MIRC reactions of 2-bromo-5-(l-menthyloxy)furan-2(5H)-one with stabilized anions. Preparation of homochiral bicyclic γ-butyrolactones

Article abstract of DOI:10.1016/S0957-4166(99)00378-X

Homochiral (5R)-4-bromo-5-(l-menthyloxy)furan-2(5H)-one with stabilized carbanions (from nitroalkanes, malononitrile and ethyl acetoacetate) afforded enantiopure bicyclic compounds in good yield (70-90%). 3- Oxabicyclic[3.1.0]hexan-2-one derivatives were obtained with nitromethane and malonic acid derivatives. However, dihydrofuro[3,4-d]isoxazol-6-one and dihydrofuro[3,4-b]furan-6(4H)-one derivatives were obtained from nitroethane and ethyl acetoacetate, respectively.

Full text of DOI:10.1016/S0957-4166(99)00378-X

Pergamon
Tetrahedron: Asymmetry 10 (1999) 3593–3599
MIRC reactions of 2-bromo-5-(l-menthyloxy)furan-2(5H)-one
with stabilized anions. Preparation of homochiral bicyclic
γ-butyrolactones†
M. Carmen Maestro,∗ M. Cruz Barquilla and M. Rosario Martín
Departamento de Química Orgánica, Universidad Autónoma, Cantoblanco 28049, Madrid, Spain
Received 2 August 1999; accepted 26 August 1999
Abstract
Homochiral (5R)-4-bromo-5-(l-menthyloxy)furan-2(5H)-one with stabilized carbanions (from nitroalkanes,
malononitrile and ethyl acetoacetate) afforded enantiopure bicyclic compounds in good yield (70–90%). 3-
Oxabicyclic[3.1.0]hexan-2-one derivatives were obtained with nitromethane and malonic acid derivatives. How-
ever, dihydrofuro[3,4-d]isoxazol-6-one and dihydrofuro[3,4-b]furan-6(4H)-one derivatives were obtained from
nitroethane and ethyl acetoacetate, respectively. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
5-Alkoxyfuran-2(5H)-ones have attracted considerable attention since its skeleton comprises a cyclic
structure, a latent carbonylic functionality on C-5 and the α,β-unsaturated ester moiety. They also have
a high conformational rigidity and the steric requirements of the alkoxy group brings about an important
shielding of one of the faces of the conjugated system.
Some years ago we reported that bromine addition to the double bond of 5-methoxyfuran-2(5H)-one
followed by HBr elimination under different experimental conditions affords a regioselective synthesis
of 3- and 4-bromo derivatives.1,2 The 3-bromo-5-methoxyfuran-2(5H)-one 11 behaves as an excellent
Michael acceptor towards oxygen,3,4 nitrogen,4,5 sulfur4,5 and stabilized carbon nucleophiles,4,6 while
4-bromo-5-methoxyfuran-2(5H)-one is a suitable substrate for the preparation of the 4-alkylamino and
4-alkylthio furanones by nucleophilic substitution of the halogen.7
Due to the synthetic versatility of these haloderivatives we prepared the corresponding
enantiomerically pure menthol analogues. In this sense, we obtained homochiral (5S)-4-bromo-5-
(l-menthyloxy)furan-2(5H)-one8 from the 4-bromo-5-methoxyfuran-2(5H)-one. Since the publication of
∗
†
Corresponding author. E-mail: carmen.maestro@uam.es
Dedicated to the late Dr. M. Victoria Martín for her valuable contribution to 5-alkoxyfuran-2(5H)-ones chemistry.
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00378-X

