Palladium-catalyzed C-O and C-C coupling reactions of electron-rich indoles

Article abstract of DOI:10.1055/s-2007-990819

A novel palladium-catalyzed formation of indole aryl ethers is described. In general, the corresponding indole ethers are obtained in the presence of Pd(OAc)₂ combined with N-phenyl-2-(di-1-adamantylphosphino)pyrrole in high yields. Georg Thiem

Full text of DOI:10.1055/s-2007-990819

3722
PAPER
Palladium-Catalyzed C–O and C–C Coupling Reactions of Electron-Rich
Indoles
Coupling
R
eaction
i
s
of Ele
c
ctron-Rich
o
Indoles lle Schwarz, Anahit Pews-Davtyan, Karolin Alex, Annegret Tillack, Matthias Beller*
Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Fax +49(381)12815000; E-mail: matthias.beller@catalysis.de
Received 14 August 2007; revised 17 August 2007
with the in-house-developed ligand N-phenyl-2-(di-1-ad-
Abstract: A novel palladium-catalyzed formation of indole aryl
ethers is described. In general, the corresponding indole ethers are
obtained in the presence of Pd(OAc)2 combined with N-phenyl-2-
(di-1-adamantylphosphino)pyrrole in high yields.
amantylphosphino)pyrrole (7) (Table 1, entry 7).12
Apparently, a subtle balance of steric and electronic fac-
tors of the ligand is important to activate the Pd center.
Hence, the replacement of the dicyclohexyl substituents
of ligand 10 by di-tert-butyl and, more importantly, by di-
1-adamantyl substituents (ligand 11 and 7, respectively)
led to a significant increase of the product yield. Further
variation of different bulky ligands showed no appreci-
able improvements. Apart from 7 only the Buchwald
ligand 12 (Table 1, entry 12) gave the corresponding in-
dole in noticeable yield (15%). Apparently, our model re-
action was challenging and further modification of the
reaction parameters was necessary.
Key words: indoles, diaryl ethers, palladium, cross-coupling
Diaryl ethers form an important class of organic com-
pounds throughout the life science and polymer indus-
tries.1 Aryl ethers, including oxygen heterocycles, have
been reported to possess significant biological activity;
for example, natural products of the isodityrosin family,
vancomycin,2 angiotensin-converting enzyme inhibitor
K-13,3 (+)-piperazinomycin,4 and antitumor compounds
such as bouvardin and bastadin.5 Until recently, the most
general synthesis for the preparation of diaryl ethers was
the classic Ullmann ether synthesis, but it is often limited
by harsh reaction conditions, use of stoichiometric
amounts of copper and the necessity of a large excess of
the phenolic substrate.6 In the last decade a number of in-
teresting and improved methods for diaryl ether formation
have been reported.7 For instance, the palladium-cata-
lyzed coupling of phenols and aryl halides is an important
extension of other reported carbon–heteroatom bond-
forming reactions.8 In this regard intermolecular palladi-
um-catalyzed C–O bond formation in the presence of
electron-rich bulky aryldialkylphosphines by Buchwald
and co-workers is also noteworthy.9
Therefore, we examined the influence of different bases,
metal precursors, temperatures (100–160 °C), and the cat-
alyst concentration (0.5–6 mol% Pd). The results of this
optimization study are shown in Table 2. Neither the
change of base nor the variation of the palladium source
raised the product yield. However, applying 2 mol%
Pd(OAc)2 at 120 °C enhanced the yield of 16 from 34%
(Table 2, entry 2) to 83% (Table 2, entry 5). Doubling the
catalyst concentration gave a similar yield at 100 °C
(Table 2, entry 13). Also ligand 12 gave an improved
yield, however, somewhat lower compared to 7 (Table 2,
entry 4 vs entry 3). As expected the reaction did not work
without any ligand, base, or catalyst.
Next, we were interested in the scope and limitation of the
catalyst system for different phenols and indoles. All re-
actions in Table 3 were performed at 120 °C for 24 hours
in toluene in the presence of 2 mol% Pd(OAc)2, 4 mol%
N-phenyl-2-(di-1-adamantylphosphino)pyrrole (7) and 2
equivalents of K3PO4.
Based on our continuing interest in the synthesis and de-
rivatization of indoles10 as well as in Pd-catalyzed cou-
pling reactions,11 very recently we developed a
convenient protocol for electron-rich 3-siloxy- and 3-
alkoxyindoles.10d In the present paper we describe for the
first time the Pd-catalyzed aryl ether synthesis of different
5-bromoindoles.
