Solid-phase synthesis of dihydropyrans by Eu(fod)3-catalysed [4+2] heterocycloaddition of vinyl ethers with benzylidenepyruvic acid esters. Comparison with conventional homogeneous liquid phase conditions

Article abstract of DOI:10.1002/(SICI)1099-0690(200002)2000:4<639::AID-EJOC639>3.0.CO;2-6

The OH groups of Wang resin were esterified with benzylidenepyruvic acid (1) to give the immobilized 1-oxabutadiene 2. The latter reacted with vinyl ethers 3a-h (dienophiles) in the presence of Eu(fod)₃, and the resulting adducts 4a-h underwent reductive cleavage with LiAlH₄ to afford the dihydropyrans 5a-h in high (62 to 100%) overall yields. A similar sequence carried out under conventional homogeneous liquid phase conditions led to significantly lower yields. The endo/exo selectivity of the cycloaddition reaction was the same in both cases.

Full text of DOI:10.1002/(SICI)1099-0690(200002)2000:4<639::AID-EJOC639>3.0.CO;2-6

FULL PAPER
Solid-Phase Synthesis of Dihydropyrans by Eu(fod)3-Catalysed [4؉2]
Heterocycloaddition of Vinyl Ethers with Benzylidenepyruvic Acid Esters.
Comparison with Conventional Homogeneous Liquid Phase Conditions
[a]
[a]
[a]
´
Stephane Leconte, Gilles Dujardin,* and Eric Brown*
Keywords: Solid phase synthesis / Wang resin / Hetero Diels–Alder reactions / Dihydropyrans / Reductive cleavage
The OH groups of Wang resin were esterified with benzylid-
dropyrans 5a–h in high (62 to 100%) overall yields. A similar
enepyruvic acid (1) to give the immobilized 1-oxabutadiene
sequence carried out under conventional homogeneous li-
2. The latter reacted with vinyl ethers 3a–h (dienophiles) in quid phase conditions led to significantly lower yields. The
the presence of Eu(fod)3, and the resulting adducts 4a–h un-
endo/exo selectivity of the cycloaddition reaction was the
derwent reductive cleavage with LiAlH4 to afford the dihy-
same in both cases.
Introduction
from vinyl ethers of primary and secondary alcohols), with
endo/exo ratios ranging from 94:6 to Ͼ97:3.
In view of developing combinatorial chemistry, which is
expected to become a powerful tool for accelerating the dis-
covery of useful new drugs, in recent years a growing num-
ber of organic reactions have been carried out with reac-
tants linked to insoluble polymeric carriers. Accordingly, a
few examples of Diels–Alder and hetero Diels–Alder reac-
tions performed under such heterogeneous conditions have
been reported.[1]
We describe herein the Eu(fod)3-catalyzed [4ϩ2] hetero-
cycloadditions of various soluble electron-rich dienophiles
with an insoluble carrier-bound 1-oxabutadiene (2) obtai-
ned by esterification of the free OH groups of Wang resin
with benzylidenepyruvic acid 1 in the presence of diisopro-
pylcarbodiimide (DIC)/DMAP (Scheme 1). Completion of
this anchoring reaction was ascertained by subsequent Li-
AlH4 reduction which afforded the diol 6 in quantitative
yield. The supported heterodiene 2 was treated with the die-
nophilic vinyl ethers 3a–h in the presence of a catalytic
amount (5 mol-%) of Eu(fod)3 in refluxing dichlorome-
thane. Reductive cleavage of the expected supported hetero-
cycloadducts 4a–h was then smoothly achieved by means of
LiAlH4 in ether/THF at 20 °C followed by mild hydrolysis
with aqueous Na2SO4, and gave high overall yields[2] of epi-
meric mixtures of the primary allylic alcohols endo-5a–h
(major epimer) and exo-5a–h (Table ). The products were
found to be practically free of impurities, as evidenced from
Scheme 1
1
the H- and 13C-NMR spectra. When this three-step solid-
phase sequence was conducted without any Eu(fod)3 cata-
lyst in the second step, diol 6 was obtained as the sole pro-
duct, which shows the failure of such uncatalyzed hetero-
cycloaddition under solid-phase conditions. Another stri-
king feature, readily demonstrated by the results in Table 1,
is that the solid-phase cycloaddition is very endo-selective,
particularly so in the case of the adducts 5a–c,e (obtained
The syntheses of the adducts 5a–h were then carried out
under conventional liquid phase conditions, as previously
[3]
described. Thus, the Eu(fod)3-catalyzed heterocycloaddi-
tion of methyl benzylidenepyruvate 7 with the vinyl ethers
3a–h in dichloromethane gave the epimeric adducts 8a–h,
which were in turn reduced to the allylic alcohols 5a–h by
means of LiAlH4 in ether at room temperature. The results
are displayed in Table 1. It appears that the endo/exo selecti-
vity is almost the same both under solid-phase and under
homogeneous liquid-phase conditions. With the exception
[a]
`
´
Laboratoire de Synthese Organique, (ESA 6011), Faculte des
Sciences,
Avenue Olivier Messiaen, F-72085 Le Mans Cedex 9, France
Eur. J. Org. Chem. 2000, 639Ϫ643
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0204Ϫ0639 $ 17.50ϩ.50/0
639

S. Leconte, G. Dujardin, E. Brown
FULL PAPER
of the β-naphthyl adduct 5g, it can be seen that the overall owing to the bulkiness of both possible endo-directing
yields are substantially higher under solid-phase syntheses groups. Some support for this phenomenon was already gi-
than under conventional homogeneous conditions. Yield incre- ven above in the case of the β-naphthyl vinyl ether 3g
ase is particularly striking in the case of the adduct 5h (yield (Table 2).
is 22% in liquid phase and 86% in solid phase conditions).
