Synthesis and oxidative rearrangement of selenenylated dihydropyrans

Article abstract of DOI:10.1039/b718825k

Selenenylated dihydropyrans prepared by inverse demand hetero-Diels-Alder reactions undergo oxidative rearrangement when treated with H₂O ₂, leading to tetrahydrofuran-2-ones by ring contraction. The Royal Society of Chemistry.

Full text of DOI:10.1039/b718825k

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis and oxidative rearrangement of selenenylated dihydropyrans†
Se´bastien Redon, Xavier Pannecoucke, Xavier Franck* and Francis Outurquin*
Received 6th December 2007, Accepted 1st February 2008
First published as an Advance Article on the web 27th February 2008
DOI: 10.1039/b718825k
Selenenylated dihydropyrans prepared by inverse demand hetero-Diels–Alder reactions undergo
oxidative rearrangement when treated with H2O2, leading to tetrahydrofuran-2-ones by ring
contraction.
In these cases, 2-phenylselenylated enals (Table 1, entries 1–
11) proved to be more reactive than the corresponding enones
Oxidized organoselenium derivatives are sources of molecular
(Table 1, entries 12–19) and the reaction worked well with 3–10
Introduction
diversity due to the richness of their chemistry.1 Indeed, oxi-
dation of aliphatic organoselenium derivatives is often used to
mol% of the commonly used Eu(FOD)3 as the catalyst, at either
room temperature or 50 ◦C.
When R1 = aryl (Table 1, entries 6–11), the reaction is
introduce unsaturation by b-elimination (selenoxide) or to sub-
stitute the organoselenium residue by nucleophilic displacement
slower and high pressure can help, shortening the reaction time.
(e.g.activation with NBS and substitution by an amine).2 Allylic or
propargylic phenylselanyl derivatives, when treated by an oxidant,
undergo [2,3]-sigmatropic rearrangement leading to allylic alco-
hols (selenoxide), amines (selenylimine) or halides (halo-adduct).3
In these cases, no catalyst was necessary. Cyclic vinyl-ethers
such as dihydrofuran can also be used (Table 1, entries 3–
5), leading to bicyclic compounds 3c–d in good yields. Bulkier
vinyl-ethers such as n-butyl- and even t-butyl- ethers can be
On the other hand, vinylic or aromatic phenylselanyl derivatives
used without loss of efficiency (Table 1, entries 9–10). With less
can be oxidized to the selenoxide, which can be isolated in certain
reactive phenylselenylated enones (Table 1, entries 12–19), the
cases, or give rise to allenols by [2,3]-sigmatropic rearrangement
reaction became slower and high pressure was needed to maintain
in the case of 1,3-dienes.4
efficiency, especially when R1 or R2 was an aryl group. When
both R1 and R2 are aryl groups (Table 1, entries 18–19), no
reaction occurred at all in the absence of high pressure. In order
to have access to thio- or phenylselanyl- acetals, ethylvinylsulfide
(Table 1, entries 20–23) and phenylvinylselenide (Table 1, entry 24)
were engaged as dienophiles in the hetero-Diels–Alder reactions.
The reactions were always high yielding, and high pressure was
only needed in the case of the enone substituted by a phenyl
group (Table 1, entry 23); thus 2-ethylsulfanyl-5-phenylselanyl-3,4-
dihydro-2H-pyrans 3m–p and the bis-selenenylated 2-ethylselanyl-
5-phenylselanyl-3,4-dihydro-2H-pyran 3q could be obtained. With
less electron rich dienophiles such as vinylacetate or styrene, the
hetero-Diels–Alder reaction with a reactive enal never proceeded
with vinylacetate, (Table 1, entry 25) and required high pressure
and longer reaction times for styrene, leading to 2-phenyl-5-
phenylselanyl-3,4-dihydro-2H-pyran 3s (Table 1, entries 26–27).
It is noteworthy that in this case, no polymerisation of styrene was
observed.
In continuation of our studies on the reactivity of selenenylated
carbonyl derivatives of type 1,4 we became interested in their use as
dienes in hetero-Diels–Alder reactions (Scheme 1) and studied the
particular reactivity of these cycloadducts toward oxidants. Maybe
owing to the sensitivity of selenenylated derivatives to Lewis acids
or heat, only a few examples of Diels–Alder reactions with a-
phenylselanyl-enals, -enones or dienes have been described.5
Scheme 1 Hetero-Diels–Alder reaction between 2-phenylselanyl-enals or
-enones 1 and an alkene 2 leading to dihydropyrans 3a–s.
Once we had the cycloadducts in hand, we studied their
oxidation. Using standard mild conditions (H2O2 35% in water,
4 eq., in CH2Cl2) the oxidation of acetals (R4 = OR) ended up
with an unprecedented ring contraction affording, when R2 = H,
5-alkoxy-tetrahydrofuran-2-ones 5. From acetal 3k where R2 =
Me and R4 = OR, a mixture of 5-alkoxy-tetrahydrofuran-2-one
5e and acetylfuran 6 was observed (Scheme 2).
Results and discussion
Inverse demand hetero-Diels–Alder reactions have been con-
ducted mainly with electron-rich alkenes (vinyl ethers), leading to
2-alkoxy-5-phenylselanyl-3,4-dihydro-2H-pyrans 3a–l in excellent
yields (Table 1, entries 1–19).
In order to elucidate the mechanism and characterize the
intermediates, we performed the oxidation of 3a in EtOAc or
THF and, in these cases, only the selenoxide 4a could be obtained,
without rearrangement. When this selenoxide 4a was reacted with
H2O2 in CH2Cl2, rearrangement cleanly occurred, allowing us to
propose that 4a is the first intermediate in the rearrangement.
Universite´ de Rouen, INSA de Rouen, CNRS UMR 6014, C.O.B.R.A. -
I.R.C.O.F, 1 Rue Tesnie`re, 76131, Mont-Saint-Aignan cedex, France.
Email: xavier.franck@insa-rouen.fr, francis.outurquin@univ-rouen.fr;
Fax: +33 (0)235522959; Tel: +33 (0)235522402
† Electronic supplementary information (ESI) available: NOESY spectra
of the cis- and trans- isomers of tetrahydrofuran-2-one 5e. See DOI:
10.1039/b718825k
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Table 1 Synthesis of dihydropyrans 3
Entry
R1
R2
R3
R4
Conditions
Compound (yield%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Me
H
H
H
H
H
H
H
H
H
H
OEt
OEt
4% Eu(FOD)3, r.t., 12 h
3% Eu(FOD)3, r.t., 12 h
1.0 Gpa, 50 ◦C, 36 h
3a (93)
3b (86)
3c (84)
3c (78)
3d (73)
3e (90)
3e (50)
3e (99)
3f (98)
3g (97)
3h (89)
3i (93)
3i (93)
3j (35)
3j (91)
3k (46)
3k (94)
3l (N.R.)
3l (93)
3m (95)
3n (90)
3o (91)
3p (90)
3q (80)
3r (N.R.)
3s (24)
3s (64)
CH2OTBDMS
Me
Me
H
Ph
Ph
Ph
Ph
Ph
p-OMePh
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Me
Ph
-CH2CH2O-
-CH2CH2O-
-CH2CH2O-
5% Eu(FOD)3, 40 ◦C, 12 h
3% Eu(FOD)3, r.t., 12 h
10% Eu(FOD)3, 40 ◦C, 48 h
1.0 Gpa, r.t., 15 h
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OEt
OEt
OEt
On-Bu
Ot-Bu
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
SEt
SEt
SEt
SEt
SePh
OCOCH3
Ph
1.0 Gpa, 50◦C, 10 h
H
H
H
5% Eu(FOD)3, 80 ◦C, 12 h
10% Eu(FOD)3, 80 ◦C, 12 h
5% Eu(FOD)3, 40 ◦C, 12 h
10% Eu(FOD)3, 40 ◦C, 48 h
1.0 Gpa, r.t., 20 h
Me
Me
Ph
Ph
Me
Me
Ph
Ph
H
10% Eu(FOD)3, 40 ◦C, 20 h
1.2 Gpa, 50 ◦C, 20 h
10% Eu(FOD)3, 40 ◦C, 48 h
1.2 Gpa, 50 ◦C, 20 h
10% Eu(FOD)3, r.t., 48 h
1.2 Gpa, 50 ◦C, 20 h
4% Eu(FOD)3, r.t., 12 h
10% Eu(FOD)3, 40 ◦C, 12 h
10% Eu(FOD)3, r.t., 12 h
1.2 Gpa, 40 ◦C, 20 h
H
Me
Ph
Me
Me
Me
Me
Me
Me
H
H
H
10% Eu(FOD)3, 80 ◦C, 24 h
1.0 Gpa, 50 ◦C, 24 h
1.2 Gpa, 50 ◦C, 16 h
H
Ph
1.2 Gpa, 50 ◦C, 48 h
Scheme 2 Different products arising from oxidation of dihydropyrans 3.
