EuFOD-catalyzed Hetero-Diels-Alder (HDA) reaction under microwave heating

Article abstract of DOI:10.1055/s-2007-965985

An efficient EuFOD-catalyzed hetero-Diels-Alder reaction between azadienes and aldehydes under microwave irradiation is reported. The reaction proceeds under microwave heating with 5 mol% of EuFOD in 45-83% yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-965985

2060
PRACTICAL SYNTHETIC PROCEDURES
EuFOD-Catalyzed Hetero-Diels–Alder (HDA) Reaction under Microwave
Heating
E
uFO
D
-Catalyzed
H
et
a
ero-Diels–A
u
lde
r
R
eactio
r
n
o Panunzio,*a Elisa Bandini,b Antonio D’Aurizio,b Alessia Millemaggi,a Zhining Xiac
a
ISOF-CNR, Dipartimento Ciamician, Via Selmi 2, 40126 Bologna, Italy
Fax +39(051)2099456; E-mail: mauro.panunzio@unibo.it
b
c
ISOF-CNR, Area Ricerca di Bologna, Via Gobetti 101, 40129 Bologna, Italy
Institute of Chemistry and Chemical Engineering, Chongqing University, Chongqing 400044,
P. R. of China
PSP
Received 2 February 2007
No89
Abstract: An efficient EuFOD-catalyzed hetero-Diels–Alder reaction between azadienes and aldehydes under microwave irradiation is re-
ported. The reaction proceeds under microwave heating with 5 mol% of EuFOD in 45–83% yields.
Key words: azadiene, Diels–Alder reaction, lactams, lanthanides, amino alcohols
Ph
Ph
Ph
H
H
H
N
1
Ph
H
TMSCl, MeCOCl
Et3N
PhCHO, EuFOD (5%)
MW
H
LiHMDS
O
O
+
N
O
TMSO
Ph
N
H
TMS
N
H
Ph
O
O
Ph
2
3
Scheme 1 Preparation of 2,6-diphenyl[1,3]oxazinan-4-ones
Introduction
strata (Scheme 1 and Table 1). As underlined in Table 1,
entry 5, the best conversion of azadiene 1 into HDA ad-
The chemistry of hetero-substituted dienes is rich and var- duct was achieved in chlorobenzene as solvent and Eu-
ied, and has recently been reviewed.1,2 In particular 2-aza- FOD as lanthanide catalyst.
dienes have emerged as reactive dienes which readily
participate in hetero-Diels–Alder (HDA)3–5 reactions with
several types of dienophiles with or without the presence
Table 1 Reaction of Azadiene 1 with Benzaldehyde in Chloroben-
zene at Reflux Using Different Lanthanides
of a Lewis acid as catalyst. Many of the pioneering studies
on this class of compounds were carried out by the groups
of Ghosez6–8 and Barluenga.9–11 As contributions from our
research group we have reported, in the last few years, the
synthesis and applications of 2-aza-3-trialkylsilyloxy-1,3-
dienes for the preparation of biologically active com-
pounds.12 In this paper, we disclose our results on the use
of dielectric heating (DH) in HDA reaction in the pres-
ence of catalytic amount of lanthanides Lewis acid13–16
such as EuFOD and YtFOD, taking advantage of the high-
ly efficient microwave-assisted organic synthesis
(MAOS) technique.17–20
Entry LA
Time Yield cis/transb
Method
CHc
(min) (%)a
1
2
3
EuFOD (5%)
60
30
40
59
78:22
EuCl3 (10%)
traces not determined DHd
traces not determined DH
Eu(Tf)3·10H2O
(10%)
4
5
6
7
EuFOD (1%)
EuFOD (5%)
YtFOD (5%)
Sc(Tf)3 (5%)
40
10
40
30
traces not determined DH
83
47
20
78:22
86:14
69:31
DH
DH
DH
The HDA-cycloadducts thus obtained have been demon-
strated to serve as useful intermediates for the preparation
of 1,3-aminols, scaffolds of a wide range of biologically
active compounds including CNS drugs as Prozac®.21,22
The synthesis of the target compounds was extensively
optimized using azadiene 1 and benzaldehyde as test sub-
a All the yields refer to pure compounds, isolated chromatographically
whose structures have been confirmed by 1H NMR and 13C data.
b The cis/trans ratio was determined by HPLC and 1H NMR on the
crude reaction mixture.
c CH: Convective heating at reflux in chlorobenzene.
d DH: Dielectric heating (Prolabo oven MW power 300 W in chloro-
benzene at reflux).