As shown in Table 3, the corresponding indole products
16–23 were obtained in moderate to good yields (52–
85%). The Pd catalyst system works well with various
alkylated phenols and different N-protected indole deriv-
atives. There is no significant difference in reactivity be-
tween 2-, 3-, and 4-methylphenol and 2,6-dimethylphenol
(Table 3, entries 1,4,5,6). The N-benzyl- and N-Boc-pro-
tected indoles gave an improved yield of the coupling
product (Table 3, entries 2,3). Unfortunately, under the
same reaction conditions 5-bromoindole and 6-bromoin-
dole with a free NH-group gave either no ether products
or only traces (<2%). In none of these reactions we have
observed reductive dehalogenation of the bromoindoles.
Noteworthy, the C–O coupling reaction of the simple N-
Boc-indole proceeded smoothly in 85% yield (Table 3,
entry 8).
In exploratory experiments, we investigated the influence
of different electron-rich sterically demanding ligands on
the coupling of 5-bromo-3-(tert-butyldimethylsiloxy)-
1,2-dimethyl-1H-indole (13) with o-cresol, which served
as our model reaction. As shown in Table 1, most of the
ligands gave only traces of the desired product. The best
yield of the corresponding indole 16 (34%) was achieved
SYNTHESIS 2007, No. 23, pp 3722–3730
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x
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Advanced online publication: 10.10.2007
DOI: 10.1055/s-2007-990819; Art ID: Z18907SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Coupling Reactions of Electron-Rich Indoles
3723
Table 1 Model Reaction of Indole 13 with o-Cresola
1 mol% ligand
2 mol% Pd(OAc)2
K3PO4
OH
OTBDMS
O
OTBDMS
Br
+
toluene
100°C
24 h
N
N
Me
Me
13
16
Entry
1
Ligand
Yield (%)b
P
1
2
<1
<1
P
2
P
3
3
1
P
4
4
<1
O
O
P
5
6
7
5
6
7
<1
<1
34
N
O
P
O
O
P
N
Synthesis 2007, No. 23, 3722–3730 © Thieme Stuttgart · New York

3724
N. Schwarz et al.
PAPER
Table 1 Model Reaction of Indole 13 with o-Cresola (continued)
1 mol% ligand
2 mol% Pd(OAc)2
K3PO4
OH
OTBDMS
OTBDMS
O
Br
+
toluene
100°C
24 h
N
N
Me
Me
13
16
Entry
8
Ligand
Yield (%)b
P
8
9
<1
P
9
10
11
<1
<1
2
P
N
N
10
11
P
12
12
15
P
a Reaction conditions: indole 13 (0.14 mmol), o-cresol (0.17 mmol), Pd(OAc)2 (1 mol%), ligand (2 mol%), K3PO4 (0.28 mmol), solvent: toluene
(3 mL), 24 h, 100 °C.
b GC yield based on 13 with hexadecane as internal standard.
Interestingly, in the case of the coupling reaction with a- generally applicable, our reaction presented here allows
naphthol we could not isolate the desired ether com- for a much easier access of such compounds.
pounds. To our surprise instead of the indole ethers, we
In conclusion, we have presented a general palladium-cat-
obtained 5-(4-hydroxynaphthyl)indoles by selective C–C
alyzed diaryl ether formation of electron-rich indoles to
coupling reaction (Table 4). It should be noted that the re-
3,5-dioxyindole derivatives, which constitute a novel
sulting 5-arylindole motif is reported to be present in po-
class of electron-rich indoles. Different alkylated phenols
reacted in the presence of Pd(OAc)2 and N-phenyl-2-(di-
1-adamantylphosphino)pyrrole (7) to give potentially bio-
active indole derivatives.
tent agonists of the CNS neurotransmitter serotonin.13 For
example Yang reported the first preparation of this class
of compounds via the Suzuki cross-coupling of indolylbo-
ronic acids with aryl bromides.14 Although probably not
Synthesis 2007, No. 23, 3722–3730 © Thieme Stuttgart · New York

PAPER
Coupling Reactions of Electron-Rich Indoles
3725
Table 2 Optimization of the Model Reaction of Indole 13 with o-Cresola
OH
OTBDMS
N
OTBDMS
O
Br
+
N
Me
Me
13
16
Entry Pd source
Catalyst (mol%)
Ligand 7 (mol%) Solvent
Base
Temperature (°C) Yield (%)b
1
2
3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
0.5
1
1
2
4
toluene
K3PO4
K3PO4
K3PO4
100
100
100
25
34
75
toluene
toluene
2
4
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2dba3
2
2
2
2
2
2
2
2
3
4
4
4
4
4
4
4
4
4
4
4
6
4c
4
4
4
4
4
4
4
6
8
8
8
8
8
8
8
8
8
8
8
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
LiHMDS
LiHMDS
t-BuONa
t-BuONa
Cs2CO3
Cs2CO3
t-BuOK
t-BuOK
–
100
120
140
160
100
120
100
120
100
100
100
100
100
100
100
100
100
100
100
100
100
60
83
75
71
44
38
<1
1
Pd2dba3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
PdCl2
PdCl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
76
77
25
1
toluene
THF
<1
2
toluene
THF
<1
15
3
toluene
THF
toluene
THF
10
<1
<1
70
toluene
toluene
12
K3PO4
a Reaction conditions: indole 13 (0.14 mmol), o-cresol (0.17 mmol), Pd complex (0.5–6 mol%) and ligand 7 (1–12 mol%), base (0.28 mmol),
solvent: (3 mL), 24 h.
