Catalytic decarboxylation of 2-alkynoic acids

Article abstract of DOI:10.1021/jo901377b

(Chemical Equation Presented) A very efficient protocol enabling catalytic decarboxylation of a wide range of 2-alkynoic acids is described. The reaction conditions and the scope of the process are examined. The method is further utilized in a model decar

Full text of DOI:10.1021/jo901377b

pubs.acs.org/joc
whereas method B relies on a relatively high loading of the
Catalytic Decarboxylation of 2-Alkynoic Acids
costly catalyst. Additionally, the presence of morpholine is
incompatible with sensitive substrates.
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Andrej Kolarovic* and Zuzana Faberova
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SCHEME 1. Methods of Decarboxylation of 2-Alkynoic Acids
Institute of Organic Chemistry, Catalysis and Petrochemistry,
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Slovak University of Technology, Radlinskeho 9, 81237
Bratislava, Slovak Republic
andrej.kolarovic@stuba.sk
Received June 29, 2009
Our initial aim was to find a simple but general catalytic
system allowing a redox rearrangement of propargylic alco-
hols.4 During screening of selected catalysts, we found out
that Pd(OH)2/C induces decarboxylation of the model sub-
strate 4 (Scheme 2).
SCHEME 2. Observed Catalytic Decarboxylation5
A very efficient protocol enabling catalytic decarboxyla-
tion of a wide range of 2-alkynoic acids is described. The
reaction conditions and the scope of the process are
examined. The method is further utilized in a model
decarboxylative coupling.
Over the past years much attention has been paid to the
chemistry of alkynes,1 originating in the richness of the
unique chemical transformations and geometric/electronic
properties of alkynes. A relatively high reactivity of the
terminal C-H bond frequently requires utilization of pro-
tecting groups, among which 2-hydroxypropyl 1 and tri-
methylsilyl 2 have a privileged position (Figure 1).
Bearing in mind the information expressed in the Intro-
duction, we were intrigued by the indicated transformation.
To systematically evaluate the catalytic activity of Pd(OH)2/
C, we prepared an array of 2-alkynoic acids 8a-i, putting
emphasis on functional groups potentially interfering with
the catalyst (Scheme 3).
SCHEME 3. Synthesis of 2-Alkynoic Acids
FIGURE 1. Protection for terminal alkynes.
Alkoxycarbonyl group 3 is employed much less fre-
quently; however, its presence might be necessary to achieve
a high stereoselectivity.2a As well, after hydrolysis to the
related carboxylic acid, one can take advatage of a classic
resolution as an alternative. So far the most convenient
methods of decarboxylation of 2-alkynoic acids and related
esters involve decarboxylation with a stochiometric amount
of CuCl (A)2 and Pd-catalyzed deallylation-decarboxyla-
tion (B) (Scheme 1).3a In the first case, use of an excess of the
transition metal reagent might be considered to be problematic,
(1) Acetylene Chemistry: Chemistry, Biology and Material Science; Die-
derich, F., Stang, P., Tykwinski, R. R., Eds.; Wiley-VCH: Weinheim, 2005.
(2) (a) Trost, B. M.; Weiss, A. H. Org. Lett. 2006, 8, 4461–4464. For other
examples, see: (b) Zimmerman, H. E.; Dodd, J. R. J. Am. Chem. Soc. 1970,
112, 6507–6515. (c) Caporusso, A. M.; Lardicci, L. J. Chem. Soc., Perkin
Trans. 1 1983, 949–953.
(4) 2-Acylacrylic acids serve as substrate in crystallization-induced asym-
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metric transformations: (a) Jakubec, P.; Berkes, D.; Kolarovic, A.;
Povazanec, F. Synthesis 2006, 4032–4040. (b) Berkes, D.; Kolarovic, A.;
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ꢀ
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€
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Manduch, R.; Baran, P.; Povazanec, F. Tetrahedron: Asymmetry 2005,
(3) (a) Poulsen, T. B.; Bernardi, L.; Aleman, J.; Overgaard, J.; Jorgensen,
K. A. J. Am. Chem. Soc. 2007, 129, 441–449. Original example: (b) Okamoto,
S.; Ono, N.; Tani, K.; Yoshida, Y.; Sato, F. Chem. Commun. 1994, 279–280.
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16, 1927–1934. (c) Kolarovic, A.; Berkes, D.; Baran, P.; Povazanec, F.
Tetrahedron Lett. 2005, 46, 975–978.
DOI: 10.1021/jo901377b
r
Published on Web 08/24/2009
J. Org. Chem. 2009, 74, 7199–7202 7199
2009 American Chemical Society

