Room-Temperature Decarboxylative Alkynylation of Carboxylic Acids Using Photoredox Catalysis and EBX Reagents

Article abstract of DOI:10.1002/anie.201505111

Alkynes are used as building blocks in synthetic and medicinal chemistry, chemical biology, and materials science. Therefore, efficient methods for their synthesis are the subject of intensive research. Herein, we report the direct synthesis of alkynes fr

Full text of DOI:10.1002/anie.201505111

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International Edition: DOI: 10.1002/anie.201505111
German Edition: DOI: 10.1002/ange.201505111
Photocatalysis
Room-Temperature Decarboxylative Alkynylation of Carboxylic Acids
Using Photoredox Catalysis and EBX Reagents
Franck Le Vaillant, Thibaut Courant, and Jerome Waser*
Abstract: Alkynes are used as building blocks in synthetic and
medicinal chemistry, chemical biology, and materials science.
Therefore, efficient methods for their synthesis are the subject
of intensive research. Herein, we report the direct synthesis of
alkynes from readily available carboxylic acids at room
temperature under visible-light irradiation. The combination
of an iridium photocatalyst with ethynylbenziodoxolone
(EBX) reagents allowed the decarboxylative alkynylation of
carboxylic acids in good yields under mild conditions. The
method could be applied to silyl-, aryl-, and alkyl- substituted
alkynes. It was particularly successful in the case of a-amino
and a-oxo acids derived from biomass.
which themselves need to be introduced into the molecules.
New approaches are urgently needed to make the synthesis of
structurally diverse alkynes more efficient. To meet this
challenge, the direct alkynylation of sp2[3] or sp3[4] C H bonds
À
has been intensively investigated in the last decade (Fig-
ure 1B). Nevertheless, many of these methods still suffer from
limited scope and the need for harsh conditions, and directing
groups or adjacent heteroatoms to control the selectivity in
À
C H functionalization reactions.
À
As an alternative to classical cross-coupling or C H
functionalization reactions, decarboxylative methods have
recently attracted strong interest (Figure 1C).[5] Indeed, the
required carboxylic acid starting materials are derived from
biomass, and are therefore often even cheaper than the
A
lkynes are among the most versatile functional groups in
À
synthetic chemistry, as they are sufficiently stable, yet reactive
enough to be easily modified. These properties make them
ideally suited for applications not only in organic synthesis,
but also in chemical biology and materials science
(Figure 1).[1] All the potential applications of alkynes are
dependent on their efficient synthesis. In particular, the
metal-catalyzed Sonogashira cross-coupling reaction is now
broadly applicable to the formation of alkynes (Figure 1A).[2]
However, the Sonogashira reaction requires starting materi-
als that are functionalized with adequate leaving groups,
corresponding C H compounds. Furthermore, the carboxyl
group allows control of the site of functionalization and only
carbon dioxide is generated as waste. Despite these advan-
tages, examples of decarboxylative alkynylation of aliphatic
carboxylic acids are rare (Scheme 1). In 2009, Chao-Jun Li
and co-workers reported the decarboxylative alkynylation of
amino acids using a copper catalyst and di-tert-butyl peroxide
as stoichiometric oxidant at 1108C (Scheme 1A).[6] In 2010,
Seidel and co-workers[7] and Chao-Jun Li and co-workers[8]
Figure 1. Synthesis and applications of alkynes.
[*] F. Le Vaillant, Dr. T. Courant,[+] Prof. Dr. J. Waser
Laboratory of Catalysis and Organic Synthesis
Ecole Polytechnique FØdØrale de Lausanne
EPFL SB ISIC LCSO, BCH 4306
1015 Lausanne (Switzerland)
E-mail: jerome.waser@epfl.ch
Homepage: http://lcso.epfl.ch/
[+] Current address: Laboratoire de Chimie & Biochimie
Pharmacologiques et Toxicologiques
UniversitØ Paris Descartes, CNRS-UMR 8601
45 rue des Saints-P›res, 75006 Paris (France)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201505111.
Scheme 1. Synthesis of acetylenes by decarboxylative alkynylation.