b GC yield based on 13 with hexadecane as internal standard.
c Reaction with ligand 12 (Table 1, entry 12).
were recorded on a MAT 95XP spectrometer (Thermo Electron
Corporation). IR spectra were recorded on a FTIR Nicolet 6700
(Thermo Electron Corporation). GC was performed on a Hewlett
Packard HP 6890 chromatograph with a 30 m HP5 column. All
yields reported in Tables 1 and 2 refer to GC yields using hexade-
cane as an internal standard. The spectral data of compounds 13 and
14 prepared by literature procedure10d are reported below.
All reactions were carried out under an argon atmosphere. Chemi-
cals were purchased from Aldrich, Fluka, Acros, and Strem, and un-
less otherwise noted were used without further purification. All
compounds were characterized by 1H NMR, 13C NMR, MS, HRMS,
and IR spectroscopy. 1H and 13C NMR spectra were recorded on a
Bruker AV 300, AV 400, and AV 500 spectrometer. The 1H and 13
C
NMR chemical shifts are reported relative to the center of solvent
resonance [CDCl3: 7.25 ppm(1H), 77.0 ppm (13C)]. Mass spectra
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N. Schwarz et al.
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Table 3 Reaction of Indole Derivatives with Different Phenolsa
R3
R3
Br
13 R1 = Me, R2 = Me, R3 = OTBDMS
14 R1 = Bn, R2 = Me, R3 = OTBDMS
15 R1 = Boc, R2 = H, R3 = H
O
Ar
R2
R2
ArOH
N
R1
N
R1
13–15
16–23
Entry
1
ArOH
Product
Yield (%)b
60
OTBDMS
OH
O
16
17
18
19
N
Me
OTBDMS
OH
OH
O
O
2
3
4
80
75
52
N
Bn
N
Boc
OTBDMS
OH
OH
O
O
N
Me
OTBDMS
5
6
20
21
50
50
N
Me
OTBDMS
O
OH
N
Bn
OH
OH
OTBDMS
O
O
7
8
22
23
80
85
N
Bn
N
Boc
a Reaction conditions: indole derivative (0.35 mmol), substituted phenol (0.42 mmol), Pd(OAc)2 (2 mol%), 7 (4 mol%), K3PO4 (0.7 mmol),
solvent: toluene (3 mL), 24 h, 120 °C.
b Isolated yield based on the starting indole.
5-Bromo-3-(tert-butyldimethylsiloxy)-1,2-dimethyl-1H-indole
(13)10d
1H NMR (300.13 MHz, CDCl3): d = 7.53 (d, J = 1.9 Hz, 1 H), 7.15
(dd, J = 1.9, 8.5 Hz, 1 H), 7.03 (d, J = 8.5 Hz, 1 H), 3.56 (s, 3 H),
2.27 (s, 3 H), 1.07 (s, 9 H), 0.14 (s, 6 H).
13C NMR (75.5 MHz, CDCl3): d = 132.5 (q), 129.9 (q), 124.2 (q),
123.4, 123.3 (q), 119.7, 111.8 (q), 110.1, 29.8, 26.1, 18.3 (q), 9.5,
–3.8.
FTIR (KBr): 3072, 2955, 2933, 2896, 2858, 1479, 1377, 1286,
1245, 891, 839, 806, 780 cm–1.
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Coupling Reactions of Electron-Rich Indoles
3727
Table 4 Reaction of Indole Derivatives with a-Naphthola
HO
R3
OH
R3
Br
R2
R2
+
N
R1
N
R1
24 R1 = Me, R2 = Me, R3 = OTBDMS
25 R1 = Bn, R2 = Me, R3 = OTBDMS
26 R1 = Boc, R2 = H, R3 = H
13–15
Entry
1
Product
Yield (%)b
HO
OTBDMS
24
25
26
60
N
Me
HO
OTBDMS
2
3
65
85
N
Bn
HO
N
Boc
a Reaction conditions: indole derivative (0.35 mmol), a-naphthol (0.42 mmol), Pd(OAc)2 (2 mol%), 7 (4 mol%), K3PO4 (0.7 mol), solvent: tol-
uene (3 mL), 24 h, 120 °C.
b Isolated yield based on the starting indole.
