Diastereoselective synthesis of 4,5-dihydrofurans by iodoenolcyclisation of 2-allyl-1,3-dicarbonyl compounds

Article abstract of DOI:10.1016/S0040-4020(02)01064-5

A study of the stereochemical aspects of I₂-induced cyclisation of 2-alkenyl-1,3-dicarbonyl compounds reveals that the iodoenolcyclisation is strictly dependent on the dicarbonyl species and the substituents in the allylic position.

Full text of DOI:10.1016/S0040-4020(02)01064-5

Tetrahedron 58 (2002) 8825–8831
Diastereoselective synthesis of 4,5-dihydrofurans by
iodoenolcyclisation of 2-allyl-1,3-dicarbonyl compounds
*
Roberto Antonioletti, Savina Malancona and Paolo Bovicelli
`
C.N.R. Istituto di Chimica Biomolecolare-Sezione di Roma, c/o Dipartimento di Chimica, Universita di Roma ‘La Sapienza’,
p.le A.Moro 5 Box 34 Roma 62, I-00185 Roma, Italy
Received 6 March 2002; revised 30 July 2002; accepted 22 August 2002
Abstract—A study of the stereochemical aspects of I2-induced cyclisation of 2-alkenyl-1,3-dicarbonyl compounds reveals that the
iodoenolcyclisation is strictly dependent on the dicarbonyl species and the substituents in the allylic position. q 2002 Elsevier Science Ltd.
All rights reserved.
Owing to the importance of dihydrofuran derivatives as
chemical units present in a large variety of naturally
occurring substances,1 their synthesis has attracted increas-
ing attention, and a whole series of new synthetic methods
have recently been reported.2 In previous papers3 we
reported preliminary results for a general route to sub-
stituted dihydrofurans and dihydropyrans from 2-alkenyl-
1,3-dicarbonyl compounds by I2-induced cyclisation.
stereochemical course of the process. Performing the
iodoenolcyclisation reaction on substrates 1a–d6 [iodine
(2 equiv.) and anhydrous Na2CO3 (2 equiv.) in CH2Cl2,
0.1 M] we observed that b-diketones (1c and 1d) gave cis
isomers 2 as main products, while b-keto esters (1a and 1b)
gave products with diastereoselectivities depending on R.
These results prompted us to better investigate the effects
controlling the stereochemistry of iodoenolcyclisation
reactions, also in the light of literature reports7 on
iodolactonisations and iodoetherifications. Initially we had
to fully characterise reaction products since data reported in
the literature are few and uncertain.8 To this end, 1c was
submitted to iodoenocyclisation to give 2c and 3c as a
mixture of two diastereoisomers of which we determined
In the course of our studies on the iodocyclisation reaction
with the aim of preparing tetrasubstituted furans,4 we
observed that the reaction was regioselective.5 2-Allyl-1,3-
dicarbonyl compounds carrying an allylic substituent, such
as 1 (R¼Ph or Me) lead to cis- and trans-5-iodomethyl-4,5-
dihydrofurans (2 and 3, respectively) in different ratios.
Table 1 shows the effects that the active methylene
compounds and the allylic substituents have on the
1
the ratio (82:18) by H NMR spectroscopy. The chemical
shift of the proton on C-5 was 4.68 ppm for the most
Table 1. Iodoenolcyclisation of 1,3-dicarbonyl compounds
Entry
Compound
X
Y
R
%
Time (h)
cis/trans
1
2
3
4
1a
1b
1c
1d
Me
Me
Me
Me
OMe
OMe
Me
Me
Ph
Me
Ph
90
84
86
70
4
6
0.6
1
23:77
78:22
82:18
80:20
Me
Keywords: cyclisation; furans; enols and derivatives.
*
Corresponding author. Tel.: þ39-6470422; fax: þ39-649913628; e-mail: roberto.antonioletti@uniromal.it
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01064-5

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R. Antonioletti et al. / Tetrahedron 58 (2002) 8825–8831
Table 2. Differential NMR characteristics of diastereoisomers resulting
from the cyclisation reaction
methyl group on C-5. In contrast, 5 showed an NOE effect
of 4% for the methyl group on C-5 and no effect for the
proton H-4. The coupling constant Jcis (8–9 Hz) is thus
larger than Jtrans (4–6 Hz).2a,i
We also noticed a significant solvent effect on the
stereochemical course of the reaction; indeed, performing
the reaction on 1a in non polar solvents (CH2Cl2 and CCl4)
trans-selectivity was observed, while in polar or aromatic
solvents (CHCl3, ethers, acetone, benzene) cis-selectivity
was obtained. For our studies we chose CH2Cl2 as the
solvent because in it the highest diastereoselectivity and the
best chemical yields were obtained: indeed, from 1a, in
CH2Cl2 solvent, 2þ3 formed in 90% yield with 54% de
relative to the trans isomer.10
H–C
Major isomer
Minor isomer
H-4 d¼3.22, dq, J¼6.9, 7.0 Hz
d¼3.04, dq, J¼4.2, 6.0 Hz
H-5 d¼4.68, ddd, J¼7.0, 7.0, 7.8 Hz d¼4.19, ddd, J¼4.2, 5.4, 7.1 Hz
Ha-6 d¼3.29, dd, J¼7.8, 10.1 Hz
Hb-6 d¼3.38, dd, J¼7.0, 10.1 Hz
d¼3.19, dd, J¼7.1, 10.0 Hz
d¼3.21, dd, J¼5.4, 10.0 Hz
Our experiments showed that the course of the iodocycli-
sation reaction is strongly affected also by the nature of the
1,3-dicarbonyl compound. Under identical experimental
conditions, 1,3-diketones gave products having mainly cis
stereochemistry (Table 3), while with 1,3-keto esters trans
stereoselectivity was prevalent (Table 4).
abundant isomer, and at 4.19 ppm for the minor one. By
decoupling techniques we gauged the chemical shifts and
the coupling constants for both isomers and their values are
reported in Table 2.
