Design, synthesis and biological activity of new CDK4-specific inhibitors, based on fascaplysin

Article abstract of DOI:10.1039/b518019h

We present the design, synthesis, and biological activity of three classes of tryptamine derivatives, which are non-planar analogues of the toxic anti-cancer agent fascaplysin. We show these compounds to be selective inhibitors of CDK4 over CDK2, the most active compound 9q has an IC₅₀ for the inhibition of CDK4 of 6 M. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b518019h

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Design, synthesis and biological activity of new CDK4-specific inhibitors,
based on fascaplysin
Carine Aubry,a A. James Wilson,a Paul R. Jenkins,*a Sachin Mahale,b Bhabatosh Chaudhuri,b
Jean-Didier Mare´chal†c and Michael J. Sutcliffe‡c
Received 19th December 2005, Accepted 12th January 2006
First published as an Advance Article on the web 1st February 2006
DOI: 10.1039/b518019h
We present the design, synthesis, and biological activity of three classes of tryptamine derivatives, which
are non-planar analogues of the toxic anti-cancer agent fascaplysin. We show these compounds to be
selective inhibitors of CDK4 over CDK2, the most active compound 9q has an IC50 for the inhibition of
CDK4 of 6 lM.
Introduction
Fascaplysin 1 (Fig. 1), is a pentacyclic quaternary salt originally
isolated from the Fijian sponge Fascaplysinopsis Bergquist sp.,1
which inhibits the growth of several microbes, including Staphy-
lococcus aureus, Escherichia coli, Candida albicans, and Saccha-
romyces cerevisiae, and suppresses the proliferation of mouse
leukemia cells L-1210 with ED50 = 0.2 lm mL−1. Fascaplysin has
also been reported to specifically inhibit CDK4, causing G1 arrest
of tumour (U2-OS, HCT-116) and normal (MRC-5) cells.2
The inhibition of cyclin-dependent kinases, CDKs, by small
molecules is an area of major current interest in the anti-cancer
field.3 CDKs are a vital component of the check-points in the
various phases of the cell division cycle,4 they are required for
healthy cell growth and proliferation. CDK4 has a very specific
function in the G0–G1 phase of the cell division cycle—the CDK4–
cyclin D1 complex phosphorylates the protein retinoblastoma
(pRB), an active repressor of the E2F family of transcription
factors. CDK4-mediated hyperphosphorylation of pRB facilitates
liberation of E2F proteins and allows them to carry out their
Fig. 1 Strategy used to produce the non-planar tryptamine derivatives
7a, 9, 12a and 15 from fascaplysin 1.
transcriptional activation roles. This enables the cell to pass
through the restriction point, an early G1 checkpoint, where the
cell commits itself to complete one cell division cycle.5 Inhibition
of CDK4 is therefore a vital factor in controlling the rate of cell
proliferation. In normal cells this is carried out by CDK4-specific
cyclin-dependent kinase inhibitors (CKIs) such as p16; in tumour
cells, inactivating mutations which result in the underproduction
of p16 are common.6 Moreover, the activating partner cyclin D1
and the catalytic subunit CDK4 are often either overproduced or
hyper-activated in many tumour cells. A small-molecule inhibitor
of CDK4 would result in early G1 arrest of the cell cycle and
thus prevent uncontrolled cell growth, the hallmark of all tumour
cells. Given that CDK4 is a kinase, the most obvious structures to
act as inhibitors of CDK4 are analogues of ATP.7 Additionally,
it is known that structures totally unrelated to ATP, such as
staurosporine and flavopiridol, are also effective inhibitors of
CDK4.3
Fascaplysin 1 cannot be used as an anti-cancer drug because it
is highly toxic—the potential for its planar structure to intercalate
with DNA has been suggested as a possible explanation.8 The aim
of the current study is therefore to devise a potent, non-toxic (non-
planar) CDK4 inhibitor based on the structure of fascaplysin.
aDepartment of Chemistry, University of Leicester, Leicester, UK LE1 7RH.
E-mail: kin@le.ac.uk; Fax: +44(0)116 252 3789; Tel: +44(0)116 252 2124
bSchool of Pharmacy, De Montfort University, Leicester, UK LE1
9BH. E-mail: bchaudhuri@dmu.ac.uk; Fax: +44(0)116 257 7287;
Tel: +44(0)116 250 7280
cDepartments of Biochemistry and Chemistry, University of Leicester,
Leicester, UK LE1 7RH
† Present address: Laboratoire de Mode´lisation et Inge´nierie des Prote´ines,
Institut de Biochimie et de Biophysique Mole´culaire et Cellulaire,
Baˆt. 430, Universite´ Paris-Sud, 91405 Orsay Cedex, France; E-mail:
jean-didier.marechal@ibbmc.u-psud.fr; Fax: +33.(0)1.69.85.37.15; Tel:
+33.(0)1.69.15.63.20.
‡ Present address: Manchester Interdisciplinary Biocentre, School
of Chemical Engineering and Analytical Science, University of
Manchester, The Mill, PO Box 88, Manchester, UK M60 1QD;
E-mail: michael.sutcliffe@manchester.ac.uk; Fax: +44(0)161 306 9321;
Tel: +44(0)161 306 5153.
Results and discussion
The general approach we adopt for generating non-toxic inhibitors
of CDK4 involves the synthesis of non-planar analogues of
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fascaplysin, thus avoiding their interchelation with DNA. To
enhance the chances of success, these compounds are designed
to maintain most of the key interactions thought to occur
between fascaplysin and CDK4. Since the 3-dimensional structure
of CDK4 has not been determined, structural information is
obtained by molecular modelling. Thus, prior to embarking on
the synthesis of potential inhibitors, we first carried out in silico
studies based on our homology model of CDK4, produced using
the known crystal structures of CDK2 and CDK6 as templates
(Fig. 3). Our dockings of ATP and fascaplysin suggest that
inhibition of CDK4 activity by fascaplysin arises from binding
to the same site as ATP (Fig. 2a). This suggests that a key feature
of fascaplysin binding is the double hydrogen bond to Val 967
(Fig. 2b).
In this study, the general strategy we adopt for removing
toxicity10 (Fig. 1) comprises releasing bonds a and b in fascaplysin
1 and changing double bond c into a single bond, leading
to the tryptamine derivative 7a. This compound contains the
structural components of fascaplysin, but it is non-planar and
is therefore not likely to intercalate with DNA. This was our
first generation compound, which had a great deal of flexibility
due to rotation around six bonds. Herein we also describe the
second generation compounds 9a–q which have a shorter chain
between the indole and the benzene ring and an amide bond
leading to fewer degrees of rotational freedom in the molecules. In
third generation compounds 12a–q and 16 we have reduced still
further the rotational freedom of the structure by incorporating the
tetrahydro b-carboline structure. Hence, compounds 5a–c, 7a–c,
9a–q, 10, 12a–q, and 13–16 were synthesised (Schemes 1–3). These
compounds are not planar and so intercalation in DNA is very
unlikely.
Fig. 2 The active site of our CDK4 model. (a) Cartoon representation of
the overall structure of the CDK4, with the positions of ATP–Mg2+ (C in
grey, N in slate, O in salmon, P in yellow) and fascaplysin (C in magenta,
N in cyan, O in red) shown. (b) Predicted binding mode of fascaplysin.
(c) Predicted binding mode of the most potent compound, 9q; note the p–p
interactions of the benzoid ring with Phe 93 and Phe 159. (d) Predicted
binding mode of 12q—this weaker inhibitor is structurally similar to, but
more conformationally constrained than, 9q. Hydrogen bonds are shown
as dashed lines. Figures produced using PyMol.9
First generation compounds
The synthesis of 7a is shown in Scheme 1. Tryptamine 2 was
reacted with ethyl chloroformate to give the urethane 3 in 95%
yield.11 Reduction with lithium aluminium hydride produced
Scheme 1 Reagents and conditions. (a) Ethyl chloroformate, NaOH 4 M, CHCl3, 3 h, 95%; (b) LiAlH4, THF, N2, reflux, 1 h, 89%; (c) BrCH2COC6H4R,
toluene, N2, NaHCO3, Na2SO4, H2O, 4 h, 49–61%; (d) methyl-p-toluenesulfonate, acetonitrile, reflux, 4 h; (e) DowexꢀR Cl− 1 × 8–400 ion exchange resin,
overnight stirring and column, 46–53%; (f) HCl gas, Et2O or CH2Cl2, <1 min, 46–88%.
788 | Org. Biomol. Chem., 2006, 4, 787–801
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Scheme 2 Reagents and conditions. (a) ClCOC6H4R, NaOH(aq) 4 M, CH2Cl2, 0 ◦C, 15 min then RT, 3 h, 37–99%; (b) ClCOCH2C6H5, NaOH(aq) 4 M,
CH2Cl2, 0 ◦C, 15 min then RT, 3 h, 37–99%.
N-methyltryptamine 4 in 89% yield.11 This intermediate 4 was
then reacted with different 4-substituted bromoacetophenone
derivatives to afford the compounds 5a–c in yields between 49%
and 61% after column chromatography.12 The tertiary amines 5a–c
compounds (7a–c), like fascaplysin, block growth of cancer cells
in the G1 phase of the cell division cycle and they also maintain the
G1 block of serum-starved cells. However, unlike fascaplysin, the
compounds do not intercalate DNA or inhibit topoisomerase I
which we believe contributes to the general toxicity of fascaplysin
(manuscript in preparation).
◦
were unstable after a week when stored at −25 C, as indicated
by NMR. These materials were reacted separately with methyl-p-
toluene sulfonate to furnish the tosylate salts 7a–c. Ion exchange
R
using Dowexꢀ Cl− 1 × 8–400 ion exchange resin produced the
Second generation compounds
chloride salts 7a–c in yields between 46% and 53%.13
The CDK4 activities of compounds 7a–c and 5a–c have been
tested for some of the biochemical features that would identify a
CDK4 inhibitor. In accord with our predictions, the IC50 values
(Table 1) show that all compounds are CDK4 active. Furthermore,
the CDK2 activities of compounds 7a–c and 5a–c, measured in
terms of IC50 values, reveal that all twelve tryptamine derivatives
are CDK4 selective compared to CDK2 (Table 1). Representative
As mentioned above the second generation compounds 9a–q and
10 are amide derivatives of N-methyl tryptamine. The series of
compounds were readily synthesised as shown in Scheme 2 and
the results for the inhibition of CDK4 and CDK2 are shown in
Table 1. The first clear trend from the results is the selectivity for
inhibition of CDK4 compared to CDK2. The parent compound
9a shows a modest IC50 of 88 lM; this activity changes when
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Table 1 CDK4 activity versus CDK2 activity
aCDK4 measured IC50/lM bCDK2 measured IC50/lM
Compound
Fascaplysin 1 0.5510
500
7a
68
50
50
8
7
6
720 16
605 10
665 18
1310 21 (860 14)c
910 7 (911 24)c
921 16 (932 20)c
1523 38
658 23
1230 29
765 27
850 34
784 20
1120 38
731 26
635 40
584 24
580 38
849 30
938 47
1125 40
830 31
790 27
521 12
959 18
490 40
720 24
800 22
680 20
851 22
1197 30
873 38
674 25
679 31
675 30
875 37
861 42
766 33
750 31
818 35
751 34
829 28
1450 42
926 35
1301 21
1467 39
7b
7c
5a
212 16 (91 7)c
90 11 (110 9)c
80 11.5 (84 9)c
5b
5c
9a
88
49
103
88
59
46
109
38
74
95
37
79
81
113
78
63
6
6
7
9
9
7
4
8
6
7
7
5
9
4
8
8
6
1
4
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
9m
9n
9o
9p
9q
Scheme 3 Reagents and conditions. (a) ClCOC6H4R, NaOH(aq) 4 M,
CH2Cl2, 0 ◦C, 15 min then RT, 3 h, 63–91%; (b) BrCH2COC6H5, toluene,
N2, NaHCO3, Na2SO4, H2O, 4 h, 61%; (c) HCl gas, CH2Cl2, 3 min, 95%.
10
28
92 10
12a
12b
12c
12d
12e
12f
12g
12h
12i
12j
12k
12l
12m
12n
12o
12p
12q
13
44
61
72
55
98 10
56
76 10
44
32
51
26
24
68
27
45
64
9
7
5
6
halogen substituents are present on the benzenoid ring and shows
a consistent improvement for para substituted derivatives (9e, p-F,
IC50 59; 9h, p-Cl, IC50 38 and 9k, p-Br, IC50 37 lM). The trend of
improved activity, lower IC50, for para substituted compounds is
continued with 9p, p-Me, IC50 63; 9b, p-tBu, IC50 49 lM and the
best result 9q, p-Ph, IC50 6 lM. The phenyl substitution in the para
position appears responsible for enhanced inhibition of the series
9 compounds.
6
5
6
4
6
4
8
5
6
9
Third generation compounds
In the third generation compounds 12a–q and 13–16 we have
investigated the effect of a tetrahydro b-carboline structure,
which further reduced the degree of conformational flexibility
of the inhibitor. The series of compounds 12a–q, 13 and 14
were readily synthesised by the same method used for 9a–q as
shown in Schemes 2 and 3. The b-carboline 11 was reacted
with 2-bromoacetophenone in the presence of sodium hydrogen
carbonate and sodium sulfate to produce 15 in 61% yield. The HCl
salt 16 was then formed by bubbling HCl gas into a solution of
15 in dichloromethane. Surprisingly the resultant salt was soluble
in dichloromethane, as no precipitate was formed, so the mixture
was evaporated off to give the HCl salt 16 with 95% yield which
was then characterized by NMR and mass spectroscopy. NMR
clearly showed two NH signals (10.98 and 11.23 ppm) and the
expected mass was recorded in a FAB experiment.
95 11
14
15
54
62
34
5
7
4
16
a CDK4–cyclin D1 assay, using GST-RB152 fusion protein as the substrate.
b CDK2–cyclin A assay using histone H1 as the substrate. c The values in
parentheses () indicate the results of the HCl salts of 5a–c, e.g. 8a–c.
derivative 12o has an IC50 of 27 lM making it the best of the three
methyl derivatives, while p-tBu, 12b, IC50 44 and p-phenyl, 12q,
IC50 64 lM are better inhibitors than the parent compound 12a.
The meta-methoxy compound 12m, IC50 24 lM, is the best result
of this series and follows the trend of meta compounds being most
active.
The results for the inhibition of CDK4 and CDK2 are shown
in Table 1. Again we see that all compounds tested are selective
inhibitors of CDK4 compared to CDK2. The parent structure
12a has a modest IC50 of 92 lM, which is improved by halogen
substituents of which 12e, p-F, IC50 55; 12g, m-Cl, IC50 56 and 12j,
m-Br, IC50 32 lM are the most active. It is not clear at this stage why
the m-Cl, 12g, and m-Br, 12j, compounds are better inhibitors in
this series compared with p-Cl, 9h, and p-Br, 9k. The meta methyl
Biphenyl-4-carboxylic acid [2-(1H-indol-3-yl)-ethyl]-methylamide
9q, the most potent inhibitor
The interactions of the most potent inhibitor, 9q, were rationalised
by in silico modelling. When docking our full set of compounds
into the CDK4 model, only 9q and 12q (Chemscore values of
the respective best solutions 32.8 kJ mol−1 and 32.2 kJ mol−1)
show similar Chemscore values to that observed for fascaplysin
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1 (Chemscore 30.0 kJ mol−1). All the other compounds are
predicted to be weaker binders with Chemscore values in the
range of 20 to 25 kJ mol−1. The binding mode of 9q with the best
Chemscore value (Fig. 2c) clearly overlaps with the best binding
mode of fascaplysin (Fig. 2b). In both complexes, the indole
group occupies a similar position and the interaction between the
quinole nitrogen and the backbone of Val 96 is maintained. With
fascaplysin 1, an additional hydrogen bond is predicted between
the carbonyl of the ligand and the backbone amide of His 95; in
9q this is predicted to be replaced by an interaction with the side
chain N of His 95. The protein–ligand interactions elsewhere on
the ligand differ more substantially. The larger aromatic moiety of
9q is predicted to form a new p–p interaction with the side chain
phenyl rings of both Phe 93 and Phe 159.
