Silver-catalyzed decarboxylative alkynylation of aliphatic carboxylic acids in aqueous solution

Article abstract of DOI:10.1021/ja306638s

C(sp³)-C(sp) bond formations are of immense interest in chemistry and material sciences. We report herein a convenient, radical-mediated and catalytic method for C(sp³)-C(sp) cross-coupling. Thus, with AgNO₃ as the catalyst and K₂S₂O₈ as the oxidant, various aliphatic carboxylic acids underwent decarboxylative alkynylation with commercially available ethynylbenziodoxolones in aqueous solution under mild conditions. This site-specific alkynylation is not only general and efficient but also functional group compatible. In addition, it exhibits remarkable chemo- and stereoselectivity.

Full text of DOI:10.1021/ja306638s

Communication
pubs.acs.org/JACS
Silver-Catalyzed Decarboxylative Alkynylation of Aliphatic
Carboxylic Acids in Aqueous Solution
Xuesong Liu,† Zhentao Wang,‡ Xiaomin Cheng,*,† and Chaozhong Li*,‡
†College of Chemistry and Chemical Engineering, Anhui University, Hefei, Anhui 230039, P.R. China
‡Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P.R. China
S
* Supporting Information
ABSTRACT: C(sp3)−C(sp) bond formations are of
immense interest in chemistry and material sciences. We
report herein a convenient, radical-mediated and catalytic
method for C(sp3)−C(sp) cross-coupling. Thus, with
AgNO3 as the catalyst and K2S2O8 as the oxidant, various
aliphatic carboxylic acids underwent decarboxylative
alkynylation with commercially available ethynylbenzio-
doxolones in aqueous solution under mild conditions. This
site-specific alkynylation is not only general and efficient
but also functional group compatible. In addition, it
exhibits remarkable chemo- and stereoselectivity.
Figure 1. Overview of radical C-alkynylation reactions.
lkynes are not only important tools and structural
one-pot procedure with the use of catecholborane.13 Landais et
Aelements in material sciences and chemical biology but
also versatile building blocks in organic synthesis.1 The
al. extended this method to radical carboalkynylation of
olefins.14 Nevertheless, these radical methods rely heavily on
introduction of an alkynyl group into a molecule, in particular
the use of alkynyl sulfones as alkynylating agents.15 In view of
C-alkynylation, has thus drawn considerable attention.
Enormous progress has been achieved in the Sonogashira
reaction, which provides a convenient entry to C(sp2)−C(sp)
bond formations.2 Significant efforts have also been made in
C(sp3)−C(sp) coupling reactions in the past decade. Fu et al.
first extended the Sonogashira reaction to the use of primary
alkyl halides as the electrophiles.3 A number of transition-metal-
catalyzed cross-coupling reactions were later developed for the
C(sp3)−C(sp) bond formation.4−6 Nevertheless, these meth-
ods are mainly restricted to primary or secondary alkyl−alkynyl
cross coupling while the tertiary alkyl−alkynyl coupling remains
a difficult task. More recently, electrophilic C(sp3)-alkynyla-
tion7 with the use of ethynylbenziodoxolones was reported by
Waser et al.8 and found an immediate application in the total
synthesis of drimane-type sesquiterpenoids by Yang and co-
workers.9 However, this method requires the use of active
methylene compounds as nucleophiles. The development of
more general and efficient methods for C(sp3)−C(sp) bond
formation is thus of great importance.
Compared to nucleophilic or electrophilic alkynylation,
radical alkynylation reactions have received much less attention
(Figure 1). Russell et al. first studied the radical alkynylation
reactions of alkylmercury halides with various alkynes.10 Fuchs
et al. successfully developed the metal-free radical alkynylation
of C−H bonds via reaction with acetylenic triflones.11 This
method was then extended to the chemospecific alkynylation of
alkyl iodides.12 Renaud and co-workers nicely introduced the
alkynylation of B-alkylcatecholboranes with alkynyl sulfones,
thus allowing the hydroalkynylation of alkenes to proceed in a
the excellent functional group compatibility and mild reaction
conditions for radical reactions, it is highly desirable to develop
new radical strategies for more convenient and efficient
C(sp3)−C(sp) bond formations. Herein we report the silver-
catalyzed decarboxylative alkynylation of aliphatic carboxylic
acids with ethynylbenziodoxolones in aqueous solution.
