New route to the 5,12-dihydro-7H-benzo[2,3]azepino[4,5-b]indol-6-one core via a tin-mediated indole synthesis

Article abstract of DOI:10.1055/s-2006-950328

A new route to the paullone scaffold was designed. The key step consisted in a free radical indole formation from an o-alkenyl arylisonitrile followed by Stille coupling with N-Boc-o-iodoaniline. After deprotection and closure of the seven-membered ring by lactamisation, parent or cyano-substituted paullones were obtained in moderate to good yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950328

PAPER
3895
New Route to the 5,12-Dihydro-7H-benzo[2,3]azepino[4,5-b]indol-6-one Core
via a Tin-Mediated Indole Synthesis
T
in-Mediated Indo
i
le Synt
c
hesis olas Henry, Jérôme Blu, Valérie Bénéteau,* Jean-Yves Mérour
Institut de Chimie Organique et Analytique, UMR CNRS 6005, Université d’Orléans, Rue de Chartres, B.P. 6759, 45067 Orléans Cédex 2,
France
Fax +33(2)38417281; E-mail: valerie.beneteau@univ-orleans.fr
Received 6 July 2006; revised 19 July 2006
clin B inhibition by enhancing the basicity of the amide
Abstract: A new route to the paullone scaffold was designed. The
carbonyl group. Other substitutions proved to be un-
key step consisted in a free radical indole formation from an o-al-
favourable for CDK-1 inhibition, except in positions 2
and 3 where substituents are tolerated. The last generation
kenyl arylisonitrile followed by Stille coupling with N-Boc-o-iodo-
aniline. After deprotection and closure of the seven-membered ring
by lactamisation, parent or cyano-substituted paullones were ob- of paullones achieved stricking CDK-1 inhibition in the
subnanomolar range6 (Figure 2).
tained in moderate to good yields.
Key words: paullone, CDK inhibitor, tin, radical reaction, seven-
membered lactam
O
NH
R
Since the validation of kenpaullone as a potential cyclin-
dependent kinase (CDK) inhibitor by the NCI, the
paullones have been the focus of much interest in the sci-
entific community1 (Figure 1).
N
H
R'
2, R = SO2Me, R' = OMe, IC50(CDK-1) = 9 nM
3, R = NO2, R' = -(CH2)2CN, IC50(CDK-1) = 0.23 nM
O
6
Figure 2 The most efficient CDK-1 inhibitors in the paullone series
5
NH
7
8
R
9
C
4
As far as antiproliferative activity in vitro is concerned,
most of the paullones display significant IC50 on a wide
variety of tumoral cell lines. Anyway, it appears very dif-
ficult to correlate antiproliferative activity and CDK inhi-
bition. In 2003, Senderowicz et al. proved that
alsterpaullone (9-NO2) induces apoptosis.7 Recently,
compound 4, a new thiophene analogue of kenpaullone
was reported to combine CDK-1 inhibition, antiprolifera-
tive and pro-apoptotic properties in breast cancer cells.8 In
the continuing effort to improve the biological properties
of paullones, it appears that an epoxide-containing side
chain in position 2 (see compound 5) enhances the anti-
proliferative activity on human tumor cell lines9
(Figure 3). Besides their CDK inhibitory effect and anti-
proliferative activity, paullones are very potent inhibitors
of GSK-3b and neuronal CDK-5/p25. 1-Azakenpaullone
(6) was reported as a selective inhibitor of GSK-3b10
(Figure 3).
B
A
D
10
3
N12
1
11
H
2
1, R = Br kenpaullone
Figure 1 General core of the paullones
The paullones are kinase inhibitors, being particularly ef-
ficient against three disease-relevant kinases: GSK-3,
CDK-1 and CDK-5.2 Most of them possess a remarkable
in vitro antiproliferative activity as well.3 Moreover, mi-
tochondrial malate deshydrogenase has been found as an
intracellular target of paullones.4
From the basic heterocyclic core of the paullones, many
functional modifications have been achieved, leading to a
better understanding of the structure–activity relation-
ships of this family.5 From the CDK inhibition point of
view, the paullones can fit into the ATP binding pocket of
the kinases, anchored by four main hydrogen bondings:
the lactam carbonyl and nitrogen, a free indolic nitrogen
and a substituent in position 9 are required structural fea-
tures for a good inhibition. It has been proven that an elec-
tron-withdrawing group (Br, NO2, CF3, CN) in the 9-
position of the paullone structure enhances the CDK-1/cy-
Historically, the synthesis of the paullone core by Kunick
et al. relies on a Fischer indolisation from 3,4-dihydro-
1H-benzo[b]azepine-2,5-diones 7 and phenylhydrazines 8
(pathway A).3a Other groups have developed strategies
based on the final formation of the seven-membered ring
by lactam cyclisation (pathway B),11 free-radical cyclisa-
tion approach (pathway C)12 or Pd-catalysed C–C bond
induction (pathway D)13 (Scheme 1). Indeed, the lactami-
sation strategy (51% yield) has been used by Baudoin et
al., following the formation of the biaryl 9 via a Pd-catal-
ysed borylation/Suzuki-coupling reaction (62% yield).