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our report, the synthesis of other diastereoisomerically pure halogenated menthyloxyfuranones, such as
the 4-chloro-,9 the 3,4-dibromo-10 and the (5R)-3-bromo-5-(l-menthyloxy)furan-2(5H)-one 2a,11 have
appeared in the literature. The recent communication of Chen and Huang11 describing the synthesis and
the reactions with alcohols of enantiomerically pure furanone 2a in a solid–liquid two-phase system,
previously reported by us for the racemic methoxy analogue 1,4 prompted us to present our results on
the preparation of (5R)-3-bromo-5-(l-menthyloxy)furan-2(5H)-one 2a and its use in the synthesis of
enantiomerically pure bicyclic systems containing the 2(5H)-furanone ring by MIRC (Michael Initiated
Ring Closure) reactions. We describe herein the reactions of 2a with stabilized carbon nucleophiles from
nitroalkanes, ethyl acetoacetate and malonic acid derivatives. These reagents have similar pKa values
and at least two acidic protons, that allow them to act twice as nucleophiles by successive deprotonations
and therefore behave as excellent MIRC reagents.
2. Results and discussion
We prepared menthyloxy bromofuranone 2 by transacetalization of 3-bromo-5-methoxyfuran-2(5H)-
one 11 with l-menthol in the presence of p-toluenesulfonic acid, by heating at 60°C in toluene solution
(Scheme 1). The crystallization from hexane at −18°C of the 54:46 epimeric mixture of 2a:2b afforded 2a
as a single diastereoisomer. The mother liquor that contained the mixture of both compounds (enriched
in 2b) had been epimerized by heating, in the presence of p-toluenesulfonic acid as catalyst, to obtain
additional amounts of 2a. A global yield of 55% in pure (5R)-bromofuranone 2a was obtained by this
procedure.
Scheme 1.
The reactions of furanone 2a with nitromethane (Table 1, entries 1–3) and malononitrile (Table 1, en-
tries 4 and 5) anions afforded cyclopropane-furanones 3 and 4, respectively, as sole products (Scheme 2),
although with variable yield according to the procedure used. The best results were obtained in THF at
−18°C, with NaH as the base and in a 1:3:3 ratio of 2a:nucleophile:base. However, in all of the tested
conditions (Table 1, entries 6–8), the major product from the reaction of 2a with diethyl malonate anion
was the spiro-cyclopropane derivative 6, although the reaction at room temperature yielded a significant
amount of bicyclic cyclopropane-furanone 5.
Unlike the above nucleophiles, the reactions of nitroethane and ethyl acetoacetate anions with furanone
2a exclusively afforded diastereoisomerically pure dihydroisoxazole N-oxide 7 and dihydrofuro[3,4-
d]furanone 8, respectively (Scheme 3 and Table 2). It is important to mention the different behaviour
of these nucleophiles giving O-alkylation instead of C-alkylation as above. On the other hand, DBU in
THF instead of NaH/DMF (suitable for preparing cyclopropane derivatives) is preferred to obtain these
[3.3.0] bicyclic compounds (Table 2, entries 3 and 6).
Compound 7 was deoxygenated by hydrogenolysis in the presence of Pd–C to yield the furodihydro-
isoxazole derivative 9 which, according to the literature, is the opposite regioisomer to the one obtained
by 1,3-dipolar cycloaddition of acetonitrile oxide to the 5-(l-menthyloxy)furan-2(5H)-one.12 Therefore,
this procedure represented a complementary process to 1,3-cycloaddition reactions of non-halogenated
furanones.

M. C. Maestro et al. / Tetrahedron: Asymmetry 10 (1999) 3593–3599
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Table 1
Reaction of 2a with Z-CH2-Z0
Scheme 2.
Table 2
Reaction of 2a with nitroethane and ethyl acetoacetate
Scheme 3.

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The structure of all the above compounds was determined according to their spectral and analytical
data. A rationalization of the results is presented in Scheme 4.
Scheme 4.
In conclusion, the presence of the halogen atom on the menthyloxyfuranone skeleton considerably
increased the reactivity and the synthetic potential of these conjugated systems, providing a convenient
route to different enantiomerically pure bicyclic systems.
3. Experimental
Melting points were determined on a Gallenkamp apparatus. NMR spectra were recorded on a Bruker
WP-200-SY instrument. Optical rotations were measured on a Perkin–Elmer 241-MC polarimeter. Mass
spectra were registered on a VG AutoSpec instrument in the electron impact mode (EI) at 70 eV unless
stated otherwise. IR spectra were obtained in a Philips PU-9716. All reactions were monitored by TLC,
that was performed on precoated sheets of silica gel 60 (F254), and flash chromatography was effected
with silica gel 60 (230–400 mesh). The apparatus for inert atmosphere experiments was dried by flaming
in a stream of dry argon. Dry THF was obtained by distillation from sodium/benzophenone under argon.
DMF was distilled and dried over 4 Å molecular sieves.
3.1. (5R)-3-Bromo-5-(l-menthyloxy)furan-2(5H)-one 2a11
(−)-Menthol (9.74 g, 62.66 mmol) was added to a solution of 3-bromo-5-methoxyfuran-2(5H)-one
(1, 7.115 g, 36.86 mmol) and p-toluenesulfonic acid (2.13 g, 11.16 mmol) in toluene (35 mL) and the
mixture was maintained for 4 days at 60°C. The solvent was evaporated in vacuo, the crude mixture
was dissolved in ethyl acetate and the solution washed with a saturated solution of sodium hydrogen
carbonate. The organic extracts were dried (Na2SO4) and the solvent evaporated. The crude product was
mainly a diastereoisomeric mixture (54:46) of 2a:2b and recovered 1. Compounds 2a:2b were isolated

