Synthesis of nonsymmetrical 5-Aryl-2-indolopyrrole derivatives via controlled mono Suzuki-Miyaura cross-coupling on N-Boc-2,5-dibromopyrrole

Article abstract of DOI:10.1055/s-0030-1258284

The first example of mono Suzuki-Miyaura cross-coupling of N-Boc-2,5-dibromopyrrole with a boronic acid (indol-2-ylboronic acid) is reported. The resulting 2-indolyl-5-bromopyrrole derivative was in turn coupled with a variety of aryl- or heteroarylboronic acids thereby providing the corresponding non-symmetrical 2,5-disubstituted pyrroles in good to excellent yields. The tert-butoxycarbonyl (Boc) groups could be easily removed to give the completely deprotected products. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258284

PAPER
4033
Synthesis of Nonsymmetrical 5-Aryl-2-indolopyrrole Derivatives via
Controlled Mono Suzuki–Miyaura Cross-Coupling on N-Boc-2,5-dibromo-
pyrrole
Synthesis of
N
l
onsym
o
metrical 5-A
r
ryl-2-ind
i
olopyr
a
role
D
eriva
n
tives e Beaumard, Philippe Dauban, Robert H. Dodd*
Institut de Chimie des Substances Naturelles, UPR 2301, Campus de Recherche de Gif, Centre National de la Recherche Scientifique,
Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Fax +33(1)69077247; E-mail: robert.dodd@icsn.cnrs-gif.fr
Received 3 August 2010; revised 16 August 2010
Dedicated to Professor Akira Suzuki on the occasion of his receiving the Nobel Prize in Chemistry
sion of the latter was obtained in low yield by way of
Abstract: The first example of mono Suzuki–Miyaura cross-cou-
direct palladium-catalyzed 2-arylation of N-methylpyr-
pling of N-Boc-2,5-dibromopyrrole with a boronic acid (indol-2-yl-
boronic acid) is reported. The resulting 2-indolyl-5-bromopyrrole
role using phenyl iodide.7
derivative was in turn coupled with a variety of aryl- or heteroaryl-
More challenging is the preparation of unsymmetrical 2,5-
boronic acids thereby providing the corresponding non-symmetri-
diarylpyrroles, that is, in which two different coupling
cal 2,5-disubstituted pyrroles in good to excellent yields. The tert-
partners are introduced. Most of the methods described
butoxycarbonyl (Boc) groups could be easily removed to give the
for this purpose resort to step-wise coupling/pyrrole acti-
vation/coupling strategies. For example, two successive
in situ generations of pyrrolezinc chloride allowed
Sadighi to introduce, at high temperature and under air-
free conditions, different aryl groups at the C-2 and C-5
completely deprotected products.
Key words: cross-coupling, Suzuki–Miyaura, indole, pyrrole, pal-
ladium-catalyzed
positions of pyrrole via a C–H activation process.8 Using
As part of a medicinal chemistry project aimed at the
a similar strategy, Sames prepared 2-phenyl-5-(4-car-
preparation of rigid analogues of the calcium sensing
boxymethyl)phenyl pyrrole, but in moderate yield and re-
receptor1 agonist, calindol (1),2 developed in our laborato-
quiring a long reaction time.9 Vachal and co-workers
ry, the synthesis of 2-(2-indolyl)-5-arylpyrrole derivatives
described the palladium-catalyzed cross-coupling of 1-
of type 2 was targeted (Scheme 1).
methyl-2-(tri-n-butyl)stannylpyrrole with iodobenzene,
followed by C-5 bromination of the product and subse-
quent Suzuki–Miyaura coupling with a substituted phe-
Ar
nylboronic acid.10 Willis, on the other hand, successfully
developed the desymmetrization of N-Boc-2,5-dibro-
mopyrrole (3) by prior n-butyllithium-mediated exchange
of one bromine atom with a trimethylsilyl group and sub-
sequent reversion to the bromine after the first Suzuki–
Miyaura cross-coupling reaction (Scheme 2).11
N
H
N
H
NH
NH
2
calindol (1)
Scheme 1 Rigidification strategy
3 steps
Recent efforts toward the preparation of 2,5-di(hete-
ro)arylpyrroles have mainly made use of metal-catalyzed,
particularly palladium-catalyzed, coupling reactions start-
ing from suitably functionalized pyrroles.3 Two different
substitution patterns can be distinguished, each of which
requires a separate strategy. Thus, the more easily acces-
sible symmetrically substituted 2,5-diarylpyrroles have
been obtained, for example, by Sinha using Stille coupling
of a 2,5-di(tri-n-butyl)stannylpyrrole with two equiva-
lents of aryl bromide,4 while Sugihara and co-workers de-
scribed the single-step, double Suzuki–Miyaura coupling
of N-Boc-2,5-dibromopyrrole (3) with an azulene pina-
colboronate.5 Alternatively, a double C–H activation on
1-(2,6-dichlorobenzoyl)pyrrole allowed Itahara6 to pre-
pare 2,5-diphenyl pyrroles, whereas an N-methylated ver-
Ar2
Br
Ar1
Ar1
Br
Br
N
N
N
Boc
Boc
Boc
our work
1 step
3
Scheme 2 Willis’ desymmetrization strategy and our approach
None of these studies included indole as one of the cou-
pling partners with pyrrole. Moreover, all these methods
are multistep procedures, and for an eventual structure–
activity study of molecules of type 2, we were interested
in developing a more rapid access to these compounds. As
a wide variety of aryl and heteroarylboronic acids are
commercially available the application of two successive
Suzuki–Miyaura couplings on an easily accessible 2,5-di-
bromopyrrole derivative appeared to be the best route to
this goal.12 Only a few examples of mono Suzuki–
Miyaura cross-couplings on a symmetrical dihalogenated
substrate (phenyl,13 pyridine,12a,14 thiophene15), followed
SYNTHESIS 2010, No. 23, pp 4033–4042
x
x.
x
x
.
2
0
1
0
Advanced online publication: 05.10.2010
DOI: 10.1055/s-0030-1258284; Art ID: Z20010SS
© Georg Thieme Verlag Stuttgart · New York

4034
F. Beaumard et al.
PAPER
by a second coupling have been described. The success of pling of 7 with pyrrole-2-triflate, treatment of 3 with 1.2
such reactions depends on the deactivation of the second equivalents of 7 in 1,2-dimethoxyethane in the presence
oxidative addition of palladium after the first coupling of of tetrakis(triphenylphosphine)palladium(0) (8 mol%),
an electron-donating boronic acid.12a As far as the selec- sodium carbonate and lithium chloride provided, after
tive introduction of two different aryl groups at the C-2 three hours at 85 °C, the mono-coupled product 9 in 51%
and C-5 positions of pyrrole is concerned, only the use of yield (Scheme 4). The only by-products observed were
1-methyl-2,3,4,5-tetrabromopyrrole as substrate has been the bis-indole homo-coupled derivative 10, formed in ap-
1
described.16 However, the reaction failed when cleavable proximately 18% yield, as estimated by H NMR spec-
N-protecting groups were used instead of N-methyl. troscopy, and N-Boc-2,5-diindolylpyrrole 11, the yield of
Since, in the context of our medicinal chemistry program which was estimated to be less than 10%. Attempts to in-
mentioned above, only N-deprotected pyrrole derivatives crease the yield of 9 by varying the number of equivalents
of type 2 were required, this procedure was not suitable of lithium chloride (1–3) or the amount of palladium cat-
for our objectives. In this paper, we report the first con- alyst were not successful.21 Interestingly, attempted
trolled mono-coupling of an arylboronic acid (that is, an mono-coupling of 3 with phenylboronic acid or pyridin-3-
N-protected indol-2-ylboronic acid) with N-Boc-2,5-di- ylboronic acid, instead of with 7, was unsuccessful, pro-
bromopyrrole (3) followed by a second coupling reaction viding mainly starting material and unidentified degrada-
with a different arylboronic acid to give the corresponding tion products.
non-symmetrical 2,5-disubstituted-N-Boc-pyrrole deriva-
tives. The latter could be easily deprotected to give the de-
sired compounds of type 2.17
N
For purposes of comparison, we decided to first synthe-
size the simplest derivative of type 2, that is, the 2-indolyl-
N
Boc
Boc
10
5-phenylpyrrole derivative 8a, by a classical step-wise
18%
procedure.17 Thus, N-Boc-pyrrol-2-ylboronic acid (4)18
B(OH)2
was coupled with bromobenzene using tetrakis(triphe-
nylphosphine)palladium(0) and sodium carbonate in 1,2-
N
Boc
Br
N
7
dimethoxyethane to give the 2-phenylpyrrole derivative 5
in 87% yield (corresponding to an 81% yield starting from
pyrrole) (Scheme 3). Compound 5 was treated with n-bu-
tyllithium and 2,2,6,6-tetramethylpiperidine (TMP) in tet-
rahydrofuran for two hours followed by the addition of 1.1
equivalents of iodine to afford, selectively, the 5-iodopy-
rrole derivative 6 which was isolated in 91% yield. A sec-
ond Suzuki–Miyaura coupling between 6 and N-Boc-
indol-2-ylboronic acid (7) then provided the desired un-
symmetrical disubstituted pyrrole 8a in 41% yield. The
overall yield for the five-step preparation of 8a from pyr-
role was 30%.
