Synthesis of aminopyrimidylindoles structurally related to meridianins

Article abstract of DOI:10.1016/j.tet.2007.07.095

The synthesis of new meridianin derivatives substituted at the C-5′ position of the 2-aminopyrimidine ring by various aryl groups and substituted or not by a methyl group on the indole nitrogen is described. The 2-aminopyrimidine ring was obtained via a B

Full text of DOI:10.1016/j.tet.2007.07.095

Tetrahedron 63 (2007) 10169–10176
Synthesis of aminopyrimidylindoles structurally
related to meridianins
*
Emilie Rossignol, Ali Youssef, Pascale Moreau, Michelle Prudhomme and Fabrice Anizon
´
Universite Blaise Pascal, SEESIB-UMR CNRS 6504, 24 Avenue des Landais, 63177 Aubiere Cedex, France
ꢀ
Received 22 June 2007; revised 23 July 2007; accepted 26 July 2007
Available online 1 August 2007
Abstract—The synthesis of new meridianin derivatives substituted at the C-50 position of the 2-aminopyrimidine ring by various aryl groups
and substituted or not by a methyl group on the indole nitrogen is described. The 2-aminopyrimidine ring was obtained via a Bredereck
synthesis. Aryl groups were introduced by Suzuki cross-coupling after bromination of the 2-aminopyrimidine ring at the C-50 position.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
3-(2-aminopyrimidin-4-yl)-indoles substituted at the C-50
and C-60 positions and/or on the amino group of the 2-ami-
nopyrimidine ring have been described in the literature.16–37
Compounds substituted at C-50 position by cyano, carbo-
hydrazonamido, carboxy, and methyl groups or by a chlo-
rine or a fluorine atom have previously been reported
(Fig. 1).16,17,19 These recent publications prompted us to re-
port our own results. Substituent at the C-50 position
appeared to be important in terms of biological activity.
Indeed, we observed a dramatic increase of kinase inhibitory
properties when the C-50 position of meridianin G was
substituted by a bromine atom (Scheme 1 and Table 1).
The kinase activities of compounds 3 (meridianin G) and 5
toward eight protein kinases were evaluated by Upstate’s
kinase profiler screening service (Dundee, Scotland). Both
compounds were tested at a compound concentration of
10 mM under standard conditions determined by Upstate38–40
for each selected kinase (MKK1, ERK2, RSK2, PKC-a,
GSK3-b, CDK2/A, CK2, and MST2—Table 1). Compound
5 exhibited a significantly higher inhibitory activity than
meridianin G (compound 3) against all the kinases tested. In-
deed, compound 5 inhibits all the kinases tested with percent-
ages of inhibition over 80%, and is particularly potent toward
MKK1 and MST2 (percentage of inhibition higher than
95%), whereas the inhibitory properties of compound 3
were found to be much lower, with percentages of inhibition
from 9% (RSK2) to 66% (MKK1). These results encouraged
us to synthesize meridianin derivatives bearing other substit-
uents at the C-50 position. Since the late 1980s11,12 and re-
cently,41 it was reported that aryl groups at the C-4 position
of 3-indolylmaleimides led to compounds exhibiting inter-
esting kinase inhibitory properties. Therefore, we decided
to introduce aryl rings at the C-50 position of the pyrimidine
ring of meridianin G. Compounds bearing an aryl group at the
C-60 position were reported,22,25 but to our knowledge,
Many kinase inhibitors from natural origin are sources of in-
spiration for the discovery of new biologically active com-
pounds. A large number of nitrogen aromatic heterocycles
containing an indole or a carbazole framework exhibit ki-
nase inhibitory properties. Granulatimide and isogranulati-
mide, carbazoles isolated from the ascidian Didemnum
granulatum, and structurally related analogs are Checkpoint
kinase 1 (Chk1) inhibitors (Fig. 1).1,2 Purine derivatives like
roscovitine and olomoucine, two compounds isolated from
starfish oocytes, are potent cyclin-dependent kinase inhibi-
tors.3 Indirubin, the active ingredient of the Chinese prepara-
tion Danggui Longhui Wan used to treat chronic diseases,
indirubin derivatives,4,5 as well as indolocarbazole bacterial
metabolites staurosporine,6,7 UCN-01,8 and K252-c9 are
also described as potent kinase inhibitors. Synthetic com-
pounds such as bisindolylmaleimides10 and 4-aryl-3-indo-
lylmaleimides11,12 are known kinase inhibitors (Fig. 1).
Meridianin alkaloids, which were isolated and characterized
from the south atlantic tunicate Aplidium meridianum,13
are indole derivatives substituted at the C-3 position by a
2-aminopyrimidine ring. Meridianins A–G13–15 (Fig. 1)
were described as potent kinase inhibitors15 and some deriv-
atives displayed antitumor activity.16
In the course of the synthesis of new kinase inhibitors,
we were interested in meridianin derivatives substituted at
the C-50 position of the 2-aminopyrimidine ring. Various
Keywords: Meridianins; Kinase inhibitors; Pyrimidine; Indole; Antitumor
agents.
* Corresponding author. Fax: +33 4 73 40 77 17; e-mail: Fabrice.
ANIZON@univ-bpclermont.fr
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.095

10170
E. Rossignol et al. / Tetrahedron 63 (2007) 10169–10176
H
N
H
N
O
O
O
O
NH
N
N
N
H
N
N
H
Granulatimide
Isogranulatimide
H
N
H
N
O
O
R
N
H
N
H
N
N
O
CH3
K252-c
OCH3
NHCH3
Staurosporine, R = H
UCN-01, R = OH
H
N
H
N
O
O
O
O
Ar
N
H
N
R
N
R
R = H, alkyl
bisindolylmaleimides
4-Aryl-3-indolylmaleimides
R3HN
1'
2'
N
6' R5
5'
R4
H2N
3'
meridianin A, R1=OH, R2=R3=R4=H
meridianin B, R1=OH, R2=R4=H, R3=Br
meridianin C, R1=R3=R4=H, R2=Br
meridianin D, R1=R2=R4=H, R3=Br
meridianin E, R1=OH, R2=R3=H, R4=Br
meridianin F, R1=H, R2=R3=Br, R4=H
meridianin G, R1=R2=R3=R4=H
N
N
4'
N
4
7
R1
3
5
6
R2
R3
2
1
N
R2
R1
N
H
meridianin derivatives
R4
R4= CN, Cl, F, CH3, CO2H
CH(NH2)=N-NH2
Figure 1. Kinase inhibitors and meridianin derivatives described in the literature.
meridianin derivatives with an aryl group at the C-50 position
have never been described. The replacement of the male-
imide ring of 4-aryl-3-indolylmaleimides previously men-
tioned by the 2-aminopyrimidine ring could reinforce the
interaction inside the ATP-binding pocket of the target ki-
nase. To get an insight into the importance of the NH of the
indole moiety, we also prepared derivatives substituted on
the indole nitrogen with a methyl group. The introduction
H2N
N
N
O
O
N
c
a or b
N
N
N
R
H
R
3 R = H
4 R = CH3
1 R = H
2 R = CH3
7 R = H, Ar = phenyl
8 R = H, Ar = 4-acetylphenyl
9 R = H, Ar = 4-biphenyl
d
10 R= H, Ar = 4-fluorophenyl
11 R = H, Ar = 2,4-difluorophenyl
12 R = H, Ar = 4-trifluoromethylphenyl
H2N
H2N
N
N
13 R = H, Ar = 4-trifluoromethoxyphenyl
14 R = CH3, Ar = phenyl
15 R = CH3, Ar = 4-acetylphenyl
16 R = CH3, Ar = 4-biphenyl
N
N
Ar
Br
e
17 R= CH3, Ar = 4-fluorophenyl
18 R = CH3, Ar = 2,4-difluorophenyl
19 R = CH3, Ar = 4-trifluoromethylphenyl
20 R = CH3, Ar = 4-trifluoromethoxyphenyl
N
N
R
R
5 R = H
6 R = CH3
Scheme 1. Synthesis of meridianin derivatives. (a) DMF/DMF-di-tert-butylacetal, reflux, R¼H; (b) DMF/DMF-DMA, reflux, R¼CH3; (c) iso-propanol, gua-
nidine, NaOMe, reflux; (d) NBS, THF, 0 ꢀC; (e) ArB(OH)2, Na2CO3, Pd(PPh3)4, EtOH/H2O/toluene, reflux.

