Synthesis of α-carbolines by copper-catalyzed radical cyclization of β-(3-indolyl) ketone O-pentafluorobenzoyloximes

Article abstract of DOI:10.1246/bcsj.78.1659

Radical cyclization of β-(3-indolyl) ketone O-pentafluorobenzoyloximes proceeds by the treatment with a catalytic amount of copper powder in 1,2-dichloroethane to generate 3,4-dihydro-α-carbolines, which are oxidized to α-carbolines with chloranil.

Full text of DOI:10.1246/bcsj.78.1659

Ó 2005 The Chemical Society of Japan
Bull. Chem. Soc. Jpn., 78, 1659–1664 (2005) 1659
Synthesis of ꢀ-Carbolines by Copper-Catalyzed Radical Cyclization
of ꢁ-(3-Indolyl) Ketone O-Pentafluorobenzoyloximes
ꢀ
Kenichi Tanaka, Mitsuru Kitamura, and Koichi Narasaka
Department of Chemistry, Graduate School of Science, The University of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033
Received March 4, 2005; E-mail: narasaka@chem.s.u-tokyo.ac.jp
Radical cyclization of ꢀ-(3-indolyl) ketone O-pentafluorobenzoyloximes proceeds by the treatment with a catalytic
amount of copper powder in 1,2-dichloroethane to generate 3,4-dihydro-ꢁ-carbolines, which are oxidized to ꢁ-carbo-
lines with chloranil.
Pyrido[2,3-b]indoles (ꢁ-carbolines) have attracted consider-
able interest due to recent discoveries of their marked pharma-
Results and Discussion
cological activities as antitumor1 and anxiloytic2 agents, and
much effort has been devoted to develop synthetic methods.3
The typical approaches for ꢁ-carbolines involve the formation
of an indole ring from substituted anilines and pyridines,4 or
construction of the pyridine moiety from 2-aminoindoles or
their equivalents.5 However, these methods have difficulties
to control the regioselectivity, preparation and/or handling6
of the starting materials. To overcome the above problems,
the intramolecular amination of indole derivatives was recent-
ly reported for the synthesis of ꢁ-carboline.7 For instance, a
functionalized ꢁ-carboline has been prepared by the palla-
dium-catalyzed cyclization of 3-(3-amino-1-propenyl)-2-bro-
moindole derivative.7a Ila et al. demonstrated that the displace-
ment of the alkylthio group of ꢀ,ꢀ-bis(alkylthio)enones with
oxindole enolates and successive condensation with ammo-
nium acetate afforded 4-alkylthio-ꢁ-carbolines.7b While the
above synthetic methods employed 2-functionalized indoles
as the starting materials, there was little precedent for ꢁ-car-
boline synthesis by direct intramolecular amination of the 2-
nonfunctionalized indole ring.8
Our group has communicated that ꢁ-carbolines are synthe-
sized from ꢀ-(3-indolyl) ketone O-2,4-dinitrophenyloximes by
treatment with sodium hydride and sodium cyanoborohydride
(Eq. 1).9e Although the detailed reaction mechanism is not ob-
vious, the reaction proceeds by radical cyclization10 initiated
by the one-electron reduction of O-dinitrophenyloximes.9a–d
Our attention was then directed to improve this radical cycli-
zation to a catalytic process. This paper describes the synthesis
of ꢁ-carbolines by the copper-catalyzed radical cyclization of
ꢀ-(3-indolyl) ketone O-pentafluorobenzoyloximes.
Copper-Catalyzed Radical Cyclization of ꢁ-(3-Indolyl)
Ketone O-Pentafluorobenzoyloxime. As reported from our
laboratory,9f the radical cyclization of ꢂ,ꢃ-unsaturated O-me-
thoxycarbonyl- or O-pentafluorobenzoyloximes is effected by
a catalytic amount of CuBr Me2S, giving 3,4-dihydro-2H-pyr-
ꢁ
roles. It was, therefore, expected that ꢀ-(3-indolyl) ketone O-
acyloximes would also undergo radical cyclization by treat-
ment with copper compounds. We chose 4-(1-acetyl-3-in-
dolyl)butan-2-one O-methoxycarbonyloxime 2a and O-penta-
fluorobenzoyloxime 3a as cyclization precursors for prelimina-
ry investigations (Table 1). Oxime derivatives 2a and 3a were
readily prepared by the Michael addition of indole to methyl
vinyl ketone.11a
Oxime 2a and 3a were firstly treated with a 0.05 molar
amount of CuBr Me2S and 3.0 molar amounts of lithium bro-
ꢁ
mide in 1,4-dioxane at 80 ꢂC. Although the reaction completed
within 30 min, 3,4-dihydro-ꢁ-carboline 4a and ꢁ-carboline 5a
were obtained only in ca. 40% combined yield (Entries 1 and
2). Then, diamines were added instead of LiBr, because Itoh
developed the copper-catalyzed radical cyclization of polyhalo
ketones in the presence of TMEDA and 2,20-bipyridine.12
However, the cyclization did not take place by the use of
CuBr Me2S with TMEDA or 2,20-bipyridine. The combina-
ꢁ
tion of copper powder (0.2 molar amount) and an equimolar
amount of N,N0,N0,N00,N00-pentamethyldiethylenetriamine
(PMDETA) in 1,2-dichloroethane was found to effect the
smooth cyclization of O-pentafluorobenzoyloxime 3a, yielding
3,4-dihydro-ꢁ-carboline 4a in 75% yield and a trace amount of
ꢁ-carboline 5a (Entry 3). The addition of LiBr into the above
catalyst system resulted to slow the reaction with a lower yield
of the cyclized products 4a and 5a (Entry 4). Interestingly,
when oxime 3a was treated with copper powder and PMDETA
in 1,4-dioxane, the reaction did not take place at all (Entry 5,
vide infra).