The ready availability, high stability, and low cost of
carboxylic acids make them extremely promising raw materials
for chemical synthesis.16 We recently reported the silver-
catalyzed oxidative decarboxylative chlorination and fluorina-
tion of aliphatic carboxylic acids.17 We were then interested in
whether the alkyl radical generated by oxidative decarboxylation
could be efficiently trapped by a suitable alkynylating agent.
Thus, with K2S2O8 (1 equiv) as the oxidant and AgNO3 (10
mol %) as the catalyst,18 the reactions of adamantane-1-
carboxylic acid (A-1) with a number of alkynylating agents were
tested (Scheme 1). The reactions with phenylacetylene,
phenylethynyl bromide, or phenyl phenylethynyl sulfone in
various solvents gave either no or a very low yield (<5%) of the
expected alkynylation product 1, the major products being
adamantane or adamantan-1-ol. We then turned to electrophilic
alkynylating agents for help. The use of phenylethynyl
phenyliodonium triflate did not show any improvement.
However to our delight, when phenylethynylbenziodoxolone
(I-1)19 was employed, the reaction with A-1 in aqueous DMF
Received: July 8, 2012
© XXXX American Chemical Society
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Journal of the American Chemical Society
Communication
product 7 in 94% isolated yield. The control experiments
indicated that both AgNO3 and K2S2O8 were essential for the
decarboxylation. Other Ag(I) salts such as AgBF4 and AgOTf
exhibited behavior similar to that of AgNO3. Various aliphatic
carboxylic acids were then tested under the optimized
conditions, and the results are summarized in Scheme 3. The
Scheme 1. Decarboxylative Phenylethynylation of
Adamantane-1-carboxylic Acid
Scheme 3. Silver-Catalyzed Decarboxylative Alkynylation of
Aliphatic Acids in CH3CN/H2O
(or acetone) solution proceeded smoothly at room temper-
ature, furnishing the expected alkyne 1 in 72% yield. In
addition, 2-iodobenzoic acid was also isolated in >70% yield.
Since 2-iodobenzoic acid serves as the starting material for the
preparation of the benziodoxolone,19 this catalytic alkynylation
method is thus highly sustainable. To the best of our
knowledge, this is the first example of alkynyliodine(III)
compounds serving as radical acceptors.20
The above alkynylation reaction with I-1 was then extended
to other tertiary alkyl carboxylic acids without further
optimization. As shown in Scheme 2, tertiary alkyl−phenyl-
Scheme 2. Decarboxylative Alkynylation of Tertiary Alkyl
Acids in Aqueous Solution
a
Reaction conditions: acid (0.3 mmol), AgNO3 (0.03 mmol), K2S2O8
(0.3 mmol), alkynylating agent (0.45 mmol), DMF or acetone (3 mL),
b
H2O (3 mL), rt, 10 h. Isolated yield based on the starting acid.
c
d
Solvent: acetone/H2O. Solvent: DMF/H2O.
ethynyl coupling products 2 and 3 were achieved in good yields
in acetone/water solution. p-Chlorophenylethynylbenziodox-
olone (I-2) exhibited the reactivity similar to I-1, as evidenced
by the synthesis of 4 and 5. On the other hand, triisopropylsilyl
(TIPS)-substituted ethynylbenziodoxolone I-3 afforded the
expected product 6 in only 10% yield.