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Kolarovic and Faberova
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JOCNote
For the substrate synthesis we employed a combination
procedure published by Midland (t-COOR/n-BuLi)6 and
Tishler (t-COOH/EtMgBr).7 The synthetic approach cho-
sen turned out to be reliable and enabled access to derivatives
8a-i in good to excellent yields. Acids 8e-f,i proved to be
prone to decomposition, evincing as gradual darkening on
manipulation. This was particularly true for acid 8i, which
we did not isolate as a pure compound, and the samples used
contained 15-20% of products of decomposition (purity
determined by 1H NMR with internal standard). Under
similar conditions, Koide reports a yield of <2%, in our
opinion as a result of low stability of the compound.8
Decarboxylative experiments on acids 8a,b,f,g were disap-
pointing and led to just average or low yields (Scheme 4).5
TABLE 1. Effect of Reaction Conditions on the Decarboxylation of
Acids 8a,ba
catalyst
(5 mol %)
additive
(3 equiv)
time conv
(min) (%)
yield
(%)b
entry acid
1
2
3
4
5
6
7
8
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8b
8b
8b
8b
8b
120
45
45
120
120
120
120
60
60
60
60
60
60
60
60
20
20
10
120
120
30
60
60
60
60
0
12
8
100
100
31
100
100
9
45
35
0
0
0
100
35
100
89
44
54
100
100
21
42
49
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OAc)2
CuCl2
Et3N
57
25
28
94
92
8
CuCl
CuCl
9
Cu bronze
Cu/CuCl2
e
10
11
12
13
14
15
16
17
18
19
20d
21
22
23
24
25
41
32
f
CuCl/CuCl2
CuSO4
CuSO4.5H2O
CuO
Cu2O
CuCl
CuCl
CuCl
SCHEME 4. Decarboxylation Catalyzed by Pd(OH)2/C
90
Et3N
Et3N
Et3N
Et3N
Et3N
90c
86
39
49
96
95c
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
AcOH
NH4Cl
HCtCTMS
aReactions were performed on 50.0 mg scale in MeCN (1 mL) under
argon. Experiments 9 and 14 were executed on 200.0 mg scale. bYields
based on 1H NMR with internal standard are reported unless other-
wise noted. cAfter isolation. dReaction at rt. e2.5 mol % of Cu bronze/
2.5 mol % CuCl2. f2.5 mol % of CuCl/2.5 mol % CuCl2.
We set out to perform a short screening of reaction condi-
tions. As model substrates we chose acids 8a,b (Table 1).
When using 5 mol % Pd(OH)2/C, we observed a gradual
increase in rate of conversion (entries 2 and 4), as was con-
firmed by screening of the reaction in 15-min intervals.
Addition of an amine base (entry 3) caused a slight retarding
of the reaction. Pd(OAc)2 as an alternative catalyst led to low
yields (entry 5). Much better results were provided by 5 mol
% CuCl, which induced a complete decarboxylation of the
substrate and yielded 94% of 9a (entry 7). Catalytic activity
of CuCl2 compared to CuCl is lower (entry 6). In this context
it was interesting to observe that quality of the CuCl used had
a profound impact on the rate of decarboxylation. Older
samples of CuCl (green color) exhibited a significantly higher
activity in comparison with the newer ones (white color).
When using stock solutions of CuCl/MeCN, catalytic activ-
ity of a freshly prepared solution was lower in comparison
with older solutions as well. For instance, when we employed
a 3-day-old solution of CuCl/MeCN in entry 20, in 120 min
the conversion was complete. For the purpose of reproduci-
bility, in all experiments in Table 1 new packages of CuCl
(from white to light-green color) were used or freshly pre-
pared solutions of CuCl/MeCN (maximum age of 24 h).
However, one can expect faster conversions when using older
samples of CuCl. The samples of CuCl, if exposed to air
moisture, undergo disproportionation to Cu0 and CuII,
which we assume might be the cause of their increas-
ing activity. The catalytic activity of CuCl2 was lower in
comparison to that of CuCl (entries 6 and 7). Equimolar
mixtures of Cu bronze/CuCl2 or CuCl/CuCl2 (entries 10 and 11)
were less active than CuCl itself (entry 8). On the other hand,
Cu2O (entry 15) led to a complete conversion as well.
Additional experiments with CuCl revealed that addition
of a base (3 equiv of Et3N) was reflected in accelerated
reaction (entries 16-18) and similar yields of terminal alkyne
9a (entries 7 and 17). As expected, addition of an acid (entries
23 and 24) or a competitive triple bond (entry 25) retarded the
reaction. Striking was the fact that under these mild conditions
Et3N itself can perform decarboxylation, though much more
slowly (entry 19). Our idea was to take advantage of the
synergic effect of the CuCl-Et3N combination, potentially
leading to the best performance, whereas in inevitable cases
one can optionally choose not to use the base at the cost of
prolonged reaction times (Table 2, acids 8g,h).
In the case of substrate 8c the method enabled a selective
deprotection (decarboxylation) of one triple bond. As pub-
lished, presence of CuI 9 or a base (DBU)10 triggers cleavage
of TMS from triple bonds. Under the present conditions we
observed desilylation as a side reaction only in a limited
range (<5%). With acid 8e we did not succeed in finding
chemoselective conditions leading to one major product and
with both methods we observed formation of a mixture of
several compounds. In the presence of base (method B),
substrates 8g,h containing strong electron-withdrawing
groups underwent a redox isomerization, in accordance with
published data.11 In both cases we isolated a mixture
(5) The yields were determined by 1H NMR with internal standard.
(6) Midland, M. M.; Tramontano, A.; Cable, J. R. J. Org. Chem. 1980, 45,
28–29.
(7) Jakubowski, A. A.; Guziec, F. S. Jr.; Sugiura, M.; Chan Tam, C.;
Tishler, M.; Omura, S. J. Org. Chem. 1982, 47, 1221–1228.
(8) Shahi, S. P.; Koide, K. Angew. Chem., Int. Ed. 2004, 43, 2525–2527;
methyl propiolate was used instead of propiolic acid.
(9) Ito, H.; Arimoto, K.; Sensui, H.; Hosomi, A. Tetrahedron Lett. 1997,
38, 3977–3980.
(10) Yeom, Ch. E.; Kim, M. J.; Choi, W.; Kim, B. M. Synlett 2008, 565–
568.
(11) (a) Koide, K.; Sonye, J. P. J. Org. Chem. 2006, 71, 6254–6257.
(b) Koide, K.; Sonye, J. P. Org. Lett. 2006, 8, 199–202. (c) Arcadi, A.; Cacchi,
S.; Marinelli, F.; Misiti, D. Tetrahedron Lett. 1988, 29, 1457–1460.
7200 J. Org. Chem. Vol. 74, No. 18, 2009