Table 1. Syntheses of dihydropyrans 5a–h
Conclusion
Solid phase synthesis
Liquid phase synthesis
The present study shows that the solid phase Eu(fod)3-
catalysed [4ϩ2] heterocycloaddition of simple vinyl ethers
may have advantages over the conventional homogeneous
liquid-phase syntheses in terms of overall yields. However,
the rather low ‘‘capacity’’ of the Wang resin is a drawback
which cannot be neglected. For this reason, we are currently
investigating other types of insoluble carriers which bear
larger amounts of reactive OH groups than the Wang resin.
From a more general point of view, our present results
exemplify the efficiency of LiAlH4 as reductive cleavage re-
agent of ester linkages. Indeed, the overall sequence is fully
compatible with clean preparations of sensitive products.[4]
overall yield (%) endo/exo ratio overall yield (%)endo/exo ratio
5a
5b
5c
5d
5e
5f
100
92
Ͼ 97:3
96:4
Ͼ97:3
74:26
94:6
80:20
74:26
–
87
61
47
70
57
79
77
22
Ͼ 97:3
96:4
Ͼ97:3
75:25
96:4
80:20
80:20
–
100
92
82
100
62
5g
5h
86
We next considered applying the above reaction schemes
to other types of dienophiles of somewhat lower reactivity,
such as the styrenes 9, 10, and the O-silyl vinyl ether 11.
Starting from methyl benzylidenepyruvate 7, the epimeric
endo/exo adducts 15–17 were obtained by LiAlH4 reduction
of the intermediate ester adducts 12–14 (Scheme 2). Solid
phase synthesis of 15–17 was then carried out as described
above for the adducts 5a–h.
Experimental Section
General: IR: Nicolet 5DX and Genesis (Mattson). – NMR: Bruker
1
AC 400 (400 MHz for H; 100 MHz for 13C). CDCl3 was used as
solvent and TMS as internal standard. – High resolution mass
spectra were performed on a Varian MAT311 at the C.R.M.P.O.
(Rennes).
General Experimental Procedure for Solid-Phase Syntheses: A solu-
tion of DIC (3 equiv.) in DMF (10 mL) was added at 0 °C to a
suspension of commercial Wang resin (1 g; 0.8–1.1 mmol of OH
groups; 1 equiv.) in a solution of benzylidenepyruvic acid 1 (3
equiv.) and DMAP (0.3 equiv.) in DMF (10 mL). After shaking for
1 h at 0 °C and 17 h at 20 °C, the mixture was filtered. The recove-
red resin was washed successively with CH2Cl2 (twice), petroleum
ether, ether, acetone, CH2Cl2 (twice), and was dried at 20 °C. The
resin was next suspended in a solution of the requisite vinyl ether
(3a–h), Eu(fod)3 (5.5 10–2 mmol) in CH2Cl2 (10 mL) and the resul-
ting mixture refluxed for 2 days with shaking. The resin was washed
with CH2Cl2 (twice) and ether (twice). The dried resin was then
added to a solution of LiAlH4 (1 molar equiv.) in ether at 0 °C.
After 1 h at 0 °C and 17 h at 20 °C, the reaction medium was
hydrolyzed with saturated aqueous Na2SO4 (160 µL) and filtered
through Celite. The solid was washed with CH2Cl2 and the combi-
ned filtrates evaporated under reduced pressure to afford the unsta-
ble dihydropyrans 5a–h, which were then analyzed by 1H- and 13C-
NMR spectroscopy.
Scheme 2
The results displayed in Table 2 show that in these cases,
and contrary to our observations when the vinyl ethers
3a–h were used as dienophiles, the yields of the adducts 15–
17 are much lower under solid phase conditions compared
with those obtained by homogeneous liquid phase synthe-
ses. The lack of reactivity of styrenic dienophiles 9, 10 un-
der solid-phase conditions might be due to unfavorable in-
teractions in the endo-transition state between the aromatic
nucleus and the matrix of the insoluble conjugate 2. In the
case of the silyl enol ether 11, steric hindrance might restrict
Methyl
2-Ethoxy-4-phenyl-3,4-dihydro-2H-pyran-6-carboxylate
(8a):[5] – A Typical Procedure for the Homogeneous Syntheses of the
the formation of adducts 17 under solid phase conditions, Adducts 8a–g: Ethyl vinyl ether 3a (530 µL; 5 mmol) and the cata-
Table 2. Syntheses of dihydropyrans 15–17
Compounds
Solid phase synthesis
Liquid phase synthesis
overall yield (%)
endo/exo ratio
overall yield (%)
endo/exo ratio
Ͼ 97:3
15
16
17
12
4
Ͼ 97:3
–
97
63
76
Ͼ 97:3
24
68:32
75:25
640
Eur. J. Org. Chem. 2000, 639Ϫ643

Dihydropyrans by Eu(fod)3-Catalysed [4ϩ2] Heterocycloaddition
FULL PAPER
lyst Eu(fod)3 (0.055 g, 5% molar) were added to a solution of me-
thyl benzylidenepyruvate 7[3a] (0.190 g, 1.0 mmol) in CH2Cl2
(5 mL) contained in a 10 mL flask equipped with a reflux conden-
ser and a silica gel drying tube. The mixture was refluxed for 48 h,
the solvent evaporated and the residue chromatographed on silica
gel (ratio 40:1, eluent cyclohexane/AcOEt 90:10) to afford the ad-
duct 8a[5] (0.255 g, 0.97 mmol; 97%), endo/exo ratio Ͼ99:1.
Methyl 3,4-Dihydro-2-methoxy-2(2-naphthyl)-4-phenyl-2H-pyran-6-
carboxylate (8g): From 3g and 7, oil (98%). endo/exo ratio 80:20. –
IR (film): ν˜ ϭ 1731 cm–1, 1681, 1650. –1H NMR (CDCl3): endo-
8g, δ ϭ 2.38 (dd, J ϭ 8.0, 13.5 Hz, 1 H), 2.56 (dd, J ϭ 7.0, 14.0 Hz,
1 H), 3.16 (s, 3 H), 3.31 (ddd, J ϭ 3.3, 7.0, 8.0 Hz, 1 H), 3.91 (s, 3
H), 6.28 (d, J ϭ 3.1 Hz, 1 H) 7.20–8.50 (m, 12 H); exo-8g, δ 1.80
(dd, J ϭ 12.4, 13.5 Hz, 1 H), 2.53 (ddd; J ϭ 1.5, 6.2, 13.6 Hz, 1
H), 3.19 (s, 3 H), 3.89 (s, 3 H), 4.01 (ddd, J ϭ 2.6, 6.1, 12.2 Hz, 1
H), 6.39 (t, J ϭ 1.8 Hz, 1 H), 7.20–8.15 (m, 12 H). – 13C NMR
(CDCl3): endo-8g, δ ϭ 36.8, 41.2, 50.3, 52.3, 103.0, 115.2, 123.6,
126.0, 126.3, 126.5, 126.7, 127.8, 128.0, 128.4, 128.5, 128.6, 129.5,
130.2, 132.9, 133.2, 136.5, 142.3, 142.9, 163.2; exo-8g: δ ϭ 36.3,
42.8, 50.6, 52.2, 101.4, 116.4, 123.7, 125.9, 126.2, 126.4, 126.8,
127.5, 128.2, 128.4, 128.7, 133.1, 133.2, 137.3, 141.1, 142.7, 163.4. –
MSHR: calcd. for Mϩ: 374.1518 (C24H22O4), found 374.1515.
Methyl 2-Isobutoxy-3,4-dihydro-4-phenyl-2H-pyran-6-carboxylate
(8b): From 3b and 7, oil (99%). endo/exo ratio 98:2. – IR (film):
1
ν˜ ϭ 1737 cm–1, 1643. – H NMR (CDCl3): δ ϭ 0.89 (broad d, J ϭ
6.6 Hz, 3 H), 0.90 (d, J ϭ 6.5 Hz, 3 H), 1.90 (m, 1 H), 2.07 (ddd,
J ϭ 7.5, 8.3, 13.7 Hz, 1 H), 2.37 (ddd, J ϭ 1.5, 7.2, 13.7 Hz, 1 H),
3.34 (dd, J ϭ 6.8, 9.1 Hz, 1 H), 3.76 (dt, J ϭ 3.1, 8.3 Hz, 1 H),
3.84 (s, 3 H), 3.88 (dd, J ϭ 6.5, 9.1 Hz, 1 H), 5.35 (d, J ϭ 6.4 Hz,
1 H), 6.29 (d, J ϭ 2.9 Hz, 1 H), 7.21–7.33 (m, 5 H). – 13C NMR
(CDCl3): δ ϭ 19.2, 19.3, 28.5, 35.9, 37.5, 52 .2, 76.2, 100.6, 114.5,
126.7, 127.6, 128.6, 142.6, 143.0, 163.6. – MSHR: calcd. for Mϩ
290.1518 (C17H22O4), found 290.1506.
Methyl 2,2-Bis(ethoxy)-3,4-dihydro-4-phenyl-2H-pyran-6-carboxy-
late (8h): From 3h and 7, oil (64%). – IR (film): ν˜ ϭ 1731 cm–1,
1648. – 1H NMR (CDCl3) δ ϭ 1.20, 1.24 (2t, J ϭ 7.1 Hz, 6 H),
1.86 (dd, J ϭ 12.0, 13.1 Hz, 1 H), 2.38 (ddd, J ϭ 1.3, 6.5, 13.2 Hz,
1 H), 3.67 (dq, J ϭ 6.8, 7.0 Hz, 2 H), 3.69 (dq, J ϭ 7.0, 9.8 Hz, 2
H), 3.78 (m, 1 H), 3.82 (s, 3 H), 6.22 (dd, J ϭ 1.4, 2.2 Hz, 1 H),
7.22–7.91 (m, 5 H). – 13C NMR (CDCl3): δ ϭ 15.0, 15.2, 36.4,
37.9, 52.2, 56.9, 58.8, 113.2, 115.5, 126.9, 127.5, 128.7, 129.0, 129.1,
141.6, 142.5, 162.8. – C17H22O5 calcd. C 66.65, H 7.24 found C
66.35, H 7.09.
Methyl 2-cyclohexyloxy-3,4-dihydro-4-phenyl-2H-pyran-6-carboxy-
late (8c): From 3c and 7, oil (99%). endo/exo ratio Ͼ 97:3. – IR
1
(film): ν˜ ϭ 1733 cm–1, 1643. – H NMR (CDCl3): δ ϭ 1.20–2.10
(m, 11 H); 2.28 (dd, J ϭ 7.4, 13.7 Hz, 1 H), 3.74 (ddd, J ϭ 3.1,
7.1, 8.9 Hz, 1 H), 3.82 (s, 3 H); 3.86 (m, 1 H), 5.36 (d, J ϭ 7.2 Hz,
1 H), 6.18 (d, J ϭ 2.7 Hz, 1 H), 7.20–7.35 (m, 5 H). – 13C NMR
(CDCl3): δ ϭ 23.1, 23.2, 24.9, 31.0, 32.7, 35.8, 37.1, 51.5, 97.5,
113.7, 126.0, 126.8, 127.8, 141.9, 142.3, 162.8.
