Iodoenolcyclisation of 2-(1,3-disubstituted-1-allyl)-1,3-dicarbonyl compounds: Diastereoselective synthesis of tetrasubstituted dihydrofurans

Article abstract of DOI:10.1016/S0040-4020(03)00136-4

The I₂-induced cyclisation of 2-alkenyl-1,3-dicarbonyl compounds with the mono- and di-substituted double bond occurred with good diastereoselectivity. A study of stereochemical aspects for different substituents on the allyl side chain was car

Full text of DOI:10.1016/S0040-4020(03)00136-4

Tetrahedron 59 (2003) 1673–1678
Iodoenolcyclisation of 2-(1,3-disubstituted-1-allyl)-1,3-dicarbonyl
compounds: diastereoselective synthesis of
tetrasubstituted dihydrofurans
*
Roberto Antonioletti, Savina Malancona, Fabrizio Cattaruzza and Paolo Bovicelli
C.N.R. Istituto di Chimica Biomolecolare—Sezione di Roma, c/o Dipartimento di Chimica, Universit a` di Roma “La Sapienza”,
p.le A. Moro 5, Box 34 Roma 62, I-00185 Rome, Italy
Received 14 October 2002; revised 19 December 2002; accepted 23 January 2003
2
Abstract—The I -induced cyclisation of 2-alkenyl-1,3-dicarbonyl compounds with the mono- and di-substituted double bond occurred with
good diastereoselectivity. A study of stereochemical aspects for different substituents on the allyl side chain was carried out. When the
substituents were alkyl groups, the trans isomers formed preferentially, in the case of aromatic substituents the reaction lead instead to cis
isomers. q 2003 Elsevier Science Ltd. All rights reserved.
In consideration of the increasing attention that the synthesis
1
tuted. With this aim we submitted a number of a-allyl-
acetoacetic derivatives to the iodoenolcyclisation reaction
(Scheme 1), the results of which are presented in Table 1.
of dihydrofuran derivatives has attracted in the last years,
we have investigated the I -induced cyclisation of 2-allyl-
2
1
,3-dicarbonyl compounds. As reported, we observed that
the reaction leading to dihydrofuran derivatives is regio-
specific when the double bond is monosubstituted and regio-
and stereospecific when the double bond is a disubstituted
When the R substituent in the allylic position was an alkyl
group the trans isomers formed preferentially, and the larger
the bulk of R the higher the diastereoselectivity. Compound
1d represented an exception due to the strong steric
hindrance exerted by the t-butyl group which made the
approach of an electrophile in conformer A (see Scheme 3
and discussion below) very difficult. When the substituent
was an aromatic group, a coordination with the approaching
electrophile appears possible thus leading the reaction
towards the cis isomer.
2
one. Compounds with trisubstituted double bonds led to
3
mixtures of dihydrofurans and dihydropyrans. In our
4
previous papers we reported that the 4,5-diastereo-
selectivity is dependent on the nature of the b-dicarbonyl
starting materials and on that of the groups (methyl or
phenyl) substituting the allyl side chain. In the same paper
the stereochemical assignments were made on the basis of
the coupling constant of the prontons on C-4 and C-5 (larger
in the cis isomers), confirmed by NOE experiments. The
same criteria were used to assign the stereochemistry of the
products described in the present paper.
We then extended our investigation to substrates with
disubstituted double bonds and found that the course of the
I2-induced cyclisation was essentially independent of the
nature of the b-dicarbonyl moiety giving, in all cases, trans
tetrasubstituted dihydrofurans with high diastereo-
selectivities. Table 2 shows the results for both b-keto
esters and b-diketones (Scheme 2).
Pursuing the matter further we investigated the effect of the
substituent borne by the allyl side chain on the 4,5-
diastereoselectivity when the double bond is monosubsti-
Scheme 1. I
2
-induced cyclisation of 2-(1-substituted-1-allyl)acetoacetic esters.
Keywords: iodocyclization; 1,3-dicarbonyl compounds; 2,3-dihydrofurans; furans.
*
Corresponding author. Tel.: þ39-6490422; fax: þ39-649913628; e-mail: roberto.antonioletti@uniroma1.it
040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
0
doi:10.1016/S0040-4020(03)00136-4

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R. Antonioletti et al. / Tetrahedron 59 (2003) 1673–1678
Table 1. Effect of the substituent on the cyclisation of 2-(1-substituted-1-
allyl)acetoacetic esters
These findings seem to confirm the mechanism proposed by
4
us for the I -induced cyclisation (Scheme 3).
2
Entry
Compound
R
2/3 ratio
Time (h)
Yield (%)
The relative stability and reactivity of the two conformers,
A and B, of the substrate should determine the stereo-
chemistry of the products. In this model, the cis products
derive from the less stable and more reactive conformer B,
since the electrophile approaches from the less hindered
face, and the intermediate undergoes nucleophilic attack
before rearranging to the more stable conformer A.