Me
Me 1000 mol% NaH
500 mol% NaBH3CN
N
N
H
N
Na+
N
H
Me
O
N
O
N
H
1,4-Dioxane, rt
NO2
The results given in Table 1 suggest that the copper-cata-
lyzed cyclization of ꢀ-(3-indolyl) ketone O-acyloximes 2a
and 3a gave 3,4-dihydro-ꢁ-carboline 4a as a preliminary prod-
uct, which was partially oxidized to ꢁ-carboline 5a during iso-
NO2
60%
O2N
O2N
A
ð1Þ
Published on the web August 30, 2005; DOI 10.1246/bcsj.78.1659

1660 Bull. Chem. Soc. Jpn., 78, No. 9 (2005)
Catalytic Synthesis of ꢁ-Carbolines
Table 1. Reaction of ꢀ-(3-Indolyl) Ketone Oxime Derivatives 2a and 3a with Catalytic Copper Compounda)
Cu Catalyst
Additive
+
+
Me
Me
Me
Me
Solvent, 80 °C, Time
(0.02 mol/L of 2a and 3a)
N
N
N
O
N
Ac
N
Ac
N
Ac
N
Ac
OR
2a (R = CO2Me)
3a (R = COC6F5)
4a
5a
1a
Entry Oxime Cu catalyst (mol %)
Additive (mol %)
Solvent
Time
4a
5a
1a
1
2
3
2a
3a
3a
CuBr SMe2
CuBr SMe2
(5)
(5)
LiBr
LiBr
(300)
(300)
(100) ClCH2CH2Cl
1,4-Dioxane
1,4-Dioxane
<0:5 h 22% 15% 14%
<0:5 h 18% 26% 18%
ꢁ
ꢁ
Cu
Cu
Cu
(20) MeN(CH2CH2NMe2)2
MeN(CH2CH2NMe2)2
2 h 75% trace
5 h 34% 8% 37%
6 h trace trace trace
9%
(100)
4b)
5c)
3a
3a
(20)
ClCH2CH2Cl
(100)
LiBr
(20) MeN(CH2CH2NMe2)2
(100)
1,4-Dioxane
a) Yields were estimated by NMR (anthracene as an internal standard). b) 3a was recovered in 13% yield. c) Almost no
reaction.
lation or in the reaction mixture (Entries 1, 2, and 4). Dihydro-
carboline 4a was readily oxidized with chloranil to afford ꢁ-
carboline 5a quantitatively. On the whole, the cyclization of
O-pentafluorobenzoyloxime 3a in with a catalytic amount of
copper powder and PMEDTA in 1,2-dichloroethane gave ꢁ-
carboline 5a in 75% yield, after the oxidation of the crude
products with chloranil (Eq. 2).
cat. Cu
Me
OCOC6F5
Me
N
N
N
N
Ac
Ac
3a
4a
− C6F5CO2H
3
E
Me
20 mol% Cu
100 mol% MeN(CH2CH2NMe2)2
Me
N
See
Text
N
−OCOC6F5
H
Ac
ClCH2CH2Cl, 80 °C, 2 h
(0.02 mol/L of 3a)
N
N
CuX (B)
OCOC6F5
Ac
3a
ð2Þ
O
Cl
Cl
Cl
Me
Me
[CuIIX]+
+ CuIIX(OCOC6F5)
4
N
N
3
N
N
Cl
O
OCOC6F5
Ac
Ac
Me
Me
C
D
CH2Cl2, rt
N
N
N
N
Ac
4a
Ac
5a 75%
CuIIX(OCOC6F5)
In Scheme 1 is depicted the plausible mechanism of the
present copper-catalyzed reaction. It is assumed that copper(I)
species B are in situ generated by one-electron transfer from
copper powder to oxime derivatives 3a and/or by the reaction
with 1,2-dichloroethane. The latter path would explain that
the cyclization of oxime 3a proceeded much faster in 1,2-di-
chloroethane than in 1,4-dioxane (Table 1, Entries 3 vs 5). El-
emental copper reacts with 1,2-dichloroethane to afford cop-
per(II) chloride, which is converted to copper(I) salt by copro-
portionation with copper powder. In fact, when the copper
Me
N
N
Ac
F
1) trapped by solvent or CuX (B)
2) hydrolysis
Me
O
X = Cl or OCOC6F5
N
Ac
ꢂ
powder and PMDETA were warmed up to 80 C in 1,2-di-
1a
chloroethane, the reaction mixture gradually became blue
due to the formation of copper salts. The generation of active
copper(I) spieces by oxidation with 1,2-dichloroethane is also
supported by the fact that the cyclization of oxime 3a in 1,4-
dioxane with excess 1,2-dibromoethane or a trace amount of
iodine as an additive gave a similar yield of the cyclized prod-
ucts (4a and 5a) within 2 h. Although copper(I) species such as
Scheme 1. Plausible mechanism.
oxime 3a, giving anion radical C and the copper(II) species.
Anion radical C cyclizes to the 2-position of the indolyl moie-
ty with cleavage of the N–O bond. Subsequently, copper(II)
salt in the reaction mixture rapidly oxidizes the resulting radi-
cal D with the regeneration of the copper(I) species. Finally,
the elimination of a proton from cation E yields 3,4-dihydro-
ꢁ-carboline 4a and pentafluorobenzoic acid. As a side reac-
tion, radical anion C suffers from cleavage of the N–O bond
to afford the free alkylideneaminyl radical F and copper(II)
CuBr Me2S would work as an active catalyst, the use of cop-
per(I) salt as a catalytic reagent did not give satisfactory results
(Table 1, Entries 1 and 2).
ꢁ
The cyclization proceeds as follows: one-electron transfer
occurs from the copper(I) species to O-pentafluorobenzoyl-

K. Tanaka et al.
Bull. Chem. Soc. Jpn., 78, No. 9 (2005) 1661
Table 2. Synthesis of ꢁ-Carbolines Having a Substituent on the Indole Nitrogen
O
Cl
Cl
Cl
Cl
4
3
20 mol% Cu
100 mol% MeN(CH2CH2NMe2)2
O
Me
Me
OCOC6F5
Me
N
N
N
N
R
ClCH2CH2Cl, 80 °C, 2-4 h
(0.02 mol/L of 3)
N
R
CH2Cl2, rt
N
R
3
4
5
Entry
1
3
R
Ac
5
1
3a
75% (5a)
64% (5b)
74% (5c)
46% (5d)
33% (5e)
9% (1a)
12% (1b)
15% (1c)
22% (1d)
35% (1e)
2
3b
3cc)
Me
3
SiMe2t-Bu
CO2t-Bu
H
4a),b)
5a),b)
3d
3ed)
a) Oxidation with chloranil was not required.
b) 20 mol % amount of PMDETA was used.
c) E:Z = 3:1 mixture. d) E:Z = 3:5 mixture.
Me
O
N
R
1
Table 3. Synthesis of ꢁ-Carbolines Having Substituents on the Pyridine Ring
O
R3
R3
R3
Cl
Cl
Cl
Cl
R2
R1
OCOC6F5
R2
R1
R2
R1
20 mol% Cu
100 mol% MeN(CH2CH2NMe2)2
O
CCHl2CH2Cl, 80 °C, 2 h
(0.02 mol/L of 3f-h)
CH2Cl2, rt
N
N
N
N
N
N
Ac
Ac
Ac
3f-h
4f-h
5f-h
Entry
Oxime
R1
R2
R3
H
CO2t-Bu
H
Yield
1
2
3a)
3f
Me
Me
Me
H
83% (5f)
67% (5g)
39% (5h)
3gb)
3h
–(CH2)4–
a) Oxidation with chloranil was not needed. b) E:Z = 3:2 mixture.
salt. Free radical F, which might cyclize to yield dihydrocarbo-
line 4a via intermediate D, is trapped by solvent or copper(I)
compounds to afford imine or alkylideneaminyl copper(II)
species, respectively, which were converted to ketone 1a after
hydrolysis.
derivative 3h gave tetracyclic ꢁ-carboline 5h without oxida-
tion (Entry 3), which can be transformed to 6H-indolo[2,3-b]-
quinoline by oxidation with DDQ.7d Various 6H-indolo[2,3-b]-
quinoline derivatives such as cryptotackiene13,14 are known to
show biological activities.