Methyl 3,4-Dihydro-2-(4-methoxyphenyl)-4-phenyl-2H-pyran-6-car-
boxylate (12): From 7 and 9, solid (98%), m.p. 116 °C (Et2O). en-
Methyl 2-tert-Butoxy-3,4-dihydro-4-phenyl-2H-pyran-6-carboxylate
(8d): From 3d and 7, oil (97%). endo/exo ratio 77:23. – IR (film):
1
do/exo ratio 100:0. – IR (film): ν˜ ϭ 1716 cm–1, 1653. – H NMR
1
(CDCl3) δ ϭ 1.98 (dt, J ϭ 11.4, 13.8 Hz, 1 H), 2.34 (ddt, J ϭ 1.2,
6.4, 13.8 Hz, 1 H), 3.79 (s, 3 H), 3.83 (s, 3 H), 3.86 (m, 1 H), 5.06
(dd, J ϭ 1.2, 11.4 Hz, 1 H), 6.25 (t, J ϭ 1.2 Hz, 1 H), 6.88 (d, J ϭ
8.7 Hz, 2 H), 7.20–7.40 (m, 7 H). – 13C NMR (CDCl3): δ ϭ 39.4,
39.7, 52.3, 55.3, 78.7, 113.9, 114.3, 126.9, 127.2, 127.6, 128.8, 132.4,
143.2, 145.2, 159.5, 163.4. – MSHR: calcd. for Mϩ: 324.1361
(C20H20O4), found 324.1367. – C20H20O4 calcd. C 74.05, H 6.20,
found C 74.01, H 6.36.
ν˜ ϭ 1735 cm–1, 1643. – H NMR (CDCl3): endo-8d, δ ϭ 1.31 (s, 9
H), 1.97 (ddd, J ϭ 8.4, 9.4, 13.4 Hz, 1 H), 2.19 (dddd, J ϭ 1.1, 1.9,
7.0, 13.4 Hz, 1 H), 3.75 (ddd, J ϭ 2.9, 7.0, 12.8 Hz, 1 H), 3.80 (s,
3 H), 5.38 (dd, J ϭ 1.9, 8.3 Hz, 1 H), 6.13 (dd, J ϭ 1.0, 2.9 Hz, 1
H), 7.19–7.34 (m, 5 H); exo-8d, δ ϭ 1.33 (s, 9 H), 1.82 (dd, J ϭ
2.5, 11.5 Hz, 1 H), 2.07 (m, 1 H), 3.80 (s, 3 H), 3.83 (m, 1 H), 5.65
(s, 1 H), 6.25 (dd, J ϭ 1.5, 2.5 Hz, 1 H), 7.19–7.34 (m, 5 H). – 13C
NMR (CDCl3): endo-8d, δ ϭ 28.7, 37.4, 38.3, 52.1, 95.0, 113.9,
126.6, 127.4, 128.5, 142.8, 142.9, 163.3; exo-8d, δ ϭ26.9, 34.1, 36.1,
52.1, 92.1, 115.2, 126.7, 127.6, 128.6, 140.9, 143.6, 163.7. – MSHR:
calcd. for Mϩ: 290.1518 (C17H22O4), found 290.1506.
Methyl 3,4-Dihydro-2-(2-naphthyl)-4-phenyl-2H-pyran-6-carboxy-
late (13): From 7 and 10, oil (91%). endo/exo ratio Ͼ97:3. – IR
(film): ν˜ ϭ 1729 cm–1, 1643. – 1H NMR (CDCl3): endo-13, δ ϭ
2.05 (dt, J ϭ 11.5, 13.8 Hz, 1 H), 2.46 (tdd, J ϭ 1.8, 6.4, 13.8 Hz,
1 H), 3.85 (s, 3 H), 3.91 (m, 1 H), 5.26 (dd, J ϭ 1.8, 11.4 Hz, 1 H),
6.27 (t, J ϭ 1.9 Hz, 1 H), 7.20–7.90 (m, 12 H); exo-13, δ ϭ 2.19
(m, 1 H), 2.42 (m, 1 H), 3.80 (m, 1 H), 3.87 (s, 3 H), 5.16 (dd, J ϭ
2.6, 9.3 Hz, 1 H), 6.30 (dd, J ϭ 1.2, 5.1 Hz, 1 H), 7.24–7.89 (m, 12
H). – 13C NMR (CDCl3): endo-13, δ ϭ 39.4, 39.6, 52.3, 79.0, 114.6,
124.0, 125.2, 126.0, 126.1, 126.9, 127.2, 127.6, 128.0, 128.3, 128.7,
129.0, 129.1, 133.1, 133.2, 137.6, 142.9, 145.1, 163.4; exo-13, δ ϭ
36.2, 37.3, 52.3, 74.5, 112.4, 123.7–133.2, 137.7, 142.9, 143.9, 144.8,
163.3. – MSHR: calcd. for Mϩ: 344.1423 (C23H20O3), found
344.1422.
Methyl 3,4-Dihydro-2-(4-hydroxybutoxy)-4-phenyl-2H-pyran-6-car-
boxylate (8e): From 3e and 7, oil (84%). endo/exo ratio 87:13. – IR
(film): ν˜ ϭ 3339 cm–1, 1729. – 1H NMR (CDCl3): endo-8e, δ ϭ
1.64 (m, 4 H), 1.84 (s, 1 H), 1.99 (ddd, J ϭ 7.8, 8.8, 13.6 Hz, 1 H),
2.30 (m, 1 H), 3.62 (m, 3 H), 3.72 (ddd, J ϭ 3.1, 7.1, 8.9 Hz, 1 H),
3.81 (s, 3 H), 4.01 (dt, J ϭ 5.8, 9.7 Hz, 1 H), 5.15 (dd, J ϭ 2.1,
7.6 Hz, 1 H), 6.17 (dd, J ϭ 1.0, 2.6 Hz, 1 H), 7.15–7.32 (m, 5 H). –
13C NMR (CDCl3): endo-8e, δ ϭ 26.1, 29.4, 35.8, 37.4, 52.2, 62.5,
69.2, 100.1, 114.4, 126.8, 127.4, 128.5, 142.1, 142.7, 163.1; exo-8e,
δ ϭ25.1, 26.8, 35.7, 37.5, 52.2, 64.9, 68.5, 99.9, 114.2, 126.8, 127.5,
128.7, 142.1, 142.7, 162.9.