a
Reaction conditions: carboxylic acid (0.3 mmol), AgNO3 (0.09
mmol), I-3 (0.45 mmol), K2S2O8 (0.9 mmol), CH3CN (3 mL), H2O
(3 mL), 50 °C, 10 h. Isolated yield based on the corresponding
carboxylic acid. 20 mol % AgNO3 was used. 10 mol % AgNO3 was
used. Reaction time: 1 h.
b
c
d
e
The low product yield in the reaction of I-3 indicated above
urged us to optimize the experimental conditions. Our
extensive study using 2-ethylhexanoic acid as the model
substrate revealed that, in the presence of AgNO3 (30 mol
%) and K2S2O8 (3 equiv), the reaction of I-3 with 2-
ethylhexanoic acid in CH3CN/H2O (1:1, v:v) solution at 50
°C for 10 h led to the clean formation of the expected alkyne
decarboxylative alkynylation proceeded smoothly for all the
primary, secondary, and tertiary alkyl acids, and the
corresponding products 6−24 were achieved in good to
excellent yields. For tertiary alkyl acids and α-heteroatom-
substituted alkyl acids, the amount of the catalyst AgNO3 could
be reduced to 10 or 20 mol %. Note that alkyne 6 was now
B
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Journal of the American Chemical Society
Communication
obtained in 70% yield. The catalytic processes enjoy the
tolerance of a variety of functional groups, including amide,
ester, carbonyl, halide, ether, aryl, etc., which encourages their
application to more complexed organic molecules. For example,
alkyne 28 was obtained in 61% yield as a 1:2 mixture of two
diastereoisomers from the corresponding dehydrolithocholic
acid derivative. It is interesting to note that this reaction was in
fact diastereoselective. To explore the stereoselectivity of
alkynylation, acid A-29 was employed as the probe. Indeed,
both trans-A-29 and cis-A-29 led to the exclusive formation of
trans-substituted product 29 (eq 1). Similarly, acid A-30 as the
mixture of two stereoisomers yielded the trans-configured
product 30 only (eq 1). Nevertheless, racemic product 27 was
obtained from the reaction of optically pure N-protected (S)-
phenylalanine.
On the basis of the above results, a plausible mechanism was
proposed for the catalytic decarboxylative alkynylation (Figure
2). Oxidation of Ag(I) by persulfate generates the Ag(II)
Figure 2. Proposed mechanism of decarboxylative alkynylation.
Unlike aliphatic acids, aromatic acids such as 4-chlorobenzoic
acid or 2-nitrobenzoic acid failed to give any desired products
under the above experimental conditions, while all the starting
acids were recovered. This allows the successful implementa-
tion of chemoselective alkynylation. As illustrated in eq 2, the
alkylic carboxyl group in diacid A-31 was selectively removed to
provide alkyne 31 while the benzoic carboxyl group remained
intact.
The above results have clearly demonstrated the generality of
decarboxylative alkynylation. Moreover, the TIPS group in the
products (such as 13 and 25) can be easily removed by
treatment with tetrabutylammonium fluoride to give the
terminal alkynes (see the Supporting Information), which can
be utilized for further transformations such as the Sonogashira
cross-coupling.
intermediate, which then undergoes single electron transfer
with a carboxylate to produce the carboxyl radical.18 Fast
decarboxylation of the carboxyl radical gives the corresponding
alkyl radical. Addition of the alkyl radical to the triple bond of I-
3 followed by subsequent β-elimination of the adduct radical
affords the final product alkyne along with the formation of
benziodoxolonyl radical (X). 2-Iodobenzoic acid is then
produced from the benziodoxolonyl radical via either H-
abstraction or reduction−protonation sequence.