M. C. Maestro et al. / Tetrahedron: Asymmetry 10 (1999) 3593–3599
3597
by column chromatography (hexane:ethyl acetate, 30:1). Pure 2a was separated as a white solid by
crystallization of the diastereoisomeric mixture with hexane at −18°C. Additional amounts of pure 2a
were recovered from the remained diastereoisomeric mixture by successive epimerization at 70°C in
toluene using p-toluenesulfonic acid as a catalyst, followed by the above-mentioned hexane treatment.
Global yield 55%. Mp 92–94°C; [α]D −134.1 (c 1, CHCl3). Anal. calcd for C14H21O3Br: C, 53.01; H,
6.67; Br, 25.19. Found: C, 53.14; H, 6.69; Br, 24.94.
3.2. Reaction with nucleophiles: general procedure
Procedure A: bromofuranone (2a, 50 mg, 0.16 mmol) was added to a mixture of anhydrous potassium
carbonate (109 mg, 0.79 mmol), tetrabutylammonium bromide (2.5 mg, 0.0079 mmol) and the nucleo-
phile (0.16 mmol) in acetonitrile (1 mL). The mixture was vigorously stirred at room temperature until
the starting bromofuranone disappeared or a practically constant concentration was obtained (1–2 days).
The salts were filtered after dilution with ethyl acetate or acetonitrile, and were washed with the same
solvent. The solution was evaporated under reduced pressure to yield the crude mixture.
Procedure B: to a solution of NaH (23 mg, 0.95 mmol) in dry DMF (2.5 mL) under argon at −18°C, the
nucleophile (0.95 mmol) was slowly added. The reaction mixture was stirred at the indicated temperature
(Tables 1 and 2) for ca. 30 min and furanone 2a (100 mg, 0.32 mmol) in DMF (1 mL) was added. After
completion (0.5–2 h), the mixture was added onto an NH4Cl saturated solution (containing some drops
of 10% aqueous HCl) and was extracted with ether. Organic extracts were dried (Na2SO4) and removed
in vacuo.
Procedure C: to a DBU (146 mg, 0.96 mmol) solution in dry THF (1 mL) at 0°C under argon the
nucleophile (0.48 mmol) was slowly added. The mixture was stirred on an ice bath for ca. 30 min and
the temperature was taken down to −40°C (Table 2, entries 3 and 6) or maintained at 0°C (Table 1, entry
3) before the addition of 2a (100 mg, 0.32 mmol) in THF (1 mL). The reaction was stirred at the same
temperature until consumption of 2a (15 min). The reaction work-up was effected as in procedure B.
3.3. Reaction with nitroalkanes
3.3.1. (1R,4R,5S,6R)-4-(l-Menthyloxy)-6-nitro-3-oxabicyclo[3.1.0]hexan-2-one 3
The compound was obtained diastereoisomerically pure from nitromethane following the general
procedure B at −18°C (Table 1, entry 2). Column chromatography on silica gel (hexane:acetone, 5:1)
25
afforded pure 3 as a white solid (yield 90%). Mp 147–149°C; [α]D −116.8 (c 1, CHCl3). Anal. calcd
for C15H23NO5: C, 60.59; H, 7.80; N, 4.71. Found: C, 60.23; H, 7.81; N, 4.50. 1H NMR: 5.65 (s, 1H),
4.33 (dd, 1H, J=2.1, 1.6), 3.6 (dt, 1H, ment., J=10.7 and 4.2), 3.19 (m, 2H), 2.2–0.8 (m, 18H, ment.); 13
C
NMR: 168.0, 98.2, 78.3, 58.5, 47.5, 39.9, 34.0, 31.4, 29.7, 26.6, 25.3, 23.0, 22.1, 20.8, 15.5. IR (CHCl3):
3100, 1790, 1560, 1365, 1340. MS (15 eV) m/z (relative intensity): 251 (M+−46, 1), 223 (4), 212 (4),
138 (100), 95 (33), 81 (56).
3.3.2. (3aR,4R,6aS)-4-(l-Menthyloxy)-3-methyl-3a,6a-dihydrofuro[3,4-d]isoxazol-6-(4H)-one N-oxide
7
The compound was obtained as a sole diastereomer from nitroethane following the general procedure
C (Table 2, entry 3). Purification was effected by column chromatography (hexane:acetone:ether, 7:1:1)
(yield 86%). Mp 117–119°C; [α]D25 −83.7 (c 1, CHCl3). Anal. calcd for C16H25NO5: C, 61.72; H, 8.09;
1
N, 4.50. Found: C, 61.72; H, 8.03; N, 4.58. H NMR: 5.69 (s, 1H,), 5.20 (d, 1H, J=9.1), 4.0 (dq, 1H,
J=9.1 and 2.0), 3.58 (dt, 1H, ment., J=10.7 and 4.3), 2.09 (d, 3H, J=2.0), 2.2–0.7 (m, 18H, ment.); 13
C

