A two steps synthesis of γ-substituted and γ,γ-disubstituted α-(alkylmethylene)-γ-butyrolactones

Full text of DOI:10.1021/jo982131c

2954
J . Org. Chem. 1999, 64, 2954-2957
Sch em e 1
A Tw o Step s Syn th esis of γ-Su bstitu ted a n d
γ,γ-Disu bstitu ted
r-(Alk ylm eth ylen e)-γ-bu tyr ola cton es
Roberto Ballini,* Enrico Marcantoni, and Silvia Perella
Dipartimento di Scienze Chimiche dell’Universita`, Via S.
Agostino n. 1, 62032 Camerino, Italy
Received October 23, 1998
γ-Butyrolactones are an important class of compounds,
because they may be easily transformed into butenolides,
furans, cyclopentenones, etc.1 The lactone moiety is also
present in many natural products,2 expecially insect
pheromones,3 antifungal substances, and flavor compo-
nents or occurs in the essential oils of plants.4
Recently there has been an increasingly large amount
of research devoted to develop synthetic routes to polysub-
stituted γ-butyrolactones, in particular of R-methylene-
γ-butyrolactones.5 This has been due in large part to the
interest in several biologically active natural products,
which have the R-methylenelactone moiety as a major
structural feature.6-10
Although several methods are available for the syn-
thesis of R-methylene-γ-butyrolactones,11 the utility of
these methods suffer from certain drawbacks such as
restricted generality, the need for tedious procedures,
and/or expensive chemicals. Much attention has been
focused on the synthesis of R-methylene unit from
R-phosphono-γ-butyrolactones,12 but their synthesis re-
quires multisteps sequence, high temperature, and R-halo-
γ-lactones as starting material, and some of these are
not easily available.13
(1) (a) Sharpless, K. B.; Lauer, R. F.; Teranishi, A. Y. J . Am. Chem.
Soc. 1973, 95, 6137. (b) Trost, B. M.; Salzmann, T. N.; Hiroi, K. J .
Am. Chem. Soc. 1976, 98, 4887. (c) Grimm, E. L. Reissig, H.-U. J . Org.
Chem. 1985, 50, 242.
(2) For a review, see Kano, S.; Shibuya, S.; Ebata, T. Heterocycles
1980, 14, 661.
(3) Mori, K. Tetrahedron 1988, 45, 3233.
In the course of our program to explore the novel
utilities of functionalized nitroalkanes in the Michael
reaction,14 we disclosed that the nitro group may, simul-
taneously, behave both as an electron-withdrawing and
as a leaving group.15 Herein we report that γ-alkyl and
γ,γ-dialkyl-R-(alkylmethylene)-γ-lactones 6 and 7, re-
spectively, can be conveniently prepared, in two steps,
starting from nitroalkanes 1 and the commercially avail-
able methyl trans-4-oxo-2-pentenoate 2 (Scheme 1).
It is well know that Michael addition of nitroalkanes
to enones can be catalyzed by bases.16 We have thought
to carry out the regiospecific conjugated addition of the
nitro compound 1 to methyl trans-4-oxo-2-pentenoate 2
in THF using DBU as base. We found that reaction at
room-temperature results in full conversion and gives
satisfactory yields of the Michael adducts 4 (Table 1) after
(4) Dubs, P.; Stussi, R. Helv. Chim. Acta 1978, 61, 990.
(5) (a) Carlson, R. M.; Yang, Q. Tetrahedron Lett. 1994, 35, 7919.
(b) Lu, X.; Wang, Z.; J i, J . Tetrahedron Lett. 1994, 35, 613. (c) Dulcere,
J .-P.; Mihaubi, M. N.; Rodriguez, J . J . Org. Chem. 1993, 58, 5709. (d)
Lu, X.; Zhu, G. Synlett 1993, 68. (e) Petragnani, N.; Ferraz, H. M. C.;
Silva, G. V. J . Synthesis 1986, 157. (g) Grieco P. A. Synthesis 1975,
67. (h) Martin, V. S.; Rodriguez, C. M.; Martin, T. Org. Prep. Proc. Int.
1998, 30, 291.
(6) Kupchan, S. M.; Britto, R. W.; Ziegler, M. P.; Gilmore, C. J .;
Restivo, R. G.; Bryan, R. F. J . Am. Chem. Soc. 1973, 95, 1335 and
references therein.
(7) Amos, R. A.; Katzenellenbogen, J . J . Org. Chem. 1978, 43, 560.