Synthesis of Various ꢀ-Carbolines. Concerning the sub-
stituent on the indole nitrogen, it was revealed that several pro-
tecting groups other than the acetyl group could be introduced
in the synthesis of ꢁ-carbolines from ꢀ-(3-indolyl) ketone O-
pentafluorobenzoyloximes (Table 2). N-Methylindolyl oxime
3b gave the corresponding ꢁ-carboline 5b in 64% yield (Entry
2). Also, ꢁ-carboline 5c having a bulky tert-butyldimethylsilyl
group on the indole nitrogen was prepared in good yield from
oxime 3c (Entry 3). The cyclization of ꢀ-(3-indolyl) oximes
3d and 3e having a tert-butoxycarbonyl group or no substituent
at the indole nitrogen gave the corresponding ꢁ-carbolines
without the oxidation with 4-chloranil. However, the yields
were lower than 50% with an increased formation of by-prod-
ucts such as ꢀ-(3-indolyl) ketones 1d and 1e (Entries 4 and 5).
The copper-catalyzed radical cyclization was further at-
tempted by employing ꢀ-(3-indolyl) ketone O-pentafluoro-
benzoyloximes having substituents at the ꢁ- and ꢀ-positions
(Table 3). 3- and 4-substituted ꢁ-carbolines 5f and 5g were ob-
tained in good yields from ꢁ- and ꢀ-substituted oximes 3f and
3g, respectively (Entries 1 and 2). The cyclohexanone oxime
In conclusion, ꢁ-carbolines were synthesized by the copper-
catalyzed radical cyclization of ꢀ-(3-indolyl) ketone O-penta-
fluorobenzoyloximes followed by oxidation with chloranil.
Since ꢀ-(3-indolyl) ketones are readily prepared from enones
and indoles,11 this method would provide a convenient method
for the synthesis of a variety of ꢁ-carbolines.
Experimental
General. 1H NMR (500 MHz) spectra were recorded on Bruk-
er DRX 500 and Bruker AVANCE 500 spectrometers in CDCl3
using chloroform (for 1H, ꢃ ¼ 7:24) as internal standard.
13C NMR (125 MHz) spectra were recorded on Bruker DRX
500 and Bruker AVANCE 500 spectrometers in CDCl3 using
chloroform (for 13C, ꢃ ¼ 77:0) as an internal standard. IR spectra
were recorded on a Horiba FT 300-S spectrophotometer by the
ATR method. High-resolution mass spectra were obtained with
a JOEL JMS700P mass spectrometer. The melting points were un-
corrected. Elemental analyses were carried out at The Elemental
Analysis Laboratory, Department of Chemistry, Faculty of Sci-
ence, The Univerisity of Tokyo. Flash column chromatography

1662 Bull. Chem. Soc. Jpn., 78, No. 9 (2005)
Catalytic Synthesis of ꢁ-Carbolines
was performed on Merck silica gel 60N and Kanto Chemical silica
gel 60N (spherical, neutral). Preparative thin-layer chromatogra-
phy was carried out using Wako gel B-5F. Dichloromethane and
1,2-dichloroethane were distilled from phosphorus pentoxide,
and then from calcium hydride, and were stored over molecular
sieves 4A. Triethylamine and pyridine were distilled from calcium
hydride, and stored over potassium carbonate. Pentafluorobenzoyl
plex, J ¼ 259:3 Hz), 156.5, 168.8; Z isomer: ꢃ ꢃ4:1, 19.4, 20.1,
21.6, 26.2, 31.7, 107.2 (m), 114.0, 115.8, 118.2, 119.2, 121.4,
128.1, 130.3, 137.7 (d complex, J ¼ 255:3 Hz), 141.5, 143.2 (d
complex, J ¼ 260:3 Hz), 145.4 (d complex, J ¼ 259:3 Hz),
156.3, 169.3; Anal. Found: C, 58.62; H, 5.53; N, 5.28%. Calcd
for C25H27F5N2O2Si: C, 58.81; H, 5.33; N, 5.49%.
4-(1-tert-Butoxycarbonyl-3-indolyl)butan-2-one (E)-O-Pen-
chloride
and
N,N0,N0,N00,N00-pentamethyldiethylenetriamine
tafluorobenzoyloxime (3d):
ꢂC (ethyl acetate–hexane); IR 2983, 1757, 1732, 1651, 1496,
1454, 1373, 1325, 1196, 1159, 1088, 1003, 866 cmꢃ1 1H NMR
Colorless needles; mp 121–137
(PMDETA) were purchased from Tokyo Chemical Industry and
used after distillation. Indium(III) chloride tetrahydrate was pur-
chased from Kanto Chemical and used as-received. Chloranil
was purchased form Tokyo Chemical Industry and used after
recrystallization from toluene.
Synthesis of ꢁ-(3-Indolyl) Ketone O-Pentafluorobenzoyl-
and O-Methoxycarbonyloximes. The Michael addition of in-
doles to enones mediated by acetic acid11a or catalyzed by in-
dium(III) chloride11c gave ꢀ-(3-indolyl) ketones, which were con-
verted to O-pentafluorobenzoyloximes 3a–h by treating the corre-
sponding oximes with pentafluorobenzoyl chloride and triethyl-
amine. O-Methoxycarbonyloxime 2a was prepared from the
corresponding ꢀ-(3-indolyl) ketone oxime by a reaction with
methyl chloroformate and excess pyridine.
;
ꢃ 1.65 (9H, s), 2.08 (3H, s), 2.79–2.82 (2H, m), 3.00–3.04 (2H,
m), 7.23 (1H, dd, J ¼ 7:7, 7.2 Hz), 7.31 (1H, dd, J ¼ 8:3, 7.2
Hz), 7.43 (1H, s), 7.51 (1H, d, J ¼ 7:7 Hz), 8.12 (1H, d, J ¼
8:3 Hz); 13C NMR ꢃ 16.1, 21.4, 28.0, 35.4, 83.5, 107.0 (m),
115.2, 118.6, 118.9, 122.4, 122.6, 124.4, 130.0, 135.4, 137.6 (d
complex, J ¼ 254:0 Hz), 143.3 (d complex, J ¼ 255:8 Hz),
145.3 (d complex, J ¼ 258:2 Hz), 149.6, 156.4, 168.2; Anal.
