Metal-free decarboxylative three-component coupling reaction for the synthesis of propargylamines

Article abstract of DOI:10.1021/ol401358t

A metal-free decarboxylative three-component coupling reaction was developed. When alkynyl carboxylic acids, paraformaldehyde, and amines were reacted in CH₃CN at 65 °C for 3 h, the desired propargylamines were obtained in good yields. This coupling reaction also showed good yield in water solvent. This reaction showed higher selectivity toward alkynyl carboxylic acids than a terminal alkyne.

Full text of DOI:10.1021/ol401358t

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Metal-Free Decarboxylative
Three-Component Coupling Reaction
for the Synthesis of Propargylamines
Kyungho Park, Yumi Heo, and Sunwoo Lee*
Department of Chemistry, Chonnam National University, Gwangju, 500-757,
Republic of Korea
sunwoo@chonnam.ac.kr
Received May 15, 2013
ABSTRACT
A metal-free decarboxylative three-component coupling reaction was developed. When alkynyl carboxylic acids, paraformaldehyde, and amines
were reacted in CH3CN at 65 °C for 3 h, the desired propargylamines were obtained in good yields. This coupling reaction also showed good yield
in water solvent. This reaction showed higher selectivity toward alkynyl carboxylic acids than a terminal alkyne.
A number of decarboxylative coupling reactions have
been developed for the formation of CÀC, CÀN, CÀS,
and CÀP bonds.1 A variety of carboxylic acids such as
alkyl, aryl, benzyl, and alkynyl carboxylic acids have been
employed as coupling substrates and have exhibited good
activity in coupling reactions. Much attention has been
paid to decarboxylative coupling due to the release of CO2,
which is less harmful than the metal waste derived from the
classical organometallic coupling substrates. However,
most of the decarboxylative coupling reactions that have
been reported so far have still required transition-metal
catalysts, which give rise to the release of metal waste in the
process(Scheme1, reaction 1). Therefore, the development
of a metal-free system has been needed.
the efficient methods for the synthesis of diaryl alkynes,2
diynes,3 alkynyl ketones,4 and aryl propiolic acids.5 In the
course of our effort to expand the decarboxylative coupling
reactions, we found that phenyl propiolic acid was decar-
boxylated to produce phenyl acetylene in the absence of
metal when the reaction was run with an organic base
at 80 °C.6
From this result, we envisioned that alkynyl carboxylic
acid could be transformed to the activated terminal alkyne
in the absence of metal. With this concept in mind, we have
focused on developing a metal-free decarboxylative cou-
pling for the synthesis of propargylamine.
Propargylamines are important building blocks for the
synthesis of heterocyclic compounds bearing nitrogen
atoms, such as pyrroles,7 pyrrolidine,8 pyrrolophane,9
Recently, we developed the palladium-catalyzed decarbo-
xylative coupling reaction of alkynyl carboxylic acids and
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r
10.1021/ol401358t
XXXX American Chemical Society