(8) (a) Yamamoto, M. J . Chem. Soc, Perkin Trans 1 1981, 582. (b)
J ellal, A.; Grimaldi, J .; Santelli, M. Tetrahedron Lett. 1984, 25, 3179.
(c) Gollin, I. J . Chem. Soc., Perkin Trans 1 1998, 1869.
(9) Hoffman, H. M. R.; Rabe, J . Angew. Chem., Int. Ed., Engl. 1985,
24, 94.
(10) Mulzer, J . In Comprehensive Organic Synthesis; Flemming, I.,
Trost, B. M., Eds.; Pergamon: Oxford, 1991; Vol. 6, p 323.
(11) (a) Andrews, R. C.; Marshall, J . A.; De Hoff, B. S. Synth.
Commun. 1986, 16, 1593. (b) Patterson, J . W.; McMurry, J . E. J . Chem.
Soc., Chem. Commun. 1971, 488. (c) Chan, D. M. T.; Marder, T. B.;
Milstein, D.; Taylor, N. J . J . Am. Chem. Soc. 1987, 109, 6385 and
references therein. (d) Bryan, V. J .; Chan, T.-H. Tetrahedron Lett. 1996,
37, 5341. (e) Tamaru, Y.; Hojo, M.; Yoshida, Z. J . Org. Chem. 1991,
56, 1099 and references therein. (f) Rosini, G.; Laffi, F.; Marotta, E.;
Pagani, I.; Righi, P. J . Org. Chem. 1998, 63, 2389.
(14) (a) Rosini, G.; Marotta, E.; Ballini, R.; Petrini, M. Synthesis
1986, 237. (b) Rosini, G.; Ballini, R.; Petrini, M.; Marotta, E.; Angew.
Chem., Int. Ed., Engl. 1986, 25, 941. (c) Ballini, R.; Petrini, M.; Rosini,
G. Synthesis 1987, 711. (d) Ballini, R.; Marziali, P.; Mozzicafreddo, A.
J . Org. Chem. 1996, 61, 3209. (e) Ballini, R.; Bosica, G. Tetrahedron
Lett. 1996, 37, 8027.
(12) Lee, C.-W.; Gil, J . M.; Oh, D. Y. Heterocycles 1997, 45, 943.
(13) (a) Buechel, K. H.; Roechling, H.; Korte, F. Liebigs Ann. Chem.
1965, 685, 10. (b) J ackson, J . A.; Hammond, G. B.; Wiemer, D. F. J .
Org. Chem. 1989, 54, 4750.
(15) (a) Ballini, R.; Rinaldi, A. Tetrahedron Lett. 1994, 35, 9247. (b)
Ballini, R.; Bosica, G. Tetrahedron 1995, 51, 4213. (c) Ballini, R.; Bosica,
G. Synlett 1996, 1115.
(16) Ballini, R.; Bosica, G. Eur. J . Org. Chem. 1998, 355.
10.1021/jo982131c CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/24/1999

Notes
Ta ble 1. Syn th esis of En on es 4 a n d La cton es 6
J . Org. Chem., Vol. 64, No. 8, 1999 2955
Ta ble 2. Syn th esis of
γ,γ-Dia lk yl-r-(a lk ylm eth ylen e)-γ-la cton es 7
tions, and this result is probably due to competing
additions of the Grignard reagents to the ester function
of 4 or, above all, to the rapid deprotonation of the active
methylene hydrogens, leading, after quenching, to the
unchanged starting material. On the other hand, adding
the keto esters 4 to a suspension of dry cerium(III)
chloride19 in THF, followed by subsequent addition of the
organomagnesium reagents at low temperature (-70 °C),
results in the selective addition of the organometallic
species to the ketone functionality,20 and the usual
workup with acidic quenching gives the γ,γ-dialkyl-R-
(alkylmethylene)-γ-butyrolactones 7 in satisfactory yields
(Table 2). The success of this strategy can be attributed
to the important role that cerium(III) chloride plays in
increasing the nucleophilicity and decreasing the basicity
of the Grignard reagents.21
In summary, we have developed a new alternative way
for the synthesis of γ-substituted R-(alkylmethylene)-γ-
butyrolactones with one more functional group (ester,
hydroxyl, and ketone), and, since a wide range of proce-
dures for their transformation into other functionalities
is available, their presence in the molecule provides
important chances for further elaborations. Thus, the
mild reaction conditions and the use of easily available
reagents render this method synthetically useful.
elimination of nitrous acid from the adduct 3. The
E-isomers of the keto esters 4 were highly predominant
(up to 93%, determined by NMR analysis of the crude
reaction mixture), and this facilitates their purification.