Br
Br
N
Pd(PPh3)4
Na2CO3 (aq)
LiCl
DME
85 °C, 3 h
N
Boc
Boc
Boc
3
9
51%
N
N
N
Boc
Boc
Boc
11
<10%
Scheme 4 Mono Suzuki–Miyaura cross-coupling on pyrrole 3
We next attempted to prepare compound 8a directly from
N-Boc-2,5-dibromopyrrole (3)19by way of two successive
Suzuki–Miyaura coupling reactions. Thus, using condi-
tions described by Fürstner20for palladium-catalyzed cou-
Compound 9 was then engaged in a second Suzuki cou-
pling reaction with phenylboronic acid using the same re-
action conditions as for the first indole-pyrrole coupling
Br
Boc
Boc
1) n-
BuLi
2) I2
Boc
Pd(PPh3)4
Na2CO3 (aq)
I
N
N
N
TMP
B(OH)2
DME
THF
–78 °C, 2 h
91%
85 °C, 2 h
87%
5
4
6
B(OH)2
Pd(PPh3)4
Na2CO3 (aq)
DME
N
Boc
Boc
N
7
85 °C, 15 h
41%
N
Boc
8a
Scheme 3 Linear strategy for the preparation of target compound 8a
Synthesis 2010, No. 23, 4033–4042 © Thieme Stuttgart · New York

PAPER
Synthesis of Nonsymmetrical 5-Aryl-2-indolopyrrole Derivatives
4035
reaction. This provided the unsymmetrical 2,5-disubsti- the yield of compound 8a to 84%. The latter was thus ob-
tuted pyrrole derivative 8a in 55% yield (Table 1, entry 1). tained in only four steps and in 38% overall yield starting
However, the use of toluene–ethanol (4:1) instead of 1,2- from pyrrole, thereby demonstrating the superiority of this
dimethoxyethane as reaction solvent, allowing heating of methodology compared to the step-wise procedure
the reaction mixture at 100 °C instead of 85 °C, improved (Scheme 3) in which 8a was obtained in five steps and in
Table 1 Second Suzuki–Miyaura Cross-Coupling on N-Boc-2-Bromo-5-indolopyrrole Derivative 9a
Pd(PPh3)4
Na2CO3 (aq)
Ar
Br
N
N
ArB(OH)2
+
toluene–EtOH
100 °C, 3 h
N
N
Boc
Boc
12
Boc
Boc
8
9
Entry
1
Ar
Product
Yield (%)
84 (55)b
8a
2
3
8b
8c
79
52
N
O
4
5
6
8d
8e
8f
75
81
98
NO2
OMe
F
F
7
8
8g
8h
82
54
Cl
OMe
9
8i
88
OMe
OMe
N
10
11
8j
33
76
N
8k
N
O
N
12
8l
32
a Reactions were performed with 9, ArB(OH)2 (1.5 equiv), Pd(PPh3)4 (10 mol%) and Na2CO3 (2 M, 6.0 equiv) in a mixture of toluene–EtOH
(4:1) at 100 °C for 3 h.
b Reaction was performed with 9, PhB(OH)2 (1.2 equiv), Pd(PPh3)4 (8 mol%), Na2CO3 (2 M, 4.0 equiv) and LiCl (1.0 equiv) in DME at 85 °C
for 3 h.
Synthesis 2010, No. 23, 4033–4042 © Thieme Stuttgart · New York

4036
F. Beaumard et al.
PAPER
30% overall yield from pyrrole. These improved condi-
tions were then applied to a variety of aryl- and hetero-
arylboronic acids 12, as shown in Table 1.
B(OH)2
N
N
Boc
Boc
Boc
13
In the case of arylboronic acids, the yields of the unsym-
metrical coupling products 8b–8i were consistently good
to excellent. Thus, introduction of the sterically hindered
biphenyl group gave product 8b in 79% yield (Table 1,
entry 2) while the presence of either electron-withdrawing
(nitro) or electron-donating (methoxy, trimethoxy) pro-
vided the corresponding products 8d, 8e and 8i, respec-
tively, in 75–88% yields (Table 1, entries 4, 5 and 9). The
lower yield of the 4-phenylmorpholine derivative 8c
(52%, Table 1, entry 3) was ascribed to the relative insta-
bility of the starting non-commercial boronic acid.22 The
use of halogenated arylboronic acids was also successful
as demonstrated by formation of the 4-fluorophenyl and
3-fluorophenyl derivatives 8f and 8g in yields of 98% and
82%, respectively (Table 1, entries 6 and 7); however, the
4-chlorophenyl derivative 8h was obtained in a more
moderate 54% yield (Table 1, entry 8).
7
10
+
Br
Br
N
Pd(PPh3)4
Na2CO3 (aq)
toluene–EtOH
100 °C, 3 h
N
Boc
N
Boc
3
14
Scheme 5 Importance of the nature of the solvent on the first mono
cross-coupling
of compounds 8 with trifluoroacetic acid in dichloro-
methane (1:1) at room temperature for one hour gave
good (61%) to high (86%) yields of the bis-deprotected
products 2a and 2e–2i (Table 2, entries 1 and 3–7). Only
the nitrophenyl derivative 8d gave a less satisfactory yield
of deprotected product 2d (32%, Table 2, entry 2). In the
case of the two substrates having a heteroaryl moiety (8j
and 8l), the use of tetrabutylammonium fluoride instead of
trifluoroacetic acid, under the same reaction conditions,
proved to be necessary to remove the protecting groups in
high yield (100% and 75%, respectively, Table 2, entries
8 and 9).
Altogether, electronic effects seemed to have little effect
on the outcome of the second Suzuki coupling reaction.
This second coupling reaction was also attempted using
heteroarylboronic acids. Interestingly, while the pyridino-
morpholine product 8k was obtained in higher yield than
its phenylmorpholine analogue 8c (76% versus 52%,
Table 1, entries 11 and 3), the unsubstituted pyridine de-
rivative 8j was obtained in considerably lower yield than
its phenyl counterpart 8a (33% and 84%, Table 1, entries
10 and 1) using, in all cases, exactly the same reaction
conditions. The 5-isoquinolinyl derivative 8l was ob-
tained in a relatively modest but exploitable 32% yield
(Table 1, entry 12). The use of stronger bases, different
palladium catalysts and solvents, as well as microwave ir-
radiation, did not lead to higher yields of 8j and 8l.
Table 2 Double Deprotection of Compounds 8
TFA, CH2Cl2
Ar
Ar
r.t., 1 h
N
H
N
NH
N
Boc
Boc
8
2
Entry
Substrate
Product
2a
Yield (%)
61
1
2
3
4
5
6
7
8
9
8a
8d
8e
8f
2d
2e
32
As noted above, the second Suzuki coupling to form com-
pounds 8 from 2-bromo-5-indolylpyrrole derivative 9 was
favored using toluene–ethanol (4:1) as the reaction medi-
um, while the first coupling reaction to give 9 itself was
conducted in 1,2-dimethoxyethane. With the objective of
conducting both coupling reactions in the same solvent
system (thereby avoiding the necessity of an intermediate
work-up step), coupling of N-Boc-dibromopyrrole (3)
with indol-2-ylboronic acid 7 was attempted in toluene–
ethanol, that is, under the optimized reaction conditions of
the second coupling reaction (Scheme 5). Surprisingly, no
trace of the mono-coupled indole–pyrrole product 9 was
found. Instead, only the debrominated form of 9 was ob-
served (that is, compound 14 obtained in 10% isolated
yield) together with the products of indole homocoupling
10 (14% yield) and deborylation 13 (27%). The necessity
of using different solvent systems in order to optimize the
yields of each of the two coupling steps thus seems appar-
ent.
78
2f
86
8g
8h
8i
2g
73
2h
2i
86
78
8j
2j
100a
75a
8l
2l
a TBAF–THF (1:1) at reflux for 4 h.
