Synthesis of polyalkylated indoles using a thallium(III)-mediated ring-contraction reaction

Article abstract of DOI:10.1055/s-2007-990907

A new approach to the synthesis of cyclopenta[g]indole derivatives possessing structural features of natural alkaloids, such as trikentrins and herbindols, is described. The key step in the sequence is a thallium(III)- mediated ring-contraction reaction t

Full text of DOI:10.1055/s-2007-990907

PAPER
3851
Synthesis of Polyalkylated Indoles Using a Thallium(III)-Mediated
Ring-Contraction Reaction
S
ynthesis of Po
u
I
i
a
Instituto de Química, Universidade de São Paulo, CP 26077, CEP 05513-970, São Paulo SP, Brazil
E-mail: luizfsjr@iq.usp.br
b
Instituto de Química de São Carlos, Universidade de São Paulo, CP 780, CEP 13560-970, São Carlos SP, Brazil
Received 7 May 2007; revised 27 July 2007
present the synthesis of new cyclopenta[g]indole deriva-
tives, such as 1, through the thallium(III)-mediated ring-
contraction reaction of the six-membered-ring substrate 2
(Scheme 2).
Abstract: A new approach to the synthesis of cyclopenta[g]indole
derivatives possessing structural features of natural alkaloids, such
as trikentrins and herbindols, is described. The key step in the se-
quence is a thallium(III)-mediated ring-contraction reaction to
transform a cyclohexene moiety into a functionalized cyclopentyl
unit.
MeO
OMe
Key words: cyclopenta[g]indoles, thallium trinitrate, ring contrac-
tion
TTN, MeOH, 0 °C
87%
Cycloalkylindole alkaloids constitute a large number of
compounds, on which usually the carbocyclic moiety is
fused to the C2–C3 position.1,2 However, the cytotoxic
herbindoles and trikentrins, that were isolated from ma-
rine sponges, feature an unusual skeleton, on which the
cyclopentane ring is fused to the C6–C7 position. In addi-
tion, there is no substituent at the C2 and the C3 positions
(Figure 1).3 Furthermore, synthetic molecules with simi-
lar tricyclic ring systems can inhibit the human nonpan-
creatic secretory phospholipase A2, which is associated
with some diseases including arthritis, septic shock and
atherosclerosis.4 Thus, several approaches have been de-
veloped to construct the challenging framework of these
bioactive natural molecules.5
Scheme 1
MeO
N
N
MeO
PG
PG
1
2
Scheme 2
Indoles are known to be very reactive toward electrophilic
species, particularly at the 3-position. Among the electro-
philes utilized in functionalizations of indoles are thalli-
um(III) salts, such as thallium tris-trifluoroacetate
(TTFA) and thallium triacetate (TTA).9 In this scenario,
we started the present work investigating the reactivity of
the N-protected indole 3 with TTN, using one of the stan-
dard conditions for the ring-contraction reaction.8a This
reaction gave the indoline derivatives 4, 5, and 6 in 23%,
40%, and 9% isolated yields, respectively (Scheme 3).
Considering the behavior of the indole 3, the main chal-
lenge to obtain the desired cyclopenta[g]indole 1 using
thallium(III) would be the discovery of a reaction condi-
tion that could promote the rearrangement of the indole 2,
avoiding the oxidation of its very reactive C3 position.
3
3
2
2
6
6
N
N
7
H
7
H
cis-trikentrin A
trans-trikentrin A
Figure 1 Structure of cis- and trans-trikentrin A
We considered that a ring-contraction approach could be
used to obtain the cyclopentane ring of this class of alka-
loids. A reagent that could efficiently promote this rear-
rangement would be thallium trinitrate (TTN),6,7 which
has already been used in the synthesis of several indanes
through the rearrangement of 1,2-dihydronaphthalenes
(Scheme 1),8 including the total synthesis of the sesquiter-
pene ( )-mutisianthol.8b Based on these results, we herein
The indoline 4 is a crystalline solid, whose X-ray crystal
structure analysis showed a trans relationship between the
nitrate and methoxy groups (Figure 2). Thus, by analogy
with the NMR data of compound 4, the relative configu-
ration of the trans-dimethoxy derivative 5 could be as-
signed. The NMR data of the indolines 4, 5 and 6 deserve
some comments. The signals of Ha in 4 and 5 are broad
singlets. On the other hand, Ha appears as a doublet with
a coupling constant of J = 5.1 Hz in the indoline 6. Addi-
tionally, Ha and Hb of the cis isomer 6 are deshielded when
compared to the same hydrogens of the corresponding
SYNTHESIS 2007, No. 24, pp 3851–3857
x
x.
x
x
.
