Efficient ruthenium and copper cocatalzyed five-component coupling to form dipropargyl amines under mild conditions in water

Article abstract of DOI:10.1039/b613596j

Dipropargyl amines are synthesized by a double direct alkynylation of primary followed by secondary imines formed in situ during an efficient, five-component, one-pot coupling reaction cocatalyzed by ruthenium and copper in water. The Royal Society of Che

Full text of DOI:10.1039/b613596j

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Efficient ruthenium and copper cocatalzyed five-component coupling to form
dipropargyl amines under mild conditions in water†
E. Ryan Bonfield and Chao-Jun Li*
Received 18th September 2006, Accepted 28th November 2006
First published as an Advance Article on the web 4th December 2006
DOI: 10.1039/b613596j
Dipropargyl amines are synthesized by a double direct
alkynylation of primary followed by secondary imines formed
in situ during an efficient, five-component, one-pot coupling
reaction cocatalyzed by ruthenium and copper in water.
from a range of simple amines, aldehydes, and alkynes in one pot
under mild conditions in water (Scheme 1).
Propargyl amines are important components of biologically
1
2
active compounds and useful synthetic precursors. Recently
we and others have developed methods allowing for the direct
alkynylation of imines formed in situ to generate propargyl amines
Scheme 1 Five component-coupling to form dipropargyl amines.
Initial screening of reaction conditions showed that increasing
the reaction temperature can substantially decrease the yield
3–8
in one step. Depending on the substrates, this aldehyde–alkyne–
3
amine coupling (A -coupling) can be successful using copper
(
Table 1, entries 1–2, 4–6), indicating that side reactions are a
3
in solid phase systems, copper-doped alumina with microwave
◦
problem. At 60 C the yield is slightly better in toluene compared
to water, whereas at room temperature, with increased reaction
time, the opposite is true (Table 1, entries 4, 7, 10–11). This could
indicate that hydrolysis of one or both of the imine intermediates is
4
5
6
7
assistance, ruthenium–copper cocatalysis and gold, silver, and
8
iridium catalysis. The ruthenium–copper, gold, and silver solution
phase systems have shown greatest overall scope. Furthermore, the
use of copper catalysis has led to the development of asymmetric
3
9
10
A -couplings by us and others.
Dipropargyl amines are also important components of biologi-
3
a
Table 1 Optimization of conditions for the double A -coupling
11
cally active compounds. Furthermore, the biological activity can
differ significantly from the analogous compound with a mono-
propargyl amine substructure. More importantly, dipropargyl
amines have an important role in many current synthetic re-
search efforts. These include various types of cycloaddition and
cycloisomerization reactions, hydrative and reductive cycliza-
12
b
Entry
Catalyst loading
Solvent
Temp/time
rt/20 h
Yield (%)
13
c
1
2
3
4
5
6
7
8
9
RuCl
CuBr (15.3%)
RuCl (6.7%)
CuBr (17.7%)
RuCl (5.9%)
3
(6.4%)
Neat
82
62
54
53
14
15
16
17
18
c
◦
tions, aza-Wittig rearrangements, and macrocycle synthesis.
3
Neat
60 C/20 h
Yet, despite their widespread use, currently reported methods for
the synthesis of dipropargyl amines have serious limitations. For
d
◦
3
H
2
O
60 C/20 h
CuBr (15.4%)
1
9
◦
example, the use of highly reactive bases such as sodium hydride,
RuCl (5.4%)
2
H O
60 C/19 h
3
20
or organometallic reagents in a separate step limits the efficiency.
CuBr (14.9%)
◦
21
RuCl
CuBr (17.2%)
RuCl (6.7%)
3
(5.9%)
H
H
2
2
O
O
100 C/19 h 30
An alternative has been to use propargyl bromides directly, but
these would also have to be pre-prepared in a separate step and
can be difficult to handle. Ishii et al. recently reported an iridium
catalyzed five component double A -coupling leading directly to
dipropargyl amines. Yet, with this system the terminal alkyne is
limited to trimethylsilylacetylene and 1,4-dioxane or cyclopentyl
3
rt/24 h
rt/36 h
rt/61 h
rt/20 h
rt/36 h
61
70
60
78
64
60
CuBr (14.7%)
3
RuCl (4.9%)
2
H O
3
22
CuBr (16.3%)
RuCl
CuBr (15.5%)
RuCl (9.5%)
CuBr (16.6%)
RuCl (5.5%)
3
(5.4%)
H
H
2
2
O
O
methyl ether were required as solvents at temperatures exceeding
3
◦
75
C for up to 15 h to get satisfactory yields. Formation of
1
0
3
Toluene
Toluene
dipropargyl amines by the microwave-assisted copper–alumina
systems was also reported possible, but this methodology is limited
CuBr (15.3%)
◦
11
RuCl (5.3%)
3
60 C/20 h
4
CuBr (17.6%)
to aminomethylation of alkynes.
Herein we report the use of a ruthenium–copper cocatalyzed five
component double A -coupling to synthesize dipropargyl amines
a
7
5 lL (0.82 mmol) aniline, 200 lL (1.8 mmol) phenylacetylene, 135 lL
3
(1.8 mmol at 37 wt% in H O) formaldehyde, and 500 lL water were sealed
2
3
in a tube containing the specified mol% of RuCl and CuBr based on the
