Palladium-catalyzed direct ethynylation of C(sp3)-H bonds in aliphatic carboxylic acid derivatives

Article abstract of DOI:10.1021/ja206002m

The first catalytic alkynylation of unactivated C(sp³)-H bonds has been accomplished. The method allows for the straightforward introduction of an ethynyl group into aliphatic acid derivatives under palladium catalysis. This new reaction can be

Full text of DOI:10.1021/ja206002m

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Palladium-Catalyzed Direct Ethynylation of C(sp3)ÀH Bonds in
Aliphatic Carboxylic Acid Derivatives
Yusuke Ano,† Mamoru Tobisu,*,†,‡ and Naoto Chatani*,†
†Department of Applied Chemistry, Faculty of Engineering, and ‡Center for Atomic and Molecular Technologies,
Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
S Supporting Information
b
15 h afforded the corresponding alkynylated product 3a in 65%
isolated yield (eq 1):12
ABSTRACT: The first catalytic alkynylation of unactivated
C(sp3)ÀH bonds has been accomplished. The method
allows for the straightforward introduction of an ethynyl
group into aliphatic acid derivatives under palladium cata-
lysis. This new reaction can be applied to the rapid elabora-
tion of complex aliphatic acids, for example, via azide/alkyne
cycloaddition.
lkynes are powerful building blocks in chemical synthesis
Replacement of the 8-aminoquinoline moiety in 1a with a 1-
aminonaphthyl group (G in Figure 1) or N-methylation of the
amide group (H) completely prevented the alkynylation, indi-
cating that both the quinoline and the NH group are essential for
the reaction.
A
because of the diverse range of reactivity of carbonÀcarbon
triple bonds toward addition, cycloaddition, and metathesis
reactions, among others.1 Installation of the alkyne functionality
conventionally requires functionalized starting materials such as
halides or unsaturated bonds. If CÀH bonds2 could be alkyny-
lated directly, it would provide methods with tremendous poten-
tial value. Nevertheless, this type of CÀH bond alkynylation has
been accomplished only within the realm of aromatic3 and
heteroaromatic substrates,4 and unactivated C(sp3)ÀH bonds
have been inapplicable.5 Herein we report a palladium-catalyzed
alkynylation of unactivated C(sp3)ÀH bonds in aliphatic car-
boxylic acid derivatives. In view of the prevalence of aliphatic
acids in nature, the reaction allows for the direct introduction of
an alkyne moiety into naturally occurring substances as a handle
for further structural modification, for example, via azideÀalkyne
cycloaddition.1b
We recently reported the palladium-catalyzed direct alkynyla-
tion of C(aryl)ÀH bonds in acylated anilides using bromo-
alkynes.3c Our initial attempts to extend this catalytic system to
aliphatic substrates were unsuccessful (A in Figure 1). We reaso-
ned that the lack of reactivity may be due to an inappropriate
directing group. Although less explored than the reaction involving
C(sp2)ÀH bonds, catalytic carbonÀcarbon bond formation via
the activation of unactivated C(sp3)ÀH bonds has recently been
achieved by the research groups of Daugulis,6 Yu,7 and Sanford8
as well as by us9 through the use of suitable directing groups,
which facilitate the difficult cyclometalation process.10 It
was envisaged that the putative metallacycles formed by the
activation of C(sp3)ÀH bonds can serve as viable catalytic
intermediates for the alkynylation reactions. After an examina-
tion of several directing groups (BÀF in Figure 1), 8-amino-
quinoline6 proved to be an optimal directing group to promote
the desired alkynylation reaction. Thus, the reaction of aliphatic
amide 1a with bromoalkyne 211 in the presence of Pd(OAc)2
(5 mol %), AgOAc (1 equiv), and LiCl (1 equiv) at 110 °C for
A variety of aliphatic carboxylic acid derivatives were success-
fully alkynylated using an 8-aminoquinoline directing group
(Table 1). Substrates bearing the sterically demanding isopropyl
(1b) or cyclohexyl (1c) groups were accommodated. This alky-
nylation was also tolerant of a wide range of functional groups,
including ethers (1d, 1f, and 1l), esters (1g), halides (1h, 1i, 1m,
and 1o), and a nitro group (1n). C(sp3)ÀH bonds adjacent to
heteroatoms (1d) and those at the benzylic position (1kÀo)
underwent the alkynylation similarly without reoptimization of
the catalytic system. Interestingly, the electronic nature of ben-
zylic substrates had a minimal impact on the yield, which is in
sharp contrast to our previously reported palladium-catalyzed
C(aryl)ÀH bond alkynylation.3c The current limitation for this
Figure 1. Ineffective Directing Groups.
