Synthesis of 4-substituted 7-azaindole derivatives via Pd-catalyzed C-N and C-O coupling

Article abstract of DOI:10.1055/s-2006-926310

The efficient substitution of 4-chloro-7-azaindoles by anilines and phenols via palladium-catalyzed C-N and C-O coupling is reported. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926310

PAPER
629
Synthesis of 4-Substituted 7-Azaindole Derivatives via Pd-Catalyzed C–N and
C–O Coupling
4
-Substituted 7-Azaind
i
oles chael Thutewohl,*1 Hartmut Schirok, Samir Bennabi,2 Santiago Figueroa-Pérez
Bayer HealthCare AG, Pharma Research, 42096 Wuppertal, Germany
Fax +41(81)7552736; E-mail: mthutewohl@europe.sial.com
Received 15 June 2005; revised 21 September 2005
tected (SEM-protected) (1d) azaindole, the yields were in
the same range as with 4-chloroazaindole (1a) and 3-
methyl-4-chloroazaindole (1b). The formation of rear-
ranged products of type 4 was not observed. A compara-
ble result was obtained with 4-nitroaniline (2b) (entry 5).
In the case of 2-chloro-4-nitroaniline (2c), Pd-catalyzed
aniline dimerisation occurred reducing the yield (entry 6).
The reaction of the electron-rich 4-bisbenzylamino-sub-
stituted aniline 2d10 also proceeded smoothly (entries 7
and 8). However, in this case the protection of azaindole
N1 as tosylate improved the yield significantly (entry 9),
because otherwise a yield-reducing N1–C4 azaindole–
azaindole self-coupling to products of type 8 took place.
To the best of our knowledge, the compounds 3a–i are the
first members of this structural class.
Abstract: The efficient substitution of 4-chloro-7-azaindoles by
anilines and phenols via palladium-catalyzed C–N and C–O cou-
pling is reported.
Key words: 7-azaindoles, palladium catalysis, C–N coupling, C–O
coupling, heterocycles
An increasing number of pharmaceutically active com-
pounds with application in various therapeutic areas
contain the 7-azaindole (1H-pyrrolo[2,3-b]pyridine) phar-
macophore,3 including 4-substituted compounds.4 The
nucleophilic aromatic substitution of 4-chloro-7-azain-
dole 15 with suitable nucleophiles should provide a conve-
nient access to these derivatives. However, there are only
some scattered reports on this kind of reaction, and they
appear to be limited to particular reagents like secondary
anilines or simple aliphatic alcohols.6 It was reported that
the reaction between 1 and primary anilines 2 does not
yield the 4-substituted 7-azaindole 3. Instead, the rear-
ranged 4-amino-5-azaindole 4 is formed exclusively.6 The
analogous introduction of phenols 5 towards arylethers 6
is not known either.
The palladium-catalyzed ether formation is still a chal-
lenging field, especially because of the disfavored reduc-
tive elimination to form the C–O bond due to the Pd–C
(LUMO) and Pd–O (HOMO) energy gap.11 Whilst
Hartwig reported ferrocene-based ligands for the genera-
tion of diaryl ethers,12 Buchwald disclosed that electron-
rich, sterically bulky monodentate biphenyl dialkylphos-
phanes are versatile ligands for the Pd-catalyzed C–O
bond formation.13 Recently, Beller described the applica-
tion of 2-phosphino-N-arylpyrrole and -indole ligands
(cataCXium®P ligands) for the synthesis of diaryl ethers
from aryl chlorides.14 Even though ligand 7 was only de-
scribed for Pd(0)-catalyzed C–N coupling, we wanted to
study its possible application to a C–O bond formation to
introduce phenols into the 4-position of azaindole 1. In ac-
cordance with a general observation reported in the litera-
ture, toluene proved to be by far the best solvent for this
transformation. In comparison to the conditions described
for the anilines, a much longer reaction time was required.
Moreover, the outcome of the reaction strongly depended
on the electronic character of the appropriate phenol
(Table 1). The particularly electron-poor 2-fluoro-4-nitro-
phenol (5a) did not show any reaction (entries 10 and 11).
