Highly efficient cadmium-catalyzed three-component coupling of an aldehyde, alkyne, and amine via C-H activation under microwave conditions

Article abstract of DOI:10.1055/s-0030-1259323

The first use of Cd²⁺ as catalyst for a facile three-component coupling of an aldehyde, alkyne, and amine has been demonstrated to synthesize propargylamines under microwave irradiation in chlorobenzene without the use of a co-catalyst or activator in the absence of inert atmosphere. This method has been proved to be applicable to a wide range of substrates. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1259323

LETTER
373
Highly Efficient Cadmium-Catalyzed Three-Component Coupling of
an Aldehyde, Alkyne, and Amine via C–H Activation under Microwave
Conditions
C
u
e
d
A
Coupli
s
ng hyant Singh Raghuvanshi, Krishna Nand Singh*
Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi 221005, India
Fax +91(542)2368127; E-mail: knsinghbhu@yahoo.co.in
Received 25 October 2010
wave,8a,16a and ultrasonic irradiation16b have also been
used in the presence of Cu(I) salts.
Abstract: The first use of Cd2+ as catalyst for a facile three-compo-
nent coupling of an aldehyde, alkyne, and amine has been demon-
strated to synthesize propargylamines under microwave irradiation
in chlorobenzene without the use of a co-catalyst or activator in the
absence of inert atmosphere. This method has been proved to be ap-
plicable to a wide range of substrates.
Despite the availability of a number of methods for the
synthesis of propargylamines, the improved and alterna-
tive approach to propargylamines employing new transi-
tion-metal-catalyzed multicomponent strategies remains
of current interest to organic chemists in terms of efficien-
cy, yield, cost, and simplicity of operations involved. The
long reaction time, which is frequently required for full
conversions, has limited the exploitation of catalyses in
high-throughput synthesis. Rapid and reliable applica-
tions are therefore desired not only for high-speed produc-
tion of new chemical entities,17 but also for catalysis in
general. As a part of our ongoing program on multicom-
ponent reactions,18 we found that a combination of CdI2
catalysis and microwave irradiation leads to very strong
acceleration of the process (the reaction time shortens
from hours to minutes) and considerable increase in prod-
uct yields (Scheme 1).
Key words: transition-metal catalyst, multicomponent reaction, al-
dehydes, A3 coupling, propargylamines
Transition-metal-catalyzed multicomponent reactions are
of utmost importance in organic synthesis, comprising a
plethora of versatile carbon–carbon and carbon–heteroat-
om bond-forming processes and asymmetric transforma-
tions.1 Such processes are endowed with high yields and
impressive regio- and stereoselectivities; thus becoming a
part of an ever-growing armory of useful synthetic tools
available to organic chemists today. Improved syntheses
of propargylamines via the activation of a terminal alkyne
C–H bond using metal-catalyzed multicomponent strate-
gies remain of continued interest to organic chemists in
terms of operational simplicity and cost effectiveness. Be-
ing important building blocks and versatile synthons,
propargylamines are highly featured in organic syntheses
of many biologically active nitrogen-containing
compounds2 such as conformationally restricted peptide
isosteres, oxotremorine analogues, allylamines, oxazoles,
pyrroles, and b-lactams.3 Classical methods for the prepa-
ration of propargylamines have usually exploited the rel-
atively high acidity of a terminal acetylenic C–H bond to
form alkynyl-metal reagents by the reaction with strong
bases such as butyllithium,4a organomagnesium com-
pounds,4b or LDA.5 These reagents are, however, highly
moisture sensitive and are required in stoichiometric
quantities under strictly controlled reaction conditions. In
recent years, enormous progress has been made in ex-
panding the scope of the direct addition of alkynes to car-
bon–nitrogen double bonds either preformed (imines) or
in one-pot (from aldehyde and amine) by employing var-
ious complexes and salts of transition metals, such as
iron,6 zinc,7 copper,8 ruthenium–copper,9 silver,10 indi-
um,11 iridium,12 gold,13 mercury,14 and nickel.15 Micro-
R2
R3
R3
R2
N
CdI2 (7 mol%)
R1CHO
N
H
+
+
R4
R1
MW, 300 W, 130 °C
chlorobenzene, 6–8 min
R4
1
2
3
4
Scheme 1 CdI2-catalyzed A3 coupling
This is the first example of a truly catalytic synthesis of
propargylamines using cadmium salts, motivated by its
use as catalyst.19 In order to develop a viable approach, a
variety of catalysts was first investigated for the typical
multicomponent reaction of benzaldehyde (1a), morpho-
line, and phenylacetylene under conventional as well as
microwave irradiation conditions. The outcome is given
in Table 1. The data reveal that CdI2 under conventional
conditions brings about the reaction to afford the product
4a in 87% yield (Table 1, entry 26). Application of mono-
mode MW irradiation at the same temperature, however,
brought about a notable increase in the yield as well as a
dramatic reduction in the reaction time, the best result be-
ing obtained using 300 W at 130 °C in just 7 minutes using
7 mol% CdI2 (cf. entry 26). It is noticed that, in the ab-
sence of CdI2, no conversion to the product was obtained
even after 20 minutes of MW heating or 10 hours of re-
flux.
SYNLETT 2011, No. 3, pp 0373–0377
x
x.
x
x.
2
0
1
1
Advanced online publication: 13.01.2011
DOI: 10.1055/s-0030-1259323; Art ID: D28610ST
© Georg Thieme Verlag Stuttgart · New York