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Table 1: Optimization of the decarboxylative alkynylation.
reported the condensation of aldehydes or ketones instead of
the peroxide oxidant (Scheme 1B). The copper-catalyzed
method was extended to a-cyano carboxylic acids by using
alkynyl bromides, as reported by Xu and co-workers in 2013
(Scheme 1C).[9] Finally, in 2012, Chaozhong Li and co-work-
ers reported a different approach based on the oxidative
generation of radicals from carboxylic acids using a persulfate
and a silver catalyst at 508C (Scheme 1D).[10] Key to success
was the use of ethynylbenziodoxolone (EBX, 1) reagents,
a class of reagents discovered by Ochiai and Zhdankin,[11] and
intensively investigated by our group[12] and others,[13] to
intercept the formed radical. Nevertheless, the use of these
methods remains limited by the higher temperatures needed
and/or the use of strong stoichiometric oxidants.
In order to develop a decarboxylative alkynylation
method under milder conditions, we envisaged the use of
photoredox catalysis.[14] Indeed, this approach has been highly
successful for the decarboxylative functionalization of car-
boxylic acids.[15] In 2015, Chen and co-workers reported
a decarboxylative alkynylation method with alkynyl sulfones
as reagents,[16] but in this case activation of the carboxylic acid
as a N-hydroxy phthalimide ester was required,[17] which
diminished the efficiency of the reaction (Scheme 1E). Based
on the exceptional reactivity of EBX reagents, we considered
them to be well-suited for the development of a photoredox
process starting directly from the free acids. Indeed, Chen and
co-workers had demonstrated that EBX reagents were
compatible with a photoredox process in the alkynylation of
boronic acid esters.[13g] Herein, we report a method for the
decarboxylative alkynylation of free carboxylic acids under
photoredox conditions (Scheme 1F). The reaction proceeds
at room temperature for a broad range of acids, and allows the
introduction of silyl-, alkyl-, and aryl- substituted alkynes.
We started our investigations with Cbz-protected proline
(2a) as substrate using iridium complex 3a as photocatalyst
and a simple commercially available blue LED as light source
(Table 1) as MacMillan and co-workers have reported that
similar conditions are highly successful.[15d–h] We decided to
target specifically silylated alkynes as products, as they give
easy access to the most versatile terminal acetylenes. Gratify-
ingly, when TIPS-EBX (1a; TIPS = triisopropylsilyl) was
used as reagent[18] and cesium acetate as base, the desired
alkynylation product 4a could be isolated in 31% yield
(entry 1). Intensive investigation of the reaction conditions
showed that both the composition and amount of the base
were essential to obtain a good yield.[19] With four equivalents
of cesium acetate, the yield could be raised to 68% (entry 2).
Other acetate salts such as potassium and sodium acetates
were less efficient (entries 3–4). Use of cesium carbonate gave
the desired product 4a only in 35% yield (entry 5).[20] The
best yield (74%) was finally obtained when cesium benzoate
was used as base (entry 6). Compound 4a was obtained in
68% yield when catalyst 3b was used, whereas the use of
other iridium (3c and 3d) and ruthenium (3e and 3 f)
complexes or organocatalyst 3g did not lead to formation of
the desired product (entries 7–12). A final optimization of
base stoichiometry, concentration, and reaction flask (the use
of a thin long test tube with efficient stirring and maximal
light exposition was important) finally allowed to improve the
Entry Catalyst Base
Reagent Conversion[a] Yield[b]
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3a
3b
3c
3d
3e
3 f
3g
3a
3a
3a
3a
3a
1.1 equiv CsOAc 1a
4.0 equiv CsOAc 1a
4.0 equiv KOAc
>95%
>95%
<50%
<50%
>95%
>95%
>95%
<10%
<10%
<10%
<10%
<10%
> 95%
>95%
>95%
>95%
> 95%
31%
68%
9%
1a
4.0 equiv NaOAc 1a
4.0 equiv Cs2CO3 1a
4.0 equiv CsOBz 1a
4.0 equiv CsOBz 1a
4.0 equiv CsOBz 1a
4.0 equiv CsOBz 1a
4.0 equiv CsOBz 1a
4.0 equiv CsOBz 1a
4.0 equiv CsOBz 1a
3.0 equiv CsOBz 1a
3.0 equiv CsOBz 1b
3.0 equiv CsOBz 1c
3.0 equiv CsOBz 1d
3.0 equiv CsOBz 1e
22%
35%
74%
68%
<5%
<5%
<5%
<5%
<5%
92%
38%
<5%
82%
<5%
9
10
11
12
13[c]
14[c]
15[c]
16[c]
17[c]
[a] Reaction conditions: 0.1 mmol 2a (1 equiv), 0.15 mmol 1 (1.5 equiv),
1 mmol 3 (0.01 equiv) in dichloroethance (DCE; 1 mL) for 22 h at RT. The
conversion of 2a by NMR is given. The values for reduction potentials
are given in volts for catalyst 3 relative to the SCE, except for 3b which is
reported relative to ferrocene.[14f,22] [b] Isolated yield after preparative
TLC. [c] In 0.5 mL DCE. Bz=benzoyl.
