Synthesis of 3-aryl- and 3-heteroaryl-7-azaindoles

Article abstract of DOI:10.1055/s-1999-3446

The synthesis of 1-protected 3-trimethylstannyl-7-azaindoles and their coupling with aryl and heteroaryl halides is described.

Full text of DOI:10.1055/s-1999-3446

PAPER
615
Synthesis of 3-Aryl- and 3-Heteroaryl-7-azaindoles
Mercedes Alvarez,*a David Fernández,a and John A. Jouleb
a Laboratori de Química Orgànica, Facultat de Farmàcia, Universitat de Barcelona, ES-08028 Barcelona, Spain
Fax +34(9)34021896; E-mail: malvarez@farmacia.far.ub.es
b Chemistry Department, The University of Manchester, Manchester M13 9PL, U.K.
E-mail: j.a.joule@man.ac.uk
Received 3 August 1998; revised 14 September 1998
butyllithium in THF to deprotonate producing an anion
which was then trapped at low temperature giving 2a–d
(Scheme 1). Although the anion from 1 is ambident, in
only one case (trapping with MEM chloride) a product 3
from the alkylation at the six-membered ring nitrogen was
obtained (2b:3; 3.5:1). Differentiation between the two
derivatives was based on the observation of a NOE be-
tween H-2 or H-6 and the methylene (N-CH2-O) for 2b
and 3, respectively. The difference in the coupling con-
stant between the protons 5 and 6 of 2b (J5,6 = 4.8 Hz) and
3 (J5,6 = 6.2 Hz) confirms by analogy the introduction of
R at N-1 for 2a (J5,6 = 4.4 Hz), 2c (J5,6 = 4.9 Hz) and 2d
(J5,6 = 4.8 Hz).
Abstract: The synthesis of 1-protected 3-trimethylstannyl-7-azain-
doles and their coupling with aryl and heteroaryl halides is de-
scribed.
Key words: variolins, marine alkaloids, 3-trimethylstannyl-7-aza-
indole, palladium catalysis, coupling reactions
The variolins, which occur in the Antarctic sponge Kirk-
patrickia varialosa, are a small group of marine heterocy-
clic substances1,2 of which variolins B and D are typical.
These substances were isolated after the examination of
extracts which were shown to be active against P388 mu-
rine leukemia cells. Subsequent in vitro testing showed
variolin B to be the most active in tests which included an-
tiviral activity (Herpes simplex Type I, polio Type I).
Each of these variolins is based on a fused pyrimidino-7-
azaindole, strictly a pyrido[3’,2’:4,5]pyrrolo[1,2-c]pyrim-
idine. There is only one report on the synthesis of this tri-
cyclic heterocyclic ring system.3
Scheme 1
Each of the 1-protected 3-bromo-7-azaindoles 2 was con-
verted into the corresponding 3-trimethylstannyl deriva-
tive 4 by treatment with tert-butyllithium at low
temperature followed by chlorotrimethylstannane
(Scheme 2). There was considerable variation in the effi-
ciency of these transformations, conversion to the tert-bu-
tyldimethylsilyl protected 7-azaindole 4a being the most
efficient while the yield from 2c was insufficient to allow
The retrosynthetic analysis of the structures of these mol-
ecules necessitate the conversion of a 3-halo-7-azaindole
into a 3-aryl(heteroaryl)-7-azaindole. Consequently we
describe here an investigation into the synthesis of 3-aryl-
7-azaindoles via the palladium(0)-catalyzed coupling of
3-stannyl-7-azaindoles. We have selected organotin re-
agents rather than other possibilities such as boronic acids
or organozinc reagents for coupling reactions because of
its easier manipulation and purification. Although the
coupling reactions of 1-protected 2-tributylstannylin-
doles,4–7 1-tosyl-3-trimethylstannylindole8 and 2-trimeth-
ylstannyl-1-phenylsulfonyl-7-azaindole9
have
been
described no reports on the synthetic utility of 3-stannyl-
7-azaindoles are known.
7-Azaindole10 was converted into the known 3-bromo-7-
azaindole (1)11 and protected at the pyrrole nitrogen using
Scheme 2
Synthesis 1999, No. 4, 615–620 ISSN 0039-7881 © Thieme Stuttgart · New York

616
M. Alvarez et al.
PAPER
proper characterization. In the case of the 1-(p-toluene- Settling for the efficiency and simple N-protecting group
sulfonyl)-protected azaindole 2d, lithiation on the arylsul- removal during workup, we examined the coupling of
fonyl ring12 also occurred, and with excess tert- stannane 4a with a wide range of aryl and heteroaryl ha-
butyllithium it was possible to produce the doubly stanny- lides, and the results are given in Scheme 5.
lated 5 in 85% yield.
1-tert-Butyldimethylsilyl-3-trimethylstannyl-7-azaindo-
le (4a) was chosen for further study to seek optimum cou-
pling conditions with 2-bromopyridine. This protected
azaindole has the further advantage that simple extraction
into dilute acid, following the coupling procedure, was
sufficient to remove the N-protection. Scheme 3 shows
the results of this study: the best condition, tetrakis(triph-
enylphosphine)palladium(0) with lithium chloride in re-
fluxing tetrahydrofuran, was used subsequently in the
couplings summarized in Schemes 4 and 5.
Scheme 5
The coupling of the bis(trimethylstannyl)indole 5 with 5-
bromopyrimidine produced 6l in a yield of 62%. Taking
into account a yield of 63% for the hydrolytic removal of
the N-protecting group to give 6d, this also represents an
efficient method for the synthesis of 3-aryl-7-azaindoles.
Scheme 3
The influence of the different protecting groups on the
coupling process was assessed using both 2-bromopyri-
dine and 5-bromopyrimidine and these experiments are
summarized in Scheme 4. There was not much difference
in the reactivities of TBDMS, MEM and Ts protected 7-
azaindoles. The pyrimidine couplings were consistently
somewhat more efficient than those with 2-bromopyri-
dine.
Melting points were determined in a capillary tube and are uncor-
rected. TLC was carried out on silica gel 60 F254 (Merck 0.063–
0.200 mm) and spots were located with UV light. Column chroma-
tography was carried out on silica gel 60 SDS (0.060–0.2 mm).
