Direct arylation of pyrrole derivatives in superbasic media

Article abstract of DOI:10.1055/s-0030-1260128

Direct arylation of N-alkyl- and N-arylpyrroles with aryl iodides can be performed in superbasic media, without external addition of a transition-metal catalyst. Lithium hydroxide in dimethyl sulfoxide promotes this reaction in a regioselective manner, le

Full text of DOI:10.1055/s-0030-1260128

PAPER
2833
Direct Arylation of Pyrrole Derivatives in Superbasic Media
D
irec
t
A
rylation o
l
f
P
yrrol
e
e
D
erivativ
n
es in Superb
a
a
sic Media Vakuliuk,a,b Beata Koszarna,a Daniel T. Gryko*a,b
a
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland
Fax +48(22)3432036; E-mail: daniel@icho.edu.pl
b
Received 29 April 2011; revised 10 June 2011
vate-separated ion pairs, with active anions, dominate in
such systems.
Abstract: Direct arylation of N-alkyl- and N-arylpyrroles with aryl
iodides can be performed in superbasic media, without external ad-
dition of a transition-metal catalyst. Lithium hydroxide in dimethyl
sulfoxide promotes this reaction in a regioselective manner, leading
to the expected 2-arylated products in good yield.
Thus, we wondered if known superbasic media can pro-
mote a reaction between N-methylpyrrole (1) and 4-iodo-
benzonitrile (2), leading to the formation of a
heteroarylated product 3 (Scheme 1). Initially, our focus
was aimed on the use of simple inorganic bases, such as
lithium hydroxide, sodium hydroxide, and potassium
hydroxide in N,N-dimethylformamide (in analogy to
t-BuOLi in DMF). Among the screened bases, lithium
hydroxide showed the highest efficiency (Table 1, entries
1–3).
Key words: pyrrole, heterocycles, C–C coupling, C–H activation,
aryl halides
Direct arylation of aromatic heterocycles continues to at-
tract the attention of synthetic chemists as a more conve-
nient alternative to classical methods for the construction
of biaryl linkages.1 Most published protocols are cata-
lyzed by transition-metal salts; however, recently, a num-
ber of metal-free protocols have been reported.2
I
base, additive
+
solvent
N
N
NC
Although the use of pyrroles and their derivatives in
cross-coupling reactions is relatively rare in comparison
to indole3 and thiophene,4 these compounds are very valu-
able building blocks for the synthesis of more complex
compounds with important properties.5 In spite of the re-
markable progress achieved in direct arylation, research
focused on the exploration of new, inexpensive, and effi-
cient methods for the formation of arylated products is
still necessary. Over the past few years, several research
groups have investigated the formation of pyrrole–aryl
linkages.6 Recently, we reported that catalysts containing
transition metals are not necessary to perform direct ary-
lation of electron-rich heterocycles with aryl iodides and
bromides.7 Lithium tert-butoxide in N,N-dimethylform-
amide promotes this reaction for variety of N-alkyl- and
N-arylpyrroles, as well as for benzofuran and some other
electron-rich aromatic compounds, and provides the de-
sired products at moderate to high yields.
CN
Me
1
Me
2
3
Scheme 1
Interestingly, DMSO is also known to form complexes
with lithium hydroxide,8a,c and use of dimethyl sulfoxide
as a reaction medium resulted in increase in the yield of
product 3 to 73% (Table 1, entry 4). Surprisingly, in con-
trast to lithium tert-butoxide,7 it was noticed that in the
case of lithium hydroxide there was no need to prepare a
base solution prior to use (Table 1, entry 5). The reactivity
of hydroxideanions may also depend on the number of as-
sociated water molecules in the media, and based on our
experimental data, the presence of increasing amounts of
water in the reaction mixture results in decreasing yields
of product 3 (Table 1, entries 6–8).
Pyrroles bearing electron-donating groups on their nitro-
gen are relatively sensitive to the presence of oxidants,
which could cause oxidation of the pyrrole core.11 Be-
cause of this, we were interested in determining if the
presence of dissolved oxygen in dimethyl sulfoxide inhib-
its the formation of the desired arylated product. When
dimethyl sulfoxide was first degassed under a stream of
argon for 10 minutes before use, compound 3 was ob-
tained in 83% yield (Table 1, entry 9). Subsequently the
effect of the amount of base was analyzed (Table 1, en-
tries 10 and 11). The apparent need for excess lithium hy-
droxide may be explained by its incomplete solubility in
organic solvent.