MS (EI, 70 eV): m/z (%) = 353 (69), 299 (12), 239 (13), 225 (21),
217 (100), 202 (18), 158 (42), 143 (14), 131 (13), 115 (11), 75 (19),
57 (22).
5-Aryloxyindole Derivatives 16–26; General Procedure
In an Ace pressure tube under argon, N-protected 5-bromoindole
derivative (0.35 mmol), phenol derivative (0.42 mmol), Pd(OAc)2
(2 mol%), N-phenyl-2-(di-1-adamantylphosphino)pyrrole (7; 4
mol%), and K3PO4 (0.7 mmol) were dissolved in toluene (3 mL).
The pressure tube was fitted with a Teflon cap and heated at 120 °C
for 24 h. After removal of the solvent in vacuo, the corresponding
indole product is isolated by column chromatography in hexane–
EtOAc.
HRMS: m/z calcd for C16H24BrNOSi: 353.0805; found: 353.0807.
1-Benzyl-5-bromo-3-(tert-butyldimethylsiloxy)-2-methyl-1H-
indole (14)10d
FTIR (KBr): 3065, 2950, 2925, 2856, 1578, 1471, 1454, 1372,
1289, 1253, 1182, 1087, 896, 873, 839, 824, 807, 790, 782, 732, 699
cm–1.
1H NMR (300.13 Hz, CDCl3): d = 7.39 (d, J = 1.8 Hz, 1 H), 7.04
(m, 3 H), 6.93 (dd, J = 1.8, 8.6 Hz, 1 H), 6.81 (d, J = 8.6 Hz, 1 H),
6.68 (m, 2 H), 5.02 (s, 2 H), 2.02 (s, 3 H), 0.87 (s, 9 H), –0.03 (s, 6
H).
13C NMR (75.5 MHz, CDCl3): d = 137.9 (q), 132.5 (q), 130.4 (q),
129.0, 127.5, 125.9, 124.0 (q), 123.8, 123.7 (q), 119.9, 112.1 (q),
110.6, 46.7, 26.1, 18.3 (q), 9.5, –3.9.
3-(tert-Butyldimethylsiloxy)-1,2-dimethyl-5-(2-methylphen-
oxy)-1H-indole (16)
FTIR (KBr): 3052, 2941, 1481, 1437, 1375, 1282, 1244, 1223, 1211,
1186, 1141, 1130, 1069, 932, 892, 872, 843, 828, 782, 756 cm–1.
1H NMR (300.13 MHz, CDCl3): d = 7.22 (m, 1 H), 7.13 (d, J = 8.7
Hz, 1 H), 7.06 (m, 1 H), 6.97 (m, 2 H), 6.80 (dd, J = 2.4, 8.7 Hz, 1
H), 6.75 (dd, J = 1.1, 8.0 Hz, 1 H), 3.59 (s, 3 H), 2.33 (s, 3 H), 2.28
(s, 3 H), 1.01 (s, 9 H), 0.09 (s, 6 H).
13C NMR (75.5 MHz, CDCl3): d = 157.1 (q), 150.2 (q), 131.3, 130.7
(q), 130.5 (q), 128.8 (q), 127.0, 124.0 (q), 122.5, 122.0 (q), 177.7,
113.4, 109.4, 106.7, 29.8, 26.1, 18.3 (q), 16.5, 9.5, –4.0.
MS (EI, 70 eV): m/z (%) = 431 (100), 429 (95), 293 (30), 234 (4),
202 (31), 115 (10), 91 (63), 73 (98), 59 (11), 57 (3).
HRMS: m/z calcd for C22H28BrNOSi: 429.11181; found:
429.111561.
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N. Schwarz et al.
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MS (EI, 70 eV): m/z (%) = 381 (41), 276 (19), 275 (100), 218 (59),
MS (EI, 70 eV): m/z (%) = 381 (100), 325 (7), 266 (9), 251 (8), 217
177 (14), 163 (7), 144 (26), 112 (7), 75 (6), 57 (7).
(26), 73 (12), 56 (2).
HRMS: m/z calcd for C23H31NO2Si: 381.21186; found: 381.211376.
HRMS: m/z calcd for C23H31NO2Si: 381.21186; found: 381.211563.
1-Benzyl-3-(tert-butyldimethylsiloxy)-2-methyl-5-(2-methyl-
phenoxy)-1H-indole (17)
FTIR (KBr): 3064, 3031, 2958, 2929, 2852, 1586, 1570, 1477,
1373, 1358, 1298, 1256, 1235, 1212, 1185, 1143, 935, 867, 838,
781, 728 cm–1.
