Silver(I)-Catalyzed conia-ene reaction: Synthesis of 3-pyrrolines via a 5-endo-dig cyclization

Article abstract of DOI:10.1002/adsc.201300844

A novel method has been developed for the synthesis of 3-pyrrolines from β-ketopropargylamines via a 5-endo-dig carbocyclization. This transformation involves a silver-catalyzed Conia-ene type reaction tolerating broad substrate scope with good to excellent yields. Furthermore, this methodology has been extended for the construction of 2-substituted pyrroles under base-mediated conditions. Copyright

Full text of DOI:10.1002/adsc.201300844

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DOI: 10.1002/adsc.201300844
Silver(I)-Catalyzed Conia-Ene Reaction: Synthesis of 3-Pyrrolines
via a 5-endo-dig Cyclization
Siva Senthil Kumar Boominathan,a Wan-Ping Hu,b Gopal Chandru Senadi,a
and Jeh-Jeng Wanga,*
a
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung City 807, Taiwan
E-mail: jjwang@kmu.edu.tw
Department of Biotechnology, Kaohsiung Medical University, Kaohsiung City 807, Taiwan
b
Received: September 18, 2013; Published online: November 27, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300844.
Abstract: A novel method has been developed for
the synthesis of 3-pyrrolines from b-ketopropargyla-
mines via a 5-endo-dig carbocyclization. This trans-
formation involves a silver-catalyzed Conia-ene
type reaction tolerating broad substrate scope with
good to excellent yields. Furthermore, this method-
ology has been extended for the construction of 2-
substituted pyrroles under base-mediated condi-
tions.
such as cyclopentane derivatives.[12] Over the last
decade, transition metal-catalyzed Conia-ene reac-
tions have been developed and replaced classic high
temperature reactions, for the synthesis of such carbo-
cycles.[12a] However, the synthesis of heterocycles by
this method has been much less exploited. Recently,
the syntheses of oxygen- and nitrogen-containing het-
erocycles were reported independently by Hatakeya-
ma[13] and Burton[14] via indium and zinc catalysis, re-
spectively. Although it should be noted that all of the
reported metal-catalyzed reactions were restricted to
dialkyl malonates or b-keto esters as precursors, as
shown in Scheme 2a. To the best of our knowledge no
other transition metal-catalyzed Conia-ene reactions
have employed monocarbonyl groups as the starting
material.[12a] Recently, we have been working on such
Keywords: alkynes; Conia-ene reaction; 2-pyrroles;
3-pyrrolines; silver
3-Pyrrolines are important heterocycles because of cycloisomerization reactions in our group.[15] Herein
their broad applications in biology[1] and chemistry.[2] we report a novel method for the synthesis of 3-pyrro-
This class of heterocycles features in numerous bioac- lines from b-ketopropargylamines via 5-endo-dig cy-
tive molecules, natural products and pharmaceutical
drugs. Of particular note are those molecules with
3,4-unsaturation, capable of being either oxidized to
pyrroles[3] or reduced to pyrrolidines.[4] The most
common methods in the literature for the synthesis of
these molecules are ring closing metathesis,[5] Birch
reduction of electron-deficient pyrroles,[6] 1,3-dipolar
cycloaddition of azomethine ylides,[7] a-aminoallene
cyclization,[8] and vinylphosphonium cascade reac-
tions[9] (Scheme 1). However, some of these methods
are limited by low reaction yields, poor substrate
scope and the difficulty of preparing the necessary
precursors. Therefore the development of a mild and
complementary approach to the synthesis of 3-pyrro-
lines is highly desirable due to their widespread im-
portance.[10]
The addition of enolates and enols to unactivated
À
alkynes is a widely employed method for C C bond
formation.[11] In particular, Conia-ene reactions repre-
Scheme 1. Previous reports and our strategy to synthesize 3-
sent a robust strategy for synthesizing carbocycles, pyrrolines.
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Adv. Synth. Catal. 2013, 355, 3570 – 3574