In conclusion, we have developed an efficient strategy for
the synthesis of non-symmetrical 2-indolyl-5-aryl- and
-heteroarylpyrroles from symmetrical N-Boc-2,5-dibro-
mopyrrole (3) by successive and selective coupling of
first, an indol-2-ylboronic acid, followed by an aryl- or
heteroarylboronic acid. Structural diversity can thus be
achieved in only two steps instead of the multi-step pro-
cesses described until now. Furthermore, the use of the
tert-butoxycarbonyl N-protecting group allows deprotec-
In view of the pharmacological potential of this new fam-
ily of triaromatic compounds, simultaneous removal of
both N-Boc groups was then studied (Table 2). Treatment
Synthesis 2010, No. 23, 4033–4042 © Thieme Stuttgart · New York

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Synthesis of Nonsymmetrical 5-Aryl-2-indolopyrrole Derivatives
4037
Rf = 0.54 (heptanes–EtOAc, 90:10).
IR (neat): 2925, 1681, 1316, 1140 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.42–7.28 (m, 5 H), 6.56 (d,
J = 3.4 Hz, 1 H), 6.22 (d, J = 3.4 Hz, 1 H), 1.33 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 149.1, 138.9, 134.2, 128.2, 128.0,
127.4, 123.2, 114.8, 85.0, 66.2, 27.3.
HRMS (ESI): m/z calcd for C15H16INO2Na [M + Na+]: 392.0124;
tion of the final products in typically high yields under
mild conditions. Finally, the present procedure is comple-
mentary to our recently-described one-pot, simultaneous
double Suzuki–Miyaura coupling reaction on N-Boc-2,5-
dibromopyrrole (3) the success of which required the use,
however, of arylboronic acids possessing significantly di-
vergent electronic characters.23
found: 392.0135.
Melting points were measured in capillary tubes on a Büchi B-540
apparatus and are uncorrected. Infrared spectra were recorded on a
Perkin-Elmer Spectrum BX FT-IR spectrometer. Proton NMR (1H)
spectra were recorded using Bruker 500 MHz or 300 MHz Avance
spectrometers. Carbon NMR (13C) spectra were recorded at 125
MHz or 75 MHz, using a broadband decoupled mode with the mul-
tiplicities obtained using a JMOD or DEPT sequence. Chemical
shifts (d) are reported in parts per million (ppm). NMR experiments
were carried out in deuterochloroform (CDCl3), deuteromethanol
(CD3OD) or deuterodimethylsulfoxide [(CD3)2SO]. Mass spectra
were obtained either with an LCT (Micromass) instrument using
electrospray ionization (ES), or using a Time-of-Flight analyzer
(ESI-MS) for the high-resolution mass spectra (HRMS). Elemental
analyses were performed on a Perkin Elmer CHN 2400 analyzer
with detection by catharometry. Thin-layer chromatography was
performed on silica gel 60 F254 on aluminum plates (Merck) and
visualized under a UVP Mineralight UVLS-28 lamp (254 nm) and
with ninhydrin and phosphomolybdic acid in ethanol. Flash chro-
matography was conducted on Merck silica gel 60 (40–63 mm) at
medium pressure (300 mbar) or on CombiFlash (Serlabo Technolo-
gies). All reagents were obtained from commercial suppliers unless
otherwise stated. Where necessary, organic solvents were routinely
dried and/or distilled prior to use and stored over molecular sieves
under nitrogen.
N-tert-Butoxycarbonyl-2-(N-tert-butoxycarbonyl-2-phenyl-1H-
pyrrol-5-yl)-1H-indole (8a)
To a stirred soln of 6 (70 mg, 190 mol) in DME (1.5 mL) at r.t. under
Ar were added N-Boc-indol-2-ylboronic acid (7) (45 mg, 172
mmol), a soln of Na2CO3 (77 mg, 724 mmol) in H2O (0.5 mL) and
Pd(PPh3)4 (10 mg, 9 mmol). The resulting mixture was heated at 85
°C for 15 h, then cooled and evaporated. CH2Cl2 (5 mL) was added
and the organic layer was washed with H2O (3 × 3 mL) and brine (3
mL), dried over MgSO4 and evaporated in vacuo. Chromatography
(PE–EtOAc–heptanes, 63:7:30) of the crude reaction product gave
8a (32 mg, 41%) as a white powder.
Mp 141–142 °C; Rf = 0.36 (heptanes–CH2Cl2, 50:50).
IR (neat): 2982, 1753, 1724, 1332, 1297 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.35 (d, J = 8.5 Hz, 1 H), 7.59 (d,
J = 7.6 Hz, 1 H), 7.42–7.39 (m, 4 H), 7.38–7.35 (m, 2 H), 7.29–7.26
(m, 1 H), 6.69 (s, 1 H), 6.32 (d, J = 3.1 Hz, 1 H), 6.28 (d, J = 3.1 Hz,
1 H), 1.47 (s, 9 H), 1.13 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 150.0, 149.2, 137.0, 136.8, 134.4,
132.1, 128.8, 128.5, 128.2, 127.8, 127.2, 124.6, 122.7, 120.5, 115.8,
114.1, 112.7, 111.6, 83.6, 83.2, 27.9, 27.2.
Anal. Calcd for C28H30N2O4: C, 73.34; H, 6.59; N, 6.11. Found: C,
73.34; H, 6.63; N, 6.13.
N-tert-Butoxycarbonyl-2-phenyl-1H-pyrrole (5)
N-tert-Butoxycarbonyl-2-(N-tert-butoxycarbonyl-2-bromo-1H-
pyrrol-5-yl)-1H-indole (9), N,N¢-Di-tert-butoxycarbonyl-
1H,1¢H-2,2¢-biindole (10) and N,N¢-Di-tert-butoxycarbonyl-2,2¢-
(N-tert-butoxycarbonyl-1H-pyrrole-2,5-diyl)-di-1H-indole (11)
To an oven-dried round-bottomed flask was added N-Boc-2,5-di-
bromo-1H-pyrrole (3)18 (1.20 g, 3.71 mmol) and Pd(PPh3)4 (0.36 g,
0.31 mmol) in DME (40 mL). The mixture was degassed with Ar.
N-Boc-indol-2-ylboronic acid (7) (1.16 g, 4.46 mmol), a soln of
Na2CO3 (2.36 g, 14.84 mmol) in H2O (11 mL) and LiCl (0.16 g,
3.71 mmol) were added. The reaction mixture was degassed with Ar
and heated at 85 °C for 3 h. After cooling to r.t., the soln was filtered
through a thin pad of Celite, the pad rinsed with EtOAc (15 mL) and
the filtrate concd under reduced pressure. Chromatography (hep-
tanes–EtOAc, 98:2) of the crude residue gave the desired product 9
(875 mg, 51% by NMR) as a colorless oil contaminated with the ho-
mocoupled indole product 10 (C26H28N2O4) (179 mg, 18% by
NMR).
To a stirred soln of 4 (0.25 g, 1.18 mmol), bromobenzene (0.13 g,
0.86 mmol), Pd(PPh3)4 (0.05 g, 43 mmol) in DME (15 mL) at r.t. un-
der Ar was added a soln of Na2CO3 (0.38 g, 3.56 mmol) in H2O (5
mL). The mixture was heated at reflux for 2 h, cooled and evaporat-
ed. CH2Cl2 (15 mL) was added and the organic layer was washed
with H2O (3 × 10 mL) and brine (10 mL), dried over MgSO4 and
evaporated in vacuo. Chromatography (heptanes–EtOAc, 90:10) of
the crude reaction product gave 5 (0.16 g, 87%) as a yellow oil.
Rf = 0.58 (heptanes–EtOAc, 90:10).
IR (neat): 1650, 1316, 1044 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.43–7.35 (m, 6 H), 6.30–6.28 (m,
1 H), 6.26–6.24 (m, 1 H), 1.41 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 149.4, 135.1, 134.5, 129.2, 127.6,
127.2, 122.5 (C-4), 114.4 (C-3), 110.6 (C-2), 83.5, 27.6.
MS (ESI): m/z = 266.1 [M + Na+].
Rf = 0.40 (heptanes–EtOAc, 90:10).
IR (neat): 2981, 2933, 1745, 1720, 1334, 1307 cm–1.
N-tert-Butoxycarbonyl-5-iodo-2-phenyl-1H-pyrrole (6)
To a dry 25 mL round-bottomed flask was added THF (1 mL) and
2,2,6,6-tetramethylpiperidine (TMP) (169 ml, 994 mmol). The mix-
ture was cooled to –80 °C and n-BuLi (0.62 mL of a 1.6 M soln in
hexanes, 994 mmol) was added dropwise, the temperature being
maintained below –65 °C. The mixture was stirred for 1 h at –78 °C,
compound 5 (161 mg, 662 mmol) in THF (1 mL) was added and the
mixture stirred for 2 h at –78 °C. I2 (185 mg, 729 mmol) in THF (1
mL) was then added and stirring was continued for 2 h at –78 °C.