2
0
0
7
Advanced online publication: 15.11.2007
DOI: 10.1055/s-2007-990907; Art ID: M03007SS
© Georg Thieme Verlag Stuttgart · New York

3852
L. F. Silva, Jr. et al.
PAPER
ONO2
OMe
TlX2
R
TTN
MeOH, 0 °C
TTN
Path a
3
+
– X–, – H+
X = ONO2
MeOH
or ONO2–
N
N
N
N
Boc
Boc
Boc
Boc
7
3
4 23%
OMe
Path b
OMe
MeOH
TlX2
MeOH
OMe
OMe
+
4 and 5
N
MeOH
N
6
OMe
Boc
Boc
N
5 40%
6 9%
Boc
8
Scheme 3
OMe
MeOH
5
N
Boc
9
Scheme 4
The diastereoselectivity observed in the oxidation of the
indole 3, where the trans diastereoisomers (4 and 5) pre-
dominate over the cis (6), agrees with previous results8c
and can be explained by the mechanism shown in
Scheme 4.8c,d,12 The electrophilic addition of a thalli-
um(III) species at the C3 position of 3 would lead to the
iminium ion 7. This ion could either suffer a nucleophilic
attack at C3eitherby MeOH or by a nitrate ion, displacing
thallium(I) nitrate, and thus giving the trans-indolines 4
and 5, after addition of a second molecule of MeOH at C2
(Path a, Scheme 4). Other possibility would be the attack
at C2of 7 by MeOH, which would lead to the oxythallated
intermediate 8 (Path b). This organometallic species could
suffer an intramolecular displacement of thallium(I) ni-
trate generating the oxonium ion 9, that would give the
trans-indoline 5, after anti addition of a second molecule
of solvent. Furthermore, the MeOH displacement of thal-
lium(I) nitrate in 8 by MeOH would give the cis-isomer 6.
Figure 2 ORTEP diagram of 411
trans isomer 5. This observation agrees with the data on
some analogous indolines previously reported in the liter-
ature (Figure 3).10
ONO2
OMe
Ha
OMe
Ha
Ha
OMe
OMe
Hb
OMe
Hb
N
N
N
Hb
Boc
Boc
Boc
4
5
6
Ha: 5.90 (br s)
Hb: 5.48 (br s)
Ha: 4.40 (br s)
Hb: 5.42 (br s)
Ha: 4.87 (d, J = 5.1 Hz)
Hb: 5.60 (br s)
C2: 92.6; C3:
84.1
C2: 93.7; C3: 83.2
C2: 89.1; C3: 80.5
OH
OH
Ha
Ha
OH
Hb
SO2Ph
Ha: 4.90 (s)
Hb: 5.61 (s)
OH
N
N
Hb
SO2Ph
Ha: 5.06 (s)
Hb: 5.77 (s)
Desarbre et al., ref. 10
Figure 3 Selected NMR data for indolines
Synthesis 2007, No. 24, 3851–3857 © Thieme Stuttgart · New York

PAPER
Synthesis of Polyalkylated Indoles
3853
The tricyclic indole 12 was prepared from the tetralone observed when the solvent MeOH is replaced by trimethyl
10, which was obtained as described by Zhang et al.13 Re- orthoformate (TMOF).6a Thus, we decided to perform the
duction of the ketone moiety of 10 was carried out using reaction of 12 with TTN using TMOF as solvent and at
NaBH4 in MeOH. The crude 1-tetralol was treated with p- low temperature. The addition of TTN was made at –78
toluenesulfonic acid (PTSA) in toluene, affording the de- °C and the solution was allowed to warm up. Under these
sired 1,2-dihydronaphthalene 11, in excellent yield. At conditions, the cyclopenta[g]indole 16 was obtained as a
this point, we had two possible routes: the rearrangement single product in 85% yield. The reaction of 14 was per-
of the cyclohexene moiety could be performed before or formed in a similar manner affording the ring-contraction
after the formation of the indole skeleton. Considering product 17, also in excellent yield. These reaction condi-
that the thallium(III)-mediated oxidation of 1,2-dihy- tions are crucial to obtain the desired product in good
dronaphthalenes bearing electron-withdrawing groups in yields. For instance, when the oxidation of 12 was per-
the 7-position, analogous to 11, led to several by-prod- formed using TTN in MeOH at 0 °C which is the typical
ucts,8c we rationalized that the best alternative would be condition for the rearrangement of 1,2-dihydronaphtha-
the construction of the indole skeleton before the rear- lenes, the ring-contraction product 16 was obtained in
rangement. Thus, the indole 12 was prepared from the 1,2- only 24% yield. In this case, the main product was the
dihydronaphthalene 11 using the Bartoli reaction,14 which trans-indoline derivative 18 isolated in 40% yield, which
was best performed using six equivalents of the Grignard was presumably formed by ring-contraction reaction and
reagent (Scheme 5).
by an electrophilic addition to the double bond of the in-
dole moiety. The compound 18 was isolated as a 1:1 mix-
ture of diastereomers, which could not be separated
(Scheme 7).