Intriguingly, we found that the reaction outcome strongly
depended on the use of a pre-prepared solution of lithium
tert-butoxide in N,N-dimethylformamide. Lithium cations
have a well-known tendency to associate with chelating or
chiral diamines, as well as organic solvents (DMF,
DMSO),8 and such donor-acceptor systems are of interest
in modern organic chemistry. For example, the successful
use of alkali metal hydroxide–dimethyl sulfoxide,9 to-
gether with other super bases,10 has been reported. Sol-
SYNTHESIS 2011, No. 17, pp 2833–2837
Advanced online publication: 20.07.2011
DOI: 10.1055/s-0030-1260128; Art ID: Z46011SS
x
x.
x
x
.
2
0
1
1
Recently, an efficient, organocatalyzed protocol for the
direct arylation of benzene was described.12 Inspired by
© Georg Thieme Verlag Stuttgart · New York

2834
O. Vakuliuk et al.
PAPER
Table 1 Influence of the Reaction Conditions on the Coupling of N- entry 17), reactions conducted at 145 °C were complete
Methylpyrrole (1) with 4-Iodobenzonitrile (2)a
after only five hours (Table 1, entry 18).
Entrya
1
Base
Solvent
Yield (%) of 3
Optimum reaction conditions were chosen based on the
above results. A fresh solution of lithium hydroxide in de-
gassed dimethyl sulfoxide was found to be the most effi-
cient combination among all of the tested reaction
systems, giving 83% of the expected product 3. These op-
timal reaction conditions were also confirmed in prepara-
tive reactions conducted on a 1 mmol scale.
KOH
DMF
27
36
65
73
74
34
67
65–71
83
49
82
44
70
61
14
43
37
75
2
NaOH
LiOH
DMF
3
DMF
4
LiOH
DMSO
Using these new conditions as a starting point, the scope
and limitations of the reaction were investigated. N-Meth-
ylpyrrole, together with N-phenyl- and N-benzylpyrrole,
were reacted with a range of aryl iodides bearing electron-
withdrawing groups, giving corresponding products in
good yields (50–86%). 1-Iodo-4-methoxybenzene (11)
showed lower reactivity, resulting in the formation of the
5
LiOH
DMSO (fresh soln)
DMSO (wet)
DMSO
6
LiOH
7
LiOH·H2O
LiOH
8b
DMSO
9
LiOH
DMSO (degassed)
DMSO
corresponding
N-methyl-2-(4-methoxyphenyl)pyrrole
(17) in only 26% yield (Table 2).
10
11
12c
13d
14e
15f
16g
17h
18i
LiOH (1 equiv)
LiOH (4 equiv)
LiOH
DMSO
Table 2 Scope of the Optimized Conditions for the Arylation of
Pyrrole Derivativesa
DMSO
I
LiOH
DMSO
LiOH, DMSO
R2
+
R2
N
R1
N
R1
145 °C, overnight
LiOH
DMSO
LiOH
DMSO
Pyrrole R1
Aryl iodide
R2
Product Yield (%)b
LiOH
DMSO
1
1
1
1
1
1
1
4
5
Me
Me
Me
Me
Me
Me
Me
Ph
2
6
7
8
9
4-CN
4-NO2
3-CN
3-NO2
2-CN
2-NO2
4-MeO
4-CN
4-CN
3
78
69
72
77
86
72
26
54
50
LiOH
DMSO
12
13
14
15
16
17
18
19
LiOH
DMSO
a Unless otherwise noted, reactions were performed under the follow-
ing conditions: 4-iodobenzonitrile (1 equiv), N-methylpyrrole (15
equiv), base (2 equiv), 145 °C, overnight; yields were determined by
HPLC.
b Reactions were performed with the addition of increasing amounts
of H2O (1–5 equiv).
