2,5,6-Trisubstituted N-methylindoles from site-selective Suzuki-Miyaura cross-coupling, twofold Heck and 6π-electrocyclization-dehydrogenation reactions of 2,3,5-tribromo-N-methylpyrrole

Article abstract of DOI:10.1055/s-0030-1259552

Site-selective Suzuki-Miyaura reactions of 2,3,5-tribromo-N-methylpyrrole afforded 5-aryl-2,3-dibromo-N-methylpyrroles. These products were transformed into 2,5,6-trisubstituted N-methylindoles by twofold Heck reactions and subsequent 6π-electrocyclizatio

Full text of DOI:10.1055/s-0030-1259552

LETTER
513
2,5,6-Trisubstituted N-Methylindoles from Site-Selective Suzuki–Miyaura
Cross-Coupling, Twofold Heck and 6p-Electrocyclization–Dehydrogenation
Reactions of 2,3,5-Tribromo-N-methylpyrrole
Synthesis of
2
e
r
tituted
N
g
-Methylindo
e
le
s
-Mithérand Tengho Toguem,a Peter Langer*a,b
a
Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
Fax +49(381)4986412; E-mail: peter.langer@uni-rostock.de
b
Received 5 November 2010
known site-selective Suzuki–Miyaura reactions of 2,3,5-
tribromo-N-methylpyrrole with twofold Heck and 6p-
electrocyclization reactions. The building block strategy
reported herein provides a powerful method for the syn-
thesis of indoles which are not readily available by other
methods.
Abstract: Site-selective Suzuki–Miyaura reactions of 2,3,5-tribro-
mo-N-methylpyrrole afforded 5-aryl-2,3-dibromo-N-methylpyr-
roles. These products were transformed into 2,5,6-trisubstituted
N-methylindoles by twofold Heck reactions and subsequent 6p-
electrocyclization–dehydrogenation reactions.
Key words: catalysis, palladium, Heck reaction, electrocyclization,
indoles
2,3,5-Tribromo-N-methylpyrrole (2) was prepared by
reaction of N-methylpyrrole (1) with NBS (3.1 equiv) in
88% yield (Scheme 1).13 The Suzuki–Miyaura reaction of
2 with arylboronic acids (1.1 equiv) afforded the 5-aryl-
2,3-dibromo-1-methyl-1H-pyrroles 3a–d (Scheme 1,
Table 1).14,15 The best yields were obtained when the re-
actions were carried out using Pd(PPh3)4 as the catalyst
and K3PO4 as the base in a 1:1 mixture of dioxane and tol-
uene (100 °C, 12 h). The formation of 3a–d proceeded
with excellent site-selectivity. Palladium-catalyzed reac-
tions of 2 have, to the best of our knowledge, not been pre-
viously reported.
Indole derivatives are found in many natural, synthetic,
agrochemical and pharmaceutical compounds.1 Indole de-
rivatives influence the neurotransmitter serotonin,2 act as
hallucinogen agents,3 potent PPAR-c binding agents with
potential application for the treatment of osteoporosis,4
neuroprotective agents affecting oxidative stress,5 potent
anti-inflammatory agents,6 and antimicrobial agents.7 In-
doles constitute a privileged scaffold capable of providing
useful ligands for diverse receptors.8 Indoles can be pre-
pared by various classical methods, e.g. the Fischer indole
synthesis, the Plieninger indole synthesis, the Madelung
cyclization of N-acyl-o-toluidines, the Bischler indole
synthesis, the Batcho–Leimgruber synthesis of indoles
from o-nitrotoluenes and dimethylformamide acetals, and
the reductive cyclization of o-nitrobenzyl ketones.9 Most
of the known methods allow to vary the substituents locat-
ed at positions 2 and 3 of the indole moiety. Positions 5
and 6 are much more difficult to access.