Found: C, 57.96; H, 4.48; N, 5.41%. Calcd for C24H21F5N2O4:
C, 58.07; H, 4.26; N, 5.64%.
4-(3-Indolyl)butan-2-one O-Pentafluorobenzoyloxime (3e):
E:Z = 3:5 mixture; white powder; mp 146–148 ꢂC (dichloro-
methane–hexane); IR (ZnSe) 3340, 1743, 1496, 1324, 1203,
1003, 744 cmꢃ1 1H NMR E isomer: ꢃ 2.06 (3H, s), 2.80–2.83
;
Spectral Data for ꢁ-(3-Indolyl) Ketone O-Pentafluoroben-
zoyloximes.15 4-(1-Acetyl-3-indolyl)butan-2-one (E)-O-Penta-
(0.75H, m), 2.87 (1.25H, t, J ¼ 7:4 Hz), 3.01 (1.25H, t, J ¼ 7:4
Hz), 3.07–3.11 (0.75H, m), 6.96 (0.63H, s), 6.99 (0.63H, dd,
J ¼ 8:2, 7.1 Hz), 7.07–7.13 (1.37H, m), 7.19 (0.37H, dd,
J ¼ 8:1, 7.0 Hz), 7.28 (0.63H, d, J ¼ 8:2 Hz), 7.36 (0.37H, d, J ¼
8:1 Hz), 7.95 (0.63H, s), 8.00 (0.37H, s); 13C NMR E isomer: ꢃ
16.1, 21.9, 36.2, 107.1 (m), 111.2, 114.5, 118.5, 119.4, 121.6,
122.2, 127.1, 136.2, 137.7 (d complex, J ¼ 247:9 Hz), 143.2 (d
complex, J ¼ 259:8 Hz), 145.3 (d complex, J ¼ 259:3 Hz),
156.7, 168.9; Z isomer: ꢃ 20.1, 21.6, 31.8, 107.1 (m), 111.2,
114.0, 118.3, 119.2, 121.5, 122.1, 126.9, 136.2, 137.7 (d complex,
J ¼ 247:9 Hz), 143.2 (d complex, J ¼ 259:8 Hz), 145.3 (d com-
plex, J ¼ 259:3 Hz), 156.4, 169.1; HRMS (FABþ) Found: m=z
397.0973, Calcd for C19H14F5N2O2: ðM þ HÞþ, 397.0975.
fluorobenzoyloxime (3a):
(dec.) (dichloromethane–hexane); IR (ZnSe) 3116, 2935, 1749,
1704, 1493, 1448, 1383, 1321, 1194, 989, 854, 750 cmꢃ1
Colorless solid; mp 122–127 ꢂC
;
1H NMR ꢃ 2.06 (3H, s), 2.62 (3H, s), 2.83 (2H, t, J ¼ 7:3 Hz),
3.06 (2H, t, J ¼ 7:3 Hz), 7.28 (1H, ddd, J ¼ 8:4, 7.7, 1.0 Hz),
7.35 (1H, ddd, J ¼ 8:4, 7.0, 1.2 Hz), 7.41 (1H, s), 7.51 (1H, dd,
J ¼ 7:7, 1.2 Hz), 8.42 (1H, dd, J ¼ 7:0, 1.0 Hz); 13C NMR ꢃ
16.2, 20.9, 23.9, 35.1, 106.9 (complex), 116.7, 118.4, 120.5,
122.9, 123.4, 125.3, 130.2, 135.8, 137.8 (d complex, J ¼ 243:2
Hz), 143.4 (d complex, J ¼ 260:6 Hz), 145.4 (d complex, J ¼
249:3 Hz), 156.5, 168.0, 168.6; Anal. Found: C, 57.30; H, 3.67;
N, 6.12%. Calcd for C21H15F5N2O3: C, 57.54; H, 3.45; N, 6.39%.
4-(1-Methyl-3-indolyl)butan-2-one (E)-O-Pentafluoroben-
zoyloxime (3b): White powder; mp 154–156 ꢂC (dec.) (ethyl
acetate–hexane); IR (ZnSe) 1751, 1506, 1321, 1198, 991, 854,
4-(1-Acetyl-3-indolyl)-3-methylbutan-2-one
fluorobenzoyloxime (3f):
Colorless solid; mp 131–134 ꢂC
(dec.) (dichloromethane–hexane); IR (ZnSe) 2974, 2935, 1753,
1701, 1496, 1450, 1387, 1325, 1192, 1001, 862, 748 cmꢃ1
;
(E)-O-Penta-
771 cmꢃ1
;
1H NMR ꢃ 2.06 (3H, s), 2.78–2.81 (2H, m), 3.06–
3.09 (2H, m), 3.74 (3H, s), 6.92 (1H, s), 7.10 (1H, dd, J ¼ 7:9,
7.0 Hz), 7.22 (1H, dd, J ¼ 8:1, 7.0 Hz), 7.28 (1H, d, J ¼ 8:2
Hz), 7.57 (1H, d, J ¼ 7:9 Hz); 13C NMR ꢃ 16.1, 21.8, 32.6,
36.5, 107.2 (t, J ¼ 16:2 Hz), 109.2, 112.8, 118.6, 118.8, 121.7,
126.5, 127.5, 136.9, 137.7 (d complex, J ¼ 255:3 Hz), 143.3 (d
complex, J ¼ 260:2 Hz), 145.4 (d complex, J ¼ 256:4 Hz),
156.6, 168.9; Anal. Found: C, 58.62; H, 3.96; N, 6.65%. Calcd
for C20H15F5N2O3: C, 58.54; H, 3.68; N, 6.83%.
