Site-selective Suzuki-Miyaura reactions of 2,3,5-tribromo-N-methylpyrrole

Article abstract of DOI:10.1016/j.tetlet.2011.05.044

The first Suzuki-Miyaura reactions of 2,3,5-tribromo-N-methylpyrrole are reported. These reactions proceed with very good site-selectivity in favour of position 5 which is more reactive than position 2, due to steric reasons. The second attack occurs at position 2 which is more electron deficient than position 3.

Full text of DOI:10.1016/j.tetlet.2011.05.044

Tetrahedron Letters 52 (2011) 3732–3735
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Site-selective Suzuki–Miyaura reactions of 2,3,5-tribromo-N-methylpyrrole
Serge-Mithérand Tengho Toguem a, Olumide Fatunsin a, Alexander Villinger a, Peter Langer a,b,
⇑
a Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b Leibniz-Institut für Katalyse e. V. An der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 March 2011
Revised 6 May 2011
Accepted 10 May 2011
Available online 24 May 2011
The first Suzuki–Miyaura reactions of 2,3,5-tribromo-N-methylpyrrole are reported. These reactions pro-
ceed with very good site-selectivity in favour of position 5 which is more reactive than position 2, due to
steric reasons. The second attack occurs at position 2 which is more electron deficient than position 3.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Catalysis
Palladium
Suzuki–Miyaura reaction
Site-selectivity
Pyrroles
The pyrrole system is of great importance in organic chemistry,
due to its occurrence in many natural products and pharmacolog-
ically active molecules.1 For example, a pyrrole core structure is
present in marine natural products, such as the lamellarines, stor-
niamide A, ningalin A and halitulin, which show considerable po-
tential for the treatment of various cancers and AIDS.2 Pyrroles
also occur in the structure of atorvastatin (lipitor), an oral drug
which lowers the level of cholesterol in the blood.3 They are also
found in the natural product porphobilinogen, a trisubstituted pyr-
role which is a biosynthetic precursor of many natural products
such as haemoglobin.4 Structurally more simple pyrroles have
been also isolated as natural products, for example, pyrrolnitrin,
isolated from Pseudomonas pyrrocinia, which possesses potent anti-
fungal and antibiotic activities (Chart 1).5
Site-selective palladium(0)-catalyzed cross-coupling reactions
of polyhalogenated heterocycles provide an efficient approach to
more complex substituted derivatives.6,7 This methodology has
been applied also to the synthesis of natural products and pharma-
ceuticals.8 Schröter and Bach studied Suzuki–Miyaura (S–M)
reactions of 2,3,4-tribromopyrrole-5-carboxylate and of 2,3-dibro-
mo-5-nitropyrrole and observed site-selectivity in favour of posi-
tion 2.9 Handy and co-workers reported site-selective one-pot
double S–M reactions of 4,5-dibromopyrroles using ligand free
conditions.10 Beaumard and co-workers reported one-pot S–M
reactions of 2,5-dibromo-N-Boc-pyrrole.11
methylpyrrole, tetrabromothiophene, tetrabromo–selenophene,
tribromopyrazoles, and tribromothiophenes. The site-selectivity
of such reactions is controlled by electronic and steric effects.
Directing groups at sites neighbouring the reactive position also
play a significant role in the selectivity. Herein, we report what
are, to the best of our knowledge, the first site-selective Suzuki–
Miyaura reactions of 2,3,5-tribromo-N-methylpyrrole. These
reactions provide a convenient approach to novel 5-aryl-2,3-dibro-
mo-N-methylpyrroles, 2,5-diaryl-3-bromo-N-methylpyrroles and
2,3,5-triaryl-N-methylpyrrole.
2,3,5-Tribromo-N-methyl-pyrrole 2 was prepared, following a
known procedure,12 by reaction of N-methylpryrrole (1) with
NBS (3.1 equiv) in THF (Scheme 1).
The S–M reaction of 2 with 1.1 equiv of various arylboronic
acids afforded 5-aryl-2,3-dibromo-N-methylpyrroles 3a–g in 43–
82% yields (Scheme 2, Table 1).13 The reactions proceeded with
HO
OH
CO2Me
O
N
Recently, we have reported site-selective S–M reactions of
various polyhalogenated heterocycles, such as tetrabromo-N-
Pyrrolnitrin
OH
⇑
Corresponding author. Fax: +49 381 4986412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
Chart 1. Structure of pyrrolnitrin.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.044

S.-M. Tengho Toguem et al. / Tetrahedron Letters 52 (2011) 3732–3735
3733
Br
Br
NBS
i
N
Me
Br
N
Me
1
2 (88%)
Scheme 1. Synthesis of 2. Reagents and Conditions: 1 (1.0 equiv), NBS (3.1 equiv),
THF, À78? 20 °C, 12 h.