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
Me
Pr
i-Pr
t-Bu
Ph
77:23
78:22
95:5
77:23
22:78
3:97
4
4
6
6
6
5
90
85
77
72
84
20
2-Furyl
When the allyl chain is disubstituted the transition state
leading to the cis compound becomes hindered and
conformer B, for this reason, less reactive. In this case,
the transition state for the reaction between iodine and
conformer A is lower in energy than that resulting from
conformer B.
Table 2. Iodoenolcyclisation of 2-(1,3-dimethyl-1-allyl)-1,3-dicarbonyl
compounds at 258C
Entry Compound
X
Y
5/6 ratio Yield (%) Time (h)
1
2
3
4
5
6
7
8
9
1
4a
4b
4c
4d
4e
4f
4g
4h
4i
Me
i-Pr
t-Bu MeO
MeO
MeO
95:5
91:9
98:2
97:3
91:9
–
60:40
97:3
99:1
97:3
80
92
91
95
92
–
95
95
47
95
3.5
3.5
3
1.5
4
3.5
1
1
Ph
MeO
EtO
t-BuO
Me
By examining a number of substrates we noted that when a
b-keto t-butyl ester was used (Table 2, entry 6), the reaction
took a different course and a lactonisation product was
obtained instead (Scheme 4). The driving force for this
process is the loss of a stable t-butyl cation, as proposed by
Me
Me
Me
Et
t-Bu t-Bu
Ph Ph
Et
3
1
5
0
4j
Bartlett, who studied its mechanism.
Scheme 2. Iodoenolcyclisation of 2-(1,3-dimethyl-1-allyl)-1,3-dicarbonyl compounds.
With the aim of inhibiting this undesired process we
performed the reaction at lower temperatures (Table 3, entry
) and found that at 2308C the correct trans dihydrofuran
2
was obtained (although in moderate yield, 45%) together
with the lactone (50% yield). It is worth noting that in this
case the diastereoselectivity was high whereas, with the
other substrates, under the same conditions (2308C), lower
selectivities were observed. These results are in agreement
with the proposed mechanism (Scheme 3). The more
hindered is the ester moiety, the lower is the reactivity of
conformer B and the larger is the amount of the trans
product. For compound 4f this is true also at low
temperature. For the other compounds, at low temperature
the equilibration between the two conformers is slower and
some of conformer B reacts to give the cis product. For the t-
butyl ester, instead, conformer B is energetically so
disfavoured that it exists only in traces. In the case of 1,3-
diketones the trend was the same and t-butyl groups made
again an exception.
Compund 4i afforded lower yields of dihydrofuran deriva-
tive because a competitive process takes place giving 8. The
driving force for this process is the reduced steric hindrance
in 8 which was probably formed upon hydration of the
intermediate dihydrofuran by a Michael-like reaction during
the work-up. Also in this case, lower temperatures resulted
in lower diastereoselectivities (Scheme 5).
Scheme 3. Proposed mechanism for the iodoenolcyclisation.

R. Antonioletti et al. / Tetrahedron 59 (2003) 1673–1678
1675
2
Scheme 4. I -induced lactonisation of t-butyl esters.
Subsequently we submitted 4g to the iodoenolcyclisation
reaction in the absence of the base. In this case an almost
complete formation of the trans dihydrofuran derivative
was noticed, which strongly supports the correctness of the
proposed mechanism. Indeed, in the presence of the base
Table 3. Iodoenolcyclisation of 2-(1,3-dimethyl-1-allyl)-1,3-dicarbonyl
compounds 4 at 2308C (Scheme 2)
6
a
Entry Compound
X
Y
5/6 ratio
Yield (%) Time (h)
1
2
3
4
5
6
4a
4f
4b
4g
4i
Me
Me
i-Pr
Me
t-Bu t-Bu
Ph Ph
MeO 67:33
t-BuO 98:2
95
45
80
95
–
24
2
3
4
20
20
(Na CO ) the iodide anion precipitates as NaI, insoluble in
2 3
the reaction medium, and the ring closure thus becomes
irreversible. The reaction was under kinetic control and the
trans/cis ratio was 60:40. The effect was more evident at
2308C, temperature at which a trans/cis ratio of 25:75 was
obtained.
MeO
Me
75:25
25:75
–
4j
90:10
77
a
1
Determined by H NMR analysis in mixture.
Scheme 5. Formation of a cyclic hemiketal from 4i.
Scheme 6. Iodoenolcyclisation of 2-(3-cyclohexenyl)-1,3-dicarbonyl compounds with Z configuration.
þ
allows the I to remain in solution. This anion could capture
In the absence of the base, the lack of the counter-ion Na
2
Table 4. Iodoenolcyclisation of 2-(3-cyclohexenyl)-1,3-dicarbonyl com-
pounds with Z configuration
þ
I
from the cyclisation product (5, 6) making the ring
closure an equilibrium process. Moreover, the nucleophilic
attack of the enol form was slowed down allowing the
equilibration between conformers B and A. The reaction
was under thermodynamic control and the more stable trans
isomer was thus produced.
