g-Butyrolactone1

[96-48-0]  · C4H6O2  · g-Butyrolactone  · (MW 86.09)

(useful source of di- and trifunctional acyclic synthons; can be converted into various types of substituted g-lactones and tetrahydrofurans)

Alternate Names: 4-hydroxybutyric acid g-lactone; dihydro-2(3H)-furanone.

Physical Data: bp 204 °C; mp -43.5 °C; d 1.129 g cm-3.

Solubility: misc with water; sol most organic solvents (e.g. CH2Cl2, Et2O, benzene, THF, and MeOH).

Form Supplied in: colorless liquid (>99%); inexpensive.

Purification: hygroscopic; water can be removed by distillation from CaH2, CaSO4, or BaO under dry Ar. When the commercial reagent is distilled twice from CaH2, the fraction boiling at 80-81 °C/11 mmHg contains 99.8% g-butyrolactone.2

Handling, Storage, and Precautions: avoid contact with skin or eyes; do not inhale or ingest; vapor is irritating to the eyes and upper respiratory tract. Anhydrous g-butyrolactone should be used immediately after distillation for best results. Use in a fume hood.

Formation of Halo Acid Derivatives.

The proclivity of lactones to undergo halide-assisted ring opening has often been exploited for easy access to valuable synthetic intermediates.3 Thus alcoholysis in the presence of Hydrogen Bromide provides 4-bromobutyrates (eq 1).4,5 Related procedures involving Bromotrimethylsilane,6 Boron Tribromide,7 or Phosphorus(III) Bromide3d as the bromide source are also effective. Similarly, 4-iodobutyrates are obtained by using Iodotrimethylsilane,6a,8 BBr3/Sodium Iodide,7 or the Boron Triiodide-N,N-diethylaniline complex (eq 2).9 Alternatively, they can be prepared on a large scale from bromo or chloro esters by halogen exchange.3f The latter are readily available through alcoholysis of 4-chlorobutanoyl chloride (eq 3).10

Reaction of g-butyrolactone with 2.1 equiv of Bromine in the presence of red phosphorus affords a-bromo-g-butyrolactone.11 When 4 equiv of bromine are used, ring opening ensues to furnish 2,4-dibromobutyric acid bromide, which upon methanolysis affords methyl 2,4-dibromobutyrate in high overall yield (eq 4).12 Dibromobutyrates are useful for preparing cyclopropanes (eq 4),12 azetidines,13 and b-lactams (eq 5).14

Aminolysis.

In the presence of an Aluminum Chloride-Triethylamine couple, lactones smoothly react with primary or secondary amines to give the corresponding o-hydroxyalkanamides (eq 6).15

Lewis Acid-Induced Carbon-Carbon Bond Formation.

The outcome of the Friedel-Crafts reaction of g-butyrolactone with benzene can be manipulated by simply varying the amount of AlCl3 so that either 4-phenylbutyric acid or a-tetralone can be obtained at will (eq 7).16 In the presence of Triethylsilane and a catalytic amount of a trityl salt, lactones undergo condensation with silyl ketene acetals and in situ reduction of the resulting unsaturated esters to give a-substituted cyclic ethers (eq 8).17 When a carbon nucleophile is used in place of Et3SiH, a,a-disubstituted cyclic ethers are obtained.17

Formation of Hydroxy Esters.

Although 4-hydroxybutyrates may be prepared by acid-catalyzed alcoholysis of g-butyrolactone, their isolation from the resulting lactone-hydroxy ester equilibrium is tedious and yields are low.18 The practical alternative entails lactone saponification and subsequent reaction of the carboxylate with a suitable electrophile (eq 9).19 Silyl esters can be prepared in a similar manner.20

One of the most commonly used methods for converting lactones into acyclic compounds involves reduction with Diisobutylaluminum Hydride and Wittig homologation of the resulting lactol21 (see also Dihydro-5-(hydroxymethyl)-2(3H)-furanone). A related, more recent procedure22 provides a,b-unsaturated esters in a single operation (eq 10).23

Reactions with Organometallics.