Ar1B(OH)2
Br
Br
Br
1.1 equiv
Br
Br
Ar1
N
Me
2
N
Me
3a-f
i
Ar2B(OH)2
3.0 equiv
ii
Ar2
Figure 1. Ortep plot of 3a.
Ar2
Ar1
N
Table 2
Synthesis of 2,3,5-triaryl-N-methylpyrrole 4a
Me
4a
4
a
Ar1
Ar2
(%) (4)a
74
Scheme 2. Synthesis of 3a–g and 4a. Reagents and Conditions: (i) 2 (1.0 equiv),
Ar1B(OH)2 (1.1 equiv), Pd(PPh3)4 (5 mol %), K3PO4 (4.0 equiv), 1,4-dioxane/tolu-
ene = 1:1, 100 °C, 8 h; (ii) 3d (1.0 equiv), Ar2B(OH)2 (3 equiv), Pd(PPh3)4 (5 mol %),
K3 PO4(4.0 equiv), toluene, 110 °C, 36 h.
4-tBuC6H4
4-(MeO)C6H4
a
Yields of isolated products.
Ar1B(OH)2
2.3 equiv
very good site-selectivity in favour of position 5. The relatively low
yield of 3a can be explained by the steric hindrance of 2,6-
di(methoxy)phenylboronic acid. Good yields were obtained for
nearly all products when Pd(PPh3)4 (5 mol %) and K3PO4 (4.0 equiv)
were employed as the catalyst and as the base, respectively, when
1.1 equiv of the boronic acid was used and when the reaction was
carried out at 100 °C (8 h). The temperature should not be too high
and the reaction time not too long to avoid multiple coupling.
Employment of a solvent mixture dioxane/toluene proved to be
important, due to reasons of solubility of the boronic acids. Analy-
sis of the crude product mixture (GC–MS, 1H NMR) shows that
small amounts of products derived from double-coupling are pres-
ent which could, however, be removed by chromatography. The
structure of 3a was independently confirmed by X-ray crystal
structure analysis (Fig. 1).14
Br
Br
Ar1
Ar1
Br
Br
N
N
i
Me
Me
2
5a-f
Ar2B(OH)2
Ar2
2.0 equiv
Ar1
Ar1
ii
N
Me
6a,b
Scheme 3. Synthesis of 5a–d and 6a,b. Reagents and Conditions: (i) 2 (1.0 equiv),
Ar1B(OH)2 (2.3 equiv), Pd(PPh3)4 (5 mol %), K3PO4 (4.0 equiv), 1,4-dioxane/tolu-
ene = 1:1, 100 °C, 12 h; (ii) 5d,f (1.0 equiv), Ar2B(OH)2 (2.0 equiv), Pd(PPh3)4
(5 mol %), K3PO4 (4.0 equiv), toluene, 110 °C, 36 h.
The S–M reaction of 3d with 4-methoxyphenylboronic acid
afforded the 2,3,5-triaryl-N-methylpyrrole 4a in 74% yield (Scheme
2, Table 2). The best yield of this compound was obtained when an
excess of the boronic acid was employed (3.0 equiv) and when the
reaction time was extended to 36 h and the temperature elevated
to 110 °C. The yield of the one-pot synthesis of 4a from 2 (sequen-
tial addition of the boronic acids) was less than the yield of the
stepwise process. Therefore, the one-pot synthesis was not further
studied.
Table 3
Synthesis of 2,5-diaryl-3-bromo-N-methylpyrroles 5a–f
5
Ar1
(%) (5)a
a
b
c
d
e
f
3-(MeO)C6H4
3,5-Me2C6H3
2-(EtO)C6H4
4-(MeO)C6H4
2,6-(MeO)2C6H3
4-tBuC6H4
53
42
45
58
40
37
Table 1
a
Yields of isolated products.