Acetylated or Boc-protected p-aminophenols gave the
products 6c and 6d in moderate yields (entries 12 and 13),
while the more-electron-rich nucleophiles 5d–f furnished
the desired ethers 6e–g in moderate and good yields, re-
spectively (entries 14–16). This seems to be consistent
with literature presenting electron-rich phenols as favored
substrates.
In this work, we describe the efficient Pd-mediated syn-
thesis of arylaniline- and phenol-substituted compounds
of type 3 and 6 (Scheme 1), interesting intermediates in
one of our own medicinal chemistry programs based on 7-
azaindoles. Recently, the Pd-catalyzed 4-arylation of 7-
azaindoles was described,7 as well as the analogous intro-
duction of allylamine.8 In our case, we applied a highly
active catalyst system containing the bulky and air-stable
XPHOS-ligand 7, offering advantageous properties and
versatile applicability for C–N bond formation.9
To our delight, attempts to react the electron-poor p-ni-
troanilines 2a–c (Table 1) with 4-chloroazaindoles 1a–d
by using tert-butanol as solvent and potassium carbonate
as base according to literature procedures9b proceeded
quite well. Other bases like potassium tert-butoxide or ce-
sium carbonate, as well as toluene as solvent, gave lower
yields. The reaction of 1a–d with 2-fluoro-4-nitroaniline
(2a) furnished the desired bisarylanilines 3a–d in excel-
lent yields (entries 1–4). In these reactions, the protection
of the azaindole N-1 position was not required. With the
tosylated (1c) or [2-(trimethylsilyl)ethoxy]methyl-pro-
SYNTHESIS 2006, No. 4, pp 0629–0632
Advanced online publication: 19.01.2006
DOI: 10.1055/s-2006-926310; Art ID: T07805SS
x
x
.
x
x
.2
0
0
6
In conclusion, we have developed a novel access to 7-aza-
indole-4-arylanilines and 7-azaindole-4-arylethers via Pd-
© Georg Thieme Verlag Stuttgart · New York

630
M.Thutewohl et al.
PAPER
N4,N4-Dibenzyl-2,6-difluorobenzene-1,4-diamine (2d)
Ar
N
Ethyl [4-(dibenzylamino)-2,6-difluorophenyl]carbamate was pre-
pared from N,N-dibenzyl-3,5-difluoroaniline15 by carboxylation
and subsequent Schmidt rearrangement following a procedure dis-
closed previously.10
N
NH2
Ethyl [4-(dibenzylamino)-2,6-difluorophenyl]carbamate (2.10 g,
5.30 mmol) was dissolved in EtOH (40 mL). Powdered KOH
(3.0 g, 53 mmol) was added and the mixture was heated to reflux for
20 h. The solvent was evaporated and H2O (20 mL) and CH2Cl2 (40
mL) were added. The organic layer was separated and washed with
H2O (3 × 10 mL), then dried over Na2SO4, and concentrated in vac-
uo. The residue was dissolved in EtOAc, and charcoal was added.
Upon filtration, the solvent was evaporated. After the addition of
pentane, the product precipitated and was collected in a suction fil-
ter to yield 1.20 g (70%) of the desired aniline as pink crystals.
4
R5
R4
without
catalyst
R1, R2 = H
b)
R5
R4
NH2
2
R3
NH
R2
R3
Pd cat., a)
N
R1
N
1H NMR (300 MHz, DMSO-d6): d = 4.56 (s, 4 H), 6.21–6.36 (m, 2
H), 7.19–7.36 (m, 10 H).
Cl
R2
3
13C NMR (125 MHz, DMSO-d6): d = 54.5, 97.0 (dd,
3
2
2JC,F = 17.9 Hz, JC,F = 8.7 Hz), 115.0 (t, JC,F = 17.7 Hz), 126.6,
N
N
3
R1
126.7, 128.4, 138.8, 139.3 (t, JC,F = 11.9 Hz), 152.3 (dd,
1JC,F = 235 Hz, 3JC,F = 11.6 Hz).
