Synthesis of tertiary propargylamines via a rationally designed multicomponent reaction of primary amines, formaldehyde, arylboronic acids and alkynes

Article abstract of DOI:10.1039/c4ob01055h

A novel approach for the synthesis of tertiary propargylamines is achieved through a Cu(OAc)₂-catalyzed multicomponent reaction of primary amines, formaldehyde, arylboronic acids and alkynes, where a combination of PBM and A³-coupling reactions is involved in this new multicomponent reaction. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob01055h

Organic &
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Synthesis of tertiary propargylamines via a
rationally designed multicomponent reaction of
primary amines, formaldehyde, arylboronic acids
and alkynes†
Cite this: Org. Biomol. Chem., 2014,
12, 5597
Received 22nd May 2014,
Accepted 13th June 2014
DOI: 10.1039/c4ob01055h
Jiayi Wang,a,b Qiaoying Shen,a Pinzhen Li,a Yanqing Penga and Gonghua Song*a
www.rsc.org/obc
A novel approach for the synthesis of tertiary propargylamines is secondary amines produced from PBM reaction could serve as
achieved through a Cu(OAc)2-catalyzed multicomponent reaction the amine component in further A3-coupling to construct the
of primary amines, formaldehyde, arylboronic acids and alkynes, final propargylamines. Thus, a novel five-component MCR2 of
where a combination of PBM and A3-coupling reactions is involved PBM and A3-coupling reactions has been accomplished and
in this new multicomponent reaction.
reported herein (Scheme 1).
At the outset, CuI was chosen as the catalyst to screen the
effect of solvents on the model reaction of aniline, formal-
dehyde, phenylboronic acid and phenylacetylene at 80 °C for
24 h. The nature of the solvent significantly affected the reac-
tion (Table 1). Among the solvents screened, 1,2-dichloro-
ethane (DCE) was found to be the most suitable solvent for
the combination of PBM and A3-coupling reactions with a
desired product yield of 86% (Table 1, entry 1). Toluene was
inferior and generated the corresponding product in 72% yield
(Table 1, entry 2), whereas acetonitrile and 1,4-dioxane
afforded lower yields of the desired products (Table 1, entries
3 and 4). Tetrahydrofuran (THF), ethanol and water delivered
less than 5% yield (Table 1, entries 5–7), and no desired
product was achieved when the reactions were performed in
N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO)
(Table 1, entries 8 and 9). When the reaction was performed in
the absence of a solvent, a lower yield of 22% was obtained
Multicomponent reactions (MCR), generally with high selecti-
vity, flexibility and atom economy, are among the most power-
ful synthetic strategies to access diverse complex structures
from small molecular compounds,1 and a variety of new MCRs
have been developed.2,3 Among them, the combination of
MCR (MCR2), which combines two different types of MCRs in
a single process, has gained considerable attention.4 However,
the Ugi reaction as well as isonitriles are indispensably involved
in most of the MCR2 cases.2a,c,4 Therefore, the development of
novel MCR2 without the Ugi reaction is highly valuable.
The three-component reaction of aldehydes, amines and
alkynes (A3-coupling) provides an efficient strategy to the syn-
thesis of propargylamines, which are often useful key inter-
mediates and building blocks for the preparation of many
biologically active compounds.5,6 A number of metal catalysts,
such as Au salts,7a Ag salts,7b FeCl3/Fe2O3/Fe3O4,7c,d InCl3,7e Cu
salts,7f,i and so on,5,6b have been applied for this reaction via
C–H activation of terminal alkynes. Meanwhile, the Petasis
borono–Mannich (PBM) reaction of aldehydes, amines and
boronic acids, developed by Petasis in 1993,8 has attracted
considerable attention in the synthesis of diverse α-hydroxyl
amines, α-amino acids and nitrogen-containing hetero-
cycles.9,10 Realizing both amines and aldehydes are involved in
A3-coupling and PBM reactions, and a secondary amine is gener-
ally preferable to a primary one in A3 reaction;5,7 it is possible
to develop a novel multicomponent reaction in which the
aShanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China
University of Science and Technology, Shanghai, 200237, P. R. China.
E-mail: ghsong@ecust.edu.cn; Fax: +86-21-64252603; Tel: +86-21-64253140
bShanghai Key Laboratory of Catalysis Technology for Polyolefins, Shanghai Research
Institute of Chemical Industry, Shanghai, 200062, P. R. China
†Electronic supplementary information (ESI) available: Experimental section,
spectroscopic data. See DOI: 10.1039/c4ob01055h
Scheme 1 A combination of PBM and A3-coupling reactions.
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Table 1 Effect of solvent for the five-component reactiona
Table 3 Substrate scope and limitationsa
Entry
Solvent
Yieldb (%) Entry
R1
Ar
R2
Yieldb (%)
1
2
3
4
5
6
7
8
DCE
86
72
12
32
<5
<5
<5
0
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
92
91
78
60
66
74
86
0
Toluene
1,4-Dioxane
MeCN
THF
EtOH
H2O
DMF
DMSO
Neat
p-(MeO)–Ph
p-Me–Ph
p-Cl–Ph
p-F–Ph
o-Me–Ph
m-Me–Ph
p-NO2–Ph
Bn
9
10
11
0
90
22
10
n-Butyl
71c
DCE
0c
11
Ph
Ph
64c
60c
a Reaction conditions: aniline (1 mmol), formaldehyde (40% aqueous
solution) (2.2 mmol), phenylboronic acid (1.05 mmol), phenylacetylene
