Regioselective Sonogashira reactions of N-methyltetrabromopyrrole: First synthesis of tri- and tetra(1-alkynyl)pyrroles

Article abstract of DOI:10.1055/s-0028-1087947

N-Methyl-2,3,4,5-tetrabromopyrrole is transformed into a variety of alkynyl-substituted pyrroles by regioselective Sonogashira cross-coupling reactions. In this context, the synthesis of the first tri- and tetra(1-alkynyl)pyrroles is reported. Georg Thiem

Full text of DOI:10.1055/s-0028-1087947

838
LETTER
Regioselective Sonogashira Reactions of N-Methyltetrabromopyrrole:
First Synthesis of Tri- and Tetra(1-alkynyl)pyrroles
First Synthesis
a
of
T
ri- and
r
T
etra(1
m
-
alkynyl)pyrroles an Ullah,a Tung T. Dang,b Joachim Heinicke,a Alexander Villinger,b Peter Langer*b,c
a
Institut für Biochemie, Universität Greifswald, Felix-Hausdorff-Str. 4, 17487 Greifswald, Germany
Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
Fax +49(381)4986412; E-mail: peter.langer@uni-rostock.de
b
c
Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
Received 11 November 2008
Sonogashira reactions of ethyl 2,3,4-tribromopyrrole-5-
carboxylate and of 2,3-dibromo-5-nitropyrrole.12 Recent-
ly, we reported the synthesis of aryl-substituted
thiophenes13 and pyrroles14 by Suzuki reactions of tetra-
bromothiophene and tetrabromo-N-methylpyrrole, re-
spectively. Herein, we disclose our preliminary results
related to what are, to the best of our knowledge, the first
Sonogashira cross-coupling reactions of tetrabromo-N-
methylpyrrole. These reactions allow a convenient syn-
thesis of a variety of novel alkynylated pyrroles. In this
context, we report what are, to the best of our knowledge,
the first syntheses of tri- and tetra(1-alkynyl)pyrroles.
Abstract: N-Methyl-2,3,4,5-tetrabromopyrrole is transformed into
a variety of alkynyl-substituted pyrroles by regioselective Sono-
gashira cross-coupling reactions. In this context, the synthesis of the
first tri- and tetra(1-alkynyl)pyrroles is reported.
Key words: catalysis, palladium, carbon–carbon bond formation,
regioselectivity, pyrroles
Hydrocarbons bearing multiple alkynyl groups have re-
ceived considerable attention, due to their interesting
physicochemical properties, as synthetic building blocks
of new and interesting arenes and because of their æsthet-
ic attraction (Figure 1).1 For example, Vollhardt and co-
workers reported the synthesis and characterization of
hexaethynylbenzene A and its application to the first syn-
thesis of the so-called archimedanes containing only ben-
zene and cyclobutane moieties.2 In contrast to their
hydrocarbon counterparts, multiply alkynylated heterocy-
cles are relatively rare. Whitesides et al. reported the syn-
S
N
R
thesis of tetra(1-alkynyl)thiophenes
B
based on
B
A
C
regioselective Sonogashira couplings of tetraiodo-
thiophene.3 Later, related reactions of tetrabro-
mothiophene were reported.4
Figure 1 Molecules with multiple alkynyl groups
Pyrroles constitute an important class of heterocycles
which are present in natural products (e.g., in the tetra-
pyrrole pigments porphobilinogen and bilirubin)5 and in
various synthetic drugs (e.g., zomepirac and atorvasta-
tin).6 Pyrroles and oligopyrroles show promising proper-
ties as new materials (e.g., as synthetic metals).7 In recent
years, syntheses of 2,5-8 and 3,4-di(1-alkynyl)pyrroles9
have been reported. These molecules have been used for
the synthesis of polymers and fused heterocycles. The
synthesis of tri- and tetra(1-alkynyl)pyrroles C has, to the
best of our knowledge, not been reported to date.
