γ

-BUTYROLACTONE

1

γ-Butyrolactone

1

O

O

[96-48-0]

C

4

H

6

O

2

(MW 86.09)

InChI = 1/C4H6O2/c5-4-2-1-3-6-4/h1-3H2
InChIKey = YEJRWHAVMIAJKC-UHFFFAOYAC

(useful source of di- and trifunctional acyclic synthons; can be
converted into various types of substituted γ-lactones and tetrahy-

drofurans)

Alternate Names:

4-hydroxybutyric acid γ-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.

CH

2

Cl

2

, Et

2

O, benzene, THF, and MeOH).

Form Supplied in:

colorless liquid (>99%); inexpensive.

Purification:

hygroscopic; water can be removed by distillation

from CaH

2

, CaSO

4

, or BaO under dry Ar. When the commercial

reagent is distilled twice from CaH

2

, the fraction boiling at

80–81

◦

C/11 mmHg contains 99.8% γ-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 γ-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 pro-
vides 4-bromobutyrates (eq 1).

4,5

Related procedures involving

Bromotrimethylsilane,

6

Boron Tribromide,

7

or Phosphorus(III)

Bromide

3d

as the bromide source are also effective. Similarly,

4-iodobutyrates are obtained by using Iodotrimethylsilane,

6a,8

BBr

3

/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 lat-

ter are readily available through alcoholysis of 4-chlorobutanoyl
chloride (eq 3).

10

Br

CO

2

Et

R

R = H, Me

(1)

O

R

O

HBr, EtOH

77–98%

(2)

O

O

BI

3

·

NEt

2

Ph

I(CH

2

)

3

CO

2

Me

benzene, rt; then MeOH

90%

(3)

O

O

SOCl

2

, ZnCl

2

BnOH

Cl(CH

2

)

3

COCl

Cl(CH

2

)

3

CO

2

Bn

py, rt

93%

55 °C

65–70%

Reaction of γ-butyrolactone with 2.1 equiv of Bromine in the

presence of red phosphorus affords α-bromo-γ-butyrolactone.

11

When 4 equiv of bromine are used, ring opening ensues to fur-
nish 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 β-lactams (eq 5).

14

O

O

(4)

CO

2

H

Br

CO

2

Me

Br

Br

Br

Br

COBr

4 Br

2

, P

MeOH

base

88%; 2 steps

63%

–10 to 80 °C

100 g scale

–5 °C

O

O

Ph

N

CO

2

-t-Bu

CO

2

-t-Bu

Br

Br

1. PBr

3

, Br

2

, 115 °C

Ph(CH

2

)

2

NH

2

(5)

ClO

4

–

O

Ph

N

N

+

Ph

1. TFA, CH

2

Cl

2

m

-CPBA, py

2. (COCl)

2

, HClO

4

100%

2. Me

2

C=CH

2

, H

2

SO

4

80%

MeCN

25 to 55 °C

65%

0 °C

71%

Aminolysis.

In the presence of an Aluminum Chloride–

Triethylamine couple, lactones smoothly react with primary
or secondary amines to give the corresponding ω-hydroxyalkana-
mides (eq 6).

15

(6)

( )

n

( )

n

n

= 1–3

+

N

OH

O

NH

O

O

AlCl

3

, Et

3

N

ClCH

2

CH

2

Cl

15–25 °C

85–91%

Lewis Acid-induced Carbon–Carbon Bond Formation.

The outcome of the Friedel–Crafts reaction of γ-butyrolactone
with benzene can be manipulated by simply varying the amount
of AlCl

3

so that either 4-phenylbutyric acid or α-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 un-
saturated esters to give α-substituted cyclic ethers (eq 8).

17

When

a carbon nucleophile is used in place of Et

3

SiH, α,α-disubstituted

cyclic ethers are obtained.