Dihydropyran 3s (R4 = Ph) was also subjected to H2O2 oxidation
in CH2Cl2 and we only isolated acid 7s, resulting from an oxidative
cleavage of the double bond. In the case of dihydropyran 3l
(R1 = R2 = Ph), only the selenoxide 4l could be obtained and
no rearrangement occurred. When we used simple dihydropyran
with no phenylselanyl residue, no oxidation occurred at all and
the starting material was recovered unchanged (not shown). This
surprising susceptibility of such 5-phenylselanyl-3,4-dihydro-2H-
pyrans 3 to oxidation is due to the presence of the selenium residue
and is reported for the first time.
Having identified intermediates and characterized the different
reaction products according to the substitution of the dihydropy-
rans 3, we can now propose a mechanism.
The presence of the selenium residue, first oxidized to the
corresponding selenoxide 4, is then responsible for the high
polarization of the enolic double bond, which could easily be
epoxidized by H2O2. Then, depending on the substitution at
position 6 (R2 = H or R2 = Me), two different pathways can
be observed (Scheme 3).
Firstly, when R2 = H, water (solvent of H2O2) can attack
at position 6 to give, after expulsion of “PhSeOH”, the keto-
hemiacetal 8. PhSeOH can then be further oxidized by the
excess of H2O2 to PhSe(O)OOH, phenylperseleninic acid, which
is know as a strong but selective oxidant able to perform Baeyer–
Villiger reactions.6 Indeed, Baeyer–Villiger oxidation of the keto-
hemiacetal 8 gives rise to the correponding lactone-hemiacetal
97 which can rearrange with expulsion of formic acid and ring
closure of the carboxylate onto the formed oxonium ion. This
mechanism is supported by the isolation of carboxylic acid 7s, from
the reaction of dihydropyran 3s where R4 = Ph. Indeed, the same
lactone-hemiacetal can be drawn but, in this case, R4 is not electron
donating enough to open the ring and fragmentation occurs,
leading to carboxylic acid 7s with a hydroxyl group functionalized
as a formyl ester.
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Scheme 3 Proposed mechanism.
Secondly, when R2 = Me, the attack of water on the epoxide
is slowed down (but still exists) by steric factors, thus the second
pathway occurs thanks to the electron donating ability of R4 =
OEt, which can help open the 6-membered cycle and form an
oxonium ion. The liberated hydroxyl in position 5 can then attack
the oxonium, giving rise to a five-membered ring (5-exo-trig).
This rearrangement is similar to the one observed by Armstrong
and Chung in the synthesis of tetrahydrofuranones.8 Then the
selenoxide can b-eliminate to give a dihydrofuran which can
further lose EtOH to yield the corresponding furan 6.
cis, the spectroscopic data being in accordance with previously
published data.9
Both pathways are competitive and depend on the substitution
pattern (R2). The presence of the selenium residue increases the
reactivity of these dihydropyrans and makes it possible for the
whole oxidation process to occur in very mild conditions. 5-
alkoxy-tetrahydrofuran-2-ones 5 have been prepared in moderate
yields, which can be explained by the relative instability of the
intermediates and by the presence of water, which can trap
oxonium ions. All attempts to remove water from the reaction
were unsuccessful (use of urea–H2O2 complex).
Concerning the diastereoselectivity of the rearrangement
through the oxocarbenium ion, it appears that the resulting
tetrahydrofuran-2-ones 5a–b and 5e–h are isolated mainly as
the trans diastereomer (>90 : 10 in all cases), as the minor cis
shows nOe correlations between H-3 and H-5 (Scheme 4). On the
contrary, the stereochemistry of tetrahydrofuran-2-ones 5c-d is all
Scheme 4 Stereochemistry of tetrahydrofuran-2-one 5e.
Conclusion
To conclude, we have developed an efficient route toward sele-
nenylated dihydropyrans through a high yielding inverse demand
hetero-Diels–Alder reaction. This pathway allowed general access
to various dihydropyrans, including thio- and seleno-acetals.
Further oxidation of these selenenylated dihydropyrans (R4 = OR)
with H2O2 proceeded to give an unprecedented rearrangement, af-
fording 5-alkoxy-tetrahydrofuran-2-ones 5 through a contraction
of the intermediate selenoxide 4. A mechanism was postulated,
passing through an epoxide that could then be transformed
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into either a furan moiety or a 5-alkoxy-tetrahydrofuran-2-one,
depending on the substitution pattern.
2-Ethoxy-3,4-dihydro-4-[(tert-butyl)dimethylsilyl-methoxy]-5-
phenylselanyl-2H-pyran (3b). Yield = 86%; yellow oil; Rf = 0.41
1
(AcOEt–cyclohexane, 3 : 97); 77Se NMR d (ppm) 339.2 ppm; H
NMR d (ppm) −0.04 (s, 3H), −0.02 (s, 3H), 0.83 (s, 9H), 1.24 (t, J =
7.0 Hz, 3H), 1.97–2.05 (m, 1H, H-3), 2.16–2.25 (m, 1H, H-3),
2.43 (m, 1H, H-4), 3.52–3.67 (m, 2H), 3.81–3.91 (m, 2H), 5.12
(dd, J = 2.70, 4.1 Hz, 1H, H-2), 6.86 (d, J = 1.65 Hz, 1H, H-6),
7.19–7.26 (m, 3H), 7.38–7.40 (m, 2H). 13C NMR d (ppm) −5.2,
15.4, 18.4, 26.1, 30.1 (C-3), 37.7 (C-4), 64.5, 64.9, 98.4 (C-2),
103.7 (C-5), 126.3, 129.1, 129.8, 132.4, 149.8 (C-6); IR (neat):
2954, 2920, 2856, 1621, 1578, 1476, 1438, 1378, 1360, 1253, 1227,
1130, 1066, 1022, 995, 838, 776, 734, 690 cm−1; MS (EI, 70 eV)
m/z: 428 (M+, 6), 371 (M+ − C(Me)3, 4), 297 (M+ − OSiTBDM,
10), 237 (20), 219 (14), 157 (PhSe+, 22), 73 (100); Anal. calcd for
C20H32O3SeSi (427.50): C, 56.19; H, 7.54. Found: C, 56.43; H,
7.45.
Experimental
General methods
NMR spectra were recorded on a Bruker DPX 300 spectrometer
operating at 300 MHz for protonand 75.4MHzfor carbonspectra.
This probe is equipped with pulsed-field (z) gradients. 77Se NMR
spectra were recorded at 21 ◦C on a Bruker DPX 400 spectrometer
operating at 76.29 MHz for 77Se, using a pulse length of 19 ls
(90◦ pulse = 19 ls) and an optimized relaxation delay of 2 s.
An average of 1500 scans for 77Se NMR was necessary to obtain
reliable information. Chemical shifts (d) are expressed in ppm
relative to TMS for 1H and 13C nuclei and to Me2Se for 77Se nuclei;
coupling constants (J) are given in Hertz; coupling multiplicities
are reported using conventional abbreviations. Elemental analyses
were obtained on a Carlo-Erba 1106 analyzer and mass spectra on
a HP5890 (electronic impact 70eV) using GC-MS coupling with a
Jeol AX 500.