In general, unsubstituted lactones tend to undergo double attack by organometallics to give diols, whereas substituted lactones are more susceptible to monoaddition.24,25 However, the outcome strongly depends on the nature of the organometallic reagent and reaction conditions.24-26 Monoaddition can be achieved with organolithium compounds (eq 11),24a although yields of keto alcohols are rarely high.27 Lithium acetylides have been widely exploited for the synthesis of natural spiroacetals,28 such as the insect pheromone (1) (eq 12).28a The highly oxophilic organocerium reagents give superior yields of monoaddition products when compared to their lithium precursors (eq 13).25 Organocerates are also advantageous for converting lactones into hydroxyallylsilanes (see also Cerium(III) Chloride).29

Grignard compounds exhibit an innate preference for double addition24,30 giving high yields of diols which can be easily transformed into g,g-disubstituted-g-butyrolactones (eq 14).31 Analogously, a,o-di-Grignard reagents provide spirolactones (see also 1,5-Bis(bromomagnesio)pentane).32

Alkylation and C-Silylation.

Clean a-monoalkylation of g-butyrolactone is usually achievable by exposure to LDA and reaction of the enolate with a primary alkyl, allyl, or propargyl halide in the presence of HMPA (in the absence of HMPA, a,a-dialkylation is also observed).33,34 An example is depicted in eq 15.35 A highly effective but equally elaborate procedure, suitable for both alkylation and acylation, utilizes a crown ether-potassium complex instead of LDA.2 C-Silylation of g-lactones can be realized in a highly selective fashion by using g-Butyrolactone as silylating agent. Addition of a Grignard reagent to the resulting a-silyl-g-butyrolactone, followed by alkenation and eventual oxidation delivers 4-oxocarboxylic acids in good overall yields (eq 16).36

Aldol Reaction.

Generally speaking, lactone-derived enolates and silyl ketene acetals show poor simple diastereoselection.37 Thus reaction of lithiated g-butyrolactone with benzaldehyde provides a modest 30:70 ratio of syn and anti adducts which can be reversed by the intervention of Zinc Chloride (eq 17).38 In the latter case a zinc enolate is involved. Higher anti-selectivity has been encountered with a sterically more demanding aldehyde.39a Useful levels of syn selectivity are conferred by Lewis acid-mediated aldol reaction of 2-(trimethylsilyloxy)-4,5-dihydrofuran40 (prepared from g-butyrolactone) with propynal-hexacarbonylcobalt complexes (eq 18).41

Exposure of the easily prepared a,a-bis(phenylthio)-g-butyrolactone to Ethylmagnesium Bromide leads to a magnesium enolate which undergoes aldol reaction in excellent yields (eq 19).42a The resulting adducts can be transformed into 3-(1-hydroxyalkyl)-2(5H)-furanones by oxidation of the phenylthio group and elimination of the resulting sulfoxide.42 Alternatively, 3-(1-hydroxyalkyl)-2(5H)-furanones are accessible in one step from butenolides (see also a,b-Butenolide).43

Alkylidenation.

Many methods exist for the a-methylenation44,45 and a-alkylidenation45a,46-48 of lactones. An appealing procedure for preparing a-methylene-g-butyrolactone entails a-formylation and subsequent condensation with formaldehyde.45a (E)-a-Alkylidene-g-butyrolactones, essentially free of their (Z) isomers, are available from g-butyrolactone in high yields through the vinylogous carbamate (2) and a-butylthiolactone (3) (eq 20).46 Usefully, a-alkylidene-lactones can be isomerized to 3-alkyl-2(5H)-furanones by heating with deactivated W-2 Raney Nickel.46