The two protons on C-6 (CHaHbI) are diastereotopic and
appeared as the AB portion of an ABX spin system. In the
major isomer the lines were well separated while in the
minor one the signals collapsed to an apparent doublet. By
modelling examination, dihedral angles between H-4 and
H-5 resulted qcis¼108 and qtrans¼1108, respectively, the
larger coupling constant being assigned to the cis isomer.9
Moreover, full characterisation was made by NOE
measurement between the protons on C-4 and C-5. To
simplify these experiments the mixture of isomers 2cþ3c
was reductively dehalogenated, by means of (Me3Si)3SiH,
to the two 4,5-dihydrofurans 4 and 5, respectively
(Scheme 1). Results were in agreement with the preceding
observation. Indeed, upon irradiating proton H-5, 4 showed
an NOE effect of 12.5% for the proton H-4 and no effects for
Moreover, 1,3-keto esters bearing a phenyl group as the
allylic substituent led to lower stereoselectivities and, in
some cases, to an opposite one (Table 4, entries 5 and 6). To
rationalise these results we referred to models used for
iodolactonisations11 and iodoetherifications.12 The resulting
stereochemistry of the reaction is due to the diastereotopic
faces of the double bond and the presence of the substituent
R in the allylic position. The model of Chamberlain
indicates that the stereochemistry is dependent on the
relative stability of the different conformers.13
In the iodocyclisation the electrophile (Iþ) and the
nucleophile (enolic –OH) must attack from opposite faces
of the double bond and the rate-determining step of the
Scheme 1. NOE studies on diastereoisomers obtained from the cyclisation reaction.
Table 3. Cyclisation of compounds 1 with R¼Me
Entry
Compound
X
Y
Time
%
2/3
1
2
3
4
5
6
1c
1e
1a
1f
1g
1h
Me
Et
Me
Ph
iPr
nPr
Me
Et
OMe
OEt
OEt
OEt
10 min
80 min
4 h
18 h
2 h
86
82
90
90
78
91
82:18
82:18
23:77
3:97
15:85
12:88
4 h

R. Antonioletti et al. / Tetrahedron 58 (2002) 8825–8831
Table 4. Cyclisation of compounds 1 with R¼Ph
8827
Entry
Compound
X
Y
Time (h)
%
2/3
1
2
3
4
5
6
7
1d
1i
1l
1b
1m
1n
1o
Me
Et
Ph
Me
Ph
iPr
nPr
Me
Et
Ph
OMe
OEt
OEt
OEt
1
3
1
70
79
88
84
95
91
81
80:20
83:17
62:38
78:22
42:58
36:64
60:40
6
24
48
48
reaction is the formation of a p-complex between the
iodonium ion and the olefinic system, which immediately
undergoes intramolecular nucleophilic attack.14 The sub-
strate is present in two conformers: A and B (Scheme 2). In
conformer A the allylic proton is in the plane of the double
bond and R is out of plane, while in conformer B the allylic
group (R) is in the plane. When R¼Me, conformer B is the
less stable one because of the steric interaction between the
methyl group and the olefinic H, but the approach of the
electrophile is easier because the attack is on the free face.
Conversely, in conformer A there are no steric interactions,
but the approach of the electrophile is partially hindered by
the presence of the methyl group.
Thus the cis stereochemistry observed for b-diketones can
be explained on the basis of their high reactivity; Iþ
approaching from the less hindered face of conformer B and
the intermediate undergoing nucleophilic attack before
rearranging to the more stable conformer A. In the case of
the less reactive b-keto esters the two conformers have time
to equilibrate and the attack of the enol occurs on the more
stable one, leading to trans products.
When a phenyl group is present in the allylic position it is
able instead to anchimerically assist the attack of the
electrophile thus allowing preferential formation of the cis
product (Table 4, Scheme 3).
Data presented in this work show that the iodoenolcyclisa-
tion is strictly dependent on the dicarbonyl species and on
the substituents in the allylic position. Our main project is to
further investigate this reaction and to exploit the method
for the synthesis of biologically interesting natural
compounds.
Scheme 2. Proposed mechanism for the I2-induced cyclisation when
R¼Me.
1. Experimental
1.1. General procedures
1H and 13C NMR spectra were recorded in CDCl3 with
either Varian XL-300 or Varian ‘Gemini’ 200-MHz
instruments, while IR spectra were recorded in CCl4 and
CHCl3 with a Shimadzu IR-740 instrument. MS spectra
were recorded by an HP5971A/MS detector coupled with an
HP5890 gas chromatograph. The stereoselective ratios were
determined on HP 5880 and HP 5890 gas chromatographs
equipped with capillary columns. CH2Cl2 was dried by
distillation on CaH2 and stored on molecular sieves. Column
chromatography, unless otherwise stated, was carried out on
Kieselgel Merck (70–230 mesh and 230–400 mesh). All
Scheme 3. Proposed mechanism for the I2-induced cyclisation when R¼Ph.