The reaction of N-methylpyrrole with N-bromosuccin-
imide (NBS) afforded tetrabromo-N-methylpyrrole (1).
The synthesis was carried out following the procedure of
Gilow and Burton,15 but with some variations (related to
the temperature, reaction time, and amount of NBS). No-
tably, we observed that it is crucial to isolate 1 in analyti-
cally pure form as colorless crystals. The oily form is
generally slightly impure, tends to be considerably less
stable and decomposes within a few days. The presence of
impurities results in a failure of Pd(0)-catalyzed cross-
coupling reactions. In contrast, the crystalline solid can be
stored under argon atmosphere at –18 °C (in the dark) for
a few weeks. Then, the compound starts to slightly darken
and it cannot be successfully used anymore in Pd(0)-
catalyzed reactions.
Heterocycles have been widely functionalized by palladi-
um(0)-catalyzed cross-coupling reactions.10 In recent
years, it has been shown that polyhalogenated heterocy-
cles may be regioselectively functionalized in such reac-
tions by selective activation of a single halogen atom – a
process which is controlled by electronic and steric pa-
rameters.11 Bach and Schröter reported regioselective
In general, the Sonogashira cross-coupling reactions re-
ported herein only proved to be possible when tetra-
bromo-N-methylpyrrole was employed. The employment
of benzyl-, carbamate-, and sulfonyl-protected tetra-
bromopyrroles was unsuccessful and resulted in the for-
mation of complex mixtures and decomposition. In most
of the Sonogashira reactions reported herein, the best
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Advanced online publication: 24.02.2009
DOI: 10.1055/s-0028-1087947; Art ID: G34708ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
First Synthesis of Tri- and Tetra(1-alkynyl)pyrroles
839
yields were obtained when (freshly prepared) the same time to avoid the formation of symmetrical 2,5-
PdCl2(MeCN)2 (10 mol%), CuI (10 mol%), Ph3P (20 di(alkynyl)pyrroles.
mol%), and (rigorously dried and freshly distilled) i-
The reaction of 1 with 2-methylbut-3-yn-2-ol and phenyl-
Pr2NH were employed. The yields dramatically decrease
acetylene (1.05 equiv each) and, subsequently, with phenyl-
when traces of water are present. The temperature and the
acetylene (1.05 equiv) afforded the 2,4,5-tri(1-alkynyl)-3-
bromopyrrole 4.
reaction time also proved to be important parameters (vide
infra). The yields of most products reported herein could
be slightly increased when 20 mol% rather than 10 mol%
of catalyst were employed. The best yields were generally
obtained for nonvolatile alkynes, due to the high reaction
temperatures.
Table 1 Synthesis of 2a–e
Entry
Compd 2
R1
Yield (%)a
1
2
3
4
5
2a
2b
2c
2d
2e
n-Pr
30
32
30
35
40
The Sonogashira reaction of 1 with various alkynes (1.1
equiv) regioselectively afforded the novel 5-(1-alkynyl)-
2,3,4-tribromopyrroles 2a–e (Scheme 1, Table 1).16,17 The
formation of a 4-(1-alkynyl)-2,3,5-tribromopyrrole was
not observed. The relatively low yields of 2a–e can be ex-
plained by the formation of considerable amounts of 2,5-
di(1-alkynyl)-3,4-dibromopyrroles. Therefore, it proved
to be important during the optimization to use not more
than 1.1 equivalents of the alkyne and to stir the solution
at 90 °C for not more than 1 hour. Stirring for 3 h resulted
in the formation of a mixture of 2,5-di(1-alkynyl)-3,4-di-
bromopyrroles and starting material 1. Likewise, the
yields of 2a–e decreased when the reactions were carried
out at temperatures lower than 90 °C. The yields could be
slightly increased when 20 mol% rather than 10 mol% of
catalyst were employed.
CMe2OH
(CH2)3OH
CH2CH(OH)Me
4-MeC6H4
a Yields of isolated products.