Sequential treatment of g-butyrolactone with LDA and bis(methoxy(thiocarbonyl)) disulfide provides a lithium enolate which reacts with aldehydes to give preferentially either (E)- or (Z)-a-alkylidene-g-butyrolactones, depending on whether ZnCl2 is added before the aldehyde (eq 21).47 Apparently, these reactions involve episulfides and the double bond geometry depends on the stereochemical outcome of the initial aldol process. Methylenation or alkylidenation of the lactone carbonyl group can be effected by using the Tebbe reagent (m-Chlorobis(cyclopentadienyl)(dimethylaluminum)-m-methylenetitanium) and its variants.49


1. (a) Fieser, L. F.; Fieser, M. FF 1967, 1, 101. (b) Fieser, M. FF 1980, 8, 304, 447. (c) Sutherland, I. O. In Comprehensive Organic Chemistry; Barton, D. H. R.; Ollis, W. D., Eds.; Pergamon: Oxford, 1979; Vol. 2, pp 869-956.
2. Jedlinski, Z.; Kowalczuk, M.; Kurcok, P.; Grzegorzek, M.; Ermel, J. JOC 1987, 52, 4601.
3. Examples: (a) ApSimon, J.; Seguin, R. SC 1980, 897. (b) Baldwin, J. E.; Li, C.-S. CC 1988, 261. (c) Wright, J.; Drtina, G. J.; Roberts, R. A.; Paquette, L. A. JACS 1988, 110, 5806. (d) Ziegler, F. E.; Sobolov, S. B. JACS 1990, 112, 2749. (e) Viala, J.; Munier, P.; Santelli, M. T 1991, 47, 3347. (f) Xu, Y.-C., Roughton, A. L.; Plante, R.; Goldstein, S.; Deslongchamps, P. CJC 1993, 71, 1152.
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21. Examples: (a) Corey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W. JACS 1969, 91, 5675. (b) Barrett, A. G. M.; Carr, R. A. E.; Attwood, S. V.; Richardson, G.; Walshe, N. D. A. JOC 1986, 51, 4840. (c) Lee, E.; Hur, C.-U.; Park, J.-H. TL 1989, 30, 7219. (d) Roy, R.; Rey, A. W. CJC 1991, 69, 62.
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30. For an exception see: Nicolaou, K. C.; Papahatjis, D. P.; Claremon, D. A.; Magolda, R. L.; Dolle, R. E. JOC 1985, 50, 1440.
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39. (a) Sansbury, F. H.; Warren, S. TL 1992, 33, 539. See also: (b) Gennari, C.; Oliva, A.; Molinari, F.; Piarulli, U. TL 1990, 31, 2453.
40. RajanBabu, T. V. JOC 1984, 49, 2083.
41. Mukai, C.; Suzuki, K.; Nagami, K.; Hanoaka, M. JCS(P1) 1992, 141.
42. (a) Trost, B. M.; Mao, M. K.-T.; Balkovec, J. M.; Buhlmayer, P. JACS 1986, 108, 4965. See also: (b) Calderón, A.; de March, P.; de Arrad, M.; Font, J. T 1994, 50, 4201.
43. Jefford, C. W.; Jaggi, D.; Boukouvalas, J. CC 1988, 1595.
44. Reviews: (a) Grieco, P. A. S 1975, 67. (b) Hoffmann, H. M. R.; Rabe, J. AG(E) 1985, 24, 94.
45. (a) Murray, A. W.; Reid, R. G. S 1985, 35. (b) Andrews, R. C.; Marshall, J. A.; DeHoff, B. S. SC 1986, 16, 1593.
46. Martin, S. F.; Moore, D. R. TL 1976, 4459.
47. Matsui, S. BCJ 1987, 60, 1853.
48. Larson, G. L.; Betancourt de Perez, R. M. JOC 1985, 50, 5257.
49. Pine, S. H. OR 1993, 43, 1.

John Boukouvalas

Université Laval, Québec, Canada



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