Trimethylaluminum-assisted alkynylation of nitrones

Article abstract of DOI:10.1016/j.tetlet.2006.12.086

Reaction of nitrones with terminal alkynes occurs in the presence of 1 equiv of trimethylaluminum and leads to the corresponding propargylic hydroxylamines in yields ranging from 49 to 90%.

Full text of DOI:10.1016/j.tetlet.2006.12.086

Tetrahedron Letters 48 (2007) 1457–1459
Trimethylaluminum-assisted alkynylation of nitrones
Tanasri Bunlaksananusorn, Thomas Lecourt and Laurent Micouin*
`
´
´
Laboratoire de Chimie The´rapeutique, UMR 8638 associe´e au CNRS et a l’Universite Rene Descartes,
Faculte´ des Sciences Pharmaceutiques et Biologiques 4, av de l’Observatoire, 75270 Paris cedex 06, France
Received 29 November 2006; accepted 13 December 2006
Available online 16 January 2007
Abstract—Reaction of nitrones with terminal alkynes occurs in the presence of 1 equiv of trimethylaluminum and leads to the
corresponding propargylic hydroxylamines in yields ranging from 49 to 90%.
Ó 2006 Elsevier Ltd. All rights reserved.
Ph
Nitrones are powerful tools in organic synthesis, not
only as 1,3-dipolar reagents in cycloadditions1 or elec-
trophiles toward organometallic compounds,2 but also
in many other reactions, as recently highlighted.3 Dur-
ing our investigations on the preparation and the use
of mixed alkynylaluminum reagents,4 we were surprised
to see that the reactivity of nitrones toward alanes was
almost unknown, despite numerous reports on alumi-
num-based Lewis acid activation of nitrones.5 We report
in this Letter our investigations in this field.
HO
Ph
O
N
Ph
Ph
N
Ph
CH2Cl2
+
r.t., 2 h
89%
Ph
AlMe2
3a
2
1
1.3 equiv.
1 equiv.
Ph
HO
Ph
Ph
N
Ph
Ph
O
iBu2Al
N
Ph
Toluene
r.t., 16 h
86%
+
O
Ph
N
Ph
AliBu2
Ph
3a
Et3N
Preliminary experiments were conducted with nitrone 1
and mixed alane 2 prepared by triethylamine-catalyzed
metalation (Scheme 1).4c These two components reacted
in a fast manner to deliver the corresponding hydroxyl-
amine 3a in an 89% yield.
4
5
1
2 equiv.
1 equiv.
Scheme 1.
More surprisingly, we found that stoichiometric com-
plex 4, generally not reactive with aldehydes or oxazoli-
dines, was also able to react in a similar manner with
nitrone 1. This result could be explained by a complex-
ation shift between complex 4 and intermediate 5, lead-
ing to the final product 3a by an intramolecular delivery
of the alkynyl group. We then realized that nitrone itself
could act as a Lewis base in the metalation step,
enabling a one-pot transformation, as proposed by
(Table 1). Propargylic hydroxylamines 3a–d were
obtained in 48–86% yield after a hydrolytic work-up.
A significant improvement was found by changing the
solvent from toluene to refluxing methylene chloride,
leading to a better solubility of nitrone 1 (and probably
its metallic complexes) under these conditions. Thus, a
wide range of propargylic hydroxylamines were ob-
tained under very simple experimental conditions from
aromatic nitrone 1 (Table 2).7
´
Chavant and Vallee in closely related studies on dialkyl-
zinc-assisted alkynylations.6
In such conditions, the reaction becomes efficient and
general with various nitrones, as exemplified in Table
3. Interestingly, even functional groups possessing a
Lewis base character such as pyridine (Table 1, entry 4
or Table 2, entry 4) or furan (Table 3, entry 5) are well
tolerated, as well as aliphatic (Table 1 or 2, entry 3) or
aromatic (Table 2, entries 5 and 6) halogens.
First experiments were conducted in toluene at 70 °C
with a stoichiometric amount of trimethylaluminum
*
Corresponding author. Tel.: +33 153739751; fax: +33 143291403;
e-mail: Laurent.micouin@univ-paris5.fr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.086