Flash chromatography was carried out on silica gel (60 A CC, Mer-
ck). Organic extracts were dried over anhyd Na2SO4, and solutions
were evaporated under reduced pressure with a rotatory evaporator.
IR spectra were recorded on a Nicolet 205 FT-IR spectrophotome-
ter. NMR spectra were measured with Varian Gemini-200 (200
MHz), Varian Gemini-300 (300 MHz) and Varian VXR-500 (500
MHz) spectrometers; data are given in d referenced to TMS. Mass
spectra were recorded in the electron impact (EI) mode with a
Hewlett-Packard model 5989A. High resolution mass spectra were
performed on a Autospec/VG by Departament de Química Orgàni-
ca Biològica (C.S.I.C.) Barcelona. Elemental analyses were per-
formed on a C. E. Instrument EA-1108 in the Serveis Científico-
Tècnics de la Universitat de Barcelona.
3-Bromo-7-azaindole (1)
This compound was prepared as described11 in 80% yield; mp 186–
187 °C (CH2Cl2) (Lit11 mp 188 °C).
IR (KBr): n = 3077 cm–1.
Scheme 4
Synthesis 1999, No. 4, 615–620 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-Aryl- and 3-Heteroaryl-7-azaindoles
617
1H NMR (CDCl3, 300 MHz): d = 7.19 (dd, J = 8.0, 4.8 Hz, 1 H, H-
5), 7.41 (s, 1 H, H-2), 7.93 (dd, J = 8.0, 1.4 Hz, 1H, H-4), 8.37 (dd,
J = 4.8, 1.4, 1 H, H-6), 11.4 (br s, 1 H, NH).
MS (EI): m/z (%) = 286 (81BrM+, 2), 284 (79BrM+, 2), 227 (2), 225
(79BrM – MeOC2H4, 2), 198 (18), 196 (79BrM – MEM, 22), 149
(25).
13C NMR (CDCl3, 50 MHz): d = 89.0 (s, C-3), 116.4 (d, C-5), 119.9
(s, C-3a), 124.3 (d, C-2), 127.9 (d, C-4), 143.5 (d, C-6), 147.4 (s, C-
7a).
MS (EI): m/z (%) = 198 (81BrM+, 97), 197 (11), 196 (79BrM+, 100),
117 (M – Br, 54), 90 (100).
HRMS: m/z calcd for C11H1379BrN2O2: 284.0160, experimental:
284.0155.
3-Bromo-1-tert-butoxycarbonyl-7-azaindole (2c)
From 1 (500 mg, 3.53 mmol) and Boc2O (554 mg, 3.53 mmol). Re-
action time 2 h; yield: 594 mg (79%); red oil.
IR (film): n = 1736, 1410, 1314, 1251, 1155 cm–1.
1H NMR (CDCl3, 300 MHz): d = 1.67 (s, 9 H, t-C4H9), 7.29 (dd, J
= 7.9, 4.9 Hz, 1 H, H-5), 7.71 (s, 1 H, H-2), 7.86 (dd, J = 7.9, 1.6
Hz, 1 H, H-4), 8.55 (dd, J = 4.9, 1.6 Hz, 1 H, H-6).
13C NMR (CDCl3, 50 MHz): d = 28.0 [q, C(CH3)3], 84.7 [s,
C(CH3)3], 94.9 (s, C-3), 119.0 (d, C-5), 122.4 (s, C-3a), 125.4 (d, C-
2), 128.0 (d, C-4), 146.3 (d, C-6), 147.1 (s, C-7a).
N-Protection of 3-Bromo-7-azaindole (1); General Procedure
To a solution of 1 (1 equiv) in THF, cooled at –78 °C, was added
slowly BuLi (1.6 M in hexane, 1.1 equiv). After stirring for 15 min,
the alkylating agent (in THF for solids, 1.1 equiv) was added. When
the addition was complete, the cooling bath was removed and the
mixture was allowed to rise to r.t. Et2O was added and the organic
layer was washed with brine, dried and evaporated. The crude prod-
uct was purified by flash column chromatography using mixtures of
hexane and CH2Cl2.
MS (EI): m/z (%) = 298 (81BrM+, 0.3), 296 (79BrM+, 0.4), 198
(79BrM – Boc, 17), 196 (17), 116 (7).
3-Bromo-1-tert-butyldimethylsilyl-7-azaindole (2a)
From 1 (2.7 g, 13.71 mmol) and TBDMS-Cl (2.3 g, 15.07 mmol).
Reaction time 3 h. After purification, 2a (3.2 g, 76%) was obtained
as a white solid; mp 80 °C (hexane/CH2Cl2).
IR (KBr): n = 2950, 1397, 793 cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.64 (s, 6 H, 2 CH3), 0.95 (s, 9 H,
t-C4H9), 7.11 (dd, J = 8.0, 4.4 Hz, 1 H, H-5), 7.26 (s, 1 H, H-2), 7.83
(dd, J = 8.0, 1.4 Hz, 1 H, H-4), 8.32 (dd, J = 4.4, 1.4 Hz, 1 H, H-6).
13C NMR (CDCl3, 50 MHz): d = –4.3 (q, 2 CH3), 18.9 [s, C(CH3)3],
26.4 [q, C(CH3)3], 91.2 (s, C-3), 116.5 (d, C-5), 121.6 (s, C-3a),
126.6 (d, C-2), 129.4 (d, C-4), 143.5 (d, C-6), 152.5 (s, C-7a).
MS (EI): m/z (%) = 312 (81BrM+, 30), 310 (79BrM+, 29), 256 (44),
255 (100), 254 (44), 253 (79BrM – t-Bu, 90), 240 (47), 238 (79BrM
– t-Bu – Me, 51).
HRMS: m/z calcd for C12H1379BrN2O2: 296.0160, found: 296.0163.
3-Bromo-1-(4-methylphenylsulfonyl)-7-azaindole (2d)
From 1 (2 g, 10.15 mmol) and TsCl (2.32 g, 11.16 mmol). Reaction
time 2 h; yield: 2.93 g (82%); white solid; mp 133–134 °C (CH2Cl2).
IR (KBr): n = 1375, 1175 cm–1.
