Regioselective Suzuki cross-coupling reactions of 2,3,4,5-tetrabromo-1-methylpyrrole

Article abstract of DOI:10.1016/j.tetlet.2007.12.126

Regioselective Suzuki cross-coupling reactions of 2,3,4,5-tetrabromo-1-methylpyrrole allow a convenient synthesis of functionalized pyrroles.

Full text of DOI:10.1016/j.tetlet.2007.12.126

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1698–1700
Regioselective Suzuki cross-coupling reactions
of 2,3,4,5-tetrabromo-1-methylpyrrole
Tung T. Dang a, Rasheed Ahmad a, Tuan T. Dang a, Helmut Reinke a, Peter Langer a,b,
*
a Institut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Strasse 3a, 18059 Rostock, Germany
b Leibniz-Institut fu¨r Katalyse e. V. an der Universita¨t Rostock, Albert-Einstein-Strasse 29a, 18059 Rostock, Germany
Received 28 November 2007; revised 20 December 2007; accepted 21 December 2007
Available online 8 January 2008
Abstract
Regioselective Suzuki cross-coupling reactions of 2,3,4,5-tetrabromo-1-methylpyrrole allow a convenient synthesis of functionalized
pyrroles.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Heterocycles; Pyrroles; Regioselectivity; Suzuki reactions
Pyrroles are of considerable pharmacological relevance.
They occur in a number of synthetic drugs (e.g., zomepirac
and atorvastatin) and natural products (e.g., in the tetra-
pyrrole pigments porphobilinogen and bilirubin).1–3 Oligo-
pyrroles proved to be important as organic materials
(e.g., as synthetic metals).4 Heterocycles have been widely
functionalized by palladium(0)-catalyzed cross-coupling
reactions.5 In recent years, it has been shown that poly-
halogenated heterocycles may be regioselectively function-
alized in such reactions by selective activation of a single
halogen atom—a process which is controlled by electronic
and steric parameters.6 Recently, we reported the synthesis
of tetraarylthiophenes based on regioselective Suzuki reac-
tions of tetrabromothiophene.7 Despite their potential syn-
thetic utility, regioselective functionalization reactions of
polyhalogenated pyrroles have only scarcely been reported
to date. Bach and Schro¨ter recently reported regioselective
Suzuki reactions of ethyl 2,3,4-tribromopyrrole-5-carbox-
ylate and of 2,3-dibromo-5-nitropyrrole.8 Herein, we
disclose our preliminary results related to Suzuki cross-
coupling reactions of 2,3,4,5-tetrabromo-1-methylpyrrole.
Palladium(0)-catalyzed cross-coupling reactions of tetra-
halopyrroles have, to the best of our knowledge, not been
reported to date. In general, reactions of tetrahalogenated
pyrroles are rather rare, which can be explained by the
unstable nature of these compounds.9
2,3,4,5-Tetrabromo-1-methylpyrrole (1) was prepared
by NBS-mediated bromination of N-methylpyrrole. The
published procedure10 for the synthesis of 1 was modi-
fied,11 as we were not able to isolate the pure product by
the original protocol. The reaction was carried out at
ꢀ78 °C for 8 h. It proved to be helpful for the separation
of succinimide to add heptane to the reaction mixture,
which results in the precipitation of succinimide and of
side-products. The yellowish crude product was purified
by repeated washing with cold ethyl acetate to give the pure
material in the form of colourless crystals. Noteworthy,
impure product fails to undergo the desired Suzuki reac-
tions and also more rapidly decomposes. The solid can
be stored under argon at ꢀ18 °C for a few weeks. After a
few weeks, the compound starts to become slightly yellow
and the quality is not sufficient anymore for Suzuki
reactions.
