Copper(I)-Catalysed Multicomponent Reaction: Straightforward Access to 5-Hydroxy-1H-pyrrol-2(5H)-ones

Article abstract of DOI:10.1002/adsc.201500994

A copper-catalysed multicomponent coupling reaction between readily available (Z)-3-iodoacrylic acids, terminal alkynes, and primary amines was developed to smoothly access a small library of 5-hydroxy-1H-pyrrol-2(5H)-ones in good yields. This practical and general process was applied to a short-steps synthesis of the natural product pulchellalactam.

Full text of DOI:10.1002/adsc.201500994

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DOI: 10.1002/adsc.201500994
Copper(I)-Catalysed Multicomponent Reaction: Straightforward
Access to 5-Hydroxy-1H-pyrrol-2(5H)-ones
Muhammad Idham Darussalam Mardjan,a Jean-Luc Parrain,a,*
and Laurent Commeirasa,*
a
Aix Marseille UniversitØ, Centrale Marseille, CNRS, iSm2 UMR 7313, 13397 Marseille, France
Fax: (+33)-(0)491-288-861; Phone: (+33)-(0)491-289-126; e-mail: jl.parrain@univ-amu.fr or
laurent.commeiras@univ-amu.fr
Received: October 30, 2015; Revised: November 24, 2015; Published online: January 26, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500994.
Abstract: A copper-catalysed multicomponent cou-
pling reaction between readily available (Z)-3-io-
doacrylic acids, terminal alkynes, and primary
amines was developed to smoothly access a small li-
brary of 5-hydroxy-1H-pyrrol-2(5H)-ones in good
yields. This practical and general process was ap-
plied to a short-steps synthesis of the natural prod-
uct pulchellalactam.
Keywords: copper catalysis; 5-hydroxy-1H-pyrrol-
2(5H)-ones; multicomponent reaction
The 5-hydroxy-1H-pyrrol-2(5H)-one framework (1) is
Figure 1. Examples of biologically active compounds having
an interesting target since these five-membered heter-
ocyclic compounds are not only present in numerous
natural products[1] and designed pharmaceutical mole-
cules[2] displaying significant biological properties but
a g-hydroxylactam moiety.
In this context, we wish to propose a new MCR
also they are versatile building blocks in organic syn- process to prepare 5-hydroxylactams (1). We have re-
thesis (Figure 1).[3] In this context, the development of cently shown that g-alkylidenebutenolides 2 could ef-
new strategies for the construction of these scaffolds ficiently be obtained via a palladium-free Sonoga-
has triggered considerable attention and several ap- shira-type coupling between (Z)-b-iodo-a,b-unsaturat-
proaches have been reported in the literature.[4] How- ed acids 3 and terminal alkynes 4 in the presence of
ever, many of them suffer from drawbacks like poor a catalytic amount of copper(I).[6]
selectivity, low chemical yields, substrate limitations
Furthermore, it has been reported on several occa-
and/or commercially unavailable starting materials. In sions that g-alkylidenebutenolides 2 could be convert-
this context, the development of a broad scope ed into the corresponding g-hydroxylactams 1 upon
method is highly desirable and still constitutes a signif- treatment with an excess of primary amines 5.[7] In
icant and attractive synthetic challenge. To this pur- order to expand the synthetic possibilities of copper-
pose,
multiple
bond-forming
transformations catalysed formation of heterocyclic moieties, we sup-
(MBFTs) appear to be one of the most efficient tools. posed that this one-pot palladium-free procedure
Among them, multicomponent reactions (MCRs) are could be conducted in the presence of a primary
especially attractive synthetic strategies[5] to provide amine and should directly furnish the corresponding
large libraries of diversely substituted organic com- 5-hydroxypyrrol-2(5H)-ones 1 (Scheme 1). This new
pounds from readily available starting materials and multicomponent reaction would allow a straightfor-
in a simple and atom economical transformation.
ward access to these 5-membered heterocyclic deriva-
tives via a copper-catalysed MBFT.
