Manganese(ii) chloride catalyzed highly efficient one-pot synthesis of propargylamines and fused triazoles via three-component coupling reaction under solvent-free condition

Article abstract of DOI:10.1039/c4ra03232b

A one-pot green and highly efficient method for the synthesis of propargylamines and diastereoselective synthesis of fused triazoles via three-component coupling in the presence of manganese(ii) chloride as a catalyst and a catalyst-free 1,3-dipolar cycloaddition reaction, respectively, without using a co-catalyst or activator is reported. This methodology is efficient, eco-friendly, operationally simple and effective for reactions involving aromatic, aliphatic, and heterocyclic aldehydes, and provides an easy access to propargylamines in excellent yields, fused triazoles in good yield and excellent diastereoselectivities.

Full text of DOI:10.1039/c4ra03232b

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Manganese(II) chloride catalyzed highly efficient
one pot synthesis of propargylamines and fused
triazoles via three component coupling reaction
under solvent free condition†
Cite this: DOI: 10.1039/x0xx00000x
Shakil N. Afraj,a Chinpiao Chen,a,* and GeneꢀHsian Lee b
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
A oneꢀpot green and highly efficient method for synthesis of propargylamines and diastereoselective
synthesis of fused triazoles via three component coupling in the presence of manganese(II) chloride as
catalyst followed by catalyst free 1,3ꢀdipolar cycloaddition reaction respectively, without using coꢀ
catalyst or activator is reported. This methodology is efficient, ecoꢀfriendly, operationally simple and
effective for reactions involving aromatic, aliphatic, and heterocyclic aldehydes and provides an easy
access to propargylamines in excellent yields and fused triazoles in good yield and excellent
diastereoselectivities.
www.rsc.org/greenchem
In recent years to overcome such problems, tremendous progress
has made to develop an alternative atomꢀeconomical approach to
Introduction
Development of environmentally benign methods by avoiding toxic
reagents and solvent has become increasingly important for
industrial applications.1 Multicomponent coupling reaction2, 3 (MCR)
is potential interest as it enables the coupling of aldehyde, amine and
alkyne resulting in propargylamine with new C–C bond.2, 3 Solventꢀ
free reaction4 is an important synthetic boon from the view point of
green and sustainable chemistry. Over the last few years, solventꢀ
free heterocyclic synthesis5 has rapidly increased. This paved the
way for the development of greener synthesis.6 Synthesis of
propargylamine is an intense research area in organic synthesis
because propargylamine is versatile building block in natural product
synthesis7 and acts as precursors in the synthesis of nitrogen
containing heterocyclic compound.8aꢀ8f, 9 Moreover, propargylamines
are frequent skeletons10a and synthetically versatile key
intermediate11 for the synthesis of biologically active compounds
such as βꢀlactams, oxotremorine analogues, conformationally
restricted peptides, isosteres and therapeutic drug molecules.10b,12
Traditionally, propargylamines are synthesized by nucleophilic
attack of lithium acetylides or Grignard reagents to imines or their
derivatives.13 However, these reagents are stoichiometric, highly
moisture sensitive and require strictly controlled reaction condition.
their synthesis and perform this type of reaction by catalytic
coupling of three components (A3 coupling) by C–H activation,
where water is only theoretical byꢀproduct.3 There are various
transition metal catalysts for C–H bond activation of terminal
alkyne, such as, CuI salts,14 CuII derivatives,15a Cu/RuII bimetallic
systems,15b IrI complexes,16 AuI/AuIII salts,17 AuIII salen complexes,18
AgI salts,19 InIII salts,20 NiII salts,21 and FeIII salts22 have been used for
this reaction under homogeneous reaction condition. Recently,
Ag(I)23a and Cu(I)23b in ionic liquids, Zn dust,24 supported Au(III),25a
Ag(I),25bꢀ25d or Cu(I),26cꢀ26h Fe3O4 nanoparticles,27 and nano indium
oxide26 were successfully used to catalyze A3 coupling reaction
under heterogeneous reaction condition with recyclability and
reusability of the transition metal catalyst.25h, 28
Huisgen 1,3ꢀdipolar cycloaddition is the reaction of
a
dipolarophile (alkyne) with a 1,3ꢀdipolar (azide) compound that
leads to 1,2,3ꢀtriazole (5ꢀmembered ring) have attracted significant
attention as one of the most important heterocycles.29 Within the past
few years, applications of this building block have been extended
widely into various research fields,30 such as chemical biology,
material science, and medicinal chemistry. 1,2,3ꢀTriazole moiety is
present in many compounds exhibiting different biological
properties such as antibacterial31 (cefmatilen), antiꢀHIV,32
antiallergic,33
and
inhibitory
(tazobactam)
activities.