1-Benzyl-3-(tert-butyldimethylsiloxy)-5-(2,6-dimethylphen-
oxy)-2-methyl-1H-indole (21)
FTIR (KBr): 3027, 2954, 2925, 2856, 1588, 1571, 1495, 1472,
1374, 1359, 1299, 1266, 12221, 1191, 1143, 1082, 935, 858, 837,
781 cm–1.
1H NMR (300.13 MHz, CDCl3): d = 7.23 (m, 4 H), 7.07 (m, 2 H),
7.00 (d, J = 2.3 Hz, 1 H), 6.97 (dd, J = 1.4, 7.4 Hz, 1 H), 6.92 (m, 2
H), 6.77 (m, 2 H), 5.23 (s, 2 H), 2.32 (s, 3 H), 2.22 (s, 3 H), 1.01 (s,
9 H), 0.11 (s, 6 H).
1H NMR (300.13 MHz, CDCl3): d = 7.24 (m, 3 H), 7.06 (m, 4 H),
6.92 (m, 2 H), 6.74 (dd, J = 2.3, 8.6 Hz, 1 H), 6.59 (d, J = 2.3 Hz, 1
H), 5.20 (s, 2 H), 2.19 (s, 3 H), 2.15 (s, 3 H), 0.96 (s, 9 H), 0.03 (s,
6 H).
13C NMR (75.5 MHz, CDCl3): d = 156.9 (q), 150.5 (q), 138.4 (q),
131.3, 131.0 (q), 130.5 (q), 129.0 (q), 129.1, 127.4, 127.0, 126.0,
123.8 (q), 122.6, 122.4 (q), 117.9, 113.6, 109.9, 106.6, 46.8, 26.1,
18.3 (q), 9.5, –4.0.
13C NMR (75.5 MHz, CDCl3): d = 152.2 (q), 151.9 (q), 138.5 (q),
132.0 (q), 130.8 (q), 129.5 (q), 129.0, 128.9, 127.4, 126.1, 124.8,
123.6 (q), 122.2 (q), 110.6, 109.8, 101.0, 46.8, 25.9, 18.3 (q), 16.6,
9.4, –4.2.
MS (CI, isobutane): m/z (%) = 458 (34), 457 (63), 351 (100), 295
MS (EI, 70 eV): m/z (%) = 472 (37), 471 (100), 297 (3), 202 (5), 91
(6), 91 (12), 73 (30).
(21), 73 (43).
HRMS: m/z calcd for C29H35NO2Si: 457.24316; found: 457.242447.
HRMS: m/z calcd for C30H37NO2Si: 471.25881; found: 471.258729.
tert-Butyl 5-(2-Methylphenoxy)indole-1-carboxylate (18)
FTIR (KBr): 3151, 3120, 3058, 2974, 2921, 1733, 1490, 1462,
1372, 1350, 1278, 1258, 1231, 1213, 1186, 1160, 1118, 1082, 1024
cm–1.
1-Benzyl-3-(tert-butyldimethylsiloxy)-5-(2-tert-butyl-4-meth-
ylphenoxy)-2-methyl-1H-indole (22)
FTIR (KBr): 3060, 3027, 2925, 2856, 1588, 1570, 1456, 1373,
1360, 1300, 1254, 1228, 1145, 1089, 936, 839, 815, 780 cm–1.
1H NMR (300.13 MHz, CDCl3): d = 8.07 (d, J = 8.8 Hz, 1 H), 7.59
(d, J = 3.7 Hz, 1 H), 7.25 (m, 1 H), 7.13 (m, 1 H), 7.04 (m, 2 H),
6.99 (dd, J = 1.3, 7.9 Hz,1 H), 6.46 (dd, J = 0.6, 3.7 Hz, 1 H), 2.29
(s, 3 H), 1.67 (s, 9 H).
1H NMR (300.13 MHz, CDCl3): d = 7.25 (m, 3 H), 7.16 (d, J = 2.0
Hz, 1 H), 7.07 (m, 2 H), 6.93 (m, 2 H), 6.86 (m, 1 H), 6.76 (dd,
J = 2.5, 8.7 Hz, 1 H), 6.66 (d, J = 8.3 Hz, 1 H), 5.23 (s, 2 H), 2.30
(s, 3 H), 2.22 (s, 3 H), 1.45 (s, 9 H), 1.02 (s, 9 H), 0.12 (s, 6 H).
13C NMR (75.5 MHz, CDCl3): d = 155.8 (q), 153.6 (q), 149.9 (q),
131.7 (q), 131.6, 131.4 (q), 129.7 (q), 127.2, 127.1, 123.5, 119.0,
116.2, 115.8, 109.4, 107.3, 83.9 (q), 28.5, 16.6.
