Palladium (0)-catalysed arylations using pyrrole and indole 2-boronic acids

Article abstract of DOI:10.1055/s-1998-1834

A versatile synthesis of 2-arylpyrroles and 2-arylindoles is described based on the use of either N-(Boc) pyrrole-2-boronic acid or N-(Boc) indole-2-boronic acid as components for Suzuki coupling.

Full text of DOI:10.1055/s-1998-1834

September 1998
SYNLETT
1025
Palladium (0)-Catalysed Arylations using Pyrrole and Indole 2-Boronic Acids
a
a
b
b
b
Christopher N. Johnson* , Geoffrey Stemp , Neel Anand , Susanna C. Stephen and Timothy Gallagher
a
SmithKline Beecham Pharmacueticals, New Frontiers Science Park (North), Third Avenue, Harlow CM19 5AW, UK
b
School of Chemistry, University of Bristol, Bristol BS8 1TS, UK
Received 23 May 1998
Abstract: A versatile synthesis of 2-arylpyrroles and 2-arylindoles is
described based on the use of either N-(Boc) pyrrole-2-boronic acid or
N-(Boc) indole-2-boronic acid as components for Suzuki coupling.
We have described the design of a series of 2,5-disubstituted pyrroles 1
as selective dopamine D receptor antagonists, the synthesis of which
3
1
required 2-arylpyrroles 2 as key intermediates. Initial approaches to 2
involved reaction of the appropriate benzoyl chloride 3 with Grignard
reagent 4 and subsequent treatment with ammonium acetate in a
2
modification of
a
known procedure. This method is, however,
incompatible with the presence of acidic protons or basic nitrogens in 2,
and each desired substitution pattern requires repetition of a lengthy
reaction sequence. An alternative strategy based on palladium-catalysed
aryl cross-coupling methodology offered promise as a shorter, direct and
more flexible route and here we describe the successful implementation
of this approach.
The few literature examples of palladium-catalysed cross coupling
involving metallated pyrroles have mainly described the use of
3,4,5
magnesium,
zinc
and
tin
species.
The
use
of
N-(triisopropylsilyl)pyrrole-3-boronic acid as
a Suzuki coupling
5
substrate has been reported, and more recently, the coupling of N-(Boc)
6
7
pyrrole-2-boronic acid 5 to a pyrrole-2-triflate has been described.
For the simple monosubstituted and unsubstituted aryl halides (entries
1-7), a trend was observed towards greater reactivity with increased
electron deficiency of the Ar group. In the case of Ar = Ph, iodobenzene
(entry 1) gave a cleaner reaction than bromobenzene (entry 2).
The use of N-(phenylsulfonyl) pyrrole-2-boronic acid in Suzuki
couplings has also been reported. However, the synthesis of this boronic
8
acid starting material proceeds in only 7.5% yield.
In all instances the major competing side reactions were deboronation of
5 to give N-(Boc) pyrrole and production of the homodimer 7. The
The wide availability of aryl halides, together with the reported
stability of 5 suggested a general methodology for the synthesis of
2-arylpyrroles. The N-Boc pyrrole 5 can be readily prepared on a 20 g
11
2-methoxy substituted halides (entries 8-11) gave particularly high
yields, possibly due to participation by the 2-methoxy group in the
coordination of the intermediate arylpalladium species, and this
methodology proved to be compatible with the presence of acidic NH
residues (entries 9 and 10) and with the presence of a basic nitrogen
centre (entry 11). Removal of the Boc group could be effected in high
yield in each case by treatment of 6 with an excess of sodium methoxide
in methanol at room temperature.
6
scale according to the procedure of Martina et al. and the cross
coupling reactions of 5 with a range of aryl halides were carried out
9
using the Gronowitz conditions. A mixture of the appropriate aryl
iodide or bromide (ArX), tetrakis-(triphenylphosphine)palladium(0) (5
mol%) and 5 (1.4 equivalents) in 1,2-dimethoxyethane, with an excess
of aqueous sodium carbonate as base, was heated at reflux for 0.5-18 h
10
to give the corresponding N-Boc aryl pyrroles 6 (Scheme 1). The
results of the study are summarised in Table 1.