Br
Br
ArB(OH)2
ii
NBS
i
Br
Br
Br
N
N
N
Ar
Me
Me
Me
3a–d
1
2 (88%)
Scheme 1 Synthesis of 2 and 3a–d. Reagents and conditions: (i) 1
(1.0 equiv), NBS (3.1 equiv), THF, –78 °C → 20 °C, 12 h; (ii) 2 (1.0
equiv), ArB(OH)2 (1.1 equiv), Pd(PPh3)4 (5 mol%), K3PO4 (4.0
equiv), 1,4-dioxane–toluene (1:1), 100 °C, 12 h
De Meijere and co-workers reported the synthesis of ben-
zene derivatives by twofold Heck reactions of 1,2-dibro-
mocycloalk-1-enes and related substrates and subsequent
6p-electrocyclization.10 In recent years, we have studied
the application of this approach to the synthesis of hetero-
cyclic systems, such as carbazoles, benzothiophenes,
dibenzofurans, and benzimidazoles.11 We have also stud-
ied site-selective Suzuki reactions of 2,3,4,5-tetra-
Table 1 Synthesis of 3a–d
3
a
b
c
Ar
Yield (%)a of 3
4-MeC6H4
4-EtC6H4
4-t-BuC6H4
3,5-Me2C6H3
82
73
64
58
bromothiophene,
2,3,4,5-tetrabromoselenophene,
pentachloropyridine, 2,3,4-tribromothiophene, 2,3,4,5-
tetrabromo-N-methylpyrrole and other substrates.12 Due
to the importance of indoles in organic and medicinal
chemistry, we studied a new approach to 2,5,6-trisubsti-
tuted indoles based on the combination of hitherto un-
d
a Yields of isolated products.
The first attack in palladium-catalyzed reactions of poly-
halogenated substrates usually occurs at the electronically
most deficient and sterically least hindered position. The
site-selective formation of products 3a–d can be ex-
SYNLETT 2011, No. 4, pp 0513–0516
Advanced online publication: 11.02.2011
DOI: 10.1055/s-0030-1259552; Art ID: G33110ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
1

514
S.-M. T. Toguem, P. Langer
LETTER
plained by the fact that carbon atom C-5 of tribromopyr-
role 2 is, on the one hand, more electron-deficient than C-
3 and, on the other hand, less sterically hindered than C-2
(Figure 1).
Table 2 Synthesis of 5a–n and 6a–n
3
4
5,6 Ar
R
Yield
Yield
(%)a of 5 (%)a of 6
a
a
b
b
b
b
b
c
a
b
a
c
a
b
c
d
e
f
4-MeC6H4
i-Bu
n-Hex
i-Bu
t-Bu
n-Hex
Et
72
75
69
65
60
47
91
80
72
74
90
69
94
70
77
89
81
75
77
88
electron-deficient
2
4-MeC6H4
4-EtC6H4
4-EtC6H4
4-EtC6H4
4-EtC6H4
4-EtC6H4
sterically hindered
Me
N
Br
Br
Br
1
electron-deficient
not sterically hindered
b
d
e
less electron-deficient
not sterically hindered
3
g
h
i
CH2CH(Et)(CH2)3Me 61
Figure 1 Possible explanation for the site-selectivity of the reac-
tions of 2
f
4-t-BuC6H4 CO2Me
4-t-BuC6H4 i-Bu
4-t-BuC6H4 n-Bu
4-t-BuC6H4 n-Hex
4-t-BuC6H4 Et
53
76
56
71
48
c
a
g
b
d
e
The Heck reaction of 3a–d with acrylates 4a–g afforded
the 5-aryl-2,3-di(alkenyl)-N-methylpyrroles 5a–n in 47–
76% yield (Scheme 2, Table 2).16,17 The best yields were
obtained when the reactions were carried out using
Pd(OAc)2 (5 mol%) as the catalyst in the presence of tri-
cyclohexylphosphine (TCHP, 10 mol%; Table 3). The
yields significantly dropped when Pd(PPh3)4 was em-
ployed.
c
j
c
k
l
c
d
d
m
n
3,5-Me2C6H3 CH2CH(Et)(CH2)3Me 51
g
3,5-Me2C6H3 n-Bu
66
a Yields of isolated products.
CO2R
Br
CO2R
4a–g
Ar
Br
Table 3 Influence of the Catalyst
i
N
CO2R
N
Ar
Me
Me
3a–d
Catalyst
Yield
Yield
Yield
5a–n
(%)a of 5c (%)a of 5f (%)a of 5j
10 mol% Pd(PPh3)4
37
45
47
19
56
ii, iii
CO2R
CO2R
5 mol% Pd(OAc)2 + 10 mol% THCP 69
a Yields of isolated products.