yield to 92% using commercially available catalyst 3a
(entry 13).[21] As a final control, we then decided to examine
other alkynylation reagents under the optimized reaction
conditions (entries 14–17). With benziodoxole 1b, compound
4a was obtained in 38% yield (entry 14), whereas no product
was formed with alkynyliodonium salt 1c, (entry 15). Alkyne
4a could still be obtained in 82% yield using simple alkynyl
iodide 1d (entry 16). Although the yield was lower than with
EBX reagent 1a, this result is noteworthy and in good
À
agreement with the alkynylation of C H bonds under photo-
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redox conditions using alkynyl iodides recently developed by
Hashmi and co-workers.[4d] No product was obtained when
using alkynyl sulfone 1e as reagent (entry 17).
With the optimized conditions etablished, we investigated
the scope of the decarboxylative alkynylation (Scheme 2). We
adjacent heteroatom were examined (Scheme 2C). The
desired products were obtained in moderate yields without
further optimization for secondary (products 4k and 4l) and
tertiary (product 4m) carboxylic acids.
The scope of alkynes in the decarboxylative alkynylation
reaction was examined next (Scheme 3). In the case of silyl
alkynes, a bulky group was required: The tert-butyldimethyl-
silyl-protected proline derivative 4n was obtained in 78%
yield, whereas no product could be isolated with triethylsilyl
or trimethylsilyl groups (results not shown). This is probably
due to the lower stability of these reagents under basic
conditions. Aryl-substituted EBX reagents worked very well
in the alkynylation process, giving products 4o–s in 62–97%
yield. In particular, the introduction of bromide-substituted
benzene rings in 4r and 4s will allow easy further function-
alization. Finally, EBX reagents bearing both primary and
tertiary alkyl groups could also be used (products 4t and 4u).
We then wondered if the reaction could also be carried out
using natural sunlight. Indeed, product 4a was obtained in
88% yield after only five hours at room temperature when the
reaction flask was directly exposed to sunlight (Sche-
me 4A).[24] One of the main advantages of the alkynylation
Scheme 2. Scope of carboxylic acids in the decarboxylative alkynylation.
[a] Yield determined by NMR spectroscopy. [b] Using 1 mol% of
catalyst 3a. [c] Using 2 mol% of catalyst 3a.
started with the examination of amino acids (Scheme 2A).
On the preparative scale with only 0.5 mol% of catalyst 3a,
both Cbz- and Boc-protected proline derivatives 4a and 4b
could be obtained in 90% yield. Piperidine 4c could also be
obtained in 66% yield. Tetrahydroquinoline 4d was formed in
87% yield. This result is particularly interesting when
Scheme 3. Scope of alkynes in the decarboxylative alkynylation.
[a] Using 1 mol% of catalyst 3a.
À
considering that direct C H alkynylation cannot be used to
À
obtain this regioisomer, as the C H bond adjacent to the
benzene ring is more reactive. The reaction was not limited to
cyclic amino acids: propargylic amine 4e could also be
isolated in 70% yield.
