InBr3-catalyzed three-component reaction: a facile synthesis of propargyl amines

Article abstract of DOI:10.1016/j.tetlet.2009.03.014

Indium(III) bromide has been used for the first time for the synthesis of propargyl amines in a one-pot operation from aldehydes, amines and alkynes.

Full text of DOI:10.1016/j.tetlet.2009.03.014

Tetrahedron Letters 50 (2009) 3493–3496
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Tetrahedron Letters
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InBr3-catalyzed three-component reaction: a facile synthesis
of propargyl amines
*
J. S. Yadav , B. V. Subba Reddy, A. V. Hara Gopal, K. S. Patil
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Indium(III) bromide has been used for the first time for the synthesis of propargyl amines in a one-pot
operation from aldehydes, amines and alkynes.
Received 12 January 2009
Revised 27 February 2009
Accepted 4 March 2009
Available online 9 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Indium reagents
Three-component reaction
Propargylic amines
The stereoselective addition of organometallic reagents to alde-
hydes and imines is one of the most important carbon-carbon bond
formation reactions in organic synthesis.1 Propargyl amines or b-
aminoalkynes are versatile intermediates for the construction of
nitrogen-containing biologically active molecules and for the syn-
thesis of polyfunctional amino derivatives.2 The direct method for
the synthesis of propargyl amines involves the addition of alkynyl-
metal reagents to imines.3 Addition of alkynes to imines, enamines,
nitrones, and acyliminium ions using copper salts has been re-
ported to produce propargyl amines.4 Asymmetric versions of en-
amine–alkyne and imine–alkyne additions have also been
reported to produce enantiomerically pure propargyl amines.5
Propargyl amines can also be synthesized by one-pot three-compo-
nent coupling of aldehydes, alkynes, and amines via C–H activa-
tion. Several transition metal salts such as gold, copper, silver,
and Cu/Ru system have been employed in water as well as in ionic
liquids.6 Recently, solid-supported metal catalysts such as CuI/
Al2O3, AuCl4/LDH, and Cu/HAP and alternative energy sources like
microwave and ultrasound have been utilized in the presence of
CuI to accomplish this reaction via C–H activation.7,8 However,
many of these three-component coupling reactions are mainly lim-
ited to the aromatic aldehydes and cyclic amines and also involve
the use of expensive iridium, gold, and silver salts. Moreover, low
conversions are reported with aliphatic aldehydes.7d
Compared to conventional Lewis acids, it has advantages of water
stability, recyclability, operational simplicity, strong tolerance to
oxygen and nitrogen-containing substrates and functional groups,
and it can often be used in catalytic amounts.10 Recently, InBr3 has
also been used for the alkynylation of aldehydes and acetals.11
In continuation of our interest on the catalytic use of indium tri-
bromide,12 we herein report a simple and efficient method for the
preparation of propargyl amines by means of a three-component
coupling of aldehyde, amine, and alkyne. Accordingly, we first at-
tempted the coupling of benzaldehyde (1) with morpholine (2)
and phenyl acetylene (3) in the presence of 10 mol % of InBr3 in tol-
uene. The reaction went to completion in 4.5 h and the desired
product, 4-(1,3-diphenylprop-2-ynyl)morpholine, 4a was obtained
in 85% yield (Scheme 1).
Encouraged by this result, we turned our attention to various
aldehydes, amines, and alkynes. Interestingly, various aldehydes
such as p-methoxybenzaldehyde, p-methylbenzaldehyde, p-chlo-
robenzaldehyde, and p-bromobenzaldehyde reacted effectively
with morpholine and phenyl acetylene to produce the correspond-
ing propargylic amines in good yields (Table 1, entries b–e).
Similarly, heteroaromatic aldehydes such as thiophene-2-carbox-
aldehyde and furan-2-carboxaldehyde also participated well in this
reaction (Table 1, entries f and g). In addition to aromatic alde-
hydes, aliphatic aldehydes such as pentanal, formaldehyde and
cyclohexanecarboxaldehyde were also equally effective for this
conversion (Table 1, entries i–k and g). Next, we studied the reac-
tivity of various alkynes in the 3CC reaction. Interestingly, several
alkynes such as 1-octyne, 2-ethynylpyridine, 1-tert-butyl-4-ethyn-
ylbenzene, and but-3-ynyl-benzene underwent smooth coupling
to provide a wide range of propargyl amines (Table 1, entries k
Recently, indium tribromide has received increasing attention
as a water-tolerant, green Lewis acid catalyst for organic synthesis
demonstrating highly chemo-, regio-, and stereo-selective results.9
* Corresponding author. Tel.: +91 40 27193030; fax: +91 40 27160512.
E-mail address: yadavpub@iict.res.in (J.S. Yadav).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.014

