Neighboring group reactions—V

Tetrahedron,

1%2, Vol. 18.

pp_893

to 901. Pergamon Press Ltd. Printed in Northern Ireland

NEIGHBORING AN UNUSUAL H. E.

GROUP REACTIONS-V ASSISTED

ZAUGG

METHANOLYSIS

and R. J.

MICHAELS

Organic Chemistry Department Research Division, Abbott Laboratories North Chicago, Illinois (Received 10 January 1962)

Abstract-Methanolysis of 3-@-bromoethylb3-phenyl-Z&nz.ofuranone (I, n = 2) gives high yields of 2-(o-hydroxyphenyl)-2-phenyl4hydroxybutyric acid y-la&one (Ill) and methyl bromide. The reaction is acid catalyzed and is restricted to the second member of the homologous series of bromoalkylbenzofuranones I (n = 1,2, 3). A mechanism consistent with the experimental data and with previous findings of Winstein et al. is proposed. It involves anchimeric assistance by the methoxyl group of the tetrahedral intermediate which is first formed by the addition of the elements of methanol to the lactonic carbonyl group of I (n = 2). Utilizing B-pinene as an acid “trap”, the slow uncatalyzed methanolysis was also studied. Of four products formed in yields varying from O-25% to 3.9 o/ three were identified by gas chromatography.

papers2 described the base catalyzed rearrangement of the three homologous benzofuranones I (n = 1,2, 3) to the corresponding methyl esters IL (n = 1,2, 3). This reaction obviously results from preferential nucleophilic attack of methoxide

PREVIOUS

a

I

ion or methanoI at the carbonyl carbon atom, followed by intramolecular displacement of bromide ion by phenoxide ion. The present paper reports the outcome of attempts to solvolyze these three bromides I in methanol under neutral or acidic conditions. . The first and third members (n = 1 and 3) of this series can be disposed of briefly. Both were totally inert to refluxing methanol, even in the presence of strong acid catalysts. In contrast, when the bromoethyl derivative (I, n = 2) was refluxed in dry methanol for 16 to 20 hours, the lactone IIP was obtained in better than 80 % yield together with a roughly equivalent amount of methyl bromide. I

(n ~2)

CH,OH

r@,

+a

OH

I

\

1

,HO c’ ‘0 C4H~-CH2 In

l

w,er

l Part IV, H. E. Zaugg, R. W. DcNet and E. T. Kimura, J. Med. Pttarm. C&m. 5,430 (1962). * 0 H. E. Zaugg, R. W. DeNet and R. J. Michaels, J. Org. Gem. Z&4821 (1961); b Ibid. Z&4828 (1961). n H. E. Zaugg, R. W. DeNet, R. J. Michaels, W. H. Washburn and F. E. Chadde, J. Org. Chem. 26, 4753 (1961).

H. E. ZAUGG and R. J. MICHAEIS

894

Although only 12% of the displaced bromide could be accounted for as hydrogen bromide, the latter proved to be indispensable to solvolysis. . Two experimental observations made this quite clear. First, the presence of less than an equivafent amount of the neutral mineral acid “trap”, @-pinene,* almost completely inhibited the solvolysis leading to III. Second, kinetic studies showed (Table 1) that in the absence of added acid the solvolysis rate increased slowly during an induction period while acid was being formed endogenously, presumabIy in a slow concurrent solvoIysis of another kind. At sufficiently high acid concentrations the solvofysis reaction (I --+ III) leading to methyl bromide acceferated to the point where it predominated overwhelmingly and couId proceed essentially at a constant rate. Exogenous acid (Table 1) abolished the TABLE 1. OF

THE

PZXWIDFIRST*RDEB

METHANOLYSIS

CONSTANTS

j-(8-BROMOETHYL)-3-

(O*167M) AT 60" + 0.1

PHENYL-h3ENXWURANONE

Initial HBr (M)

RATE

OF

LiClO,(M)

0

0

0

0.500

0.063 0.126 0.126 O-126

0.437 o-374 0 1.0

k,x104(min-l) 2*02* 7.14 & 1.58* 7.58 & 8.78 * 14.0 & 12.4 f 13.6 f

0.33 0.57 0.74 0.28 0.71 1-l

Average rate (determined by only two points) during the induction period.

l

induction period and effected a solvolysis rate roughly first-order with respect to itself? Although the chloro analog of I (n = 2) underwent methanolysis in the same way to give III, reaction was exceedingly SIOW.In the presence of O-38 N hydrogen chloride only a 6-5 % yield of III (80% recovery of starting material) was obtained after 20 hours at reflux temperature, In addition, the occurrence of a slow uncatalyzed methanolysis was demonstrated using gas chromatographic techniques. The product, obtained after refluxing the bromide I (n = 2) with methanol in the presence of ,9-pinene for 2 weeks, contained starting material (875 % yield), the methyl ester II (n = 2) (O-8% yield), 3-@-methoxyethyl)-3-phenyl-2-benzofuranone (IV) (O-8% yield), the lactone III (0*26 % yieId), and 4 P. R. Austin, U.S. Pat. 2,316,215 (1943). Utilization of a neutral acid trap such as @-pinene (ethylene oxide would likely serve as well) was necessitated by the fact that in methanol in the presence of a base even as weak as sodium acetate, I (n - 2) undergoes the rearrangement to 11 (n = 2)ab. s The somewhat less than first-order dependence of the rate on HBr concentration (Table 1) very likely stems from either one or both of two sources: (1) the demonstrateda reversibility of the overall reaction (i.e., III + HBr - I), and (2) a faster reaction of HBr with solvent (CH,OH i- HBr CH;Br + H,O) at the higher HBr concentrations, thus reducing effective acid levels more than at lower initial concentrations of I-I&. The observed absence of a significant salt effect is not surprising since minimal ionic strengths necessitated by the presence of HBr (ca., O*lM) are in the range where the capacity to detect salt effects times marginal.