We then turned to the alkynylation of a-oxo acids
(Scheme 2B). Alkynylated tetrahydrofuran 4 f could be
obtained in quantitative yield. The reaction also worked
well in the case of a pyran derivative (product 4g) or simple
acyclic substrates (product 4h and 4i). As an example of the
formation of an alkyne at a tertiary position, we attempted
the more challenging functionalization of the drug fenofibric
acid, which has been extensively used to treat hyperlipidemia
and diabetes.[23] Gratifyingly, the desired product 4j could still
be obtained in 47% yield. Finally, carboxylic acids lacking the
Scheme 4. Reaction with natural sunlight (A) and derivatization of
product 4a (B). CBz=benzyloxycarbonyl.
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using TIPS-EBX (1a) is that the obtained products are easily
deprotected to give the versatile terminal acetylenes. For
example, proline derivative 4a was obtained on the millimole
scale in 89% yield. Desilylation and [3+2] cycloaddition with
benzyl azide gave then triazole 5 in 90% yield (Scheme 4B).
In the future, in-depth investigations will be needed to
gain a good understanding of the reaction mechanism.
Nevertheless, based on the extensive research already done
in the field of photoredox catalysis,[14,15] a tentative mecha-
nism can be proposed (Scheme 5). The catalytic cycle would
photoredox catalysis. The process can be carried out at room
temperature by using visible light with only 0.5 mol% of an
iridium photocatalyst. a-amino acids could be converted to
the corresponding alkynes in good yields. The process was
also successful in the case of a-oxo acids and simple aliphatic
carboxylic acids, and could be applied to the transfer of silyl-,
aryl- and alkyl- substituted alkynes. The obtained products
could be easily further functionalized. When considering the
mild reaction conditions and broad functional-group toler-
ance, the method is expected to become highly useful for the
alkynylation of complex organic compounds and biomole-
cules in the future.
Acknowledgements
We thank European Research Council (ERC; Starting Grant
iTools4MC, number 334840) and the EPFL for financial
support. Dr. Durga Hari, Daniele Perrotta, and Paola
Caramenti are further acknowledged for the synthesis of
reagents and starting materials and for the purification and
characterization of compounds.
Keywords: alkynes · amino acids · carboxylic acids ·
hypervalent iodine · photocatalysis
How to cite: Angew. Chem. Int. Ed. 2015, 54, 11200–11204
Angew. Chem. 2015, 127, 11352–11356
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The values for reduction potentials are given in volts for catalyst 3a
and substrate 2b.
start with the activation of the iridium catalyst 3 by visible
light, which occurs at 380 nm for 3a. The obtained activated
complex I has a reduction potential of + 1.21 Vand should be
able to oxidize the cesium carboxylate salt of protected
proline derivatives (reduction potential of + 0.95 V for the
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and reaction conditions.
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the sensitivity of silyl-EBX reagents to basic conditions, which
lead to desilylation and decomposition. In fact, good yields were
also obtained when cesium carbonate was used with aryl-
substituted EBX reagents.
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[24] This experiment was performed in Lausanne (46851ꢀ N, 6857ꢀ E)
on May 29, 2015 from 12:00 to 17:00 with a light intensity of 600 –
850 WmÀ2 according to: http://www.meteolausanne.com/soleil-
et-uv.html. See the Supporting Information for a detailed
irradiation spectrum.
[25] P. Wardman, J. Phys. Chem. Ref. Data 1989, 18, 1637. We prefer
this mechanism over an alternative pathway involving alkynyl
radicals because of the very high energy of the latter (see
Ref. [4d]). Data for the reduction potential of radical interme-
diate Vare currently not available and difficult to obtain because
of its high instability.
[16] a) J. Yang, J. Zhang, L. Qi, C. Hu, Y. Chen, Chem. Commun.
2015, 51, 5275; During the preparation of this manuscript, Chen
Received: June 4, 2015
Published online: July 24, 2015
11204 www.angewandte.org
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