1H NMR (CDCl3, 200 MHz): d = 2.36 (s, 3 H, CH3), 7.20–7.30 (m,
3 H, H-5, H-3', 5'), 7.78 (s, 1 H, H-2), 7.79 (dd, J = 7.6, 1.2 Hz, 1 H,
H-4), 8.07 (d, J = 8.0 Hz, 2 H, H-2', 6'), 8.47 (dd, J = 4.8, 1.2 Hz, 1
H, H-6).
13C NMR (CDCl3, 50 MHz): d = 21.6 (q, CH3), 95.3 (s, C-3), 119.3
(d, C-5), 122.3 (s, C-3a), 124.8 (d, C-2), 128.0 (d, C-3', 5'), 128.4 (d,
C-4), 129.5 (s, C-4'), 129.7 (d, C-2', 6'), 134.8 (s, C-1'), 145.5 (s, C-
7a), 145.9 (d, C-6).
MS (EI): m/z (%) = 352 (81BrM+, 2), 350 (79BrM+, 2), 288 (13), 286
HRMS: m/z calcd for C13H1979BrN2Si: 310.0501, found: 310.0503.
(13), 197 (2), 195 (79BrM – Ts, 2), 116 (12).
3-Bromo-1-methoxyethoxymethyl-7-azaindole (2b)
From 1 (500 mg, 3.38 mmol) and MEM-Cl (315 mL, 3.72 mmol).
Reaction time 4 h. A mixture of 2b and 3 was obtained. Separation
by column chromatography eluting with CH2Cl2/MeOH (9:1) pro-
duced 2b (418 mg, 58%) as a colourless oil and 3 (120 mg, 17%) as
a yellow oil.
HRMS: m/z calcd for C14H1179BrN2O2S: 349.9725, found:
349.9734.
Anal. calcd for C14H11BrN2O2S (350.0): C, 47.88; H, 3.16; N, 7.98;
S, 9.13. Found C, 47.98; H, 3.24; N, 7.78; S, 9.23
3-Trimethylstannyl-7-azaindoles 4; General Procedure
IR (film): n = 1560, 1420, 1310, 1150, 1087 cm–1.
To a solution of 2 (1 equiv) in THF cooled at –90 °C was added
quickly t-BuLi (1.7 M in pentane, 2 equiv) and the mixture was
stirred for 5 min at the same temperature. After this time, Me3SnCl
(1 M in THF) was added and the mixture was stirred for 1 h at
–90 °C and then for 1 h at r.t. The mixture was diluted with Et2O and
the organic layer washed with brine, dried and evaporated.
1H NMR (CDCl3, 200 MHz): d = 3.34 (s, 3 H, OCH3), 3.50–3.60 (m,
4 H, CH2), 5.73 (s, 2 H, CH2), 7.17 (dd, J = 7.6, 4.8 Hz, 1 H, H-5),
7.41 (s, 1 H, H-2), 7.86 (d, J = 7.6 Hz, 1 H, H-4), 8.36 (d, J = 4.8
Hz, 1 H, H-6).
13C NMR (CDCl3, 50 MHz): d = 58.9 (q, OCH3), 68.0 (t, CH2), 71.4
(t, CH2), 73.5 (t, CH2), 90.2 (s, C-3), 116.9 (d, C-5), 119.9 (s, C-3a),
126.7 (d, C-2), 127.6 (d, C-4), 144.3 (d, C-6), 146.9 (s, C-7a).
1-tert-Butyldimethylsilyl-3-trimethylstannyl-7-azaindole (4a)
From 2a (1g, 3.21 mmol) and Me3SnCl (4.82 mmol); yield: 1.26 g
(99%); white solid; mp 87–88 °C (Et2O).
IR (film): n = 2950, 1484, 1398, 1166 cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.35 (s, 9 H, 3 CH3), 0.63 (s, 6 H,
2 CH3), 0.94 (s, 9 H, t-C4H9), 7.01 (dd, J = 7.7, 4.7 Hz, 1 H, H-5),
7.13 (s, 1 H, H-2), 7.81 (dd, J = 7.7, 1.5 Hz, 1 H, H-4), 8.26 (dd, J
= 4.7, 1.5 Hz, 1 H, H-6).
13C NMR (CDCl3, 50 MHz): d = –9.2 (q, CH3), –4.3 (q, CH3), 19.5
[s, C(CH3)3], 26.5 [q, C(CH3)3], 109.7 (s, C-3), 115.6 (d, C-5), 128.6
(s, C-3a), 129.7 (d, C-2), 136.9 (d, C-4), 142.2 (d, C-6).
MS (EI): m/z (%) = 286 (81BrM+, 2), 284 (79BrM+, 2), 211 (14), 209
(79BrM – OC2H4OMe, 15), 198 (18), 196 (79BrM – MEM, 18).
HRMS: m/z calcd for C11H1379BrN2O2: 284.0160, found: 284.0161.
3-Bromo-7-methoxyethoxymethyl-7-azaindole (3)
IR (film): n = 3019, 1216, 1108, 1017, 770 cm–1.
1H NMR (CDCl3, 200 MHz): d = 3.33 (s, 3 H, OCH3), 3.42–3.60 (m,
2 H, CH2), 3.65–3.82 (m, 2 H, CH2), 6.17 (s, 2 H, CH2), 7.06 (dd, J
= 7.2, 6.2 Hz, 1 H, H-5), 7.79 (s, 1 H, H-2), 8.98 (d, J = 6.2 Hz, 1 H,
H-6), 8.12 (d, J = 7.2 Hz, 1 H, H-4).
13C NMR (CDCl3, 50 MHz): d = 58.8 (q, OCH3), 69.8 (t, CH2), 71.1
(t, CH2), 80.0 (t, CH2), 87.7 (s, C-3), 109.6 (d, C-5), 119.9 (s, C-3a),
128.5 (d, C-2), 130.9 (d, C-4), 142.7 (d, C-6), 147.0 (s, C-7a).
MS (EI): m/z (%) = 396 (120SnM+, 21), 395 (5), 394 (118SnM+, 17),
392 (116SnM+, 6), 385 (M, 12), 383 (13), 382 (18), 381 (M – Me,
100), 380 (42), 379 (81), 232 (M – SnMe3, 2).
HRMS: m/z calcd for C16H28N2Si120Sn: 396.1044, found: 396.1039.