3494
J. S. Yadav et al. / Tetrahedron Letters 50 (2009) 3493–3496
O
N
O
10 mol% InBr3
Toluene, 80 ºC
CHO
+
+
N
H
1
2
4a
3
Scheme 1.
and m–o). Ketones did not give the desired product under these
reaction conditions. This method was also successful with various
amines such as piperidine, pyrrolidine, and aniline (Table 1, entries
k and o–r). In all cases, no propargylic alcohol (an adduct between
the aldehyde and alkyne) was obtained under similar reaction con-
ditions. This is because of a rapid formation of the carbon-nitrogen
bond from aldehydes and amines. The effects of various indium(III)
salts such as InCl3, In(OTf)3, In(OAc)3, and In(ClO4)3 were screened
Table 1
Inbr3-Catalyzed preparation of propargyl amines
Entry
a
Aldehyde
Alkyne
Amine
Producta
Reaction time (h)
Yieldb (%)
O
O
O
N
H
N
H
4.5
85
Ph
O
O
O
N
H
N
H
b
4.5
5.0
6.0
5.5
70
85
80
85
MeO
Me
Cl
Ph
MeO
Me
Cl
O
O
O
O
O
H
N
H
N
c
Ph
Ph
Ph
O
O
N
H
H
N
H
d
O
O
N
N
H
e
Br
Br
O
O
N
CHO
CHO
S
N
H
f
4.0
4.5
95
92
S
Ph
O
O
N
O
N
H
g
O
Ph

J. S. Yadav et al. / Tetrahedron Letters 50 (2009) 3493–3496
3495
Table 1. (continued)
Entry
Aldehyde
Alkyne
Amine
Producta
Reaction time (h)
Yieldb (%)
O
O
O
N
H
N
H
h
6.0
78
Br
Me
Me
Br
O
O
O
N
H
N
H
i
j
6.0
75
Ph
O
O
O
O
H
H
H
N
H
N
4.0
5.5
90
75
H
H
Ph
H
H
O
N
N
H
k
H
H
O
O
H
N
H
N
l
5.0
4.5
82
70
Ph
O
O
N
N
CHO
S
N
H
m
S
N
O
O
O
N
H
N
H
n
5.0
85
Br
Br
O
O
H
H
N
H
N
o
p
7.0
6.5
70
78
Cl
Cl
Cl
N
H
N
Cl
(continued on next page)