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NMR: 170.7, 108.0, 98.8, 77.8, 70.1, 54.3, 47.4, 39.4, 34.0, 31.2, 25.4, 22.9, 22.1, 20.7, 15.4, 10.8. IR
(CHCl3): 1800, 1785, 1650. MS (15 eV) m/z (relative intensity): 312 (M++1, 9), 268 (2), 239 (6), 139
(100), 138 (24), 123 (3), 99 (36), 83 (65), 81 (18).
3.4. Reaction with malononitrile
3.4.1. (1S,4R,5R)-6,6-Dicyano-4-(l-menthyloxy)-3-oxabicyclo[3.1.0]hexan-2-one 4
The compound prepared according to the general procedure A was purified by column chromatography
(hexane:acetone, 9:1), yield 63% (Table 1, entry 4). Pure 4 (yield 70%) was also obtained following
the general procedure B by (hexane:acetone, 10:1) chromatographic separation (Table 1, entry 5). Mp
200–202°C; [α]D25 −194.7 (c 1, CHCl3). Anal. calcd for C17H22N2O3: C, 67.53; H, 7.33; N, 9.26. Found:
C, 67.26; H, 7.35; N, 9.08. 1H NMR: 5.73 (s, 1H), 3.68 (dt, 1H, J=10.9 and 4.7), 3.32, 3.24 (AB system,
2H, J=5.5), 2.2–0.7 (m, 18 H); 13C NMR: 165.3, 110.9, 97.8, 79.5, 47.5, 39.8, 36.1, 33.9, 31.8, 31.3,
25.4, 22.9, 20.7, 15.5, 9.2. MS m/z (relative intensity): 257 (M+−45, 1), 217 (11), 138 (43), 123 (40), 95
(67), 81 (100).
3.5. Reaction with diethyl malonate
Following the general procedure B at 25°C, a 42:51:7 mixture (1H NMR) of compounds 5, 6 and
unreacted diethyl malonate was obtained (Table 1, entry 8). The separation of the mixture was obtained by
column chromatography (hexane:acetone, 5:0.3) to afford compounds 5 (40%) and 6 (50%). Compound
6 was obtained as sole product at lower temperature (−18°C) with the same yield (50%) (Table 1, entry
7).
3.5.1. (1S,4R,5R)-6.6-Diethoxycarbonyl-4-(l-menthyloxy)-3-oxabicyclo[3.1.0]hexan-2-one 5
1H NMR: 5.61 (s, 1H), 4.22 (m, 4H), 3.52 (dt, 1H, J=10.2 and 4.3), 2.88 (s, 2H) 1.30 (t, 6H, J=7.2),
2.2–0.7 (m, 18H); 13C NMR: 166.6, 165.9, 98.2, 77.9, 62.9, 62.6, 47.6, 41.6, 40.0, 34.5, 34.1, 31.3, 29.7,
25.3, 23.0, 20.8, 15.5, 14.0, 13.8, 13.7. MS m/z (relative intensity): 323 (M+−73, 1), 241 (100), 213 (61),
185 (66), 167 (25), 139 (40), 138 (35), 123 (30), 95 (73), 81 (55).
3.5.2. (1S,4R,40R,5S,50R,6S)1-Bromo-4,50-di(l-menthyloxy)-2-oxo-40 -[bis(ethoxycarbonyl]methyl)-3-
oxabicyclo[3.1.0]hexane-6-spiro-tetrahydrofuran-2-one 6
25
Mp 57–59°C; [α]D −99.0 (c 1, CHCl3). Anal. calcd for C35H53O10Br: C, 58.90; H, 7.49; Br, 11.20.
Found: C, 59.17; H, 7.45; Br, 11.18. 1H NMR: 5.95 (s, 1H), 5.75 (s, 1H), 4.22 (m, 4H), 3.61, 3.52 (2dt,
2×1H, J=10.2 and 4.3), 3.35 (d, 1H, J=4.3), 3.05 (s, 1H), 2.72 (d, 1H, J=4.3), 1.30, 1.35 (t, 2×3H,
J=7.1), 2.3–0.7 (m, 18H); 13C NMR: 168.7, 167.4, 166.2, 166.0, 100.0, 95.9, 78.0, 76.0, 62.6, 62.2, 50.6,
47.1, 44.2, 39.6, 38.8, 38.5, 37.2, 34.2, 33.8, 33.7, 31.0, 25.2, 24.3, 22.9, 22.4, 21.8, 21.7, 20.6, 20.3,
15.3, 15.1, 13.6, 13.4. IR (CHCl3): 1780, 1740, 1720. MS m/z (relative intensity): 712–714 (M++1, 0.2),
557–559 (7), 249 (7), 161 (25), 139 (58), 138 (49), 123 (30), 95 (91), 83 (100), 81 (84).
3.6. Reaction with ethyl acetoacetate
3.6.1. (3aR,4R,6aS)-3-Ethoxycarbonyl-4-(l-menthyloxy)-2-methyl-3a,6a-dihydrofuro[3,4-b]furan-
6(4H)-one 8
The compound was obtained as a sole diastereoisomer following procedures A (yield 60%), B (yield
50%) or C (yield 75%) (Table 2, entries 4–6). Purification was effected by column chromatography on