CO2R
CO2R
Ar
N
N
Ar
Table 4 Influence of the Temperature
Me
Me
Temp (°C) Yield (%)a of 5a
Yield (%)a of 5l Yield (%)a of 5j
A
6a–n
Scheme 2 Synthesis of 5a–n and 6a–n. Reagents and conditions: (i)
3a–d (1 equiv), 4a–g (2.5 equiv), Pd(OAc)2 (5 mol%), TCHP (10
mol%), Et3N, DMF, 100 °C, 24 h; (ii) diphenyl ether, 200 °C, 24 h;
(iii) Pd/C (10 mol%), diphenyl ether, 200 °C, 48 h
90
100
120
59
72
63
30
48
41
50
56
42
a Yields of isolated products.
The reactions were carried out at 100 °C in DMF. The
yields dropped when the temperature was increased or de-
creased (Table 4). The employment of styrene instead of
acrylates proved to be unsuccessful, due to decomposition
under the reaction conditions employed.
Table 5 Influence of the Temperature on the 6p-Electrocyclization
Temp (°C)
160
time (h)
96
Yield (%)a of 6a Yield (%)a of 6b
63
91
71
80
5-Aryl-2,3-di(alkenyl)-N-methylpyrroles 5a–n were
transformed into the indoles 6a–n in 69–94% yield.18,19
The pyrroles were heated in diphenyl ether for 24 hours at
200 °C. Subsequently, Pd/C was added and the mixture
was heated for further 48 hours at 200 °C. The indoles
were formed by 6p-electrocyclization and subsequent de-
hydrogenation. The yields dropped when the reaction was
200
72
a Yields of isolated products.
carried out at 160 °C for 96 hours instead of at 200 °C for
72 hours (Table 5).
Synlett 2011, No. 4, 513–516 © Thieme Stuttgart · New York

LETTER
Synthesis of 2,5,6-Trisubstituted N-Methylindoles
515
(12) (a) Dang, T. T.; Dang, T. T.; Rasool, N.; Villinger, A.;
In conclusion, we have reported an efficient synthesis of
2,5,6-trisubstituted indoles based on Suzuki and Heck
reactions of 2,4,5-tribromo-N-methylpyrrole and subse-
quent 6p-electrocyclization–dehydrogenation reactions.
This methodology provides a convenient access to various
indoles which are not readily available by other methods.
Langer, P. Adv. Synth. Catal. 2009, 351, 1595. (b) Dang,
T. T.; Villinger, A.; Langer, P. Adv. Synth. Catal. 2008, 350,
2109. (c) Ehlers, P.; Reimann, S.; Erfle, S.; Villinger, A.;
Langer, P. Synlett 2009, 1528. (d) Toguem, S.-M. T.;
Villinger, A.; Langer, P. Synlett 2010, 909. (e) Dang, T. T.;
Dang, T. T.; Ahmad, R.; Reinke, H.; Langer, P. Tetrahedron
Lett. 2008, 49, 1698.
(13) Gilow, H. M.; Burton, D. E. J. Org. Chem. 1981, 46, 2221.
(14) Synthesis of 5-Aryl-2,3-dibromo-N-methylpyrroles 3a–
d: To a mixture of 2(0.159 g, 0.5 mmol), aryl boronic acid
(0.55 mmol), and Pd(PPh3)4 (5 mol%) was added a mixture
of 1,4-dioxane and toluene (1:1; 5 mL) and K3PO4 (4.0
equiv, 424 mg) under an argon atmosphere. The reaction
mixture was stirred at 100 °C for 12 h and was subsequently
allowed to cool to 20 °C. The solution was poured into H2O
and EtOAc (25 mL each) and the organic and the aqueous
layers were separated. The latter was extracted with EtOAc
(3 × 25mL), dried (Na2SO4), filtered, and concentrated in
vacuo. The residue was purified by flash column
chromatography (flash silica gel, eluent: n-heptane).
