Synthesis of indolylpyrimidines via cross-coupling of indolylboronic acid with chloropyrimidines facile synthesis of meridianin D

Article abstract of DOI:10.3987/COM-00-8890

Palladium catalyzed cross-coupling reaction of 3-indolylboronic acid with 2,4-dichloropyrimidines proceeded regioselectively to yield indolyl-or bis(indolyl)pyrimidines in high yield, depending on the projection of 3indolylboronic acid. The marine indole alkaloid meridianin D and an analogue were synthesised via the palladium catalyzed cross-coupling reaction as a key step.

Full text of DOI:10.3987/COM-00-8890

HETEROCYCLES, Vol.53, No.7, 2000, p.1489 - 1498, Received, 2nd March, 2000
SYNTHESIS OF INDOLYLPYRIMIDINES VIA CROSS-COUPLING
OF INDOLYLBORONIC ACID WITH CHLOROPYRIMIDINES:
FACILE SYNTHESIS OF MERIDIANIN D
Biao Jiang* and Cai-guang Yang
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
Abstract - Palladium catalyzed cross-coupling reaction of 3-indolylboronic
acid with 2,4-dichloropyrimidines proceeded regioselectively to yield indolyl-
or bis(indolyl)pyrimidines in high yield, depending on the projection of 3-
indolylboronic acid. The marine indole alkaloid meridianin D and an analogue
were synthesised via the palladium catalyzed cross-coupling reaction as a key
step.
Marine invertebrates are a very important source of antitumor secondary metabolites. Numerous
biologically active indole alkaloids have been isolated from the marine environment over the past few
years.1-4 Interest in methodology for preparation of marine indole alkaloids has been stimulated both by
their novel molecular structures and by their wide range of biological properties. The palladium catalyzed
cross-coupling reaction of aryl bromides, aryl iodides, and triflates with arylboronic acids has emerged as
an extremely powerful method employed for the formation of C-C bonds.5 Recently, nortopsentins A-D,
antifungal marine 1,4-bis(indolyl)imidazole alkaloids, were synthesised through palladium catalyzed
cross-coupling of halogenoimidazoles with 3-indolylboronic and 6-bromo-3-indolylboronic acids.6 It was
noted that the synthesis of bis(indolyl)pyrazine was achieved in low yield (10-15%) by palladium
catalyzed reaction of dichloropyrazine with substituted indole.7 To the best of our knowledge there are
few reports about cross-coupling reactions between indole derivatives and halogenopyrimidines. In this
paper we report an efficient synthesis of indolylpyrimidines and bis(indolyl)pyrimidines via cross-
coupling reaction of 3-indolylboronic acid with 2,4-dichloropyrimidines and its application to the
synthesis of meridianin D.
Phenylboronic acid (4) was initially chosen to examine its cross-coupling with 2,4-dichloropyrimidine
catalyzed by tetrakis(triphenylphosphine)palladium (Scheme 1). The results are summarized in Table 1.

R
N
R
N
N
Cl
Ph
N
Cl
N
Ts
R
2 a-b
6 a-b
Pd(PPh3)4
Pd(PPh3)4
N
Cl
N
Cl
PhB(OH)2(4)
R
InB(OH)2 (5)
R
N
N
N
1 a R = H
N
Ph
Ph
1 b R = OMe
N
N
Ts
Ts
3 a-b
7 a-b
B(OH)2
B(OH)2
PhB(OH)2
=
InB(OH)2
=
N
Ts
4
5
Scheme 1
Table 1. Palladium Catalyzed Cross-Coupling of Phenyl and Indolyl Boronic Acids
with Dichloropyrimidinesa
entry
boronic acid (eq)
R in 1
time (h)
product
2a
yield (%)b
80
10
86
9
1
2
PhB(OH)2 (1 eq)
H
4
3a
2b
PhB(OH)2 (1 eq)
OCH3
4
3b
3
4
5
6
7
8
PhB(OH)2 (2 eq)
PhB(OH)2 (2 eq)
InB(OH)2 (1 eq)
InB(OH)2 (1 eq)
InB(OH)2 (2 eq)
InB(OH)2 (2 eq)
H
OCH3
H
6
6
4
6
5
8
3a
90
92
91
90
82
81
3b
6a
OCH3
H
6b
7a
OCH3
7b
a All reactions were carried out with 0.1 molar eq. of tetrakis(triphenylphosphine)palladium and 1 eq.
molar of 2M Na2CO3 in benzene-methanol under reflux; b Isolated yields.

