Copper-catalyzed alkynylation of amides with potassium alkynyltrifluoroborates: A room-temperature, base-free synthesis of ynamides

Article abstract of DOI:10.1021/ol101322k

(Figure Presented) An efficient copper-mediated method for the coupling of potassium alkynyltrifluoroborates with nitrogen nucleophiles is reported. This reaction provides the first base-free and room-temperature synthesis of ynamides and allows for an easy preparation of these useful building blocks.

Full text of DOI:10.1021/ol101322k

ORGANIC
LETTERS
2010
Vol. 12, No. 14
3272-3275
Copper-Catalyzed Alkynylation of
Amides with Potassium
Alkynyltrifluoroborates: A
Room-Temperature, Base-Free Synthesis
of Ynamides
Ke´vin Jouvin, Franc¸ois Couty, and Gwilherm Evano*
Institut LaVoisier de Versailles, UMR CNRS 8180, UniVersite´ de Versailles
Saint-Quentin en YVelines, 45, aVenue des Etats-Unis, 78035 Versailles Cedex, France
eVano@chimie.uVsq.fr
Received June 9, 2010
ABSTRACT
An efficient copper-mediated method for the coupling of potassium alkynyltrifluoroborates with nitrogen nucleophiles is reported. This reaction
provides the first base-free and room-temperature synthesis of ynamides and allows for an easy preparation of these useful building blocks.
Heteroatom-substituted acetylenes probably represent the
most versatile class of alkynes. An especially useful subgroup
is the one containing a nitrogen atom directly attached to
the triple bond: ynamides.1 They display an exceptionally
fine balance of stability and reactivity, offer unique and
multiple opportunities for the inclusion of nitrogen-based
functionalities into organic molecules, and are emerging as
especially useful and versatile building blocks. The beginning
of the 21st century has witnessed an ever increasing number
of new reactions or synthetic sequences starting from
ynamides2 which have been used for the synthesis of various
natural products3 and for the rapid elaboration of complex
scaffolds.
alkynes,6 1,1-dihalo-1-alkenes,7 or propiolic acids8 have
emerged as efficient strategies for the preparation of yna-
mides. While these procedures did clearly contribute to
(2) For selected recent examples, see: (a) Saito, N.; Katayama, T.; Sato,
Y. Org. Lett. 2008, 10, 3829. (b) Istrate, F. M.; Buzas, A. K.; Jurberg,
I. D.; Odabachian, Y.; Gagosz, F. Org. Lett. 2008, 10, 925. (c) Zhang, Y.;
DeKorver, K. A.; Lohse, A. G.; Zhang, Y.-S.; Huang, J.; Hsung, R. P. Org.
Lett. 2009, 11, 899. (d) Gourdet, B.; Lam, H. W. J. Am. Chem. Soc. 2009,
131, 3802. (e) Das, J. P.; Chechik, H.; Marek, I. Nat. Chem. 2009, 1, 128.
(f) Dooleweerdt, K.; Ruhland, T.; Skrydstrup, T. Org. Lett. 2009, 11, 221.
(g) Coste, A.; Couty, F.; Evano, G. Org. Lett. 2009, 11, 4454. (h) DeKorver,
K. A.; Hsung, R. P.; Lohse, A. G.; Zhang, Y. Org. Lett. 2010, 12, 1840. (i)
Gourdet, B.; Rudkin, M. E.; Lam, H. W. Org. Lett. 2010, 12, 2554. (j)
Banerjee, B.; Litvinov, D. N.; Kang, J.; Bettale, J. D.; Castle, S. L. Org.
Lett. 2010, 12, 2650.
(3) (a) Zhang, Y.; Hsung, R. P.; Zhang, X.; Huang, J.; Slafer, B. W.;
Davis, A. Org. Lett. 2005, 7, 1047. (b) Couty, S.; Meyer, C.; Cossy, J.
Tetrahedron Lett. 2006, 47, 767. (c) Alayrac, C.; Schollmeyer, D.; Witulski,
B. Chem. Commun. 2009, 1464.
Over the past decades, the use of hypervalent alkynyli-
odonium salts as alkynylating agents4 and the copper-
catalyzed coupling of amides with alkynyl halides,5 terminal
(4) Witulski, B.; Stengel, T. Angew. Chem., Int. Ed. 1998, 37, 489.
(5) (a) Frederick, M. O.; Mulder, J. A.; Tracey, M. R.; Hsung, R. P.;
Huang, J.; Kurtz, K. C. M.; Shen, L.; Douglas, C. J. J. Am. Chem. Soc.
2003, 125, 2368. (b) Dunetz, J. R.; Danheiser, R. L. Org. Lett. 2003, 5,
4011. (c) Zhang, Y.; Hsung, R. P.; Tracey, M. R.; Kurtz, K. C. M.; Vera,
E. L. Org. Lett. 2004, 6, 1151.
(1) For reviews, see: (a) Zificsak, C. A.; Mulder, J. A.; Hsung, R. P.;
Rameshkumar, C.; Wei, L.-L. Tetrahedron 2001, 57, 7575. (b) Mulder,
J. A.; Kurtz, K. C. M.; Hsung, R. P. Synlett 2003, 1379. (c) Katritzky,
A. R.; Jiang, R.; Singh, S. K. Heterocycles 2004, 63, 1455. (d) Evano, G.;
Coste, A.; Jouvin, K. Angew. Chem., Int. Ed. 2010, 49, 2840. (e) DeKorver,
K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P.
Chem. ReV., 2010, DOI: 10.1021/cr100003s.
(6) Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833.
(7) Coste, A.; Karthikeyan, G.; Couty, F.; Evano, G. Angew. Chem.,
Int. Ed. 2009, 48, 4381.
(8) Jia, W.; Jiao, N. Org. Lett. 2010, 12, 2000.
10.1021/ol101322k  2010 American Chemical Society
Published on Web 06/21/2010

revitalizing the chemistry of nitrogen-substituted alkynes,
general methods are still needed for ynamide formation,
particularly since existing protocols often have limited
substrate scope and typically require elevated temperatures,
rigorous exclusion of air and/or water, and the use of a base.
Therefore, there is still a strong need for procedures that
would allow for a room-temperature, base-free preparation
of ynamides. Drawing from recent experiences in the field
of copper-catalyzed cross-coupling reactions9,10 and initially
inspired by the work of the Batey group in the copper-
catalyzed N-arylation11 or vinylation12 of amides, we thought
that an efficient and attractive alternative for the preparation
of ynamides would rely on the use of potassium alkynyl
trifluoroborates as alkynyl transfer agents.13 The tetracoor-
dinate salts are readily prepared in a one-pot, two-step
procedure from terminal alkynes. In addition to their high
stability (to air, moisture, heating...), they have been shown
to smoothly participate in various coupling reactions for the
formation of C-C bonds.14 However, there are still no
reports on their use in cross-coupling involving heteroatoms,
which could provide a straightforward entry to ynamides
starting from N-nucleophiles. Herein we report that potassium
alkynyltrifluoroborates can be used in copper-catalyzed cross-
coupling with amides. These results represent the first
catalytic synthesis of ynamides at room temperature and
under base-free conditions.
such as DMSO resulted in exclusive formation of the
undesired homodimer 4,15 optimal results were observed
when switching to dichloromethane where the low solubility
of 1a allows for a really low concentration of this reagent
in the reaction mixture (ca. 5 × 10-3 mol/L) and notably
reduces the amount of homodimer in favor of the desired
ynamide 3a which was still however formed in relatively
low yield (10%).
Figure 1. Solvent optimization. All reactions were carried out using
20 mol % of Cu(OAc)2·2H2O, 4 Å MS, at 1 mol/L (based on 2a),
at rt, and under O2 (1 atm) for 48 h.
Further screening of the catalytic reaction conditions
involved examination of various ligands to promote the
formation of the ynamide (Figure 2). While bidentate diamine
L1, phenanthroline L2, or bipyridine L3 completely inhibited
the reaction, its efficiency was greatly improved when using
electron-rich monodentate ligands such as imidazoles12
(L4-L6) or benzimidazoles (L7-L9), the most efficient one
being 1,2-dimethylimidazole (DMI, L6) which allowed for
the isolation of ynamide 3a in 51% yield together with 38%
of diyne 4.
Scheme 1. System Selected for the Optimization
We initiated our studies by examining the reaction of
potassium phenylethynyltrifluoroborate 1a and oxazolidinone
2a as test substrates (Scheme 1). The influence of the solvent
was first examined using 20 mol % of copper(II) acetate and
4 Å molecular sieves, without ligand, and under 1 atm of
O2 at rt (Figure 1). While the use of a highly polar solvent
Figure 2. Ligand optimization. All reactions were carried out using
20 mol % of Cu(OAc)2·2H2O, 40 mol % of ligand, 4 Å MS, in
DCM at 1 mol/L (based on 2a), at rt, and under O2 (1 atm) for
48 h.
(9) Evano, G.; Toumi, M.; Coste, A. Chem. Commun. 2009, 4166
.
(10) (a) Evano, G.; Blanchard, N.; Toumi, M. Chem. ReV. 2008, 108,
3054. (b) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 6954
.
(11) Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 4397.
(12) Bolshan, Y.; Batey, R. A. Angew. Chem., Int. Ed. 2008, 47, 2109.
(13) (a) Molander, G. A.; Figueroa, R. Aldrichimica Acta 2005, 38, 49.
(b) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275. (c) Darses,
S.; Genet, J.-P. Chem. ReV. 2008, 108, 288.
The outcome of the reaction was finally examined using
various copper(II) salts (Figure 3), which turned out to be a