(15) Synthesis of 2,3-Dibromo-5-(4-tert-butylphenyl)-N-
methylpyrrole (3c): Starting with 2 (0.318 g, 1.0 mmol) and
4-tert-butylphenylboronic acid (0.178 g, 1.1 mmol), 3c was
isolated (237 mg, 64%) as a colorless oil. 1H NMR (300
MHz, acetone-d6): d = 1.34 (s, 9 H, 3 × Me), 3.61 (s, 3 H,
NMe), 6.29 (s, 1 H, CHpyrrole), 7.34 (d, 2 H, J = 8.6 Hz, ArH),
7.59 (d, 2 H, J = 8.6 Hz, ArH). 13C NMR (62 MHz, acetone-
d6): d = 31.6 (3 × Me), 35.2 (C), 35.4 (NMe), 98.5, 105.5
(CBr), 111.3 (CHpyrrole), 126.4 (2 × CH), 129.4 (2 × CH),
130.2, 137.4, 151.7 (C). IR (KBr): 2959 (m), 2903, 2866,
1783, 1697, 1650, 1606, 1537 (w), 1499, 1456, 1362, 1318,
1265 (m), 1216, 1201 (w), 1109, 1086, 1017, 946 (m), 837
(s), 821, 779 (m), 741, 668, 595 (w), 574 (m), 532 (w) cm–1.
GC–MS (EI, 70 eV): m/z (%) = 373 (36) [M+ (81Br, 81Br)],
371 (73) [M+ (79Br, 81Br)], 369 (36) [M+, (79Br, 79Br)], 358
(50), 357 (16), 356 (100) [M+], 354 (53), 164 (15). HRMS
(EI, 70 eV): m/z [M+ (Br, 81Br)] calcd for C15H17NBr2:
370.97018; found: 370.97046.
(16) Synthesis of 2,3-Di(alkenyl)pyrroles 5a–n: In a pressure
tube (glass bomb) a suspension of Pd(OAc)2 (12 mg, 0.05
mmol, 5 mol%) and TCHP (28.04 mg, 0.10 mmol, 10 mol%)
in DMF (5 mL) was purged with Ar and stirred at 20 °C to
give a yellowish or brownish clear solution. To the stirred
solution were added 3a–d (1.0 mmol), Et3N (1.1 mL, 8.0
mmol) and the acrylate (5.0 equiv). The reaction mixture
was stirred at 100 °C for 24 h. The solution was cooled to 20
°C, poured into H2O and CH2Cl2 (25 mL each), and the
organic and the aqueous layers were separated. The latter
was extracted with CH2Cl2 (3 × 25 mL). The combined
organic layers were washed with H2O (3 × 20 mL), dried
(Na2SO4), and concentrated in vacuo. The residue was
purified by chromatography (flash silica gel, eluent:
heptanes–EtOAc).
(17) (2E,2¢E)-Isobutyl 3,3¢-[5-(4-Ethylphenyl)-N-methyl-
pyrrole-2,3-diyl]diacrylate (5c): Compound 5c was
prepared starting with 3b (343 mg, 1.0 mmol) as a brown
highly viscous oil (301 mg, 69%). 1H NMR (300 MHz,
CDCl3): d = 0.90 (d, 6 H, J = 6.7 Hz, 2 × Me), 0.91 (d, 6 H,
J = 6.7 Hz, 2 × Me), 1.20 (t, 3 H, J = 7.6 Hz, Me), 1.87–1.99
(m, 2 H, 2 × CH), 2.62 (q, 2 H, J = 7.6 Hz, CH2), 3.57 (s, 3
H, NMe), 3.90 (d, 2 H, J = 6.8 Hz, CH2O), 3.92 (d, 2 H, J =
6.8 Hz, CH2O), 6.10 (d, 1 H, J = 16.0 Hz, CH), 6.18 (d, 1 H,
J = 15.6 Hz, CH), 6.42 (s, 1 H, CHpyrrole), 7.20–7.25 (m, 4 H,
Ar), 7.71 (d, 1 H, J = 16.0 Hz, ArH), 7.78 (d, 1 H, J = 15.7
Hz, ArH). 13C NMR (75 MHz, CDCl3): d = 15.4 (Me), 19.2
(4 × Me), 27.8, 27.9 (CH), 28.6 (CH2), 33.9 (NMe), 70.4,
Acknowledgment
Financial support by the DAAD (scholarship for S.-M.T.T.) is gra-
tefully acknowledged.
References and Notes
(1) (a) The Chemistry of Indoles; Sundberg, R. J., Ed.;
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Academic Press: San Diego, 1996. (d) Schmidt, A. M.;
Eilbracht, P. J. Org. Chem. 2005, 70, 5528. (e) Fukuyama,
T.; Chen, X. J. Am. Chem. Soc. 1994, 116, 3125.
(f) Comprehensive Heterocyclic Chemistry III; Katritzky,
A. R.; Ramsden, C. A.; Scriven, E. F. V.; Taylor, R. J. K.,
Eds.; Elsevier Science & Technology: Amsterdam, 2008, 3.