Thus, 2,4-dichloropyrimidine (1a) was refluxed with two equivalents of phenylboronic acid (4) in a
mixture of benzene and methanol for 6 h in the presence of palladium catalyst and aqueous sodium
carbonate to give the corresponding 2,4-diphenylpyrimidine (3a) in good yield (entry 3). The carbon-
chlorine bond at the 4-position in pyrimidine (1) was more reactive than that at the 2-position, and
treatment of dichloropyrimidine (1a) with one equivalent of phenylboronic acid (4) gave 2-chloro-4-
phenylpyrimidine (2a) and 2,4-diphenylpyrimidine (3a) in a ratio of 8:1 in 90% yield (entry 1). Reaction
of 2-chloro-4-phenylpyrimidine (2a) with additional equivalent of phenylboronic acid (4) furnished 2,4-
diphenylpyrimidine (3a) in 92% yield. 5-Methoxy-2,4-dichloropyrimidine (1b) with one or two
equivalents of phenylboronic acid (4) gave phenyl or diphenylpyrimidine (2b or 3b) respectively in high
yields (entries 2 and 4).
With the above results in mind, we further examined the reaction of 2,4-dichloropyrimidines (1a-b) with
N-tosyl-3-indolylboronic acid (5) under the same condition (Scheme 1, Table 1). When 2,4-
dichloropyrimidines (1a-b) were treated with one equivalent of N-tosyl-3-indolylboronic acid (5), the
reaction proceeded exclusively at the 4-position of the pyrimidine to afford 2-chloro-4-indolylpyrimidines
(6a-b) (entries 5 and 6). While it was reacted with two equivalents of N-tosyl-3-indolylboronic acid (5)
the 2,4-bis(indolyl)pyrimidines (7a-b) were obtained in high yields (entries 7 and 8).
With the view to extend the synthetic utility of cross-coupling reaction of the chloropyrimidines with 3-
indolylboronic acid, we contemplated its incorporation into a reaction aimed at the synthesis of the indole
alkaloid. Five novel indole alkaloids, meridianin A-E, have been isolated from the tunicate Aplidium
meridianum recently.8 All of these compounds have a brominated and/or hydroxylated indole ring linking
a 2-aminopyrimidine at 3-position of indole and showed cytotoxicity toward murine tumer cell lines.
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
R1
N
R2
R3
N
NH2
N
H
R4
Meridianin D was chosen as a representative of meridianin family to be synthesised. Retrosynthetically, a
strategy for the synthesis of meridianin D would be palladium catalyzed cross-coupling reaction between
2-amino-4-halogenopyrimidine and 3-indolylboronic acid. Thus, 2-amino-4-chloropyrimidine (9) was
prepared simply by amination of 2,4-dichloropyrimidine (1a) in ethanolic ammonia at room temperature
along with its isomer 2-chloro-4-aminopyrimidine (8) in a ratio of 1:1, which could be separated by
recrystallization.9 Examining the palladium catalyzed cross-coupling reaction of both 8 and 9, it was
found that the reaction of 4-amino-2-chloropyrimidine (8) with N-tosyl-3-indolylboronic acid (5) was
sluggishly and completed after prolonged heating for 10 h in 60% yield, while 2-amino-4-

chloropyrimidine (9) proceeded smoothly within 5 h to offer 2-amino-4-(N-tosyl-3′-indolyl)pyrimidine
(11) in 79% yield (Scheme 2). Deprotection of N-tosyl group in 11 with sodium hydroxide in methanol
afforded 6-debromomeridianin D (12) in 80% yield, an analogue of meridianin.
