Ligand-Enabled Alkynylation of C(sp3)?H Bonds with Palladium(II) Catalysts

Article abstract of DOI:10.1002/anie.201610426

The palladium(II)-catalyzed β- and γ-alkynylation of amide C(sp³)?H bonds is enabled by pyridine-based ligands. This alkynylation reaction is compatible with substrates containing α-tertiary or α-quaternary carbon centers. The β-methylene C(sp<

Full text of DOI:10.1002/anie.201610426

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201610426
German Edition: DOI: 10.1002/ange.201610426
À
C H Activation
3
À
Ligand-Enabled Alkynylation of C(sp ) H Bonds with Palladium(II)
Catalysts
Haiyan Fu+, Peng-Xiang Shen+, Jian He, Fanglin Zhang, Suhua Li, Peng Wang, Tao Liu, and Jin-
Quan Yu*
Abstract: The palladium(II)-catalyzed b- and g-alkynylation
3
À
of amide C(sp ) H bonds is enabled by pyridine-based ligands.
This alkynylation reaction is compatible with substrates
containing a-tertiary or a-quaternary carbon centers. The
3
À
b-methylene C(sp ) H bonds of various carbocyclic rings were
also successfully alkynylated.
A
lkynes are important synthetic moieties in materials
science and organic synthesis as they can be utilized as
pivotal handles for further transformations.[1] Aside from the
palladium(0)-catalyzed Sonogashira reaction,[2] transition-
À
metal-catalyzed direct C H alkynylation reactions provide
À
a complementary method to install C C triple bonds into
complex molecules. Over the past several years, the alkyny-
2
À
lation of C(sp ) H bonds has been achieved using a number
of transition-metal catalysts.[3–7] In sharp contrast, the alky-
3
À
nylation of inert C(sp ) H bonds remains underdeveloped,
and only a few examples have been reported.[8–10] Chatani and
3
À
Scheme 1. Palladium-catalyzed C(sp ) H alkynylation of amides.
co-workers reported a palladium(II)-catalyzed alkynylation
3
À
of methylene C(sp ) H bonds using a bidentate auxiliary
(Scheme 1A).[8a] Our group also developed
a
À
distinct
Encouraged by our recent finding that pyridine- and
3
3
À
approach for the alkynylation of b-methyl C(sp ) H bonds
using Pd0/phosphine and Pd0/N-heterocyclic carbene (NHC)
catalysts (Scheme 1B).[8b] Despite the success with the
palladium-catalyzed alkynylation of amide substrates con-
taining a-hydrogen atoms, amides derived from aliphatic
acids bearing a-quaternary carbon centers gave poor reac-
tivity.[8] Cobalt- and nickel-catalyzed b-alkynylation reactions
that involve the use of a bidentate auxiliary have also been
developed, but are limited to amide substrates containing
quinoline-based ligands facilitate C(sp ) H arylation through
a PdII/PdIV catalytic cycle,[11,12] we envisioned that a modified
ligand scaffold might also promote C(sp ) H alkynylation
3
À
through the same redox chemistry. A preliminary test was
carried out by reacting 1a with triisopropyl (TIPS) protected
ethynyl bromide (2.0 equiv) in the presence of Pd(OAc)2
(10 mol%), AgOAc (1.0 equiv), and pyridine L1 (12 mol%)
in toluene at 1108C for 20 h (Table 1). To our delight, the
desired alkynylated product 3aa was obtained in 28% yield,
along with 5% of cyclized product 4aa. Control experiments
revealed that both the pyridine ligand and AgOAc were
required (see the Supporting Information). To further explore
the ligand effect, a series of pyridine-based ligands were
screened. Noticeably, 2-picoline increased the yield of 3aa
from 38% to 58%. Ligands containing a methyl group at the
2-position and alkyl substituents at other positions (L3, L5,
L8, and L9) further increased the yield to 66%. In contrast,
ligands without alkyl substituents at the 2-position (L4 and
L6) decreased the yield to 34% and 40%, respectively. Based
on these results, cycloalkane-fused pyridines were then
exploited to improve the reaction efficiency. Gratifyingly,
2,3,4,5-di-cyclohexane-fused pyridine L14 gave the desired
product 3aa in 85% yield, with no detectable side product
4aa. Quinoline- and isoquinoline-based ligands did not
further increase the yield of 3aa.