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Kolarovic and Faberova
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TABLE 2. Substrate Scope of the Decarboxylation of 2-Alkynoic Acids
FIGURE 2. Products of redox isomerization.
containing 10g or 10h (Figure 2), whereas decarboxylation
was complete.
To exclude a direct dependence of the described decarbox-
ylative method on the assistance of hydroxyl group at C-4,
the reaction conditions were analogically used on substrates
8j,k (Table 2, entries 10 and 11).
Transition-metal-catalyzed decarboxylative cross-cou-
pling represents a particularly topical area of organic synth-
esis.12 Carboxylic acids are in general easily available and
thus constitute an appealing source of carbon nucleophiles.
Furthermore, thanks to the carboxylic function, they can be
easily isolated and purified or eventually resolved. Decar-
boxylation releases CO2, which is considered to be a harmless
human metabolite in low concentrations. To the best of our
knowledge, there is only one precedent describing decarbox-
ylative cross-coupling of 2-alkynoic acids, which appeared
very recently and is based on Pd-chemistry.13a We consider
the presented method of decarboxylation of 2-alkynoic acids
as inviting to be utilized for the purpose. The illustrative
verification of the concept was executed under standard
Sonogashira coupling conditions (Scheme 5).
SCHEME 5. Illustrative Decarboxylative Coupling
In 1 h, the one-pot decarboxylation/coupling reaction
product 12 was isolated in 78% yield. We believe this
approach has a potential to become a straightforward and
efficient method allowing synthesis of unsymmetrical al-
kynes, a highly desired class of compounds.
In summary, we have established an efficient and straight-
forward method for catalytic decarboxylation of 2-alkynoic
acids, tolerating a wide range of functional groups. The
method was further utilized in illustrative decarboxylative
coupling.
Experimental Section
Representative Procedure: Preparation of 8a. A 100-mL three-
necked flask was charged with dry THF (60 mL) and propynoic
(12) Free carboxylic acids, selected examples: (a) Baudoin, O. Angew.
Chem., Int. Ed. 2007, 46, 1373–1375. (b) Goossen, L. J.; Zimmermann, B.;
Knauber, T. Angew. Chem., Int. Ed. 2008, 47, 7103–7106. (c) Wang, Z.; Ding,
Q.; He, X.; Wu, J. Org. Biomol. Chem. 2009, 7, 863–865. Allyl or dienyl
esters, selected examples: (d) Rayabarapu, D. K.; Tunge, J. A. J. Am. Chem.
Soc. 2005, 127, 13510–13511. (e) Yeagley, A. A.; Chruma, J. J. Org. Lett.
2007, 9, 2879–2882. (f) Sim, S. H.; Park, H. J.; Lee, S. I.; Chung, Y. K. Org.
Lett. 2008, 10, 433–436. (g) Shintani, R.; Park, S; Shirozu, F.; Murakami, M.;
Hayashi, T. J. Am. Chem. Soc. 2008, 130, 16174–16175. (h) Pi, S. F.; Tang, B.
X.; Li, J. H.; Liu, Y. L.; Liang, Y. Org. Lett. 2009, 11, 2309–2312.
(13) (a) Moon, J.; Jang, M.; Lee, S. J. Org. Chem. 2009, 74, 1403–1406.
Analogy in synthesis of diarylalkynes: (b) Moon, J.; Jeong, M.; Nam, H.;
Jinhun, J.; Moon, J. H.; Jung, H. M.; Lee, S. Org. Lett. 2008, 10, 945–948.
J. Org. Chem. Vol. 74, No. 18, 2009 7201