Methyl 3,4-Dihydro-2-methoxy-2-methyl-4-phenyl-2H-pyran-6-car-
boxylate (8f): From 3f and 7, oil (92%). endo/exo ratio 80:20. – IR
(film): ν˜ ϭ 1724 cm–1, 1650. – 1H NMR (CDCl3): endo-8f, δ ϭ 1.51
(s, 3 H), 2.09 (d, J ϭ 7.3 Hz, 2 H), 3.30 (s, 3 H), 3.63 (dt, J ϭ 3.3,
Methyl 2-(tert-Butyldimethylsiloxy)-3,4-dihydro-2-(2-naphthyl)-4-
phenyl-2H-pyran-6-carboxylate (14): From 7 and 11, oil (96%). en-
1
do/exo ratio 75:25. – IR (film): ν˜ ϭ 1734 cm–1, 1649. – H NMR
(CDCl3): endo-14, δ ϭ –0.32 (s, 3 H), –0.03 (s, 3 H), 0.92 (s, 9 H),
7.3 Hz, 1 H), 3.83 (s, 3 H), 6.24 (d, J ϭ 3.2 Hz, 1 H), 7.21–7.33 1.65 (dd, J ϭ 12.8, 13.0 Hz, 1 H), 2.51 (ddd, J ϭ 1.7, 5.6, 13.3 Hz,
(m, 5 H); exo-8f, δ ϭ 1.56 (s, 3 H), 2.20 (m, 2 H), 3.35 (s, 3 H),
3.77 (m, 1 H), 3.81 (s, 3 H), 6.24 (d, J ϭ 3.2 Hz, 1 H), 7.21–7.33
(m, 5 H). 13C NMR (CDCl3): endo-8f, δ ϭ 22.2, 37.2, 38.9, 49.1,
1 H), 3.88 (s, 3 H), 3.95 (ddd, J ϭ 2.2, 5.6, 12.3 Hz, 1 H), 6.37
(broad t, J ϭ 1.8 Hz, 1 H), 7.13–8.47 (m, 12 H); exo-14, δ ϭ –0.16
(s, 3 H), –0.15 (s, 3 H), 0.82 (s, 9 H), 2.21 (dd, J ϭ 11.4, 13.5 Hz,
52.2, 101.2, 113.6, 126.6, 125.7, 128.4, 142.4, 143.2, 163.3; exo-8f, 1 H), 2.65 (ddd, J ϭ 1.4, 5.8, 11.4 Hz, 1 H), 3.09 (ddd, J ϭ 2.4,
δ ϭ 22.7, 35.7, 40.9, 49.3, 52.1, 99.6, 116.0, 126.8, 127.6, 128.7,
141.0, 143.1, 163.6.
5.7, 11.4 Hz, 1 H), 3.91 (s, 3 H), 6.17 (dd, J ϭ 1.3, 2.4 Hz, 1 H),
7.13–8.47 (m, 12 H). – 13C NMR (CDCl3): endo-14, δ ϭ –4.5, –
Eur. J. Org. Chem. 2000, 639Ϫ643
641

S. Leconte, G. Dujardin, E. Brown
FULL PAPER
4.8, 17.3, 25.0, 35.2, 43.7, 51.3, 98.5, 114.3, 123.1, 123.6, 125.3,
125.9, 126.5, 126.7, 126.8, 127.6, 127.8, 132.0, 132.1, 140.3, 140.9,
(dd, J ϭ 5.9, 6.9 Hz, 1 H), 1.89 (ddd, J ϭ 9.4, 11.2, 13.3 Hz, 1 H),
2.12 (ddt, J ϭ 1.7, 6.6, 13.2 Hz, 1 H), 3.67 (m, 1 H), 4.04 (m, 2 H),
142.0, 162.5; exo-14, δ ϭ –2.8, –3.4, 16.5, 26.0, 37.3, 43.9, 52.4, 4.82 (broad s, 1 H), 5.31 (dd, J ϭ 2.1, 9.4 Hz, 1 H), 7.20–7.30 (m,
102.0, 114.5, 123.7–128.7, 133.1, 133.2, 140.4, 142.7, 143.3, 163.1. –
C26H34O4Si calcd. C 73.38, H 7.21, found C 73.33, H 7.29.
5 H); exo-5d, δ ϭ 1.68 (t, J ϭ 6.2 Hz, 1 H), 1.78 (dd, J ϭ 2.8,
10.3 Hz, 1 H), 2.01 (m, 1 H), 3.67 (m, 1 H), 4.04 (m, 2 H), 4.93
(m, 1 H), 5.38 (t, J ϭ 3.0 Hz, 1 H), 7.20–7.30 (m, 5 H). – 13C NMR
(CDCl3): endo-5d δ ϭ 28.7, 38.4, 38.7, 63.1, 75.7, 95.1, 101.1, 126.5,
127.2, 128.5, 144.4, 151.9; exo-5d, δ ϭ 28.8, 33.5, 37.0, 63.7, 74.9,
91.5, 101.4, 126.3, 127.5, 128.4, 145.3, 150.0. – MSHR: calcd. for
Mϩ: 262.1569 (C16H22O3), found 262.1584.
2-[(1-tert-Butyldimethylsiloxy)vinyl]naphthalene (11): A solution of
sodium iodide (9.4 g, 62.5 mmol) in MeCN (65 mL) was added
dropwise under nitrogen to a stirred mixture of 2-acetylnaphtha-
lene (8.5 g, 50 mmol), Et3N (8.7 mL; 62.5 mmol), and tBuMe2SiCl
(9.4 g, 62.5 mmol). The mixture was stirred for 18 h at 20 °C, filte-
red, and the filtrate extracted with petroleum ether (3 ϫ 50 mL). [3,4-Dihydro-2-(4-hydroxybutoxy)-4-phenyl-2H-pyran-6-yl]methanol
The petroleum extract was evaporated and the residue distilled un-
(5e): From 8e, oil (68%). endo/exo ratio 80:20. – IR (film): ν˜ ϭ 3360
1
der vacuum to give the unstable O-silyl enol ether 11 (10.3 g, 72%), cm–1, 1679. – H NMR (CDCl3): endo-5e, δ ϭ 1.65 (m, 4 H), 1.86
b.p. (0.35 Torr) 135–140 °C. – IR (film): ν˜ ϭ 1594 cm–1, 1133. – 1H (ddd, J ϭ 8.7, 10.2, 13.2 Hz, 1 H), 2.23 (ddt, J ϭ 1.6, 6.4, 13.2 Hz,
NMR (CDCl3): δ ϭ 0.23 (s, 6 H), 1.04 (s, 9 H), 4.53 (d, J ϭ 1.6 Hz, 1 H), 2.67 (s, 1 H), 3.02 (s, 1 H), 3.61 (m, 4 H), 3.94 (m, 1 H), 4.03
1 H), 5.02 (d, J ϭ 1.6 Hz, 1 H), 7.41–8.08 (m, 7 H). – 13C NMR (d, J ϭ 13.2 Hz, 1 H), 4.08 (d, J ϭ 13.7 Hz, 1 H), 4.87 (broad s, 1
(CDCl3): δ ϭ –4.60, 25.9, 91.8, 123.4, 124.3, 126.1, 126.7, 127.6,
128.5, 133.1, 133.2, 135.0, 155.8. – C20H20O4 calcd. C 74.05, H (CDCl3): endo-5e, δ ϭ 26.3, 29.4, 37.0, 37.45, 62.4, 62.8, 69.0,
H), 5.08 (dd, J ϭ 2.0, 8.8 Hz, 1 H), 7.17–7.30 (m, 5 H). – 13C NMR
6.20, found C 74.01, H 6.36.
100.3, 101.5, 126.5, 127.5, 128.5, 144.3, 151.6; exo-5e, δ ϭ 26.5,
29.7, 33.5, 35.7, 62.5, 63.2, 68.5, 97.0, 102.3, 127.2, 127.5, 128.5,
144.8, 150.0 – MSHR: calcd for [Mϩ – C4H10O2]: 188.0890
(C12H12O2), found 188.0837.
(2-Ethoxy-3,4-dihydro-4-phenyl-2H-pyran-6-yl)methanol (5a) from
8a: A Typical Procedure for the Homogeneous Syntheses of the Al-
lylic Alcohols 5a–h from the Esters 8a–h: LiAlH4 (0.071 g, 1.8
equiv.) was added portionwise to a solution of the ester 8a (0.255 g,
0.97 mmol) in anhydrous ether (20 mL), contained in a two-necked
50 mL flask equipped with a septum, a stopper and an argon inlet
with ice cooling. After complete transformation of the starting ma-
terial (TLC), the reaction mixture was hydrolyzed with saturated
(3,4-Dihydro-2-methoxy-2-methyl-4-phenyl-4H-pyran-6-yl)methanol
(5f): From 8f, oil (86%). endo/exo ratio 80:20. – IR (film): ν˜ ϭ 3421
1
cm–1, 1679. – H NMR (CDCl3): endo-5f, δ ϭ 1.48 (s, 3 H), 1.56
(s, 1 H), 2.00 (d, J ϭ 8.0 Hz, 2 H), 3.32 (s, 3 H), 3.53 (dt, J ϭ 2.4,
8.0 Hz, 1 H), 4.10 (AB, J ϭ 7.2 Hz, 2 H), 4.91 (d, J ϭ 2.4 Hz, 1
aqueous Na2SO4 solution (160 µL) and stirred for a few minutes. H), 7.20–7.32 (m, 5 H); exo-5f, δ ϭ 1.48 (s, 3 H), 1.65 (t, J ϭ
The mixture was filtered through Celite, dried (MgSO4) and evapo- 12.8 Hz, 1 H), 2.16 (ddd, J ϭ 1.5, 6.2, 13.4 Hz, 1 H), 3.33 (s, 3 H),
rated. The residue (0.277 g) was chromatographed on silica gel (ra-
tio 1:x40, eluent cyclohexane/AcOEt from 90:10 to 70:30), to give
5a as a colourless oil (0.203 g, 0.89 mmol; 89%). endo/exo ratio
3.66 (ddd, J ϭ 1.6, 6.3, 12.2 Hz, 1 H), 4.06 (d, J ϭ 6.6 Hz, 1 H),
4.14 (d, J ϭ 6.6 Hz, 1 H), 4.97 (broad s, 1 H), 7.20–7.32 (m, 5 H). –
13C NMR (CDCl3): endo-5f, δ ϭ 22.8, 37.9, 40.0, 49.7, 63.8, 100.7,
101.7, 127.1, 128.2, 129.2, 145.3, 152.5; exo-5f, δ ϭ 23.5, 35.6, 42.4,
1
Ͼ98:2. – IR (film): ν˜ ϭ 3400 cm–1, 1652, 1602, 1128. – H NMR
(CDCl3): δ ϭ 1.25 (t, J ϭ 7.1 Hz, 3 H), 1.64 (s, 1 H), 1.86 (m, 1 49.6, 64.0, 99.5, 103.3, 127.3, 127.9, 129.1, 145.5, 150.7. – MSHR:
H), 2.26 (ddt, J ϭ 1.7, 6.4, 13.2 Hz, 1 H), 3.63 (m, 2 H), 3.98 (dq, calcd for Mϩ: 234.1256 (C14H18O3), found 234. 1240.
J ϭ 7.1, 9.5 Hz, 1 H), 4.05 (dd, J ϭ 6.3, 13.0 Hz, 1 H), 4.12 (dd,
[3,4-Dihydro-2-methoxy-2-(2-naphthyl)-4-phenyl-2H-pyran-6-yl]-
J ϭ 5.7, 13.0 Hz, 1 H), 4.87 (broad s, 1 H), 5.11 (dd, J ϭ 1.9,
methanol (5g): From 8g, oil (79%). endo/exo ratio 80:20. – IR (film):
9.1 Hz, 1 H), 7.19–7.31 (m, 5 H). – 13C NMR (CDCl3): δ ϭ 15.2,
37.2, 37.8, 63.0, 64.5, 100.2, 101.6, 126.5, 127.2, 128.5, 144.2, 151.4.
