Copper-catalyzed oxidative alkynylation of diaryl imines with terminal alkynes: A facile synthesis of ynimines

Article abstract of DOI:10.1021/ol2032152

An efficient copper-mediated method for the oxidative alkynylation of diaryl imines with terminal alkynes is reported. This reaction provides the first catalytic and general synthesis of ynimines and allows for an easy preparation of these useful building blocks. An improved copper-catalyzed oxidative dimerization of imines to azines and the synthesis of dienes and azadienes from ynimines are also described.

Full text of DOI:10.1021/ol2032152

ORGANIC
LETTERS
2012
Vol. 14, No. 1
6–9
Copper-Catalyzed Oxidative Alkynylation
of Diaryl Imines with Terminal Alkynes:
A Facile Synthesis of Ynimines
‡
‡
†
Anouar Laouiti,†,‡ Mohamed M. Rammah, Mohamed B. Rammah, Jerome Marrot,
ꢀ
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,
ꢀ ꢀ
ꢀ
and Laboratoire de Chimie Organique Heterocyclique, Departement de Chimie,
ꢀ
ꢀ
Faculte des Sciences de Monastir, Universite de Monastir, avenue de l’environnement,
5019 Monastir, Tunisia
*evano@chimie.uvsq.fr
Received August 24, 2011
ABSTRACT
An efficient copper-mediated method for the oxidative alkynylation of diaryl imines with terminal alkynes is reported. This reaction provides the
first catalytic and general synthesis of ynimines and allows for an easy preparation of these useful building blocks. An improved copper-catalyzed
oxidative dimerization of imines to azines and the synthesis of dienes and azadienes from ynimines are also described.
Nitrogen-substituted alkynes, ynamines 1, probably
represent the most versatile class of acetylenic compounds.
The electron-donating ability of the nitrogen strongly
polarizes the triple bond, which allows for an exceptionally
high level of reactivity together with a strong differentia-
tion of the two sp carbon atoms.1 Despite their enormous
potential, their synthetic use remains rather limited, which
is most certainly due to their difficult preparation, hand-
ling, and their high sensitivity. A solution to this problem
was found in the use of ynamides 2, in which one of the
alkyl groups on the nitrogen atom is replaced by an
electron-withdrawing group (Figure 1). They display an
exceptionally fine balance of stability and reactivity, offer
unique and multiple opportunities for the insertion of
nitrogen-based functionalities into organic molecules,
and are emerging as especially useful and versatile building
blocks.2À4
Another option to increase the stability of ynamines
would rely on the use of ynimines 3. While these building
blocks clearly hold great potential and would benefit from
the use of an easily removable protecting group, they have
been only scarcely studied and their use in organic synth-
esis is still rather limited,5 which is in sharp contrast with
ynamides.
†
ꢀ
Universite de Versailles Saint-Quentin en Yvelines.
‡
ꢀ
Universite de Monastir.
(1) For reviews on the chemistry of ynamines, see: (a) Ficini, J.
Tetrahedron 1976, 32, 1449. (b) Himbert, G. In Methoden Der Orga-
nischen Chemie (Houben-Weyl); Kropf, H., Schaumann, E., Eds.; Georg
Thieme: Stuttgart, 1993; p 3267.
(2) 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, 110, 5064.
Figure 1. Ynamines, ynamides, and ynimines.
The develoment of the chemistry of ynimines 3 has been
in fact hampered by the lack of general and practical
methods for their preparation. There is indeed to date a
r
10.1021/ol2032152
Published on Web 12/15/2011
2011 American Chemical Society

single procedure available for their synthesis based on the
reaction between oxime tosylates 4 with higher-order
alkynylcuprates 5 which produces the corresponding yni-
mines 3 in low to moderate yields (typically 15%À55%).5,6
Table 1. Screening Results for the Copper-Mediated Alkynyla-
tion of Benzophenone Imine
Scheme 1. Synthesis of Ynimines: Previous Method and Strat-
egy
Based on our recent interest in the chemistry of
ynamides3e,g,7 and copper catalysis,8,9 we decided to in-
vestigate whether ynimines could be obtained through a
copper-mediated alkynylation of imines with alkynylating
agents such as bromoalkynes 7,3aÀc terminal alkynes 8,3d
potassium alkynyltrifluoroborates 9,3g or vinyl dibromides
10,3e which might provide a straightforward entry to these
useful and underdeveloped building blocks (Scheme 1).
a All reactions were run using 3 equiv of imine 11. b Yield of pure,
isolated product.
(3) For selected methods for the synthesis of ynamides, see:
(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. (d) Hamada, T.; Ye, X.; Stahl, S. S. J. Am.
Chem. Soc. 2008, 130, 833. (e) Coste, A.; Karthikeyan, G.; Couty, F.;
Evano, G. Angew. Chem., Int. Ed. 2009, 48, 4381. (f) Jia, W.; Jiao, N.
Org. Lett. 2010, 12, 2000. (g) Jouvin, K.; Couty, F.; Evano, G. Org. Lett.
2010, 12, 3272. (h) Jouvin, K.; Heimburger, J.; Evano, G. Chem. Sci.
DOI: 10.1039/c2sc00842d.
(4) For the use of ynamides in synthetic organic chemistry in 2011
alone, see: (a) Barbazanges, M.; Meyer, C.; Cossy, J.; Turner, P.
Chem.;Eur. J. 2011, 17, 4480. (b) Davies, P. W.; Cremonesi, A.;
Martin, N. Chem. Commun. 2011, 47, 379. (c) DeKorver, K. A.;
Johnson, W. L.; Zhang, Y.; Hsung, R. P.; Dai, H. F.; Deng, J.; Lohse,
A. G.; Zhang, Y. S. J. Org. Chem. 2011, 76, 5092. (d) Garcia, P.; Evanno,
Y.; George, P.; Sevrin, M.; Ricci, G.; Malacria, M.; Aubert, C.; Gandon,
V. Org. Lett. 2011, 13, 2030. (e) Garcia, P.; Harrak, Y.; Diab, L.;
Cordier, P.; Ollivier, C.; Gandon, V.; Malacria, M.; Fensterbank, L.;
Aubert, C. Org. Lett. 2011, 13, 2952. (f) Hashmi, A. S. K.; Schuster,
A. M.; Zimmer, M.; Rominger, F. Chem.;Eur. J. 2011, 17, 5511.
(g) Kramer, S.; Friis, S. D.; Xin, Z.; Odabachian, Y.; Skrydstrup, T.
Org. Lett. 2011, 13, 1750. (h) Kramer, S.; Odabachian, Y.; Overgaard, J.;
Rottlander, M.; Gagosz, F.; Skrydstrup, T. Angew. Chem., Int. Ed. 2011,
50, 5090. (i) Li, C. Q.; Zhang, L. M. Org. Lett. 2011, 13, 1738. (j) Mak,
X. Y.; Crombie, A. L.; Danheiser, R. L. J. Org. Chem. 2011, 76, 1852.
(k) Nissen, F.; Detert, H. Eur. J. Org. Chem. 2011, 2845. (l) Nissen, F.;
Richard, V.; Alayrac, C.; Witulski, B. Chem. Commun. 2011, 47, 6656.
(m) Pizzetti, M.; Russo, A.; Petricci, E. Chem.;Eur. J. 2011, 17, 4523.
(n) Saito, N.; Saito, K.; Shiro, M.; Sato, Y. Org. Lett. 2011, 13, 2718.
(o) Schotes, C. S. C.; Mezzetti, A. Angew. Chem., Int. Ed. 2011, 50, 3072.
(p) Shindoh, N.; Kitaura, K.; Takemoto, Y.; Takasu, K. J. Am. Chem.
Soc. 2011, 133, 8470. (q) Wang, Y. P.; Danheiser, R. L. Tetrahedron Lett.
2011, 52, 2111–2114. (r) Xu, C. F.; Xu, M.; Jia, Y. X.; Li, C. Y. Org. Lett.
2011, 13, 1556.
To evaluate the feasibility of such cross-coupling reac-
tions, we initiated our studies by examining the reaction of
commercially available benzophenone imine 11 with re-
presentative reagents and conditions typically used for the
synthesis of ynamides (Table 1). While the use of bro-
moalkyne 12a,3b,c potassium alkynyl trifluoroborate
12b,3g or vinyl dibromide 12c3e only led to the formation
of 1,4-diphenylbuta-1,3-diyne 14 without a trace of the
desired ynimine, the use of Stahl’s copper-catalyzed oxida-
tive conditions3d turned out to be a lot more efficient.
Indeed, the combination of copper(II) chloride, pyridine,
and sodium carbonate in toluene at 70 °C significantly
reduced the formation of GlaiserÀHay dimer 14 and gave
ynimine 13 in a synthetically useful yield (72%, Table 1,
entry 5). While we were pleased tonote that this compound
(5) For reactions involving ynimines, see: (a) David, W. M.; Kerwin,
S. M. J. Am. Chem. Soc. 1997, 119, 1464. (b) Hoffner, J.; Schottelius,
M. J.; Feichtinger, D.; Chen, P. J. Am. Chem. Soc. 1998, 120, 376.
(c) Feng, L.; Kumar, D.; Kerwin, S. M. J. Org. Chem. 2003, 68, 2234.
(d) Feng, L.; Kerwin, S. M. Tetrahedron Lett. 2003, 44, 3463. (e) Feng,
L.; Zhang, A.; Kerwin, S. M. Org. Lett. 2006, 8, 1983.
€
(6) Wurthwein, E.-U.; Weigmann, R. Angew. Chem., Int. Ed. Engl.
1987, 26, 923. For an isolated example involving reaction of an imine
with perchlorobut-1-en-3-yne, see:Himbert, G.; Faul, D. Tetrahedron
Lett. 1988, 29, 5355. For an isolated report involving preparation from
€
N,N-bis(trimethylsilyl)ynamines, see:Weigmann, R. H.; Wurthwein,
E.-U. Tetrahedron Lett. 1989, 30, 6147.
Org. Lett., Vol. 14, No. 1, 2012
7