To provide further evidence on the above mechanism, tert-
butyl 2-ethylhexaneperoxoate (34) was used as the alkyl radical
precursor (via O−O bond cleavage followed by decarbox-
ylation).17b The reactions of 34 with I-1 or I-3 in refluxing
benzene for 12 h afforded the corresponding alkynylation
product 35 or 7 in around 40% yield (eq 5). This result
The radical mechanism can also be inferred from the above
experiments. A more direct evidence was the reaction of acid A-
32 in which the alkynylation product 32 (49%) was
accompanied by the cyclization product 32C (41%), as
indicated in eq 3. To provide solid evidence on the radical
mechanism, cyclopropylacetic acid A-33 was designed as the
radical probe.21 The reaction of A-33 with I-3 under the
optimized conditions gave the ring-opening product 33 in 74%
yield as a 4:1 mixture of two stereoisomers determined by
HPLC (eq 4). These two experiments strongly support the
involvement of free radical mechanism in the decarboxylative
alkynylation.
supports our hypothesis in Figure 2, i.e., once the alkyl radical is
generated, Ag+/S2O8 is unlikely to be involved in the
2−
subsequent processes. Further mechanistic investigations are
certainly required to understand the interaction of alkyl radicals
with ethynylbenziodoxolones.
C
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Journal of the American Chemical Society
Communication
(11) (a) Gong, J.; Fuchs, P. L. J. Am. Chem. Soc. 1996, 118, 4486.
(b) Xiang, J.; Jiang, W.; Fuchs, P. L. Tetrahedron Lett. 1997, 38, 6635.
(12) Xiang, J.; Fuchs, P. L. Tetrahedron Lett. 1998, 39, 8597.
(13) Schaffner, A.-P.; Darmency, V.; Renaud, P. Angew. Chem., Int.
Ed. 2006, 45, 5847.
(14) Liautard, V.; Robert, F.; Landais, Y. Org. Lett. 2011, 13, 2658.
(15) Copper- or silver-catalyzed oxidative C(sp3)−H alkynylation
with alkynes was reported by Li et al. The mechanism is likely the
oxidation of radical intermediates followed by nucleophilic alkynyla-
tion. See: (a) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2004, 126, 11810.
(b) Correia, C. A.; Li, C.-J. Heterocycles 2010, 82, 555.
In conclusion, we have developed the decarboxylative
alkynylation of aliphatic carboxylic acids in aqueous solution
with AgNO3 as the catalyst and the commercially available
ethynylbenziodoxolones as alkynylating agents. This radical-
mediated C(sp3)−C(sp) cross-coupling is not only efficient and
general but also functional group compatible. In addition, it also
exhibits remarkable chemo- and stereoselectivity. In view of the
mild experimental conditions and ready availability of both
substrates and reagents, this convenient and site-specific
alkynylation method should find practical applications in
organic synthesis.
(16) Gooßen, L. J.; Rodríguez, N.; Gooßen, K. Angew Chem., Int. Ed.
2008, 47, 3100.
(17) (a) Wang, Z.; Zhu, L.; Yin, F.; Su, Z.; Li, Z.; Li, C. J. Am. Chem.
Soc. 2012, 134, 4258. (b) Yin, F.; Wang, Z.; Li, Z.; Li, C. J. Am. Chem.
Soc. 2012, 134, 10401.
ASSOCIATED CONTENT
■
S
* Supporting Information
(18) (a) Anderson, J. M.; Kochi, J. K. J. Am. Chem. Soc. 1970, 92,
1651. (b) Anderson, J. M.; Kochi, J. K. J. Org. Chem. 1970, 35, 986.
(19) Zhdankin, V. V.; Kuehl, C. J.; Krasutsky, A. P.; Bolz, J. T.;
Simonsen, A. J. J. Org. Chem. 1996, 61, 6547.
Full experimental details, characterization of new compounds,
and 1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
(20) For selected reviews on the chemistry of hypervalent iodine
compounds, see: (a) Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96,
1123. (b) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102, 2523.
(c) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299.
(21) Newcomb, M. In Radicals in Organic Synthesis; Renaud, P., Sibi,
M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 1, pp 317−336.