1) NaBH4, MeOH
2) PTSA
O
NO2
NO2
95%
TTN, TMOF
MeO
–50 °C to –35 °C
10
11
N
N
85%
Boc
Boc
MeO
MgBr
13
16
THF, –45 °C
N
H
56%
TTN, TMOF
MeO
MeO
–50 °C to –35 °C
12
N
N
93%
Ts
Ts
Scheme 5
14
17
OMe
Substrates bearing an N–H bond usually give complex
mixtures when treated with thallium(III)8c,15 and the same
was observed for 12.16 Consequently, the indole was pro-
tected with the usual Boc and Ts groups. The N-protection
with Boc2O was performed as described by Ghren,17 af-
fording 13 in good yield. The reaction of 12 with TsCl us-
ing the procedure described by Ottoni and co-workers18
led to two isomers, 14 and 15, which were separated by
column chromatography (Scheme 6).
TTN, MeOH
0 °C
MeO
MeO
OMe
N
13
16
+
Boc
24%
18 40%
Scheme 7
The formation of 16 can be explained by the mechanism
shown in Scheme 8.8c,d,10 The trans-diaxial ring opening
of a thallonium intermediate by a molecule of MeOH
(formed by the reaction of TMOF with the hydration wa-
ter of TTN) would generate the oxythallated adduct 19.
After the ring contraction, the oxonium ion intermediate
20 would be converted to the cyclopenta[g]indole 16 by
addition of a second molecule of MeOH.
In the thallium(III)-mediated oxidation of 1,2-dihy-
dronaphthalenes lowering the temperature favors the ring
contraction instead of addition.8a,19 A similar tendency is
Boc2O, DMAP,
MeCN
12
N
85%
Boc
13
The relative configuration of the indoline moiety of the
tricyclic 18 was assigned by comparison to the NMR data
of the indolines 5 and 6. Clearly, the 1H and 13C NMR data
of the 1,2-dimethoxy moiety of 18 match with those of the
indoline 5 (Figure 4).
Ts
1) NaOH, CH2Cl2
2) TsCl
12
+
N
N
H
73%
Ts
In summary, a new and short approach for the synthesis of
cyclopenta[g]indole derivatives was developed. The in-
doles obtained feature the carbocyclic ring system of nat-
14
15
Scheme 6
Synthesis 2007, No. 24, 3851–3857 © Thieme Stuttgart · New York

3854
L. F. Silva, Jr. et al.
PAPER
Reaction of tert-Butyl-1H-indole-1-carboxylate (3) with TTN in
MeOH at 0 °C
TTN, MeOH
MeO
– TlX, – X–
N
To a stirred cooled (0 °C) solution of 3 (0.469 g, 2.16 mmol) in
MeOH (14 mL) was added TTN·3H2O (1.06 g, 2.37 mmol, 1.1
equiv). After 10 min, a white precipitated was formed and the mix-
ture was filtered through a silica gel pad (10 cm, 70–230 mesh) us-
ing CH2Cl2 as eluent (150 mL). The resulting solution was washed
with H2O (50 mL), brine (50 mL), and dried (MgSO4). The solvent
was removed under reduced pressure and the residue was purified
by flash chromatography (10% EtOAc in hexanes) affording 4
(0.157 g, 23%), 5 (0.243 g, 40%), and 6 (0.0528 g, 9%).
13
– X–, – H+
X
Boc
X = ONO2
Tl
19
X
MeOH
– H+
16
N
MeO
Boc
20
trans-1-tert-Butoxycarbonyl-2-methoxyindoline 3-Nitrate (4)
Scheme 8
White solid; mp 97–98 °C.
IR (KBr): 2984, 2938, 1708, 1644, 1394, 1274, 1150 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.60 (s, 9 H), 3.58 (s, 3 H), 5.48
(br s, 1 H), 5.90 (s, 1 H), 7.08 (dt, J = 7.8, 1.2 Hz, 1 H), 7.43 (d, J =
7.8 Hz, 2H), 7.86 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 28.3, 57.0, 82.7, 84.1, 92.6, 116.3,
122.3, 123.5, 127.3, 132.1, 144.0, 151.7.
OMe
Ha
MeO
MeO
OMe
Hb
N
Boc
18
LRMS: m/z (%) = 247 (9, [M+ – HNO3]), 57 (100).
HRMS: [ESI (+)]: m/z [M + Na]+ calcd for C14H18N2O6: 333.1063;
Ha: 4.25 (s)
Hb: 5.44 (s)
C2: 95.9; C3: 83.2
found: 333.1065.
Figure 4 Selected NMR data for indoline 18.
tert-Butyl trans-2,3-Dimethoxyindoline-1-carboxylate (5)
Light yellow oil.
IR (KBr): 2978, 2934, 1710, 1482, 1392, 1168, 1062 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.58 (s, 9 H), 3.43 (s, 3 H), 3.58
(s, 3 H), 4.40 (s, 1 H), 5.42 (br s, 1 H), 7.03 (dt, J = 7.2, 0.9 Hz, 1
ural products and biologically active molecules, which
makes this route attractive to the synthesis of those mole-
cules. The key step in the sequence is a chemoselective
ring-contraction reaction mediated by thallium trinitrate. H), 7.26–7.38 (m, 2 H), 7.80 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 28.3, 56.0, 56.1, 81.9, 83.2, 93.7,
116.3, 122.8, 126.3, 128.3, 130.3, 142.7, 152.5.