SYNTHESIS 2006, No. 22, pp 3895–3901
Advanced online publication: 20.10.2006
DOI: 10.1055/s-2006-950328; Art ID: Z14106SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.
2
0
0
6

3896
N. Henry et al.
PAPER
O
employed by Joseph et al. to form in the last step the
C12a–C1a bond from protected compound 11 (92%
yield).
O
NH
Br
NH
Br
According to the retrosynthetic pathway reported in
Scheme 2, we preferred to access the paullone molecular
scaffold in a straightforward manner using a tin-mediated
indole synthesis described by Fukuyama.14
N
H
N
S
H
n
5
O
4
O
NH
The main advantage of this synthesis is a concomitant
one-pot formation of the indole core and two C–C bonds
in position 2 and 3. Besides, a protecting group on the in-
dole nitrogen is not necessary for the palladium coupling.
Above all, it should allow a large structural diversity on
the final product, depending on the nature of the haloge-
nated partner 17. We present here the scope and limita-
tions of this new way to access the 5,12-dihydro-7H-
benzo[2,3]azepino[4,5-b]indol-6-one system 1. In agree-
ment with Fukuyama’s work, the synthesis of isonitriles
15 precursors of the indole proved to be quite efficient14a
(Scheme 3).
Br
N
N
H
6, 1-azakenpaullone
Figure 3 Paullone derivatives with significant antiproliferative ac-
tivity (4, 5) or GSK-3b inhibition (6)
More recently, Bremner used a free-radical cyclisation of
an indole-haloacetamide precursor 10 to form the C7–C7a
bond (52% yield). Finally, a Heck-type reaction has been
O
O
CN
7
HN
NH
NHNH2
pathway A
pathway B
7a
R
R'
+
1a
R
N
H
R'
12a
N
H
R'
O
H2N
8
7
9
pathway C
pathway D
O
I
O
N
BnN
R'
EOM
R
I
N
N
H
EOM
R'
11
10
Scheme 1 Previous retrosyntheses of the Paullone core
O
CO2Me
CO2Me
R'
NH
R
R
R'
X
R
SnBu3
+
N
N
H
NHBoc
N
H
H
BocHN
R'
17
1
R = H, CN
R' = H, CN
X = I, Br
R' = H, CN
R
CO2Me
NC
15
Scheme 2 New retrosynthesis of the paullone core
Synthesis 2006, No. 22, 3895–3901 © Thieme Stuttgart · New York

PAPER
Tin-Mediated Indole Synthesis
3897
I
R
R
I
CO2Me
a or b
R
CO2Me
c or d
R
a
NH2
NHCHO
SnBu3
NC
N
H
12a: R = H
12b: R = CN
13a: R = H
15a: R = H
15b: R = CN
13b: R = CN
16a: R = H
CO2Me
R
16b: R = CN
CO2Me
R
e
CO2Me
CO2Me
R'
NHCHO
NC
R
b
14a: R = H
15a: R = H
15b: R = CN
or
14b: R = CN
R'
X
N
N
H
H
BocHN
19
Scheme 3 Reagents and conditions: a) NaH (1.25 equiv), HCO2Et
(5 equiv), THF, r.t., 24 h (13a: quant); b) NaH (2.5 equiv), HCO2Et
(10 equiv), THF, r.t., 24 h (13b: 90%); c) methyl acrylate (1.2 equiv),
Pd(OAc)2 (5 mol%), Et3N (1.1 equiv), P(o-tol)3 (10%), MeCN, reflux,
2.5 h (14a: 81%); d) methyl acrylate (1.2 equiv), Pd(OAc)2 (5 mol%),
Et3N (1.1 equiv), As(Ph)3 (10%), DMF, 50 °C, 18 h (14b: 74%); e)
triphosgene (0.36 equiv), Et3N (3 equiv), CH2Cl2, 0 °C to r.t., 1 h
(15a: 85%, 15b: 50%).
NHBoc
17
18a: R = H, R' = H
18b: R = CN, R' = H
18c: R = H, R' = CN
Scheme 4 Reagents and conditions a) Bu3SnH (1.1 or 1.5 equiv),
AIBN (0.04 equiv), MeCN, reflux, 1 h; b) 17 (1.4 equiv), Pd(PPh3)4
(10%), CuI (1 equiv), DMF, 50 °C, 1–3 h (18a: 80%, 18b: 32%, 18c:
88%).
In the first step, the primary amine of an o-iodoaniline 12
was converted into a formamide 13 by reaction with ethyl
formate and sodium hydride.15 Then a Heck palladium
coupling allowed the introduction of a methyl acrylate
moiety in the place of the iodine.14g Compound 14b was
obtained in only 42% yield when the conditions used for
the unsubstituted substrate were applied. By changing the
ligand from tri-o-tolylphosphine to triphenylarsine, the
solvent from acetonitrile to DMF and reducing the reac-
tion temperature, 14b was isolated in 74% yield. Finally,
the dehydration of the formamide into isonitrile with
triphosgene proceeded smoothly when no substituent was
present on the phenyl group (85% yield). With a cyano
group in para position anyway, the yield did not exceed
50%. We observed that 15b is not very stable in solution,
partially leading to the corresponding aniline after a few
hours. Other methods usually employed to synthesise an
isonitrile from a formamide have been tested: the use of
POCl3/pyridine,14j cyanuric chloride/triethylamine under
microwave irradiation16 or Burgess reagent17 led to the
degradation or partial recovery of the starting material.