N
N
Pd(PPh3)4
InB(OH) (5)
/
2
N
NH2
60%
NH2
N
Cl
N
Ts
8
10
NH3/EtOH
N
Cl
N
Cl
N
N
Pd(PPh3)4
/
InB(OH) (5)
1a
N
NH2
2
Cl
N
NH2
79%
N
R
9
11 R=Ts
12 R=H
NaOH/MeOH
80%
6-debromomeridianin D
Scheme 2
Finally meridianin D was synthesised from 3-bromoindole as following steps. N-Tosyl-3-bromoindole
(13) was converted to N-tosyl-3,6-dibromoindole (14), which was treated with tert-butyllithium in
tetrahydrofuran at -78 oC followed by addition of trimethoxyborane and aqueous work-up to give N-tosyl-
6-bromo-3-indolylboronic acid (15).10 The crude N-tosyl-6-bromo-3-indolylboronic acid (15) was reacted
with one equivalent of 2-amino-4-chloropyrimidine (9) under the above-mentioned condition to afford N-
tosylmeridianin D (16) in 53% yield. A trace amount of the homo-coupling product of 15 between C-
B(OH)2 and C-Br was also observed by GC-MS in this process. Removal of the N-tosyl group with
sodium hydroxide yielded meridianin D in 76% yield (Scheme 3). 1H NMR and 13C NMR chemical shifts
of synthetic meridianin D correspond to those reported for meridianin D isolated from nature (Table 2).
In summary, indolyl- and bis(indolyl)pyrimidines were synthesised efficiently by the Suzuki type cross-
coupling reaction of 3-indolylboronic acid with 2,4-dichloropyrimidines in high yield. The coupling
reaction between 2-amino-4-chloropyrimidine and 3-indolylboronic acid offered a practical method for
the synthesis of meridianins and their analogues.

Br
t-BuLi/B(OMe)3
1.
2.
B(OH)2
Br2
H3O+
Br
N
96%
Br
N
Br
N
Ts
Ts
60%
Ts
15
13
14
N
Pd(PPh3)4
53%
Cl
N
9
NH2
1'
5'
N
N
4
NaOH
/ MeOH
9
5
N
3'
NH2
N
NH2
2
76%
Br
N
Br
N
8
H
Ts
Meridianin D
16
Scheme 3
Table 2. 1H NMR and 13C NMR Data (DSMO-d6) for Synthetic and Natural Meridianin D
Position of
1H NMR
synthetic
11.81 (br s)
Position of
13C NMR
proton
natural
carbon
synthetic
natural
129.2
114.8
124.3
123.1
1-NH
11.76 (br s)
2
3
4
5
129.1
114.7
124.2
123.0
2
4
5
8.24 (d, J = 2.4 Hz) 8.21 (d, J = 2.6 Hz)
8.58 (d, J = 8.6 Hz) 8.55 (d, 8.4)
7.25 (dd, J = 8.6 and 7.24 (dd, J = 8.4 and
1.5 Hz)
7.64 (d, J = 1.5 Hz) 7.63 (d, J = 1.8 Hz)
6.49 (s, 2H) 6.43 (s, 2H)
1.8 Hz)
7
2′-NH2
5′
6
7
8
9
113.8
114.4
137.9
124.4
113.9
114.5
138.0
124.5
7.02 (d, J = 5.3 Hz) 7.00 (d, J = 5.1 Hz)
8.13 (d, J = 5.3 Hz) 8.12 (d, J = 5.1 Hz)
6′
163.5
162.2
105.3
157.2
163.6
162.3
105.4
157.2
2′
4′
5′
6′

EXPERIMENTAL
All melting points were measured with a WRS-1A digital melting point apparatus, without correction. IR
1
spectra were determined with a Shimadzu IR-440 spectrometer. H NMR and 13C NMR spectra were
recorded on a Bruker AM-300 instrument. The chemical photo shifts are expressed in ppm and coupling
constants are given in Hz. Low-resolution MS spectra were obtained on a VG-Quattro or HP-5969A
spectrometer and high-resolution MS spectra were recorded on a Finnigan MAT-95 spectrometer.