quaternary carbon centers.[9] To broaden the substrate scope
of C(sp ) H alkynylation, it is highly desirable to develop new
ligands that can promote alkynylation reactions under mild
3
À
conditions. Herein, we report the first example of ligand-
3
enabled C(sp ) H alkynylation by PdII/PdIV catalysis
À
(Scheme 1, bottom). This reaction is compatible with a wide
range of carboxylic acid derivatives, including a-amino acid
substrates as well as a-quaternary and cyclic amide substrates.
[*] Dr. H. Fu,[+] P.-X. Shen,[+] J. He, Dr. F. Zhang, Dr. S. Li, Dr. P. Wang,
T. Liu, Prof. Dr. J.-Q. Yu
Department of Chemistry
The Scripps Research Institute (TSRI)
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
E-mail: yu200@scripps.edu
[+] These authors contributed equally to this work.
With optimized reaction conditions in hand, we then
explored the scope of alkynyl bromides using L14 as the
ligand (Table 2). TIPS-protected ethynyl bromide afforded
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201610426.
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

Angewandte
Communications
Chemie
Table 1: Ligand screening.[a]
yield, respectively. The sterically less demanding tripropyl-
and TES-protected ethynyl bromides could also be used as
coupling partners, but resulted in lower yields. Alkynylation
with trityl ethynyl bromide gave the final product 3af in 52%
yield.
Using TIPS-protected ethynyl bromide as the coupling
partner, we then studied the alkynylation of other types of
amino acid derived amides. In the alkynylation of a-quater-
nary substrates (1b and 1c), the corresponding products were
prone to cyclization, providing 4ba and 4ca, respectively,
possibly owing to the Thorpe–Ingold effect from the
a-substituents (Scheme 2). This method can also be applied
Scheme 2. Alkynylation of amino acids bearing a-quaternary carbon
centers.
[a] Reaction conditions: 1a (0.1 mmol), Pd(OAc)2 (0.01 mmol), AgOAc
(0.1 mmol), TIPS alkynyl bromide (0.2 mmol), ligand (0.012 mmol),
toluene (1.0 mL), 1108C, 24 h. Yields determined by NMR spectroscopy
with CH2Br2 as the internal standard. Phth=phthaloyl.
3
À
to remote g-C(sp ) H alkynylation. For example, the alky-
nylation of valine-derived N-aryl amide 1d with TIPS-
protected ethynyl bromide in t-AmylOH afforded g-alkyny-
lated product 3da in 46% yield when L16 and Ag2CO3 were
used as ligand and oxidant, respectively (Scheme 3a). Iso-
leucine derivative 1e also provided the g-alkynylated product
in 22% yield (Scheme 3b).
Table 2: Alkynylation of amino acid amides.[a]
Under slightly modified reaction conditions (see the
Supporting Information), we systematically tested the scope
of the reaction with respect to aliphatic amides using L3 as the
optimal ligand (Table 3). For amides containing a-hydrogen
atoms (5a–5h), the alkynylated products (6a–6h) were
obtained in good yields. When both b-methyl and
3
À
b-methylene C(sp ) H bonds were present in the substrate
3
À
(5a, 5c, 5e, 5 f, and 5h), the b-methyl C(sp ) H bonds were
[a] 1a (0.1 mmol), alkynyl bromide (0.2 mmol), Pd(OAc)2 (0.01 mmol),
AgOAc (0.1 mmol), L14 (0.012 mmol), toluene (1.0 mL), 1108C, 20 h.
Yields of isolated products are given. TBDPS=Si(t-Bu)Ph2, TBS=
Si(t-Bu)Me2, TES=SiEt3, TIPS=Si(i-Pr)3.
the desired alkynylated product in 81% yield after isolation,
and the reaction could be scaled up to 5.0 mmol without
a decrease in yield. TBS- and TBDPS-protected ethynyl
bromide gave the corresponding products in 76% and 72%
3
À
Scheme 3. g-C(sp ) H alkynylation of a-amino acid amides.
2
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
These are not the final page numbers!