Sat. aq Na2SO3 soln (2 mL) was introduced and after 15 min,
CH2Cl2 (10 mL) was added. The organic layer was washed with
H2O (3 × 5 mL) and brine (5 mL), dried over MgSO4 and evaporated
in vacuo to give 6 (293 mg, 91%) as a red oil.
1H NMR (500 MHz, CDCl3): d = 8.35–8.31 (m, 1 H), 7.60–7.54 (m,
1 H), 7.40–7.33 (m, 1 H), 7.32–7.23 (m, 1 H), 6.58 (s, 1 H), 6.37 (d,
J = 3.6 Hz, 1 H), 6.24 (d, J = 3.6 Hz, 1 H), 1.44 (s, 9 H), 1.21 (s, 9
H).
13C NMR (75 MHz, CDCl3): d = 149.9, 148.0, 137.0, 132.1, 131.7,
128.7, 124.8, 122.9, 120.5, 115.8, 115.6, 114.9, 111.3, 102.6, 84.7,
83.6, 27.8, 27.4.
Anal. Calcd for C22H25N2O4Br·0.22C26H28N2O4: C, 59.83; H, 5.64;
N, 6.14. Found: C, 59.74; H, 5.59; N, 6.11.
Continued elution of the column gave pure compound 10.17
Synthesis 2010, No. 23, 4033–4042 © Thieme Stuttgart · New York

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F. Beaumard et al.
PAPER
Rf = 0.36 (heptanes–EtOAc, 90:10).
1H NMR (500 MHz, CDCl3): d = 8.34 (d, J = 8.5 Hz, 1 H), 7.67–
7.62 (m, 4 H), 7.59 (d, J = 7.9 Hz, 1 H), 7.49–7.46 (m, 4 H), 7.39–
7.36 (m, 2 H), 7.29–7.26 (m, 1 H), 6.67 (s, 1 H), 6.33 (s, 2 H), 1.47
(s, 9 H), 1.14 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 150.0, 142.9, 140.8, 140.0, 137.0,
136.5, 133.3, 132.0, 128.8, 128.7, 128.4, 127.3, 127.2, 127.1, 126.6,
124.6, 122.8, 120.5, 115.8, 114.2, 113.0, 111.6, 83.8, 83.3, 27.9,
27.3.
1H NMR (500 MHz, CDCl3): d = 8.34 (d, J = 8.2 Hz, 2 H), 7.59 (d,
J = 7.6 Hz, 2 H), 7.38 (t, J = 7.6 Hz, 2 H), 7.27 (t, J = 8.2 Hz, 2 H),
6.67 (s, 2 H), 1.26 (s, 18 H).
13C NMR (75 MHz, CDCl3): d = 149.9, 137.0, 132.1, 128.7, 124.8,
122.8, 120.6, 115.7, 111.2, 83.4, 27.7.
MS (ESI): m/z = 455.2 [M + Na+], 355.1 [M – Boc + Na+].
Further elution of the column gave pure compound 11.
Rf = 0.28 (heptanes–EtOAc, 90:10).
HRMS (ESI): m/z calcd for C34H34N2O4Na [M + Na+]: 557.2426;
found: 557.2416.
IR (neat): 2980, 1741, 1720, 1331, 1315, 745 cm–1.
4-Morpholinophenylboronic Acid
1H NMR (500 MHz, CDCl3): d = 8.33 (d, J = 8.5 Hz, 2 H), 7.57 (d,
J = 7.5 Hz, 2 H), 7.35 (t, J = 8.5 Hz, 2 H), 7.25 (t, J = 7.5 Hz, 2 H),
6.57 (s, 2 H), 6.31 (s, 2 H), 1.48 (s, 18 H), 1.08 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 150.0, 148.7, 137.0, 132.3, 128.9,
128.4, 124.6, 122.8, 120.5, 116.0, 114.2, 111.2, 83.5, 83.2, 28.0,
27.5.
To a dry 25 mL round-bottomed flask was added 4-(4-bromophe-
nyl)morpholine (500 mg, 2.40 mmol) in THF (10 mL). The mixture
was cooled to –80 °C and n-BuLi (4.81 mmol) was added dropwise
whilst keeping the temperature below –65 °C. The mixture was
stirred for 1 h at –78 °C and then trimethylborate (749 mg, 7.21
mmol) was added. The resulting mixture was stirred for 10 min at
–78 °C and then for 1 h at r.t. NaOH (4% aq soln in H2O, 5 mL) was
added and the reaction mixture was evaporated. EtOAc (10 mL)
was added and the soln was acidified to pH 5–6 using HCl (1 M; 2
mL). The organic layer was washed with H2O (3 × 5 mL) and brine
(5 mL), dried over MgSO4 and evaporated in vacuo to give 4-mor-
pholinophenylboronic acid as a white powder which was used in the
Suzuki cross-coupling step without further purification.
HRMS (ESI): m/z calcd for C35H39N3O6Na [M + Na+]: 620.2724;
found: 620.2737.
N-tert-Butoxycarbonyl-2-(N-tert-butoxycarbonyl-2-aryl-1H-
pyrrol-5-yl)-1H-indoles 8; General Procedure
To an oven-dried round-bottomed flask was added compound 9 (1.0
equiv) and Pd(PPh3)4 (10 mol%) in a mixture of toluene–EtOH
(4:1). The reaction mixture was degassed with Ar, and aryl or het-
eroaryl boronic acid [ArB(OH)2] 12 (1.5 equiv) and a soln of
Na2CO3 (6.0 equiv) in H2O (1 mL) were added. The reaction mix-
ture was again degassed with Ar and heated to 100 °C for 3 h before
cooling to r.t. The soln was then filtered through a thin pad of Celite
(eluting with EtOAc) and the filtrate was concd under reduced pres-
sure. Chromatography (gradient elution) using the appropriate sol-
vents gave the desired product.
N-tert-Butoxycarbonyl-2-[N-tert-butoxycarbonyl-2-(4-mor-
pholinophenyl)-1H-pyrrol-5-yl]-1H-indole (8c)
Following the general procedure, compound 9 (54 mg, 117 mmol)
was treated with 4-morpholinophenylboronic acid (36 mg, 175
mmol). Chromatography (PE–EtOAc–heptanes, 63:7:30) of the
crude reaction product gave 8c (33 mg, 52%) as a brownish-colored
oil.
Rf = 0.36 (heptanes–EtOAc, 70:30).
IR (neat): 1735, 1724, 1332, 1303, 1138 cm–1.
N-tert-Butoxycarbonyl-2-(N-tert-butoxycarbonyl-2-phenyl-1H-
pyrrol-5-yl)-1H-indole (8a)
Following the general procedure, compound 9 (61 mg, 132 mmol)
was treated with phenylboronic acid (24 mg, 198 mmol). Chroma-
tography (PE–EtOAc–heptanes, 63:7:30) of the crude reaction
product gave 8a (50 mg, 84%) as a white powder which was identi-
cal to that prepared from compound 6.
1H NMR (500 MHz, CDCl3): d = 8.33 (d, J = 8.2 Hz, 1 H), 7.57 (d,
J = 7.6 Hz, 1 H), 7.35 (t, J = 8.2 Hz, 1 H), 7.30 (d, J = 8.9 Hz, 2 H),
7.26 (t, J = 7.6 Hz, 1 H), 6.93 (d, J = 8.9 Hz, 2 H), 6.63 (s, 1 H), 6.28
(d, J = 3.4 Hz, 1 H), 6.20 (d, J = 3.4 Hz, 1 H), 3.89 (t, J = 4.6 Hz, 4
H), 3.23 (t, J = 4.6 Hz, 4 H), 1.44 (s, 9 H), 1.12 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 150.3, 150.1, 149.3, 137.0, 136.9,
132.3, 129.4, 128.8, 127.7, 125.8, 124.5, 122.7, 120.4, 115.8, 114.8,
114.0, 112.1, 111.4, 83.4, 83.2, 66.9, 49.0, 27.9, 27.3.
Biphenyl-4-ylboronic Acid
To a dry 25 mL round-bottomed flask was added 4-bromobiphenyl
(990 mg, 4.25 mmol) in THF (20 mL). The mixture was cooled to
–80 °C and n-BuLi (8.49 mmol) was added dropwise whilst keeping
the temperature below –65 °C. The reaction mixture was stirred for
1 h at –78 °C and then trimethylborate (1.32 g, 12.74 mmol) was
added, and the mixture stirred for a further 10 min at –78 °C and
then for 1 h at r.t. NaOH (4% aq soln in H2O, 10 mL) was added and
the mixture was evaporated. EtOAc (20 mL) was added and the soln
acidified to pH 5–6 using HCl (1 M; 4 mL). The organic layer was
washed with H2O (3 × 10 mL) and brine (10 mL), dried over MgSO4
and evaporated in vacuo to give biphenyl-4-ylboronic acid as a
white powder which was used in the Suzuki cross-coupling step
without further purification.
HRMS (ESI): m/z calcd for C32H37N3O5Na [M + Na+]: 566.2631;
found: 566.2647.
N-tert-Butoxycarbonyl-2-[N-tert-butoxycarbonyl-2-(4-nitro-
phenyl)-1H-pyrrol-5-yl]-1H-indole (8d)
Following the general procedure, compound 9 (71 mg, 154 mmol)
was treated with 4-nitrophenylboronic acid (39 mg, 231 mmol).
Chromatography (PE–EtOAc–heptanes, 63:7:30) of the crude reac-
tion product gave 8d (58 mg, 75%) as a yellow oil.
Rf = 0.40 (heptanes–EtOAc, 80:20).
IR (neat): 1753, 1727, 1511, 1316, 1303 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.32 (d, J = 8.3 Hz, 1 H), 8.27 (d,
J = 8.5 Hz, 2 H), 7.60 (d, J = 7.5 Hz, 1 H), 7.54 (d, J = 8.5 Hz, 2 H),
7.38 (dd, J = 8.3 Hz, J = 2.1 Hz, 1 H), 7.28 (dd, J = 7.5 Hz, J = 2.1
Hz, 1 H), 6.67 (s, 1 H), 6.41 (d, J = 3.4 Hz, 1 H), 6.35 (d, J = 3.4 Hz,
1 H), 1.46 (s, 9 H), 1.13 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 149.9, 149.0, 146.6, 140.7, 136.9,
134.5, 131.2, 130.1, 128.8, 128.7, 124.9, 123.3, 122.9, 120.6, 115.8,
114.9, 114.6, 111.8, 84.5, 83.5, 27.9, 27.3.
N-tert-Butoxycarbonyl-2-[N-tert-butoxycarbonyl-2-(biphenyl-
4-yl)-1H-pyrrol-5-yl]-1H-indole (8b)
Following the general procedure, compound 9 (110 mg, 238 mmol)
was treated with biphenyl-4-ylboronic acid (71 mg, 358 mmol).
Chromatography (heptanes–EtOAc, 85:15) of the crude reaction
product gave 8b (100 mg, 79%) as a brown oil.
Rf = 0.79 (heptanes–EtOAc, 85:15).
IR (neat): 1743, 1726, 1333, 1304, 1154, 1138 cm–1.
Synthesis 2010, No. 23, 4033–4042 © Thieme Stuttgart · New York

PAPER
Synthesis of Nonsymmetrical 5-Aryl-2-indolopyrrole Derivatives
4039
Anal. Calcd for C28H29N3O6: C, 66.79; H, 5.80; N, 8.34. Found: C,
66.51; H, 5.93; N, 7.96.
N-tert-Butoxycarbonyl-2-[N-tert-butoxycarbonyl-2-(4-chloro-
phenyl)-1H-pyrrol-5-yl]-1H-indole (8h)
Following the general procedure, compound 9 (64 mg, 139 mmol)
was treated with 4-chlorophenylboronic acid (33 mg, 208 mmol).
Chromatography (PE–EtOAc–heptanes, 63:7:30) of the crude reac-
tion product gave 8h (37 mg, 54%) as a brown oil.
N-tert-Butoxycarbonyl-2-[N-tert-butoxycarbonyl-2-(4-meth-
oxyphenyl)-1H-pyrrol-5-yl]-1H-indole (8e)
Following the general procedure, compound 9 (83 mg, 180 mmol)
was treated with 4-methoxyphenylboronic acid (41 mg, 270 mmol).
Chromatography (PE–EtOAc–heptanes, 63:7:30) of the crude reac-
tion product gave 8e (71 mg, 81%) as a white powder.
Rf = 0.72 (heptanes–EtOAc, 80:20).
IR (neat): 3048, 1748, 1720, 1330, 1309 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.34–8.31 (m, 1 H), 7.59–7.57 (m,
1 H), 7.39–7.33 (m, 4 H), 7.30–7.24 (m, 2 H), 6.65 (s, 1 H), 6.30 (d,
J = 3.4 Hz, 1 H), 6.26 (d, J = 3.4 Hz, 1 H), 1.45 (s, 9 H), 1.12 (s, 9
H).
13C NMR (75 MHz, CDCl3): d = 150.0, 149.1, 136.9, 135.5, 133.2,
132.8, 131.9, 129.8, 128.8, 128.6, 128.1, 124.7, 122.8, 120.5, 115.8,
114.2, 113.1, 111.6, 83.9, 83.3, 27.9, 27.3.
Mp 108–109 °C; Rf = 0.41 (heptanes–EtOAc, 80:20).
IR (neat): 1747, 1729, 1333, 1310, 1132 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.34–8.33 (m, 1 H), 7.58–7.55 (m,
1 H), 7.38–7.26 (m, 4 H), 6.94 (d, J = 8.7 Hz, 2 H), 6.64 (s, 1 H),
6.28 (d, J = 3.4 Hz, 1 H), 6.21 (d, J = 3.4 Hz, 1 H), 3.86 (s, 3 H,
CH3O), 1.45 (s, 9 H), 1.12 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 158.9, 150.0, 149.3, 137.0, 136.6,
132.3, 129.7, 128.8, 127.8, 126.9, 124.5, 122.7, 120.4, 115.8, 114.0,
113.4, 112.3, 111.4, 83.5, 83.2, 55.2, 27.9, 27.3.
Anal. Calcd for C28H29ClN2O4·0.1H2O: C, 67.97; H, 5.95; N, 5.66.
Found: C, 68.01; H, 5.94; N, 5.48.
Anal. Calcd for C29H32N2O5: C, 71.29; H, 6.60; N, 5.73. Found: C,
71.33; H, 6.58; N, 5.52.
N-tert-Butoxycarbonyl-2-[N-tert-butoxycarbonyl-2-(3,4,5-tri-
methoxyphenyl)-1H-pyrrol-5-yl]-1H-indole (8i)
Following the general procedure, compound 9 (82 mg, 180 mmol)
was treated with 3,4,5-trimethoxyphenylboronic acid (57 mg, 270
mmol). Chromatography (PE–EtOAc–heptanes, 63:7:30) of the
crude reaction product gave 8i (87 mg, 88%) as a white powder.
N-tert-Butoxycarbonyl-2-[N-tert-butoxycarbonyl-2-(4-fluoro-
phenyl)-1H-pyrrol-5-yl]-1H-indole (8f)
Following the general procedure, compound 9 (87 mg, 189 mmol)
was treated with 4-fluorophenylboronic acid (40 mg, 283 mmol).
Chromatography (PE–EtOAc–heptanes, 63:7:30) of the crude reac-
tion product gave 8f (88 mg, 98%) as a white powder.
Mp 78–79 °C; Rf = 0.20 (heptanes–EtOAc, 80:20).
IR (neat): 3129, 1736, 1730, 1333, 1310, 1128 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.31 (d, J = 8.3 Hz, 1 H), 7.57 (d,
J = 7.5 Hz, 1 H), 7.36 (dd, J = 8.3 Hz, J = 1.1 Hz, 1 H), 7.26 (dd,
J = 7.5 Hz, J = 1.1 Hz, 1 H), 6.65 (s, 1 H), 6.61 (s, 2 H), 6.29 (d,
J = 3.4 Hz, 1 H), 6.26 (d, J = 3.4 Hz, 1 H), 3.90 (s, 3 H, CH3O), 3.88
(s, 6 H, 2 × CH3O), 1.46 (s, 9 H), 1.13 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 152.8, 150.0, 149.2, 137.5, 136.9,
136.6, 131.8, 129.8, 128.8, 128.2, 124.7, 122.8, 120.4, 115.8, 113.9,
112.6, 111.7, 105.8, 83.6, 83.2, 60.9, 56.0, 27.9, 27.3.
Mp 161–162 °C; Rf = 0.54 (heptanes–CH2Cl2, 30:70).
IR (neat): 1747, 1720, 1315, 1145, 1134 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.35–8.32 (m, 1 H), 7.60–7.57 (m,
1 H), 7.40–7.33 (m, 3 H), 7.29–7.28 (m, 1 H), 7.13–7.07 (m, 2 H),
6.66 (s, 1 H), 6.31 (d, J = 3.2 Hz, 1 H), 6.24 (d, J = 3.2 Hz, 1 H),
1.47 (s, 9 H), 1.13 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 163.8–160.5 (d, 1JC–F = 246.5 Hz),
150.0, 149.2, 136.9, 135.7, 132.0, 130.5–130.3 (d, 3JC–F = 8.2 Hz),
130.2, 128.8, 128.3, 124.6, 122.8, 120.5, 115.8, 115.0–114.7 (d,
2JC–F = 22.0 Hz), 114.1, 112.9, 111.5, 83.8, 83.3, 27.9, 27.3.