1H NMR ꢃ 1.29 (3H, d, J ¼ 6:7 Hz), 1.98 (3H, s), 2.61 (3H, s),
2.83 (1H, dd, J ¼ 14:7, 6.0 Hz), 3.03–3.11 (2H, m), 7.27 (1H,
dd, J ¼ 7:9, 7.3 Hz), 7.34 (1H, dd, J ¼ 8:1, 7.3 Hz), 7.43 (1H,
s), 7.49 (1H, d, J ¼ 7:9 Hz), 8.42 (1H, d, J ¼ 8:1 Hz); 13C NMR
ꢃ 13.5, 18.3, 23.9, 28.7, 39.6, 107.0 (m), 116.8, 118.5, 119.3,
123.4, 123.7, 125.3, 130.5, 135.7, 137.7 (d complex, J ¼ 258:3
Hz), 143.3 (d complex, J ¼ 260:7 Hz), 145.4 (d complex, J ¼
254:4 Hz), 156.6, 168.7, 171.7; Anal. Found: C, 58.33; H, 3.98;
N, 6.03%. Calcd for C22H17F5N2O3: C, 58.41; H, 3.79; N, 6.19%.
tert-Butyl 2-(1-Acetyl-3-indolyl)-4-(O-pentafluorobenzoyl-
oxyimino)pentanoate (3g): E:Z = 3:2 mixture; colorless oil;
IR (ZnSe) 2979, 1759, 1712, 1496, 1450, 1325, 1196, 1146,
4-(1-tert-Butyldimethylsilyl-3-indolyl)butan-2-one O-Penta-
fluorobenzoyloxime (3c): E:Z = 3:1 mixture; colorless plates;
mp 132–134 ꢂC (dec.) (dichloromethane–hexane); IR (ZnSe)
2929, 1757, 1495, 1452, 1323, 1192, 1138, 995, 837, 810, 788,
1
739 cmꢃ1; H NMR E isomer: ꢃ 0.56 (6H, s), 0.88 (9H, s), 2.05
1003 cmꢃ1 1H NMR E isomer: ꢃ 1.39 (3H, s), 2.02 (3H, s),
;
(3H, s), 2.80–2.83 (2H, m), 3.05–3.08 (2H, m), 7.02 (1H, s),
7.09–7.12 (1H, m), 7.13–7.16 (1H, m), 7.46 (1H, d, J ¼ 8:0
Hz), 7.55 (1H, d, J ¼ 8:0 Hz); Z isomer: ꢃ 0.55 (6H, s), 0.88
(9H, s), 2.04 (3H, s), 2.86 (2H, t, J ¼ 7:6 Hz), 2.99 (2H, t, J ¼
7:6 Hz), 6.91 (1H, s), 6.99–7.02 (1H, m), 7.06–7.07 (1H, m),
7.42 (1H, d, J ¼ 8:3 Hz), 7.48 (1H, d, J ¼ 7:1 Hz); 13C NMR E
isomer: ꢃ ꢃ4:0, 16.0, 19.4, 21.9, 26.2, 35.9, 107.2 (m), 114.0,
116.1, 118.4, 119.4, 121.5, 128.4, 130.5, 137.7 (d complex, J ¼
255:3 Hz), 141.4, 143.2 (d complex, J ¼ 260:3 Hz), 145.4 (d com-
2.63 (3H, s), 2.90 (1H, dd, J ¼ 16:2, 6.7 Hz), 3.20 (1H, dd,
J ¼ 16:2, 8.4 Hz), 4.29 (1H, dd, J ¼ 8:4, 6.7 Hz), 7.27 (1H, dd,
J ¼ 7:7, 7.2 Hz), 7.34 (1H, dd, J ¼ 8:3, 7.2 Hz), 7.47 (1H, s),
7.62 (1H, d, J ¼ 7:7 Hz), 8.43 (1H, d, J ¼ 8:3 Hz); Z isomer: ꢃ
1.37 (3H, s), 2.02 (3H, s), 2.60 (3H, s), 3.12 (1H, dd, J ¼ 13:7,
8.3 Hz), 3.16 (1H, dd, J ¼ 13:7, 7.2 Hz), 4.03 (1H, dd, J ¼ 8:3,
7.2 Hz), 7.18 (1H, dd, J ¼ 8:1, 7.1 Hz), 7.28 (1H, dd, J ¼ 7:8,
7.1 Hz), 7.32 (1H, s), 7.53 (1H, d, J ¼ 7:8 Hz), 8.36 (1H, d, J ¼
8:1 Hz); 13C NMR E isomer: ꢃ 16.8, 23.9, 27.8, 38.0, 39.9, 82.0,

K. Tanaka et al.
Bull. Chem. Soc. Jpn., 78, No. 9 (2005) 1663
107.0 (m), 116.8, 119.1, 119.2, 123.6, 123.7, 125.5, 129.0, 135.9,
137.7 (d complex, J ¼ 259:3 Hz), 143.4 (d complex, J ¼ 252:1
Hz), 145.4 (d complex, J ¼ 258:2 Hz), 156.2, 166.3, 168.7,
171.4; Z isomer: ꢃ 20.6, 23.9, 33.4, 40.6, 82.4, 107.0 (m),
116.7, 118.8, 119.0, 123.0, 123.4, 125.6, 128.6, 135.9, 137.7 (d
complex, J ¼ 259:3 Hz), 143.4 (d complex, J ¼ 252:1 Hz),
145.4 (d complex, J ¼ 258:2 Hz), 156.2, 167.0, 168.3, 171.1;
HRMS (FABþ) Found: m=z 539.1592, Calcd for C26H24F5N2O5:
ðM þ HÞþ, 539.1605.
13C NMR ꢃ 24.7, 28.0, 116.3, 117.7, 118.4, 119.5, 123.0, 123.8,
127.8, 128.2, 138.0, 150.9, 155.5, 171.6.
2,9-Dimethyl-9H-pyrido[2,3-b]indole16b (5b): Pale-yellow
oil; IR (ZnSe) 3051, 2922, 1591, 1576, 1474, 1435, 1402, 1227,
1124, 779, 733 cmꢃ1 1H NMR ꢃ 2.70 (3H, s), 3.93 (3H, s),
;
7.01 (1H, d, J ¼ 7:8 Hz), 7.25 (1H, dd, J ¼ 7:8, 7.1 Hz), 7.42
(1H, d, J ¼ 8:1 Hz), 7.48 (1H, dd, J ¼ 8:1, 7.1 Hz), 8.01 (1H,
d, J ¼ 7:8 Hz), 8.18 (1H, d, J ¼ 7:8 Hz); 13C NMR ꢃ 24.9,
27.5, 108.9, 113.1, 114.7, 119.5, 120.5, 120.5, 125.9, 128.2,
140.0, 151.8, 154.4.
2-[(1-Acetyl-3-indolyl)methyl]cyclohexanone (E)-O-Penta-
fluorobenzoyloxime (3h): Colorless powder; mp 138–142 ꢂC
(dec.) (dichloromethane–petroleum ether); IR 2939, 2862, 1753,
9-tert-Butyldimethylsilyl-2-methyl-9H-pyrido[2,3-b]indole
(5c): Pale-yellow oil; IR (ZnSe) 2952, 2925, 2856, 1589, 1452,
1392, 1296, 1252, 1215, 1194, 825 cmꢃ1; 1H NMR ꢃ 0.77 (6H, s),
0.98 (9H, s), 2.59 (3H, s), 6.97 (1H, d, J ¼ 7:8 Hz), 7.20 (1H, t,
J ¼ 7:4 Hz), 7.34 (1H, dd, J ¼ 8:3, 7.4 Hz), 7.60 (1H, d, J ¼
8:3 Hz), 8.10 (1H, d, J ¼ 7:8 Hz); 13C NMR ꢃ ꢃ1:5, 20.1, 24.7,
26.9, 113.9, 114.9, 114.9, 119.7, 120.1, 124.3, 125.4, 127.3,
143.7, 154.5, 157.7; HRMS (FABþ) Found: m=z 297.1810, Calcd
for C18H25N2Si: ðM þ HÞþ, 297.1787.