The end of the sequence consisted in the deprotection of
the Boc carbamate, followed by lactamisation. For 18a
and 18b, the deprotection proceeded smoothly using tri-
fluoroacetic acid in dichloromethane in 96 and 81%, re-
spectively (Scheme 5). Surprisingly, biaryl 18c, under the
same conditions, gave directly the cyclised product 1c in
43% yield. The lactamisation of 20a and 20b were per-
formed in DMF at 100 °C in the presence of one equiva-
lent of DBU. Paullones 1a and 1b were then obtained in
respectively 56% and 55% yield. These moderate yields
may be due to purification difficulties related to the poor
solubility of these compounds.
In conclusion, we have achieved the synthesis of the
paullone core 1 via a Fukuyama’s indolic cyclisation/
Stille coupling sequence from isonitriles 15. The synthetic
MeO2C
MeO2C
R'
R'
R
R
a
N
N
H
H
For the unsubstituted isonitrile 15a, the radical cyclisation
to the intermediate stannyl indole 16a proved to be quan-
titative by TLC using 1.1 equivalents of tributyltin hy-
dride, at reflux of acetonitrile, in the presence of a
catalytic amount of AIBN (Scheme 4). Then, without iso-
lation of 16, a Stille coupling was used to generate the
C(1a)–C(12a) bond. We found that use of palladium tet-
rakistriphenylphosphine (10%), copper(I) iodide (1
equiv) and Boc-protected o-iodoanilines (1.4 equiv) in
DMF at 50 °C gave the best yields (Table 1). The pres-
ence of a nitrile group on the starting isonitrile 15b proved
to be detrimental to the cyclisation/coupling sequence
(see entry 4, Table 1). This may due to the instability and
partial decomposition of 15b in solution. Surprisingly,
none of the bromo derivatives 17c or 17d tested were able
to perform the Stille coupling, leading only to the isola-
tion of (1H-indol-3-yl)acetic acid methyl ester (19) (56%
yield).
BocHN
H2N
18a: R = H, R' = H
18b: R = CN, R' = H
18c: R = H, R' = CN
20a: R = H, R' = H
20b: R = CN, R' = H
O
NH
R
b
N
H
R'
1a: R = H, R' = H
1b: R = CN, R' = H
1c: R = H, R' = CN
Scheme 5 Reagents and conditions: a) TFA (5 equiv), CH2Cl2, r.t.,
18 h (20a: 96%, 20b: 81%, 1c: 43%); b) DBU (1 equiv), DMF,
100 °C, 18 h (1a: 56%, 1b: 55%).
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N. Henry et al.
PAPER
Table 1 ‘Semi One-Pot’ Cyclisation/Coupling Sequence
Entry
Isonitrile 15
15a
Halogenated partner 17
17a: X = I, R¢ = H
17a: X = I, R¢ = H
17a: X = I, R¢ = H
17a: X = I, R¢ = H
17b: X = I, R¢ = CN
17c: X = Br, R¢ = Me
17d: X = Br, R¢ = CF3
Temp (°C)
Producta
18a
18a
18a
18b
18c
Yield (%)
56b
1
2
3
4
5
6
7
100
50c
50
15a
18
15a
80
15b
50
32
15a
50
88
15a
50
19
56
15a
50
19
n.d.d
a Experimental conditions: 17 (1.4 equiv), Pd(PPh3)4 (10%), CuI (1 equiv), DMF.
b Partial Boc deprotection of 17a was observed.
c CuI (20%), CsF (2 equiv) were used.
d Not determined.
IR (KBr): 3312, 2229, 1711 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 9.72 (br s, 1 H, NH), 8.46 (s,
pathway proved to be very efficient for the paullone with
no substituent in position 9, but the key step remained
low-yielding for the 9-CN derivative. Current work in our 1 Harom), 8.35 (d, J = 2 Hz, 1 Harom), 8.14 (br s, 1 H, CHO), 7.82 (dd,
J = 2, 8.5 Hz, 1 Harom).
13C NMR (75 MHz, DMSO-d6): d = 161.2 (CHO), 142.9, 142.7
(CH), 132.8 (CH), 122.3 (CH), 117.3 (CN), 108.1, 90.4.
laboratory is intended to solve this drawback. The pres-
ence of an electron-withdrawing group in position 2 of the
final paullone did not cause any difficulty during the
course of the whole synthesis.
HRMS (EI): m/z calcd for C8H5IN2O: 271.94466; found: 271.9457.
This new access to the paullone core may be useful in or-
der to achieve a wide diversity on the D ring, as the key
cyclisation/coupling reaction could be made in a multi-
hole reactor with different iodoaniline partners.