13C NMR (75.5 MHz, CDCl3): d = 155.7 (q), 150.7 (q), 139.7 (q),
138.4 (q), 131.2 (q), 130.9 (q), 130.5 (q), 128.9, 127.7, 127.5, 127.4,
126.1, 123.8 (q), 122.5 (q), 119.0, 114.2, 109.8, 107.3, 46.8, 34.9
(q), 30.9, 26.1, 21.2, 18.4 (q), 9.5, –4.0.
MS (EI, 70 eV): m/z (%) = 323 (45), 268 (32), 267 (100), 223 (73),
222 (19), 207 (11), 161 (17), 117 (86), 104 (8), 91 (12), 85 (5), 69
(11), 57 (66).
MS (EI, 70 eV): m/z (%) = 514 (62), 513 (100), 293 (4), 223 (3), 202
(5), 149 (4), 117 (4), 91 (18), 73 (43), 57 (11).
HRMS: m/z calcd for C20H21NO3: 323.15160; found: 323.150899.
HRMS: m/z calcd for C33H43NO2Si: 513.30576; found: 513.305329.
3-(tert-Butyldimethylsiloxy)-1,2-dimethyl-5-(3-methylphen-
oxy)-1H-indole (19)
tert-Butyl 5-(2-tert-Butyl-4-methylphenoxy)indole-1-carbox-
ylate (23)
FTIR (KBr): 3452, 3153, 2954, 2864, 1731, 1494, 1463, 1372,
1350, 1332, 1258, 1210, 1161, 1116, 1082, 1024, 955, 844, 826,
811, 763, 722 cm–1.
1H NMR (300.13 MHz, CDCl3): d = 8.26 (d, J = 8.8 Hz, 1 H), 7.58
(d, J = 3.6 Hz, 1 H), 7.19 (d, J = 2.1 Hz, 1 H), 7.10 (d, J = 2.4 Hz, 1
H), 6.98 (dd, J = 2.4, 9.0 Hz, 1 H), 6.92 (ddd, J = 0.6, 2.2, 8.2 Hz, 1
H), 6.70 (d, J = 8.2 Hz, 1 H), 6.47 (dd, J = 0.5, 3.8 Hz, 1 H), 2.33 (s,
3 H), 1.66 (s, 9 H), 1.43 (s, 9 H).
13C NMR (75.5 MHz, CDCl3): d = 154.4 (q), 153.8 (q), 149.7 (q),
140.4 (q), 132.1 (q), 131.6 (q), 131.1 (q), 127.8, 127.5, 126.8, 119.8,
116.2, 116.0, 109.9, 107.2, 83.7 (q), 34.7 (q), 30.2, 28.2, 21.1.
FTIR (KBr): 3054, 3036, 2950, 2929, 2860, 1481, 1376, 1283,
1254, 1212, 1157, 837, 778 cm–1.
1H NMR (300.13 MHz, CDCl3): d = 7.09 (m, 2 H), 7.05 (d, J = 2.1
Hz, 1 H), 6.76 (m, 2 H), 6.67 (m, 2 H), 3.54 (s, 3 H), 2.22 (s, 3 H),
2.21 (s, 3 H), 0.96 (s, 9 H), 0.05 (s, 6 H).
13C NMR (75.5 MHz, CDCl3): d = 159.8 (q), 149.0 (q), 139.7 (q),
131.1 (q), 130.5 (q), 129.3, 124.1 (q), 122.7, 122.0 (q), 117.8, 144.4,
114.3, 109.4, 108.4, 29.8, 26.0, 21.6, 18.3 (q), 9.5, –4.0.
MS (EI, 70 eV): m/z (%) = 381 (100), 324 (9), 267 (4), 251 (9), 218
(4), 217 (22), 73 (12), 56 (2).
HRMS: m/z calcd for C23H31NO2Si: 381.21186; found: 381.211345.
MS (EI, 70 eV): m/z (%) = 379 (37), 323 (100), 308 (85), 279 (65),
264 (65), 248 (16), 147 (28), 117 (15), 57 (73), 41 (26).
3-(tert-Butyldimethylsiloxy)-1,2-dimethyl-5-(4-methylphen-
oxy)-1H-indole (20)
HRMS: m/z calcd for C24H29NO3: 379.21420; found: 379.214105.
FTIR (KBr): 3027, 2954, 2925, 2852, 1579, 1507, 1483, 1463,
1377, 1289, 1243, 1228, 1205, 1133, 932, 892, 871, 858, 837, 800,
785 cm–1.
4-[3-(tert-Butyldimethylsiloxy)-1,2-dimethyl-1H-indol-5-
yl]naphthalen-1-ol (24)
FTIR (KBr): 3058, 3044, 2953, 2925, 2852, 1588, 1472, 1375,
1H NMR (300.13 MHz, CDCl3):d = 7.17 (d, J = 8.8 Hz, 1 H), 7.13
(d, J = 2.1 Hz, 1 H), 7.09 (m, 2 H), 6.85 (m, 3 H), 3.62 (s, 3 H), 2.32
(s, 3 H), 2.31 (s, 3 H), 1.05 (s, 9 H), 0.14 (s, 6 H).