R5
R4
1
HRMS: m/z [M+] calcd for C20H18N2F2: 324.1438; found: 324.1431.
R5
R4
O
OH
Compounds 3 and 6; General Procedure
R3
5
A solution of 4-chloroazaindole 1, nucleophile 2 or 5 (1.2 equiv),
tris(dibenzylideneacetone)dipalladium (0.05 equiv), dicyclohexyl-
phosphino-2¢,4¢,6¢-triisopropylbiphenyl (0.1 equiv), and K2CO3
(2.2 equiv) in degassed t-BuOH (for 3) or degassed toluene (for 6)
(1.5 mL per mmol 1) was stirred for 3 h at 100 °C (for 3) or over-
night at 110 °C (for 6) in a sealed pressure tube. After cooling to r.t.,
the mixture was filtered over celite, washed with EtOAc, and the fil-
trates were concentrated in vacuo. The residue was purified by flash
chromatography (eluents are indicated below) giving the desired
products 3 or 6.
R2
R3
Pd cat., c)
N
R1
N
Cl
N
6
PCy2
N
N-(2-Fluoro-4-nitrophenyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
(3a)
Eluent: cyclohexane–EtOAc (1:1); 78% yield as a yellow solid.
N
N
H
1H NMR (300 MHz, DMSO-d6): d = 6.36–6.42 (m, 1 H), 6.81 (d,
J = 5.4 Hz, 1 H), 7.28–7.37 (m, 2 H), 8.04 (dd, J = 8.8, 2.7 Hz, 1 H),
8.10 (d, J = 5.2 Hz, 1 H), 8.18 (dd, J = 11.5, 2.7 Hz, 1 H), 9.32 (s, 1
H), 11.68 (s, 1 H).
7
8
Scheme 1 Synthesis of 4-arylamino substituted 7-azaindoles.
Reagents and conditions: a) Pd2(dba)3 (0.05 equiv), 7 (0.1 equiv),
K2CO3 (2.2 equiv), t-BuOH, sealed tube, 100 °C, 3 h; b) Neat,
180 °C, 3 h; c) Pd2(dba)3 (0.05 equiv),
(2.2 equiv), toluene, sealed tube, 110 °C, overnight.
13C NMR (125 MHz, DMSO-d6): d = 98.7, 104.9, 111.1, 111.9 (d,
7 (0.1 equiv), K2CO3
2JC,F = 24.0 Hz), 118.2 (d, 3JC,F = 3.2 Hz), 121.1 (d, 4JC,F = 2.3 Hz),
2
3
124.1, 137.6 (d, JC,F = 11.6 Hz), 139.6 (d, JC,F = 8.1 Hz), 139.9,
143.4, 150.1, 151.1 (d, 1JC,F = 247 Hz).
HRMS: m/z [M+] calcd for C13H9N4O2F: 272.0710; found:
272.0711.
catalyzed cross-coupling reactions. A number of anilines
was introduced in high yields via this method, avoiding a
known side reaction. In case of phenols, electron-rich sub-
strates also provided good yields, while electron-poor
ones gave only modest yields or did not react at all. More-
over, this is the first example of the application of the
XPHOS-ligand for the Pd-catalyzed C–O bond formation.
N-(2-Fluoro-4-nitrophenyl)-1-{[2-(trimethylsilyl)ethoxy]meth-
yl}-1H-pyrrolo[2,3-b]pyridin-4-amine (3d)
Eluent: gradient cyclohexane–EtOAc (10:1–8:2); 84% yield as a
yellow solid.
1H NMR (400 MHz, DMSO-d6): d = –0.09 (s, 9 H), 0.83 (t,
J = 8.1 Hz, 2 H), 3.52 (t, J = 8.1 Hz, 2 H), 5.60 (s, 2 H), 6.51 (d,
J = 3.7 Hz, 1 H), 6.85 (d, J = 5.1 Hz, 1 H), 7.38 (t, J = 8.8 Hz, 1 H),
7.51 (d, J = 3.4 Hz, 1 H), 8.05 (dd, J = 8.8, 2.6 Hz, 1 H), 8.14 (d,
J = 5.4 Hz, 1 H), 8.19 (dd, J = 11.3, 2.6 Hz, 1 H), 9.39 (s, 1 H).
