Palladium(0)-catalyzed alkynylation of C(sp3)-H bonds

Article abstract of DOI:10.1021/ja400648w

The alkynylation of β-C(sp³)-H bonds in aliphatic amides with alkynyl halides has been enabled using Pd(0)/N-heterocyclic carbene (NHC) and Pd(0)/phosphine (PR₃) catalysts. This is the first example of utilizing [AlkynylPd(II)L_n

Full text of DOI:10.1021/ja400648w

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Palladium(0)-Catalyzed Alkynylation of C(sp3)–H Bonds
Jian He, Masayuki Wasa, Kelvin S. L. Chan, and Jin-Quan Yu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja400648w • Publication Date (Web): 13 Feb 2013
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Palladium(0)-Catalyzed Alkynylation of C(sp3)–H Bonds
Jian He, Masayuki Wasa, Kelvin S. L. Chan, Jin-Quan Yu*
Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037
RECEIVED DATE (automatically inserted by publisher); yu200@scripps.edu
Abstract: The alkynylation of β-C(sp3)–H bonds in aliphatic
amides with alkynyl halides has been enabled using
Pd(0)/N-heterocyclic carbene (NHC) and Pd(0)/phosphine
(PR3) catalysts. This is the first example of utilizing
[AlkynylPd(II)Ln] complexes to activate C(sp3)–H bonds.
oxidative addition of alkynyl halide have not been demonstrated
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to cleave inert C(sp3)–H bonds. In addition, upon C(sp3)–H
activation, reductive elimination to generate the desired C(sp3)–
alkynyl bond from a Pd(II) center has no precedent, although a
rare example of Sonogashira coupling with alkyl halides was
achieved by Fu.13
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With these considerations in mind, we initiated our
investigation of the Pd(0)-catalyzed β-C(sp3)–H alkynylation of
N-arylamide 1a. Initial screening of the ligands (0.2 equiv.) was
carried out by reacting 0.1 mmol of amide 1a with 10 mol% of
Pd(OAc)2, 2 equiv. of TIPS-alkynyl iodide and 2 equiv. of
Cs2CO3 in toluene at 80 °C under nitrogen for 8 hours (Table 1).
To our delight, using PCy3·HBF4 as the ligand,14 we obtained the
desired alkynylation product 2a in 41% yield; however, we also
identified that 2a could undergo Pd-catalyzed aminoalkynylation
of the initially installed alkynyl group to give the undesired
product 3a (Table 1, entry 1).15 In order to suppress this undesired
side reaction, we changed the alkynyl iodide to the corresponding
bromide, which gave 40% of 2a and improved the product ratio
between 2a and 3a to 5:1 (Table 1, entry 2). TIPS-alkynyl
chloride yielded no product, presumably due to its sluggish
oxidative addition onto Pd(0). Subsequently, we carried out an
extensive screening of solvents using PCy3·HBF4 and TIPS-
alkynyl bromide to find that freshly distilled Et2O gave the best
yield of 2a in 61% yield while affording only 2% of 3a (Table 1,
entry 8). Polar, strongly coordinating solvents such as DMF and
DMSO promoted the decomposition of the alkynyl bromide and
gave no desired product.
The Pd(0)-catalyzed Sonogashira coupling reaction, which
couples alkynes with aryl halides or pseudohalides, is a pivotal C–
C bond forming reaction in modern organic synthesis.1 The
development of complementary methods to convert C–H bonds
into C–alkynyl bonds is highly attractive, as the alkyne moiety
remains an essential functional group in many cross-coupling,
metathesis and cycloaddition reactions.2 In a pioneering study,
Gevorgyan demonstrated the feasibility of coupling heterocyclic
C(sp2)–H bonds with alkynyl halides using Pd(0)/PR3 catalysts.3a
Pd(II)/Pd(0) catalysis has also been successfully employed in the
cross-coupling of heterocycles with alkynes.4 However, despite a
number of reports concerning C(sp2)–H alkynylation reactions,3-7
methods to convert inert C(sp3)–H bonds to C(sp3)–alkynyl bonds
remain rare, with only a single example reported by Chatani
illustrating the Pd(II)-catalyzed coupling of C(sp3)–H bonds with
alkynyl halides via Pd(II)/Pd(IV) catalysis.8 Herein, we report the
first example of Pd(0)/NHC and Pd(0)/PR3-catalyzed alkynylation
of β-C(sp3)–H bonds using an N-arylamide auxiliary.