17

(7)

+

O

O

COOH

O

AlCl

3

(1.25 equiv)

AlCl

3

(3.7 equiv)

reflux

91–96%

reflux

73%

Avoid Skin Contact with All Reagents

2

γ

-BUTYROLACTONE

(8)

Et

3

SiH, TrSbCl

6

– t-BuMe

2

SiOH

TrSbCl

6

+

75%

O

CO

2

Et

OSiMe

2

-t-Bu

OEt

O

CO

2

Et

CO

2

Et

O

OSiMe

2

-t-Bu

O

O

CH

2

Cl

2

, –78 °C

-23 °C to rt

Formation of Hydroxy Esters. Although 4-hydroxybutyrates

may

be

prepared

by

acid-catalyzed

alcoholysis

of

γ

-

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

(9)

1. aq NaOH, 70 °C

( )

n

n

= 1–2

( )

n

O

O

CO

2

Bn

HO

2. BnBr, Bu

4

NBr

acetone,

∆

76–78%

One of the most commonly used methods for converting

lactones into acyclic compounds involves reduction with Diiso-
butylaluminum Hydride and Wittig homologation of the resulting
lactol

21

(see also Dihydro-5-(hydroxymethyl)-2(3H)-furanone).

A related, more recent procedure

22

provides α,β-unsaturated

esters in a single operation (eq 10).

23

(10)

(EtO)

2

P(O)CH

2

CO

2

Et, THF

O

HO

CO

2

Et

O

–78 °C, BuLi, DIBAL-H

54%

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 condi-
tions.

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 syn-

thesis of natural spiroacetals,

28

such as the insect pheromone (1)

(eq 12).

28a

The highly oxophilic organocerium reagents give su-

perior yields of monoaddition products when compared to their
lithium precursors (eq 13).

25

Organocerates are also advanta-

geous for converting lactones into hydroxyallylsilanes (see also
Cerium(III) Chloride).

29

BuLi (1.12 equiv)

58%

+

~4%

Bu

OH

O

OH

OH

O

Bu

Bu

O

(11)

Et

2

O, –90 °C

(12)

OTHP

O

O

OTHP

OH

O

O

O

1. MeLi, Et

2

O, 0–5 °C

1. H

2

, Rh/Al

2

O

3

(1)

2. aq. HCl

27% overall

2.

O

O

1. CeCl

3

, THF, –80 °C

(13)

58%

O

O

Li

OLi

2.

Grignard compounds exhibit an innate preference for double

addition

24,30

giving high yields of diols which can be easily trans-

formed into γ,γ-disubstituted-γ-butyrolactones (eq 14).

31

Analo-

gously, α,ω-di-Grignard reagents provide spirolactones (see also
1,5-Bis(bromomagnesio)pentane).

32

(14)

O

O

Et

Et

Et

Et

OH

OH

O

O

EtMgBr

KMnO

4

, Bu

3

BnNCl

ether,

∆

86%

benzene, water, rt

68%

Alkylation and C-Silylation. Clean α-monoalkylation of γ-

butyrolactone is usually achievable by exposure to LDA and reac-
tion of the enolate with a primary alkyl, allyl, or propargyl halide in
the presence of HMPA (in the absence of HMPA, α,α-dialkylation
is also observed).

33,34

An example is depicted in eq 15

35

A highly

effective but equally elaborate procedure, suitable for both alky-
lation and acylation, utilizes a crown ether–potassium complex
instead of LDA.

2

C

-Silylation of γ-lactones can be realized in a

highly selective fashion by using γ-Butyrolactone as silylating
agent. Addition of a Grignard reagent to the resulting α-silyl-
γ

-butyrolactone, followed by alkenation and eventual oxidation

delivers 4-oxocarboxylic acids in good overall yields (eq 16).

36

(15)

1. LDA, THF, –78 °C

O

O

O

O

2. HMPA, allyl iodide

71%

O

O

(16)

Jones [O]

EtMgBr

1. LDA, THF
–78 °C

O

SiPh

2

Me

SiPh

2

Me

O

OMgBr

Et

O

Et

Et

CO

2

H

O

O

2. Ph

2

MeSiCl

95%

Et

2

O, rt

73%

Aldol

Reaction.

Generally

speaking,

lactone-derived

enolates and silyl ketene acetals show poor simple diastereo-
selection.