374
D. S. Raghuvanshi, K. N. Singh
LETTER
The use of catalysts such as Cd(OAc)2·2H2O, tries 2–6), but other catalysts such as Cd2+-K10, SnCl4,
Cd(NO3)2·2H2O, CdCl2·H2O, SnCl2, and SnCl2·2H2O also MnCl2·6H2O, and Sc(OTf)3 did not work well (Table 1,
promoted the reaction to a reasonable extent (Table 1, en- entries 1, 7–9).
Table 1 Screening of Reaction Parameters for the Synthesisa of 4a
O
CHO
O
CdI2 (7 mol%)
N
+
+
MW, 300 W, 130 °C
chlorobenzene
N
H
1a
2a
3
4a (94%)
Entry Catalyst (mol%)
Solvent
Conventional
Microwave
Temp (°C) Time (h) Yield (%)b Power (W) Temp (°C) Time (min) Yield (%)b
1
2
Cd2+-K10
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
EtOH
130
130
130
130
130
130
130
130
130
130
78
8
10
8
45
300
300
300
300
300
300
300
300
300
300
300
300
300
300
300
300
300
300
300
300
300
300
300
300
300
300
300
130
130
130
130
130
130
130
130
130
130
78
20
20
20
20
20
20
20
20
20
10
20
20
20
20
20
20
20
20
20
20
20
20
20
20
15
7
58
Cd(OAc)2×2H2O (10)
Cd(NO3)2×2H2O (10)
CdCl2×H2O (10)
SnCl2(10)
65
78
3
50
62
4
8
78
85
5
8
55
68
6
SnCl2×2H2O(10)
SnCl4 (10)
MnCl2×6H2O (10)
Sc(OTf)3 (10)
CdI2 (10)
10
10
10
10
8
50
60
7
45
54
8
30
42
9
25
30
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
88
94
CdI2 (10)
8
25
35
CdI2 (10)
MeOH
68
8
30
68
40
CdI2 (10)
THF
65
8
trace
38
65
trace
46
CdI2 (10)
ethylene glycol
DCE
130
83
10
8
130
83
CdI2 (10)
trace
20
trace
35
CdI2 (10)
H2O
100
130
81
8
100
130
81
CdI2 (10)
Bimim[BF4]
MeCN
8
35
47
CdI2 (10)
10
10
10
10
10
10
10
10
5
60
75
CdI2 (10)
toluene
111
130
130
100
130
130
100
130
130
81
110
130
130
100
130
130
100
130
130
55
CdI2 (10)
dichlorobenzene
nitrobenzene
nitromethane
NMP
60
68
CdI2 (10)
65
70
CdI2 (10)
trace
trace
n.r.c
68
trace
20
CdI2 (10)
CdI2 (10)
no solvent
n.r.c
75
CdI2 (7)
chlorobenzene
chlorobenzene
chlorobenzene
CdI2 (7)
87
94
CdI2 (5)
8
74
15
85
a Used benzaldehyde–morpholine–phenylacetylene (1:1.1:1.2).
b Isolated yield based on benzaldehyde.
c n.r. = no reaction.
Synlett 2011, No. 3, 373–377 © Thieme Stuttgart · New York

