Synthesis of 2-(pyrimidin-4-yl)indoles

Article abstract of DOI:10.1248/cpb.51.975

The synthesis of 2-substituted isomers of the meridianins, a familiy of bioactive indole alkaloids isolated from the tunicate Aplidium meridianum, was undertaken. The synthetic route comprises six steps, with a microwave promoted Fischer cyclization as th

Full text of DOI:10.1248/cpb.51.975

August 2003
Notes
Chem. Pharm. Bull. 51(8) 975—977 (2003)
975
Synthesis of 2-(Pyrimidin-4-yl)indoles1)
Laura Hernández FRANCO and Jorge Alejandro PALERMO*
Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires; Ciudad
Universitaria, Pabellón 2, (1428) Buenos Aires, Argentina. Received November 18, 2002; accepted May 6, 2003
The synthesis of 2-substituted isomers of the meridianins, a familiy of bioactive indole alkaloids isolated
from the tunicate Aplidium meridianum, was undertaken. The synthetic route comprises six steps, with a mi-
crowave promoted Fischer cyclization as the key reaction.
Key words meridianin; Fischer indole synthesis; microwave
conditions,7) and then the hydroxyl group was substituted by
chlorine (POCl3) to yield the 4-chloro derivative 13.8) Intro-
duction of a methyl ketone at position 4 was achieved by a
cross-coupling reaction of compound 13 with tri-n-butyl(1-
ethoxyvinyl)tin to yield the vinyl ether 14, which by acid hy-
drolysis gave the desired methyl ketone 15.9—11) The latter af-
forded the corresponding phenylhydrazones 16 and 17 under
standard conditions.
The meridianins (1—6) are a family of indole alkaloids
which were isolated by our group from the subantarctic tuni-
cate Aplidium meridianum collected near the South Georgia
islands.2) The basic structure of these compounds consists of
an indole nucleus substituted at C-3 by a 2-aminopyrimidine
ring. Other examples of heterocycles substituted by an
aminopyrimidine ring have been reported among marine nat-
ural products, such as the psammopemmins (7—9), isolated
from the sponge Psammopemma sp.,3) and variolin B (10),
from the sponge Kirkpatrickia varialosa,4) all of which show
promising antitumor activity. Prompted by this, we decided
to synthesize analogs of the natural meridianins in order to
study the structure–activity relationship of this type of com-
pounds. In this paper, we report the synthesis of two analogs
of meridianins which we designated iso-meridianins, that
bear the pyrimidine ring at C-2 instead of C-3, starting from
isocytosine, and using a microwave-assisted Fischer indole
cyclization as the key step.
The natural meridianins have previously been synthesized
by two different strategies: either the construction of the 2-
aminopyrimidine ring from a b-dicarbonylic substituted in-
dole precursor,5) or by a cross-coupling reaction between the
indole and pyrimidine moieties.6) Both strategies have in
common the use of a conveniently substituted indole precur-
sor. Since we wanted to study, among other aspects, the influ-
ence of diverse substituents on the indole ring, we decided to
take a different approach, building the indole ring by a Fis-
cher indole synthesis. This route would give us greater flexi-
bility in the preparation of a wide variety of analogs with dif-
ferent substituents on the indole ring, since available substi-
tuted phenylhydrazines or anilines are much more numerous
than substituted indoles.
The Fischer indole synthesis was the key step of this work.
Numerous attempts using a variety of catalysts, solvents and
heating conditions are listed in Table 1. The use of ZnCl2 at
reflux in a variety of solvents of increasing boiling point gave
either no reaction or decomposition of the starting material.
Heating the sample in an oven with ZnCl2 at high tempera-
ture (180 °C) without solvent for short times gave a low yield
of the desired indole, with extense decomposition. Prompted
by this we tried heating 16 with ZnCl2 in a domestic mi-
crowave oven, which resulted in a low yield of 18. Use of
montmorillonite K-10 and ZnCl2 under microwave condi-
tions gave yields lower than 20%. However, addition of a
small volume of DMF prior to microwave heating with ZnCl2
afforded the corresponding indoles 18 and 19 in good yield.
In all cases, the use of ZnCl2 and microwave heating pro-
duced a fast, clean and quantitative removal of the Boc
group. There have been some previous reports on microwave
assisted Fischer indole syntheses, either using dry ZnCl2,12)
dry montmorillonite K-10,13) or formic acid.14) All these pro-
cedures were used for the preparation of indoles bearing sim-
pler and more stable substituents than the 2-aminopyrimidine
group. Under all these conditions our compounds mostly
failed to give the desired products; for this reason our proce-
dure represents the first successful preparation of an
aminopyrimidine substituted indole by a Fischer indole cy-
clization.