Elemental analyses were carried out on a Heraeus Rapid-CHNO instrument. Column chromatography
was performed on silica gel H (10-40 µm). Reagents purchased commercially were used without further
purification. Solvents were dried using standard procedures.
General procedure for palladium catalyzed cross-coupling reaction of 2,4-dichloropyrimidines (1a-
b) with phenylboronic acid (4) or N-tosyl-3-indolylboronic acid (5):
A mixture of phenylboronic acid (4) or N-tosyl-3-indolylboronic acid (5) (1 or 2 mmol), 2,4-
dichloropyrimidines (1a-b) (1 mmol), benzene (20 mL), methanol (4 mL), aqueous sodium carbonate (1
or 2 mL, 2 M) and tetrakis(triphenylphosphine)palladium (0.1 or 0.2 mmol) was refluxed under an argon
atmosphere. The reaction was monitored with TLC. When the reaction completed, anhydrous sodium
sulfate was added. The mixture was filtered and the filtrate was evaporated under reduced pressure. The
residue was subjected to flash column chromatography (eluted with ethyl acetate/hexane) to give cross-
coupling products.
o
o
2-Chloro-4-phenylpyrimidine (2a): mp 86.9-88.7 C (CH2Cl2/Hexane) (lit.,11 89 C); IR (KBr) νmax
1
3064, 2927, 1570, 1532, 1450, 1348, 1287, 1180 cm -1; H NMR (CDCl3) δ 7.54 (m, 3H), 7.66 (dd, J =
13
5.2 and 1.3 Hz, 1H), 8.08 - 8.12 (m, 2H), 8.64 (d, J = 5.2 Hz, 1H); C NMR (CDCl3) δ 115.1, 127.4,
129.1, 131.8, 135.0, 159.7, 161.8, 167.1; EIMS m/z (%) 190 (M+, 100), 155 (52), 129 (83), 77 (29), 51
(25).
2-Chloro-5-methoxy-4-phenylpyrimidine (2b): mp 61.8-62.7 oC (CH2Cl2/Hexane); IR (KBr) νmax 3062,
1565, 1531, 1429, 1359, 1295, 1209, 1163, 1060, 1009 cm -1; 1H NMR (CDCl3) δ 3.98 (s, 3H), 7.45-7.52
13
(m, 3H), 8.08-8.31 (m, 2H), 8.30 (s, 1H); C NMR (CDCl3) δ 56.6, 128.2, 129.6, 130.7, 133.9, 142.9,
150.4, 152.2, 156.6; EIMS m/z (%) 220 (M+, 72), 219 (100), 155 (18), 102 (41), 89 (40); Anal. Calcd for
C11H9N2OCl: C, 59.88; H, 4.11; N, 12.69. Found: C, 60.17; H, 4.10; N, 12.49.
o
o
2,4-Diphenylpyrimidine (3a): mp 62-63.7 C (CH2Cl2/Hexane) (lit.,12 69-70 C); IR (KBr) νmax 1586,
1
1562, 1546, 1425, 1382, 1282, 1024 cm -1; H NMR (CDCl3) δ 7.50 - 7.56 (m, 6H), 7.60 (d, J = 5.3 Hz,
1H), 8.22 - 8.25 (m, 2H), 8.58 - 8.62 (m, 2H), 8.84 (d, J = 5.3 Hz, 1H); 13C NMR (CDCl3) δ 114.5, 127.4,
128.5, 128.7, 129.0, 131.2, 131.4, 136.4, 136.6, 156.5, 163.7, 164.8; EIMS m/z (%) 232 (M+, 100), 231
(17), 129 (34), 103 (51), 77 (21).