It is well documented, in fact, that a â-alkyl substituent
syn to a carbonyl moiety in R,â-conjugated enones
resonates downfield relative to the anti alkyl substituent
in the NMR spectrum.17 Consequently, the NMR chemi-
cal shifts of the â-methylene or γ-methylene protons, or
â-methylene or γ-methine protons of â-secondary alkyl
substituents, provide a reliable guide for the assignment
of the olefin configuration. The readily available methyl
2-(alkylmethylene)-4-oxopentenoates 4 react with sodium
borohydride in the presence of a catalytic amount (12.5
mol %) of sodium hydrogenphosphate dodecahydrate
(Na2HPO4‚12H2O) to provide γ-hydroxy carboxylates 5.
However, no attempt to isolate these intermediates is
undertaken. Instead, treatment with acid during the
workup, directly, affords the R-(alkylmethylene)-γ-meth-
yl-γ-lactones 6. Under these conditions the carbon-
carbon double bond was preserved and the lactonization
occurred in satisfactory to good yields (Table 1). It should
be emphasized that the presence of other functionalities
such as the ester (entry 7, Table 1) or hydroxyl group
(entry 8, Table 1: in this case any other lactones different
from the γ-ones are not observed) are preserved. How-
ever, in the case of 2-(alkylmethylene)-4-oxopentenoate
contains an acetal moiety 4i the hydrolysis occurs to the
parent ketone, during the acidic workup, to afford the
lactone 6i in good yield (70%).
Exp er im en ta l Section
Gen er a l. All 1H NMR spectra were collected on a 200 MHz
NMR spectrometer in CDCl3. All mass spectra were determined
on a HP5890 Series II capillary GC operating in split mode with
helium carrier gas and fitted with a mass selective detector
(MSD). The column used was a HP5 capillary column 30 m ×
0.25 mm, with 0.25 µm film thickness of 5% phenylmethylsili-
cone gum. The temperature program used the initial tempera-
ture of 65 °C for 3 min and then ramped at 15 °C min-1 to 280
°C. The products were purified by flash chromatography22 on
Merck silica gel (0.040-0.063 mm). Methyl trans-4-oxo-2-pen-
tenoate 2 was purchased from Fluka. The Grignard reagents
We also examined the reaction of methyl 2-(alkylm-
ethylene)-4-oxopentenoates 4 with Grignard reagents as
nucleophiles.18 To control the chemoselectivity the reac-
tions were executed at low temperature (-70 °C) and
with only a very slight excess of the Grignard reagent.
Nevertheless, yields were rarely good under these condi-
(19) Imamoto, T.; Taliyama, N.; Nakamura, K.; Hatajima, T.;
Hamiya, Y. J . Am. Chem. Soc. 1989, 111, 4392.
(20) Kinney, W. A.; Coghlan, M. J .; Paquette, L. A. J . Am. Chem.
Soc. 1985, 107, 7352.
(21) (a) Bartoli, G.; Marcantoni, E.; Petrini, M. Angew. Chem., Int.
Ed., Engl. 1993, 32, 1061. (b) Bartoli, G.; Marcantoni, E.; Petrini, M.;
Sambri, L. Tetrahedron Lett. 1994, 35, 8453. (c) Bartoli, G.; Marcantoni,
E.; Sambri, L.; Tamburini, M. Angew. Chem., Int. Ed., Engl. 1995, 34,
2046.
(17) Dieter, R. K.; Silks, L. A., III; Fishpang, J . R.; Kastner, M. E.
J . Am. Chem. Soc. 1985, 107, 4679.
(18) (a) Kunz, T.; J anowitz, A.; Reissig, H.-U. Chem. Ber. 1989, 122,
2165. (b) Reissig, H.-U.; Angert, H.; Kunz, T.; J anowitz, A.; Handke,
G.; Bruce-Adjei, E. J . Org. Chem. 1993, 58, 6280.