The Suzuki reaction of 1 with various boronic acids
(1.1 equiv) afforded 5-aryl-2,3,4-tribromopyrroles 2a–f in
good yields and with very good regioselectivity (Scheme 1,
Table 1). During the optimization, it proved to be
*
Corresponding author. Tel.: +49 381 4986410; fax: +49 381 4986412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.126

T. T. Dang et al. / Tetrahedron Letters 49 (2008) 1698–1700
1699
Br
Br
Br
Br
Br
Br
Br
Br
Br
Ar1
Br
Ar1
Ar1 B(OH)2
i
Br
Ar1
Br
Br
Ar1 B(OH)2
i
N
Me
N
Me
N
Me
N
Me
2a-f
Ar2 B(OH)2
4a-f
1
1
Br
Ar1
Br
iii
Ar B(OH)2
Ar2 B(OH)2
ii
ii
Ar2
N
Me
Ar2
Ar1
Ar2
Ar1
Ar
Ar
Ar
Ar
3a (45%) Ar1 = 4-MeC6H4; Ar2 = 3-ClC6H4
3b (51%) Ar1 = 4-MeC6H4; Ar2 = 4-(MeO)C6H4
N
N
Me
Me
Scheme 1. Synthesis of 5-aryl-2,3,4-tribromopyrroles 2a–f and of 2,5-
diaryl-3,4-dibromopyrroles 3a,b. Reagents and conditions: (i)
(1.0 equiv), Ar1B(OH)2 (1.1 equiv), Pd(PPh3)4 (6 mol %), K3PO4
(4.0 equiv), solvent (see Table 1), 90 °C, 12 h; (ii) 2c (1.0 equiv),
Ar2B(OH)2 (1.1 equiv), Pd(PPh3)4 (10 mol %), K3PO4 (4.0 equiv), DMF/
toluene/EtOH/H2O (4:1:1:1), reflux, 48 h.
6a (65%)
5a (78%)
1
Ar1 = 4-MeC6H4
Ar = 4-EtC6H4
Ar2 = 4-(MeO)C6H4
5b (57%)
Ar = 3-ClC6H4
6b (85%)
Ar1 = 4-MeC6H4
Ar2 = 3,5-Me2C6H3
Table 1
Synthesis of 2a–f
Scheme 2. Synthesis of 2,5-diaryl-3,4-dibromopyrroles 4a–f and of
tetraarylpyrroles 5a,b and 6a,b. Reagents and conditions: (i) 1 (1.0 equiv),
Ar1B(OH)2 (2.5 equiv), Pd(PPh3)4 (6–10 mol %), K3PO4 (4.0 equiv), sol-
vent (see Table 2), 90 °C, 12 h; (ii) 4c (1.0 equiv), Ar2B(OH)2 (3.0 equiv),
Pd(PPh3)4 (20 mol %), K3PO4 (4.0 equiv), DMF/toluene/EtOH/H2O
2
Ar
Solventa
Yieldb (%)
a
b
c
d
e
f
3-PhC6H4
3-ClC6H4
4-EtC6H4
2-(MeO)C6H4
4-MeC6H4
3,5-Me2C6H3
Toluene/H2O
Toluene/H2O
Toluene/H2O
1,4-Dioxane/H2O
1,4-Dioxane/H2O
1,4-Dioxane/H2O
66
71
75
70
81
72
(4:1:1:1), reflux, (6a: 48 h, 6b: 96 h); (iii)
1 (1.0 equiv), ArB(OH)2
(5.0 equiv), Pd(PPh3)4 (20 mol %), K3PO4 (5.0 equiv), DMF/toluene/
EtOH/H2O (4:1:1:1), reflux, 96 h.
a
Solvent/H2O = 4:1.
Yields of isolated products.
b
Table 2
Synthesis of 4a–f
important to suppress the formation of 2,5-diaryl-3,4-di-
bromopyrroles, as their separation from the desired prod-
ucts proved to be difficult and tedious. The stoichiometry,
temperature, solvent and the presence of water proved to
play an important role in terms of yield (Table 1). Note-
worthy, the employment of benzyl-, carbamate- and
sulfonyl-protected pyrroles was unsuccessful (decomposi-
tion). The reaction of 2e with 1.1 equiv of (3-chlorophenyl)-
and (4-methoxyphenyl)boronic acid resulted in regioselec-
tive formation of 2,5-diaryl-3,4-dibromopyrroles 3a and
3b, respectively (Scheme 1).
The Suzuki reaction of 1 with 2.5 equiv of various aryl-
boronic acids afforded 2,5-diaryl-3,4-dibromopyrroles 4a–f
in good yields and with very good regioselectivity (Scheme
2, Table 2).12 The solvent proved again to be a very impor-
tant parameter during the optimization of the yield. The
reaction of 4c with (4-methoxyphenyl)- and (3,5-dimethyl-
phenyl)boronic acid gave tetraarylpyrroles 6a and 6b,
respectively, containing two different types of aryl groups.