E. Rossignol et al. / Tetrahedron 63 (2007) 10169–10176
Table 1. Percentage of inhibition of various kinases at a compound concen-
tration of 10 mM, for compounds 3 and 5
10171
NOE
7.53 H
N 2.79-3.17
Compound MKK1 ERK2 RSK2 PKC-a GSK3-b CDK2/A CK2 MST2
O
5.77
NOE
NOE
3
5
66
98
36
92
9
85
56
91
43
87
54
85
38 31
93 96
H
H
8.15
N
MKK1, Mitogen-activated Kinase Kinase 1; ERK2, Extracellular signal-
Regulated Kinase 2; RSK2, p90 ribosomal S6 kinase 2; PKC-a, Protein Ki-
nase C-a; GSK3-b, Glycogen Synthase 3-b; CDK2/A, Cyclin-Dependent
Kinase 2/cyclin A; CK2, Casein Kinase 2; MST2, Mammalian STE20-
like kinase 2.
H
Figure 2. Determination of the configuration of the b-enaminone double
bond of compound 1 by 2D-NOESY NMR experiment.
b-enaminone double bond of compound 1. Surprisingly, in
the 1H NMR spectra of enaminones 1 and 2 in DMSO-d6 or
in CDCl3, the two methyl groups of the b-enaminone
moiety appeared as a broad signal between 2.79 ppm and
3.17 ppm for 1 and between 2.85 ppm and 3.09 ppm for 2.
of an alkyl group at this position could be relevant for biolog-
ical activity, as it was shown in bisindolylmaleimide
series.10,42
1
The H and 13C NMR spectra of structurally related com-
pounds16,45 reported in the literature showed two indepen-
dent peaks for each methyl of the N(CH3)2 group (Fig. 3).
This suggests that the rotation energy barrier around the
]C–N bond is sufficient to make the N-methyl groups mag-
netically non-equivalent. This high rotation energy could be
explained by the partial p character of the C–N bond, part of
the conjugated b-enaminone system. In the case of com-
pounds 3 and 4, the absence of electron-withdrawing protect-
ing group potentially decreases the p character of the C–N
bond. This would lower the rotation energy barrier and pro-
voke coalescence of the two CH3 peaks. Consequently, the
two methyl groups of the b-enaminone moiety were not vis-
ible on the 1D 13C NMR in DMSO-d6 or in CDCl3. Neverthe-
less, 1H–13C HSQC experiment showed the correlation
between these 1H broad signal and two carbons.
2. Chemistry
Meridianins have previously been synthesized from indole
derivatives. The first of the three reported approaches con-
sisted in a Suzuki cross-coupling with indole-3-boronic
acid derivatives.43 A Bredereck synthesis was also described
from b-enaminones, which were, in turn, obtained from 3-
acetylindole derivatives.16,44,45 More recently, meridianins
were obtained from trimethylsilylynones indole deriva-
tives.46 Commercially available 3-acetylindole was the start-
ing point of our synthesis, which gave access to the
meridianin analogs 5 and 6 in a straightforward three-step
synthesis following the Bredereck approach (Scheme
1).16,44,45,47 While the reported Bredereck routes started
from N-tosylated 3-acetylindole, our synthesis was initiated
with non-protected 3-acetylindole. This allowed us to obtain
both meridianins 5 and 6 with the indole nitrogen methylated
or simply protonated without the need for protection–depro-
tection steps. When 3-acetylindole was treated with DMF/
dimethylformamide-dimethylacetal (DMF-DMA),48 N-
methylated compound 2 was obtained in 85% yield. Using
DMF/dimethylformamide-di-tert-butylacetal instead of
DMF/DMF-DMA led to compound 1 in 71% yield. When
refluxing in toluene/DMF-DMA, compound 1 was obtained
in only 24% yield but no N-methylated compound 2 was
observed. Increasing the reflux temperature by replacement
of toluene by xylene led to compound 2 in a poor yield.
Compounds 1 and 2 were treated with guanidine in iso-prop-
anol in the presence of sodium methoxide to give com-
pounds 3 and 4 in 74% and 44% yield, respectively.
Meridianins 3 and 4 were then brominated with N-bromo-
succinimide (NBS) in THF. Compounds 5 and 6 were
obtained in 95% and 94% yield, respectively. The
electrophilic substitution by the bromine atom was clearly
directed to the 5-position of the pyrimidine ring.51 The posi-
tion of the bromine atom was unambiguously determined by
NMR. 1H and 13C NMR signals were assigned from 1D and
2D (COSY 1H–1H, HSQC 1H–13C, and HMBC 1H–13C) ex-
periments. The two aromatic protons of the pyrimidine ring
of compound 4 correspond to two doublets at 6.94 ppm for
H-50 and at 8.10 ppm for H-60. After bromination of 3,
only one singlet corresponding to H-60 was observed at
8.31 ppm. The 13C NMR spectra of compounds 4 and 6
also show the low field methine carbon corresponding to
C-60 at 157.1 ppm and 159.5 ppm, respectively.
The E configuration of the enaminone double bond in 1 and 2
was determined by NMR spectrometry. From the coupling
constant between the two ethylenic protons (J¼12.5 Hz),
configuration could not be unambiguously determined.
Therefore, a 2D-NOESY NMR experiment was performed
on compound 1 (Fig. 2). The similar NOE effects between
each two ethylenic protons at 5.77 ppm and 7.53 ppm and
the CH3 groups showed that compound 1 has an E configura-
tion. We confirmed the E configuration by the measurement
of the 3J(1H, 13C]O) coupling constant existing between the
ethylenic proton at the b-position relative to the carbonyl
group and the 13C of the ketone function. Indeed, the config-
uration of the double bond of a,b-unsaturated carbonyl com-
pounds can be determined on the basis of this long range
Suzuki cross-couplings were then performed between bro-
minated compound 5 or 6 and substituted phenylboronic
N
CN
N
O
O
R1
R2
3
1
heteronuclear coupling constant. The J(H, C) between H
and 13C]O nuclei with a Z orientation around the double
bond are usually smaller (2–6 Hz) than those with an E orien-
tation (8–12 Hz).49,50 Thus, in our case, the measured
3J(H, C) value of 4 Hz indicated the E configuration for
N
N
H
Ts
ref 16
ref 45
Figure 3. Examples of the literature in which the two methyl groups of
N(CH3)2 appeared as distinct signals in the 1H NMR spectra.

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E. Rossignol et al. / Tetrahedron 63 (2007) 10169–10176
acids. Phenyl group of boronic acids was variously
substituted by either halogen atoms (compounds 10, 11,
17, and 18), aryl (9 and 16), acetyl (8 and 15), trifluoro-
methyl (12 and 19), and trifluoromethoxy (13 and 20)
groups. Couplings were carried out using palladium tetra-
kis(triphenylphosphine) in a 1:1:1 toluene/EtOH/H2O mix-
ture in the presence of sodium carbonate,52 leading to
compounds 7–20 in 21–60% isolated yields.
(1H, s), 8.28 (1H, d, J¼7.5 Hz), 11.53–11.65 (1H, br s,
NH). 13C NMR (100 MHz, DMSO-d6): 93.3, 111.6, 120.5,
121.8 (2C), 130.1, 151.0 (CH), 118.0, 126.1, 136.5 (C),
183.5 (C]O).
