, 984.; Chem Ab-
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(p) Prakash, O.; Rani, N.; Tanwar, M. P.; Moriarty, R. M.
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(q) Stang, P. J. In Supplement C2: The Chemistry of Triple-
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Anal. Calcd for C10H9BrO2S: C, 43.97; H, 3.32. Found: C, 44.07;
H, 3.36.
2-Azido-5-bromo-6-hydroxy-2,3-dihydrobenzothiophene (18)
To a stirred solution of 15e (43.1 mg, 0.137 mmol) in MeOH (7 mL)
was added 5% aq NaOH (3.5 mL). After stirring for 5 h, the result-
ing mixture was quenched with 10% HCl, and extracted with
EtOAc. The organic layer was washed with brine, dried, and evap-
orated. The residue was purified by column chromatography (hex-
ane/acetone =9:1) to give 18 (33.5 mg, 90%) as a white solid.
IR (KBr): n = 3460, 2115, 1475 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.22 (d, J = 15.9 Hz, 1H, 3-CH),
3.45 (dd, J = 15.9, 6.1 Hz, 1H, 3-CH), 5.37 (d, J = 6.1 Hz, 1H, 2-
CH), 5.48 (s, 1H, 6-OH), 6.96 (s, 1H, 7-CH), 7.33 (s, 1H, 4-CH).
13C NMR (67.9 MHz, CDCl3): d = 42.7, 71.1, 106.5, 110.0, 127.6,
130.5, 139.6, 152.0.
HRMS m/z calcd for C8H6BrN3OS (M+) 270.9414, found 270.9406.
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(x) Kitamura, T.; Fujiwara, Y. Organic Preparations and Pro-
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Makaluvamine F (1)
A solution of 18 (19.2 mg, 0.071 mmol) in EtOH/trifluoroacetic
acid (5 mL: 0.02 mL) was hydrogenated over 10% Pd–C (16.1 mg)
for 2 h under hydrogen (3.5 atm). After filtration through Celite, the
filtrate was evaporated to give 3 as a white solid.
IR (KBr): n = 3100, 2330, 1685 cm–1.
1H NMR (300 MHz, CD3OD): d = 3.32 (d, J = 16.8 Hz, 1H, 3-CH),
3.65 (dd, J = 16.8, 7.0 Hz, 1H, 3-CH), 5.24 (d, J = 7.0 Hz, 1H, 2-
CH), 6.84 (s, 1H, 7-CH), 7.44 (s, 1H, 4-CH).
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To a stirred solution of 2 (12.4 mg, 0.061 mmol) in MeOH (1 mL)
was added dropwise a solution of 3 in MeOH (3 mL) under N2, and
stirred for overnight. The mixture was concentrated, then the resi-
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IR (KBr): n = 3150, 1680, 1630, 1540, 1485, 1430 cm–1.
1H NMR (500 MHz, CD3OD): d = 2.99 (t, J = 7.9 Hz, 2H, 3-CH2),
3.47 (dd, J = 16.5, 2.4 Hz, 1H, 11-CH), 3.60 (dd, J = 16.5, 7.3 Hz,
1H, 11-CH), 3.93 (t, J = 7.9 Hz, 2H, 4-CH2), 5.52 (s, 1H, 6-CH),
5.63–5.68 (m, 1H, 10-CH), 6.68 (s, 1H, 16-CH), 7.14 (s, 1H, 2-CH),
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Synthesis 1999, No. 5, 885–897 ISSN 0039-7881 © Thieme Stuttgart · New York

896
Y. Kita et al.
FEATURE ARTICLE
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Synthesis 1999, No. 5, 885–897 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Development of Novel Reactions Using Hypervalent Iodine(III) Reagents
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Synthesis 1999, No. 5, 885–897 ISSN 0039-7881 © Thieme Stuttgart · New York