1705, 1523, 1497, 1450, 1387, 1327, 1198, 1003, 750 cmꢃ1
;
1H NMR ꢃ 1.49–1.61 (3H, m), 1.81–1.86 (2H, m), 2.03–2.06
(1H, m), 2.10–2.15 (1H, m), 2.64 (3H, s), 2.75–2.81 (1H, m),
2.83–2.87 (1H, m), 2.97–3.01 (1H, m), 3.24–3.29 (1H, m), 7.27
(1H, dd, J ¼ 7:7, 7.1 Hz), 7.33 (1H, dd, J ¼ 8:3, 7.1 Hz), 7.49
(1H, d, J ¼ 7:7 Hz), 7.60 (1H, s), 8.43 (1H, d, J ¼ 8:3 Hz);
13C NMR ꢃ 23.7, 24.1, 25.8, 26.5, 27.0, 33.6, 43.1, 107.2 (m),
116.8, 118.4, 119.5, 123.3, 124.9, 125.0, 130.9, 135.7, 137.8 (d
complex, J ¼ 243:1 Hz), 143.3 (d complex, J ¼ 253:5 Hz),
145.4 (d complex, J ¼ 257:2 Hz), 156.9, 169.0, 172.2.
tert-Butyl 9-Acetyl-2-methyl-9H-pyrido[2,3-b]indole-9-car-
boxylate (5d):
1720, 1456, 1392, 1333, 1252, 1153, 1119, 781 cmꢃ1
Colorless oil; IR (ZnSe) 3053, 2979, 2929,
1H NMR
;
4-(1-Acetyl-3-indolyl)butan-2-one (E)-O-Methoxycarbonyl-
oxime (2a): Colorless powder; mp 92–94 ꢂC (dec.) (dichloro-
methane–hexane); IR 3012, 2956, 1770, 1699, 1450, 1387,
;
1333, 1234, 883, 750 cmꢃ1 1H NMR ꢃ 2.01 (3H, s), 2.60 (3H,
s), 2.75 (2H, dd, J ¼ 7:9, 7.2 Hz), 2.99 (2H, dd, J ¼ 7:9, 7.2
Hz), 3.87 (3H, s), 7.27 (1H, dd, J ¼ 7:6, 7.5 Hz), 7.34 (1H, dd,
J ¼ 7:7, 7.6 Hz), 7.36 (1H, s), 7.49 (1H, d, J ¼ 7:5 Hz), 8.41
(1H, d, J ¼ 7:7 Hz); 13C NMR ꢃ 15.3, 21.0, 23.8, 34.8, 55.0,
116.6, 118.4, 120.6, 122.6, 123.3, 125.2, 130.1, 135.7, 154.4,
165.3, 168.5; Anal. Found: C, 63.57; H, 6.06; N, 9.11%. Calcd
for C16H18N2O4: C, 63.56; H, 6.00; N, 9.27%.
ꢃ 1.75 (9H, s), 2.72 (3H, s), 7.16 (1H, d, J ¼ 7:8 Hz), 7.34 (1H,
dd, J ¼ 7:7, 7.2 Hz), 7.46 (1H, dd, J ¼ 8:5, 7.2 Hz), 7.91 (1H,
d, J ¼ 7:7 Hz), 8.11 (1H, d, J ¼ 7:8 Hz), 8.23 (1H, d, J ¼ 8:5
Hz); 13C NMR ꢃ 25.2, 28.4, 84.0, 116.0, 116.2, 118.4, 119.8,
122.8, 123.1, 127.2, 128.0, 137.5, 149.8, 151.4, 156.7; HRMS
(FABþ) Found: m=z 283.1443, Calcd for C17H29N2O2:
ðM þ HÞþ, 283.1446.
2-Methyl-9H-pyrido[2,3-b]indole16c (5e): Pale-yellow solid;
IR (ZnSe) 3136, 3080, 2966, 1603, 1583, 1458, 1417, 1338, 1274,
1223, 733 cmꢃ1
;
1H NMR ꢃ 2.73 (3H, s), 7.06 (1H, d, J ¼ 7:8
Hz), 7.24 (1H, dd, J ¼ 8:1, 7.5 Hz), 7.43 (1H, dd, J ¼ 7:8, 7.5
Hz), 7.49 (1H, d, J ¼ 8:1 Hz), 8.00 (1H, d, J ¼ 7:8 Hz), 8.21
(1H, d, J ¼ 7:8 Hz), 9.53 (1H, s); 13C NMR ꢃ 24.5, 111.1,
113.9, 115.1, 119.9, 120.6, 121.2, 126.3, 128.6, 138.4, 151.9,
155.0.
Synthesis of ꢀ-Carbolines by the Copper-Catalyzed Radical
Cyclization of ꢁ-(3-Indolyl) Ketone O-Pentafluorobenzoyl-
oximes. The experimental procedure is shown below as a typical
example for the synthesis of tert-butyl 9-acetyl-2-methyl-9H-pyr-
ido[2,3-b]indole-4-carboxylate (5g) (Table 3, Entry 3).
9-Acetyl-2,3-dimethyl-9H-pyrido[2,3-b]indole (5f): Color-
less needles; mp 130–131 ꢂC (dichloromethane–hexane); IR
Copper powder (2.7 mg, 0.0425 mmol) and N,N0,N0,N00,N00-pen-
tamethyldiethylenetriamine (PMDETA) (0.058 mL, 0.278 mmol)
(ZnSe) 2993, 2922, 1693, 1402, 1367, 1313, 1188, 750 cmꢃ1
;
ꢂ
were warmed up to 80 C in 1,2-dichloroethane (7 mL). After 5
1H NMR ꢃ 2.05 (3H, s), 2.59 (3H, s), 3.13 (3H, s), 7.35 (1H,
ddd, J ¼ 7:7, 7.3, 1.0 Hz), 7.47 (1H, ddd, J ¼ 8:4, 7.3, 1.3 Hz),
7.86 (1H, ddd, J ¼ 7:7, 1.3, 0.6 Hz), 7.99 (1H, s), 8.68 (1H,
ddd, J ¼ 8:4, 1.0, 0.6 Hz); 13C NMR ꢃ 19.2, 23.1, 27.8, 116.8,
117.6, 119.4, 123.0, 123.7, 126.5, 127.6, 128.8, 138.0, 149.2,
154.1, 171.5; Anal. Found: C, 75.37; H, 6.03; N, 11.57%. Calcd
for C15H14N2O: C, 75.61; H, 5.92; N, 11.76%.
min, a solution of tert-butyl 2-(1-acetyl-3-indolyl)-4-(O-penta-
fluorobenzoyloxyimino)pentanoate (3g) (148.6 mg, 0.276 mmol)
in 1,2-dichloroethane (7 mL) was added in one-portion and the re-
action mixture was vigorously stirred at the same temperature.
