Identifying a Highly Active Copper Catalyst for KA2 Reaction of Aromatic Ketones

Article abstract of DOI:10.1002/chem.201504823

The well-established A³ coupling reaction of terminal alkynes, aldehydes, and amines provides the most straightforward approach to propargylic amines. However, the related reaction of ketones, especially aromatic ketones, is still a significant challenge. A highly efficient catalytic protocol has been developed for the coupling of aromatic ketones with amines and terminal alkynes, in which Cu^I, generated in situ from the reduction of CuBr₂ with sodium ascorbate, has been identified as the highly efficient catalyst. Since propargylic amines are versatile synthetic intermediates and important units in pharmaceutical products, such an advance will greatly stimulate research interest involving the previously unavailable propargylic amines.

Full text of DOI:10.1002/chem.201504823

DOI: 10.1002/chem.201504823
Communication
&
Multicomponent Reactions
Identifying a Highly Active Copper Catalyst for KA2 Reaction of
Aromatic Ketones
Yujuan Cai,[a] Xinjun Tang,[a] and Shengming Ma*[a, b]
Table 1. Optimization of the reaction conditions.[a]
Abstract: The well-established A3 coupling reaction of ter-
minal alkynes, aldehydes, and amines provides the most
straightforward approach to propargylic amines. However,
the related reaction of ketones, especially aromatic ke-
tones, is still a significant challenge. A highly efficient cata-
Entry Cat. x [mol%] y [equiv] Yield of 4a [%][b] Recovery of 2a [%][b]
lytic protocol has been developed for the coupling of aro-
1[c,d]
2
CuBr
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
–
–
–
–
–
2
2
2
2
52
39
70
96
98
48
61
30
4
2
5
matic ketones with amines and terminal alkynes, in which
CuI, generated in situ from the reduction of CuBr2 with
sodium ascorbate, has been identified as the highly effi-
cient catalyst. Since propargylic amines are versatile syn-
thetic intermediates and important units in pharmaceuti-
cal products, such an advance will greatly stimulate re-
search interest involving the previously unavailable prop-
argylic amines.
3[c]
4
20
20
20
20
20
5[e]
6[e,f]
7[e,g] CuBr2
89
quant.
–
[a] Reaction conditions (unless otherwise stated): alkyne (2.0 mmol),
ketone (1.0 mmol) and amine (1.0 mmol) at 1008C in toluene (1 mL);
[b] determined by 1H NMR analysis with mesitylene as the internal stan-
dard; [c] 4 Š MS (300 mg) was used and the reaction time was 12 h;
[d] 5 equivalents of alkyne were used; [e] 1.1 mmol of pyrrolidine were
used; [f] 1.5 mmol alkyne were used; [g] the reaction concentration for
2a was 0.2m.
Propargylic amines are a very important class of compounds in
organic and medicinal chemistry. The direct aldehyde–amine–
alkyne (A3) coupling is a well-established means to form secon-
dary propargylic amines.[1–19] However, in contrast, such three-
component couplings involving ketones, amines and alkynes
(KA2 reaction) are far from being well developed because of
the extremely low reactivity observed for ketones.[20–27] Recent-
ly, Larsen and co-workers utilized CuCl2 and Ti(OEt)4 as the cat-
alyst to address the problem for the reaction with alkyl ke-
tones.[28] However, such reactions with aromatic ketones
remain a fundamental challenge.[29] Herein, we report a highly
efficient CuI catalyst, generated in situ from the reduction of
CuBr2 with sodium ascorbate, for the coupling of aromatic ke-
tones, amines, and alkynes to form propargylic amines in good
to excellent yields with a very broad scope.
yield dropped to 39% with 61% of 2a recovered (Table 1,
entry 2). When we used a copper(I) species that was generated
in situ from CuBr2 and sodium ascorbate,[30] the yield was im-
proved to 70% with 30% of 2a recovered (Table 1, entry 3).