Adv. Synth. Catal. 2016, 358, 543 – 548
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Muhammad Idham Darussalam Mardjan et al.
Table 1. Selected examples for the conditions optimization.
Entry
4a
[equiv.]
5a
[equiv.]
Solvent
Catalyst
Nature
1a [%]
[equiv.]
1
2
3
4
5
6
7
8
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
2
2
2
2
2
2
2
2
2
2
2
1.1
3
2
3
2
2
2
DMF
DMF
DMF
DMF
CuI
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.05
0.1
1
31
31
25
24
20
42
13
57
3
1a:6a=1:0.4
1a:6a=1:0.5
1a:6a=1:0.5
1a:6a=1:0.5
1a:6a=1:0.7
Cu(OAc)2·H2O
CuOAc
Cu(OAc)2
Cu(OTf)2
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
DMF
DMSO
CH3CN
i-PrOH
CF3CH2OH
CF3Tol.
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
1a:2a=1:0.45
9
10
11
12
13
14
15
16
17
3
1a:2a=1:1.2
1a:2a=1:0.4
49
78
84
89
13
31
79
2
2
2
2
–
–
1a:2a=1:0.05
[a]
Reaction conditions: 3a (2.0 mmol, 1 equiv.), K2CO3 (2 equiv.), solvent (7 mL).
proved significantly but also we observed an increas-
ing amount of transamidification product 6a (up to
60%). In order to eliminate the formation of the un-
desired formamide by-product, we turned our atten-
tion to the nature of the solvent (entries 6–11) and
best results in terms of yield (57%) were observed
with isopropyl alcohol (entry 8). The amounts of
alkyne 4a (1.3 and 2 equiv.) and primary amine 5a
Scheme 1. Retrosynthetic plan for the synthesis of g-hydrox-
ylactam.
First, (Z)-3-iodobutenoic acid 3a,[8] phenylacetylene (1.1, 2 and 3 equiv.) were then investigated (en-
4a and butylamine 5a were chosen as benchmark sub- tries 11–14). The best compromise between yield and
strates to find the optimised catalytic system amount of starting material was reached when
(Table 1). The reaction was initially performed by 2 equiv. of both alkyne and primary amine were used
using the catalytic system of our developed copper- (84%, entry 13). Finally, reducing the catalyst loading
catalysed
tandem
coupling
heterocyclisation[6] (entries 15 and 16) afforded 1a in lower yield and the
(1 equiv. of 3a, 1.3 equiv. of 4a, 20 mol% of CuI in use of a stoichiometric amount of copper iodide did
DMF at 508C) in the presence of 2 equiv. of 5a not affect the efficiency of the MCR (entry 17). How-
(entry 1).
ever, less than 5% of g-alkylidenebutenolide 2a was
After stirring for 12 h, we were delighted to ob- still present in the crude mixture. It was also interest-
serve the formation of hydroxylactam 1a in a moder- ing to note that the selectivity of this sequence for
ate isolated yield of 31%. It is worthy of note that the which neither 1,4 or 1,6 Michael addition products
analysis of the crude mixture also revealed the pres- nor enamine products (resulting from the cross cou-
ence of butylformamide 6a in a 0.4/1 mixture with 1a. pling of vinyl iodide and amine) were observed.