Received: June 28, 2011
Published: July 26, 2011
r
2011 American Chemical Society
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Table 1. Pd-Catalyzed Direct Alkynylation of Aliphatic CÀH
Bonds with Bromoalkyne 2a
Figure 2. Pd-catalyzed direct alkynylation of bioactive carboxylic acid
derivatives. Reaction conditions: amide (Q = 8-quinolinyl, 0.5 mmol), 2
(0.75 mmol), Pd(OAc)2 (0.025 mmol), AgOAc (0.5 mmol), and LiCl
(0.5 mmol) in toluene (1 mL) at 110 °C for 15 h. Numbers refer to
isolated yields based on the amides, and those in parentheses refer to
yields based on the reacted amides. In the case of the reaction of 1s to
give 3s, 0.05 mmol of Pd(OAc)2 was used, and the product was obtained
as a 1.5:1 mixture of diastereomers.
Scheme 2. Installation of a Fluorophore via Sequential CÀH
Bond Alkynylation/AzideÀAlkyne Cycloaddition
a Reaction conditions: amide (0.5 mmol), 2 (0.75 mmol), Pd(OAc)2
(0.025 mmol), AgOAc (0.5 mmol), and LiCl (0.5 mmol) in toluene
(1 mL) at 110 °C for 15 h. The numbers refer to isolated yields based on
the amides, and those in parentheses refer to yields based on the reacted
amides. b The reaction was run for 24 h. c Pd(OAc)2 (0.05 mmol)
was used.
functionalization occurs at the γ-position of aliphatic carboxylic
acid derivatives.6d
Scheme 1. Recovery of the Directing Group
One of the eminent advantages of using an 8-aminoquinoline
director is its readily attachable and detachable nature. This
amide bond can be formed by applying the conventional conden-
sation procedure to aliphatic acids.14 After serving as a directing
group, the amide can be transformed into a versatile ester func-
tionality while the silylalkyne moiety remains intact (Scheme 1).
We also found that the palladium-catalyzed alkynylation
reaction was applicable to some natural-product-derived sub-
strates (Figure 2). An aliphatic CÀH bond at the β-position of
oleic acid could be alkynylated in a regioselective manner, even in
the presence of normally more reactive allylic CÀH bonds,10 to
produce 3q. γ-Aminobutyric acid (GABA) derivative 1r under-
went the alkynylation, with which the N-Boc and N-benzyl pro-
tecting groups were compatible. Moreover, substrate 1s containing
a steroidal architecture was successfully utilized in this protocol.
These results highlight the potential utility of this alkynylation in
the postsynthetic elaboration of complex natural products. Thus,
the obtained alkynylated products can serve as versatile synthetic
intermediates. For example, fluorophore labeling of GABA
derivative 1r with a dansyl group was successfully accomplished
via a CÀH alkynylation/desilylation/copper-catalyzed azideÀ
alkyne cycloaddition sequence (Scheme 2).1b
method is that only secondary CÀH bonds are alkynylated in
synthetically useful yields, while primary and tertiary CÀH bonds
undergo alkynylation with a lower efficiency.13 This preference
for secondary CÀH bonds is a notable feature of an 8-amino-
quinoline directing group.6 Importantly, when substrates bearing
no hydrogen at the β-position (e.g., 1j) were used, alkynylation
proceeded regioselectively at the γ-position. This demonstrates
one of the rare examples wherein catalytic C(sp3)ÀH
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In conclusion, we have developed a palladium-catalyzed alkynyla-
tion reaction of aliphatic CÀH bonds in carboxylic acids simply
by attaching an 8-aminoquinoline directing group to the acid.
Functional group tolerance and applicability to natural-product-
based substrates have been demonstrated. In view of the wide-
spread utility of the copper-catalyzed azide/alkyne cycloaddition
in modifying natural and non-natural products, the present
protocol offers a new method for preparing complex alkyne
components in a more straightforward manner. Further studies
to explore catalytic methods for the functionalization of C(sp3)À
H bonds are now in progress.
(c) Seregin, I. V.; Ryabova, V.; Gevorgyan, V. J. Am. Chem. Soc. 2007,
129, 7742. (d) Trofimov, B. A.; Sobenina, L. N.; Stepanova, Z. V.;
Vakul’skaya, T. I.; Kazheva, O. g. N.; Aleksandrov, G. G.; Dyachenko,
O. A.; Mikhaleva, A. b. I. Tetrahedron 2008, 64, 5541. (e) Gu, Y.; Wang,
X.-m. Tetrahedron Lett. 2009, 50, 763. (f) Rodriguez, A.; Fennessy, R. V.;
Moran, W. J. Tetrahedron Lett. 2009, 50, 3942. (g) Matsuyama, N.;
Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2009, 11, 4156. (h) Brand,
J. P.; Charpentier, J.; Waser, J. Angew. Chem., Int. Ed. 2009, 48, 9346.
(i) Besseliꢀevre, F.; Piguel, S. Angew. Chem., Int. Ed. 2009, 48, 9553.