Finally, new aspects of the reactivity and of the properties
of indoles and indolines were discovered.
LRMS: m/z (%) = 279 (6, [M+]), 57 (100).
HRMS [ESI (+)]: m/z [M + K]+ calcd for C15H21NO4: 318.1108;
found: 318.1093.
THF and MeCN were freshly distilled from sodium/benzophenone
and from CaH2, respectively. 3,4-Dihydro-5-nitronaphthalen-1-
(2H)-one (10) was prepared as described by Zhang et al.13 Other re-
agents were used as received. Column chromatography was per-
formed using silica gel Acros 200–400 mesh. TLC analyses were
performed with silica gel plates Merck, using UV-254 nm, p-anis-
aldehyde and phosphomolybdic acid solutions for visualization. 1H
and 13C NMR spectra were recorded on Bruker and Varian spec-
trometers. IR spectra were measured on a PerkinElmer 1750-FT.
The X-ray (monocrystal diffraction) crystal structure determination
was performed on an Enraf-Nonius CAD4-Mach instrument. Gas
chromatography analyses were performed in a HP-6890 series II.
CG-MS analyses were performed using Finnigan-MAT INCOS
50B and GC Varian 2400. Elemental analyses were performed us-
ing PerkinElmer 2400 apparatus. High-resolution mass spectra
were performed on a Bruker Daltonics Micro-TOF electrospray in-
strument.
tert-Butyl cis-2,3-Dimethoxyindoline-1-carboxylate (6)
Light yellow oil.
IR (KBr): 2978, 2934, 1710, 1482, 1392, 1168, 1062 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.59 (s, 9 H), 3.50 (s, 3 H), 3.63
(s, 3 H), 4.87 (d, J = 5.1 Hz, 1 H), 5.60 (br s, 1 H), 7.00–7.05 (m, 1
H), 7.21–7.32 (m, 2 H), 7.60 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 28.3, 56.6, 58.7, 80.5, 81.8, 89.1,
115.7, 123.3, 124.0, 128.9, 130.4, 140.0, 152.6.
LRMS: m/z (%) = 279 (6, [M+]), 57 (100).
HRMS [ESI (+)]: m/z [M + Na]+ calcd for C15H21NO4: 302.1368;
found: 302.1357.
1,2-Dihydro-8-nitronaphthalene (11)
tert-Butyl 1H-Indole-1-carboxylate (3)
To a stirred cooled (0 °C) solution of 3,4-dihydro-5-nitronaphtha-
len-1-(2H)-one (10; 0.426 g, 2.22 mmol) in MeOH (10 mL) was
added NaBH4 (0.0830 g, 2.20 mmol). The mixture was stirred for 1
h. After this period, H2O (10 mL) was added followed by neutral-
ization with 10% aq HCl. Extraction was performed using EtOAc
(3 × 50 mL). The organic phase was washed with H2O (50 mL),
brine (50 mL) and dried (MgSO4). The solvent was removed under
reduced pressure, affording 1,2,3,4-tetrahydro-5-nitronaphthalen-
1-ol (0.425 g, 99%), as a brown oil, which was used in the next step
without purification. An analytical sample was obtained for charac-
terization.
To a stirred solution of 1H-indole (0.240 g, 2.05 mmol), MeCN (6
mL), and DMAP (cat.) in a two-necked flask was added Boc2O
(0.672 g, 3.08 mmol, 1.5 equiv). Liberation of CO2 was then ob-
served. After 1.5 h, the mixture was extracted with Et2O (3 × 50 mL)
and the organic layer was washed with H2O (50 mL), aq sat.
NaHCO3 (50 mL), brine (50 mL), and dried (MgSO4). The solvent
was removed under reduced pressure and the residue was purified
by flash chromatography (20% EtOAc in hexanes) to afford 32
(0.436 g, 98%); colorless oil.
Synthesis 2007, No. 24, 3851–3857 © Thieme Stuttgart · New York

PAPER
Synthesis of Polyalkylated Indoles
3855
1,2,3,4-Tetrahydro-5-nitronaphthalen-1-ol
brine (20 mL), and dried (MgSO4). The solvent was removed under
reduced pressure and the residue was purified by flash chromatog-
raphy (gradient 10–20% EtOAc in hexanes) to afford 13 (0.265 g,
85%); colorless oil.
IR (film): 3183, 2947, 1525, 1352, 1056 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.80–2.04 (m, 4 H), 2.38 (br s, 1
H), 2.89–2.99 (m, 2 H), 4.78 (m, 1 H), 7.32 (t, J = 7.9 Hz, 1 H),
7.70–7.76 (m, 2 H).
IR (film): 3455, 3031, 2971, 1739, 1336, 1150 cm–1.