However, this first result validated the sequence
For the MCR process, two mechanistic scenarios
À
À
during which one C C bond, one C O bond and two could be considered. The first one could involve a So-
À
C N bonds were created in a one-pot fashion.
nogashira-type coupling (without palladium) and the
In order to increase the yield of 1a, we have second one a Castro–Stephens-type coupling. Howev-
screened several copper salts [CuOAc, Cu(OAc)2, er, preliminary experiments run in our group have
Cu(OTf2), Cu(OAc)2·H2O, entries 2–5]. Unfortunate- shown that when the reaction of the formation of the
ly, not only the yields of isolated 1a were not im- lactone 2 is conducted with one equivalent of alkynyl
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Copper(I)-Catalysed Multicomponent Reaction
Scheme 2. Plausible mechanism.
copper reagent, no lactone 2a was formed in the straightforwardly prepared in good yields (up to
crude mixture. This result led us to disregard the 93%), demonstrating the versatility of this new MCR
Castro–Stephens-type coupling. Therefore, a plausible process. As a general trend, the methodology is toler-
mechanism is depicted in Scheme 2. The first step is ant to a large variety of alkynes with electron-donat-
likely to be an oxidative addition of the copper(I) ing and electron-withdrawing groups (for example, al-
À
into the C I bond of A to give copper(III) intermedi- kynes bearing aromatic, heteroaromatic, protected
ate B. The next steps would involve copper coordina- propargyl alcohol, acetal and ester groups, products
tion to the triple bond of 4, followed by an oxidative 1a–g). When non-activated alkynes possessing
addition to furnish D. Reductive elimination then 5- a longer alkyl chain were used, such as oct-1-yne or
exo-dig cyclisation assisted by copper(I) would lead to TBS-protected but-4-ynol, the yields of the desired
vinyl copper intermediate F which would give lactone products 1h and 1i were lower (50% and 44%, respec-
2 via protodemetallation. Finally, addition of the pri- tively). This decrease of yield was due to a 6-endo
mary amine 5 onto the lactone would furnish the de- cyclisation of enynoic acid intermediates affording the
sired hydroxylactams 1. This last step was confirmed corresponding pyran-2-ones (10% and 13%, respec-
by treating 2a with 5a in i-PrOH at 508C for 12 h tively) which were found to be inert under these con-
with or without K2CO3 (2 equiv.) to give 1a in 77 and ditions.[9]
86% yields, respectively.
While nucleophilic amines such as homoallylamine,
With the optimised protocol in hand, the scope of tryptamine and 3-aminopropanol furnished the de-
this MCR process was then assessed through the var- sired products (1j–l) in fair to good yields, the use of
iation of (Z)-b-iodo-a,b-unsaturated acids 3, terminal less nucleophilic primary amines required modified
alkynes 4 and the primary amines 5 (Scheme 3). The conditions. Indeed, 3 equiv. of benzylamine, para-me-
reaction was found to be general, and diversely substi- thoxybenzylamine or allylamine were necessary to
tuted and functionalised g-hydrolactams 1 could be provide the corresponding g-hydrolactams 1m (77%),
Adv. Synth. Catal. 2016, 358, 543 – 548
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Muhammad Idham Darussalam Mardjan et al.
Scheme 3. Scope of the multicomponent reaction.
1n (71%) and 1o (87%) with satisfactory yields. Pleas- NH4OAc. Best results were obtained with NH3 but it
ingly, compared to benzylamine, only 2 equiv. of is worthy of note that 10 equiv. of NH3 and a time re-
ortho-methoxybenzylamine
(more
nucleophilic action of 72 h were necessary to obtain the desired
amine) could be used to obtain 1p in 61% yield with- hydroxylactam 1aa (without the presence of 2a) in
out detecting the presence of the intermediate g-alky- 25% yield. Further investigations by varying the sub-
lidenebutenolide. The limitation of the reaction was stituent on the b position of 3 were also undertaken.
obtained with deactivated amines such as aromatic In all these cases, the MCR process afforded g-hy-
amines (for example, aniline). We have also per- droxylactams 1s–z in acceptable to good yields, giving
formed the reaction with hex-5-ynylamine. Interest- the proposed method a general and straightforward
ingly, the MCR was totally chemoselective and only character.