(1.2 mmol), CuI (10 mol%), solvent (3 mL), 80 °C, 24 h. b Yields were
determined by GC using an internal standard. c Without catalyst.
12
Ph
Ph
13
14
15
16
17
18
19
20
21
22
23
24
25
Ph
Ph
Ph
Ph
Ph
Ph
p-(MeO)–Ph
p-Me–Ph
p-Cl–Ph
p-F–Ph
o-(MeO)–Ph
p-CF3–Ph
p-(MeO)–Ph
Ph
p-Cl–Ph
p-(MeO)–Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-Me–Ph
p-Me–Ph
p-Me–Ph
p-Cl–Ph
n-Butyl
n-Pentyl
95
87
61
60
79
0
Table 2 Catalyst and conditions screening for the five-component
reactiona
p-(MeO)–Ph
Ph
Ph
86c
82
61c
82
70
82c
78c
p-(MeO)–Ph
Ph
Ph
Ph
26
Ph
Ph
40c
Entry
Catalyst
Temp. (°C)
Time (h)
Yieldb (%)
a A mixture of aniline 1 (1 mmol), formaldehyde 2 (40% aqueous
solution) (2.2 mmol), arylboronic acid (1.05 mmol), alkyne 4
1
2
3
4
5
6
7
8
CuI
CuBr
CuCl
CuOAc
Cu2O
Cu(OAc)2
CuBr2
CuCl2
CuSO4
CuO
Cu
Cu(CF3SO3)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
80
80
80
80
80
80
80
80
80
80
80
80
25
60
80
80
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
12
86
89
71
89
68
96
46
51
68
54
65
32
<5
72
62c
71
3
(1.2 mmol), Cu(OAc)2 (10 mol%) and DCE (3 mL) was stirred at 80 °C
for 24 h. b Isolated yields. c The reaction time is 48 h.
catalyst with a high yield of 96% (Table 2, entry 6). Interest-
ingly, except for CuOAc/Cu(OAc)2, Cu(I) catalysts showed better
catalytic activities than Cu(II) catalysts (Table 2, entries 1–12).
Cu(OAc)2 was therefore adopted for the optimization of other
reaction conditions. As to the temperature, 80 °C was found to
be optimal. The reactions at lower temperatures generated less
product (Table 2, entries 13 and 14). Lowering the catalyst load
amount to 5 mol%, or reducing the reaction time to 12 h also
resulted in decrease of yield (Table 2, entries 15 and 16).
On the basis of the optimized reaction conditions (Table 2,
entry 6), the scope of this five-component reaction was
evaluated (Table 3). In general, for all components in this reac-
tion, electron-donating substituents (–MeO and –Me) on the
9
10
11
12
13
14
15
16
a Reaction conditions: aniline (1 mmol), formaldehyde (40% aqueous
solution) (2.2 mmol), phenylboronic acid (1.05 mmol), phenylacetylene
(1.2 mmol), catalyst (10 mol%), DCE (3 mL) at a temperature indicated
in the table, 12–24 h. b Yields were determined by GC using an internal
standard. c 5 mol% of Cu(OAc)2 was used.
(Table 1, entry 10), and no desired product was detected phenyl ring lead to higher yields than electron-withdrawing
without the catalyst (Table 1, entry 11).
groups (–Cl and –F) (Table 3, entries 1–7, 13–17 and 19–23).
We next investigated the catalytic activity of various copper The reaction almost ceased when a reactant with a highly
salts (Table 2). Cu(OAc)2 was found to be the most effective electron deficient substituent, such as 4-nitroaniline or
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4-(trifluoromethyl)phenylboronic acid was adopted (Table 3,
Financial support for this work from the National Basic
entries 8 and 18). For the amine component, substituted ani- Research Program of China (973 program) (grant no.
lines delivered the corresponding products in 60–92% yields 2010CB126101), the National Natural Science Foundation of
(Table 3, entries 1–7). Aliphatic amines, such as phenylmetha- China (grant 20972052) and the Shanghai Key Laboratory of
namine and butan-1-amine, also delivered desired products in Catalysis Technology for Polyolefins (LCTP-201301) are grate-
satisfactory yields (Table 3, entries 9 and 10). Furthermore, the fully acknowledged.
successful application of methyl 2-aminoacetate and methyl
2-aminopropanoate in this MCR2 (Table 3, entries 11 and 12)
might provide a complementary approach to the functionali-
Notes and references
zation of NH2-terminal amino acid esters or peptides.7h,i As for
the alkyne component, in addition to the success of phenylace-
tylenes (Table 3, entries 1–7, 9–17 and 19–23), aliphatic
alkynes also worked smoothly and desired products were
obtained in moderate yields with prolonged reaction time of
48 h (Table 3, entries 24–26).
A tentative mechanism for this five-component reaction is
proposed in Scheme 2. The reaction of primary amine 1, for-
maldehyde 2, and arylboronic acid 3 afforded a secondary
amine 6 via the PBM reaction,8,9,11 which was detected by
GC-MS throughout the reaction. The secondary amine 6 might
further react with formaldehyde 2 to produce an iminium
intermediate B. The copper acetylide intermediate, generated
from alkyne 4 and Cu(OAc)2, reacted with iminium B to give
the corresponding propargylamine 5 and regenerated the
copper catalyst for further reactions.5,7 Thus, this five-com-
ponent reaction involved a MCR2 of PBM and A3-coupling
reactions.
In conclusion, we have developed a novel approach to the
synthesis of tertiary propargylamines via a rationally designed
Cu-catalyzed multicomponent reaction of primary amines, for-
maldehydes, arylboronic acids and alkynes. The combination
of PBM and A3-coupling reactions provides an efficient and
fast one-pot approach to the tertiary propargylamines. Both
aromatic and aliphatic amines and alkynes are applicable.
Furthermore, the MCR2 also provided a complementary pathway
to the functionalization of NH2-terminal amino acid esters and
peptides.
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Scheme 2 Proposed reaction mechanism.
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