The binding mode of 12q is noteworthy for different reasons.
This structurally similar, but more conformationally constrained,
compound is a much weaker inhibitor. Analysis of the docking
solutions for 12q with the best Chemscore values predicts two main
clusters. In the cluster with the best Chemscore, 12q is predicted not
to bind in the ATP binding site of CDK4 but instead in a distinctly
different part of the binding site that would not necessarily inhibit
ATP binding. In the second cluster of solutions 12q is located in
the ATP binding site in a similar orientation to that predicted for
fascaplysin and 9q (Fig. 2d). This mode, like that predicted for
9q, has a strong lipophylic component and the p–p interaction
with Phe 93 and Phe 159 is maintained. In contrast, the position
predicted to be occupied by the indole moiety is substantially
differenttothat observed for bothfascaplysin and 9q. In particular,
the position of the ring is incompatible with the double interaction
with the backbone of His 95/Val 96. We therefore suggest that
the good binding affinity of 9q is facilitated both by retaining a
double hydrogen bond with the backbone of His 95/Val 96 and
introducing a new p interaction14 from sandwiching the phenyl
moiety of the ligand between the side chains of Phe 93 and Phe 159.
In conclusion, we have used a homology model of CDK4 to
design specific inhibitors based on fascaplysin. The most potent
compound, 9q, has an IC50 value for the inhibition of CDK4 of
6 lM. Three additional compounds—12l, 12m and 12o—have IC50
values below 30 lM. The molecular basis of the affinity of 9q is
suggested to be due to the presence of a double hydrogen bond of
the ligand with the backbone of His 95/Val 96 coupled with a p–p
interaction—not present with fascaplysin—with the side chains of
Phe 93 and Phe 159. This predicted new stabilising interaction will
be studied elsewhere and will serve as a basis for the development
of further potential inhibitors of CDK4.
Experimental
Modelling
Our homology model of CDK4 was produced using Modeller15
with CDK2 (PDB16 accession code 1HCK14; containing ATP–
Mg2+ and sharing 40% sequence identity with CDK4) and CDK6
(1BLX17; sharing 70% sequence identity with CDK4) as templates
(Fig. 3; sequence alignment produced using ClustalX18 combined
with structural alignment). Docking studies were then performed
to generate 10 solutions for each of the compounds 7a–c, 5a–c, 9a–
q, 10, 12a–q and 13–16, using GOLD v3.019 with the Chemscore
fitness function.20
Bio assays
Expression and purification of CDK4–GST–cyclin D1, CDK2–
GST–cyclin A and GST–RB152. Fusion proteins of human
cyclins A and D1, covalently linked to glutathione S-transferase
(GST), were co-expressed with the catalytic subunits CDK2 and
CDK4 in Sf-9 insect cells as described previously.22–24
Active enzyme complexes, containing a catalytic subunit bound
to GST–cyclin, were bound to glutathione–agarose columns
(Sigma, Cat. No. G3907) and were eluted from the columns with
reduced glutathione. The reduced glutathione was removed by
dialysing the enzymes in 10 000 MCO dialysis cassettes (Pierce,
Cat. No. 66830) with two buffer changes.
The GST–RB152 fusion construct was transformed into the
Escherichia coli strain BL21(DE3)pLysS (Novagen Cat. No.
69451-4). For expression of GST–RB152, the cells were induced
in the presence of a final concentration of 4 mM isopropyl-b-
thiogalactopyranoside (IPTG, Invitrogen Cat. No. 15529-091) and
were allowed to grow for 4 h in a shaking incubator at 37 ◦C and
220 rpm. Purification of the GST–RB152 protein was carried out
Fig. 3 Sequence alignment used to generate the homology model of CDK4 based on the structures of CDK2 and CDK6. Residues that are identical in
all three sequences are shown on a black background, and residues that are similar are boxed. (Figure produced using ESPRIPT.21)
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as described previously.24 Protein estimation was performed using
the Bradford protein assay (Bio-Rad Laboratories) with bovine
serum albumin (BSA) as the standard and the purity of the fusion
protein was assessed by SDS-PAGE analysis. Proteins were stained
with Coomassie blue for visualisation.
62.4 mmol). After addition, the mixture was stirred for 3 h
at room temperature, and then washed with water (150 mL).
The two layers were separated and the aqueous phase was
extracted with dichloromethane (2 × 150 mL). The chloroform
and dichloromethane layers were combined, dried (MgSO4), and
evaporated under reduced pressure to give an orange oil. No
purification was needed. The oil was dried in vacuo to give the
title compound 3 (13.78 g, 95%). 1H NMR (300 MHz, CDCl3) d
1.33 (3H, t, J 7.0), 3.05 (2H, t, J 6.5), 3.60 (2H, q, J 6.5), 4.24
(2H, q, J 7.0), 5.12 (1H, br s), 6.99 (1H, s), 7.23 (1H, t, J 6.0), 7.30
(1H, td, J 6.0 and 1.2), 7.42 (1H, d, J 7.7), 7.71 (1H, d, J 7.7), 8.75
(1H, s). 13C NMR (75 MHz, CDCl3) d 14.57 (CH3), 25.64 (CH2),
41.21 (CH2), 60.72 (CH2), 111.33 (CH), 112.33 (Cq), 118.54 (CH),
119.11 (CH), 121.83 (CH), 122.26 (CH), 127.18 (Cq), 136.39 (Cq),
156.93 (Cq). Rf (ethyl acetate–NH3(aq) 100 : 5) 0.76. m/z (FAB+)
232 (M+), 233 (M + H)+, 465 (2M + H)+ (found: M+, 232.12126.
C13H16N2O2 requires M, 232.12118).
Kinase assays and IC50 determination. The assay measures the
depletion in ATP concentration as a result of phosphorylation of
retinoblastoma (GST–RB152) and histone H1 (Upstate Biotech
Cat. No. 14–155) by CDK4 and CDK2, respectively. The assay
was run in a 96 well format and all steps in one assay were carried
out in a single white polystyrene plate (Sarstedt, Catalogue No.
DPS-134-050A). The compounds were dissolved in DMSO as
10 mM stock solutions. Compounds were further serially diluted
in kinase buffer (40 mM Tris (pH 7.5), 20 mM MgCl2, 0.1 mg ml−1
BSA) in order to obtain the desired concentrations. The kinase
assay was performed in 50 ll of kinase buffer containing 2 lg
of purified GST–RB152 (in case of CDK4–GST–cyclin D1) or
3 lg of histone H1 (in case of CDK2–GST–cyclin A) and 6 lM
ATP. The phosphatase and protease inhibitor cocktail containing
b-glycerophosphate, sodium fluoride and sodium orthovanadate
in the presence of reducing agent dithiothreitol was added at the
final concentrations of 10 mM, 0.1 mM, 0.1 mM and 1 mM,
respectively. The assay was initiated by adding 200 ng of active
enzyme complexes and the plate was incubated for 30 min at
30 ◦C in a humidified incubator. The reaction was stopped by
the addition of an equal volume of the Kinase Glow ReagentTM
(Promega Cat. No. V6711). The luminescence was measured using
the Packard Luminometer (Fusion 3.50) and the rate of ATP
depletion (rate of reaction) in the control blank reactions (i.e.
without substrate or enzyme) was calculated and used to determine
the IC50 concentrations of compounds. In the case of the CDK4–
cyclin D1 assay, the two compounds fascaplysin and flavopiridol
with known IC50 values were used to validate the assay. For the
CDK2–cyclin A assay, roscovitine and flavopiridol were used as
standards for the assay.
[2-(1H-Indol-3-yl)-ethyl]-methylamine 425. To a solution of 3
(1◦3.78 g, 59.4 mmol) in dry THF (110 mL) under N2 flux at
0 C was added portionwise LAH (6.76 g, 178 mmol). After the
addition was complete the mixture was heated under reflux for
1 h. The reaction was then cooled to 0 ◦C and the excess of LAH
was hydrolysed by adding successively and very carefully: water
(13.25 mL), 15% aqueous solution of NaOH (13.25 mL) and water
(3 × 13.25 mL). During these steps it was necessary to add THF
(100 mL) to avoid the mixture becoming very thick. The suspen
sion was filtered and the white solid, made up of LiOH and
Al(OH)3, was washed with THF (30 mL). The organic layer was
dried (MgSO4) and evaporated under reduced pressure to give the
title compound 4 (9.24 g, 89%) as a beige solid. 1H NMR
(300 MHz, CDCl3) d 1.47 (1H, s), 2.35 (3H, s), 2.81–2.86 (2H, m),
2.89–2.94 (2H, m), 6.80 (1H, s), 7.03 (1H, td, J 7.4 and 1.2), 7.10
(1H, td, J 7.4 and 1.2), 7.19 (1H, d, J 7.6), 7.54 (1H, d, J 7.6), 9.52
(1H, s). 13C NMR (75 MHz, CDCl3) d 25.42 (CH2), 35.99 (CH3),
51.82 (CH2), 111.32 (CH), 112.91 (Cq), 118.65 (CH), 118.85 (CH),
121.59 (CH), 122.45 (CH), 127.30 (Cq), 136.53◦(Cq). Rf (ethyl
acetate–MeOH–NH3(aq) 9 : 0.5 : 0.5) 0.4. Mp 82 C. m/z (FAB+)
175 (M + H)+ (found: C, 75.74; H, 8.04; N, 16.00; MH+, 175.12354.
C11H15N2 requires C, 75.82; H, 8.10; N, 16.08%; MH, 175.12352).
Chemistry
General
NMR spectra were recorded on a Bruker DPX 300 (1H,
300.13 MHz; 13C, 75.47 MHz) spectrometer. Chemicals shifts were
measured relative to chloroform (13C d 77.0) or dimethylsulfoxide
(13C d 39.5) and are expressed in ppm. Coupling constants J
are expressed in Hertz and the measured values are corrected to
one decimal place. Fast Atom Bombardment (FAB) mass spectra
were recorded on a Kratos Concept 1H using xenon and m-
nitrobenzyl alcohol as the matrix. Electrospray (ES) mass spectra
were recorded on a Micromass Quattro LC spectrometer. Accurate
mass was measured on a Kratos Concept 1H spectrometer
using peak matching to a stable reference peak. Flash column
chromatography was carried out using Merck Kieselgel 60 (230–
400 mesh). Dry solvents were provided by the system PURE
SOLVTM, Innovative Technology Inc.
General procedure for the preparation of {[2-(1H-indol-3-yl)-
ethyl]-methylamino}-ethanone derivatives
1-(4-Bromophenyl)-2-{[2-(1H-indol-3-yl)-ethyl]-methylamino}-
ethanone 5c. To a solution of 4 (1.00 g, 5.74 mmol) in toluene
(28 mL) was added a solution of NaHCO3 (1.12 g, 13.3 mmol)
and Na2SO3 (0.56 g, 4.48 mmol) in water (11.2 mL). The mixture
was stirred under a N2 atmosphere and 2,4ꢀ-dibromoacetophenone
(1.59 g, 5.74 mmol) was added. The stirring was maintained for
4 h at room temperature, and the reaction mixture was washed
with a saturated aqueous solution of Na2HPO4 (28 mL). The
organic layer was dried (MgSO4) and evaporated under reduced
pressure. The crude product was purified by chromatography
on silica gel. Elution was made successively with: ethyl acetate–
cyclohexane 7 : 3; ethyl acetate; ethyl acetate–methanol 1 :
1, to give the title compound 6c as a hard and sticky paste
(1.09 g, 51%). The identical procedure using as starting material
2-bromo-4ꢀ-chloroacetophenone and 2-bromoacetophenone was
[2-(1H-Indol-3-yl)-ethyl]-carbamic acid ethyl ester 313. To a
solution of tryptamine 2 (10.00 g, 62.4 mmol) in chloroform
(156 mL) at 0 ◦C was added ethylchloroformate (5.97 mL,
62.4 mmol) and an aqueous solution of NaOH 4 M (15.60 mL,
792 | Org. Biomol. Chem., 2006, 4, 787–801
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used toward the synthesis of 5b and 5a in yields of 61% and 49%,
respectively. Note: these compounds can be kept for up to one week
at −23 ◦C.
7.7), 7.85 (2H, dt, J 8.7 and 1.8), 7.94 (2H, dt, J 8.7 and 1.8), 10.34
(1H, s), 11.02 (1H, s). 13C NMR (75 MHz, DMSO) d 20.31 (CH2),
41.68 (CH3), 57.09 (CH2), 60.87 (CH2), 109.32 (CH), 112.05 (Cq),
118.75 (CH), 118.95 (CH), 121.72 (CH), 123.76 (CH), 127.14 (Cq),
129.34 (Cq), 130.61 (2CH), 132.57 (2CH), 133.32 (Cq), 136.71
(Cq), 191.66 (Cq). m/z (FAB+) 371 (M − Cl−)+ (found: C, 55.88;
H, 4.87; N, 6.76; (M − Cl−)+, 371.07600. C19H20BrN2O requires
C, 55.97; H, 4.94; N, 6.87%; (M − Cl−), 371.07590).
1H NMR (300 MHz, CDCl3) d 2.49 (3H, s), 2.89–2.94 (2H,
m), 2.98–3.03 (2H, m), 3.87 (2H, s), 6.94 (1H, d, J 2.0), 7.08
(1H, td, J 7.4 and 1.1), 7.16 (1H, td, J 7.4 and 1.1), 7.31 (1H, br
d, J 7.9), 7.47 (2H, dt, J 8.6 and 2.0, para benzene), 7.56 (1H,
d, J 7.6), 7.75 (2H, dt, J 8.6 and 2.0, para benzene), 8.35 (1H,
s). 13C NMR (75 MHz, CDCl3) d 23.12 (CH2), 42.42 (CH3), 58.07
(CH2), 63.60 (CH2), 111.69(CH), 113.91 (Cq), 119.09(CH), 119.64
(CH), 122.34 (2CH), 127.76 (Cq), 128.82 (Cq), 130.20 (2CH),
132.17 (2CH), 134.84 (Cq), 136.98 (Cq), 196.38 (Cq). Rf (ethyl
acetate–cyclohexane 7 : 3) 0.58. m/z (FAB+) 371 (M+) (found: M+,
371.07600. C19H19BrN2O requires M, 371.07590).
[2-(4-Chlorophenyl)-2-oxoethyl]-[2-(1H-indol-3-yl)-ethyl]-methyl-
ammonium chloride 8b. 1H NMR (300 MHz, DMSO) d 3.00
(3H, d, J 3.9), 3.23 (2H, t, J 7.8), 3.50 (2H, signal obscured by
the water in the solvent), 5.09 (1H, dd, J 18 and 4.8), 5.19 (1H,
dd, J 18 and 2.7), 7.02 (1H, td, J 7.3 and 0.9), 7.10 (1H, td, J
7.3 and 0.9), 7.24 (1H, d, J 2.4), 7.37 (1H, d, J 7.3), 7.65 (1H, d,
J 7.3), 7.71 (2H, br d, J 8.7), 8.03 (2H, br d, J 8.7), 10.35 (1H,
s), 11.02 (1H, s). 13C NMR (75 MHz, DMSO) d 20.31 (CH2),
41.68 (CH3), 57.10 (CH2), 60.88 (CH2), 109.32 (CH), 112.05 (Cq),
118.76 (CH), 118.94 (CH), 121.72 (CH), 123.76 (CH), 127.14
(Cq), 129.62 (2CH), 130.58 (2CH), 133.02 (Cq), 136.72 (Cq),
140.05 (Cq), 191.44 (Cq). m/z (FAB+) 327 (M − Cl−)+ (found: C,
62.84; H, 5.47; N, 7.63; (M − Cl−)+, 327.12649. C19H20Cl2N2O
requires C, 62.82; H, 5.55; N, 7.71%; (M − Cl−), 327.12642).