Table 2 Synthesis of 3a–e
Entry Compd 3 R1
R2
Yield of (%)a
1
2
3
4
5
3a
3b
3c
3d
3e
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
CMe2OH
CH2CH(OH)Me
(CH2)3OH
CMe2OH
n-Hex
40
40
44
41
37
The Sonogashira reaction of 1 with two different alkynes
(1.05 equiv each) afforded the unsymmetrical 2,5-(1-alkynyl)-
3,4-tribromopyrroles 3a–e (Scheme 1, Table 2).16,18 Dur-
ing the optimization, it proved to be important that
alkynes of considerably different reactivity were em-
ployed. In addition, it was crucial to add both alkynes at
n-Hex
a Yields of isolated products.
The Sonogashira reaction of 1 with 2.5 equivalents of var-
ious alkynes afforded the symmetrical 2,5-di(1-alkynyl)-
3,4-dibromopyrroles 5a–k in good yields and with very
good regioselectivity (Scheme 2, Table 3).16,19 Products
5a,b,d,g–k were obtained in good yields when the reac-
tion was carried out using PdCl2(MeCN)2, Ph3P and
HNi-Pr2 (procedure A). The best yields were obtained
when the reaction mixture was stirred at 100 °C for 6–8
hours. Longer and shorter reaction times resulted in a de-
crease in yield, due to decomposition and uncomplete
conversion, respectively. However, product 5b could be
isolated in equally good yield after stirring for only 3
hours when the reaction was carried out in an autoclave (at
90 °C). The yields of products 5a,b could be improved
when Pd(OAc)2, the novel ligand L20 and Cs2CO3 were
employed (procedure C). This method was also success-
fully applied to the synthesis of 5c,e,f. The yields of 5a,b,i
considerably decreased when the (freshly prepared) car-
bene-ligated catalyst 7 (5 mol%, Figure 2) was employed
(procedure B).
Br
Br
Br
Br
R1
Br
Br
Br
R1
N
Me
N
i
Me
1
2a–e
R1
R2
(see Table 1)
R1
R2
ii
iii
R2
Br
Br
Br
R1
R2
N
N
R1
R2
Me
Me
3a–e
(see Table 2)
4 (41%)
R1 = CMe2OH, R2 = Ph
Scheme 1 Synthesis of 2a–e, 3a–e, and 4. Reagents and conditions:
(i) 1 (1.0 equiv), R1C≡CH (1.2 equiv), PdCl2(MeCN)2 (10 mol%), CuI
(10 mol%), Ph3P (20 mol%), i-Pr2NH, 90 °C, 1 h; (ii) 1 (1.0 equiv),
R1C≡CH and R2C≡CH (1.05 equiv each, addition at the same time),
PdCl2(MeCN)2 (10 mol%), CuI (10 mol%), Ph3P (20 mol%), i-
Pr2NH, 90 °C, 6–8 h; (iii) 1) 1 (1.0 equiv), R1C≡CH and R2C≡CH
(1.05 equiv each, addition at the same time), PdCl2(MeCN)2 (10
mol%), CuI (10 mol%), Ph3P (20 mol%), i-Pr2NH, 100 °C, 6–8 h; 2)
R2C≡CH (1.05 equiv), 12–16 h.
The structure of 5b was independently confirmed by X-
ray crystal structure analysis (Figure 3).21
The Sonogashira reaction of 5a,b with 2-methylbut-3-yn-
2-ol (4.0 equiv) afforded the tetra(1-alkynyl)pyrroles 6a,b
containing two different types of alkynyl substituents.
