Cross-Dehydrogenative Coupling of Tertiary Amines and Terminal Alkynes Catalyzed by Copper Nanoparticles on Zeolite

Article abstract of DOI:10.1002/adsc.201500787

A wide range of catalysts based on supported copper nanoparticles have been prepared and tested in the cross-dehydrogenative coupling of tertiary amines and terminal alkynes. Copper nanoparticles on zeolite Y were found to be the most effective catalyst in the presence of tert-butyl hydroperoxide as the oxidant. Contrary to the previously reported methodologies involving copper catalysts, reactions have been accomplished without the need of an inert atmosphere and in the absence of solvent, using 1.5mol% catalyst. A variety of tertiary amines, including aromatic, benzylic and aliphatic ones, have been coupled with both aromatic and aliphatic alkynes to furnish the corresponding propargylamines in moderate-to-excellent yields. The procedure has been successfully scaled-up to 12mmol with a high conversion (93%). Moreover, the catalyst has been reused in seven cycles maintaining a good performance. Its catalytic activity has been compared with that of an array of commercial copper catalysts, being superior as regards the conversion and minimizing the alkyne homocoupling as a side reaction. The negative filtration test points to a heterogeneous nature of the process. Based on compelling experimental evidence, a novel reaction mechanism has been delineated which outlines the essential role of free radicals and the couple copper(I)/copper(II).

Full text of DOI:10.1002/adsc.201500787

FULL PAPERS
DOI: 10.1002/adsc.201500787
Cross-Dehydrogenative Coupling of Tertiary Amines and
Terminal Alkynes Catalyzed by Copper Nanoparticles on
Zeolite
Francisco Alonso,a,* Adriµn Arroyo,a Iris Martín-García,a and Yanina Mogliea,b
a
Instituto de Síntesis Orgµnica (ISO) and Departamento de Química Orgµnica, Facultad de Ciencias, Universidad de
Alicante, Apdo. 99, 03080 Alicante, Spain
Fax: (+34)-96-590-3549; phone: (+34)-96-590-9614; e-mail: falonso@ua.es
Present address: Departamento de Química, Instituto de Química del Sur (INQUISUR-CONICET), Universidad
b
Nacional del Sur, Avenida Alem 1253, 8000 Bahía Blanca, Argentina
Received: August 21, 2015; Revised: October 8, 2015; Published online: November 18, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500787.
Abstract: A wide range of catalysts based on sup- conversion (93%). Moreover, the catalyst has been
ported copper nanoparticles have been prepared and reused in seven cycles maintaining a good per-
tested in the cross-dehydrogenative coupling of terti- formance. Its catalytic activity has been compared
ary amines and terminal alkynes. Copper nanoparti- with that of an array of commercial copper catalysts,
cles on zeolite Y were found to be the most effective being superior as regards the conversion and mini-
catalyst in the presence of tert-butyl hydroperoxide mizing the alkyne homocoupling as a side reaction.
as the oxidant. Contrary to the previously reported The negative filtration test points to a heterogeneous
methodologies involving copper catalysts, reactions nature of the process. Based on compelling experi-
have been accomplished without the need of an inert mental evidence, a novel reaction mechanism has
atmosphere and in the absence of solvent, using been delineated which outlines the essential role of
1.5 mol% catalyst. A variety of tertiary amines, in- free radicals and the couple copper(I)/copper(II).
cluding aromatic, benzylic and aliphatic ones, have
been coupled with both aromatic and aliphatic al-
kynes to furnish the corresponding propargylamines Keywords: alkynes; amines; copper; cross-dehydro-
in moderate-to-excellent yields. The procedure has genative coupling; heterogeneous catalysis; nanopar-
been successfully scaled-up to 12 mmol with a high ticles; supported catalysts; zeolites
Introduction
(Aniprilꢁ) and rasagiline (Azilectꢁ) are current prop-
argylamine-containing drugs for monotherapy in pa-
Propargylamines are a versatile class of compounds tients with early Parkinsonꢀs disease and for adjunc-
extensively applied as precursors in the synthesis of tive therapy in patients with moderate to advanced
heterocyclic compounds such as quinolines,[1a] phenan- disease.[5c] Pargyline (Eutonylꢁ) is an irreversible in-
throlines,[1b] pyrroles,[1c] pyrrolidines,[1d] indolizines,[1e] hibitor of monoamine oxidase (MAO) with antihyper-
or oxazolidinones,[1f] among others.[2] They have also tensive properties (Figure 1).[5d]
been utilized as intermediates in the total syntheses
Conventional methods for the formation of the
of some natural and pharmaceutical products.[3] The propargylamine moiety include the direct amination
propargylamine moiety can be found in a variety of
bioactive compounds,[4] some of which have been con-
firmed to be potent anti-apoptotic agents that protect
neurons against cell death in cellular and animal
models of neurodegenerative disorders. Indeed, they
have been shown to delay the necessity for sympto-
matic therapy in untreated Parkinsonꢀs disease pa-
tients, results consistent with a neuroprotection role
for compounds of this type.[5] For instance, selegiline Figure 1. Some examples of bioactive propargylamines.
Adv. Synth. Catal. 2015, 357, 3549 – 3561
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3549

FULL PAPERS
Francisco Alonso et al.
the limited substrate scope covered, as well as the
presence of an inert atmosphere, generally a require-
ment under copper catalysis.[11,12]
In the last decade, nano-catalysis has been estab-
lished as a sustainable and competitive alternative to
conventional catalysis since the metal nanoparticles
possess a high surface-to-volume ratio, which enhan-
ces their activity and selectivity, while at the same
time maintaining the intrinsic features of a heteroge-
neous catalyst.[18] Owing to our increasing interest in
metal colloids,[19] we have developed some supported
copper catalysts with diverse applications in organic
synthesis.[20] We wish to present herein a full study on
the CDC access to propargylamines, by means of re-
usable supported copper nanoparticles, without the
requisite of an inert atmosphere and under solvent-
free conditions; our efforts to clarify the reaction
mechanism are also included.
Results and Discussion
Scheme 1. Some general methods for the synthesis of prop-
argylamines.
Initially, a variety of supported copper catalysts was
prepared by addition of the support to a suspension
of propargyl halides,[6a] triflates,[6b] phosphates, or ace- of the freshly prepared copper nanoparticles
tates,[6c] or the more widely practiced addition of alky- (CuNPs), with the latter being readily generated from
nylmetal reagents to imines [Scheme 1, Eq. (1) and copper(II) chloride, lithium metal and a catalytic
Eq. (2)].[7] The latter approach, normally involving amount of DTBB (10 mol%) in THF at room temper-
stoichiometric amounts of lithium or magnesium ace- ature.[21] The as-prepared catalysts were tested in the
tylides, requires strict control of the reaction condi- CDC of N,N-dimethylaniline (1a) and phenylacety-
tions and its application is precluded in the presence lene (2a) as model substrates, using t-BuOOH-decane
of reactive functional groups. More interesting is the as oxidizing agent[22] (Table 1). A control experiment
metal-catalyzed multicomponent coupling of alde- in the absence of catalyst led to the unchanged start-
hydes, amines, and alkynes (A3 coupling)[8] or the nu- ing materials (entry 1). Solvent optimization with acti-
cleophilic substitution of in-situ generated chlorome- vated carbon as support[20c,d] (entries 2–10) allowed us
thylamines catalyzed by copper or silver [Scheme 1, to conclude that the absence of solvent and the pres-
Eq. (3) and Eq, (4), respectively].[9]
ence of an inert atmosphere had a beneficial effect on
In recent years, the catalytic cross-dehydrogenative the conversion (entry 10). Other inorganic supports
coupling (CDC) has emerged as a powerful tool in or- such as TiO2, montmorillonite K-10 and zeolite Y ex-
ganic synthesis which enables the construction of hibited better performance in comparison with acti-
carbon-carbon bonds in an atom-economic and effi- vated carbon or MgO, either in the presence or ab-
cient manner [Scheme 1, Eq. (5)].[10] In particular, the sence of an inert atmosphere (entries 11–18). The
effective synthesis of propargylamines by CDC of ter- conversion attained with these three catalysts could
minal alkynes and tertiary amines, pioneered by Li be notably improved by using a slight excess of the
et al.,[11] has been accomplished under copper,[11,12] alkyne and t-BuOOH-H2O as the oxidant under an
iron[13] or zinc[14] catalysis in the presence of an oxi- argon atmosphere (entries 19–21). However, only Cu
dant. Photoredox catalysis with ruthenium complexes on zeolite Y could be effectively reused (entries 19–
is an alternative CDC path when the synthesis of 21, footnotes [f] and [g]). A control experiment with
propargylamines derived from tetrahydroisoquino- zeolite Y (without Cu) demonstrated the inertness of
lines is pursued.[15] However, all the aforementioned this support towards the title reaction (entry 22).
methodologies are based on homogeneous catalysis,
Parallel to the above experiments with zeolite Y
making the recovery and reutilization of the catalyst (ZY) and TBHP-decane, we studied any possible
troublesome. During the development of the present effect of the method of preparation of the catalyst on
work,[16] reusable copper ferrite and metal-organic the outcome of the CDC reaction (Table 2). Three
framework catalysts have been published for the methods were implemented: impregnation (A), re-
CDC of terminal alkynes and tertiary amines.[17] An- duction-supporting (B, the general method in Table 1)
other common feature for the reported methods is and impregnation-reduction (C), with or without
3550
asc.wiley-vch.de
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 3549 – 3561

FULL PAPERS
Cross-Dehydrogenative Coupling of Tertiary Amines and Terminal Alkynes
Table 1. Optimization of the type of support.[a]
Table 2. Optimization of the method for catalyst prepar-
ation.[a]
Entry
Support
[wt% Cu]
Solvent/
atmosphere
Conv.
[%][b]
Entry
Method[b]
[wt% Cu]
Conv. [%][c]
1
2
3
4
5
6
7
8
no catalyst
none
0
23
0
0
0
16
0
0
24
33
63
53
62
67
43
9
1
2
3
4
5
6
7
A-THF/Ar
A-THF/Ar[d]
A-H2O/air
B-THF/Ar
B-THF/Ar[d]
C-THF/Ar[d]
C-H2O/air
1.0
2.1
4.4
3.8
3.7
1.7
3.6
86
77
65
69
56
53
48
act. carbon[c] [1.4]
act. carbon [1.4]
act. carbon [1.4]
act. carbon [1.4]
act. carbon [1.4]
act. carbon [1.4]
act. carbon [1.4]
act. carbon [1.4]
act. carbon [1.4]
TiO2 [3.0]
MeCN
CH2Cl2
MeOH
H2O
i-PrOH
PhMe
THF
none
none/Ar
none
none/Ar
none
none/Ar
none
none/Ar
none
none/Ar
none/Ar
none/Ar
none/Ar
none/Ar
[a]
1a (1.0 mmol), 2a (1.2 mmol), CuNPs/ZY (1.5 mol%), t-
BuOOH-decane (1.2 equiv.), 708C, 20 h, Ar.
Method of preparation of the catalyst: A, impregnation;
B, reduction–supporting; C, impregnation–reduction.
Conversion determined by GLC.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
[b]
TiO2 [3.0]
[c]
[d]
mont K-10[d] [1.8]
mont K-10 [1.8]
MgO [1.5]
ZY was previously dried at 1008C for 0.5 h.
Table 3. Optimization of the conditions.[a]
MgO [1.5]
zeolite Y [3.0]
zeolite Y [3.0]
TiO2 [3.0][e]
62
67
88 (0)[f]
mont K-10 [1.8][e]
zeolite Y [3.0][e]
zeolite Y [0]
92 (63)[f] (0)[g]
89 (91)[f] (93)[g]
0
Entry
Atmosphere
Catalyst
[mg][b]
TBHP
Conv.
[%][d]
[a]
1a (0.5 mmol), 2a (0.5 mmol), CuNPs/support (20 mg), t-
BuOOH-decane (1.0 equiv.), solvent (1 mL), 708C, 24 h.
Conversion determined by GLC.
Activated carbon.
(equiv.)[c]
[b]
[c]
[d]
[e]
1
2
3
4
5
6
7
8
Ar
Ar
Ar
Ar
Ar
air
air
Ar
Ar
Ar
Ar
air
air
air
air
100
50
25
12.5
50
50
50
25
50
50
decane (1.2)
decane (1.2)
decane (1.2)
decane (1.2)
decane (2.0)
decane (1.2)
decane (2.0)
H2O (1.2)
H2O (1.2)
H2O (1.5)
H2O (2.0)
H2O (1.2)
38
69
80
83
76
67
77
76
73
82
>99
84
>99
91
Montmorillonite K-10.
1a (1.0 mmol), 2a (1.2 mmol), CuNPs/support (50 mg), t-
BuOOH-H2O (1.2 equiv.), 708C, 24 h.
Second cycle.
[f]
[g]
Third cycle.
9
10
11
12
13
14
15
prior thermal treatment. In general, the presence of
water, either in the original zeolite or in the impreg-
nation step, favored the incorporation of copper
(Table 2, compare entries 1 and 2 with 3, and 6 with
7). In spite of the fact that method A provided higher
conversions, only catalysts prepared by method B
could be reused.
Finally, the possibility of performing the CDC with-
out the need of an inert atmosphere was explored by
varying the amount of catalyst, and type and amount
of TBHP (Table 3). The reactions in TBHP-decane
(1.2 equiv.) under Ar showed an interesting trend: the
50
50
50
25
H2O (2.0)
H2O (2.0)
H2O (2.0)
12.5
90
[a]
1a (1.0 mmol), 2a (1.2 mmol), CuNPs/ZY, t-BuOOH,
708C, 20 h.
Prepared by the method B (Table 2, entry 4).
6M in decane or 80% in H2O.
[b]
[c]
[d]
Conversion determined by GLC.
conversion increased when decreasing the amount of ence in the conversion of both the TBHP solvent and
catalyst (Table 3, entries 1–4), whereas larger the atmosphere (compare entries 2, 3, and 11 with 9,
a
amount of the oxidant did not exert any significant 8 and 13, respectively). High-to-quantitative conver-
improvement, either under Ar or air (Table 3, en- sions were reached when using 2 equiv. of the oxidant
tries 5–7). Careful analysis of the data in Table 3 (Table 3, entries, 11 and 13–15), even at a lower cata-
allows us to conclude that there is a minimum influ- lyst loading (entry 15, 0.38 mol%). Therefore, the
Adv. Synth. Catal. 2015, 357, 3549 – 3561
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3551

