A novel one-pot synthesis of carbazole-1,4-quinones through Pd-catalyzed cyclocarbonylation, desilylation and oxidation processes from 3-iodo-2-propenylindoles

Article abstract of DOI:10.1016/j.tet.2014.01.015

A novel one-pot synthesis of carbazole-1,4-quinone by consecutive Pd-catalyzed cyclocarbonylation, desilylation, and oxidation reactions is described. We propose a possible mechanism of the cyclocarbonylation reaction between 3-iodo-2-propenylindole and CO (1 atm) in the presence of a tributyl(vinyl)tin and Pd-catalyst and the resulting acylpalladium species was directly coupled with a terminal alkene to produce the carbazole-1,4-quinone. To our knowledge, this is the first example of this type of reaction. A new formal total synthesis of a carbazole-1,4-quinone alkaloid, murrayaquinone A was established using this reaction.

Full text of DOI:10.1016/j.tet.2014.01.015

Tetrahedron 70 (2014) 1805e1810
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A novel one-pot synthesis of carbazole-1,4-quinones through
Pd-catalyzed cyclocarbonylation, desilylation and oxidation
processes from 3-iodo-2-propenylindoles
,
a
Mami Fujii a, Takashi Nishiyama a, Tominari Choshi a , Nanase Satsuki ,
*
Takaya Fujiwaki a, Takumi Abe b, Minoru Ishikura b, Satoshi Hibino a
,
*
a Faculty of Pharmacy & Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan
b School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel one-pot synthesis of carbazole-1,4-quinone by consecutive Pd-catalyzed cyclocarbonylation,
desilylation, and oxidation reactions is described. We propose a possible mechanism of the cyclo-
carbonylation reaction between 3-iodo-2-propenylindole and CO (1 atm) in the presence of a tribu-
tyl(vinyl)tin and Pd-catalyst and the resulting acylpalladium species was directly coupled with a terminal
alkene to produce the carbazole-1,4-quinone. To our knowledge, this is the first example of this type of
reaction. A new formal total synthesis of a carbazole-1,4-quinone alkaloid, murrayaquinone A was es-
tablished using this reaction.
Received 5 December 2013
Received in revised form 7 January 2014
Accepted 8 January 2014
Available online 17 January 2014
Keywords:
One-pot synthesis
Cyclocarbonylation
Carbazole-1,4-quinone
Murrayaquinone A
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
dehydrogenation reaction with Grubbs second generation catalyst,
and a total synthesis of murrayaquinone A (1)5c (Scheme 1). In our
Quinones are very important compounds in many biochemical
functions. In addition, quinone moieties are essential fragments of
a large number of pharmacologically active compounds, especially
in the anticancer drugs.1 Among quinones, the carbazolequinones
previous study, allyl alcohols 2 were synthesized in two steps by
a three-component Pd-catalyzed cross-coupling reaction between
3-iodoindole-2-carbaldehyde, CO (1 atm), and alkenyl tributyltin
under Fukuyama’s conditions,10 followed by the Grignard reaction
of the resulting 3-acryroylindole-2-carbaldehydes with vinyl-
magnesium bromide. The yields of 2a and 2b, however, were only
exhibit
a variety of biological activities, including cytotoxic
activities.2e4 Many biologically active carbazole alkaloids have been
isolated from various natural sources.4 The development of efficient
methods to prepare a scaffold has been a major focus for synthetic
organic chemists, and new strategies against functionalized car-
bazoles are in high demand.4
O
O
R
Grubbs 2th
O2
R
We are interested in the unique structure and biologic activity of
the carbazolequinone, and have reported several total syntheses of
carbazolequinone alkaloids (murrayaquinone A,2,5 carbazomycin
G,6 carquinostatin A,7 carbazoquinocins BeF,8 calothrixins9) based
on the allene-mediated electrocyclic reaction of the 6p-electron
system as a key step. Furthermore, we recently reported a new
toluene
70 oC
N
N
OH
O
MOM
2a: R=Me
2b: R=H
MOM
3
O
Me
efficient synthesis of carbazole-1,4-quinone 3 from allyl alcohol
2
using
a
tandem ring-closing metathesis (RCM) and
N
O
H
1: murrayaquinone A
* Corresponding author. Tel.: þ81 84 936 2111; fax: þ81 84 936 2024; e-mail
Scheme 1. Our previous work.
address: choshi@fupharm.fukuyama-u.ac.jp (T. Choshi).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.01.015

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M. Fujii et al. / Tetrahedron 70 (2014) 1805e1810
46% and 6%, respectively.5c The yield of the allyl alcohol 2b was
extremely low.
Table 1
Optimization of reaction conditions for the synthesis of carbazole-1,4-quinone
O
To obtain the carbazole-1,4-quinones 7 more efficiently, we
attempted to improve the synthesis of the 3-acryloylindole 2b us-
ing the 2-propenylindole 4, as shown in Scheme 2.
HO
I
1)
2)
N
MOM
5
N
N
I
OTBS
O
SnBu3
BHT, CO (1 atm)
PdCl2(dppf)
OTBS
MOM
7
MOM
8
N
OR
run
BHT
Vinyltin (equiv)
Temp (ꢀC)
Time (h)
Yield (%) of 7
MOM
DMF
1
2
3
4
5
6
7
8
9
þ
þ
þ
þ
þ
þ
ꢁ
þ
þ
þ
1.5
0
0.5
3
5
3
3
3
3
3
70
70
70
70
70
70
70
50
100
70
20
20
20
20
20
20
20
20
20
48
18
d
(18)b
(52)
(d)
(20)
(17)
(10)
(d)
(20)
(34)
(34)
TBSCl
imidazole
DMF
70 oC, 20 h
4 : R=H
5 : R=TBS
15
51
40
60a
36
20
34
34
93%
O
O
+
N
N
OR
O
10
MOM
2b: R=H
6: R=TBS
MOM
Reaction conditions: (1) 5, tributyl(vinyl)tin, BHT (1.2 equiv), CO (1 atm),
7: 18%
PdCl2(dppf) (20 mol %), DMF (0.01 M). (2) KF aq in air.