(22) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

2956 J . Org. Chem., Vol. 64, No. 8, 1999
Notes
were purchased (Aldrich) as solutions in the corresponding
solvent and used as received, and they were titrated before use
according to the ref 23. The nitroalkanes 1 were commercially
available or prepared by reported procedures.24
Gen er a l P r oced u r e for th e Con ju ga te Ad d ition of Ni-
tr oa lk a n es (1) to Meth yl tr a n s-4-Oxo-2-p en ten oa te (2). To
a solution of nitroalkane 1 (20 mmol) and methyl trans-4-oxo-
2-pentenoate 2 (2.56 g, 20 mmol) in THF (70 mL) was added
DBU (3.04 g, 20 mmol) at room temperature. After stirring
for 3 h and evaporation of the solvent, the crude product
was purified by flash chromatography, affording the pure
compound 4.
with 6 M HCl, extracted with Et2O (3 × 10 mL), dried (MgSO4),
and evaporated to give the crude lactone. Further purification
by flash chromatography afforded the pure compound 6.
5-Meth yl-3-[(E)-ph en ylm eth yliden e]dih ydr ofu r an -2(3H)-
1
on e (6a ): IR (film) 3057, 1747, 1651 cm-1; H NMR δ 1.45 (d,
3H, J ) 6.3 Hz), 2.72-2.9 (m, 1H), 3.3-3.5 (m, 1H), 4.68-4.85
(m, 1H), 7.4-7.6 (m, 6H); EIMS (70 eV) m/z 188 [M+], 159, 128,
116, 77, 63, 51. Anal. Calcd for C12H12O2 C, 76.57; H, 6.43.
Found: C, 76.67; H, 6.47.
5-Meth yl-3-[(E)-p h en yleth ylid en e]d ih yd r ofu r a n -2(3H)-
1
on e (6b): IR (film) 2977, 1751, 1679 cm-1; H NMR δ 1.45 (d,
3H, J ) 6.2 Hz), 2.4-2.6 (m, 1H), 3.0-3.2 (m, 1H), 3.50 (d, 2H,
J ) 7.7 Hz), 4.5-4.8 (m, 1H), 6.45-6.55 (m, 1H), 7.1-7.4 (m,
4H); EIMS (70 eV) m/z 202 [M+], 143, 129, 91, 77. Anal. Calcd
for C13H14O2 C, 72.20; H, 6.98. Found: C, 72.17; H, 6.97.
5-Met h yl-3-(1-m et h ylet h ylid en e)d ih yd r ofu r a n -2(3H )-
Met h yl
(E)-2-(2-Oxop r op yl)-3-p h en ylp r op -2-en oa t e
(4a ): IR (film) 1711, 1640 cm-1; 1H NMR δ 2.25 (s, 3H), 3.62 (s,
2H), 3.80 (s, 3H), 7.22-7.42 (m, 5H), 7.92 (s, 1H). Anal. Calcd
for C13H14O3 C, 71.54; H, 6.46. Found: C, 71.64; H, 6.39.
Meth yl (E)-2-(2-Oxop r op yl)-4-p h en ylbu t-2-en oa te (4b):
IR (film) 1716, 1649 cm-1; 1H NMR δ 2.2 (s, 3H), 2.65-2.75 (dd,
1H, J ) 4.8 and 17.9 Hz), 3.05-3.2 (m, 1H), 3.45-3.55 (m, 2H),
3.7 (s, 3H), 7.1-7.4 (m, 6H). Anal. Calcd for C14H16O3 C, 72.39;
H, 6.94. Found: C, 72.46; H, 6.88.
1
on e (6c): IR (film) 2930, 1742, 1667 cm-1; H NMR δ 1.35 (d,
3H, J ) 6.2 Hz), 1.8 (s, 3H), 2.2 (s, 3H), 2.4-2.5 (m, 1H), 2.9-
3.1 (m, 1H), 4.45-4.6 (m, 1H); EIMS (70 eV) m/z 140 [M+], 125,
107, 79, 68, 41. Anal. Calcd for C8H12O2 C, 68.54; H, 8.63.
Found: C, 68.47; H, 8.67.
3-Cycloh e xylid e n e -5-m e t h yld ih yd r ofu r a n -2(3H )-on e
(6d ): IR (film) 2929, 1741, 1658 cm-1; 1H NMR δ 1.38 (d, 3H, J
) 6.3 Hz), 1.5-1.8 (m, 6H), 2.15-2.25 (m, 2H), 2.43 (dd, 1H, J
) 6.2 and 15.2 Hz), 2.9-3.0 (m, 2H), 4.5-4.65 (m, 1H); EIMS
(70 eV) m/z 180 [M+], 135, 107, 79, 41. Anal. Calcd for C11H16O2
C, 73.30; H, 8.95. Found: C, 73.40; H, 8.87.