SYNTHESIS 2007, No. 13, pp 2060–2062
x
x.
x
x
.
2
0
0
7
Advanced online publication: 12.03.2007
DOI: 10.1055/s-2007-965985; Art ID: Z03007SS
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
EuFOD-Catalyzed Hetero-Diels–Alder Reaction
2061
R1
R1
H
H
N
R
H
R1CHO, EuFOD, MW
R
H
TMSCl, MeCOCl
Et3N
LiHMDS
H
O
O
+
N
O
TMSO
R
N
H
R
N
H
O
O
R
TMS
4
5
6
Scheme 2 Preparation of 2,6-disubstituted[1,3]oxazinan-4-ones
Table 2 Reaction of Azadiene 4 with Different Aromatic Aldehydes To Give Cycloadducts 5 and 6
Entry
1
R
R1
LA
Time
8
Yield (%)a
49
cis/transb
Methodc
EuFOD (5%)
54:46
DH
OTIPS
2
3
EuFOD (5%)
EuFOD (5%)
40
40
49
35
80:20
50:50
DH
DH
OMe
OMe
4
5
EuFOD (5%)
YbFOD (5%)
30
30
50
43
75:25
79:21
DH
DH
OMe
OMe
OMe
OMe
6
EuFOD (5%)
40
10
67:33
DH
NO2
a All the yields refer to pure compounds, isolated chromatographically, the structures of which have been confirmed by 1H and 13C NMR data.
b The cis/trans ratio was determined by HPLC and 1H NMR on the crude reaction mixture.
c DH: Dielectric heating (Prolabo oven MW power 300W in chlorobenzene at reflux).
Comments on Table 1
was observed after fast silica gel chromatographic purifi-
cation, as confirmed by H NMR analysis performed on
1
a) Although the formation of the cycloadducts 2 and 3 crude reaction mixtures before the separation procedure,
takes place even under classical heating conditions (CH, but a certain degree of isomerization to the trans form
Table 1, entry 1), as expected better yields and shorter re- takes place on leaving the reaction mixture (78:22 dr) on
action times have been achieved under MAOS conditions. silica gel in the eluting solvent during the course of 2–3
b) Among the Eu catalysts, EuFOD displays the best re- days. Nevertheless this isomerization at C2 stereocenter
sults, probably due to a better solubility in the reaction has been demonstrated 21,22 in all cases, immaterial of the
medium. c) YtFOD is effective as well, but lower yields final goal of the production of 1,3-aminols, scaffolds of
and longer reaction times are noted. d) As far as the for- CNS drugs like Prozac®, and its congeners.
mation of the trans cycloadduct is concerned, we feel that,
Having established a satisfactory protocol for the synthe-
as already reported,22 the reaction is highly stereoselective
sis of HDA adduct by lanthanide catalyst, we turned our
according to a HDA cycloaddition mechanism, but some
attention to extend this procedure to the production of dif-
degree of isomerization may take place in the reaction me-
ferent other substrates to ascertain the feasibility of the de-
dium. It should be noted that in all experiments reported
scribed method (Scheme 2 and Table 2). It was gratifying
in Table 1 no significant change of diastereomeric ratios
Synthesis 2007, No. 13, 2060–2062 © Thieme Stuttgart · New York

2062
M. Panunzio et al.
PRACTICAL SYNTHETIC PROCEDURES
References
to find out that the above reported procedure must be con-
sidered efficient and valuable in view of the possibility to
build up a small library of oxazinan-2-ones, which may in
turn, be elaborated to a 1,3-aminols according to already
published protocols.21,22
(1) Barluenga, J.; Suarez-Sobrino, A.; Lopez, L. A.