We chose isocytosine as an adequate starting material,
since the hydroxyl group at position 4 allows a convenient
functionalization and introduction of the required C-2 car-
bonyl group. As a first step, the amino group of isocytosine
(11) was protected with a Boc group (12) under standard
The activity results of these meridianin analogs were poor
and will be included in a more comprehensive structure–ac-
tivity study. For this reason the preparation of further deriva-
Chart 1
To whom correspondence should be addressed. e-mail: palermo@qo.fcen.uba.ar
© 2003 Pharmaceutical Society of Japan

976
Vol. 51, No. 8
Fig. 1
Jϭ6.9 Hz), 6.06 (1H, d, Jϭ6.9 Hz), 1.57 (9H, s); 13C-NMR (CDCl3) d:
160.5 (s), 153.1 (s), 153 (d), 152.2 (s), 109.1 (d), 84.1 (s), 27.9 (q); MS m/z:
211 (Mϩ), 169, 155, 138, 111.
Table 1. Conditions for Fischer Indole Synthesis of Iso-Meridianin G
Solvent or
additive
Time Yield
(min) (%)
Catalysis
Heating
tert-Butyl (4-Chloropyrimidin-2-yl)carbamate (13) Compound 12
(1.2 g, 5.7 mmol) was suspended in a mixture of 42 ml of dichloromethane
and 3.3 ml of N,N-dimethylaniline. POCl3 (1.58 ml, 17.1 mmol) was then
slowly added while cooling on an ice bath with stirring. After the addition
was completed, the solution was further stirred at room temperature for 2 h.
The solution was washed with aqueous 2 M hydrochloric acid, sodium bicar-
bonate and water. Evaporation of the dichloromethane layer in vacuo gave
0.98 g (4.3 mmol) (75%) of a white residue (13). Compound 13: mp: 134—
137 °C (MeOH–H2O); IR (film) cmϪ1: 3213, 3049, 1767, 1568, 1512, 1237,
765; UV lmax (methanol) nm (e): 232 (23310), 275 (4380); 1H-NMR
(CDCl3) d: 8.46 (d, 1H, Jϭ5.2 Hz), 7.85 (br s, 1H), 6.98 (d, 1H, Jϭ5.2 Hz),
1.53 (s, 9H); 13C-NMR (CDCl3) d: 162.0 (s), 159.5 (d), 157.9 (s), 129.7 (s),
116.0 (d), 82.3 (s), 28.3 (q); MS m/z: 229 (Mϩ), 227, 174, 158, 156, 131,
129.
tert-Butyl [4-(1-Ethoxyvinyl)pyrimidin-2-yl]carbamate (14) Tri-n-
butyl(1-ethoxyvinyl)tin (387 ml, 1.15 mmol) was added to a suspension of
compound 13 (0.263 g, 1.15 mmol) and LiCl (0.146 g, 3.44 mmol) in dry
THF (2.6 ml) under nitrogen at room temperature. After adding
tetrakis(triphenylphosphine)palladium (0.039 g, 0.034 mmol) the solution
was heated under reflux for 3.5 h. The cold reaction mixture was diluted
with THF, treated with an aqueous 0.16 M potassium fluoride solution
(10 ml) and stirred at ambient temperature for 1 h. The precipitated tri-n-
butylstannyl fluoride was removed by filtration. The filtrate was evaporated
under reduced pressure to give an aqueous suspension which was extracted
with ethyl acetate. The organic layer was washed with water, evaporated in
vacuo and the residual material was flash chromatographed on reversed
phase silica using a H2O–MeOH (100 : 0—30 : 70) gradient to yield 0.274 g
of 14 (1.03 mmol) (91%). Compound 14 had mp: 133—137 °C
(MeOH–H2O); IR (film) cmϪ1: 3186.4, 2977.7, 1752.3, 1600, 1556.3,
1366.8, 1243.1, 768.7; UV lmax (methanol) nm (e): 202 (10430), 228
(15940), 294 (5590); 1H-NMR (CDCl3) d: 8.61 (d, 1H, Jϭ5.1 Hz), 7.38
(br s, 1H), 7.27 (d, 1H, Jϭ5.1 Hz), 5.58 (d, 1H, Jϭ2.2 Hz), 4.46 (d, 1H,
Jϭ2.2 Hz), 3.94 (q, 2H, Jϭ6.8 Hz), 1.54 (s, 9H), 1.42 (t, 3H, Jϭ6.8 Hz);
13C-NMR (CDCl3) d: 161.7 (s), 159.3 (d), 157.1 (s), 156.5 (s), 150.5 (s),
110.5 (d), 88.1 (t), 81.3 (s), 63.7 (t), 28.2 (q), 14.3 (q); MS m/z: 250
(MϩϪ15), 221, 194, 192, 165, 150, 121. HR-MS (EI): Found: 250.1185
(MϩϪ15). Calcd for C12H16N3O3: 250.1192.