1H and 13C NMR spectra were recorded on Bruker Avance spec-
trometers operating at 300 MHz, 400 MHz (1H), and 125 MHz (13C)
in DMSO-d6 or CDCl3. Flash column chromatography was per-
formed with silica gel 60 (0.063–0.200 mm) from Merck KGaA,
Darmstadt, Germany.
13C NMR (125 MHz, DMSO-d6): d = –1.38, 17.2, 65.3, 72.4, 99.2,
2
3
105.3, 111.3, 112.1 (d, JC,F = 24.0 Hz), 118.9 (d, JC,F = 2.8 Hz),
121.2 (d, 4JC,F = 2.0 Hz), 127.3, 137.3 (d, 2JC,F = 11.3 Hz), 140.4 (d,
3JC,F = 8.3 Hz), 140.7, 143.8, 149.3, 151.5 (d, 1JC,F = 247 Hz).
Solvents used as reaction media were purchased in absolute grade
and used as received. Commercial reagents were used without puri-
fication.
Synthesis 2006, No. 4, 629–632 © Thieme Stuttgart · New York

PAPER
4-Substituted 7-Azaindoles
631
Table 1 Synthesis of 4-N- (3) and 4-O-Substituted (6) 7-Azaindolesa
Entry
1
SMb
1a
1b
1c
R1
R2
H
Nucl.
2a
2a
2a
2a
2b
2c
R3
F
R4
H
H
H
H
H
H
F
R5
Prod.
3a
3b
3c
3d
3e
3f
Yield
H
NO2
NO2
NO2
NO2
NO2
NO2
NBn2
NBn2
NBn2
NO2
NO2
NHAc
NHBoc
H
78%
87%
75%
84%
68%
26%
42%
37%
78%
–
2
H
Me
H
F
3
Ts
F
4
1d
1a
1a
1a
1b
1e
SEM
H
H
F
5
H
H
Cl
F
6
H
H
7
H
H
2d
2d
2d
5a
5a
5b
5c
3g
3h
3i
8
H
Me
Me
H
F
F
9
Ts
F
F
10
11
12
13
14
15
16
1a
1c
H
F
H
H
H
H
H
H
H
6a
6b
6c
6d
6e
6f
Ts
H
F
–
1d
1d
1d
1d
1d
SEM
SEM
SEM
SEM
SEM
H
F
22%
37%
56%
64%
73%
H
F
H
5d
5e
H
H
Me
H
Me
H
5f
H
6g
a Method A for anilines 2: 0.05 equiv Pd2(dba)3, 0.1 equiv 7, 1.2 equiv 2, 2.2 equiv K2CO3, t-BuOH, sealed tube, 100 °C, 3 h. Method B for
phenols 5: 0.05 equiv Pd2(dba)3, 0.1 equiv 7, 1.2 equiv 5, 2.2 equiv K2CO3, toluene, sealed tube, 110 °C, overnight.
b Starting material.
HRMS: m/z [M+H]+ calcd for C19H24N4O3FSi: 403.1597; found:
403.1599.
N4,N4-Dibenzyl-2,6-difluoro-N1-{3-methyl-1-[(4-methylphen-
yl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}benzol-1,4-diamine
(3i)
N-(4-Nitrophenyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (3e)
Eluent: cyclohexane–EtOAc (5:1); 78% yield as a yellowish solid.
Purification by filtration; 68% yield as a purple solid.
1H NMR (300 MHz, DMSO-d6; rotamers in brackets): d = 2.30
[2.32] (s, 3 H), 2.36 [2.41] (s, 3 H), 4.77 (s, 4 H), 5.89 (d, J = 5.7 Hz,
1 H), 6.47 [6.49] (d, J = 5.7 Hz, 2 H), 7.16 [7.20] (s, 1 H), 7.17–7.31
(m, 6 H), 7.32–7.42 (m, 6 H), 7.77 [7.82] (d, J = 5.7 Hz, 1 H), 7.91
(d, J = 8.31 Hz, 2 H), 8.33 (s, 1 H).