a Department of Chemistry, National Dong Hwa University, Soufeng, Hualien
974, Taiwan, Fax: (+886)ꢀ3ꢀ863ꢀ0475;eꢀmail: chinpiao@mail.ndhu.edu.tw
b National Taiwan University, Instrumentation Center, Taipei10617, Taiwan,
Triazolobenzodiazepines34 have shown high affinity toward
benzodiazepine receptors. Triazole chemistry was revisited and has
seen exponential growth over the years and enormous gain in
popularity in areas of chemistry such as dyes, photostabilizers,
agrochemicals35 and in the designining of new drugs.36 Among the
†Electronic Supplementary Information (ESI) available. See
DOI: 10.1039/b000000x/
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DOI: 10.1039/C4RA03232B
nitrogen heterocycles, tetrahydropyrazine represents important class DMF, DMSO, dioxane, and DCM, at 100 °C, 80 °C, 101 °C, and
of organic molecules that attracts the interest of both synthetic and
medicinal chemists due to their significant biological activities.37
Recently, we have described a practical and efficient two step proꢀ
tocol for the synthesis of 4,6,7,8,8a,9ꢀhexahydropyrrolo[1,2ꢀ
a][1,2,3]triazolo[1,5ꢀd]pyrazines,38 (Scheme 1) the first step
involved AuBr3 catalyzed three component coupling of aldehyde,
amine and alkyne to form propargylamines and in second step
propargylamine undergos intramolecular 1,3ꢀdipolar cycloaddition
using DMF as solvent. Considering briefly importance of
propargylamine, 1,2,3ꢀtriazole moiety, tetrahydropyrazine and ecoꢀ
friendly reaction condition, in this paper we like to present the use
for the first time Mn(II) chloride as an efficient catalyst for the
synthesis of propargylamine via three componant coupling and one
35 °C, respectively, generated the corresponding products in very
few amount (Table 1, entries 2, 3, 5, 7). Using ethanol and
acetonitrile as solvent afforded the desired products in 45% and 61%
yield respectively at 80 °C (Table 1, entries 5, 6) , whereas, toluene
was inferior and generated corresponding product in moderate yield
(88%) at 120 °C (Table 1, entry 8). To further investigate the
reaction condition, the same reaction with 10 mol% of MnCl2 was
carried out at solvent free condition at 90 °C which afforded the
desired product in 98% yield (Table 1, entry 9). In order to seek the
most effective catalyst for the coupling of aldehyde, amine and
alkyne, we used 10 mol% of Mn powder, MnO2, and
Mn(OAc)2·4H2O to catalyze the reaction at solvent free condition at
90 °C with conversion 51, 20, and 62% respectively (Table 1, entries
10–12). We next performed the reaction with 2 mol % MnCl2 and 5
mol % MnCl2 which generated desired product in 69% and 82%
yield (Table 1, entries 13, 14), and we observed that higher catalyst
loading increased the yield of desired product and decreased reaction
time, therefore, using MnCl2 (10 mol%), 90 °C and solvent free
(Table 1, entry 9) was selected as the best condition for A3 coupling
reaction of aldehyde, amine and alkyne.
pot
diastereoselective
synthesis
of
4,6,7,8,8a,9ꢀ
hexahydropyrrolo[1,2ꢀa][1,2,3]triazolo[1,5ꢀd]pyrazines via three
component coupling followed by Huisgen intramolecular 1,3ꢀdipolar
cycloaddition reaction at solvent free condition. To the best of our
knowledge, the utilization of manganese chloride for three
component coupling of aldehyde, amine and alkyne has never been
reported. Manganese chloride has received a great deal of interest
because, it is inexpensive, easily available, easy to handle and
relatively insensitive to air and moisture and have been used for
crossꢀcoupling reactions between aryl Grignard reagents and simple
alkenyl halides.39
Table 1. Optimization studies for the MnCl2 catalyzed multicomponent
synthesis of propargylamine 4aa
Entry Mn source (mol%)
Solvent
Temp
(°C)
100
Time
(h)
24
4a (%)
1
MnCl2 (10)
MnCl2 (10)
MnCl2 (10)
MnCl2 (10)
MnCl2 (10)
MnCl2 (10)
MnCl2 (10)
MnCl2 (10)
MnCl2 (10)
Mn (10)
H2O
0
2
DMF
100
80
24
24
24
24
24
72
14
12
18
12
16
15
14
traces
traces
45
3
DMSO
4
ethanol
80
5
dioxane
101
80
traces
61
6
CH3CN
7
CH2Cl2
35
traces
88
Scheme 1. Diastereoselective synthesis of propargylamines and
4,6,7,8,8a,9ꢀhexahydropyrrolo[1,2ꢀa][1,2,3]triazolo[1,5ꢀd]pyrazines.
8
toluene
120
90
9
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
98
10
11
12
13
14
90
51
MnO2 (10)
Mn(OAc)2·4H2O (10)
MnCl2 (2)
90
20
Results and Discussion
90
62
90
69
Manganese(II) chloride catalyzed three component coupling
reaction
MnCl2 (5)
90
82
Reaction conditions: 1a ꢀ aldehyde (1 mmol), 2a ꢀ amine (1.2 mmol), 3a ꢀ
alkyne (1.5 mmol), with 10 mol% manganese source heated with solvents
We focused our initial investigation on the effect of various types
of solvents and catalyst loading on the reaction of benzaldehyde, and without solvent at different temperature.
piperidine and phenylacetylene at different temperatures (Table 1).
Having optimized the conditions in hand the catalysis was then
The results indicates that reaction temperature, solvent and catalyst
loading influence the product yield in the A3 coupling reaction. After
several screening experiments, the best condition proved to be, a
mixture of benzaldehyde (1 mmol), piperidine (1.2 mmol), phenyl
acetylene (1.5 mmol), MnCl2 (10 mol%) was stirred at 90 °C without
solvent for 12 h (Table 1, entry 9). we started to screen solvents first
with water but there was no formation of desired product (Table 1,
entry 1). Then we screened various organic solvents on A3 coupling
of model substrates by using 10 mol% of MnCl2 as catalyst such as
applied to various aldehydes, alkynes and amines as summarized in
Table 2. Initially we performed coupling of benzaldehyde and
phenylacetylene with cyclic amines such as piperidine and
morpholine leading to products 1a and 1b with yields of 98 and 90%
respectively (Table 1, entries 1, 2). Considering high reactivity of
benzaldehyde with morpholine and phenylacetylene in A3 coupling
reaction, we also studied reactivity of aliphatic and heterocyclic
aldehyde such as isobutyraldehyde and 3ꢀthienyl carbaldehyde with
morpholine and phenylacetylene under optimized reaction condition.