4.2.2. 1-Methyl-3-(3-N,N-dimethylamino-1-oxoprop-2-
enyl)-1H-indole 2. Dimethylformamide-dimethylacetal
(45.0 mL, 339 mmol) was added to a solution of 3-acetylin-
dole (5.00 g, 31.4 mmol) in DMF (63 mL) and the solution
was refluxed for 24 h. Brine (100 mL) was added to the re-
action mixture. After extraction with CH2Cl2 (3ꢂ100 mL),
the combined organic fractions were dried over MgSO4
and concentrated under vacuum. The residue was dissolved
in EtOAc (50 mL) and precipitated with cyclohexane
(350 mL). The precipitate was collected by filtration and
3. Conclusion
Encouraging preliminary biological evaluation of bromi-
nated derivative 5 led us to synthesize new meridianin deriv-
atives. The synthetic approach described here allowed the
substitution at the C-50 position of the pyrimidine moiety
by diversely substituted phenyl rings (compounds 7–20).
Moreover, since in bisindolylmaleimide series substitution
of the indole nitrogen with an alkyl group led to potent ki-
nase inhibitors, compounds 14–20, substituted on the indole
nitrogen by a methyl group, were also prepared. The biolog-
ical evaluation of compounds 7–20 is currently in progress.
washed with Et2O (3ꢂ20 mL) to give
2 (6.11 g,
26.8 mmol, 85% yield) as a pale yellow powder.
Mp 157–158 ꢀC. IR (KBr) 3448, 1642, 1631, 1552, 1523,
1466, 1368, 1083. MS m/z (EI) 228 (M+). 1H NMR
(400 MHz, DMSO-d6): 2.85–3.09 (6H, br s, CH3), 3.83
(3H, s, CH3), 5.71 (1H, d, J¼12.5 Hz), 7.14 (1H, t,
J¼7.5 Hz), 7.20 (1H, t, J¼7.0 Hz), 7.46 (1H, d, J¼8.0 Hz),
7.53 (1H, d, J¼12.5 Hz), 8.15 (1H, s), 8.28 (1H, d,
J¼8.0 Hz). 13C NMR (100 MHz, DMSO-d6): 32.8 (CH3),
93.2, 110.0, 120.8, 121.9 (2C), 134.1, 151.0 (CH), 116.9,
126.5, 137.1 (C), 183.0 (C]O).
4. Experimental
4.1. General
IR spectra were recorded on a Perkin–Elmer Paragon 500
spectrometer (nmax in cmꢁ1). NMR spectra were recorded
on a Bruker AVANCE 400 (1H: 400 MHz, 13C: 100 MHz)
or AVANCE 500 (1H: 500 MHz, 13C: 125 MHz); chemical
shifts d are noted in parts per million and the following ab-
breviations are used: singlet (s), doublet (d), triplet (t), qua-
druplet (q), doubled doublet (dd), doublet of doublet of
doublet (ddd), doubled triplet (dt), multiplet (m), broad sig-
nal (br s). Mass spectra (ESI+) were recorded on a high res-
olution Waters Micro Q-Toff apparatus. Chromatographic
purifications were performed on flash silica gel Geduran SI
60 (Merck) 0.040–0.063 mm column chromatography.
TLC were performed on fluorescent silica gel plates (60
F254 from Merck).
4.2.3. 3-(2-Aminopyrimidin-4-yl)-1H-indole 3. Sodium
methoxide (1.48 g, 27.4 mmol) and guanidine hydrochloride
(788 mg, 8.25 mmol) were added to a solution of 1 (1.15 g,
5.37 mmol) in iso-propanol (6 mL) and the mixture was re-
fluxed for 48 h. Water (25 mL) was added to the reaction
mixture. After extraction with EtOAc (3ꢂ15 mL), the or-
ganic fractions were dried over MgSO4 and concentrated un-
der vacuum. The residue was dissolved in EtOAc (5 mL) and
precipitated with cyclohexane (25 mL). The precipitate was
collected by filtration and washed with CH2Cl2 (3ꢂ5 mL) to
give 3 (831 mg, 3.95 mmol, 74% yield) as a beige powder.
Spectral data are in agreement with literature data.16
4.2.4. 3-(2-Amino-5-bromopyrimidin-4-yl)-1-methyl-1H-
indole 4. Sodium methoxide (5.79 g, 107 mmol) and gua-
nidine hydrochloride (3.84 g, 40.2 mmol) were added to a
solution of 2 (6.11 g, 26.8 mmol) in iso-propanol (135 mL)
and the mixture was refluxed for 48 h. Water (250 mL) was
added to the reaction mixture. After extraction with EtOAc
(3ꢂ150 mL), the organic fractions were dried over MgSO4
and concentrated under vacuum. The residue was dissolved
in EtOAc (20 mL) and precipitated with cyclohexane
(250 mL). The precipitate was collected by filtration and
washed with CH2Cl2 (3ꢂ20 mL) to give 4 (2.64 g,
11.8 mmol, 44% yield) as a beige powder.
4.2. Synthesis
4.2.1. 3-(3-N,N-Dimethylamino-1-oxoprop-2-enyl)-1H-
indole 1. Dimethylformamide-di-tert-butylacetal (2.4 mL,
10.0 mmol) was added to a solution of 3-acetylindole
(318 mg, 2.0 mmol) in DMF (6 mL) and the solution was re-
fluxed for 48 h. Brine (10 mL) was added to the reaction
mixture. After extraction with CH2Cl2 (3ꢂ10 mL), the com-
bined organic fractions were dried over MgSO4 and concen-
trated under vacuum. The residue was dissolved in EtOAc
(5 mL) and precipitated with cyclohexane (15 mL). The pre-
cipitate was collected by filtration and washed with Et2O
(3ꢂ10 mL) to give 1 (303 mg, 1.41 mmol, 71% yield) as
a pale yellow powder.
Mp 191–193 ꢀC. IR (KBr) 3454, 1624, 1576, 1534, 1458,
1219. HRMS (ESI+) calcd for C13H13N4 (M+H)+ 225.1140,
found 225.1130. 1H NMR (400 MHz, DMSO-d6): 3.85
(3H, s), 6.37–6.45 (2H, br s, NH2), 6.94 (1H, d, J¼5.5 Hz),
7.17 (1H, ddd, J1¼8.0 Hz, J2¼7.0 Hz, J3¼1.0 Hz), 7.24
(1H, ddd, J1¼8.0 Hz, J2¼7.0 Hz, J3¼1.5 Hz), 7.49 (1H, d,
J¼8.0 Hz), 8.10 (1H, d, J¼5.5 Hz), 8.17 (1H, s), 8.59 (1H,
d, J¼8.0 Hz). 13C NMR (100 MHz, DMSO-d6): 33.0
Mp 219–221 ꢀC. IR (KBr) 3448, 1630, 1508, 1446, 1416,
1376, 1304, 1284, 1164, 1114, 1095, 1011. MS m/z (EI)
214 (M+). 1H NMR (400 MHz, DMSO-d6): 2.79–3.17 (6H,
br s, CH3), 5.77 (1H, d, J¼12.5 Hz), 7.06–7.16 (2H, m),
7.40 (1H, d, J¼7.5 Hz), 7.53 (1H, d, J¼12.5 Hz), 8.15

E. Rossignol et al. / Tetrahedron 63 (2007) 10169–10176
10173
(CH3), 105.2, 110.2, 120.6, 122.1, 122.5, 132.2, 157.1 (CH),
112.7, 125.7, 137.5, 162.3, 163.5 (C).
Mp 226–228 ꢀC. IR (KBr) 3420, 3316, 1648, 1576, 1528,
1474. HRMS (ESI+) calcd for C18H15N4 (M+H)+
287.1297, found 287.1299. H NMR (400 MHz, DMSO-
1
4.2.5. 3-(2-Amino-5-bromopyrimidin-4-yl)-1H-indole 5.