1458
T. Bunlaksananusorn et al. / Tetrahedron Letters 48 (2007) 1457–1459
Table 1. One-pot alkynylation of nitrone 1 in toluene
Table 3. Nitrone variation in one-pot alkynylation
Me3Al
HO
Ph
HO
R
Ph
Me3Al
O
O
R
N
Ph
N
Ph
N
Ph
1 equiv.
N
Ph
1 equiv.
+
+
R
Ph
Toluene, 70 ºC, 7 h
CH2Cl2, Δ
R
3a-d
Ph
1
3a, 6a-d
1.3 equiv.
1 equiv.
1.3 equiv.
1 equiv.
Entry
1
R
Time (h)
Compound
Yielda (%)
88
Entry
1
R
Compound
Yielda (%)
86
Ph
2
7
3a
Ph
3a
2
3
4
5
6a
6b
6c
6d
62
47
90
75
2
3
4
3b
3c
3d
60
48
49
7
4
7
Cl
N
O
a Isolated chemical yield.
a Isolated chemical yield.
Table 2. One-pot alkynylation of nitrone 1 in CH2Cl2
Me3Al
HO
O
R
O
N
Ph
O
Me3Al
N
Ph
Ph
N
Ph
1 equiv.
Me3Al
N
Ph
+
R1
Ph
3a-g
R1
Ph
CH2Cl2, Δ
7
R
8
1
R2
H
1.3 equiv.
1 equiv.
Entry
1
R
Time (h)
Compound
Yielda (%)
88
Me Me
Al
CH4
Ph
Ph
2
4
3a
3b
O
Me
Me
O
N
Al
N
2
3
4
81
64
46
R1
R1
R2
R2
7
5
3c
3d
Cl
N
10
9
Scheme 2.
In conclusion, we have shown in this study that mixed
alkynylalanes readily react with nitrones. Furthermore,
the Lewis basicity of these electrophiles promotes the
in situ metalation of alkynes, enabling a simple one-
pot procedure.8 Once again, the preparation of acetyl-
ides using a widely available, non-toxic metal source
can provide a useful alternative route to reactive acetyl-
ides generally prepared with strongly basic reagents,
and might present an attractive functional group
tolerance.
5
6
5
3e
3f
75
68
Br
I
16
7
8
(CH3)Si
(CH3)Si
16
48
3g
3g
57
70
a Isolated chemical yield.
Although the mechanism of this transformation was not
fully investigated, it might be slightly different from the
one proposed for the dialkylzinc-assisted alkynylation
(Scheme 2). Only 0.2 equiv of dialkylzinc is indeed
required for the transformation of 1 equiv of nitrone,6e
whereas all attempts to perform our reaction with less
than 1 equiv of trimethylaluminum led to a significant
decrease of a chemical yield.
Acknowledgments
T.B. thanks the Alexander von Humboldt Foundation
for a Feodor Lynen Research Fellowship.
Supplementary data
Thus, the initial complexation of trimethylaluminum by
the nitrone activates the metalation of the alkyne and
leads, probably in an intramolecular way, to the meta-
lated hydroxylamine 10, which is not able to enter a cat-
alytic metalation–alkynylation process, as proposed
with dialkylzinc. This compound is however, probably
able to release some trimethylaluminum by dispropor-
tionation since nitrone 3a was isolated in a 49% yield
when alkynylation was conducted with 1 in the presence
of only 0.4 equiv of trimethylaluminum.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.tetlet.2006.12.086.
References and notes
1. Gothelf, K. V.; Jorgensen, K. A. Chem. Rev. 1998, 98, 863–
909.

T. Bunlaksananusorn et al. / Tetrahedron Letters 48 (2007) 1457–1459
1459
2. Merino, P. C.R. Chimie 2005, 8, 775–788.
3. Cardona, F.; Goti, A. Angew. Chem., Int. Ed. 2005, 44,
7832–7835.
7. Typical procedure: The preparation of 3a is representative.
A dry and argon-flushed flask equipped with a magnetic
stirrer and condenser was charged with N-benzylidene-
benzylamine N-oxide (0.22 g, 1 mmol) and phenylacetylene
(0.14 mL, 1.3 mmol) in distilled CH2Cl2 (1.5 mL), and
AlMe3 (0.5 mL, 1 mmol, 2 M in toluene) was added
dropwise. The reaction mixture was refluxed, until the gas
evolution ceased. A 2 M aqueous solution of Rochelle’s salt
(4 mL) was added and stirred for 1 h at rt, and extracted
with CH2Cl2. The combined organic layers were washed
with brine, dried over MgSO4, and concentrated in vacuo.
Purification by flash chromatography (5% EtOAc in
cyclohexane) yielded 3a (0.275 g, 88%) as a white solid.
N-Benzyl-N-(1,3-diphenyl-prop-2-ynyl)-hydroxylamine (3a):
1H NMR (300 MHz, CDCl3) d (ppm) 7.70–7.58 (m, 4H),
7.50–7.26 (m, 11H), 6.14 (br s, 1H), 4.86 (s, 1H), 4.03 and
3.85 (2d, JAB = 12 Hz, 2H). 13C NMR (75 MHz, CDCl3) d
(ppm) 137.4, 137.1, 132.0, 129.8, 129.0, 128.4, 128.2, 127.6,
122.9, 88.7, 84.6, 62.9, 60.4.
4. (a) Wang, B.; Bonin, M.; Micouin, L. J. Org. Chem. 2005,
70, 6126–6128; (b) Wang, B.; Bonin, M.; Micouin, L. Org.
Lett. 2004, 6, 3481–3484; (c) Feuvrie, C.; Blanchet, J.;
Bonin, M.; Micouin, L. Org. Lett. 2004, 6, 2333–2336; (d)
Blanchet, J.; Bonin, M.; Micouin, L.; Husson, H.-P. Eur.
J. Org. Chem. 2002, 2598–2602; (e) Blanchet, J.; Bonin,
M.; Micouin, L.; Husson, H.-P. Tetrahedron Lett. 2001,
42, 3171–3173; (f) Blanchet, J.; Bonin, M.; Micouin, L.;
Husson, H.-P. J. Org. Chem. 2000, 65, 6423–6426; (g)
Blanchet, J.; Bonin, M.; Chiaroni, A.; Micouin, L.; Riche,
C.; Husson, H.-P. Tetrahedron Lett. 1999, 40, 2935–
2938.
5. (a) Merino, P.; Jimenez, P.; Tejero, T. J. Org. Chem. 2006,
71, 4685–4688; (b) Dondoni, A.; Junquera, F.; Merchan, F.
L.; Merino, P.; Schermann, M.-C.; Tejero, T. J. Org. Chem.
1997, 62, 5484–5496, and Ref. 1.
6. (a) Pernet-Poil, A.; Cantagrel, F.; Le Jeune, K.; Philouze,
C.; Chavant, P. Y. Tetrahedron: Asymmetry 2006, 17, 1969–
1974; (b) Cantagrel, F.; Pinet, S.; Gimbert, Y.; Chavant, P.
Y. Eur. J. Org. Chem. 2005, 2694–2701; (c) Pandya, S. U.;
8. This one-pot procedure is mechanistically different from the
well established Carreira’s method, which is based on an
in situ metal-assisted deprotonation of alkyne by an organic
base, whereas this work is based on an organic base-assisted
metalation of alkyne by a Lewis acid. For mechanistic
details of the Carreira’s procedure, see: Fa¨ssler, R.;
Tomooka, C. S.; Frantz, D. E.; Carreira, E. M. Proc.
Nat. Acad. Sci. U.S.A. 2004, 101, 5843–5845, and references
cited.
´
Pinet, S.; Chavant, P. Y.; Vallee, Y. Eur. J. Org. Chem.
2003, 3621–3627; (d) Patel, S. K.; Py, S.; Pandya, S. U.;
´
Chavant, P. Y.; Vallee, Y. Tetrahedron: Asymmetry 2003,
14, 525–528; (e) Pinet, S.; Pandya, S. U.; Chavant, P. Y.;
´
Ayling, A.; Vallee, Y. Org. Lett. 2002, 4, 1463–1466.