1H NMR (300 MHz, DMSO-d6): d = 6.48–6.58 (m, 1 H), 6.97 (d,
J = 5.3 Hz, 1 H), 7.28–7.42 (m, 3 H), 8.08 (d, J = 5.3 Hz, 1 H), 8.19
(d, J = 9.2 Hz, 2 H), 9.55 (s, 1 H), 11.62 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 98.3, 103.3, 112.3, 116.4,
123.9, 125.7, 139.5, 140.1, 143.6, 148.9, 150.1.
HRMS: m/z [M+] calcd for C13H10N4O2: 254.0804; found:
254.0808.
13C NMR (125 MHz, DMSO-d6): d = 12.9, 21.0, 54.1, 95.8 (d,
2
2JC,F = 28.0 Hz), 101.4, 103.4 (t, JC,F = 17.8 Hz), 109.4, 114.4,
119.9, 128.6, 128.61, 127.0, 127.4, 128.6, 129.8, 134.9, 138.0,
145.1, 145.7, 148.3, 160.0 (dd, 1JC,F = 244 Hz, 3JC,F = 8.3 Hz).
N4,N4-Dibenzyl-2,6-difluoro-N1-1H-pyrrolo[2,3-b]pyridin-4-yl-
benzol-1,4-diamine (3g)
HRMS: m/z [M+] calcd for C35H30N4O2F2S: 608.2058; found:
608.2070.
Eluent: gradient cyclohexane–EtOAc (1:1), EtOAc, MeOH–EtOAc
(1:100); 42% yield as a yellow solid.
1H NMR (400 MHz, DMSO-d6): d = 4.76 (s, 4 H), 5.82 (d,
J = 5.5 Hz, 1 H), 6.41–6.50 (m, 1 H), 6.49 (d, J = 11.5 Hz, 2 H),
7.07–7.12 (m, 1 H), 7.21–7.43 (m, 10 H), 7.76 (d, J = 5.5 Hz, 1 H),
7.91 (s, 1 H), 11.25 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 54.1, 95.9 (d,
2JC,F = 28.2 Hz), 97.2, 97.7, 104.4 (t, 2JC,F = 17.8 Hz), 107.4, 121.7,
126.6, 127.0, 128.6, 138.1, 143.8, 146.4, 147.8 (t, 3JC,F = 13.2 Hz),
149.4, 159.9 (dd, 1JC,F = 243 Hz, 3JC,F = 8.6 Hz).
tert-Butyl-{3-fluoro-4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-
1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl}carbamate (6d)
Eluent: gradient cyclohexane–EtOAc (10:1–2:1); 37% yield as a
colorless oil.
1H NMR (400 MHz, CDCl3): d = –0.07 (s, 9 H), 0.92 (t, J = 8.1 Hz,
2 H), 1.53 (s, 9 H), 3.54 (t, J = 8.1 Hz, 2 H), 5.66 (s, 2 H), 6.40 (d,
J = 5.5 Hz, 1 H), 6.47 (d, J = 3.4 Hz, 1 H), 6.58 (s, 1 H), 7.03 (d,
J = 9.0 Hz, 1 H), 7.14 (t, J = 9.0 Hz, 1 H), 7.24 (d, J = 3.4 Hz, 1 H),
7.52 (d, J = 12.5 Hz, 1 H), 8.15 (d, J = 5.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = –1.47, 17.7, 28.3, 66.2, 73.1,
HRMS: m/z [M+] calcd for C27H22N4F2: 440.1813; found: 440.1802.
2
81.2, 98.5, 101.8, 107.7 (d, JC,F = 23.6 Hz), 110.6, 114.2, 123.6,
Synthesis 2006, No. 4, 629–632 © Thieme Stuttgart · New York

632
M.Thutewohl et al.
PAPER
2
126.5, 136.8 (d, JC,F = 9.5 Hz), 144.7, 150.6, 152.4, 154.7 (d,
1JC,F = 249 Hz), 158.2.