Tetraarylpyrroles 5a,b, containing four identical aryl
groups, were prepared by reaction of 1 with (4-ethylphe-
nyl)- and (3-chlorophenyl)boronic acid (5.0 equiv). The
best yields of 5a,b and 6a,b were obtained when the reac-
tions were carried out using a quaternary solvent mixture
(DMF/toluene/EtOH/H2O = 4:1:1:1) and an increased
amount of catalyst and reagents and when the reaction
time was extended. Considerable amounts of 2,3,5-triaryl-
4
Ar1
Solvent
Yielda (%)
a
b
c
d
e
f
3-ClC6H4
4-EtC6H4
4-MeC6H4
4-ClC6H4
4-(MeO)C6H4
Thien-2-yl
Toluene/H2O (5:1)
Toluene/H2O (5:1)
Toluene/H2O (5:1)
1,4-Dioxane/H2O (5:1)
1,4-Dioxane/H2O (5:1)
Toluene/MeOH/H2O (2:2:1)
57
52
79
67
79
50
a
Yields of isolated products.
4-bromopyrroles were formed when the amounts of
reagents and catalyst were too low. Noteworthy, the bro-
mide groups of 2,5-diaryl-3,4-dibromopyrroles 4a–f proved
to be considerably less reactive than those of 2,5-diaryl-3,4-
dibromothiophenes.7 This must be explained by electronic
reasons, as the steric hindrance is similar for both types of
substrates. The conditions developed for the synthesis of
Fig. 1. ORTEP plot of 4b (50% probability level).

1700
T. T. Dang et al. / Tetrahedron Letters 49 (2008) 1698–1700
Biomol. Chem. 2004, 2, 3060; (y) Dieltiens, N.; Stevens, C. V.; De Vos,
D.; Allaert, B.; Drozdzak, R.; Verpoort, F. Tetrahedron Lett. 2004,
45, 8995.
5a,b and 6a,b could be successfully applied to the synthesis
of related tetraarylpyrroles.
All products were characterized by spectroscopic meth-
ods. The structure of 4b was independently confirmed by
X-ray crystal structure analysis (Fig. 1).13
In conclusion, we have reported a new strategy for
the synthesis of 5-aryl-2,3,4-tribromopyrroles, 2,5-diaryl-
3,4-dibromopyrroles and tetraarylpyrroles based on
regioselective Suzuki cross-coupling reactions of N-
methyltetrabromopyrrole.
4. Reviews (a) Ba¨uerle, P. Adv. Mater. 1993, 5, 879; (b) Tour, J.-M.
Chem. Rev. 1996, 96, 537; (c) Roncali, J. Chem. Rev. 1992, 92, 711.
5. Reviews (a) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic
Chemistry; Pergamon Press: Oxford, 2000; (b) Kalinin, V. N.
Synthesis 1992, 413.
6. Review Schro¨ter, S.; Stock, C.; Bach, T. Tetrahedron 2005, 61, 2245.
7. Dang, T. T.; Rasool, N.; Dang, T. T.; Reinke, H.; Langer, P.
Tetrahedron Lett. 2007, 48, 845.
8. Schro¨ter, S.; Bach, T. Synlett 2005, 1957.
9. (a) Ciamician, G.; Dennstedt, M. Ber. Dtsch. Chem. Ges. 1882, 15,
2582; (b) Pieroni, G.; Moggi, P. Gazz. Chim. Ital. 1923, 53, 134; (c)
Treibs, A.; Kolm, H. G. Liebigs Ann. Chem. 1958, 614, 176; (d) Duan,
X.-G.; Rees, C. W. J. Chem. Soc., Perkin Trans. 1 1997, 2695; (e)
Moreau, C.; Serein-Spirau, F.; Bordeau, M.; Biran, C. Synth.
Commun. 1998, 28, 3403; (f) Bock, H.; Holl, S.; Krenzel, V. Z.
Naturforsch. B 2001, 56, 13.
Acknowledgements
Financial support by the State of Vietnam (MOET
scholarships for T.T.D. and T.T.D.) and by the State of
Pakistan (HEC scholarship for R.A.) is gratefully
acknowledged.