2 | J. Name., 2012, 00, 1-3
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Table 2. MnCl2 catalyzed one pot synthesis of propargylamines 1a–1afa
Surprisingly both generated desired products 1c and 1d with
excellent yields of 96 and 93% (Table 1, entries 3, 4). In case of
diisopropylamine and aniline formation of desired products 1e and
1f with 65 and 69 % yield (Table 2, entries 5, 6). We also tried
various aliphatic primary amines in A3 coupling reaction, but there
was no formation of desired product. Benzaldehyde bearing
electronꢀdonating and electronꢀwithdrawing groups at oꢀ, mꢀ, and pꢀ
position such as alkyl, chloro, and fluoro were able to undergo threeꢀ
component coupling and generated the corresponding products, 1g–
1m, in excellent yields (91–97%) respectively (Table 2, entries 7–
13 ). The electronic properties of the substituents on the phenyl ring
did not have an obvious effect on the yields of corresponding
product. 1ꢀNapthaldehyde and biphenylꢀ2ꢀcarbaldehyde reacted well
under optimized condition even though they are bulky and furnished
desired products 1n and 1o with 96 and 94 % yields respectively
(Table 2, entries 14, 15). Aliphatic alkynes such as trimethylsilyl
acetelyne worked effectively and furnished product 1p in good yield
89%, (Table 2, entry 16). Whereas aromatic alkyne bearing electron
donating group (methoxy) shown good reactivity in A3 coupling
reaction under optimized condition and generated desired product 1q
in very high yield 97% (Table 2, entry 17). Due to excellent yield in
case of benzaldehyde, we also studied reactivity of pꢀmethoxyphenyl
acetylene with substitutedꢀbenzaldehyde bearing electron donating
and electron withdrawing group in A3 coupling reaction such as pꢀ
tolualdehyde, mꢀchlorobenzaldehyde and also with aliphatic
aldehyde such as trimethylacetaldehyde in A3 coupling reaction
generated desired products 1r, 1s and 1t with excellent yields 96, 94
and 98% respectively (Table 2, entries 18–20). Aliphatic aldehydes
displayed high reactivity under the optimized reaction condition
generated desired products 1u–1ad in excellent yields (95–98%)
(Table 2, entries 21–30). Trimerization in case of aliphatic aldehydes
was never observed, even though it has been major limitation of the
A3 coupling reaction.14, 17 heterocyclic aldehyde such as 2ꢀthienyl
carbaldehyde and 3ꢀthienyl carbaldehyde reacted smoothly under
optimized reaction condition to give 1ae and 1af in 91 and 97%
yields (Table 2, entries 31, 32). The structure of the 1a in CDCl3
methine proton (NꢀCH–) at δ = 4.79 ppm was observed as a
characteristic singlet and in the 13C NMR spectrum, two peaks at δ =
85.97 and 87.80 ppm corresponded to the two acetylenic carbons
were observed, these observation supported to formation of
propargylamine (1a).
Entry Aldehyde (R1)
Amine
Alkyne (R4)
Product Yieldb
(%)
(R2, R3)
1
ph
piperidine ph
morpholine ph
morpholine ph
1a
1b
1c
1d
98
90
96
93
2
ph
3
isopropyl
4
5
3ꢀthienyl
morpholine ph
diisopropyl
ph
amine
ph
1e
65
69
91
95
97
93
92
96
94
96
94
89
97
96
94
98
95
97
96
95
97
96
97
98
96
97
91
97
6
ph
Aniline
ph
1f
7
oꢀCH3C6H4
mꢀCH3C6H4
pꢀCH3C6H4
oꢀClC6H4
mꢀClC6H4
pꢀClC6H4
pꢀFC6H4
1ꢀnapthyl
piperidine ph
piperidine ph
piperidine ph
piperidine ph
piperidine ph
piperidine ph
piperidine ph
piperidine ph
1g
1h
1i
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
1j
1k
1l
1m
1n
1o
1p
1q
1r
2ꢀ(1,1'ꢀbiphenyl) piperidine ph
(CH ) Si
ph
piperidine
3
3
pꢀCH OC H
ph
piperidine
3
6
4
4
4
4
pꢀCH OC H
pꢀCH3C6H4
mꢀClC6H4
tertꢀbutyl
cyclohexyl
tertꢀbutyl
ethyl
piperidine
3
6
pꢀCH OC H
piperidine
1s
3
6
pꢀCH OC H
piperidine
1t
3
6
piperidine ph
piperidine ph
piperidine ph
piperidine ph
piperidine ph
piperidine ph
piperidine ph
piperidine ph
piperidine ph
piperidine ph
piperidine ph
piperidine ph
1u
1v
1w
1x
1y
1z
propyl
pentyl
hexyl
heptyl
1aa
1ab
1ac
1ad
1ae
1af
octyl
nonyl
Phꢀ(CH2)2ꢀ
2ꢀthienyl
3ꢀthienyl
a Reaction conditions: aldehyde (1.0 mmol), amine and (1 mmol),
phenylacetylene (1 mmol), MnCl2 (10 mol %) heated at solvent free
condition at 90 °C, in sealed tube. b Isolated yields after flash
chromatography.
Manganese(II) chloride catalyzed three component coupling
followed by catalyst free 1,3-dipolar cycloaddition
Having established optimal reaction condition in case of the
synthesis of propargylamine via three component coupling of
benzaldehyde, piperidine and phenyl acetylene, we tested scope of
three components such as benzaldehyde, (S)ꢀazidomethylpyrrolidine
and phenyl acetylene at above optimized condition and fortunately
found that both reactions, coupling and intramolecular Huisgen [3 +
2] dipolar cycloaddition were going well in one pot operation and
furnished desired product 2a with 84% yield and excellent
diastereoselectivity (Table 3, entry 1). Next we tested DMF, toluene
as solvent for the synthesis of 4,6,7,8,8a,9ꢀhexahydropyrrolo[1,2ꢀ
a][1,2,3]triazolo[1,5ꢀd] via three component coupling followed by
1,3ꢀdipolar cycloaddition, these solvents also generated desired
product in good yield but considering toxicity of these solvents we
With this simple and effective method in hand, our next step was
to develop one pot synthesis of 4,6,7,8,8a,9ꢀhexahydropyrrolo[1,2ꢀ
a][1,2,3]triazolo[1,5ꢀd]pyrazines via three component coupling of
aldehyde, amine and alkyne followed by 1,3ꢀdipolar cycloaddition.