M. C. Maestro et al. / Tetrahedron: Asymmetry 10 (1999) 3593–3599
3599
25
silica gel (hexane:ether, 4:0.5). Mp 97–99°C; [α]D −22.0 (c 1, CHCl3). Anal. calcd for C20H30O6: C,
65.55; H, 8.25. Found: C, 65.30; H, 8.38. 1H NMR: 5.78 (s, 1H), 5.17 (d, 1H, J=9.1), 4.2 (m, 2H), 3.85
(dq, 1H, J=9.1 and 2.2), 3.54 (dt, 1H, J=10.2 and 3.8), 2.28 (d, 3H, J=2.2), 1.30 (t, 3H, J=7.2), 2.3–0.7
(m, 18H); 13C NMR: 172.6, 169.6, 164.3, 103.5, 78.1, 77.9, 60.1, 51.2, 47.6, 39.8, 34.2, 31.3, 25.4, 23.0,
22.1, 20.8, 15.5, 14.3, 14.0. IR (CHCl3): 1780, 1680, 1620. MS m/z (relative intensity): 321 (M+−45, 2),
182 (7), 154 (100), 138 (10), 137 (12), 126 (17), 125 (16), 123 (8), 109 (24), 95 (30), 81 (28).
3.7. Hydrogenolysis of the N-oxide 7
3.7.1. (3aR,4R,6aS)-4-(l-Menthyloxy)-3-methyl-3a,6a-dihydrofuro[3,4-d]isoxazol-6-(4H)-one 9
To a stirred 10% suspension of Pd–C (10 mg) in ethyl acetate (2 mL), isoxazol N-oxide 7 (0.05 g,
0.16 mmol) was added. The reaction was maintained for 24 h at room temperature under a hydrogen
balloon at atmospheric pressure. The catalyst was filtered and washed with the solvent, and the solution
was evaporated in vacuo to afford 9 (yield 90%). Mp 132–134°C; [α]D +161.6 (c 0.5, MeOH). Anal.
calcd for C16H25NO4: C, 65.06; H, 8.53; N, 4.74. Found: C, 65.33; H, 8.55; N, 4.81. 1H NMR: 5.55 (s,
1H, H4), 4.83 (d, 1H, J=7.3), 3.50 (dt, 1H, ment., J=10.2, 3.8), 3.22 (d, 1H, J=7.3), 2.2–0.7 (m, 18H,
ment.), 1.97 (s, 3H); 13C NMR: 176.1, 153.2, 98.3, 77.3, 68.1, 51.6, 47.2, 39.1, 33.8, 30.9, 25.2, 22.6,
21.8, 20.5, 15.1, 13.8. IR (CHCl3): 1800, 1700. MS m/z (relative intensity): 296 (M++1, 1), 240 (5), 158
(12), 139 (15), 138 (32), 123 (30), 95 (96), 83 (98), 81 (83), 55 (100).
Acknowledgements
We thank the Direccion General de Investigación Científica y Técnica (PB 95-210) for financial
support.
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