(3) Mérour, J.-Y.; Joseph, B. Curr. Org. Chem. 2001, 5, 471;
and references cited therein.
(4) (a) Henry, J. R.; Dodd, J. H. Tetrahedron Lett. 1998, 39,
8763. (b) Hodge, C. N.; Aldrich, P. E.; Wasserman, Z. R.;
Fernandez, C. H.; Nemeth, G. A.; Arvanitis, A.; Cheeseman,
R. S.; Chorvat, R. J.; Ciganek, E.; Christos, T. E.; Gilligan,
P. J.; Krenitsky, P.; Scholfield, E.; Strucely, P. J. Med.
Chem. 1999, 42, 819. (c) Ishizaki, T.; Uehata, M.;
Tamechika, I.; Keel, J.; Nonomura, K.; Maekawa, M.;
Narumiya, S. Mol. Pharm. 2000, 57, 976. (d) Wang, T.;
Zhang, Z.; Wallace, O. B.; Deshpande, M.; Fang, H.; Yang,
Z.; Zadjura, L. M.; Tweedie, D. L.; Huang, S.; Zhao, F.;
Ranadive, S.; Robinson, B. S.; Gong, Y.-F.; Riccardi, K.;
Spicer, T. P.; Deminie, C.; Rose, R.; Wang, H.-G. H.; Blair,
W. S.; Shi, P.-Y.; Lin, P.-F.; Colonno, R. J.; Meanwell, N.
A. J. Med. Chem. 2003, 46, 4236. (e) Hilmy, K. M. H. Arch.
Pharm. Pharm. Med. Chem. 2004, 337, 15.
HRMS: m/z [M+H]+ calcd for C24H33N3O4FSi: 474.2219; found:
474.2218.
4-Phenoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrro-
lo[2,3-b]pyridine (6e)
Eluent: cyclohexane–EtOAc (10:1); 56% yield as yellowish oil.
1H NMR (300 MHz, CDCl3): d = 0.01 (s, 9 H), 0.97 (t, J = 8.2 Hz,
2 H), 1.60 (s, 9 H), 3.62 (t, J = 8.2 Hz, 2 H), 5.73 (s, 2 H), 6.46 (d,
J = 3.6 Hz, 1 H), 6.56 (d, J = 5.5 Hz, 1 H), 7.21–7.32 (m, 4 H),
7.45–7.50 (m, 2 H), (d, J = 12.5 Hz, 1 H), 8.22 (d, J = 5.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3) d = –1.47, 17.8, 66.2, 73.1, 98.7,
103.0, 111.4, 120.5, 124.8, 126.4, 129.9, 144.8, 150.8, 155.1, 158.1.
HRMS: m/z [M+H]+ calcd for C19H25N2O2Si: 341.1680; found:
341.1685.
(5) Schneller, S. W.; Luo, J.-K. J. Org. Chem. 1980, 45, 4045.
(6) Girgis, N. S.; Larson, S. B.; Robins, R. K.; Cottam, H. B. J.
Heterocycl. Chem. 1989, 26, 317.
4-(4-Methylphenoxy)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-
pyrrolo[2,3-b]pyridine (6f)
Eluent: cyclohexane–EtOAc (10:1); 64% yield as colorless oil.
1H NMR (300 MHz, CDCl3): d = –0.06 (s, 9 H), 0.97 (t, J = 8.3 Hz,
2 H), 2.44 (s, 3 H), 3.61 (t, J = 8.3 Hz, 2 H), 5.73 (s, 2 H), 6.47 (d,
J = 5.5 Hz, 1 H), 6.52 (d, J = 5.5 Hz, 1 H), 7.08 (d, J = 8.5 Hz, 2 H),
7.25 (d, J = 3.5 Hz, 1 H) overlapping with 7.27 (d, J = 8.6 Hz, 2 H),
8.21 (d, J = 5.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = –1.7, 17.7, 20.8, 66.1, 73.1, 98.7,
103.0, 111.2, 120.5, 126.2, 130.4, 134.6, 144.8, 150.7, 152.7, 158.5.
HRMS: m/z [M+H]+ calcd for C20H27N2O2Si: 355.1837; found:
355.1835.