3-(5-Cyano-2-formylaminophenyl)acrylic Acid Methyl Ester
(14b)
Under argon, a solution of 13b (2.60 g, 9.57 mmol) in degassed
DMF (50 mL) was successively treated with methyl acrylate (1.03
mL, 11.48 mmol), Pd(OAc)2 (107 mg, 0.48 mmol), triphenylarsine
(293 mg, 0.96 mmol) and Et3N (1.47 mL, 10.53 mmol). The mixture
was heated at 50 °C overnight. DMF was removed under vacuum
and the crude product purified by flash chromatography (CH2Cl2–
EtOAc, 9:1 then 8:2, then 1:1) to afford the title compound as a co-
lourless solid; yield: 1.63 g (74%); mp 153–155 °C.
IR (KBr): 2229, 1728 cm–1.
1H NMR (250 MHz, DMSO-d6, 80 °C): d = 10.22 (br s, 1 H, NH),
8.44 (s, 1 Harom), 8.20 (s, 1 Harom), 7.93–7.72 (m, 2 H, CHO and
1H and 13C NMR spectra were recorded on a Bruker 250 instrument
using CDCl3 or DMSO-d6. The chemical shifts are reported in ppm
(d scale) and all J values are in Hz. Melting points are uncorrected.
IR absorption spectra were recorded on a PerkinElmer PARAGON
1000 PC spectrometer and values were reported in cm–1. HRMS
were performed by the Centre Régional de Mesures Physiques de
l’Ouest (CRMPO, Rennes) on a High Resolution Mass Spectrome-
ter with double focalisation Varian Mat 311 using Electronic Im-
pact. Monitoring of the reactions was performed using silica gel
TLC plates silica Merck 60 F254. Spots were visualised by UV light
at 254 and 356 nm. Column chromatography was performed using
silica gel 60 (0.063–0.200 mm, Merck). Only the unavailable prod-
ucts are described (not found on CAS-online). Compounds 12b,18
13a,15 14a14g and 15a14g were synthesised according to published
procedures. Petroleum ether (PE) refers to the fraction boiling in the
range 40–60 °C.
Harom), 7.84 (d, J = 15.5 Hz, 1 H, ArCH=), 6.68 (d, J = 15.5 Hz, 1
H, =CHCO2CH3), 3.75 (s, 3 H, CH3).
13C NMR (75 MHz, DMSO-d6): d = 163.3 (CO2CH3), 160.7 (CHO),
139.7, 137.5, 133.9, 131.7, 126.5, 123.7, 121.8, 118.4, 107.4, 51.72
(CH3).
HRMS (EI): m/z calcd for C12H10N2O3: 230.06914; found:
230.0695.
N-(4-Cyano-2-iodophenyl)formamide (13b)
3-(5-Cyano-2-isocyanophenyl)acrylic Acid Methyl Ester (15b)
At 0 °C and under argon, a solution of 14b (435 mg, 1.89 mmol) in
anhyd CH2Cl2 (12 mL) was treated with Et3N (0.79 mL, 5.67
mmol). A solution of triphosgene (202 mg, 0.68 mmol) in anhyd
CH2Cl2 (3 mL) was then added dropwise. The mixture was allowed
to reach r.t. over 3 h. MeOH (3 mL) was added to neutralise the re-
sidual triphosgene. The solvents were removed in vacuo and the
crude product was purified by flash chromatography (CH2Cl2–PE,
8:2) to afford the desired compound which could be recrystallised
from EtOH to give a colourless solid; yield: 203 mg (50%); mp
141–143 °C.
At 0 °C and in anhydrous conditions, a solution of 4-amino-3-iodo-
benzonitrile (4.02 g, 16.47 mmol) was added to a solution of ethyl
formate (13.3 mL, 0.16 mol) in anhyd THF (50 mL). After stirring
for 10 min, the mixture was then allowed to warm to r.t. overnight
and treated with portions of NaH (60% in mineral oil, 1.65 g, 41.17
mmol). A few drops of H2O were slowly added before diluting with
EtOAc. The organic phase was washed successively with H2O and
brine, and dried (MgSO4). After removal of the solvents under re-
duced pressure, the crude product was recrystallised from EtOH to
afford the desired compound as a colourless solid; yield: 4.03 g
(90%); mp 173–175 °C.
IR (KBr): 2242, 2130, 1721 cm–1.
Synthesis 2006, No. 22, 3895–3901 © Thieme Stuttgart · New York

PAPER
Tin-Mediated Indole Synthesis
3899
1H NMR (250 MHz, DMSO-d6): d = 8.61 (d, J = 1.5 Hz, 1 Harom),
8.03 (dd, J = 1.5, 8 Hz, 1 Harom), 7.89 (d, J = 8 Hz, 1 Harom), 7.72 (d,
J = 16 Hz, 1 H, ArCH=), 7.00 (d, J = 16 Hz, 1 H, =CHCO2CH3),
3.78 (s, 3 H, CO2CH3).
[2-(2-tert-Butoxycarbonylamino-phenyl)-5-cyano-1H-indol-3-
yl]acetic Acid Methyl Ester (18b)
Eluent: PE–EtOAc (8:2, then 7:3); yield: 32%; colourless solid; mp
179 °C.
13C NMR (75 MHz, DMSO-d6): d = 171.2 (NC), 165.7 (CO2CH3),
135.2 (CH), 134.5 (CH), 131.7 (CH), 131.0, 128.6 (CH), 128.0,
124.2 (CH), 117.5, 113.0 (CN), 51.9 (CH3).