Synthesis 1999, No. 4, 615–620 ISSN 0039-7881 © Thieme Stuttgart · New York

618
M. Alvarez et al.
PAPER
1-Methoxyethoxymethyl-3-trimethylstannyl-7-azaindole (4b)
From 2b (700 mg, 2.45 mmol) and Me3SnCl (3.68 mmol) following
the general procedure was obtained an oil (900 mg) which was char-
acterized as a mixture of 4b and 1-MEM-7-azaindole. Microdistil-
lation (120 °C/0.5 Torr) permitted the separation of byproduct and
isolation of 4b (510 mg, 56%) as a colourless oil.
fluxed for 48 h under argon. The mixture was diluted with Et2O and
the organic layer washed with brine. The organic layer was dried
and evaporated to give the crude product which was purified by
flash column chromatography on silica gel using mixtures of
CH2Cl2 and MeOH as eluents. When the azaindole was protected
with TBDMS, the reaction mixture was extracted with aq HCl
(10%), the aqueous extract was basified with NaOH (50%) and ex-
tracted with CH2Cl2. The organic solution was dried and evaporated
to give the crude product which was purified by column chromatog-
raphy on silica gel.
IR (film): n = 2926, 1497, 1420, 1130, 1090, 770 cm–1.
1H NMR (CDCl3, 300 MHz): d = 0.36 (s, 9 H, 3 CH3), 3.34 (s, 3 H,
OCH3), 3.42–3.52 (m, 2 H, CH2), 3.60–3.68 (m, 2 H, CH2), 5.74 (s,
2 H, CH2), 7.08 (dd, J = 7.7, 4.7 Hz, 1 H, H-5), 7.29 (s, 1 H, H-2),
7.85 (dd, J = 7.7, 1.5 Hz, 1 H, H-4), 8.32 (dd, J = 4.7, 1.5 Hz, 1 H,
H-6).
13C NMR (CDCl3, 75 MHz): d = –8.8 (q, CH3), 59.0 (q, OCH3), 67.9
(t, CH2), 71.4 (t, CH2), 73.4 (t, CH2), 108.3 (s, C-3), 116.1 (d, C-5),
126.5 (s, C-3a), 129.7 (d, C-2), 134.1 (d, C-4), 142.8 (d, C-6), 150.0
(s, C-7a).
3-(Pyridin-2-yl)-7-azaindole (6a)
From 4a (100 mg, 0.25 mmol) and 2-bromopyridine (50 mL, 0.5
mmol). Reaction time 24 h; yield: 22 mg (45%); white solid; mp
180–181°C (CH2Cl2/MeOH).
IR (KBr): n = 1592, 1583, 1534, 1459, 1416, 1278 cm–1.
1H NMR (CDCl3, 200 MHz): d = 7.14 (ddd, J = 6.6, 5.0, 1.4 Hz, 1
H, H-5’), 7.21 (dd, J = 7.8, 4.8, 1 H, H-5), 7.69–7.72 (m, 2 H, H-3',
4'), 7.95 (s, 1 H, H-2), 8.39 (dd, J = 4.8, 1.0 Hz, 1 H, H-4), 8.67 (d,
J = 5.0 Hz, 1 H, H-6'), 8.75 (dd, J = 7.8, 1.0 Hz, 1 H, H-6), 11.8 (br
s, 1 H, NH).
13C NMR (CDCl3, 50 MHz): d = 115.6 (s, C-3), 116.0 (d, C-5),
118.6 (s, C-3a), 119.7 (d, C-5'), 120.4 (d, C-3'), 124.6 (d, C-2),
130.4 (d, C-4), 136.3 (d, C-4'), 142.8 (d, C-6), 148.6 (s, C-7a), 149.5
(d, C-6'), 154.5 (s, C-2').
MS (EI): m/z (%) = 370 (120SnM+, 7), 368 (118SnM+, 4), 366
(
116SnM+, 2), 355 (120SnM-Me, 46), 353 (34), 351 (19), 131 (52).
HRMS: m/z calcd for C14H22N2O2120Sn: 370,0703, found: 370,
0693.
1-(4-Methylphenylsulfonyl)-3-trimethylstannyl-7-azaindole
(4d)
From 2d (500 mg, 1.80 mmol) and Me3SnCl (1.99 mmol); yield:
307 mg (50%); colourless oil.
MS (EI): m/z (%) = 195 (M+, 100), 194 (M – H, 50), 167 (15).
IR (film): n = 1389, 1375, 1175, 1152 cm–1.
HRMS: m/z calcd for C12H9N3: 195.0780, found: 195.0806.
1H NMR (CDCl3, 200 MHz): d = 0.38 (s, 9 H, 3 CH3), 2.36 (s, 3 H,
CH3), 7.14 (dd, J = 7.8, 4.8 Hz, 1 H, H-5), 7.27 (d, J = 8.0 Hz, 2 H,
H-3’, 5’), 7.58 (s, 1 H, H-2), 7.77 (dd, J = 7.8, 1.4 Hz, 1 H, H-4), 8.10
(d, J = 8.0 Hz, 2 H, H-2’, 6’), 8.41 (dd, J = 4.8, 1.4 Hz, 1 H, H-6).
13C NMR (CDCl3,50 MHz): d = –9.1 (q, CH3), 21.5 (q, CH3), 114.1
(s, C-3), 119.2 (d, C-5), 119.5 (s, C-3a), 128.6 (d, C-3', 5'), 129.2 (s,
C-4'), 130.2 (d, C-2', 6'), 140.0 (d, C-2), 132.0 (d, C-4), 136.2 (s, C-
1'), 145.0 (d, C-6), 145.6 (s, C-7a).
Anal. calcd for C12H9N3 (195.2): C, 73.83; H, 4.65; N,21.53.
Found C, 73.74; H, 4.52; N, 21.58.
1-Methoxyethoxymethyl-3-(pyridin-2-yl)-7-azaindole (6b)
From 4b (200 mg, 0.54 mmol) and 2-bromopyridine (103 mL, 1.08
mmol). Reaction time 24 h; yield: 64 mg (45%); yellow oil.
IR (film): n = 1591, 1543, 1438, 1429, 1092 cm–1.