1-(4-Chlorophenyl)-2-{[2-(1H-indol-3-yl)-ethyl]-methylamino}-
ethanone 5b. 1H NMR (300 MHz, CDCl3) d 2.44 (3H, s),
2.84–2.90 (2H, m), 2.95–3.00 (2H, m), 3.81 (2H, s), 6.93 (1H,
d, J 2.3), 7.08 (1H, td, J 7.8 and 1.2), 7.15 (1H, td, J 7.8 and
1.2), 7.30 (3H, 2 br d, J 7.8 and 7.8), 7.56 (1H, br d, J 7.8),
7.83 (2H, dt, J 7.8 and 2.3), 8.40 (1H, br s). 13C NMR (75 MHz,
CDCl3) d 23.25 (CH2), 42.58 (CH3), 58.34 (CH2), 64.08 (CH2),
111.32 (CH), 113.64 (Cq), 118.71 (CH), 119.17 (CH), 121.87 (CH),
121.97 (CH), 127.42 (Cq), 128.74 (2CH), 129.77 (2CH), 134.15
(Cq), 136.30 (Cq), 139.52 (Cq), 196.58 (Cq). Rf (ethyl acetate–
cyclohexane 7 : 3) 0.68. m/z (FAB+) 327 (M + H)+ (found MH+,
327.12635. C19H20ClN2O requires MH, 327.12642).
[2-(1H-Indol-3-yl)-ethyl]-methyl-(2-oxo-2-phenylethyl)-ammo-
nium chloride 8a. 1H NMR (300 MHz, DMSO) d 3.02 (3H, d,
J 4.5), 3.21–3.29 (2H, m), 3.42–3.47 (1H, m), 3.49–3.54 (1H, m),
5.16 (1H, dd, J 18.3 and 5.4), 5.24 (1H, dd, J 18.3 and 4.2), 7.25
(1H, d, J 2.1), 7.38 (1H, d, J 6.9), 7.60 (1H, t, J 7.6), 7.62 (1H, d,
J 7.8), 7.68 (1H, d, J 7.8), 7.75 (1H, tt, J 7.2 and 1.5), 8.02 (2H, d,
J 7.2), 10.66 (1H, s), 11.14 (1H, s). 13C NMR (75 MHz, DMSO) d
20.38 (CH2), 41.51 (CH3), 57.00 (CH2), 60.74 (CH2), 109.40 (CH),
112.06 (Cq), 118.80 (CH), 118.90 (CH), 121.66 (CH), 123.75 (CH),
127.18 (Cq), 128.67 (2CH), 129.45 (2CH), 134.36 (Cq), 135.10
(CH), 136.73 (Cq), 192.30 (Cq). m/z (FAB+) 293 (M − Cl−)+,
621 (2M − Cl−)+ (found: (M − Cl−)+, 293.16534. C19H21ClN2O
requires (M − Cl−), 293.16539).
2-{[2-(1H-Indol-3-yl)-ethyl]-methylamino}-1-phenylethanone
5a. 1H NMR (300 MHz, CDCl3) d 2.36 (3H, s), 2.75–2.81 (2H,
m), 2.86–2.92 (2H, m), 3.78 (2H, s), 6.82 (1H, d, J 2.1), 6.94–7.06
(2H, m), 7.18 (1H, d, J 7.8), 7.26 (2H, apparent t, J 7.5), 7.39
(1H, tt, J 7.8 and 1.8), 7.47 (1H, d, J 7.5), 7.82 (2H, d, J 7.2),
8.51 (1H, s). 13C NMR (75 MHz, CDCl3) d 23.34 (CH2), 42.75
(CH3), 58.49 (CH2), 63.79 (CH2), 111.44 (CH), 113.63 (Cq), 118.77
(CH), 119.15 (CH), 121.84 (CH), 122.13 (CH), 127.54 (Cq), 128.23
(2CH), 128.63 (2CH), 133.33 (CH), 136.07 (Cq), 136.42 (Cq),
197.65 (Cq). Rf (ethyl acetate–cyclohexane 7 : 3) 0.37. m/z (FAB+)
293 (M + H)+ (found: MH+, 293.16544. C19H21N2O requires MH,
293.16539).
General procedure for the formation of 2-(1H-indol-3-yl)-ethyl
ammonium tosylate salts
[2-(4-Bromophenyl)-2-oxoethyl]-[2-(1H -indol-3-yl)-ethyl]-di-
methylammonium toluene-4-sulfonate 6c. To a solution of the 5c
(1.07 g, 2.89 mmol) in acetonitrile (14.5 mL) was added methyl-p-
toluenesulfonate (0.54 g, 2.89 mmol). The mixture was heated
under reflux for 4 h. After cooling at room temperature, the
solvent was removed to give the title compound as a crude yellow
powder 6c (1.62 g, >100%). Further purification was not attempted
according to the nature of the compound. NMR showed the
presence of the starting material methyl-p-toluenesulfonate which
was conveniently removed in the subsequent ion exchange step,
this explains why the yield is more than 100%. The identical
procedure using as starting material 5b and 5a was used toward
the synthesis of 6b and 6a in quantitative yields for both.
General procedure for the formation of 2-(1H-indol-3-yl)-ethyl
hydrochloride salts
[2-(4-Bromophenyl)-2-oxoethyl]-[2-(1H-indol-3-yl)-ethyl]-methyl-
ammonium chloride 8c. To a solution of 5c in a minimum
of diethyl ether (also for compound 5b), or dichloromethane
(for compound 5a) was flushed HCl gas. After a few seconds a
precipitate was formed, the colour generally white at the beginning
and changing to tan afterwards. The mixture was filtered and
the solid dried under vacuum to give the title compound 8c
(0.61 g, 77%). The identical procedure using as starting material
5b and 5a was used toward the synthesis of 8b and 8a in yields of
1
46% and 88%, respectively. H NMR showed traces of ether in
these products which could not be removed by treatment at high
vacuum for several days.
1H NMR (300 MHz, DMSO) d 3.00 (3H, s), 3.23 (2H, t, J 7.8),
3.40 (2H, signal obscured by the water in solvent), 5.09 (1H, d, J
16.5), 5.18 (1H, d, J 16.5), 7.02 (1H, td, J 7.7 and 0.9), 7.10 (1H, td,
J 7.7 and 0.9), 7.24 (1H, d, J 2.1), 7.37 (1H, d, J 7.7), 7.65 (1H, d, J
1H NMR (300 MHz, DMSO) of the expected compound 6c d
2.29 (3H, s), 3.23–3.26 (2H, m), 3.39 (6H, s), 3.83–3.88 (2H, m),
5.35 (2H, s), 7.03–7.13 (4H, m), 7.27 (1H, d, J 2.3), 7.37 (1H, d,
J 8.0), 7.48 (2H, d, J 8.0), 7.59 (1H, d, J 7.7), 7.85 (2H, d, J 8.7),
7.93 (2H, d, J 8.7), 10.98 (1H, s). 13C NMR (75 MHz, DMSO) d
19.04 (CH2), 21.24 (CH3), 51.86 (2CH3), 65.23 (CH2), 65.38 (CH2),
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108.52 (CH), 112.10 (Cq), 118.63 (CH), 119.05 (CH), 121.81 (CH),
124.13 (CH), 125.96 (2CH), 127.02 (Cq), 128.50 (2CH), 129.39
(Cq), 130.47 (2CH), 132.52 (2CH), 133.90 (Cq), 136.73 (Cq),
138.06 (Cq), 146.22 (Cq), 191.24 (Cq). m/z (FAB+) 386 (M −
d, J 2.3), 7.43 (1H, d, J 7.8), 7.66 (1H, d, J 7.8), 7.91 (2H, d, J 8.6),
8.02 (2H, d, J 8.6), 11.13 (1H, s). 13C NMR (75 MHz, DMSO) d
19.09 (CH2), 51.74 (2CH3), 65.04 (CH2), 65.49 (CH2), 108.53 (CH),
112.11 (Cq), 118.66 (CH), 118.99 (CH), 121.73 (CH), 124.13 (CH),
127.03 (Cq), 129.35 (Cq), 130.55 (2CH), 132.50 (2CH), 133.96
(Cq), 136.72 (Cq), 191.50 (Cq). m/z (FAB+) 385 (M − Cl−)+,
807 (2(M − Cl−)+ + Cl−)+ (found: C, 57.00; H, 5.27; N, 6.62;
(M − Cl−)+, 385.09152. C20H22BrN2O requires C, 56.96; H, 5.26;
N, 6.64%; (M − Cl−), 385.09155).
[2-(4-Chlorophenyl)-2-oxoethyl]-[2-(1H -indol-3-yl)-ethyl]-di-
methylammonium chloride 7b. 1H NMR (300 MHz, DMSO) of
the expected compound 7b d 3.20–3.27 (2H, m), 3.50 (6H, s),
3.87–3.93 (2H, m), 5.53 (2H, s), 7.02 (1H, td, J 6.8 and 1.0),
7.11 (1H, td, J 6.8 and 1.0), 7.29 (1H, d, J 2.3), 7.37 (1H, d,
J 7.8), 7.60 (1H, d, J 7.8), 7.70 (2H, d, J 8.6), 8.05 (2H, d, J
8.6), 11.10 (1H, s). 13C NMR (75 MHz, DMSO) d 19.08 (CH2),
51.76 (2CH3), 65.08 (CH2), 65.49 (CH2), 108.53 (CH), 112.10 (Cq),
118.65 (CH), 118.99 (CH), 121.74 (CH), 124.13 (CH), 127.03 (Cq),
129.55 (2CH), 130.50 (2CH), 133.65 (Cq), 136.70 (Cq), 140.05
(Cq), 191.23 (Cq). m/z (FAB+) 341 (M − Cl−)+, 717 (2(M − Cl−) +
Cl−)+ (found: C, 63.57; H, 5.67; N, 7.32; (M − Cl−)+, 341.14209.
C20H22ClN2O requires C, 63.67; H, 5.88; N, 7.42%; (M − Cl−),
341.14207).
CH3C6H4SO3−)+, 943 (2(M − CH3C6H4SO3−)+ + CH3C6H4SO3
)
−
+
(found: (M − CH3C6H4SO3−)+, 385.09152. C20H22BrN2O requires
(M − CH3C6H4SO3−), 385.09155).
[2-(4-Chlorophenyl)-2-oxoethyl]-[2-(1H -indol-3-yl)-ethyl]-di-
methylammonium toluene-4-sulfonate 6b. 1H NMR (300 MHz,
DMSO) of the expected compound 6b d 2.28 (3H, s), 3.21–3.26
(2H, m), 3.40 (6H, s), 3.83–3.89 (2H, m), 5.37 (2H, s), 7.00–
7.13 (4H, m), 7.28 (1H, d, J 2.2), 7.37 (1H, d, J 8.0), 7.48 (2H,
d, J 8.0), 7.60 (1H, d, J 7.7), 7.71 (2H, d, J 8.6), 8.02 (2H,
d, J 8.6), 10.99 (1H, s). 13C NMR (75 MHz, DMSO) d 19.04
(CH2), 21.24 (CH3), 51.85 (2CH3), 65.25 (CH2), 65.41 (CH2),
108.52 (CH), 112.11 (Cq), 118.64 (CH), 119.04 (CH), 121.80
(CH), 124.14 (CH), 125.96 (2CH), 127.03 (Cq), 128.50 (2CH),
129.57 (2CH), 130.45 (2CH), 133.60 (Cq), 136.73 (Cq), 138.03
(Cq), 140.09 (Cq), 146.27 (Cq), 191.04 (Cq). m/z (FAB+) 341 (M −
CH3C6H4SO3−)+, 854 (2(M − CH3C6H4SO3−)+ + CH3C6H4SO3
)
−
+
(found: (M − CH3C6H4SO3−)+, 341.14202. C20H22ClN2O requires
(M − CH3C6H4SO3−), 341.14207).
[2-(1H-Indol-3-yl)-ethyl]-dimethyl-(2-oxo-2-phenylethyl)-amm-
onium toluene-4-sulfonate 6a. 1H NMR (300 MHz, DMSO) of
the expected compound 6a d 2.28 (3H, s), 3.21–3.36 (2H, m),
3.41 (6H, s), 3.84–3.90 (2H, m), 5.39 (2H, s), 7.03–7.14 (4H, m),
7.28 (1H, d, J 2.3), 7.38 (1H, d, J 8.0), 7.48 (2H, d, J 8.0), 7.60
(1H, d, J 6.9), 7.63 (2H, t, J 7.6), 7.78 (1H, t, J 7.6), 8.02 (2H,
d, J 7.2), 10.99 (1H, s). 13C NMR (75 MHz, DMSO) d 19.06
(CH2), 21.24 (CH3), 51.82 (2CH3), 65.22 (CH2), 65.47 (CH2),
108.52 (CH), 112.11 (Cq), 118.62 (CH), 119.05 (CH), 121.81 (CH),
124.12 (CH), 125.96 (2CH), 127.03 (Cq), 128.49 (2CH), 128.53
(2CH), 129.47 (2CH), 134.89 (Cq), 135.21 (CH), 136.73 (Cq),
138.00 (Cq), 146.30 (Cq), 192.00 (Cq). m/z (FAB+) 307 (M −
[2-(1H-Indol-3-yl)-ethyl]-dimethyl-(2-oxo-2-phenylethyl)-ammo-
nium chloride 7a. 1H NMR (300 MHz, DMSO) d 3.19–3.27
(2H, m), 3.48 (6H, s), 3.86–3.92 (2H, m), 5.48 (2H, s), 7.03 (1H,
td, J 7.0 and 1.2), 7.11 (1H, td, J 8.2 and 1.2), 7.29 (1H, d, J 2.4),
7.38 (1H, dt, J 7.9 and 0.9), 7.58–7.65 (3H, m), 7.77 (1H, tt, J 7.4
and 1.3), 8.00–8.06 (2H, m), 11.06 (1H, s). 13C NMR (75 MHz,
DMSO) d 18.57 (CH2), 51.25 (2CH3), 64.61 (CH2), 65.00 (CH2),
108.01 (CH), 111.61 (Cq), 118.12 (CH), 118.52 (CH), 121.27
(CH), 123.60 (CH), 126.52 (Cq), 128.06 (2CH), 128.95 (2CH),
134.40 (Cq), 134.68 (CH), 136.21 (Cq), 191.61 (Cq). m/z (FAB+)
307 ((M − Cl−) + H)+, 649 (2(M − Cl−) + Cl−)+ (found: (M −
Cl−)+, 307.18103. C20H23N2O requires (M − Cl−), 307.18104).
N-[2-(1H-Indol-3-yl)-ethyl]-N-methylbenzamide 9a§. Yellow
paste. Yield 37%. Rf (ethyl acetate–petroleum ether 50 : 50) 0.15.
Rotamers 1 : 1.4 (from the duplicated triplet signal (1H) at 3.48
and 3.81 ppm). 1H NMR (300 MHz, DMSO) d (major rotamer)
2.89 (2H, t, J 7.2), 3.11 (3H, br s), 3.48 (2H, t, J 7.2), 6.81–7.29
(10H, m), 8.01 (1H, br s). d (distinct peaks for minor rotamer) 2.80
(3H, s), 3.81 (2H, t, J 6.9), 7.65 (1H, d, J 6.9). 13C NMR (75 MHz,
DMSO) d (major rotamer) 24.33 (CH2), 32.78 (CH3), 51.89 (CH2),
110.91 (Cq), 111.82 (CH), 118.68 (CH), 121.39 (CH), 123.26 (CH),
123.43 (CH), 126.70 (CH), 127.38 (Cq), 128.67 (3CH), 129.26
(CH), 137.36 (2Cq), 171.17 (Cq). d (distinct peaks for minor
rotamer) 23.01 (CH2), 37.83 (CH3), 48.24 (CH2), 118.32 (CH),
127.16 (CH), 127.76 (Cq), 129.66 (CH), 136.62 (Cq), 170.33 (Cq).
m/z (ES+) 279 (MH+), 557 (2M + H)+; (ES−) 277 (M − H)−,
555 (2M − H)−; m/z (FAB+) 279 MH+ (found: MH+, 279.14977.