Not detected
a
workup: TBAF, O2, rt, 1 h.
SM recovered (%).
b
Scheme 2. Synthesis of 3-acryloylindoles.
First, 3-iodo-2-propenylindole 4 was prepared by the Grignard
reaction of 3-iodoindole-2-carbaldehyde with vinylmagnesium
bromide. Next, we examined a three-component Pd-catalyzed
cross-coupling reaction with 3-iodo-2-propenylindole 4 and trib-
utyl(vinyl)tin in CO atmosphere, but the desired acryroylindole 2b
was not obtained. Therefore, the 3-acryroylindole 5, protected with
TBSCl, was subjected to a cross-coupling reaction between CO
(1 atm) and alkenyl tributyltin in the presence of a PdCl2(dppf)
catalyst. The carbazole-1,4-quinone 7 was isolated as the sole
product in 18% yield, but the expected 3-acryroylindole 6 was not
detected at all.
effective for increasing the yield to 60% (run 6). The effects of the
catalyst and solvent were also examined in the model reaction.
PdCl2(dppf) produced the best results (Table 1, run 6), but the ef-
fects of other catalysts such as Pd(OAc)2þdppf, Pd(OAc)2þPPh3, and
PdCl2(dppe) were also investigated (Table 2, runs 1e3). Among
several solvents, such as DMF, DMA, toluene, THF and CH3CN, DMF
was found to be the most suitable solvent for these reaction con-
ditions (Table 2, runs 3e7).
Table 2
Effect of Pd-catalysts and solvents
Based on this result, we assumed that an initial cyclo-
carbonylation reaction was consecutively followed by desilylation
and oxidation through treatment with aqueous KF in air. Some
run
Pd-catalystsa
Solvents
Yield (%) of 7
1
2
3
4
5
6
7
Pd(OAc)2þdppf (1:2)
Pd(OAc)2þPPh3 (1:2)
PdCl2(dppe)
PdCl2(dppf)
PdCl2(dppf)
DMF
DMF
DMF
DMA
Toluene
THF
26
41
23
0
(62)b
(16)
(16)
(d)
(20)
(33)
(34)
addition reactions of acylmetallates with a,b-unsaturated carbonyl
compounds are known to undergo a similar process.11 In addition,
Negishi and co-workers reported that the cyclic acylpalladation
reaction by o-iodo-m-tolyl 4-methylcyclohexen-1-yl ketone, CO
(600 psi), and triethylamine in the presence of Pd2(dba)3 gave the
anthraquinone derivative.12 The cyclocarbonylation, in which an
acylpalladium compound was coupled directly with a terminal al-
kene, has been reported in few examples.13 To the best of our
knowledge, however, this one-pot reaction is the first example.
Herein, we wish to report a new cyclocarbonylation method for the
synthesis of carbazole-1,4-quinone, including murrayaquinone A
(1).2,5
0
PdCl2(dppf)
PdCl2(dppf)
Trace
Trace
CH3CN
a
Reaction conditions: (1) 5, tributyl(vinyl)tin, BHT (1.2 equiv), CO (1 atm), Pd-
catalysts (20 mol %), solvents (0.01 M). (2) TBAF, O2, rt, 1 h.
b
SM recovered (%).
Next, we investigated additives other than tributyl(vinyl)tin
(Table 3). The reaction was performed under the same conditions
using other tin compounds, but the yield did not increase (runs
1e3). When 3 equiv of Bu3SnH was used as an additive, the
2. Results and discussion
Table 3
Effects of reagents on cyclocarbonylation
To optimize the cyclocarbonylation conditions, we used 3-
iodo-2-(1-hydroxyprop-2-en-1-yl)indole 5 as a model substrate
(Table 1). First, the effect of the amount of tributyl(vinyl)tin was
studied in the model reaction, and the use of 3 equiv of tribu-
tyl(vinyl)tin afforded the carbazole-1,4-quinone 7 in 51% yield (runs
1e5). In particular, tributyl(vinyl)tin was found to be necessary to
promote this reaction (run 2). The reaction also proceeded under
the same conditions without BHT, but the yield decreased to 36%
(run 7). In addition, the yield tended to decrease when the reaction
temperature was lowered to 50 ꢀC (run 8) or rised to 100 ꢀC (run 9),
or when the reaction time was extended (run 10). After a cyclo-
carbonylation occurred, treatment of the reactant with TBAF under
oxygen atmosphere instead of aqueous KF solution in the air was an
Run
Reagents (equiv)a
Yield (%) of 7
1
2
3
4
5
6
7
8
9
Tributyl(isopropenyl)tin (3 equiv)
Allyl(tributyl)tin (3 equiv)
Tributyl(phenyl)tin (3 equiv)
Bu3SnH (3 equiv)
Bu3SnH (1.5 equiv)
Bu3SnH (5 equiv)
Vinylboronic acid pinacol ester (3 equiv)
AlMe3 (3 equiv)
Et3N (1.1 equiv)
36
26
15
53
16
d
d
d
d
d
(17)b
(21)
(21)
(8)
(10)
(12)
(d)
(10)
(20)
(20)
10
i-Pr2NEt (1.1 equiv)
a
Reaction conditions: (1) 5, reagents, BHT (1.2 equiv), CO (1 atm), PdCl2(dppf)
(20 mol %), DMF (0.01 M), 70 NC, 20 h. (2) TBAF, O2 rt, 1 h.
b
SM recovered (%).

