Heterogeneously catalyzed selective aerobic oxidative cross-coupling of terminal alkynes and amides with simple copper(ii) hydroxide

Article abstract of DOI:10.1039/c2cc31159c

Simple copper(ii) hydroxide Cu(OH)₂ could act as an efficient heterogeneous catalyst for selective oxidative cross-coupling of a broad range of terminal alkynes and amides using air as a sole oxidant, giving the corresponding ynamides in moderate to high yields (56-93% yields). The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc31159c

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COMMUNICATION
Heterogeneously catalyzed selective aerobic oxidative cross-coupling of
terminal alkynes and amides with simple copper(II) hydroxidew
Xiongjie Jin, Kazuya Yamaguchi and Noritaka Mizuno*
Received 16th February 2012, Accepted 23rd March 2012
DOI: 10.1039/c2cc31159c
Simple copper(II) hydroxide Cu(OH)2 could act as an efficient
heterogeneous catalyst for selective oxidative cross-coupling of a
broad range of terminal alkynes and amides using air as a sole
oxidant, giving the corresponding ynamides in moderate to high
yields (56–93% yields).
formation of undesirable diynes through the Glaser alkyne
self-coupling8 is inevitable in some cases when using commonly
utilized copper catalysts. Therefore, the development of efficient
green synthetic routes to ynamides is a subject of urgency in
this field.
With regard to synthesis of ynamides, Stahl and co-workers have
reported cross-coupling of terminal alkynes and amides with CuCl2
(20 mol%).9 To the best of our knowledge, this is the only example
of direct cross-coupling of terminal alkynes and amides. In this
case, tedious slow addition of terminal alkynes to the reaction
mixture containing large excess amounts of amides (at least
5 equivalents with respect to terminal alkynes) and additives
such as Na2CO3 (2 equivalents) and pyridine (2 equivalents) is
required to obtain high selectivities to the desired ynamides.9
We demonstrate herein that it is possible to realize selective
aerobic oxidative cross-coupling of terminal alkynes and amides
with simple copper(II) hydroxide Cu(OH)2 (Fig. 1). The present
procedure has several outstanding features in comparison with
previously reported ones; (i) various kinds of structurally
diverse ynamides can selectively be synthesized even upon
simply mixing catalytic amounts of Cu(OH)2 and inorganic
bases as well as the two coupling partners in a single step (without
slow addition), which makes this procedure more useful and
practicable, (ii) the amount of amides can be reduced (3 equivalents
or less), (iii) readily available and inexpensive Cu(OH)2 can be used
as a catalyst, (iv) no ligands are necessary, (v) catalytic
amounts of inorganic bases (20 mol% or less) are sufficient
to promote the cross-coupling, (vi) catalyst/product separation is
very easy (heterogeneous catalysis), (vii) air can be used as a
terminal oxidant, and (viii) only water is formed as a by-product.
Initially, various kinds of copper-based catalysts were applied
to the cross-coupling of ethynylbenzene (1a) and 2-oxazolidinone
(2a) to produce 3-(phenylethynyl)oxazolidin-2-one (3aa) in 1 atm
of air (Table 1).y Under the conditions described in Table 1, no
reaction proceeded in the absence of catalysts. Surprisingly, simple
copper(II) hydroxide, Cu(OH)2, showed the highest selectivity to
the desired product 3aa among various catalysts examined; for
example, when the cross-coupling was carried out in the presence
of catalytic amounts of Cu(OH)2 (5 mol% with respect to 1a) and
KHCO3 (10 mol%), 3aa was obtained in 92% yield with
99% selectivity upon ‘‘simply mixing the two coupling partners
in a single step’’ (even without slow addition of substrates)
(Table 1). We confirmed in separate experiments that Cu(OH)2
was intrinsically inactive for the Glaser alkyne self-coupling.
Nitrogen-substituted alkynes are a very important class of
compounds and are utilized for highly regio- and stereoselective
synthesis of bioactive compounds, natural products, and organic
functionalized materials because their triple bonds are strongly
polarized by the nitrogen atoms.1 Recently, ynamides have
especially been regarded as the most useful and versatile synthons
because of their superior stabilities over other nitrogen-substituted
alkynes.1 Although various kinds of useful chemicals have been
synthesized from ynamides,2 ynamides themselves have generally
been synthesized via ‘‘non-green’’ procedures (Fig. 1). For
example, the most utilized procedure is cross-coupling of
alkynyl halides and amides.3 Other alkyne derivatives such
as alkynyl trifluoroborates,4 alkynyl carboxylic acids,5 and
copper acetylides6 have been employed as coupling partners of
amides. However, the above cross-coupling reactions require
‘‘pre-functionalization’’7z of terminal alkynes, resulting in
inevitable formation of large amounts of by-products during the
pre-functionalization steps as well as the reactions. In addition,
Fig. 1 Synthetic procedures for ynamides.
Department of Applied Chemistry, School of Engineering,
The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656,
Japan. E-mail: tmizuno@mail.ecc.u-tokyo.ac.jp;
Fax: +81-3-5841-7220; Tel: +81-3-5841-7272
w Electronic supplementary information (ESI) available: Experimental
details, data of ynamide products, Fig. S1, Table S1, and Scheme S1.
See DOI: 10.1039/c2cc31159c
c
4974 Chem. Commun., 2012, 48, 4974–4976
This journal is The Royal Society of Chemistry 2012