During our investigation, it was observed that MnCl2 could provide
4,6,7,8,8a,9ꢀhexahydropyrrolo[1,2ꢀa][1,2,3]triazolo[1,5ꢀd]pyrazines
in good yield and excellent diastereoselectivity without solvent in
one pot operation. Encouraged by this result we started our
methodology by preparing (S)ꢀazidomethylpyrrolidine from
commercially available Lꢀproline by using reported procedure.40
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ARTICLE
DOI: 10.1039/C4RA03232B
decided to carry out further reactions with different substrate at 1H NMR, 13C NMR, IR and mass spectrometry. In 1H NMR
solvent free condition. This method applicable for aromatic, aliphatic, spectrum of compound 2a in CDCl3 methine proton (N–CH–) at δ =
heterocyclic aldehydes and also for aliphatic and aromatic alkynes 5.52 ppm was observed as a characteristic singlet and in the 13C
and avoids isolation, purification and characterization of coupling NMR spectrum, two peaks at δ = 128.9 and 141.6 ppm corresponded
product (1). Aromatic aldehydes formed the desired products 2b–2l to olefinic carbon atoms of triazole ring, these observation supported
in good yield (75–83%) and excellent diastereoselectivities, via three to confirm formation of desired product 2a. The absolute
component coupling followed by 1,3ꢀdipolar cycloaddition reaction configuration
(Table 3, entries 2–12). 1ꢀNapthaldehyde also worked well under hexahydropyrrolo[1,2ꢀa][1,2,3]triazolo[1,5ꢀd]pyrazines
of
(4S,8aS)ꢀ3ꢀphenylꢀ4ꢀ(thienꢀ3ꢀyl)ꢀ4,6,7,8,8a,9ꢀ
was
optimized condition and furnished desired product 2m in 81% yield confirmed by X ray diffraction analysis of monocrystals which
and excellent diastereoselectivity. Also alkyne such as pꢀ clarified that new formed stereocenter had (S) configuration. The
methoxyphenyl acetylene and 1ꢀhexyne reacted well under configuration of other products were assigned (S) by analogy.
optimized reaction condition and generated desired products 2n and
2o in 83 and 74% yields and excellent diastereoselectivities
respectively (Table 3, entries 14, 15). Aliphatic aldehydes such as 3ꢀ
phenylpropanal, isovaleraldehyde and butanal displayed good
reactivity under optimized reaction condition, this time we also
screened various kind of heterocyclic aldehydes but only 3ꢀthienyl
carbaldehyde and 2ꢀthienyl carbaldehyde were shown good
reactivity under optimized reaction condition and generated desired
products 2s and 2t in 82 and 78
% yield, and excellent
diastereoselectivities respectively (Table 3, entries 19, 20). The
structure of the fused tricyclic compound 2a was confirmed by
Table 3. One pot diastereoselective synthesis of 4,6,7,8,8a,9ꢀ
hexahydropyrrolo[1,2ꢀa][1,2,3]triazolo[1,5ꢀd]pyrazines 2a–2t at solvent free
condition.a
Yieldc
(%)
84
83
81
79
76
77
79
77
75
82
79
76
81
83
74
77
76
75
82
78
Time
(h)
12
Figure 1. Crystal structure of (4
4,6,7,8,8a,9ꢀhexahydropyrrolo[1,2ꢀ
CCDC-956372).
S
,8a
a
S
)ꢀ3ꢀphenylꢀ4ꢀ(thienꢀ3ꢀyl)ꢀ
Entry R1
R2
Produc
t
][1,2,3]triazolo[1,5ꢀ ]pyrazine (2s)
d
(
1
Ph
Ph
2a
2b
2c
2d
2e
2f
2
4ꢀMeC6H4
3ꢀMeC6H4
2ꢀMeC6H4
4ꢀMeOC6H4
3ꢀBrC6H4
4ꢀFC6H4
3ꢀFC6H4
3ꢀCNC6H4
4ꢀClC H
Ph
12
The possible mechanism was involved, manganese(II) chloride
was reacted with alkyne, manganese acetylide intermediate and
hydrochloric acid thus generated. We predicted formed HCl
3
Ph
12
4
Ph
12
5
ph
12
accelerate the formation of immonium ion generated in situ from
6
Ph
12
aldehydes and secondary amine.41a,
, resulting manganese
41b
7
Ph
2g
2h
2i
12
acetylide subsequently reacted with immonium salt formed in situ to
form propargylamine and regenerate the Mn(II) catalyst for
further reactions.
8
Ph
12
9
Ph
12.5
12
10
11
12
13
14
15
16
17
18
19
20
Ph
2j
6
4
3ꢀClC6H4
2ꢀClC6H4
1ꢀnapthyl
ph
Ph
2k
2l
12
R2
MnIICl2
Ph
12
N
R1
R3
ph
2m
2n
2o
2p
2q
2r
2s
13
pꢀCH3OC6H4
13.5
12.5
12
R4
R4
Ph
1ꢀhexyne
Ph(CH2)2
isobutyl
propyl
ph
ph
ph
ph
ph
12
H
12
3ꢀthienyl
2ꢀthienyl
14
R4
R2
MnICl
R3
2t
14
O
R1
a
HCl
N
Reaction condition: aldehyde (1.0 mmol.), (S)ꢀazidomethylpyrrolidine (1.2
H2O
R1
R2
R3
mmol), phenylacetylene (1.5 mmol.), MnCl2 (10 mol %), heated at solvent
free condition at 90 °C in sealed tube. b Diastereomeric ratio was determined
by 1H NMR spectroscopy. c Isolated yields after flash chromatography.
N
H
Cl
Scheme 3. Possible mechanism for manganese(II) chloride catalyzed
three component coupling reaction of aldehyde, amine and alkyne
.
4 | J. Name., 2012, 00, 1-3
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1
were identified by FT-IR, H and 13C NMR spectroscopy, LRMS
and HRMS.