M. Fujii et al. / Tetrahedron 70 (2014) 1805e1810
1807
R2
carbazole-1,4-quinone 7 was obtained in 53% yield (run 4). Fur-
R3
R2
R3
thermore, changing the amount of Bu3SnH to 1.5 equiv or 5 equiv
did not improve the yield (runs 5 and 6). The reaction was then
examined by using vinylboronic pinacol ester and trimethylalu-
minium instead of tributyl(vinyl)tin, but the desired product was
not obtained (runs 7 and 8). In addition, when Et3N and i-Pr2NEt
were used as a base (runs 9 and 10), this reaction gave no desired
product 7.
Based on the above-described results, a plausible mechanism for
this reaction is illustrated in Scheme 3. At the beginning of the
cycle, oxidative addition between the 3-iodoindole 5 and Pd0 spe-
cies should proceed to form 9. Coordination insertion of CO would
lead to PdeCO species 10. Subsequently, transmetallation would
proceed between tributyl(vinyl)tin and PdeCO species 10. Next, the
desired 3-acryloylindole 6 should be produced by reductive elim-
ination of 11, but the reaction did not undergo this process. Instead
an alkenylpalladium intermediate 12 was generated by an alkene
insertion reaction of the vinyl group into the PdeCO bond. Finally,
I
I
MgBr
CHO
THF
0 oC, 30 min
N
N
OH
R1
R1
14a: R1=R2=R3=H (97%)
13a:R1=H
14b: R1=SO2Ph, R2=R3=H (71%)
14c: R1=MOM, R2=Me, R3=H (90%)
14d: R1=MOM, R2=H, R3=Me (93%)
13b:R1=SO2Ph
13c:R1=MOM
1) organic tin
R3
BHT, CO (1 atm)
PdCl2(dppf),DMF
70 oC, 20 h
I
TBSCl
imidazole
R2
OTBS
N
2) TBAF, O2
R1
DMF
50 oC
1
2
3
15a:
R =R =R =H (71%)
1
2
3
15b:
15c:
15d:
O
R =SO2Ph, R =R =H (87%)
1
2
3
R =MOM, R =Me, R =H (45%)
our unexpected carbazole product 7 was released by
b-hydride
1
2
3
R =MOM, R =H, R =Me (72%)
R3
elimination, and the resulting palladium(II) hydride was reduced to
a Pd0 species with a loss of ethylene. Although it is not clear why
reductive elimination from the AreCOePdevinyl species did not
occur, we propose a possible reaction mechanism.
R2
N
O
Bu3SnH
SnBu3
46%
R1
2
8
7
1
3
O
16a:
16b:
16c:
16d:
R =R =R =H
−
−
46%
46%
PdCl2(dppf)
1
2
3
R =SO2Ph, R =R =H
−
52%
59%
1
2
3
R =MOM, R =Me, R =H
BHT and/or
SnBu3
1
2
3
N
R =MOM, R =H, R =Me
OTBS
MOM
5
Scheme 4. One-pot synthesis of carbazole-1,4-quinones 16aed.
Pd(0)Ln
L
(II)
H Pd L
oxidative
addition
L
L
synthesis of the carbazole-1,4-quinones 16c,d from 2-(2-
methylprop-2-enyl)indole 15c and 2-(but-2-enyl)indole 15d un-
der two conditions (tributyl(vinyl)tin and/or Bu3SnH). These de-
sired 2- and 3-methylcarbazolequinones 16c,d were obtained in
moderate yield by using tributyl(vinyl)tin. We synthesized the N-
MOM-3-methylcarbazole-1,4-quinone 16d in three steps from 13c,
and achieved the formal synthesis of murrayaquinone A (1).
(II)
Pd
β-elimination
I
O
L
N
(II)
OTBS
9
Pd
L
MOM
N
OTBS
12
MOM
CO
alkene
insertion
3. Conclusion
L
L
(II)
(II)
L
O
O
L
We have developed a one-pot synthesis of carbazole-1,4-
quinones by Pd-catalyzed cyclocarbonylation, followed by a desi-
lylation and oxidation reaction under treatment with TBAF in O2
atmosphere. The cyclocarbonylation reaction occurred between 3-
iodo-2-propenylindole and CO (1 atm) in the presence of tribu-
tyl(vinyl)tin and Pd-catalyst. This is the first example, in which an
acylpalladium compound was coupled directly with a terminal al-
kene. Thus carbazole-1,4-quinones 16a,c,d were provided in three
steps from 13 using this new method. Among them, carbazole-1,4-
quinone 16d was a synthetic precursor of murrayaquinone A (1),5
and a new formal synthesis was achieved. Based on this result,
we present an efficient method for synthetic studies of carbazole
alkaloids and/or other natural products with a 1,4-quinone struc-
ture. Further studies of the synthesis of carbazolequinone alkaloids
are ongoing.
Pd
Pd
I
Bu3SnI
N
N
OTBS
OTBS
11
MOM
MOM
10
transmetalation
reductive
elimination
SnBu3
6
Scheme 3. Our plausible mechanism for this reaction SnBu3.
To realize this reaction, we prepared important substrates
15aed for the synthesis of carbazole-1,4-quinones (Scheme 4). The
Grignard reaction of 3-iodoindole-2-carbaldehydes 13aec with
alkenylmagnesium bromide gave the 2-allyl alcohols 14aed, fol-
lowed by treatment of 2-allyl alcohols 14aed with TBSCl in the
presence of imidazole produced O-TBS ethers 15aed.