10
11
2
c Reaction was performed with the addition of 20 mol% L-proline.
d Reaction was performed with the addition of 20 mol% DMEDA.
e Reaction was performed with the addition of 20 mol% TMEDA.
f For 5 equiv of N-methylpyrrole.
Bn
2
g For 10 equiv of N-methylpyrrole.
h Reaction was performed at 100 °C.
a Reactions were performed under the following conditions: aryl io-
dide (1 equiv), N-substituted pyrroles (15 equiv), LiOH (4 equiv),
DMSO.
i Yield was recorded after 5 h.
b Yields of isolated products after column chromatography.
these results, we decided to investigate the effect of L-pro-
line, N,N¢-dimethylethane-1,2-diamine (DMEDA), and
N,N,N¢,N¢-tetramethylethylenediamine (TMEDA) on the
formation of compound 3. As can be seen (Table 1, entries
12–14), these bases system do not appear to participate in
the lithium hydroxide–dimethyl sulfoxide promoted
transformation reaction.
In contrast with the lithium tert-butoxide promoted sys-
tem,7 under the current protocol, bromides display lower
reactivity than iodides. For example, in the reaction be-
tween 4-bromobenzonitrile (20), and N-methylpyrrole
(1), the desired product 3 was obtained in only 49% yield.
Similarly, as expected, 4-chlorobenzonitrile (21) gave
only 20% of the corresponding product.
In agreement with our observations of lithium tert-butox-
ide promoted arylation, decreasing the ratio of N-meth-
ylpyrrole to 4-iodobenzonitrile led to a sharp decrease in
the yield of compound 3 (Table 1, entries 15 and 16). The
influence of other factors, such as time and temperature,
were also investigated. While lowering the reaction tem-
perature to 100 °C resulted in decreased yield (Table 1,
Unfortunately, pyrrole itself, as well as N-TIPS-pyrrole
and N-benzoylpyrrole, could not be transformed into their
corresponding products under these reaction conditions.
In order to further clarify the reaction mechanism, N-sub-
stituted pyrrole was reacted with iodoarene in the pres-
Synthesis 2011, No. 17, 2833–2837 © Thieme Stuttgart · New York

PAPER
Direct Arylation of Pyrrole Derivatives in Superbasic Media
2835
duced pressure. Finally, reaction products were purified by column
chromatography (Table 2).
ence of a radical scavenger. Reaction between N-
phenylpyrrole and 4-iodobenzonitrile was completely in-
hibited in the presence of TEMPO (2,2,6,6-tetramethylpi-
peridine-1-oxyl).
N-Methyl-2-(4-cyanophenyl)pyrrole (3)
Reaction of N-methylpyrrole (1; 800 mL, 9 mmol) with 4-iodoben-
zonitrile (2; 137 mg, 0.6 mmol) was performed following the above
general procedure. The product was further purified by column
chromatography (silica gel, Et2O–hexanes, 1:9); fine white crystals;
yield: 85 mg (78%); mp 102 °C (Et2O–pentane) (Lit.7 mp 102–103
°C).
We could not exclude the possibility that trace amounts of
transition metal salts in lithium hydroxide are responsible
for catalyzing the above described transformation.13 The
presence of impurities in lithium hydroxide was examined
by inductively coupled plasma-atomic emission spec-
trometry (ICP-AES, see Table in SI). These results clearly
show that the concentrations of most of transition metals
(Pd, Fe, Cu, Rh, and Ru) were in the range of 0.1–0.2 ppm.
Among metals, which are known to be able to catalyze
Spectral properties concur with the published data.7
N-Methyl-2-(4-nitrophenyl)pyrrole (12)
Reaction of N-methylpyrrole (1; 800 mL, 9 mmol) with 1-iodo-4-ni-
trobenzene (6; 149.4 mg, 0.6 mmol) was performed following the
such coupling reactions, only nickel was present at a level above general procedure. The product was further purified by col-
umn chromatography (silica gel, Et2O–hexanes, 1:9); fine yellow
of 7 ppm; furthermore, experiments testing the addition of
crystals; yield: 84 mg (69%); mp 115–116 °C (CH2Cl2) (Lit.7 mp
114–115 °C).
Spectral properties concur with the published data.7
nickel, palladium, copper, or iron salts to the model reac-
tion did not improve the yield of product 3. In addition, no
difference was observed when the model reaction was
performed in brand-new glassware. Still, in view of the
fundamental study by Leadbeater, which demonstrated
N-Methyl-2-(3-cyanophenyl)pyrrole (13)
Reaction of N-methylpyrrole (1; 800 mL, 9 mmol) with 3-iodoben-
zonitrile (7; 137 mg, 0.6 mmol) was performed following the above
that Suzuki coupling is catalyzed by palladium present in
sodium carbonate at only 50 ppb,13b we cannot definitive-
general procedure. The product was further purified by column
ly conclude that the process studied here is metal-free.
However, ever to minimize the likelihood of contamina-
tion, all reaction glassware were exhaustively cleaned
prior to use.
chromatography (silica gel, Et2O–hexanes, 1:9); fine white crystals;
yield: 79 mg (72%); mp 113 °C (Et2O–pentane) (Lit.7 mp 112–113
°C).
Spectral properties concur with the published data.7
In summary, we have demonstrated that direct arylation of
pyrrole derivatives bearing N-alkyl and N-aryl substitu-
ents with aryl iodides can be promoted using a lithium hy-
droxide–dimethyl sulfoxide system, which is known for
its superbasic properties. The corresponding 2-arylated
products were prepared in good yields, and with high re-
gioselectivity. Based on our results, we propose that the
reaction proceeds via a radical type mechanism. Taking
into consideration the absence of a transition-metal cata-
lyst, the applied base, and substrate availability, the above
described methodology may be useful for the synthesis of
aromatic compounds.
N-Methyl-2-(3-nitrophenyl)pyrrole (14)
Reaction of N-methylpyrrole (1; 800 mL, 9 mmol) with 1-iodo-3-ni-
trobenzene (8; 149.4 mg, 0.6 mmol) was performed following the
above general procedure. The product was further purified by col-
umn chromatography (silica gel, Et2O–hexanes, 1:9); fine yellow
crystals; yield: 93 mg (77%); mp 118–109 °C (CH2Cl2–hexanes)
(Lit.7 mp 118.5–119.5 °C).
Spectral properties concur with the published data.7
N-Methyl-2-(2-cyanophenyl)pyrrole (15)
Reaction of N-methylpyrrole (1; 800 mL, 9 mmol) with 2-iodoben-
zonitrile (9; 137 mg, 0.6 mmol) was performed following the above
general procedure. The product was further purified by column
chromatography (silica gel, Et2O–hexanes, 1:9); fine white crystals;
yield: 94 mg (86%); mp 83 °C (Et2O–pentane) (Lit.7 mp 83–84 °C).
All reagents and solvents were purchased from commercial sources
and were used as received, unless otherwise noted. Flash chroma-
Spectral properties concur with published data.7
tography was performed on silica gel (200–400 mesh). 1H and 13
C
N-Methyl-2-(2-nitrophenyl)pyrrole (16)
NMR spectra were measured on a Bruker AV 400 or a Bruker AV
500 spectrometer. All chemical shifts are reported in ppm. Mass
spectra were obtained via EI-MS or ESI-MS. The optimization
study was performed by HPLC (samples were prefiltered through a
silica pad).
Reaction of N-methylpyrrole (1; 800 mL, 9 mmol) with 1-iodo-2-ni-
trobenzene (10; 149.4 mg, 0.6 mmol) was performed following the
above general procedure. The product was further purified by col-
umn chromatography (silica gel, Et2O–hexanes, 1:9); fine yellow
crystals; yield: 87 mg (72%); mp 62–63 °C (CH2Cl2–hexanes) (Lit.7
mp 62–63 °C).
‘Aged’ Solution of LiOH in DMSO
LiOH (240 mg, 10 mmol) was dissolved in anhyd DMSO (6.25 mL)
and the resulting mixture was stirred at 80 °C overnight. Subse-
quently, the mixture was cooled down and used for the final
coupling reactions. The resulting base solution was stored for 12 h
before use.
Spectral properties concur with the published data.7
N-Methyl-2-(4-methoxyphenyl)pyrrole (17)
Reaction of N-methylpyrrole (1; 800 mL, 9 mmol) with 1-iodo-4-
methoxybenzene (11; 140.4 mg, 0.6 mmol) was performed follow-
ing the above general procedure. The product was further purified
by column chromatography (silica gel, Et2O–hexanes, 5:95), fine
white crystals; yield: 29 mg (26%); mp 58 °C (Et2O–pentane) (Lit.7
mp 59–60 °C).
Arylation of Pyrrole Derivatives; General Procedure
Aryl iodide (0.6 mmol, 1 equiv), LiOH (2.4 mmol, 4 equiv), pyrrole
(9 mmol, 15 equiv), and DMSO (250 mL) were placed in a glass
tube, and flushed with argon. The resulting reaction mixture was
stirred at 145 °C overnight, and subsequently evaporated under re-
Spectral properties concur with published data.7
Synthesis 2011, No. 17, 2833–2837 © Thieme Stuttgart · New York

2836
O. Vakuliuk et al.
PAPER
N-Phenyl-2-(4-cyanophenyl)pyrrole (18)
2006, 1379. (c) Lebrasseur, N.; Larrosa, I. J. Am. Chem. Soc.
2008, 130, 2926. (d) Kozikowski, A. P.; Ma, D.
Reaction of N-phenylpyrrole (4; 1.29 g, 9 mmol) with 4-iodoben-
zonitrile (2; 137 mg, 0.6 mmol) was performed following the above
general procedure. The product was further purified by column
chromatography (silica gel, Et2O–hexanes, 5:95); fine crystals;
yield: 82 mg (82%); mp 125–126 °C (Et2O–pentane) (Lit.7 mp 124–
125 °C).
Tetrahedron Lett. 1991, 32, 3317. (e) Fagnou, K.; Lautens,
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Chem. 2008, 73, 5529. (i) Yanagisawa, S.; Sudo, T.; Noyori,
R.; Itami, K. J. Am. Chem. Soc. 2006, 128, 11748.
Spectral properties concur with the published data.7
(4) For selected examples, see: (a) David, E.; Perrin, J.; Pellet-
Rostaing, S.; Lemaire, M. J. Org. Chem. 2005, 70, 3569.
(b) Kobayashi, K.; Sugie, A.; Takahashi, M.; Masui, K.;
Mori, A. Org. Lett. 2005, 7, 5083. (c) Takahashi, M.;
Masui, K.; Sekiguchi, H.; Kobayashi, N.; Mori, A.;
Funahashi, M.; Tamaoki, N. J. Am. Chem. Soc. 2006, 128,
10930. (d) Masuda, N.; Tanba, S.; Sugie, A.; Monguchi, D.;
Koumura, N.; Hara, K.; Mori, A. Org. Lett. 2009, 11, 2297.
(e) Glover, B.; Harvey, K. A.; Liu, B.; Sharp, M. J.;
Tymoschenko, M. F. Org. Lett. 2003, 5, 301. (f) Roger, J.;
Pozgan, F.; Doucet, H. Green Chem. 2009, 11, 425.
(g) Dong, J. J.; Roger, J.; Doucet, H. Tetrahedron Lett. 2009,
50, 2787. (h) Roger, J.; Pozgan, F.; Doucet, H. Adv. Synth.
Catal. 2010, 352, 696. (i) Yanagisawa, S.; Ueda, K.;
Sekizawa, H.; Itami, K. J. Am. Chem. Soc. 2009, 131,
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Int. Ed. 2009, 48, 3644. (k) Do, H.-Q.; Khan, R. M. K.;
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N-Benzyl-2-(4-cyanophenyl)pyrrole (19)
Reaction of N-benzylpyrrole (5; 1.40 mL, 9 mmol) with 4-iodoben-
zonitrile (2; 137 mg, 0.6 mmol) was performed following the above
general procedure. The product was further purified by column
chromatography (silica gel, Et2O–hexanes, 5:95); yellowish oil;
yield: 77.6 mg (50%).
Supporting Information for this article is available online at:
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
This study was financed by the European Community [RTN Net-
work (R) Evolutionary Catalysis MRTN-CT-2006-035866].
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