Anal. Calcd for C31H36N2O7: C, 67.87; H, 6.61; N, 5.11. Found: C,
67.66; H, 6.55; N, 4.84.
Anal. Calcd for C28H29FN2O4·0.2H2O: C, 70.04; H, 6.17; N, 5.83.
Found: C, 70.14; H, 6.22; N, 5.86.
N-tert-Butoxycarbonyl-2-[N-tert-butoxycarbonyl-2-(pyridin-3-
yl)-1H-pyrrol-5-yl]-1H-indole (8j)
Following the general procedure, compound 9 (102 mg, 221 mmol)
was treated with pyridin-3-ylboronic acid (41 mg, 332 mmol). Chro-
matography (heptanes–EtOAc, 70:30) of the crude reaction product
gave 8j (33 mg, 33%) as an orange oil.
N-tert-Butoxycarbonyl-2-[N-tert-butoxycarbonyl-2-(3-fluoro-
phenyl)-1H-pyrrol-5-yl]-1H-indole (8g)
Following the general procedure, compound 9 (96 mg, 207 mmol)
was treated with 3-fluorophenylboronic acid (44 mg, 311 mmol).
Chromatography (PE–EtOAc–heptanes, 63:7:30) of the crude reac-
tion product gave 8g (80 mg, 82%) as a white powder.
Rf = 0.20 (heptanes–EtOAc, 70:30).
IR (neat): 1726, 1302, 1134 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.67 (br s, 1 H), 8.57 (d, J = 4.9
Hz, 1 H), 8.31 (d, J = 8.2 Hz, 1 H), 7.70 (d, J = 7.9 Hz, 1 H), 7.58
(d, J = 7.6 Hz, 1 H), 7.38–7.32 (m, 2 H), 7.26 (t, J = 7.6 Hz, 1 H),
6.66 (s, 1 H), 6.34 (d, J = 3.4 Hz, 1 H), 6.32 (d, J = 3.4 Hz, 1 H),
1.46 (s, 9 H), 1.12 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 149.9, 149.3, 149.0, 148.1, 136.9,
135.8, 133.1, 131.7, 130.5, 129.2, 128.7, 124.7, 122.8, 122.7, 120.5,
115.8, 114.4, 114.0, 111.6, 84.2, 83.3, 27.9, 27.3.
Mp 118–119 °C; Rf = 0.74 (heptanes–EtOAc, 80:20).
IR (neat): 1748, 1725, 1330, 1321, 1154, 1140, 1128 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.34–8.32 (m, 1 H), 7.60–7.57 (m,
1 H), 7.40–7.34 (m, 2 H), 7.29–7.28 (m, 1 H), 7.18–7.17 (m, 1 H),
7.08–7.01 (m, 2 H), 6.66 (s, 1 H), 6.31 (d, J = 3.4 Hz, 1 H), 6.29 (d,
J = 3.4 Hz, 1 H), 1.46 (s, 9 H), 1.13 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 164.0–160.7 (d, 1JC–F = 245.4 Hz),
150.0, 149.0, 136.9, 136.5–136.4 (d, 3JC–F = 2.7 Hz), 135.4, 131.7,
Anal. Calcd for C27H29N3O4·0.3EtOAc: C, 69.61; H, 6.63; N, 8.64.
Found: C, 69.52; H, 6.27; N, 8.37.
3
129.3, 129.2, 128.8–128.7 (d, JC–F = 3.3 Hz), 124.7, 124.3–124.2
(d, 4JC–F = 2.2 Hz), 122.8, 120.5, 115.8, 115.7–115.4 (d, 2JC–F = 22.1
2
Hz), 114.2–113.9 (d, JC–F = 22.1 Hz), 114.1, 113.3, 111.7, 83.9,
N-tert-Butoxycarbonyl-2-[N-tert-butoxycarbonyl-2-(6-mor-
pholinopyridin-3-yl)-1H-pyrrol-5-yl]-1H-indole (8k)
83.3, 27.9, 27.3.
Anal. Calcd for C28H29FN2O4·0.2H2O: C, 70.04; H, 6.17; N, 5.83.
Found: C, 70.04; H, 6.07; N, 5.76.
Following the general procedure, compound 9 (57 mg, 123 mmol)
was treated with 6-morpholinopyridin-3-ylboronic acid (54 mg, 185
mmol). Chromatography of the crude reaction product (PE–EtOAc–
heptanes, 63:7:30) gave 8k (51 mg, 76%) as a white powder.
Synthesis 2010, No. 23, 4033–4042 © Thieme Stuttgart · New York

4040
F. Beaumard et al.
PAPER
Mp 111–112 °C; Rf = 0.28 (heptanes–EtOAc, 90:10).
Rf = 0.46 (heptanes–CH2Cl2, 65:35).
IR (neat): 1726, 1604, 1305, 1111, 744 cm–1.
IR (neat): 1726, 1452, 1334, 1319, 1153, 1123 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.32 (d, J = 8.2 Hz, 1 H), 8.25 (d,
J = 2.1 Hz, 1 H), 7.57–7.53 (m, 2 H), 7.35 (t, J = 8.2 Hz, 1 H), 7.26
(t, J = 7.9 Hz, 1 H), 6.68 (d, J = 8.2 Hz, 1 H), 6.63 (s, 1 H), 6.30 (d,
J = 3.4 Hz, 1 H), 6.22 (d, J = 3.4 Hz, 1 H), 3.85 (t, J = 4.9 Hz, 4 H),
3.57 (t, J = 4.9 Hz, 4 H), 1.43 (s, 9 H), 1.12 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 158.3, 150.0, 149.2, 147.1, 145.3,
138.2, 136.9, 134.0, 132.2, 128.8, 128.1, 124.6, 122.8, 120.4, 115.8,
114.4, 112.7, 111.3, 105.7, 83.8, 83.3, 66.8, 45.6, 27.9, 27.3.
1H NMR (500 MHz, CDCl3): d = 8.28 (d, J = 7.9 Hz, 1 H), 7.55 (d,
J = 7.6 Hz, 1 H), 7.48–7.45 (m, 1 H), 7.34 (t, J = 7.9 Hz, 1 H), 7.24
(t, J = 7.6 Hz, 1 H), 6.58 (s, 1 H), 6.30–6.28 (m, 1 H), 6.26–6.25 (m,
1 H), 1.42 (s, 9 H), 1.27 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 150.0, 149.0, 137.0, 131.9, 128.7,
126.4, 124.5, 122.6, 122.2, 120.4, 115.7, 115.6, 111.1, 110.4, 83.6,
82.8, 27.9, 27.6.
MS (ESI): m/z = 382.2 [M+].
Anal. Calcd for C31H36N4O5: C, 68.36; H, 6.66; N, 10.29. Found: C,
68.24; H, 6.63; N, 10.11.
Further elution of the column gave pure compound 10 (20 mg, 10%)
identical with that prepared above.
Isoquinolin-5-ylboronic Acid
Deprotection of Compounds 8; General Procedures
Procedure A
A soln of 8 in CH2Cl2 (1 mL) was treated under Ar with TFA (1 mL)
and the resulting soln was stirred at r.t. for 1 h. The mixture was
evaporated and the residue was taken up in acetone, filtered through
a thin pad of K2CO3 (eluting with acetone) and the solvent was
evaporated under reduced pressure to give product 2.
To a dry 25 mL round-bottomed flask was added 5-bromoisoquin-
oline (500 mg, 2.40 mmol) in THF (10 mL). The mixture was
cooled to –80 °C and n-BuLi (4.81 mmol) was added dropwise
whilst keeping the temperature below –65 °C. The mixture was
stirred for 1 h at –78 °C and then trimethylborate (749 mg, 7.21
mmol) was added. The mixture was stirred for 10 min at –78 °C and
then for 1 h at r.t. NaOH (4% aq soln in H2O, 5 mL) was added and
the reaction mixture was evaporated. EtOAc (10 mL) was added
and the soln was acidified to pH 5–6 using HCl (1 M; 4 mL). The
organic layer was washed with H2O (3 × 5 mL) and brine (5 mL),
dried over MgSO4 and evaporated in vacuo to give isoquinolin-5-yl-
boronic acid as a white powder which was used in the Suzuki cross-
coupling step without further purification.
Procedure B
A soln of 8 in THF (1 mL) was treated under Ar with TBAF in THF
(1.33 mL) and the resulting soln was heated at reflux for 4 h. The
mixture was then cooled and evaporated. EtOAc (5 mL) was added
and the organic layer was washed with H2O (3 × 3 mL) and brine (3
mL), dried over MgSO4 and evaporated in vacuo. Chromatography
(gradient elution) using appropriate solvents gave the desired prod-
uct 2.