(14) For examples, see: (a) Molander, G. A.; Katona, B. W.; Machrouhi,
F. J. Org. Chem. 2002, 67, 8416. (b) Kabalka, G. W.; Dong, G.; Venkataiah,
B. Tetrahedron Lett. 2005, 46, 763. (c) Bertolini, F.; Woodward, S. Synlett
2009, 51.
(15) Paixa˜o, M. W.; Weber, M.; Braga, A. L.; de Azeredo, J. B.;
Deobald, A. M.; Stefani, H. A. Tetrahedron Lett. 2008, 49, 2366.
Org. Lett., Vol. 12, No. 14, 2010
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crucial parameter. While Cu(CO3) and Cu(acac)2 were found
to be totally inefficient, the homodimer was still formed
predominantly with Cu(OTf)2, and no differences were
observed with Cu(OAc)2·2H2O, Cu(SO4)·5H2O, or
Cu(NO3)2·3H2O. It was not until CuCl2·2H2O was used that
the ynamide 3a could be isolated in 71% yield with almost
complete suppression of homocoupling. Using this salt,
catalyst loading could be slightly decreased to 15 mol %:
the use of lower amounts did not allow for full conversion.
optimized conditions. Thus, a variety of ynamides were
prepared in moderate-to-good yields and are shown in Figure
4. The reaction is compatible with a variety of aromatic-
and alkyl-substituted alkynyltrifluoroborates, even in the
presence of a bulky substituent. Notably, propargyl alcohol
derivatives (3g and 3h), aliphatic chlorides (3k), and even
free alcohols (3l) are tolerated.
The reaction scope was also investigated with respect to
the N-nucleophile using two representative trifluoroborates
1a and 1b (Figure 5). Oxazolidinones, imidazolidinones, and
tosylamines, including N-tosylaniline, were shown to react
smoothly and gave the corresponding ynamides 5-10 and
12-14 in good yields. For reasons that are still unclear,
pyrrolidinone did not perform as well as other nucleophiles,
and the corresponding ynamides 11a and 11b were obtained
in lower yields. The reaction was however found to be rather
general and allowed for the synthesis of a wide range of
ynamides possessing representative substitution patterns,
including TMS-substituted ynamides (15).
Figure 3. Optimization of the copper source. 20 mol % of Cu(II),
40 mol % of 1,2-dimethylimidazole, 4 Å MS, in DCM at 1 mol/L
(based on 2a), at rt, and under O2 (1 atm) for 48 h.
Interestingly, other complexes such as PdCl2(CH3CN)2 or
FeCl3 did not catalyze the reaction: even if the counteranion
for copper clearly plays a crucial role in the reaction, other
metals do not work as well and copper is clearly really
needed.
Figure 5. Copper-catalyzed alkynylation of N-nucleophiles with
potassium phenylethynyl and hex-2-ynyl trifluoroborates.
Finally, the reaction is not limited to the small scale used
for the coupling described above and could conveniently be
performed on a gram scale for compounds 3a and 12b in
comparable yields.
Figure 4. Copper-catalyzed alkynylation of oxazolidinone with
potassium alkynyltrifluoroborates.
The coupling of oxazolidinone 2a with various potassium
alkynyltrifluoroborates 1 was next investigated using our
In conclusion, we have developed an efficient copper-
mediated method for the coupling of potassium alkynyltri-
3274
Org. Lett., Vol. 12, No. 14, 2010

fluoroborates with nitrogen nucleophiles. This reaction
provides the first base-free and room-temperature synthesis
of ynamides and allows for an easy preparation of these
useful building blocks. Further studies on the use of other
nucleophiles will be reported in due course.
Elyane Kizilian (Lavoisier Institute) for her help with mass
spectrometry analyses.
Supporting Information Available: Experimental pro-
1
cedures, characterization, and copies of H and 13C NMR
spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. The authors thank the CNRS and the
ANR for funding. K. J. acknowledges the Ministe`re de la
Recherche for a graduate fellowship. We are indebted to Dr.
OL101322K
Org. Lett., Vol. 12, No. 14, 2010
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