4-Methyl-5-phenylselanyl-2,3,3a,7a-tetrahydro-4H-furo [2,3-
b]pyran (3c). Yield = 84%; yellow oil; Rf = 0.28 (AcOEt–
cyclohexane, 5 : 95); 1H NMR d (ppm) 1.06 (d, J = 7.1 Hz, 3H),
1.80–1.98 (m, 2H, H-3), 2.49 (m, 1H, H-9), 2.87 (m, 1H, H-4),
3.98 (m, 1H, H-2), 4.21 (m, 1H, H-2), 5.49 (d, J = 3.7 Hz, 1H,
H-8), 6.84 (d, J = 2.0 Hz, 1H, H-6), 7.17–7.25 (m, 3H), 7.41–7.45
(m, 2H). 13C NMR d (ppm) 18.4, 23.6, 30.2 (C-4), 44.8 (C-9), 68.4,
100.5 (C-8), 104.9 (C-5), 126.3, 129.0, 130.0, 132.3, 148.6 (C-6).
IR (neat): 2955, 2974, 2360, 1622, 1615, 1575, 1476, 1465, 1436,
1373, 1336, 1308, 1170, 1099, 1043, 1022, 995, 922, 891, 836, 736,
691 cm−1; MS (EI, 70 eV) m/z: 296 (38), 294 (20), 226 (100), 224
(51), 157 (PhSe+, 33), 117 (47), 77 (44, Ph+), 51 (47), 41(80). Anal.
calcd for C14H16O2Se (295.23): C, 56.95; H, 5.46. Found: C, 56.72;
H, 5.40.
Typical procedure for the synthesis of dihydropyrans 3
Method under high pressure
The enal 1a (1 mmol, 225 mg) in ethyl vinyl ether (10 mmol,
0.96 ml) was introduced to a high-pressure vessel and compressed
to the desired pressure and temperature. After decompression,
the mixture was concentrated under vacuum. The residue was
chromatographed on silica gel (eluent: ethyl acetate–cyclohexane,
3 : 97) to give 282 mg (95%) of 2-ethoxy-4-methyl-5-phenylselanyl-
3,4-dihydro-2H-pyran 3a.
5-Phenylselanyl-2,3,3a,7a-tetrahydro-4H-furo[2,3-b]pyran (3d).
Yield = 73%; white crystals; m.p. = 48–50 ◦C; Rf = 0.29 (AcOEt–
1
cyclohexane, 5 : 95); H NMR d (ppm) 1.84–2.05 (m, 2H, H-3),
Method with Eu(FOD)3
2.27 (d, 1H, J = 17.7 Hz, H-4), 2.49 (m, 1H, H-9), 2.68 (dd, 1H, J =
1.9, 17.7 Hz, H-4), 3.95–4.01 (m, 1H, H-2), 4.18–4.25 (m, 1H, H-
2), 5.40 (d, J = 3.8 Hz, 1H, H-8), 6.82 (s, 1H, H-6), 7.18–7.30 (m,
3H), 7.35–7.50 (m, 2H). 13C NMR d (ppm) 27.7, 28.3, 38.5 (C-9),
68.5 (C-2), 98.5, 98.7 (C-8), 126.6, 129.2, 130.4, 131.1, 147.5 (C-6).
IR (neat): 2897, 1628, 1577, 1476, 1437, 1157, 1102, 1066, 1022,
933, 918, 857, 737, 691 cm−1; MS (EI, 70 eV) m/z: 312 (32), 310
(17), 266 (8), 218 (85), 216 (44), 191 (50), 157 (51, PhSe+), 129
(100), 115 (85), 105 (42), 77 (51, Ph+), 53 (58), 51 (81), 44 (42).
Anal. calcd for C13H14O2Se (281.20): C, 55.52; H, 5.02. Found: C,
55.14; H, 5.06.
To a mixture of enal 1a (1 mmol, 225 mg) in ethyl vinyl ether
(10 mmol, 0.96 ml), Eu(FOD)3 (2%, 21 mg) was introduced under
nitrogen, and the mixture stirred at the desired temperature. After
the reaction was completed, monitored by TLC, the mixture was
concentrated under vacuum. The residue was chromatographed
on silica gel (eluent: ethyl acetate–cyclohexane, 3 : 97) to give
275 mg (93%) of 2-ethoxy-4-methyl-5-phenylselanyl-3,4-dihydro-
2H-pyran 3a.
2-Ethoxy-4-methyl-5-phenylselanyl-3,4-dihydro-2H-pyran (3a).
Yield = 93%; yellow oil; Rf = 0.24 (AcOEt–cyclohexane, 5 : 95);
77Se NMR d (ppm) 331.7; 1H NMR d (ppm) 1.14 (d, J = 7.0 Hz,
3H), 1.25 (t, J = 7.0 Hz, 3H), 1.82 (ddd, 1H, J = 6.2, 6.4, 13.6 Hz,
H-3), 2.13 (ddd, 1H, J = 2.5, 6.9, 15.1 Hz, H-3), 2.40 (ddd, 1H, J =
1.5, 6.9, 13.6 Hz, H-4), 3.58 (m, 1H), 3.91 (m, 1H), 5.10 (dd, J =
2.5, 6.2 Hz, 1H, H-2), 6.82 (d, J = 1.7 Hz, 1H, H-6), 7.17–7.25 (m,
3H), 7.40–7.44 (m, 2H). 13C NMR d (ppm) 15.4, 20.6, 30.3 (C-4),
36.3 (C-3), 64.6, 98.8 (C-2), 108.9 (C-5), 126.2, 129.1, 129.8, 132.6,
148.3 (C-6). IR (neat): 2975, 2928, 2873, 1622, 1578, 1476, 1438,
1373, 1130, 1070, 990, 840, 736, 691 cm−1; MS (EI, 70 eV) m/z:
298 (48), 296 (25), 226 (100), 224 (53), 197 (15), 157 (50, PhSe+),
117 (46), 115 (26), 91 (17), 78 (32), 77 (38, Ph+), 51 (41), 41 (45).
Anal. calcd for C14H18O2Se (297.25): C, 56.57; H, 6.10. Found: C,
56.63; H, 6.07.
2-Ethoxy-4-phenyl-5-phenylselanyl-3,4-dihydro-2H-pyran (3e).
Yield = 99%; yellow solid; m.p. = 73–74 ◦C; Rf = 0.26 (AcOEt–
cyclohexane, 5 : 95); 77Se NMR d (ppm) 348.5; 1H NMR d (ppm)
1.21 (t, J = 7.0 Hz, 3H), 2.19 (ddd, 1H, J = 2.2, 8.1, 13.6 Hz,
H-3), 2.38 (ddd, 1H, J = 2.2, 6.9, 13.6 Hz, H-3), 3.54–3.66 (m,
2H), 3.95 (m, 1H), 5.17 (dd, J = 7.4, 1.9 Hz, 1H, H-2), 7.03 (d, J =
1.7 Hz, 1H, H-6), 7.06–7.11 (m, 2H), 7.17–7.25 (m, 6H), 7.31–7.35
(m, 2H). 13C NMR d (ppm) 15.2, 38.0 (C-3), 42.6 (C-4), 64.6, 99.2
(C-2), 106.96 (C-5), 126.5, 126.7, 128.2, 128.4, 129.0, 130.7, 131.9,
142.8, 149.8 (C-6). IR (KBr): 2982, 2932, 2867, 1603, 1576, 1476,
1437, 1378, 1127, 1040, 906, 768, 730, 700 cm−1; MS (EI, 70 eV)
m/z: 360 (15), 358 (8), 314 (10), 288 (33), 286 (19), 237 (14), 179
(36), 178 (36), 158 (48), 157 (100, PhSe+), 131 (78), 128 (56), 115
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(44), 103 (31), 78 (64), 77 (73, Ph+), 51 (69), 44 (40). Anal. calcd
for C19H20O2Se (359.31): C, 63.51; H, 5.61. Found: C, 63.48; H,
5.53.
31.9 (C-4), 36.4 (C-3), 64.4, 98.7 (C-2), 104.1 (C-5), 125.6, 128.7,
129.1, 133.2, 154.9 (C-6). IR (neat): 2975, 2928, 2873, 1638, 1623,
1578, 1476, 1438, 1377, 1236, 1201, 1157, 1123, 1096, 1054, 1019,
957, 840, 734, 690 cm−1; MS (EI, 70 eV) m/z: 312 (10), 310 (10),
251 (9), 240 (42), 238 (24), 197 (27), 171 (15), 157 (24, PhSe+),
116 (28), 115 (33), 91 (21), 77 (38, Ph+), 51 (39), 44 (54), 43 (100).
Anal. calcd for C15H20O2Se (311.28): C, 57.87; H, 6.48. Found: C,
57.53; H, 6.37.
2-Butoxy-4-phenyl-5-phenylselanyl-3,4-dihydro-2H-pyran (3f).
Yield = 98%; yellow oil; Rf = 0.35 (cyclohexane–EtOAc, 97 : 3),
77Se NMR d (ppm) 350.0; 1H NMR d (ppm) 1.03 (t, J = 7.3 Hz,
3H), 1.47 (m, 2H), 1.68 (m, 2H), 2.33 (ddd, 1H, J = 1.8, 7.9,
13.7 Hz, H-3), 2.50 (ddd, 1H, J = 2.2, 6.9, 13.7 Hz, H-3), 3.64 (m,
1H), 3.75 (m, 1H, H-4), 4.02 (m, 1H), 5.28 (dd, J = 2.2, 7.3 Hz, 1H,
H-2), 7.17 (d, J = 1.7 Hz, 1H, H-6), 7.20–7.24 (m, 2H), 7.30–7.35
(m, 6H), 7.44–7.50 (m, 2H). 13C NMR d (ppm) 13.9, 19.3, 31.7,
37.9 (C-3), 42.5 (C-4), 69.0, 99.3 (C-2), 106.8 (C-5), 126.4, 126.6,
128.1, 128.4, 129.0, 130.7, 131.9, 142.9, 149.9 (C-6). IR (neat):
3060, 2959, 2932, 2872, 1622, 1578, 1493, 1476, 1455, 1438, 1372,
1345, 1231, 1123, 1072, 1050, 1021, 911, 839, 823, 736, 699 cm−1;
MS (EI, 70 eV) m/z: 388 (20), 386 (10), 288 (80), 286 (42), 179 (28),
157 (PhSe+, 42), 131 (92), 115 (43), 77 (38, Ph+), 57 (34), 41(100).
Anal. calcd for C21H24O2Se (387.36): C, 65.11; H, 6.24. Found: C,
64.99; H, 6.29.
2-Ethoxy-3,4-dihydro-4-methyl-6-phenyl-5-phenylselanyl-2H-
pyran (3j). Yield = 91%; white solid; m.p. = 66 ◦C; Rf = 0.31
(AcOEt–cyclohexane, 5 : 95); 77Se NMR d (ppm) 339.2; 1H NMR
d (ppm) 1.27 (dd, J = 1.2, 6.9 Hz, 3H), 1.29 (t, J = 7.0 Hz, 3H),
1.93 (ddd, 1H, J = 5.9, 7.0, 13.7 Hz, H-3), 2.21 (ddd, 1H, J = 2.6,
7.2, 13.7 Hz, H-3), 2.49 (m, 1H), 3.67 (m, 1H), 4.03 (m, 1H), 5.24
(dd, J = 2.6, 5.9 Hz, 1H, H-2), 7.15–7.45 (m, 10H). 13C NMR d
(ppm) 15.4, 21.7, 31.4 (C-4), 36.3 (C-3), 64.55, 99.4 (C-2), 106.7
(C-5), 126.0, 127.7, 128.8, 129.1, 129.3, 129.9, 132.8, 137.2, 155.2
(C-6). IR (KBr): 3055, 2960, 2926, 1620, 1596, 1578, 1476, 1438,
1372, 1264, 1134, 1093, 1063, 1023, 1008, 996, 884, 831, 765, 736,
696 cm−1; MS (EI, 70 eV) m/z: 374 (14), 302 (40), 300 (20), 221
(10), 157 (28, PhSe+), 145 (44), 105 (100), 77 (58, Ph+), 51 (18).
Anal. calcd for C20H22O2Se (373.34): C, 64.34; H, 5.94. Found: C,
64.49; H, 5.97.
2-tert-Butoxy-4-phenyl-5-phenylselanyl-3,4-dihydro-2H-pyran
(3g). Yield = 97%; yellow oil; Rf = 0.35 (cyclohexane–EtOAc,
97 : 3); 77Se NMR d (ppm) 347.3; 1H NMR d (ppm) 1.34 (s, 9H),
2.28 (m, 2H, H-3), 3.73 (m, 1H, H-4), 5.43 (dd, J = 2.6, 7.2 Hz,
1H, H-2), 7.08 (d, J = 1.8 Hz, 1H, H-6), 7.14–7.17 (m, 2H),
7.25–7.32 (m, 6H), 7.35–7.40 (m, 2H); 13C NMR d (ppm) 28.7,
39.5 (C-3), 43.2 (C-4), 75.8, 94.1 (C-2), 106.5 (C-5), 126.4, 126.6,
128.1, 128.4, 128.9, 129.3, 132.1, 143.0, 150.3 (C-6). IR (neat):
3045, 2958, 2831, 1622, 1614, 1580, 1494, 1477, 1455, 1436, 1393,
1367, 1267, 1240, 1179, 1118, 1057, 1021, 962, 916, 840, 735,
699 cm−1; MS (EI, 70 eV) m/z: 388 (7), 386 (4), 332 (32), 288 (26),
286 (14), 179 (12), 157 (PhSe+, 38), 131 (32), 115 (30), 77 (25,
Ph+), 57 (100). Anal. calcd for C21H24O2Se (387.36): C, 65.11; H,
6.24. Found: C, 65.21; H, 6.16.
2-Ethoxy-3,4-dihydro-6-methyl-4-phenyl-5-phenylselanyl-2H-
pyran (3k). Yield = 94%; yellow oil; Rf = 0.33 (AcOEt–
cyclohexane, 5 : 95); 77Se NMR d (ppm) 333.7; 1H NMR d (ppm)
1.25 (t, J = 7,2 Hz, 3H), 2.14 (ddd, 1H, J = 7.8, 9.0, 13.6 Hz, H-3),
2.24 (d, J = 1.8 Hz, 3H), 2.37 (ddd, 1H, J = 2.2, 7.2, 13.6 Hz,
H-3), 3.57–3.73 (m, 2H), 3.98 (m, 1H), 5.14 (dd, J = 2.2, 7.8 Hz,
1H, H-2), 7.10–7.35 (m, 10H). 13C NMR d (ppm) 15.3, 20.8, 38.9
(C-3), 44.7 (C-4), 64.6, 99.3 (C-2), 102.1 (C-5), 125.9, 126.6, 128.3
(2C overlap), 129.1, 129.4, 132.8, 144.4, 156.8 (C-6). IR (neat):
3059, 2975, 2928, 1694, 1627, 1578, 1476, 1438, 1377, 1233, 1156,
1052, 1022, 871, 761, 691 cm−1; MS (EI, 70 eV) m/z: 374 (8), 372
(4), 302 (24), 300 (13), 259 (11), 179 (22), 178 (26), 157 (14, PhSe+),
145 (30), 128 (18), 115 (16), 77 (23, Ph+), 51 (20), 44 (46), 43 (100).
Anal. calcd for C20H22O2Se (373.34): C, 64.34; H, 5.94. Found: C,
64.05; H, 5.68.