Synthesis of 5-aryl-2,3-dibromo-N-methylpyrroles 3a–g
3
Ar1
T [°C]
t [h]
(%) (3)a
a
b
c
d
e
f
2,6-(MeO)2C6H3
4-MeC6H4
4-EtC6H4
4-tBuC6H4
2-(MeO)C6H4
3,5-Me2C6H3
3-FC6H4
90
100
100
90
90
110
90
8
8
6
8
8
6
8
43
82
73
64
61
58
51
Table 4
Synthesis of 2,3,5-triaryl-N-methylpyrroles 6a,b
6
Ar1
Ar2
(%) (6)a
a
4-(MeO)C6H4
4-ClC6H4
72
83
g
b
4-tBuC6H4
2-(EtO)C6H4
a
a
Yields of isolated products.
Yields of isolated products.

3734
S.-M. Tengho Toguem et al. / Tetrahedron Letters 52 (2011) 3732–3735
Figure 2. Ortep plot of 6a.
Br
Table 5
Ar
ArB(OH)2
4.0 equiv
Synthesis of 2,3,5-triaryl-N-methylpyrroles 7a–f
Br
Br
7
Ar1
(%) (7)a
Ar
Ar
N
N
i
Me
Me
a
b
c
d
e
f
4-MeC6H4
68
89
76
72
92
62
4-(MeO)C6H4
3-(MeO)C6H4
4-tBuC6H4
2,3,4-(MeO)3C6H2
3-FC6H4
2
7a-f
Scheme 4. Synthesis of 7a–f. Reagents and Conditions: (i) 2 (1.0 equiv), ArB(OH)2
(4.0 equiv), Pd(OAc)2 (5 mol %)/P(Cy)3 (10 mol %), K3PO4 (4.0 equiv), toluene, 110 °C,
36 h.
a
Yields of isolated products; Cy = cyclohexyl.
Br
Br
Ar2B(OH)2
1.1 equiv
Br
Ar2
Table 6
Synthesis of 2,3,5-triaryl-N-methylpyrrole 8a
Ar1
Ar1
N
N
Ar1
Ar2
Ar3
(%) (8)
43
i
Me
Me
8%
4-tBuC6H4
2-(MeO)C6H4
4-Et C6H4
3d
aYields of isolated products.
Ar3B(OH)2
Ar3
2.0 equiv
ii
Ar2
Ar1
N
Me
electron-deficient
less electron-deficient
not sterically hindered
less sterically hindered
Br
Br
8 (43%)
electron-deficient
sterically hindered
Br
Scheme 5. Synthesis of 8. Reagents and Conditions: (i) 3d (1.0 equiv), Ar2B(OH)2
(1.1 equiv), Pd(PPh3)4 (5 mol %), K3PO4 (4.0 equiv), 1,4-dioxane/toluene = 1:1,
100 °C, 6 h; (ii) Ar3B(OH)2 (2.0 equiv), K3PO4 (2.0 equiv), 110 °C, 24 h.
N
Me
Figure 3. Possible explanation for the site-selectivity of the reactions of 2.
The S–M reaction of 2 with 2.3 equiv of arylboronic acids gave
2,5-diaryl-3-bromo-N-methylpyrroles 5a–f in 40–53% yields
(Scheme 3, Table 3).15 The reactions were carried out at 100 °C
(12 h). The S–M reactions of 5d,f with 2.0 equiv of arylboronic
acids afforded the 2,3,5-triaryl-N-methylpyrroles 6a,b (Scheme 3,
Table 4). Similar to the synthesis of 4a, the yield of the one-pot syn-
thesis of 6a was lower compared to the stepwise synthesis. The
structure of 6a was independently confirmed by X-ray crystal
structure analysis (Fig. 2).14
The moderate yields of compounds 5a–f can be explained by
the need to separate small amounts of trisubstituted compounds
and of starting material by chromatography. Due to close Rf values,
the separations were difficult and resulted in a decrease of the
yield.
68–92% yields (Scheme 4, Table 4).16 The reactions were carried
using Pd(OAc)2/P(Cy)3 (Cy = cyclohexyl) which gave better yields
than Pd(PPh3)4.
The reaction of 5-aryl-3,4-dibromopyrazoles 4 with arylboronic
acids 3a,b,d,g,o afforded the 3,4,5-triarylpyrazoles 7a–i in 74–92%
yield (Scheme 5, Table 5).
One-pot reaction of 3d with two different arylboronic acids,
which were sequentially added, gave 2,3,5-triaryl-N-methylpyrrole
8 containg three different aryl groups in 43% yield (Scheme 5, Table
6).
The site-selectivites can be explained by electronic and steric
parameters.6,17 Position 5 is the most reactive because it is more
electron deficient than position 3 and less sterically hindered than
position 2 (Fig. 3). From the electronic viewpoint, positions 2 and 5
are similar.