C18H18N2O requires MH, 279.14974).
CH3C6H4SO3−)+, 786 (2(M − CH3C6H4SO3−)+ + CH3C6H4SO3
)
−
+
−
+
(found: (M − CH3C6H4SO3
) 307.18104. C20H23N2O requires
(M − CH3C6H4SO3−), 307.18104).
General procedure for the ion exchange of tosylate salts to chloride
salts
[2-(4-Bromophenyl)-2-oxoethyl]-[2-(1H -indol-3-yl)-ethyl]-di-
methylammonium chloride 7c. To a solution of the crude tosylate
salt 6c (0.96 g, 1.73 mmol) in acetonitrile–water 2.3 : 5 (19.7 mL),
R
was added Dowexꢀ Cl− 1 × 8–400 ion exchange resin (3.60 g). The
suspension was stirred overnight at room temperature. A column
R
was packed with Dowexꢀ Cl− 1 × 8–400 ion exchange resin (10 g)
with the same solvent mixture. The suspension was poured onto
the column and eluted with acetonitrile–water 2.3 : 5 (150 mL) and
acetonitrile (100 mL). The combined eluate was evaporated under
reduced pressure, an aqueous solution of HCl 2 N (3.2 mL) was
added, and removed after a few minutes to give the title compound
7c as a tan solid (0.33 g, 46%). The identical procedure using as
starting material 6b and 6a was used toward the synthesis of 7b
and 7a in yields of 50% and 53%, respectively.
4-tert-Butyl-N-[2-(1H-indol-3-yl)-ethyl]-N-methylbenzamide
9b. White solid. Yield 57%. Mp 194 ◦C. Rotamers 1 : 1.6 (from
1H NMR (300 MHz, DMSO) of the expected compound 2c d
3.25–3.32 (2H, m), 3.51 (6H, s), 3.92–3.97 (2H, m), 5.54 (2H, s),
7.09 (1H, td, J 7.4 and 1.0), 7.17 (1H, td, J 7.4 and 1.0), 7.34 (1H,
§ The general procedure for the synthesis of compounds 9a–q and 10 is
the same as the general procedure for the synthesis of compounds 12a–q,
except that methyltryptamine 4 was used as a starting material and not 11.
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the duplicated triplet signal (1H) at 3.47 and 3.79 ppm). Rf (ethyl
acetate–petroleum ether, 50 : 50) 0.20. 1H NMR (300 MHz,
CDCl3) d (major rotamer) 1.23 (9H, s), 2.86 (2H, distorted t,
J 6.8), 3.09 (3H, s), 3.47 (2H, t, J 6.8), 6.75–7.31 (9H, m), 8.43
(1H, br s). d (distinct peaks for minor rotamer) 2.81 (3H, s), 3.79
(2H, br t, J 7.1), 7.62 (1H, d, J 6.3). 13C NMR (75 MHz, CDCl3)
d (major rotamer) 24.49 (CH2), 31.27 (3CH3), 33.06 (CH3), 34.74
(Cq), 51.99 (CH2), 111.32 (CH), 111.60 (Cq), 118.15 (CH), 119.21
(CH), 121.86 (2CH), 125.22 (3CH), 126.20 (CH), 127.10 (Cq),
133.52 (Cq), 136.34 (Cq), 152.23 (Cq), 172.76 (Cq). d (distinct
peaks for minor rotamer) 22.97 (CH2), 38.29 (CH3), 48.51 (CH2),
112.86 (Cq), 118.70 (CH), 122.28 (2CH), 126.89 (CH), 127.57
(Cq), 133.72 (Cq), 152.55 (Cq), 171.62 (Cq). m/z (ES+) 335 (MH+);
(ES−) 333 (M − H)−; m/z (FAB+) 335 (MH+), 670 (2M + 2H)+
(found: C, 78.92; H, 7.88; N, 8.25; MH+, 335.21232. C22H26N2O
requires C, 79.01; H, 7.84; N, 8.38%; MH, 335.21234).
(found: C, 72.85; H, 5.70; N, 9.35; MH+, 297.14034. C18H17FN2O
requires C, 72.96; H, 5.78; N, 9.45%; MH, 297.14032).
4-Fluoro-N-[2-(1H-indol-3-yl)-e◦thyl]-N-methylbenzamide 9e.
White solid. Yield 58%. Mp 180 C. Rotamers 1 : 1.5 (from the
duplicated singlet signal (19F) observed at room temperature at
−112.22 and −111.49 ppm). Rf (ethyl acetate–petroleum ether
1
50 : 50) 0.14. H NMR (400 MHz, DMSO, 363 K) d 2.98 (2H,
distorted t, J 5.7), 3.05 (3H, s), 3.61 (2H, t, J 5.7), 6.94 (1H, t,
J 6.5), 7.05–7.14 (6H, m), 7.27 (1H, br t, J 7.0), 7.35 (1H, d,
J 8.4), 10.54 (1H, br s). 13C NMR (75 MHz, CDCl3) d (major
rotamer) 24.15 (CH2), 32.85 (CH3), 51.88 (CH2), 110.86 (Cq),
111.85 (CH), 115.41 (2CH, br d, J 20.0), 118.64 (2CH), 121.40
(CH), 123.57 (CH), 127.42 (Cq), 129.13 (2CH, d, J 11.0), 133.63
(Cq), 136.68 (Cq), 162.50 (Cq, d, J 259.6), 170.31 (Cq). d (distinct
peaks for minor rotamer) 23.01 (CH2), 37.91 (CH3), 48.40 (CH2),
115.48 (CH, d, J 29.8), 115.68 (CH, d, J 19.9), 118.24 (CH),
123.29 (CH), 127.74 (Cq), 129.80 (CH, d, J 9.2), 169.43 (Cq). 13
C
2-Fluoro-N-[2-(1H-indol-3-yl)-ethyl]-N-methylbenzamide 9c.
Tan solid. Yield 59%. Mp 125 ◦C. Rotamers 1 : 1.4 (from the
duplicated triplet signal (1H) at 3.40 and 3.79 ppm). Rf (ethyl
acetate–petroleum ether, 50 : 50) 0.27. 1H NMR (300 MHz,
CDCl3) d (major rotamer) 2.84 (2H, t, J 7.4), 3.10 (3H, s), 3.40
(2H, t, J 7.4), 6.73–7.29 (9H, m), 8.39 (1H, br s). d (distinct peaks
for minor rotamer) 2.73 (3H, s), 3.05 (2H, distorted t, J 7.4), 3.79
(2H, t, J 7.4), 7.62 (1H, d, J 7.5). 13C NMR (75 MHz, CDCl3) d
(major rotamer) 24.29 (CH2), 32.92 (CH3), 48.42 (CH2), 111.33
(CH), 111.43 (Cq), 112.62 (Cq), 115.83 (CH, d, J 15.5), 117.96
(CH), 118.66 (CH), 119.25 (CH), 121.90 (CH), 124.43 (CH, d, J
6.3), 127.24 (Cq, d, J 32.5), 128.64 (CH, d, J 4.6), 130.76 (CH,
d, J 7.7), 136.35 (Cq), 158.00 (Cq, d, J 224.8), 166.78 (Cq). d
(distinct peaks for minor rotamer) 23.05 (CH2), 37.01 (CH3),
51.53 (CH2), 115.55 (CH, d, J 15.6), 122.34 (CH), 124.66 (CH,
d, J 7.4), 128.92 (CH, d, J 3.2), 131.13 (CH, d, J 8.0), 136.35
(Cq), 157.78 (Cq, d, J 302.2), 167.21 (Cq). 19F NMR (282 MHz,
CDCl3) d (major rotamer) −115.55. d (minor rotamer) −115.15.
m/z (ES+) 297 (MH+), 593 (2M + H)+; (ES−) 295 (M − H)−, 591
(2M − H)−; m/z (FAB+) 297 (MH+), 594 (2M + 2H)+ (found: C,
72.89; H, 5.70; N, 9.39; MH+, 297.14027. C18H17FN2O requires
C, 72.96; H, 5.78; N, 9.45%; MH, 297.14032).
NMR (100 MHz, 363 K, DMSO) d 23.75 (CH2), 111.69 (Cq),
111.84 (CH), 115.29 (CH), 115.51 (CH), 118.45 (CH), 118.73
(CH), 121.40 (CH), 123.32 (CH), 127.77 (Cq), 129.34 (CH),
129.43 (CH), 133.93 (Cq), 136.96 (Cq), 162.77 (Cq, d, J 245.0),
170.06 (Cq). At this temperature, one CH2 and one CH3 were
not observed. 19F NMR (282 MHz, CDCl3) d (major rotamer)
−112.22. d (minor rotamer) −111.49. m/z (ES+) 297 (MH+), 593
(2M + H)+; (ES−) 295 (M − H)−, 591 (2M − H)−; m/z (FAB+)
297 (MH+), 593 (2M + H)+ (found: C, 72.85; H, 5.93; N, 9.52;
MH+, 297.14035. C18H17FN2O requires C, 72.96; H, 5.78; N,
9.45%; MH, 297.14032).
2-Chloro-N-[2-(1H-indol-3-yl)-ethyl]-N-methylbenzamide 9f.
Tan solid. Yield 55%. Mp 176 ◦C. Rotamers 1 : 1.2 (from the
duplicated singlet signal (1H) at 2.75 and 3.09 ppm). Rf (ethyl
acetate–petroleum ether 50 : 50) 0.26. 1H NMR (300 MHz,
DMSO) d (major rotamer) 2.85–2.93 (2H, m), 3.09 (3H, s),
3.26–3.33 (2H, m), 6.77–7.81 (9H, m), 10.82 (1H, br s). d (distinct
peaks for minor rotamer) 2.75 (3H, s), 3.01–3.07 (2H, m), 3.75
(2H, br s), 10.86 (1H, s). 13C NMR (75 MHz, DMSO) d (major
rotamer) 24.26 (CH2), 32.38 (CH3), 51.25 (CH2), 110.71 (Cq),
111.86 (CH), 118.09 (CH), 118.77 (CH), 121.39 (CH), 123.52
(CH), 127.33 (Cq), 127.69 (CH), 128.44 (CH), 129.43 (Cq),
129.63 (CH), 130.56 (CH), 131.08 (Cq), 136.63 (Cq), 167.48 (Cq).
d (distinct peaks for minor rotamer) 22.99 (CH2), 36.39 (CH3),
47.66 (CH2), 111.64 (Cq), 118.68 (CH), 121.41 (CH), 123.40
(CH), 128.06 (CH), 128.16 (CH), 129.83 (CH), 130.76 (CH),
137.04 (Cq), 172.00 (Cq). m/z (ES+) 313 (MH+), 625 (2M + H)+;
(ES−) 311 (M − H)−, 623 (2M − H)−; m/z (FAB+) 313 (MH+),
(found: C, 68.95; H, 5.57; N, 8.83; MH+, 313.11071. C18H17ClN2O
requires C, 69.12; H, 5.48; N, 8.96%; MH, 313.11077).
3-Fluoro-N-[2-(1H-indol-3-yl)-ethyl]-N-methylbenzamide 9d.
Tan solid. Yield 54%. Mp 144 ◦C. Rotamers 1 : 1.4 (from the
duplicated triplet signal (1H) at 3.44 and 3.76 ppm). Rf (ethyl
acetate–petroleum ether 50 : 50) 0.20. 1H NMR (300 MHz,
CDCl3) d (major rotamer) 2.83 (2H, t, J 7.0), 3.07 (3H, s), 3.44
(2H, t, J 7.0), 6.63–7.22 (9H, m), 8.54 (1H, br s). d (distinct peaks
for minor rotamer) 2.73 (3H, s), 3.76 (2H, t, J 7.1), 7.60 (1H, d,
J 7.2). 13C NMR (75 MHz, CDCl3) d (major rotamer) 24.20
(CH2), 33.03 (CH3), 51.81 (CH2), 111.22 (Cq), 111.42 (CH),
112.52 (Cq), 113.75 (CH, d, J 22.8), 116.06 (CH, d, J 21.0), 117.88
(CH), 118.62 (CH), 119.28 (CH), 121.95 (CH), 122.19 (CH, d,
J 10.6), 127.01 (Cq), 130.02 (CH, d, J 7.6), 136.33 (Cq), 138.26
(Cq, d, J 6.8), 162.28 (Cq, d, J 246.2), 170.96 (Cq). d (distinct
peaks for minor rotamer) 22.92 (CH2), 30.95 (CH3), 48.62 (CH2),
114.16 (CH, d, J 23.7), 116.48 (CH, d, J 20.9), 122.41 (CH),
122.51 (CH, d, J 15.1), 127.51 (Cq), 130.28 (CH, d, J 11.3), 138.75
(Cq, d, J 10.4), 162.50 (Cq, d, J 225.0), 169.99 (Cq). 19F NMR
(282 MHz, CDCl3) d (major rotamer) −111.84. d (minor rotamer)
−111.87. m/z (ES+) 297 (MH+), 593 (2M + H)+; (ES−) 295 (M −
H)−, 591 (2M − H)−; m/z (FAB+) 297 (MH+), 593 (2M + H)+
3-Chloro-N-[2-(1H-indol-3-yl)-ethyl]-N-methylbenzamide 9g.
Beige solid. Yield 52%. Mp 152 ◦C. Rotamers 1 : 1.4 (from the
duplicated triplet signal (1H) at 3.55 and 3.86 ppm). Rf (ethyl
acetate–petroleum ether 50 : 50) 0.23. 1H NMR (300 MHz,
CDCl3) d (major rotamer) 2.96 (2H, t, J 7.1), 3.17 (3H, s), 3.55
(2H, t, J 7.1), 6.89–7.38 (9H, m), 8.11 (1H, br s). d (distinct
peaks for minor rotamer) 2.85 (3H, s), 3.86 (2H, t, J 7.1), 7.71
(1H, d, J 7.5). 13C NMR (75 MHz, CDCl3) d (major rotamer)
24.20 (CH2), 33.04 (CH3), 51.89 (CH2), 111.35 (CH), 111.49 (Cq),
117.97 (CH), 119.44 (CH), 122.14 (2CH), 124.58 (CH), 126.64
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(CH), 126.94 (Cq), 129.56 (2CH), 134.22 (Cq), 136.22 (Cq),
137.96 (Cq), 170.76 (Cq). d (distinct peaks for minor rotamer)
22.89 (CH2), 38.15 (CH3), 48.57 (CH2), 112.78 (Cq), 118.69 (CH),
122.26 (CH), 125.02 (CH), 127.11 (CH), 127.51 (Cq), 129.16
(CH), 129.79 (CH), 134.40 (Cq), 138.40 (Cq), 169.83 (Cq). m/z
(ES+) 313 (MH+), 625 (2M + H)+; (ES−) 311 (M − H)−, 623
(2M − H)−; m/z (FAB+) 313 (MH+), 625 (2M + H)+ (found: C,
69.00; H, 5.54; N, 8.88; MH+, 313.11073. C18H17ClN2O requires
C, 69.12; H, 5.48; N, 8.96%; MH, 313.11077).
136.22 (Cq), 138.15 (Cq), 170.65 (Cq). d (distinct peaks for minor
rotamer) 22.88 (CH2), 38.18 (CH3), 48.61 (CH2), 118.66 (CH),
125.45 (CH), 127.52 (Cq), 129.45 (CH), 130.06 (CH), 132.51
(CH), 135.95 (Cq), 138.59 (Cq), 169.73 (Cq). m/z (ES+) 357 (M+),
358 (MH+); (ES−) 356 (M − H)−; m/z (FAB+) 357 (M+) (found:
C, 60.38; H, 4.80; N, 7.73; M+, 357.06030. C18H17BrN2O requires
C, 60.52; H, 4.80; N, 7.84%; M, 357.06025).