LETTER
Cadmium-Catalyzed A3 Coupling
375
Table 2 One-Pot Synthesis of Propargylaminesa Using CdI2 as Cat-
alyst
In order to screen the solvent effect, the model reaction
was carried out in different solvents using 10 mol% of
CdI2 under conventional and MW conditions (cf.
Table 1). In all the solvents tried, the optimum conversion
was observed at reflux temperature. An advantage of
chlorobenzene (at 130 °C) was conspicuous as compared
to toluene (at 110 °C; Table 1, entries 10, 19). With other
solvents, the yield of the product was either very low
(Table 1, entries 11–17, 22, and 23), or medium (Table 1,
entries 18, 20, and 21). In terms of the catalyst concentra-
tion, 7 mol% of cadmium iodide was sufficient and neces-
sary for completion of the A3-coupling reaction (entry
26), albeit the reaction remained incomplete when 5
mol% of the catalyst was used (Table 1, entry 27). When
the test reaction was conducted under inert atmosphere us-
ing argon or nitrogen, the yields were comparable to those
obtained under aerobic conditions.
Entry R1
Amine
R3
ProductTime Yield
(min) (%)b
1
2
Ph
morpholine
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4a
4b
4c
4d
4e
4f
7
7
8
7
8
7
8
7
7
8
8
8
8
8
7
6
7
7
7
8
8
7
94
92
90
92
89
88
n.r.c
93
92
90
82
90
n.r.c
72
80
96
94
92
92
90
89
94
4-MeOC6H4 morpholine
3
4-MeC6H4
4-BrC6H4
4-ClC6H4
3-ClC6H4
morpholine
morpholine
morpholine
morpholine
4
5
6
7
4-O2NC6H4 morpholine
2-furan morpholine
2-thiophene morpholine
4g
4h
4i
8
9
Intrigued by these observations, the reaction was carried
out under controlled microwave irradiation by varying
different parameters such as MW power (200 W, 250 W,
and 300 W), temperature, time, and solvents. The 300 W
power output and reflux temperature of the solvent was
required to accomplish the maximum conversion and
therefore the same was applied to test the efficacy of other
catalysts for 20 minutes (Table 1). As evident from
Table 1, the best result is obtained using 300 W at 130 °C
in 7 minutes in the presence of 7 mol% CdI2 in chloroben-
zene (cf. entry 26); further increase in temperature of the
sealed reaction vessel and time did not enhance the prod-
uct yield. Other solvents did not work well under micro-
wave irradiation. Under the optimized set of MW reaction
conditions (300 W, 130 °C), benzaldehyde (1a) under-
went multicomponent reaction with morpholine and phe-
nyl acetylene in a molar ratio of 1:1.1:1.2 with CdI2 (7
mol%) in chlorobenzene to afford propargylamine 4a in
94% yield in 7 minutes (Table 1). Under the optimized set
of reaction conditions, a number of aldehydes and amines
was subsequently reacted with phenylacetylene to afford
various propargylamines in excellent yields (Table 2).20
Interestingly, aldehydes such as benzaldehyde, p-meth-
oxybenzaldehyde, p-methylbenzaldehyde, p-chlorobenz-
aldehyde, m-chlorobenzaldehyde, and p-bromo-benz-
aldehyde reacted effectively with morpholine/piperidine
and phenyl acetylene to produce the corresponding prop-
argylic amines in exellent yields (Table 2, entries 1–6 and
17–21); but p-nitrobenzaldehyde did not react (Table 2,
entry 7). Similarly, heteroaromatic aldehydes such as
thiophene-2-carboxaldehyde and furan-2-carboxaldehyde
also participated well in these reactions (Table 2, entries
8, 9, and 22). In addition to aromatic aldehydes, the ali-
phatic aldehydes formaldehyde and pentanal also under-
went efficient conversion (Table 2, entries 10 and 11). As
regards the reactivity of various amines, piperizine, ben-
zylamine, aniline, and piperidine, (Table 2, entries 12 and
14–16) gave rise to smooth coupling, whereas methy-
lamine did not react (Table 2, entry 13). The analytical
data of all the products are in full agreement with the as-
signed structures.
10
11
12
13
14
15
16
17
18
19
20
21
22
H
morpholine
morpholine
piperazine
4j
Bu
Ph
Ph
Ph
Ph
Ph
4k
4l
methylamine Ph
benzylamine Ph
4m
4n
4o
4p
4q
4r
4s
aniline
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
piperidine
4-MeOC6H4 piperidine
4-MeC6H4
4-BrC6H4
4-ClC6H4
3-ClC6H4
2-furan
piperidine
piperidine
piperidine
piperidine
piperidine
4t
4u
4v
a Reaction conditions: aldehyde (1 mmol), amine (1.1 mmol), phenyl-
acetylene (1.2 mmol), CdI2 (7 mol%), chlorobenzene (2 mL), MW,
300 W, 130 °C.
b Isolated yield based on aldehyde.
c n.r. = no reaction.
R2
N
R3
Ph
2
H
Ph
C
H
2
CdIII2
R1
4
3
R2
R3
+
N
2R1CH
2 HI
Ph
R2
CdII
Ph
R1CHO
+ HN
R3
1
2
Scheme 2 Plausible mechanism for the cadmium-catalyzed synthe-
sis of propargylamines
Synlett 2011, No. 3, 373–377 © Thieme Stuttgart · New York