Entry
11
X
Y
Time (h)
Yield (%)
1
3
a
b
Me
Me
Me
OMe
20
30
60
75

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R. Antonioletti et al. / Tetrahedron 59 (2003) 1673–1678
Table 5. Tetrasubstituted furan synthesis from iodoenolcyclisation
products
in dry CH Cl (4 mL) was added to a mixture of anhydrous
2 2
Na CO (4 mmol) and iodine (4 mmol) in dry CH Cl
2
2
3
2
(40 mL). The mixture was stirred at rt until the substrate
disappeared (TLC and GC monitoring). Et O was added and
Entry
12
X
R
Solvent
Yield (%)
2
the organic phase was repeatidly washed with sodium
thiosulfate (2 M) and brine and finally dried over Na SO .
The solvent was removed under reduced pressure and the
crude products were purified by flash chromatography.
1
2
3
4
a
b
c
OMe
Me
OMe
Me
H
H
Me
Me
Benzene
Benzene
Toluene
Toluene
84
65
80
90
2
4
d
Scheme 7. Tetrasubstituted furan synthesis from iodoenolcyclisation products.
In order to complete our investigation we used another
substrate, viz. 9, in which the allyl group was a
Elution with hexane/EtOAc mixtures afforded pure
5-iodoalkyl-4,5-dihydrofurans, as colourless oils.
3
bond. The usual reaction led to the bicycle 10 having the
ring junction cis, the only obtainable upon an anti-coplanar
attack of the nucleophile (Scheme 6) (Table 4).
-cyclohexenyl, with the Z configuration of the double
1.1.1. trans-5-Iodomethyl-2-methyl-4-propyl-4,5-di-
1
7
hydro-furan-3-carboxylic acid methyl ester (2b).
H
NMR (d) 0.90 (t, J¼7.2 Hz, 3H), 1.1–1.7 (m, 4H), 2.19
(
d, J¼1.2 Hz, 3H), 2.8 (m, 1H), 3.14 (dd, J¼6.8, 10.2 Hz,
To confirm the synthetic pathway leading to tetrasubstituted
8
furans, as previously reported, selected iododihydrofurans
part A of an ABX system, 1H), 3.19 (dd, J¼5.6, 10.2 Hz,
part B of an ABX system, 1H), 3.70 (s, 3H), 4.32 (ddd,
J¼3.9, 5.6, 6.8 Hz, 1H). C NMR (d) 7.8, 13.8, 14.1, 18.9,
1
3
were dehydroiodinated by treatment with a non-nucleo-
philic, sterically hindered amine (DBU) under reflux in
benzene or toluene and the obtained products were
isomerised to furan derivatives by treatment with sulfuric
acid in diethyl ether. All compounds gave good yields of
tetrasubstituted furans (Table 5) (Scheme 7).
30.0, 35.4, 47.6, 85.7, 105.7, 166.4, 167.4. MS (m/z) 324
21
þ
(12, M ), 281 (100), 154 (34), 95 (26). IR (cm ) 2980,
1708, 1385, 1087. Calcd for C H IO C 40.76, H 5.29;
found C 40.5, H 5.1.
1
1
17
3
1
.1.2. cis-5-Iodomethyl-2-methyl-4-propyl-4,5-dihydro-
1
In conclusion the developed methodology provides an
efficient entry to tetrasubstituted 4,5-dihydrofurans, the
diastereoselection of the process strictly depending on the
substitution degree of the double bond in the starting
materials. The obtained iododerivatives can also be
employed for the synthesis of tetrasubstituted furans.
furan-3-carboxylic acid methyl ester (3b). H NMR (d)
0.90 (t, J¼7.2 Hz, 3H), 1.1–1.5 (m, 4H), 2.19 (d, J¼1.2 Hz,
3H), 2.9 (m, 1H), 3.36 (dd, J¼6.8, 10.2 Hz, part A of an
ABX system, 1H), 3.42 (dd, J¼7.6, 10.2 Hz, part B of an
ABX system, 1H), 3.68 (s, 3H), 4.70 (ddd, J¼6.8, 6.9,
1
3
7.6 Hz, 1H). C NMR (d) 0.5, 13.8, 14.1, 19.9, 29.8, 43.3,
þ
100), 165 (10), 155 (11), 154 (56), 153 (13), 139 (18), 95
5
(
0.6, 86.2, 108.0, 167.3, 168.2. MS (m/z) 324 (7, M ), 281
2
1
1. Experimental
(53), 59 (10). IR (cm ) 2890, 1650, 1460, 1210. Calcd for
C H IO C 40.76, H 5.29; found C 40.6, H 5.4.