Angewandte
Communications
Chemie
Table 3: Alkynylation of aliphatic amides.[a]
Scheme 4. Removal of the auxiliary and TIPS moieties. Reaction
conditions: a) BF3·Et2O (2.0 equiv), MeOH, 1008C, 30 h; b) ethylenedi-
amine (5.0 equiv), MeOH/CH2Cl2 (1:1), 408C, 4 h; c) (Boc)2O
(1.5 equiv), CH2Cl2, RT; d) TBAF (1.05 equiv), THF, 08C, 0.5 h. Boc=
tert-butoxycarbonyl, TBAF=tetrabutylammonium fluoride.
of TBAF, compound 9 could be easily converted into
synthetically useful intermediate 10, which allows for the
synthesis of various unnatural amino acids. The terminal
triple bond could be effectively transformed into a triazole to
give compound 11 in a click reaction (Scheme 5).[13] It could
also be coupled with the tert-butyl imines of ortho-halogen-
ated aldehydes to form isoquinolines 12 and 13 after cycliza-
tion.[14]
[a] Reaction conditions: 5 (0.1 mmol), TIPS-protected alkynyl bromide
(0.2 mmol), Pd(OAc)2 (0.01 mmol), AgOAc (0.1 mmol), KHCO3
(0.4 mmol), L3 (0.01 mmol), CH2Cl2 (1.0 mL), 708C, 36 h. Yields of
isolated products are given. [b] Toluene (1.0 mL), 1008C. [c] 1008C.
[d] AgOPiv (0.1 mmol), KF (0.2 mmol), 1008C. [e] Ag2CO3 (0.2 mmol),
L16 (0.02 mmol), t-AmylOH (1.0 mL), 808C, 10 h.
3
À
selectively alkynylated over the methylene C(sp ) H bonds.
3
À
Encouragingly, the b-methylene C(sp ) H bonds of cyclic
substrates (5i–5l) could be alkynylated at higher temper-
atures. Cyclopropanecarboxylic acid amide 5i afforded the
alkynylated product in 65% overall yield (mono/di = 2.5:1)
Scheme 5. Transformations of alkynyl amino acid 10. a) CuSO4·5H2O
(1.0 mol%), sodium ascorbate (5 mol%), H2O/t-BuOH (2:1), RT,
overnight; b) 1) PdCl2(PPh3)2 (2.0 mol%), CuI (1.0 mol%), NEt3, 558C,
3 h; 2) CuI (10 mol%), DMF, 1008C; c) 1) PdCl2(PPh3)2 (2.0 mol%),
CuI (1.0 mol%), NEt3, 558C, 5 h; 2) CuI (10 mol%), DMF, 1008C.
after only 10 h. The present method was also found to be
3
À
effective for the alkynylation of b-methyl C(sp ) H bonds of
substrates containing a-quaternary carbon centers (5m–5o).
AgOPiv and KF were used as the optimal additive and base
for this type of substrates. Alkynylation of pivalic acid amide
5m gave a mixture of the mono- and difunctionalized
products in a total yield of 70%, and the monoalkynylated
product was isolated in 50% yield. It is worth noting that
a-quaternary substrates (5k–5o) were not compatible with
our previously developed Pd0/NHC and Pd0/phosphine sys-
tems[8b] nor with other reported methods.[8] For a substrate
without b-hydrogen atoms (5p), the use of L16 enabled
alkynylation at the g-position, albeit in moderate yield.
Propionic acid derived amide 5q also gave the desired
product in 38% yield (see the Supporting Information).
The auxiliary can be readily removed by treatment with
BF3·Et2O to transform 3aa into methyl ester 7 (Scheme 4).
The phthaloyl group was removed in ethylenediamine
solution to give the free amine 8, which was then protected
with Boc2O. After removal of the TIPS group in the presence
In conclusion, pyridine-based ligands have been utilized
to enable alkynylation reactions of b-methyl as well as
3
À
b-methylene C(sp ) H bonds in carboxylic acid derivatives.
Substrates containing a-quaternary carbon centers were
successfully alkynylated by palladium catalysis for the first
time. The development of chiral pyridine-based ligands to
3
À
realize an enantioselective version of this C(sp ) H alkyny-
lation is currently underway in our laboratory.
