Metal-free multicomponent coupling reaction of aliphatic amines, formaldehyde, organoboronic acids, and propiolic acids for the synthesis of diverse propargylamines

Article abstract of DOI:10.1016/j.tetlet.2014.12.142

A metal-free multicomponent coupling reaction of aliphatic amines, formaldehyde, organoboronic acids, and propiolic acids has been reported for the synthesis of diverse propargylamines. This transformation involves a MCR² of PBM and decarboxylative three-component coupling reactions.

Full text of DOI:10.1016/j.tetlet.2014.12.142

Accepted Manuscript
Metal-free multicomponent coupling reaction of aliphatic amines, formalde-
hyde, oganoboronic acids and propiolic acids for the synthesis of diverse
propargylamines
Jiayi Wang, Qiaoying Shen, Jiayu Zhang, Gonghua Song
PII:
S0040-4039(14)02231-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.12.142
TETL 45667
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
23 November 2014
22 December 2014
29 December 2014
Please cite this article as: Wang, J., Shen, Q., Zhang, J., Song, G., Metal-free multicomponent coupling reaction of
aliphatic amines, formaldehyde, oganoboronic acids and propiolic acids for the synthesis of diverse
propargylamines, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2014.12.142
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Metal-free multicomponent coupling
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reaction of aliphatic amines, formaldehyde,
oganoboronic acids and propiolic acids for
the synthesis of diverse propargylamines
Jiayi Wang, Qiaoying Shen, Jiayu Zhang and Gonghua Song*

1
Tetrahedron Letters
jour nal homepage: w ww.elsevier. com
Metal-free multicomponent coupling reaction of aliphatic amines, formaldehyde,
oganoboronic acids and propiolic acids for the synthesis of diverse propargylamines
Jiayi Wang, Qiaoying Shen, Jiayu Zhang and Gonghua Song∗
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, 200237, P. R. China.
1
ARTICLE INFO
ABSTRACT
Article history:
Received
A metal-free multicomponent coupling reaction of aliphatic amines, formaldehyde,
oganoboronic acids and propiolic acids has been reported for the synthesis of diverse
propargylamines. This transformation involves a MCR2 of PBM and decarboxylative three-
component coupling reactions.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent reaction
Metal-free
Propargylamines
Petasis-borono Mannich reaction
Decarboxylative coupling
Propargylamines are important intermediates and skeletons for
the preparation of diverse heterocyclic compounds, such as
pyrroles,1 pyrrolidines,2 pyrrolophanes,3 aminoindolizines,4
Ugi reported the first MCR2 of a modified Asinger four-
component reaction (4CR) and the Ugi 4CR.14 However, most of
the reported MCR2 cases are limited in isonitrile based
5 isoindoline,5 imidazolidinones,6
2-aminoimidazoles7
and
multicomponent reactions.15 Recently, we developed
a
oxazolidinones.8 Among variety strategies for the synthesis of 30 combination of Petasis borono-Mannich (PBM)
and A3-
16-17
propargylamines, the three-component coupling reaction of an
aldehyde, an amine and an alkyne (A3-coupling) has been
recognized as the most efficient and powerful method.9-10
coupling reactions, where the secondary amines produced from
PBM reaction participated in further A3-coupling affording the
final propargylamines.18 However,
a
catalytic amount of
Cu(OAc)2 was needed. As our interest in the development of
to generate metal acetylide intermediate to fulfill the reaction. 35 novel MCR2 and metal-free MCR,19 we reported herein a metal-
10 However, transition metal catalysts are necessary in A3-coupling
Lee and coworkers11 reported the synthesis of propargylamines
via a metal-free decarboxylative three-component reaction of
propiolic acids,12 paraformaldehyde and secondary amines. The
15 replacement of alkynes with propiolic acids in their reported
reaction can lead to easily generation of carbon nucleophile for
further attacking the iminium salt, avoiding the use of metal
catalysts. However, only secondary amines were adoptable in this
reaction restricting its application. Therefore, it is of high demand
20 to develop a more applicable metal-free strategy for the synthesis
of propargylamines.
free multicomponent reaction of amines, formaldehyde,
organoboronic acids and propiolic acids for the direct synthesis
of diverse propargylamines (Scheme 1).
R3
B(OH)2
R1
40
O
R2
3
metal-free
2
R1
NH2
N
R3
H
H
1
2
5
R2
COOH
The combination of multicomponent reactions (MCR2),13
which combines different types of MCRs in one pot process
4
inheriting the high selectivity, efficiency and atom economy of 45 Scheme 1 Metal-free synthesis of propargylamines.
25 MCR, has gained more and more attentions, since Dömling and
———
∗ Corresponding author. Tel.: +86 21 64253140; fax: +86 21 6425 2603; e-mail: ghsong@ecust.edu.cn

2
Tetrahedron
Table 2 Reaction of various primary amines with formaldehyde,
phenylboronic acid and phenylpropiolic acid.a
Table 1 Optimization of conditions for the synthesis of
propargylamine.a
Entry
1
1a/2/3a/4a (ratio)
T/oC
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
25
60
100
80
80
time/h
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
solvent
toluene
xylene
DCE
Yieldb/%
1.0/2.5/1.2/1.2
1.0/2.5/1.2/1.2
1.0/2.5/1.2/1.2
1.0/2.5/1.2/1.2
1.0/2.5/1.2/1.2
1.0/2.5/1.2/1.2
1.0/2.5/1.2/1.2
1.0/2.5/1.2/1.2
1.0/2.5/1.2/1.2
1.0/2.5/1.2/1.2
1.0/2.5/1.1/1.2
1.0/2.5/1.4/1.2
1.0/2.5/1.5/1.2
1.0/2.5/1.6/1.2
1.0/2.5/1.5/1.1
1.0/2.5/1.5/1.3
1.0/2.5/1.5/1.4
1.0/2.5/1.5/1.3
1.0/2.5/1.5/1.3
1.0/2.5/1.5/1.3
1.0/2.5/1.5/1.3
1.0/2.5/1.5/1.3
1.0/2.5/1.5/1.3
1.0/2.5/1.5/1.3
81
61
64
2
3
4
THF
6
<5
<5
<5
5
6
dioxane
MeCN
water
7
8
9
EtOH
DMF
nd
nd
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
DMSO
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
nd
68
84
89
88
85
94 (87)
87
78
82
75
78
82
a
The reaction conditions were the same as entry 16 in Table 1. Isolated
45 yields were given in parentheses.
84
<5c + 45c,d
b The reaction time is 30 h.
The bold values are the most effective conditions for the model reaction.
a
Table 3 Reaction of various arylboronic acids with
phenylmethanamine, formaldehyde and phenylpropiolic acid.a
5
All reactions were performed on a 1.0 mmol-scale with 2.5 mL solvent
under a nitrogen atmosphere. Formaldehyde aqueous solution (40%) was
used. nd = not detected.
R3
B(OH)2
Ph
O
b Yields were determined by GC using an internal standard. Isolated yield
was given in parentheses.
3a
Ph
toluene
2
Ph
NH2
N
R3
H
H
10 c Under air atmosphere.
80 oC, 20 h
1a
2
d Isolated yield of N-benzyl-N-methyl-3-phenylpropargylamine.
5
Ph
COOH
4a
The optimization of reaction conditions were initially
performed on the model reaction of phenylmethanamine (1a),
15 formaldehyde (2), phenylboronic acid (3a) and phenylpropiolic
acid (4a) with a ratio of 1.0:2.5:1.2:1.2. Toluene was found to be
the most suitable solvent for the multicomponent reaction with a
desired product yield of 81% (Table 1, entry 1), while xylene and
1,2-dichloroethane (DCE) were less effective and afforded the
20 product in 61% and 64% yields, respectively (Table 1, entries 2-
3). Replacement of toluene with other solvents, such as
tetrahydrofuran (THF), dioxane, acetonitrile, water, ethanol, N,N-
dimethylformamide (DMF) and dimethyl sulfoxide (DMSO),
either delivered quite low yields (Table 1, entries 4-7) or gave no
25 products (Table 1, entries 8-10). Investigation on the ratio of
reactants indicated that a 1.0:2.5:1.5:1.3 ratio of 1a/2/3a/4a gave
the best result with an isolated yield of 87% (Table 1, entries 11-
19). Further screening of the reaction conditions revealed that
decreasing the temperature down to 60 or 25 oC (Table 1, entries
30 20-21) or elevating up to 100 oC (Table 1, entriy 22) or
increasing the reaction time to 30 h (Table 1, entry 23) did not
promote the reaction yields. While the reaction was conducted
under air atmosphere, less than 5% yield of desired product was
=
, R = 4-Cl (45%)
, R = 4-F (72%)
5aba 5caa
=
5aca 5daa
Ph
5ada = 5faa, R = 4-Me (77%)
5aea = 5gaa, R = 4-OMe (85%)
, R = 2-Me (78%)
5afa
5aga, R = 2,4-diF (51%)
5aha = 5eea, R = 4-CF3 (25%)
Ph
R
N
Ph
N
N
N
N
Ph
Ph
Ph
Ph
Ph
Ph
5aia (70%)
5aja (0%)
5aka (0%)
a
50
The reaction conditions were the same as entry 16 in Table 1. Isolated
yields were given in parentheses.
ortho- and meta-substituents such as fluoro, chloro, bromo,
trifluoromethyl, methyl, methoxyl groups on the benzene ring
participated in the reaction to afford the desired products 5aaa-
detected,
and
45%
yield
of
N-benzyl-N-methyl-3-
35 phenylpropargylamine was obtained as the main byproduct
(Table 1, entry 24).20
55 5iaa in moderate to good yields. Naphthalen-1-ylmethanamine
and 2-phenylethanamine also produced their corresponding
products 5jaa and 5maa in 66% and 68% yields, respectively.
Derivation from the phenyl substituent to aromatic heterocycles
such as pyridinyl and furanyl decreased the yield (5kaa and 5laa).
60 Other simple aliphatic amines such as propan-2-amine, butan-1-
With the reaction conditions in entry 16 of Table 1, we began
to explore the scope of the multicomponent reaction. First,
various primary amines were subjected to the reaction with 2, 3a
40 and 4a (Table 2). In general, phenylmethanamine bearing para-,

3
amine and methyl 2-aminoacetate, were also applicable with
lower yields (5naa, 5oaa and 5paa).
Subsequently, the scope of propiolic acids was then
25 investigated (Table 4). A nitro group on the phenyl ring or an
aliphatic propiolic acid delivered the desired products (5aae and
5aaf) with lower yields. However, both arylpropiolic acids and
aliphatic propiolic acid were applicable in the multicomponent
reaction in satisfactory yields (5aab-5aaf). Finally, the
30 munticomponent coupling reaction of amines, formaldehyde,
organoboronic acids and propiolic acids was applied for the
synthesis of diverse propargylamines (Table 5).
Table 4 Reaction of various propiolic acids with
phenylmethanamine, formaldehyde and phenylboronic acid.a
A tentative mechanism for the metal-free, five-component
reaction is proposed in Scheme 2. The reaction of primary amine
35 1, formaldehyde 2, and organoboronic acid 3 afforded a
secondary amine 6 via the PBM reaction,16 which could undergo
a second PBM reaction with formaldehyde 2 and organoboronic
acid 3 to produce the byproduct 7 as detected by GC-MS.19a The
reaction of the secondary amine 6 and formaldehyde 2 generated
40 hemiaminal B. The proton from propiolic acid 4 accelerated the
formation of iminium salt C, which was further attacked by the
alkynyl carbon bonded to carboxylate to form intermediate D.
And the final desired propargylamine was generated through
5
a
The reaction conditions were the same as entry 16 in Table 1. Isolated
yields were given in parentheses.
decarboxylation of D.11,21 Thus,
a
MCR2 of PBM and
Table 5 Synthesis of diverse propargylamines.a
45 decarboxylative three-component coupling reactions was
involved in this new five-component reaction.
R3
B(OH)2
R1
O
3a
R2
2
toluene
80 oC, 20 h
R1
NH2
N
R3
H
H
1a
2
5
R2
COOH
4a
F
Cl
OMe
Ph
OMe
N
N
(86%)
5dea
(83%)
5aed
F3C
F3C
F
N
N
5eda (82%)
5eca (80%)
Cl
OMe
Scheme 2 Proposed mechanism.
In conclusion, we have successfully developed a novel
50 approach for the synthesis of propargylamines through a metal-
free five-component coupling reaction of aliphatic amines,
formaldehyde, oganoboronic acids and propiolic acids. The
starting material is easily available. Both aromatic and aliphatic
alkynyl carboxylic acids are applicable in this approach. Notably,
55 this protocol avoids the use of any metal catalysts making this
method more environmentally benign. Further studies on the
synthetic applications are ongoing in our laboratory.
N
N
5fea (87%)
(55%)
5fad
MeO
Cl
OMe
N
5ged (83%)
The reaction conditions were the same as entry 16 in Table 1. Isolated
a
10
Acknowledgments
yields were given in parentheses.
Next, the reaction of phenylmethanamine (1a), formaldehyde
The financial support for this work from the National Key
(2), phenylpropiolic acid (4a) and various organoboronic acids 60 Technology R&D Program (Grant No. 2011BAE06B05-4) and
was examined (Table 3). Generally, electron-donating
Shanghai Key Laboratory of Catalysis Technology for
Polyolefins (LCTP-201301) are gratefully acknowledged.
15 substituents (–OMe and –Me) on the phenyl ring of arylboronic
acids resulted in higher yields than electron-withdrawing groups
(–Cl and –F) (see 5aba-5aga). While a highly electron
withdrawing group on the phenyl ring led to a dramatic decrease
in product yield (see 5aha). Furthermore, the use of (E)-
Supplementary Material
Experimental procedures, characterization data of products,
1
20 styrylboronic acid delivered corresponding 1,6-enyne product 65 and copies of H and 13C NMR can be found, in the online
version, at http://....
(5aia) with 70% yield. Unfortunately, aromatic heterocycle and
aliphatic boronic acids shut down the reaction (see 5aja and
5aka).

4
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