13C NMR (75.5 MHz, CDCl3): d = 157.5 (q), 149.4 (q), 131.3 (q),
131.0 (q), 130.5 (q), 130.1, 124.1 (q), 122.1 (q), 117.3, 114.1, 109.4,
108.1, 29.8, 26.1, 20.8, 18.4 (q), 9.6, –4.0.
1345, 1272, 1252, 870, 840, 825, 803, 781, 762 cm–1.
1H NMR (300.13 MHz, CDCl3): d = 8.12 (d, J = 8.4 Hz, 1 H), 7.83
(d, J = 8.4 Hz, 1 H), 7.38 (d, J = 1.3 Hz, 1 H), 7.35 (m, 1 H), 7.26
(m, 1 H), 7.11 (m, 3 H), 6.73 (d, J = 7.7 Hz, 1 H), 5.14 (s, 1 H, OH),
3.53 (s, 3 H), 2.20 (s, 3 H), 0.89 (s, 9 H), 0.03 (s, 6 H).
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Coupling Reactions of Electron-Rich Indoles
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13C NMR (75.5 MHz, CDCl3): d = 150.5 (q), 135.0 (q), 133.5 (q),
133.2 (q), 131.0 (q), 130.6 (q), 127.2, 126.9, 126.3, 125.5 (q), 125.2,
124.6 (q), 123.5, 123.4 (q), 121.8, 118.9, 108.5, 108.2, 29.8, 26.1,
18.4 (q), 9.5, –4.0.
(4) (a) Tamai, S.; Kaneda, M.; Nakamura, S. J. Antibiot. 1982,
35, 1130. (b) Kaneda, M.; Tamai, S.; Nakamura, S.; Hirata,
T.; Kushi, Y.; Suga, T. J. Antibiot. 1982, 35, 1137.
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M. A.; Penn, S. G.; Lebrilla, C. B.; Lam, T. H.; Pessah, I. N.;
Molinski, T. F. J. Nat. Prod. 1996, 59, 1121.
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43, 679. (c) Lindley, J. Tetrahedron 1984, 40, 1433. (d)
For a review, see: Frlan, R.; Kikelj, D. Synthesis 2006, 2271.
(7) (a) Beugelmans, R.; Zhu, J.; Husson, N.; Bois-Choussy, M.;
Singh, G. P. J. Chem. Soc., Chem. Commun. 1994, 439.
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6488. (c) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron
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Chem. Commun. 1998, 2091. (f) For an excellent review,
see: Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed. 2003,
42, 5400; Angew. Chem. 2003, 115, 5558.
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Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem.
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Am. Chem. Soc. 2005, 127, 8146. (c) Anderson, K. W.;
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2005, 128, 10694.
(10) (a) Tillack, A.; Jiao, H.; Garcia Castro, I.; Hartung, C. G.;
Beller, M. Chem. Eur. J. 2004, 10, 2409. (b) Khedkar, V.;
Tillack, A.; Michalik, M.; Beller, M. Tetrahedron Lett.
2004, 45, 3123. (c) Khedkar, V.; Tillack, A.; Michalik, M.;
Beller, M. Tetrahedron 2005, 61, 7622. (d) Schwarz, N.;
Alex, K.; Sayyed, I. A.; Khedkar, V.; Tillack, A.; Beller, M.
Synlett 2007, 1091. (e) Sayyed, I. A.; Alex, K.; Tillack, A.;
Schwarz, N.; Michalik, D.; Beller, M. Eur. J. Org. Chem.
2007, 4525.
(11) (a) Hartung, C.; Köhler, K.; Beller, M. Org. Lett. 1999, 1,
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(d) Michalik, D.; Kumar, K.; Zapf, A.; Tillack, A.; Arlt, M.;
Heinrich, T.; Beller, M. Tetrahedron Lett. 2004, 45, 2057.
(e) Zapf, A.; Jackstell, R.; Rataboul, F.; Riermeier, T.;
Monsees, A.; Fuhrmann, C.; Shaikh, N.; Dingerdissen, U.;
Beller, M. Chem. Commun. 2004, 38. (f) Harkal, S.;
Rataboul, F.; Zapf, A.; Fuhrmann, C.; Riermeier, T.;
Monsees, A.; Beller, M. Adv. Synth. Catal. 2004, 346, 1742.
(g) Zapf, A.; Beller, M. Chem. Commun. 2005, 431.