In one pot synthesis of fused triazoles there is in situ formation of
propargylamine (1), using Mn(II) chloride, mechanistic path way for
formation of (1) is same as drawn in scheme 3. Further
propargylamines undergo catalyst free intramolecular 1,3ꢀdipolar
cycloaddition by heating.38, 42
4S,8aS)-3,4-diphenyl-4,6,7,8,8a,9-hexahydropyrrolo[1,2-
a][1,2,3]triazolo[1,5-d]pyrazine 2a: Rf = 0.31 (EtOAc/hexane 3:7),
Yield:84%. Diastereomeric ratio: >99, [α]25 –79.2° (c 1.0,
D
CHCl3), brown solid, mp: 198–199 °C. 1H NMR (300 MHz, CDCl3,
ppm, δ): 7.49–7.47 (d, J = 6.0 Hz, 2H), 7.32–7.30 (d, J = 6.0 Hz,
3H), 7.25–7.17 (m, 3H), 7.10–7.01 (m, 2H), 5.56 (s, 1H), 4.83–4.77
(m, 1H), 4.12–4.04 (t, J = 12.0 Hz, 1H), 3.25–3.22 (m, 1H), 2.96–
2.92 (m, 1H), 2.38–2.25 (q, J = 9.0 Hz, 1H), 1.99–1.90 (m, 2H),
1.76–1.72 (m, 1H), 1.60–1.50 (m, 1H); 13C NMR (100 MHz, CDCl3,
ppm, δ): 141.92, 134.71, 130.83, 130.74, 129.23, 128.87, 128.33,
128.16, 127.99, 127.92, 127.41, 127.33, 126.20, 58.02, 51.67, 49.97,
48.63, 27.69, 21.92; IR (KBr, thin film, cm–1): 3056, 3027, 2950,
2876, 2808, 1493, 1448, 1127, 1007, 722, 696; LRMS-EI (m/z): 317
(80), 287 (20), 277 (23), 191 (22), 138 (69), 106 (100), 65 (39);
HRMS-EI (m/z) M+ calcd for C20H20N4, 316.1688; found 316.1681.
Conclusion
We have successfully developed
a
novel, efficient,
operationally simple economically and enviornmental friendly,
MnCl2 catalyzed one pot synthesis of propargylamines via three
component coupling. Meanwhile, one pot diastereoselective
synthesis of 4,6,7,8,8a,9ꢀhexahydropyrrolo[1,2ꢀa][1,2,3]triazolo[1,5ꢀ
d]pyrazines via three component coupling followed by catalyst free
1,3ꢀdipolar cycloaddition reaction at solvent free condition. The
process requires manganese chloride as an inexpensive catalyst and
generated diverse range of propargylamine and interesting fused
heterocycle, 4,6,7,8,8a,9 hexahydropyrrolo[1,2ꢀa][1,2,3]triazolo[1,5ꢀ
d]pyrazines. Manganese catalysis is an interesting field of
investigation for sustainable development. The synthetic application
of A3 coupling reaction and 1,3ꢀdipolar cycloaddition are currently
under investigation.
Acknowledgements
The authors thank Ms. L. M. Hsu, at the Instruments Center,
National Chung Hsing University, for her help in obtaining mass
spectral data, and the National Science Council of the Republic of
China, for financially supporting this research under the contract
NSC 100ꢀ2113ꢀMꢀ259ꢀ006ꢀMY3.
Experimental section
General experimental procedure for manganese(II) chloride
catalyzed three component coupling reaction
A mixture of aldehyde (1.0 mmol), amine (1.2 mmol), alkyne (1.5
mmol) and MnCl2 (10 mol%) in sealed tube was stirred without
solvent for 12 h at 90 °C. The progress of reaction was monitored by
TLC. After completion of reaction, the product was purified by
Notes and references
1
For recent reviews, see: (a) R. A. Sheldon, Green Chem., 2005, 7, 267–
278; (b) R. Noyori, Chem. Commun., 2005, 1807–1811; (c) M. J.
Eckelman, J. B. Zimmerman and P. T. Anastas, J. Ind. Ecol., 2008, 12,
316–328; (d) R. A. Sheldon, Chem. Commun., 2008, 3352–3365.
C. J. Li, Acc. Chem. Res., 2010, 43, 581–590.
column chromatography using nꢀhexane/EtOAc as eluent to give the
1
desired product. The products were identified by FT-IR, H and 13
C
NMR spectroscopy, LRMS and HRMS.
2
3
1-(1,3-Diphenylprop-2-yn-1-yl)piperidine 1a. Rf = 0.44
(EtOAc/hexane 1:9), Yield: 98%, Pale yellow solid; mp: 66–67 °C.
1H NMR (300 MHz, CDCl3, ppm δ): 7.64–7.62 (d, J = 6.0 Hz, 2H),
7.53–7.50 (m, 2H), 7.38–7.28 (m, 6H), 4.79 (s, 1H), 2.57–2.54 (m,
4H), 1.61–1.56 (m, 4H), 1.47–1.42 (m, 2H); 13C NMR (75 MHz,
CDCl3, δ): 138.52, 131.69, 128.38, 128.15, 127.93, 127.34, 123.27,
87.80, 85.97, 62.29, 50.61, 26.10, 24.36; IR (KBr, thin film, cm–1):
3049, 2923, 2802 1596, 1486, 1445, 1270, 1152, 1094, 758, 691;
LRMS-EI (m/z): 275 (12), 246 (3), 232 (4), 198 (50), 191 (100),
165 (7), 139 (2), 115 (9), 86 (5), 56 (6); HRMS-EI (m/z): M+ calcd
for C20H21N, 275.1674; found: 275.1669.
V. A. Peshkov, O. P. Pereshivko and E. V. Van der Eycken, Chem. Soc.
Rev., 2012, 41, 3790–3807.
4
(a) N. R. Candeias, L. C. Branco, P. M. P. Gois, C. A. M. Afonso and A.
F. Trindade, Chem. Rev., 2009, 109, 2703–2802; (b) J. Gálvez, M.
GálvezꢀLlompart and R. GarcíaꢀDomenech, Green Chem., 2010, 12,
1056–1061; (c) J.ꢀN. Tan, M.ꢀH. Li and Y.ꢀL. Gu, Green Chem., 2010,
12, 908–914; (d) Y.ꢀN. Zhao, J. Li, C.ꢀJ. Li, K. Yin, D.ꢀY. Ye and X.ꢀS.
Jia, Green Chem., 2010, 12, 1370–372; (e) D. B. Ramachary and S. Jain,
Org. Biomol. Chem., 2011, 9, 1277–1300; (f) B. Jiang, X. Wang, F. Shi,
S.ꢀJ. Tu and G.ꢀG. Li, Org. Biomol. Chem., 2011, 9, 4025–4028.
(a) M. A. P. Martins, C. P. Frizzo, D. N. Moreira, L. Buriol and P.
Machado, Chem. Rev., 2009, 109, 4140–4182; (b) G.ꢀW. Wang and C.ꢀ
B. Miao, Green Chem., 2006, 8, 1080–1085; (c) S.ꢀJ. Yan, Y.ꢀL. Chen,
L. Liu, N.ꢀQ. He and J. Lin, Green Chem., 2010, 12, 2043–2052.
(a) B. Ganem, Acc. Chem. Res., 2009, 42, 463–472; (b) B. T. Barry and
G. H. Dennis, Chem. Rev., 2009, 109, 4439–4486; (c) K. Kumaravel
and G. Vasuki, Green Chem., 2009, 11, 1945–1947; (d) B. Jiang, S.ꢀJ.
Tu, P. Kaur, W. Wever and G.ꢀG. Li, J. Am. Chem. Soc., 2009, 131,
11660–11661; (e) K. Aditya and T. Béla, Green Chem., 2010, 12, 875–
878; (f) N. R. Candeias, L. F. Veiros, C. A. M. Afonso and P. M. P.
Gois, Eur. J. Org. Chem., 2009, 12, 1859–1863; (g) N. Ma, B. Jiang, G.
5
General experimental procedure for manganese(II) chloride
catalyzed three component coupling followed by catalyst free
1,3-dipolar cycloaddition reaction.
6
A mixture of aldehyde (1.0 mmol), (S)-azidomethylpyrrolidine (1.2
mmol), alkyne (1.5 mmol) and MnCl2 (10 mol%) in sealed tube was
stirred without solvent for 12–14 h at 90 °C. The progress of
reaction was monitored by TLC. After completion of reaction, the
product was purified by column chromatography using nꢀ
hexane/EtOAc as eluent to give the desired product. The products
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Zhang, S.ꢀJ. Tu, W. Wever and G.ꢀG. Li, Green Chem., 2010, 12, 1357– 21 S. Samai, G. C. Nandi and M. S. Singh, Tetrahedron Lett., 2010, 51,
1361; (h) C. Cheng, B. Jiang, S.ꢀJ. Tu and G.ꢀG. Li, Green Chem.,
2011, 13, 2107–2115.
5555–5558.
22 P. Li, Y. Zhang and L. Wan, Chem. Eur. J., 2009, 15, 2045–2049.
7
8
(a) M. Shibasaki, Y. Ishida, G. Iwasaki and T. Iimori, J. Org. Chem., 23 (a) Z. Li, C. Wei, L. Chen, R. S. Varmab and C. J. Li, Tetrahedron Lett.,
1987, 52, 3488–3489; (b) B. Jiang and M. Xu, Angew. Chem., 2004,
116, 2597–2600; Angew. Chem. Int. Ed., 2004, 43, 2543–2546; (c) Q.
Xu and E. Rozners, Org. Lett., 2005, 7, 2821–2824.
2004, 45, 2443–2446; (b) S. B. Park and H. Alper, Chem. Commun.,
2005, 1315–1317.
24 M. L. Kantam, V. Balasubrahmanyam, K. B. Shiva Kumar and G. T.
Venkanna, Tetrahedron Lett., 2007, 48, 7332–7334.
(a) F. Xiao, Y. Chen, Y. Liu and J. Wang, Tetrahedron, 2008, 64,
2755–2761; (b) D. Shibata, E. Okada, J. Molette and M. Médebielle, 25 (a) X. Zhang and A. Corma, Angew. Chem., 2008, 120, 4430–4433;
Tetrahedron Lett., 2008, 49, 7161–7164; (c) Y. Yamamoto, H. Hayashi,
T. Saigoku and H. Nishiyama, J. Am. Chem. Soc., 2005, 127, 10804–
10805; (d) D. F. Harvey and D. M. Sigano, J. Org. Chem., 1996, 61,
2268–2272; (e) B. Yan and Y. Liu, Org. Lett., 2007, 9, 4323–4326; (f)
E.ꢀS. Lee, H.ꢀS. Yeom, J.ꢀH. Hwang and S. Shin, Eur. J. Org. Chem.,
2007, 21 3503–3507.
Angew. Chem. Int. Ed., 2008, 47, 4358–4361; (b) R. Maggi, A. Bello,
C. Oro, G. Sartori and L. Soldi, Tetrahedron, 2008, 64, 1435–1439; (c)
K. M. Reddy, N. S. Babu, I. Suryanarayana, P. S. Sai Prasad and N.
Lingaiah, Tetrahedron Lett., 2006, 47, 7563–7566; (d) S. Wang, X. He,
L. Song and Z. Wang, Synlett, 2009, 447–450; (e) P. Li and L. Wang,
Tetrahedron Lett., 2007, 63, 5455–5459; (g) B. M. Choudary, C.
Sridhar, M. L. Kantam and B. Sreedhar, Tetrahedron Lett., 2004, 45,
7319–7329; (h) M. Wang, P. Li and L. Wang, Eur. J. Org. Chem., 2008,
13, 2255–2261.
9
For some recent examples, see: (a) C. Jiang, M. Xu, S. Wang, H. Wang
and Z.ꢀJ. Yao, J. Org. Chem., 2010, 75, 4323–4325; (b) F. J. Fañanás,
T. Arto, A. Mendoza and F. Rodríguez, Org. Lett., 2011, 13, 4184–
4187; (c) T. S. Symeonidis, M. G. Kallitsakis and K. E. Litinas, 26 B. Sreedhar, A. Suresh Kumar and P. S. Reddy, Tetrahedron Lett.,
Tetrahedron Lett., 2011, 52, 5452–5455. 2010, 51, 1891–1895.
10 (a) M. A. Huffman, N. Yasuda, A. E. DeCamp and E. J. J. Grabowski, 27 M. Rahman, A. K. Bagdi, A. Majee and A. Hajra, Tetrahedron Lett.,
J. Org. Chem., 1995, 60, 1590–1594; (b) M. Konishi, H. Ohkuma, T. 2011, 52, 4437–4439.
Tsuno, T. Oki, G. D. VanDuyne and J. Clardy, J. Am. Chem. Soc., 1990, 28 (a) Z. Li, C. Wei, L. Chen, R. S. Varma and C. J. Li, Tetrahedron Lett.,
112, 3715–3716.
2004, 45, 2443–2446; (b) M. L. Kantam, B. V. Prakash, C. R. V. Reddy
and B. Sreedhar, Synlett, 2005, 2329–2332; (c) X. Zhang and A. Corma,
Angew. Chem., Int. Ed., 2008, 47, 4358–4361; (d) P. Li and L. Wang,
Tetrahedron, 2007, 63, 5455–5459.
11 (a) M. Miura, M. Enna, K. Okuro and M. Nomura, J. Org. Chem., 1995,
60, 4999–5004; (b) A. Jenmalm, W. Berts, Y. L. Li, K. Luthman, I.
Csoregh and U. Hacksell, J. Org. Chem., 1994, 59, 1139–1148.
12 (a) G. Dyker, Angew. Chem., Int. Ed., 1999, 38, 1698–1712; (b) T. 29
Naota, H. Takaya and S. I. Murahashi, Chem. Rev., 1998, 98, 2599–
2660.
(a) R. Huisgen, in 1,3ꢀDipolar Cycloaddition Chemistry, (Ed.: A.
Pawda), Wiley, New York, 1984, pp. 1–176; (b) R. Huisgen, Proc.
Chem. Soc., 1961, 357–396; (c) R. Huisgen, Pure Appl. Chem., 1989,
61, 613–628; (d) H. C. Kolb, M. G. Finn and K. B. Sharpless, Angew.
Chem., Int. Ed., 2001, 40, 2004–2021; (e) V. V. Rostovtsev, L. G.
Green, V. V. Fokin and K. B. Sharpless, Angew. Chem., Int. Ed., 2002,
41, 2596–2599; (f) P. Wu and V. V. Fokin, Aldrichimica Acta,, 2007,
40, 7–17; (g) A. E. Cohrt, J. F. Jensen and T. E. Nielsen, Org. Lett.,
2011, 12, 5414–5417.
13 For selected examples, see: (a) C. W. Ryan and C. Ainsworth, J. Org.
Chem., 1961, 26, 1547–1550; (b) F. Tubéry, D. S. Grierson and H.ꢀP.
Husson, Tetrahedron Lett., 1987, 28, 6457–6460; (c) M. E. Jung and A.
Huang, Org. Lett. 2000, 2, 2659–2661; (d) T. Murai, Y. Mutoh, Y. Ohta
and M. Murakami, J. Am. Chem. Soc., 2004, 126, 5968–5969.
14 (a) N. Gommermann, C. Koradin, K. Polborn and P. Knochel, Angew.
Chem., 2003, 115, 5941–5944; Angew. Chem. Int. Ed., 2003, 42, 5763– 30 (a) A. Maliakal, G. Lem, N. J. Turro, R. Ravichandran, J. C.
5766; (b) A. Bisai and V. K. Singh, Org. Lett., 2006, 8, 2405–2408; (c)
L. Shi, Y. Q. Tu, M. Wang, F. M. Zhang and C. A. Fan, Org. Lett.,
2004, 6, 1001–1003; (d) N. Gommermann and P. Knochel, Chem.
Commun., 2004, 2324–2325; (e) N. Gommermann and P. Knochel,
Synlett, 2005, 18, 2799–2801; (f) V. A. Peshkov, O. P. Pereshivko, P. A.
Donets, V. P. Mehta and E. V. Van der Eycken, Eur. J. Org. Chem.,
2010, 4861–4867; (g) C. McDonagh, P. O’Conghaile, R. J. M. Klein
Gebbink and P. O’Leary, Tetrahedron Lett., 2007, 48, 4387–4390.
15 (a) I. Luz, F. X. Llabrés i Xamena and A. Corma, J. Catal., 2012, 285,
285–291; (b) C. J. Li and C. Wei, Chem. Commun., 2002, 268–269.
16 C. Fischer and E. M. Carreira, Org. Lett., 2001, 3, 4319–4321.
17 C. Wei and C. J. Li, J. Am. Chem. Soc., 2003, 125, 9584–9585.
18 V. K. Y. Lo, Y. Liu, M. K. Wong and C. M. Che, Org. Lett., 2006, 8,
1529–1532.
Suhadolnik, A. D. DeBellis, M. G. Wood and J. Lau, J. Phys. Chem. A,
2002, 106, 7680–7689; (b) H. C. Kolb and K. B. Sharpless, Drug
Discovery Today, 2003, 8, 1128–1137; (c) P. Wu, A. K. Feldman, A. K.
Nugent, C. J. Hawker, A. Scheel, B. Voit, J. Pyun, J. M. J. Frechet, K.
B. Sharpless and V. V. Fokin, Angew. Chem., Int. Ed., 2004, 43, 3928–
3932; (d) N. J. Agard, J. A. Prescher and C. R. Bertozzi, J. Am. Chem.
Soc., 2004, 126, 15046–14507; (e) S. Wacharasindhu, S. Bardhan, Z.ꢀK.
Wan, K. Tabei and T. S. Mansour, J. Am. Chem. Soc., 2009, 131, 4174–
4175.
31 M. J. Genin, D. A. Allwine, D. J. Anderson, M. R. Barbachyn, D. E.
Emmert, S. E. Garmon, D. R. Graber, K. C. Grega, J. B. Hester, D. K.
Hutchinson, J. Morris, R. J. Reischer, C. W. Ford, G. E. Zurenko, J. C.
Hamel, R. D. Schaadt, D. Stapert and B. H. Yagi, J. Med. Chem.,
2000,43, 953–970.
19 C. Wei, Z. Li and C. J. Li, Org. Lett., 2003, 5, 4473–4475.
20 (a) Y. Zhang, P. Li, M. Wang and L. Wang, J. Org. Chem., 2009, 74,
4364–4367; (b) J. S. Yadav, B. V. Subba Reddy, A. V. Hara Gopal and
K. S. Patil, Tetrahedron Lett., 2009, 50, 3493–3496.
32 R. Alvarez, S. Velazquez, A. SanꢀFelix, S. Aquaro, E. De Clercq, C.ꢀF.
Perno, A. Karlsson, J. Balzarini and M. J. Camarasa, J. Med. Chem.,
1994, 37, 4185–4194.
33 D. R. Buckle, C. J. M. Rockell, H. Smith and B. A. Spicer, J. Med.
Chem., 1986, 29, 2262–2267.
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

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ARTICLE
DOI: 10.1039/C4RA03232B
34 M. Tanaka, T. Yamazaki and M. Kajitani, Eur. Pat., 158494, 1985;
Chem. Abstr. 1986, 104, 186239.
G. Lobeck, J. D. Catt, J. L. Minielli, M. S. Eison, D. P. Taylor, L. A.
Riblet and D. L. Temple, J. Med. Chem., 1986, 29, 359–369.
35 (a) R. K. Smalley and M. Teguiche, Synthesis, 1990, 654–656; (b) L. 38 A. P. Dhondge, S. N. Afraj, C. Nuzlia, C. Chen and G.ꢀH. Lee, Eur. J.
Bertelli, G. Biagi, I. Giorgi, O. Livi, C. Manera, V. Scartoni, C. Martini, Org. Chem., 2013, 19, 4119–4130.
G. Giannaccini, L. Trincavelli and P. L. Barili, Farmaco, 1998, 53, 39 For Mnꢀcatalyzed reactions of activated aryl halides with RMgX: (a) G.
305–311.
Cahiez, F. Lepifre and P. Ramiandrasoa, Synthesis, 1999, 2138–2144;
(b) G. Cahiez, D. Luart and F. Lecomte, Org. Lett., 2004, 6, 4395–4398;
(c) M. Rueping and W. Ieawsuwan, Synlett, 2007, 247–250; For a Mnꢀ
catalyzed reaction of RMgX with 1ꢀchloroꢀ1,3ꢀdienes and 1ꢀchloroꢀ1,3ꢀ
enynes: (d) M. Alami, P. Ramiandrasoa and G. Cahiez, Synlett, 1998,
325–327; (e) For a Mnꢀcatalyze reaction with aryl or alkynyltin: S.ꢀK.
Kang, J.ꢀS. Kim and S.ꢀC. Choi, J. Org. Chem., 1997, 62, 4208–4209;
For a Mnꢀcatalyzed reaction with organoalanes: (f) K. Fugami, K.
Oshima and K. Utimoto, Chem. Lett., 1987, 16, 2203–2206; For various
Mnꢀcatalyzed homocoupling reactions: (g) G. Cahiez, D. Bernard and J.
F. Normant, J. Organomet. Chem., 1976, 113, 99–106; (h) S.ꢀK. Kang,
T.ꢀG. Baik, X. H. Jiao and Y.ꢀT. Lee, Tetrahedron Lett., 1999, 40,
2383–2384.
36 (a) W.Q. Fan and A. R. Katritzky, in: Comprehensive Heterocyclic
Chemistry (Eds.: A. R. Katritzky, C. W. Rees and E. F. V. Scriyen),
Elsevier Science, Oxford, 1996, vol. 4, p. 1–126; (b) B. S. Holla, M.
Mahalinga, M. S. Karthikeyan, B. Poojary, P. M. Akberali and N. S.
Kumari, Eur. J. Med. Chem., 2005, 1173–1178; (c) M. A. Elmorsi and
A. M. Hassanein, Corros. Sci., 1999, 41, 2337–2352; (d) D. K. Kim, J.
Kim and H. Park, Bioorg. Med. Chem. Lett., 2004, 14, 2401–2405.
37 (a) R. D. Norcross and I. Paterson, Chem. Rev., 1995, 95, 2041–2114;
(b) D. J. Faulkner, Nat. Prod. Rep., 2002, 19, 1–48; (c) D. Askin, K. K.
Eng, K. Rossen, R. M. Purick, K. M. Wells, R. P. Volante and P. J.
Reider, Tetrahedron Lett., 1994, 35, 673–676; (d) K. Rossen, S. A.
Weissman, J. Sagar, A. Reamer, D. A. Askin, R. P. Volante and P. J.
Reider, Tetrahedron Lett., 1995, 36, 6419–6422; (e) B. D. Dorsey, R. B. 40 D. Nils, B. Anders and A. Hans, Adv. Synth. Catal., 2004, 346, 1101–
Levin, S. L. McDaniel, J. P. Vacca, J. P. Guare, P. L. Darke, J. A. 1105.
Zugay, E. A. Emini, W. A. Schleif, J. C. Quintero, J. H. Lin, I. W. 41 (a) S. J. Benkovic, P. A. Benkovic and D. R. Comfort, J. Am. Chem.
Chen, M. K. Holloway, P. M. D. Fitzgerald, M. G. Axel, D. Ostovic, P.
Soc., 1969, 91, 1860–1861; (b) N. J. Leonad and J. V. Pauketelis, J. Org.
Chem., 1963, 28, 3021–3024.
S. Anderson and J. R. Huff, J. Med. Chem., 1994, 37, 3443–3451; (f) P.
Choudhary, R. Kumar and K. Verma, Bioorg. Med. Chem., 2006, 14, 42 (a) R. Brawn, M. Welzel, J. Lowe, and J. Panek, Org. Lett., 2010, 12,
1819–1826; (g) R. S. Upadhayaya, N. Sinha, S. Jain, N. Kishore, R.
Chandra and S. K. Arora, Bioorg. Med. Chem., 2004, 12, 2225–2238;
(h) M. Kimura, T. Masuda, K. Yamada, N. Kobuta, N. Kawakatsu, M.
Mitani, K. Kishi, M. Inazu and T. Namiki, Bioorg. Med. Chem. Lett.,
2002, 12, 1947–1950; (i) A. Ryckebusch, R. Poulain, L. Maes, M. A.
DebreuꢀFontaine, E. Mouray, P. Grellier and C. Sergheraert, J. Med.
Chem., 2003, 46, 542–557; (j) J. P. Yevich, J. S. New, D. W. Smith, W.
336‒339. (b) V. Fiandanese, I. Marino, A. Punzi, Tetrahedron, 2012,
68, 10310‒10317.
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