NBS (372 mg, 2.09 mmol) was added to a solution of 3
(440 mg, 2.09 mmol) in THF (18 mL) and the reaction mix-
ture was stirred at 0 ꢀC for 1.5 h. After evaporation of the
solvent, water was added to the reaction mixture and the
solid was filtered and washed with water to give 5
(573 mg, 1.98 mmol, 95% yield) as a red powder.
d6): 6.54–6.59 (2H, br s, NH2), 6.60 (1H, d, J¼3.0 Hz),
7.06 (1H, ddd, J1¼8.0 Hz, J2¼7.0 Hz, J3¼1.0 Hz), 7.12
(1H, ddd, J1¼8.0 Hz, J2¼7.0 Hz, J3¼1.5 Hz), 7.27–7.31
(2H, m), 7.32–7.43 (4H, m), 8.00 (1H, s), 8.45 (1H, d,
J¼8.0 Hz), 11.24–11.30 (1H, br s, NH). 13C NMR
(100 MHz, DMSO-d6): 111.4, 120.0, 121.9, 122.8, 127.1,
128.8 (3C), 129.5 (2C), 157.9 (CH), 112.8, 121.0, 126.2,
135.8, 139.0, 159.9, 162.5 (C).
Mp 183–185 ꢀC. IR (KBr) 3483, 1654, 1648, 1638,
1559, 1542, 1520, 1460, 1435. HRMS (ESI+) calcd
4.2.9. 3-(2-Amino-5-(4-acetylphenyl)pyrimidin-4-yl)-1H-
indole 8. Compound 8 was prepared according to the above
general procedure, starting from 5 (289 mg, 1.00 mmol).
The residue was dissolved in EtOAc (2 mL) and cyclo-
hexane (25 mL) was added. The resulting precipitate was
collected by filtration and further purified by flash chromato-
graphy (EtOAc/cyclohexane 8:2). The residue was dissolved
in EtOAc (2 mL) and cyclohexane (25 mL) was added. The
resulting precipitate was filtered to give 8 (90 mg, 27%
yield) as a pale yellow powder.
1
for C12H1079BrN4 (M+H)+ 289.0089, found 289.0097. H
NMR (400 MHz, DMSO-d6): 6.70–6.80 (2H, br s,
NH2), 7.13 (1H, ddd, J1¼8.0 Hz, J2¼7.0 Hz, J3¼1.0 Hz),
7.20 (1H, ddd, J1¼8.0 Hz, J2¼7.0 Hz, J3¼1.0 Hz), 7.47
(1H, d, J¼8.0 Hz), 8.31 (1H, s), 8.48 (1H, d, J¼3.0 Hz),
8.54 (1H, d, J¼8.0 Hz), 11.72–11.81 (1H, br s, NH).
13C NMR (100 MHz, DMSO-d6): 111.7, 120.4, 122.2,
123.0, 130.1, 160.0 (CH), 102.1, 111.8, 126.3, 136.0, 159.2,
161.8 (C).
4.2.6. 3-(2-Amino-5-bromopyrimidin-4-yl)-1-methyl-1H-
indole 6. NBS (1.15 g, 6.46 mmol) was added to a solution
of 4 (1.45 g, 6.46 mmol) in THF (65 mL) and the reaction
mixture was stirred at 0 ꢀC for 2 h. Diethylether (100 mL)
was added to the reaction mixture and the resulting precipi-
tate was collected by filtration and washed with Et2O to give
6 (1.84 g, 6.07 mmol, 94% yield) as a brown powder.
Mp 221–222 ꢀC. IR (KBr) 3502, 3313, 1676, 1627, 1603,
1584, 1529, 1508, 1458, 1269, 1242. HRMS (ESI+) calcd
for C20H17N4O (M+H)+ 329.1402, found 329.1403. 1H
NMR (400 MHz, DMSO-d6): 2.59 (3H, s, CH3), 6.67–6.74
(2H, br s, NH2), 6.74 (1H, d, J¼3.0 Hz), 7.05 (1H, ddd,
J1¼8.0 Hz, J2¼7.0 Hz, J3¼1.0 Hz), 7.13 (1H, ddd, J1¼
8.0 Hz, J2¼7.0 Hz, J3¼1.5 Hz), 7.35 (1H, d, J¼8.0 Hz),
7.44 (2H, d, J¼8.5 Hz), 7.96 (2H, d, J¼8.5 Hz), 8.07 (1H,
s), 8.33 (1H, d, J¼8.0 Hz), 11.26–11.34 (1H, br s, NH).
13C NMR (100 MHz, DMSO-d6): 26.7 (CH3), 111.5,
120.1, 122.0, 122.5, 128.6 (2C), 128.9, 129.6 (2C), 158.1
(CH), 112.6, 120.1, 126.0, 128.9, 135.2, 135.9, 144.1,
159.9, 162.7 (C), 197.5 (C]O).
Mp 211–213 ꢀC. IR (KBr) 3479, 1630, 1561, 1531, 1513,
1450, 1370. HRMS (ESI+) calcd for C13H1279BrN4
1
(M+H)+ 303.0245, found 303.0228. H NMR (400 MHz,
DMSO-d6): 3.90 (3H, s, N–CH3), 6.68–6.92 (2H, br s,
NH2), 7.18 (1H, t, J¼7.5 Hz), 7.27 (1H, t, J¼7.5 Hz), 7.52
(1H, d, J¼8.0 Hz), 8.31 (1H, s), 8.53 (1H, s), 8.59 (1H, d,
J¼8.0 Hz). 13C NMR (100 MHz, DMSO-d6): 32.8 (N–
CH3), 109.8, 120.5, 122.1, 123.0, 133.9, 159.5 (CH),
101.6, 110.5, 126.5, 136.3, 158.7, 161.4 (C).
4.2.10. 3-(2-Amino-5-(4-biphenyl)pyrimidin-4-yl)-1H-in-
dole 9. Compound9 was preparedaccordingtotheabovegen-
eral procedure, starting from 5 (289 mg, 1.00 mmol). The
residue was dissolved in EtOAc (2 mL) and cyclohexane
(25 mL) was added. The solid was collected by filtration
and further purified by flash chromatography (EtOAc/cyclo-
hexane 8:2). The residue was dissolved in EtOAc (2 mL)
andcyclohexane(25 mL)wasadded. Theresultingprecipitate
was filtered to give 9 (178 mg, 49% yield) as a beige powder.
4.2.7. General procedure for the preparation of com-
pounds 7–20. A solution of Na2CO3 (2.5 equiv) in H2O
(2 mL/mmol) was added to a suspension of 6, the required
boronic acid (1.1 equiv) and Pd(PPh3)4 (5 mol%) in EtOH
(2 mL/mmol), and toluene (2 mL/mmol). The resulting
mixture was refluxed for 12 h under argon. The reaction
mixture was extracted with CHCl3 (3ꢂ20 mL) and the
combined organic layers were washed with H2O
(10 mL), 0.5 N aqueous NaOH (10 mL), H2O (10 mL),
and brine (10 mL), and then dried over MgSO4 and con-
centrated under vacuum.
Mp 240–242 ꢀC. IR (KBr) 3474, 3406, 1630, 1576, 1528,
1457. HRMS (ESI+) calcd for C24H19N4 (M+H)+ 363.1610,
found 363.1606. H NMR (400 MHz, DMSO-d6): 6.58–
1
6.64 (2H, br s, NH2), 6.75 (1H, d, J¼3.0 Hz), 7.07 (1H,
ddd, J1¼8.0 Hz, J2¼7.0 Hz, J3¼1,0 Hz), 7.13 (1H, ddd,
J1¼8.0 Hz, J2¼7.0 Hz, J3¼1,5 Hz), 7.35 (d, 1H, J¼
8.0 Hz), 7.36–7.40 (3H, m), 7.48 (2H, t, J¼7.5 Hz), 7.70–
7.75 (4H, m), 8.06 (1H, s), 8.47 (1H, d, J¼8.0 Hz), 11.27–
11.33 (1H, br s, NH). 13C NMR (100 MHz, DMSO-d6):
111.5, 120.0, 121.9, 122.8, 126.5 (2C), 126.9 (2C), 127.5,
128.9, 129.0 (2C), 130.0 (2C), 158.0 (CH), 112.8, 120.6,
126.2, 135.8, 138.1, 138.6, 139.5, 160.0, 162.6 (C).