1H NMR (CDCl3, 200 MHz): d = 3.34 (s, 3 H, OCH3), 3.46–3.55 (m,
2 H, CH2), 3.60–3.70 (m, 2 H, CH2), 5.82 (s, 2 H, CH2), 7.12 (ddd,
J = 7.0, 5.0, 1.8 Hz, 1 H, H-5'), 7.21 (dd, J = 8.0, 4.8 Hz, 1 H, H-5),
7.65 (m, 2 H, H-3', 4'), 7.93 (s, 1 H, H-2), 8.38 (dd, J = 4.8, 1.6 Hz,
1 H, H-6), 8.65 (d, J = 5.0 Hz, 1 H, H-6'), 8.72 (dd, J = 8.0, 1.6 Hz,
1 H, H-4).
13C NMR (CDCl3,50 MHz): d = 59.7 (q, OCH3), 68.8 (t, CH2), 72.2
(t, CH2), 74.5 (t, CH2), 116.7 (s, C-3), 118.2 (d, C-5), 119.5 (s, C-
3a), 120.6 (d, C-5'), 121.4 (d, C-3'), 127.6 (d, C-2), 131.0 (d, C-4),
137.0 (d, C-4'), 144.5 (d, C-6), 149.5 (s, C-7a), 150.3 (d, C-6'),
154.8 (s, C-2').
MS (EI): m/z (%) = 436 (120SnM+, 8), 435 (2), 434 (118SnM+, 6), 432
(
(
116SnM+, 3), 421 (120SnM – Me, 100), 420 (39), 419 (74), 391
120SnM – 3Me, 32), 390 (12), 389 (24).
HRMS: m/z calcd for C17H20N2O2Si120Sn: 436.0267, found:
436.0279.
1-(4-Methyl-2-trimethylstannylphenylsulfonyl)-3-trimethyl-
stannyl-7-azaindole (5)
From 2d (100 mg, 0.36 mmol) and Me3SnCl (0.76 mmol) following
the general procedure 5 (147 mg, 85%) was obtained as a colourless
oil.
MS (EI): m/z (%) = 284 (M+1, 4), 283 (M+, 21), 209 (40), 208 (M
– OC2H4OMe, 68), 195 (M – MEM, 100).
IR (film): n = 1380, 1360, 1175, 1152 cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.38 (s, 9 H, 3 CH3), 0.46 (s, 9 H,
3 CH3), 2.36 (s, 3 H, CH3), 7.10–7.30 (m, 2 H, H-5, 5'), 7.48 (s, 1 H,
H-3'), 7.55 (s, 1 H, H-2), 7.76 (dd, J = 7.6, 1.4 Hz, 1 H, H-4), 8.30–
8.44 (m, 2 H, H-6, 6').
13C NMR (CDCl3, 50 MHz): d = –9.2 (q, CH3), –5.9 (q, CH3), 21.5
(q, CH3), 118.5 (d, C-5), 128.9 (s, C-3a), 129.8 (d, C-6'), 129.7 (d,
C-5'), 130.8 (d, C-2), 132.3 (d, C-4), 137.6 (d, C-3'), 141.6 (s, C-2'),
143.1 (s, C-4'), 143.4 (s, C-7a), 144.7 (d, C-6), 148.6 (s, C-1').
HRMS: m/z calcd for C16H17N3O2: 283.1321, found: 283.1326.
1-(4-Methylphenylsulfonyl)-3-(pyridin-2-yl)-7-azaindole (6c)
From 4d (100 mg, 0.23 mmol) and 2-bromopyridine (44 mL, 0.46
mmol). Reaction time 28 h; yield: 33 mg (42%); yellow solid; mp
117–118 °C (CH2Cl2).
IR (KBr): n = 1605, 1395, 1360, 1175 cm–1.
1H NMR (CDCl3, 500 MHz): d = 2.36 (s, 3 H, CH3), 7.20 (ddd, J =
7.5, 4.5, 1.5 Hz, 1 H, H-5’), 7.26 (dd, J = 8.0, 4.5 Hz, 1 H, H-5), 7.27
(d, J = 8.0 Hz, 2 H, H-3’’, 5’’), 7.67 (dt, J = 7.5, 1.5 Hz, 1 H, H-3’),
7.74 (td, J = 7.5, 1.5 Hz, 1 H, H-4’), 8.11 ( d, J = 8.0 Hz, 2 H, H-2’’,
6’’), 8.22 (s, 1 H, H-2), 8.47 (dd, J = 4.5, 1.5 Hz, 1 H, H-6), 8.67 (dt,
J = 4.5, 1.5 Hz, 1 H, H-6’), 8.72 (dd, J = 8.0, 1.5 Hz, 1 H, H-4).
MS (EI): m/z (%) = 585 (120SnM – Me, 22), 584 (15), 583 (28), 582
(19), 581 (25), 165 (100), 105 (54).
Anal. calcd for C20H28N2O2SSn2 (597.8): C, 40.17; H, 4.72; N, 4.69;
S, 5.36. Found C, 40.41; H, 4.87; N, 4.62; S, 5.09.
13C NMR (CDCl3, 50 MHz): d = 21.6 (q, CH3), 119.3 (s, C-3a),
119.5 (d, C-5), 120.6 (d, C-3’), 121.2 (s, C-3), 121.9 (d, C-5’), 124.4
(d, C-2), 128.1 (d, C-3’’, 5’’), 129.6 (d, C-2’’, 6’’), 131.4 (d, C-4),
Coupling Reactions of Aryl Bromides with N-Protected 3-Tri-
methylstannyl-7-azaindoles 4; General Procedure
A solution of 4 (1 equiv), the appropriate aryl bromide (2 or 5
equiv), LiCl (3 equiv), and (Ph3P)4Pd (0.2 equiv) in THF was re-
Synthesis 1999, No. 4, 615–620 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-Aryl- and 3-Heteroaryl-7-azaindoles
619
135.1 (s, C-4’’), 136.6 (d, C-4’), 145.3 (d, C-6), 147.7 (s, C-7a),
149.6 (d, C-6’), 152.6 (s, C-2’).
MS (EI): m/z (%) = 351 (M+1, 1), 350 (M+, 8), 287 (6), 286 (33),
196 (10), 195 (M – Ts, 11), 142 (10), 141 (24), 91 (100).
MS (EI): m/z (%) = 350 (M+1, 10), 349 (M+, 40), 286 (29), 285
HRMS: m/z calcd for C18H14N4O2S: 350.0837, found: 350.0832.
(100), 195 (25), 194 (M – Ts, 58), 167 (48).
Anal. calcd for C18H14N4O2S (350.3): C, 61.69; H, 4.03; N, 15.99.
Found C, 61.58; H, 3.98; N, 15.67.
HRMS: m/z calcd for C19H15N3O2S: 349.0885, found: 349.0874.
3-(Pyrimidin-5-yl)-7-azaindole (6d)
3-(4-Methoxyphenyl)-7-azaindole (6g)
Method A: From 4a (100 mg, 0.25 mmol) and 5-bromopyrimidine
(200 mg, 1.25 mmol). Reaction time 48 h; yield: 36 mg (74%);
white solid; mp 247–248 °C (CH2Cl2/MeOH).
From 4a (200 mg, 0.50 mmol) and 4-bromoanisole (126 mL, 1.01
mmol). Reaction time 32 h; yield: 42 mg (38%); white solid; mp
215–217 °C (CH2Cl2/MeOH).
IR (KBr): n = 3036, 1581, 1428, 1296, 1277 cm–1.
1H NMR (CDCl3+CD3OD, 200 MHz): d = 7.21 (dd, J = 7.6, 4.8 Hz,
1H, H-5), 7.65 (s, 1 H, H-2), 8.19 (d, J = 7.6 Hz, 1 H, H-4), 8.32 (d,
J = 4.8 Hz, 1 H, H-6), 9.00 (s, 2 H, H-4’, 6’), 9.08 (s, 1 H, H-2’).
13C NMR (CDCl3+CD3OD, 50 MHz): d = 108.9 (s, C-3), 117.4 (d,
C-5), 119.0 (s, C-3a), 124.9 (d, C-2), 129.2 (d, C-4), 130.1 (s, C-5’),
143.5 (d, C-6), 148.5 (s, C-7a), 154.9 (d, C-4’, 6’), 156.3 (d, C-2’).
IR (KBr): n = 3128, 1537, 1242 cm–1.
1H NMR (CDCl3+CD3OD, 300 MHz): d = 3.87 (s, 3 H, OCH3), 7.01
(d, J = 8.8 Hz, 2 H, H-3’, 5’), 7.18 (dd, J = 7.9, 4.9 Hz, 1 H, H-5),
7.48 (s, 1 H, H-2), 7.56 (d, J = 8.8 Hz, 2 H, H-2', 6'), 8.22–8.32 (m,
2 H, H-4, 6).
13C NMR (DMSO-d6, 75 MHz): d = 55.3 (q, OCH3), 114.5 (s, C-3),
114.6 (d, C-3', 5'), 116.0 (d, C-5), 117.9 (s, C-3a), 123.2 (d, C-2),
127.6 (s, C-1'), 127.7 (d, C-2', 6'), 128.1 (d, C-4), 142.4 (d, C-6),
148.5 (s, C-7a), 157.8 (s, C-4').
MS (EI): m/z (%) = 197 (M+1, 14), 196 (M+, 100), 195 (M – H, 18),
142 (M – C2H2N2, 40).
MS (EI): m/z (%) = 225 (M+1, 14), 224(M+, 88), 209 (M – Me,
100), 181 (44).
HRMS: m/z calcd for C11H8N4: 196.0749, found: 196.0744.
Anal. calcd for C11H8N4•1/8H2O (198.5): C, 66.57; H, 4.19; N,
28.23. Found C, 66.61; H, 4.13; N, 28.14.
HRMS: m/z calcd for C14H22N2O: 224.0949, found: 224.0949
3-(4-Nitrophenyl)-7-azaindole (6h)
Method B: A solution of 6l in 10% methanolic NaOH (10 mL) was
stirred at r.t. for 2 h. The solvent was evaporated and the residue was
dissolved in CH2Cl2 and washed with brine. The organic solution
was dried and evaporated to give a crude product which was puri-
fied by column chromatography on silica gel. Elution with CH2Cl2/
MeOH 95:5 gave 6d (20 mg, 63%).
From 4a (100 mg, 0.25 mmol) and 4-bromonitrobenzene (102 mg,
0.50 mmol). Reaction time 24 h; yield: 30 mg (50%); yellow solid;
mp 258–259 °C (CH2Cl2/MeOH).
IR (KBr): n = 3500, 1591, 1508, 1332, 1284 cm–1.
1H NMR (DMSO-d6, 200 MHz): d = 7.23 (dd, J = 7.8, 4.8, 1 H, H-
5), 7.56 (s, 1 H, H-2), 8.04 (d, J = 8.6 Hz, 2 H, H-2’, 6’), 8.26 (d, J
= 8.6 Hz, 2 H, H-3’, 5’), 8.32 (d, J = 4.8 Hz, 1 H, H-6), 8.42 (d, J =
7.8 Hz, 1 H, H-4), 12.35 (br s, 1 H, NH).
13C NMR (DMSO-d6, 50 MHz): d = 112.5 (s, C-3), 115.7 (s, C-3a),
117.0 (d, C-5), 124,6 (d, C-2’, 6’), 126.4 (d, C-3’, 5’), 127.2 (d, C-2),
128.1 (d, C-4), 142.7 (s, C-7a), 143.8 (d, C-6), 144.8 (s, C-1’), 149.6
(s, C-4’).
1-Methoxyethoxymethyl-3-(pyrimidin-5-yl)-7-azaindole (6e)
From 4b (100 mg, 0.27 mmol) and 5-bromopyrimidine (87 mg, 0.54
mmol). Reaction time 20 h. Compound 6e (37 mg, 50%) was ob-
tained as a yellow gum.
IR (KBr): n = 1530, 1425, 1099, 1072 cm–1.
1H NMR (CDCl3,200 MHz): d = 3.36 (s, 3 H, OCH3), 3.42–3.55 (m,
2 H, CH2), 3.62–3.75 (m, 2 H, CH2), 5.84 (s, 2 H, CH2), 7.24 (dd, J
= 8.0, 4.8 Hz, 1 H, H-5), 7.71 (s, 1 H, H-2), 8.16 (dd, J = 8.0, 1.4
Hz, 1 H, H-4), 8.44 (dd, J = 4.8, 1.4 Hz, 1 H, H-6), 9.03 (s, 2 H, H-
4', 6'), 9.16 (s, 1 H, H-2').
13C NMR (CDCl3, 50 MHz): d = 59.0 (q, OCH3), 68.4 (t, CH2), 71.5
(t, CH2), 73.9 (t, CH2), 109.8 (s, C-3), 117.6 (d, C-5), 118.1 (s, C-
3a), 125.8 (d, C-2), 127.7 (d, C-4), 128.9 (s, C-5'), 144.5 (d, C-6),
148.6 (s, C-7a), 154.4 (d, C-4', 6'), 156.5 (d, C-2').
MS (EI): m/z (%) = 240 (M+1, 16), 239 (M+, 100), 209 (M – NO,
51), 193 (M – NO2, 38), 166 (M – NO2 – CH2N, 40).
HRMS: m/z calcd for C13H9N3O2: 239.0695, found: 239.0693.
Anal. Calcd for C13H9N3O2•1/3 H2O(245.7): C, 63.67, H, 3.97; N,
17.13. Found C, 63.64; H, 3.72; N, 17.20.
3-(Thien-3-yl)-7-azaindole (6i)
From 4a (200 mg, 0.50 mmol) and 3-bromothiophene (240 mL, 2.57
mmol). Reaction time 48 h; yield: 57 mg (57%); white solid; mp
165 °C (CH2Cl2).
MS (EI): m/z (%) = 285 (M+1, 5), 284 (M+, 26), 210 (37), 209 (M
– OC2H4OMe, 72), 197 (13), 196 (M – MEM, 100).
HRMS: m/z calcd for C15H16N4O2: 284.1273, found: 284.1273.
IR (KBr): n = 3142, 1562, 1409, 1288 cm–1.
1-(4-Methylphenylsulfonyl)-3-(5-pyrimidin-5-yl)-7-azaindole
(6f)
From 4d (100 mg, 0.23 mmol) and 5-bromopyrimidine (73 mg, 0.46
mmol). Reaction time 29 h; yield: 48 mg (60%); white solid mp
185–186 °C (CH2Cl2).
1H NMR (CDCl3, 300 MHz): d = 7.23 (dd, J = 7.8, 4.8 Hz, 1 H, H-
5), 7.56 (d, J = 1.2 Hz, 1 H, H-2’), 7.59 (d, J = 2.7 Hz, 1 H, H-5’),
7.73 (dd, J = 2.7, 1.2 Hz, 1 H, H-4’), 7.87 (br s, 1 H, H-2), 8.25 (dd,
J = 4.8, 1.4 Hz, 1 H, H-6), 8.32 (d, J = 7.8, 1.4 Hz, 1 H, H-4), 11.80
(br s, 1 H, NH).
13C NMR (CDCl3+CD3OD, 75MHz): d = 110.6 (s, C-3), 116.3 (d,
C-5), 117.6 (s, C-3a), 118.1 (d, C-4’), 124.1 (d, C-2), 126.5 (d, C-5’),
127.0 (d, C-2’), 128.1 (d, C-4), 135.9 (s, C-3’), 143.3 (d, C-6), 149.2
(s, C-7a).
IR (KBr): n = 1377, 1189, 1006 cm–1.
1H NMR (CDCl3,200 MHz): d = 2.39 (s, 3 H, CH3), 7.20–7.38 (m,
3 H, H-5, 3'', 5''), 8.02 (s, 1 H, H-2), 8.04 (dd, J = 7.8, 1.2 Hz, 1 H,
H-4), 8.15 (d, J = 8.4 Hz, 2 H, H-2'', 6''), 8.53 (dd, J = 4.8, 1.2 Hz,
1 H, H-6), 9.99 (s, 2 H, H-4', 6'), 9.22 (s, 1 H, H-2').
13C NMR (CDCl3, 75 MHz): d = 22.4 (q, CH3), 113.6 (s, C-3), 120.2
(d, C-5), 121.1 (s, C-3a), 124.4 (d, C-2), 128.0 (s, C-5'), 128.9 (d, C-
4), 129.0 (d, C-3'', 5''), 130.5 (d, C-2'', 6''), 135.1 (s, C-4''), 146.4 (s,
C-1''), 146.6 (d, C-6), 148.0 (s, C-7a), 155.6 (d, C-4', 6'), 158.2 (d,
C-2').
MS (EI): m/z (%) = 201 (M+1, 14), 200 (M+, 100), 173 (15), 155
(16).
Anal. Calcd for C11H8N2S (200.2): C, 65.97; H, 4.03; N, 13.99; S,
16.01. Found C, 65.70; H, 4.00; N, 13.91 S, 15.90.
Synthesis 1999, No. 4, 615–620 ISSN 0039-7881 © Thieme Stuttgart · New York

620
M. Alvarez et al.
PAPER
3-(2-Methylthiopyrimidin-4-yl)-7-azaindole (6j)
1.5 Hz, 1 H, H-4), 8.34 (d, J = 8.5 Hz, 1 H, H-6’’), 8.50 (dd, J = 4.5,
From 4a (100 mg, 0.25 mmol) and 4-chloro-2-
methylthiopyrimidine13 (203 mg, 1.26 mmol). Reaction time 48 h;
yield: 37 mg (60%); mp: 217–218 °C (CH2Cl2/MeOH).
IR (KBr): n = 1570, 1406, 1339 cm–1.
1H NMR (DMSO-d6, 300 MHz): d = 2.60 (s, 3 H, SCH3), 7.24 (dd,
J = 8.0, 4.4, 1 H, H-5), 7.63 (d, J = 5.2, 1 H, H-5’), 8.32 (d, J = 4.4,
1 H, H-6), 8.46 (d, J = 5.2, 1 H, H-6’), 8.56 (s, 1 H, H-2), 8.75 (d, J
= 8.0, 1 H, H-4), 12.2 (br s, 1 H, NH).
13C NMR (DMSO-d6, 75 MHz): d = 13.7 (q, SCH3), 111.2 (d, C-5),
111.5 (s, C-3), 117.3 (d, C-2), 117.5 (s, C-3a), 130.1 (d, C-5’), 130.2
(d, C-4), 143.8 (d, C-6), 149.3 (s, C-7a), 156.5 (d, C-6’), 161.6 (s, C-
4’), 171.2 (s, C-2’).
1.5 Hz, 1 H, H-6), 9.02 (s, 2 H, H-4’, 6’), 9.24 (s, 1 H, H-2’).
13C NMR (CDCl3, 50 MHz): d = –5.98 (q, CH3), 21.6 (q, CH3),
112.3 (s, C-3), 119.4 (d, C-5), 120.3 (s, C-3a), 123.9 (d, C-2), 127.3
(s, C-5'), 128.0 (d, C-4), 129.4 (d, C-6''), 129.8 (d, C-5''), 137.7 (d,
C-3''), 140.7 (s, C-4''), 143.7 (s, C-2''), 144.1 (s, C-7a), 145.6 (d, C-
6), 147.3 (s, C-1''), 154.8 (d, C-4', 6'), 157.4 (d, C-2').
MS (EI): m/z (%) = 499 (120SnM – Me, 44), 498 (19), 497 (33), 435
(9), 434 (3), 433 (7), 405 (26), 404 (11), 403 (21), 196 (M – Ts, 35),
141 (79), 105 (100).
HRMS: m/z calc. for C20H19N4O2Si120Sn (M+ – Me): 499.0251,
found: 499.0241.
MS (EI): m/z (%) = 243 (6), 242 (M+, 84), 196 (26), 195 (M – MeS,
67).
Acknowledgement
We acknowledge the financial support from CIRIT (Generalitat de
Catalunya) (Grant QFN 95-4701) and Comissionat per a Universi-
tats i Recerca (Generalitat de Catalunya) (Grant 97-SGR00075).
HRMS: m/z calcd for C12H10N4S: 242.0626, found: 242.0631.
3-(2-Methylthiopyrimidin-5-yl)-7-azaindole (6k)
From 4a (50 mg, 0.12 mmol) and 5-bromo-2-
methylthiopyrimidine14 (52 mg, 0.24 mmol). Reaction time 32 h;
yield: 16 mg (53%); white solid; mp 212–213 °C (CH2Cl2/MeOH).
IR (KBr): n = 3120, 1530, 1460, 1424, 1408, 1299 cm–1.
1H NMR (CDCl3, 200 MHz): d = 2.64 (s, 3 H, SCH3), 7.13 (dd, J =
7.8, 4.6 Hz, 1 H, H-5), 7.51 (s, 1 H, H-2), 8.06 (d, J = 7.8 Hz, 1 H,
H-4), 8.21 (d, J = 4.6 Hz, 1 H, H-6), 8.71 (s, 2 H, H-4’, 6’), 10.8 (br,
1 H, NH).
References
(1) Perry, N. B.; Ettouati, L.; Litaudon, M.; Blunt, J. W.; Munro,
M. H. G.; Parkin, S.; Hope, H. Tetrahedron 1994, 50, 3987.
(2) Trimurtulu, G.; Faulkner, D. J.; Perry, N. B.; Ettouati, L.;
Litaudon, M.; Blunt, J. W.; Munro, M. H. G.; Jameson, G. B.
Tetrahedron 1994, 50, 3993.
(3) Capuano, L. ; Schrepfer, H. J.; Müller, K.; Roos, H. Chem.
Ber. 1974, 107, 929.
(4) Palmisano, G.; Santagostino, M. Synlett 1993, 771.
(5) Labadie, S. S.; Teng, E. J. Org. Chem. 1994, 59, 4250.
(6) Hudkins, R. L.; Diebold, J. L.; Marsh, F. D. J. Org. Chem.
1995, 60, 6218.
(7) Palmisano, G.; Santagostino, M. Helv. Chim. Acta 1993, 76,
2356.
(8) Ciattini, P.G.; Morera, E.; Ortar, G. Tetrahedron Lett. 1994,
35, 2405.
(9) Desarbre, E.; Coudret, S.; Meheust, C.; Mérour, J.-Y.
Tetrahedron 1997, 53, 3637.
(10) Lorenz, R. R.; Tullar, B. F.; Koelsch, C. F.; Archer, S. J. Org.
Chem. 1965, 30, 2531.
(11) Robinson, M. M.; Robinson, B. L. J. Am. Chem. Soc. 1956,
78, 1247.
(12) Sundberg, R. J.; Broome, R.; Walters, C. P.; Schnur, D. J.
Heterocycl. Chem. 1981, 18, 807.
13C NMR (CDCl3+CD3OD, 50 MHz): 13.8 (q, SCH3), 108.3 (s, C-
3), 116.5 (d, C-5), 118.1 (s, C-3a), 123.2 (d, C-2), 124.2 (s, C-5’),
127.9 (d, C-4), 143.0 (d, C-6), 148.0 (s, C-7a), 154.6 (d, C-4’, 6’),
170.0 (s, C-2’).
MS (EI): m/z (%) = 243 (M+1, 16), 242 (M+, 100), 241 (M – H, 10),
209 (72), 195 (M – MeS, 20), 170 (27), 142 (41), 115 (34).
HRMS: m/z calcd for C12H10N4S: 242.0626, found 242.0626.
3-(5-Pyrimidin-5-yl)-1-(2-trimethylstannyl-4-methylphenylsul-
fonyl)-7-azaindole (6l)
From 5 (270 mg, 0.45 mmol) and 5-bromopyrimidine (287 mg, 1.80
mmol). Reaction time 24 h; yield: 145 mg (62%); white solid; mp
141–142 °C (CH2Cl2).
IR (KBr): n = 1414, 1399, 1187, 1006 cm–1.
1H NMR (CDCl3, 500 MHz): 0.49 (s, 9 H, 3 CH3), 2.39 (s, 3 H,
CH3), 7.25 (br d, J = 8.5 Hz, 1 H, H-5’’), 7.30 (dd, J = 8.0, 4.5 Hz, 1
H, H-5), 7. 52 (br s, 1 H, H-3’’), 7.99 (s, 1 H, H-2), 8.06 (dd, J = 8.0,
(13) Matzukawa, T.; Ohta, B. J. Pharm. Soc. Jpn 1949, 69, 489.
(14) Brown, D. J.; Foster, R. V. Aust. J. Chem. 1966, 19, 2321.
Synthesis 1999, No. 4, 615–620 ISSN 0039-7881 © Thieme Stuttgart · New York