Meth yl 3-Meth yl-2-(2-oxop r op yl)bu t-2-en oa te (4c): IR
(film) 1718, 1650 cm-1; 1H NMR δ 1.75 (s, 3H), 2.12 (s, 3H), 2.2
(s, 3H), 3.45 (s, 2H), 3.72 (s, 3H). Anal. Calcd for C9H14O3 C,
63.51; H, 8.29. Found: C, 63.47; H, 8.37.
Meth yl 2-Cycloh exyliden e-4-oxopen tan oate (4d): IR (film)
1
1718, 1632 cm-1; H NMR δ 1.52-1.62 (m, 8H), 2.08-2.21 (m,
3-[(E )-Bu t ylid e n e ]-5-m e t h yld ih yd r ofu r a n -2(3H )-on e
2H), 2.18 (s, 3H), 2.6-2.7 (m, 2H), 3.45 (s, 2H), 3.71 (s, 3H).
Anal. Calcd for C12H18O3 C, 68.55; H, 8.63. Found: C, 68.47; H,
8.67.
1
(6e): IR (film) 2961, 1754 cm-1; H NMR δ 0.9 (t, 3H, J ) 7.1
Hz), 1.4 (d, 3H, 6.2 Hz), 1.4-1.6 (m, 2H), 2.1-2.2 (m, 2H), 2.35-
2.5 (m, 1H), 2.9-3.1 (m, 1H), 4.55-4.7 (m, 1H), 6.55-6.75 (m,
1H); EIMS (70 eV) m/z 154 [M+], 125, 95, 83, 67, 41. Anal. Calcd
for C9H14O2 C, 70.10; H, 9.15. Found: C, 70.04; H, 9.17.
5-Met h yl-3-[(E)-p r op ylid en e]d ih yd r ofu r a n -2(3H )-on e
Meth yl (E)-2-(2-Oxop r op yl)h ex-2-en oa te (4e): IR (film)
1713, 1640 cm-1; 1H NMR δ 0.92 (t, 3H, J ) 7.3 Hz), 1.38-1.58
(m, 2H), 2.02-2.2 (m, 2H), 2.18 (s, 3H), 3.41 (s, 2H), 3.71 (s,
3H), 6.98 (t, 1H, J ) 7.5 Hz). Anal. Calcd for C10H16O3 C, 65.19;
H, 8.75. Found: C, 65.27; H, 8.67.
1
(6f): IR (film) 1755, 1681 cm-1; H NMR δ 1.1 (t, 3H, J ) 7.5
Hz), 1.4 (d, 3H, J ) 6.2 Hz), 2.1-2.25 (m, 2H), 2.3-2.5 (m, 1H),
2.8-3.1 (m, 1H), 4.55-4.75 (m, 1H), 6.6-6.75 (m, 1H); EIMS
(70 eV) m/z 140 [M+], 111, 95, 81, 67, 41. Anal. Calcd for C8H12O2
C, 68.54; H, 8.63. Found: C, 68.61; H, 8.67.
Meth yl (E)-2-(2-Oxop r op yl)p en t-2-en oa te (4f): IR (film)
1713, 1650 cm-1; 1H NMR δ 1.05 (t, 3H, J ) 7.5 Hz), 2.05-2.15
(m, 2H), 2.2 (s, 3H), 3.4 (s, 2H), 3.7 (s, 3H), 6.95 (t, 1H, J ) 7.5
Hz). Anal. Calcd for C9H14O3 C, 63.51; H, 8.29. Found: C, 63.58;
H, 8.27.
Dim et h yl (E)-2-(2-Oxop r op yl)h ex-2-en ed ioa t e (4g): IR
(film) 1717, 1649 cm-1; 1H NMR δ 2.2 (s, 3H), 2.4-2.5 (m, 4H),
3.4 (s, 3H), 3.67 (s, 3H), 3.71 (s, 3H), 6.96-7.00 (m, 1H). Anal.
Calcd for C11H16O5 C, 57.88; H, 7.07. Found: C, 57.95; H, 7.02.
Meth yl 4-[(E)-5-Meth yl-2-oxodih ydr ofu r an -3(2H)-yliden e]-
bu ta n oa te (6g): IR (film) 2954, 1750, 1683 cm-1 1H NMR δ
;
1.4 (d, 3H, J ) 6.2 Hz), 2.35-2.55 (m, 5H), 3.0-3.15 (m, 1H),
3.68 (s, 3H), 4.6-4.75 (m, 1H), 6.65-6.75 (m, 1H); EIMS (70
eV) m/z 198 [M+], 183, 151, 107, 93, 79, 67. Anal. Calcd for
C10H14O4 C, 68.54; H, 8.63. Found: C, 68.61; H, 8.67.
3-[(E)-4-H yd r oxyp en t ylid en e]-5-m et h yld ih yd r ofu r a n -
2(3H)-on e (6h ): IR (film) 1748, 1711 cm-1; 1H NMR δ 1.39 (d,
3H, J ) 6.2 Hz), 2.15 (s, 3H), 2.3-2.45 (m, 2H), 2.45-2.55 (m,
1H), 2.56-2.65 (m, 2H), 2.38-3.14 (m, 1H), 4.55-4.75 (m, 1H),
6.5-6.6 (m, 1H); EIMS (70 eV) m/z 182 [M+], 149, 140, 111, 79,
43. Anal. Calcd for C10H14O3 C, 65.19; H, 8.75. Found: C, 65.21;
H, 8.67.
Met h yl
(E)-6-H yd r oxy-2-(2-oxop r op yl)h ep t -2-en oa t e
(4h ): IR (film) 3430, 1712, 1650 cm-1; 1H NMR δ 1.18 (d, 3H, J
) 6.2 Hz), 1.5-1.6 (m, 2H), 2.2 (s, 3H), 2.18-2.35 (m, 2H), 3.45
(s, 2H), 3.7 (s, 3H), 3.7-3.8 (m, 1H), 6.95 (t, 1H, J ) 7.6 Hz).
Anal. Calcd for C11H19O4 C, 61.37; H, 8.90. Found: C, 61.42; H,
8.87.
Meth yl (E)-5-(2-Meth yl-1,3-d ioxola n -2-yl)-2-(2-oxop r op y-
l)p en t-2-en oa te (4i): IR (film) 1712, 1649 cm-1; 1H NMR δ 1.3
(s, 3H), 1.68-1.7 (m, 2H), 2.2 (s, 3H), 2.12-2.26 (m, 2H), 3.44
(s, 2H), 3.72 (s, 3H), 3.86-3.98 (m, 4H), 7.00 (t, 1H, J ) 7.5 Hz).
Anal. Calcd for C14H22O5 C, 62.20; H, 8.20. Found: C, 62.27; H,
8.27.
5-Met h yl-3-[(E)-4-oxop en t ylid en e)d ih yd r ofu r a n -2(3H )-
on e (6i): IR (film) 2954, 1750, 1683 cm-1 1H NMR δ 1.4 (d,
;
3H, J ) 6.2 Hz), 2.35-2.55 (m, 5H), 3.0-3.15 (m, 1H), 3.68 (s,
3H), 4.6-4.75 (m, 1H), 6.65-6.75 (m, 1H); EIMS (70 eV) m/z
198 [M+], 183, 151, 107, 93, 79, 67. Anal. Calcd for C10H14O4 C,
65.91; H, 7.74. Found: C, 65.81; H, 7.67.
Meth yl (E)-2-(2-Oxop r op yl)h ep t-2-en oa te (4e): IR (film)
1
1713, 1640 cm-1; H NMR δ 0.92 (t, 3H, J ) 7.3 Hz), 1.38-1.6
Gen er a l P r oced u r e for P r ep a r in g γ,γ-Dia lk yl-r-(a lk yl-
m eth ylen e)-γ-bu tyr ola cton es (7). Finely ground CeCl3‚7H2O
(1.5 mmol) was dried by heating at 140 °C/0.1 Torr for 2 h.25
Dry THF (10 mL) was then added at 0 °C, and the milky
suspension was stirred overnight under nitrogen at room tem-
perature. At this temperature, a solution of 4 (1 mmol) in THF
(5 mL) was added and left to stir for 1 h. Then, it was cooled to
-70 °C, and Grignard reagent (1.5 mmol) was added by syringe.
The reaction mixture was then left to stir until TLC indicated
that no starting material remained. The reaction was quenched
with 10% AcOH and extracted with Et2O (3 × 10 mL). The
ethereal extract was washed with water (2 × 10 mL) and brine
(m, 4H), 2.02-2.2 (m, 2H), 2.18 (s, 3H), 3.41 (s, 2H), 3.71 (s,
3H), 6.98 (t, 1H, J ) 7.5 Hz). Anal. Calcd for C11H18O3 C, 66.63;
H, 9.15. Found: C, 66.77; H, 9.07.
Gen er a l P r oced u r e for P r ep a r in g r-(Alk ylm eth ylen e)-
γ-m eth yl-γ-la cton es (6). To a cooled (0 °C) solution of com-
pound 4 (1.5 mmol) in MeOH (10 mL) were consecutively added
Na2HPO4‚12H2O (0.067 g, 0.188 mmol) and NaBH4 (0.057 g, 1.5
mmol). The mixture was stirred for 2 h at 0 °C and then at room
temperature for 10 h. The mixture was then acidified to pH 1-2
(23) Berbreiter, D. E.; Pendergrass, E. J . Org. Chem. 1981, 46, 219.
(24) (a) Kornblum, N.; Larson, H. O.; Blackwood, R. K.; Mooberry,
D. D.; Oliveto, E. P.; Graham, G. E. J . Am. Chem. Soc. 1956, 78, 1497.
(b) Rosini, G.; Ballini, R. Synthesis 1988, 833. (c) Rosini, G.; Ballini,
R.; Petrini, M.; Marotta, E.; Righi, P. Org. Prep. Proc. Int. 1990, 22,
707. (d) Ballini, R.; Petrini, M. J . Chem. Soc., Perkin Trans. 1 1992
3159. (e) Ballini, R.; Bartoli, G. Synthesis 1993, 965. (f) Ballini, R.;
Bosica, G.; Rafaiani, G. Helv. Chim. Acta 1995, 78, 879. (g) Ballini,
R.; Marziali, P.; Mozzicafreddo, A. J . Org. Chem. 1996, 61, 3209.
(25) It has been recently reported (Evans, W. J .; Feldman, J . D.;
Ziller, J . W. J . Am. Chem. Soc. 1996, 118, 4581) that the material
obtained after drying of CeCl3‚7H2O (at 150 °C and 0.03 Torr for 12 h)
was [CeCl3‚(H2O)]n. We have not analyzed the CeCl3 prepared by the
present procedure, however, the material was highly efficient without
the need of a large excess of Grignard reagent.

Notes
J . Org. Chem., Vol. 64, No. 8, 1999 2957
(10 mL), dried over anhydrous MgSO4, and concentrated in
vacuo. The crude product was purified by flash chromatography
to give the corresponding lactone 7.
5-Ben zyl-3-cycloh exyliden e-5-m eth yldih ydr ofu r an -2(3H)-
1
on e (7f): IR (film) 1765 cm-1; H NMR δ 1.25 (s, 3H), 1.5-1.7
(m, 10H), 2.05-2.15 (m, 2H), 2.2-2.3 (m, 2H), 7.15-7.35 (m,
5H); EIMS (70 eV) m/z 270 [M+], 151, 107, 91, 77, 43. Anal. Calcd
for C18H22O2 C, 79.96; H, 8.20. Found: C, 80.01; H, 8.14.
5,5-Dim eth yl-3-(1-m eth yleth yliden e)dih ydr ofu r an -2(3H)-
5,5-Dim et h yl-3-[(E)-p en t ylid en e]d ih yd r ofu r a n -2(3H )-
on e (7a ): IR (film) 1755 cm-1 1H NMR δ 0.9 (t, 3H, J ) 7.0
;
Hz), 1.42 (s, 6H), 1.25-1.55 (m, 4H), 2.1-2.2 (m, 2H), 2.7 (s,
2H), 6.65-6.75 (m, 1H); EIMS (70 eV) m/z 182 [M+], 167, 82,
67, 43. Anal. Calcd for C11H18O2 C, 72.49; H, 9.95. Found: C,
72.51; H, 9.87.
1
on e (7 g): IR (film) 1740 cm-1; H NMR δ 1.39 (s, 6H), 1.82-
1.84 (m, 3H), 2.2-2.8 (m, 3H), 2.62-2.68 (m, 2H); EIMS (70 eV)
m/z 154 [M+], 121, 107, 81, 68, 43. Anal. Calcd for C9H14O2 C,
70.10; H, 9.15. Found: C, 70.01; H, 9.24.