Synlett 2009, No. 5, 838–842 © Thieme Stuttgart · New York

840
F. Ullah et al.
LETTER
Br
Br
Br
Br
Br
R
Br
i
N
N
R
R
Me
Me
1
5a–h
ii
(see Table 3)
Me
HO
Me
Me
Me
HO
Me
OH
Figure 3 ORTEP plot of 5b (50% probability level)
Me
2,4,5-Tri(1-alkynyl)-3-bromopyrroles 8a–e, containing
three identical alkynyl groups, were selectively prepared
by Sonogashira reaction of 1 with 3.3 equivalents of vari-
ous alkynes (Scheme 3, Table 4).16,22 The best yields were
obtained when the reaction mixture was stirred at 100 °C
for 12–16 hours. The success of these transformations re-
lies on the fact that the formation of the fourth carbon–
carbon bond is significantly slower than the formation of
the third one. In fact, no competing formation of a tetra(1-
alkynyl)pyrrole was observed.
N
R
R
Me
6a R = Ph 33%
6b R = 4-Tol 15%
Scheme 2 Synthesis of 5a–h and 6a,b. Reagents and conditions: (i)
procedure A: 1 (1.0 equiv), RC≡CH (2.5 equiv), PdCl2(MeCN)2 (10
mol%), CuI (10 mol%), Ph3P (20 mol%), i-Pr2NH, 100 °C, 6–8 h;
procedure B: 1 (1.0 equiv), 7 (5 mol%, structure see below), Ph3P (5
mol%), CuI (10 mol%), Cs2CO3 (1.5 equiv), DMF; procedure C:
Pd(OAc)2 (5 mol%), L (15 mol%), Cs2CO3 (3.0 equiv), MeCN, re-
flux, 6 h; (ii) 5a,b (1.0 equiv), RC≡CH (4.0 equiv), PdCl2(MeCN)2
(10 mol%), CuI (10 mol%), Ph3P (20 mol%), i-Pr2NH, 100 °C, 20 h.
R
Br
Br
Br
R
CO2Me
Me
Br
Br
i
N
N
R
R
Cl
Pd
Cl
N
Me
PCy2
i-Pr
N
Me
Cy = cyclohexyl
L =
i-Pr
1
8a–e
N
N
(see Table 4)
Me
7
MeO2C
Scheme 3 Synthesis of 8a–e. Reagents and conditions: (i) 1 (1.0
equiv), RC≡CH (3.3 equiv), PdCl2(MeCN)2 (10 mol%), CuI (10
mol%), Ph3P (20 mol%), i-Pr2NH, 100 °C, 12–16 h.
i-Pr
Figure 2
Table 4 Products and Yields
Table 3 Synthesis of 5a–h
Entry Compd 5 Ar
Yield (%)a
Yield (%)a
Entry
Compd 8
R
1
2
3
4
5
8a
8b
8c
8d
8e
Ph
36
42
40
40
44
Procedure
A
B
C
4-MeC6H4
CMe2OH
(CH2)3OH
CH2CH(OH)Me
1
2
5a
5b
5c
5d
5e
5f
Ph
59
71
17
19
84
79
47
4-MeC6H4
4-FC6H4
n-Pr
3
a Yields of isolated products.
4
45
5
n-Pent
n-Oct
67
72
Tetra(1-alkynyl)pyrroles 9a and 9b, containing four iden-
tical alkynyl groups, were prepared by reaction of 1 with
an excess (6.0 equiv) of phenylacetylene and 4-tolylacet-
ylene, respectively (Scheme 4).16,23 The best yields were
obtained when the reaction mixture was stirred at 100 °C
for 20 hours. Although the yields of 9a,b are relatively
low, it should be taken into account that four carbon–
carbon bonds are formed in one reaction. A theoretical
yield of 71% for each C–C bond formation would result in
a 25% overall yield. Notably, products derived from
alkyl-substituted alkynes proved to be rather unstable and
could not be isolated in pure form. We have not yet tried
to prepare the unsubstituted parent compound, tetraethy-
6
7
5g
5h
5i
n-Undec
(CH2)3OH
65
61
70
74
67
8
9
CH2CH(OH)Me
CMe2OH
TMS
15
10
11
5j
5k
a Yields of isolated products using procedures A, B, and C (see
Scheme 2).
