Experimental evidence for a [2 + 2] mechanism in the Lewis acid-promoted formation of α,β-unsaturated esters from ethoxyacetylene and aldehydes. Synthesis and characterisation of 4-ethoxyoxetes

Article abstract of DOI:10.1039/a803395a

4-Ethoxy-2H-oxetes 3a-c were prepared from ethoxyacetylene and alkoxy aldehydes 1a-c through MgBr₂-Et₂O promoted [2 + 2] cycloaddition reaction and were characterized at room temperature; their synthesis, which could occur via the formation of a chelate, establishes cycloaddition as the initial step in the formation of α,β-unsaturated esters 4a-c.

Full text of DOI:10.1039/a803395a

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Experimental evidence for a [2 + 2] mechanism in the Lewis acid-promoted
formation of a,b-unsaturated esters from ethoxyacetylene and aldehydes.
Synthesis and characterisation of 4-ethoxyoxetes.
Magali Oblin,a Jean-Luc Parrain,b Michel Rajzmannb and Jean-Marc Pons*a†
a Laboratoire Re´activite´ en Synthe`se Organique (Re´So), UMR 6516, Faculte´ de St-Je´roˆme, boˆıte D12,13397 Marseille Cedex 20,
France
b Laboratoire de Synthe`se Organique, ESA 6009, Faculte´ de St-Je´roˆme, boˆıte D12, F-13397 Marseille Cedex 20, France
4-Ethoxy-2H-oxetes 3a–c were prepared from ethoxyacetyl-
Br
O
Br
O
Br
O
Br
O
Cl
O
Cl
O
OEt
O
R2
R1
R2
R1
ene and alkoxy aldehydes 1a–c through MgBr2–Et2O
promoted [2 + 2] cycloaddition reaction and were charac-
terized at room temperature; their synthesis, which could
occur via the formation of a chelate, establishes cycloaddi-
tion as the initial step in the formation of a,b-unsaturated
esters 4a–c.
Mg
Mg
Mg
(
)
( )
n
n
A
B
C
cycloadduct-chelate B. The rigidity of the chelate structure of B,
i.e. its ‘bicyclic’ structure, under the reaction conditions, could
then prevent the ring opening rearrangement. We have
undertaken ab initio calculations on a model chelate C to
establish that such an intermediate is indeed a minimum on a
potential energy surface. Calculations were run at the HF/
6-31G* level of theory. The total energy of C was found to be
21693.424205 au.
The formation of a,b-unsaturated esters from aldehydes or
ketones and alkoxyacetylenes, under Lewis acid catalysis was
first reported by Vieregge et al. in 1959.1 The reaction
immediately met with success as demonstrated in a review
article published seven years later by the same authors.2 In the
same paper, the authors proposed that the mechanism involves
the formation of an intermediate alkoxyoxete and its con-
rotatory ring-opening to give the corresponding a,b-unsaturated
ester (Scheme 1).
EtO
LA
OEt
LA
OEt
O
O
Lewis Acid
+
R
H
R
R'
R
R'
R'
Scheme 1
The strongest evidence supporting such a mechanism at that
Further support for this explanation was found in the
following experimental results (Table 1). When 2 and 1a react
under BF3–Et2O catalysis, the only product we were able to
observe is a,b-unsaturated ester 4a (Table 1, entry 2). Only
traces of 3a were identified during the monitoring of the
reaction by TLC. The reaction between 2 and 3-(tert-butyldi-
methylsiloxy)tetradecanal 1d (R1 = C11H23; R2 = TBDMS; n
= 1) or hexanal 1e under BF3–Et2O or MgBr2–Et2O catalysis
leads, in all four cases (Table 1, entries 5–8), to the expected
corresponding (E)-unsaturated esters 4d,e. Indeed, in all these
cases, the formation of chelates analogous to chelates A and
time was the isolation by Middleton of an alkoxyoxete resulting
from the non-catalyzed reaction between hexafluoroacetone
and ethoxyacetylene.3 Furthermore this oxete underwent a
rearrangement to yield the corresponding unsaturated ester.
Since then this reaction has attracted many experimental
studies4 and has even found application in synthesis where it
can sometimes be used instead of the Wittig reaction.5
However, to the best of our knowledge, no experimental
evidence of the occurrence of a non-metallated oxete6 in a
Lewis acid catalyzed process has yet been reported. This is
probably due to the instability of oxetes which have been
seldom isolated or characterized.7 Examples of alkoxyoxetes
are also very scarce: in addition to the examples reported by
Middleton3 and Zaitseva et al.,6 two others can be found in the
literature.8,9
As part of an ongoing interest in Lewis acid-promoted [2 + 2]
cycloadditions involving aldehydes,10 we report the observation
and characterization, at room temperature, of 2-ethoxy-
2H-oxetes 3a–c.
3-Benzyloxytetradecanal 1a reacts with ethoxyacetylene 2
under MgBr2–Et2O catalysis in CH2Cl2 to yield after 30 min
2-(2-benzyloxytridecyl)-4-ethoxy-2H-oxete 3a as a 4:1 mix-
ture of diastereomers (Scheme 2, Table 1, entry 1).‡ 4-Ethoxy-
2H-oxetes 3b,c§ were also obtained (both as 9:1 mixtures of
diastereomers) from aldehydes 1b,c and were observed under
the same conditions (Scheme 2, Table 1, entries 3 and 4).
The obtention of oxetes 3a–c could result from the formation
of chelate A11 which then would lead to the ‘bicyclic’
OEt
OEt
OR2
(
O
OR2
(
O
i
+
R1
n
)
R1
H
)
n
H
3a–c (crude)
2
iv or
v (for 1d,e)
1a R1 = C11H23, R2 = Bn, n = 1
b R1 = C11H23, R2 = Me, n = 1
c R1 = C5H11, R2 = Bn, n = 0
d R1 = C11H23, R2 = TBS, n = 1
e hexanal
ii or iii
EtO
OR2
O
R1
(
)
n
4a–e
Scheme 2 Reagents and conditions: i, MgBr2–OEt2 (3 equiv.), CH2Cl2, 15
min, 260 °C; ii, BF3–OEt2 (cal.), CH2Cl2, 1 min, 230 °C; iii, CH2Cl2 or
CDCl3, 2–3 h, room temp.; iv, BF3–OEt2 (1 equiv.), CH2Cl2, 30 min,
260 °C; v, MgBr2–OEt2 (3 equiv.), CH2Cl2, 15 min, 260 °C
Chem. Commun., 1998
1619

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Table 1 Preparation of oxetes 3a–c and esters 4a–e (yields are unoptimized)
from aldehydes 1a–e
–O–CHHb–Ph), 3.89 (1 H, part A of ABX3 system, JAB 9.6, JAX 7.1,
O–CHaH–Me), 3.86 (1 H, part B of ABX3 system, JAB 9.6, JAX 7.0,
O–CHHb–Me), 3.66 (1 H, m, CH–OBn), 1.82 (1 H, part A of ABXY system,
JAB 14.5, JAX 8.7, JAY 3.7, O–CH–CHaH–CH–O), 1.72 (1 H, part B of
ABXY system, JAB 14.5, JAX 7.1, JAY 3.3, O–CH–CHHb–CH–O),
1.88–1.46 (6 H, m), 1.37–1.18 (14 H, m), 0.87 (3 H, t, J 7.0, –Me), 0.85 (3
H, br t, O–CH2–Me); dc (50.3 MHz, CDCl3) 138.3 (s), 138.0 (s), 128.5 (d,
2C), 128.0 (d, 2C), 127.9 (d), 111.8 (d), 77.0 (d), 77.1 (t), 68.7 (t), 68.6 (d),
39.8 (t), 33.4 (t), 32.0 (t), 29.8 (t), 29.7 (t, 2C), 29.6 (t, 2C), 29.4 (t), 25.4 (t),
22.8 (t), 14.2 (q, 2C).
§ 1H and 13C NMR data of 3b,c are similar to those described for 3a.
¶ Oxete 3c was, for example, kept over 2 months in a NMR tube (1H
concentration). We first imagine that the relative stability of Lewis acid-free
3a could result from an intramolecular p-stacking (between the double bond
and the aromatic ring), but both the formation of 3b and semiempirical
(AM1) calculations were in disagreement with such an explanation.
(E)-Ester
Entry Aldehyde
Lewis acid
Oxete (d.r.)
(yield)
1
2
3
4
5
6
7
8
1a
1a
1b
1c
1d
1d
1e
1e
MgBr2–OEt2
BF3–OEt2
MgBr2–OEt2
MgBr2–OEt2
BF3–OEt2
MgBr2–OEt2
BF3–OEt2
MgBr2–OEt2
3a (4:1)
—
3b (9:1)
3c (9:1)
—
—
—
—
4a (88%)
4a (70%)
4b (67%)
4c (75%)
4d (60%)
4d (71%)
4e (56%)
4e (73%)
therefore B is not possible12 and hence the conrotatory ring
opening takes place.
1 H. Vieregge, H. J. T. Bos and J. F. Arens, Recl. Trav. Chim. Pays-Bas,
1959, 78, 664; see also H. Vieregge and J. F. Arens, Recl. Trav. Chim.
Pays-Bays, 1959, 78, 921.
2 H. Vieregge, H. M. Schmidt, J. Renema, H. J. T. Bos and J. F. Arens,
Recl. Trav. Chim Pays-Bas, 1966, 85, 929.
Finally, although 3a–c are stable in CDCl3 solution at
220 °C,¶ their life-time at room temperature does not exceed 1
or 2 h and is a few seconds in solution at 230 °C in the presence
of BF3–Et2O (in all three cases, ring opening leads to esters
4a–c). This last observation gives further support for the
structure of 3a–c and to our hypothesis of the rigidity of chelate
B.
In conclusion, we have provided the first evidence of a [2 +
2] mechanism for the studied reaction. We think that the
isolation of oxetes 3a–c at room temperature rests upon the
formation of stable chelates B which prevents the conrotatory
ring opening step of the reaction. Since the formation of 3a–c
occurs with good diasteroselectivity, studies are currently
underway to use these as intermediates in synthesis.
We are grateful to Dr François Volatron (CNRS-Orsay) for
useful discussions, and to Mrs Roselyne Rosas and Dr Robert
Faure (Universite´ d’Aix-Marseille) for NMR experiments.
3 W. J. Middleton, J. Org. Chem., 1965, 30, 1307.
4 J. Pornet, A. Rayadh and L. Miginiac, Tetrahedron Lett., 1986, 27,
5479; J. Pornet, A. Rayadh and L. Miginiac, Tetrahedron Lett., 1988,
29, 3065; D. Zakarya, A. Rayadh, M. Samih and T. Lakhlifi,
Tetrahedron Lett., 1994, 35, 405; D. Zakarya, A. Rayadh, M. Samih and
T. Lakhlifi, Tetrahedron Lett., 1994, 35, 2345; C. J. Kowalski and S.
Sakdarat, J. Org. Chem., 1990, 55, 1977.
5 D. Crich and J. Z. Crich, Tetrahedron Lett., 1994, 35, 2469.
6 A trimethylgermyloxete resulting from the Lewis acid catalyzed
cyclization of the O-(trimethylgermyl) derivative of 4-ethoxy-1,1,1-tri-
fluoro-2-(trifluoromethyl)but-3-yn-2-ol has been described: G. S.
Zaitseva, L. I. Livantsova, N. A. Orlova, Yu. L. Baukov and I. F.