(7) Allegretti, M.; Arcadi, A.; Marinelli, F.; Nicolini, L. Synlett
2001, 609.
(8) Thibeault, C.; L’Heureux, A.; Bhide, R. S.; Ruel, R. Org.
Lett. 2003, 5, 5023.
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A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653.
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A. R.; Buchwald, S. L. Cross-Coupling Reactions, In Topics
in Current Chemistry, Vol. 219; Miyaura, N., Ed.; Springer:
Berlin, 2002, 131–209. (f) Prim, D.; Campagne, J.-M.;
Joseph, D.; Andrioletti, B. Tetrahedron 2002, 58, 2041.
(g) Schlummer, B.; Scholz, U. Adv. Synth. Catal. 2004, 346,
1599. (h) Scholz, U.; Schlummer, B. Tetrahedron 2005, 61,
6379.
4-(2-Methylphenoxy)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-
pyrrolo[2,3-b]pyridine (6g)
Eluent: cyclohexane–EtOAc (10:1); 73% yield as yellowish oil.
1H NMR (300 MHz, CDCl3): d = –0.06 (s, 9 H), 0.91 (t, J = 8.1 Hz,
2 H), 2.20 (s, 3 H), 3.62 (t, J = 8.1 Hz, 2 H), 5.67 (s, 2 H), 6.31 (d,
J = 5.5 Hz, 1 H), 6.41 (d, J = 5.5 Hz, 1 H), 7.08 (dd, J = 7.6, 1.6 Hz,
1 H), 7.13–7.29 (m, 4 H), 8.13 (d, J = 5.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = –1.48, 16.0, 17.7, 66.1, 73.1,
98.6, 102.2, 110.8, 121.4, 125.4, 126.2, 127.3, 130.7, 131.6, 144.8,
150.7, 152.8, 158.3.
(10) The aniline was prepared in a three-step procedure disclosed
in: Alonso-Alija, C.; Michels, M.; Peilstöcker, K.; Schirok,
H. Tetrahedron Lett. 2004, 45, 95.
(11) Bäckvall, J.-E.; Björkman, E. E.; Pettersson, L.; Siegbahn, P.
J. Am. Chem. Soc. 1984, 106, 4369.
(12) (a) Mann, G.; Hartwig, J. F. Tetrahedron Lett. 1997, 38,
8005. (b) Mann, G.; Incarvito, C.; Rheingold, A. L.;
Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 3224.
(c) Shelby, Q.; Kataoka, N.; Mann, G.; Hartwig, J. F. J. Am.
Chem. Soc. 2000, 122, 10718. (d) Kataoka, N.; Shelby, Q.;
Stambuli, J. P.; Hartwig, J. F. J. Org. Chem. 2002, 67, 5553.
(13) (a) Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.;
Sadighi, J.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121,
4369. (b) Parrish, C. A.; Buchwald, S. L. J. Org. Chem.
2001, 66, 2498.
HRMS (ESI): m/z [M+H]+ calcd for C20H27N2O2Si: 355.1837;
found: 355.1836.
Acknowledgment
We are grateful to Dr. P. Schmitt, C. Streich, and D. Bauer for re-
cording NMR spectra. In addition, we thank M. Stoltefuß, G. Wie-
fel-Hübschmann, and S. Brauner for HRMS measurements.
(14) Harkal, S.; Kumar, K.; Michalik, D.; Zapf, A.; Jackstell, R.;
Rataboul, F.; Riermeier, T.; Monsees, A.; Beller, M.
Tetrahedron Lett. 2005, 46, 3237.
(15) Florvall, L.; Fagervall, I.; Larsson, L.-G.; Ross, S. B. Eur. J.
Med. Chem. 1999, 34, 137.
References
(1) Current address: Sigma-Aldrich Production GmbH,
Industriestraße 25, 9471 Buchs, SG, Switzerland.
(2) Current address: Bayer CropScience SA, Fungicide
Research, BP 9163, 69263 Lyon, France.
Synthesis 2006, No. 4, 629–632 © Thieme Stuttgart · New York