We examined the synthesis of carbazole-1,4-quinones by one-
pot cyclocarbonylation using O-TBS ethers 15aed. The indole 15a
gave the carbazolequinone 16a in 46% yield. The N-phenyl-
sulfonylindole 15b, however, did not give the desired carbazole-
4. Experimental section
4.1. General
All non-aqueous reactions were carried out under an atmo-
sphere of nitrogen in dried glassware unless otherwise noted.
Solvents were dried and distilled according to standard protocols.
quinone 16b. The phenylsulfonyl group was not
protecting group in this reaction. Thus, we established the novel
a suitable

1808
M. Fujii et al. / Tetrahedron 70 (2014) 1805e1810
Analytical thin-layer chromatography was performed with Silica
gel 60PF254 (Merck). Silica gel column chromatography was per-
formed with Silica gel 60 (70e230 mesh, Canto Co. Lit.). All melting
points were determined on Yanagimoto micro melting point ap-
paratus and are uncorrected. Proton nuclear magnetic resonance
(1H NMR) spectra were recorded on a JEOL AL-300 at 300 MHz.
4.5. 2-(1-Hydroxy-2-methylprop-2-en-1-yl)-3-iodo-N-(me-
thoxymethyl)indole 14c
The same procedure as above was carried out using 3-
iodoindole-2-carbaldehyde 13c (365 mg, 1.16 mmol) to give the
alcohol 14c (322 mg, 90%). IR (ATR) n
: 3421 cmꢁ1. 1H NMR (CDCl3)
Chemical shifts are reported relative to Me4Si (
d
0.00). NMR spectra
d
: 7.46 (1H, d, J¼7.4 Hz), 7.40 (1H, d, J¼7.7 Hz), 7.31 (1H, dt, J¼7.7,
were measured with CDCl3 unless otherwise noted. Multiplicity is
indicated by one or more of the following: s (singlet); d (doublet); t
(triplet); q (quartet); m (multiplet); br (broad). Carbon nuclear
magnetic resonance (13C NMR) spectra were recorded on a JEOL AL-
1.3 Hz), 7.23 (1H, dt, J¼7.4, 1.3 Hz), 5.73 (1H, d, J¼11.0 Hz), 5.60
(1H, d, J¼6.6 Hz), 5.43 (1H, d, J¼11.0 Hz), 5.37 (1H, br s), 5.09e5.10
(1H, m), 3.64 (1H, d, J¼7.9 Hz, disappeared with D2O), 3.28 (3H, s),
1.64 (3H, s). 13C NMR (CDCl3)
d: 144.8, 138.6, 138.5, 129.8, 124.0,
300 at 75 MHz. Chemical shifts are reported relative to CDCl3
(
d
122.0, 121.3, 110.7, 109.6, 74.3, 71.8, 65.2, 56.0, 19.6. MS m/z: 357
(Mþ). HRMS (EI) m/z: 357.0229 (Mþ) (calcd for C14H16INO2:
357.0226).
77.0) and DMSO-d6 39.7). Infrared spectra were recorded with
(d
ATR method using a Shimadzu FTIR-8000 spectrophotometer and
Technologies DuraScop. Low and High-resolution mass spectra
were recorded on JEOL JMS-700 spectrometers by direct inlet
system.
4.6. 2-(1-Hydroxybut-2-en-1-yl)-3-iodo-N-(methoxymethyl)
indole 14d
4.2. 2-(1-Hydroxyprop-2-en-1-yl)-3-iodo-N-(methoxymethyl)
indole 4
The same procedure as above was carried out using 3-
iodoindole-2-carbaldehyde 13c (500 mg, 1.59 mmol) to give the
alcohol 14d (526 mg, 93%). IR (ATR) n d:
: 3398 cmꢁ1. 1H NMR (CDCl3)
A solution of vinylmagnesium bromide (1.0 M in THF, 3.16 mL,
3.16 mmol) was added dropwise to a solution of 3-iodoindole-2-
carbaldehyde 3 (500 mg, 1.58 mmol) in THF (20 mL) under cool-
ing with ice-water. After stirred at rt for 1 h, the reaction mixture
was quenched with aqueous NH4Cl solution (saturated), and then
was extracted with EtOAc. The organic layer was washed with
brine, dried over Na2SO4, and evaporated in vacuo. The residue was
purified by column chromatography using EtOAc/hexane (1:9) as
7.38e7.46 (2H, m), 7.30 (1H, dt, J¼7.0, 1.3 Hz), 7.22 (1H, dt, J¼7.0,
1.3 Hz), 5.79e5.84 (2H, m), 5.72e5.76 (1H, m), 5.71 (1H, d,
J¼11.0 Hz), 5.57 (1H, d, J¼11.0 Hz), 3.29 (3H, s), 3.12 (1H, d,
J¼6.0 Hz), 1.72e1.76 (3H, m). 13C NMR (CDCl3)
d: 140.1, 138.4, 130.2,
130.0, 128.3, 123.9, 121.9, 121.2, 109.9, 75.1, 66.2, 62.9, 56.1, 14.1. MS
m/z: 357 (Mþ). HRMS (EI) m/z: 357.0234 (Mþ) (calcd for
C14H16INO2: 357.0226).
an eluent to give the alcohol 4 (463 mg, 92%). IR (ATR)
n .