2-Ethoxy-4-(4-methoxyphenyl)-5-phenylselanyl-3,4-dihydro-
2H-pyran (3h). Yield = 89%; yellow oil; Rf = 0.26 (AcOEt–
cyclohexane, 3 : 97); 1H NMR d (ppm) 1.22 (t, J = 7.0 Hz, 3H),
2.14 (ddd, 1H, J = 2.2, 8.1, 13.7 Hz, H-3), 2.33 (ddd, 1H, J =
2.2, 6.9, 13.7 Hz, H-3), 3.53–3.65 (m, 2H), 3.77 (s, 3H), 3.93 (m,
1H), 5.13 (dd, J = 2.2, 7.3 Hz, 1H, H-2), 6.73–6.76 (m, 2H),
6.97–7.01 (m, 2H), 7.00 (d, J = 1.8 Hz, 1H, H-6), 7.17–7.21 (m,
3H), 7.31–7.35 (m, 2H). 13C NMR d (ppm) 15.2, 38.1 (C-3), 41.9
(C-4), 55.2, 64.6, 99.2 (C-2), 107.6 (C-5), 113.5, 126.4, 129.0,
129.4, 130.7, 131.9, 134.8, 149.5 (C-6), 158.3; IR (neat): 3056,
2975, 2930, 2834, 1614, 1579, 1514, 1476, 1455, 1439, 1378, 1360,
1344, 1303, 1281, 1251, 1177, 1122, 1057, 1033, 913, 876, 830,
780, 736, 691 cm−1; MS (EI, 70 eV) m/z: 390 (30), 388 (16), 318
(100), 316 (52), 210 (57), 161 (80), 121 (63), 77 (50, Ph+). Anal.
calcd for C20H22O3Se (389.34): C, 61.69; H, 5.69. Found: C, 61.55;
H, 5.88.
2-Ethoxy-3,4-dihydro-4,6-diphenyl-5-phenylselanyl-2H-pyran
(3l). Yield = 93%; yellow oil; Rf = 0.40 (AcOEt–cyclohexane, 5:
1
95); 77Se NMR d (ppm) 356.0; H NMR d (ppm) 1.25 (t, J =
7.2 Hz, 3H), 2.20 (ddd, 1H, J = 8.2, 9.2, 17.3 Hz, H-3), 2.42 (ddd,
1H, J = 2.0, 7.4, 13.6 Hz, H-3), 3.69 (m, 1H), 4.07 (m, 1H), 5.27
(dd, J = 2.0, 8.2 Hz, 1H, H-2), 7.10–7.35 (m, 13H), 7.50–7.53 (m,
2H). 13C NMR d (ppm) 15.3, 39.1 (C-3), 44.4 (C-4), 64.7, 100.3
(C-2), 105.1 (C-5), 126.5, 126.7, 127.7, 128.4, 128.5, 129.0, 129.1,
129.6, 131.3, 131.9, 136.6, 144.3, 156.8 (C-6). IR (neat) 2973, 2929,
2873, 1691, 1660, 1445, 1376, 1099, 770, 740, 697 cm−1. MS (ESI,
positive mode) m/z: 451 and 453 [M + H + O]+. Anal. calcd
for C25H24O2Se (435.40): C, 68.96; H, 5.56. Found: C, 68.76; H,
5.64.
2-Ethoxy-3,4-dihydro-4,6-dimethyl-5-phenylselanyl-2H-pyran
(3i). Yield = 93%; yellow oil; Rf = 0.30 (AcOEt–cyclohexane, 5
1
: 95); 77Se NMR d (ppm) 318.9; H NMR d (ppm) 1.18 (d, J =
2-Ethylsulfanyl-4-methyl-5-phenylselanyl-3,4-dihydro-2H-pyran
(3m). Yield = 95%; yellow oil; Rf = 0.25 (EtOAc–cyclohexane,
7.1 Hz, 3H), 1.26 (t, J = 6.8 Hz, 3H), 1.80 (ddd, 1H, J = 6.0,
6.4, 13.6 Hz, H-3), 2.11 (ddd, 1H, J = 2.3, 6.8, 13.6 Hz, H-3),
2.12 (s, 3H), 2.41 (ddd, 1H, J = 1.2, 6.8, 13.9 Hz, H-4), 3.59 (m,
1H), 3.92 (m, 1H), 5.08 (dd, J = 2.3, 6.0 Hz, 1H, H-2), 7.13–7.25
(m, 3H), 7.30–7.34 (m, 2H). 13C NMR d (ppm) 15.4, 20.7, 21.5,
1
5: 95); H NMR d (ppm): 1.11 (d, J = 6.9 Hz, 3H), 1.33 (t, J =
7.6 Hz, 3H), 1.84 (ddd, J = 4.6, 9.4, 13.7 Hz, 1H, H-3), 2.33 (ddd,
J = 2.6, 6.3, 13.7 Hz, 1H, H-3ꢀ), 2.49 (m, 1H, H-4), 2.77 (m, 2H),
5.24 (dd, J = 2.6, 9.4 Hz, H-2), 6.90 (d, J = 1.9 Hz, 1H, H-6),
1264 | Org. Biomol. Chem., 2008, 6, 1260–1267
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7.18–7.26 (m, 3H), 7.42–7.47 (m, 2H). 13C NMR d (ppm): 15.2,
20.8, 25.1, 31.8 (C-4), 37.65 (C-3), 80.75 (C-2), 108.9 (C-5), 126.3,
129.1, 130.0, 132.3, 150.1 (C-6). IR (neat): 2963, 2925, 2869, 1607,
1578, 1476, 1438, 1375, 1299, 1266, 1202, 1143, 1112, 1000, 844,
735, 690 cm−1. MS (ESI, positive mode) m/z: 431 ([M + H + O]+)
(63), 429 (40), 243 (28), 193 (30), 191 (100), 166 (46), 143 (37), 122
(53). Anal. calcd for C14H18OSSe (313.31): C, 53.66; H, 5.79; S,
10.23. Found: C, 53.34; H, 5.68; S, 10.36.
4-Methyl-2-phenyl-5-phenylselanyl-3,4-dihydro-2H-pyran (3s).
Yield = 64%; yellow oil; Rf = 0.38 (AcOEt–cyclohexane, 3 : 97);
1H NMR d (ppm) 0.97 (d, J = 7.0 Hz, 3H), 1.69 (ddd, J = 2.4,
11.5, 13.7 Hz 1H, H-3), 2.16 (ddd, J = 1.8, 5.9, 13.7 Hz, 1H, H-3ꢀ),
2.48–2.59 (m, 1H, H-4), 4.91 (dd, J = 1.8, 11.5 Hz, 1H, H-2), 6.98
(d, J = 1.8 Hz, 1H, H-6), 7.10–7.40 (m, 10H). 13C NMR d (ppm)
20.7, 32.2 (C-4), 40.9 (C-3), 78.6 (C-2), 109.0 (C-5), 126.0, 126.2,
128.1, 128.6, 129.1, 129.9, 132.7, 140.9, 151.9 (C-6). IR (KBr):
3057, 1694, 1607, 1577, 1477, 1438, 1388, 1369, 1167, 1068, 1022,
737, 691 cm−1; MS (EI, 70 eV) m/z: 330 (34), 328 (18), 226 (100),
224 (50), 207 (26), 157 (36, PhSe+), 117 (44), 115 (40), 105 (42), 77
(52, Ph+), 51 (46), 44 (38).
2-Ethylsulfanyl-4-phenyl-5-phenylselanyl-3,4-dihydro-2H-pyran
(3n). Yield = 90%; yellow oil; Rf=0.29 (EtOAc–cyclohexane, 5:
1
95); H NMR d (ppm): 1.33 (t, 3H, J = 7.6 Hz), 2.17–2.29 (m,
1H, H-3), 2.50 (ddd, 1H, J = 2.2, 6.8, 11.7 Hz, H-3), 2.70–2.85
(m, 2H), 3.67 (ddd, J = 1.5, 6.5, 10.2 Hz, 1H, H-4), 5.26 (dd, 1H,
J = 1.9, 10.6 Hz, H-2), 7.07–7.10 (m, 2H), 7.09 (d, J = 1.5 Hz,
1H, H-6), 7.18–7.37 (m, 8H). 13C NMR d (ppm): 15.2, 24.8, 39.2
(C-3), 44.4 (C-4), 80.85 (C-2), 107.5 (C-5), 126.6, 127.0, 128.2,
128.4, 129.0, 130.9, 131.8, 142.5 (C-9), 151.6 (C-6). IR (neat):
3060, 2965, 2926, 1607, 1475, 1452, 1437, 1134, 1053, 1021, 758,
737, 700 cm−1. MS (ESI) m/z: 393 (M + H + O)+.
Typical procedure for the synthesis of selenoxides (4)
To a mixture of dihydropyran 3a (1 mmol, 297 mg) in tetrahy-
drofuran (10 ml), was added slowly H2O2 35%w in water (0.4 ml,
4 eq.) at room temperature. After the reaction was completed,
monitored by TLC (usually 2 hours), the layers were separated and
the organic one dried and concentrated under vacuum. The residue
was chromatographed on silica gel (eluent: MeOH–EtOAc, 1 : 99)
to give 200 mg (64%) of 2-ethoxy-4-methyl-5-phenylseleninyl-3,4-
dihydro-2H-pyran 4a.
2-Ethylsulfanyl-4,6-dimethyl-5-phenylselanyl-3,4-dihydro-2H-
pyran (3o). Yield = 91%; yellow oil; Rf = 0.27 (EtOAc–
1
cyclohexane, 5 : 95); H NMR d (ppm): 1.15 (d, 3H, J = 6.9
Hz), 1.34 (t, 3H, J = 7.4 Hz), 1.84 (ddd, J = 4.2, 9.4, 13.6 Hz, 1H,
H-3), 2.15 (d, 3H, J = 1.8 Hz), 2.30 (ddd, J = 2.4, 6.5, 13.6 Hz,
1H, H-3ꢀ), 2.50 (m, 1H, H-4), 2.78 (m, 2H), 5.21 (dd, 1H, J = 2.4,
9.4 Hz, H-2), 7.15–7.25 (m, 3H), 7.35–7.38 (m, 2H). 13C NMR
d (ppm): 15.3, 21.0, 21.8, 25.2, 33.3 (C-4), 38.1 (C-3), 80.5 (C-2),
104.4 (C-5), 125.7, 128.9, 129.2, 133.0, 157.2 (C-6). IR (neat): 2970,
2927, 2870, 1610, 1578, 1476, 1438, 1236, 1201, 1151, 1115, 1019,
957, 920, 734, 690 cm−1; MS (EI, 70 eV) m/z: 330 (2), 328 (5), 240
(53), 238 (30), 197 (24), 171 (13), 157 (25, PhSe+), 116 (28), 115
(34), 88 (30), 77 (24, Ph+), 60 (56), 51 (24), 44 (41), 43 (100). Anal.
calcd for C15H20OSSe (327.34): C, 55.03; H, 6.16; S, 9.80. Found:
C, 55.05; H, 5.81; S, 10.13.
2-Ethoxy-4-methyl-5-phenylseleninyl-3,4-dihydro-2H -pyran
(4a). Mixture of 2 diastereomers: 53 : 47. Yield = 64%; yellow
1
oil; Rf = 0.31 (MeOH–AcOEt, 1 : 99); H NMR d (ppm) (0.90,
1.26) (d, J = 7.0 Hz, 3H), 1.21 (t, J = 7.0 Hz, 3H), 1.76 (m, 1H,
H-3), 1.94 (m, 1H, H-3), (2.41, 2.55) (m, 1H, H-4), 3.55 (m, 1H),
3.87 (m, 1H), 5.05 (dd, J = 2.6, 5.1 Hz, 1H, H-2), (6.91, 7.04)
(s, 1H, H-6), 7.48–7.55 (m, 3H), 7.70–7.74 (m, 2H). 13C NMR d
(ppm) (15.1, 15.2), (19.8, 20.4), (24.4, 26.4, C-4), (35.4, 35.7, C-3),
(64.7, 64.8), (99.0, 99.1, C-2), (121.0, 122.2, C-5), (126.1, 126.6),
(129.2, 129.6), (131.2, 131.4), (138.2, 140,1), (146.1, 148.6, C-6).
IR (neat): 3418, 3054, 2930, 1732, 1622, 1456, 1442, 1378, 1279,
1139, 1096, 1076, 1021, 990, 816, 744, 691 cm−1; MS (EI, 70 eV)
m/z: 314 (44), 312 (40), 234 (20), 232 (12), 157 (100, PhSe+), 154
(60), 117 (15), 78 (16), 77 (75, Ph+), 51 (68), 50 (38).
2-Ethylsulfanyl-6-methyl-4-phenyl-5-phenylselanyl-3,4-dihydro-
2H-pyran (3p). Yield = 90%; yellow oil; Rf = 0.33 (EtOAc–
Cyclohexane, 5 : 95); 1H NMR d (ppm): 1.34 (t, 3H, J = 7.4 Hz),
2.21 (d, J = 1.8 Hz, 3H), 2.15–2.25 (m, 1H, H-3), 2.46 (ddd, J =
1.9, 6.9, 15.6 Hz, 1H, H-3ꢀ), 2.80 (m, 2H), 3.73 (m, 1H, H-4), 5.23
(dd, 1H, J = 1.9, 10.8 Hz, H-2), 7.07–7.10 (m, 2H), 7.18–7.28 (m,
8H). 13C NMR d (ppm): 15.3, 20.95, 24.8, 40.2 (C-3), 46.35 (C-4),
80.7 (C-2), 102.8 (C-5), 126.0, 126.85, 128.0, 128.5, 129.1, 129.6,
132.6, 144.1, 158.85 (C-6). IR (neat): 3058, 3026, 2964, 2925,
2869, 1626, 1577, 1492, 1475, 1453, 1436, 1375, 1265, 1211, 1052,
1014, 972, 735, 701 cm−1; MS (ESI, positive mode) m/z: 407 ([M
+ H+O]+, 100), 405 (55), 319 (29); Anal. calcd for C20H22OSSe
(389.40): C, 61.68; H, 5.69; S, 8.23. Found: C, 61.35; H, 5.85; S,
8.57.
2-Ethoxy-3,4-dihydro-4,6-diphenyl-5-phenylseleninyl-2H-pyran
(4l). Yield = 80%; yellow oil; Rf = 0.34 (AcOEt–cyclohexane,
1
80 : 20); H NMR d (ppm) 1.16 (t, J = 7.1 Hz, 3H), 2.07–2.26
(m, 2H, H-3), 3.54–3.65 (m, 2H), 3.96 (m, 1H), 5.14 (dd, J =
2.4, 7.1 Hz, 1H, H-2), 7.10–7.53 (m, 13H), 7.73–7.78 (m, 2H).
13C NMR d (ppm) 15.1, 39.3 (C-4), 39.7 (C-3), 64.8, 100.6 (C-2),
118.1 (C-5), 126.8, 126.9, 128.0, 128.4, 128.8, 129.0, 129.8, 130.6,
130.7, 134.1, 140.6, 141.3, 160.3 (C-6). IR (neat) 3418, 3061, 2976,
2931, 2360, 2340, 1652, 1615, 1574, 1494, 1455, 1445, 1379, 1275,
1134, 1058, 938, 808, 741, 699 cm−1. MS (ESI, positive mode)
m/z: 453 [M + H]+ (100), 451 (80).
Typical procedure for the synthesis of tetrahydrofuranones (5)
4-Methyl-2,5-bis-phenylselanyl-3,4-dihydro-2H-pyran
(3q).
Yield = 80%; yellow oil; Rf = 0.60 (EtOAc–cyclohexane, 5 : 95);
1H NMR d (ppm): 1.15 (d, 3H, J = 6.9 Hz), 1.98–2.07 (m, 1H,
H-3), 2.45–2.59 (m, 2H, H-4, H-3), 5.76 (dd, 1H, J = 3.2, 8.2 Hz,
H-2), 6.89 (d, 1H, J = 1.5 Hz, H-6), 7.15–7.67 (m, 10H). 13C
NMR d (ppm): 21.1, 31.6 (C-4), 38.2 (C-3), 78.9 (C-2), 109.1
(C-5), 126.4, 128.2, 129.1, 129.2, 129.3, 130.1, 134.5, 135.3, 149.5
(C-6). IR (neat): 3056, 2961, 2922, 1686, 1579, 1476, 1436, 1301,
1229, 1190, 1140, 1107, 1022, 999, 847, 741, 690 cm−1.
To a mixture of dihydropyran 3a (1 mmol, 297mg) in
dichloromethane (10 ml), was added slowly H2O2 35%w in water
(0.4 ml, 4 eq.) at room temperature. After the reaction was
completed, monitored by TLC, the layers were separated and
the organic one dried and then concentrated under vacuum. The
residue was chromatographed on silica gel (eluent: ethyl Acetate–
cyclohexane, 10 : 90) to give 36 mg (25%) of 5-ethoxy-3-methyl-
tetrahydrofuran-2-one 5a.