8828
R. Antonioletti et al. / Tetrahedron 58 (2002) 8825–8831
reactions were carried out in amber-glass flasks under an
argon atmosphere.
1.2.5. cis-3-Acetyl-5-iodomethyl-2,4-dimethyl-4,5-dihydro-
1
furan (2c). H NMR (d) 1.03 (d, J¼6.9 Hz, 3H), 2.18 (d,
J¼1.0 Hz, 3H), 2.22 (s, 3H), 3.22 (dq, J¼6.9, 7.0 Hz, 1H),
3.29 (dd, J¼7.8, 10.1 Hz, part A of an ABX system, 1H),
3.38 (dd, J¼7.0, 10.1 Hz, part B of an ABX system, 1H),
4.68 (ddd, J¼6.9, 7.0, 7.8 Hz, 1H). 13C NMR (d) 1.9, 12.1,
21.6, 26.0, 38.9, 80.9, 108.5, 176.9, 199.5. MS (m/z) 280
(100, Mþ), 265 (35), 153 (65), 138 (93), 127 (20), 11 (90),
95 (74). IR (cm21) 1690, 1532, 1129, 947. Calcd for
C9H13IO2 C 38.59, H 4.68; found C 38.4, H 4.9.
1.2. General procedure for cyclisation
A solution of the a-allyl-b-dicarbonyl compound (2 mmol)
in dry CH2Cl2 (4 ml) was added to a mixture of anhydrous
Na2CO3 (4 mmol) and iodine (4 mmol) in dry CH2Cl2
(40 ml). The mixture was stirred at rt until the substrate
disappeared (TLC and GC monitoring). Et2O was added and
the organic phase was repeatedly washed with sodium
thiosulphate (2 M) and brine and finally dried over Na2SO4.
The solvent was removed under reduced pressure and the
crude products were purified by flash chromatography.
Elution with hexane/EtOAc mixtures afforded pure 5-iodo-
alkyl-4,5-dihydrofurans, as oils.
1.2.6. trans-3-Acetyl-5-iodomethyl-2,4-dimethyl-4,5-
1
dihydrofuran (3c). H NMR (d) 1.22 (d, J¼6.8 Hz, 3H),
2.20 (d, J¼1.2 Hz, 3H), 2.23 (s, 3H), 3.04 (dq, J¼6.8,
4.2 Hz, 1H), 3.19 (dd, J¼7.1, 10.0 Hz, part A of an ABX
system, 1H), 3.21 (dd, J¼5.4, 10.0 Hz, part B of an ABX
system, 1H), 4.19 (ddd, J¼4.2, 5.4, 7.1 Hz, 1H). 13C NMR
(d) 12.0, 14.2, 19.1, 26.9, 40.2, 89.0; 110.6; 176.4; 199.5.
MS (m/z) 280 (24, Mþ), 265 (19), 153 (22), 138 (100), 123
(19), 111 (98), 95 (76), 67 (21). IR (cm21) 3004, 1687,
1560, 1452, 1470, 923. Calcd for C9H13IO2 C 38.59, H 4.68;
found C 38.7, H 4.6.
1.2.1. cis-5-Iodomethyl-3-methoxycarbonyl-2,4-di-
1
methyl-4,5-dihydrofuran (2a). H NMR (d) 1.04 (d, J¼
6.9 Hz, 3H), 2.15 (d, J¼1.2 Hz, 3H), 2.97 (m, 1H), 3.30 (dd,
J¼7.3, 10.2 Hz, part A of an ABX system, 1H), 3.32 (dd,
J¼7.7, 10.2 Hz, part B of an ABX system, 1H), 3.70 (s, 3H),
4.70 (ddd, J¼7.3, 7.7, 7.8 Hz, 1H). 13C NMR (d) 1.3, 11.7,
21.1, 43.0, 52.9, 80.4, 107.6, 166.5, 171.4. MS (m/z) 296
(21, Mþ), 281 (18), 265 (10), 169 (35), 154 (41), 139 (15),
1.2.7. cis-3-Acetyl-5-iodomethyl-2-methyl-4-phenyl-4,5-
1
dihydrofuran (2d). H NMR (d) 1.87 (s, 3H); 2.37 (d, J¼
137 (31), 127 (33), 95 (100), 67 (26), 59 (30). IR (cm21
)
1.5 Hz, 3H); 2.74 (dd, J¼6.3 and 10.6 Hz, 1H, part A of an
ABX system), 2.92 (dd, J¼8.0 and 10.6 Hz, 1H, part B of an
ABX system) 4.36 (bd, J¼8.9 Hz, 1H), 5.00 (ddd, J¼6.3,
8.0, 8.9 Hz, 1H); 7.1–7.3 (m, 5H). 13C NMR (d) 1.7, 14.8,
29.2, 51.7, 86.1, 117.5, 128.0, 128.9 (2C), 129.1 (2C),
136.7, 169.1, 195.3. MS (m/z) 342 (18, Mþ), 215 (100), 173
(40), 150 (38), 128 (48), 91 (51). IR (cm21) 1640, 1596,
1392, 1219, 938. Calcd for C14H15IO2 C 49.14, H 4.42;
found C 48.9, H 4.7.
1180, 1420, 1366, 1118, 921. Calcd for C9H13IO3 C 36.51,
H 4.43; found C 36.2, H 4.6.
1.2.2. trans-5-Iodomethyl-3-methoxycarbonyl-2,4-di-
1
methyl-4,5-dihydrofuran (3a). H NMR (d) 1.21 (d, J¼
6.7 Hz, 3H), 2.18 (d, J¼1.2 Hz, 3H), 2.95 (m, 1H), 3.15 (dd,
J¼7.2, 10.0 Hz, part A of an ABX system, 1H), 3.23 (dd,
J¼5.2, 10.0 Hz, part B of an ABX system, 1H), 3.69 (s, 3H),
4.20 (ddd, J¼4.7, 5.2, 7.2 Hz, 1H). 13C NMR (d) 7.2, 11.7,
21.2, 39.1, 52.9, 79.8, 105.7, 166.3, 170.5. MS (m/z) 296
(95, Mþ), 281 (100), 265 (27), 154 (57), 137 (34), 127 (24),
95 (60), 59 (12). IR (cm21) 1601, 1385, 1320, 1080. Calcd
for C9H13IO3 C 36.51, H 4.43; found C 36.5, H 4.9.
1.2.8. trans-3-Acetyl-5-iodomethyl-2-methyl-4-phenyl-
1
4,5-dihydrofuran (3d). H NMR (d) 1.90 (s, 3H), 2.37 (d,
J¼1.5 Hz, 3H), 3.35 (bd, J¼5.6 Hz, 2H), 4.14 (bd, J¼
4.6 Hz, 1H), 4.43 (dt, J¼4.6, 5.6 Hz, 1H), 7.1–7.4 (m, 5H).
13C NMR (d) 7.6, 14.8, 29.5, 55.0, 88.7, 117.1, 127.6, 128.7
(2C), 129.2 (2C), 136.5, 168.6, 195.5. MS (m/z) 342 (19,
Mþ), 215 (100), 200 (20), 173 (38), 150 (32), 128 (52), 91
(60). IR (cm21) 1597, 1450, 1200, 940. Calcd for C14H15IO2
C 49.14, H 4.42; found C 48.9, H 4.4.
1.2.3. cis-5-Iodomethyl-3-methoxycarbonyl-2-methyl-4-
1
phenyl-4,5-dihydrofuran (2b). H NMR (d) 2.35 (d, J¼
1.1 Hz, 3H), 2.74 (dd, J¼6.3, 10.6 Hz, part A of an ABX
system, 1H), 2.92 (dd, J¼8.0, 10.6 Hz, part B of an ABX
system, 1H), 3.52 (s, 3H), 4.30 (bd, J¼8.9 Hz, 1H), 5.00
(ddd, J¼6.3, 8.0, 8.9 Hz, 1H), 7.1–7.4 (m, 5H). 13C NMR
(d) 1.9, 13.9, 50.9, 54.1, 86.1, 108.2, 127.2, 128.4 (2C),
128.7 (2C), 136.9, 165.9, 169.0. MS (m/z) 358 (40, Mþ),
199 (96), 157 (84), 128 (90), 91 (100). IR (cm21) 1645,
1333, 1200, 1094, 984. Calcd for C14H15IO3 C 46.95, H
4.22; found C 47.0, H 4.1.
1.2.9. cis-2-Ethyl-5-iodomethyl-4-methyl-3-propionyl-
4,5-dihydrofuran (2e). 1H NMR (d) 1.0–1.2 (m, 9H),
2.4–2.7 (m, 4H), 3.2 (m, 1H), 3.21 (dd, J¼6.6, 10.0 Hz, part
A of an ABX system, 1H), 3.33 (dd, J¼8.1, 10.0 Hz, part B
of an ABX system, 1H), 4.63 (ddd, J¼6.6, 8.1, 8.3 Hz, 1H).
13C NMR (d) 0.5, 7.9, 10.9, 12.6, 22.1, 33.6, 38.9, 85.3,
118.5, 171.6, 197.4. MS (m/z) 308 (14, Mþ), 279 (27), 151
(17), 95 (15), 57 (100). IR (cm21) 1686, 1561, 1389, 1268,
900. Calcd for C11H17IO2 C 42.87, H 5.56; found C 42.6, H
5.4.
1.2.4. trans-5-Iodomethyl-3-methoxycarbonyl-2-methyl-
4-phenyl-4,5-dihydrofuran (3b). 1H NMR (d) 2.34 (d,
J¼1.1 Hz, 3H), 3.28 (dd, J¼5.6, 10.4 Hz, part A of an ABX
system, 1H), 3.35 (dd, J¼6.6, 10.4 Hz, part B of an ABX
system, 1H), 3.53 (s, 3H), 4.14 (bd, J¼4.6 Hz, 1H), 4.43
(ddd, J¼4.6, 5.6, 6.6 Hz, 1H), 7.1–7.4 (m, 5H). 13C NMR
(d) 7.4, 14.1, 50.7, 54.1, 88.6, 106.4, 127.1, 127.6 (2C),
128.7 (2C), 142.8, 166.0, 168.2. MS (m/z) 358 (50, Mþ),
199 (100), 157 (88), 128 (76), 91 (46). IR (cm21) 1645,
1445, 1216, 1129, 984. Calcd for C14H15IO3 C 46.95, H
4.22; found C 46.7, H 4.4.
1.2.10. trans-2-Ethyl-5-iodomethyl-4-methyl-3-propio-
1
nyl-4,5-dihydrofuran (3e). H NMR (d) 1.0–1.2 (m, 9H),
2.4–2.7 (m, 4H), 3.0 (m, 1H), 3.10 (dd, J¼4.5, 10.0 Hz, part
A of an ABX system, 1H), 3.19 (dd, J¼5.3, 10.0 Hz, part B
of an ABX system, 1H), 4.18 (ddd, J¼4.5, 5.3, 7.6 Hz, 1H).