Acknowledgements
We gratefully acknowledge The Scripps Research Institute
and the NIH (NIGMS, 2R01 GM084019) for financial
support. H.F. is a visiting scholar from Sichuan University
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

Angewandte
Communications
Chemie
Feng, Y. Luo, T.-P. Loh, Org. Lett. 2014, 16, 5956; h) C. Feng, D.
Feng, T.-P. Loh, Chem. Commun. 2014, 50, 9865; i) K. D. Collins,
sponsored by the Young Teacher Abroad Training Program of
Sichuan University.
F. Lied, F. Glorius, Chem. Commun. 2014, 50, 4459.
2
À
[5] For selected examples of copper-catalyzed C(sp ) H alkynyla-
tion, see: a) Z. P. Li, C. J. Li, J. Am. Chem. Soc. 2004, 126, 11810;
b) Z. P. Li, P. D. MacLeod, C. J. Li, Tetrahedron: Asymmetry
2006, 17, 590; c) M. Shang, H.-L. Wang, S.-Z. Sun, H.-X. Dai, J.-
Conflict of interest
The authors declare no conflict of interest.
Q. Yu, J. Am. Chem. Soc. 2014, 136, 11590.
[6] For a rare example of gold-catalyzed C(sp ) H alkynylation,
see: J. P. Brand, J. Waser, Org. Lett. 2012, 14, 744.
[7] For selected examples of nickel-catalyzed C(sp ) H alkynyla-
2
À
À
Keywords: alkynylation · amino acids · C H activation ·
2
À
palladium · pyridine
tion, see: a) N. Matsuyama, K. Hirano, T. Satoh, M. Miura, Org.
Lett. 2009, 11, 4156; b) E. Brachet, J.-D. Brion, M. Alami, S.
Messaoudi, Chem. Eur. J. 2013, 19, 15276; c) Y. Liu, Y.-H. Liu, S.-
Y. Yan, B.-F. Shi, Chem. Commun. 2015, 51, 6388.
3
À
[8] For rare examples of palladium-catalyzed C(sp ) H alkynyla-
[1] a) F. Diederich, P. J. Stang, R. R. Tykwinski, Acetylene Chemis-
try: Chemistry, Biology and Material Science, Wiley-VCH,
Weinheim, 2005; b) A. Fꢀrstner, P. W. Davies, Chem.
Commun. 2005, 2307; c) H. C. Kolb, M. G. Finn, K. B. Sharpless,
Angew. Chem. Int. Ed. 2001, 40, 2004; Angew. Chem. 2001, 113,
2056.
tion, see: a) Y. Ano, M. Tobisu, N. Chatani, J. Am. Chem. Soc.
2011, 133, 12984; b) J. He, M. Wasa, K. S. L. Chan, J.-Q. Yu, J.
Am. Chem. Soc. 2013, 135, 3387; c) B. Wang, C. Lu, S.-Y. Zhang,
G. He, W. A. Nack, G. Chen, Org. Lett. 2014, 16, 6260; d) B.
Wang, G. He, G. Chen, Sci. China Chem. 2015, 58, 1345; e) X. Ye,
C. Xu, L. Wojtas, N. G. Akhmedov, H. Chen, X. Shi, Org. Lett.
2016, 18, 2970.
[2] a) K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett.
1975, 16, 4467; b) K. Sonogashira, J. Organomet. Chem. 2002,
[9] a) J. Zhang, H. Chen, C. Lin, Z. Liu, C. Wang, Y. Zhang, J. Am.
Chem. Soc. 2015, 137, 12990; b) F.-X. Luo, Z.-C. Cao, H.-W.
Zhao, D. Wang, Y.-F. Zhang, X. Xu, Z.-J. Shi, Organometallics
2016, DOI: 10.1021/acs.organomet.6b00529.
653, 46.
2
À
[3] For selected examples of palladium-catalyzed C(sp ) H alkyny-
lation, see: a) I. V. Seregin, V. Ryabova, V. Gevorgyan, J. Am.
Chem. Soc. 2007, 129, 7742; b) Y. Gu, X. Wang, Tetrahedron Lett.