The mixture was extracted 3 times with dichloromethane 5 min
after quenching the reaction with brine and N,N,N0,N0-tetramethyl-
pentanediamine (1 mL). The combined extracts were washed with
water and brine and dried over anhydrous sodium sulfate. Remov-
al of the solvent in vacuo afforded crude 3,4-dihydro-ꢁ-carboline,
which was dissolved with dichloromethane (5 mL) and treated
with chloranil (68.1 mg, 0.277 mmol) for 1 h. Solvent was re-
moved again and the crude product was purified by thin-layer
chromatography (Wako gel B-5F, ethyl acetate:hexanes = 1:3)
to give tert-butyl 9-acetyl-2-methyl-9H-pyrido[2,3-b]indole-4-
carboxylate (5g) (60.4 mg, 67%).
tert-Butyl 9-Acetyl-2-methyl-9H-pyrido[2,3-b]indole-4-car-
boxylate (5g): Colorless needles; mp 148 ꢂC (dichlorometh-
ane–hexane); IR (ZnSe) 2981, 2933, 1722, 1697, 1589, 1450,
1
1365, 1313, 1244, 1149, 1090, 1018, 764 cmꢃ1; H NMR ꢃ 1.69
(9H, s), 2.69 (3H, s), 3.13 (3H, s), 7.36–7.39 (1H, m), 7.47 (1H,
s), 7.51–7.54 (1H, m), 8.58 (1H, d, J ¼ 8:0 Hz), 8.73 (1H, d, J ¼
8:3 Hz); 13C NMR ꢃ 24.4, 28.2, 28.5, 82.9, 114.0, 116.8, 118.4,
121.7, 123.8, 124.4, 128.5, 134.9, 138.6, 151.8, 154.9, 165.5,
171.5; Anal. Found: C, 70.22; H, 6.18; N, 8.48%. Calcd for
C19H20N2O3: C, 70.35; H, 6.21; N, 8.64%.
6-Acetyl-1,2,3,4-tetrahydro-6H-indolo[2,3-b]quinoline (5h):
Colorless needles; mp 147–148 ꢂC (dichloromethane–hexane);
IR 3006, 2935, 1682, 1577, 1375, 1319, 1232, 746 cmꢃ1; 1H NMR
ꢃ 1.85–1.89 (2H, m), 1.92–1.96 (2H, m), 2.91 (2H, t, J ¼ 6:3 Hz),
3.01 (2H, t, J ¼ 6:3 Hz), 3.11 (3H, s), 7.34 (1H, dd, J ¼ 7:7, 7.3
Spectral Data for ꢀ-Carbolines.
9-Acetyl-2-methyl-9H-
pyrido[2,3-b]indole16a (5a): Colorless solid; IR (ZnSe) 3039,
2925, 1689, 1587, 1450, 1371, 1309, 1180, 1014, 779, 748, 734
cmꢃ1
;
1H NMR ꢃ 2.64 (3H, s), 3.12 (3H, s), 7.13 (1H, d, J ¼
7:8 Hz), 7.34–7.37 (1H, m), 7.46–7.49 (1H, m), 7.86 (1H, d, J ¼
7:7 Hz), 8.07 (1H, d, J ¼ 7:8 Hz), 8.67 (1H, d, J ¼ 8:4 Hz);

1664 Bull. Chem. Soc. Jpn., 78, No. 9 (2005)
Catalytic Synthesis of ꢁ-Carbolines
Hz), 7.46 (1H, dd, J ¼ 8:3, 7.3 Hz), 7.85 (1H, d, J ¼ 7:7 Hz), 8.67
(1H, d, J ¼ 8:3 Hz); 13C NMR ꢃ 23.0, 23.1, 27.8, 28.9, 33.1,
116.9, 117.6, 119.5, 123.1, 123.7, 127.4, 127.7, 128.4, 138.3,
149.4, 154.5, 171.5; Anal. Found: C, 77.14; H, 6.10; N, 10.39%.
Calcd for C19H20N2O3: C, 77.25; H, 6.10; N, 10.60%.
See: a) G. T. Bourne, D. Crich, J. W. Davies, and D. C. Horwell,
J. Chem. Soc., Perkin Trans. 1, 1991, 1693. b) M. Somei, A.
Tanimoto, H. Orita, F. Yamada, O. Fumio, and T. Ohta, Hetero-
cycles, 54, 425 (2001).
9
a) K. Uchiyama, Y. Hayashi, and K. Narasaka, Synlett,
1997, 445. b) A. Ono, K. Uchiyama, Y. Hayashi, and K. Narasaka,
Chem. Lett., 1998, 437. c) K. Uchiyama, Y. Hayashi, and K.
Narasaka, Chem. Lett., 1998, 1261. d) K. Uchiyama, A. Ono, Y.
Hayashi, and K. Narasaka, Bull. Chem. Soc. Jpn., 71, 2945
(1998). e) A. Ono and K. Narasaka, Chem. Lett., 2001, 146. f)
Y. Koganemaru, K. Kitamura, and K. Narasaka, Chem. Lett.,
2002, 784.
10 Example of the radical cyclization to the indolyl moiety at
the 2-position: F. E. Ziegler and L. O. Jeroncic, J. Org. Chem., 56,
3479 (1991).
This research was supported by a Grant-in-Aid for Scientific
Research on Priority Areas (A) ‘‘Exploitation of Multi-
Element Cyclic Molecules’’ and a Grant-in-Aid for The 21st
Century COE Program for Frontiers in Fundamental Chemis-
try from the Ministry of Education, Culture, Sports, Science
and Technology, Japan.
References
1
a) C. Moquin-Pattey and M. Guyot, Tetrahedron Lett., 45,
11 a) J. Szmuszkovicz, J. Am. Chem. Soc., 79, 2819 (1957). b)
K. B. Jensen, J. Thorhauge, R. G. Hazell, and K. A. Jørgensen,
Angew. Chem., Int. Ed., 40, 160 (2001). c) J. S. Yadav, S.