FULL PAPERS
Francisco Alonso et al.
conditions in entry 13 were considered as the opti-
mum for the substrate scope study (see below).
The copper-on-zeolite Y catalyst prepared by the
method B was characterized by different means. The
copper content in the catalysts, ca. 3.0–3.8 wt%, was
determined by inductively coupled plasma optical
emission spectroscopy (ICP-OES). Analysis by TEM
revealed the presence of spherical monodisperse
nanoparticles (s=0.347) unevenly distributed on the
zeolite surface with diameters of ca. 1.7Æ0.7 nm
(Figure 2). Energy-dispersive X-ray (EDX) analysis
on various regions confirmed the presence of cop-
per,[20a] with energy bands of 8.04, 8.90 keV (K lines)
and 0.92 keV (L line) (Figure 3). X-ray diffraction
(XRD) and selected area electron diffraction
(SAED) analyses mainly showed signals correspond-
ing to zeolite Y (see the Supporting Information).[23a]
XPS analysis showed four Cu (2p3/2) peaks at 932.6,
934.6, 941.5 and 944.1 eV. These peaks could be as-
signed to Cu2O (932.6 eV) and CuO (934.6 eV), with
the peaks at 941.5 and 944.1 eV being the satellite
shake-up features characteristic of Cu2+ species (Fig-
ure 4).[23b,c]
Figure 3. EDX spectrum of CuNPs/ZY.
With the optimized catalyst and conditions in hand,
we next studied the substrate scope (Table 4). First,
Figure 4. XPS spectrum of CuNPs/ZY at the Cu 2p3/2 level.
N,N-dimethylaniline was combined with aromatic al-
kynes bearing either electron-donating or electron-
withdrawing groups to give the corresponding prod-
ucts 3aa–3ad in good-to-excellent yields (Table 4, en-
tries 1–4). The method was equally effective for ali-
phatic alkynes, including alkyl-chain, cyclic and func-
tionalized alkynes (Table 4, entries 5–9). It is notewor-
thy that the reaction conditions were compatible with
the presence of chloro, ester and alcohol functionali-
ties (Table 4, entries 7–9). Then, the electronic charac-
ter of the starting aniline was changed; electron-do-
nating groups at the para position favored the CDC
to furnish the propargylamines 3ba and 3ca in high
yields (Table 4, entries 10 and 11). In contrast, N,N-di-
methylanilines with electron-withdrawing groups at
the para position reacted sluggishly, even at 1008C, af-
fording the expected products 3da and 3ea in modest
yields (Table 4, entries 12 and 13). This result is not
so unexpected if we consider that electron-withdraw-
ing groups at the para position can destabilize the in-
termediate iminium species.
Concerning benzylamines, the coupling of the N,N-
dimethyl derivatives was highly regioselective, taking
place at the methyl group instead of at the benzylic
position, in good yields (Table 4, entries 14 and 15). 2-
Phenyl-1,2,3,4-tetrahydroisoquinoline gave the ex-
pected product 3ha in moderate yield (Table 4,
entry 16). Finally, we must point out that the same
Figure 2. TEM micrograph (top) and particle size distribu-
tion (bottom) of CuNPs/ZY. The sizes were determined for
200 nanoparticles selected at random.
3552
asc.wiley-vch.de
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 3549 – 3561

FULL PAPERS
Cross-Dehydrogenative Coupling of Tertiary Amines and Terminal Alkynes
Table 4. CDC of tertiary amines and terminal alkynes catalyzed by CuNPs/ZY.[a]
Adv. Synth. Catal. 2015, 357, 3549 – 3561
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3553

FULL PAPERS
Francisco Alonso et al.
Table 4. (Continued)
[a]
1 (1.0 mmol), 2 (1.2 mmol), CuNPs/ZY (1.5 mol%), t-BuOOH-H2O (2.0 equiv.), 708C, 15–20 h.
Isolated yield.
Yield after distillation.
Reaction at 1008C.
NMR yield.
[b]
[c]
[d]
[e]
catalytic system was successfully applied to the CDC
Under the same conditions as above but using
of aliphatic amines and alkynes; aliphatic amines are TMEDA (1l) as the tertiary amine, a mixture of mon-
very rarely studied substrates[14] and, in general, oalkynylated 1l (3la) and aminomethylated 2a (4) was
copper catalysis in the presence of an oxidant leads to obtained. This result is in agreement with the obser-
poor yields of the CDC products.[12a] We were delight- vations of Li et al.,[25] namely: TBHP favored the for-
ed to check that the CDC of both N,N-dimethylcyclo- mation of 4 versus 3la, contrary to what is observed
hexylamine (1i) and tropinone (1j) with phenylacety- with molecular oxygen (Scheme 3).
lene (2a) provided the propargylamines 3ia and 3ja in
excellent and modest yields, by exclusive reaction at tions were carried out without air exclusion. In addi-
the methyl group (Table 4, entries 17 and 18). tion, the catalyst could be easily recovered by centri-
It is worthwhile mentioning that all the CDC reac-
Interestingly, the CDC of the secondary amine N- fugation and reutilized, leading to propargylamine
methylaniline (1k) with phenylacetylene (2a) pro- 3aa in high yield over seven consecutive cycles
duced quantitatively the same propargylamine 3aa as (Figure 5). Furthermore, the standard procedure was
that derived from 1a (Scheme 2). This methylation–al- successfully scaled-up to 12 mmol, giving rise to the
kynylation process has been recently described by
Phan and Truong et al. using copper ferrite (5%
CuFe2O4, DMA, 1408C)[24a] and a copper MOF (5%
catalyst, DMA, 1208C)[24b] in the presence of TBHP
(3 equiv.) as the oxidant under argon.
Scheme 2. CDC of 1k and 2a catalyzed by CuNPs/ZY.
Scheme 3. CDC of 1l and 2a catalyzed by CuNPs/ZY.
3554
asc.wiley-vch.de
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 3549 – 3561