4.2.8. 3-(2-Amino-5-phenylpyrimidin-4-yl)-1H-indole 7.
Compound 7 was prepared according to the above general
procedure, starting from 5 (289 mg, 1.00 mmol). The resi-
due was dissolved in Et2O (2 mL) and cyclohexane
(25 mL) was added. The resulting precipitate was collected
by filtration and further purified by flash chromatography
(EtOAc/cyclohexane 8:2). The residue was dissolved in
EtOAc (2 mL) and cyclohexane (25 mL) was added. The re-
sulting precipitate was filtered to give 7 (59 mg, 21% yield)
as a beige powder.
4.2.11. 3-(2-Amino-5-(4-fluorophenyl)pyrimidin-4-yl)-
1H-indole 10. Compound 10 was prepared according to
the above general procedure, starting from 5 (289 mg,

10174
E. Rossignol et al. / Tetrahedron 63 (2007) 10169–10176
1.00 mmol). The residue was dissolved in EtOAc (2 mL) and
cyclohexane (25 mL) was added. The resulting precipitate
was collected by filtration and further purified by flash chro-
matography (EtOAc/cyclohexane 8:2). The residue was dis-
solved in EtOAc (2 mL) and cyclohexane (25 mL) was
added. The resulting precipitate was filtered to give 10
(141 mg, 46% yield) as a pale yellow powder.
calcd for C19H14F3N4 (M+H)+ 355.1171, found 355.1168.
1H NMR (400 MHz, DMSO-d6): 6.68–6.75 (2H, br s,
NH2), 6.72 (1H, d, J¼3.0 Hz), 7.05 (1H, ddd, J1¼8.0 Hz,
J2¼7.0 Hz, J3¼1.0 Hz), 7.13 (1H, ddd, J1¼8.0 Hz, J2¼
7.0 Hz, J3¼1.5 Hz), 7.35 (1H, dt, J1¼8.0 Hz, J2¼1.0 Hz),
7.52 (2H, d, J¼8.0 Hz), 7.72 (2H, d, J¼8.0 Hz), 8.09 (1H,
s), 8.29 (1H, d, J¼8.0 Hz), 11.30–11.37 (1H, br s, NH).
13C NMR (100 MHz, DMSO-d6): 111.5, 120.0, 122.0,
122.4, 125.5 (2C, q, JCF¼4 Hz), 128.9, 130.2 (2C), 158.3
(CH), 112.5, 119.7, 124.4 (q, JCF¼272 Hz), 126.0, 127.3
(q, JCF¼32 Hz), 135.9, 143.3, 159.9, 162.8 (C).
Mp 232–234 ꢀC. IR (KBr) 3410, 1585, 1526, 1458, 1426,
1209. HRMS (ESI+) calcd for C18H14FN4 (M+H)+
305.1202, found 305.1204. H NMR (400 MHz, DMSO-
1
d6): 6.56–6.62 (2H, br s, NH2), 6.65 (1H, d, J¼3.0 Hz),
7.05 (1H, ddd, J1¼8.0 Hz, J2¼7.0 Hz, J3¼1.0 Hz), 7.12
(1H, ddd, J1¼8.0 Hz, J2¼7.0 Hz, J3¼1.5 Hz), 7.19–7.26
(2H, m), 7.29–7.37 (3H, m), 8.01 (1H, s), 8.40 (1H, d,
J¼8.0 Hz), 11.25–11.34 (1H, br s, NH). 13C NMR
(100 MHz, DMSO-d6): 111.5, 115.7 (d, JCF¼21 Hz),
120.1, 122.0, 122.7, 128.8, 131.5 (d, JCF¼8 Hz), 158.1
(CH), 112.8, 120.0, 126.2, 135.2 (d, JCF¼3 Hz), 135.8,
160.1, 161.5 (d, JCF¼243 Hz), 162.6 (C).
4.2.14. 3-(2-Amino-5-(4-trifluoromethoxyphenyl)pyrimi-
din-4-yl)-1H-indole 13. Compound 12 was prepared ac-
cording to the above general procedure, starting from 5
(289 mg, 1.00 mmol). The residue was dissolved in EtOAc
(2 mL) and cyclohexane (25 mL) was added. The resulting
precipitate was collected by filtration and further purified
by flash chromatography (EtOAc/cyclohexane 8:2). The res-
idue was dissolved in EtOAc (2 mL) and cyclohexane
(25 mL) was added. The resulting precipitate was filtered
to give 13 (106 mg, 29% yield) as a pale yellow powder.
4.2.12. 3-(2-Amino-5-(2,4-difluorophenyl)pyrimidin-4-
yl)-1H-indole 11. Compound 11 was prepared according
to the above general procedure, starting from 5 (289 mg,
1.00 mmol). The residue was dissolved in EtOAc (2 mL)
and cyclohexane (25 mL) was added. The resulting precipi-
tate was collected by filtration and further purified by flash
chromatography (EtOAc/cyclohexane 8:2). The residue
was dissolved in EtOAc (2 mL) and cyclohexane (25 mL)
was added. The resulting precipitate was filtered to give 11
(110 mg, 34% yield) as a beige powder.
Mp 104–106 ꢀC. IR (KBr) 3485, 3372, 1627, 1583, 1535,
1464, 1254, 1161. HRMS (ESI+) calcd for C19H14F3N4O
1
(M+H)+ 371.1120, found 371.1105. H NMR (400 MHz,
DMSO-d6): 6.63–6.67 (2H, br s, NH2), 6.70 (1H, d,
J¼3.0 Hz), 7.04 (1H, ddd, J1¼8.0 Hz, J2¼7.0 Hz, J3¼
1.0 Hz), 7.12 (1H, ddd, J1¼8.0 Hz, J2¼7.0 Hz, J3¼1.5 Hz),
7.33–7.43 (5H, m), 8.06 (1H, s), 8.31 (1H, d, J¼8.0 Hz),
11.32–11.39 (1H, br s, NH). 13C NMR (100 MHz, DMSO-
d6): 111.5, 120.0, 121.3 (2C), 121.9, 122.5, 128.7, 131.3
(2C), 158.1 (CH), 112.7, 119.7, 120.1 (q, JCF¼256 Hz),
126.0, 135.9, 138.3, 147.4 (q, JCF¼2 Hz), 159.9, 162.7 (C).
Mp 222–224 ꢀC. IR (KBr) 3509, 3409, 1607, 1587, 1530,
1458, 1423, 1138. HRMS (ESI+) calcd for C18H13F2N4
1
(M+H)+ 323.1108, found 323.1104. H NMR (400 MHz,
DMSO-d6): 6.64 (1H, d, J¼3.0 Hz), 6.67–6.73 (2H, br s,
NH2), 7.09 (1H, ddd, J1¼8.0 Hz, J2¼7.0 Hz, J3¼1.0 Hz),
7.14 (1H, ddd, J1¼8.0 Hz, J2¼7.0 Hz, J3¼1.5 Hz), 7.20
(1H, dt, J1, CH+CF¼8.5 Hz, J2¼2.5 Hz), 7.31 (1H, dt, J1,
4.2.15. 3-(2-Amino-5-phenylpyrimidin-4-yl)-1-methyl-
1H-indole 14. Compound 14 was prepared according to
the above general procedure, starting from 6 (306 mg,
1.01 mmol). The residue was dissolved in EtOAc (2 mL)
and cyclohexane (25 mL) was added. The resulting precipi-
tate was collected by filtration and washed with Et2O
(3ꢂ2 mL) to give 14 (133 mg, 0.443 mmol, 44% yield) as
a pale yellow powder.