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Table 1 Effect of catalysts on the cross-coupling of 1a and 2aa
Table 2 Effect of bases on the cross-coupling of 1a and 2aa
Yield (%)
Yield (%)
Entry
Catalyst
Conv. of 1a (%)
3aa
4a
Entry
Base (mol%)
Conv. of 1a (%)
3aa
4a
1
2
3
4
5
6
7
8
Cu(OH)2
Cu2O
93
94
92
91
77
nd
53
8
75
51
61
18
10
nd
nd
1
2
2
nd
2
48
20
31
24
2
2
nd
nd
1
2
3
4
5
6
7
8
Na2CO3 (10)
K2CO3 (10)
K2CO3 (5)
K2CO3 (2.5)
Cs2CO3 (10)
NaHCO3 (10)
KHCO3 (10)
K3PO4ꢀnH2O (10)
Et3N (10)
15
75
76
48
26
28
67
46
o1
27
o1
13
73
75
47
17
25
65
42
nd
16
nd
nd
1
1
1
2
nd
1
2
nd
8
nd
Cu(OH)2ꢀCuCO3
80
o1
CuO
Cu(acac)2
Cu(OTf)2
Cu(OAc)2ꢀH2O
CuI
57
60
95
83
86
27
9
CuCl2
9
10
11
10
11
12
13
CuSO4ꢀ5H2O
Cu(OH)x/TiO2
Cu(OH)x/Al2O3
None
DBU (10)
None
13
o1
a
nd
=
not detected. Reaction conditions: 1a (0.1 mmol), 2a
o1
(0.3 mmol), Cu(OH)2 (Cu: 5 mol%), mesitylene (1 mL), 100 1C, under
air (1 atm), 0.5 h. Conversions and yields (based on 1a) were
determined by GC using biphenyl as an internal standard.
a
not detected. Reaction conditions: 1a (0.1 mmol), 2a
nd
=
(0.3 mmol), catalyst (Cu: 5 mol%), KHCO3 (10 mol%), mesitylene
(1 mL), 100 1C, under air (1 atm), 2 h. Conversions and yields (based
on 1a) were determined by GC using biphenyl as an internal standard.
in mesitylene at room temperature. Thus, the ynamide products
could easily be isolated by simple filtration followed by chromato-
graphy on a short silica gel column.y The isolated yields of the
ynamide products obtained from the present oxidative cross-
coupling of terminal alkynes and amides are summarized in
Fig. 2 (unless otherwise noted). In the Cu(OH)2-catalyzed cross-
coupling, no further conversions of substrates were observed upon
separation of the catalyst by simple hot filtration during
the reaction. Thus, this can rule out any contribution to the
observed catalysis from copper species that leached into the
reaction solution, and the observed catalysis is intrinsically
heterogeneous.
This is likely a key point to obtain high selectivity to the desired
cross-coupling product 3aa. Cu2O and Cu(OH)2ꢀCuCO3
also showed high catalytic activities and selectivities for the
cross-coupling. No reaction proceeded in the presence of CuO.
Other commonly utilized copper salts such as Cu(acac)2 (acac =
acetylacetonate), Cu(OTf)2 (OTf = triflate), Cu(OAc)2ꢀH2O
(OAc = acetate), CuI, CuCl2, and CuSO4ꢀ5H2O showed lower
activities and/or selectivities than those of Cu(OH)2. Highly
dispersed copper(II) hydroxide species supported on Al2O3 and
TiO2 (Cu(OH)x/TiO2 and Cu(OH)x/Al2O3)10 were not effective
for the cross-coupling.
Kinds of bases were also crucial for the cross-coupling; for
example, K2CO3 and KHCO3 were suitable bases for the
Cu(OH)2-catalyzed cross-coupling of 1a and 2a (Table 2),
while organic bases such as triethylamine (Et3N) and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) were not effective. It is
generally known that at least stoichiometric amounts of bases
are required for cross-coupling of alkyne derivatives (alkynyl
halides3 or terminal alkyne9) and amides. In sharp contrast,
catalytic amounts of bases (5 mol%) were sufficient to effectively
promote the Cu(OH)2-catalyzed cross-coupling of 1a and 2a
(Table 2). The role of bases is likely the abstraction of amide
protons. The best solvent was mesitylene, and the reaction hardly
proceeded in polar solvents such as DMF, DMSO, acetonitrile,
2-propanol, ethyl acetate, and 1,4-dioxane (Table S1, ESIw).
Next, we investigated the scope of the present Cu(OH)2-catalyzed
oxidative cross-coupling of terminal alkynes and amides
using air as a terminal oxidant. The suitable reaction conditions
(i.e., amounts of Cu(OH)2, kinds and amounts of bases,
temperatures, and alkyne/amide ratios) were dependent on
the types of substrates. Under the optimized reaction conditions,
various kinds of structurally diverse ynamides could be synthesized
from terminal alkynes and amides (Fig. S1, ESIw).z After
completion of the cross-coupling, the reaction mixture was cooled
to room temperature. Cu(OH)2 and bases were intrinsically
insoluble, and the remaining amides were only slightly soluble
Aromatic alkynes with electron-donating as well as electron-
withdrawing substituents were all good coupling partners of 2a.
It is noteworthy that aromatic alkynes with electron-withdrawing
substituents such as p-F, p-Cl, p-Br, and p-CF3 also reacted well.
This outcome is in contrast with previously reported cross-
coupling of alkyne derivatives and amides, in which aromatic
alkynes with electron-withdrawing substituents are likely poor
coupling partners.3–6,9 Reactions of 2-, 3-, and 4-ethynyltoluenes
proceeded well, and the yields were almost equal, suggesting that
the steric effect of substituents on aromatic rings is negligible. In the
case of halo-substituted aromatic alkynes, the desired ynamides
were obtained in high yields without dehalogenation. Thus, it
would be possible to utilize these halo-functionalities for
further modification of the ynamide molecules. Sulfur- and
nitrogen-containing alkynes such as 3-ethynylthiophene and
N,N-dimethylpropargylamine efficiently reacted with 2a to
afford the corresponding ynamides in high yields. The reaction
of an enyne and 2a also efficiently proceeded to give the
corresponding enynamide. In addition, not only aromatic
alkynes but also aliphatic ones could act as good coupling
partners. Oxazolidinone, azetidinone, and sulfonamide derivatives
could be utilized as nitrogen nucleophiles in the present
Cu(OH)2-catalyzed cross-coupling.
In summary, we successfully developed herein an efficient
synthetic route to ynamides by selective aerobic oxidative
c
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Chem. Commun., 2012, 48, 4974–4976 4975

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Notes and references
z Some efficient catalytic cross-couplings without pre-functionalization
of coupling partners (i.e., direct C–H and/or X–H activation with
catalysts, X = heteroatom) have been achieved.7
y A typical procedure for oxidative cross-coupling: into a Pyrex-glass
screw cap vial (volume: ca. 20 mL) were successively placed Cu(OH)2
(5 mol% with respect to an alkyne), a base (5–20 mol%), an alkyne
(0.1 mmol), an amide (2–3 equivalents with respect to an alkyne), and
mesitylene (1 mL). A Teflon-coated magnetic stir bar was introduced,
and the reaction mixture was vigorously stirred at 100–120 1C, under
1 atm of air. After the reaction was complete, an internal standard
(biphenyl) was added to the reaction mixture, and the conversion of
alkyne and the product yield were analyzed by GC. As for the isolation of
products (ynamides), an internal standard was not added, and the crude
reaction mixture was directly subjected to column chromatography on
silica gel (Silica Gel 60N (63–210 mm), Kanto Chemical, 2.5 cm ID ꢁ 15 cm
length, initial: n-hexane only, after mesitylene, an alkyne and a diyne
byproduct were eluted: n-hexane/ethyl acetate = 9/1 to 3/2 (v/v)), giving
the pure ynamide. The isolated products were identified by MS and NMR
(see the ESIw for data of ynamide products).
z For the gram-scale cross-coupling of 1a and 2a, 1.23 g of 3aa could
be obtained (see Scheme S1 in the ESIw).
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Reaction conditions: A: 1 (0.1 mmol), 2 (0.3 mmol), Cu(OH)2 (0.5 mg,
5 mol%), K2CO3 (5 mol%), mesitylene (1 mL), 100 1C, under air
(1 atm). B: 1 (0.1 mmol), 2 (0.3 mmol), Cu(OH)2 (1.0 mg, 10 mol%),
Cs2CO3 (5 mol%), mesitylene (1 mL), 100 1C, under air (1 atm). C: 1
(0.2 mmol), 2 (0.4 mmol), Cu(OH)2 (1.0 mg, 10 mol%), Cs2CO3
(5 mol%), mesitylene (1 mL), 110 1C, under air (1 atm). D: 1
(0.1 mmol), 2 (0.3 mmol), Cu(OH)2 (1.0 mg, 10 mol%), CsOH
(5 mol%), mesitylene (1 mL), 110 1C, under air (1 atm). E: 1 (0.1 mmol),
2 (0.3 mmol), Cu2O (1.4 mg, 20 mol%), Cs2CO3 (20 mol%), mesitylene
(1 mL), 120 1C, under air (1 atm). aCu(OH)2 (1.0 mg, 10 mol%). bYields
were determined by GC using biphenyl. c110 1C.
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cross-coupling of a wide range of terminal alkynes and amides
with simple copper(II) hydroxide and inorganic bases.
This work was supported in part by the Global COE
Program (Chemistry Innovation through Cooperation of
Science and Engineering) and Grants-in-Aid for Scientific
Researches from Ministry of Education, Culture, Sports,
Science and Technology.
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4976 Chem. Commun., 2012, 48, 4974–4976
This journal is The Royal Society of Chemistry 2012