The S–M reaction of 2 with 4.0 equiv of arylboronic acids
resulted in the formation of the 2,3,5-triarylpyrroles 7a–f in

S.-M. Tengho Toguem et al. / Tetrahedron Letters 52 (2011) 3732–3735
3735
Starting with
2 (0.159 g, 0.5 mmol) and 3,5-dimethylphenylboronic acid
In conclusion, we have reported the first Suzuki–Miyaura reac-
tions of 2,3,5-tribromo-N-methylpyrrole. The reactions provide a
convenient and site-selective approach to various arylated pyrroles
which are not readily available by other methods.
(0.082 g, 0.55 mmol), 3f was isolated (0.099 g, 58%) as a colourless oil. 1H
NMR (300 MHz, acetone-d6): d = 2.21 (s, 3H, CH3), 2.22 (s, 3H, CH3), 3.50 (s, 3H,
NCH3), 6.16 (s, 1H, CHpyrrole), 6.92 (s, 3H, Ar). 13C NMR (75 MHz, acetone-d6): d
= 21.3 (2CH3), 35.4 (NCH3), 98.4, 105.5 (CBr), 111.3 (CH), 127.4 (2CH), 130.3
(CH), 132.9, 137.7 (C), 138.9 (2C). IR (KBr, cmÀ1):
m = 3120, 2947, 2915, 2855
(w), 1600, 1466, 1450, 1372, 1322, 1302, 1273 (m), 1205, 1181 (w), 1086, 1036,
950 (m), 899 (w), 851, 840, 775, 695 (s), 663, 602 (m). GC/MS (EI, 70 eV): m/z
Acknowledgments
(%) = 343 (100) [M+ 81Br, 79Br)], 183 (10), 168 (13). HRMS (EI, 70 eV): m/z [M+
(
(
81Br, 79Br)] calcd for C13H13NBr2: 342.93888; found: 342.939847.
The financial support by the DAAD (scholarship for S.-M. T.-T.
and Stibet scholarship for O. F.) and by the State of Mecklenburg-
Vorpommern (scholarship for O. F.) is gratefully acknowledged.
14. CCDC-824509 (3a) and CCDC-824510 (6a) contain all crystallographic details
of this publication and is available free of charge at www.ccdc.cam.ac.uk/conts/
retrieving.html or can be ordered from the following address: Cambridge
Crystallographic Data Centre, 12 Union Road, GB-Cambridge CB21EZ; Fax:
(+44)1223-336-033; or deposit@ccdc.cam.ac.uk.
References and notes
15. Synthesis of 2,5-diaryl-3-bromo-N-methylpyrroles 5a–f. To
(0.159 g, 0.5 mmol), aryl boronic acid (1.15 mmol), and Pd(PPh3)4 (5 mol %)
was added mixture of 1,4-dioxane and toluene (1:1; 5 mL) and K3PO4
a mixture of 2
1. (a) Jones, R. A.; Bean, G. P. The chemistry of pyrrole; Academic Press: London,
1977; (b)Pyrroles Part 1; Jones, R. A., Ed.; Wiley-Interscience: New York, 1990;
(c) Jefford, C. W. Curr. Org. Chem. 2000, 4, 205; (d) Banwell, M. G.; Beck, D. A. S.;
Stanislawski, P. C.; Sydnes, M. O.; Taylor, R. M. Curr. Org. Chem. 2005, 9, 1589;
(e) Baumann, K. L.; Butler, D. E.; Deering, C. F.; Mennen, K. E.; Millar, A.;
Nanninga, T. N.; Palmer, C. W.; Roth, B. D. Tetrahedron Lett. 1992, 33, 2283; (f)
Sternberg, E. D.; Dolphin, D.; Brückner, C. Tetrahedron 1998, 54, 4151; (g) Sato,
A.; McNulty, L.; Cox, K.; Kim, S.; Scott, A.; Daniell, K.; Summerville, K.; Price, C.;
Hudson, S.; Kiakos, K.; Hartley, J. A.; Asao, T.; Lee, M. J. Med. Chem. 2005, 48,
3903.
2. (a) Bailly, C. Curr. Med. Chem. Anti-Cancer Agents 2004, 4, 363; (b) Handy, S. T.;
Zhang, Y. Org. Prep. Proceed. Int. 2005, 37, 411; (c) Pla, D.; Marchal, A.; Olsen, C.
A.; Albericio, F.; Álvarez, M. J. Org. Chem. 2005, 70, 8231.