(h) Schwarz, N.; Tillack, A.; Alex, K.; Sayyed, I. A.;
Jackstell, R.; Beller, M. Tetrahedron Lett. 2007, 48, 2897.
(12) (a) Rataboul, F.; Zapf, A.; Jackstell, R.; Harkal, S.;
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Chem. Eur. J. 2004, 10, 2983. (b) Harkal, S.; Kumar, K.;
Michalik, D.; Zapf, A.; Jackstell, R.; Rataboul, F.;
MS (EI, 70 eV): m/z (%) = 417 (100), 360 (11), 287 (5), 167 (4), 149
(13), 97 (9), 83 (11), 73 (7), 57 (18), 43 (17).
HRMS: m/z calcd for C26H31NO2Si: 417.21186; found: 417.211468.
4-[1-Benzyl-3-(tert-butyldimethylsiloxy)-2-methyl-1H-indol-5-
yl]naphthalen-1-ol (25)
FTIR (KBr): 3023, 2929, 2864, 1471, 1452, 1376, 1347, 1278,
1253, 1231, 1212, 1048, 862, 842, 822, 803, 783, 764, 732 cm–1.
1H NMR (300.13 MHz, CDCl3): d = 8.24 (d, J = 8.3 Hz, 1 H), 7.99
(d, J = 8.3 Hz, 1 H), 7.57 (d, J = 1.1 Hz, 1 H), 7.48 (m, 1 H), 7.41
(m, 1 H), 7.27 (m, 5 H), 7.16 (dd, J = 1.1, 6.3 Hz, 1 H), 7.00 (m, 2
H), 6.87 (d, J = 7.7 Hz, 1 H), 5.31 (s, 2 H), 5.28 (s, 1 H, OH), 2.27
(s, 3 H), 1.04 (s, 9 H), 0.18 (s, 6 H).
13C NMR (75.5 MHz, CDCl3): d = 150.4 (q), 138.3 (q), 134.8 (q),
133.3 (q), 133.0 (q), 131.2 (q), 131.0 (q), 128.8, 127.3, 127.0, 126.8,
126.2, 126.0, 125.0, 124.4 (q), 123.7, 123.0 (q), 122.0 (q), 121.6,
118.8, 108.4, 108.3, 46.8, 26.2, 18.1 (q), 9.4, –4.1.
MS (EI, 70 eV): m/z (%) = 493 (100), 402 (4), 345 (2), 319 (3), 261
(2), 218 (3), 153 (2), 112 (16), 91 (12), 73 (33), 57 (12), 44 (15).
HRMS: m/z calcd for C32H35NO2Si: 493.24316; found: 493.242367.
tert-Butyl 5-(4-Hydroxynaphthalen-1-yl)indole-1-carboxylate
(26)
FTIR (ATR): 3358, 3150, 3110, 3044, 2981, 2932, 1368, 1334,
1239, 1155, 1133, 1078, 1044, 1022, 812, 763, 726 cm–1.
1H NMR (300.13 MHz, CDCl3): d = 8.28 (m, 1 H), 8.21 (d, J = 8.5
Hz, 1 H), 7.89 (m, 1 H), 7.67 (d, J = 3.7 Hz, 1 H), 7.63 (d, J = 1.6
Hz, 1 H), 7.50 (m, 1 H), 7.42 (m, 2 H), 7.27 (d, J = 7.6 Hz, 1 H),
6.89 (d, J = 7.6 Hz, 1 H), 6.62 (d, J = 3.7 Hz, 1 H), 5.82 (s, 1 H,
OH), 1.71 (s, 9 H).
13C NMR (75.5 MHz, CDCl3): d = 151.0 (q), 149.9 (q), 135.4 (q),
134.1 (q), 133.4 (q), 133.0 (q), 130.7 (q), 127.1, 126.8, 126.4 (two
signals, detected by CORE), 126.2, 125.0, 124.5 (q), 122.4, 121.9,
114.7, 108.1, 107.5, 83.8 (q), 28.2.
MS (EI, 70 eV): m/z (%) = 359 (40), 304 (31), 303 (96), 260 (52),
259 (100), 258 (83), 242 (21), 231 (17), 230 (39), 229 (11), 228
(27), 202 (19), 101 (10), 57 (30).
HRMS: m/z calcd for C23H21NO3: 359.15160; found: 359.151449.
Acknowledgment
This work has been funded by the State of Mecklenburg-Western
Pomerania, the BMBF (Bundesministerium für Bildung und For-
schung), the Deutsche Forschungsgemeinschaft (Leibniz prize,
Graduiertenkolleg 1213), and the Fonds der Chemischen Industrie
(FCI). We thank Dr. W. Baumann, Dr. D. Michalik, Dr. C. Fischer,
S. Buchholz, S. Schareina, and K. Mevius for their excellent techni-
cal and analytical support.
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