¼9.5 Hz, J2¼2.5 Hz), 7.36 (1H, d, J¼8.0 Hz), 7.45 (1H,
CF
dt, J1¼8.5 Hz, J2, CF¼7.0 Hz), 8.01 (1H, s), 8.52 (1H, d,
J¼8.0 Hz), 11.24–11.36 (1H, br s, NH). 13C NMR
(100 MHz, DMSO-d6): 104.5 (t, J¼26 Hz), 111.5, 112.2
(dd, JCF1¼21 Hz, JCF2¼4 Hz), 120.1, 122.1, 122.9, 127.6,
133.2 (dd, JCF1¼10 Hz, JCF2¼4 Hz), 158.5 (CH), 112.9,
113.3, 122.8 (dd, JCF1¼17 Hz, JCF2¼4 Hz), 126.1, 135.9,
159.6 (dd, JCF1¼246 Hz, JCF2¼12 Hz), 160.7, 162.0 (dd,
JCF1¼247 Hz, JCF2¼12 Hz), 163.0 (C).
Mp 210–212 ꢀC. IR (KBr) 3489, 1625, 1583, 1528, 1459,
1370. HRMS (ESI+) calcd for C19H17N4 (M+H)+
301.1453, found 301.1438. H NMR (400 MHz, DMSO-
1
d6): 3.58 (3H, s, CH3–N), 6.56–6.60 (2H, br s, NH2), 6.63
(1H, d, J¼3.0 Hz), 7.07 (1H, ddd, J1¼8.0 Hz, J2¼7.0 Hz,
J3¼1.0 Hz), 7.18 (1H, ddd, J1¼8.0 Hz, J2¼7.0 Hz,
J3¼1.0 Hz), 7.26–7.30 (2H, m), 7.35–7.42 (4H, m), 8.02
(1H, s), 8.32 (1H, d, J¼8.0 Hz). 13C NMR (100 MHz,
DMSO-d6): 32.8 (CH3–N), 109.8, 120.2, 121.9, 122.8,
127.1, 128.8 (2C), 129.3 (2C), 132.6, 158.1 (CH), 112.1,
121.0, 126.5, 136.4, 138.7, 159.5, 162.5 (C).
4.2.13. 3-(2-Amino-5-(4-trifluoromethylphenyl)pyrimi-
din-4-yl)-1H-indole 12. Compound 12 was prepared ac-
cording to the above general procedure, starting from 5
(289 mg, 1.00 mmol). The residue was dissolved in EtOAc
(2 mL) and cyclohexane (25 mL) was added. The resulting
precipitate was collected by filtration and further purified
by flash chromatography (EtOAc/cyclohexane 8:2). The
residue was dissolved in EtOAc (2 mL) and cyclohexane
(25 mL) was added. The resulting precipitate was
filtered to give 12 (106 mg, 30% yield) as a pale yellow
powder.
4.2.16. 3-(2-Amino-5-(4-acetylphenyl)pyrimidin-4-yl)-1-
methyl-1H-indole 15. Compound 15 was prepared accord-
ing to the above general procedure, starting from 6 (289 mg,
0.95 mmol). The residue was dissolved in EtOAc (2 mL)
and Et2O (25 mL) was added. The resulting precipitate was
collected by filtration and washed with Et2O (3ꢂ2 mL) to
give 15(192 mg, 0.56 mmol, 59%yield)as an orangepowder.
Mp 125–127 ꢀC. IR (KBr) 3484, 3365, 1636, 1615, 1585,
1528, 1464, 1439, 1323, 1172, 1107, 1068. HRMS (ESI+)

E. Rossignol et al. / Tetrahedron 63 (2007) 10169–10176
10175
Mp 201–203 ꢀC. IR (KBr) 3402, 1654, 1578, 1528, 1508,
1478, 1459, 1364. HRMS (ESI+) calcd for C21H19N4O
Mp >235 ꢀC. IR (KBr) 3490, 1629, 1583, 1542, 1534, 1478,
1459. HRMS (ESI+) calcdforC19H15F2N4 (M+H)+ 337.1265,
found337.1258. 1H NMR(500 MHz,DMSO-d6):3.63(3H, s,
N–CH3), 6.67 (1H, s), 6.69–6.75 (2H, br s, NH2), 7.12 (1H,
ddd, J1¼8.0 Hz, J2¼7.0 Hz, J3¼1.0 Hz), 7.17–7.23 (2H,
m), 7.29 (1H, dt, J1,CF¼9.5 Hz, J2¼2.5 Hz), 7.41 (1H, d,
J¼8.0 Hz), 7.44 (1H, dt, J1¼8.5 Hz, J2,CF¼7.0 Hz), 8.01
(1H, s), 8.45 (1H, d, J¼8.0 Hz). 13C NMR (125 MHz,
DMSO-d6): 32.8 (N–CH3), 104.5 (t, JCF¼26 Hz), 109.9,
112.2 (dd, JCF1¼21 Hz, JCF2¼3 Hz), 120.4, 122.1, 122.9,
131.5, 133.1 (dd, JCF1¼10 Hz, JCF2¼4 Hz), 158.8 (CH),
112.2, 113.4, 122.6 (dd, JCF1¼16 Hz, JCF2¼4 Hz), 126.4,
136.5, 159.5 (dd, JCF1¼246 Hz, JCF2¼12 Hz), 160.3, 162.0
(dd, JCF1¼246 Hz, JCF2¼12 Hz), 163.0 (C).
1
(M+H)+ 343.1559, found 343.1566. H NMR (400 MHz,
DMSO-d6): 2.59 (3H, s, CH3), 3.63 (3H, s, N–CH3), 6.68–
6.74 (2H, br s, NH2), 6.85 (1H, s), 7.05 (1H, t, J¼7.5 Hz),
7.18 (1H, t, J¼7.5 Hz), 7.41 (1H, d, J¼8.5 Hz), 7.44 (2H,
d, J¼8.0 Hz), 7.94 (2H, d, J¼8.0 Hz), 8.09 (1H, s), 8.16
(1H, d, J¼8.0 Hz). 13C NMR (100 MHz, DMSO-d6): 26.7
(CH3), 32.8 (CH3–N), 109.9, 120.2, 122.0, 122.4, 128.6
(2C), 129.3 (2C), 132.7, 158.4 (CH), 111.9, 120.0, 126.3,
135.1, 136.5, 143.7, 159.4, 162.7 (C), 197.5 (C]O).
4.2.17. 3-(2-Amino-5-(4-biphenyl)pyrimidin-4-yl)-1-
methyl-1H-indole 16. Compound 16 was prepared accord-
ing to the above general procedure, starting from 6
(289 mg, 0.95 mmol). The residue was dissolved in EtOAc
(2 mL) and Et2O (25 mL) was added. The resulting precipi-
tate was collected by filtration and washed with Et2O
(3ꢂ2 mL) to give 16 (168 mg, 0.45 mmol, 47% yield) as
an orange powder.
4.2.20. 3-(2-Amino-5-(4-trifluoromethylphenyl)pyrimi-
din-4-yl)-1-methyl-1H-indole 19. Compound 19 was pre-
pared according to the above general procedure, starting
from 6 (289 mg, 0.95 mmol). The residue was dissolved in
Et2O (2 mL) and cyclohexane (25 mL) was added. The re-
sulting precipitate was collected by filtration and washed
with cyclohexane (3ꢂ2 mL) to give 19 (105 mg,
0.285 mmol, 30% yield) as a pale orange powder.
Mp 210–212 ꢀC. IR (KBr) 3490, 1624, 1578, 1528, 1478,
1459, 1364. HRMS (ESI+) calcd C25H21N4 (M+H)+
377.1766, found 377.1747. H NMR (400 MHz, DMSO-
1
Mp 185–187 ꢀC. IR (KBr) 3449, 1637, 1582, 1542, 1528,
1478, 1466, 1323, 1107. HRMS (ESI+) calcd for
d6): 3.60 (3H, s, N–CH3), 6.60–6.65 (2H, br s, NH2), 6.82
(1H, s), 7.07 (1H, t, J¼7.5 Hz), 7.18 (1H, t, J¼7.5 Hz),
7.35–7.42 (4H, m), 7.48 (2H, t, J¼7.5 Hz), 7.68–7.74 (4H,
m), 8.09 (1H, s), 8.31 (1H, d, J¼8.0 Hz). 13C NMR
(100 MHz, DMSO-d6): 32.8 (N–CH3), 109.9, 120.2, 121.9,
122.8, 126.5 (2C), 126.9 (2C), 127.5, 129.0 (2C), 129.8
(2C), 132.7, 158.3 (CH), 112.1, 120.5, 126.5, 136.5, 137.8,
138.6, 139.6, 159.5, 162.5 (C).