2009, 50, 763; c) S. H. Kim, S. Chang, Org. Lett. 2010, 12, 1868;
d) L. Yang, L. Zhao, C.-J. Li, Chem. Commun. 2010, 46, 4184;
e) S. H. Kim, J. Yoon, S. Chang, Org. Lett. 2011, 13, 1474; f) F.
Shibahara, Y. Dohke, T. Murai, J. Org. Chem. 2012, 77, 5381;
g) A. S. Dudnik, V. Gevorgyan, Angew. Chem. Int. Ed. 2010, 49,
2096; Angew. Chem. 2010, 122, 2140; h) M. Tobisu, Y. Ano, N.
Chatani, Org. Lett. 2009, 11, 3250; i) S. H. Kim, S. H. Park, S.
Chang, Tetrahedron 2012, 68, 5162; j) Y. Ano, M. Tobisu, N.
Chatani, Org. Lett. 2012, 14, 354; k) J. P. Brand, J. Waser, Chem.
Soc. Rev. 2012, 41, 4165; l) G. L. Tolnai, S. Ganss, J. P. Brand, J.
[10] S. Tang, P. Wang, H. Li, A. Lei, Nat. Commun. 2016, 7, 11676.
3
À
[11] For selected examples of C(sp ) H activation reactions that are
promoted by pyridine-based ligands and proceed via a PdII/PdIV
catalytic cycle, see: a) J. He, S. Li, Y. Deng, H. Fu, B. N.
Laforteza, J. E. Spangler, A. Homs, J.-Q. Yu, Science 2014, 343,
1216; b) Y. Deng, W. Gong, J. He, J.-Q. Yu, Angew. Chem. Int.
Ed. 2014, 53, 6692; Angew. Chem. 2014, 126, 6810; c) R. Y. Zhu,
J. He, X. C. Wang, J. Q. Yu, J. Am. Chem. Soc. 2014, 136, 13194;
d) J. He, R. Takise, H. Fu, J.-Q. Yu, J. Am. Chem. Soc. 2015, 137,
4618.
[12] J. He, M. Wasa, K. S. L. Chan, Q. Shao, J.-Q. Yu, Chem. Rev.
2017, DOI: 10.1021/acs.chemrev.6b00622.
[13] V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless,
Angew. Chem. Int. Ed. 2002, 41, 2596; Angew. Chem. 2002, 114,
2708.
Waser, Org. Lett. 2013, 15, 112.
[4] For selected examples of rhodium-catalyzed C(sp ) H alkyny-
2
À
lation, see: a) X. Zhang, Z. Qi, J. Gao, X. Li, Org. Biomol. Chem.
2014, 12, 9329; b) X.-F. Yang, X.-H. Hu, C. Feng, T.-P. Loh,
Chem. Commun. 2015, 51, 2532; c) F. Xie, Z. Qi, S. Yu, X. Li, J.
Am. Chem. Soc. 2014, 136, 4780; d) H. Wang, F. Xie, Z. Qi, X. Li,
Org. Lett. 2015, 17, 920; e) J. Jeong, P. Patel, H. Hwang, S. Chang,
Org. Lett. 2014, 16, 4598; f) C. Feng, T. P. Loh, Angew. Chem. Int.
Ed. 2014, 53, 2722; Angew. Chem. 2014, 126, 2760; g) C. Feng, D.
[14] K. R. Roesch, R. C. Larock, Org. Lett. 1999, 1, 553.
Manuscript received: October 25, 2016
Final Article published: && &&, &&&&
4
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
À
C H Activation
Pyridine-enabled: The palladium(II)-cata-
lyzed b- and g-alkynylation of amide
3
À
H. Fu, P.-X. Shen, J. He, F. Zhang, S. Li,
P. Wang, T. Liu, J.-Q. Yu*
C(sp ) H bonds is enabled by pyridine-
&&& — &&&
based ligands. This alkynylation reaction
is compatible with substrates containing
3
À
Ligand-Enabled Alkynylation of C(sp ) H
Bonds with Palladium(II) Catalysts
a-tertiary or a-quaternary carbon centers.
3
À
The b-methylene C(sp ) H bonds in
various carbocyclic rings were also suc-
cessfully alkynylated.
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!