Synlett 2009, No. 5, 838–842 © Thieme Stuttgart · New York

LETTER
First Synthesis of Tri- and Tetra(1-alkynyl)pyrroles
841
Springer: Vienna, 1989, 355. (e) Montforts, F.-P.;
R
R
Schwartz, U. M. Angew. Chem., Int. Ed. Engl. 1985, 24,
775. (f) Dutton, C. J.; Fookes, C. J. R.; Battersby, A. R.
J. Chem. Soc., Chem. Commun. 1983, 1237. (g) Stork, G.;
Nakahara, Y.; Nakahara, Y.; Greenlee, W. J. J. Am. Chem.
Soc. 1978, 100, 7775. (h) Stork, G.; Nakamura, E. J. Am.
Chem. Soc. 1983, 105, 5510. (i) For a review of pyrrole-
imidazole alkaloids, see: Hoffmann, H.; Lindel, T. Synthesis
2003, 1753.
Br
Br
R
i
Br
N
Br
N
R
R
Me
Me
1
9a R = Ph 25%
9b R = 4-Tol 32%
(6) (a) Huisgen, R.; Gotthard, H.; Bayer, H. O.; Schäfer, 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. G.; Sádaba, 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, 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, I. M.; Sesenoglu, 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) Flögel, 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.; Knölker, H.-J. Org. 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.
Scheme 4 Synthesis of 9a,b. Reagents and conditions: (i) 1 (1.0
equiv), RC≡CH (6.0 equiv), PdCl2(MeCN)2 (10 mol%), CuI (10
mol%), Ph3P (20 mol%), i-Pr2NH, 100 °C, 20 h.
nyl-N-methylpyrrole, as its thiophene analogue has been
reported to be highly explosive.3
In conclusion, we have studied the synthesis of a variety
of alkynyl-substituted pyrroles based on the first regio-
selective Sonogashira cross-coupling reactions of tetra-
bromo-N-methylpyrrole (1). In this context, the synthesis
of what are, to the best of our knowledge, the first tri- and
tetra(1-alkynyl)pyrroles has been reported. The Sono-
gashira reactions of 1 first occur at carbon atoms C2 and
C5 which are more electron deficient than C3 and C4. In
fact, the formation of 2,5-di(1-alkynyl)pyrroles is rela-
tively fast. Therefore, the best yields were obtained for the
synthesis of symmetrical di(alkynyl)pyrroles 5. In con-
trast, the synthesis of the monoalkynylated pyrroles 2 was
more difficult and required a thorough optimization of the
reaction time. Unsymmetrical di(alkynyl)pyrroles 3 could
be directly prepared from 1 when two alkynes of different
reactivity were employed and added at the same time. The
first tri(1-alkynyl)pyrroles were prepared. Their success-
ful synthesis relies on the fact that the formation of the
fourth carbon–carbon bond is significantly slower than
the formation of the third one. Finally, we reported the
synthesis of what are, to the best of our knowledge, the
first tetra(1-alkynyl)pyrroles.
Acknowledgment
Financial support by the State of Vietnam (MOET scholarship for
T.T.D.) is gratefully acknowledged.
(7) Reviews: (a) Bäuerle, P. Adv. Mater. 1993, 5, 879.
(b) Tour, J.-M. Chem. Rev. 1996, 96, 537. (c) Roncali, J.
Chem. Rev. 1992, 92, 711.
(8) (a) Yasuda, T.; Imase, T.; Nakamura, Y.; Yamamoto, T.
Macromolecules 2005, 38, 4687. (b) Ono, N.; Yamamoto,
T.; Shimada, N.; Kuroki, K.; Wada, M.; Utsunomiya, R.;
Yano, T.; Uno, H.; Murashima, T. Heterocycles 2003, 61,
433.