13C NMR (d) 7.1, 7.9, 10.9, 12.6, 22.0, 33.8, 43.0, 87.5,
125.2, 171.6, 199.5. MS (m/z) 308 (42, Mþ), 279 (100), 223

R. Antonioletti et al. / Tetrahedron 58 (2002) 8825–8831
8829
(12), 166 (18), 151 (20), 95 (18), 57 (74). IR (cm21) 1698,
1571, 1409, 1380, 900. Calcd for C11H17IO2 C 42.87, H
5.56; found C 42.8, H 5.8.
7.4, Hz, 1H). 13C NMR (d) 7.7, 12.9, 13.0, 14.5, 20.9, 30.1,
39.2, 59.9, 88.0, 107.5, 166.1, 171.0. MS (m/z) 338 (100,
Mþ), 323 (90), 295 (22), 293 (47), 196 (23), 165 (34), 123
(55) 71 (42). IR (cm21) 2986, 1600, 1369, 1309, 1120, 910.
Calcd for C12H19IO3 C 42.62, H 5.66; found C 42.6, H 5.6.
1.2.11. trans-5-Iodomethyl-3-ethoxycarbonyl-4-methyl-
1
2-phenyl-4,5-dihydrofuran (3f). H NMR (d) 1.19 (t, J¼
7.0 Hz, 3H), 1.34 (d, J¼6.6 Hz, 3H), 3.20 (dq, J¼4.6,
6.6 Hz, 1H), 3.28 (dd, J¼7.4, 10.2 Hz, part A of an ABX
system, 1H), 3.32 (dd, J¼5.5, 10.2 Hz, part B of an ABX
system, 1H), 4.12 (d, J¼7.0 Hz, 2H), 4.33 (ddd, J¼4.6, 5.5,
7.4 Hz, 1H), 7.3–7.5 (m, 3H), 7.6–7.8 (m, 2H). 13C NMR
(d) 7.7, 14.4, 21.0, 44.9, 60.1, 87.4, 108.1, 128.1 (2C), 130.1
(2C); 130.4; 131.0, 164.6, 165.6. MS (m/z) 372 (17, Mþ),
1.2.16. cis-2-Ethyl-5-iodomethyl-4-phenyl-3-propionyl-
4,5-dihydrofuran (2i). 1H NMR (d) 0.82 (t, J¼7.2 Hz,
3H); 1.20 (t, J¼7.5 Hz, 3H); 1.90 (dq, J¼7.2, 17.7 Hz, 1H);
2.30 (dq, J¼7.2, 17.7 Hz, 1H); 2.71 (dd, J¼6.7, 10.4 Hz,
part A of an ABX system, 1H); 2.81 (bq, J¼7.5 Hz, 2H);
2.95 (dd, J¼7.5 and 10.4 Hz, part B of an ABX system, 1H);
4.34 (bd, J¼8.8 Hz, 1H); 4.97 (ddd, J¼6.7, 7.5, 8.8 Hz, 1H);
7.4–7.1 (m, 5H). 13C NMR (d) 1.7, 7.4, 11.0, 21.8, 34.1,
51.3, 86.1, 115.9, 127.4, 128.0 (2C), 128.8 (2C), 136.8,
173.5, 198.1. MS (m/z) 370 (10, Mþ), 293 (75), 236 (51),
152 (100), 129 (43), 90 (33), 77 (79); IR (cm21) 1656, 1520,
1407, 1298, 900. Calcd for C16H19IO2 C 51.91, H 5.17;
found C 51.8, H 5.3.
199 (10), 157 (29), 128 (11), 105 (100), 77 (38). IR (cm21
)
1700, 1611, 1325, 1210, 1034, 980. Calcd for C15H17IO3 C
48.40, H 4.60; found C 48.2, H 4.4.
1.2.12. cis-3-Ethoxycarbonyl-5-iodomethyl-2-isopropyl-
4-methyl-4,5-dihydrofuran (2g). 1H NMR (d) 1.06 (d,
J¼7.1 Hz, 6H), 1.21 (t, J¼7.1 Hz, 3H), 1.28 (d, J¼7.0 Hz,
3H), 2.87 (dq, J¼7.0, 8.4 Hz, 1H), 3.28 (dd, J¼8.0, 9.9 Hz,
part A of an ABX system, 1H), 3.34 (dd, J¼6.3, 9.9 Hz, part
B of an ABX system, 1H), 3.51 (heptet, J¼7.1 Hz, 1H), 4.16
(q, J¼7.1 Hz, 2H), 4.68 (ddd, J¼6.3, 8.0, 8.4 Hz, 1H). 13C
NMR (d) 0.5, 12.3, 13.9, 18.1, 20.5, 29.5, 47.1, 61.5, 84.5,
1.2.17. trans-2-Ethyl-5-iodomethyl-4-phenyl-3-propio-
nyl-4,5-dihydrofuran (3i). 1H NMR (d) 0.86 (t, J¼
7.2 Hz, 3H); 1.22 (t, J¼7.5 Hz, 3H); 1.95 (dq, J¼7.2,
17.7 Hz, 1H); 2.30 (dq, J¼7.2, 17.7 Hz, 1H); 2.80 (bq,
J¼7.5 Hz, 2H); 3.31 (ddd, J¼5.4, 6.4, 10.2 Hz, 2H); 4.12
(bd, J¼4.3 Hz, 1H); 4.36 (ddd, J¼4.3, 5.4, 6.4 Hz, 1H);
7.1–7.4 (m, 5H). 13C NMR (d) 1.6, 7.8, 11.1, 21.8, 34.5,
54.6, 88.4, 113.6, 128.0, 128.9 (2C), 129.0 (2C), 142.8;
173.1; 198.2. MS (m/z) 370 (12, Mþ), 293 (81), 236 (28),
152 (100), 129 (45), 90 (23), 77 (87). IR (cm21) 1670, 1587,
1467, 1390, 910. Calcd for C16H19IO2 C 51.91, H 5.17;
found C 51.7, H 5.2.