o
5-Methoxy-2,4-diphenylpyrimidine (3b): mp 74.4-75.8 C (CH2Cl2/Hexane); IR (KBr) νmax 3059,
1
1561, 1540, 1452, 1429, 1380, 1288, 1233, 1014 cm -1; H NMR (CDCl3) δ 3.99 (s, 3H), 7.44 - 7.54 (m,
13
6H), 8.22 - 8.25 (m, 2H), 8.46 - 8.49 (m, 2H), 8.51 (s, 1H); C NMR (CDCl3) δ 56.4, 127.8, 128.2,
128.6, 129.9, 130.2, 130.4, 135.4, 136.7, 139.8, 150.0, 154.3, 156.6; EIMS m/z (%) 262 (M+, 76), 144
(13), 116 (64), 103 (42), 89 (100), 77 (29); Anal. Calcd for C17H14N2O: C, 77.84; H, 5.38; N, 10.68.
Found: C, 77.72; H, 5.40; N, 10.55.
2-Chloro-4-(N-tosyl-3′-indolyl)pyrimidine (6a): mp 171.8-173.2 oC (CH2Cl2/Hexane); IR (KBr) νmax
1
3113, 1574, 1525, 1444, 1385, 1335, 1288, 1199, 1173, 1138, 1091 cm -1; H NMR (CDCl3) δ 2.34 (s,
3H), 7.24 - 7.27 (m, 2H), 7.35 - 7.44 (m, 2H), 7.57 (d, J = 5.3 Hz, 1H), 7.83 (d, J = 8.4 Hz, 2H), 8.00 -
8.03 (m, 1H), 8.33 (s, 1H), 8.36 - 8.40 (m, 1H), 8.58 (d, J = 5.3 Hz, 1H); 13C NMR (CDCl3) δ 21.6, 113.5,
115.4, 118.6, 122.4, 124.6, 125.7, 127.1, 127.3, 128.6, 130.2, 134.5, 135.5, 145.8, 158.8, 161.4, 163.1;
EIMS m/z (%) 383 (M+, 30), 228 (25), 201 (12), 155 (45), 91 (100), 65 (29); Anal. Calcd for
C19H14N3O2ClS: C, 59.45; H, 3.68; N, 10.95. Found: C, 59.66; H, 3.69; N, 10.79.
2-Chloro-5-methoxy-4-(N-tosyl-3′-indolyl)pyrimidine (6b): mp 239.6-241.7 oC (CH2Cl2/Hexane); IR
1
(KBr) νmax 3178, 1598, 1560, 1550, 1475, 1446, 1421, 1379, 1355, 1267, 1176, 1136 cm –1; H NMR
(CDCl3) δ 2.34 (s, 3H), 4.13 (s, 3H), 7.22 - 7.26 (m, 2H), 7.35 - 7.65 (m, 2H), 7.81 (d, J = 8.4 Hz, 2H),
7.96 - 8.00 (m, 1H), 8.27 (s, 1H), 8.62 (s, 1H), 8.72 - 8.76 (m, 1H); 13C NMR (CDCl3) δ 21.6, 56.7, 113.0,
115.1, 123.9, 124.4, 125.5, 127.0, 128.5, 130.0, 132.1, 134.5, 134.7, 140.4, 145.6, 149.5, 151.4, 152.3;
EIMS m/z (%) 413 (M+, 100), 258 (99), 155 (23), 102 (24), 91 (67), 65 (24); HRMS Calcd for
C20H16N3O3ClS: 413.0578. Found: 413.0589; Anal. Calcd for C20H16N3O3ClS: C, 58.04; H, 3.87; N,