37

Thus reaction of lithiated γ-butyrolactone with ben-

zaldehyde provides a modest 30:70 ratio of syn and anti adducts

A list of General Abbreviations appears on the front Endpapers

γ

-BUTYROLACTONE

3

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-
dihydrofuran

40

(prepared from γ-butyrolactone) with propynal–

hexacarbonylcobalt complexes (eq 18).

41

(17)

+

PhCHO, –78 °C, 44%
or ZnCl

2

, PhCHO, –30 °C, 83%

LDA, THF, –78 °C

O

O

O

O

Ph

OH

H

H

OH

Ph

O

O

30:70
70:30

then

(18)

+

+

1. TiCl

4

, CH

2

Cl

2

, –78 °C

O

Me

3

SiO

H

OH

O

O

Bu

Bu

O

O

OH

H

Bu

H

O

Co

2

(CO)

6

87:13

2. CAN, MeOH, 0 °C

77%

Exposure of the easily prepared α,α-bis(phenylthio)-γ-butyro-

lactone to Ethylmagnesium Bromide leads to a magnesium eno-
late which undergoes aldol reaction in excellent yields (eq 19).

42a

The resulting adducts can be transformed into 3-(1

′

-hydroxy-

alkyl)-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 α,β-Butenolide).

43

(19)

LiNEt

2

THF, –78 °C

EtMgBr

MeCHO

1. m-CPBA
CH

2

Cl

2

, –78 °C

O

O

OMgBr

O

SPh

O

O

PhS

OH

O

PhS

SPh

O

O

O

OH

2. CCl

4

, reflux

64%

98%

then PhSSO

2

Ph

–78 to –25 °C

87%

THF, –10 °C

Alkylidenation.

Many methods exist for the α-methyle-

nation.

44,45

and α-alkylidenation

45a,46

–

48

of lactones. An ap-

pealing procedure for preparing α-methylene-γ-butyrolactone
entails α-formylation and subsequent condensation with formal-
dehyde.

45a

(E)-α-Alkylidene-γ-butyrolactones, essentially free of

their (Z) isomers, are available from γ-butyrolactone in high yields
through the vinylogous carbamate (2) and α-butylthiolactone (3)
(eq 20).

46

Usefully, α-alkylidene-lactones can be isomerized to

3-alkyl-2(5H)-furanones by heating with deactivated W-2 Raney
Nickel.

46

(20)

(3)

(2)

>98% E

Raney Ni

BuSH, TsOH

(Me

2

N)

3

CH

O

O

O

O

Me

2

N

BuS

O

O

O

O

Bu

O

O

Bu

2

CuLi

∆

96%

benzene,

∆

92%

Et

2

O, –78 °C

85%

benzene,

∆

92%

Sequential treatment of γ-butyrolactone with LDA and bis-

(methoxy(thiocarbonyl)) disulfide provides a lithium enolate
which reacts with aldehydes to give preferentially either (E)- or
(Z)-α-alkylidene-γ-butyrolactones, depending on whether ZnCl

2

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. Methyle-
nation or alkylidenation of the lactone carbonyl group can be
effected by using the Tebbe reagent (µ-Chlorobis(cyclopenta-
dienyl)(dimethylaluminum)-µ-methylenetitanium)

and

its

variants.

49

96:4
9:91

(21)

1. LDA, THF, –78 °C

n-

PrCHO, 57%

ZnCl

2

, n-PrCHO, 58%

O

O

OLi

O

S

S

OMe

O

O

Pr

O

O

Pr

+

2. (MeOCS

2

)

2

1.

(a) Fieser, L. F.; Fieser, M., Fieser & Fieser 1967, 1, 101. (b) Fieser, M.,
Fieser & Fieser 1980

, 8, 304, 447. (c) Sutherland, I. O. In Comprehensive

Organic Chemistry

; Barton, D. H. R.; Ollis, W. D., Eds.; Pergamon:

Oxford, 1979; 2, p 869.

2.

Jedli´nski, Z.; Kowalczuk, M.; Kurcok, P.; Grzegorzek, M.; Ermel, J., J.
Org. Chem. 1987

, 52, 4601.

3.

Examples: (a) ApSimon, J.; Seguin, R., Synth. Commun. 1980, 897.
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110

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4.