107.3, 165.7, 175.8. MS (m/z) 338 (100, Mþ). IR (cm21
)
1620, 1460, 1325, 1024, 910. Calcd for C12H19IO3 C 42.62,
H 5.66; found C 42.5, H 5.4.
1.2.13. trans-3-Ethoxycarbonyl-5-iodomethyl-2-isopro-
pyl-4-methyl-4,5-dihydrofuran (3g). 1H NMR (d) 1.08
(d, J¼7.0 Hz, 6H), 1.21 (d, J¼6.7 Hz, 3H), 1. 25 (t, J¼
7.1 Hz, 3H), 2.95 (dq, J¼4.1, 6.7 Hz, 1H), 3.13 (dd, J¼7.3,
10.1 Hz, part A of an ABX system, 1H), 3.21 (dd, J¼5.2,
10.1 Hz, part B of an ABX system, 1H), 3.55 (heptet,
J¼7.0 Hz, 1H), 4.14 (q, J¼7.1 Hz, 2H), 4.16 (ddd, J¼4.1,
5.2, 7.3, Hz, 1H). 13C NMR (d) 7.3, 14.1, 19.1, 19.5, 20.5,
26.7, 42.8, 59.3, 87.3, 105.1, 165.9, 174.8. MS (m/z) 338
(100, Mþ), 323 (93), 295 (25), 293 (41), 196 (23), 167 (22),
165 (31), 123, (50), 95 (20), 71 (35). IR (cm21) 1620, 1460,
1325, 1024, 910. Calcd for C12H19IO3 C 42.62, H 5.66;
found C 42.8, H 5.6.
1.2.18. cis-3-Benzoyl-5-iodomethyl-2,4-diphenyl-4,5-
1
dihydrofuran (2l). H NMR (d) 2.88 (dd, J¼6.3, 10.5 Hz,
part A of an ABX system, 1H), 3.15 (dd, J¼7.9, 10.5 Hz,
part B of an ABX system, 1H), 4.71 (d, J¼8.7 Hz, 1H), 5.25
(ddd, J¼6.3, 7.9, 8.7 Hz, 1H), 7.0–7.5 (m, 15H). 13C NMR
(d) 1.8, 54.3, 85.8, 116.9, 127.8 (2C), 128.0 (4C), 128.8
(2C), 129.1 (2C), 129.5, 129.8 (2C), 130.7, 131.5, 136.7,
138.9, 166.1, 192.7. MS (m/z) 235 (36), 105 (100), 77 (82),
51 (18). IR (cm21) 1723, 1685, 1478, 1378. Calcd for
C24H19IO2 C 61.82, H 4.11; found C 61.6, H 3.9.
1.2.14. cis-3-Ethoxycarbonyl-5-iodomethyl-4-methyl-2-
1
propyl-4,5-dihydrofuran (2h). H NMR (d) 0.91 (t, J¼
1.2.19. trans-3-Benzoyl-5-iodomethyl-2,4-diphenyl-4,5-
1
7.5 Hz, 3H), 1.05 (d, J¼7.4 Hz, 3H), 1.18 (t, J¼7.1 Hz, 3H),
1.5–1.7 (m, 2H), 2.4–2.7 (m, 3H), 3.26 (dd, J¼6.9,
10.4 Hz, part A of an ABX system, 1H), 3.37 (dd, J¼7.3,
10.4 Hz, part B of an ABX system, 1H), 4.15 (q, J¼7.1 Hz,
2H), 4.67 (ddd, J¼6.9, 7.3, 8.1 Hz, 1H). 13C NMR (d) 0.3,
12.8, 13.9, 14.5, 20.4, 29.9, 43.3, 59.7, 85.6, 109.7, 166.3,
171.6. MS (m/z) 338 (15, Mþ), 323 (12), 196 (16), 165 (32),
123 (65), 95 (22), 71 (100). IR (cm21) 2990, 1702, 1501,
1381, 1111, 910. Calcd for C12H19IO3 C 42.62, H 5.66;
found C 42.9, H 5.9.
dihydrofuran (3l). H NMR (d) 3.49 (dd, J¼5.3, 10.5 Hz,
part A of an ABX system, 1H), 3.56 (dd, J¼5.7 and 10.5 Hz,
part B of an ABX system, 1H), 4.57 (d, J¼6.0 Hz, 1H), 4.68
(ddd, J¼5.3, 5.7, 6.0 Hz, 1H), 7.0–8.0 (m, 15H). 13C NMR
(d) 7.4, 57.6, 88.0, 115.8, 127.6 (2C), 127.8 (4C), 128.5,
128.6, 128.9, 129.0 (4C), 130.4, 136.0, 131.5, 140.0, 142.0,
164.5, 196.1. MS (m/z) 235 (57), 105 (100), 77 (60), 51 (16).