b
moles of aniline and agitated for the time specified. Yields based on NMR
internal standard mesitylene. 10 equivalents (900 lL) phenylacetylene
Department of Chemistry, McGill University, 801 Sherbrooke St. West,
Montreal, Quebec, H3A 2K6, Canada. E-mail: cj.li@mcgill.ca; Fax: +1
c
2
used (reaction not strictly neat since 93 lL H O present from the 37 wt%
5
14-3983797; Tel: +1 514-3988457
d
formaldehyde). Solids were sealed in a tube which was subsequently
purged with nitrogen (liquids were degassed together by three freeze–
pump–thaw cycles before transferring to solids under nitrogen by cannula).
†
Electronic supplementary information (ESI) available: Experimen-
tal details and characterizations of all new compounds. See DOI:
0.1039/b613596j
1
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a major side reaction in water, which is enhanced by temperature
substantially more than the desired A -coupling. The exclusion
of oxygen from the reaction did not improve the yield (Table 1,
entry 3) indicating that the Glaser-type alkyne coupling was not
an important side reaction. When the reaction was performed
neat at room temperature, the yield was increased considerably
an aliphatic alkyne instead of phenylacetylene (Table 2, entries 3–
4). The yield, however, was highly dependent upon the nature of the
primary amine used. This substantiates the possibility that imine
stability/hydrolysis is a critical factor influencing the yields. The
linear aliphatic amines used gave the best yields (Table 2, entries 1–
2). However, methyl amine gave the lowest yield (Table 2, entry 9),
which could indicate that all or part of the reaction cycle occurs on
the water surface since the propargyl amine/imine intermediates
as well as methyl amine itself would be more soluble in water
than any of the other corresponding amines/imines. The lower
yield seen with cyclopentylamine (Table 2, entry 7) is likely the
result of steric effects; whereas, allylamine could have undergone
side reactions specific to the alkene functionality. Solid amines
can be used directly even though the system was heterogeneous
for all the reactions (Table 2, entries 5–6). A direct comparison of
para-anisidine and para-toluidine shows that electron donation to
the nitrogen improves the yield. Whether this is due to increased
stability of the imine to hydrolysis is unclear. When formaldehyde
was substituted with benzaldehyde in the reaction shown in
Table 2, entry 3, only the monopropargyl amine coupling product
was observed. Conditions are being optimized to allow for efficient
3
(
Table 1, entries 1–2). This could indicate that even at room
temperature imine hydrolysis is still a problem. The water in
the neat examples comes from the formaldehyde solution, yet
3
the A -coupling becomes more competitive over imine hydrolysis
because there is now almost double the number of equivalents
of alkyne relative to water. Increased temperature under these
pseudo-neat conditions substantially decreased the yield (Table 1,
entry 2). The conditions of entry 7 were used in preference to
the neat conditions since it was not practical to perform the
reaction neat with only 2.2 equivalents of alkyne due to insufficient
mixing/stirring. Increasing the ruthenium catalyst loading to
almost double can give an appreciable increase in yield, but
whether or not this increased expense is worth an increase in yield
of 8% is questionable. Optimum yield was obtained after reacting
between 24–36 h at room temperature (Table 1, entries 6–8), and
therefore lower temperatures were not attempted.
3
double A -couplings using substituted aldehydes.
With optimized conditions (Table 1, entry 7) various substrates
were examined. The yield was only modestly reduced upon using
In conclusion we have developed a highly efficient method to
synthesize a variety of dipropargyl amines under mild conditions.
3
a
Table 2 Synthesis of bis-propargyl amines via [Ru]–[Cu] catalyzed double A -coupling
b
Entry
1
Amine
Alkyne
Product
Yield (%)
84 (82)
2
3
4
5
6
7
8
9
79 (78)
70 (62)
63 (53)
63 (51)
47 (44)
45 (45)
60 (59)
15
PhNH
PhNH
2
2
MeNH
2
a
Conditions used based on entry 7 in Table 1. All reactions were performed at 0.82 mmol scale with 2.2 equiv. alkyne, 2.2 equiv. formaldehyde, 5 mol%
◦
b
3 2
RuCl , 15 mol% CuBr, 500 lL H O, agitated at room temperature (22 C) for 36 h; Yields based on NMR with an internal standard (mesitylene) and
isolated yields after column chromatography (50:1 hexanes : EtOAc) in parentheses.
4
36 | Org. Biomol. Chem., 2007, 5, 435–437
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The scope of the system and the application of the methodology
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Acknowledgements
We are grateful to the Canada Research Chair (Tier I) program
(
to CJL), the CFI, and NSERC for support of our research.
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