AUTHOR INFORMATION
■
Corresponding Author
clig@mail.sioc.ac.cn; xmcheng211@yahoo.com.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This project was supported by the National Natural Science
Foundation of China (grants 20832006 and 21072211) and by
the National Basic Research Program of China (973 Program)
(grants 2011CB710805 and 2010CB833206).
REFERENCES
■
(1) Diederich, F.; Stang, P. J.; Tykwinski, R. R. Acetylene Chemistry:
Chemistry, Biology and Material Science; Wiley-VCH: Weinheim, 2005.
(2) Chinchilla, R.; Naj
(3) Eckhardt, M.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 13642.
́
era, C. Chem. Rev. 2007, 107, 874.
(4) (a) Altenhoff, G.; Wurtz, S.; Glorius, F. Tetrahedron Lett. 2006,
̈
47, 2925. (b) Vechorkin, O.; Barmaz, D.; Proust, V.; Hu, X. J. Am.
Chem. Soc. 2009, 131, 12078.
(5) (a) Yang, L.-M.; Huang, L.-F.; Luh, T.-Y. Org. Lett. 2004, 6, 1461.
(b) Ohmiya, H.; Yorimitsu, H.; Oshima, K. Org. Lett. 2006, 8, 3093.
(c) Zhao, Y.; Wang, H.; Hou, X.; Hu, Y.; Lei, A.; Zhang, H.; Zhu, L. J.
́
Am. Chem. Soc. 2006, 128, 15048. (d) Nicolai, S.; Erard, S.; Gonzalez,
D. F.; Waser, J. Org. Lett. 2010, 12, 384. (e) Cahiez, G.; Gager, O.;
Buendia, J. Angew. Chem., Int. Ed. 2010, 49, 1278. (f) Chen, M.; Zheng,
X.; Li, W.; He, J.; Lei, A. J. Am. Chem. Soc. 2010, 132, 4101.
(g) Nicolai, S.; Piemontesi, C.; Waser, J. Angew. Chem., Int. Ed. 2011,
50, 4680. (h) Vechorkin, O.; Godinat, A.; Scopelliti, R.; Hu, X. Angew.
Chem., Int. Ed. 2011, 50, 11777. (i) Hatakeyama, T.; Okada, Y.;
Yoshimoto, Y.; Nakamura, M. Angew. Chem., Int. Ed. 2011, 50, 10973.
(j) Ye, F.; Ma, X; Xiao, Q.; Li, H.; Zhang, Y.; Wang, J. J. Am. Chem.
Soc. 2012, 134, 5742.
(6) (a) Rayabarapu, D. K.; Tunge, J. A. J. Am. Chem. Soc. 2005, 127,
13510. (b) Bi, H.-P.; Zhao, L.; Liang, Y.-M.; Li, C.-J. Angew. Chem., Int.
Ed. 2009, 48, 792. (c) Zhang, W.-W.; Zhang, X.-G.; Li, J.-H. J. Org.
Chem. 2010, 75, 5259.
(7) Brand, J. P.; Waser, J. Chem. Soc. Rev. 2012, 41, 4165.
(8) Gonzal
9457.
́
ez, D. F.; Brand, J. P.; Waser, J. Chem. −Eur. J. 2010, 16,
(9) Shi, H.; Fang, L.; Tan, C.; Shi, L.; Zhang, W.; Li, C.-c.; Luo, T.;
Yang, Z. J. Am. Chem. Soc. 2011, 133, 14944.
(10) (a) Russell, G. A.; Ngoviwatchai, P. Tetrahedron Lett. 1986, 27,
3479. (b) Russell, G. A.; Ngoviwatchai, P.; Tashtoush, H. I.; Pla-
Dalmau, A.; Khanna, R. K. J. Am. Chem. Soc. 1988, 110, 3530.
(c) Russell, G. A.; Ngoviwatchai, P. J. Org. Chem. 1989, 54, 1836.
D
dx.doi.org/10.1021/ja306638s | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX