Room temperature lewis base-catalyzed alumination of terminal alkynes

Article abstract of DOI:10.1002/adsc.200900414

An efficient and mild access to mixed dimethylalkynylaluminum reagents has been developed via a direct Lewis base-catalyzed alumination of terminal alkynes by trimethylaluminum. The use of bis(trimethylsilyl)methylamine enables the metalation at room temp

Full text of DOI:10.1002/adsc.200900414

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DOI: 10.1002/adsc.200900414
Room Temperature Lewis Base-Catalyzed Alumination of
Terminal Alkynes
a,b
a
a,
Yuhan Zhou, Thomas Lecourt, and Laurent Micouin *
a
Laboratoire de Chimie Thꢀrapeutique, UMR 8638 associꢀe au CNRS et ꢁ l’Universitꢀ Paris Descartes, Facultꢀ des
Sciences Pharmaceutiques et Biologiques, 4 av de l’Observatoire, 75270 Paris cedex 06, France
Fax : (+33)-1-4329-1403; e-mail: laurent.micouin@parisdescartes.fr
State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian
b
116012, Peopleꢂs Republic of China
Received: June 17, 2009; Revised: August 26, 2009; Published online: October 21, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900414.
Abstract: An efficient and mild access to mixed di-
methylalkynylaluminum reagents has been devel-
oped via a direct Lewis base-catalyzed alumination
of terminal alkynes by trimethylaluminum. The use
of bis(trimethylsilyl)methylamine enables the met-
alation at room temperature with only 1% of cata-
lyst loading.
procedure avoids the experimental difficulties en-
countered with the classical deprotonation-metal ex-
change procedure (use of strong bases, presence of
[
8]
salts or Lewis acid traces…).
With DIBAL, this reaction can be conducted at
08C with 5% of triethylamine, but the presence of
transferable hydrides on the resulting mixed diisobu-
tylalkynides can complicate their reactivity. On the
other hand, mixed dimethylalkynides can be obtained
with trimethylaluminum, but the metalation requires
Keywords: acetylides; alanes; alkynes; Lewis base
catalysis; organoaluminum reagents
1
0% of triethylamine and harsher reaction conditions
6 h at 608C). While a Lewis acid-catalyzed deproto-
nation by a Brønsted base is generally used for the
(
[
9]
generation of nucleophilic alkynides, this terminal
The use of metalated terminal alkynes as nucleophiles alumination is mechanistically different, and involves
[
10]
for transition metal-catalyzed or direct CÀC bond for- a Lewis base-catalyzed process.
In this work, we
[
1]
mation is a well established strategy. Although report that an appropriate choice of the Lewis base
alkali or alkaline earth metal acetylides are popular can lead to a room temperature metalation with re-
reagents known to add to numerous electrophiles, duced amount of catalyst loading. Some insight into
other reactive alkynides such as aluminum acetylides the mechanism of this reaction is also provided.
have been reported to present interesting reactivity
patterns. Their scope in organic synthesis is however minum in the presence of various Lewis bases was
The reaction of phenylacetylene with trimethylalu-
[2]
still under-investigated. One of the reasons may be first investigated. The conversion was estimated by
1
the need for a simpler access to this class of reagents
H NMR experiments. As previously reported, almost
than their preparation from the corresponding lithium full conversion was obtained with 10% of triethyl-
or sodium acetylide, generated under strongly basic
conditions.
ACHTUNGTRENNUNG
While the reaction between a terminal alkyne and more sluggish (entry 2), an 83% conversion being ob-
an organoaluminum reagent usually delivers a com- tained only after 72 h (entry 3). Similar results were
[
3]
plex mixture of metalated species, the same reaction obtained with tributylamine (entries 4–8). The use of
conducted in triethylamine had been reported by MeN(SiMe ) led to a dramatic rate enhancement.
Binger to furnish solely the aluminum acetylide- Thus, full conversion was obtained within 6 h at room
AHCTUNGTRENNUNG
3
2
[
4]
triethyl
ACHTUNGTRENNUNGa mine complex. We have recently shown that temperature with 10% of this silylated base (entry 9),
a similar metalation can occur using only one equiva- and 91% conversion was achieved with only 1% of
[5]
lent or even a sub-stoichiometric amount of triethyl- catalyst after 7 h (entry 10). A longer reaction time
[6]
amine,
dialkylalk
vents with a unique reactivity pattern. This salt-free a slightly reduced conversion (entries 12–14). Mono-
delivering
a stable solution of mixed enables a full conversion (entry 11). This catalyst is
ACHTUNGTRENNUNGy nylaluminum reagents in non-polar sol- active enough to conduct the metalation at 08C, with
[
7]
Adv. Synth. Catal. 2009, 351, 2595 – 2598
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2595

Yuhan Zhou et al.
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Table 1. Lewis base screening for the catalyzed alumination
of phenylacetylene.
Table 2. MeN
kynes and reaction with benzaldehyde.
ACHTUNGTNERNGNU( SiMe ) -catalyzed alumination of terminal al-
3 2
[a]
Entry Catalyst
Load
T
t
Conv.
[b]
[
mol%] [8C] [h] [%]
[
a]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
NEt3
NEt3
NEt3
10
10
10
10
10
10
10
10
10
1
1
1
1
1
10
10
10
10
10
10
10
10
10
60
r.t.
6
7
97
41
Entry
R
Compound
Yield [%]
1
2
3
4
Ph
2a
2b
2c
2d
96
88
93
95
r.t. 72 83
r.t. 39
r.t. 24 58
r.t. 48 74
r.t. 72 83
r.t. 144 97
Pent
n-Pr
t-Bu
N
N
N
N
N
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(n-Bu)
7
3
3
3
3
3
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(n-Bu)
(n-Bu)
(n-Bu)
(n-Bu)
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
[a]
Isolated yield of compounds 2a–d.
MeN
MeN
MeN
MeN
MeN
MeN
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(SiMe )
(SiMe )
(SiMe )
(SiMe )
(SiMe )
(SiMe )
r.t.
r.t.
6
7
99
91
3
2
2
2
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
The exceptional efficiency of MeN ACHTUNGTNERNUNG( SiMe ) in this
3 2
3
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
r.t. 17 100
0
0
0
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
reaction was confirmed by the room temperature
metalation of various alkynes and their reaction in a
standard test alkynylation (Table 2). The use of this
base does not only improve the metalation rate, but
also enables the metalation of 3,3-dimethylbut-1-yne,
a reaction that proved to be difficult with the triethyl-
amine-catalyzed process. The metalation can be con-
ducted with Et Al instead of Me Al, but 24 h are
needed to reach 98% metalation of phenylacetylene
at room temperature.
3
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
17 86
24 92
41 94
3
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
3
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
3
Me NSiMe3
7
7
7
7
7
7
7
7
7
18
11
11
3
15
6
15
5
–
2
N ACHTUNGTRENNUNG( SiMe )
pyridine
NPh3
PhSPh
MeSMe
PPh3
3 3
3
3
Me PPh
The exact reason for the high catalytic activity of
MeN ACHTUNGTRENUNG( SiMe ) is difficult to establish, as the mecha-
2
t-BuNC
3 2
nism of this base-catalyzed alumination is unknown.
A possible transition state involving a tetracoordinat-
ed complex has been proposed by Surtees to explain
the metalation observed by Binger in an excess of
triethylamine, based on the knowledge that terminal
alkynes react more readily with alkali alanates than
the corresponding trialkylalanes (Figure 1, mechanis-
2
4
10
r.t.
7
24
2
2
5
6
Et NO
THF
10
10
r.t.
r.t.
7
7
14
18
3
[
11]
m I).
A pentacoordinated intermediate could also
[
[
a]
General reaction conditions: phenylacetylene (1 equiv.),
AlMe (2M in heptane, 1 equiv,), Lewis base (X mol%).
Determined by integration of the acetylenic proton
H NMR signal in the presence of mesitylene as internal
be involved, in a competitive pathway between a
base-catalyzed deprotonation and a thermodynamical-
ly favoured decoordination of a preformed triethyl-
3
b]
1
standard.
ACHTUNGTRENNUNGs ilylated (entry 15) or trisilylated (entry 16) amines
proved to be much less active, showing that both
steric and electronic properties of the Lewis base
have to be carefully adjusted in this catalytic process.
Other amines such as pyridine (entry 17) or triphenyl-
amine (entry 18) were almost inactive, as were also
aromatic (entry 19) or aliphatic (entry 20) thioethers
or phosphines (entries 21 and 22). tert-Butyl isonitrile
completely inhibited the reaction (entry 23), whereas
a small catalytic activity could be obtained with an N-
heterocyclic carbene (entry 24). An N-oxide
(
entry 25) or THF (entry 26) were poorly active.
Figure 1. Plausible metalation pathways.
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Adv. Synth. Catal. 2009, 351, 2595 – 2598

