Iron-catalyzed three-component coupling of aldehyde, alkyne, and amine under neat conditions in air

Article abstract of DOI:10.1016/j.tetlet.2009.03.182

Various iron-salts (and complexes) and especially iron(III) chloride catalyzed the three-component coupling of aldehyde, alkyne, and amine to generate propargylic amines with high efficiency under neat conditions in air. The iron-catalyzed reaction is par

Full text of DOI:10.1016/j.tetlet.2009.03.182

Tetrahedron Letters 50 (2009) 2895–2898
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Tetrahedron Letters
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Iron-catalyzed three-component coupling of aldehyde, alkyne, and amine under
neat conditions in air
*
Wen-Wen Chen, Rene V. Nguyen, Chao-Jun Li
Department of Chemistry, McGill University, 801 Sherbrooke St. West, Montreal, QC, Canada H3A 2K6
a r t i c l e i n f o
a b s t r a c t
Article history:
Various iron-salts (and complexes) and especially iron(III) chloride catalyzed the three-component cou-
pling of aldehyde, alkyne, and amine to generate propargylic amines with high efficiency under neat con-
ditions in air. The iron-catalyzed reaction is particularly effective for reactions involving aliphatic
aldehydes. The reaction is not sensitive to and occurs smoothly in water and in air. No additional co-cat-
alyst or activator is required.
Received 13 March 2009
Revised 26 March 2009
Accepted 26 March 2009
Available online 1 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Iron-catalyzed
Three-component coupling
Aldehyde
Alkyne
Amine
C–H activation
Neat
In air
Environmentally benign, economical, practical, and efficient
processes for chemical synthesis have become increasingly impor-
tant in the chemical community.1 During the past decade, one-pot
multi-component reactions to make new carbon–carbon bonds
have attracted much attention and have achieved great progress.2
In the past few years, we3 and others4 have reported various highly
efficient three-component couplings of aldehyde, alkyne, and
amine (A3-coupling) in water, organic media, ionic liquid, or under
solvent-free condition catalyzed by copper, silver, gold, and other
catalysts via catalytic C–H reaction to afford various propargylam-
ines. A highly enantioselective addition of alkynes to imines to
generate optical propargylamines in water or in organic media
by using a chiral copper catalyst (AA3-coupling) has also been
developed by us and others.5 Propargylic amines, product of the
A3-coupling, are useful building blocks as well as important skele-
tons of biologically active compounds.6 Because of our continued
interest in synthesizing propagylamines via activation of alkynes,
we have been searching for other cheap, nontoxic, and benign cat-
alysts for this coupling.
tion,9 rearrangement,10 and other carbon–carbon bond, carbon-
heteroatom bond and heteroatom–heteroatom bond forming reac-
tions have been described recently.11 During our investigation of
A3-couplings several years ago, we discovered that iron could cata-
lyze the A3 coupling in toluene.12 However, subsequent studies
showed that the reaction yields were not repeatable (changing from
high yields to only trace amounts with different runs under identical
conditions). To overcome this problem, we tried a variety of condi-
tions to pin down the cause of irregularity in product yields without
much success. Recently, we found and herein we wish to report that,
under neat conditions and in air, FeCl3 is an effective catalyst for the
three-component coupling of aldehyde, alkyne and amine with
good repeatability in reaction yields at 70 °C (Scheme 1). Further-
more, a reversal of the reactivity of aliphatic and aromatic aldehydes
was observed compared to our early reported Au or Cu systems,3 in
which aliphatic aldehydes were much more reactive than aromatic
aldehydes (similar to the silver system).
In our initial attempt to seek a more effective and more repeat-
able iron catalyst for the coupling of aldehyde, alkyne, and amine,
several iron salts were utilized (Table 1). When using 10 mol % of
Iron catalysts are readily available, inexpensive, and environ-
mental friendly with special reactivities. These features make them
valuable and advantageous in synthetic processes. Many iron-cata-
lyzed reactions such as oxidation,7 hydroamination,8 Michael addi-
n
n
10 mol % FeCl3
R1-CHO
R2
H
N
+
+
neat, 70 oC, in air
N
H
R1
R2
R
1 =aryl, alkyl n=0,1,2
* Corresponding author. Fax: +1 514 398 3797.
E-mail address: cj.li@mcgill.ca (C.-J. Li).
Scheme 1. Iron-catalyzed A3 coupling.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.182

2896
W.-W. Chen et al. / Tetrahedron Letters 50 (2009) 2895–2898
Table 1
the catalyst, all the Fe(III) salts, Fe(II) salts, and Fe(0) sources exam-
ined including FeCl3, FeCl3Á6H2O, Fe(acac)3, FeCl2, FeBr2, FeF2,
FeSO4, FeCp2, Fe2(CO)9, and iron powder catalyzed the reaction of
cyclohexanecarbaldehyde, piperidine, and phenylacetylene in neat
and under an air atmosphere to give the corresponding propargyl-
amine products in moderate to good yields, with FeCl3 being the
most effective and giving the three-component coupling product
in 93% yield (Table 1, entries 1–10). It is worth noting that iron
powder can also catalyze the reaction, albeit the yield is lower.
The reaction yield decreased considerably when carried out either
under a nitrogen or oxygen atmosphere (Table 1, entries 11 and
12). Almost similar yield was obtained when slightly increasing
or decreasing the catalyst loading (Table 1, entries 13 and 14).
The reaction could also proceed even at room temperature,
although in a lower conversion (Table 1, entry 15). No significant
difference was observed when a ligand such as TMEDA was pre-
sented (Table 1, entry 16). The addition of various solvents such
as THF, DCE, and toluene all led to lower yields (Table 1, entries
17–19). The iron-catalyzed reaction could also proceed smoothly
in the presence of a small amount of water. However, a large
amount of water resulted in a lower yield (Table 1, entries 20
and 21). No desired product was obtained in the absence of FeCl3.
The optimized reaction conditions include 1.0 equiv of aldehyde,
1.2 equiv of amine, 1.5 equiv of alkyne, and 10 mol % of FeCl3 in
neat at 70 °C in air.
Three-component coupling of aliphatic aldehydes, amines, and alkynes catalyzed by
iron in neat
a
CHO
iron catalyst
N
+
+
Ph
H
N
H
Ph
4
3
2
1
Entry
Catalyst (mol %)
Additive or solvent (mol %)
Yieldb (%)
1
2
3
4
5
6
7
8
FeCl3 (10)
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
93
84
53
70
90
46
66
73
42
37
36
74
94
90
38
94
60
60
21
74
38
FeCl3Á6H2O (10)
Fe(acac)3 (10)
FeCl2 (10)
FeCp2 (10)
Fe2(CO)9 (10)
FeF2 (10)
FeBr2 (10)
9
FeSO4 (10)
Iron powder (10)
FeCl3 (10) (in O2)
FeCl3 (10) (in N2)
FeCl3 (20)
FeCl3 (5)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
10
11
12
13
14
15c
16
17
18
19
20
21
TMEDA (20)
THF (200)
Toluene (200)
DCE (200)
H2O (10)
H2O (200)
Subsequently, various aldehyde, alkyne, and amine were cou-
pled similarly and the results are summarized in Table 2. Both aro-
matic and aliphatic aldehydes underwent the addition reaction to
afford the corresponding three-component propargylic amines
effectively. However, the reaction was found to be strongly influ-
enced by the nature of the aldehyde, in the same manner as in
the silver-catalyzed A3-coupling in water.3g The use of aromatic
a
All reactions were carried out with aldehyde 1 (0.5 mmol), amine 2 (0.6 mmol),
and alkyne 3 (0.75 mmol) in neat and in air at 70 °C for 14 h.
b
Measured by 1H NMR with CH3NO2 as the internal standard.
The reaction was carried out in room temperature.
c
Table 2
Coupling of aldehyde, alkyne, and amine catalyzed by FeCl3 in neat and in air
Entry
Aldehyde
Amine
Alkyne
Product
Yielda,b (%)
81 (93)
CHO
N
1
H
H
H
N
H
Ph
Ph
CHO
CHO
N
N
2
3
60 (70)
67 (74)
55 (71)
N
H
N
H
Ph
N
CHO
4
5
H
H
Ph
N
H
Ph
Ph
CHO
N
32 (52)
N
H
Ph
(continued on next page)

W.-W. Chen et al. / Tetrahedron Letters 50 (2009) 2895–2898
2897
Table 2 (continued)
Entry
Aldehyde
Amine
Alkyne
Product
Yielda,b (%)
N
6
n-C4H9CHO
61 (72)
H
N
H
n-C4H9
Ph
N
7
8
n-C6H13CHO
60 (71)
45 (52)
H
H
N
H
n-C6H13
Ph
N
HCHO (37 wt % in H2O)
N
H
Ph
N
9
55 (66)
60 (72)
34 (52)
56 (73)
43 (58)
58 (79)
H
H
H
N
H
CHO
CHO
Ph
O
O
N
10
11
12
13
N
H
Ph
CHO
CHO
CHO
CHO
N
N
H
Ph
Ph
N
N
N
TMS
H
N
H
TMS
n-C4H9
H
N
H
n-C4H9
n-C10H21
H
14
N
H
n-C10H21
a
Isolated yields based on aldehyde were reported; carried out on a 0.5 mmol scale with aldehyde/amine/alkyne = 1:1.2:1.5 and 10 mol % FeCl3, 70 °C, neat, in air.
b
The data in the parentheses are the yields measured by 1H NMR with CH3NO2 as the internal standard.
aldehydes gave lower conversions and lower yields. Aliphatic alde-
the propargylamines in moderate to good yields (Table 2, entries
1, 2, 3, and 10). However, acyclic dialkylamines (such as diallyl-
amine) was less effective. Various terminal alkynes were also
examined. Both aromatic alkynes and aliphatic alkynes reacted
smoothly with aldehyde and amine to give the corresponding
products in good yields (Table 2, entries 1, 13, and 14). Trimethyl-
silylacetylene also reacted smoothly in which the silyl group could
tolerate the reaction conditions (Table 2, entry 12).
hydes, on the other hand, displayed higher reactivity and cleaner
reactions. The reactions involving aliphatic aldehydes such as iso-
butyraldehyde, valeraldehyde, heptaldehyde, cyclohexanecarbox-
aldehyde, and 3-phenylpropanal all showed both higher
conversions and greater yields than benzaldehyde (Table 2, entries
1, 4, 6, 7, 9, and 11). Formaldehyde (37 wt % in water) and 2-ethyl-
butanal afforded the desired products in moderate yields (Table 2,
entries 5 and 8).
A tentative mechanism for the iron-catalyzed aldehyde–al-
kyne–amine (A3) coupling is proposed in Scheme 2. The reaction
is catalyzed most likely by Fe+3 ion. Reaction of Fe+3 with terminal
Cyclic dialkylamines such as piperidine, pyrrolidine, azepane,
and morpholine reacted smoothly under these conditions to give

2898
W.-W. Chen et al. / Tetrahedron Letters 50 (2009) 2895–2898
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N
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n
R1
R2
N
H
Scheme 2. Tentative mechanism for the iron-catalyzed A3 coupling.
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alkyne in the presence of the amine base generated the terminal
iron-acetylide, which undergoes nucleophilic addition to the imin-
ium ion, generated in situ, to give the propargyl amine product and
regenerates the Fe+3
.
In conclusion, we have developed an effective, economical, and
simple three-component coupling of aldehyde, alkyne, and amine
(A3-coupling) with various iron catalysts to give a diverse range
of propargylamines in moderate to high yield under mild condi-
tions. The operation is very simple and can be carried out at a rel-
atively low temperature, without any solvent in air. The reaction
can also tolerate a small amount of water without substantially
sacrificing the yield. The asymmetric version, mechanism, and syn-
thetic application of this reaction are currently under further
investigation.
General experimental procedure: To a test tube charged with
FeCl3 (8.1 mg, 0.05 mmol, 10 mol %) in air, aldehyde (0.5 mmol),
amine (0.6 mmol), and alkyne (0.75 mmol) were added. The tube
was then stoppered. The reaction mixture was stirred at 70 °C
(oil bath temperature) for 14 h. After cooling to room temperature,
the reaction mixture was filtered through Celite in a pipette eluting
with ethyl acetate. The volatile was removed under vacuum and
the residue was purified by flash column chromatography on silica
gel (eluent:hexane/ethyl acetate = 10:1) to give the corresponding
product.
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Chem. Res. 2008, 41, 1500. and references cited therein; For recent selected
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Acknowledgments
We are grateful to the Canada Research Chair (Tier I) foundation
(to C.-J.L.), the CFI, NSERC, and McGill University for support of our
research.
References and notes
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12. During the preparation of the present Letter, Wang et al. reported their iron-
catalyzed three-component coupling reaction of aldehydes, alkynes, and
amines with 4 Å molecular sieves in toluene under N2 atomsphere at 120 °C,
see: Li, P. H.; Zhang, Y. C.; Wang, L. Chem. Eur. J. 2009, 15, 2045.