(g) Science of Synthesis, Vol. 10; Joule, J. A.; Thomas, E. J.,
Eds.; Georg Thieme Verlag: Stuttgart / Germany, 2000.
(h) Tolkachev, O. N.; Abizov, E. A.; Abizova, E. V.;
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Synlett 2011, No. 4, 513–516 © Thieme Stuttgart · New York

516
S.-M. T. Toguem, P. Langer
LETTER
starting with 5j (465 mg, 1.0 mmol) as a brown highly
70.8 (CH2O), 107.7, 116.5, 117.5 (CH), 123.7 (C), 128.2 (2
× CH), 129.0 (C), 129.1 (2 × CH), 130.9 (C), 131.1, 136.3
(CH), 140.7, 144.6 (C), 167.2, 167.5 (CO). IR (KBr): 2959
(m), 2932, 2872 (w), 1699, 1615 (s), 1548, 1504 (w), 1468,
1453 (m), 1424, 1392 (w), 1368, 1284, 1260, 1241, 1220
(m), 1148 (s), 1015, 966, 839, 799 (m), 773, 723, 703, 672,
610, 533 (w) cm–1. EI+ (70 eV): m/z (%) = 437 (7) [M]+, 280
(14), 236 (11), 66 (13), 44 (16), 43 (100), 42 (30), 41 (55).
HRMS (EI, 70 eV): m/z [M]+ calcd for C27H35O4N:
437.25606; found: 437.25529.
viscous oil (412 mg, 89%). 1H NMR (250 MHz, CDCl3): d =
0.89 (t, 6 H, J = 8.7 Hz, 2 × Me), 1.29 (s, 9 H, 3 × Me), 1.33–
1.42 (m, 4 H, 2 × CH2), 1.61–1.72 (m, 4 H, 2 × CH2), 3.71 (s,
3 H, NMe), 4.23 (t, 2 H, J = 6.7 Hz, CH2O), 4.25 (t, 2 H, J =
6.7 Hz, CH2O), 6.52 (s, 1 H, CHpyrrole), 7.36 (d, 2 H, J = 8.4
Hz, ArH), 7.43 (d, 2 H, J = 8.5 Hz, ArH), 7.65 (s, 1 H, ArH),
7.92 (s, 1 H, ArH). 13C NMR (75 MHz, CDCl3): d = 12.8 (2
× Me), 18.2 (2 × CH2), 29.6, 29.7 (CH2), 30.3 (3 × Me), 30.5
(NMe), 33.7 (C), 64.1, 64.3 (CH2O), 101.5, 110.1, 121.1
(CH), 123.2, 124.5 (C), 124.6 (2 × CH), 127.8 (C), 128.0 (2
× CH), 128.0, 137.2, 144.1, 150.7 (C), 167.8, 168.0 (CO). IR
(KBr): 2956 (m), 2870 (w), 1711 (s), 1611, 1562, 1494 (w),
1475, 1461 (m), 1430, 1390 (w), 1360, 1339 (m), 1256, 1243
(s), 1209, 1157 (m), 1103 (s), 1060, 1036, 1004 (m), 962,
944, 896 (w), 839, 783, 736 (m), 672, 625, 602, 565 (w) cm–1.
GC–MS (EI, 70 eV): m/z (%) = 463 (100) [M]+, 448 (13),
407 (10), 355 (14), 334 (54), 318 (13), 290 (11). HRMS (EI,
70 eV): m/z [M]+ calcd for C29H37O4N: 463.27171; found:
463.27286.
(18) Synthesis of Indoles 6a–n: A diphenyl ether solution (3 mL)
of 5a–n was stirred at 200 °C for 24 h in a pressure tube. The
solution was allowed to cool to 20 °C and Pd/C (30 mg, 10
mol%) was added. The solution was stirred at 200 °C for 48
h under an argon atmosphere. The reaction mixture was
filtered and the filtrate was concentrated in vacuo. The
residue was purified by chromatography (flash silica gel,
eluent: heptanes–EtOAc).
(19) Dibutyl 2-(4-tert-Butylphenyl)-N-methylindole-5,6-
dicarboxylate Diacrylate (6j): Compound 6j was prepared
Synlett 2011, No. 4, 513–516 © Thieme Stuttgart · New York

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