The yield was further improved to 96% in the presence of
sodium ascorbate and Ti(OEt)4 (Table 1, entry 4). Increasing the
loading of pyrrolidine improved the yield to 98% (Table 1,
entry 5). Reducing the amount of terminal alkyne 1a led to
a lower yield (Table 1, entry 6). When we conducted the reac-
tion at a lower concentration of 0.2m for 2a, a quantative
yield was obtained (Table 1, entry 7). Thus, 1a (2 equiv), 2a
(1 equiv), 3a (1.1 equiv), CuBr2 (10 mol%), sodium ascorbate
(20 mol%), and Ti(OEt)4 (2 equiv) in toluene at 1008C under
argon were defined as the optimized reaction conditions for
further study.
Our initial work began with phenylacetylene 1a, acetophe-
none 2a, and pyrrolidine 3a under the catalysis of CuBr in the
presence of 4 Š MS in toluene at 1008C. Propargylic amine 4a
was afforded only in 52% yield with 48% of 2a recovered
(Table 1, entry 1). When CuBr2 was used as the catalyst, the
With the optimized reaction conditions in hand, we then in-
vestigated the scope of the reaction. Firstly, different aromatic
ketones were examined (Table 2). Acetophenone 2a and pro-
piophenone 2b afforded excellent yields of the propargylic
amines 4a and 4b (Table 2, entries 1 and 2). Long-chain alkyl
aromatic ketone 3c was also suitable for this reaction, with
a yield of 94% (Table 2, entry 3). The cyclohexyl phenyl ketone
2d, with a larger steric hindrance, also formed propargylic
amine 4d successfully in 95% yield (Table 2, entry 4).
[a] Y. Cai, Dr. X. Tang, Prof. Dr. S. Ma
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (P. R. China)
E-mail: masm@sioc.ac.cn
[b] Prof. Dr. S. Ma
Department of Chemistry, Fudan University
220 Handan Road, Shanghai 200433 (P. R. China)
Acetophenone analogues with p-Cl, p-Ph, p-MeO, m-Br, m-Cl
or o-Cl substituents all afforded good to excellent yields of the
corresponding products (Table 2, entries 5–10). The reaction
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201504823.
Chem. Eur. J. 2016, 22, 2266 – 2269
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Communication
Table 2. The scope of aromatic ketones.[a]
Table 3. The scope of terminal alkynes.[a]
R1
Yield [%][b]
Entry
Ar
R2
Yield [%][b]
Entry
1
2
3[c]
4[c]
5
6
7
8
9
10
11
12
13[d]
Ph
Ph
Ph
Me
Et
(CH2)10Me
Cy
92 (4a)
96 (4b)
94 (4c)
95 (4d)
91 (4e)
89 (4 f)
83 (4g)
82 (4h)
83 (4i)
57 (4j)
86 (4k)
78 (4l)
77 (4m)
1
2
3
4[c]
5
4-BrC6H4 (1b)
3-BrC6H4 (1c)
2-ClC6H4 (1d)
n-C5H11 (1e)
3-H2NC6H4 (1 f)
4-O2NC6H4 (1g)
4-EtO2CC6H4 (1h)
93 (4o)
94 (4p)
92 (4q)
85 (4r)
46 (4s)
27 (4t)
74 (4u)
Ph
4-ClC6H4
4-PhC6H4
4-MeOC6H4
3-BrC6H4
3-ClC6H4
2-ClC6H4
4-NCC6H4
4-O2NC6H4
4-EtO2CC6H4
Me
Me
Me
Me
Me
Me
Me
Me
6
7[d]
[a] Reaction conditions (unless otherwise stated): alkyne (2.0 mmol),
ketone (1.0 mmol), amine (1.1 mmol), CuBr2 (10 mol%), Na-ascorbate
(20 mol%) and Ti(OEt)4 (2.0 mmol) at 1008C in toluene (5 mL) for 5 h;
[b] isolated product; [c] the reaction time was 12 h; [d] the reaction was
conducted at 1308C for 7 h.
Me
[a] Reaction conditions (unless otherwise stated): alkyne (2.0 mmol),
ketone (1.0 mmol), amine (1.1 mmol), CuBr2 (10 mol%), Na-ascorbate
(20 mol%) and Ti(OEt)4 (2.0 mmol) at 1008C in toluene (5 mL) for 5 h;
[b] isolated product; [c] the reaction time was 8 h; [d] the reaction was
conducted at 1308C for 7 h.
The reaction was easily scaled up to 50 mmol scale, afford-
ing the propargylic amine 4b in 90% yield with only 1 equiva-
lent of Ti(OEt)4 required [Eq. (3)]. Furthermore, the propargylic
amines could also be easily converted into trisubstituted al-
lenes in the presence of CdI2 [Eq. (4)].[31]
also worked well with cyano, nitro, and ester groups on aro-
matic ketones (Table 2, entries 11–13). Moreover, cyclic aromat-
ic ketone 1-tetralone 2n also yielded the corresponding prod-
uct 4n in 80% [Eq. (1)].
Various differently substituted terminal alkynes 1 were
tested in this reaction with acetophenone 2a (Table 3). Ana-
logues of phenylacetylene 1a substituted with p-Br, m-Br and
o-Cl groups all afforded excellent yields of the corresponding
products (Table 3, entries 1–3). The terminal alkyl-substituted
alkyne, 1-heptyne 1e, was also suitable for this reaction, pro-
ceeding in 62% yield (Table 3, entry 4). However, alkynes with
cyano or nitro groups did not work very well, forming product
4s in 46% yield (Table 3, entry 5) and product 4t in 27% yield
(Table 3, entry 6), respectively. In addition, ethyl 4-ethynylben-
zoate 1h afforded moderate yield of product 4u (Table 3,
entry 7).
We noted that CuI that was generated in situ from CuBr2
and sodium ascorbate[30] gave a quantitative yield in the reac-
tion of (Table 4, entry 1). As a comparison, if we used CuBr di-
rectly, the propargylic amine 4a was obtained in only 88%
Table 4. The effect of different copper sources.[a]
Other cyclic amines, such as piperidine 3b, can also be ap-
plied in this reaction to afford the propargylic amine 4v in
89% yield [Eq. (2)]. However, acyclic secondary amines, such as
dibutylamine, and primary amines, such as n-butylamine, were
not suitable for this reaction.
Entry Cat.
Sodium ascorbate
Yield of 4a
Recovery of 2a
(10 mol%) [mol%]
[%][b]
[%][b]
1
2
3
CuBr2
CuBr
CuBr
20
–
20
quant.
88
98
–
2
2.5
[a] Reaction conditions: alkyne (2.0 mmol), ketone (1.0 mmol), amine
(1.1 mmol), Na ascorbate (20 mol%) and Ti(OEt)4 (2.0 mmol) at 1008C in
1
toluene (5 mL); [b] determined by H NMR analysis with mesitylene as the
internal standard.
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yield (Table 4, entry 2). The yield was improved to 98% with
the addition of sodium ascorbate to CuBr, indicating a unique,
albeit unidentified, role of sodium ascorbate for this reaction
(Table 4, entry 3).
tablish the oxidation state of the highly active Cu catalyst, Cu
KLL X-ray Auger electron spectroscopy (XAES) was carried out:
The characteristic peak of CuI at a kinetic energy (KE) of 916 eV
was detected, indicating that the actual Cu oxidation state in
A is CuI, not Cu0 (Figure 1b).[32–34]
To investigate the nature of the real catalyst in this reaction,
we treated 5 mmol of CuBr2 with10 mmol sodium ascorbate in
toluene at 1008C for 5 h. The resulting metal salt A was then
applied under the standard reaction conditions, affording the
corresponding propargylic amine 4a in quantitative yield
[Eq. (5)].
In conclusion, we have developed a highly efficient CuBr2/
sodium ascorbate-catalyzed coupling of aromatic ketones,
amines, and alkynes to form propargylic amines with a very
broad scope. This unique protocol has addressed the issue
that aromatic ketones cannot easily be applied in KA2 reac-
tions. Our investigations indicated that CuBr2 was reduced in
situ to CuI, which efficiently catalyzed the reaction. Sodium as-
corbate is not only a reducing reagent but also works with the
in situ-generated CuI to catalyze the reaction, although the
precise mechanism by which this occurs remains unidentified.
The broad substrate scope and high efficiency of the reaction
show the potential synthetic utility of this method. Further
studies, including an asymmetric version of this reaction, are
being conducted in our laboratory.
The oxidation state of Cu in metal salt A was then studied
by X-ray photoelectron spectroscopy (XPS). The XPS detected
the Cu2p3/2 and Cu2p1/2 at 931.4 and 951.6 eV respective-
ly,[32–34] which is in agreement with CuI or Cu0. The characteris-
tic satellite peak associated with CuII at 942 eV was not ob-
served (Figure 1a),[32] excluding the role of CuII. To further es-
Experimental Section
Preparation of 1-(2,4-diphenylbut-3-yn-2-yl)pyrrolidine 4a
(Table 2, entry 1): To a dried Schlenk tube were added CuBr2
(23.5 mg, 0.1 mmol), sodium ascorbate (39.8 mg, 0.2 mmol),
Ti(OEt)4 (456.3 mg, 2 mmol) in toluene (1 mL), 1a (204.5 mg,
2 mmol)/toluene (2 mL), 2a (121.7 mg, 1 mmol) in toluene (2 mL),
and 3a (92.0 mL, d=0.852 gmLÀ1, 78.2 mg, 1.1 mmol) sequentially
under Ar atmosphere. The Schlenk tube was then placed in a pre-
heated oil bath at 1008C with stirring for 5 h and the reaction
monitored by TLC. After cooling to room temperature, the crude
reaction mixture was filtered through a short pad of aluminum
oxide (basic, 200–300 mesh) with a sand-core funnel eluted with
acetone (20 mL). After evaporation of the solvent, mesitylene
1
(70 mL) was added to the residue for H NMR analysis and the resi-
due was then purified by column chromatography on aluminum
oxide (basic, 200–300 mesh; eluent: petroleum ether/ethyl ace-
tate=500:1 to 300:1) to afford 4a (254.0 mg, 92%) as an oil:
1H NMR (400 MHz, CDCl3) d=7.84–7.72 (m, 2H, ArÀH), 7.57–7.45
(m, 2H, ArÀH), 7.38–7.21 (m, 6H, ArÀH), 2.82–2.71 (m, 2H, NCH2),
2.67–2.55 (m, 2H, NCH2), 1.83–1.69 ppm (m, 7H, 2”CH2 +CH3);
13C NMR (100 MHz, CDCl3) d=145.7, 131.8, 128.2, 128.0, 127.9,
127.0, 126.4, 123.4, 89.4, 87.2, 62.5, 48.4, 32.4, 23.8 ppm; IR (neat):
n˜ =2964, 2932, 2873, 2810, 1598, 1488, 1444, 1365, 1261, 1223,
1136, 1105, 1070, 1027, 1000 cmÀ1; MS (ESI): m/z: 276 [M+H+], 205
[M+H+Àpyrrolidine].
Preparation of 1,3-diphenylpenta-1,2-diene 5a [Eq. (4)]: To
a dried Schlenk tube was added CdI2 (293.5 mg, 0.8 mmol) inside
a glove box. The Schlenk tube was then taken out and dried under
vacuum with a heating gun until the white CdI2 turned to yellow-
green. 4b (289.8 mg, 1 mmol) and toluene (5 mL) were then added
under Ar atmosphere. The Schlenk tube was then equipped with
a condenser and placed in a pre-heated oil bath at 1308C with stir-
ring for 10 h and the reaction monitored by TLC. After cooling to
room temperature, the crude reaction mixture was filtered through
a short pad of silica gel eluted with ether (20 mL). After evapora-
tion of the solvent, the residue was purified by column chromatog-
raphy on silica gel (eluent: petroleum ether) to afford 5a[35]
(160.1 mg, 73%) as a liquid: 1H NMR (400 MHz, CDCl3) d=7.47–
7.41 (m, 2H, Ar-H), 7.36–7.25 (m, 6H, Ar-H), 7.24–7.14 (m, 2H, Ar-
Figure 1. Cu 2p XPS (a) and Cu KLL XAES (b) studies.
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H), 6.56 (t, J=3.2 Hz, 1H, CH=), 2.67–2.48 (m, 2H, CH2), 1.19 ppm
(t, J=7.6 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) d=206.2, 136.2,
134.7, 128.7, 128.4, 126.99, 126.96, 126.7, 126.0, 111.6, 98.6, 23.1,
12.5 ppm; IR (neat): n˜ =3082, 3059, 3027, 2967, 2933, 2876, 1934,
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Published online on January 12, 2016
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