(9) (a) Alvarez, A.; Guzman, A.; Ruiz, A.; Velarde, E.;
Muchowski, J. M. J. Org. Chem. 1992, 57, 1653. (b) Liu,
J.-H.; Chan, H.-W.; Wong, H. N. C. J. Org. Chem. 2000, 65,
3274. (c) Sugihara, Y.; Miyatake, R.; Murata, I.; Imamura,
A. J. Chem. Soc., Chem. Commun. 1995, 1249.
(10) Reviews: (a) Li, J. J.; Gribble, G. W. Palladium in
Heterocyclic Chemistry; Pergamon Press: Oxford, 2000.
(b) Kalinin, V. N. Synthesis 1992, 413.
(11) Review: Schröter, S.; Stock, C.; Bach, T. Tetrahedron 2005,
61, 2245.
References and Notes
(1) Classics in Hydrocarbon Chemistry; Hopf, H., Ed.; Wiley-
VCH: Weinheim, 2000, Chap. 15, and references cited
therein.
(2) Diercks, R.; Armstrong, J. C.; Boese, R.; Vollhardt, K. P. C.
Angew. Chem., Int. Ed. Engl. 1986, 25, 268.
(3) Neenan, T. X.; Whitesides, G. M. J. Org. Chem. 1988, 53,
2489.
(4) Eichhorn, S. H.; Paraskos, A. J.; Kishikawa, K.; Swager,
T. M. J. Am. Chem. Soc. 2002, 124, 12742.
(5) (a) Sundberg, R. J. In Comprehensive Heterocyclic
Chemistry, Vol. 4; Bird, C. W.; Cheeseman, G. W. H., Eds.;
Pergamon Press: Oxford, 1984, 331. (b) Gribble, G. W.
Comprehensive Heterocyclic Chemistry II, Vol. 2;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Elsevier: Oxford, 1996, 207. (c) Bean, G. P. Pyrroles;
Jones, R. A., Ed.; Wiley: New York, 1990, 105. (d)Falk,H.
The Chemistry of Linear Oligopyrroles and Bile Pigments;
(12) Schröter, S.; Bach, T. Synlett 2005, 1957.
(13) Dang, T. T.; Rasool, N.; Dang, T. T.; Reinke, H.; Langer, P.
Tetrahedron Lett. 2007, 48, 845.
Synlett 2009, No. 5, 838–842 © Thieme Stuttgart · New York

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F. Ullah et al.
LETTER
(14) Dang, T. T.; Dang, T. T.; Ahmad, R.; Reinke, H.; Langer, P.
Tetrahedron Lett. 2008, 49, 1698.
(19) Synthesis of 5b
Procedure A16
(15) Gilow, H. M.; Burton, D. E. J. Org. Chem. 1981, 46, 2221.
(16) General Procedure for Sonogashira Reactions
Tetrabromo-N-methylpyrrole (1, 750 mg, 1.87 mmol), Ph3P
(98 mg, 20 mol%), PdCl2 (MeCN)2 (49 mg, 10 mol%), and
CuI (36 mg, 10 mol%) were added to an oven-dried Schlenk
flask, evacuated for 10 min, and then flushed with argon. To
the mixture was added thoroughly dried, freshly distilled and
oxygen-free diisopropylamine (20 mL). The clear yellow
solution was stirred for 15 min at 20 °C for the generation of
the catalyst. The solution was subsequently cooled to 0 °C,
and the alkyne was dropwise added by syringe. The solution
was stirred for 1 h at 0 °C and for 3 h at 20 °C. The dark
brown mixture was heated at 90 °C. The solution was
allowed to cool to ambient temperature, filtered, and the
filtrate was concentrated in vacuo. To the residue was added
CH2Cl2, and the solution was extracted with H2O. The
combined organic layers were dried (MgSO4), filtered, and
the filtrate was concentrated in vacuo. The residue was
purified by column chromatography (neutral silica gel,
n-hexane). For the synthesis of products 3, the two alkynes
were added at the same time.