(j) Kitahara, M.; Hirano, K.; Tsurugi, H.; Satoh, T.; Miura, M. Chem.—
Eur. J. 2010, 16, 1772. (k) Kawano, T.; Matsuyama, N.; Hirano, K.;
Satoh, T.; Miura, M. J. Org. Chem. 2010, 75, 1764. (l) Kim, S. H.; Chang,
S. Org. Lett. 2010, 12, 1868. (m) Yang, L.; Zhao, L.; Li, C.-J. Chem.
Commun. 2010, 46, 4184. (n) Berciano, B. P.; Lebrequier, S.; Besseliꢀevre,
F.; Piguel, S. Org. Lett. 2010, 12, 4038. (o) Brand, J. P.; Waser, J. Angew.
Chem., Int. Ed. 2010, 49, 7304. (p) Brand, J. P.; Gonzalez, D. F.; Nicolai,
S.; Waser, J. Chem. Commun. 2011, 47, 102. (q) Kim, S. H.; Yoon, J.;
Chang, S. Org. Lett. 2011, 13, 1474. Also see refs 3fÀ3h.
’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental procedu-
b
res and characterization of products. This material is available
free of charge via the Internet at http://pubs.acs.org.
(5) Alkynylation of activated C(sp3)ÀH bonds is known. For
selected examples involving C(sp3)ÀH bonds R to heteroatoms, see:
(a) Murata, S.; Teramoto, K.; Miura, M.; Nomura, M. J. Chem. Res.,
Synop. 1993, 434. (b) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2004, 126, 11810.
(c) Li, Z.; Bohle, D. S.; Li, C.-J. Proc. Natl. Acad. Sci. U.S.A. 2006,
103, 8928. For benzylic and allylic CÀH bonds, see:(d) Correia, C. A.;
Li, C.-J. Adv. Synth. Catal. 2010, 352, 1446. For C(sp3)ÀH bonds R to
carbonyls, see:(e) Gonzꢁalez, D. F.; Brand, J. P.; Waser, J. Chem.—Eur. J.
2010, 16, 9457.
’ AUTHOR INFORMATION
Corresponding Author
tobisu@chem.eng.osaka-u.ac.jp; chatani@chem.eng.osaka-u.ac.jp
’ ACKNOWLEDGMENT
(6) (a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
2005, 127, 13154. (b) Shabashov, D.; Daugulis, O. Org. Lett. 2005, 7,
3657. (c) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2010, 132, 3965.
For elegant applications of the method to complex-molecule synthesis, see:
(d) Reddy, B. V. S.; Reddy, L. R.; Corey, E. J. Org. Lett. 2006, 8, 3391.
(e) Feng, Y.; Chen, G. Angew. Chem., Int. Ed. 2010, 49, 958. (f) Feng, Y.;
Wang, Y.; Landgraf, B.; Liu, S.; Chen, G. Org. Lett. 2010, 12, 3414. (g) He,
G.; Chen, G. Angew. Chem., Int. Ed. 2011, 50, 5192.
(7) (a) Chen, X.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006,
128, 12634. (b) Giri, R.; Maugel, N.; Li, J.-J.; Wang, D.-H.; Breazzano,
S. P.; Saunders, L. B.; Yu, J.-Q. J. Am. Chem. Soc. 2007, 129, 3510. (c)
Wang, D.-H.; Wasa, M.; Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008,
130, 7190. (d) Shi, B.-F.; Maugel, N.; Zhang, Y.-H.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2008, 47, 4882. (e) Wasa, M.; Engle, K. M.; Yu, J.-Q.
J. Am. Chem. Soc. 2009, 131, 9886. (f) Wasa, M.; Engle, K. M.; Yu, J.-Q.
J. Am. Chem. Soc. 2010, 132, 3680. (g) Yoo, E. J.; Wasa, M.; Yu, J.-Q.
J. Am. Chem. Soc. 2010, 132, 17378. (h) Wasa, M.; Yu, J.-Q. Tetrahedron
2010, 66, 4811.