aminoindolizine,10 2-aminoimidaozels,11 and oxazolidinones12
and work as key elements for the construction of natural
products and biologically active compounds, such as
therapeutic drug molecules.13 There are several classical
methods for the preparation of propargylamines.14 How-
ever, these methods have some drawbacks, such as the
requirement of a stoichiometric amount of metal reagents,
moisture sensitivity, and low functional-group tolerance.
To solve these problems, the transition-metal-catalyzed
three-component coupling of an aldehyde, amine, and
alkyne (A3 coupling) has been developed and widely used
under mild conditions. (Scheme 1, reaction 2). Therefore,
there has been much effort to develop efficient transition
metal catalysts for the CÀH bond activation of terminal
alkyne. Several transition metals such as copper,15 gold,16
silver,17 iridium,18 indium,19 iron,20 and zinc21 have been
used in such three-component reactions. However, there
are intrinsic drawbacks with the employment of metal,
which give rise to problems regarding environmental
pollution, cost, and complication in the purification pro-
cesses. Moreover, the employment of metal catalysts oc-
casionally affords the Glaser homocoupling compound as
a byproduct, which gives rise to a decrease in the yield of
the product. Although base-catalyzed synthesis of propar-
gylamine from terminal acetylene has been reported,
DMSO was employed as the solvent which is not a good
solvent for the purification step.22 In addition, it is not easy
to use highly volatile terminal alkynes such as 1-propyne
and 1-butyne, even in the case of metal-catalyzed A3
coupling. To overcome these problems, we report a metal-
free decarboxylative three-component coupling reaction
for the synthesis of propargylamine from the three-
component reaction of an amine, aldehyde, and alkynyl
carboxylic acid. To the best of our knowledge, this reac-
tion is the first example of the employment of a carbon
nucleophile in EschweilerÀClarke methylation (Scheme 1,
reaction 3).23
Scheme 1. Metal-Free Decarboxylative Coupling
To this end, phenyl propiolic acid, paraformaldehyde,
and morpholinewere chosen asmodel substrates. A variety
of solvents were first screened, as shown in Table 1. When an
equal amount of phenyl propiolic acid, paraformaldehyde,
and morpholine were reacted in DMSO, which was a good
solvent in the decarboxylative coupling reaction, the desired
product was formed in 15% yield at 65 °C (entry 1). A
variety of solvents were tested (entries 2À7). Among them,
CH3CN showed the best result and afforded phenyl pro-
pargyl amine 3aa in 83% yield. An attempt to add a base to
accelerate the decarboxylation of phenyl propiolic acid
resulted in no product (entries 8À10). However, when the
reaction was run under acidic conditions with acetic acid
and benzoic acid, the yields were similar, regardless of the
amount of acid used (entries 11À13). When the ratios of the
three starting materials were varied, 1.2 equiv of phenyl
propiolic acids and paraformaldehyde and 1.0 equiv of
morpholine produced an almost quantitative yield of pro-
duct (entry 16). With decreasing reaction temperature, the
yields of product decreased (entries 17 and 18). Interest-
ingly, the desired product was formed with 97% yield even
in water solvent at 100 °C (entry 19). When phenyl acetylene
was employed instead of phenyl propiolic acid, a trace
amount of desired product was formed (entry 20). To
investigate the metal-free conditions in this reaction solu-
tion, the solution was subjected to ICP-MS. The concentra-
tion of transition metal ions in the solution was below the
detection limit of the instrument, so the metal concentra-
tions were estimated to not exceed hundreds of ppb.
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Keersmaecker, S. C. J.; Van der Eycken, E. V. Angew. Chem., Int. Ed.
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1980, 45, 4616–4622. (c) Tubery, F.; Grierson, D. S.; Husson, H.-P.
Tetrahedron Lett. 1987, 28, 6457–6460. (d) Imada, Y.; Yuassa, M.;
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With these optimized conditions, a variety of secondary
amines were evaluated in the three-component coupling
reaction. The results are summarized in Scheme 2. First,
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B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Optimized Metal-Free Conditions for the Synthesis of
Propargylamine 3aaa
Scheme 2. Synthesis of Propargylamines Form a Variety of
Aminesa
yield
entry
ratiob
solvent
DMSO
additivec
temp
(%)d
1
1.0/1.0/1.0
1.0/1.0/1.0
1.0/1.0/1.0
1.0/1.0/1.0
1.0/1.0/1.0
1.0/1.0/1.0
1.0/1.0/1.0
1.0/1.0/1.0
1.0/1.0/1.0
1.0/1.0/1.0
1.0/1.0/1.0
1.0/1.0/1.0
1.0/1.0/1.0
1.0/1.2/1.2
1.2/1.0/1.2
1.2/1.2/1.0
1.2/1.2/1.0
1.2/1.2/1.0
1.2/1.2/1.0
1.2/1.2/1.0
À
65
65
65
65
65
65
65
65
65
65
65
65
65
65
65
65
55
25
100
65
15
44
48
54
73
54
83
0
2
toluene
THF
À
3
À
4
dioxane
ClCH2CH2Cl
EtOH
À
5
À
6
À
a Reaction conditions: 1 (6.0 mmol), paraformaldehyde (6.0 mmol),
and 2 (5.0 mmol) were reacted in CH3CN at 65 °C for 3 h.
7
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
H2O
À
8
DBU
9
Et3N
0
desired coupled products 3la, 3ma, 3na, 3oa, and3pa in good
yields. 2-Thiophenyl (3q) and 1-naphthyl propiolic acids
(3r) gave the desired products in 83% and 95% yields,
respectively. The substituted phenyl propiolic acids 3e and
3s coupled with N-methylbenzyl amine and diallylamine to
produce the corresponding propargyl amines in good yields.
When N-methyl formamide was employed as an amine
source, dipropargyl-substituted amines were formed in good
10
11
12e
13
14
15
16
17
18
19
20f
Cs2CO3
0
AcOH
76
77
78
78
84
98
79
11
97
trace
AcOH
PhCO2H
À
À
À
À
À
À
À
CH3CN
a Reaction conditions: The limiting reagent was employed at 3.0 mmol
scale. b Ratio of 1a/paraformaldehyde/2a. c 3.0 mmol of additives. d Isolated
yield. e 3 mL of AcOH. f Phenylacetylene was used instead of 1a.
Scheme 3. Synthesis of Propargylamines from a Variety of
Alkynyl Carboxylic Acidsa
secondary amines were reacted with phenyl propiolic acid
and paraformaldehyde in CH3CN at 65 °C. As expected,
all secondary amines afforded the corresponding phenyl
propargyl amines in good yields. Cyclic amines such as
morpholine (2a), piperidine (2b), azepane (2c), and pyrro-
lidine (2d) afforded the corresponding phenylpropagyl
amines in 98%, 91%, 83%, and 87% yields, respectively.
Diallylamine (2e), dibenzylamine (2f), and N-methylben-
zylamine (2g) showed good yields in the formation of 3ae,
3af, and 3ag. In addition, to evaluate the feasibility of this
reaction systemon alargescale, weconducted the synthesis
of 3aa at the 20 g scale. The desired product 3aa was
obtained in 98% yield without column chromatography.
Next, substituted aryl alkynyl carboxylic acids5 were
employed in the three-component coupling reaction as
shown in Scheme 3.
2-Butynoic acid (1b) and 2-pentynoic acid (1c), which
were propyne and butyne surrogates, respectively, gave the
desired coupled products in 84% and 81% yields, respec-
tively. 2-Octynoic acid (1d) produced 3da in 76% yield.
Para- and ortho-tolyl propiolic acids coupled with para-
formaldehyde and morpholine to produce the correspond-
ing propargyl amines 3ea and 3fa in 98% and 91% yields,
respectively. Methoxy-, bromo-, and chloro-substituted
phenyl propiolic acids showed good product yields. Aryl
propiolic acids with electron-withdrawing groups such
as nitro, nitrile, ketone, ester, and aldehyde afforded the
a Reaction conditions: 1 (6.0 mmol), paraformaldehyde (6.0 mmol)
and 2 (5.0 mmol) were reacted in CH3CN at 65 °C for 3 h. b 1 (7.5 mmol)
was employed and the reaction temperature was 90 °C.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Double Propargylation of N-Methylformamide
Scheme 6. Proposed Mechanism
Scheme 5. Selective Coupling Reaction toward Alkynyl Car-
boxylic Acid
form intermediate C and then affords the desired propar-
gylamine through decarboxylation.
In summary, we have developed metal-free conditions
for the synthesis of propargylamine from the one-pot,
three-component reaction of an aldehyde, amine, and
alkynyl carboxylic acid. This reaction system has several
advantages as follows: (1) no column chromatography
method is needed to purify the final product. Therefore,
a large scale reaction is feasible; (2) no metal waste was
released; (3) the Glaser byproduct occasionally observed
in metal-catalyst systems was not formed; (4) the employ-
ment of an alkynyl carboxylic acid as a surrogate for
alkynes having a low boiling point was effective for easy
handling; (5) the survival of the terminal alkyne and
benzaldehyde offered the opportunity for further function-
alization. To the best of our knowledge, this is the first
report of a metal-free system in the decarboxylative cou-
pling reaction.
yields. As shown in Scheme 4, phenyl propiolic acid and
p-tolyl propiolic acid gave the corresponding dipropargyl
amines 4a and 4d in 50% and 46% yields. The transforma-
tion of both methylenes from the paraformaldehyde was
defined using D2CO experiments.
The result of entry 20 in Table 1, with no coupled
product from the terminal alkyne in the metal-free condi-
tions, is expected to afford the selective coupling reaction
toward alkynyl carboxylic acids, even in the presence of a
terminal alkyne. As expected, when propiolic acid 5 bear-
ing a terminal alkyne was reacted with paraformaldehyde
and azepane (2c) or dibenzylamine (2f), the desired pro-
ducts 6c and 6f, which have a terminal alkyne, were
afforded in 68% and 77% yields, respectively (Scheme 5).
We propose a mechanism for the metal-free, one-pot,
three-component decarboxylative coupling reaction as
shown in Scheme 6. This is similar with the mechanism
of EschweilerÀClarke methylation.23 The reaction with an
aldehyde and amine generated the corresponding hemi-
aminal A. The acid proton of an alkynyl carboxylic acid
accelerates the formation of iminium salt B. The alkynyl
carbon bonded to carboxylate attacks iminium salt B to
Acknowledgment. This research was supported by Basic
Science Research Program through the National Research
Foundation of Korea (NRF) funded by the Ministry of
Education, Science and Technology (2012R1A1B3000871)
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX