that that of U, *) A for the

Teljes szövegt


The Acyllactone R e a r r a n g e m e n t ; A M e t h o d for the Preparation of Heterocyclic Ring Systems U, *)

F. KORTE AND K . H . BtJCHEL Chemisches Institut der Universitat Bonn


Cyclic derivatives of carboxylic acids, such as lactones, thiolactones, or lactams can be converted by partial reduction into heterocycles of the same ring size. Lactones thus form cyclohemiacetals or diols, which can be cyclized by the addition of acid. This process presents certain preparative difficulties however, and is not much investigated from the point of view of its general applicability. Furthermore, the unsubstituted heterocycles thus obtained offer few possibilities of building up a second ring system at a definite position. In the course of our investigations into

the gentian bitter principle, gentiopicrin, it became necessary to synthe­

size bicyclic hemiacetallactones (I) in order to confirm the proposed constitution (3). During the course of this work, we discovered a rear­

rangement reaction characteristic of a-acyllactones, in which di- and tetrahydrofuran or pyran derivatives are readily obtained by the proton- catalyzed alcoholysis of substituted y- or 8-lactones. We designated this reaction the «-hydroxyalkylidenelactone rearrangement.

Lactones with other «-acyl esters, e.g., a-hydroxymethylenearyl or a-oximino can also be converted. /3-Acyllactones are also capable of undergoing a rearrangement (see p. 218). We should therefore prefer to name the reaction more generally and briefly the acyllactone rearrange­

ment. Further investigation showed that the reaction can also be effected in an aqueous medium; heterocyclic acids or their decarboxylation products are then produced. Inspection of the literature revealed that the rearrangement in H20 / H+ had successfully been applied to synthetic wrork on many previous occasions. All the reactions can be included under the common heading of acyllactone rearrangement and, depending on the constitution of the acyl compound and on the rearrangement medium, they can be classified according to definite reaction sequences. In this review, we hope to give a survey of the work to date and the results




obtained, and to show the limitations in the application of the acyllac- tone rearrangement.

and is to be regarded as a sequence of equilibrium reactions (4,5). The a-acyllactones, -lactams and -thiolactones required as starting ma­

terials can be prepared in the following ways.


Lactones or thiolactones, being internal esters, can be condensed with esters in the presence of an equimolar quantity of a base. The mixed ester condensation thus constitutes a general practical method for the preparation of a-acyllactones, in which the a-acyl group can be varied within wide limits. Since many lactones are sensitive to bases and are converted into their open-chain isomers, the success of the reaction fre­

quently depends on the condensing base employed. The following are among the condensing agents which can be used: powdered sodium or potassium, sodium ethoxide, sodium hydride, sodium amide, diisopro- pylaminomagnesium bromide, triphenylmethylsodium, sodium methyl- anilide, etc. (4,6-12).

Stable mono- and bicyclic y- and S-lactones condense with oxalic or formic ester, and give yields of up to 80% when powdered sodium is used as the condensing agent (IS). Condensations with ethyl acetate give better yields with sodium hydride (9), as the autocondensation of ethyl acetate in the presence of sodium to give acetoacetic ester reduces the yield of a-acetyllactone.

y-Carbethoxy-8-lactones (II) isomerize to a-ethylideneglutaric acid half-esters (Ha) in the presence of sodium ethoxide; dihydrocoumarin

(III) yields a,/?-dihydrocoumaric ester ( I l i a ) . Preparative Methods

P r e p a r a t i o n of the a-Acyl Derivatives

The rearrangement proceeds according to the general scheme

X = O, S, N


N a O C8H6

H6C , OaC

)=o C 02H

I l a


V ^ N N a O C , H5

u O H

III I l i a

The condensation of these lactones with ethyl formate or ethyl oxalate can nevertheless be accomplished by the use of Grignard bases such as diisopropylaminomagnesium bromide (10, IS).

(3,y- or a,/?-Unsaturated 8-hydroxypentenoic acid lactones, e.g., IV, do not condense with esters, but isomerize under the influence of basic condensing agents to give substituted sorbic acids (10).

C H , C H ,


=o r

Rx O R


The unstable thiolactones are also best condensed by means of Grig­

nard bases (14-16). Ruzicka (17) and Spath (18) have reported on the condensation of lactams and both quinolinecarboxylic ester and nico­

tinic ester by the use of sodium ethoxide. Table 1 shows the yields of a-ethoxalyl-N-methylpyrrolidone obtained under constant working con­

ditions, and their dependence on the condensing base utilized (11,12).

The preparation of a-acetyllactams by ester condensation has thus far been unsuccessful. The activation of the a-position is weaker in the

T A B L E 1

Dependence of the Yield of a -Ethoxalyl- N-methylpyrrolidone on the Condensing Agent

Yield of _ . . a-Ethoxalyl- Condensing agent N-methyl-

pyrrolidone (%) Diisopropylamino-Mg-Br 0

Sodium ethoxide 5.7

NaNH, 6.1

Powdered sodium 4.8

(C6H8),Na 11. 1

(CeILNHCHj) (Na) 21.1

Potassium 45.6

NaH 70.0

case of lactams than it is in that of lactones, with the result that the condensation does not proceed as readily. The a-acylcarboxylic acid de­

rivatives exhibit a higher ring stability compared to the unsubstituted parent substances, i.e., the lactones, thiolactones, and lactams (15).




Ring closure is especially effective for the one-step preparation of a-acetyllactones. Thus, according to Lacey (19), various substituted a-acetyl-y- and -8-lactones are obtained from a- or /?-hydroxyaldehydes or -ketones with diketene, e.g., a-acetylcoumarin (VI) from salicylalde- hyde and diketene.


a-Acetyllactones are similarly formed by the reaction between sub­

stituted propargyl alcohols and diketene (19). Dehydroacetic acid (VII) is obtained by the condensation of acetoacetic ester (20) or diketene

(21). According to Knunjanz (22), a-acetyl-y-lactones (VIII) can be prepared from ethylene, propylene, or butylene (23) oxides and aceto­

acetic ester. a-Acyllactones containing nitrogen in the ring are also formed by a simple ring closure. 4-Hydroxyalkylideneoxazolin-5-one (IX) can be prepared from sodium hippurate and acetic anhydride (24) or orthoformic ester (25) in this manner.


RX O H . C / O


M e t h o d s o f R e a r r a n g e m e n t


Lactones which are readily opened by alcoholysis, e.g. mono- and bicyclic a-acyl-S-lactones, rearrange even at room temperature. In order to effect the reaction, the a-acyllactone is dissolved in 5-10 times its quantity of absolute alcohol to which 3-6% of hydrochloric or other acid has been added, and the solution allowed to stand for one or two days. The acid is then neutralized with saturated potassium carbonate or bicarbonate solution and the rearrangement product extracted with

( 5 ) /OH ® r n » '

< HaC )a Tr / ^R R'OH/H* < H» 9 M > H ( H* 98T 5 | + R'OH

o - U ^ LJ/


' ^


~ \



ether. Yields of 80-95% are obtained throughout. More stable acyllac- tones, e.g. a-acyl-y-lactones, are rearranged in boiling alcohol/H+.

As shown in examples X , X I , and X I I , heterocyclic carboxylic esters (XI) in equilibrium with the dihydrofuran or pyran form, X I I , can thus be prepared from «-acyllactones. The R group in the a-acyl grouping appears in the rearrangement product X I at position 2, while the R ' group contained in the rearrangement solvent becomes linked to position 2 via the oxygen atom and to position 3 in the ester grouping. Distilla­

tion of the rearrangement product X I in the presence of catalytic amounts of polyphosphoric or sulfuric acid yields the pure dihydro com­

pound X I I via R'OH elimination. The preparation of the pure tetra- hydrofuran or pyran compound X I is best achieved by effecting the re­

arrangement in higher alcohols, since the mixtures of dihydro and tetra- hydro forms obtained are then more readily separated by distillation

(see Experimental section). The rearrangement, consisting of a sequence of equilibrium reactions, is reversible. If the ester X I I is dissolved in 30% perchloric acid and 2,4-dinitrophenylhydrazine added, the 2,4-di- nitrophenylhydrazone of the a-acyl compound X is obtained. The com­

position of the mixture of X I and X I I resulting from the rearrangement is affected by both the ring size and the substitution. In the case of the six-membered a-hydroxymethylene- and a-ethoxalyllactones the propor­

tion of dihydro product X I I lies between 10 and 20%, while with the corresponding five-membered lactones it is 1-5%. If, as in the rearrange­

ment of the a-acetyl-y- and 8-lactones, the product contains a methyl group in position 2, the proportion of dihydro product rises appreciably and lies between 40 and 60%. In the pyrancarboxylic esters XIa, an ad­

ditional methyl group in the C6-position causes a further displacement in the equilibrium, to 90% of X l l a . This phenomenon can be accounted for by the steric hindrance resulting from the

reciprocal effect of the two axial 2,6-methyl groups. The unsaturated dihydropyran X l l a , which exists in the strainless half-chair conforma­

tion X l l b , is formed by the elimination of methanol (9).


If the rearrangement is carried out in concentrated hydrochloric acid, the acyl compound is dissolved in the acid—which contains added






acetic acid or dioxane in the case of more insoluble compounds—and the solution allowed to stand at room temperature or in the refrigerator (0°).

In rearrangements involving decarboxylation the equilibrium is shifted in favor of the rearrangement product by the crystallization of the heterocyclic carboxylic acid or the evolution of C 02. The isolation of soluble rearrangement products is accomplished by neutralizing the solution with alkali carbonate and extracting with ether.

Rearrangement of stable acyllactones in dilute acids (e.g., 2 N HCI, 2N H2S 04, 2N HCIO4) is effected by heating under reflux, when de­

carboxylation usually occurs. This can be avoided in some cases by working at room temperature or by cooling in ice.


The rearrangement of a,/?-unsaturated a-acyl-y-lactones to furan-3- carboxylic acids is carried out in acetic acid/HCl or acetic acid/H2S04

(19). The double bond migrates to the /?,y-position during the reaction.

BF3 etherate or A1C13 can also be used (19).

In the rearrangement of acyl-y-lactams by hydrolysis with concen­

trated HCI, the ring closure to the pyrrolidine presents some difficulty.

It can be accomplished by the hydrogenation of the carbonyl of the acyl group followed by iodination of the hydroxyl group and elimination of HI (see pp. 211-213).

a-Acyloxazolin-5-ones can be opened by alcoholysis, and only ring- close to the oxazole-4-carboxylic ester after heating with SOCl2 or a mixture of H2S 04 and acetic anhydride (26).

The method of Cornforth represents a special variant of the rear­

rangement process; according to this modification, the sodium salts of oxazole-4-carboxylic acids are obtained by heating the sodium salts of the hydroxyalkylideneoxazolin-5-ones (see p. 213). The rearrangement of some nitrogen heterocycles is favored by the presence of strong alkali hydroxides (27-29) (seep. 214).

Special Reactions

R e a r r a n g e m e n t o f a- A c y l- S- l a c t o n e s

The preparation of alkyl-substituted a-acyl-8-lactones presents no difficulty. The ester condensations with formic, oxalic, and acetic ester proceed in good yield when powdered sodium or sodium hydride is used as the condensing agent. Table 2 shows a number of rearrangement prod­

ucts (XIVa to XIVI) and the yields obtained. The corresponding di- hydropyran compounds XVa to XVI are readily obtained by distillation with polyphosphoric acid.


R3 O H R3 R8 I c I C 0, R5 P o l y p h o s p h o r i c I C02R »



R 4 R 5


Q H / H






a c i d



v / Y

R1 O O R1 O RX4 R i O XR.

X I I I ( a - 1 ) X I V ( a - 1 ) X V ( a - 1 )

y-Carbethoxy-8-caprolactones isomerize to a-ethylideneglutaric esters when the condensation with powdered sodium or sodium ethoxide is at­

tempted [10). The ester condensation can nevertheless be accomplished by the use of strongly basic condensing agents such as sodium amide,

T A B L E 2

Products of the Rearrangement of Alkyl-Substituted a -Acyl-6 - lactones

x m XIV a XV

R1 R2 R3 R4 R5 Yield

(%) (°C/mm Hg) B p . Yield



(°C/mm Hg) Lit.


a CH, H H H CH, 80 4 3 - 4 4 7 0 . 05 88 91711 (7) b CH, CH, CH, H CH, 79 50 5170.05 92 104-105712 (7) c CH, H CH, H CH, 58 5 6 - 5 7 7 2 82 91-92712 (6) d H H CH, H CH, 48 3 8 - 4 0 7 0 . 2 56 5371.5 (30) e CH(CH,)2 H H H CH, 67 5 8 - 5 9 7 0 . 01 90 5770. 03 (31) f CH, H H C02C,Hs CH,

RB* = H 66 Mp90° 90 9570. 03 (32) g CH, CH, CH, COaCjH, CH, 85 7470.01 96 7970. 01 (32) h CH, H CH, CO,C2H9 C,HS

R5* = H

73 103-10471 _ ~ (32) i H H CH, COfC,H5 CfH,

R** = H

73 8 7 - 8 8 7 0 . 2 77 9270.2 (30) i CH, H H CH, CH, 80* 4 1 - 4 4 7 0 . 05 87 92712 (9) k H H H CH, CH, 80* 4 5 - 4 6 7 0 . 0 4 88 97712 (9) 1 CH, H CH, CH, CH, 70* 4 2 - 4 5 7 0 . 1 85 86710 (8)

"When not indicated otherwise, R5* = R5.

* Mixed with XV.

sodium hydride, and especially diisopropylaminomagnesium bromide [10, 33). The rearrangement of the a-acyl-y-carbethoxylactones in ethanol/

H+ gives good yields of dihydropyran-3,5-di- and 2,3,5-tricarboxylic esters (Table 3).


H6C202C I C H6C202C i C 02R * P o l y p h o s p h o r i c H6C202C 1" C 02R4

N ^ V XRs R * Q H / H ^ Y Y o R4* a c i d ) V Y

R1 ° R3 R / O R3 X X V I ( a - c ) X V I I ( a - c ) X V I 1 1 ( a - c )

The formation of stable cyclohemiacetals of type X I X during the re­

arrangement of primary and secondary a-ethoxalyl-8-lactones is not without interest. The structural evidence was adduced by degradation


206 F . K O R T E A N D K . H . B U C H E L T A B L E 3

Products of the Rearrangement ofa-Acyl- y-carbethoxy-b-lactones

XVI x v n a xvra

R1 Ra Rs R4 Yield (%)

B . p . ( ° C / m m Hg)

Yield (%)

B . p .

(°C/mm Hg) Lit.


a CH, H H 78 95 7 0 . 0 5 88 8670. 05 (10) b CH, H CO,C,Hg

R4* * H

71 1 2 5 - 1 2 6 7 0 . 0 1 90 1 2 4 7 0 . 02 (10)

c CH, CH, H C,H, 50 5 8 - 5 9 7 0 . 0 1 70 65 - 6 7 7 0 . 01 (33) 'When not indicated otherwise R4* * R4.

reactions (32). The formation of the 2-hydroxy compounds can be ex­

plained by solvolysis and steric hindrance (see the section on ring open­

ing of a-acyl-S-lactones).

C 02CtH5

H X' V

xC O C H ,

- O C H3O H / H20 / H +


/ \ / c o'H

I P C 08C H3

A C O C H , O H

/ C O , C H , / > C H , O C H ,

X X , C 02C Hs

- C H , O H


H , C ° C H , X X I

CO.CH, r c O j C H , ( / O C H , H.CT <> C H ,


An exceptional reaction course is followed during the rearrangement of compound X I X (9). Apart from the normal rearrangement product X X I I , the decarboxylation products X X and X X I can also be isolated.

The reaction can be explained by the formation of a methanetricar- boxylic acid-type intermediate and the latter's subsequent decarboxyla­

tion (9).

R e a r r a n g e m e n t o f a- A c y l- y- l a c t o n e s

Good yields of a-acyl-y-lactones are obtained via ester condensation by the use of powdered sodium. a-Acetyl-y-lactones can also be prepared according to the method described by Knunjanz (22,9,23). The rear­

rangement in methanol or ethanol/H+ results in the formation of 2-al- koxytetrahydrofurans, which are readily converted into the correspond­

ing dihydrofuran derivatives by the elimination of alcohol (Table 4 ) . a-Benzoylbutyrolactone ( X X V I ) rearranges in an analogous manner, yielding 2-phenyl-substituted tetrahydro or dihydrofuran derivatives

(XXVIIa and b) (34).


/ 0 H

:CV _ YC OTR *

O R * R* r - f V R4Q H / H + Ra

X X I I I ( a - i ) X X I V ( a - I ) P o l y p h o s p h o r i c C OTR *

R A \ ,

X X V ( a - i )

T A B L E 4

Products of the Rearrangement of a-Acyl-y- lactones

xxin XXIV a XXV



R1 R2 R3 Yield (%)

B . p . (°C/mm Hg)

Yield (%)

B . p . (°C/mra Hg)



a H H H CH, 82 N8 5 - 8 6 7 1 3 79 70710 (4) b H H CO,C2H8 CH, 54 72-7370.03 88 7570. 02 (32) c H H CH, CH, 40° 7 4 - 7 7 7 1 2 93 72-73711 (9)

d CHS H H CH, 60 8479 81 7579 (30)

e CH, H CH,CH, CH, 71 6670. 01 -



f CH3 H CH, CH, 43 a 75-78711 92 7 6 7 H (32) g CH, CH, H CH, 64 8 4 - 8 5 7 9 86 7 5 - 7 6 7 9 (30) h CH3 CH, COaC2H5 C2H5 61 7 6 - 7 8 7 0 . 0 1 91 7470. 1 (30) i CH, CH, CH, CH, 70 a 3 6 - 4 1 7 0 . 2 90 81-82712 (30)

a Mixed with XXVI.

P o l y -

£ 0 - C . H5 . C O . C H , p h o s p h o r i c £ O X H3

c ^ ^ r / O C > ^ uH r / O X X V I O \ 6 H 5 O \ - HA

X X V I I a X X V I I b

a-Oximino-y-butyrolactone ( X X V I I I ) , obtainable from a-aceto-y- butyrolaetone and ethyl nitrite {35), can be rearranged in methanol/H+ to give 2-hydroxy-3-carbomethoxyisoxazolidine ( X X I X ) (34).

/ N - O H YC O X H , .—f M e t h a n o l / H + /



a-Hydroxymethylene-y-butyrolactone couples with diazotized p- methoxyaniline at pH 7. Deformylation yields the azo compound or its tautomeric form, the p-methoxyphenylhydrazone X X X ; the latter is re-



arranged and decarboxylated in boiling methanol containing traces of alkali, to give the pyrazoline derivative X X X I (27). An analogous re­

arrangement to the pyridazine system is known in the case of a 8-lactone hydrazone (35a).

• « N N - N H - { > - O C H8

~f C H3O H ^ /=° T r a c e s of alkali


X X X I O C H3

R e a r r a n g e m e n t o f Bicyclic a- A c y l- y - a n d - 8- l a c t o n e s

Bicyclic 8-lactones, which possess the same skeleton as the ant poison iridomyrmecin (36), can be condensed with esters in the presence of powdered sodium (8). The rearrangement in methanol or ethanol/H+ of the a-acyllactones ( X X X I I ) wThich are formed results in good yields of hexahydroisochroman ( X X X I I I ) or hexahydroisochromene deriva­

tives ( X X X I V ) (8).

cv C 02Ra P o l y - C 02Ra I O R2* p h o s p h o r i c I R I

R * O H / H + / V V a c i d ^ / V V

X X X I I a , b X X X I I I a , b X X X I V a , b a: R * = H R2= R « * = C H3 Y i e l d 67% Y i e l d 9 1 % b : Rx= C 02C2H5 R2= C2H8, R2* - H Y i e l d 9 5 % Y i e l d 6 8 %

Ester condensations of dihydrocoumarin and formic or oxalic ester can be effected by diisopropylaminomagnesium bromide; the use of so­

dium or sodium ethoxide results mainly in the formation of o-dihydro- coumaric ester. The rearrangement of the acyl compounds, X X X V a , b, yields derivatives of chroman ( X X X V I ) or chromene ( X X X V I I ) (8).

O H P o l y -

C C O R2 p h o s p h o r i c C O RA

W " ° ^ o \ , ^ O ^ R ,

X X X V a , b X X X V I a , b X X X V I I a , b a: Rl = H Ra = R2* = C H3 Y i e l d 8 4 % Y i e l d 7 1 %

R1 = C 02C2H6 Ra = C2H „ R2* = H Y i e l d 8 8 % Y i e l d 7 5 %

Bicyclic a-acyl-y-lactones ( X X X V I I I ) are readily prepared via an ester condensation in the presence of sodium. Rearrangement in meth­

anol or ethanol/H+ yields derivatives of hexahydrocoumaran ( X X X I X ) or hexahydrocoumarone (XL) (8).


R1 K2 Q/HHt

X X X V I I I a , b a: R1 = H

b : Rl= C 02CsH5

/ : 02R2 , O R2

P o l y ­ p h o s p h o r i c

a c i d

, C O , R2

- O


X X X I X a , b R* = C HS Y i e l d 8 1 % R2= C2H6 Y i e l d 7 8 %

R] X L a , b Y i e l d 9 2 % Y i e l d 8 0 %

Ester condensations with hemiacetallactones afford only small yields.

The a-ethoxalyllactone X L I rearranges to the diketal XLIa in ethanol/

H+ (8).

The acylation by ester condensation of macrocyclic lactones from e-caprolactone upwards has thus far not been accomplished in satisfac­

tory yield. The fundamental difficulty resides in the strong tendency shown by these lactones to polymerize in the presence of traces of soluble alkali. Thus c-caprolactone could only be acylated to the extent of 1-2%

by formic ester/sodium. Ester condensations using heptanolide (7-hy- droxyheptanolactone) raised the yield to 10-15%; the major products are polymers such as di-, tetra-, or heptameric lactones (37). Grignard bases are completely useless as condensing agents. Alkyl-substituted lactones show in general a lower tendency to undergo polymerization.

Thus, while say, S-valerolactone cannot be subjected to ester condensa­

tion on account of the immediate onset of polymerization, a-acyl-S- caprolactones are formed in good yield. Even /3-methyl-e-isopropyl-e- caprolactone (mentholide) however, affords yields of only 2-5% of acyllactone by the ester condensation with sodium, potassium, or Grig­

nard bases (38). Ring stabilization by alkyl substitution is no longer adequate in the case of €-lactones. According to the investigations of Huisgen and Ott (39), a cis to trans change in configuration occurs in lactones of medium ring size. The £rans-lactones, from approximately

O ° O C2H5

X L I a Y i e l d 55%


R e a r r a n g e m e n t o f M a c r o c y c l i c a- A c y l l a c t o n e s


210 F . K O R T E A N D K . H . B U C H E L

nonalide onwards, again display an increased stability; this is evidenced by the hydrolysis constants, for example, which are of the same order as the constants of open-chain trans-esters. Ester condensations should therefore proceed more favorably again from nonalide upwards. In con­

densation experiments with 15,1-hexadecanolide, however, no acyl prod­

uct could be detected (40). Compared to the y- and 8-lactones, the macrocyclic £mns-lactones manifestly occupy a special position in chemi­

cal reactions; also, they are hardly comparable to the homologous open- chain esters in their chemical behavior [cf. their behavior during Friedel- Crafts reaction (41)]-

If the crude condensation products of mentholide containing 2-5%

of the acyl compound XLII are dissolved in methanol/H+, the enol re­

action with FeCl3 and the UV absorption band at 240 m/x due to the acyl compound both disappear after a certain time. This can be ex­

plained by either a rearrangement to XLIII or the formation of the acetal XLIIa. No well-defined products have thus far been isolated in pure form.

H / O R

H3C C H3 H3C C H3 H3C C H3

X L I I X L I I I X L I I a

R e a r r a n g e m e n t o f a- A c y l- y - a n d - 8- t h i o l a c t o n e s

In the ester condensation of y- and 8-thiolactones, the best yields are obtained by the use of diisopropylaminomagnesium bromide or sodium hydride as condensing agent (8,14-16). In contrast to the oxygen homo- logs, no 2-alkoxytetrahydro compounds are formed during the rearrange­

ment; instead, the elimination of alcohol results in the immediate forma­

tion of the 2-alkoxydihydro compounds. The elimination of alcohol is promoted by the pronounced participation of the free electron pairs of sulfur in the mesomeric system (cf. the section on optical measure­

ments). a-Acyl-y-thiolactones (XLIV) and a-acyl-8-thiolactones (XLVI) yield 4,5-dihydrothiophene-3-carboxylic esters or -2,3-dicar- boxylic esters (XLV, Table 5) and 5,6-dihydrothiopyran-3-carboxylic

/ O H

/ C OaR »

b o b R4

X L I V ( a - c ) X L V ( a - c )


T A B L E 5

Products of the Rearrangement of at -Ac\l-y-thiolactones


R1 Ra Yield (%)

B . p . (°C/mm Hg) a H CH, 84 4 3 - 4 6 7 0 . 5 b CH, CH, 73 5 2 - 5 4 7 0 . 5 c CO,C,H, C,H, 86 9 6 - 9 8 7 0 . 05

esters or -2,3-dicarboxylic esters (XLVII, Table 6), respectively. The corresponding acids are obtained by the alkaline saponification of the

( X L V I ( a - f ) X L V I I ( a - f )

esters. Unlike the dihydrofuran-3-carboxylic acids, the dihydrothiophene- 3-carboxylic acids are not readily decarboxylated; nor is it possible to add methanol to the double bond under normal conditions (14).

T A B L E 6

Products of the Rearrangement of a-Acyl-6-thiolactones


R1 Ra Rs Yield


B . p .

(°C/mm Hg) Lit.


a H H CH, 82 6 4 - 6 6 7 0 . 15 (15)

b H CH, CH, 91 6 5 - 6 7 7 0 . 4 (15)

c H C O j ^ H , C,H5 83 1 1 9 - 1 2 0 7 0 . 3 (15)

d CH, H C,H5 80 6 3 7 0 . 2 (16)

e CH, CH, CH, 81 10370.1 (16)

f CH, CO,C,HB C,H, 78 5870. 01 (16)

R e a r r a n g e m e n t o f a - A c y l l a c t a m s

In order to avoid the N-acylation of lactams during the course of the ester condensation, it is best to effect the reaction on N-alkylated or N-arylated lactams. The difficulties encountered during the condensation of lactams have been referred to earlier. The solvolysis of the amide linkage is an essential prerequisite in the rearrangement of a-ethoxalyl- N-methyl-y-butyrolactam (11) in alcohol/H+. Ring stabilization of the cyclic carboxylic acid derivatives generally results from the acylation (see the section on optical measurements). a-Acyllactones are less sus­

ceptible to hydrolysis than are the unsubstituted lactones. Since lactams are more resistant to alcoholysis than lactones, it follows that a-acyllac-


212 F . K O R T E A N D K . H . B U C H E L

tams are particularly stable to proton-catalyzed alcoholysis. Thus no change worth mentioning is observed in the a-acyl-y-lactams (XLVIII) even after heating for 180 hr in ethanol containing 5% HCI. Though it is true that the UV absorption band at 301 imx due to the acyl bond is diminished by 50-60% on boiling in absolute methanol/H2S04, no pyr- rolidinecarboxylic esters ( X L V i l l a ) or pyrroline derivatives of type XLVIIIb could be isolated (11).

C O - C OtC , H5 C 02C2H5 C 02C2Hf t

rfo CA

C 0





' o(

N N 0CaH , N C OaC2H8

R R R X L V I I I X L V I I I a X L V I I I b

R = C H3; CeH6

The amide linkage in y-lactams is weakened by acylation with a strongly electronegative acyl group, such as the nicotinyl group (XLVIIId).

o r

N X L V I I I d

The fission of the a-nicotinyl-y-lactams and their simultaneous decar­

boxylation is thus rendered possible by heating with concentrated HCI in a bomb tube. The ring-opened compound can be cyclized to the pyr­

rolidine (see p. 222). As in the case of the corresponding lactones, the 8-lactams are also opened solvolytically more readily than are the y-lac­

tams. Thus a-ethoxalyl-N-methyl-2-piperidone ( X L I X ) can be rear­

ranged in boiling absolute ethanol/14%HCl (42); decarboxylation yields 2-carbethoxy-N-methyltetrahydropyridine (L) (42,43).

The rearrangement to L involves the loss of one molecule of C 02. In order to explain the course of the reaction, it must be assumed that the lactam ring is partially opened hydrolytically by the water present, as a result of the equilibrium due to the high concentration of HCI in the reaction medium.

C , H5O H + HCI C8H5C I + H20

This results in the formation of a /?-ketoacid (XLIXa) which has a low stability like oxalacetic acid, and is decarboxylated to give the amino- ketone X L I X b or hemiaminal XLIXc. Elimination of water stabilizes the latter as the tetrahydropyridinecarboxylic ester L.

We have reported earlier on similar conditions of decarboxylation and esterification (5) (see also sections on Rearrangement of a-Acyl-8- lactones and Rearrangement in Aqueous Mineral Acid). Other rearrange-



, C O - C 02R H20 1= 0

C H , X L I X

C 0 - C 02R C 02H H I C HS

X L I X a

- C 02

C - C 02R

C H , X L I X b

- H20 C 02R C HS






X L I X c

merits undergone by a-acyllactams in boiling hydrochloric acid are also described in the section on rearrangement in mineral acid.

R e a r r a n g e m e n t o f 4- A c y l o x a z o l i n- 5- o n e s

The process used by Cornforth for the synthesis of oxazolecarboxylic acids (44,45) may be regarded as an original variant of the a-acyllac- tone rearrangement. When the sodium salts of the 4-hydroxyalkylidene- oxazolin-5-ones (LI) are heated, the sodium salts of the 5-alkyloxazole- 4-carboxylic acids (LII) are obtained. This method has been applied to various oxazoline derivatives (44, 4@) (s e e Table 7).


N ,

R{ o

LI ( a - g ) O N a


R( o


LII ( a - g ) , C OtN a

The rearrangement of oxazolones in alcoholic hydrochloric acid gives no satisfactory results. Only 2-benzyl-4-hydroxymethyleneoxazolin-5-one (Lib) rearranges in small yield in methanol/ethereal hydrochloric acid.

The ester thus formed can be saponified with NaOH to give 2-benzyl-

T A B L E 7

Yields of 5-Alkyloxazole-4- carboxylic Acids (LII) Resulting from the Rearrangement of 4-Hydroxyalkyl- ideneoxazolin-5-ones (LI) by the Method of Cornforth

R1 Yield


a C . H9 H 78

b C g H , C H , H 29

c CeH9— C H = C H H 63

d C . H8 C H , 67

e CeH8— C H = C H C H , 42

f n - C , Hn H -

g C J H T— C H ^ C H H -



oxazole-4-carboxylic acid (LHb) {47). Alcoholytic ring opening of the oxazolones (LI) causes the stabilization of the enolic y-OH group as an acid amide group. With the exception of 2-benzyloxazolone, Lib, no ring closure of this ketoester (LIA) in methanol/H+ to the oxazole-4- carboxylic ester (LIIA) could be observed (26). The cyclization of the open-chain acylaminoacetoacetic ester (LIA) can, however, be accom­

plished by heating with thionyl chloride or H2S 04/ A c20 . Saponification of the oxazolecarboxylic esters (LIIA) with NaOH yields the oxazolecar- boxylic acids (LII) (26).

yC X O , C H , N — / R « C H 3 O H / H + N H — / S O C lX t

R1 0 { HOy



LI ( a , d ) LI A

X 08C H , XOtH

N- V N a O H N-Y

Ak ' AK

o R * R


o R *

L I I A L I I (a, d )

The 4-phenylazo-2-phenyloxazolones can be rearranged in similar manner to the a-phenylazo-y-lactones ( X X X ) . Heating of LIII in methanol/20% KOH affords a high yield of l,5-diphenyl-3-carboxy- 1,2,4-triazole (LIHa) (28). Tetrazolecarboxylic acids were obtained from 4-phenylazo-l,2,3-triazolones in corresponding manner (47a).

^ N - N H - C J H J .COOH / X ' N



^ C H 3 O H / K O H 9 1 % c


L6N5 I I L I I I L I H a CeH5

Isoxazolecarboxylic acids are also accessible via the acyllactone re­

arrangement. Thus treatment of 3-phenyl-4-benzoylisoxazol-5-one (LIV) with concentrated NaOH yields 3,5-diphenylisoxazole-4-carboxylic acid

(LIVa) (29). Phenylfurazancarboxylic acids are formed from 3-aryl-4- oximinoisoxazol-5-ones in an analogous manner (47b, 47c).

H6C9 C O - C . H . H . C ,V yC O O H

xi l —( 1. c o n e . NaOH



° ^rTci


\ / \

° ° C6H5

L I V L I V a

R e a r r a n g e m e n t o f a-Substituted a- A c y l i a c t o n e s


a-Hydroxyalkylidene-y-lactones possess an additional acidic CH group in the a-position. The a-methylated lactones are obtained by heat-


ing under reflux with an excess of methyl iodide in absolute acetone [48).

The method of Marshall and Cannon (benzene/dimethylformamide) also affords good yields (49).

The substitution of the ^-hydrogen atom fixes the a-alkyl-a-acyllac- tones LV in the keto form, and no enol reaction with FeCl3 is conse­

quently observed. If LV (a-c) are heated for approximately 24 hr in absolute methanol containing 3% HC1, the tetrahydrofurancarboxylic esters LVI are obtained.

C H , O C H , LC^ C H , Q H / H ^ ^ _C OC H , s

o o R X

L V ( a - c ) L V I ( a - c ) ( Y i e l d 7 0 % ) a: R = H b : R = C H , c : R = C O , C2H5

These examples show that even nonenolizable a-acyllactones can be rearranged.


a-Acyllactones can react as ^-substituted /5-dicarbonyl compounds by a Michael addition with ^-unsaturated carbonyl compounds such as methyl vinyl ketone. The substituted a-acyl-y-lactones LVII (a-b) thus obtained rearrange to the tetrahydrofurancarboxylic esters LVIII (a-b) in methanol/H+ (27).

( C H2)2- C O - C H ,

L V I I (a, b )

C H , O H / H +

H b : R = C 02C2H5

( C H2)2- C O - C Ha

/ C 02C H3

— O C H , R L V I I I (a, b )


a-Acyllactones couple with diazonium salts in an aqueous medium.

The acyl group is usually eliminated, and the azo compound is stabilized as the a-hydrazone of the corresponding lactone. In some instances, how­

ever, the azo compound can be isolated. Thus the azo compound L I X is obtained by coupling a-benzoylbutyrolactone ( X X V I ) with p-nitroani- linediazonium chloride (49a).

C O - C . H , C O - C , H j / Q2N - C „ H4- N2C 1 - N = N - C , H4- N 02

k A pH = 3 - 4 , C H , O H / HtO k A

o Xo ° O

X X V I L I X ( 6 0 % )



R e a r r a n g e m e n t o f S p e c i a l A c y l l a c t o n e s

The rearrangement of dilactones of type LXa (50), L X b (51), L X c (52) offers interesting synthetic possibilities.

H8C C H8


I o I o o o


L X a L X b L X c


v = °

Ester condensations do not proceed uniformly with these unstable lactones. The use of NaH as condensing agent affords the best yields, and the monoacyllactones (e.g. L X I ) are formed (53). Rearrangement of L X I in ethanol/H+ results in the formation of a tetrahydrofuran ester lactone LXII, which is converted into the dihydrofuran derivative LXIII by distillation with polyphosphoric acid (53).

o 6

yC 0 C 02C2H5 xCO.C.H,

I , ( C8H6O H / H + / | L C 08C2H5

I / \ > 0 • H5C802C N/ X

° O C8H6

O H6C20

C8H5 C2H8


/C 02C2H5

P o l y p h o s p h o r i c / f] []

— • H5C202C A \

a cd Hl 5C2 O \ o2C2Hf i


The condensation accompanied by the alcoholytic fission of the lac­

tone ring of the spirolactone L X b with formic ester and sodium yields approximately 80% of the y-ketopimelic acid half-ester LXIV, and only a small quantity of a-acyllactone which is difficult to separate from the by-products (53).

H 08C - C H8- C H8- C - C H8- C H8- C 08C8H5

o L X I V

R e a r r a n g e m e n t in A q u e o u s M i n e r a l A c i d s


The a-acyllactone rearrangement essentially also proceeds in water/

H+. The rearrangement of acyllactones in both absolute alcohol/H+ and water/H+ involves the solvolytic fission of the lactone ring; the former case results in the £rcms-esterification of the lactonecarboxyl group, the


latter in the formation of the heterocyclic 3-carboxylic acid. This crystal­

lizes out, so that the equilibrium is displaced in the direction of the re­

arrangement product. If the open-chain intermediate or the carboxylic acid readily loses C 02, various decarboxylation products dependent on the acid concentration are obtained.

The rearrangement can usually be effected extremely simply. If a-hydroxymethylene-8-lactones (LXVa-g) are dissolved in concentrated hydrochloric acid at 25°, the corresponding dihydropyran-3-carboxylic acids (LXVIa-g) are precipitated after some time as colorless crystals in yields of 80-90%.

The ester group in the a-hydroxymethylene-y-carbethoxy-8-lactones LXVf and g remains unsaponified, and the half-esters LXVIf and g

can be isolated.

R8 O H R8

^ HX H80 / H + V ^ '

Rl O / O R

L X V ( a - g ) L X V I ( a - g ) a : Rl = C HS, Ra = R8 = R* = H b : R1 — C H ( C HS)8, Ra = R8 = R* = H c : R1 = Ra = R» = R* = H

d : R i = R « = R8= C HS, R4 = H e: R1 = R» = R* = H , Rs = C H8

f: R1 = C H „ Ra = R8 = H , R* = C 08C8H6 g : R i = R» = C H „ R* = H , R4 = C 08CTH5

Rearrangement of a-ethoxalyl-S-caprolactone (LXVII) in concen­

trated hydrochloric acid yields the 6-methyl-5,6-dihydro-4H-pyran-2,3- dicarboxylic acid (LXVIII) or its half-ester (5).

^ X : O C O8C8H5 / \ / C *0H


a-Acetyl-8-lactones (LXIXa,b) dissolved in concentrated hydro­

chloric acid are decarboxylated even at room temperature and 8-ehloro- ketones (LXXa,b) can be isolated. The rearrangement to the carboxylic acids LXXIa,b can, however, be accomplished in ice-cooled dilute hydro­

chloric acid.

R8 R8 R*

I C OTH 1 C O C H , I R!Y Y 2N HC1 R» Y Y c o n e . HC1 R8Y^ O

/ \ X

< o ° c

/ ° * Xv.



RS O \ H t U R / O R / CI C H8 L X X I ( a , b ) L X I X ( a , b ) L X X ( a , b )

a : R i = C H „ R » = R ' = H b : R* = R« = R ' = C H ,


Table 9 shows a few examples of the position of the absorption maxima  of the dihydropyrancarboxylic esters and their S and N homologs

Table 9

shows a few examples of the position of the absorption maxima of the dihydropyrancarboxylic esters and their S and N homologs p.27



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