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(2) Jayakumar, S.; Ishar, M. P.; Mahajan, M. P. Tetrahedron
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(3) Kobayashi, S.; Jørgensen, K. A. Cycloaddition Reactions in
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(4) Boger, D. L.; Weinreb, S. M. Hetero Diels–Alder
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(5) Boger, D. L. Chemtracts: Org. Chem. 1996, 9, 149.
(6) Sainte, F.; Serckx-Poncin, B.; Ghosez, L. J. Am. Chem. Soc.
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(7) Ghosez, L.; Bayard, P.; Nshimyumukiza, P.; Gouverneur,
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Hetero-Diels–Alder Reaction of Azadienes 1, 4 with Aromatic
Aldehydes; trans-2,6-Diphenyl[1,3]oxazinan-4-one (3) and cis-
2,6-Diphenyl[1,3]oxazinan-4-one (2); Typical Procedure
An oven-dried, 100 mL, three-necked, round-bottomed flask,
equipped with a Teflon-coated magnetic stirring bar, a spirit ther-
mometer and a needle for N2 inlet, was charged with anhyd hexane
(30 mL) and 1 M solution of LiN(SiMe3)2 in THF (6 mL, 6 mmol),
and placed in an ice bath. At 0 °C, benzaldehyde (0.500 mL, 5
mmol) in hexane (2 mL) was added by a dropping funnel and the
mixture was stirred for 1.5 h at 0 °C. A solution of Me3SiCl (0.760
mL, 6 mmol) in hexane (2 mL) was added at 0 °C and the stirring
was maintained for 1 h at r.t. A white precipitate was observed. At
0 °C, were added Et3N (1.390 mL, 10 mmol) in hexane (1 mL) and
AcCl (0.430 mL, 6 mmol) in hexane (2 mL), and the mixture was
stirred for 2 h at r.t. The mixture was filtered through a Celite pad
and the solvent was evaporated. The formation of 3-trimethylsilyl-
(10) Barluenga, J.; Tomas, M.; Ballesteros, A.; Lopez, L. A. J.
Org. Chem. 1991, 56, 5680.
(11) Barluenga, J.; Joglar, J.; Gonzales, A.; Fustero, S.; Kruger,
C.; Tsay, Y.-H. Synthesis 1991, 387.
(12) Panunzio, M.; Vicennati, P. In Recent Research
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683–707.
(13) Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W. L.
Chem. Rev. 2002, 102, 2227.
(14) Steel, P. G. J. Chem. Soc., Perkin Trans. 1 2001, 2727.
(15) Aspinall, H. C. Chem. Rev. 2002, 102, 1807.
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7569.
(17) Kappe, C. O.; Dallinger, D. Nat. Rev. Drug Discovery 2006,
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1
oxy-1-phenyl-1,3-azadiene (1) was controlled by H NMR spec-
troscopy. This product was dissolved in anhyd chlorobenzene (5
mL) and put in a flask for microwave oven synthesis (Prolabo).
Benzaldehyde (0.255 mL, 2.5 mmol) and EuFOD (260 mg, 0.25
mmol) were added and the mixture was submitted to microwave ir-
radiation for 40 min at 300 Watt power. The solvent was evaporated
and the mixture was purified by flash column chromatography on
silica gel eluting with a mixture of EtOAc–cyclohexane (7:3).
trans-2,6-Diphenyl[1,3]oxazinan-4-one (3; 140 mg) and cis-2,6-
diphenyl[1,3]oxazinan-4-one (2; 385 mg) were obtained as white
solids (525 mg, 83% total yield). Spectral data were superimposable
with literature data.21,22
(18) Mavandadi, F.; Pilotti, A. Drug Discovery Today 2006, 11,
165.
(19) De Maria, G. Chem. Today 2006, 24(3), 27.
(20) Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250.
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Martelli, G. Tetrahedron:Asymmetry 2004, 15, 3489.
(22) Panunzio, M.; Tamanini, E.; Bandini, E.; Campana, E.;
D’Aurizio, A.; Vicennati, P. Tetrahedron 2006, 62, 12270.
Acknowledgment
One of us (A.D.) thanks Farchemia (Treviglio) for financial sup-
port. Thanks are due to Mr. G. A. De Giorgi for valuable contribu-
tion.
Synthesis 2007, No. 13, 2060–2062 © Thieme Stuttgart · New York