was perfectly stable and could be stored for months with-
out noticeable degradation, it however turned out to be
more sensitive than regular ynamides to acidic conditions,
mostly giving benzophenone and traces of phenylaceta-
mide as byproducts, and its purification on silica gel
required prior deactivation with triethylamine.
corresponding ynimines 16À20, which was attributed to
the lower volatility of octyne compared to pentyne.
Attempts at lowering the reaction temperature did not
however significantly improve the yields since most reac-
tions did not go to completion at 40 °C. The substitution
pattern of the starting imine was found to have a strong
impact on the outcome of the reaction: while ortho-sub-
stituted diaryl imines yielded to the formation of a single
stereoisomer of ynimines 16À19,10 the use of a remote
meta-substituent gave rise to equimolar amounts of E- and
Z-isomers of the corresponding ynimine 20. The reaction
was however found tobe rather general and allowed for the
synthesis of a wide range of ynimines possessing represen-
tative substitution patterns. Only (2-bromophenyl)(phenyl)
methanimine (19) and 2,2,4,4-tetramethylpentan-3-imine
(21) led to notably inferior results, which could be attrib-
uted to the presence of the ortho-activated aromatic bro-
mide and steric hindrance, respectively.
With optimized conditions in hand for the copper-
mediated synthesis of ynimines, we next turned our atten-
tion to the scope of this reaction. The coupling of benzo-
phenone imine 11 with various terminal alkynes 8 was
therefore investigated: results from these studies are shown
in Figure 2. Thus, a representative set of ynimines 13
was prepared in moderate-to-good yields, and the reaction
was found to be compatible with a variety of aromatic-
and alkyl-substituted alkynes. Terminal enynes were also
found to be excellent substrates, yielding to the corre-
sponding enynimines 13j and 13k in good yields. However,
the presence of a chelating group such as a benzoate (13l)
was found to have a detrimental effect on the oxidative
cross-coupling since all starting materials were completely
recovered at the end of the reaction.
Figure 3. Copper-catalyzed alkynylation of representative imi-
nes with pent-1-yne and oct-1-yne.
In all these oxidative cross-coupling reactions, we no-
ticed the formation of azine byproducts 22 (Figure 4)
resulting from a copper-catalyzed dimerization of the
starting imines, a reaction that is usually performed start-
ing from 25 to 50% weight solutions of ketimines and
copper(I) chloride.11 Because the scope of this reaction
yielding to valuable azine building blocks has not been
extensively studied and is still mostly restricted to the
dimerization of benzophenone imine, we therefore in-
itiated a brief study of this oxidative dimerization. We
found that the reaction was best conducted in 1,4-dioxane
Figure 2. Copper-catalyzed alkynylation of benzophenone
imine with terminal alkynes.
The reaction scope was also investigated in respect to the
imine cross-coupling partner using two representative
terminal alkynes: pentyne 15a and octyne 15b (Figure 3).
The use of the later typically gave higher yields of the
(7) (a) Coste, A.; Couty, F.; Evano, G. Org. Lett. 2009, 11, 4454.
(b) Fadel, A.; Legrand, F.; Evano, G.; Rabasso, N. Adv. Synth. Catal.
2011, 353, 263.
(10) The Z-stereochemistry of compound 16c was demonstrated by
X-ray analyses. See Supporting Information for details.
(8) Evano, G.; Toumi, M.; Coste, A. Chem. Commun. 2009, 4166.
(9) (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) (a) Meyer, R.; Pillon, D. U.S. Patent 2,870,206, Jan 20, 1959.
(b) Nawata, T.; Sakaguchi, S.; Kohzaki, T.; Aoki, O.; Takeda, N.; Shimpo, M.
U.S. Patent 4,751,326, Jun 14, 1988. (c) Jautelat, M.; Leidinger, W. U.S.
Patent US2002/0013495, Jan 31, 2002.
8
Org. Lett., Vol. 14, No. 1, 2012