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Kolarovic and Faberova
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acid (780 μL, 1.1 equiv, 12.6 mmol) under an argon atmosphere.
The solution was stirred and cooled to -70 °C, and MeLi (3.0 M
in diethoxymethane, 8.4 mL, 25.2 mmol, 2.2 equiv) was added
over 5 min. The resulting milky suspension was stirred for ca.
25 min at -70 to -40 °C, and successively a solution of 2,4-
dichlorobenzaldehyde (7a, 2.00 g, 11.4 mmol) in dry THF
(10 mL) was added over 1 min. The mixture was stirred for 50
min at -40 to 0 °C and poured into 0.5 M H2SO4 (35 mL), the
aqueous layer was extracted with ethyl acetate (3 Â 40 mL), and
the combined organics were washed with a half-diluted brine
(30 mL), dried over Na2SO4, filtered, and concentrated to yield a
yellow oil. The crude product was dissolved in toluene (ca. 3
Pasteur pipettes) and placed in a freezer. After the acid started to
crystallize, the slurry was gently diluted with hexanes under
vigorous stirring. The mixture was allowed to stand for several
hours in a refrigerator. Successive filtration yielded 2.49 g (89%)
of acid 8a as a sandy light-brown precipitate. Mp 114-117 °C;
1H NMR (300 MHz, acetone-d6) δ 5.91 (s, 1H), 7.49 (dd, J =
2.1, 8.4 Hz, 1H), 7.54 (d, J = 2.1 Hz, 1H), 7.80 (d, J = 8.4 Hz,
1H); 13C NMR (75 MHz, acetone-d6) δ 60.7, 77.6, 86.1, 128.6,
130.0, 130.2, 133.6, 135.2, 137.6, 153.9; HR-MS-MS (m/z) calcd
for C10H5Cl2O3 [M - H]- 242.9616, found 242.9705.
was charged with acid 8b (200 mg, 0.784 mmol) and CuCl
(3.9 mg, 0.039 mmol, 5 mol %), sealed with septum, and gently
flushed with a stream of argon. MeCN (4.0 mL) was added via
syringe, and the resulting solution was placed in an oil bath
(60 °C) and stirred for 1 h. The mixture was cooled in a water
bath and concentrated under reduced pressure, and the residue
was purified by flash chromatography on silica gel (CH2Cl2/
hexanes = 7/3) to give 156 mg (95%) of alkyne 9b as a pale
yellow amorphous glass. 1H NMR (300 MHz, CDCl3) δ 2.67 (d,
J = 2.1 Hz, 1H), 3.20 (bs, 1H), 5.37 (bs, 1H), 7.21 (dd, J = 8.1,
8.1 Hz, 1H), 7.40-7.45 (m, 2H), 7.67 (s, 1H); 13C NMR (75
MHz, CDCl3) δ 63.4, 75.4, 82.7, 122.5, 125.2, 129.6, 130.1,
131.4, 141.9; GC-MS (EI, 70 eV) m/z 212, 210.
Acknowledgment. This work was supported by the Slovak
Research and Development Agency under contract no. LPP-
0238-06
Supporting Information Available: Experimental details,
characterization data, and copies of NMR spectra of 8a-j,
9a-d,f-j, 12, HR-MS-MS of 8a, and GC-MS of 9b. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Representative Procedure: Preparation of 9b. (Table 1, entry
14; method A). A 10-mL flask equipped with a magnetic stir bar
7202 J. Org. Chem. Vol. 74, No. 18, 2009