IR (cm21) 1623, 1600, 1500, 1360, 1210, 1123. Calcd for
C24H19IO2 C 61.82, H 4.11; found C 61.6, H 4.0.
1.2.20. cis-3-Ethoxycarbonyl-5-iodomethyl-2,4-diphe-
nyl-4,5-dihydrofuran (2m). 1H NMR (d) 0.98 (t, J¼
7.0 Hz, 3H), 2.84 (dd, J¼6.8, 10.4 Hz, part A of an ABX
system, 1H), 3.10 (dd, J¼7.5, 10.4 Hz, part B of an ABX
system, 1H), 3.95 (q, J¼7.0 Hz, 2H), 4.52 (d, J¼8.9 Hz,
1H), 5.15 (ddd, J¼6.8, 7.5, 8.9 Hz, 1H), 7.1–7.4 (m, 10H).
13C NMR (d) 1.5, 13.6, 55.7, 59.7, 85.4, 106.9, 127.2 (2C),
127.6, 127.8 (2C), 128.7 (2C), 128.9 (2C), 131.0, 137.0,
1.2.15. trans-3-Ethoxycarbonyl-5-iodomethyl-4-methyl-
2-propyl-4,5-dihydrofuran (3h). 1H NMR (d) 0.92 (t,
J¼7.2 Hz, 3H), 1.22 (d, J¼6.6 Hz, 3H), 1.26 (t, J¼7.1 Hz,
3H), 1.5–1.7 (m, 2H), 2.4–2.7 (m, 2H), 2.97 (dq, J¼4.4,
6.6 Hz, 1H), 3.14 (dd, J¼7.4, 10.1 Hz, part A of an ABX
system, 1H), 3.23 (dd, J¼5.5, 10.1 Hz, part B of an ABX
system, 1H), 4.14 (q, J¼7.2 Hz, 2H), 4.16 (ddd, J¼4.4, 5.5,

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R. Antonioletti et al. / Tetrahedron 58 (2002) 8825–8831
142.9, 164.7, 165.6. MS (m/z) 434 (4, Mþ), 261 (15), 105
(100), 77 (19). IR (cm21) 1685, 1512, 1380, 1210, 1086.
Calcd for C20H19IO3 C 56.31, H 4.41; found C 56.5, H 4.6.
J¼4.2 Hz, 1H), 4.46 (ddd, J¼4.2, 5.6, 7.1 Hz, 1H), 7.1–
7.4 (m, 5H). 13C NMR (d) 7.5, 13.7, 13.8, 20.3, 30.1, 54.3,
59.3, 88.3, 108.3, 127.0, 127.5 (2C), 128.5 (2C), 143.1,
165.5, 171.5. MS (m/z) 400 (25, Mþ), 227 (45), 157 (100),
129 (35), 91 (32), 71 (50). IR (cm21) 1640, 1325, 1200,
1117. Calcd for C17H21IO3 C 51.01, H 5.29; found C 51.3, H
5.3.
1.2.21. trans-3-Ethoxycarbonyl-5-iodomethyl-2,4-diphenyl-
1
4,5-dihydrofuran (3m). H NMR (d) 0.98 (t, J¼7.0 Hz,
3H), 3.45 (d, J¼6.0 Hz, 2H), 3.95 (q, J¼7.0 Hz, 2H), 4.28
(d, J¼4.5 Hz, 1H), 4.60 (dt, J¼4.5, 6.0 Hz, 1H), 7.2–7.5 (m,
8H), 7.8–8.0 (m, 2H). 13C NMR (d) 7.5, 13.6, 52.5, 59.7,
87.5, 106.9, 127.5 (2C), 127.8 (2C), 128.5 (2C), 128.8,
129.7 (2C), 130.9, 137.0, 142.9, 164.8, 165.6. MS (m/z) 434
(8, Mþ), 261 (14), 105 (100), 77 (19). IR (cm21) 1615,
1467, 1310. Calcd for C20H19IO3 C 56.31, H 4.41; found C
56.3, H 4.5.
1.3. Dehalogenation of 3-acetyl-5-iodomethyl-2,4-dimethyl-
4,5-dihydrofuran
1.1 mmol of tris(trimethylsilyl)silane and AIBN (0.1 mmol)
were added to a solution of iododihydrofuran 2cþ3c in
benzene (10 ml). The solution was refluxed (808C) for 1 h
until all substrate was used up (TLC).Then the solvent was
evaporated and the crude was purified by chromatography
on silica gel, eluting with hexane/diethyl ether 9:1, in order
to obtain dihydrofurans 4 and 5.
1.2.22. cis-2-Isopropyl-3-ethoxycarbonyl-4-phenyl-5-
1
iodomethyl-4,5-dihydrofuran (2n). H NMR (d) 0.99 (t,
J¼7.0 Hz, 3H), 1.16 (d, J¼6.0 Hz, 3H), 1.23 (d, J¼5.8 Hz,
3H), 2.74 (dd, J¼7.0, 10.3 Hz, part A of ABX system, 1H),
3.01 (dd, J¼7.3, 10.3 Hz, part B of ABX system, 1H), 3.7
(m, 1H), 3.97 (q, J¼7.0 Hz, 2H), 4.30 (d, J¼8.9 Hz, 1H),
4.93 (ddd, J¼7.0, 7.3, 8.9 Hz, 1H), 7.17.4 (m, 5H). 13C
NMR (d) 1.8, 13.8, 19.4 (2C), 26.9, 50.9, 59.3, 85.8, 106.6,
127.3 (2C), 128.4 (2C), 128.8, 137.4, 165.4, 176.6. MS (m/z)
400 (4, Mþ), 274 (21), 233 (91), 204 (37), 203 (42), 189
(30), 185 (65), 159 (100), 134 (46), 131 (60), 117 (79), 115
(56), 91 (51), 77 (18), 71 (40). IR (cm21) 1687, 1467, 1347,
1101. Calcd for C17H21IO3 C 51.01, H 5.29; found C 50.9, H
5.3.
1.3.1. cis-3-Acetyl-2,4,5-trimethyl-4,5-dihydrofuran (4).
1H NMR (d) 0.98 (d, J¼6.9 Hz, 3H), 1.31 (d, J¼6.6 Hz,
3H), 2.17 (d, J¼1.5 Hz, 3H), 2.20 (s, 3H), 3.02 (ddq, J¼1.5,
6.9, 8.3 Hz, 1H), 4.60 (dq, J¼6.6, 8.3 Hz, 1H). 13C NMR(d)
16.1, 25.2, 26.45, 26.8, 43.1, 89.2, 102.3, 176.7, 194.5.
Calcd for C9H14O2 C 70.10, H 9.15; found C 69.9, H 9.1.
1.3.2. trans-3-Acetyl-2,4,5-trimethyl-4,5-dihydrofuran
(5). 1H NMR (d) 1.13 (d, J¼6.6 Hz, 3H), 1.25 (d, J¼
6.2 Hz, 3H), 2.15 (d, J¼1.5 Hz, 3H), 2.25 (s, 3H), 2.75 (ddq,
J¼1.5, 4.8, 6.6 Hz, 1H), 4.19 (dq, J¼4.8, 6.2 Hz, 1H). 13C
NMR (d) 16.3, 26.3, 27.0, 27.5, 47.2, 95.2, 109.5, 176.3,
196.6. Calcd for C9H14O2 C 70.10, H 9.15; found C 69.8, H
9.4.
1.2.23. trans-2-Isopropyl-3-ethoxycarbonyl-5-iodo-
methyl-4-phenyl-4,5-dihydrofuran (3n). 1H NMR (d)
1.01 (t, J¼7.2 Hz, 3H), 1.16 (d, J¼4.9 Hz, 3H), 1.21 (d,
J¼5.5 Hz, 3H), 3.27 (dd, J¼6.4, 10.0 Hz, part A of an ABX
system, 1H), 3.32 (dd, J¼5.6, 10.0 Hz, part B of an ABX
system, 1H), 3.7 (m, 1H), 3.95 (q, J¼7.2 Hz, 2H), 4.02 (d,
J¼4.0 Hz, 1H), 4.46 (ddd, J¼4.0, 5.6, 6.4 Hz, 1H); 7.1–7.4
(m, 5H). 13C NMR (d) 7.6, 13.8, 19.6 (2C), 26.8, 54.1, 59.3,
88.0, 104.6, 127.1, 127.5 (2C), 128.7 (2C), 143.3, 165.5,
175.7. MS (m/z) 400 (7, Mþ), 274 (63), 226 (35), 210 (21),
185 (100), 159 (15), 129 (22), 117 (18), 115 (15), 91 (18), 77
(10). IR (cm21) 1623, 1577, 1322, 1023. Calcd for
C17H21IO3 C 51.01, H 5.29; found C 50.9, H 5.6.
References
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1.2.24. cis-3-Ethoxycarbonyl-5-iodomethyl-4-phenyl-2-
1
propyl-4,5-dihydrofuran (2o). H NMR (d) 1.01 (t, J¼
7.2 Hz, 3H), 1.03 (t, J¼7.3 Hz, 3H), 1.6–1.8 (m, 2H), 2.6–
2.8 (m, 2H), 2.75 (dd, J¼6.4, 10.6 Hz, part A of an ABX
system, 1H), 2.97 (dd, J¼7.8, 10.6 Hz, part B of an ABX
system, 1H), 3.98 (q, J¼7.2 Hz, 2H), 4.31 (d, J¼9.2 Hz,
1H), 4.96 (ddd, J¼6.4, 7.8, 9.2 Hz, 1H), 7.1–7.4 (m, 5H).
13C NMR (d) 2.0, 13.8 (2C), 20.3, 29.6, 51.1, 59.3, 85.8,
106.4, 128.4 (2C), 128.7 (2C), 128.8, 137.3, 165.4, 172.4.
MS (m/z) 400 (16, Mþ), 227 (37), 157 (100), 129 (46), 91
(86), 71 (68). IR (cm21) 1690, 1381, 1208, 1100. Calcd for
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1.2.25. trans-3-Ethoxycarbonyl-5-iodomethyl-4-phenyl-
2-propyl-4,5-dihydrofuran (3o). 1H NMR (d) 0.97 (t,
J¼7.0 Hz, 3H), 1.04 (t, J¼7.2 Hz, 3H), 1.6–1.8 (m, 2H),
2.6–2.8 (m, 2H), 3.25 (dd, J¼5.6, 10.2 Hz, part A of an
ABX system, 1H), 3.31 (dd, J¼7.1, 10.2 Hz, part B of an
ABX system, 1H), 3.92 (q, J¼7.2 Hz, 2H), 4.06 (d,

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hexane 35:65 (38%), CHCl3 70:30 (43%), DME 69:31 (81%),
Et2O 72:28 (40%), acetone 58:42 (35%), benzene 57:43
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