Room Temperature Lewis Base-Catalyzed Alumination of Terminal Alkynes
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Table 3. Et N-catalyzed alumination of phenylacetylene:
base stoichiometry.
Table 4. Base-catalyzed alumination of phenylacetylene:
competition experiment with hex-2-yne.
3
[a]
[a]
[b]
Entry
Loading [%]
Time [h]
Conv. [%]
Entry
Catalyst
[%, T]
Hex-2-yne
[equiv.]
t
Conv.
[%]
1
2
3
4
5
6
10
30
50
70
90
100
7
7
7
7
7
24
41
54
65
53
41
16
[b]
A
H
U
G
R
N
U
G
A
H
U
G
E
N
N
[h]
1
2
3
4
5
6
7
8
NEt
NEt
NEt
NEt
[10, 60]
[10, 60]
[10, 60]
[10, 60]
0
1
2
5
0
1
2
5
6
6
6
6
7
7
7
7
97
87
86
78
91
60
49
42
3
3
3
3
MeN
MeN
MeN
MeN
ACHTUNGTNERNU(GN SiMe ) [1, r.t.]
3 2
[
a]
Reaction conditions: phenylacetylene (1 equiv.), AlMe3
A
H
U
G
R
N
U
G
3
3
3
2
2
2
(
2M in heptane, 1 equiv.).
Determined by integration of the acetylenic proton
H NMR signal in the presence of mesitylene as internal
A
H
U
G
R
N
U
G
[
b]
A
H
U
G
R
N
U
G
1
[
a]
standard.
Reaction conditions: phenylacetylene (1 equiv.), AlMe
2M in heptane, 1 equiv).
3
(
[b]
Determined by integration of the acetylenic proton
1
H NMR signal in the presence of mesitylene as internal
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
aluminum-alkyne complex (Figure 1, mechanism II),
standard.
[
12]
as proposed by Allen and Lough. Finally, a synergy
between alkyne complexation and aluminum activa-
tion could also explain the efficiency of the metala-
tion step (Figure 1, mechanism III).
Table 5. Base-catalyzed alumination of phenylacetylene:
ratio of AlMe to phenylacetylene.
[a]
3
Some experimental results are noteworthy. First, we
found that this base-catalyzed reaction is faster with
1
0% of Et N than with a stoichiometric amount of cat-
3
alyst. The conversion after 7 h of reaction at room
temperature increases up to 65% with the amount of
triethylamine, but decreases once the Et N/AlMe
Entry
Catalyst
%]
AlMe3/
t
Conv.
[b]
[
alkyne
A[ min]
H
U
G
R
N
U
G
[%]
3
3
ratio exceeds 0.5 (Table 3, entries 1–6). Moreover, a
similar amount of metalated alkyne (41%) is obtained
using 0.1 or 0.9 equivalents of triethylamine, whereas
a stoichiometric amount of the Lewis base dramatical-
ly slows down the metalation process, showing that a
small amount of uncomplexed trimethylaluminum is
needed for a good catalytic activity.
This hypothesis was further investigated using a
competition experiment with an internal alkyne
having a coordinating ability between a terminal
alkyne and triethylamine. A similar inhibitory effect
was indeed observed (Table 4). The conversion de-
creased with the number of equivalents of hex-2-yne,
1
2
3
4
5
6
7
8
NEt [10]
1/1
2/1
3/1
4/1
1/1
2/1
3/1
4/1
30
30
30
30
10
10
10
10
9
3
NEt [10]
14
19
28
5
12
17
21
3
NEt [10]
3
NEt
MeN
MeN(SiMe ) [1]
MeN(SiMe ) [1]
MeN(SiMe ) [1]
[10]
3
AHCTUNGTRENN(GUN SiMe ) [1]
3
2
A
T
N
T
E
N
N
3
2
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
3
2
3
2
[a]
Reaction conditions: phenylacetylene (0.4M, 1 equiv.),
room temperature.
Determined by integration of the acetylenic proton
H NMR signal in the presence of mesitylene as internal
standard.
[b]
1
both in Et N- or MeN ACHTUNGTRNEGNU( SiMe ) -catalyzed metalation,
3
3 2
indicating that coordination of trimethylaluminum to
the terminal alkynes is required in the deprotonation the result of a fine balance between electronic effects
step. (electron-donating groups) favouring complexation
Finally, the reaction rate was also impacted by the and polarization of the AlÀMe bond, and steric ef-
[
13]
amount of AlMe , as outlined in Table 5, with a signif- fects (frontal repulsion) favouring dissociation and/
3
icant metalation rate improvement at low conversion or AlÀMe bond cleavage. It is also interesting to note
correlated with the amount of alane.
that no stable complex between MeN ACHTUNGTNERGUN( SiMe ) and tri-
3 2
These sets of experiments support a mechanism of methylaluminum or mixed aluminum phenylacetylide
type III, involving two molecules of trimethylalumi- could be observed by NMR in heptane, whereas Et N
3
num with ambiphilic reactivities. The high efficiency quantitatively forms stable complexes with both or-
[
14]
of MeN ACHTUNGTRENNUNG( SiMe ) in this deprotonation step might be ganometallic species. This different behaviour could
3 2
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ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2597