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5-Ethoxy-3-methyl-tetrahydrofuran-2-one (5a). Yield = 25%;
1456, 1378, 1342, 1206, 1140, 1108, 1040, 996, 935, 899, 752, 695,
642 cm−1; MS (EI, 70 eV) m/z: 207 (24), 162 (66), 133 (56), 105
(100), 104 (31), 103 (30), 92 (10), 77 (35), 51 (22), 44 (48). Anal.
calcd for C12H14O3 (206.23): C, 69.88; H, 6.84. Found: C, 69.84;
H, 6.85.
1
yellow oil; Rf = 0.20 (cyclohexane–EtOAc, 80 : 20); H NMR d
(ppm) 1.18–1.27 (m, 6H), 1.97 (m, 1H, H-4), 2.35 (m, 1H, H-4),
2.83 (m, 1H, H-3), 3.58 (m, 1H), 3.83 (m, 1H), 5.44 (d, 1H, J =
5.6 Hz); 13C NMR d (ppm) 14.95, 15.25, 32.7 (C-3), 37.3 (C-4),
64.94, 101.8 (C-5), 180.0 (C-2). IR (neat): 2978, 2936, 1778, 1738,
1446, 1378, 1349, 1213, 1169, 1112, 1040, 981, 951, 917 cm−1; MS
(EI, 70 eV) m/z: 143 (2), 100 (42), 99 (32), 85 (43), 72 (19), 57 (96),
43 (95), 42 (95), 41 (100). Anal. calcd for C7H12O3 (144.166): C,
58.31; H, 8.39. Found: C, 57.96; H, 8.43.
1
Minor cis isomer: H NMR d (ppm) 1.29 (t, 3H, J = 7.0 Hz),
2.33 (ddd, 1H, J = 4.8, 8.2, 13.8 Hz, H-4), 2.92 (ddd, 1H, J = 5.9,
10.3, 13.8 Hz, H-4ꢀ), 3.71 (dt, J = 7.1, 9.5 Hz, 1H), 3.84 (dd, J =
8.2, 10.3 Hz, 1H, H-3), 3.98 (dt, J = 7.1, 9.5 Hz, 1H), 5.62 (dd,
1H, J = 4.8, 5.9 Hz, H-5), 7.25–7.38 (m, 5H); 13C NMR d (ppm)
15.1, 37.1 (C-4), 46.0 (C-3), 66.1, 102.9 (C-5), 127.7, 128.2, 129.0,
137.0, 176.0 (C-2). IR (neat): 2978, 2929, 1773, 1719, 1498, 1456,
1378, 1353, 1146, 1120, 1043, 996, 927, 753, 698 cm−1.
5-Ethoxy-3-((tert -butyl)dimethylsilyl-methoxy)-tetrahydro-
furan-2-one (5b). Yield = 42%; yellow oil; Rf = 0.35 (cyclo-
1
hexane–EtOAc, 90 : 10); major trans isomer: H NMR d (ppm)
0.05 (s, 6H), 0.87 (s, 9H), 1.22 (t, 3H, J = 7.1 Hz), 2.19 (ddd, 1H,
J = 1.6, 9.4, 13.4 Hz, H-4), 2.46 (ddd, 1H, J = 5.9, 8.6, 13.4 Hz,
H-4ꢀ), 2.88 (m, 1H, H-3), 3.59 (dq, J = 7.1, 9.5 Hz, 1H), 3.75 (dd,
J = 3.1, 9.9 Hz, 1H), 3.86 (dq, J = 7.0, 9.5 Hz, 1H), 3.99 (dd, J =
3.7, 10.0 Hz, 1H), 5.48 (dd, 1H, J = 1.6, 5.9 Hz, H-5); 13C NMR
d (ppm) -5.5, 15.0, 18.2, 25.8, 31.6 (C-4), 41.6 (C-3), 61.3, 65.1,
102.8 (C-5), 177.3 (C-2); IR (neat): 2956, 2931, 2858, 1782, 1472,
1446, 1377, 1349, 1259, 1116, 1004, 955, 901, 837, 779, 736 cm−1;
MS (EI, 70 eV) m/z: 230 (2), 229 (8), 218 (20), 217 (100), 171 (70),
143 (94), 129 (16), 99 (24), 75 (84). Anal. calcd for C13H26O4Si
(274.43): C, 56.90; H, 9.55. Found: C, 57.18; H, 9.63.
Minor cis isomer: 1H NMR d (ppm) 0.06 (s, 6H), 0.89 (s, 9H),
1.23 (t, 3H, J = 7.1 Hz), 2.18 (ddd, 1H, J = 4.6, 7.5, 13.5 Hz, H-4),
2.51 (ddd, 1H, J = 6.0, 9.7, 13.5 Hz, H-4), 2.78 (m, 1H, H-3), 3.63
(dq, 1H, J = 7.1, 9.3 Hz), 3.83–3.94 (m, 3H), 5.50 (dd, J = 4.6,
6.0 Hz, 1H, H-5); 13C NMR d (ppm) -5.4, 15.1, 18.4, 25.9, 31.6
(C-4), 43.2 (C-3), 62.0, 65.9, 103.6 (C-5), 176.2 (C-2).
5-Butoxy-3-phenyl-tetrahydrofuran-2-one (5f). Yield = 24%;
1
yellow oil; Rf = 0.26 (cyclohexane–EtOAc, 90 : 10); H NMR
d (ppm) 0.94 (t, 3H, J = 7.3 Hz), 1.40 (m, 2H), 1.60 (m, 2H), 2.49
(ddd, 1H, J = 5.5, 11.2, 13.3 Hz, H-4), 2.64 (ddd, 1H, J = 0.9, 8.8,
13.3 Hz, H-4), 3.58 (dt, 1H, J = 6.6, 9.5 Hz), 3.86 (dt, 1H, J =
6.6, 9.3 Hz), 4.05 (ddd, J = 0.9, 8.8, 11.2 Hz, 1H, H-3), 5.59 (d,
1H, J = 5.5 Hz, H-5), 7.25–7.40 (m, 5H); 13C NMR d (ppm) 13.9,
19.3, 31.5, 38.4 (C-4), 44.3 (C-3), 69.5, 102.0 (C-5), 127.8, 128.1,
129.0, 136.6, 177.2 (C-2), IR (neat): 3031, 2958, 2873, 1778, 1770,
1728, 1715, 1605, 1497, 1456, 1345, 1264, 1204, 1137, 1107, 1060,
998, 933, 800, 751, 696, 643 cm−1; MS (EI, 70 eV) m/z: 191 (10),
190 (52), 161 (12), 134 (28), 133 (40), 105 (100), 92 (61), 78 (28), 77
(29), 57 (21). Anal. calcd for C14H18O3 (234.29): C, 71.77; H, 7.74.
Found: C, 72.10; H, 7.69.
5-tert-Butoxy-3-phenyl-tetrahydrofuran-2-one (5g). Yield
=
30%; yellow oil; Rf = 0.20 (cyclohexane–EtOAc, 90 : 10); 1H NMR
d (ppm) 1.32 (s, 9H), 2.53 (m, 2H, H-4), 4.08 (t, 1H, J = 9.8 Hz),
5.87 (dd, 1H, J = 2.8, 3.9 Hz), 7.24–7.38 (m, 5H); 13C NMR d
(ppm) 28.8, 29.8, 39.5 (C-4), 44.7 (C-3), 97.2 (C-5), 127.7, 128.1,
129.1, 136.9, 177.3 (C-2). IR (neat): 2979, 2930, 2854, 1778, 1770,
1738, 1732, 1606, 1498, 1455, 1395, 1368, 1338, 1266, 1180, 1138,
1102, 995, 933, 900, 858, 798, 750, 694, 641 cm−1; MS (EI, 70 eV)
m/z: 191 (2), 190 (8), 161 (12), 134 (61), 133 (25), 105 (40), 104
(18), 103 (18), 92 (22), 77 (16), 57(100). Anal. calcd for C14H18O3
(234.284): C, 71.77; H, 7.74. Found: C, 71.74; H, 7.81.