IR (KBr): 2225, 1746, 1720 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 11.83 (s, 1 H, NH), 8.20 (s, 1
Harom), 8.06 (s, 1 Harom), 7.70 (d, J = 8 Hz, 1 Harom), 7.54–7.21 (m, 5
Harom + NH), 3.65 (s, 2 H, CH2), 3.57 (s, 3 H, OCH3), 1.31 (s, 9 H,
t-C4H9).
HRMS (EI): m/z calcd for C12H8N2O2: 212.05858; found: 212.0577.
(2-Bromo-4-trifluoromethylphenyl)carbamic Acid tert-Butyl
Ester (17d)
13C NMR (75 MHz, DMSO-d6): d = 171.4 (C=O), 152.9 (C=O),
137.8, 136.8, 136.1, 131.1, 129.3, 127.8, 124.5, 124.3, 123.9, 123.5,
120.7, 112.3, 106.4, 100.6, 79.1, 51.6 (OCH3), 29.7 (CH2), 27.8
[C(CH3)3].
A solution of 2-bromo-4-(trifluoromethyl)aniline (276 mg, 1.15
mmol) in anhyd THF (5 mL) was treated dropwise with a solution
of NaHMDS (2.87 mL, 1 M in THF, 2.5 equiv) and stirred for 15
min. Boc2O (226 mg, 0.9 equiv) was then added and the mixture
stirred at r.t. overnight. THF was removed at reduced pressure be-
fore an aq 0.1 N HCl (0.1 N) was added to the residue. The product
was extracted with EtOAc, the combined organic phases were
washed with brine and dried (MgSO4). After removal of the solvent
in vacuo, the crude product was purified by flash chromatography
(PE–EtOAc, 9:1) to afford the desired compound as an orange oil;
yield: 284 mg (96%).
HRMS (EI): m/z calcd for C23H23N3O4: 405.16886; found:
405.1664.
[2-(2-tert-Butoxycarbonylamino-5-cyanophenyl)-1H-indol-3-
yl]acetic Acid Methyl Ester (18c)
Eluent: PE–EtOAc (8: 2); yield: 88%; yellow solid; mp 143–
144 °C.
IR (KBr): 3310, 2250, 1722, 1695 cm–1.
IR (KBr): 3385, 1634 cm–1.
1H NMR (250 MHz, CDCl3): d = 8.44 (d, J = 8.75 Hz, 1 Harom), 8.25
(br s, 1 H, NH), 7.71–7.61 (m, 3 Harom), 7.44 (d, J = 8 Hz, 1 Harom),
1H NMR (250 MHz, CDCl3): d = 8.51 (d, J = 1.6 Hz, 1 Harom), 7.62
(dd, J = 0.8, 8.3 Hz, 1 Harom), 7.14 (m, 1 Harom), 7.11 (br s, 1 H, NH),
1.55 (s, 9 H, t-C4H9).
7.32 (dd, J = 4.65, 4.65 Hz, 1 Harom), 7.22–7.20 (m, 2 H, Harom
+
NH), 3.68 (s, 3 H, OCH3), 3.62 (s, 2 H, CH2), 1.46 (s, 9 H, t-C4H9).
13C NMR (75 MHz, CDCl3): d = 171.85 (C=O), 152.39 (C=O),
142.13, 136.53, 135.23 (CH), 134.04 (CH), 129.43, 128.07, 126.01,
123.73 (CH), 121.42, 120.84 (CH), 119.49 (CH), 119.42 (CH),
111.54 (CH), 109.52, 105.68, 82.10, 52.36 (OCH3), 30.52 (CH2),
28.32 [C(CH3)3].
13C NMR (75 MHz, CDCl3): d = 152.17 (C=O), 137.16, 132.82
(CH), 131.25, 130.74, 125.96–121.63 (d, J = 1083 Hz, CF3), 120.18
(m, CH), 116.64 (m, CH), 115.54, 81.99, 28.35 (CH3).
HRMS (EI): m/z calcd for C12H1379BrF3NO2: 339.00817; found:
339.061.
HRMS (EI): m/z calcd for C23H23N3O4: 405.16886; found:
405.1677.
Radical Cyclisation/Pd Coupling; General Procedure
Under argon, Bu3SnH (1.1 to 1.5 equiv) was slowly added to a so-
lution of 15 (0.5 mmol) and AIBN (0.04 equiv) in degassed MeCN
(5 mL). The mixture was heated at 100 °C until consumption of the
starting material (1–2 h). After removal of the solvent under vacu-
um, DMF (5 mL) was added, followed by 17 (1.4 equiv), CuI (1
equiv) and Pd(PPh3)4 (10%). The mixture was heated at 50 °C for
1–3 h. After cooling, CH2Cl2 was added and the organic phase was
washed with 10% aq KF solution and brine. After drying (MgSO4),
the solvent was removed in vacuo and the crude product was puri-
fied by flash chromatography.