FULL PAPERS
Cross-Dehydrogenative Coupling of Tertiary Amines and Terminal Alkynes
We next compared the CuNPs/ZY catalyst with
some commercially available copper catalysts in the
standard reaction of N,N-dimethylaniline (1a) and
phenylacetylene (2a) at 1–10 mol% catalyst loading
(Table 5 and Figure 7). CuCl (10 mol%), CuBr
(10 mol%) and CuBr·SMe2 (2 mol%) gave the highest
conversions into 3aa (Table 5, entries 4, 6 and 14). All
the other commercial catalysts led to substantial
amounts of the by-product 1,4-diphenylbuta-1,3-diyne
(5a), resulting from the alkyne homocoupling.[28] The
CuNPs/ZY catalyst was found to be distinctly superi-
or, reaching the highest conversion without producing
the undesired diyne (Table 5, entry 16). Therefore, the
nanosized character of the catalyst seems to be funda-
mental.
Figure 5. Recycling of CuNPs/ZY in the synthesis of 3aa.
There has been much debate around the mecha-
nism of the CDC, particularly concerning the radical
or ionic generation of the intermediate iminium
product in 93% conversion at 1.5 mol% catalyst load- ion.[11d,29] A series of control experiments were con-
ing and 67% at 0.38 mol%. The kinetic profile for the ducted, including the use of radical scavengers, in
CDC of 1a and 2a at 12 mmol scale shows an induc- order to gain an insight into the reaction mechanism
tion period of ca. 1 h (Figure 6).
(Table 6). Among the different radical traps tested,
In order to unveil the nature of the catalysis, the 2,6-di-tert-butylphenol and, more markedly, TEMPO
standard reaction of 1a and 2a was run up to a 5% inhibited considerably the CDC, with the concomitant
conversion. Then, the catalyst was filtered and the re- formation of 2,6-di-tert-butylanisole (ca. 40%) and 1-
sulting filtrate was subjected to additional heating at methoxy-2,2,6,6-tetramethylpiperidine (ca. 75%), re-
708C for 12 h; the original conversion remained con-
stant (5%). The negligible amount of copper
(0.78 ppb) detected by ICP-MS analysis of a filtrate
sample, confirmed the absence of leaching and points
Table 5. CDC of 1a and 2a catalyzed by commercial Cu cat-
alysts.[a]
to a heterogeneous nature of the process. The likeli-
hood of the catalyst acting as a reservoir for metal
species that leach into solution and readsorb cannot
be fully rejected.[26] However, recently, Scaiano et al.
combined standard bench-scale techniques with
single-molecule spectroscopy to monitor the CuNP-
catalyzed azide-alkyne cycloaddition (which also in-
volves copper acetylides) and proved that catalysis
Entry
Catalyst
mol [%]
1a/3aa/5a [%][b]
occurs at the surface of the CuNPs.[27]
1
2
3
4
5
6
7
8
Cu(0)
Cu2O
CuO
CuCl
CuCl2
CuBr
CuI
Cu(OAc)2
CuBr·SMe2
Cu(OTf)2
CuBr
10
10
10
10
10
10
10
10
10
10
1
37/50/13
22/53/25
93/5/2
11/74/15
11/39/50
14/79/7
12/68/20
26/61/13
27/67/6
44/40/16
50/42/8
24/62/14
17/59/24
20/75/5
24/56/20
0/>99/0
9
10
11
12
13
14
15
16
CuI
1
2
2
2
Cu(OAc)2
CuBr·SMe2
Cu(OTf)2
CuNPs/ZY
1.5
[a]
Figure 6. Plot showing the evolution of the CDC of 1a and
2a at 12 mmol scale (standard conditions, 1.5 mol% CuNPs/
ZY).
1a (1.0 mmol), 2a (1.2 mmol), Cu catalyst, t-BuOOH-
H2O (2.0 equiv.), 708C, 24 h, in air.
The ratio was determined by GLC.
[b]
Adv. Synth. Catal. 2015, 357, 3549 – 3561
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3555

FULL PAPERS
Francisco Alonso et al.
Figure 7. Graphic showing the CDC product (3aa)/alkyne homocoupling (5a) ratio in the reaction of 1a and 2a catalyzed by
commercial Cu catalysts and CuNPs/ZY (see the conditions in Table 5).
Table 6. CDC of 1a and 2a in the presence of radical scaven-
nylhydrazine (2,4-DNPH) as an acetone scavenger to
detect its presence as the corresponding hydrazone.
Certainly, the addition of 2,4-DNPH to a standard re-
action, that had run fo0r 5 h, led to the formation of
a white precipitate which was identified as acetone
2,4-dinitrophenylhydrazone (6) (Scheme 4). Notwith-
standing the fact that transition metals can catalyze
the fragmentation of TBHP into tert-butoxyl radi-
cals,[30] two control experiments proved that b-cleav-
age in TBHP can take place at the CDC standard
temperature in the absence of the copper catalyst
(Scheme 5). Additional essays performed under sol-
vent-less conditions for 5 h with different oxidants
were really very enlightening (Scheme 6): (a) benzoyl
peroxide, which decomposes into PhCO2C and PhC did
not give 3aa at all; (b) di-tert-butyl peroxide, which is
able to generate t-BuOC and MeC, formed 3aa in ca.
10% conversion; (c) a similar percentage was record-
ed with acetyl peroxide, which can split into MeC. This
gers.[a]
Entry
Radical scavenger
Conv. [%][b]
1
2
3
4
norbornene
cumene
92
80
2,6-di-tert-butylphenol
65[c]
10[e]
TEMPO[d]
[a]
1a (1.0 mmol), 2a (1.2 mmol), CuNPs/ZY (1.5 mol%), t-
BuOOH-H2O (2.0 equiv.), radical scavenger (1.0 equiv.),
708C, 20 h, air.
Conversion determined by GLC.
2,6-Di-tert-butylanisole was formed in ca. 40% conver-
sion.
2,2,6,6-Tetramethylpiperidin-1-oxyl.
1-Methoxy-2,2,6,6-tetramethylpiperidine was formed in conversion is within the expected range for a standard
ca. 75% conversion.
[b]
[c]
[d]
[e]
reaction after 5 h (Figure 6), albeit the reaction condi-
spectively; that is, the reaction products between
those traps and a methyl radical (Table 6, entries 3
and 4).
In principle, methyl radicals could be formed
through a b-cleavage of TBHP, followed by a homolyt-
À
ic Me CO bond cleavage, to eventually release ace-
tone as a neutral molecule. We used 2,4-dinitrophe- tone in the CDC of 1a and 2a.
Scheme 4. Experiment demonstrating the generation of ace-
3556
asc.wiley-vch.de
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 3549 – 3561