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Scheme 1. C–H Alkynylation using Pd(II) and Pd(0) Catalysts
Table 1. Screening of Alkynyl Halide and Solventa,b
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Recently, substantial progress has been made in the
development of Pd(II)-catalyzed C(sp3)–H activation reactions.8,9
In contrast, Pd(0)/PR3-catalyzed intermolecular C(sp3)–H bond
activation remains underdeveloped, with only one example of -
arylation of amides reported by our group in 2009.10 Since
Pd(0)/Pd(II)-catalysis is compatible with a wide range of ligands
and does not require co-oxidants, we embarked on expanding the
scope of C(sp3)–H activation reactions using Pd(0)/Pd(II)-
catalysis. We envisioned that β-alkynylation of C(sp3)–H bonds
would be highly desirable, as it installs a versatile handle for
further structural elaboration of aliphatic acid derivatives.
However, unlike the active [ArylPd(II)Ln] species generated from
ArX/Pd(0) catalysis,11,12 [AlkynylPd(II)Ln] complexes formed via
a
Conditions: substrate (0.1 mmol), Pd(OAc)2 (10 mol%), PCy3·HBF4 (20 mol%),
b
alkynyl halide (2.0 equiv.), Cs2CO3 (2.0 equiv.), Et2O (0.5 mL), 80 °C, 8 h. The
yield was determined by 1H NMR analysis of the crude product using CH2Br2 as the
internal standard. c 6 h. d 24 h.
Having identified the optimal alkynyl halide and solvent, we
screened a wide range of PR3 and NHC ligands (Table 2). The
trialkyl phosphine ligands, such as PiPr3·HBF4 and
PAd2nBu·HBF4 both gave 2a in 55% yields, while suppressing the
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formation of 3a. PtBu2Ph·HBF4 diminished the yield to 7%; in
form 2j in 77% yield. This method was also found to be effective
for the activation of cyclohexyl and tetrahydropyranyl C(sp3)–H
bonds. Alkynylation of N-arylcyclohexanecarboxamide 1k gave a
mixture of mono- and di-alkynylated products (2k mono, 2k di)
in 70% combined yield; 2k mono was isolated as a single cis-
substituted diastereomer. Tetrahydropyran 1l could also be
alkynylated to provide a mono-cis-alkynylated product 2l without
further di-alkynylation.
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contrast, Buchwald ligands that possess dialkyl-biaryl phosphine
backbone gave improved yields. In particular, highly sterically
hindered and electron-donating tBuXPhos·HBF4 afforded 2a in
73% yield. Notably, unprotected phosphine ligand such as
DavePhos was not as effective as its HBF4 salt14 and gave a
significantly lower yield (Table 2, entries 7–8). Subsequently, we
investigated the use of a range of NHC ligands. Although
cyclohexyl- and aryl-substituted NHC ligands led to poor yields
(Table 2, entries 11–13), we were delighted to find that tert-butyl-
substituted SItBu·HBF4, adamantyl-substituted IAd·HBF4, and
SIAd·HCl ligands were as effective as tBuXPhos·HBF4,
furnishing the desired product 2a in over 70% yield (Table 2,
entries 14–16). Overall, IAd·HBF4 gave the best yield and
selectivity for 2a. Further tuning of the reaction conditions were
carried out using IAd·HBF4. We found that the use of
[Pd(allyl)Cl]2 (5 mol%) as the catalyst and running the reaction at
85 oC improved the yield of 2a to 81% (see Supporting
Information). Diisopropyl ether (i-Pr2O) with higher boiling point
was also tested as a solvent to run the reaction of substrate 1a and
the desired product 2a was obtained in 84% yield.
TBS-alkynyl bromide was also used for alkynylation of 1a and
2c mono to give 2m and 2n in 75% and 78%, respectively.
However, other less hindered bromoalkynes were not reactive,
most likely due to their propensity of coordinating with Pd center
via the π bonds. Importantly, the TBS group was readily removed
by treatment with TBAF to fashion the terminal alkyne unit,
which could be utilized for further synthetic elaborations (see SI).
It is worth noting that alkynyl group in substrate 2c mono is
tolerated, allowing for the installation of two distinct alkynyl
groups in product 2n. At this stage, amides derived from pivalic
acid and other aliphatic acids that possess a quaternary α-carbon
center gave poor yields. We presume that these sterically hindered
amide substrates prevent coordination of the large
[AlkynylPd(II)Ln] complex to the auxiliary, thus retarding C(sp3)–
H activation. Further screenings of ligands and alkynyl halides are
ongoing to overcome this limitation.
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Table 2. Screening of Liganda
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Table 3. β-Alkynylation of Carboxylic Acid Amidesa,b
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a The reaction conditions are identical to those described in Table 1.