N-tert-Butoxycarbonyl-2-[N-tert-butoxycarbonyl-2-(isoquino-
lin-5-yl)-1H-pyrrol-5-yl]-1H-indole (8l)
Following the general procedure, compound 9 (108 mg, 234 mmol)
was treated with isoquinolin-5-ylboronic acid (49 mg, 281 mmol).
Chromatography (heptanes–EtOAc, 70:30) of the crude reaction
product gave 8l (38 mg, 32%) as a brown oil.
2-(5-Phenyl-1H-pyrrol-2-yl)-1H-indole (2a)
Following procedure A, compound 8a (25 mg, 55 mmol) and TFA
(1 mL) were stirred in CH2Cl2 (1 mL). After treatment, the eluent
was evaporated to give 2a (9 mg, 61%) as a brown powder.
Rf = 0.29 (heptanes–EtOAc, 70:30).
IR (neat): 1737, 1731, 1310, 1142, 1119 cm–1.
Mp 210–212 °C; Rf = 0.36 (heptanes–EtOAc, 70:30).
IR (neat): 3333, 3254 cm–1.
1H NMR (500 MHz, CDCl3): d = 9.30 (s, 1 H), 8.51 (d, J = 6.1 Hz,
1 H), 8.19 (br s, 1 H), 8.00 (d, J = 7.9 Hz, 1 H), 7.74–7.72 (m, 1 H),
7.68–7.65 (m, 1 H), 7.61–7.60 (m, 1 H), 7.36 (t, J = 7.6 Hz, 1 H),
7.28–7.25 (m, 2 H), 6.75 (s, 1 H), 6.46 (d, J = 3.1 Hz, 1 H), 6.36 (d,
J = 3.1 Hz, 1 H), 1.61 (s, 9 H), 0.80 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 152.2, 150.1, 148.6, 142.4, 142.3,
135.9, 130.9, 130.6, 129.1, 128.9, 128.0, 127.7, 127.6, 127.3, 127.2,
127.1, 124.5, 122.7, 120.7, 115.8, 114.6, 114.5, 111.2, 83.5, 83.3,
28.2, 26.9.
1H NMR (500 MHz, C3D6O): d = 10.57 (br s, 1 H, NH), 10.31 (br s,
1 H, NH), 7.64–7.62 (m, 2 H), 7.39–7.35 (m, 1 H), 7.29–7.23 (m, 3
H), 7.11–7.07 (m, 1 H), 6.96–6.92 (m, 1 H), 6.89–6.86 (m, 1 H),
6.86 (s, 1 H), 6.58–6.56 (m, 1 H), 6.54–6.52 (m, 1 H).
13C NMR (75 MHz, C3D6O): d = 137.7, 134.0, 133.7, 132.9, 130.3,
129.6, 127.8, 126.8, 124.7, 121.9, 120.5, 120.3, 111.5, 108.5, 108.2,
97.4.
HRMS (ESI): m/z calcd for C18H15N2 [M + H+]: 259.1235; found:
259.1209.
HRMS (ESI): m/z calcd for C31H32N3O4 [M + H+]: 510.2383; found:
510.2369.
2-[5-(4-Nitrophenyl)-1H-pyrrol-2-yl]-1H-indole (2d)
Following procedure A, compound 8d (42 mg, 83 mmol) and TFA
(1 mL) were stirred in CH2Cl2 (1 mL). After treatment, the eluent
was evaporated to give 2d (8 mg, 32%) as a black oil.
N,N¢-Di-tert-Butoxycarbonyl-1H,1¢H-2,2¢-biindole (10), N-tert-
Butoxycarbonylindole (13) and N-tert-Butoxycarbonyl-2-(N-
tert-butoxycarbonyl-2-1H-pyrrolyl)-1H-indole (14)
Rf = 0.16 (heptanes–EtOAc, 80:20).
IR (neat): 3350, 3305, 1678, 1594, 1511, 1261 cm–1.
To an oven-dried round-bottomed flask was added compound 3
(109 mg, 337 mmol) and Pd(PPh3)4 (39 mg, 34 mmol) in a mixture
of toluene–EtOH (4:1) and the mixture degassed with Ar. N-Boc-in-
dol-2-ylboronic acid (7) (132 mg, 506 mmol) and a soln of Na2CO3
(215 mg, 2.02 mmol) in H2O (1 mL) were added. The reaction mix-
ture was degassed with Ar and heated at 100 °C for 3 h. After cool-
ing to r.t., the soln was filtered through a thin pad of Celite, the pad
rinsed with EtOAc (10 mL) and the filtrate concd under reduced
pressure. Chromatography (heptanes–EtOAc, 98:2) of the crude re-
action product gave N-Boc-indole 13 (20 mg, 27%).
1H NMR (500 MHz, C3D6O): d = 11.10 (br s, 1 H, NH), 10.59 (br s,
1 H, NH), 8.24 (d, J = 9.2 Hz, 2 H), 7.98 (d, J = 9.2 Hz, 2 H), 7.53
(d, J = 7.6 Hz, 1 H), 7.39 (d, J = 7.6 Hz, 1 H), 7.11 (t, J = 7.6 Hz, 1
H), 7.02 (t, J = 7.6 Hz, 1 H), 6.98 (d, J = 3.7 Hz, 1 H), 6.89 (s, 1 H),
6.79 (d, J = 3.7 Hz, 1 H).
13C NMR (75 MHz, C3D6O): d = 147.0, 139.6, 139.5, 137.9, 131.9,
131.7, 128.2, 125.2, 124.5, 122.5, 120.8, 120.5, 112.2, 111.7, 109.5,
98.7.
Continued elution of the column gave pure 14 (21 mg, 24%) as a
colorless oil.
HRMS (ESI): m/z calcd for C18H12N3O2 [M – H+]: 302.0941; found:
302.0930.
Synthesis 2010, No. 23, 4033–4042 © Thieme Stuttgart · New York

PAPER
Synthesis of Nonsymmetrical 5-Aryl-2-indolopyrrole Derivatives
4041
2-[5-(4-Methoxyphenyl)-1H-pyrrol-2-yl]-1H-indole (2e)
Following procedure A, compound 8e (39 mg, 80 mmol) and TFA
(1 mL) were stirred in CH2Cl2 (1 mL). After treatment, the eluent
was evaporated to give 2e (18 mg, 78%) as a black powder.
13C NMR (75 MHz, C3D6O): d = 137.6, 132.6, 132.5, 131.7, 130.2,
129.6, 128.1, 126.1, 126.0, 122.0, 120.5, 120.3, 111.5, 108.8, 108.6,
99.8.
Anal. Calcd for C18H13ClN2·0.55H2O·0.55C3H6O: C, 70.53; H,
5.24; N, 8.37. Found: C, 70.58; H, 5.21; N, 8.25.
Mp 196–197 °C; Rf = 0.19 (heptanes–EtOAc, 80:20).
IR (neat): 3434, 3387, 1237 cm–1.
2-[5-(3,4,5-Trimethoxyphenyl)-1H-pyrrol-2-yl]-1H-indole (2i)
Following procedure A, compound 8i (36 mg, 65 mmol) and TFA (1
mL) were stirred in CH2Cl2 (1 mL). After treatment, the eluent was
evaporated to give 2i (18 mg, 78%) as a black powder.
1H NMR (500 MHz, C3D6O): d = 10.64 (br s, 1 H, NH), 10.48 (br s,
1 H, NH), 7.68 (d, J = 8.9 Hz, 2 H), 7.49 (d, J = 7.6 Hz, 1 H), 7.35
(d, J = 7.9 Hz, 1 H), 7.05 (t, J = 7.3 Hz, 1 H), 7.00–6.99 (m, 1 H),
6.96 (d, J = 8.9 Hz, 2 H), 6.76 (s, 1 H), 6.67–6.66 (m, 1 H), 6.52–
6.51 (m, 1 H), 3.82 (s, 3 H, CH3O).
13C NMR (75 MHz, C3D6O): d = 159.3, 137.7, 134.2, 130.4, 126.6,
126.1, 126.0, 125.4, 121.8, 120.3, 120.2, 115.0, 111.4, 108.3, 107.0,
97.0, 55.6.
Mp 193–194 °C; Rf = 0.06 (heptanes–EtOAc, 80:20).
IR (neat): 3395, 3337, 1120 cm–1.
1H NMR (500 MHz, C3D6O): d = 11.44 (br s, 1 H, NH), 11.27 (br s,
1 H, NH), 7.31–7.26 (m, 2 H), 7.00 (br s, 2 H), 6.88–6.78 (m, 2 H),
6.51–6.50 (m, 2 H), 6.44–6.43 (m, 1 H), 3.77 (s, 6 H, 2 × CH3O),
3.60 (s, 3 H, CH3O).