Starting with 1 (750 mg, 1.87 mmol) and p-tolylacetylene
(0.6 mL, 4.67 mmol), 5b (620 mg, 71%) was isolated as a
white solid. 1H NMR (250 MHz, CDCl3): d = 2.36 (s, 6 H,
CH3, p-tolyl), 3.77 (s, 3 H, NCH3), 7.14 (d, 3J = 8.1 Hz, 4 H,
p-tolyl), 7.56 (d, 3J = 8.1 Hz, 4 H, p-tolyl). 13C NMR (62.8
MHz, CDCl3): d = 21.6 (CH3, p-tolyl), 34.6 (NCH3), 77.9
(C≡C), 97.7 (C, pyrrole), 104.1 (C≡C), 117.9 (C, pyrrole),
119.1 (C, p-tolyl), 129.2 (CH, p-tolyl), 131.3 (CH, p-tolyl),
139.1 (C, p-tolyl). IR (KBr): 3435 (br, m), 3023 (m), 2717
(s), 2206 (w), 1537 (s), 1441 (s), 1377 (s), 1345 (s), 817 (s),
809 (8 s), 535 (s), 520 (s) cm–1. MS (EI, 70 eV, 320 °C):
m/z (%) = 465.6 (51) [M+, 79Br, 79Br], 403 (16), 306.5 (10),
292.5 (14), 277 (42). HRMS: m/z calcd for C23H17Br2N:
464.97223; found: 464.97163.
(20) Billingsley, K.; Buchwald, S. L. J. Am. Chem. Soc. 2007,
129, 3358; and references cited therein.
(21) CCDC-689251 contains 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)336033; or
(17) Synthesis of 2a
Starting with 1 (500 mg, 1.25 mmol) and 2-pentyne (1.3
mmol), 2a was isolated (134 mg, 30%) as a brownish highly
viscous oil. 1H NMR (250 MHz, CDCl3): d = 1.06 (t, 3J = 7.5
Hz, 3 H, Me), 1.64 (sext, 3J = 7.2 Hz, 2 H, CH2), 2.47 (t,
3J = 7.0 Hz, 2 H, CH2), 3.64 (s, 3 H, NCH3). 13C NMR (62.8
MHz, CDCl3): d = 13.5 (CH3), 21.6, 22.0 (CH2), 35.6
(NCH3), 70.1, 98.8 (C≡C), 100.4, 102.93, 104.19, 118.34 (C,
pyrrole). IR (KBr): 3436 (br, s), 2958 (s), 2932 (m), 2872
(m), 2228 (w), 1717 (m), 1529 (m), 1456 (s), 1431 (m), 1378
(m), 1330 (s), 1092 (m) cm–1. MS (EI, 70 eV, 85 °C): m/z
(%) = 381 (19) [M+, 79Br, 79Br, 79Br], 356 (67), 354 (58), 275
(14), 224 (54), 194 (60), 115 (100). HRMS: m/z calcd for
C10H10Br3N [M+, 79Br, 79Br, 79Br]: 380.83579; found:
380.83501.
deposit@ccdc.cam.ac.uk.
(22) Synthesis of 8c
Starting with 1 (500 mg, 1.25 mmol) and 2-methyl-3-
pentyne-2-ol (0.4 mL, 4.12 mmol), 8c was isolated (198 mg,
40%) as a brownish solid. 1H NMR (250 MHz, DMSO-d6):
d = 1.45, (s, 12 H, 4 CH3), 1.48 (s, 6 H, 2 CH3), 3.60 (s, 3 H,
NCH3), 5.42, 5.60, 5.61 (3 s, 3 OH). 13C NMR (62.8 MHz,
DMSO-d6): d = 31.35, 31.38, 31.8, (6 CH3), 33.8 (NCH3),
63.8, 63.9, (C, CMe2OH), 69.8, 70.0, 72.4, (C≡C), 100.1,
102.6, 103.7 (C, pyrrole), 104.1, 110.0 (C≡C), 116.8 (C,
pyrrole), 119.9 (C, pyrrole). IR (KBr): 3435 (br, s), 2980 (s),
2933 (s), 2226 (w), 1634 (m), 1452 (m), 1374 (s), 1374 (s),
1238 (s), 1164 (s), 1137 (s), 989 (w), 938 (s), 939 (m), 892
(w), 841 (m) cm–1. MS (EI, 70 eV, 130 °C): m/z (%) = 405
(99) [M+, 79Br], 403 (16), 390 (14), 388 (28), 374 (65), 372
(71), 278 (40), 235 (23). HRMS: m/z calcd for C20H24BrNO3
[M+, 79Br]: 405.09341; found: 405.09328.
(18) Synthesis of 3c
Starting with 1 (500 mg, 1.25 mmol), 2-methyl-3-pentyne-2-
ol (1.3 mmol), and p-tolylacetylene (1.3 mmol), 3c was
isolated (238 mg, 44%) as a red to brown solid. 1H NMR
(250 MHz, CDCl3): d = 1.65 (s, 6 H, CH3), 2.36 (s, 3 H, Me-
tolyl), 3.72 (s, 3 H, CH3), 7.16 (d, 3J = 8.1 Hz, 2 H, tolyl),
7.43 (d, 3J = 8.1 Hz, 2 H, tolyl). 13C NMR (62.8 MHz,
CDCl3): d = 21.6 (CH3, tolyl), 31.3 (CH3), 34.4 (NCH3),
65.9 (C, CMe2OH), 71.7, 71,6 (C≡C), 97.5, 97.7 (C,
pyrrole), 102.2, 103.9 (C≡C), 116.9, 117.9 (C, pyrrole),
119.1, 131.4 (CH, p-tolyl), 139.2 (C, p-tolyl). IR (KBr):
3324 (br, s), 2983 (s), 2929 (s), 2865 (w), 2249 (m), 1906
(w), 1728 (s), 1534 (m), 1509 (m), 1440 (s), 1232 (s), 1160
(br, s), 910 (s), 815 (s), 730 (br, s) cm–1. MS (EI, 70 eV,
110 °C): m/z (%) = 433 (49) [M+, 79Br, 79Br], 418 (40) [M+ –
CH3, 79Br, 79Br], 417 (11), 405 (17), 377 (18), 356 (15)
[M+ – 79Br].
(23) Synthesis of 9a.
Starting with 1 (500 mg, 1.25 mmol) and phenylacetylene
(0.82 mL, 7.5 mmol), 9a was isolated (150 mg, 25%) as an
orange-red oil. 1H NMR (250 MHz, CDCl3): d = 3.81 (s, 3
H, NCH3), 7.32 (br s, 4 H, Ph), 7.35 (m, 8 H, Ph), 7.56 (m, 8
H, Ph). 13C NMR (62.8 MHz, CDCl3): d = 33.8 (NCH3),
79.2, 82.3, 94.3 (C≡C), 112.7 (C, pyrrole), 120.6 (C,
pyrrole), 122.5 (C, Ph), 123.9 (C, Ph), 127.9, 128.3, 128.46,
128.7, 131.46, 131.52 (CH, Ph). IR (KBr): 3435 (m), 3058
(w), 2959 (s), 2927 (s), 2871 (m), 2204 (s), 1728 (s), 1597
(s), 1478 (s), 1454 (s), 1376 (m), 1255 (m), 1067 (m), 910
(m), 754 (s), 688 (s) cm–1. MS (EI, 70 eV, 85 °C): m/z
(%) = 482 (10), 481 (39) [M+], 480 (100), 476 (6), 401 (4),
338 (6), 239 (22), 230 (2). HRMS: m/z calcd for C37H23N;
481.18301; found: 481.18276.
Synlett 2009, No. 5, 838–842 © Thieme Stuttgart · New York

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