13C NMR (75 MHz, CDCl3): d = 18.1, 26.0, 31.2, 67.7, 123.5,
1H NMR (300 MHz, CDCl3): d = 1.61 (s, 9 H), 2.23–2.31 (m, 2 H),
3.12 (m, 2 H), 6.01 (dt, J = 9.5, 4.4 Hz, 1 H), 6.47 (d, J = 3.7 Hz, 1
H), 6.57 (dt, J = 9.5, 1.7 Hz, 1 H), 6.97 (d, J = 7.8 Hz, 1 H), 7.32 (d,
J = 7.8 Hz, 1 H), 7.48 (d, J = 3.7 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 23.0, 25.8, 28.1, 83.3, 107.6,
118.5, 122.7, 122.9, 127.0, 128.8, 128.9, 131.4, 131.5, 134.1, 149.9.
126.4, 131.9, 133.4, 141.6, 149.5.
LRMS: m/z (%) = 193 (2, [M+]), 158 (100).
Anal. Calcd for C10H11NO3: C, 62.17; H, 5.74; N, 7.25. Found: C,
61.83; H, 5.64; N, 7.01.
To a solution of the above 1,2,3,4-tetrahydro-5-nitronaphthalen-1-
ol (0.605 g, 3.12 mmol) in toluene (15 mL) was added some crystals
of PTSA. The mixture was refluxed in a Dean–Stark apparatus for
1.5 h. After this period, the mixture was cooled to r.t. and 10% aq
NaHCO3 (10 mL) was added. The solution was washed with H2O
(30 mL), brine (30 mL) and dried (MgSO4). The solvent was re-
moved under reduced pressure and the residue was purified by flash
chromatography (5% EtOAc in hexanes) to afford 11 (0.527 g,
96%); yellow oil.
LRMS: m/z (%) = 169 (74, [M+ – Boc]), 168 (100).
Anal. Calcd for C17H19NO2: C, 75.81; H, 7.11; N, 5.20. Found: C,
76.04; H, 7.54; N, 4.92.
Reaction of 8,9-Dihydro-1H-benzo[g]indole (12) with Tosyl
Chloride
To a stirred solution of 12 (0.0900 g, 0.530 mmol) in CH2Cl2 (5 mL)
was added NaOH (0.032 g, 0.80 mmol, 1.5 equiv). After 25 min,
TsCl (0.202 g, 1.06 mmol, 2.0 equiv) was added. The mixture was
stirred for 24 h, diluted with CH2Cl2 (10 mL) and then washed with
H2O (3 × 10 mL) and dried (MgSO4). The solvent was removed un-
der reduced pressure and the residue was purified by flash chroma-
tography (gradient 10–20% EtOAc in hexanes) affording 14
(0.0671 g, 39%) and 15 (0.0601 g, 35%), both as brown oils.
11
IR (film): 3044, 2956, 1513, 1347 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.29–2.36 (m, 2 H), 3.03–3.06 (m,
2 H), 6.16 (dt, J = 9.6, 4.4 Hz, 1 H), 6.50 (dt, J = 9.6, 1.9 Hz, 1 H),
7.20–7.28 (m, 2 H), 7.64 (dd, J = 7.3, 2.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 22.2, 23.0, 122.5, 126.7, 126.7,
8,9-Dihydro-1-tosyl-1H-benzo[g]indole (14)
IR (film): 3034, 2928, 1355, 1173 cm–1.
129.9, 130.1, 130.7, 136.3, 149.2.
LRMS: m/z (%) = 175 (63, [M+]), 128 (100).
1H NMR (300 MHz, CDCl3): d = 2.11–2.19 (m, 2 H), 2.34 (br s, 3
H), 3.17 (t, J = 8.3 Hz, 2 H), 5.98 (dt, J = 9.5, 4.4 Hz, 1 H), 6.48 (dt,
J = 9.5, 1.7 Hz, 1 H), 6.61 (d, J = 3.8 Hz, 1 H), 6.93 (d, J = 7.8 Hz,
1 H), 7.17 (d, J = 8.5 Hz, 2 H), 7.28 (d, J = 7.8 Hz, 1 H), 7.49 (m, 2
H), 7.70 (d, J = 3.8 Hz, 1 H).
Anal. Calcd for C10H9NO2: C, 68.56; H, 5.18; N, 8.00. Found: C,
68.54; H, 5.25; N, 7.76.
8,9-Dihydro-1H-benzo[g]indole (12)
13C NMR (75 MHz, CDCl3): d = 21.6, 22.8, 24.6, 109.6, 119.6,
122.8, 123.5, 126.5, 127.5, 128.6, 129.7, 130.6, 131.9, 132.5, 134.6,
136.3, 144.5.
LRMS: m/z (%) = 323 (17, [M+]), 168 (100), 167 (60).
HRMS [ESI (+)]: m/z [M + H]+ calcd for C19H19NO2S: 323.0980;
To a stirred and cooled (–45 °C) solution of 11 (1.44 g, 8.20 mmol)
in anhyd THF (15 mL) under N2 was added a THF solution of vi-
nylmagnesium bromide20 (6.42 g, 49.0 mmol, 6 equiv) in one por-
tion. After 45 min, sat. aq NH4Cl (15 mL) was added and the
mixture was allowed to warm to r.t. Extraction was performed with
Et2O (3 × 100 mL) and the organic layer was washed with sat. aq
NH4Cl (70 mL), H2O (70 mL), brine (70 mL), and dried (MgSO4).
The solvent was removed under reduced pressure and the residue
was purified by flash chromatography (gradient 10–20% EtOAc in
hexanes) affording first the starting material (0.144 g, 10%) and
then 12 (0.638 g, 51%) as a white solid, which turned yellow upon
storage; mp 96–97 °C.
found: 323.0982.
8,9-Dihydro-3-tosyl-1H-benzo[g]indole (15)
IR (film): 3169, 3.039, 2935, 1595, 1372, 1174 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.14–2.21 (m, 2 H), 2.35 (br s, 3
H), 3.19 (t, J = 8.3 Hz, 2 H), 6.03 (dt, J = 9.5, 4.4 Hz, 1 H), 6.49 (dt,
J = 9.5, 1.7 Hz, 1 H), 7.01 (d, J = 7.9 Hz, 1 H), 6.93 (d, J = 7.8 Hz,
1 H), 7.20 (d, J = 8.5 Hz, 2 H), 7.30 (d, J = 7.9 Hz, 1 H), 7.50 (m, 2
H), 7.67 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 21.6, 22.7, 24.5, 114.7, 116.8,
123.4, 124.0, 126.4, 126.7, 128.4, 128.4, 129.8, 130.0, 133.1, 134.1,
135.5, 144.9.
IR (film): 3520, 3026, 2924, 1431, 1318 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.34–2.42 (m, 2 H), 2.84 (t,
J = 8.5, 2 H), 5.92 (dt, J = 9.6, 4.4 Hz, 1 H), 6.49 (dd, J = 2.0, 3.2
Hz, 1 H), 6.56 (dt, J = 9.6, 1.9 Hz, 1 H), 6.87 (d, J = 8.0 Hz, 1 H),
7.09 (dd, J = 1.5, 3.1 Hz, 1 H), 7.42 (dd, J = 8.0, 0.6 Hz, 1 H), 7.83
(br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 21.9, 22.6, 103.1, 116.9, 118.1,
tert-Butyl-7,8-dihydro-6-(dimethoxymethyl)cyclopenta[g]in-
dole-1(6H)-carboxylate (16)
119.5, 124.6, 125.0, 127.5, 127.7, 128.5, 134.2.
LRMS: m/z (%) = 169 (97.5, [M+]), 168 (100), 39 (62).
To a stirred and cooled (–78 °C) solution of 13 (0.0726 g, 0.270
mmol) in TMOF (3 mL) was added TTN·3H2O (0.133 g, 0.290
mmol, 1.1 equiv). The solution was allowed to warm up (1.5 h) and
TLC analysis was made during every change of 10 °C showing that
all starting material was consumed between –50 °C and –35 °C. A
white precipitate was formed and the mixture was filtered through
a silica gel pad (10 cm, 70–230 Mesh) using CH2Cl2 as eluent (100
mL). The resultant solution was washed with H2O (20 mL), brine
(20 mL), and dried (MgSO4). The solvent was removed under re-
duced pressure and the residue was purified by flash chromatogra-
Anal. Calcd for C12H11N: C, 85.17; H, 6.55; N, 8.28. Found: C,
85.03; H, 6.52; N, 7.89.
tert-Butyl-8,9-dihydrobenzo[g]indole-1-carboxylate (13)
To a stirred solution of 12 (0.196 g, 1.16 mmol), MeCN (5 mL), and
DMAP (cat) in a two-necked flask was added Boc2O (0.381 g, 1.74
mmol, 1.5 equiv). Liberation of CO2 was then observed. After 1.5
h, the mixture was extracted with Et2O (3 × 50 mL) and the organic
layer was washed with H2O (50 mL), sat. aq NaHCO3 (20 mL),
Synthesis 2007, No. 24, 3851–3857 © Thieme Stuttgart · New York

3856
L. F. Silva, Jr. et al.
PAPER
phy (10% EtOAc in hexanes) to afford 16 (0.0760 g, 85%);
colorless oil.
Acknowledgment
We wish to thank FAPESP and CNPq for financial support. We also
thank Prof. Helena M. C. Ferraz for fruitful discussions.
IR (film): 2977, 1746, 1337, 1160, 1099, 1059 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.63 (s, 9 H), 1.98–2.26 (m, 2 H),
3.31–3.39 (m, 1 H), 3.39 (s, 3 H), 3.42 (s, 3 H), 3.48–3.58 (m, 2 H),
4.35 (d, J = 7.4 Hz, 1 H), 6.51 (d, J = 3.8 Hz, 1 H), 7.34 (s, 2 H),
7.49 (d, J = 3.8 Hz, 1 H).