13C NMR (75 MHz, C3D6O): d = 154.7, 137.9, 137.6, 134.1, 133.3,
130.3, 129.8, 127.8, 121.4, 120.0 (2 × C), 111.9, 108.6, 108.0,
102.6, 97.1, 60.6, 56.6.
Anal. Calcd for C19H16N2O·0.5H2O·0.5C3H6O: C, 73.63; H, 6.03;
N, 8.38. Found: C, 73.61; H, 5.93; N, 7.99.
2-[5-(4-Fluorophenyl)-1H-pyrrol-2-yl]-1H-indole (2f)
Following procedure A, compound 8f (35 mg, 73 mmol) and TFA (1
mL) were stirred in CH2Cl2 (1 mL). After treatment, the eluent was
evaporated to give 2f (17 mg, 86%) as a grey powder.
HRMS (ESI): m/z calcd for C21H21N2O3 [M + H+]: 349.1549; found:
349.1552.
Mp 198–199 °C; Rf = 0.38 (heptanes–EtOAc, 80:20).
2-[5-(Pyridin-3-yl)-1H-pyrrol-2-yl]-1H-indole (2j)
Following procedure B, compound 8j (31 mg, 67 mmol) in THF (1
mL) was treated with TBAF in THF (1.33 mL). Chromatography
[20% EtOAc in a mixture of CH2Cl2–MeOH–NH4OH, 38:17:2
(soln B)] of the crude reaction product gave 2j (17 mg, 100%) as an
orange oil.
IR (neat): 3440, 3415, 1231 cm–1.
1H NMR (500 MHz, C3D6O): d = 10.72 (br s, 1 H, NH), 10.45 (br s,
1 H, NH), 7.80–7.75 (m, 2 H), 7.52–7.49 (m, 1 H), 7.37–7.35 (m, 1
H), 7.20–7.14 (m, 2 H), 7.10–7.04 (m, 1 H), 7.02–6.97 (m, 1 H),
6.80–6.79 (m, 1 H), 6.70–6.69 (m, 1 H), 6.62–6.61 (m, 1 H).
13C NMR (75 MHz, C3D6O): d = 162.9–159.7 (d, 1JC–F = 243.0 Hz),
136.8, 132.2, 131.9, 129.4, 126.9, 125.7, 125.6, 121.1, 119.6, 119.4,
115.4 (d, 2JC–F = 21.4 Hz), 110.6, 107.6, 107.3, 96.5.
Rf = 0.62 (CH2Cl2–soln B, 80:2).
IR (neat): 3374, 3354, 1596 cm–1.
1H NMR (500 MHz, CD3OD): d = 8.89 (d, J = 1.8 Hz, 1 H), 8.33–
8.32 (m, 1 H), 8.11 (dt, J = 7.9 Hz, J = 1.8 Hz, 1 H), 7.50 (d, J = 7.6
Hz, 1 H), 7.43–7.42 (m, 1 H), 7.35 (d, J = 7.9 Hz, 1 H), 7.07 (t,
J = 7.9 Hz, 1 H), 6.99 (t, J = 7.6 Hz, 1 H), 6.77 (s, 1 H), 6.71 (d,
J = 4.0 Hz, 1 H), 6.65 (d, J = 4.0 Hz, 1 H).
13C NMR (75 MHz, CD3OD): d = 146.6, 145.5, 138.3, 132.8, 132.7,
131.1, 130.6, 130.3, 129.9, 125.4, 122.3, 120.7, 120.4, 111.6, 109.8,
108.7, 97.7.
Anal. Calcd for C18H13FN2·0.3H2O·0.3C3H6O: C, 75.89; H, 5.19; N,
9.36. Found: C, 76.09; H, 5.55; N, 8.96.
2-[5-(3-Fluorophenyl)-1H-pyrrol-2-yl]-1H-indole (2g)
Following procedure A, compound 8g (37 mg, 78 mmol) and TFA
(1 mL) were stirred in CH2Cl2 (1 mL). After treatment, the eluent
was evaporated to give 2g (16 mg, 73%) as a grey powder.
Mp 191–192 °C; Rf = 0.45 (heptanes–EtOAc, 80:20).
IR (neat): 3434, 3410, 1184 cm–1.
1H NMR (500 MHz, C3D6O): d = 10.65 (br s, 1 H, NH), 10.36 (br s,
1 H, NH), 7.45–7.35 (m, 3 H), 7.29–7.21 (m, 2 H), 6.95–6.77 (m, 3
H), 6.67 (s, 1 H), 6.59–6.54 (m, 2 H).
HRMS (ESI): m/z calcd for C17H14N3 [M + H+]: 260.1187; found:
260.1188.
5-[5-(1H-Indol-2-yl)-1H-pyrrol-2-yl]isoquinoline (2l)
Following procedure B, compound 8l (34 mg, 67 mmol) in THF (1
mL) was treated with TBAF in THF (1.33 mL). Chromatography
(EtOAc) of the crude reaction product gave 2l (15 mg, 75%) as a
yellow oil.
13C NMR (75 MHz, C3D6O): d = 165.0–161.8 (d, 1JC–F = 243.0 Hz),
3
4
136.9, 135.2–135.1 (d, JC–F = 8.8 Hz), 131.8 (d, JC–F = 2.7 Hz),
131.7, 130.6–130.5 (d, 3JC–F = 8.8 Hz), 129.4, 127.6, 121.2, 119.8,
119.7–119.6 (d, 4JC–F = 2.7 Hz), 119.5, 112.3–112.0 (d, 2JC–F = 21.4
Hz), 110.7, 110.3–110.0 (d, 2JC–F = 22.5 Hz), 108.4, 107.7, 96.9.
Rf = 0.33 (EtOAc).
IR (neat): 3395, 3354, 1618 cm–1.
Anal. Calcd for C18H13FN2·0.45H2O·0.45C3H6O: C, 74.84; H, 5.39;
N, 9.02. Found: C, 74.84; H, 5.28; N, 9.08.
1H NMR (500 MHz, CDCl3): d = 9.39 (br s, 1 H, NH), 9.21 (s, 1 H),
9.01 (br s, 1 H, NH), 8.44 (d, J = 6.0 Hz, 1 H), 8.07 (d, J = 6.0 Hz,
1 H), 7.86 (d, J = 8.1 Hz, 1 H), 7.79 (d, J = 7.3 Hz, 1 H), 7.64–7.59
(m, 2 H), 7.38 (d, J = 7.5 Hz, 1 H), 7.19 (td, J = 7.5 Hz, J = 1.1 Hz,
1 H), 7.13 (td, J = 7.3 Hz, J = 1.1 Hz, 1 H), 6.70–6.68 (m, 2 H),
6.61–6.59 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 155.7, 152.8, 150.4, 143.3, 143.2,
133.8, 130.1, 130.0, 129.2, 129.1 (2 × C), 127.1, 127.0, 122.0,
120.3, 120.2, 118.6, 111.6, 110.7, 107.3, 97.3.
2-[5-(4-Chlorophenyl)-1H-pyrrol-2-yl]-1H-indole (2h)
Following procedure A, compound 8h (28 mg, 57 mmol) and TFA
(1 mL) were stirred in CH2Cl2 (1 mL). After treatment, the eluent
was evaporated to give 2h (15 mg, 86%) as an orange powder.
Mp 202–203 °C; Rf = 0.40 (heptanes–EtOAc, 80:20).
IR (neat): 3430, 3390, 827 cm–1.
1H NMR (500 MHz, C3D6O): d = 7.62 (d, J = 8.7 Hz, 2 H), 7.36 (d,
J = 7.5 Hz, 1 H), 7.25 (d, J = 8.7 Hz, 2 H), 7.21 (d, J = 7.3 Hz, 1 H),
6.92 (t, J = 7.5 Hz, 1 H), 6.86 (t, J = 7.5 Hz, 1 H), 6.65 (s, 1 H), 6.55
(d, J = 3.8 Hz, 1 H), 6.53 (d, J = 3.8 Hz, 1 H).
HRMS (ESI): m/z calcd for C21H16N3 [M + H+]: 310.1344; found:
310.1349.
Synthesis 2010, No. 23, 4033–4042 © Thieme Stuttgart · New York

4042
F. Beaumard et al.
PAPER
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Acknowledgment
We thank the Institut de Chimie des Substances Naturelles for fi-
nancial support and a fellowship (F.B.). This work was supported
by an ANR (ANR-07-PHYSIO-027-02) grant to R.H.D.
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Synthesis 2010, No. 23, 4033–4042 © Thieme Stuttgart · New York