: 3401 cmꢁ1
1H NMR (CDCl3)
d
: 7.45 (1H, d, J¼7.4 Hz), 7.41 (1H, d, J¼7.7 Hz), 7.30
4.7. 2-[1-(tert-Butyldimethylsilyloxy)prop-2-en-1-yl]-3-iodo-
N-(methoxymethyl)indole 5
(1H, dt, J¼7.7, 1.1 Hz), 7.23 (1H, dt, J¼7.4, 1.1 Hz), 6.15 (1H, ddd,
J¼17.4, 10.3, 3.7 Hz), 5.79 (1H, dddd, J¼7.0, 3.7, 2.3, 2.3 Hz), 5.72 (1H,
d, J¼11.0 Hz), 5.52 (1H, d, J¼11.0 Hz), 5.47 (1H, ddd, J¼17.4, 2.3,
1.3 Hz), 5.30 (1H, ddd, J¼10.3, 2.3, 1.3 Hz), 3.36 (1H, d, J¼7.0 Hz,
A
solution of tert-butyldimethylsilyl chloride (1.17 g,
7.77 mmol) in DMF (30 mL) was added to a solution of the al-
cohol 4 (891 mg, 2.59 mmol) and imidazole (881 mg, 13.0 mmol)
at rt. After stirred at 50 ꢀC for 12 h, the reaction mixture was
quenched with H2O, and then was extracted with EtOAc. The
organic layer was washed with brine, dried over Na2SO4, and
evaporated in vacuo. The residue was purified by column chro-
matography using EtOAc/hexane (1:9) as an eluent to give the
disappeared with D2O), 3.27 (3H, s). 13C NMR (CDCl3)
d: 138.9,138.4,
137.7, 129.8, 123.9, 121.9, 121.3, 115.5, 109.7, 74.7, 69.7, 63.3, 56.0. MS
m/z: 343 (Mþ). HRMS (EI) m/z: 343.0051 (Mþ) (calcd for
C
13H14INO2: 343.0069).
4.3. 2-(1-Hydroxyprop-2-en-1-yl)-3-iodoindole 14a
silyl ether 5 (1.09 g, 93%). 1H NMR (CDCl3)
d: 7.48 (1H, d,
J¼7.9 Hz), 7.42 (1H, d, J¼7.9 Hz), 7.27 (1H, dt, J¼7.9, 1.1 Hz), 7.21
(1H, dt, J¼7.9, 1.1 Hz), 6.08 (1H, ddd, J¼17.1, 10.3, 3.9 Hz), 5.77
(1H, ddd, J¼4.0, 1.8, 1.8 Hz), 5.73 (1H, d, J¼10.3 Hz), 5.54 (1H, d,
J¼10.3 Hz), 5.44 (1H, ddd, J¼17.1, 1.8, 1.8 Hz), 5.21 (1H, td, J¼10.3,
1.8 Hz), 3.27 (3H, s), 0.91 (9H, s), 0.17 (3H, s), ꢁ0.05 (3H, s). 13C
The same procedure as above was carried out using 3-
iodoindole-2-carbaldehyde 13a (400 mg, 1.48 mmol) to give the
alcohol 14a (429 mg, 97%). IR (ATR)
(CDCl3)
n .
: 3401, 3313 cmꢁ1 1H NMR
: 8.63 (1H, br s), 7.43 (1H, d, J¼7.7 Hz), 7.33 (1H, d,
d
J¼7.7 Hz), 7.15e7.24 (2H, m), 6.05 (1H, ddd, J¼17.2, 10.6, 5.5 Hz),
NMR (CDCl3) d: 139.3, 138.9, 138.2, 130.0, 123.5, 121.5, 121.1, 114.4,
5.57e6.07 (1H, m), 5.49 (1H, ddd, J¼17.2, 1.6, 1.4 Hz), 5.31 (1H, ddd,
J¼10.6, 1.6, 1.5 Hz), 2.21 (1H, d, J¼2.7 Hz, disappeared with D2O). 13
C
111.1, 75.6, 70.8, 61.4, 55.8, 25.8, 18.2, ꢁ4.8, ꢁ4.9. MS m/z: 457
(Mþ). HRMS (EI) m/z: 457.0912 (Mþ) (calcd for C19H28INO2Si:
457.0934).
NMR (CDCl3) d: 138.5, 136.8, 135.6, 130.5, 123.4, 120.9, 120.8, 116.6,
111.4, 69.6, 57.6. MS m/z: 298 (Mþ). HRMS (EI) m/z: 298.9821 (Mþ)
(calcd for C11H10INO: 298.9807).
4.8. 2-[1-(tert-Butyldimethylsilyloxy)prop-2-en-1-yl]-3-
4.4. 2-(1-Hydroxyprop-2-en-1-yl)-3-iodo-N-(phenylsulfonyl)
iodoindole 15a
indole 14b
The same procedure as above was carried out using the alcohol
The same procedure as above was carried out using 3-
iodoindole-2-carbaldehyde 13b (500 mg, 1.12 mmol) to give the
14a (400 mg, 1.34 mmol) to give the silyl ether 15a (395 mg, 71%).
IR (ATR) n d: 8.53 (1H, br s), 7.42 (1H,
: 3463 cmꢁ1. 1H NMR (CDCl3)
alcohol 14b (379 mg, 71%). Mp 98e99 ꢀC (EtOAc). IR (ATR)
n
: 1645,
dd, J¼7.0, 1.1 Hz), 7.33 (1H, dd, J¼7.0, 1.1 Hz), 7.22 (1H, dt, J¼7.0,
1.1 Hz), 7.17 (1H, dt, J¼7.0, 1.1 Hz), 5.93 (1H, ddd, J¼16.9, 10.3,
4.8 Hz), 5.48 (1H, ddd, J¼4.8, 1.8, 1.8 Hz), 5.40 (1H, ddd, J¼16.9, 1.8,
1.8 Hz), 5.15 (1H, ddd, J¼10.3, 1.8, 1.8 Hz), 0.91 (9H, s), 0.14 (3H, s),
1616 cmꢁ1. 1H NMR (CDCl3)
d
: 7.96 (1H, d, J¼7.0 Hz), 7.83e7.88 (2H,
m), 7.50e7.56 (1H, m), 7.29e7.45 (5H, m), 6.34 (1H, ddd, J¼17.2,
10.3, 5.1 Hz), 5.95e6.03 (1H, m), 5.35 (1H, d, J¼17.2 Hz), 5.28 (1H, d,
J¼10.3 Hz), 4.11 (1H, d, J¼11.0 Hz, disappeared with D2O). 13C NMR
0.02 (3H, s). 13C NMR (CDCl3)
d: 139.7, 138.0, 135.6, 130.4, 123.0,
(CDCl3)
d
: 140.3, 137.9, 137.8, 136.7, 134.1, 131.6, 129.3, 126.8, 126.5,
120.8, 120.5, 114.5, 111.2, 70.3, 56.3, 25.8, 18.3, ꢁ4.8, ꢁ5.0. MS m/z:
413 (Mþ). HRMS (EI) m/z: 413.0684 (Mþ) (calcd for C17H24INOSi:
413.0672).
124.6, 122.7, 116.8, 114.9, 71.4. MS m/z: 438 (Mþ). HRMS (EI) m/z:
438.9736 (Mþ) (calcd for C17H14INO3S: 438.9739).

M. Fujii et al. / Tetrahedron 70 (2014) 1805e1810
1809
4.9. 2-[1-(tert-Butyldimethylsilyloxy)prop-2-en-1-yl]-3-iodo-
4.13. Carbazole-1,4-quinone 16a
N-(phenylsulfonyl)indole 15b
The same procedure as above was carried out using the silyl
The same procedure as above was carried out using the alcohol
ether 15a (100 mg, 0.24 mmol) to give the carbazole-1,4-quinone
14b (571 mg,1.30 mmol) to give the silyl ether 15b (626 mg, 87%). IR
16a (22 mg, 46%). Mp 220e221 ꢀC (EtOAc). IR (ATR)
n
: 3181,
(ATR)
n
: 1645, 1616 cmꢁ1. 1H NMR (CDCl3)
d
: 8.13 (1H, d, J¼7.7 Hz),
1812 cmꢁ1 1H NMR (DMSO-d6)
. d: 12.9 (1H, br s), 8.04 (1H, d,
7.75 (2H, d, J¼7.3 Hz), 7.50e7.55 (1H, m), 7.26e7.45 (5H, m),
6.10e6.28 (2H, m), 5.37 (1H, dd, J¼17.3, 1.1 Hz), 5.16 (1H, dd, J¼10.3,
J¼7.7 Hz), 7.55 (1H, d, J¼7.7 Hz), 7.40 (1H, dt, J¼7.7, 1.4 Hz), 7.31 (1H,
dt, J¼7.7, 1.4 Hz), 6.76 (2H, s). 13C NMR (DMSO-d6)
d: 183.3, 179.9,
1.1 Hz), 0.91 (9H, s), 0.12 (3H, s), -0.02 (3H, s). 13C NMR (CDCl3)
d:
138.8, 137.4, 135.5, 135.4, 126.5, 123.9, 123.3, 121.7, 115.4, 113.8. MS
m/z: 197 (Mþ). HRMS (EI) m/z: 197.0481 (Mþ) (calcd for C12H7NO3:
197.0477).
140.0, 138.7, 137.6, 136.4, 133.9, 132.5, 129.2, 126.5, 126.0, 124.3,
122.2, 116.0, 115.2, 69.1, 30.9, 26.0, 18.3, ꢁ4.6, ꢁ4.9. MS m/z: 553
(Mþ). HRMS (EI) m/z: 553.0602 (Mþ) (calcd for C23H28INO3SSi:
553.0604).
4.14. N-(Methoxymethyl)-2-methylcarbazole-1,4-quinone 16c
The same procedure as above was carried out using the silyl
4.10. 2-(1-tert-Butyldimethylsilyloxy-2-methylprop-2-en-1-
yl)-3-iodo-N-(methoxymethyl)indole 15c
ether 15c (50 mg, 0.11 mmol) to give the carbazole-1,4-quinone 16c
(14 mg, 52%). IR (ATR) n d: 8.31
: 1731, 1643 cmꢁ1. 1H NMR (CDCl3)
(1H, dd, J¼8.0,1.1 Hz), 7.60 (1H, dd, J¼8.0,1.1 Hz), 7.46 (1H, dt, J¼8.0,
The same procedure as above was carried out using the alcohol
14c (200 mg, 0.56 mmol) to give the silyl ether 15c (120 mg, 45%).
1.3 Hz), 7.39 (1H, dt, J¼8.0, 1.3 Hz), 6.48 (1H, q, J¼1.7 Hz), 6.01 (2H,
s), 3.33 (3H, s), 2.16 (3H, d, J¼1.7 Hz). 13C NMR (CDCl3)
d: 184.0,
1H NMR (CDCl3)
d
: 7.48 (1H, d, J¼7.2 Hz), 7.43 (1H, d, J¼7.2 Hz), 7.27
181.2, 147.2, 139.0, 133.9, 132.9, 127.2, 124.8, 123.8, 123.1, 118.1, 111.9,
75.0, 56.4, 15.7. MS m/z: 255 (Mþ). HRMS (EI) m/z: 255.0880 (Mþ)
(calcd for C15H13NO3: 255.0895).
(1H, dt, J¼7.2, 1.1 Hz), 7.21 (1H, dt, J¼7.2, 1.1 Hz), 5.67 (1H, d,
J¼10.3 Hz), 5.55e5.57 (1H, m), 5.51 (1H, d, J¼10.3 Hz), 5.36e5.38
(1H, m), 5.00e5.01 (1H, m), 3.25 (3H, s), 1.61 (3H, s), 0.90 (9H, s),
0.16 (3H, s), ꢁ0.13 (3H, s). 13C NMR (CDCl3)
d: 145.6, 138.7, 138.2,
4.15. N-(Methoxymethyl)-3-methylcarbazole-1,4-quinone 16d
130.0, 123.5, 121.5, 121.0, 111.3, 110.2, 75.5, 72.4, 63.2, 55.4, 25.8,
19.5, 18.2, ꢁ4.9, ꢁ5.1. MS m/z: 471 (Mþ). HRMS (EI) m/z: 471.1100
(Mþ) (calcd for C20H30INO2Si: 471.1090).
The same procedure as above was carried out using the silyl
ether 15d (50 mg, 0.11 mmol) to give the carbazole-1,4-quinone 16d
(16 mg, 59%). Mp 114e115 ꢀC (EtOAc). IR (ATR) : 1645, 1616 cmꢁ1
n .
1H NMR (CDCl3)
d
: 8.31 (1H, d, J¼8.0 Hz), 7.61 (1H, d, J¼8.0 Hz), 7.46
4.11. 2-[(1-tert-Butyldimethylsilyloxy)but-2-en-1-yl]-3-iodo-
N-(methoxymethyl)indole 15d
(1H, dt, J¼8.0, 1.1 Hz), 7.39 (1H, dt, J¼8.0, 1.1 Hz), 6.48 (1H, q,
J¼1.5 Hz), 6.02 (2H, s), 3.33 (3H, s), 2.16 (3H, d, J¼1.5 Hz). 13C NMR
The same procedure as above was carried out using the alcohol
15c (168 mg, 0.47 mmol) to give the silyl ether 15d (159 mg, 72%).
(CDCl3) d: 184.0, 181.3, 147.2, 139.0, 133.9, 132.9, 127.2, 124.8, 123.8,
123.1, 118.1, 111.9, 75.0, 56.4, 15.7. MS m/z: 255 (Mþ). HRMS (EI) m/z:
1H NMR (CDCl3)
d
: 7.47 (1H, dd, J¼7.7, 1.1 Hz), 7.41 (1H, dd, J¼7.7,
255.0893 (Mþ) (calcd for C15H13NO3: 255.0895).
1.1 Hz), 7.27 (1H, dt, J¼7.7, 1.5 Hz), 7.20 (1H, dt, J¼7.7, 1.5 Hz), 5.99
(1H, d, J¼8.4 Hz), 5.87e5.95 (1H, m), 5.92 (1H, d, J¼10.3 Hz),
5.50e5.57(1H, m), 5.54 (1H, d, J¼10.3 Hz), 3.34 (3H, s), 1.79 (3H, dd,
J¼7.3,1.5 Hz), 0.88 (9H, s), 0.17 (3H, s), -0.03 (3H, s). 13C NMR (CDCl3)
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2014.01.015.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
d
: 140.9,138.3, 131.8, 130.1, 126.0,123.5, 121.5, 121.0, 110.7, 75.7, 67.0,
60.9, 55.9, 25.8, 18.1, 14.4, ꢁ4.7, ꢁ4.7. MS m/z: 471 (Mþ). HRMS (EI)
m/z: 471.1062 (Mþ) (calcd for C20H30INO2Si: 471.1090).
4.12. N-(Methoxymethyl)carbazole-1,4-quinone 7
References and notes
1. For recent reviews: biochemical roles of quinones, see: (a) Hargreaves, R. H. J.;
Hartley, J. A.; Batler, J. Front. Biosci. 2000, 5, E172eE180; (b) Beall, H. D.; Winski,
S. L. Front. Biosci. 2000, 5, D639eD648; (c) Sissi, C.; Palumbo, M. Curr. Top. Med.
Chem. 2004, 4, 219e230; (d) Garuti, L.; Roberti, M.; Pizzirani, D. Mini-Rev. Med.
Chem. 2007, 7, 481e489; (e) Walker, S. R.; Carter, E. J.; Huff, B. C.; Morris, J. C.
Chem. Rev. 2009, 109, 3080e3098.
2. For isolation and biology of murrayaquinone A: see: (a) Furukawa, H.; Wu, T.-S.;
Ohta, T.; Kuoh, C.-S. Chem. Pharm. Bull. 1985, 33, 4132e4138; (b) Takeya, K.;
Itoigawa, M.; Furukawa, H. Eur. J. Pharmacol. 1989, 169, 137e145; (c) Itoigawa,
M.; Kashiwada, Y.; Ito, C.; Furukawa, H.; Tachibana, Y.; Bastow, K.; Lee, K.-H. J.
Nat. Prod. 2000, 63, 893e897.
Carbon monoxide was bubbled for 5 min to a mixture of the
silyl ether (100 mg, 0.22 mmol), tributyl(vinyl)tin (210 mg,
0.66 mmol), BHT (58 mg, 0.26 mmol), and PdCl2(dppf) (36 mg,
0.044 mmol) in DMF (22 mL) at rt. The resulting mixture was
stirred at 70 ꢀC for 20 h under a CO atmosphere. After cooling to
ambient temperature, TBAF (1 M in THF, 0.33 mL, 0.33 mmol) was
added to the mixture and then the mixture was stirred at the same
temperature for 1 h under O2 atmosphere. The mixture was
quenched with water and then the mixture was extracted with
EtOAc. The organic layer was washed with brine, dried over
Na2SO4, and evaporated in vacuo. The residue was purified by
column chromatography using EtOAc/hexane (1:9) as an eluent to
give the carbazole-1,4-quinone 7 (32 mg, 60%). Mp 136e137 ꢀC
3. Bernard, P. H.; Chai, C. L. L.; Heath, G. A.; Mahon, P. J.; Smith, G. D. J. Med. Chem.
2004, 47, 4958e4963.