3. Li, J. J.; Gribble, G. W. In Palladium in Heterocyclic Chemistry Tetrahedron Organic
Chemistry Series; Elsevier Science Ltd.: Oxford, 2000; vol. 20, Chapter 2.
4. (a) Cox, M.; Lehninger, A. L.; Nelson, D. R. Lehninger principles of biochemistry;
Worth Publishers: New York, 2000; (b) De Leon, C. Y.; Ganem, B. Tetrahedron
1997, 53, 7731; (c) Danso-Danquah, R. E.; Scott, A. I. Tetrahedron 1993, 49, 8195.
5. van Pée, K.-H.; Ligon, J. M. Nat. Prod. Rep. 2000, 17, 157.
a
(4.0 equiv, 424 mg) under an argon atmosphere. The reaction mixture was
stirred at 100ꢀC for 12 h and was subsequently allowed to cool to 20ꢀC. 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 Â
25 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was
purified by flash column chromatography (flash silica gel, eluent: heptanes/
EtOAc). Synthesis of 3-bromo-2,5-bis(3,5-dimethylphenyl)-1-methyl-1H-pyrrole
(5b). Starting with 2 (0.159 g, 0.5 mmol) and 3,5-dimethylphenylboronic acid
(0.172 g, 1.15 mmol), 5b was isolated (0.077 g, 42%) as a colourless oil. 1H NMR
(300 MHz, acetone-d6): d = 2.34 (s, 3H, CH3), 2.34 (s, 3H, CH3), 2.35 (s, 3H, CH3),
2.36 (s, 3H, CH3), 3.48 (s, 3H, NCH3), 6.26 (s, 1H, CHpyrrole), 7.00 (s, 1H, Ar), 7.04
(s, 1H, Ar), 7.10 (s, 4H, Ar). 13C NMR (75 MHz, acetone-d6): d = 21.3 (2CH3), 21.4
(2CH3), 35.0 (NCH3), 95.9 (CBr), 111.4 (CH), 127.4 (2CH), 129.1 (2CH), 129.8,
130.2 (CH), 132.2, 133.3, 134.1, 136.9 (C), 138.6 (2C), 138.8 (2C). IR (KBr, cmÀ1):
m
= 3005, 2918, 2856, 1711, 1679, 1663 (w), 1600, 1462 (m), 1376, 1330, 1270,
1191, 1038, 900 (w), 854, 841 (m), 780, 696, 659 (w). GC/MS (EI, 70 eV): m/z
(%) = 367 (99) [M+ 79Br)], 272 (10). HRMS (EI, 70 eV): m/z [M+ 79Br)] calcd for
21H22NBr: 367.09301; found: 367.09300.
(
(
C
6. For reviews of cross-coupling reactions of polyhalogenated heterocycles, see:
(a) Schröter, S.; Stock, C.; Bach, T. Tetrahedron 2005, 61, 2245; (b) Schnürch, M.;
Flasik, R.; Khan, A. F.; Spina, M.; Mihovilovic, M. D.; Stanetty, P. Eur. J. Org. Chem.
2006, 3283; (c) Wang, R.; Manabe, K. Synthesis 2009, 1405.
16. Synthesis of 2,3,5-triaryl-N-methylpyrroles 7a–f: 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 Toluene (5 mL) was purged with Ar and stirred at 20ꢀC
to give a brownish solution. To the stirred solution were added 2 (0.159 g,
0.5 mmol), arylboronic acid (2.0 mmol), and K2PO4 (4.0 equiv, 424 mg) under
argon atmosphere. The reaction mixture was stirred at 110 °C for 36 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 layer were separated. The
latter was extracted with EtOAc (3 Â 25 mL), dried (Na2SO4), filtered, and
concentrated in vacuo. The residue was purified by flash column
chromatography (flash silica gel, eluent: heptanes/EtOAc). Synthesis of 2,3,5-
7. For work from our laboratories, see: (a) Dang, T. T.; Dang, T. T.; Ahmad, R.;
Reinke, H.; Langer, P. Tetrahedron Lett. 2008, 49, 1698; (b) Dang, T. T.; Villinger,
A.; Langer, P. Adv. Synth. Catal. 2008, 350, 2109; (c) Hussain, M.; Nguyen, T. H.;
Langer, P. Tetrahedron Lett. 2009, 50, 3929; (d) Tengho Toguem, S.-M.; Hussain,
M.; Malik, I.; Villinger, A.; Langer, P. Tetrahedron Lett. 2009, 50, 4962; (e)
Hussain, M.; Malik, I.; Langer, P. Synlett 2009, 2691; (f) Dang, T. T.; Dang, T. T.;
Rasool, N.; Villinger, A.; Langer, P. Adv. Synth. Catal. 2009, 351, 1595; (g) Ullah,
I.; Khera, R. A.; Hussain, M.; Langer, P. Tetrahedron Lett. 2009, 50, 4651; (h)
Nawaz, M.; Farooq, M. I.; Obaid-Ur-Rahman, A.; Khera, R. A.; Villinger, A.;
Langer, P. Synlett 2010, 150; (i) Toguem, S.-M. T.; Villinger, A.; Langer, P. Synlett
2009, 3311; (j) Toguem, S.-M. T.; Villinger, A.; Langer, P. Synlett 2010, 909.
8. Fairlamb, I. J. S. Chem. Soc. Rev. 2007, 36, 1036.
9. Schröter, S.; Bach, T. Synlett 2005, 1957.
10. (a) Handy, S. T.; Sabatini, J. J. Org. Lett. 2006, 8, 1537; (b) Handy, S. T.; Zhang, Y.
N. Synthesis 2006, 3883.
11. Beaumard, F.; Dauban, P.; Dodd, R. H. Org. Lett. 2009, 11, 1801.
12. Gilow, H. M.; Burton, D. E. J. Org. Chem. 1981, 46, 2221.
tris(4-methoxyphenyl)-1-methyl-1H-pyrrole (7b). Starting with
2 (0.159 g,
0.5 mmol) and 4-methoxyphenylboronic acid (0.304 g, 2.0 mmol), 7b was
isolated (0.177 g, 89%) as a brownish oil. 1H NMR (300 MHz, acetone-d6): d
= 3.30 (s, 3H, NCH3), 3.59 (s, 3H, OCH3), 3.71 (s, 6H, 2OCH3), 6.19 (s, 1H,
CHPyrrole), 6.60 (dd, J = 2.1, 6.7 Hz, 2H, Ar), 6.84 (dd, J = 2.1, 6.7 Hz, 2H, Ar), 6.88
(dd, J = 2.2, 6.8 Hz, 2H, Ar), 6.98 (dd, J = 2.1, 6.7 Hz, 2H, Ar), 7.12 (dd, J = 2.1,
6.7 Hz, 2H, Ar), 7.31 (dd, J = 2.1, 6.7 Hz, 2H, Ar). 13C NMR (62 MHz, acetone-d6):
d = 33.7 (NCH3), 55.4, 55.5, 55.5 (OCH3), 108.5 (CH), 114.3 (2CH), 114.7 (2CH),
114.8 (2CH), 122.7, 126.7, 127.1 (C), 129.3 (2CH), 130.4 (C), 130.7 (2CH), 131.8
(C), 133.1 (2CH), 135.5, 158.4, 159.8, 160.1 (C). IR (KBr, cmÀ1):
m = 3004, 2952,
13. Synthesis of 5-aryl-2,3-dibromo-N-methylpyrroles 3a–f: To
(0.159 g, 0.5 mmol), aryl boronic acid (0.55 mmol), and Pd(PPh3)4 (5 mol %)
was added mixture of 1,4-dioxane and toluene (1:1; 5 mL) and K3PO4
a mixture of 2
2930, 2833, 1608, 1600, 1574, 1562 (w), 1517, 1497, 1461, 1440 (m), 1373,
1343, 1304 (w), 1285 (m), 1239, 1170 (s), 1108 (m), 1026, 832 (s), 806, 790 (m),
752, 650 (w), 585, 534 (m). GC/MS (EI, 70 eV): m/z (%) = 399 (100) [M+], 384
(35). HRMS (EI, 70 eV): m/z [M+] calcd for C26H25O3N: 399.18290; found:
399.18262.
a
(4.0 equiv, 424 mg) under an argon atmosphere. The reaction mixture was
stirred at 100ꢀC for 8 h and was subsequently allowed to cool to 20ꢀC. 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 Â
25 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was
purified by flash column chromatography (flash silica gel, eluent: n-heptane).
Synthesis of 2,3-dibromo-5-(3,5-dimethylphenyl)-1-methyl-1H-pyrrole (3f).
17. For a simple guide to predict the regioselectivity based on 1H NMR chemical
shifts of the non-halogenated parent compound, see: Handy, S. T.; Zhang, Y.
Chem. Commun. 2006, 299.