Lutsenko, Zh. Obshch. Khim., 1982, 52, 2076.
7 L. E. Friedrich and G. B. Schuster, J. Am. Chem. Soc., 1969, 91, 7204;
L. E. Friedrich and G. B. Schuster, J. Am. Chem. Soc., 1971, 93, 4603;
L. E. Friedrich and J. D. Bower, J. Am. Chem. Soc., 1973, 95, 6869; Y.
Kobayashi, Y.Hanzawa, W. Miyashita, J. Kashiwagi, T. Nakano and I.
Kumadaki, J. Am. Chem. Soc., 1979, 101, 6445.
Notes and References
8 Y. I. Baukov, G. S. Zaisteva, L. I. Livanstova, R. A. Bekker and L. A.
Savost’yanova, Zh. Obshch. Khim., 1981, 51, 1304.
† E-mail: jean-marc.pons@reso.u-3mrs.fr
‡ The structure of 3a lies upon extensive 2D homo- and hetero-nuclear 1H
NMR experiments at 400 MHz. Experimental procedure: a solution of 1a
(0.35 mmol; 111 mg) in CH2Cl2 (1 cm3) was added to a suspension of
MgBr2–OEt2 (1.05 mmol; 270 mg) in CH2Cl2 (3 cm3) at 260 °C under
argon. After 15 min, a solution of 2 (0.70 mmol; 49 mg) in CH2Cl2 (2 cm3)
at room temp. was added dropwise to the suspension at 260 °C. TLC
monitoring showed the reaction to be completed (no starting material left)
after 15 min. The reaction mixture was diluted in light petroleum (10 cm3)
and hydrolyzed with ice–water (2 cm3). Filtration and concentration in
vacuo gave 126 mg of crude product; 1H NMR (400 MHz) was used to
establish the presence of 3a as a 4:1 mixture of the two diastereomers. An
increase in the temperature of the reaction mixture, up to 230 °C, prior to
the hydrolysis led to unsaturated ester 4a (88%). Rf (light petroleum–Et2O
= 7:3) 1a:0.5; 3a:0.25; 4a:0.75.
9 D. C. England and C. G. Krespan, J. Org. Chem., 1970, 35, 3312.
10 A. Pommier, J.-M. Pons, P. J. Kocienski and L. Wong, Synthesis, 1994,
1294; A. Pommier, J.-M. Pons and P. J. Kocienski, J. Org. Chem., 1995,
60, 7334; J.-M. Pons, M. Oblin, A. Pommier, M. Rajzmann and D.
Liotard, J. Am. Chem. Soc., 1997, 119, 3333; B. W. Dymock, P. J.
Kocienski and J.-M. Pons, Chem. Commun., 1996, 1053.
11 For X-ray structure and NMR evidence of chelates similar to A, see
G. E. Keck and S. Castellino, J. Am. Chem. Soc., 1986, 108, 3847
(NMR); M. T. Reetz, K. Harmsand and W. Reif, Tetrahedron Lett.,
1988, 29, 5881 (X-ray).
12 It is well known that TBDMS ethers do not give chelates but rather 2:1
complexes with bidentate Lewis acids. G. E. Keck and S. Castellino,
Tetrahedron Lett., 1987, 28, 281. For other examples, see M. Santelli
and J.-M. Pons, in Lewis Acids and Selectivity in Organic Synthesis,
CRC Press, Boca Raton, 1996, ch. 1.
3a: major isomer: dH (400 MHz, CDCl3) 7.35–7.25 (5 H, m, PhH), 5.12
(1 H, d, J 7.9, NCH), 4.60 (1 H, m, CH–O–), 4.59 (1 H, part A of AB system,
JAB 11.9, –O–CHaH–Ph), 4.52 (1 H, part B of AB system, JAB 11.9,
Received in Liverpool, UK, 5th May 1998; 8/03395A
1620
Chem. Commun., 1998