at 80 °C for 12À14 h and that the use of both pyridine and
sodium carbonate was crucial. Using these conditions,
aromatic ketimines 6 are readily dimerized into the
corresponding azines 22 in good to excellent yields.
Ortho-substituted arylketimines typically yielded the cor-
responding dimers as single isomers while the use of a para-
substituent, such as in the case of 22d, yielded a 1/1/1
mixture of (E,E), (E,Z), and (Z,Z) isomers. Noteworthy,
the chloro-substituent was perfectly compatible with the
copper catalyst and no competitive amination or reduction
could be observed.
would then generate a metalated N-alkynyl-eneamidine E,
a compound that would be in equilibrium with F. Finally, a
[3,3] sigmatropic rearrangement followed by intramolecu-
lar nucleophilic attack from G and a second electrocyclic
ring opening from cyclobutene H would account for the
formation of highly strained dienes 24 after hydrolysis.
Scheme 2. Azadienes and Dienes from Ynimines
Figure 4. Copper-catalyzed dimerization of imines to azines.
We finally briefly assessed the synthetic utility of our
ynimines. With this goal in mind, a series of Z-azadienes 23
was first prepared by partial hydrogenation of the corre-
sponding ynimines 13 with a Lindlar catalyst (Scheme 2). This
method represents an interesting entry to the Z-enimines,
compounds for which there is no general synthesis to date.
An especially intriguing reaction was observed upon
treatment of ynimines 13 with 1 equiv of methyllithium in
THF at À78 °C. This reaction resulted in the unexpected
formation of polysubstituted dienes 24 with moderate yield,
compounds whose structure could be secured by X-ray
analysis performed on 24a.12 A possible mechanism that
would account for the formation of these highly substituted
dienes is shown in Scheme 2. Addition of methyllithium
onto the starting ynimine 13 would generate a metalated
secondary ynamine A which would be in equilibrium with
the lithiated ketenimine B. Addition of a second equivalent
of 13 would yield the formation of lithiated ketenimino-
ynamine C whose cyclization would afford a dihydroazete
D. Electrocyclic ring opening of this strained intermediate13
In conclusion, we have developed an efficient synthesis
of ynimines by copper-mediated oxidative cross-coupling
of imines with terminal alkynes. The building blocks were
shown to be especially suitable precursors for the synthesis
of azadienes and dienes, and further studies on the use of
ynimines will be reported in due time.
Acknowledgment. The authors thank the CNRS, the
Universities of Versailles and Monastir, the ANR (Project
DYNAMITE ANR-2010-BLAN-704), and the CMCU/
PHC Utique (Grant 10G1025) for support.
Supporting Information Available. Experimental pro-
1
cedures, characterization, copies of H and 13C NMR
(12) See Supporting Information for details.
(13) (a) Kurtz, K. C. M.; Hsung, R. P.; Zhang, Y. Org. Lett. 2006, 8,
231. (b) Shindoh, N.; Takemoto, Y.; Takasu, K. Chem.;Eur. J. 2009,
15, 7026.
spectra for all new compounds. Crystal data for ynimine
16c and diene 24a. This material is available free of charge
via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 14, No. 1, 2012
9