10.16. Found: C, 58.34; H, 4.06; N, 9.91.
o
2,4-Bis(N-tosyl-3′-indolyl)pyrimidine (7a): mp 132.8-134.7 C (CH2Cl2/Hexane); IR (KBr) νmax 3055,
1
1733, 1556, 1444, 1373, 1306, 1250, 1174, 1090 cm –1; H NMR (CDCl3) δ 2.32 (s, 3H), 2.34 (s, 3H),
7.21 - 7.27 (m, 4H), 7.35 - 7.44 (m, 4H), 7.50 (d, J = 5.3 Hz, 1H), 7.86 (d, J = 8.4 Hz, 4H), 8.05 (m, 2H),
8.32 (s, 1H), 8.47 (m, 1H), 8.63 (s, 1H), 8.70 (m, 1H), 8.78 (d, J = 5.3 Hz, 1H); 13C NMR (DMSO-d6) δ
21.0, 113.2, 113.3, 115.8, 119.5, 121.2, 122.3, 122.8, 124.0, 124.3, 125.3, 125.5, 127.0, 127.4, 127.7,
128.4, 129.1, 130.4, 133.6, 134.8, 146.0, 157.6, 159.6, 161.1; EIMS m/z (%) 618 (M+, 100), 463 (45), 308
(82), 262 (54), 183 (38), 91 (80); HRMS Calcd for C34H26N4O4S2: 618.1361. Found: 618.1378.
5-Methoxy-2,4-bis(N-tosyl-3′-indolyl)pyrimidine (7b): mp 178.6-180.3 oC (CH2Cl2/Hexane); IR (KBr)
1
νmax 2926, 1725, 1558, 1452, 1373, 1280, 1175, 1129, 1090, 964, 669, 574 cm –1; H NMR (CDCl3) δ
2.31 (s, 3H), 2.34 (s, 3H), 4.15 (s, 3H), 7.19 - 7.44 (m, 8H), 7.85 (dd, J = 8.4 and 2.4 Hz, 4H), 8.05 (d, J =
9.5 Hz, 2H), 8.46 (s, 1H), 8.51 (s, 1H), 8.61 (s, 1H), 8.63 (m, 1H), 8.81 (m, 1H); 13C NMR (DMSO-d6) δ
21.0, 56.7, 113.2, 115.6, 121.2, 122.6, 123.0, 123.9, 124.0, 125.2, 125.5, 126.8, 126.9, 127.7, 128.3,

130.4, 133.6, 133.7, 134.8, 140.7, 145.8, 146.0, 147.8, 148.5, 153.2; EIMS m/z (%) 648 (M+, 100), 493
(91), 338 (42), 155 (15), 127 (25), 91 (66); HRMS Calcd for C35H28N4O5S2: 648.1515. Found: 648.1508.
N-Tosyl-3,6-dibromoindole (14): A solution of N-tosyl-6-bromoindole (13) (2.07 g, 6 mmol) in CCl4
(25 mL) was slowly added dropwise to a solution of bromine (0.36 mL, 7 mmol) in CCl4 (10 mL) with
vigorous stirring for 20 min. The mixture was stirred for 4 h at rt, then CH2Cl2 (100 mL) was added to the
mixture. It was poured into saturated NaHCO3 (30 mL). Water was separated and the organic layer was
washed with a solution of 10% Na2S2O3 and brine successively, then dried with anhydrous sodium sulfate
overnight. The solvent was removed under vacuum and the crude product was purified with column
chromatography to give a white solid 14 (2.46g, 96%). mp 133.2-135.5 oC (CH2Cl2/Hexane); IR (KBr)
ν
max 1597, 1418, 1381, 1268, 1174, 1128, 1088, 1032 cm-1; 1H NMR (CDCl3) δ 2.36 (s, 3H), 7.26 (s, 2H),
7.34 (d, J = 8.5 Hz, 1H), 7.42 (dd, J = 8.4 and 1.6 Hz, 1H), 7.57 (s, 1H), 7.77 (d, J = 8.4 Hz, 2H), 8.18 (d,
13
J = 1.6 Hz, 1H); C NMR (CDCl3) δ 21.6, 99.2, 116.6, 119.6, 121.2, 125.2, 126.9, 127.3, 128.6, 130.2,
134.6, 134.8, 145.7; EIMS m/z (%) 427/431 (M+, 29/31), 429 (61), 272/276 (28/26), 274 (57), 193/195
(6/6), 155 (86), 114 (30).