5-Meth yl-3-[(E)-pen tyliden e]-5-pr opyldih ydr ofu r an -2(3H)-
on e (7b): IR (film) 1754 cm-1
;
1H NMR δ 0.85-0.95 (m, 6H),
5-Ben zyl-5-m eth yl-3-(1-m eth yleth ylid en e)d ih yd r ofu r a n -
1.3-1.5 (m, 6H), 1.4 (s, 3H), 1.6-1.7 (m, 2H), 2.1-2.2 (m, 2H),
2.6-2.7 (m, 2H), 6.66-7.66 (m, 1H); EIMS (70 eV) m/z 210 [M+],
167, 121, 81, 67, 43. Anal. Calcd for C13H22O2 C, 74.24; H, 10.54.
Found: C, 74.31; H, 10.47.
2(3H)-on e (7h ): IR (film) 1743 cm-1 1H NMR δ 1.4 (s, 3H),
;
1.73 (s, 3H), 2.11 (s, 3H), 2.48 (d, 1H, J ) 12.7 Hz), 2.8 (d, 1H,
J ) 12.7 Hz), 2.9 (dd, 2H, J ) 13.6 and 23.9 Hz), 7.15-7.3 (m,
5H); EIMS (70 eV) m/z 230 [M+], 215, 139, 111, 91, 77, 67, 43.
Anal. Calcd for C15H18O2 C, 78.23; H, 7.88. Found: C, 78.31; H,
7.94.
5-Be n zyl-5-m e t h yl-3-[(E )-p e n t ylid e n e ]d ih yd r ofu r a n -
1
2(3H)-on e (7c): IR (film) 1753 cm-1; H NMR δ 0.87 (t, 3H, J
) 7.0 Hz), 1.2-1.36 (m, 4H), 1.43 (s, 3H), 2.0-2.1 (m, 1H), 2.45-
2.85 (m, 2H), 2.86-3.05 (m, 2H), 6.5-6.6 (m, 1H), 7.15-7.3 (m,
5H); EIMS (70 eV) m/z 258, 167, 121, 91, 77, 65, 43. Anal. Calcd
for C17H22O2 C, 79.03 H, 8.58. Found: C, 79.11; H, 8.47.
5-Meth yl-3-[(E)-p h en ylm eth ylid en e]-5-p r op yld ih yd r ofu -
5-Ben zyl-5-m eth yl-3-[(E)-bu tyliden e)dih ydr ofu r an -2(3H)-
on e (7i): IR (film) 1765 cm-1 1H NMR δ 0.95 (t, 3H, J ) 7.2
;
Hz), 1.42 (s, 3H), 1.35-1.45 (m, 2H), 1.8-2.0 (m, 2H), 2.36-
2.56 (m, 2H), 2.85-3.05 (m, 2H), 6.91-6.98 (m, 1H), 7.12-7.35
(m, 5H); EIMS (70 eV) m/z 244 [M+], 153, 125, 111, 91, 77, 65,
43. Anal. Calcd for C11H20O2 C, 72.49; H, 9.95. Found: C, 72.41;
H, 10.01.
r a n -2(3H)-on e (7d ): IR (film) 1716 cm-1 1H NMR δ 1.02 (t,
;
3H, J ) 7.1 Hz), 1.32 (s, 3H), 1.35-1.50 (m, 3H), 1.63-1.75 (m,
1H), 2.52 (d, 1H, J ) 17.05 Hz), 2.74 (d, 1H, J ) 17.05 Hz), 7.01-
7.09 (m, 2H), 7.26-7.35 (m, 2H), 7.56-7.60 (m, 2H); EIMS (70
eV) m/z 230 [M+], 215, 187, 91, 82, 77, 43. Anal. Calcd for
C15H18O2 C, 78.23; H, 7.88. Found: C, 78.31; H, 7.94.
Ack n ow led gm en t. This work was carried out in the
framework of the National Project “Stereoselezione in
Sintesi Organica. Metodologie ed Applicazioni” sup-
ported by Ministero dell’Universita` e della Ricerca
Scientifica e Tecnologica, Rome, and by University of
Camerino.
5,5-Dim et h yl-3-[cycloh exylid en e]d ih yd r ofu r a n -2(3H )-
on e (7e): IR (film) 1730 cm-1; 1H NMR δ 1.4 (s, 6H), 1.55-1.7
(m, 6H), 2.15-2.22 (m, 2H), 2.68 (s, 2H), 2.9-3.0 (m, 2H); EIMS
(70 eV) m/z 194 [M+], 179, 133, 121, 79, 67. Anal. Calcd for
C
12H18O2 C, 74.19; H, 9.34. Found: C, 74.11; H, 9.24.
J O982131C