4. For recent reviews: chemistry and biology of carbazoles, see: (a) Knolker, H.-J.;
€
Reddy, K. R. Chem. Rev. 2002, 102, 4303e4428; (b) Chakraborty, D. P.; Roy, S. In
Progress in the Chemistry and Organic Natural Products; Herz, W., Grisebach, H.,
Kirby, G. W., Steglich, W., Tamm, C., Eds.; Springer: Wien, Germany, 2003; Vol.
(EtOAc). IR (ATR) n d: 8.31 (1H,
: 1739, 1647 cmꢁ1. 1H NMR (CDCl3)
€
69, pp 128e230; (c) Knolker, H.-J.; Reddy, K. R. In The Alkaloids; Cordell, G. A.,
Ed.; Academic: Amsterdam, The Netherlands, 2008; Vol. 65, pp 1e430; (d)
dd, J¼7.7, 1.1 Hz), 7.62 (1H, dd, J¼7.7, 1.1 Hz), 7.48 (1H, dt, J¼7.7,
€
Schmidt, A. W.; Reddy, K. R.; Knolker, H.-J. Chem. Rev. 2012, 112, 3193e3328; (e)
1.1 Hz), 7.40 (1H, dt, J¼7.7, 1.1 Hz), 6.71 (1H, d, J¼10.3 Hz), 6.64 (1H,
€
Bauer, I.; Knolker, H.-J. Top. Curr. Chem. 2012, 309, 203e254; (f) Roy, J.; Jana, A.
d, J¼10.3 Hz), 6.03 (2H, s), 3.35 (3H, s). 13C NMR (CDCl3)
d: 183.8,
K.; Mal, D. Tetrahedron 2012, 68, 6099e6121.
5. (a) Hagiwara, H.; Choshi, T.; Fujimoto, H.; Sugino, E.; Hibino, S. Chem. Pharm.
Bull. 1998, 46, 1948e1949; (b) Hagiwara, H.; Choshi, T.; Nobuhiro, J.; Fujimoto,
H.; Hibino, S. Chem. Pharm. Bull. 2001, 49, 881e886; (c) Nishiyama, T.; Choshi,
T.; Kitano, K.; Hibino, S. Tetrahedron Lett. 2011, 52, 3876e3878.
180.9, 139.0, 137.7, 136.3, 133.3, 127.6, 125.0, 123.5, 123.2, 118.1,
111.9, 75.0, 56.5. MS m/z: 241 (Mþ). HRMS (EI) m/z: 241.0729 (Mþ)
(calcd for C14H11NO3: 241.0739).

1810
M. Fujii et al. / Tetrahedron 70 (2014) 1805e1810
6. Hagiwara, H.; Choshi, T.; Fujimoto, H.; Sugino, E.; Hibino, S. Tetrahedron 2000,
56, 5807e5811.
7. (a) Choshi, T.; Uchida, Y.; Kubota, Y.; Nobuhiro, J.; Takeshita, M.; Hatano, T.;
Hibino, S. Chem. Pharm. Bull. 2007, 55, 1060e1064; (b) Hieda, Y.; Choshi, T.;
Uchida, Y.; Fujioka, H.; Fujii, S.; Hibino, S. Chem. Pharm. Bull. 2012, 60,
1522e1530.
8. (a) Choshi, T.; Sada, T.; Fujimoto, H.; Nagayama, C.; Sugino, E.; Hibino, S. J. Org.
Chem. 1997, 62, 2535e2543; (b) Choshi, T.; Sada, T.; Fujimoto, H.; Nagayama, C.;
Sugino, E.; Hibino, S. Tetrahedron Lett. 1996, 37, 2593e2596.
H.; Choshi, T.; Tohyama, S.; Matsumoto, K.; Ohmura, K.; Nobuhiro, J.; Hibino, S.
Tetrahedron Lett. 2006, 47, 5859e5861; (c) Tohyama, S.; Choshi, T.; Matsumoto,
K.; Yamabuki, A.; Hieda, Y.; Nobuhiro, J.; Hibino, S. Heterocycles 2010, 82,
397e416; (d) Choshi, T.; Hibino, S. Heterocycles 2009, 77, 85e97.
10. Tokuyama, H.; Kaburagi, Y.; Chen, X.; Fukuyama, T. Synthesis 2000, 429e434.
11. (a) Corey, E. J.; Hegedus, L. S. J. Am. Chem. Soc. 1969, 91, 4926e4928; (b) Gagnier,
S. V.; Larock, R. C. J. Am. Chem. Soc. 2003, 125, 4804e4807; (c) Kandnikov, D. V.;
Larock, R. C. Org. Lett. 2000, 2, 3643e3646.
12. Negishi, E.; Tour, J. M. Tetrahedron Lett. 1986, 27, 4869e4872.
9. (a) Tohyama, S.; Choshi, T.; Matsumoto, K.; Yamabuki, A.; Ikegata, K.; Nobuhiro,
13. Wu, X.-F.; Neumann, H.; Beller, M. Chem. Soc. Rev. 2011, 40, 4986e5009.
J.; Hibino, S. Tetrahedron Lett. 2005, 46, 5263e5264; (b) Yamabuki, A.; Fujinawa,