References
(1) For some examples concerning the isolation of C2–C3 fused
cycloalkylindoles, see: (a) Ondeyka, J. G.; Helms, G. L.;
Hensens, O. D.; Goetz, M. A.; Zink, D. L.; Tsipouras, A.;
Shoop, W. L.; Slayton, L.; Dombrowski, A. W.; Polishook,
J. D.; Ostlind, D. A.; Tsou, N. N.; Ball, R. G.; Singh, S. B. J.
Am. Chem. Soc. 1997, 119, 8809. (b) Kato, L.; Braga, R.
M.; Koch, I.; Kinoshita, L. S. Phytochemistry 2002, 60, 315.
(c) Singh, S. B.; Ondeyka, J. G.; Jayasuriya, H.; Zink, D. L.;
Ha, S. N.; Dahl-Roshak, A.; Greene, J.; Kim, J. A.; Smith,
M. M.; Shoop, W.; Tkacz, J. S. J. Nat. Prod. 2004, 67, 1496.
(d) Carrol, A. R.; Hyde, E.; Smith, J.; Quinn, R. J.; Guymer,
G.; Forster, P. I. J. Org. Chem. 2005, 70, 1096.
(2) For some examples concerning the synthesis of C2–C3 fused
cycloalkylindoles, see: (a) Giannini, G.; Marzi, M.; Moretti,
G. P.; Penco, S.; Tinti, M. O.; Pesci, S.; Lazzaro, F.; De
Angelis, F. Eur. J. Org. Chem. 2004, 2411. (b) Maertens,
F.; Van den Bogaert, A.; Compernolle, F.; Hoornaert, G. J.
Eur. J. Org. Chem. 2004, 4648. (c) Smith, A. B. III.; Kurti,
L.; Davulcu, A. H. Org. Lett. 2006, 8, 2167. (d) Sturino, C.
F.; Lachance, N.; Boyd, M.; Berthelette, C.; Labelle, M.; Li,
L.; Roy, B.; Scheigetz, J.; Tsou, N.; Brideau, C.; Cauchon,
E.; Carriere, M.-C.; Denis, D.; Greig, G.; Kargman, S.;
Lamontagne, S.; Mathieu, M.-C.; Sawyer, N.; Slipetz, D.;
O’Neill, G.; Wang, Z.; Zamboni, R.; Metters, K. M.; Young,
R. N. Bioorg. Med. Chem. Lett. 2006, 16, 3043.
13C NMR (75 MHz, CDCl3): d = 27.4, 28.2, 33.3, 47.9, 53.0, 54.6,
83.2, 107.4, 107.6, 118.9, 120.9, 126.7, 130.4, 130.7, 132.4, 140.7,
149.3.
LRMS: m/z (%) = 331 (2, [M+]), 200 (9), 75 (100).
Anal. Calcd for C19H25NO4: C, 68.86; H, 7.60; N, 4.23. Found: C,
68.47; H, 7.31; N, 4.29.
1,6,7,8-Tetrahydro-6-(dimethoxymethyl)-1-tosylcyclopen-
ta[g]indole (17)
The reaction was performed as for 13, but using 14 (0.125 g, 0.389
mmol), TMOF (3 mL), and TTN·3H2O (0.182 g, 0.410 mmol, 1.1
equiv). The resultant solution was washed with H2O (20 mL), brine
(20 mL), and dried (MgSO4). The solvent was removed under re-
duced pressure and the residue was purified by flash chromatogra-
phy (30% EtOAc in hexanes) to afford 17 (0.140 g, 93%); colorless
oil.
IR (film): 3150, 2936, 1360, 1170, 1126, 1061 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.92–2.21 (m, 2 H), 2.34 (s, 3 H),
3.04–3.14 (m, 1 H), 3.25–3.35 (m, 4 H), 3.38 (s, 3 H), 3.41–3.48 (m,
1 H), 4.26 (d, J = 7.4 Hz, 1 H), 6.66 (d, J = 3.7 Hz, 1 H), 7.20 (d,
J = 8.5 Hz, 2 H), 7.35 (d, J = 3.7 Hz, 2 H), 7.56 (d, J = 8.3 Hz, 2 H),
7.66 (d, J = 3.7 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 21.5, 27.4, 31.9, 47.9, 53.2, 54.5,
107.5, 108.8, 119.5, 121.5, 126.5, 128.3, 129.7, 131.5, 136.9, 141.2,
144.5.
(3) (a) Capon, R. J.; MacLeod, J. K.; Scammels, P. J.
Tetrahedron 1986, 42, 6545. (b) Herb, R.; Carrol, A. R.;
Yoshida, W. Y.; Scheuer, P. J.; Paul, V. J. Tetrahedron
1990, 46, 3089.
(4) Sawyer, J. S.; Beight, D. W.; Smith, E. C. R.; Snyder, D. W.;
Chastain, M. K.; Tielkin, R. L.; Hartley, L. W.; Carlson, D.