Abraham, B. V. S. Reddy, and G. Sabitha, Synthesis, 2001,
2165. d) M. Bandini, P. G. Cozzi, M. Giacomini, P. Melchiorre,
S. Selva, and A. Umani-Ronchi, J. Org. Chem., 67, 3700
(2002). e) D. A. Evans, K. A. Scheidt, K. R. Fandrick, H. W.
Lam, and J. Wu, J. Am. Chem. Soc., 125, 10780 (2003).
12 a) H. Nagashima, K. Ara, H. Wakamatsu, and K. Itoh,
Chem. Commun., 1985, 518. b) H. Nagashima, N. Ozaki, K. Seki,
M. Ishii, and K. Itoh, J. Org. Chem., 54, 4497 (1989). c) H.
Nagashima, N. Ozaki, M. Ishii, K. Seki, M. Washiyama, and K.
Itoh, J. Org. Chem., 58, 464 (1993). d) M. Benedetti, L. Forti,
F. Ghelfi, U. M. Pagnoni, and R. Ronzoni, Tetrahedron, 53,
14031 (1997). e) S. Iwamatsu, H. Kondo, K. Matsubara, and H.
Nagashima, Tetrahedron, 55, 1687 (1999). f) S. Iwamatsu, K.
Matsubara, and H. Nagashima, J. Org. Chem., 64, 9625 (1999).
g) A. J. Clark, F. De Campo, R. J. Deeth, R. P. Filik, S. Gatard,
and N. A. Hunt, J. Chem. Soc., Perkin Trans. 1, 2000, 671.
13 For the isolation and biological activities of cryptotack-
iene, see: a) J.-L. Pousset, M.-T. Martin, A. Jossang, and B. Bodo,
Phytochemistry, 39, 735 (1995). b) M. H. M. Sharaf, P. L. Schiff,
Jr., A. N. Tackie, C. H. Phoebe, Jr., and G. E. Martin, J. Hetero-
cycl. Chem., 33, 239 (1996). c) K. Cimanga, T. De Bruyne, L.
Pieters, M. Claeys, and A. Vlietnck, Tetrahedron Lett., 37, 1703
(1996). d) K. Cimanga, T. De Bruyne, L. Pieters, M. Claeys,
and A. Vlietnck, J. Nat. Prod., 60, 688 (1997).
3445 (1989). b) A. Badre, A. Boulanger, E. Abou-Mansour, B.
Banaigs, G. Combaut, and C. Francisco, J. Nat. Prod., 57, 528
(1994). c) T. P. Blackburn, D. Bolton, I. T. Forbes, C. N. Johnson,
R. T. Martin, D. R. Thomas, M. Thompson, and N. Upton, Bioorg.
Med. Chem. Lett., 4, 279 (1994). d) S. A. Abas, M. Bilaijet
Hossain, D. van der Helm, and F. J. Schmitz, J. Org. Chem.,
61, 2709 (1996).
2
a) D. Bolton, I. T. Forbes, C. J. Hayward, D. C. Piper, D.
R. Thomas, M. Thompson, and N. Upton, Bioorg. Med. Chem.
Lett., 3, 1941 (1993). b) J.-S. Kin, K. Shin-ya, K. Furihata, Y.
Hayakawa, and H. Seto, Tetrahedron Lett., 38, 3431 (1997).
3
A review article for the preparation of ꢁ-carbolines: A. A.
Sememov and V. V. Tolstikhina, Chem. Heterocycl. Compd.,
1984, 345.
4
a) P. Rocca, F. Marsais, A. Godard, and G. Queguiner,
Tetrahedron, 49, 49 (1993). b) S. Achab, M. Guyot, and P. Potier,
Tetrahedron Lett., 34, 2127 (1993). c) S. Achab, M. Guyot, and
P. Potier, Tetrahedron Lett., 36, 2615 (1995).
5
a) R. S. Sagitullin, N. N. Modyanov, A. N. Kost, and N. A.
Modyanov, Chem. Heterocycl. Compd., 1971, 58. b) I. T. Forbes,
C. N. Johnson, and M. Thompson, J. Chem. Soc., Perkin Trans. 1,
1992, 275. c) V. Levacher, N. Boussad, G. Dupas, J. Bourguignon,
and G. Queguiner, Tetrahedron, 48, 831 (1992). d) T. Chosi,
S. Yamada, E. Sugino, T. Kuwada, and S. Hibino, J. Org. Chem.,
60, 5899 (1995). e) M. Mayer and M. Guyot, Tetrahedron Lett.,
37, 4931 (1996). f) P. Molina, P. M. Fresneda, and M. A. Sanz,
Tetrahedron Lett., 38, 6909 (1997). g) P. Molina, P. M. Fresneda,
M. A. Sanz, C. Foces-Foces, and M. Carmen Ramirez de
Arellano, Tetrahedron, 54, 9623 (1998).
14 For the total synthesis of cryptotackiene, see: a) W.
Peczynska-Czoch, F. Pognan, L. Kaczmarek, and J. Boratynski,
J. Med. Chem., 37, 3503 (1994). b) M. Alajarin, P. Molina, and
A. Vidal, J. Nat. Prod., 60, 747 (1997). c) G. Timari, T. Soos,
and G. Hajos, Synlett, 1997, 1067. d) P. Molina, P. M. Fresneda,
and S. Delgado, Synthesis, 1999, 326. e) C. Shi, Q. Zhang, and
K. K. Wang, J. Org. Chem., 64, 925 (1999).
6
With a few exceptions, 2-aminoindoles are reported to
be unstable. See: A. Tahri, K. J. Buysens, E. V. van der Eychen,
D. M. Vandenberghe, and G. J. Hoornaert, Tetrahedron, 54, 13211
(1998).
7
a) A. Abouabdellah and R. H. Dodd, Tetrahedron Lett., 39,
15 Four 13C NMR peaks of the C6F5 moiety were split by C–F
couplings, which include geminal and vicinal couplings.
16 a) L. Stephenson and W. K. Warburton, J. Chem. Soc. C,
1970, 1355. b) P. I. Abramenko, Zh. Vses. Khim. Ova. im. D. I.
Mendeleeva, 18, 715 (1973). c) P. A. Sharbatyan, A. N. Kost,
V. V. Men’shikov, L. G. Yudin, and N. B. Chernyshova, Hetero-
cycl. Compd., 1980, 926.
2119 (1998). b) O. Barum, P. K. Patra, H. Ila, and H. Junjappa,
Tetrahedron Lett., 40, 3797 (1999). c) E. M. Beccalli, F. Clerici,
and A. Marchesini, Tetrahedron, 57, 4787 (2001). d) G. S. M.
Sundaram, C. Venkatesh, U. K. Syam Kumar, H. Ila, and H.
Junjappa, J. Org. Chem., 69, 5760 (2004).
8
For the direct amination of indole ring at the 2-position.