Silver(I)-Catalyzed Conia-Ene Reaction: Synthesis of 3-Pyrrolines
and InACTHUNTGRNE(UNG OTf)3 failed to achieve the desired transfor-
mation (entries 3–9). To our delight, reaction with
20 mol% of AgNO3 did give the desired product 1a,
in 29% yield (entry 9). Encouraged by this initial ob-
servation, various silver salts (entires 10–15) were
screened. AgOTf and AgNTf2 (entries 13 and 15) re-
sponded very well to this protocol; although of the
two, we chose to use AgOTf as it is cheaper. Solvent
screening revealed nitromethane to be the best sol-
vent for this system, giving 85% yield (entries 16–19).
Deviating from our optimum temperature (808C) in
either direction appears to lower the yield (entries 20
Scheme 2. Metal-catalyzed Conia-ene reactions.
ACHTUNGTRENNUNG
clization[16] through a silver-catalyzed Conia-ene type and 21). From recent reports,[17] we were acutely
reaction (Scheme 2b).
aware of the fact that the Brønsted acid present in
Our initial studies were carried out using 1a as the the triflate salts could also be catalyzing these reac-
model substrate to optimize the reaction conditions tions. To alleviate these concerns a control experi-
(Table 1). Evaluation of AuClACTHNUTRGENUNG(PPh3) with silver co- ment was carried out with triflic acid (entry 22), but
catalysts resulted in hydration of alkyne (Table 1, en- no reaction was observed, confirming that the reac-
tries 1 and 2). Further screening with various Lewis tion is indeed promoted by the metal catalyst.
acids such as FeCl3, ZnCl2, CuI, Cu
G
E
Finally, we fixed upon entry 18 as the optimum re-
action conditions to examine the substrate scope, with
the results summarized in Table 2. Initially, a variety
of terminal alkynes was screened with various R1
groups. When R1 is phenyl, the reaction tolerates
both electron-donating (entries 2a–2c) and electron-
withdrawing substituents (entries 2k–2m). With R1 as
an aryl halide the respective products were also
formed in good yields (entries 2d–2j). It is noteworthy
that when R1 is a fused aryl (2n), heterocycle (2o) or
alkyl group (2p) the reaction progressed well under
our standard reaction conditions.
The reaction was found to be compatible with both
tosyl and nosyl substituents at the R2 position. How-
ever, the expected product was not observed when
the substitution on R2 was alkyl, aryl and acyl.
(Table 2, 2s, 2t and 2u).
After exploring the scope with terminal alkynes, we
turned our attention to investigating the feasibility of
this reaction with internal alkynes. When R3 is methyl
(2q) and phenyl, (2r) the respective products were ob-
tained in moderate yield. The structure of compound
2a was unambiguously confirmed by X-ray analysis
(Figure 1).[18]
Table 1. Optimization of the reaction conditions.[a]
Entry
Catalyst
Solvent
1
2
AuCl
AuCl
N
DCE
DCE
3
4
5
FeCl3
ZnCl2
CuI
DCE
DCE
DMF
6
7
8
Cu
Sc(OTf)3
In(OTf)3
(OAc)2
DMF
DCE
DCE
G
G
9d
10
11
12
13
14
15
16
17
18
19
20
21
22[d]
AgNO3
Ag2CO3
Ag2O
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DMF
toluene
CH3NO2
dioxane
CH3NO2
CH3NO2
CH3NO2
AgSbF6
AgNTf2
AgOAc
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
TfOH
To demonstrate the synthetic utility of our method-
ology, we sought to prepare pyrrole derivatives from
[a]
Reaction conditions: 1a (1 mmol), catalyst (10 mol%) in
solvent (1 mL) in a Schlenk tube at the mentioned tem-
perature.
Isolated yield of pure product.
Hydration of the alkyne was observed to be quantitative.
20 mol% of catalyst was used.
[b]
[c]
[d]
Figure 1. ORTEP diagram of 2a.
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Siva Senthil Kumar Boominathan et al.
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Table 2. Substrate scope of 3-pyrroline derivatives.[a]
[a]
General reaction conditions: 1 (1 mmol), AgOTf (10 mol%), CH3NO2 (1 mL), 808C,
16 h; yields refer to isolated products.
Scheme 3. Synthetic application to pyrrole derivatives.
the synthesized 3-pyrroline compounds (Scheme 3).
The treatment of 3-pyrrolines with a stoichiometric
amount of K2CO3 in methanol afforded the corre-
sponding 2-substituted pyrroles (3a, 3d and 3e) in
shorter times and excellent yields, via desulfonylation
followed by an isomerization process.
Scheme 4. Proposed mechanism.
Based on this observation and literature prece-
dents,[8] a proposed mechanistic pathway was outlined,
as shown in Scheme 4. Initially, the carbonyl group of cyclization via a 5-endo-dig mode to produce inter-
compound A is in equilibrium with its enol form B. mediate D. In the end, protonation of D affords the
Compound B coordinates with the Lewis acid to pro- final product 2, regenerating the catalyst for the next
duce an yne-Ag(I) intermediate C, which undergoes cycle.
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Silver(I)-Catalyzed Conia-Ene Reaction: Synthesis of 3-Pyrrolines
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In conclusion, a simple and convenient method of
preparing 3-pyrrolines from b-ketopropargylamines
via 5-endo-dig carbocyclization by a silver-mediated
Conia-ene type reaction has been successfully devel-
oped. The attractive features of the work are wide
functional group tolerance, high yields and easily
available precursors. The synthetic utility of this
method in affording 2-substituted pyrroles has also
been demonstrated. Efforts to expand this strategy to
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Experimental Section
General Procedure for the Synthesis of 3-Pyrrolines
(2a–2r)
An oven-dried, 15-mL Schlenk tube was charged with
1 (1 mmol) in nitromethane (1 mL) and silver triflate
(10 mol%), then the reaction mixture was heated to 808C
for 16 h. After reaction was completed (as detected by
TLC), the reaction mass was partitioned between water and
ethyl acetate, then the combined organic phases were dried
and evaporated under vacuum. The resulting residue was
purified by flash column chromatography on silica gel (100–
200 mesh) with a suitable ratio of hexane and ethyl acetate
to afford the desired product (2). The identity and purity of
the compounds were determined by HR-MS, 1H and
13C NMR spectroscopy.
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Acknowledgements
The authors gratefully acknowledge the National Science
Council of the Republic of China for financial support.
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