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With the optimized reaction conditions in hand, we converted a
variety of commercially available carboxylic acids into the
corresponding amides to examine the scope of the alkynylation
protocol. Amides derived from aliphatic acids (1a–e) gave the
corresponding alkynylation products (2a–e) in good yields. For
substrates with both β-methyl C(sp3)–H bonds and β-methylene
C(sp3)–H bonds (1a, 1d, 1f, 1h, 1i, and 1n), the β-methyl C(sp3)–
H bond was selectively functionalized to give the corresponding
products. Ethers were well tolerated and afforded the alkynylation
products (2g, 2h, 2i and 2l) in good yields. The substrate
containing a -trifluoromethyl group could also be alkynylated to
a
Conditions: substrate (0.1 mmol), [Pd(allyl)Cl]2 (5 mol%), IAd·HBF4 (20 mol%),
b
alkyne bromide (2.0 equiv.), Cs2CO3 (2.0 equiv.), Et2O (0.5 mL), 85 °C, 8 h.
Isolated yields. c Single cis-diastereoisomer was obtained.
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The mechanistic implications of this intermolecular C−H
alkynylation reaction merit discussion. To probe whether the
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(11) (a) Dyker, G. Angew. Chem. Int. Ed. 1994, 33, 103. (b) Baudoin, O.;
palladation at the acidic α-position and subsequent β-hydride
Herrbach, A.; Guéritte, F. Angew. Chem., Int. Ed. 2003, 42, 5736. (c)
Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2005, 127, 4685. (d) Lafrance, M.; Gorelsky, S. I.; Fagnou, K.
J. Am. Chem. Soc. 2007, 129, 14570. (e) Watanabe, T.; Oishi, S.; Fujii, N.;
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Chem. Commun. 2011, 47, 11483. (g) Saget, T.; Lemouzy, S. J.; Cramer,
N. Angew. Chem. Int. Ed. 2012, 51, 2238.
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elimination was responsible for the observed reactivity, we have
prepared α-deutero substrate 1c (α-D) and subjected it to the
alkynylation reaction conditions (Scheme 2). The product
obtained (2c (α-D), 67%) fully retained the α-deuterium, thus
suggesting that the Baudoin’s -hydride elimination pathway in
the presence of LiNCy2 is unlikely in our alkynylation reactions.16
Since the cleavage of C(sp3)–H bonds by alkynylpalladium
complexes has not been shown before, we prepared these
complexes from Pd(0) and bromoalkynes in the presence of
tBuXPhos·HBF4 and reacted them with substrates under standard
conditions. The formation of the desired product further supports
the Pd(0)-catalyzed C–H activation reaction pathway (see SI).
(12) (a) Nakanishi, M.; Katayev, D.; Besnard, C.; Kündig, E. P. Angew. Chem.,
Int. Ed. 2011, 50, 7438. (b) Katayev, D.; Nakanishi, M.; Bürgi, T.;
Kündig, E. P. Chem. Sci. 2012, 3, 1422.
(13) A seminal example of Pd-catalyzed Sonogashira coupling with alkyl
halides: Eckhardt, M.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 13642.
(14) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295.
(15) Pd(0)-catalyzed aminoalkynylation of olefins: Nicolai, S. Waser, J. Org.
Lett. 2011, 13, 6324.
(16) Renaudat, A.; Jean-Gérard, L.; Jazzar, R.; Kefalidis, C. E.; Clot, E.;
Baudoin, O. Angew. Chem., Int. Ed. 2010, 49, 7261.
Scheme 2. Deuterium Labeling in C(sp3)–H Alkynylation
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In summary, alkynylation of C(sp3)–H bonds with alkynyl
bromides has been achieved using Pd(0)/NHC and Pd(0)/PR3
catalysts without the use of co-oxidants. This illustrates the first
example of utilizing [AlkynylPd(II)Ln] complexes to activate and
alkynylate β-C(sp3)–H bonds of carboxylic acid derivatives. The
extension of this method to effect enantioselective C(sp3)–H
alkynylation reactions by the use of optically active NHC and PR3
ligands is currently underway in our laboratory.
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Acknowledgements. This work was supported by NSF under
the CCI Center for Selective C-H Functionalization, CHE-
1205646. We gratefully acknowledge The Scripps Research
Institute, and Sigma-Aldrich for financial support. We thank
Bristol-Myers-Squibb (predoctoral fellowship to M.W.), and
Agency for Science, Technology and Research (A*STAR)
Singapore (predoctoral fellowship to K. S. L. C.).
Supporting Information Available: Experimental procedures and
spectral data for all new compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
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