1
C20H16N4F3 (M+H)+ 369.1327, found 369.1317. H NMR
(400 MHz, DMSO-d6): 3.64 (3H, s, N–CH3), 6.68–6.76
(2H, br s, NH2), 6.87 (1H, s), 7.04 (1H, ddd, J1¼8.0 Hz,
J2¼7.0 Hz, J3¼1.0 Hz), 7.17 (1H, ddd, J1¼8.0 Hz,
J2¼7.0 Hz, J3¼1.0 Hz), 7.41 (1H, d, J¼8.0 Hz), 7.51 (2H,
d, J¼8.0 Hz), 7.69 (2H, d, J¼8.0 Hz), 8.07 (1H, d,
J¼8.0 Hz), 8.12 (1H, s). 13C NMR (100 MHz, DMSO-d6):
32.8 (CH3–N), 110.0, 120.2, 122.0, 122.3, 125.5 (2C, q,
JCF¼4 Hz), 129.9 (2C), 132.7, 158.6 (CH), 111.9, 119.7,
124.4 (q, JCF¼272 Hz), 126.2, 127.3 (q, JCF¼32 Hz),
136.6, 143.1, 159.5, 162.7 (C).
4.2.18. 3-(2-Amino-5-(4-fluorophenyl)pyrimidin-4-yl)-1-
methyl-1H-indole 17. Compound 17 was prepared accord-
ing to the above general procedure, starting from 6
(289 mg, 0.95 mmol). The residue was dissolved in EtOAc
(2 mL) and Et2O (25 mL) was added. The resulting precipi-
tate was collected by filtration and washed with Et2O
(3ꢂ2 mL) to give 17 (156 mg, 0.49 mmol, 52% yield) as
a pale brown powder.
4.2.21. 3-(2-Amino-5-(4-trifluoromethoxyphenyl)pyrimi-
din-4-yl)-1-methyl-1H-indole 20. Compound 20 was pre-
pared according to the above general procedure, starting
from 6 (289 mg, 0.95 mmol). The residue was dissolved in
EtOAc (2 mL) and Et2O (25 mL) was added. The resulting
precipitate was collected by filtration and washed with
Et2O (3ꢂ2 mL) to give 20 (218 mg, 0.57 mmol, 60% yield)
as a brown powder.
Mp 222–224 ꢀC; IR (KBr) 3489, 1629, 1581, 1535, 1478,
1460. HRMS (ESI+) calcd for C19H16FN4 (M+H)+
319.1359, found 319.1359. H NMR (400 MHz, DMSO-
1
d6): 3.63 (3H, s, N–CH3), 6.58–6.64 (2H, br s, NH2), 6.72
(1H, s), 7.07 (1H, ddd, J1¼8.0 Hz, J2¼7.0 Hz, J3¼1.0 Hz),
7.16–7.24 (3H, m), 7.28–7.33 (2H, m), 7.40 (1H, d,
J¼8.0 Hz), 8.03 (1H, s), 8.28 (1H, d, J¼8.0 Hz). 13C
NMR (100 MHz, DMSO-d6): 32.8 (N–CH3), 109.9, 115.7
(d, JCF¼21 Hz), 120.2, 122.0, 122.7, 131.3 (d, JCF¼8 Hz),
132.6, 158.3 (CH), 112.0, 120.0, 126.4, 134.9
(d, JCF¼3 Hz), 136.5, 159.6, 161.4 (d, JCF¼244 Hz),
162.6 (C).
Mp 183–185 ꢀC. IR (KBr) 3487, 1624, 1526, 1476, 1456,
1258, 1217, 1195, 1178. HRMS (ESI+) calcd for
C20H16F3N4O (M+H)+ 385.1276, found 385.1273. 1H NMR
(400 MHz, DMSO-d6): 3.63 (3H, s, N–CH3), 6.62–6.68
(2H, br s, NH2), 6.75 (1H, s), 7.04 (1H, t, J¼7.5 Hz), 7.18
(1H, t, J¼7.5 Hz), 7.34–7.42 (5H, m), 8.09 (1H, s), 8.13
(1H, d, J¼8.0 Hz). 13C NMR (100 MHz, DMSO-d6): 32.7
(N–CH3), 109.9, 120.2, 121.4 (2C), 121.9, 122.4, 131.2
(2C), 132.6, 158.3 (CH), 112.0, 119.6, 120.1 (q, J¼256 Hz),
126.2, 136.5, 138.1, 147.4 (q, JCF¼2 Hz), 159.5, 162.6 (C).
4.2.19. 3-(2-Amino-5-(2,4-difluorophenyl)pyrimidin-4-
yl)-1-methyl-1H-indole 18. Compound 18 was prepared
according to the above general procedure, starting from 6
(289 mg, 0.95 mmol). The residue was dissolved in EtOAc
(2 mL) and Et2O (25 mL) was added. The resulting precipi-
tate was collected by filtration and washed with Et2O
(3ꢂ2 mL) to give 18 (68 mg, 0.202 mmol, 21% yield) as
a pale yellow powder.
Acknowledgements
The authors thank the European Union Prokinase Research
Consortium for financial support.

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E. Rossignol et al. / Tetrahedron 63 (2007) 10169–10176
24. Bollbuck, B.; Denholm, A.; Eder, J.; Hersperger, R.; Janser, P.;
References and notes
Revesz, L.; Schlapbach, A.; Waelchli, R. PCT Int. Appl. WO
2004089913 A1, 2004; Chem. Abstr. 2004, 141, 379931.
25. Kidwai, M.; Rastogi, S.; Saxena, S. Bull. Korean Chem. Soc.
2003, 24, 1575.
1. Jiang, X.; Zhao, B.; Britton, R.; Lim, L. Y.; Leong, D.;
Sanghera, J. S.; Zhou, B.-B. S.; Piers, E.; Andersen, R. J.;
Roberge, M. Mol. Cancer Ther. 2004, 3, 1221.
26. Kim, Y.; Hanney, B. PCT Int. Appl. WO 2002102783, 2002;
Chem. Abstr. 2003, 138, 55974.
ꢁ
2. Henon, H.; Messaoudi, S.; Anizon, F.; Aboab, B.; Kucharczyk,
N.; Leonce, S.; Golsteyn, R. M.; Pfeiffer, B.; Prudhomme, M.
ꢁ
27. Batchelor, M. J.; Moffat, D. F. C.; Davis, J. M.; Hutchings, M.
C. PCT Int. Appl. WO 2000078731 A1, 2000; Chem. Abstr.
2001, 134, 71598.
28. Berger, J.; Flippin, L. A.; Greenhouse, R.; Jaime-Figueroa, S.;
Liu, Y.; Miller, A. K.; Putman, D. G.; Weinhardt, K. K.; Zhao,
S.-H. PCT Int. Appl. WO 9744326 A1, 1997; Chem. Abstr.
1998, 128, 48235.
Eur. J. Pharmacol. 2007, 554, 106.
3. Meijer, L.; Raymond, E. Acc. Chem. Res. 2003, 36, 417.
4. Eisenbrand, G.; Hippe, F.; Jakobs, S.; Muehlbeyer, S. J. Cancer
Res. Clin. Oncol. 2004, 130, 627.
5. Sassatelli, M.; Bouchikhi, F.; Messaoudi, S.; Anizon, F.;
Debiton, E.; Barthomeuf, C.; Prudhomme, M.; Moreau, P.