FULL PAPERS
Cross-Dehydrogenative Coupling of Tertiary Amines and Terminal Alkynes
Scheme 5. Control experiments on the transformation of
TBHP into acetone.
Scheme 6. CDC of 1a and 2a catalyzed by CuNPs/ZY in the
presence of different peroxides.
tions are different: they were carried out at the de-
composition temperature of the oxidant in the ab-
sence of water (Scheme 6). These results reinforce the
hypothesis that highly reactive methyl radicals may
play a key role in the CDC with TBHP as the oxi-
dant.
Figure 8. XPS spectrum of CuNPs/ZY at the Cu 2p3/2 level
(a) at the end of the CDC and (b) after reoxidation.
The function of copper is also questionable, given was previously demonstrated by us[20b] and was found
that it can participate in the in-situ formation of the to be especially favored in aqueous medium.[32] (b)
nucleophile but also in the oxidation of the substrate. Thermal-promoted b-cleavage of TBHP to give tert-
The situation is especially intriguing when, as in our butoxyl and hydroxyl radicals, with further evolution
case, two oxidation states are present in the catalyst of the former into methyl radicals and acetone. (c)
[Cu(I) and Cu(II)]. We analyzed by XPS the recov- Amine oxidation by CuONPs to give its derived radi-
ered catalyst at the end of a typical reaction and, cal cation and Cu2ONPs; although some direct oxida-
much to our surprise, the intensity of Cu(II) was ex- tion of the amine by TBHP cannot be ruled out, the
tensively depleted (Figure 8a); the copper was mostly marked decrease in intensity of Cu(II) in such an oxi-
as Cu2O, what could be additionally corroborated by dative medium (Figure 8a) indicates its decisive part
the CuL3M45M45 Auger peak located at 571.0 eV (see in this step. (d) Re-oxidation of Cu2ONPs to CuONPs
the Supporting Information).[31] Treatment of the by the action of TBHP (or the combined action of
same catalyst sample with TBHP-H2O at 708C for 5 h TBHP and O2) and the concomitant production of
and subsequent analysis by XPS brought into view tert-butoxyl radical and hydroxyl anion. (e) Hydro-
the regeneration of Cu(II) to get nearly the original gen-atom transfer (HAT) between the amine radical
Cu(I)/Cu(II) ratio (Figure 8b). This finding unmasks cation and the methyl radical giving rise to the imini-
Cu(II) as a crucial player in the CDC, despite the um ion; the cooperation to some extent of other radi-
general trend that Cu(I) salts perform better than the cals in the HAT process cannot be fully discarded, al-
Cu(II) counterparts when an excess of oxidant is pres- though the methyl radical seems to have a prominent
ent. It is our belief that most of the success of the participation. Whether the SET comes before the
CDC with CuNPs resides on the conjunction of both HAT or vice versa is difficult to ascertain,[33] even
Cu(I) and Cu(II) species and their redox activities.
though dimers of the putative radicals of 1a in the ab-
Gathering and interpreting the above results, a ten- sence of the catalyst have not been detected, which
tative mechanism was proposed in which some of the would suggest an SET-HAT sequence. (f) The eventu-
following events could occur in parallel (Scheme 7). al addition of the copper acetylide to the iminium ion
(a) Alkyne activation by Cu2ONPs to form the corre- would afford the propargylamine.
sponding copper acetylide; the formation of the latter
Adv. Synth. Catal. 2015, 357, 3549 – 3561
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3557

FULL PAPERS
Francisco Alonso et al.
Scheme 7. Reaction mechanism proposed for the CDC of N,N-dimethylaniline and phenylacetylene catalyzed by CuNPs/ZY
in the presence of TBHP.
As a final remark, we must underline that the CDC presence of different functionalities such as methoxy,
reported herein is highly regioselective; tertiary ester, cyano, hydroxy, halogen and ketone. Not only
À
amines prone to activation in different C H bonds activated N,N-dimethylanilines have been covered in
underwent alkynylation exclusively at the methyl this study but also benzylamines and aliphatic amines.
group. Such is the case of the benzylic amines 1f and The catalyst has been successfully both reutilized in
1g, N,N-dimethylcyclohexylamine (1i) and tropinone seven successive runs and adapted to a 12 mmol scale.
(1j). Some stereoelectronic effects have been invoked Moreover, its catalytic activity surpasses that of vari-
to rationalize this selectivity, namely: the necessity of ous commercially available copper catalysts, depleting
periplanarity of the partially occupied orbital on the the formation of 1,3-diynes as by-products. We have
nitrogen of the intermediate amine radical cation with endeavored to propose a reaction pathway which dis-
[29,34]
À
the a C H bond.
Surely, this explanation can ac- closes the pivotal role of free radicals (methyl radical,
count for the selectivity attained in the case of tropi- in particular) and that of the Cu(I)/Cu(II) redox
none (1j), but it is not so obvious in the other exam- couple. The results of this study also highlight the util-
ples. Probably, in those cases, the HAT is merely ity of nanosized copper in catalysis when compared
driven by steric effects, involving the most accessible with bulk copper sources.
a C H bond to the radical, to generate the terminal
kinetic iminium ion rather than the internal thermo-
À
dynamic one.
Experimental Section
General Material and Methods
Conclusions
Anhydrous copper(II) chloride (97%, Aldrich), lithium
powder from granulated lithium (Chemetall), DTBB (4,4’-
di-tert-butylbiphenyl, Aldrich), TBHP (5–6M in decane or
In conclusion, we have presented a new heterogene-
ous catalyst for the CDC of tertiary amines and termi-
nal alkynes comprised of oxidized copper nanoparti- 70 wt% in water, Aldrich) and sodium Y zeolite (Aldrich)
were commercially available. N,N-Dimethylaniline (Carlo
Erba) was distilled before use. All other starting materials
and reagents were commercially available and of the best
grade (Aldrich, Acros, Alfa Aesar) and were used without
further purification. THF was dried in a Sharlab PS-400-
3MD solvent purification system using an alumina column.
All reactions were carried out on a multireactor apparatus
using the corresponding reactor tubes. Melting points were
obtained with a Reichert Thermovar apparatus and are un-
corrected. Optical rotations were measured using a Perkin–
cles on sodium Y zeolite, readily prepared from com-
mercially available chemicals under mild conditions.
The catalyst (1.5 mol%), in the presence of aqueous
TBHP, has been applied to the formation of an array
of propargylamines in moderate-to-excellent yields.
Contrary to other previously reported methodologies,
it has been demonstrated that the copper-catalyzed
CDC can be conducted under solvent-free conditions
and without the requirement of an inert atmosphere.
The reaction conditions were compatible with the Elmer 341 polarimeter with a thermally jacketted 5 cm cell
3558
asc.wiley-vch.de
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 3549 – 3561

FULL PAPERS
Cross-Dehydrogenative Coupling of Tertiary Amines and Terminal Alkynes
at approximately 208C. Concentrations (c) are given in g/
100 mL and [a] values are given in units of 10À1 degcm2 gÀ1.
NMR spectra were recorded on Bruker Avance 300 and 400
spectrometers (300 and 400 MHz for 1H NMR; 75 and
101 MHz for 13C NMR); chemical shifts are given in (d)
parts per million and coupling constants (J) in Hertz. Infra-
red analysis was performed with a Jasco 4100 LE (Pike
MIRacle ATR) spectrophotometer; wavenumbers (n˜) are
given in cmÀ1. Mass spectra (EI) were obtained at 70 eV on
an Agilent 5973 spectrometer; fragment ions in m/z with rel-
ative intensities (%) in parentheses. HR-MS analyses were
also carried out in the electron impact mode (EI) at 70 eV
on a Finnigan MAT95S spectrometer. Elemental analyses
were performed on a Leco Micro TruSpec CHNS microana-
lyzer. The purity of volatile compounds and the chromato-
graphic analyses (GLC) were determined with an Agilent
6890N instrument equipped with a flame ionization detector
and an HP-5 MS 30 m capillary column (0.32 mm diameter,
0.25 mm film thickness), using nitrogen (2 mLminÀ1) as carri-
er gas, Tinjector =2708C, Tcolumn =608C (3 min) and 60–2708C
(158CminÀ1); retention times (tr) are given in min. Analyti-
cal thin-layer chromatography (TLC) was carried out on
ALUGRAMꢁ Xtra SIL G UV254 aluminium sheets. Prepara-
tive thin-layer chromatography was carried on laboratory-
made TLC glass plates with silica gel 60 PF254 (Merck).
Column chromatography was performed using silica gel 60
of 40–60 microns (hexane/EtOAc as eluent). The tests for
acetone determination using 2,4-dinitrophenylhydrazine
were carried out following a standard published procedure.
argon atmosphere. The resulting mixture was stirred for 1 h
at room temperature, filtered, and the solid successively
washed with MeOH (5 mL), THF (20 mL) and dried under
vacuum (12 h).
General Procedure for the CDC of Tertiary Amines
and Terminal Alkynes Catalyzed by CuNPs/ZY
The amine (1, 1.0 mmol), the alkyne (2, 1 mmol) and t-
BuOOH-H2O (2.0 mmol) were added to a reactor tube con-
taining CuNPs/ZY (50 mg, 1.5 mol%) under air. The reac-
tion mixture was warmed to 708C and stirred at that tem-
perature for 15–20 h. The resulting mixture was diluted with
EtOAc (15 mL), filtered through Celite and subjected to
column chromatography (silica gel, hexane-EtOAc) to give
the pure propargylamines 3. The catalyst could be recovered
by diluting the reaction crude with EtOAc (15 mL), fol-
lowed by centrifugation (2500 rpm, 15 min), catalyst separa-
tion and washing (EtOAc, 15 mL), and final drying under
vacuum.
Acknowledgements
This work was generously supported by the Spanish Minister-
io de Economía y Competitividad (MINECO: CTQ2011-
24151). Y. M. acknowledges the Instituto de Síntesis Orgµnica
(ISO) of the Universidad de Alicante for a grant.
Typical Procedure for the Preparation of CuNPs/ZY
(Method A)
References
Anhydrous copper(II) chloride (135 mg, 1.0 mmol) was dis-
solved in dry THF or water (15 mL) and sodium Y zeolite
(1.28 g) was added to the resulting solution. The mixture
was stirred in the presence (for THF) or absence (for water)
of argon overnight, followed by filtration and washing with
THF or water (20 mL), and drying under vacuum (12 h).
[1] a) F. Xiao, Y. Chen, Y. Liu, J. Whang, Tetrahedron
2008, 64, 2755–2761; b) D. Shibata, E. Okada, J. Mo-
lette, M. MØdebielle, Tetrahedron Lett. 2008, 49, 7161–
7164; c) Y. Yamamoto, H. Hayashi, T. Saigoku, H.
Nishiyama, J. Am. Chem. Soc. 2005, 127, 10804–10805;
d) D. F. Harvey, D. M. Sigano, J. Org. Chem. 1996, 61,
2268–2272; e) B. Yan, Y. Liu, Org. Lett. 2007, 9, 4323–
4326; f) E.-S. Lee, H.-S. Yeom, J.-H. Hwang, S. Shin,
Eur. J. Org. Chem. 2007, 3503–3507.
Typical Procedure for the Preparation of CuNPs/ZY
(Method B)
[2] See, for instance: a) C. Jiang, M. Xu, S. Wang, H.
Wang, Z.-J. Yao, J. Org. Chem. 2010, 75, 4323–4325;
b) F. J. FaÇanµs, T. Arto, A. Mendoza, F. Rodríguez,
Org. Lett. 2011, 13, 4184–4187; c) T. S. Symeonidis,
M. G. Kallitsakis, K. E. Litinas, Tetrahedron Lett. 2011,
52, 5452–5455; d) Y. L. Zhao, C.-H. Di, S.-D. Liu, J.
Meng, Q. Liu, Adv. Synth. Catal. 2012, 354, 3545–3550;
e) H. V. Wachenfeldt, F. Paulsen, A. Sundin, D. Strand,
Eur. J. Org. Chem. 2013, 4578–4580; f) B. Alcaide, P.
Almendros, J. M. Alonso, I. Fernµndez, G. G. Campil-
los, M. R. Torres, Chem. Commun. 2014, 50, 4567–4567.
[3] See, for instance: a) A. Hoepping, K. M. Johnson, C.
George, J. Flippen-Anderson, A. P. Kozikowski, J. Med.
Chem. 2000, 43, 2064–2071; b) B. Jiang, M. Xu, Angew.
Chem. 2004, 116, 2597–2600; Angew. Chem. Int. Ed.
2004, 43, 2543–2546; c) J. J. Fleming, J. Du Bois, J. Am.
Chem. Soc. 2006, 128, 3926–3927.
Anhydrous copper(II) chloride (135 mg, 1.0 mmol) was
added to a suspension of lithium powder (14 mg, 2.0 mmol)
and 4,4’-di-tert-butylbiphenyl (DTBB, 27 mg, 0.1 mmol) in
dry THF (2 mL) at room temperature under an argon at-
mosphere. The reaction mixture, which was initially dark
blue, rapidly changed to black, indicating that the suspen-
sion of copper nanoparticles was formed. This suspension
was diluted with THF (18 mL) followed by the addition of
sodium Y zeolite (1.28 g). The resulting mixture was stirred
for 1 h at room temperature, filtered, and the solid succes-
sively washed with MeOH (5 mL) and THF (20 mL), and
dried under vacuum (5 h).
Typical Procedure for the Preparation of CuNPs/ZY
(Method C)
Following the impregnation method A, the resulting solid
was added to a suspension of lithium powder (14 mg,
2.0 mmol) and 4,4’-di-tert-butylbiphenyl (DTBB, 27 mg,
0.1 mmol) in THF (2 mL) at room temperature under an
[4] See, for instance: a) O. Bar-Am, T. Amit, O. Weinreb,
M. B. H. Youdim, S. Mandel, J. Alzheimerꢀs Dis. 2010,
21, 361–371; b) I. Bolea, A. Gella, M. Unzeta, J. Neural
Adv. Synth. Catal. 2015, 357, 3549 – 3561
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3559

FULL PAPERS
Francisco Alonso et al.
Transm. 2013, 120, 893–902; c) J. Louvel, J. F. S. Carval-
ho, Z. Yu, M. Soethoudt, E. B. Lenselink, E. Klaase, J.
Brussee, A. P. IJzerman, J. Med. Chem. 2013, 56, 9427–
9440.
[15] a) M. Rueping, R. M. Koenigs, K. Poscharny, D. C.
Fabry, D. Leonori, C. Vila, Chem. Eur. J. 2012, 18,
5170–5174; b) D. B. Freeman, L. Furst, A. G. Condie,
C. R. J. Stephenson, Org. Lett. 2012, 14, 94–97; c) I.
Perepichka, S. Kundu, Z. Hearne, C.-J. Li, Org.
Biomol. Chem. 2015, 13, 447–451.
[16] a) A. Arroyo, Coupling of Amines and Alkynes Cata-
lyzed by Supported Copper Nanoparticles, Masterꢀs
Degree, Universidad de Alicante, 2013; b) M. I. Martín
García, Cross-Dehydrogenative Coupling Catalyzed by
Copper Nanoparticles on Zeolite for the Synthesis of
Propargylic Amines, Masterꢀs Degree, Universidad de
Alicante, 2015.
[17] a) R. Hudson, S. Ishikawa, C.-J. Li, A. Moores, Synlett
2013, 24, 1637–1642 (10 mol% CuFe2O4, 1 equiv. DDQ,
decane, 1008C); b) G. H. Dang, D. T. Nguyen, D. T. Le,
T. Truong, N. T. S. Phan, J. Mol. Catal. A: Chem. 2014,
395, 300–306 (2 equiv. N,N-dimethylaniline, 5% MOF-
199, 3 equiv. TBHP, DMA, 1208C, Ar).
[18] For selected reviews and monographs, see: a) Nanopar-
ticles and Catalysis, (Ed.: D. Astruc), Wiley-VCH,
Weinheim, 2008; b) M. Kidwai, in: Handbook of Green
Chemistry, Vol. 2, (Eds.: P. T. Anastas, R. H. Crabtree),
Wiley-VCH, Weinheim, 2009, pp 81–92; c) N. Yan, C.
Xiao, Y. Kou, Coord. Chem. Rev. 2010, 254, 1179–1218;
d) V. Polshettiwar, R. S. Varma, Green Chem. 2010, 12,
743–754; e) Selective Nanocatalysts and Nanoscience,
(Eds.: A. Zecchina, S. Bordiga, E. Groppo), Wiley-
VCH, Weinheim, 2011; f) V. Polshettiwar, R. Luque, A.
Fihri, H. Zhu, M. Bouhara, J.-M. Basset, Chem. Rev.
2011, 111, 3036–3075; g) Nanocatalysis: Synthesis and
Applications, (Eds.: V. Polshettiwar, T. Asefa), John
Wiley & Sons, Hoboken (NJ), 2013; h) Nanomaterials
in Catalysis, (Eds.: P. Serp, K. Philippot), Wiley-VCH,
Weinheim, 2013; i) Metal Nanoparticles for Catalysis:
Advances and Applications, (Ed.: F. Tao), RSC, Cam-
bridge, 2014.
[19] For reviews, see: a) F. Alonso, G. Radivoy, M. Yus,
Russ. Chem. Bull. 2003, 52, 2563–2576; b) F. Alonso, M.
Yus, Chem. Soc. Rev. 2004, 33, 284–293; c) F. Alonso,
M. Yus, Pure Appl. Chem. 2008, 80, 1005–1012; d) F.
Alonso, P. Riente, M. Yus, Acc. Chem. Res. 2011, 44,
371–391; e) F. Alonso, in: Metal Nanoparticles for Cat-
alysis: Advances and Applications, (Ed.: F. Tao), RSC,
Cambridge, 2014, chapter 5, pp 83–98.
[20] For selected examples, see: a) F. Alonso, T. Melkonian,
Y. Moglie, M. Yus, Eur. J. Org. Chem. 2011, 2524–2530
(alkyne homocoupling); b) M. J. Albaladejo, F. Alonso,
Y. Moglie, M. Yus, Eur. J. Org. Chem. 2012, 3093–3104
(A3 coupling); c) F. Alonso, Y. Moglie, G. Radivoy, M.
Yus, J. Org. Chem. 2013, 78, 5031–5037 (click chemis-
try); d) M. J. Albaladejo, F. Alonso, M. Yus, Chem.
Eur. J. 2013, 19, 5242–5245 (indolizine and chalcone
synthesis).
[21] a) F. Alonso, J. J. Calvino, I. Osante, M. Yus, Chem.
Lett. 2005, 34, 1262–1263; b) F. Alonso, J. J. Calvino, I.
Osante, M. Yus, J. Exp. Nanosci. 2006, 1, 419–433.
[22] Other oxidants such as H2O2, K2S2O8, O2, oxone, DDQ,
PhI(OAc)2 or I2 were found to be inefficient in this
transformation.
[5] a) C. W. Olanow, Neurology 2006, 66, S69–S79; b) M.
Naoi, W. Maruyama, H. Yi, Y. Akao, Y. Yamaoka, M.
Shamoto-Nagai, J. Neural Transm. 2007, 72, 121–131;
c) review: V. Oldfield, G. M. Keating, C. M. Perry,
Drugs 2007, 67, 1725–1747; d) D. L. Murphy, F.
Karoum, D. Pickar, R. M. Cohen, S. Lipper, A. M.
Mellow, P. N. Tariot, T. Sunderland, J. Neural Transm.
Suppl. 1998, 52, 39–48.
[6] a) I. E. Kopka, Z. A. Fataftah, M. W. Rathke, J. Org.
Chem. 1980, 45, 4616–4622; b) S. Czernecki, J.-M.
ValØry, J. Carbohydr. Chem. 1990, 9, 767–770; c) I.
Imada, M. Yuasa, I. Nakamura, S.-I. Murahashi, J. Org.
Chem. 1994, 59, 2282–2284.
[7] For reviews, see: a) R. Bloch, Chem. Rev. 1998, 98,
1407–1438; b) V. V. Kouznetsov, L. Y. Vargas MØndez,
Synthesis 2008, 491–506; c) G. Blay, A. Monleón, J. R.
Pedro, Curr. Org. Chem. 2009, 13, 1498–1539; see also:
d) C. Fischer, E. M. Carreira, Org. Lett. 2001, 3, 4319–
4321; e) C. Fischer, E. M. Carreira, Org. Lett. 2004, 6,
1497–1499.
[8] For reviews, see: a) C. Wei, Z. Li, C.-J. Li, Synlett 2004,
1472–1483; b) L. Zani, C. Bolm, Chem. Commun. 2006,
4263–4275; c) C.-J. Li, Acc. Chem. Res. 2010, 43, 581–
590; d) W.-J. Yoo, L. Zhao, C.-J. Li, Aldrichimica Acta
2011, 44, 43–51; e) W.-J Yoo, L. Zhao, C.-J. Li, in: Sci-
ence of Synthesis, (Ed.: T. J. Mueller), Thieme, Stutt-
gart, 2014, Vol. 1, pp 189–217.
[9] a) X. Xu, Z. Ge, D. Cheng, X. Li, ARKIVOC 2012, viii,
107–118; b) X. Chen, T. Chen, Y. Zhou, C.-T. Au, L.-B.
Han, S.-F. Yin, Org. Biomol. Chem. 2014, 12, 247–250.
[10] For reviews and monographs, see: a) C.-J. Li, Acc.
Chem. Res. 2009, 42, 335–344; b) C. J. Scheuermann,
Chem. Asian J. 2010, 5, 436–451; c) C. S. Yeung, V. M.
Dong, Chem. Rev. 2011, 111, 1215–1292; d) F. W. Patur-
eau, J. Wencel-Delord, F. Glorius, Aldrichimica Acta
2012, 45, 31–41; e) G. J. Deng, C.-J. Li, in: Organic
Chemistry. Breakthroughs and Perspectives, (Eds.: K.
Ding, L.-X. Dai), Wiley-VCH, Weinheim, 2012, chapter
À
À
19; f) From C H to C C Bonds: Cross-Dehydrogena-
tive-Coupling, (Ed. C.-J. Li), RSC, Cambridge (U.K.),
2015.
[11] a) Z. Li, C.-J. Li, J. Am. Chem. Soc. 2004, 126, 11810–
11811; b) Z. Li, C.-J. Li, Org. Lett. 2004, 6, 4997–4999;
c) Z. Li, P. D. MacLeod, C.-J. Li, Tetrahedron: Asym-
metry 2006, 17, 590–597; d) Z. Li, D. S. Bohle, C.-J. Li,
Proc. Natl. Acad. Sci. USA 2006, 103, 8928–8933; e) L.
Zhao, C.-J. Li, Angew. Chem. 2008, 120, 7183–7186;
Angew. Chem. Int. Ed. 2008, 47, 7075–7078.
[12] a) M. Niu, Z. Yin, H. Fu, Y. Jiang, Y. Zhao, J. Org.
Chem. 2008, 73, 3961–3963; b) for an example using
tertiary amine N-oxides, see: Z. Xu, X. Yu, X. Feng, M.
Bao, J. Org. Chem. 2011, 76, 6901–6905.
[13] a) C. M. Rao Volla, P. Vogel, Org. Lett. 2009, 11, 1701–
1704; b) Q. Shen, L. Zhang, Y.-R. Zhou, J.-X. Li, Tetra-
hedron Lett. 2013, 54, 6735–6738.
[14] X. Jin, K. Yamaguchi, N. Mizuno, RSC Adv. 2014, 4,
34712–34715.
[23] a) A. S. Kovo, O. Hernandez, S. M. Holmes, J. Mater.
Chem. 2009, 19, 6207–6212; b) K. V. R. Chary, G. V.
3560
asc.wiley-vch.de
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 3549 – 3561

FULL PAPERS
Cross-Dehydrogenative Coupling of Tertiary Amines and Terminal Alkynes
Sagar, C. S. Srikhanth, V. V. Rao, J. Phys. Chem. B.
2007, 111, 543–550; c) J. GimØnez-MaÇogil, A. Bueno-
López, A. García-García, Appl. Catal. B: Environ.
2014, 152–153, 99–107.
[28] For a perspective on heterogeneous catalytic homocou-
pling of terminal alkynes, see: F. Alonso, M. Yus, ACS
Catal. 2012, 2, 1441–1451.
[29] For an excellent revision on the mechanism of the
CDC, see: A. S.-K. Tsang, S. J. Park, M. H. Todd, in:
[24] a) A. T. Nguyen, L. T. Pham, N. T. S. Phan, T. Truong,
Catal. Sci. Technol. 2014, 4, 4281–4288; b) G. H. Dang,
T. T. Dang, D. T. Le, T. Truong, N. T. S. Phan, J. Catal.
2014, 319, 258–264.
À
À
From C H to C C Bonds: Cross-Dehydrogenative-
Coupling, (Ed.: C.-J. Li), RSC, Cambridge (U.K.), 2015,
chapter 11, pp 254–294.
[30] W. H. Richardson, J. Am. Chem. Soc. 1965, 87, 247–
253.
[31] D. E. Diaz-Droguett, R. Espinoza, V. M. Fuenzalida,
Appl. Surf. Sci. 2011, 257, 4597–4602.
[32] F. Alonso, Y. Moglie, G. Radivoy, M. Yus, J. Org.
Chem. 2011, 76, 8394–8405.
[33] G.-J. Cheng, L.-J. Song, Y.-F. Yang, X. Zhang, O,
Wiest, Y.-D. Wu, ChemPlusChem 2013, 78, 943–951.
[34] C.-K. Chen, A. G. Hortmann, M. R. Marzabadi, J. Am.
Chem. Soc. 1988, 110, 4829–4831.
[25] Q. Shen, L. Zhang, Y.-R. Zhou, J.-X. Li, Tetrahedron
Lett. 2013, 54, 6725–6728.
[26] Reviews: a) D. Astruc, F. Lu, J. Ruiz Aranzaes, Angew.
Chem. 2005, 117, 8062–8083; Angew. Chem. Int. Ed.
2005, 44, 7852–7872; b) L. Durµn Pachón, G. Rothen-
berg, Appl. Organomet. Chem. 2008, 22, 288–299.
[27] M. R. Decan, S. Impellizzeri, M. L. Marin, J. C. Scaia-
no, Nat. Commun. 2014, 5, 4612.
Adv. Synth. Catal. 2015, 357, 3549 – 3561
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3561