1
1
17
3
1
13
H NMR and C NMR spectra were recorded in CDCl3
with either Varian XL-300 or Varian ‘Gemini’ 200-MHz
1.1.3. trans-5-Iodomethyl-4-isopropyl-2-methyl-4,5-
1
dihydro-furan-3-carboxylic acid methyl ester (2c). H
instruments, while IR spectra were recorded in CCl and
4
CHCl with a Shimadzu IR-740 instrument. MS spectra
3
NMR (d) 0.73 (d, J¼6.9 Hz, 3H), 0.90 (d, J¼7.0 Hz, 3H),
2.1 (m, 1H), 2.20 (d, J¼1.3 Hz, 3H), 2.9 (m, 1H), 3.14 (dd,
J¼6.4, 10.3 Hz, part A of an ABX system, 1H), 3.20 (dd,
J¼5.9, 10.3 Hz, part B of an ABX system, 1H), 3.68 (s, 3H),
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. CH Cl was dried by
1
3
4.35 (ddd, J¼3.6, 5.9, 6.4 Hz, 1H). C NMR (d) 8.5, 14.1,
2
2
distillation on CaH and stored on molecular sieves. Column
2
16.3, 19.9, 28.2, 50.7, 53.6, 81.5, 104.5, 166.5, 167.7. MS
(m/z) 324 (5, M ), 281 (96), 155 (11),154 (98), 153 (32),
þ
chromatography, unless otherwise stated, was carried out on
Kieselgel Merck (70–230 mesh and 230–400 mesh). All
reactions were carried out in amber-glass flasks under an
argon atmosphere.
139 (24), 95 (100), 59 (15). IR (cm2 ) 2890, 1643, 1787,
1
1210. Calcd for C11
5.0.
H17IO C 40.76, H 5.29; found C 40.5, H
3
1
.1. General procedure for cyclisation
1.1.4. trans-4-tert-Butyl-5-iodomethyl-2-methyl-4,5-
1
dihydro-furan-3-carboxylic acid methyl ester (2d). H
NMR (d) 0.82 (s, 9H), 2.19 (d, J¼1.4 Hz, 3H), 2.75 (m, 1H),
A solution of the a-allyl-b-dicarbonyl compound (2 mmol)

R. Antonioletti et al. / Tetrahedron 59 (2003) 1673–1678
1677
3
3
3
7
1
1
.08 (dd, J¼7.0, 10.2 Hz, part A of an ABX system, 1H),
2.04 (d, J¼7.0 Hz, 3H), 3.16 (dq, J¼6.6, 7.3 Hz, 1H), 3.57
(m, 1H), 3.68 (s, 3H), 4.22 (dq, J¼7.3, 10.9 Hz, 1H), 4.48
(dd, J¼7.3, 10.9 Hz, 1H).
.19 (dd, J¼6.2, 10.2 Hz, part B of an ABX system, 1H),
1
3
.68 (s, 3H), 4.4 (ddd, J¼4.2, 6.2, 7.0 Hz, 1H). C NMR (d)
.3, 14.1, 26.6 (3C), 34.1, 50.6, 56.8, 83.4, 103.9, 167.3,
67.6. MS (m/z) 338 (4, M ), 307 (5), 282 (10), 281 (100),
þ
1
1.1.11. trans-2-tert-Butyl-5-(1-iodo-ethyl)-4-methyl-4,5-
1
dihydro-furan-3-carboxylic acid methyl ester (5c). H
2
54 (42), 94 (24). IR (cm ) 3009, 1699, 1387, 1210. Calcd
for C H IO C 42.62, H 5.66; found C 42.4, H 5.5.
19
NMR (d) 1.22 (d, J¼6.6 Hz, 3H), 1.29 (s, 9H), 1.90 (d,
J¼6.8 Hz, 3H), 3.09 (dq, J¼4.0, 6.6 Hz, 1H), 3.62 (s, 3H),
3.85 (dd, J¼4.0, 7.3 Hz, 1H), 4.10 (dq, J¼6.8, 7.3 Hz, 1H).
12
3
1
.1.5. cis-4-tert-Butyl-5-iodomethyl-2-methyl-4,5-di-
1
13
hydro-furan-3-carboxylic acid methyl ester (3d).
NMR (d) 0.90 (s, 9H), 2.20 (d, J¼1.3 Hz, 3H), 2.7–2.8
m, 1H), 3.24 (dd, J¼6.4, 10.6 Hz, part A of an ABX
system, 1H), 3.35 (dd, J¼5.6, 10.6 Hz, part B of an ABX
H
C NMR (d) 21.6, 23.5, 27.6 (3C), 29.7, 34.6, 44.5, 50.8,
þ
91.3, 105.3, 165.6, 175.6. MS (m/z) 352 (18, M ), 295 (10),
(
225 (12), 137 (14), 135 (13), 127 (15), 109 (10), 79 (11), 69
(15), 67 (10), 57 (100). IR (cm2 ) 2992, 1720, 1478. Calcd
for C H IO C 44.33, H 6.01; found C 44.2, H 6.3.
1
1
3
system, 1H), 3.65 (s, 3H), 5.1–5.2 (m, 1H). C NMR (d)
1
3
21
3
1
1
1
5
.8, 14.1, 27.7 (3C), 29.2, 52.0, 57.1, 79.9, 103.9, 165.0,
1
66.1. MS (m/z) 280 (100), 154 (41), 94 (24). IR (cm2
9556, 1640, 1387, 1110. Calcd for C H IO C 42.62, H
.66; found C 42.5, H 5.9.
)
1.1.12. trans-5-(1-Iodo-ethyl)-4-methyl-2-phenyl-4,5-
1
dihydro-furan-3-carboxylic acid methyl ester (5d). H
NMR (d) 1.40 (d, J¼6.6 Hz, 3H), 2.00 (d, J¼7.0 Hz, 3H,
1
2
19
3
3
.30 (dq, J¼4.4, 6.6 Hz, 1H), 4.12 (dd, J¼4.4, 7.4 Hz, 1H),
0
bifuranyl-4 -carboxylic acid methyl ester (3f). H NMR
0
0
0
0
1
.1.6. cis-2 -Iodomethyl-5 -methyl-2 ,3 -dihydro-[2,3 ]-
1
4.28 (dq, J¼7.0, 7.4 Hz, 1H), 7.42 (m, 3H), 7.79 (m, 2H).
0
13
C NMR (d) 21.3, 23.4, 29.5, 44.3, 50.9, 91.9, 107.4, 127.6
(2C), 129.3 (2C), 128.9, 130.4, 164.3, 165.3. MS (m/z) 372
(
d) 2.29 (d, J¼1.3 Hz, 3H), 2.95 (dd, J¼7.6, 10.2 Hz, part A
þ
(cm ) 3015, 2935, 1691, 1651. Calcd for C H IO C
48.40, H 4.60; found C 48.6, H 4.6.
of an ABX system, 1H), 3.00 (dd, J¼4.5, 10.2 Hz, part B of
an ABX system, 1H), 3.59 (s, 3H), 4.45 (bd, J¼9.0 Hz, 1H),
(11, M ), 245 (10), 171 (11), 105 (100), 77 (46), 51 (11). IR
2
1
1
5
17
3
4
.90 (ddd, J¼4.5, 7.6, 9.0 Hz, 1H), 6.10 (d, J¼3.3 Hz, 1H),
1
3
6
.29 (dd, J¼1.8, 3.3 Hz, 1H), 7.32 (d, J¼1.8 Hz, 1H).
C
NMR (d) 1.5, 14.5, 45.1, 51.3, 86.1, 105.2, 108.9, 110.9,
42.7, 151.9, 166.2, 170.1. MS (m/z) 219 (63), 104 (32), 95
1.1.13. trans-5-(1-Iodo-ethyl)-2,4-dimethyl-4,5-dihydro-
1
1
furan-3-carboxylic acid ethyl ester (5e). H NMR (d)
1.26 (d, J¼7.0 Hz, 3H), 1.28 (t, J¼7.6 Hz, 3H), 1.90 (d,
2
1
(30), 92 (100), 67 (80). IR (cm ) 1645, 1333, 1200. Calcd
for C H IO C 41.40, H 3.76; found C 41.6, H 4.0.
J¼6.6 Hz, 3H), 2.19 (d, J¼1.0 Hz, 3H), 3.00–3.10 (m, 1H),
12
13
4
3
.98 (dd, J¼4.2, 7.0 Hz, 1H), 4.05 (q, J¼7.6 Hz, 2H), 4.24
1
3
1
.1.7. trans-5-(1-Iodo-ethyl)-2,4-dimethyl-4,5-dihydro-
1
(dq, J¼6.6, 7.2 Hz, 1H). C NMR (d) 13.7, 14.4, 21.1, 23.3,
furan-3-carboxylic acid methyl ester (5a). H NMR (d)
.23 (d, J¼6.6 Hz, 3H), 1.87 (d, J¼7.3 Hz, 3H), 2.19 (d,
29.5, 42.9, 59.4, 92.7, 107.3, 165.8, 166.8. MS (m/z) 324
(16, M ), 279 (11), 197 (15), 127 (13), 109 (14), 43 (100),
þ
1
41 (16). IR (cm2 ) 3450, 2935, 1691, 1651. Calcd for
1
J¼0.8 Hz, 3H), 3.03 (ddq, J¼0.8, 4.8, 6.6 Hz, 1H), 3.68 (s,
3
1
1
H), 3.95 (dd, J¼4.8, 7.0 Hz, 1H), 4.11 (dq, J¼6.6, 7.0 Hz,
C H IO C 40.76, H 5.29; found C 40.9, H 5.1.
3
1
1
17
13
H). C NMR (d) 14.4, 21.3, 23.4, 29.7, 43.0, 50.9, 92.9,
07.2, 166.3, 167.1. MS (m/z) 310 (10, M ), 183
þ
1.1.14. cis-5-(1-Iodo-ethyl)-2,4-dimethyl-4,5-dihydro-
1
2
1
(
15),127 (11), 109 (11), 43 (100). IR (cm ) 2975, 1690,
furan-3-carboxylic acid ethyl ester (5e). H NMR (d),
representative signals: 1.10 (d, J¼7.0 Hz, 3H), 1.82 (d,
1
3
648, 1446. Calcd for C H IO C 38.73, H 4.88; found C
1
0
15
3
8.9, H 4.6.
J¼6.9 Hz, 3H), 2.14 (d, J¼0.9 Hz, 3H), 4.51 (dd, J¼7.0,
11.0 Hz, 1H).
1
.1.8. cis-5-(1-Iodo-ethyl)-2,4-dimethyl-4,5-dihydro-
1
furan-3-carboxylic acid methyl ester (6a). H NMR (d)
.08 (d, J¼6.6 Hz, 3H), 2.04 (d, J¼6.6 Hz, 3H), 2.14 (d,
1.1.15. trans-5-(1-Iodo-ethyl)-2,4-dimethyl-4,5-dihydro-
1
1
furan-3-carboxylic acid tert-butyl ester (5f). H NMR
(d) 1.25 (d, J¼6.6 Hz, 3H), 1.48 (s, 9H), 1.90 (d, J¼6.6 Hz,
J¼0.8 Hz, 3H), 3.22 (m, 1H), 3.68 (s, 3H), 4.12 (dq, J¼6.6,
1
1.0 Hz, 1H), 4.55 (dd, J¼7.3, 11.0 Hz, 1H).
3H), 2.15 (d, J¼0.7 Hz, 3H), 2.99–3.02 (m, 1H), 3.97 (dd,
1
3
J¼4.8, 7.8 Hz, 1H), 4.12 (dq, J¼6.6, 7.8 Hz, 1H). C NMR
1
.1.9. trans-5-(1-Iodo-ethyl)-2-isopropyl-4-methyl-4,5-
1
(d) 13.3, 20.1, 22.4, 27.4 (3C), 28.8, 42.2, 78.7, 91.6, 107.6,
164.6, 164.7. MS (m/z) 352 (21, M ), 296 (33), 281 (14),
þ
dihydro-furan-3-carboxylic acid methyl ester (5b). H
NMR (d) 1.10 (d, J¼7.3 Hz, 6H), 1.22 (d, J¼7.0 Hz, 3H),
279 (31), 169 (39), 154 (12), 153 (14), 127 (16), 109 (17),
57 (20),43 (100), 41 (29). IR (cm2 ) 2980, 1681, 1650,
1460. Calcd for C H IO C 44.33, H 6.01; found C 44.3, H
1
1
.89 (d, J¼7.0 Hz, 3H), 3.03 (dq, J¼4.4, 7.0 Hz, 1H), 3.57
(
1
2
ept, J¼7.3 Hz, 1H), 3.68 (s, 3H), 3.95 (dd, J¼4.4, 7.4 Hz,
1
3
21
3
1
3
H), 4.09 (dq, J¼7.0, 7.4 Hz, 1H). C NMR (d) 19.5, 19.7,
6.2.
1.2, 23.4, 26.9, 29.6, 42.7, 50.6, 92.4, 104.9, 166.0, 174.6.
þ
MS (m/z) 338 (10, M ), 211 (11), 127 (12), 109 (10), 79
1
1.1.16. trans-1-[5-(1-Iodo-ethyl)-2,4-dimethyl-4,5-di-
1
(
3
4
12), 71 (22), 69 (10), 59 (15), 43 (100), 41 (46). IR (cm2
)
450, 3015, 1732, 1703, 1647, 1470. Calcd for C H IO C
2.62, H 5.66; found C 42.4, H 5.7.
hydro-furan-3-yl]-ethanone (5g). H NMR (d) 1.11 (d,
J¼7.0 Hz, 3H), 2.06 (d, J¼7.0 Hz, 3H), 2.19 (d, J¼0.8 Hz,
1
2
19
3
3H), 2.25 (s, 3H), 3.12 (m, 1H), 3.95 (dd, J¼4.4, 7.0 Hz,
1
3
1
H), 4,12 (dq, J¼7.0, 7.0 Hz, 1H). C NMR (d) 15.4, 21.4,
1
.1.10. cis-5-(1-Iodo-ethyl)-2-isopropyl-4-methyl-4,5-
1
21.6, 23.4, 29.4, 43.3, 92.9, 118.2, 166.3, 194.2. MS (m/z)
294 (2, M ), 167 (14), 127 (6), 43 (100). Calcd for
þ
C H IO C 40.83, H 5.14; found C 40.7, H 5.0.
dihydro-furan-3-carboxylic acid methyl ester (6b). H
NMR (d) 1.10 (d, J¼7.3 Hz, 6H), 1.24 (d, J¼6.6 Hz, 3H),
1
0
15
2

1678
R. Antonioletti et al. / Tetrahedron 59 (2003) 1673–1678
1
.1.17. cis-1-[5-(1-Iodo-ethyl)-2,4-dimethyl-4,5-dihydro-
1
1.1.23. 1-[2-tert-Butyl-2-hydroxy-5-(1-iodo-ethyl)-4-
methyl-tetrahydro-furan-3-yl]-2,2-dimethyl-propan-1-
one (8). It was obtained as one diastereoisomer of which we
furan-3-yl]-ethanone (6g). H NMR (d) 1.08 (d, J¼6.6 Hz,
3
H), 2.04 (d, J¼7.0 Hz, 3H), 2.16 (d, J¼0.6 Hz, 3H), 2.23
1
(
(
s, 3H), 3.25 (m, 1H), 4.15 (dq, J¼6.6, 11.4 Hz, 1H), 4.52
did not determine the stereochemistry. H NMR (d) 0.95 (s,
1
3
dd, J¼7.0, 11.4 Hz, 1H). C NMR (d) 12.5, 15.6, 20.9,
9H), 1.04 (d, J¼7.0 Hz, 3H), 1.22 (s, 9H), 1.88 (d,
J¼6.6 Hz, 3H), 2.48 (ddq, J¼3.6, 7.0, 9.5 Hz, 1H), 3.22
(dd, J¼3.6, 3.6 Hz, 1H), 3.66 (d, J¼9.5 Hz, 1H), 4.39 (dq,
2
M ), 167 (5), 127 (5), 43 (100). Calcd for C H IO C
5.8, 29.1, 40.2, 90.6, 120.4, 167.3, 194.1. MS (m/z) 294 (4,
þ
0.83, H 5.14; found C 40.9, H 5.2.