1
ν˜ ϭ 3386 cm–1, 1681. – H NMR (CDCl3): endo-5g, δ ϭ 2.06 (t,
J ϭ 6.4 Hz, 1 H), 2.29 (dd, J ϭ 9.2, 13.3 Hz, 1 H), 2.51 (ddd, J ϭ
(3,4-Dihydro-2-isobutoxy-4-phenyl-2H-pyran-6-yl)methanol
(5b): 0.8, 6.3, 13.3 Hz, 1 H), 3.10 (m, 1 H), 3.15 (s, 3 H), 4.34 (t, J ϭ
From 8b, oil (61%). endo/exo ratio 96:4. – IR (film): ν˜ ϭ 3386 cm–1, 6.1 Hz, 2 H), 5.00 (d, J ϭ 2.2 Hz, 1 H), 7.17–8.06 (m, 12 H); exo-
1
2956, 1681. – H NMR (CDCl3): δ ϭ 0.90 (d, J ϭ 6.6 Hz, 6 H), 5g, δ ϭ 1.76 (dd, J ϭ 12.3, 13.5 Hz, 1 H), 2.20 (t, J ϭ 6.4 Hz, 1
1.79 (m, 1 H), 1.89 (m, 2 H), 2.26 (ddt, J ϭ 1.8, 6.7, 13.2 Hz, 1 H),
3.27 (dd, J ϭ 6.9, 9.2 Hz, 1 H), 3.63 (m, 1 H), 3.71 (dd, J ϭ 6.5, J ϭ 1.5, 5.9, 12.2 Hz, 1 H), 4.31 (m, 2 H), 5.15 (broad s, 1 H),
9.2 Hz, 1 H), 4.05 (dd, J ϭ 6.3, 13.1 Hz, 1 H), 4.12 (dd, J ϭ 5.6,
7.17–8.06 (m, 12 H). – 13C NMR (CDCl3), endo-5g, δ ϭ 36.2, 41.9,
H), 2.46 (ddd, J ϭ 1.6, 6.0, 13.7 Hz, 1 H), 3.20 (s, 3 H), 3.90 (ddd,
13.1 Hz, 1 H), 4.88 (d, J ϭ 0.9 Hz, 1 H), 5.08 (dd, J ϭ 2.1, 8.6 Hz, 50.2, 63.3, 102.2, 102.7, 123.7, 128.4, 132.9, 133.1, 137.0, 144.2,
1 H), 7.19–7.31 (m, 5 H). – 13C NMR (CDCl3): δ ϭ 19.2, 19.3, 151.4; exo-5g, δ ϭ 35.6, 43.7, 50.3, 63.5, 100.8, 103.4, 123.7–128.4,
28.5, 37.0, 37.5, 63.1, 75.9, 100.5, 101.5, 126.5, 127.2, 128.5, 144.3,
151.4. – MSHR: calcd for Mϩ: 262.1569 (C16H22O3), found
262.1558.
133.0, 133.1, 138.1, 144.2, 149.9. – MSHR: calcd. for Mϩ: 346.1563
(C23H22O3), found 346.1557.
(2,2-Diethoxy-3,4-dihydro-4-phenyl-2H-pyran-6-yl)methanol (5h):
1
(2-Cyclohexyloxy-3,4-dihydro-4-phenyl-2H-pyran-6-yl)methanol
From 8h, oil (34%). – IR (film): ν˜ ϭ 3465 cm–1, 1681. – H NMR
(5c): From 8c, oil (47%). endo/exo ratio Ͼ 97:3. – IR (film): ν˜ ϭ
(CDCl3): δ ϭ 1.21 and 1.22 (2t, J ϭ 7.0, 7.0 Hz, 6 H), 1.77 (dd,
1
3430 cm–1, 2931, 1681. – H NMR (CDCl3): δ ϭ 0.85–2.00 (m, 11 J ϭ 12.0, 12.9 Hz, 1 H), 2.20 (s, 1 H), 2.34 (ddd, J ϭ 1.3, 6.3,
H), 2.21 (ddt, J ϭ 1.7, 6.4, 13.3 Hz, 1 H), 3.62–3.77 (m, 2 H), 4.04 12.9 Hz, 1 H), 3.62 (2q, J ϭ 6.9, 6.9 Hz, 4 H), 3.69 (m, 1 H), 4.07
(dd, J ϭ5.6, 13.0 Hz, 1 H), 4.12 (dd, J ϭ 4.6, 13.0 Hz, 1 H), 4.85
(d, J ϭ 13.2 Hz, 1 H), 4.12 (d, J ϭ 13.2 Hz, 1 H), 4.96 (broad s, 1
(br. s, 1 H), 5.23 (dd, J ϭ 2.0, 9.1 Hz, 1 H), 7.20 (m, 5 H). – 13C H), 7.19–7.33 (m, 5 H). 13C NMR (CDCl3): δ ϭ 15.1, 15.2, 37.1,
NMR (CDCl3): δ ϭ 23.9, 24.1, 25.6, 31.9, 33.6, 37.7, 37.9, 63.1, 37.4, 56.3, 58.3, 62.7, 102.4, 112.7, 126.5, 127.3, 128.51, 144.0,
76.6, 98.4, 101.4, 126.5, 127.2, 128.4, 144.4, 151.6.
150.3. – MSHR: calcd. for Mϩ: 278.1518 (C16H22O4), found
278.1536.
