Room temperature copper-catalyzed 2-functionalization of pyrrole rings by a three-component coupling reaction

Article abstract of DOI:10.1002/anie.200705940

(Chemical Equation Presented) Making rings: A new Cu-catalyzed three-component coupling reaction between 1-alkynes, sulfonyl azides, and pyrrole derivatives has been developed for making 2-functionalized pyrrole rings (see scheme). This C-C bond formation offers high efficiency and selectivity, mild reaction conditions, and a wide substrate scope.

Full text of DOI:10.1002/anie.200705940

Communications
DOI: 10.1002/anie.200705940
Pyrrole Functionalization
Room Temperature Copper-Catalyzed 2-Functionalization of Pyrrole
Rings by a Three-Component Coupling Reaction**
Seung Hwan Cho and Sukbok Chang*
Dedicated to Professor Sang Chul Shim
À
The efficient construction of a C C bond is an important
process in modern synthetic chemistry.[1] In particular, the
functionalization of heterocycles such as pyrrole units, which
have utility in organic synthesis and medicinal chemistry,[2]
presence of a copper catalyst (Table 1, entry 1). The same
result was obtained with an N-methylindole derivative
(Table 1, entry 2).[7] In contrast, when we employed a pyrrole
unit as the heterocyclic substrate, the reaction proceeded to
afford the anticipated product in good yield (78%) under
mild conditions (Table 1, entry 3).[8] The structure of the
isolated pyrrole derivative was confirmed by X-ray crystallo-
graphic analysis.[9]
À
relies on the C C bond forming strategies. Awide range of
synthetic strategies involving Friedel–Crafts reactions have
been devised.[3]
Recently, we developed a Cu-catalyzed three-component
coupling reaction of terminal alkynes and sulfonyl azides with
amines, alcohols, or water to afford amidines, imidates, and
amides, respectively.[4] The reaction was versatile with regard
to the substrate scope and the synthetic applicability. The
reaction is proposed to proceed through a ketenimine
intermediate, which is generated in situ from the triazole
cycloadduct upon release of N2 gas.[5] Our ongoing work in
Table 1: Survey of aromatic heterocycles in the Cu-catalyzed three-
component couplingreaction. [a]
Yield [%][b]
À
this area led us to propose that the construction of a C C
Entry
Heterocycles
(Het-H)
bond would be feasible by employing aromatic heterocycles
1
2
R3 =H
Me
<1
<1
in our multicomponent protocol (Scheme 1).[6]
3
R4 =H
H
H
78
70
43
4[c]
5[d]
6
Me
28
7
8
CH2Ph
tBuOC(O)
20
<1
[a] Alkyne (0.6 mmol), sulfonyl azide (0.5 mmol), Et3N (0.6 mmol),
heterocycle (1.5 mmol), and CuCl (10 mol%) in chloroform (1.0 mL).
1
[b] Yield was determined by H NMR spectroscopy by usingan internal
standard (1,1,2,2-tetrachloroethane). [c] CuI (10 mol%) was employed
as a catalyst. [d] Used 1.2 equiv of azide (to phenylacetylene).
Scheme 1. Proposed route to substituted aromatic heterocycles by
usingthe three-component reaction.
At the outset of these studies we treated a mixture of
phenylacetylene (1.2 equiv), p-toluenesulfonyl azide, and
triethylamine (1.2 equiv) in chloroform with indole
(3.0 equiv). However, no reaction was observed in the
Interestingly, the use of CuI as the catalyst, which was
most successfully employed in our previous studies,[4] resulted
in a slightly lower product yield (Table 1, entry 4). The ratio of
the three components was found to be important as it affected
the product yields. In fact, whereas the product was obtained
in 78% with a slight excess of alkyne (1.2 equiv) relative to
sulfonyl azide (Table 1, entry 3), a notably lower yield was
obtained with a reversed ratio of the two reactants (Table 1,
entry 5). More interestingly, when N-substituted pyrrole
derivatives were used, the reaction was sluggish and afforded
poor yields compared to the parent pyrrole unit (Table 1,
entries 6–8). The electronic variation of the N-substituents on
the pyrrole ring did not alter the reactivity. Different types of
heterocycles such as furan, thiophene, or imidazole rings do
not participate in the reaction under the optimized condi-
tions.[8]
[*] S. H. Cho, Prof. Dr. S. Chang
Center for Molecular Design and Synthesis (CMDS)
Department of Chemistry and
School of Molecular Science (BK21)
Korea Advanced Institute of Science and Technology (KAIST)
Daejeon, 305-701 (Republic of Korea)
Fax: (+82)42-869-2810
E-mail: sbchang@kaist.ac.kr
[**] This research was supported by CMDS at KAIST and the KOSEF
grant (No. R01-2007-000-10618-0).