Cleavage of NHBoc Derivatives 18; General Procedure
A solution of 18 (0.15 mmol) and TFA (5 equiv) in CH2Cl2 (4 mL)
was stirred at r.t. overnight. After dilution with more CH2Cl2, the or-
ganic phase was washed with aq 1 M NaOH, then H2O and dried
(MgSO4). After removal of the solvent under vacuum, the crude
product was purified by flash chromatography to afford the desired
compound.
[2-(2-Aminophenyl)-1H-indol-3-yl]acetic Acid Methyl Ester
(20a)
Eluent: PE–EtOAc (5:5); yield: 96%; pale yellow solid; mp
>300 °C.
IR (KBr): 3388, 1719 cm–1.
[2-(2-tert-Butoxycarbonylaminophenyl)-1H-indol-3-yl]acetic
Acid Methyl Ester (18a)
Eluent: PE–EtOAc (9:1); yield: 80%; colourless solid; mp 134–
135 °C.
1H NMR (250 MHz, CDCl3): d = 8.18 (br s, 1 H, NH), 7.56 (d, J = 7
Hz, 1 Harom), 7.30 (dd, J = 1, 7 Hz, 1 Harom), 7.25–7.13 (m, 4 Harom),
6.80 (dd, J = 1, 7 Hz, 1 Harom), 6.74 (dd, J = 1, 8 Hz, 1 Harom), 3.92
(br s, 2 H, NH2), 3.70 (s, 2 H, CH2), 3.66 (s, 3 H, OCH3).
13C NMR (75 MHz, CDCl3): d = 173.07 (C=O), 145.51, 135.96,
133.69, 131.28 (CH), 129.86 (CH), 128.29, 122.30 (CH), 119.88
(CH), 118.76 (CH), 118.16 (CH), 117.28, 115.68 (CH), 111.08
(CH), 106.70, 51.95 (CH3), 30.62 (CH2).
IR (KBr): 3280, 1725, 1697 cm–1.
1H NMR (250 MHz, CDCl3): d = 8.37 (br s, 1 H, NH), 8.14 (d, J = 8
Hz, 1 Harom), 7.62 (d, J = 8 Hz, 1 Harom), 7.42–7.36 (m, 2 Harom),
7.31–7.15 (m, 3 Harom), 7.09 (dd, J = 1, 8 Hz, 1 Harom), 6.92 (br s, 1
H, NH), 3.65 (s, 3 H, OCH3), 3.62 (s, 2 H, CH2), 1.45 (s, 9 H, t-
C4H9).
13C NMR (75 MHz, CDCl3): d = 172.33 (C=O), 153.33 (C=O),
137.55, 136.22, 132.44, 131.39 (CH), 130.10 (CH), 128.20, 123.05
(CH), 122.87 (CH), 121.69, 120.32 (CH), 120.26 (CH), 119.20
(CH), 111.32 (CH), 108.04, 80.87, 52.19 (OCH3), 30.68 (CH2),
28.42 [C(CH3)3].
HRMS (EI): m/z calcd for C17H16N2O2: 280.12118; found:
280.1216.
[2-(2-Aminophenyl)-5-cyano-1H-indol-3-yl]acetic Acid Methyl
Ester (20b)
Eluent: PE–EtOAc (7:3); yield: 81%; colourless solid; mp 216 °C.
IR (KBr): 2220, 1734 cm–1.
HRMS (EI): m/z calcd for C22H24N2O4: 380.17361; found:
380.1755.
Synthesis 2006, No. 22, 3895–3901 © Thieme Stuttgart · New York

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N. Henry et al.
PAPER
1H NMR (250 MHz, DMSO-d6): d = 11.75 (s, 1 H, NH), 8.01 (s, 1
arom), 7.47 (m, 2 Harom), 7.16 (dd, J = 8, 8 Hz, 1 Harom), 7.10 (d,
J = 8 Hz, 1 Harom), 6.82 (d, J = 8 Hz, 1 Harom), 6.67 (dd, J = 8, 8 Hz,
References
H
(1) Meijer, L.; Leost, M.; Lozach, O.; Schmitt, S.; Kunick, C.
Handbook of Experimental Pharmacology, 167; Pinna, L.
A.; Cohen, P. T. W., Eds.; Springer: Berlin, 2005, 47–64.
(2) (a) Zaharevitz, D. W.; Gussio, R.; Leost, M.; Senderowicz,
A. M.; Lahusen, T.; Kunick, C.; Meijer, L.; Sausville, E. A.
Cancer Res. 1999, 59, 2566. (b) Leost, M.; Schultz, C.;
Link, A.; Wu, Y.-Z.; Biernat, J.; Mandelkow, E.-M.; Bibb, J.
A.; Snyder, G. L.; Greengard, P.; Zaharevitz, D. W.; Gussio,
R.; Senderowicz, A. M.; Sausville, E. A.; Kunick, C.;
Meijer, L. Eur. J. Biochem. 2000, 267, 5983.
1 Harom), 4.93 (s, 2 H, NH2), 3.69 (s, 2 H, CH2), 3.59 (s, 3 H, OCH3).
13C NMR (75 MHz, DMSO-d6): d = 172 (C=O), 146.7, 137.9,
136.9, 130.9 (CH), 129.8 (CH), 128.1, 124.2 (CH), 123.9 (CH),
120.9, 116.1 (CH), 115.1 (2 CH), 112.4, 106.2, 100.6, 51.7 (OCH3),
29.9 (CH2).
HRMS (EI): m/z calcd for C18H15N3O2: 305.11643; found:
305.1148.
(3) (a) Schultz, C.; Link, A.; Leost, M.; Zaharevitz, D. W.;
Gussio, R.; Sausville, E. A.; Meijer, L.; Kunick, C. J. Med.
Chem. 1999, 42, 2909. (b) Kunick, C.; Schultz, C.; Lemcke,
T.; Zaharevitz, D. W.; Gussio, R.; Jalluri, R. K.; Sausville,
E. A.; Leost, M.; Meijer, L. Bioorg. Med. Chem. Lett. 2000,
10, 567. (c) Dobrov, A.; Arion, V. B.; Kandler, N.;
Ginzinger, W.; Jakupec, M. A.; Rufinska, A.; Graf von
Keyserlingk, N.; Galanski, M.; Kowol, C.; Keppler, B. K.
Inorg. Chem. 2006, 45, 1945.
(4) (a) Wieking, K.; Knockaert, M.; Leost, M.; Zaharevitz, D.
W.; Meijer, L.; Kunick, C. Arch. Pharm. Pharm. Med.
Chem. 2002, 7, 311. (b) Knockaert, M.; Wieking, K.;
Schmitt, S.; Leost, M.; Grant, K. M.; Mottram, J. C.; Kunick,
C.; Meijer, L. J. Biol. Chem. 2002, 28, 25493.
6-Oxo-5,6,7,12-tetrahydrobenzo[2,3]azepino[4,5-b]indole-2-
carbonitrile (1c)5b
Pale yellow solid; mp >300 °C.
IR (KBr): 3428, 3338, 2233, 1678 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 11.81 (s, 1 H, NH), 10.56 (s, 1
H, NH), 8.23 (d, J = 1.6 Hz, 1 Harom), 7.79 (dd, J = 1.6, 8.2 Hz, 1
H
arom), 7.69 (d, J = 7.7 Hz, 1 Harom), 7.47 (d, J = 8.1 Hz, 1 Harom),
7.39 (d, J = 8.3 Hz, 1 Harom), 7.21 (dd, J = 7.1, 7.5 Hz, 1 Harom), 7.09
(dd, J = 7.3 Hz, 1 Harom), 3.61 (s, 2 H, CH2).
13C NMR (75 MHz, DMSO-d6): d = 171.5, 139.0, 137.8, 131.3
(CH), 131.0 (CH), 130.6, 126.4, 123.2, 122.9 (2 CH), 119.5 (CH),
118.8, 118.4 (CH), 111.7 (CH), 108.5, 105.8, 31.8 (CH2).
(5) (a) Gussio, R.; Zaharevitz, D. W.; McGrath, C. F.;
Pattabiraman, N.; Kellog, G. E.; Schultz, C.; Link, A.;
Kunick, C.; Leost, M.; Meijer, L.; Sausville, E. A.
Anticancer Drug Des. 2000, 15, 53. (b) Kunick, C.;
Lauenroth, K.; Wieking, K.; Xie, X.; Schultz, C.; Gussio, R.;
Zaharevitz, D.; Leost, M.; Meijer, L.; Weber, A.; Jorgensen,
F. S.; Lemcke, T. J. Med. Chem. 2004, 47, 22.
Lactams 1a,b; General Procedure
A solution of 20 (0.25 mmol) and DBU (1 equiv) in DMF (2 mL)
was heated at 100 °C overnight. After cooling, H2O was added and
the crude product extracted with EtOAc. The organic phase was
washed with H2O and brine, dried (MgSO4) and the solvent re-
moved in vacuo. The product was purified by flash chromatogra-
phy.
(6) (a) Pies, T.; Schaper, K.-J.; Leost, M.; Zaharevitz, D.;
Gussio, R.; Meijer, L.; Kunick, C. Arch. Pharm. Pharm.
Med. Chem. 2004, 337, 486. (b) Kunick, C.; Zeng, Z.;
Gussio, R.; Zaharevitz, D.; Leost, M.; Totzke, F.;
Schachtele, C.; Kubbutat, M. H. G.; Meijer, L.; Lemcke, T.
ChemBioChem 2005, 6, 1.
5,12-Dihydro-7H-benzo[2,3]azepino[4,5-b]indol-6-one (1a)19
Pale yellow solid; mp >300 °C.
IR (KBr): 3221, 1643 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 11.58 (s, 1 H, NH), 10.08 (s, 1
H, NH), 7.74 (d, J = 8 Hz, 1 Harom), 7.66 (d, J = 8 Hz, 1 Harom), 7.44
(d, J = 8 Hz, 1 Harom), 7.36 (d, J = 6.2 Hz, 1 Harom), 7.30–7.23 (m, 2
Harom), 7.17 (dd, J = 7, 7 Hz, 1 Harom), 7.07 (dd, J = 7.6, 7.6 Hz, 1
Harom), 3.50 (s, 2 H, CH2).
13C NMR (75 MHz, DMSO-d6): d = 171.6 (C=O), 137.5, 135.45,
132.5, 128.0 (CH), 126.9 (CH), 126.6, 123.7 (CH), 122.9, 122.3
(CH), 122.2 (CH), 119.1 (CH), 118.0 (CH), 111.5 (CH), 107.6, 31.7
(CH2).
(7) Lahusen, T.; De Siervi, A.; Kunick, C.; Senderowicz, A. M.
Mol. Carcinog. 2003, 36, 183.
(8) Brault, L.; Migianu, E.; Néguesque, A.; Battaglia, E.;
Bagrel, D.; Kirsch, G. Eur. J. Med. Chem. 2005, 40, 757.
(9) Xie, X.; Lemcke, T.; Gussio, R.; Zaharevitz, D. W.; Leost,
M.; Meijer, L.; Kunick, C. Eur. J. Med. Chem. 2005, 40, 655.
(10) Kunick, C.; Lauenroth, K.; Leost, M.; Meijer, L.; Lemcke, T.
Bioorg. Med. Chem. Lett. 2004, 14, 413.
(11) Baudoin, O.; Cesario, M.; Guénard, D.; Guéritte, F. J. Org.
Chem. 2002, 67, 1199.
(12) Bremner, J. B.; Sengpracha, W. Tetrahedron 2005, 61, 5489.
(13) Joucla, L.; Putey, A.; Joseph, B. Tetrahedron Lett. 2005, 46,
8177.
6-Oxo-5,6,7,12-tetrahydrobenzo[2,3]azepino[4,5-b]indole-9-
carbonitrile (1b)3a
Pale yellow solid; mp >300 °C.
IR (KBr): 3423, 2215, 1680 cm–1.
(14) (a) Fukuyama, T.; Chen, X.; Peng, G. J. Am. Chem. Soc.
1994, 116, 3127. (b) Shinada, T.; Miyachi, M.; Itagaki, Y.;
Naoki, H.; Yoshihara, K.; Nakajima, T. Tetrahedron Lett.
1996, 39, 7099. (c) Kobayashi, Y.; Fukuyama, T. J.
Heterocycl. Chem. 1998, 35, 1043. (d) Tokuyama, H.;
Yamashita, T.; Reding, M. T.; Kaburagi, Y.; Fukuyama, T.
J. Am. Chem. Soc. 1999, 121, 3791. (e) Rainier, J. D.;
Kennedy, A. R.; Chase, E. Tetrahedron Lett. 1999, 40,
6325. (f) Rainier, J. D.; Kennedy, A. R. J. Org. Chem. 2000,
65, 6213. (g) Tokuyama, H.; Kaburagi, Y.; Chen, X.;
Fukuyama, T. Synthesis 2000, 429. (h) Tokuyama, H.;
Watanabe, M.; Hayashi, Y.; Kurokawa, T.; Peng, G.;
Fukuyama, T. Synlett 2001, 1403. (i) Tokuyama, H.;
Fukuyama, T. Chem. Rec. 2002, 2, 37. (j) Sumi, S.;
Matsumoto, K.; Tokuyama, H.; Fukuyama, T. Tetrahedron
2003, 59, 8571.
1H NMR (250 MHz, DMSO-d6): d = 12.21 (s, 1 H, NH), 10.17 (s, 1
H, NH), 8.32 (s, 1 Harom), 7.76 (d, J = 7.5 Hz, 1 Harom), 7.60–7.27 (m,
5 Harom), 3.59 (s, 2 H, CH2).
13C NMR (75 MHz, DMSO-d6): d = 171.4 (C=O), 139.0, 135.9,
135.0, 128.8, 127.1, 126.4, 124.7, 124.0, 123.7, 122.4, 121.9, 120.6,
112.6, 108.2, 101.2, 31.3 (CH2).
Acknowledgment
We are grateful for financial support from the Cancéropôle Grand-
Ouest and for technical assistance from Rémy Marron.
Synthesis 2006, No. 22, 3895–3901 © Thieme Stuttgart · New York

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Tin-Mediated Indole Synthesis
3901
(15) Hays, S. J.; Caprathe, B. W.; Gilmore, J. L.; Amin, N.;
Emmerling, M. R.; Michael, W.; Nadimpalli, R.; Nath, R.;
Raser, K. J.; Stafford, D.; Watson, D.; Wang, K.; Jaen, J. C.
J. Med. Chem. 1998, 41, 1060.
(16) Porcheddu, A.; Giacomelli, G.; Salaris, M. J. Org. Chem.
2005, 70, 2361.
(18) Jonckers, T. H. M.; van Miert, S.; Cimanga, K.; Bailly, C.;
Colson, P.; De Pauw-Gillet, M.-C.; van den Heuvel, H.;
Claeys, M.; Lemière, F.; Esmans, E. L.; Rozenski, J.;
Quirijnen, L.; Maes, L.; Dommisse, R.; Lemière, G. L. F.;
Vlietinck, A.; Pieters, L. J. Med. Chem. 2002, 45, 3497.
(19) Kunick, C. Arch. Pharm. (Weinheim, Germany) 1992, 325,
297.
(17) Creedon, S. M.; Crowley, H. K.; McCarthy, D. G. J. Chem.
Soc., Perkin Trans. 1 1998, 1015.
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