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5.

(a) Schmid, M.; Barner, R., Helv. Chim. Acta 1979, 62, 464. (b) Fray, M.
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6.

(a) Kricheldorf, H. R., Angew. Chem., Int. Ed. Engl. 1979, 18, 689.
(b) Friedrich, E. C.; DeLucca, G., J. Org. Chem. 1983, 48, 1678.

7.

Olah, G. A.; Karpeles, R.; Narang, S. C., Synthesis 1982, 963.

8.

Kolb, M.; Barth, J., Synth. Commun. 1981, 11, 763.

9.

Narayana, C.; Reddy, N. K.; Kabalka, G. W., Tetrahedron Lett. 1991, 32,
6855.

10.

Goel, O. P.; Seamans, R. E., Synthesis 1973, 538.

11.

Price, C. C.; Judge, J. M., Org. Synth., Coll. Vol. 1973, 5, 255.

12.

Hoffmann, H. M. R.; Eggert, U.; Walenta, A.; Weineck, E.; Schomburg,
D.; Wartchow, R.; Allen, F. H., J. Org. Chem. 1989, 54, 6096.

Avoid Skin Contact with All Reagents

4

γ

-BUTYROLACTONE

13.

(a) Cromwell, N. H.; Phillips, B., Chem. Rev. 1979, 79, 331. (b) Juaristi,
E.; Madrigal, D., Tetrahedron 1989, 45, 629.

14.

Wasserman, H. H.; Lipshutz, B. H.; Tremper, A. W.; Wu, J. S., J. Org.
Chem. 1981

, 46, 2991.

15.

Bigg, D. C. H.; Lesimple, P., Synthesis 1992, 277.

16.

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17.

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18.

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19.

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34

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20.

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21.

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22.

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23.

de Kermadec, D.; Prudhomme, M., Tetrahedron Lett. 1993, 34, 2757.

24.

(a) Cavicchioli, S.; Savoia, D.; Trombini, C.; Umani-Ronchi, A., J. Org.
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, 49, 1246. (b) Snowden, R. L.; Linder, S. M.; Muller, B. L.;

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25.

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26.

Tobia, D.; Baranski, J.; Rickborn, B., J. Org. Chem. 1989, 54, 4253.

27.

(a) Hernandez, J. E.; Cisneros, A. C.; Fernandez, S., Synth. Commun.
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L. S.; Mathew, R. M.; Kaiser, C.; Sherrill, R. G.; Cheng, M.; Tiffany, C.
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29.

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30.

For an exception see: Nicolaou, K. C.; Papahatjis, D. P.; Claremon, D.
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31.

Lehmann, J.; Marquardt, N., Synthesis 1987, 1064.

32.

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33.

Herrmann, J. L.; Schlessinger, R. H., Chem. Commun. 1973, 711.

34.

Posner, G. H.; Loomis, G. L., Chem. Commun. 1972, 892.

35.

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36.

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37.

(a) Heathcock, C. H., Comprehensive Organic Synthesis 1991, 2, 181.
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38.

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39.

(a) Sansbury, F. H.; Warren, S., Tetrahedron Lett. 1992, 33, 539. See
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, 31, 2453.

40.

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41.

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42.

(a) Trost, B. M.; Mao, M. K.-T.; Balkovec, J. M.; Buhlmayer, P., J. Am.
Chem. Soc. 1986

, 108, 4965. See also:(b) Calderón, A.; de March, P.; de

Arrad, M.; Font, J., Tetrahedron 1994, 50, 4201.

43.

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1988, 1595.

44.

Reviews: (a) Grieco, P. A., Synthesis 1975, 67. (b) Hoffmann, H. M. R.;
Rabe, J., Angew. Chem., Int. Ed. Engl. 1985, 24, 94.

45.

(a) Murray, A. W.; Reid, R. G., Synthesis 1985, 35. (b) Andrews,
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46.

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48.

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49.

Pine, S. H., Org. React. 1993, 43, 1.

John Boukouvalas

Université Laval, Québec City, Québec, Canada

A list of General Abbreviations appears on the front Endpapers