Supportinginformation for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Chemie
Table 2: 2-Functionalization of pyrrole rings by the Cu-catalyzed three-
component couplingreaction. [a]
The results obtained above and the
inability of the indole substrates partic-
ipate in the reaction led us to propose
that the pyrrole nitrogen atom coordi-
nates to the copper center as the pyrrole
attacks the ketenimine intermediate,
thereby facilitating the progress of the
reaction (Scheme 2). In fact, a similar
chelation assisted pathway was recently
proposed by Baran et al. in the addition
of a pyrrole unit to the a-carbon of
enolizable carbonyl compounds (e.g.
ketones, esters, amides, latones, or lac-
R1
Product
Yield [%][b]
Scheme 2. Pro-
Entry
posed Cu-chelated
ketenimine inter-
mediate for access-
ing2-functionalized
pyrrole rings.
1
2
3
R2 =H
CF3
CH3
78
70
71
4
89
85
86
75
77
82
54[d]
tams) in the presence of a stoichiometric CuII species.[10]
However, the possibility that the unbound pyrrole unit (no
coordination to copper) directly attacks the ketenimine
intermediate cannot be ruled out at the moment.
5
The substrate scope of the present three-component
coupling reaction with the parent pyrrole substrate was
investigated next (Table 2). Awide range of 1-alkynes and
sufonyl azides readily participated in the reaction with the
pyrrole reactant at ambient temperatures. Reactions with
either aromatic or aliphatic alkynes were complete within a
few hours irrespective of their electronic or steric variations
(Table 2, entries 1–5).
The presence of various functional groups such as halides,
conjugated double bonds, or alkoxy moieties did not inhibit
the catalytic reactions (Table 2, entries 6, 7, and 8, respec-
tively). Notably, the Boc-protected (Boc = tert-butylcarboxy)-
amino group was also tolerated (Table 2, entry 9).
Areaction employing an optically active unprotected
propargyl alcohol furnished an interesting product, 2-(1-
imino-3-3-hydroxyl)-pyrrole, in a respectable yield with
complete retention of the stereochemistry at the stereogenic
center (Table 2, entry 10). Such compounds can be versatile in
that they are attractive precursors for the formation of 2-(1,3-
aminohydroxyl)pyrroles by undergoing selective reduction of
the sulfonylimino group.[11]
6
7
8[c]
9
10
[a] Alkyne (0.6 mmol), sulfonyl azide (0.5 mmol), Et3N (0.6 mmol),
pyrrole (1.5 mmol), and CuCl (10 mol%) in chloroform (1.0 mL).
[b] Yield of isolated product. [c] Run with alkyne (1.0 mmol for 8 h at
the same temperature. [d] A mixture of inseparable stereoisomers (imino
1
group) with a 4.3:1 ratio determined from H NMR spectroscopy.
The scope of the sulfonyl azides was also examined and
revealed that azido compounds such as 4-acetamido benze-
nesulfonyl- or methanesulfonyl azide can be used. In each
case, satisfactory product yields were obtained from the
catalytic reactions (see the Supporting Information for
details).
equivalents of alkyne and azide used (Table 3, entries 5 and 6,
respectively). As a result, the disubstituted product 2g, having
two different sulfoniminoalkyl groups, could be obtained in
excellent yield by a sequential reaction procedure (Table 3,
entry 7). The bipyrrole or dipyrrolomethane derivatives
obtained are potentially useful as synthetic building blocks
in the areas of corrole or porphyrin chemistry.[13]
An optically active propargylsilylether was used in the
three-component coupling with subsequent hydrolysis to
deliver a pyrrole derivative substituted with a 3-hydroxy-
carbonyl group [Eq. (1)].[14] The stereochemisty of the
Next we employed pyrrole derivatives, bearing various
substituents, as reactants under the optimized conditions and
found that the reactions proceeded smoothly (Table 3).