(2-tert-Butoxy-3,4-dihydro-4-phenyl-2H-pyran-6-yl)methanol (5d):
From 8d, oil (71%). endo/exo ratio 75:25. – IR (film): ν˜ ϭ 3477 cm–1,
[3,4-Dihydro-2-(4-methoxyphenyl)-4-phenyl-2H-pyran-6-yl]methanol
1
2973, 1681. – H NMR (CDCl3): endo-5d, δ ϭ 1.30 (s, 9 H), 1.74 (15): From 12, oil (99%). endo/exo ratio Ͼ98:2. – IR (film): ν˜ ϭ
642
Eur. J. Org. Chem. 2000, 639Ϫ643

Dihydropyrans by Eu(fod)3-Catalysed [4ϩ2] Heterocycloaddition
3367 cm–1, 1673. – 1H NMR (CDCl3): δ ϭ 1.91 (dt, J ϭ 11.5,
FULL PAPER
(s, 9 H), 1.97 (t, J ϭ 6.6 Hz), 1 H), 2 .15 (dd, J ϭ 11.8, 13.1 Hz, 1
13.5 Hz, 1 H), 2.14 (m, 1 H), 2.25 (ddd, J ϭ 1.7, 6.2, 13.6 Hz, 1 H), 2.58 (ddd, J ϭ 1.3, 5.2, 13.2 Hz, 1 H), 2.95 (m, 1 H), 4.10–4.30
H), 3.74 (m, 1 H), 3.77 (s, 3 H), 4.04 (dd, J ϭ 6.6, 13.0 Hz, 1 H), (m, 2 H), 4.94 (broad s, 1 H), 7.18–8.05 (m, 12 H). – 13C NMR
4.14 (dd, J ϭ 4.8, 13.0 Hz, 1 H), 4.93 (broad s, 1 H), 4.99 (dd, J ϭ
(CDCl3): endo-17, δ ϭ –3.4, –3.4, 18.3, 26.0, 35.1, 45.9, 63.7, 99.0,
1.5, 11.5 Hz, 1 H), 6.86–7.33 (m, 9 H). – 13C NMR (CDCl3): δ ϭ 102.3, 123.7–128.6, 132.9, 133.0, 142.0, 144.5, 150.4; exo-17, δ ϭ –
39.1, 40.1, 55.2, 63.3, 78.0, 101.4, 113.8, 125.3–128.5, 133.1, 144.8,
153.9, 159.4.
3.1, –2.5, 17.9, 25.8, 36.6, 45.1, 63.3, 101.5, 101.8, 123.7–128.6,
141.0, 144.1, 152.0.
MSHR: calcd. for Mϩ: 446.2277
–
(C25H34O3Si), found 446.2268.
[3,4-Dihydro-2-(2-naphthyl)-4-phenyl-2H-pyran-6-yl]methanol (16):
From 13, oil (69%). endo/exo ratio Ͼ97:3. – IR (film): ν˜ ϭ 3401
cm–1, 1673. – 1H NMR (CDCl3): endo-16, δ ϭ 1.96 (t, J ϭ 5.6 Hz,
1 H), 2.04 (m, 1 H), 2.40 (ddt, J ϭ 1.7, 6.2, 13.6 Hz, 1 H), 3.82
(ddd, J ϭ 1.2, 6.1, 11.3 Hz, 1 H), 4.13 (m, 1 H), 4.23 (dd, J ϭ 4.5,
13.1 Hz, 1 H), 5.01 (broad s, 1 H), 5.23 (dd, J ϭ 1.5, 11.5 Hz, 1
H), 7.19–7.86 (m, 12 H). – 13C NMR (CDCl3): endo-16, δ ϭ 35.8,
38.3, 63.6, 73.8, 99.2, 124.0–128.6, 133.1, 133.3, 138.6, 145.5, 154.1;
exo-16, δ ϭ 39.1, 40.3, 63.4, 78.5, 101.8, 124.0–128.6, 133.0, 133.2,
138.4, 144.7, 153.9. – MSHR: calcd for Mϩ: 316.1463 (C22H20O3),
found 316.1457.
[1] [1a]
S. Booth, P. H. H. Hermkens, H. C. J. Ottenheijm, D. C.
Rees, Tetrahedron 1998, 54, 15385–15443. – [1b] R. C. D. Brown,
J. Chem. Soc. Perkin Trans. 1. 1998, 3293–3320 (reviews). –
[1c]
G. J. Kuster, H. W. Scheeren, Tetrahedron Lett. 1998, 39,
3613–3616.
[2]
The Wang resin (Lancaster) contained from 0.8 to 1.1 mmol of
OH groups per gram. We used the latter value when calculating
the overall yields of the syntheses of endo/exo-5a–h.
[3a] G. Dujardin, S. Rossignol, E. Brown, Tetrahedron 1994, 50,
[3]
9037–9050. – [3b] E. Brown, G. Dujardin, M. Maudet, Tetrahe-
[3c]
dron 1997, 53, 9679–9694. –
G. Dujardin, S. Rossignol, E.
[2-(tert-Butyldimethylsiloxy)-3,4-dihydro-2-(2-naphthyl)-4-phenyl-
2H-pyran-6-yl] methanol (17): From 14, oil (79%). endo/exo ratio
75:25. – IR (film): ν˜ ϭ 3411 cm–1, 1712. – 1H NMR (CDCl3): endo-
17, δ ϭ –0.27 (s, 3 H), 0.01 (s, 3 H), 0.96 (s, 9 H), 1.65 (t, J ϭ
12.7 Hz, 1 H), 1.87 (t, J ϭ 6.5 Hz, 1 H), 2.44 (ddd, J ϭ 1.6, 5.2,
13.2 Hz, 1 H), 3.84 (m, 1 H), 4.27 (m, 2 H), 5.14 (broad s, 1 H),
7.18–8.05 (m, 12 H); exo-17, δ ϭ –0.17 (s, 3 H), 0.11 (s, 3 H), 0.84
Brown, Synthesis, 1998, 763–770.
[4]
[5]
To the best of our knowledge, LiAlH4 has only been reported
for reductive cleavage of supported amides and carbamates
into amines. See for instance: C. Y. Ho, M. J. Kukla, Tetrahe-
dron Lett. 1997, 38, 2799–2302.
D. L. Boger, K. D. Robarge, J. Org. Chem. 1988, 53, 3373–3377.
Received June 1, 1999
[O99324]
Eur. J. Org. Chem. 2000, 639Ϫ643
643