376
D. S. Raghuvanshi, K. N. Singh
LETTER
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A plausible mechanism for the investigated reaction is
outlined in Scheme 2. The formation of dialkynyl cadmi-
um species is well established,21 and the presence of an
excess of phenylacetylene is expected to give a dialkynyl
cadmium species to initiate reaction.
In conclusion, we have successfully developed an effi-
cient microwave protocol using CdI2 as catalyst for one-
pot multicomponent synthesis of diverse propargylamines
in excellent yields. Notable features of the protocol in-
clude clean and simple reaction conditions, use of a readi-
ly available and inexpensive catalyst, tolerance of various
functional groups, and aerobic conditions. We believe that
this protocol will be a valuable addition to modern syn-
thetic methodologies for one-pot synthesis of propargyl-
amines.
Acknowledgment
One of the authors (D.S.R.) is grateful to the Council of Scientific
and Industrial Research, New Delhi for SRF. Thanks are also due to
the Department of Biotechnology, New Delhi for financial assi-
stance.
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Synlett 2011, No. 3, 373–377 © Thieme Stuttgart · New York

LETTER
Cadmium-Catalyzed A3 Coupling
377
(20) General Procedure for the Synthesis of Propargylamines
Aldehyde (1 mmol), amine (1.1 mmol), alkyne (1.2 mmol),
CdI2 (7 mol%), and chlorobenzene (2 mL) were placed in a
sealed pressure-regulation 10 mL pressurized vial with
‘snap-on’ cap, and the mixture was irradiated in a single-
mode microwave synthesis system at 300 W and 130 °C for
7–8 min. After completion of the reaction (as monitored by
TLC), the solvent was evaporated under vacuum. Water (20
mL) was added to the reaction mixture, and the product was
extracted with EtOAc (3 × 10 mL). The combined organic
phases were dried over anhyd MgSO4, filtered, and the
solvent was evaporated under vacuum. The residue was
purified by column chromatography on silica gel (EtOAc–
hexane, 1:9) to afford the pure propargylamines.
Representative Data
4-(1,3-Diphenylprop-2-ynyl)morpholine (4a)
FT-IR (KBr): 2935, 2756, 1590, 1490, 1451, 1319, 1152,
757, 694 cm–1. 1H NMR (300 MHz, CDCl3): d = 7.61 (d,
J = 7.2 Hz, 2 H), 7.49 (m, 2 H), 7.39–7.25 (m, 6 H), 4.78 (s,
1 H), 3.76–3.72 (m, 4 H), 2.64–2.61 (m, 4 H) ppm. 13C NMR
(75 MHz, CDCl3): d = 137.7, 131.7, 128.5, 128.2, 128.3,
128.0, 127.7, 122.9, 88.4, 84.9, 67.1, 62.0, 49.8. Anal. Calcd
for C19H19NO: C, 82.28; H, 6.90; N, 5.05. Found: C, 82.32;
H, 6.82; N, 5.12.
(21) Barr, D.; Edwards, A. J.; Raithby, P. R.; Rennie, M.-A.;
Verhorevoort, K.; Wright, D. S. Chem. Commun. 1994,
1627.
Synlett 2011, No. 3, 373–377 © Thieme Stuttgart · New York

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