Pyrrole rings susbtituted at the 2-position or at both the 2-
and 4-positions were viable components (Table 3, entries 1–
2), and the reaction of a 3-substituted pyrrole substrate
afforded a product bearing the sulfoniminoalkyl moiety at the
2-position with excellent selectivity (Table 3, entry 3). When
2,2’-bispyrrole (1a) was subjected to the reaction conditions a
monosusbtituted product 2d was provided in good yield
(Table 3, entry 4).[12] Remarkably, we found that the progress
of the reaction can be controlled by the stoichiometry of
reactants. For example, with 2,2’-dipyrrolomethane (1b)
either the monosubstituted product 2e or the disubstituted
product 2 f could be obtained depending upon the number of
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Table 3: 2-Functionalization of various pyrrole derivatives.
group was achieved by using 2,3-dichloro-5,6-dicyano-l,4-
benzoquinone (DDQ) in chloroform to provide 2-substituted
indole derivative (93%). Indole rings are usually funtional-
ized at the 3-position under Friedel–Crafts conditions,[16]
whereas our approach may be developed as a complementary
method to prepare 2-substituted indole compounds.[3c,17]
After optimizing the protocol for generating 2-function-
alized pyrroles we turned to the development of a tandem
procedure for the synthesis of 2-(a-aminoalkyl)pyrrole deriv-
atives.[18] Such a procedure would be valuable as an efficient
alternative to the conventional routes to aminoalkylated
pyrrole derivatives by using N-sulfonyl imines. The known
protocols sometimes involve double Fridel–Crafts reactions
that give dipyrrolomethane as an undesired side product,
which consequently lowers the yields of the desired prod-
ucts.[19] With regard to the above consideration,[20] the
successful synthesis of 2-(a-aminoalkyl)pyrrole compounds
from the hydride reduction of preformed 2-iminopyrroles
would be noteworthy (Scheme 3). We successfully made three
examples of the 2-(a-aminoalkyl)pyrrole derivatives and they
were obtained in excellent yields under mild conditions.
Entry Pyrrole
Product
Yield
[%][a]
1
2a 75
2[b]
2b 67
2c 71
3
4[c]
1a
1b
2d 79
5[c]
2e 80
6[d]
1b
2e
2 f 84
Scheme 3. Examples of the reduction of 2-iminopyrrole compounds.
7[e]
2g 91
We were also pleased to observe that the present protocol
can be readily used in an intramolecular reaction [Eq. (3)].
[a] Yield of isolated product. [b] CuI (10 mol%) was used as a catalyst.
[c] Used 1.0 eqiuv phenylacetylene and sulfonyl azide. [d] Used 2.1 eqiuv
phenylacetylene and sulfonyl azide. [e] Used 1.0 equiv 1-hexyne (relative
to 2e).
stereogenic center in the 1,3-difunctionalzed pyrrole product
was completely retained during the course of the trans-
formations.
The synthetic utility of the present protocol was demon-
strated by employing 4,7-dihydroindole as
a
substrate
For example, 1-(2-ethynylphenyl)pyrrole (3a) reacted with a
sulfonyl azide in the presence of a CuCl catalyst to afford an
isomeric pyrrolo[1,2-a]quinoline derivative 4a[21] in high yield
under mild conditions. Furthermore, 1-(2-ethynylnaphthalen-
1-yl)-pyrrole (3b) was transformed to the benzo[h]pyrrolo-
[1,2-a]qunoline derivative 4b in reasonable yield at slightly
higher temperatures. To the best of our knowledge, this
represents the first preparative example for multiply func-
tionalized pyrrolo[1,2-a]quinoline derivatives by the action of
Cu catalyst.
[Eq. (2)].[15] The Cu-catalyzed three-component reaction
between phenylacetylene, p-toluenesulfonyl azide, and 4,7-
dihydroindole proceeded smoothly under the optimized
conditions to afford the desired compound (82%). Aroma-
tization of the 4,7-dihydroxyindole product bearing an imino
In summary, we have developed a preparative protocol for
2-functionalized pyrroles by using the Cu-catalyzed three-
component reactions between 1-alkynes, sulfonyl azides, and
À
pyrrole derivatives. This new procedure for C C bond
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[8] For details, see the Supporting Information.
[9] For details of X-ray crystallographic data, see the Supporting
Information.
[10] P. S. Baran, J. M. Richter, D. W. Lin, Angew. Chem. 2005, 117,
615; Angew. Chem. Int. Ed. 2005, 44, 609.
formation appears to offer high selectivity, mild conditions,
and a wide substrate scope. Adiverse range of studies on the
biological activity of the compound library we have accessed
is in progress.
[11] For selected examples of the preparation of 1,3-aminoalcohols
by selective chelation-assisted reduction, see: a) T. Kochi, T. P.
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[12] For selected examples on the synthesis of corroles and their
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[13] For the preparation of 2,2’-dipyrrolomethane compounds and
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Received: December 24, 2007
Published online: March 3, 2008
À
Keywords: alkynes · azides · C C bond formation · copper ·
.
pyrrole rings
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