G. J. Med. Chem. 2005, 48, 893.
LRMS: m/z (%)= 353 (74, [M+ – MeOH]), 75 (100).
Anal. Calcd for C21H23NO4S: C, 65.43; H, 6.01; N, 3.63. Found: C,
65.76; H, 5.69; N, 3.47.
(5) (a) MacLeod, J. K.; Monahan, L. C. Tetrahedron Lett. 1988,
29, 391. (b) Muratake, H.; Natsume, M. Tetrahedron Lett.
1989, 30, 5771. (c) Muratake, H.; Watanabe, M.; Goto, K.;
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Reactionoftert-Butyl-8,9-dihydrobenzo[g]indole-1-carboxylate
(13) in MeOH at 0 °C
The reaction was performed as for 3, but using 13 (0.0910 g, 0.340
mmol) in MeOH (2 mL), TTN·3H2O (0.165 g, 0.370 mmol, 1.1
equiv), and a reaction time of 5 min. The residue was purified by
flash chromatography (10% EtOAc in hexanes) affording 16
(0.0268 g, 24%; for spectral and analytical data, see above) and 18
(0.0540 g, 40%), both as colorless oils.
(e) Boger, D. L.; Zhang, M. J. Am. Chem. Soc. 1991, 113,
4230. (f) Muratake, H.; Mikawa, A.; Natsume, M.
Tetrahedron Lett. 1992, 33, 4595. (g) Muratake, H.; Seino,
T.; Natsume, M. Tetrahedron Lett. 1993, 34, 4815.
(h) Wiedenau, P.; Monse, B.; Blechert, S. Tetrahedron 1995,
51, 1167. (i) MacLeod, J. K.; Ward, A.; Willis, A. C. Aust. J.
Chem. 1998, 51, 177. (j) Jackson, S. K.; Banfield, S. C.;
Kerr, M. A. Org. Lett. 2005, 7, 1215. (k) Huntley, R. J.;
Funk, R. L. Org. Lett. 2006, 8, 3403. (l) Jackson, S. K.;
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tert-Butyl-2,3-dimethoxy-6-(dimethoxymethyl)-1,2,3,6,7,8-
hexahydrocyclopenta[g]indole-1(6H)-carboxylate (18)
IR (film): 2934, 2829, 1721, 1455, 1374, 1198, 1062 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.55 (s, 18 H), 1.71–1.82 (m, 1 H),
2.06–2.28 (m, 3 H), 2.63–2.82 (m, 2 H), 3.15–3.27 (m, 1 H), 3.32–
3.54 (m, 3 H), 3.366 (s, 6 H), 3.374 (s, 3 H), 3.39 (s, 3 H), 3.40 (s,
3 H), 3.45 (s, 3 H), 3.47 (s, 3 H), 3.48 (s, 3 H), 4.25 (s, 1 H), 4.27 (s,
1 H), 4.30 (d, J = 7.7 Hz, 1 H), 4.34 (d, J = 7.7 Hz, 1 H), 5.438 (s, 1
H), 5.443 (s, 1 H), 7.14–7.21 (m, 3 H), 7.26 (dd, J = 7.6, 0.9 Hz, 1
H).
13C NMR (75 MHz, CDCl3): d = 27.3, 28.3, 28.4, 31.5, 31.7, 47.2,
48.2, 52.7, 52.9, 53.5, 55.0, 55.6, 55.77, 55.81, 55.83, 81.6, 81.7,
83.1, 83.2, 95.8, 95.9, 106.7, 107.0, 120.7, 122.1, 124.37, 124.42,
128.5, 128.6, 134.0, 134.1, 138.99, 139.02, 146.9, 147.0, 152.9,
153,0.
(6) For some reviews concerning thallium(III) in organic
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Wilkinson, G., Ed.; Pergamon Press: New York, 1982, 465.
(b) Ferraz, H. M. C.; Silva, L. F. Jr.; Vieira, T. O. Synthesis
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Pizey, J. S., Ed.; Ellis Horwood: Chichester, 1983, 164.
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McKillop, A.; White, J. F. J. Am. Chem. Soc. 1976, 98,
LRMS: m/z (%) = 393 (2, [M+]), 75 (100).
Synthesis 2007, No. 24, 3851–3857 © Thieme Stuttgart · New York

PAPER
6750. (d) Rigby, J. H.; Pigge, F. C. J. Org. Chem. 1995, 60,
Synthesis of Polyalkylated Indoles
3857
(11) The X-ray crystal structure data have been deposited at the
Cambridge Crystallographic Data Centre and allocated the
deposition number CCDC 656449. Copies of the data can be
obtained free of charge on application to The Director,
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (Fax:
+ 44 1223 336 033; e-mail: deposit@ccdc.cam.ac.uk).
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1.1 equiv of TTN in MeOH at 0 °C.
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Synthesis 2007, No. 24, 3851–3857 © Thieme Stuttgart · New York