Yuhan Zhou et al.
COMMUNICATIONS
in part explain the high turnover frequency obtained
[3] a) E.-I. Negishi, Organometallics of Main Group Metals
in Organic Synthesis, New York, John Wiley, 1980,
p 286; b) G. Zweifel, J. A. Miller, Org. React. 1984, 32,
with MeN ACHTUNGTRENNUNG( SiMe ) .
3 2
In conclusion, we have disclosed the first room tem-
perature catalyzed alumination of terminal alkynes.
This mild procedure enables the preparation of mixed
dialkylaluminum reagents with a low catalyst loading,
using inexpensive and largely available trimethylalu-
minum as a metalating agent. This salt-free procedure
advantageously avoids the use of strong bases (gener-
ally associated with low temperature), and only gener-
ates methane as a side product. Further mechanistic
investigations of this reaction and its use for the prep-
aration of functional organoaluminum reagents are
now in progress.
3
75–517.
[
[
4] P. Binger, Angew. Chem. 1963, 75, 918; Angew. Chem.
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3
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2
007, 72, 4882–4885.
Typical Procedure for the Alumination
[
8] For reported problems with the salt metathesis proce-
dure, see a) J. Kessabi, R. Beaudegnies, P. M. J. Jung, B.
Martin, F. Montel, S. Wendeborn, Synthesis 2008, 655–
The alumination of phenylacetylide is representative. A dry
and argon-flushed flask equipped with a magnetic stirrer
was charged with a commercial trimethylaluminum solution
6
3
59; b) Y.-S. Kwak, E. J. Corey, Org. Lett. 2004, 6,
385–3388; c) R. S. Mattews, D. J. Eickhoff, J. Org.
(
2 mL, 2M in heptane, 4 mmol) (Caution: trimethylalumi-
num is inflammable), MeN(SiMe ) (9 mL, 0.04 mmol) and
AHCTUNGTRENNUNG
3
2
Chem. 1985, 50, 3923- 3925; d) J. D. Rainier, J. M. Cox,
Org. Lett. 2000, 2, 2707–2709.
phenylacetylene (0.4 mL, 4 mmol) were added dropwise.
The reaction mixture was stirred at room temperature for
[
9] D. E. Frantz, R. Fꢄssler, C. S. Tomooka, E. M. Carreira,
Acc. Chem. Res. 2000, 33, 373–381.
10] S. G. Denmark, G. L. Beutner, Angew. Chem. 2008,
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tion can be stored under argon in the darkness for several
days.
[
1
20, 1584–1663; Angew. Chem. Int. Ed. 2008, 47, 1560–
1
638.
[
[
11] J. R. Surtees, Aust. J. Chem. 1965, 18, 14–19.
12] P. E. M. Allen, R. M. Lough, J. Chem. Soc. Faraday
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proposed for the reaction of phenylacetylene with a
stoichiometric complex of triethylamine and triethyl-
Acknowledgements
Financial support from ANR (ANR blanc AluMeth) is ac-
knowledged.
AHCTUNGTRENNGNUa luminum. A mechanism of type I has been proposed
for a tributylamine·triethylaluminum complex. A mech-
anism of type III has not been discussed, as only stoi-
chiometric complexes have been investigated.
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13] For a discussion on frontal repulsion, see: C. H. Hen-
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[
14] See Supporting Information.
2
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2598
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ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 2595 – 2598