the hydroxylactam 1r was obtained in 51%, demon-
Our next purpose was to investigate the reactivity
strating the better reactivity of terminal aromatic al- of 5-hydroxy-1H-pyrrol-2(5H)-ones 1 as an equivalent
kynes compared to alkylalkynes. The reaction was of the N-acyliminium ion for the direct synthesis of g-
also conducted with NH3 (2M in i-PrOH) and with alkylidenebutyrolactams 7 (Scheme 4). The idea was
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Copper(I)-Catalysed Multicomponent Reaction
has been developed to furnish the corresponding 5-
hydroxy-1H-pyrrol-2(5H)-ones in good yields. This se-
quence is based on a cascade in which three individu-
al steps are combined in a synthetic process (eneyne
coupling/heterocyclization/g-hydroxylactam
forma-
tion). This methodology can be extended for the
direct synthesis of g-alkylidenebutyrolactams in
a one-pot cascade.
Scheme 4. One-pot sequence.
to develop a cascade in which four individual steps Experimental Section
are combined in a synthetic sequence (enyne cou-
pling/heterocyclization/g-hydroxylactam formation/de- General Procedure for the Synthesis of 1
hydration).
The (Z)-3-substituted 3-iodoprop-2-enoic acid derivative 3
(2.0 mmol, 1 equiv.) was dissolved in i-PrOH (7 mL) in an
oven-dried-Schlenck tube. K2CO3 (553 mg, 4.0 mmol,
From a practical point of view, quenching the reac-
tion by an aqueous HCl solution (6M), in place of
a saturated aqueous NH4Cl solution and stirring the
reaction mixture for 4 h more at 508C afforded the
desired g-alkylidenebutyrolatam 7 in 76% yield as
a (Z/E=1/0.5) mixture of diastereomers. One more
time, these results demonstrated the power and the
versatility of this copper-catalysed formation of heter-
ocyclic moieties.
Finally, to illustrate this powerful MCR process, we
have next realized the total synthesis of pulchellalac-
tam, a CD45 protein tyrosine phosphatase inhibitor
(Scheme 5).[10] When (Z)-3-iodobutenoic acid 3a
(1 equiv.), para-methoxybenzylamine (3 equiv.) and
volatile 3-methylbutyne (4 equiv.) were exposed to
a catalytic amount of copper, the desired hydroxylac-
tam 8 was obtained in 41% yield.[11] The dehydration
and the deprotection of amide steps were then per-
formed in one-pot using trifluoroacetic acid (TFA) at
reflux.[12] The reaction afforded a 9:1 separable mix-
ture of (Z)- and (E)-puchellalactam 9. The (Z)-natu-
ral product was isolated in 77% yield.
2 equiv.) was then added to the solution and the suspension
was stirred for 10 min under argon. The mixture was then
degassed at À788C for 2”10 min and the reaction vessel
backfilled with argon. After warming to room temperature,
terminal alkyne 4 (4.0 mmol, 2 equiv.), primary amine 5
(4.0 mmol, 2 equiv.) and finally CuI (76 mg, 0.4 mmol,
0.2 equiv.) were added. The mixture was then rapidly de-
gassed and the vessels backfilled with argon. The sealed
Schlenck tube was placed in the preheated oil bath (508C)
and the mixture was stirred overnight. The reaction mixture
was cooled to 08C, then quenched by the addition of an
aqueous saturated solution of NH4Cl and stirred for further
15 min. The crude mixture was filtered through a pad of
Celiteꢁ. The aqueous phase was extracted with ethyl acetate
(3”40 mL) and the combined organic layers were washed
with brine (2”40 mL), dried over Na2SO4 and evaporated
under reduced pressure. The crude product was then puri-
fied by flash chromatography on silica gel.
Acknowledgements
In summary, a practical and general copper-cata-
lysed multicomponent reaction of readily accessible
alkynes, primary amines and (Z)-3-iodoacrylic acids
The Ministry of Research, Technology and Higher Education
(Republic of Indonesia), the CNRS and Aix Marseille Uni-
versitØ (UMR 7313) are gratefully acknowledged for financial
support.
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