1
0
15
2
1
3
4
J¼3.6, 6.6 Hz, 1H). C NMR (d) 18.9, 24.3, 25.7, 26.5,
1
3
4.0, 38.0, 42.4, 45.6, 48.4, 88.0, 111.2, 219.9. IR (cm2
)
1
.1.18. trans-1-[2-Ethyl-5-(1-iodo-ethyl)-4-methyl-4,5-
1
3250, 2955, 1710, 1067. Calcd for C H IO C 48.49, H
16 29 3
7.38; found C 48.6, H 7.1.
dihydro-furan-3-yl]-propan-1-one (5h). H NMR (d)
.10 (t, J¼7.3 Hz, 3H), 1.15 (t, J¼7.5 Hz, 3H), 1.25 (d,
1
4
2
9
10
11
J¼6.7 Hz, 3H), 1.91 (d, J¼7.0 Hz, 3H), 2.51 (q, J¼7.3 Hz,
Compounds 2a, 3a, 2e, 3e, 10a,b, 11a,b, 12a, 12b,
1
2
2
7
8
1
6
1
6
H), 2.60–2.80 (m, 2H), 3.16 (m, 1H), 3.96 (dd, J¼4.0,
12c,d, are already known and physical data were identical
to that reported in literature.
1
3
.2 Hz, 1H), 4,12 (dq, J¼7.0, 7.2 Hz, 1H). C NMR (d)
.3, 11.3, 21.7, 22.3, 23.5, 29.6, 34.2, 43.2, 92.7, 116.3,
70.4, 197.5. MS (m/z) 167 (85), 127 (11), 111 (6), 95 (7),
9 (16), 57 (100), 41 (40). IR (cm ) 3050, 1716, 1684,
640. Calcd for C H IO C 44.74, H 5.94; found C 44.5, H
.1.
2
1
References
1
2
19
2
1
. Westley, J. W. Polyether Antibiotics; M. Decker: New York,
1982; Vols. 1–2. Nakanishi, K. Natural Products Chemistry;
Academic: New York, 1974. Vernin, G. The Chemistry of
Heterocyclic Flavoring and Aroma Compounds; Ellis
Horwood: Chichester, 1982. Harding, K. E.; Tiner, H. T.
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon: New York, 1991; Vol. 4, p 363. Sargent,
M. V.; Cresp, T. M. Comprehensive Organic Chemistry;
Barton, D. H. R., Ollis, D. W., Eds.; Pergamon: NY, 1979;
Vol. 4, p 693. Bird, C. W.; Cheesman, G. H. W.
Comprehensive Heterocyclic Chemistry; Katritzky, A. R.,
Rees, C. W., Eds.; Pergamon: NY, 1984; Vol. 4. part 3.
Lipshutz, B. H. Chem. Rev. 1986, 86, 795.
1
4
.1.19. trans-1-[2-tert-Butyl-5-(1-iodo-ethyl)-4-methyl-
,5-dihydro-furan-3-yl]-2,2-dimethyl-propan-1-one (5i).
1
H NMR (d) 1.09 (s, 9H), 1.12 (d, J¼6.6 Hz, 3H), 1.21 (s,
9
H), 1.95 (d, J¼7.3 Hz, 3H), 3.25 (dq, J¼4.4, 6.6 Hz, 1H),
.77 (dd, J¼4.4, 7.3 Hz, 1H), 4.20 (dq, J¼7.3, 7.3 Hz, 1H).
3C NMR (d) 21.0, 23.8, 27.9 (3 C), 28.6 (3 C), 31.6, 33.5,
4.8, 47.3, 90.6, 113.4, 161.1, 211.4. MS (m/z) 269 (3), 255
3
1
4
(
(
5), 167 (5), 127 (12), 85 (9), 69 (7), 57 (100), 41 (27). IR
cm ) 2992, 1676, 1488. Calcd for C H IO C 50.80, H
16 27 2
21
7
.19; found C 50.6, H 6.9.
1
dihydro-furan-3-yl]-phenyl-methanone (5j). H NMR
.1.20. trans-[5-(1-Iodo-ethyl)-4-methyl-2-phenyl-4,5-
1
2. Antonioletti, R.; Bonadies, F.; Scettri, A. Tetrahedron Lett.
1988, 29, 4987. Antonioletti, R.; Magnanti, S.; Scettri, A.