3-Methyl-tetrahydro-furo[2,3-b]furan-2-one (5c). Yield = 36%;
1
yellow oil; Rf = 0.39 (cyclohexane–EtOAc, 50 : 50); H NMR d
(ppm) 1.27 (d, 3H, J = 7.3 Hz), 1.82–2.08 (m, 2H), 2.93 (m, 1H,
H-4), 3.12 (m, 1H, H-3), 3.96–4.10 (m, 2H), 6.00 (d, 1H, J = 4.8
Hz); 13C NMR d (ppm) 11.7, 25.1, 38.2 (C-4), 44.2 (C-3), 68.9,
106.6 (C-5), 177.1 (C-2). IR (neat): 2981, 2898, 1777, 1716, 1454,
1379, 1359, 1295, 1251, 1176, 1109, 953, 907, 868, 736 cm−1; Anal.
calcd for C7H10O3 (142.15): C, 59.14; H, 7.09. Found: C, 59.08; H,
7.34.
5-Ethoxy-3-(4-methoxyphenyl)-tetrahydrofuran-2-one
(5h).
Tetrahydro-furo[2,3-b]furan-2-one (5d). Yield = 30%; white
solid; m.p. 48–50 ◦C; Rf = 0.37 (cyclohexane–EtOAc, 50 : 50);
1H NMR d (ppm) 1.74–1.82 (m, 1H, H-4), 2.17–2.27 (m, 1H, H-
4ꢀ), 2.44 (dd, J = 3.4, 18.4 Hz, 1H, H-3), 2.88 (dd, J = 10.2,
18.4 Hz, 1H, H-3ꢀ), 3.12–3.20 (m, 1H, H-8), 3.90–3.99 (m, 1H,
Yield = 43%; yellow oil; Rf = 0.18 (cyclohexane–EtOAc, 90 : 10);
1H NMR d (ppm) 1.26 (t, 3H, J = 7.1 Hz), 2.46 (ddd, 1H, J =
5.7, 11.1, 13.2 Hz, H-4), 2.62 (ddd, 1H, J = 0.8, 8.8, 13.2 Hz,
H-4), 3.64 (m, 1H), 3.80 (s, 3H), 3.90 (m, 1H), 4.01 (dd, J = 8.8,
11.1 Hz, 1H, H-3), 5.58 (d, 1H, J = 5.5 Hz), 6.87–6.92 (m, 2H),
7.16–7.20 (m, 2H); 13C NMR d (ppm) 15.0, 38.4 (C-4), 43.4 (C-3),
55.4, 65.1, 101.7 (C-5), 114.4, 128.5, 129.2, 159.1, 177.5 (C-2); IR
(neat): 2978, 2933, 1771, 1615, 1515, 1445, 1342, 1249, 1206, 1181,
1142, 1104, 1035, 936, 905, 831, 804, 781, 760, 736, 689 cm−1;
MS (EI, 70 eV) m/z: 236 (13), 192 (46), 163 (92), 147 (50), 135
(100), 119 (20), 105 (16), 91 (40), 77 (20), 66 (19). Anal. calcd for
C13H16O4 (236.26): C, 66.08; H, 6.83. Found: C, 66.28; H, 6.62.
H-5), 4.06–4.13 (m, 1H, H-5ꢀ), 6.08 (d, J = 5.6 Hz, 1H, H-7); 13
C
NMR d (ppm) 32.3 (C-4), 35.0 (C-3), 38.4 (C-8), 67.4 (C-5), 108.5
(C-7), 175.5 (C-2). IR (neat): 2986, 1770, 1636, 1455, 1418, 1360,
1300, 1252, 1186, 1109, 1004, 968, 871, 834 cm−1; Anal. calcd for
C6H8O3 (128.12): C, 56.24; H, 6.29. Found: C, 56.16; H, 6.43.
5-Ethoxy-3-phenyl-tetrahydrofuran-2-one (5e). Yield = 44%;
yellow oil; major trans isomer: Rf = 0.28 (cyclohexane–EtOAc,
1
90 : 10); H NMR d (ppm) 1.26 (t, 3H, J = 7.1 Hz), 2.48 (ddd,
1-(3-Phenylfuran-2-yl)ethanone (6). Yield = 21%; yellow oil;
1
1H, J = 5.5, 11.2, 13.3 Hz, H-4), 2.63 (dd, 1H, J = 8.8, 13.3 Hz,
H-4), 3.64 (m, 1H), 3.90 (m, 1H), 4.05 (dd, J = 8.8, 11.2 Hz, 1H,
H-3), 5.58 (d, 1H, J = 5.5 Hz), 7.22–7.38 (m, 5H); 13C NMR d
(ppm) 15.1, 38.4 (C-4), 44.3 (C-3), 65.2, 101.8 (C-5), 127.8, 128.1,
129.1, 136.6, 177.2 (C-2). IR (neat): 2978, 2931, 1775, 1734, 1498,
Rf = 0.4 (AcOEt–cyclohexane, 15 : 85); H NMR d (ppm) 2.46
(s, 3H), 6.66 (d, 1H, J = 1.6 Hz, H-4), 7.36–7.44 (m, 3H), 7.55
(d, 1H, J = 1.6 Hz, H-5), 7.61–7.64 (m, 2H); 13C NMR d (ppm)
27.8, 115.0 (C-4), 128.2, 128.6, 129.3, 132.0, 133.5, 144.7 (C-5),
147.3, 188.0. IR (neat) 1676, 1565, 1503, 1474, 1448, 1394, 1356,
1266 | Org. Biomol. Chem., 2008, 6, 1260–1267
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1284, 1241, 1162, 1130, 1096, 1065, 1019, 978, 932, 886, 761, 694,
639 cm−1; MS (EI, 70 eV) m/z: 186 (92), 185 (75), 143 (4), 128
(4), 115 (100), 89 (30), 63 (18), 43 (20). Anal. calcd for C12H10O2
(186.20): C, 77.40; H, 5.41. Found: C,77.04; H, 5.80.
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32, 3119.
4-Formyloxy-2-methyl-4-phenylbutanoic acid (7s). Yield =
63%; yellow oil; Rf =0.66 (AcOEt–cyclohexane, 100 : 0); 1H NMR
d (ppm) 1.15 (d, J = 6.8 Hz, 3H), 1.74–1.82 (m, 1H, H-3), 2.34–
2.44 (m, 2H), 5.85 (dd, J = 5.3, 6.4 Hz, 1H, H-4), 7.16–7.28 (m,
5H), 7.98 (s, 1H). 13C NMR d (ppm) 17.1, 36.3, 39.7, 73.8, 126.7,
128.6, 128.8, 139.4, 160.4, 182.3. IR (neat): 2977, 2936, 2360, 2341,
1732, 1715, 1456, 1170, 758, 700 cm−1. MS (ESI, negative mode)
m/z: 443 ([2M − H]−, 100), 221 ([M − H]−, 37).
Acknowledgements
We gratefully acknowledge Dr Isabelle Chataigner for her help in
performing the high pressure hetero-Diels–Alder reactions. The
Conseil Re´gional Haute-Normandie is also acknowledged for
financial support to S. R. through a doctoral fellowship.
6 (a) J. Młochowski, M. Brzszcz, M. Giurg, J. Palus and H. Wo´jtowicz,
Eur. J. Org. Chem., 2003, 4329; (b) G.-J. ten Brink, J.-M. Vis, I. W. C. E.
Arends and R. A. Sheldon, J. Org. Chem., 2001, 66, 2429.
7 Such an intermediate has been observed during the oxidation of
cyclohexene to adipic acid, see: S.-O. Lee, R. Raja, K. D. M. Harris,
J. M. Thomas, B. F. G. Johnson and G. Sankar, Angew. Chem., Int. Ed.,
2003, 42, 1520.
Notes and references
8 A. Armstrong and H. Chung, Tetrahedron Lett., 2006, 47, 1617.
9 D. Enders, J. Vazquez and G. Raabe, Eur. J. Org. Chem., 2000, 893–901.
1 (a) T. Wirth, Organoselenium Chemistry: Modern developments in
Organic Synthesis, Springer, Berlin, 2000; (b) T. G. Back, Organoselenium
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