N-Tosyl-6-bromo-3-indolylboronic acid (15): A solution of tert-BuLi in n-pentane (1.5 M, 1.5 mL, 2.25
mmol) was added dropwise to a solution of N-tosyl-3,6-dibromoindole (14) (0.86 g, 2 mmol) in THF (15
o
o
mL) under an argon atmosphere at -78 C. The mixture was stirred at -78 C for 40 min, then
trimethoxyborane (1.1 mL, 9 mmol) was added dropwise at -78 oC. The reaction was remained at -78 oC
for 2 h. After methanol (2 mL) and water (2 mL) were added, the mixture was stirred for 3 h at rt and
extracted with ether. The organic layer was washed with water and dried over anhydrous sodium sulfate
overnight and evaporated to give a solid residue 15, which was used for the next reaction without further
purification.
General procedure for amino-(N-tosyl-3′-indolyl)pyrimidine:
A mixture of N-tosyl-3-indolylboronic acid (5) (0.5 mmol), amino-chloropyrimidine (8 or 9) (0.5 mmol),
benzene (10 mL), methanol (2 mL), aqueous sodium carbonate (0.5 mL, 2 M) and
tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) was refluxed under an argon atmosphere.
After the reaction was completed, anhydrous sodium sulfate was added. The mixture was filtered and the
filtrate was evaporated under reduced pressure. The residue was subjected to flash column
chromatography (eluted with ethyl acetate/hexane) to give cross-coupling products.
o
4-Amino-2-(N-tosyl-3′-indolyl)pyrimidine (10): mp 138.9-141.3 C (CH2Cl2/Hexane); IR (KBr) νmax
1
3472, 3389, 1622, 1587, 1556, 1465, 1419, 1370, 1255, 1240, 1172, 1132 cm-1; H NMR (DMSO-d6) δ
2.31 (s, 3H), 6.36 (d, J = 5.8 Hz, 1H), 6.95 (br s, 2H), 7.32 - 7.43 (m, 4H), 7.91 - 7.98 (m, 3H), 8.18 (d, J
= 5.8 Hz, 1H), 8.32 (s, 1H), 8.67 (dd, J = 7.9 and 1.0 Hz, 1H); 13C NMR (DMSO-d6) δ 21.0, 103.0, 112.9,
121.7, 123.6, 124.9, 126.8, 127.5, 128.0, 130.3, 133.7, 134.7, 145.7, 155.0, 160.6, 163.2; EIMS m/z (%)

364 (M+, 68), 210 (19), 209 (100), 182 (17), 155 (6), 91 (10); HRMS Calcd for C19H16N4O2S: 364.1002.
Found: 364.0998.
o
2-Amino-4-(N-tosyl-3′-indolyl)pyrimidine (11): mp 222.4-222.8 C (CH2Cl2/Hexane); IR (KBr) νmax
3341, 3202, 1656, 1570, 1548, 1462, 1366, 1283, 1219, 1187, 1174 cm-1; 1H NMR (DMSO-d6) δ 2.31 (s,
3H), 6.68 (br s, 2H), 7.25 (dd, J = 5.2 and 0.9 Hz, 1H), 7.33 - 7.46 (m, 4H), 7.95 - 8.01 (m, 3H), 8.28 (dd,
J = 5.2 and 1.2 Hz, 1H), 8.63 (s, 1H), 8.66 (d, J = 8.4 Hz, 1H); 13C NMR (DMSO-d6) δ 21.0, 106.5, 112.9,
120.0, 123.4, 123.8, 125.2, 126.8, 127.8, 130.3, 133.7, 134.7, 145.8, 158.0, 160.0, 163.3; EIMS m/z (%)
364 (M+, 89), 210 (20), 209 (100), 182 (23), 155 (13), 91 (21), 65 (7); HRMS Calcd for C19H16N4O2S:
364.0972. Found: 364.0983.
2-Amino-4-(N-tosyl-6′-bromo-3′-indolyl)pyrimidine (16): mp 194.4 - 194.9 oC (CH2Cl2/Hexane); IR
1
(KBr) νmax 3489, 3294, 3149, 1744, 1632, 1580, 1467, 1371, 1169, 1149 cm -1; H NMR (DMSO-d6) δ
2.34 (s, 3H), 6.73 (br s, 2H), 7.26 (d, J = 5.2 Hz, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.51 (dd, J = 8.6 and 1.8
Hz, 1H), 8.00 (d, J = 8.4 Hz, 2H), 8.11 (d, J = 1.4 Hz, 1H), 8.27 (d, J = 5.2 Hz, 1H), 8.66 (d, J = 8.6 Hz,
13
1H), 8.72 (s, 1H); C NMR (DMSO-d6) δ 21.0, 106.4, 115.4, 118.0, 119.8, 125.3, 126.9, 128.5, 130.4,
133.5, 135.3, 146.1, 158.2, 159.6, 163.3; EIMS m/z (%) 442 (M+, 59.91), 289 (95.62), 287 (100), 260
(16), 208 (63), 155 (22), 91 (84), 65 (39); HRMS Calcd for C19H15N4O2BrS: 442.0129. Found: 442.0114.
Meridianin D:
2-Amino-4-(N-tosyl-6′-bromo-3′-indolyl)pyrimidine (16) (100 mg, 0.23 mmol) and sodium hydroxide
(160 mg, 4 mmol) in methanol (20 mL) were refluxed for 1.5 h. After cooled to rt, methanol was removed
under vacuum and the residue was dispersed into water and ethyl acetate. The organic layer was separated
and washed with water and brine successively. Then the organic phase was dried over anhydrous sodium
sulfate overnight. After evaporation under vacuum, the solid residue was purified by chromatography to
o
give yellow powder meridianin D (50 mg, 76%). mp 219.5 - 221.8 C (EtOAc/MeOH); IR (KBr) νmax
1
3432, 3167, 1660, 1571, 1515, 1448, 1389, 1230, 1103, 886, 814 cm-1; H NMR (DMSO-d6) and 13C
NMR (DMSO-d6) see the Table 2; EIMS m/z (%) 288 (M+, 94), 290 (M+2, 100), 249 (29), 247 (30), 208
(12), 168 (14), 140 (13), 104 (22); HRMS Calcd for C12H9N4Br: 288.0022. Found: 288.0016.
o
6-Debromomeridianin D (12): Prepared as meridianin D. mp 262.2 - 264.3 C (EtOAc/MeOH); IR
(KBr) νmax 3408, 3329, 3174, 1661, 1568, 1453, 1414, 1246, 1119 cm-1; 1H NMR (DMSO-d6) δ 6.39 (br
s, 2H), 7.02 (d, J = 5.3 Hz, 1H), 7.15 (m, 2H), 7.45 (d, J = 7.9 Hz, 1H), 8.11 (d, J = 5.3 Hz, 1H), 8.19 (s,
1H), 8.59 (d, J = 7.4 Hz, 1H), 11.65 (br s, 1H); 13C NMR (DMSO-d6) δ 105.2, 111.7, 113.6, 120.2, 121.9,
122.3, 125.3, 128.1, 136.9, 156.9, 162.6, 163.4; EIMS m/z (%) 210 (M+, 100), 209 (35), 169 (48), 155 (4),
140 (9), 114 (8), 89 (4); HRMS Calcd for C12H10N4: 210.0923. Found: 210.0914.

ACKNOWLEDGEMENT
The authors gratefully acknowledge financial support by Shanghai Municipal Committee of Science and
Technology.
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