Tetrahedron Lett. 1994, 35, 4987. Antonioletti, R.; D’Onofrio,
F.; Rossi, B. Synth. Commun. 2001, 31, 911.
(
(
(
d) 1.39 (d, J¼6.6 Hz, 3H), 1.95 (d, J¼7.0 Hz, 3H), 3.51
dq, J¼5.4, 6.6 Hz, 1H), 4.09 (dd, J¼5.4, 6.2 Hz, 1H), 4.33
dq, J¼6.6, 7.0 Hz, 1H), 7.4–7.5 (m, 2H), 6.9–7.2 (m, 8H).
1
3
C NMR (d) 20.9, 23.3, 29.3, 45.7, 92.2, 116.6, 127.6 (2 C),
3. Antonioletti, R.; D’Onofrio, F.; Rossi, B. Synth. Commun.
2001, 31, 911.
1
1
27.7 (2 C), 128.9 (2 C), 129.1 (2 C), 130.0, 130.1, 131.3,
þ
39.1, 166.5, 193.4. MS (m/z) 418 (11, M ), 291 (6), 171
4. Antonioletti, R.; Malacona, S.; Bovicelli, P. Tetrahedron
2002, 58, 8825.
5. Bartlett, P. A.; Rychnovsky, S. J. Am. Chem. Soc. 1981, 103,
(5), 105 (100), 77 (43), 51 (8). Calcd for C H IO C 57.43,
20 19 2
H 4.58; found C 57.2, H 4.9.
3
963. Bartlett, P. A. Tetrahedron 1984, 36, 2. J. Am. Chem.
1.1.21. cis-[5-(1-Iodo-ethyl)-4-methyl-2-phenyl-4,5-di-
1
hydro-furan-3-yl]-phenyl-methanone (6j). H NMR (d)
Soc. 1978, 100, 3951. Bartlett, P. A.; Ting, P. C. J. Am. Chem.
Soc. 1984, 106, 2668.
1
.32 (d, J¼6.6 Hz, 3H), 2.10 (d, J¼6.0 Hz, 3H), 3.62 (dq,
6. cis Diastereoisomers were obtained, as inseparable mixture,
togheter with the corresponding trans diastereoisomers. They
J¼6.6, 7.3 Hz, 1H), 4.34 (dq, J¼6.6, 10.9 Hz, 1H), 4.92 (dd,
J¼7.3, 10.9 Hz, 1H), 7.0–7.5 (m, 10H). Calcd for
C H IO C 57.43, H 4.58; found C 57.6, H 4.3.
1
were then analysed by H-NMR spectroscopy and not fully
characterised.
2
0
19
2
7
. Ferraz, H. M. C.; de Oliveira, E. O.; Payret-Arrua, M. E.;
Brandt, C. A. J. Org. Chem. 1995, 60, 7357–7359. Ferraz,
H. M. C.; Sano, M. K.; Nunes, M. R. S.; Bianco, G. G. J. Org.
Chem. 2002, 67, 4122–4126.
1.1.22. 3-Acetyl-5-(1-iodo-ethyl)-4-methyl-dihydro-
furan-2-one (7). Inseparable mixture of two diastereo-
1
isomers in 9:1 ratio. Major: H NMR (d) 1.3 (d, J¼7.2 Hz,
3
4
1
H), 2.07 (d, J¼6.6 Hz, 3H), 2.4 (s, 3H), 3.2 (ddq, J¼1.1,
8. Antonioletti, R.; Cecchini, C.; Ciani, B.; Magnanti, S.
Tetrahedron Lett. 1995, 36, 9019.
.9, 7.2 Hz, 1H), 3.5 (d, J¼1.1 Hz, 1H), 3.96 (dq, J¼6.6,
1
3
1.0 Hz, 1H), 4.66 (dd, J¼4.9, 11.0 Hz, 1H); C NMR
9. Barinelli, L. S.; Nicholas, K. M. J. Org. Chem. 1988, 53,
2114–2117.
(
d) 12.4, 20.9, 25.7, 29.2, 35.9, 65.0, 86.6, 171.3, 199.1.
1
Minor: H NMR (d) 1.07 (d, J¼6.6 Hz, 3H), 2.11
10. MaGee, D. I.; Leach, J. D.; Setiadji, S. Tetrahedron 1999, 55,
2847–2856.
(
(
1
6
1
d, J¼6.6 Hz, 3H), 2.42 (s, 3H), 3.0–3.2 (m, 1H), 3.43
d, J¼7.0 Hz, 1H), 3.9–4.1 (m, 1H), 4.45 (dd, J¼5.8,
11. Sato, N.; Kondo, M.; Taylor, E. C. Heterocycles 1998, 48,
129–138.
1
3
1.0 Hz, 1H); C NMR (d) 13.7, 21.6, 25.8, 30.0, 35.5,
4.9, 86.5, 171.3, 199.1. IR (cm2 ) 2880, 1760, 1715, 1160,
060.
1
12. Chiba, T.; Okimoto, M.; Nagai, H.; Takata, Y. J. Org. Chem.
1979, 44, 3519–3523.