Eur. J. Med. Chem. 2006, 41, 88.
29. Davis, P. D.; Moffat, D. F. C.; Davis, J. M.; Hutchings, M. C.
PCT Int. Appl. WO 9719065 A1, 1997; Chem. Abstr. 1997,
127, 81461.
6. Tamaoki, T.; Nomoto, H.; Takahashi, I.; Kato, Y.; Morimoto,
M.; Tomita, F. Biochem. Biophys. Res. Commun. 1986, 135,
397.
30. Zimmerman, J.; Buchdunger, E.; Mett, H.; Meyer, T.; Lydon,
N. B. Bioorg. Med. Chem. Lett. 1997, 7, 187.
7. Omura, S.; Sasaki, Y.; Iwai, Y.; Takeshima, H. J. Antibiot. 1995,
48, 535.
31. Zimmerman, J.; Caravatti, G.; Mett, H.; Meyer, T.; Mueller,
M.; Lydon, N. B.; Fabbro, D. Arch. Pharm. (Weinheim, Ger.)
1996, 329, 371.
32. Zimmerman, J. PCT Int. Appl. WO 9509847 A1, 1995; Chem.
Abstr. 1995, 123, 313996.
33. Zimmerman, J. PCT Int. Appl. WO 9509852 A1, 1995; Chem.
Abstr. 1995, 123, 169650.
34. Paul, R.; Hallett, W. A.; Hanifin, J. W.; Reich, M. F.; Johnson,
B. D.; Lenhard, R. H.; Dusza, J. P.; Kerwar, S. S.; Lin, Y.-I.;
Pickett, W. C.; Seifert, C. M.; Torley, L. W.; Tarrant, M. E.;
Wrenn, S. J. Med. Chem. 1993, 36, 2716.
8. Mizuno, K.; Saido, T. C.; Ohno, S.; Tamaoki, T.; Suzuki, K.
FEBS Lett. 1993, 330, 114.
9. Nakanishi, S.; Matsuda, Y.; Iwahashi, K.; Kase, H. J. Antibiot.
1986, 34, 1066.
10. Toullec, D.; Pianetti, P.; Coste, H.; Bellevergue, P.; Grand-
Perret, T.; Ajakane, M.; Baudet, V.; Boissin, P.; Boursier, E.;
Loriolle, F.; Duhamel, L.; Charon, D.; Kirilovsky, J. J. Biol.
Chem. 1991, 266, 15771.
11. Davis, P. D.; Hill, C. H.; Keech, E.; Lawton, G.; Nixon, J. S.;
Sedgwick, A. D.; Wadsworth, J.; Westmacott, D.; Wilkinson,
S. E. FEBS Lett. 1989, 259, 61.
35. Torley, L. W.; Johnson, B. B.; Dusza, J. P. Eur. Pat. Appl. EP
233461 A2, 1987; Chem. Abstr. 1988, 108, 112478.
36. Kobayashi, G.; Matsuda, Y. Jpn Tokyo Koho JP 46008698,
1971; Chem. Abstr. 1971, 75, 449129.
37. Kobayashi, G.; Furukawa, S.; Matsuda, Y.; Washida, Y.
Yakugaku Zasshi 1967, 87, 857.
12. Davis, P. D.; Hill, C. H.; Lawton, G. Eur. Patent EP0328026
A1, 1989; Chem. Abstr. 1990, 112, 98378.
ꢁ
13. Franco, L. H.; Bal de Kier Joffe, E.; Puricelli, L.; Tatian, M.;
Seldes, A. M.; Palermo, J. A. J. Nat. Prod. 1998, 61, 1130.
14. Franco, L. H.; Palermo, J. A. Chem. Pharm. Bull. 2003, 51,
975.
38. Davies, S. P.; Reddy, H.; Caivano, M.; Cohen, P. Biochem. J.
2000, 351, 95.
39. Bain, J.; McLauchlan, H.; Elliott, M.; Cohen, P. Biochem. J.
2003, 371, 199.
40. http://www.upstate.com/features/kp_reference.asp.
ꢁ
15. Gompel, M.; Leost, M.; Bal de Kier Joffe, E.; Puricelli, L.;
Franco, L. H.; Palermo, J.; Meijer, L. Bioorg. Med. Chem.
Lett. 2004, 14, 1703.
16. Radwan, M. A. A.; El-Sherbiny, M. Bioorg. Med. Chem. 2007,
14, 1206.
€
41. Peifer, C.; Stoiber, T.; Unger, E.; Totzke, F.; Schachtele, C.;
Marme, D.; Brenk, R.; Klebe, G.; Schollmeyer, D.;
17. Huang, S.; Li, R.; Connolly, P. J.; Emanuel, S.; Fuentes-
Pesquera, A.; Adams, M.; Gruninger, R. H.; Seraj, J.;
Middleton, S. A.; Davis, J. M.; Moffat, D. F. C. Bioorg. Med.
Chem. Lett. 2007, 17, 2179.
18. Fischer, P. M.; Wang, S.; Meades, C. K.; Andrews, M. J. I.;
Gibson, D.; Duncan, K. PCT Int. Appl. WO 2006075152 A1,
2006; Chem. Abstr. 2006, 145, 167275.
ꢁ
Dannhardt, G. J. Med. Chem. 2006, 49, 1271.
42. Dow, R. L. Curr. Med. Chem. 1994, 1, 192.
43. Jiang, B.; Yang, C.-G. Heterocycles 2000, 53, 1489.
44. Fresneda, P. M.; Molina, P.; Delgado, S.; Bleda, J. A.
Tetrahedron Lett. 2000, 41, 4777.
45. Fresneda, P. M.; Molina, P.; Bleda, J. A. Tetrahedron 2001, 57,
2355.
46. Karpov, A. S.; Merkul, E.; Rominger, F.; M€uller, T. J. J. Angew.
Chem., Int. Ed. 2005, 44, 6951.
19. Ratcliffe, A. J.; Alam, M.; Beevers, R. E.; Davenport, R. J.;
Davies, N.; Haughan, A. F.; Jones, M. W.; Lowe, C.; Perry,
B. G.; Phillips, D. J.; Pitt, W. R.; Sharpe, A. PCT Int. Appl.
WO 2006038001 A1, 2006; Chem. Abstr. 2006, 144, 390934.
20. Bressi, J. C.; Gangloff, A. R.; Hosfield, D. J.; Jennings, A. J.;
Paraselli, B. R.; Stafford, J. A. PCT Int. Appl. WO
2005123672 A2, 2005; Chem. Abstr. 2006, 144, 88168.
21. Reddy, E. P.; Reddy, M. V. R.; Cosenza, S. C.; Gumireddy, K.
PCT Int. Appl. WO 2005065074 A2, 2005; Chem. Abstr. 2005,
143, 149136.
47. Fresneda, P. M.; Delgado, S.; Francesch, A.; Manzanares, I.;
Cuevas, C.; Molina, P. J. Med. Chem. 2006, 49, 1217.
48. Bergman, J.; Rehn, S. Tetrahedron 2002, 58, 9179.
49. Stanovnik, B.; Svete, J. Chem. Rev. 2004, 104, 2433.
50. Meissner, A.; Sørensen, W. Magn. Reson. Chem. 2001, 39, 49.
51. Byth, K. F.; Culshaw, J. D.; Green, S.; Oakes, S. E.; Thomas,
A. P. Bioorg. Med. Chem. Lett. 2004, 14, 2245.
52. Hannah, D. R.; Sherer, E. C.; Davies, R. V.; Titman, R. B.;
Laughton, C. A.; Stevens, M. F. G. Bioorg. Med. Chem.
2000, 8, 739.
22. Agarwal, A.; Srivastava, K.; Puri, S. K.; Chauhan, P. M. S.
Bioorg. Med. Chem. Lett. 2005, 15, 3133.
23. Agarwal, A.; Kumar, B.; Mehrotra, P. K.; Chauhan, P. M. S.
Bioorg. Med. Chem. 2005, 13, 1893.