3496
J. S. Yadav et al. / Tetrahedron Letters 50 (2009) 3493–3496
Table 1. (continued)
Entry
q
Aldehyde
Alkyne
Amine
Producta
Reaction time (h)
Yieldb (%)
CHO
S
N
H
N
4.5
74
S
O
Ph
HN
H
r
7.0
70
NH2
MeO
MeO
a
The products were characterized by NMR, IR and mass spectroscopy.
Yield refers to pure products after chromatography.
b
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for this transformation. Of these catalysts, indium tribromide was
found to be the most effective in terms of conversion and selectiv-
ity. For example, treatment of benzaldehyde with morpholine and
phenyl acetylene in the presence of 10 mol % of InBr3 and 10 mol %
of InCl3 for 4.5 h gave the product 4a in 85% and 70% yields, respec-
tively. Although, indium tribromide is water tolerant, the reaction
was unsuccessful either in pure water or in toluene/water (7:3)
system. The scope and generality of this process are illustrated
with respect to various aldehydes, amines and alkynes and the re-
sults are presented in Table 1.13
In summary, we have developed a simple, convenient, and effi-
cient protocol for the preparation of propargylic amines by means
of coupling of aldehyde, amine, and alkyne in a single-step opera-
tion. This method works well for both aliphatic and aromatic sub-
strates. The use of indium bromide makes this method simple,
convenient, and practical.
Acknowledgment
13. General procedure: A mixture of aldehyde (1 mmol), amine (1 mmol), alkyne
(1.5 mmol) and InBr3 (10 mol %) in toluene was stirred at 80 °C for the
appropriate time (Table 1). After completion of the reaction as indicated by
TLC, the reaction mixture was quenched with water and extracted with ethyl
acetate (3 Â 10 mL). The combined organic extracts were concentrated in
vacuo and the resulting product was directly charged onto a small silica gel
column and eluted with a mixture of ethyl acetate:n-hexane (1:9) to afford
pure propargylic amine. Spectral data for selected products: Compound 4h: 4-[3-
(4-Bromophenyl)-1-(4-methylphenyl)-2-propynyl] morpholine: solid, mp
139–142 °C. IR (KBr): 3426, 3026, 2966, 2921, 2849, 2240, 1657, 1484, 1446,
AVHG thanks CSIR, New Delhi, for the award of fellowships.
References and notes
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1388, 1268, 1112, 1069, 1000, 968, 929, 856, 814 cmÀ1
CDCl3): 7.48–7.40 (m, 4H), 7.37–7.32 (m, 2H), 7.15–7.09 (m, 2H), 4.67 (s, 1H),
3.74–3.61 (m, 4H), 2.63–2.48 (m, 4H), 2.36 (s, 3H). 13C NMR (75 MHz, CDCl3):
.
1H NMR (300 MHz,
m
m
137.4, 134.4, 133.1, 131.4, 128.8, 128.3, 122.2, 121.8, 87.0, 86.5, 67.0, 61.7,
49.7, 21.0. LCMS: m/z 370 (M+). HRMS calcd for C20H21NOBr (M+H+): 370.0799.
Found: 370.1086. Compound 4j: 4-(3-Phenyl-2-propynyl)morpholine: IR
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(KBr):
1326, 1070, 1006, 911, 861, 756, 692, 666, 560, 525 cmÀ1
CDCl3): 7.36–7.10 (m, 5H), 3.63–3.50 (m, 4H), 3.37 (s, 2H), 2.53–2.40 9 m,
4H). 13C NMR (75 MHz, CDCl3):
52.3, 48.0. LCMS: m/z 202 (M+1). HRMS calcd for C13
Found: 202.1231. Compound 4n: 4-{1-(4-bromophenyl)-3-[4-(tert-butyl)
m
3057, 2958, 2925, 2854, 2813, 2760, 2261, 1719, 1599, 1489, 1390,
.
1H NMR (300 MHz,
m
m
131.6, 128.1, 128.0, 122.9, 85.5, 83.9, 66.8,
H16NO (M+H+): 202.1225.
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4473; (d) Li, Z.; Wei, C. M.; Chen, Li.; Varma, R. S.; Li, C. J. Tetrahedron Lett. 2004,
phenyl]-2-propynyl} morpholine: IR (KBr):
m
2957, 2857, 2364, 1591, 1476,
1394, 1315, 1274, 1113, 1070, 1008, 836, 769 cmÀ1
.
1H NMR (300 MHz, CDCl3):
m
7.53–7.29 (m, 8H), 4.69 (s, 1H), 3.73–3.62 (m, 4H), 2.62–2.53 (m, 4H), 1.32 (s,
9H). 13C NMR (75 MHz, CDCl3):
m
151.5, 137.0, 131.4, 131.1, 130.0, 125.1, 121.5,
119.5, 88.9, 83.4, 66.9, 61.2, 49.6, 34.5, 31.0. LCMS: m/z 412 (M+). HRMS calcd
for C23H27NOBr (M+H+): 412.1268. Found: 412.1276.