ZnCl2 (74% w/w)
Montmorillonite Microwave
K-10 irradiation using
alumina bath
18
17
ZnCl2 (74% w/w)
ZnCl2
Montmorillonite Oven (180 °C)
K-10
120
9
18
Solvent free
Microwave
irradiation
Oven (180 °C)
Reflux
Ͻ5
ZnCl2
ZnCl2
ZnCl2
Solvent free
MeOH
50 Ͻ5
60 NR
DMF
Reflux under inert 1140
atmosphere
9
ZnCl2
Toluene
MeOH
DMF
Reflux under inert 360 NR
atmosphere
p-Toluenesulfonic
acid
ZnCl2
Reflux
120 NR
Microwave
irradiation
Microwave
irradiation
9
9
75
Formic acid 98%
NR
All experiments using microwave irradiation were performed on an Amana domestic
microwave oven and heated at full power (aproximately 1500 W).
tives with 2-substitution was not pursued. However, this syn-
thetic route remains a viable scheme for the preparation of
meridianins and analogs.
Experimental
General Anhydrous ZnCl2 was used in all cases. ZnCl2 was melted in a
porcelain crucible, then ground in a mortar and kept in a dissicator till used.
Melting points were determined with a Thomas Hoover melting point appa-
ratus and are uncorrected. UV and IR spectra were recorded on a Hewlett
Packard Model 8451 A diode array spectrophotometer and a Nicolet Magna-
IRtm Model 550 spectrometer, respectively. NMR spectra (d ppm, J in Hz)
were obtained on a Bruker AM-500 Spectrometer at 500.13 MHz (1H) and
125.77 MHz (13C). HR-EI-MS were performed with a VG-ZAB-SEQ4F in-
strument at 70 eV.
tert-Butyl (4-Acetylpyrimidin-2-yl)carbamate (15) A mixture of com-
pound 14 (6 mg, 0.022 mmol) and p-toluenesulfonic acid (0.5 mg,
2.9ϫ10Ϫ3 mmol) in acetone (0.5 ml) was heated under reflux for 75 min.
Evaporation under reduced pressure gave a white solid which was purified
using flash chromatography on silica gel (dichloromethane/acetoneϭ
100 : 0—95 : 5), to yield 4.7 mg (88%) of 15. Compound 15 had mp 136—
137 °C (MeOH–H2O); IR (film) cmϪ1: 3218.9, 2985.7, 1753, 1713, 1573.1,
1426.5, 1236.5, 769.4; UV lmax (methanol) nm (e): 204 (18420), 233
tert-Butyl (4-Hydroxypyrimidin-2-yl)carbamate (12) 4-Hydroxy-
pyrimidin-2-amine (11) (1 g, 9 mmol) was dissolved in pyridine (42 ml) and
heated at 65 °C on a water bath with magnetic stirring. After adding di-tert-
butyl dicabonate (2.94 g, 13.5 mmol) the solution was heated at 85 °C for
4 h. The solution was cooled on an ice bath and concentrated hydrochloric
acid (20 ml) was added; finally the reaction mixture was extracted with ethyl
acetate. The organic layer was washed with sodium bicarbonate and water.
Evaporation under reduce pressure gave 1.21 g (5.7 mmol) (63%) of a white
1
(16330), 300 (2600); H-NMR (CDCl3) d: 8.81 (d, 1H, Jϭ5 Hz), 7.58 (br s,
1H), 7.50 (d, 1H, Jϭ5 Hz), 2.66 (s, 3H), 1.56 (s, 9H); 13C-NMR (CDCl3) d:
198.9 (s), 160.4 (d), 159.9 (s), 157.8 (s), 150.1 (s), 111.4 (d), 81.8 (s), 28.1
(q), 25.3 (q); MS m/z: 237 (Mϩ), 193, 181, 164, 137, 121.
solid (12). Compound 12: mp: 139—142 °C (H2O–MeOH); IR (film) cmϪ1
:
3428, 3251, 1701, 1281, 796; UV lmax (methanol) nm (e): 212 (15760), 285
General Procedure for the Preparation of Phenylhydrazones 16 and
17 To a mixture of compound 15 (0.28 g, 1.029 mmol) and sodium acetate
1
(5550); H-NMR (CDCl3) d: 11.76 (2H, br s, interchangeable), 7.74 (1H, d,

August 2003
977
123.2 (d), 114.3 (d), 112.3 (s), 105.8 (d), 102.6 (d); MS m/z: 290, 288 (Mϩ),
249, 247, 208, 168, 140; HR-MS (EI): Found: 288.0002. Calcd for
C12H10N4: 288.0011.
(0.218 g, 2.67 mmol), was added 1.029 mmol of the appropriate phenylhy-
drazine hydrochloride in methanol (19.5 ml) and the reaction mixture was
stirred at room temperature for 1 h. Evaporation in vacuo gave a yellow solid
which was suspended in dichloromethane and the inorganic salts were re-
moved by filtration. The filtrate was evaporated to dryness to give 16 and 17
in 90% yield. These products were used without further purification.
Acknowledgements We are indebted to LANAIS-RMN 500 for NMR
spectra, LANAIS-EMAR (CONICET-FCEN-UBA) for mass spectra and
UMYMFOR (CONICET-FCEN-UBA) for spectroscopic determinations.
HR-MS were provided by the Washington University Mass Spectrometry
Resource, an NIH Research Resource (Grant N° P41RR0954). LHF ac-
knowledges CONICET for a doctoral fellowship. This research was partially
supported by grants from Universidad de Buenos Aires (grants EX064/J,
JX15 and X122), CONICET and Fundación Antorchas.
Iso-Meridianin G (18) A mixture of tert-butyl 4-((1E and Z)-N-
phenylethanehidrazonoyl)pyrimidin-2-ylcarbamate (16) (0.041 g, 0.125
mmol) and ZnCl2 (0.182 g, 1.325 mmol) was taken in a glass tube and sus-
pended in small amount of DMF (0.6 ml). The test tube was placed inside an
Amana domestic microwave oven and heated at full power (approximately
1500 W) for 9 min. Evaporation under reduce pressure gave a black syrup
which was purified using flash chromatography on reversed phase silica
using a H2O–MeOH (100 : 0—30 : 70) gradient to yield 0.0195 g (75%) of
References and Notes
18. Compound 18 had mp 163—164 °C (MeOH–H2O); IR (film) cmϪ1
:
1) Dedicated to the memory of Dr. Alicia M. Seldes, founder and leader
of the research group on Marine Natural Products at the Department
of Organic Chemistry, FCEN-UBA.
3463, 2927, 1627, 1592, 813.9, 733.9; UV lmax (methanol) nm (e): 218
1
(28330), 342 (26810); H-NMR (CD3OD) d: 8.17 (d, 1H, Jϭ5.5 Hz), 7.58
(br d, 1H, Jϭ7.9 Hz), 7.44 (dd, 1H, Jϭ8.2, 0.9 Hz), 7.19 (ddd, 1H, Jϭ8.2,
7.0, 0.9 Hz), 7.18 (br s, 1H), 7.12 (d, 1H, Jϭ5.5 Hz), 7.03 (ddd, 1H, Jϭ7.9,
7.0, 0.9 Hz); 13C-NMR (CD3OD) d: ppm: 164.6 (s), 160.6 (s), 158.2 (d),
139.0 (s), 136.0 (s), 129.9 (s), 124.9 (d), 122.4 (d), 121.1 (d), 112.8 (d),
107.0 (d), 105.2 (d); MS m/z: 210 (Mϩ), 169, 115; HR-MS (EI): Found:
210.0971. Calcd for C12H10N4: 210.0905. Anal. Calcd for C12H10N4: C,
68.56; H, 4.79; N, 26.65; Found: C, 68.43; H, 4.80; N, 26.37.
Iso-Meridianin C (19) A mixture of tert-butyl 4-((1E and Z)-N-(4 bro-
mophenyl)phenylethanehidrazonoyl)pyrimidin-2-ylcarbamate (17) (0.0036
g, 8.8ϫ10Ϫ3 mmol) and ZnCl2 (0.0118 g, 0.085 mmol) was taken in a glass
tube and suspended in small amount of DMF (170 ml). The test tube was
placed inside an Amana domestic microwave oven and heated at full power
(approximately 1500 W) for 25 min. Evaporation under reduce pressure gave
a black syrup which was dissolved in ethyl acetate and extracted with water.
The organic layer was evaporated in vacuo and was purified using prepara-
tive thin layer silica gel chromatography (dichloromethane : acetone 6 : 4) to
yield 0.0014 g (55%) of 19. Compound 19 had mp: 190—192 °C
(MeOH–H2O); IR (film) cmϪ1: 3408, 3308, 2930.7, 2859.4, 1622.3, 1585.4,
792.1; UV lmax (methanol) nm (e): 221 (16800), 341 (12640), 354 (11920);
1H-NMR (DMSO-d6) d: 11.7 (br s, 1H), 8.30 (d, 1H, Jϭ5.4 Hz), 7.80 (d, 1H,
Jϭ1.8 Hz), 7.44 (d, 1H, Jϭ8.8 Hz), 7.27 (dd, 1H, Jϭ8.8, 1.8 Hz), 7.18 (br d,
1H, Jϭ1 Hz), 7.13 (d, 1H, Jϭ5.4 Hz), 6.55 (br s, 2H); 13C-NMR (DMSO-d6)
d: 163.7 (s), 158.9 (d), 157.2 (s), 137.1 (s), 136.0 (s), 129.8 (s), 125.7 (d),
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