1026
LETTERS
SYNLETT
The encouraging results obtained with 5 as a cross-coupling substrate
prompted the investigation of similar methodology applied to indole
methods, which require the use of potentially toxic and comparatively
13
(Scheme 2). Deprotonation of N-(Boc) indole
8
with 1-lithio-
unstable stannane intermediates,
or in situ generation of an
3,4,14
2,2,6,6-tetramethylpiperidine (LiTMP) in THF followed by addition of
triisopropyl borate and acidic work-up then gave the desired boronic
acid 9. Coupling with aryl halides was carried out in the manner
described above to give the N-Boc 2-aryl indoles 10, and the results of
this aspect of the study are shown in Table 2.
organometallic species,
the methodology described here uses
boronic acid intermediates which are highly stable, relatively non-toxic,
and easily prepared.
References and Notes
1.
(a) Bolton, D.; Boyfield, I.; Coldwell, M. C.; Hadley, M. S.;
Healy, M. A. M.; Johnson, C. N.; Markwell, R. E.; Nash, D. J.;
Riley, G. J.; Stemp, G.; Wadsworth, H. J. Bioorg. Med. Chem.
Lett. 1996, 6, 1233. (b) Boyfield, I.; Coldwell, M. C.; Hadley, M.
S.; Healy, M. A. M.; Johnson, C. N.; Nash, D. J.; Riley, G. J.;
Scott, E. E.; Smith, S. A.; Stemp, G. Bioorg. Med. Chem. Lett.
1997, 7, 327. (c) Bolton, D.; Boyfield, I.; Coldwell, M. C.; Hadley,
M. S.; Johns, A.; Johnson, C. N.; Markwell, R. E.; Nash, D. J.;
Riley, G. J.; Scott, E. E.; Smith, S. A.; Stemp, G.; Wadsworth, H.
J.; Watts, E. A.; Bioorg. Med. Chem. Lett. 1997, 7, 327.
2.
Bouw, J. P.; den Hartog, J. A. J.; Kruse, C. G.; Van Hes, R.; Van
der Kuilen, A. Heterocycles 1987, 26, 3141. (b) EP 0 259 930
(Chem. Abstr. 1988, 109, 92773).
3.
4.
5.
6.
Minato, A.; Tamao, K.; Hayashi, T.; Suzuki, K.; Kumada, M.
Tetrahedron Lett. 1981, 22, 5319.
Filippini, L.; Gusmeroli, M.; Riva, R. Tetrahedron Lett. 1992, 33,
1755.
Alvarez, A.; Guzmán, A.; Ruiz, A.; Velarde, E. J. Org. Chem.
1992, 57, 1653.
Enkelmann, V.; Martina, S.; Schluter, A. D.; Wegner, G. Synthesis
1991, 613.
7.
8.
9.
D'Alessio, R.; Rossi, A. Synlett 1996, 513.
Grieb, J.G.; Ketcha, D.M. Synth. Commun. 1995, 25, 2145.
Gronowitz, S.; Lawitz, K. Chem. Scr. 1983, 22, 265.
10. All compounds gave satisfactory physiochemical data.
A
In general, the Suzuki coupling yields obtained with 9 were lower than
in the corresponding examples in the pyrrole series. In all cases, a
significant amount of a by-product was obtained which was assigned as
representative procedure is as follows: To a stirred solution of 2-
bromo-5-ethylsulfonyl anisole (1.0 g, 3.6 mmol), N-(Boc) pyrrole-
2-boronic acid
5
(1.06 g, 5.0 mmol) and tetrakis-
12
the 2,2´-dimer 11 on the basis of MS, IR and NMR data. In the case of
(triphenylphosphine)palladium (0) (0.21 g, 0.18 mmol) in 1,2-
dimethoxyethane (100 ml) at room temperature under argon was
added a solution of sodium carbonate (1.6 g, 15 mmol) in water (8
ml). The mixture was heated at reflux for 4 h, cooled, then
partitioned between water (300 ml) and dichloromethane (4 x 100
electron rich aryl bromides (entries 2 and 4) no desired product was
observed but iodobenzene (entry 1) and 3-bromopyridine (entry 5) each
gave a respectable yield of the corresponding N-Boc 2-aryl indole 10.
With 1-bromo-4-chlorobenzene (entry 3), in situ cleavage of the Boc
group occurred, giving 2-(4-chlorophenyl)indole 12. The lower
reactivity of 9 relative to 5 may be due to greater steric hindrance of the
N-Boc group in the indole series. This may arise because the presence of
a hydrogen atom in the indole 7-position prevents the Boc group of 9
adopting a conformation where the bulky t-butyl group points away
from the reacting C(2) site. This hypothesis is supported by data
ml). The combined extracts were dried (Na SO ) and evaporated
2
4
in vacuo to give an oil. Chromatography with gradient elution
using 10 - 50% ethyl acetate in hexane gave N-(Boc) 2-(5-
ethylsulfonyl-2-methoxy)phenyl-1H-pyrrole (1.28 g, 98%) as a
colourless solid, m.p. 135 - 139 °C (Found C, 59.39; H, 6.42; N,
3.83. C
H
NO S requires C, 59.16; H, 6.34; N, 3.83%); ν
/
max
18 23
5
13
obtained with cross-couplings of (2-indolyl)stannanes, where the Boc
-1
cm 1743 (C=O), 1315, 1130 (S=O); δ (250 MHz; CDCl ) 1.30
H
3
indole derivative gave lower yields than the corresponding SEM
protected indole.
(3 H, t, J = 7 Hz), 1.37 (9 H, s), 3.13 (2 H, q, J = 7 Hz), 3.85 (3 H,
s), 6.23 (1 H, m), 6.27 (1 H, m), 6.99 (1 H, d, J = 9 Hz), 7.38 (1 H,
m), 7.79 (1 H, d, J = 2 Hz), 7.88 (1 H, dd, J = 9, 2 Hz).
In conclusion, both the pyrrole and indole boronic acids, 5 and 9
respectively, can function as substrates for the Suzuki coupling reaction
and in the pyrrole series, particularly high yields have been obtained for
aryl halides bearing an ortho-methoxy group. In contrast with other
-1
+
11. Data for 7: ν /cm 1732; m/z (CI) 333 (MH , 80%), 277 (25),
max
233 (90), 177 (95), 133 (100); δ (400 MHz; CDCl ) 1.37 (18 H,
H
3
s), 6.17 (4 H, d, J = 3 Hz), 7.37 (2 H, t, J = 3 Hz).

September 1998
SYNLETT
1027
-1
+
12 Data for 11: ν /cm 1729 (C=O); Found M 432.2049.
13 Labadie, S. S.; Teng, E. J. Org. Chem. 1994, 59, 4250.
max
C
H N O requires 432.2051; δ (300 MHz, CDCl ) 1.24 (18
26 28 2 4 H 3
14 Kondo, Y.; Sakamoto, T.; Takazawa, N.; Yamanaka, H.
H, s), 6.65 (2 H, s), 7.25 (2 H, dt, J = 8, 1 Hz), 7.35 (2 H, dt, J = 8,
1 Hz), 7.57 (2 H, d, J = 8 Hz), 8.31 (2H, d, J = 8 Hz).
Heterocycles 1993, 36, 941.