This article is dedicated to Professor Christian Bruneau on the
occasion of his 60th birthday. This work was supported by grants
from the Ministry of Education, Culture, Sports, Science and
Technology (MEXT), Japan. M.T. acknowledges the HISHO
Program of Osaka University. Y.A. expresses his special thanks to
JSPS for a Research Fellowship for Young Scientists and to the
Global COE Program of Osaka University. We also thank the
Instrumental Analysis Center, Faculty of Engineering, Osaka Uni-
versity, for assistance with the MS, HRMS, and elemental analyses.
’ REFERENCES
(1) (a) Acetylene Chemistry; Diederich, F., Stang, P. J., Tykwinski,
R. R., Eds.; Wiley-VCH: Weinheim, Germany, 2005. For a themed issue
on click chemistry, see:(b) Finn, M. G.; Fokin, V. V. Chem. Soc. Rev.
2010, 39, 1231 and articles cited therein. For a review of alkyne meta-
thesis, see:(c) Zhang, W.; Moore, J. S. Adv. Synth. Catal. 2007, 349, 93.
For a review of cycloisomerization using alkynes, see:(d) Lee, S. I.;
Chatani, N. Chem. Commun. 2009, 371.
(2) For selected reviews of catalytic CÀH bond-functionalization
reactions, see: (a) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013.
(b) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int.
Ed. 2009, 48, 5094. (c) Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc.
Chem. Res. 2009, 42, 1074. (d) Lyons, T. W.; Sanford, M. S. Chem. Rev.
2010, 110, 1147. (e) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem.
Rev. 2010, 110, 624. (f) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2010,
111, 1293. (g) Ackermann, L. Chem. Commun. 2010, 46, 4866. (h)Hirano,
K.; Miura, M. Synlett 2011, 294.
(3) (a) Kobayashi, K.; Arisawa, M.; Yamaguchi, M. J. Am. Chem. Soc.
2002, 124, 8528. (b) Amemiya, R.; Fujii, A.; Yamaguchi, M. Tetrahedron
Lett. 2004, 45, 4333. (c) Tobisu, M.; Ano, Y.; Chatani, N. Org. Lett. 2009,
11, 3250. (d) de Haro, T.; Nevado, C. J. Am. Chem. Soc. 2010, 132, 1512.
(e) Wei, Y.; Zhao, H.; Kan, J.; Su, W.; Hong, M. J. Am. Chem. Soc. 2010,
132, 2522. (f) Matsuyama, N.; Kitahara, M.; Hirano, K.; Satoh, T.;
Miura, M. Org. Lett. 2010, 12, 2358. For reviews, see:(g) Dudnik, A. S.;
Gevorgyan, V. Angew. Chem., Int. Ed. 2010, 49, 2096. (h) Messaoudi, S.;
Brion, J.-D.; Alami, M. Eur. J. Org. Chem. 2010, 6495.
(8) Stowers, K. J.; Fortner, K. C.; Sanford, M. S. J. Am. Chem. Soc.
2011, 133, 6541.
(9) Hasegawa, N.; Charra, V.; Inoue, S.; Fukumoto, Y.; Chatani, N.
J. Am. Chem. Soc. 2011, 133, 8070.
(10) For catalytic C(sp3)ÀH bond functionalization reactions with-
out chelation assistance and those other than CÀC bond formation, see
the following leading reviews: (a) Jazzar, R.; Hitce, J.; Renaudat, A.;
Sofack-Kreutzer, J.; Baudoin, O. Chem.—Eur. J. 2010, 16, 2654. (b) Li,
H.; Li, B.-J.; Shi, Z.-J. Catal. Sci. Technol. 2011, 1, 191.
(11) (a) Bromoalkyne 2 can be readily prepared from commercially
available triisopropylacetylene in one step. See: Jiang, M. X.-W.; Rawat,
M.; Wulff, W. D. J. Am. Chem. Soc. 2004, 126, 5970.(b) The exceptional
effectiveness of TIPS-protected alkynes has often been observed in other
catalytic reactions. See refs 3c, 4h, 4o, and 4p and references therein.
(c) Bromoethynylbenzene and 1-bromooct-1-yne did not afford the
corresponding alkynylated products.
(12) See the Supporting Information for details of optimization studies.
(13) The yield for the amide of propanoic acid was 7%; the yield for
the amide of 3-methylbutanoic acid was ∼17%, and a γ-alkynylated
product was also formed.
(14) See the Supporting Information for the preparation of the
starting amides.
(4) (a) Kalinin, V. K.; Pashchenko, D. N.; She, F. M. Mendeleev
Commun. 1992, 2, 60. (b) Trofimov, B. A.; Stepanova, Z. V.; Sobenina,
L. N.; Mikhaleva, A. b. I.; Ushakov, I. A. Tetrahedron Lett. 2004, 45, 6513.
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