Potassium [1-(tert-butoxycarbonyl)-1H-indol-2-yl]trifluoroborate as an efficient building block in palladium-catalyzed Suzuki-Miyaura cross couplings

Article abstract of DOI:10.1055/s-0029-1216829

Potassium [1-(tert-butoxycarbonyl)-1H-indol-2-yl]trifluoroborate (1) was used in Suzuki-type coupling reactions. First, the best coupling conditions were assessed using bromobenzene as the electrophile. Then, 1 was successfully coupled with various aryl a

Full text of DOI:10.1055/s-0029-1216829

PAPER
2447
Potassium [1-(tert-Butoxycarbonyl)-1H-indol-2-yl]trifluoroborate as an
Efficient Building Block in Palladium-Catalyzed Suzuki–Miyaura Cross
Couplings
C
ross Couplin
a
gs
U
sing
P
o
m
tassium [1-(tert-Bu
é
toxycarbon
l
yl)-1
H
a
-indol-2-yl]trifluo
K
roborate assis, Valérie Bénéteau*, Jean-Yves Mérour, Sylvain Routier*
Institut de Chimie Organique et Analytique, Université d’Orléans, UMR CNRS 6005, Rue de Chartres, BP 6759, 45067 Orléans Cedex 2,
France
Fax +33(2)38417281; E-mail: sylvain.routier@univ-orleans.fr
Received 25 February 2009; revised 24 March 2009
Abstract: Potassium [1-(tert-butoxycarbonyl)-1H-indol-2-yl]tri-
BF3K
fluoroborate (1) was used in Suzuki-type coupling reactions. First,
the best coupling conditions were assessed using bromobenzene as
the electrophile. Then, 1 was successfully coupled with various aryl
and hetaryl bromides. Finally, the reactivity of 1 towards coupling
partners other than bromide derivatives was evaluated.
N
Boc
1
Figure 1 Potassium
fluoroborate
[1-(tert-butoxycarbonyl)-1H-indol-2-yl]tri-
Key words: Suzuki coupling, organotrifluoroborates, palladium
catalysis, indoles
a
b
B(OH)2
BF3K
N
N
N
Over the last 25 years, palladium chemistry has deeply
modified our retrosynthetic approach to the formation of
carbon–carbon bonds, especially for aromatic and het-
eroaromatic structures.
Boc
Boc
Boc
1
2
3
Scheme 1 Reagents and conditions: (a) (i) LTMP (1.3 equiv), THF,
–78 °C, 45 min; (ii) B(Oi-Pr)3 (3.0 equiv), –78 to r.t., 2 h; (iii) 10% aq
HCl, r.t.; (b) 4.5 M aq KHF2 (3.0 equiv), MeOH; 94% over 2 steps.
The palladium-catalyzed Suzuki cross coupling of aryl
halides with boronic acids is one of the most extensively
used methods, even on industrial scales.1–3 Nevertheless,
some heteroaromatic boronic acids, particularly when the
boronic acid group is a to a nitrogen atom, can be subject
to degradation by oxidation or deboronation during the
coupling process.4 In these cases, an alternative organobo-
ron coupling partner may be required. Indeed, potassium
organotrifluoroborates have emerged lately as efficient
and versatile building blocks.5–10
into the corresponding potassium trifluoroborate salt
(Scheme 1).13
Indeed, 1-(tert-butoxycarbonyl)-1H-indole (2) treated
with lithium 2,2,6,6-tetramethylpiperidide (1.3 equiv) at
–78 °C in tetrahydrofuran, followed by addition of triiso-
propyl borate (3.0 equiv) then acidic hydrolysis, led to the
corresponding boronic acid 3. Alternatively, 3 can be pre-
pared using a noncryogenic method with lithium diisopro-
pylamide at 0 °C.14 The crude boronic acid 3 was
dissolved in methanol and stirred with an aqueous potas-
sium hydrogen fluoride solution (3.0 equiv) to give 1 as a
white precipitate in a good overall yield (94%). The 11B
NMR spectrum of 1 is in agreement with the structure. We
noticed that, conveniently, 1 can be stored on the bench at
room temperature for several weeks without any decom-
position.
Indole is one of the most encountered cores in natural
products and a privileged pharmacophore in medicinal
chemistry, and new tools to access complex indolic struc-
tures are always needed.
For these reasons, we are currently interested in the for-
mation and reactivity in Suzuki-type couplings of potassi-
um
[1-(tert-butoxycarbonyl)-1H-indol-2-yl]trifluoro-
borate (1) (Figure 1).11,12 In a recent paper by Meggers
and co-workers, 1 was coupled with various pyridinic de-
rivatives to access pyridocarbazoles.12 The aim of this re-
port is to compare different catalytic systems in a model
reaction, to apply the best system to diverse functional-
ized bromide compounds, and, finally, to vary the nature
of the electrophilic partner.
As a model reaction, we investigated the Suzuki–Miyaura
coupling of 1 with bromobenzene using various palladium
species, solvents, and bases (Scheme 2, Table 1).15 In our
search for the best coupling conditions, the use of palladi-
um(II) acetate (in the presence or absence of triphe-
nylphosphine), PdCl2(PPh3)2, or PdCl2(dppf)·CH2Cl2 did
not prove better than the use of Pd(PPh3)4 (Table 1, entries
1–4, 8).
The preparation of 1 resulted from the transformation of
indole 2 into indol-2-ylboronic acid 3, then conversion
The most efficient conditions, leading to the 2-phenylin-
dole 4 in 92% yield, involved the use of tetrakis(triphe-
nylphosphine)palladium(0) (10%) in a mixture of 1,2-
SYNTHESIS 2009, No. 14, pp 2447–2453
x
x.
x
x
.
2
0
0
9
Advanced online publication: 27.05.2009
DOI: 10.1055/s-0029-1216829; Art ID: Z03109SS
© Georg Thieme Verlag Stuttgart · New York

2448
P. Kassis et al.
PAPER
Br
catalyst, base (3.0 equiv)
solvent
BF3K
+
N
N
Boc
Boc
1.5 equiv
1
4
Scheme 2 Reagents and conditions: see Table 1.
Table 1 Optimization of Coupling Conditions with Bromobenzene
Entry
Catalyst
Base (3 equiv)
Na2CO3
Solvent
Temp (°C) Time (h)
Yielda (%) of 4
1
2
3
4
5
6
7
8
9
Pd(OAc)2 (10%)
Pd(OAc)2 (5%), Ph3P (10%)
PdCl2(PPh3)2 (10%)
Pd(PPh3)4 (10%)
Pd(PPh3)4 (10%)
Pd(PPh3)4 (10%)
Pd(PPh3)4 (10%)
PdCl2(dppf)·CH2Cl2 (5%)
10% Pd/C (5%)
DME–H2O
DME–H2O
DME–H2O
DME–H2O
DME–H2O
toluene–EtOH
toluene–EtOH
EtOH
90
90
90
90
50
90
90
90
90
1
1
41
60
55
92
54
44
55
66
0b
Na2CO3
Na2CO3
1
Na2CO3
1
Na2CO3
4
Na2CO3
18
5
NaHCO3
i-PrNEt2
1
NaOH, TBAB
H2O
1
a Yield of isolated product.
b 18% of indole 2 was recovered.
dimethoxyethane and water, at 90 °C, with sodium car- was observed when an ortho-substituted bromobenzene
bonate as the base (entry 4). Performing the reaction at a was used. Satisfyingly, we could achieve a monocoupling
lower temperature for a prolonged time resulted in a lower reaction in 80% yield starting from 3,5-dibromopyridine
yield (entry 5). The use of a mixture of toluene and etha-
Table 2 Coupling of 1 with Various (Het)aryl Bromides
nol as the solvent proved detrimental (entries 6, 7). No
coupled product was detected when the reaction was car-
ried out in water with sodium hydroxide, tetrabutylammo-
nium bromide, and palladium on carbon as the catalyst.16
In this case, only the indole 2, resulting from deboronation
of 1, could be recovered in 18% yield.
Entry
1
(Het)Ar
Time (h) Product: Yield (%)
3-pyridyl
3
5
3
4
4
6
5a
5
4
4
4
3
6
6
6
5: 77
6: 80
2
5-bromo-3-pyridyl
2-pyridyl
3
7: 75
As a comparison, this coupling has been reported from the
indol-2-ylboronic acid 3 (using iodobenzene)17,18 and
from lithium [1-(tert-butoxycarbonyl)-1H-indol-2-yl]bo-
rate in 52% and 80% yield, respectively.
4
4-Tol
8: 73
5
4-F3CC6H4
4-NCC6H4
4-O2NC6H4
4-FC6H4
9: 62
6
10: 73
11: 65
12: 70
13: 77
14: 51
15: 70
16: 76
17: 95
18: 36
19: 63
Then, we examined the versatility of 1 in couplings with
various aryl and hetaryl bromides using tetrakis(triphe-
nylphosphine)palladium(0) (10%) and sodium carbonate
(3.0 equiv) in a mixture of 1,2-dimethoxyethane and water
at 90 °C (Scheme 3, Table 2).
7
8
9
3,5-Me2C6H3
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
3-thienyl
The coupling proved to be quite to very efficient with both
electron-poor electrophiles (Table 2, entries 1–3, 5–8) and
electron-rich electrophiles (entries 4, 9, 11–13). A slight
(entry 15) or sharp (entries 10, 14) decrease in the yield
10
11
12
13
14
15
a
(Het)Ar
(Het)Ar-Br
+
BF3K
N
N
2-NCC6H4
2-FC6H4
Boc
5–19
Boc
1
Scheme 3 Reagents and conditions: (a) (Het)ArBr (1.2 equiv),
Pd(PPh3)4 (10%), Na2CO3 (3.0 equiv), DME–H2O, 90 °C.
a Reaction with PdCl2(dppf)·CH2Cl2 (5%) and i-PrNEt2 (3.0 equiv) in
refluxing THF.
Synthesis 2009, No. 14, 2447–2453 © Thieme Stuttgart · New York

PAPER
Cross Couplings Using Potassium [1-(tert-Butoxycarbonyl)-1H-indol-2-yl]trifluoroborate
2449
(entry 2). It is noteworthy that aprotic conditions
[PdCl2(dppf)·CH2Cl2 (5%), i-PrNEt2 (3.0 equiv), THF, re-
flux] are needed for the coupling of para-bromonitroben-
zene (entry 7), with the use of our reference conditions
leading to no coupled product at all and recovery of the
starting material.
Table 3 Reaction of 1 with Other Electrophiles
Entry
X
Methoda Time
(h)
Yieldb,c
(%) of 4
Yieldb,c
(%) of 2
1
2
Br
I
A
A
1
1
92
90
ND
ND
The next issue in our study was to evaluate the reactivity
of 1 towards other types of electrophiles (iodide, chloride,
triflate, thioether, phosphate, and diazonium salt deriva-
tives) (Schemes 4 and 5, Tables 3 and 4).
3
4
5
OTf
A
B
B
1
1
6
64
70
73
ND
ND
ND
6
7
8
Cl
A
B
C
1
ND
13d
36
44
7d
ND
Bromo- and iodobenzene showed similar reactivities,
yielding the coupled product 4 in around 90% (Table 3,
entries 1, 2). Phenyl triflate20 proved to be an efficient
coupling partner in nonaqueous conditions (Method B,
entry 5). During the preparation of this manuscript,
Molander and co-workers reported the use of the catalytic
system palladium(II) acetate/RuPhos for the coupling of 1
with 4-chlorobenzonitrile.21 In our hands, chlorobenzene
reacted poorly, yielding only 36% of product 4 under con-
ditions using palladium(II) acetate and Xantphos (entry
8).22 It is noteworthy that the same reaction performed un-
der microwave irradiation overnight resulted mainly in
degradation products.
6
4 d
9
10
11
SMe
A
B
D
1
1
1
ND
10d
ND
44
26d
33
+
12
13
14
N2
A
B
E
1
6
3
22d
14d
ND
4d
8d
11
a A: Pd(PPh3)4 (10%), Na2CO3 (3.0 equiv), DME–H2O, 90 °C;
B: PdCl2(dppf)·CH2Cl2 (5%), i-PrNEt2 (3.0 equiv), THF, reflux;
C: Pd(OAc)2 (3%), Xantphos (6%), K2CO3 (3.0 equiv), THF–H2O,
reflux; D:19 Pd(PPh3)4 (5%), copper(I) thiophene-2-carboxylate
(3.0 equiv), THF, reflux; E: Pd(OAc)2 (5%), dioxane, r.t.
b Isolated yield, except where indicated.
In order to specify the scope and limitations of 1 as a
building block in palladium C–C bond-forming method-
c ND = not detected on TLC.
ologies, we considered utilizing less usual coupling part- d Determined by 1H NMR spectroscopy.
ners: thioethers, diazonium salts, and phosphates.
tempts, in our case only 22% of product 4 was obtained
after reaction of 1 with benzenediazonium tetrafluorobo-
First, we tried two different (het)aryl thioethers: (meth-
ylthio)benzene and 3-(methylthio)-1,2,4-triazine.23 Sur-
prisingly, only (methylthio)benzene was able to undergo
coupling with 1, in a very low yield (10%; Table 3, entry
10), using Method B [PdCl2(dppf)·CH2Cl2 (5%), i-PrNEt2
(3.0 equiv), THF, reflux].
rate salt24 using Method A (Table 3, entry 12).
Starting from the vinyl phosphates 20a and 20b, the cou-
pling reaction proceeded moderately, the best yield (36%)
being obtained with the less bulky diethyl phosphate 20b
(Table 4, entry 3). Product 22, resulting from homocou-
pling of 1, was also isolated in 10 to 20% yield. Common-
ly considered as nonreactive in Suzuki-type couplings,
Diazonium salts are described as effective coupling part-
ners with organotrifluoroborates.10 Despite several at-
X
Methods A–E
+
+
2
BF3K
N
N
Boc
Boc
1.2 equiv
1
4
X= Br, I, Cl, OTf,
–
SMe, N2+ BF4
Scheme 4 Reagents and conditions: see Table 3.
O
Method A, B or F
+
+
BF3K
R1O
R1O
P
R2
+
OR2
N
N
N
N
N
Boc
Boc
Boc
Boc
Boc
22
20a: R1 =Ph, R2
20b: R1 =Et, R2
=
4: R2 = Ph
21: R2
1
2
=
N
CO2Me
N
=
CO2Me
N
20c: R1 = R2 = Ph
CO2Me
Scheme 5 Reagents and conditions: see Table 4.
Synthesis 2009, No. 14, 2447–2453 © Thieme Stuttgart · New York

2450
P. Kassis et al.
PAPER
Table 4 Reaction of 1 with Phosphate Derivatives
Entry
Phosphate
Methoda
Time (h)
Yieldb (%) of coupled product Yieldb (%) of byproducts
1
2
20a
A
F
1
1
21: 2
21: 0
22: 11
2: 13; 22: 21
3
20b
20c
A
12
21: 36
22: 12
4
5
A
B
1
6
4: 31c
4: 10c
2: 24c
2: 13c
a A and B: see Table 3; F: PdCl2(PPh3)2 (10%), Na2CO3 (2.0 equiv), THF, reflux.
b Isolated yield, except where indicated.
c Determined by 1H NMR spectroscopy.
1-(tert-Butoxycarbonyl)-1H-indol-2-ylboronic Acid (3)17
triphenyl phosphate (20c) underwent the reaction with 1
in 31% yield when Method A was used (entry 4). To our
knowledge, this is the first example of an aryl transfer
from a phosphate via a palladium catalysis. These prelim-
inary results encourage us to further explore the coupling
of 1 with various types of phosphate derivatives.
2,2,6,6-Tetramethylpiperidine (3.10 mL, 18.2 mmol) in anhyd THF
(35 mL) was cooled to –78 °C under an atmosphere of argon and
treated dropwise with 2.5 M n-BuLi in THF (8.30 mL, 20.70
mmol). The mixture was stirred at –78 °C for 10 min, then a soln of
1-(tert-butoxycarbonyl)-1H-indole30 (2; 3.00 g, 13.8 mmol) in THF
(15 mL) was added dropwise. The mixture was stirred at –78 °C for
45 min. B(Oi-Pr)3 (9.55 mL, 41.4 mmol) was added dropwise, and
the reaction mixture was stirred for 30 min at –78 °C before being
warmed to r.t. The reaction mixture was quenched with H2O (30
mL), acidified with 10% aq HCl, and extracted with EtOAc (3 × 30
mL). The combined organic layer was washed with brine, dried
(MgSO4), and filtered. The solvents were removed under reduced
pressure to afford 3 as an off-white solid, in quantitative yield,
which was used without further purification; mp 105 °C.
In conclusion, potassium [1-(tert-butoxycarbonyl)-1H-in-
dol-2-yl]trifluoroborate (1) proved to be a convenient sub-
stitute for its boronic acid counterpart in Suzuki–Miyaura
cross couplings with various electron-poor and electron-
rich functionalized aryl and hetaryl bromides. The main
limitation may arise from the use of ortho-substituted phe-
nyl derivatives as coupling partners, which afford the re-
action products in low to modest yields. As far as other 1H NMR (250 MHz, CDCl3): d = 1.65 (s, 9 H, COOt-Bu), 6.62 (s, 1
H, H3), 7.16–7.30 (m, 2 H, H5 + H6), 7.56 (d, J = 7.5 Hz, 1 H, H4),
8.08 (d, J = 10 Hz, 1 H, H7), 8.18 (s, 2 H, OH).
electrophiles are concerned, iodobenzene and phenyl tri-
flate reacted efficiently with 1 when tetrakis(triphe-
nylphosphine)palladium(0) was used. Moderate yields
(around 35%) were obtained for vinyl and aryl phos-
phates, as well as for chlorobenzene when a bulky ligand
Potassium [1-(tert-Butoxycarbonyl)-1H-indol-2-yl]trifluorobo-
rate (1)12
A soln of 1-(tert-butoxycarbonyl)-1H-indol-2-ylboronic acid (3;
was used. In a continuation of this work, we will focus our
efforts toward the use of potassium [1-(tert-butoxycarbo-
nyl)-1H-indol-2-yl]trifluoroborate (1) in accessing com-
plex indolic structures for biological applications.
2.42 g, 9.26 mmol) in MeOH (50 mL) was cooled to 0 °C. A 4.5 M
soln of KHF2 in H2O (6.20 mL, 27.78 mmol) was slowly added and
the resulting thick suspension was stirred at r.t. for 4 h, then filtered
under reduced pressure and washed with a minimum of cold MeOH.
The solid was dried on a high-vacuum line to afford 1 as a white sol-
id; yield: 2.82 g (94%).
All reagents were purchased from Sigma–Aldrich, Acros Organics,
and Alfa Aesar, and were used without further purification. Melting
points are uncorrected. 1H and 13C NMR spectra were recorded on
a Bruker Avance DPX 250 spectrometer (1H, 250.19 MHz; 13C,
62.89 MHz) or a Bruker Avance II 400 spectrometer (1H, 400 MHz;
13C, 100 MHz) using tetramethylsilane as the internal standard;
multiplicities were determined using the DEPT 135 sequence.
Chemical shifts are reported in parts per million (ppm, d units) and
coupling constants are reported in units of hertz (Hz). Splitting pat-
terns are designated as s: singlet, d: doublet, t: triplet, and m: mul-
tiplet. IR absorption spectra were recorded on a Nicolet iS10 Smart
iTR apparatus and the values are reported in cm–1. High-resolution
mass spectra (HRMS) were recorded with a Waters micro Q-TOF
spectrometer in the electrospray ionization (ESI) mode or with a
Finnigan MAT 95 XL spectrometer in the chemical ionization (CI)
mode at the Regional Center of Physical Measurement, Blaise Pas-
cal University. Column chromatography was carried out using silica
gel 60 (spherical, neutral, 40–63 mm, Merck). Thin-layer chroma-
tography was carried out on Merck silica gel 60F254 precoated
plates. Visualization was undertaken with UV light. Spectroscopic
data for compounds 4,25 5,26 7,19 8,27 9,28 10,26 11,28 12,29 14,28 and
1629 are in agreement with the literature.
IR (film): 1730, 1450, 1368, 1330, 1249, 1213, 1144, 1121, 964 (s),
893 cm–1.
1H NMR (250 MHz, acetone-d6): d = 1.67 (s, 9 H, COOt-Bu), 6.62
(s, 1 H, H3), 7.04–7.11 (m, 2 H, H5 + H6), 7.39 (d, J = 7.5 Hz, 1 H,
H4), 8.02 (d, J = 7.5 Hz, 1 H, H7).
11B NMR (123.37 MHz, acetone-d6): d = 1.34–2.29 (relative to
BF3·OEt2) (1:3:3:1 quartet, JB-F = 40.16 Hz).
Palladium-Catalyzed Cross-Coupling Reactions; General Pro-
cedures
Method A
A soln of the electrophile (0.37 mmol, 1.2 equiv), potassium [1-
(tert-butoxycarbonyl)-1H-indol-2-yl]trifluoroborate (1; 100 mg,
0.31 mmol), and Na2CO3 (98 mg, 0.93 mmol) in a mixture of DME
(2.5 mL) and H2O (0.8 mL) was degassed by argon bubbling for 30
min. Pd(PPh3)4 (10 mol%, 0.031 mmol) was added and the mixture
was immediately plunged in a preheated oil bath and refluxed for
the indicated time. After hydrolysis with H2O (5 mL), the crude
product was extracted with EtOAc (2 × 5 mL), and the combined
organic layer was washed with brine (5 mL), then dried (MgSO4)
and filtered. The solvents were removed under reduced pressure and
the residue was purified by flash chromatography.
Synthesis 2009, No. 14, 2447–2453 © Thieme Stuttgart · New York

PAPER
Cross Couplings Using Potassium [1-(tert-Butoxycarbonyl)-1H-indol-2-yl]trifluoroborate
2451
Method B
raphy (petroleum ether–EtOAc, 9:1) to afford 6 as a white solid;
yield: 92 mg (80%).
A soln containing the electrophile (0.37 mmol, 1.2 equiv), potassi-
um [1-(tert-butoxycarbonyl)-1H-indol-2-yl]trifluoroborate (1;
100 mg, 0.31 mmol), i-PrNEt2 (0.16 mL, 0.93 mmol), and
PdCl2(dppf)·CH2Cl2 (5 mol%, 0.015 mmol) in THF (5 mL) was
plunged in a preheated oil bath and refluxed for the indicated time.
After hydrolysis with H2O (5 mL), the crude product was extracted
with EtOAc (2 × 5 mL), and the combined organic layer was
washed with brine (5 mL), then dried (MgSO4) and filtered. The sol-
vents were removed under reduced pressure and the residue was pu-
rified by flash chromatography.
Mp 134 °C; Rf = 0.41 (petroleum ether–EtOAc, 9:1).
IR (film): 3031, 2974, 1730, 1453, 1318, 1226, 1159, 1132, 1028,
1011, 845, 741 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.39 (s, 9 H, 3 × CH3), 6.65 (s, 1
H, H3), 7.28 (t, J = 7.5 Hz, 1 H, H5), 7.39 (t, J = 7.5 Hz, 1 H, H6),
7.59 (d, J = 7.5 Hz, 1 H, H4), 7.88 (t, J = 2.5 Hz, 1 H, H4¢), 8.25 (d,
J = 7.5 Hz, 1 H, H7), 8.61 (d, J = 2.5 Hz, 1 H, H2¢), 8.66 (d, J = 2.5
Hz, 1 H, H6¢).
13C NMR (100.61 MHz, CDCl3): d = 27.7 (3 × CH3), 84.3 (C),
112.0 (CH), 115.6 (CH), 119.7 (C), 120.9 (CH), 123.3 (CH), 125.3
(CH), 128.8 (C), 132.4 (C), 134.8 (C), 137.6 (C), 138.5 (CH), 147.4
(CH), 149.4 (CH), 149.6 (C).
Method C
A soln of the electrophile (0.37 mmol, 1.2 equiv), potassium [1-
(tert-butoxycarbonyl)-1H-indol-2-yl]trifluoroborate (1; 100 mg,
0.31 mmol), and K2CO3 (128 mg, 0.93 mmol) in a mixture of THF
(2.5 mL) and H2O (0.25 mL) was degassed by argon bubbling for
30 min. Pd(OAc)2 (3 mol%, 9.3 mmol) and Xantphos (11 mg, 0.019
mmol) were added and the mixture was immediately plunged in a
preheated oil bath and refluxed for the indicated time. After hydrol-
ysis with H2O (5 mL), the mixture was extracted with EtOAc (2 × 5
mL), and the combined organic layer was washed with brine (5
mL), then dried (MgSO4) and filtered. The solvents were removed
under reduced pressure and the residue was purified by flash chro-
matography.
HRMS: m/z calcd for C18H1879BrN2O2: 373.0552; found: 373.0540.
1-(tert-Butoxycarbonyl)-2-(3,5-dimethylphenyl)-1H-indole (13)
Method A was used, starting from compound 1 (100 mg, 0.31
mmol) and 1-bromo-3,5-dimethylbenzene (0.050 mL, 0.37 mmol).
The mixture was refluxed for 4 h. The residue was purified by flash
chromatography (petroleum ether–EtOAc, 98:2) to afford 13 as a
red oil; yield: 76 mg (77%).
Rf = 0.82 (petroleum ether–EtOAc, 8:2).
IR (film): 2975, 1727, 1605, 1452, 1324, 1250, 1209, 1158, 1130,
1066, 1021, 851, 810, 744 cm–1.
Method D
A soln of the electrophile (0.37 mmol, 1.2 equiv), potassium [1-
(tert-butoxycarbonyl)-1H-indol-2-yl]trifluoroborate (1; 100 mg,
0.31 mmol), and copper(I) thiophene-2-carboxylate (77 mg, 0.4
mmol) in THF (2.5 mL) was degassed by argon bubbling for 30
min. Pd(PPh3)4 (18 mg, 15.5 mmol) was added and the mixture was
immediately plunged in a preheated oil bath and refluxed for the in-
dicated time. After hydrolysis with H2O (5 mL), the mixture was ex-
tracted with EtOAc (2 × 5 mL), and the combined organic layer was
washed with brine (5 mL), then dried (MgSO4) and filtered. The sol-
vents were removed under reduced pressure and the residue was pu-
rified by flash chromatography.
1H NMR (250 MHz, CDCl3): d = 1.31 (s, 9 H, 3 × CH3), 2.35 (s, 6
H, 2 × CH3), 6.53 (s, 1 H, H3), 6.98 (s, 1 H, H4¢), 7.03 (s, 2 H, H2¢ +
H6¢), 7.19–7.34 (m, 2 H, H5 + H6), 7.53 (d, J = 7.5 Hz, 1 H, H4), 8.20
(d, J = 7.5 Hz, 1 H, H7).
13C NMR (62.5 MHz, CDCl3): d = 21.2 (2 × CH3), 27.5 (3 × CH3),
83.1 (C), 109.4 (CH), 115.0 (CH), 120.3 (CH), 122.8 (CH), 124.1
(CH), 126.5 (2 × CH), 129.1 (CH), 129.2 (C), 134.6 (C), 137.1 (2 ×
C), 137.4 (C), 140.8 (C), 150.2 (C).
HRMS: m/z calcd for C21H23NO2Na: 344.1626; found: 344.1643.
1-(tert-Butoxycarbonyl)-2-(3-methoxyphenyl)-1H-indole (15)
Method A was used, starting from compound 1 (100 mg, 0.31
mmol) and 1-bromo-3-methoxybenzene (0.047 mL, 0.37 mmol).
The mixture was refluxed for 4 h. The residue was purified by flash
chromatography (petroleum ether–EtOAc, 98:2) to afford 15 as a
yellow oil; yield: 70 mg (70%).
Method E
A soln of the electrophile (0.37 mmol, 1.2 equiv) and potassium [1-
(tert-butoxycarbonyl)-1H-indol-2-yl]trifluoroborate (1; 100 mg,
0.31 mmol) in dioxane (2.5 mL) was degassed by argon bubbling
for 30 min. Pd(OAc)2 (4 mg, 15.5 mmol) was added and the mixture
was stirred at r.t. for the indicated time. After hydrolysis with H2O
(5 mL), the mixture was extracted with EtOAc (2 × 5 mL), and the
combined organic layer was washed with brine (5 mL), then dried
(MgSO4) and filtered. The solvents were removed under reduced
pressure and the residue was purified by flash chromatography.
Rf = 0.57 (petroleum ether–EtOAc, 8:2).
IR (film): 2925, 2874, 1729, 1597, 1452, 1366, 1322, 1246, 1214,
1158, 1129, 1048, 1027, 848, 746 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.33 (s, 9 H, 3 × CH3), 3.83 (s, 3
H, OCH3), 6.57 (s, 1 H, H3), 6.91 (dd, J = 7.5 Hz, J¢ = 2.5 Hz, 1 H,
H4¢), 6.96–7.03 (m, 2 H, HAr), 7.25–7.36 (m, 3 H, HAr), 7.56 (d,
J = 7.5 Hz, 1 H, H4), 8.21 (d, J = 7.5 Hz, 1 H, H7).
Method F
A soln of the electrophile (0.37 mmol, 1.2 equiv), potassium [1-
(tert-butoxycarbonyl)-1H-indol-2-yl]trifluoroborate (1; 100 mg,
0.31 mmol), and 2 M Na2CO3 (0.32 mL) in THF (2.5 mL) was de-
gassed by argon bubbling for 30 min. PdCl2(PPh3)2 (22 mg, 0.031
mmol) was added and the mixture was immediately plunged in a
preheated oil bath and refluxed for the indicated time. After hydrol-
ysis with H2O (5 mL), the mixture was extracted with EtOAc (2 × 5
mL), and the combined organic layer was washed with brine (5
mL), then dried (MgSO4) and filtered. The solvents were removed
under reduced pressure and the residue was purified by flash chro-
matography.
13C NMR (62.5 MHz, CDCl3): d = 27.6 (3 × CH3), 55.3 (CH3), 83.3
(C), 109.8 (CH), 113.2 (CH), 114.3 (CH), 115.1 (CH), 120.4 (CH),
121.3 (CH), 122.9 (CH), 124.3 (CH), 128.8 (CH), 128.9 (C), 136.2
(C), 137.4 (C), 140.3 (C), 150.1 (C), 159.1 (C).
HRMS: m/z calcd for C20H21NO3Na: 346.1419; found: 346.1435.
1-(tert-Butoxycarbonyl)-2-(3-thienyl)-1H-indole (17)
Method A was used, starting from compound 1 (100 mg, 0.31
mmol) and 3-bromothiophene (0.034 mL, 0.37 mmol). The mixture
was refluxed for 6 h. The residue was purified by flash chromatog-
raphy (petroleum ether–EtOAc, 98:2) to afford 17 as a red oil; yield:
89 mg (95%).
2-(5-Bromo-3-pyridyl)-1-(tert-butoxycarbonyl)-1H-indole (6)
Method A was used, starting from compound 1 (100 mg, 0.31
mmol) and 3,5-dibromopyridine (88 mg, 0.37 mmol). The mixture
was refluxed for 5 h. The residue was purified by flash chromatog-
Rf = 0.51 (petroleum ether–EtOAc, 98:2).
Synthesis 2009, No. 14, 2447–2453 © Thieme Stuttgart · New York

2452
P. Kassis et al.
PAPER
IR (film): 3113, 2929, 1727, 1453, 1326, 1224, 1156, 1127, 1030,
849, 783, 767, 744 cm–1.
Rf = 0.45 (petroleum ether–EtOAc, 1:1).
IR (film): 2982, 2933, 2851, 1718, 1685, 1450, 1374, 1352, 1327,
1284, 1253, 1203, 1020, 979, 925, 902, 772 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.47 (s, 9 H, 3 × CH3), 6.63 (s, 1
H, H3), 7.18–7.20 (m, 1 H, H5¢), 7.26–7.42 (m, 4 H, HAr), 7.59 (d,
J = 7.5 Hz, 1 H, H4), 8.26 (d, J = 7.5 Hz, 1 H, H7).
1H NMR (250 MHz, CDCl3): d = 1.34 (t, J = 8.0 Hz, 6 H, 2 × CH3),
1.52 (s, 2 H, CH2), 1.74 (s, 2 H, CH2), 2.07 (s, 2 H, CH2), 3.60 (s, 2
H, CH2), 3.75 (s, 3 H, CH3), 4.12–4.16 (m, 4 H, 2 × CH2), 5.43 (s, 1
H, H6).
13C NMR (100.61 MHz, CDCl3): d = 27.7 (3 × CH3), 83.4 (C),
110.1 (CH), 115.3 (CH), 120.3 (CH), 122.9 (2 × CH), 124.3 (CH),
124.5 (CH), 129.0 (CH), 129.1 (C), 135.0 (C), 135.3 (C), 137.2 (C),
150.1 (C).
13C NMR (100.61 MHz, CDCl3): d = 16.0 (2 × CH3), 24.0 (CH2),
24.2 (CH2), 29.4 (CH2), 47.3 (CH2), 53.0 (CH3), 64.3 (2 × CH2),
69.2 (CH), 109.1 (C), 154.5 (C).
HRMS: m/z calcd for C17H18NO2S: 300.1058; found: 300.1042.
MS (ion spray): m/z = 308 [M + H]+.
1-(tert-Butoxycarbonyl)-2-(2-cyanophenyl)-1H-indole (18)
Method A was used, starting from compound 1 (100 mg, 0.31
mmol) and 2-bromobenzonitrile (68 mg, 0.37 mmol). The mixture
was refluxed for 6 h. The residue was purified by flash chromatog-
raphy (petroleum ether–EtOAc, 98:2) to afford 18 as a white solid;
yield: 35 mg (36%).
1-(tert-Butoxycarbonyl)-2-[1-(methoxycarbonyl)-4,5,6,7-tetra-
hydro-1H-azepin-2-yl]-1H-indole (21)
Method A was used, starting from compound 1 (100 mg, 0.31
mmol) and methyl 7-[(diethoxyphosphinyl)oxy]-2,3,4,5-tetrahy-
dro-1H-azepine-1-carboxylate (20b; 114 mg, 0.37 mmol). The mix-
ture was refluxed for 12 h. The residue was purified by flash
chromatography (petroleum ether–EtOAc, 9:1) to afford 21 as an
oil; yield: 44 mg (36%).
Mp 147 °C; Rf = 0.45 (petroleum ether–EtOAc, 98:2).
IR (film): 2982, 2929, 2161, 1715, 1449, 1364, 1332, 1254, 1217,
1157, 1120, 1027, 848, 819, 769, 740 cm–1.
Rf = 0.55 (petroleum ether–EtOAc, 1:1).
1H NMR (250 MHz, CDCl3): d = 1.24 (s, 9 H, 3 × CH3), 6.65 (s, 1
H, H3), 7.22–7.49 (m, 5 H, HAr), 7.57 (d, J = 7.5 Hz, 1 H, H4), 7.66
(ddd, J = 12.5 Hz, J¢ = 5 Hz, J¢¢ = 2.5 Hz, 1 H, H3¢), 8.32 (d, J = 7.5
Hz, 1 H, H7).
IR (film): 2933, 1737, 1702, 1449, 1367, 1317, 1253, 1222, 1157,
1120, 1093, 1029, 845, 767, 744 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 1.61 (s, 9 H, 3 × CH3), 1.76–
1.79 (m, 2 H, H4¢), 2.28–2.33 (m, 2 H, H5¢), 3.22–3.24 (m, 2 H, H6¢),
3.40 (s, 3 H, CH3), 3.70 (t, J = 6.0 Hz, 2 H, H7¢), 5.77 (t, J = 5.9 Hz,
1 H, H3¢), 6.63 (s, 1 H, H3), 7.18–7.32 (m, 2 H, H5 + H6), 7.53 (d,
J = 4.8 Hz, 1 H, H4), 7.82 (d, J = 5.3 Hz, 1 H, H7).
13C NMR (100.61 MHz, CDCl3): d = 27.7 (3 × CH3), 83.3 (C),
111.2 (CH), 115.7 (CH), 115.9 (C), 117.1 (C), 120.5 (CH), 122.8
(CH), 124.8 (CH), 125.3 (C), 127.6 (CH), 128.7 (C), 132.1 (C),
133.2 (CH), 133.9 (CH), 134.3 (CH), 137.0 (C), 149.8 (C).
HRMS: m/z calcd for C20H18N2O2Na: 341.1266; found: 341.1261.
13C NMR (100.61 MHz, DMSO-d6): d = 23.2 (CH2), 23.6 (CH2),
27.1 (CH2), 27.5 (3 × CH3), 28.0 (CH2), 52.3 (CH3), 83.8 (C), 113.9
(CH), 120.6 (CH), 122.5 (CH), 123.2 (C), 124.0 (CH), 124.6 (C),
128.4 (CH), 128.6 (C), 138.6 (CH), 149.4 (C), 154.3 (C), 159.4 (C).
1-(tert-Butoxycarbonyl)-2-(2-fluorophenyl)-1H-indole (19)
Method A was used, starting from compound 1 (100 mg, 0.31
mmol) and 1-bromo-2-fluorobenzene (0.040 mL, 0.37 mmol). The
mixture was refluxed for 6 h. The residue was purified by flash
chromatography (petroleum ether–EtOAc, 98:2) to afford 19 as a
red oil; yield: 61 mg (63%).
HRMS: m/z calcd for C21H26N2O4Na: 393.1790; found: 393.1809.
Acknowledgment
Rf = 0.48 (petroleum ether–EtOAc, 98:2).
We thank La Ligue contre le Cancer du Grand-Ouest and le Can-
céropôle Grand-Ouest for financial support. We also thank Prof. G.
Coudert, Dr. I. Gillaizeau, and their collaborators for a supply of
compound 20a.
IR (film): 2982, 1729, 1451, 1367, 1325, 1218, 1157, 1132, 1019,
800, 744 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.40 (s, 9 H, 3 × CH3), 6.65 (s, 1
H, H3), 7.12–7.31 (m, 3 H, HAr), 7.37–7.52 (m, 3 H, HAr), 7.62 (d,
J = 7.5 Hz, 1 H, H4), 8.31 (d, J = 7.5 Hz, 1 H, H7).
References
13C NMR (100.61 MHz, CDCl3): d = 27.7 (3 × CH3), 83.4 (C),
110.7 (CH), 115.3 (d, J = 20 Hz, CH), 120.5 (CH), 122.8 (CH),
123.4 (d, J = 10 Hz, C), 123.8 (CH), 124.5 (CH), 128.9 (d, J = 10
Hz, CH), 129.6 (CH), 130.5 (d, J = 10 Hz, CH), 134.1 (C), 137.3
(C), 149.9 (C), 158.7 (C), 161.2 (d, J = 251 Hz, C).
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