10. Gilow, H. M.; Burton, D. E. J. Org. Chem. 1981, 46, 2221.
11. Synthesis of 2,3,4,5-tetrabromo-1-methylpyrrole (1): To a THF solu-
tion (700 mL) of 1-methylpyrrole (40.5 g, 44.5 mL, 0.5 mol) was
added N-bromosuccinimide (504 g, 2.5 mol) at ꢀ78 °C and the
solution was stirred at this temperature for 8 h. To the mixture was
added n-heptane (500 mL) and the tetrahydrofuran was subsequently
removed under reduced pressure to give a colourless precipitate of
succinimide. The precipitate was filtered off and the solvent of the
filtrate was removed in vacuo. To the residue was added a saturated
aqueous solution of NaOH and the solution was heated under reflux
for 6 h. The aqueous layer and the organic layer were separated. The
latter was dried (Na2SO4), filtered, and the filtrate was concentrated in
vacuo. The residue was recrystallized from a 1:1-solution of chloro-
form and methanol at ꢀ18 °C. The crude product (in the form of
yellow crystals) was washed with very cold ethyl acetate for several
times to give 1 as colourless crystals (174.7 g, 88%), mp = 154–156 °C.
1H NMR (250 MHz, CDCl3): d = 3.65 (s, CH3). 13C NMR (75 MHz,
References and notes
1. (a) Falk, H. The Chemistry of Linear Oligopyrroles and Bile Pigments;
Springer-Verlag: Wien, 1989; p 355; (b) Montforts, F.-P.; Schwartz,
U. M. Angew. Chem. 1985, 97, 767; (c) Montforts, F.-P.; Schwartz, U.
M. Angew. Chem., Int. Ed. Engl. 1985, 24, 775; (d) Dutton, C. J.;
Fookes, C. J. R.; Battersby, A. R. J. Chem. Soc., Chem. Commun.
1983, 1237; (e) Stork, G.; Nakahara, Y.; Nakahara, Y.; Greenlee, W.
J. J. Am. Chem. Soc. 1978, 100, 7775; (f) Stork, G.; Nakamura, E. J.
Am. Chem. Soc. 1983, 105, 5510; (g) Lindel, T.; Breckle, G.;
Hochgurtel, M.; Volk, C.; Grube, A.; Ko¨ck, M. Tetrahedron Lett.
¨
2004, 45, 8149.
2. (a) Sundberg, R. J. In Comprehensive Heterocyclic Chemistry; Bird, C.
W., Cheeseman, G. W. H., Eds.; Pergamon Press: Oxford, 1984; Vol.
4, p 331; (b) Gribble, G. W. In Comprehensive Heterocyclic Chemistry
II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Elsevier:
Oxford, 1996; Vol. 2, p 207; (c) Bean, G. P. In Pyrroles; Jones, R. A.,
Ed.; Wiley: New York, 1990; p 105.
3. (a) Huisgen, R.; Gotthard, H.; Bayer, H. O.; Scha¨fer, F. C. Chem.
Ber. 1970, 103, 2611; (b) Chiu, P.-K.; Lui, K.-H.; Maini, P. N.;
Sammes, M. P. J. Chem. Soc., Chem. Commun. 1987, 109; (c) Barton,
D. H. R.; Kervagoret, J.; Zard, S. Z. Tetrahedron 1990, 46, 7587; (d)
Roskamp, E. J.; Dragovich, P. S.; Hartung, J. B.; Pederson, S. F. J.
Org. Chem. 1989, 54, 4736; (e) Tang, J.; Verkade, J. G. J. Org. Chem.
1994, 59, 7793; (f) De Kimpe, N.; Tehrani, K. A.; Stevens, C.; De
Cooman, P. Tetrahedron 1997, 53, 3693; (g) Alberala, A.; Ortega, A.
CDCl3): d = 37.0 (CH3), 101, 103.5 (CBr). IR (KBr, cmꢀ1): m ¼ 2940
~
(w), 2862 (w), 2833 (w), 2664 (w), 1492 (m), 1451 (m), 1311 (m), 1079
(m), 988 (w), 861 (w).
12. General procedure for synthesis of 3,4-dibromo-2,5-diaryl-1-methylpyr-
roles: To a toluene solution (4 mL) of 1 (0.199 g, 0.5 mmol) was added
Pd(PPh3)4 (0.058 g, 10 mol %) at 20 °C under argon atmosphere. After
stirring for 30 min, the arylboronic acid (1.25 mmol), K3PO4
(4.0 mmol) and water (1.0 mL) were added. The mixture was stirred
under reflux for 24 h. After cooling to 20 °C, the mixture was diluted
with EtOAc, dried (Na2SO4), and filtered through a short Celite pad.
The solution was concentrated in vacuo and the residue was purified
by flash column chromatography (fine flash silica gel, n-heptane) and
subsequent chromatotron chromatography (Marrison Research, ser.
no. Y63, n-heptane). Synthesis of 3,4-dibromo-2,5-di(4-tolyl)-1-meth-
ylpyrrole (4c). Starting with 1 (0.199 g, 0.5 mmol) and 4-tolylboronic
acid (0.170 g, 1.25 mmol), 4c was isolated (0.166 g, 79%) as a
colourless solid, mp = 145–150 °C. 1H NMR (250 MHz, CDCl3):
´
G.; Sadaba, M. L.; Snudo, C. Tetrahedron 1999, 55, 6555; (h) Grigg,
R.; Savic, V. Chem. Commun. 2000, 873; (i) Trofimov, B. A.;
Tarasova, O. A.; Mikhaleva, A. I.; Kalinina, N. A.; Sinegovskaya, L.
M.; Henkelmann, J. Synthesis 2000, 11, 1585; (j) Nair, V.; Vinod, A.
U.; Rajesh, C. J. Org. Chem. 2001, 66, 4427; (k) Ranu, B. C.; Hajra,
A. Tetrahedron 2001, 57, 4767; (l) Lagu, B.; Pan, M.; Wachter, M. P.
Tetrahedron Lett. 2001, 42, 6027; (m) Quiclet-Sire, B.; Wendeborn, F.;
Zard, S. Z. Chem. Commun. 2002, 2214; (n) Demir, A. S.; Akhmedov,
3
d = 2.32 (s, 6H, 2CH3), 3.26 (s, 3H, CH3), 7.15, 7.20 (d, J = 8.2 Hz,
4H, Ar). 13C NMR (75 MHz, CDCl3): d = 21.3 (CH3), 34.5 (CH3),
100.0 (CBr), 129.3, 130.4 (CH, Ar), 128.8, 133.0, 138.8 (C). IR (KBr,
cmꢀ1): ~m ¼ 1920 (w), 1910 (w), 1549 (w), 1535 (w), 1493 (m), 1445 (w),
1318 (m), 1222 (w), 1114 (w), 1020 (w), 973 (w), 825 (m), 802 (m), 770
(w), 726 (w). MS (EI, 70 eV): m/z (%) = 421 (M+, [81Br,81Br], 50), 419
(M+, [81Br,79Br], 100), 417 (M+, [79Br,79Br], 52), 244 (11). HRMS
(EI, 70 eV): calcd for C19H17Br2N (M+, [79Br]): 416.9728; found:
416.99725. All products gave satisfactory spectroscopic data and
correct elemental analyses and/or high resolution mass data.
¨
I. M.; Sesenoglu, O. Tetrahedron 2002, 58, 9793; (o) Yoshida, M.;
Kitamura, M.; Narasaka, K. Bull. Chem. Soc. Jpn. 2003, 76, 2003; (p)
Knight, D. W.; Sharland, C. M. Synlett 2003, 2258; (q) Yu, M.;
Pagenkopf, B. L. Org. Lett. 2003, 5, 5099; (r) Dhawan, R.; Arndtsen,
B. A. J. Am. Chem. Soc. 2004, 126, 468; (s) Flo¨gel, O.; Reissig, H.-U.
Synlett 2004, 895; (t) Song, Z.; Reiner, J.; Zhao, K. Tetrahedron Lett.
2004, 45, 3953; (u) Chien, T-C.; Meade, E. A.; Hinkley, J. M.;
Townsend, L. B. Org. Lett. 2004, 6, 2857; (v) Ramanathan, B.; Keith,
A. J.; Armstrong, D.; Odom, A. L. Org. Lett. 2004, 6, 2957; (w)
Trofimov, B. A.; Zaitsev, A. B.; Schmidt, E. Y.; Vasil’tsov, A. M.;
Mikhaleva, A. I.; Ushakov, I. A.; Vashchenko, A. V.; Zorina, N. V.
Tetrahedron Lett. 2004, 45, 3789; (x) Agarwal, S.; Kno¨lker, H.-J. Org.
13. CCDC-671706 contains all crystallographic details of this publication
and is available free of charge at www.ccdc.cam.ac.uk/conts/retriev-
ing.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.