4-Bromo-N-[2-(1H-indol-3-yl)-ethyl]-N-methylbenzamide 9k.
◦
White solid. Yield 73%. Mp 160 C. Rotamers 1 : 1.5 (from the
4-Chloro-N-[2-(1H-indol-3-yl)-ethyl]-N-methylbenzamide 9h.
Beige solid. Yield 62%. Mp 160 ◦C. Rotamers 1 : 1.4 (from the
duplicated triplet signal (1H) at 3.55 and 3.86 ppm). Rf (ethyl
acetate–petroleum ether 50 : 50) 0.17. 1H NMR (300 MHz,
CDCl3) d (major rotamer) 2.94 (2H, t, J 6.4), 3.17 (3H, s), 3.55
(2H, t, J 6.4), 6.87–7.42 (9H, m), 8.16 (1H, br s). d (distinct peaks
for minor rotamer) 2.86 (3H, s), 3.86 (2H, distorted t, J 5.4), 7.70
(1H, d, J 6.9). 13C NMR (75 MHz, CDCl3) d (major rotamer)
24.17 (CH2), 33.01 (CH3), 51.74 (CH2), 111.31 (CH), 112.77 (Cq),
118.01 (CH), 119.42 (CH), 122.12 (2CH), 127.03 (Cq), 127.89
(2CH), 128.38 (2CH), 135.02 (Cq), 136.27 (2Cq), 171.41 (Cq).
d (distinct peaks for minor rotamer) 22.88 (CH2), 38.20 (CH3),
48.59 (CH2), 118.69 (CH), 122.31 (CH), 127.53 (Cq), 128.51
(CH), 128.64 (CH), 134.55 (Cq), 135.50 (Cq). m/z (ES+) 313
(MH+), 625 (2M + H)+; (ES−) 311 (M − H)−, 623 (2M − H)−;
m/z (FAB+) 313 (MH+), 625 (2M + H)+ (found: C, 68.99; H,
5.54; N, 8.87; MH+, 313.11072. C18H17ClN2O requires C, 69.12;
H, 5.48; N, 8.96%; MH, 313.11077).
duplicated triplet signal (1H) at 3.45 and 3.77 ppm). Rf (ethyl
acetate–petroleum ether 50 : 50) 0.23. 1H NMR (300 MHz,
CDCl3) d (major rotamer) 2.83 (2H, t, J 6.3), 3.07 (3H, s), 3.45
(2H, t, J 6.3), 6.71–7.62 (9H, m), 8.41 (1H, br s). d (distinct peaks
for minor rotamer) 2.76 (3H, s), 3.77 (2H, distorted t, J 7.1). 13
C
NMR (75 MHz, CDCl3) d (major rotamer) 24.17 (CH2), 32.99
(CH3), 51.72 (CH2), 111.35 (CH), 112.65 (Cq), 117.98 (CH),
119.39 (CH), 122.05 (CH), 122.38 (CH), 123.27 (Cq), 127.04
(Cq), 128.09 (2CH), 131.33 (2CH), 135.02 (Cq), 136.31 (Cq),
171.44 (Cq). d (distinct peaks for minor rotamer) 22.89 (CH2),
38.18 (CH3), 48.62 (CH2), 118.65 (CH), 123.74 (Cq), 127.54 (Cq),
128.69 (CH), 131.60 (CH), 135.51 (Cq), 170.40 (Cq). m/z (ES+)
358 (MH+); (ES−) 356 (M − H)−; m/z (FAB+) 357 (M+) (found:
C, 60.58; H, 4.96; N, 7.76; M+, 357.06027. C18H17BrN2O requires
C, 60.52; H, 4.80; N, 7.84%; M, 357.06025).
N-[2-(1H-Indol-3-yl)-ethyl]-2-methoxy-N-methylbenzamide 9l.
Beige solid. Yield 57%. Mp 203 ◦C. Rotamers 1 : 1.3 (from the
multiplet and triplet signals (1H) at 3.38–3.46 and 3.88 ppm). Rf
(ethyl acetate–petroleum ether, 50 : 50) 0.09. 1H NMR (300 MHz,
CDCl3) d (major rotamer) 2.81–2.95 (2H, m), 3.17 (3H, s), 3.38–
3.46 (2H, m), 3.77 (3H, s), 7.11–7.38 (9H, m), 8.31 (1H, br s). d
(distinct peaks for minor rotamer) 2.77 (3H, s), 3.11–3.14 (2H,
m), 2.78 (3H, s), 3.88 (2H, distorted t, J 7.5), 7.71 (1H, d, J 7.5),
8.34 (1H, br s). 13C NMR (75 MHz, CDCl3) d (major rotamer)
24.51 (CH2), 32.80 (CH3), 51.57 (CH2), 55.51 (CH3), 110.96 (CH),
111.23 (CH), 112.05 (Cq), 118.24 (CH), 119.20 (CH), 120.83 (CH),
121.90 (CH), 122.04 (CH), 126.30 (Cq), 127.11 (Cq), 127.72 (CH),
130.06 (CH), 136.26 (Cq), 155.17 (Cq), 169.69 (Cq). d (distinct
peaks for minor rotamer) 23.00 (CH2), 36.70 (CH3), 47.94 (CH2),
55.56 (CH3), 112.98 (Cq), 118.74 (CH), 120.88 (CH), 121.84 (CH),
122.26 (CH), 126.72 (Cq), 127.56 (Cq), 127.78 (CH), 130.21 (CH),
136.32 (Cq), 155.27 (Cq). m/z (ES+) 309 (MH+), 617 (2M + H)+;
(ES−) 307 (M − H)−, 615 (2M − H)−; m/z (FAB+) 309 (MH+), 618
(2M + 2H)+ (found: C, 73.97; H, 6.49; N, 9.02; MH+, 309.16027.
C19H20N2O2 requires C, 74.00; H, 6.54; N, 9.08%; MH, 309.16030).
2-Bromo-N-[2-(1H-indol-3-yl)-ethyl]-N-methylbenzamide
9i.
Tan solid. Yield 48%. Mp 205 ◦C. Rotamers 1 : 1.2 (from the
duplicated triplet signal (1H) at 3.34 and 3.79 ppm). Rf (ethyl
acetate–petroleum ether 50 : 50) 0.31. 1H NMR (400 MHz, 363 K,
DMSO) d (major rotamer) 2.92 (2H, t, J 7.3), 3.10 (3H, s), 3.34
(2H, t, J 7.3), 6.90–7.10 (3H, m), 7.19–7.44 (5H, m), 7.63 (1H, br
t, estimated J 9.4), 10.61 (1H, br s). d (distinct peaks for minor
rotamer) 2.77 (3H, s), 3.79 (2H, t, J 7.6), 6.84 (1H, t, J 7.4). 13C
NMR (75 MHz, DMSO) d (major rotamer) 24.27 (CH2), 32.37
(CH3), 51.31 (CH2), 110.69 (Cq), 111.89 (CH), 118.10 (CH),
118.74 (CH), 118.82 (Cq), 121.36 (CH), 123.54 (CH), 127.66
(Cq), 128.14 (CH), 128.49 (CH), 130.68 (CH), 132.72 (CH),
136.63 (Cq), 138.79 (Cq), 168.31 (Cq). d (distinct peaks for minor
rotamer) 22.94 (CH2), 36.50 (CH3), 47.67 (CH2), 111.61 (Cq),
118.65 (CH), 118.94 (Cq), 121.42 (CH), 123.43 (CH), 127.32
(Cq), 130.87 (CH), 132.94 (CH), 136.77 (Cq), 139.16 (Cq), 168.15
(Cq). m/z (ES+) 358; (ES−) 356 (M − H)−; m/z (FAB+) 357 (M+)
(found: C, 60.38; H, 4.81; N, 7.81; M+, 357.06015. C18H17BrN2O
requires C, 60.52; H, 4.80; N, 7.84%; M, 357.06025).
N -[2-(1H -Indol-3-yl)-ethyl]-3-methoxy-N -methylbenzamide
◦
9m. Tan solid. Yield 54%. Mp 175 C. Rotamers 1 : 1.2 (from
3-Bromo-N-[2-(1H-indol-3-yl)-ethyl]-N-methylbenzamide
9j.
the duplicated triplet signal (1H) at 3.48 and 3.78 ppm). Rf (ethyl
acetate–petroleum ether 50 : 50) 0.17. 1H NMR (300 MHz, CDCl3)
d (major rotamer) 2.89 (2H, br t, J 7.2), 3.10 (3H, br s), 3.48 (2H,
t, J 7.2), 3.63 (3H, br s), 6.65–7.28 (9H, m), 8.20 (1H, br s). d
(distinct peaks for minor rotamer) 2.79 (3H, s), 3.70 (3H, s), 3.78
(2H, distorted t, J 7.1), 7.64 (1H, d, J 7.2). 13C NMR (75 MHz,
CDCl3) d (major rotamer) 24.48 (CH2), 33.03 (CH3), 51.91 (CH2),
55.25 (CH3), 111.24 (CH), 111.85 (CH), 112.92 (Cq), 115.08 (CH),
118.63 (CH), 118.70 (CH), 119.33 (CH), 122.00 (CH), 122.12
(CH), 127.12 (Cq), 129.46 (CH), 136.26 (Cq), 137.78 (Cq), 159.50
(Cq), 172.02 (Cq). d (distinct peaks for minor rotamer) 22.90
◦
White solid. Yield 76%. Mp 166 C. Rotamers 1 : 1.4 (from the
duplicated triplet signal (1H) at 3.46 and 3.78 ppm). Rf (ethyl
acetate–petroleum ether 50 : 50) 0.35. 1H NMR (300 MHz,
CDCl3) d (major rotamer) 2.87 (2H, t, J 6.9), 3.09 (3H, s), 3.46
(2H, t, J 6.9), 6.76–7.61 (9H, m), 8.25 (1H, br s). d (distinct
peaks for minor rotamer) 2.76 (3H, s), 3.78 (2H, t, J 6.9). 13C
NMR (75 MHz, CDCl3) d (major rotamer) 24.20 (CH2), 33.08
(CH3), 51.94 (CH2), 111.39 (CH), 112.72 (Cq), 117.97 (CH),
119.44 (CH), 122.13 (CH), 122.30 (CH), 125.04 (CH), 126.98
(Cq), 129.79 (CH), 129.94 (CH), 132.10 (CH), 132.99 (Cq),
796 | Org. Biomol. Chem., 2006, 4, 787–801
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(CH2), 38.13 (CH3), 48.41 (CH2), 112.14 (CH), 115.39 (CH),
118.24 (CH), 119.03 (CH), 127.26 (Cq). m/z (ES+) 309 (MH+),
617 (2M + H)+; (ES−) 307 (M − H)−, 615 (2M − H)−; m/z (FAB+)
309 MH+ (found: C, 73.87; H, 6.44; N, 9.01; MH+, 309.16031.
C19H20N2O2 requires C, 74.00; H, 6.54; N, 9.08%; MH, 309.16030).
122.26 (2CH), 127.08 (CH), 127.55 (Cq), 133.71 (Cq), 139.54
(Cq), 171.63 (Cq). m/z (ES+) 293 (MH+), 585 (2M + H)+; (ES−)
291 (M − H)−; m/z (FAB+) 293 (MH+) (found: C, 77.91; H, 6.81;
N, 9.62; MH+, 293.16543. C19H20N2O requires C, 78.05; H, 6.89;
N, 9.58%; MH, 293.16539).
N-[2-(1H-Indol-3-yl)-ethyl]-2,N-dimethylbenzamide 9n. Tan
solid. Yield 63%. Mp 188 ◦C. Rotamers 1 : 1.4 (from the duplicated
triplet signal (1H) at 3.40 and 3.91 ppm). Rf (ethyl acetate–
Biphenyl-4-carboxylic acid [2-(1H-indol-3-yl)-ethyl]-methyl-
amide 9q. Beige solid. Yield 58%. Mp 178 ◦C. Rotamers 1 : 1.5
(from the duplicated triplet signal (1H) at 3.59 and 3.89 ppm). Rf
(ethyl acetate–petroleum ether 50 : 50) 0.16. 1H NMR (300 MHz,
CDCl3) d (major rotamer) 2.95 (2H, distorted t, J 6.8), 3.18 (3H, s),
3.59 (2H, t, J 6.8), 6.84–7.55 (14H, m), 8.42 (1H, br s). d (distinct
peaks for minor rotamer) 2.91 (3H, br s), 3.89 (2H, apparent t,
estimated J 6.9), 7.72 (1H, br d, J 6.9). 13C NMR (75 MHz,
CDCl3) d (major rotamer) 24.41 (CH2), 33.06 (CH3), 51.92 (CH2),
111.33 (2CH), 111.57 (Cq), 118.15 (CH), 119.31 (2CH), 121.96
(2CH), 127.01 (2CH), 127.16 (2CH), 127.54 (Cq), 127.66 (CH),
128.87 (2CH), 135.21 (Cq), 136.34 (Cq), 140.45 (Cq), 141.95 (Cq),
172.35 (Cq). d (distinct peaks for minor rotamer) 22.98 (CH2),
38.28 (CH3), 48.55 (CH2), 112.86 (Cq), 118.73 (CH), 122.30 (CH),
135.47 (Cq), 142.34 (Cq), 171.27 (Cq). m/z (ES+) 355 (MH+);
(ES−) 353 (M − H)−; m/z (FAB+) 355 (MH+) (found: C, 81.34; H,
6.07; N, 7.84; MH+, 355.18103. C24H22N2O requires C, 81.26; H,
6.26; N, 7.90%; MH, 355.18104).
1
petroleum ether 50 : 50) 0.24. H NMR (300 MHz, CDCl3) d
(major rotamer) 2.19 (3H, s), 2.90 (2H, t, J 7.7), 3.20 (3H, s),
3.40 (2H, t, J 7.7), 6.90–7.34 (9H, m), 8.33 (1H, br s). d (distinct
peaks for minor rotamer) 2.24 (3H, s), 2.75 (3H, s), 3.16 (2H,
apparent t, estimated J 7.5), 3.91 (2H, td, J 7.5), 7.70 (1H, d, J
7.5), 8.35 (1H, br s). 13C NMR (75 MHz, CDCl3) d (major rotamer)
18.91 (CH3), 24.51 (CH2), 32.52 (CH3), 51.38 (CH2), 111.24 (CH),
111.67 (Cq), 118.22 (CH), 119.28 (CH), 121.84 (CH), 121.98 (CH),
125.80 (CH), 125.92 (CH), 127.01 (Cq), 128.67 (CH), 130.30 (CH),
133.97 (Cq), 136.28 (Cq), 136.50 (Cq), 171.86 (Cq). d (distinct
peaks for minor rotamer) 18.81 (CH3), 23.04 (CH2), 36.80 (CH3),
47.53 (CH2), 111.28 (CH), 112.72 (Cq), 118.69 (CH), 122.09 (CH),
122.21 (CH), 125.71 (CH), 127.50 (Cq), 130.32 (CH), 133.88 (Cq),
136.36 (Cq), 137.00 (Cq), 171.40 (Cq). m/z (ES+) 293 (MH+), 585
(2M + H)+; (ES−) 291 (M − H)−, 583 (2M − H)−; m/z (FAB+)
293 (MH+) (found: C, 78.08; H, 6.73; N, 9.51; MH+, 293.16541.
C19H20N2O requires C, 78.05; H, 6.89; N, 9.58%; MH, 293.16539).
N-[2-(1H-Indol-3-yl)-ethyl]-N-methyl-2-phenylacetamide 10§.
Yellow paste. Yield 55%. Rotamers 1 : 1.2 (from the duplicated
doublet signal (1H) at 7.58 and 7.69 ppm). Rf (ethyl acetate–
N -[2-(1H -Indol-3-yl)-ethyl]-◦3,N -dimethylbenzamide
9o.
White solid. Yield 56%. Mp 140 C. Rotamers 1 : 1.3 (from the
duplicated triplet signal (1H) at 3.47 and 3.80 ppm). Rf (ethyl
acetate–petroleum ether 50 : 50) 0.20. 1H NMR (300 MHz,
CDCl3) d (major rotamer) 2.15 (3H, s), 2.89 (2H, t, J 6.9), 3.10
(3H, br s), 3.47 (2H, t, J 6.9), 6.81–7.30 (9H, m), 8.07 (1H, br s). d
(distinct peaks for minor rotamer) 2.27 (3H, s), 2.80 (3H, s), 3.80
(2H, apparent t, estimated J 6.3), 7.65 (1H, d, J 7.2). 13C NMR
(75 MHz, CDCl3) d (major rotamer) 21.34 (CH3), 24.39 (CH2),
33.01 (CH3), 51.93 (CH2), 111.32 (CH), 111.61 (Cq), 118.15 (CH),
119.24 (CH), 121.92 (2CH), 122.06 (Cq), 123.42 (CH), 127.07
(CH), 128.19 (CH), 129.81 (CH), 136.30 (Cq), 136.47 (Cq),
138.22 (Cq), 172.64 (Cq). d (distinct peaks for minor rotamer)
22.96 (CH2), 38.18 (CH3), 48.47 (CH2), 112.83 (Cq), 118.71 (CH),
122.25 (2CH), 123.86 (CH), 127.53 (CH), 130.13 (CH), 136.71
(Cq), 171.54 (Cq). m/z (ES+) 293 (MH+), 585 (2M + H)+; (ES−)
291 (M − H)−; m/z (FAB+) 293 (MH+) (found: C, 77.88; H, 6.81;
N, 9.42; MH+, 293.16542. C19H20N2O requires C, 78.05; H, 6.89;
N, 9.58%; MH, 293.16539).
1
petroleum ether 50 : 50) 0.27. H NMR (300 MHz, CDCl3) d
(major rotamer) 2.98 (2H, t, J 7.1), 3.08 (3H, s), 3.62 (2H, t, J
7.1), 3.76 (2H, s), 6.84 (1H, d, J 2.4), 7.09–7.39 (8H, m), 7.58 (1H,
d, J 7.8), 8.92 (1H, br s). d (distinct peaks for minor rotamer) 2.94
(3H, s), 3.07 (2H, apparent t, estimated J 7.5), 3.44 (2H, s), 3.76
(2H, apparent t, estimated J 7.5), 6.91 (1H, d, J 2.4), 7.69 (1H,
d, J 7.5), 8.70 (1H, br s). 13C NMR (75 MHz, CDCl3) d (major
rotamer) 24.19 (CH2), 33.68 (CH3), 40.33 (CH2), 50.88 (CH2),
111.76 (CH), 112.58 (Cq), 118.09 (CH), 118.64 (CH), 119.43 (CH),
122.05 (CH), 122.40 (CH), 122.78 (CH), 126.71 (CH), 127.49 (Cq),
128.60 (CH), 128.89 (CH), 135.39 (Cq), 136.52 (Cq), 171.59 (Cq).
d (distinct peaks for minor rotamer) 23.22 (CH2), 36.50 (CH3),
41.28 (CH2), 49.25 (CH2), 111.44 (CH + Cq), 119.16 (CH), 121.77
(CH), 126.80 (CH), 127.05 (Cq), 128.73 (CH), 128.94 (CH), 135.12
(Cq), 136.42 (Cq), 171.14 (Cq). m/z (FAB+) 293 (MH+) (found:
MH+, 293.16532. C19H20N2O requires MH, 293.16539).
General procedure for the synthesis of phenyl-(1,3,4,9-tetrahydro-
b-carbolin-2-yl)-methanone and all derivatives 12a–q, 13 and 14.
To a suspension of carboline (1.2 mmol) in dichloromethane
(3 mL) at 0 ◦C was added slowly an aqueous solution of sodium
hydroxide 4 M (1.2 mmol). After 5 min stirring at 0 ◦C, the benzoyl
chloride derivative (1.2 mmol) was added dropwise. The mixture
was stirred for 5 min at 0 ◦C and 3 h at room temperature. Water
(20 mL) was added. The two layers were separated and the aqueous
phase was extracted with dichloromethane (3 × 20 mL). The
organic layers were dried (MgSO4), and evaporated under reduced
pressure. The crude product was purified by chromatography
on silica gel. Elution was made successively with: ethyl acetate–
petroleum ether 50 : 50 and ethyl acetate, to give the expected
compound.
N -[2-(1H -Indol-3-yl)-ethyl]-◦4,N -dimethylbenzamide
9p.
White solid. Yield 77%. Mp 178 C. Rotamers 1 : 1.3 (from the
duplicated broad singlet signals (1H) at 3.46 and 3.77 ppm). Rf
(ethyl acetate–petroleum ether 50 : 50) 0.24. 1H NMR (300 MHz,
CDCl3) d (major rotamer) 2.24 (3H, br s), 2.84 (2H, br s), 3.07
(3H, br s), 3.46 (2H, br s), 6.70–7.15 (9H, m), 8.51 (1H, br s). d
(distinct peaks for minor rotamer) 2.79 (3H, br s), 3.77 (2H, br s),
7.60 (1H, br s). 13C NMR (75 MHz, CDCl3) d (major rotamer)
21.35 (CH3), 24.47 (CH2), 33.14 (CH2), 52.00 (CH3), 111.36 (CH),
111.53 (Cq), 118.20 (CH), 119.11 (CH), 121.82 (2CH), 126.51
(CH), 127.08 (Cq), 128.94 (3CH), 133.56 (Cq), 136.36 (Cq),
139.15 (Cq), 172.65 (Cq). d (distinct peaks for minor rotamer)
22.98 (CH2), 38.26 (CH2), 48.57 (CH3), 112.74 (Cq), 118.67 (CH),
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Phenyl-(1,3,4,9-tetrahydro-b-carbolin-2-yl)-methanone 12a.
Yellow solid. Yield 82%. Mp 78 ◦C. Rotamers 1 : 3 (from the
duplicated broad singlet signal (1H) at 8.71 and 9.23 ppm). Rf
(ethyl acetate–petroleum ether 50 : 50) 0.27. 1H NMR (300 MHz,
CDCl3) d (major rotamer) 2.88 (2H, br s), 3.75 (2H, br s), 4.99
(2H, br s), 7.16–7.30 (4H, m), 7.54–7.56 (5H, m), 9.23 (1H, br s).
d (distinct peaks for minor rotamer) 2.97 (2H, br s), 4.16 (2H, br
s), 4.54 (2H, br s), 8.71 (1H, br s). 13C NMR (75 MHz, CDCl3)
d 22.21 (CH2), 41.28 (CH2), 46.18 (CH2), 107.51 (Cq), 111.41
(CH), 117.86 (CH), 119.44 (CH), 121.68 (CH), 126.86 (Cq), 126.99
(CH), 128.81 (2CH), 130.15 (2CH), 130.28 (Cq), 136.14 (Cq),
136.53 (Cq), 171.80 (Cq). No rotamers observed in 13C at RT. m/z
(FAB+) 276 (M+), 277 (MH+) (found: M+, 276.12624. C18H16N2O
requires M, 276.12626).
J 7.0), 7.65 (1H, br d, J 8.8), 7.83 (1H, br d, J 8.2), 11.36 (1H,
br s). 13C NMR (75 MHz, CDCl3) d 22.10 (CH2), 41.22 (CH2),
46.07 (CH2), 107.57 (Cq), 111.26 (CH), 114.24 (CH, d, J 22.6),
117.11 (CH, d, J 20.9), 117.88 (CH), 119.56 (CH), 121.83 (CH),
122.60 (CH), 126.76 (Cq), 129.85 (Cq), 130.61 (CH, d, J 7.7),
136.40 (Cq), 138.05 (Cq, d, J 6.6), 162.99 (Cq, d, J 246.7), 170.16
(Cq). No rotamers observed in 13C at RT. 19F NMR (282 MHz,
CDCl3) d (major rotamer) −111.15, d (minor rotamer) −112.77.
m/z (FAB+) 294 (M+), 295 (MH+) (found: MH+, 295.12470.
C18H15FN2O requires MH, 295.12467).
(4-Fluorophenyl)-(1,3,4,9-tetrahydro-b-carbolin-2-yl)-methanone
◦
12e. Yellow solid. Yield 97%. Mp 76 C. Rotamers 1 : 4 (from
the duplicated broad singlet signal (1H) at 4.43 and 4.75 ppm). Rf
(ethyl acetate–petroleum ether 50 : 50) 0.33. 1H NMR (300 MHz,
CDCl3) d (major rotamer) 2.70 (2H, br s), 3.56 (2H, br s), 4.75
(2H, br s), 6.63–7.35 (8H, 2m), 8.75 (1H, br s). d (distinct peaks
for minor rotamer) 4.00 (2H, br s), 4.43 (2H, br s), 8.69 (1H, br
s). 13C NMR (75 MHz, CDCl3) d 22.13 (CH2), 41.41 (CH2), 46.26
(CH2), 107.57 (Cq), 111.24 (CH), 115.81 (2CH, d, J 21.7), 117.89
(CH), 119.55 (CH), 121.81 (CH), 126.78 (Cq), 129.31 (2CH, d,
J 7.9), 130.00 (Cq), 132.00 (Cq, d, J 3.2), 136.41 (Cq), 163.63
(Cq, d, J 248.6), 170.80 (Cq). No rotamers observed in 13C at RT.
19F NMR (282 MHz, CDCl3) d −109.52. m/z (FAB+) 294 (M+)
(found: MH+, 295.12470. C18H15FN2O requires MH, 295.12467).
(4-tert-Butylphenyl)-(1,3,4,9-tetrahydro-b-carbolin-2-yl)-meth-
anone 12b. White solid. Yield 90%. Mp 217 ◦C. Rotamers 1 : 2
(from the duplicated broad singlet signal (1H) at room temperature
at 10.66 and 10.94 ppm). Rf (ethyl acetate–petroleum ether 50 :
1
50) 0.34. H NMR (400 MHz, 373 K, DMSO) d 1.36 (9H, s),
2.81 (2H, t, J 5.6), 3.83 (2H, t, J 5.6), 4.79 (2H, s), 7.01 (1H,
td, J 7.4 and 1.1), 7.08 (1H, td, J 7.4 and 1.1), 7.34 (1H, d, J
8.0), 7.41–7.43 (3H, m), 7.51 (2H, d, J 8.0), 10.53 (1H, br s). 13
C
NMR (100 MHz, 373 K, DMSO) d 21.80 (CH2), 31.48 (3CH3),
34.95 (Cq), 43.15 (CH2), 44.10 (CH2), 107.53 (Cq), 111.51 (CH),
117.92 (CH), 119.04 (CH), 121.30 (CH), 125.55 (2CH), 127.17
(2CH), 127.35 (Cq), 131.42 (Cq), 134.20 (Cq), 136.90 (Cq), 152.96
(Cq), 170.64 (Cq). No rotamers observed in 13C at RT. m/z (FAB+)
333 (MH+) (found: C, 79.56; H, 7.28; N, 8.40; MH+, 333.19665.
C22H24N2O requires C, 79.48; H, 7.28; N, 8.43%; MH, 333.19669).
(2-Chlorophenyl)-(1,3,4,9-tetrahydro-b-carbolin-2-yl)-methanone
12f. White solid. Yield 81%. Mp 97 ◦C. Rotamers 1 : 3 (from
the duplicated doublet signal (1H) at 4.56 and 5.18 ppm). Rf
(ethyl acetate–petroleum ether 50 : 50) 0.39. 1H NMR (300 MHz,
CDCl3) d (major rotamer) 2.75 (1H, t, J 6.3), 2.84 (1H, t, J 5.1),
3.63 (2H, t, J 5.7), 4.92 (1H, d, J 16.8), 5.18 (1H, d, J 16.8),
7.10–7.36 (8H, m), 8.27 (1H, br s). d (distinct peaks for minor
rotamer) 2.73 (1H, apparent t, estimated J 6.0), 2.90 (1H, t, J
6.0), 2.98 (2H, t, J 5.7), 4.40 (1H, d, J 16.5), 4.56 (1H, d, J 16.5),
7.78 (1H, br s). 13C NMR (75 MHz, CDCl3) d (major rotamer)
21.88 (CH2), 40.33 (CH2), 45.13 (CH2), 108.01 (Cq), 111.08 (CH),
117.88 (CH), 119.66 (CH), 121.94 (CH), 126.74 (Cq), 127.27
(CH), 127.65 (CH), 129.59 (Cq), 129.82 (CH), 130.34 (CH),
130.57 (Cq), 136.02 (Cq), 136.29 (Cq), 168.04 (Cq). d (distinct
peaks for minor rotamer) 21.00 (CH2), 44.71 (CH2), 110.88 (CH),
118.23 (CH), 119.83 (CH), 122.11 (CH), 127.39 (CH), 127.95
(CH), 129.71 (CH). m/z (ES+) 311 (MH+), 621 (2M + H)+; (ES−)
309 (M − H)−. m/z (FAB+) 311 (MH+) (found: MH+, 311.09503.
C18H15ClN2O requires MH, 311.09512).
(2-Fluorophenyl)-(1,3,4,9-tetrahydro-b-carbolin-2-yl)-methanone
12c. Yellow solid. Yield 95%. Mp 79 ◦C. Rotamers 1 : 2.6 (from
the duplicated broad singlet signal (1H) at 4.35 and 4.82 ppm). Rf
(ethyl acetate–petroleum ether 50 : 50) 0.29. 1H NMR (300 MHz,
CDCl3) d (major rotamer) 2.66 (2H, br s), 3.51 (2H, t, J 5.4),
4.82 (2H, s), 6.92–7.37 (8H, 2m), 8.69 (1H, br s). d (distinct peaks
for minor rotamer) 2.77 (2H, br s), 4.35 (2H, br s), 8.19 (1H, br
s). 13C NMR (75 MHz, CDCl3) d (major rotamer) 21.96 (CH2),
40.85 (CH2), 45.65 (CH2), 107.60 (Cq), 111.30 (CH), 116.10 (CH,
d, J 21.1), 117.82 (CH), 119.42 (CH), 121.71 (CH), 124.30 (Cq,
d, J 17.7), 124.83 (CH, d, J 3.0), 126.71 (Cq), 128.83 (CH, d, J
3.0), 129.80 (Cq), 131.56 (CH, d, J 8.0), 136.45 (Cq), 158.44 (Cq,
d, J 246.5), 166.63 (Cq). d (distinct peaks for minor rotamer)
21.04 (CH2), 45.11 (CH2), 109.03 (Cq), 111.09 (CH), 115.89 (CH,
d, J 18.1), 118.13 (CH), 119.59 (CH), 121.89 (CH), 126.81 (Cq),
129.36 (Cq), 136.33 (Cq), 158.39 (Cq, d, J 241.1), 166.08 (Cq). 19
F
(3-Chlorophenyl)-(1,3,4,9-tetrahydro-b-carbolin-2-yl)-methanone
12g. Pale yellow solid. Yield 73%. Mp 72 ◦C. Rotamers 1 :
3.3 (from the duplicated broad singlet signal (1H) at room
temperature at 4.46 and 4.80 ppm). Rf (ethyl acetate–petroleum
NMR (282 MHz, CDCl3) d (major rotamer) −114.86. d (minor
rotamer) −114.47. m/z (ES+) 295 (MH+), 589 (2M + H)+; (ES−)
293 (M − H)−. m/z (FAB+) 294 (M+), 295 (MH+) (found: MH+,
295.12473. C18H15FN2O requires MH, 295.12467).
1
ether 50 : 50) 0.44. H NMR (400 MHz, 373 K, DMSO) d 2.81
(3-Fluorophenyl)-(1,3,4,9-tetrahydro-b-carbolin-2-yl)-methanone
12d. Pale yellow solid. Yield 99%. Mp 65 ◦C. Rotamers 1 : 5
(from the duplicated triplet signal (1H) at 2.81 and 3.42 ppm). Rf
(ethyl acetate–petroleum ether 50 : 50) 0.35. 1H NMR (400 MHz,
373 K, DMSO) d (major rotamer) 2.81 (2H, t, J 5.6), 3.81 (2H, br
s), 4.78 (2H, s), 7.00 (1H, td, J 7.5 and 1.0), 7.08 (1H, td, J 7.5 and
1.0), 7.27–7.35 (3H, m), 7.42 (1H, d, J 8.0), 7.50–7.55 (2H, m),
10.52 (1H, br s). d (distinct peaks for minor rotamer) 3.42 (2H, t,
(2H, t, J 5.9), 3.81 (2H, br s), 4.78 (2H, s), 7.00 (1H, td, J 7.5 and
1.2), 7.08 (1H, td, J 7.5 and 1.2), 7.34 (1H, d, J 8.0), 7.42 (2H,
apparent dd, estimated J 7.2 and 1.6), 7.50–7.54 (3H, m), 10.52
(1H, br s). 13C NMR (75 MHz, CDCl3) d 22.10 (CH2), 41.17
(CH2), 46.08 (CH2), 107.69 (Cq), 111.18 (CH), 117.88 (CH),
119.63 (CH), 121.92 (CH), 124.97 (CH), 126.74 (Cq), 127.12
(CH), 129.71 (Cq), 130.10 (2CH), 134.76 (Cq), 136.32 (Cq),
137.68 (Cq), 170.03 (Cq). No rotamers observed in 13C at RT.
798 | Org. Biomol. Chem., 2006, 4, 787–801
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m/z (FAB+) 311 (MH+) (found: MH+, 311.09512. C18H15ClN2O
the duplicated broad singlet signal (1H) at room temperature at
requires MH, 311.09512).
4.59 and 4.83 ppm). Rf (ethyl acetate–petroleum ether 50 : 50)
0.45. H NMR (400 MHz, DMSO, 363 K) d 2.79 (2H, t, J 5.8),
1
(4-Chlorophenyl)-(1,3,4,9-tetrahydro-b-carbolin-2-yl)-methanone
3.79 (2H, br s), 4.75 (2H, s), 6.99 (1H, td, J 7.4 and 0.8), 7.07
(1H, td, J 7.6 and 1.2), 7.32 (1H, d, J 8.0), 7.40–7.44 (4H, m),
7.67 (1H, dt, J 8.8 and 2.4), 10.55 (1H, br s). 13C NMR (75 MHz,
CDCl3) d 22.03 (CH2), 40.94 (CH2), 45.94 (CH2), 107.05 (Cq),
111.55 (CH), 118.02 (CH), 119.06 (CH), 121.38 (CH), 123.53
(Cq), 126.97 (Cq), 129.47 (2CH), 131.01 (Cq), 132.03 (2CH),
135.84 (Cq), 136.46 (Cq), 169.56 (Cq). No rotamers observed
in 13C at RT. m/z (ES+) 356 (M + 2H)+; (ES−) 353 (M − H)−.
m/z (FAB+) 355 (MH+) (found: C, 60.87; H, 4.20; N, 7.70; M+,
354.03674. C18H15BrN2O requires C, 60.86; H, 4.26; N, 7.89%; M,
354.03677).
◦
12h. White solid. Yield 83%. Mp 196 C. Rotamers 1 : 2 (from
the duplicated broad singlet signal (1H) at room temperature at
4.60 and 4.83 ppm). Rf (ethyl acetate–petroleum ether 50 : 50)
1
0.41. H NMR (400 MHz, 373 K, DMSO) d 2.81 (2H, t, J 5.5),
3.81 (2H, br t, J 5.5), 4.78 (2H, s), 7.01 (1H, td, J 7.5 and 0.9),
7.08 (1H, td, J 7.5 and 0.9), 7.35 (1H, d, J 8.0), 7.42 (2H, d, J 7.6),
7.48–7.53 (3H, m), 10.52 (1H, br s). 13C NMR (100 MHz, 373 K,
DMSO) d 21.74 (CH2), 43.09 (CH2), 44.17 (CH2), 107.50 (Cq),
111.54 (CH), 117.94 (CH), 119.10 (CH), 121.37 (CH), 127.31
(Cq), 129.01 (2CH), 129.15 (2CH), 131.18 (Cq), 134.96 (Cq),
135.81 (Cq), 136.91 (Cq), 169.50 (Cq). No rotamers observed
in 13C at RT. m/z (ES+) 311 (MH+), 621 (2M + H)+; (ES−) 309
(M − H)−. m/z (FAB+) 311 (MH+) (found: C, 69.58; H, 4.54; N,
8.94; MH+, 311.09522. C18H15ClN2O requires C, 69.57; H, 4.86;
N, 9.01%; MH, 311.09512).
(2-Methoxyphenyl)-(1,3,4,9-tetrahydro-b-carbolin-2-yl)-metha-
none 12l. White solid. Yield 83%. Mp 92–93 ◦C. Rotamers 1 : 3.2
(from the duplicated broad singlet signals (1H) at 2.62 and 2.78
1
ppm). Rf (ethyl acetate–petroleum ether 50 : 50) 0.24. H NMR
(300 MHz, CDCl3) d (major rotamer) 2.62 (2H, br s), 3.47 (2H,
t, J 5.4), 3.69 (3H, s), 4.80 (1H, d, J 16.7), 4.92 (1H, d, J 16.7),
6.75–7.37 (8H, m), 8.89 (1H, br s). d (distinct peaks for minor
rotamer) 2.78 (2H, br s), 3.58 (3H, s), 4.25–4.31 (2H, m), 8.20 (1H,
br s). 13C NMR (75 MHz, CDCl3) d (major rotamer) 21.95 (CH2),
40.56 (CH2), 45.38 (CH2), 55.56 (CH3), 107.62 (Cq), 111.14 (CH),
111.32 (CH), 117.69 (CH), 119.23 (CH), 121.02 (CH), 121.47
(CH), 125.94 (Cq), 126.75 (Cq), 127.83 (CH), 130.29 (Cq), 130.66
(CH), 136.47 (Cq), 155.56 (Cq), 169.20 (Cq). d (distinct peaks for
minor rotamer) 21.15 (CH2), 44.85 (CH2), 108.92 (Cq), 111.04
(CH), 111.14 (CH), 118.01 (CH), 119.44 (CH), 121.02 (CH),
121.63 (CH), 126.89 (Cq), 128.13 (CH), 129.98 (Cq), 130.74 (CH),
136.30 (Cq), 168.69 (Cq). m/z (ES+) 307 (MH+), 613 (2M + H)+;
(ES−) 611 (2M − H)−. m/z (FAB+) 307 (MH+) (found: C, 74.53;
H, 5.91; N, 9.04; MH+, 307.14463. C19H18N2O2 requires C, 74.49;
H, 5.92; N, 9.14%; MH 307.14465).
(2-Bromophenyl)-(1,3,4,9-tetrahydro-b-carbolin-2-yl)-methanone
12i. White solid. Yield 64%. Mp 190 ◦C. Rotamers 1 : 3.3
(from the duplicated broad singlet signal (1H) at 8.03 and 8.59
1
ppm). Rf (ethyl acetate–petroleum ether 50 : 50) 0.35. H NMR
(300 MHz, CDCl3) d (major rotamer) 2.66 (1H, t, J 6.5), 2.73
(1H, t, J 5.0), 3.49 (2H, t, J 5.7), 4.77 (1H, d, J 16.8), 5.06 (1H,
d, J 16.8), 6.93–7.56 (8H, m), 8.59 (1H, br s). d (distinct peaks
for minor rotamer) 2.61 (1H, apparent t, estimated J 6.3), 2.79
(1H, t, J 5.0), 2.85 (2H, t, J 5.7), 4.24 (1H, d, J 16.1), 4.38 (1H,
d, J 16.1), 8.03 (1H, br s). 13C NMR (75 MHz, CDCl3) d (major
rotamer) 21.87 (CH2), 40.47 (CH2), 45.24 (CH2), 107.63 (Cq),
111.28 (CH), 117.81 (CH), 119.34 (Cq), 119.48 (CH), 121.77
(CH), 126.70 (Cq), 127.60 (CH), 127.86 (CH), 129.68 (Cq),
130.52 (CH), 133.00 (CH), 136.39 (Cq), 138.18 (Cq), 168.93 (Cq).
d (distinct peaks for minor rotamer) 21.01 (CH2), 44.87 (CH2),
109.18 (Cq), 111.03 (CH), 118.15 (CH), 119.10 (Cq), 119.66 (CH),
121.93 (CH), 126.81 (Cq), 129.15 (Cq), 132.87 (CH), 136.28 (Cq),
138.27 (Cq), 168.44 (Cq). m/z (ES+) 355 (MH+); (ES−) 354 (M)−.
m/z (FAB+) 355 (MH+) (found: C, 60.75; H, 4.17; N, 7.92; M+,
354.03678. C18H15BrN2O requires C, 60.86; H, 4.26; N, 7.89%; M,
354.03677).
(3-Methoxyphenyl)-(1,3,4,9-tetrahydro-b-carbolin-2-yl)-metha-
none 12m. Yellow solid. Yield 98%. Mp 75–78 ◦C. Rotamers 1:
2.7 (from the duplicated broad singlet signal (1H) at 4.48 and 4.81
1
ppm). Rf (ethyl acetate–petroleum ether 50 : 50) 0.34. H NMR
(300 MHz, CDCl3) d (major rotamer) 2.73 (2H, br s), 3.68 (2H,
br s), 3.73 (3H, s), 4.81 (2H, br s), 6.80–7.43 (8H, m), 8.60 (1H, br
s). d (distinct peaks for minor rotamer) 4.48 (2H, br s). 13C NMR
(75 MHz, CDCl3) d 22.15 (CH2), 41.13 (CH2), 46.06 (CH2), 55.42
(CH3), 107.72 (Cq), 111.19 (CH), 112.21 (CH), 115.94 (CH),
117.83 (CH), 118.97 (CH), 119.52 (CH), 121.77 (CH), 126.79
(Cq), 129.84 (CH), 130.07 (Cq), 136.34 (Cq), 137.32 (Cq), 159.73
(Cq), 171.40 (Cq). No rotamers observed in 13C at RT. m/z (ES+)
307 (MH+), 613 (2M + H)+. m/z (FAB+) 307 (MH+) (found:
MH+, 307.14460. C19H18N2O2 requires MH 307.14465).
(3-Bromophenyl)-(1,3,4,9-tetrahydro-b-carbolin-2-yl)-methanone
12j. White solid. Yield 91%. Mp 207 ◦C. Rotamers 1 : 1.6 (from
the duplicated broad singlet signal (1H) at room temperature at
4.60 and 4.84 ppm). Rf (ethyl acetate–petroleum ether 50 : 50)
1
0.41. H NMR (400 MHz, 373 K, DMSO) d 2.80 (2H, t, J 5.8),
3.81 (2H, br s), 4.77 (2H, s), 7.00 (1H, td, J 7.5 and 1.2), 7.08
(1H, td, J 7.5 and 1.2), 7.34 (1H, d, J 7.6), 7.41–7.48 (3H, m),
7.64–7.69 (2H, m), 10.52 (1H, br s). 13C NMR (100 MHz, 373 K,
DMSO) d 21.70 (CH2), 43.06 (CH2), 44.09 (CH2), 107.49 (Cq),
111.54 (CH), 117.96 (CH), 119.09 (CH), 121.37 (CH), 122.24
(Cq), 126.12 (CH), 127.29 (Cq), 129.93 (CH), 131.09 (CH + Cq),
132.84 (CH), 136.90 (Cq), 139.33 (Cq), 168.80 (Cq). No rotamers
observed in 13C at RT. m/z (ES+) 355 (MH+); (ES−) 353 (M −
H)−. m/z (FAB+) 355 (MH+) (found: C, 60.94; H, 4.17; N, 7.93;
MH+, 355.04478. C18H15BrN2O requires C, 60.86; H, 4.26; N,
7.87%; MH, 355.04460).
(1,3,4,9-Tetrahydro-b-carbolin-2-yl)-o-tolylmethanone
12n.
◦
White solid. Yield 83%. Mp 186 C. Rotamers 1 : 2.8 (from the
duplicated singlet signal (1H) at 2.24 and 2.39 ppm). Rf (ethyl
acetate–petroleum ether 50 : 50) 0.32. 1H NMR (300 MHz,
CDCl3) d (major rotamer) 2.39 (3H, s), 2.78 (2H, apparent d, J
4.8), 3.62 (2H, apparent q, J 5.7), 4.93 (1H, d, J 16.2), 5.18 (1H,
d, J 16.2), 7.10–7.57 (8H, m), 8.98 (1H, br s). d (distinct peaks
for minor rotamer) 2.24 (3H, s), 2.97 (2H, apparent t, estimated J
5.1), 4.35 (2H, br s), 8.24 (1H, br s). 13C NMR (75 MHz, CDCl3)
(4-Bromophenyl)-(1,3,4,9-tetrahydro-b-carbolin-2-yl)-methanone
12k. White solid. Yield 62%. Mp 217 ◦C. Rotamers 1 : 1.7 (from
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d (major rotamer) 19.13 (CH3), 22.01 (CH2), 40.38 (CH2), 45.22
(CH2), 107.52 (Cq), 111.27 (CH), 117.77 (CH), 119.42 (CH),
121.70 (CH), 125.72 (CH), 126.11 (CH), 126.74 (Cq), 129.16
(CH), 130.08 (Cq), 130.65 (CH), 134.39 (Cq), 136.34 (Cq), 136.42
(Cq), 171.33 (Cq). d (distinct peaks for minor rotamer) 18.87
(CH3), 21.14 (CH2), 45.10 (CH2), 109.05 (Cq), 111.06 (CH),
118.15 (CH), 119.62 (CH), 121.90 (CH), 126.86 (Cq), 129.52 (Cq),
130.56 (CH), 134.31 (Cq), 136.51 (Cq), 170.72 (Cq). m/z (FAB+)
291 (MH+) (found: C, 78.48; H, 6.35; N, 9.77; MH+, 291.14969.
C19H18N2O requires C, 78.59; H, 6.25; N, 9.65%; MH, 291.14974).
353.16532. C24H20N2O requires C, 81.79; H, 5.72; N, 7.95%; MH,
353.16539).
2-Phenyl-1-(1,3,4,9-tetrahydro-b-carbolin-2-yl)-ethanone
13.
White solid. Yield 63%. Mp 188–190 ◦C. Rotamers 1 : 4 (from
the duplicated singlet signal (1H) at 4.52 and 4.77 ppm). Rf
(ethyl acetate–petroleum ether 50 : 50) 0.36. 1H NMR (300 MHz,
CDCl3) d (major rotamer) 2.56 (2H, t, J 5.7), 3.70 (2H, t, J 5.7),
3.81 (2H, s), 4.77 (2H, s), 6.99 (1H, td, J 7.3 and 1.2), 7.06 (1H,
td, J 7.3 and 1.3), 7.13–7.29 (6H, m), 7.33 (1H, d, J 7.5), 8.32
(1H, br s). d (distinct peaks for minor rotamer) 2.75 (2H, t, J
5.7), 3.75 (2H, s), 3.92 (2H, t, J 5.7), 4.52 (2H, s), 7.41 (1H, d, J
7.8), 7.80 (1H, br s). 13C NMR (75 MHz, CDCl3) d 21.78 (CH2),
40.74 (CH2), 41.36 (CH2), 44.52 (CH2), 107.76 (Cq), 111.07 (CH),
117.77 (CH), 119.48 (CH), 121.71 (CH), 126.94 (CH), 128.71
(2CH), 128.83 (2CH), 130.27 (Cq), 134.96 (Cq), 136.22 (Cq),
170.59 (Cq). One 13C quaternary is not observed. No rotamers
observed in 13C at RT. m/z (ES+) 291 (MH+), 581 (2M + H)+.
m/z (ES−) 289 (M − H)−, 579 (2M − H)−. m/z (FAB+) 290
(M+), 291 (MH+) (found: M+, 290.14192. C19H18N2O requires M,
290.14191).
(1,3,4,9-Tetrahydro-b-carbolin◦-2-yl)-m-tolylmethanone 12o.
White solid. Yield 76%. Mp 170 C. Rotamers 1 : 3.5 (from the
duplicated broad singlet signal (1H) at room temperature at 4.44
and 4.82 ppm). Rf (ethyl acetate–petroleum ether 50 : 50) 0.40. 1H
NMR (400 MHz, 373 K, DMSO) d 2.39 (3H, s), 2.79 (2H, t, J 5.5),
3.81 (2H, t, J 5.5), 4.77 (2H, s), 7.00 (1H, td, J 7.5 and 1.1), 7.08
(1H, td, J 7.5 and 1.1), 7.24–7.38 (5H, m), 7.42 (1H, d, J 8.0), 10.52
(1H, br s). 13C NMR (100 MHz, 373 K, DMSO) d 21.23 (CH2),
21.76 (CH3), 43.04 (CH2), 44.13 (CH2), 107.51 (Cq), 111.51 (CH),
117.93 (CH), 119.05 (CH), 121.31 (CH), 124.18 (CH), 127.34 (Cq),
127.64 (CH), 128.73 (CH), 130.50 (CH), 131.38 (Cq), 136.89 (Cq),
137.15 (Cq), 138.37 (Cq), 170.66 (Cq). m/z (ES+) 291 (MH+), 581
(2M + H)+; (ES−) 289 (M − H)−. m/z (FAB+) 291 (MH+) (found:
C, 78.78; H, 6.06; N, 9.42; MH+, 291.14968. C19H18N2O requires
C, 78.59; H, 6.25; N, 9.65%; MH, 291.14974).
1,3,4,9-Tetrahydro-b-carboline-2-carboxylic acid diethylamide
14. White solid. Yield 91%. Mp 102 ◦C. Rf (ethyl acetate–
1
petroleum ether 50 : 50) 0.22. H NMR (300 MHz, CDCl3) d
1.09 (6H, t, J 7.1), 2.77 (2H, t, J 5.4), 3.22 (4H, q, J 7.1), 3.45 (2H,
t, J 5.4), 4.37 (2H, s), 7.00 (2H, apparent quintet, estimated J 7.3),
7.20 (1H, d, J 7.5), 7.37 (1H, d, J 7.2), 9.11 (1H, br s). 13C NMR
(75 MHz, CDCl3) d 13.35 (2CH3), 21.78 (CH2), 42.18 (2CH2),
44.69 (CH2), 47.06 (CH2), 107.94 (Cq), 111.13 (CH), 117.78 (CH),
119.17 (CH), 121.31 (CH), 126.99 (Cq), 131.79 (Cq), 136.42 (Cq),
165.03 (Cq). No rotamers observed at RT neither from the 1H nor
from the 13C NMR. m/z (FAB+) 271 (M+), 272 (MH+) (found: C,
70.93; H, 7.50; N, 15.36; M+, 271.16850. C16H21N3O requires C,
70.82; H, 7.80; N, 15.49%; M, 271.16846).
(1,3,4,9-Tetrahydro-b-carbolin-2-yl)-p-tolylmethanone 12p.
White solid. Yield 90%. Mp 186 ◦C. Rf (ethyl acetate–petroleum
1
ether 50 : 50) 0.57. H NMR (400 MHz, 373 K, DMSO) d 2.39
(3H, s), 2.80 (2H, br t, J 5.6), 3.82 (2H, t, J 5.6), 4.78 (2H, s), 7.01
(1H, td, J 7.3 and 0.8), 7.08 (1H, td, J 7.3 and 1.1), 7.28 (2H, br d,
J 7.6), 7.34 (1H, br d, J 8.0), 7.37 (2H, br d, J 8.0), 7.42 (1H, br d, J
7.6), 10.52 (1H, br s). 13C NMR (100 MHz, 373 K, DMSO) d 21.23
(CH2), 21.78 (CH3), 43.12 (CH2), 44.17 (CH2), 107.53 (Cq), 111.52
(CH), 117.93 (CH), 119.05 (CH), 121.31 (CH), 127.28 (2CH),
127.36 (Cq), 129.36 (2CH), 131.44 (Cq), 134.24 (Cq), 136.90 (Cq),
139.70 (Cq), 170.69 (Cq). No rotamers observed at RT neither
1-Phenyl-2-(1,3,4,9-tetrahydro-b-carbolin-2-yl)-ethanone
15. To a solution of 1,2,3,4-tetrahydro-b-carboline (0.40 g,
2.32 mmol) in toluene (26 mL) was added a solution of NaHCO3
(0.45 g, 5.39 mmol) and Na2SO3 (0.23 g, 1.81 mmol) in water
(8.0 mL). The mixture was stirred under N2 atmosphere and
2-bromoacetophenone (0.23 g, 1.16 mmol) was added. The
stirring was maintained for 4 h at room temperature. The crude
mixture was evaporated under reduced pressure and the resulting
crude product was purified directly by column chromatography
on silica gel. Elution was made successively with: ethyl acetate–
cyclohexane 50 : 50 and ethyl acetate to give the title compound
19 as an orange solid (0.21 g, 61%). Mp 152–153 ◦C. Rf (ethyl
acetate–petroleum ether 50 : 50) 0.37. 1H NMR (300 MHz,
CDCl3) 2.78 (2H, t, J 5.7), 2.98 (2H, t, J 5.7), 3.78 (2H, s), 3.97
(2H, s), 7.01 (1H, t, J 3.2), 7.01 (1H, ddd, J 10.5 and 6.9 and 1.8),
7.15–7.19 (1H, m), 7.34–7.40 (3H, m), 7.48 (1H, tt, J 7.4 and 1.7),
7.90–7.93 (3H, m). 13C NMR (75 MHz, CDCl3) 20.64 (CH2),
50.08 (CH2), 51.13 (CH2), 62.70 (CH2), 107.95 (Cq), 110.87 (CH),
117.92 (CH), 119.34 (CH), 121.41 (CH), 127.17 (Cq), 128.19
(2CH), 128.63 (2CH), 131.25 (Cq), 133.39 (CH), 135.91 (Cq),
136.06 (Cq), 196.80 (Cq). m/z (ES+) 291 (MH+), 581 (2M + H)+.
m/z (ES−) 289 (M − H)−, 579 (2M − H)−. m/z (FAB+) 291 (MH+)
(found: C, 78.67; H, 6.30; N, 9.71; M+, 291.14975. C19H18N2O
requires C, 78.59; H, 6.25; N, 9.65%; M, 291.14974).
1
from the H nor from the 13C NMR. m/z (FAB+) 291 (MH+)
(found: C, 78.76; H, 6.12; N, 9.63; MH+, 291.14978. C19H18N2O
requires C, 78.59; H, 6.25; N, 9.65%; MH, 291.14974).
Biphenyl-4-yl-(1,3,4,9-tetrahydro-b-carbolin-2-yl)-methanone
12q. White solid. Yield 47%. Mp 239 ◦C. Rf (ethyl acetate–
petroleum ether 50 : 50) 0.63. 1H NMR (400 MHz, 373 K, DMSO)
d 2.83 (2H, t, J 5.6), 3.86 (2H, t, J 5.6), 4.80 (2H, s), 6.99 (1H,
td, J 7.6 and 0.7), 7.07 (1H, td, J 7.6 and 1.1), 7.33 (1H, br d,
J 8.0), 7.42 (2H, br d, J 7.2), 7.50 (2H, br t, J 6.8), 7.56 (2H,
dt, J 5.2 and 1.6), 7.72 (2H, dt, J 8.0 and 2.0), 7.77 (2H, dt,
J 6.0 and 2.1), 10.54 (1H, br s). 13C NMR (100 MHz, 373 K,
DMSO) d 21.79 (CH2), 107.51 (Cq), 111.52 (CH), 117.93 (CH),
119.05 (CH), 121.32 (CH), 127.17 (2CH), 127.21 (2CH), 127.32
(Cq), 127.90 (2CH), 128.23 (CH), 129.38 (2CH), 131.35 (Cq),
135.97 (Cq), 136.88 (Cq), 140.03 (Cq), 142.02 (Cq), 170.35 (Cq).
Two CH2 are missing from the 13C NMR at 373 K. The two
signals were observed at 75 MHz, at RT, in DMSO at 41.11 and
45.49 ppm. No rotamers observed at RT neither from the 1H nor
from the 13C NMR. m/z (ES+) 353 (MH+); (ES−) 351 (M − H)−.
m/z (FAB+) 353 (MH+) (found: C, 81.86; H, 5.62; N, 7.98; MH+,
800 | Org. Biomol. Chem., 2006, 4, 787–801
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2-(2-Oxo-2-phenylethyl)-2,3,4,9-tetrahydro-1H-b-carbolin-2-ium
chloride 16. To a solution of 15 (0.20 g, 0.07 mmol) in a
minimum of dichloromethane was flushed HCl gas. After around
3 min the mixture was evaporated under reduced pressure to give
the title compound 16 (0.21 g, 95%) as a yellow sol◦id, which was
8 A. Hormann, B. Chaudhuri and H. Fretz, Bioorg. Med. Chem., 2001,
9, 917–921.
9 The PyMol Molecular Graphics System, DeLano Scientific, San Carlos,
CA, USA, 2002.
10 C. Aubry, P. R. Jenkins, S. Mahale, B. Chaudhuri, J. D. Marechal and
M. J. Sutcliffe, Chem. Commun., 2004, 1696–1697; C. Aubry, A. Patel,
S. Mahale, B. Chaudhuri, J.-D. Marechal, M. J. Sutcliffe and P. R.
Jenkins, Tetrahedron Lett., 2005, 46, 1423–1425.
11 S. C. Benson, L. Lee, L. Yang and J. K. Snyder, Tetrahedron, 2000, 56,
1165–1180.
12 J. Clews, C. J. Cooksey, P. J. Garratt, E. J. Land, C. A. Ramsden and
P. A. Riley, J. Chem. Soc., Perkin Trans. 1, 2000, 4306–4315.
13 J. M. Grisar, M. A. Petty, F. N. Bolkenius, J. Dow, J. Wagner, E. R.
Wagner, K. D. Haegele and W. Dejong, J. Med. Chem., 1991, 34, 257–
260.
14 U. Schulze-Gahmen, H. L. De Bondt and S. H. Kim, J. Med. Chem.,
1996, 39, 4540–4546; H. Adams, C. A. Hunter, K. R. Lawson, J. Perkins,
S. E. Spey, C. J. Urch and J. M. Sanderson, Chem.–Eur. J., 2001, 7,
4863–4877.
15 A. Sali and T. L. Blundell, J. Mol. Biol., 1993, 234, 779–815.
16 H. M. Berman, J. Westbrook, Z. Feng, G. Gilliland, T. N. Bhat, H.
Weissig, I. N. Shindyalov and P. E. Bourne, Nucleic Acids Res., 2000,
28, 235–242.
1
dried under vacuum for a few days. Mp 158–159 C. H NMR
(300 MHz, DMSO) 3.17 (2H, t, J 5.3), 3.74 (2H, br s), 4.70 (2H,
br s), 5.31 (2H, s), 7.10 (1H, td, J 7.6 and 1.0), 7.18 (1H, td, J
7.6 and 1.0), 7.44 (1H, d, J 7.8), 7.55 (1H, d, J 7.5), 7.67 (2H,
apparent t, estimated J 7.7), 7.82 (1H, t, J 7.4), 8.10 (2H, apparent
d, estimated J 7.2), 10.98 (1H, br s), 11.23 (1H, br s). 13C NMR
(75 MHz, DMSO) 18.29 (CH2), 49.79 (CH2), 51.67 (CH2), 60.00
(CH2), 105.43 (Cq), 111.87 (CH), 118.47 (CH), 119.47 (CH),
122.18 (CH), 126.21 (Cq), 126.32 (Cq), 128.70 (2CH), 129.49
(2CH), 134.26 (Cq), 135.20 (CH), 136.74 (Cq), 192.19 (Cq). m/z
(ES+) 291 (M − Cl)+, 582 (2(M − Cl))+. m/z (ES−) 325 (M − H)−,
615 (2(M − H) − Cl)−. m/z (FAB+) 291 (M − Cl)+ (found: (M −
Cl)+, 291.14970. C19H19ClN2O requires (M − Cl), 291.14974).
17 D. H. Brotherton, V. Dhanaraj, S. Wick, L. Brizuela, P. J. Domaille,
E. Volyanik, X. Xu, E. Parisini, B. O. Smith, S. J. Archer, M. Serrano,
S. L. Brenner, T. L. Blundell and E. D. Laue, Nature, 1998, 395, 244–
250.
Acknowledgements
This work was supported by Cancer Research UK.
18 J. D. Thompson, D. G. Higgins and T. J. Gibson, Nucleic Acids Res.,
1994, 22, 4673–4680.
19 G. Jones, P. Willett, R. C. Glen, A. R. Leach and R. Taylor, J. Mol.
Biol., 1997, 267, 727–748.
20 M. L. Verdonk, J. C. Cole, M. J. Hartshorn, C. W. Murray and
R. D. Taylor, Proteins: Struct., Funct., Genet., 2003, 52, 609–
623.
References
1 D. M. Roll, C. M. Ireland, H. S. M. Lu and J. Clardy, J. Org. Chem.,
1988, 53, 3276–3278.
2 R. Soni, L. Muller, P. Furet, J. Schoepfer, C. Stephan, S. Zumstein-
Mecker, H. Fretz and B. Chaudhuri, Biochem. Biophys. Res. Commun.,
2000, 275, 877–884.
21 P. Gouet, E. Courcelle, D. I. Stuart and F. Metoz, Bioinformatics, 1999,
15, 305–308.
3 A. Huwe, R. Mazitschek and A. Giannis, Angew. Chem., Int. Ed., 2003,
42, 2122–2138.
4 B. Alberts, A. Johnson, J. Lewis, M. Raff, K. Roberts and P. Walter,
Molecular Biology of the Cell, Garland Science, New York, 4th edn,
2002, ch. 17.
5 W. G. Kaelin, Bioessays, 1999, 21, 950–958.
6 D. O. Morgan, Nature, 1995, 374, 131–134.
7 C. McInnes, S. D. Wang, S. Anderson, J. O’Boyle, W. Jackson, G.
Kontopidis, C. Meades, M. Mezna, M. Thomas, G. Wood, D. P. Lane
and P. M. Fischer, Chem. Biol., 2004, 11, 525–534.
22 D. Phelps and Y. Xiong, Methods Enzymol., 1996, 283, 194–205.
23 L. Meijer, A. Borgne, O. Mulner, J. P. J. Chong, J. J. Blow, N. Inagaki,
M. Inagaki, J. G. Delcros and J. P. Moulinoux, Eur. J. Biochem., 1997,
243, 527–536.
24 S. Boris, L. Richard and L. S. Robert, J. Biol. Chem., 1997, 272, 33327–
33337.
25 S. Biniecki and W. Modrzejewska, Acta Pol. Pharm., 1981, 38, 407–
410; H. Adams, C. A. Hunter, K. R. Lawson, J. Perkins, S. E. Spey,
C. J. Urch and J. M. Sanderson, Chem.–Eur. J., 2001, 7, 4863–
4877.
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 787–801 | 801
©