Neighboring

group reactions--V

895

an unknown substance (3*9x yield). The formation of the ester II(n = 2) and the ether IV could account for ai Ieast part of the endogenously produced hydrogen bromide.

DISCUSSION

The interesting aspect of the acid catalyzed reaction stems mainly from the observed formation of a hydm’ysis product as a result of methundysis. This, together with the highly specsc structural requirements for reaction, suggests that a mechanism involving intramolecular assistance must be involved. For a number of reasons the carboxonium ion V (X = Br) can be ruIed out as a possible intermediate. It does not account for the requirement of acid catalysis; nor

is there any reason to believe that it would react with methanol to give III and methyl bromide in preference to the (more likely) corresponding ortho ester X and hydrogen bromide. Furthermore, the bromide I (n = 2) is relatively unreactive towards silver salts (Table 2); and neither it nor its chloro anaIog would undergo reaction with antimony pentachloride to giveV (X- = SbCJ,- or SbCl,Br- under conditions6 which led to an 88 % yield of the dioxoIenium salt VI from @hloroethyl pnitrobenzoate.7

SbCl,

p-02NC6H4COOCHzCH2CC

l

SbC$

A mechanism in accord both with the experimental facts and with other related work involves methoxy1 rather than ester (Iactone) participation. Evidence for the acid-catalyzed addition of hydroxylic substances to carboxylic acid derivatives to give tetrahedral intermediates (i.e., I + VII) is, of course, firmly established .8 Likewise, with good reason, oxonium ions (i.e., VIII) have been 6 H. Meerwein, K. Bodenbenner,P. Borner, F. Kunert and K. Wundcrlich,Lie&s Am. 632,38 (1960). 7 The apparent inability of 1(x1= 2) to form salts of type V suggests the possibility that the steric

strain resulting from the two five-ring fusion atoms being difkently hybridized (one trigonal and the other tetrahedral) over-compensates for any stabilization that might be gained through charge delocalization in the cation.

H. E. ZAUGG

and R. J. MICHAELS

postulated9-l9 as reactive intermediates in processes involving anchimeric assistance by methoxyl groups. Indeed, Winstein et a/. l3 have shown that in cases involving aliPhatic methoxyl participation, five-membered ring intermediates (i.e., VIII) are in-

I C6H5 J

tCH 3Br

_.-H”

Oh I

II

I

C6H,

C6H5

variabfy favored over those with either larger or smaller rings. This mechanism thus provides a reason for the observed limitation of methanolysis to the single homolog I (n = 2). Furthermore, the Iower reactivity of the chloride as compared to the bromide is consistent with the requirement that the assisted step (i.e. VII - VIII) must be rate-Iimiting. However, Winstein13 has also noted that cyclic aliphatic (in contrast to aromatic) methoxonium intermediates (i.e., VIII) only rarely undergo methyl-oxygen cleavage to give methyl halide. Rather methylene-oxygen cleavage generally occurs exchtsively. Of the two analogous bond cleavages in VIII, methylene-oxygen cleavage is reversible (i.e., VIII s VII). Hence, no inference regarding their relative importance can be made. With respect to the third possibihty for bond breakage, however, it can be concluded that methyl-oxygen cleavage predominates. Rupture of the bond between oxygen and the fusion atom would lead irreversibly to 3-(J-methoxyethyl)-3-phenyl3benzofuranone IV, none of which could be isolated.14 The intermediate VII is written in the one form which will permit methoxyl participation. Admittedly, there is no reason why methanol attack-could not occur on the other side of the carbonyl carbon atom to give VIIa, the diastereomer of VII, B M. L. Render, Chem. Rev. 60,53 (1960). n S. Winstein and R. B. Henderson, J. Amer. Chem. Sm. 65,2196 (1943). I0 S. Oae, J. Amer. Chem. Sm. 78,4032 (1956). l1 D. S. Noyce and B. R. Thomas, J. Amer. Chem. Sac. 79, 755 (1957). I* A. Kirrmann and N. Hamaide, Bull. Sot. Chim. Fr. [5] 24, 789 (1957). IS S. Winstein, E. Allred, R. Heck and R. Glick, Tetrahedron 3, 1 (1958). I4 Material balances of up to 90%, consisting only of reactant I and product IIi, were attainable. Since slow formation of IV in the uncatalyzed solvoIysis was definitely established, it is probably formed in minor amounts in the cataIysed reaction as well.

Neighboring

group reactions-V

897

thus allowing only hydroxyl participation and formation of the oxonium intermediate VIIIa.15 However, cleavage berween oxygen and the fusion atom in VIIIa represents the only irreversible rupture that this oxonium group can undergo. The other two Since this type of cleavage does not occur in (VIIa T+ VIIIa T+ X) are reversible. OCH3 -HBr

z

lI?-Jy? I I

C6HS

XIII9

X

preference to methyl-oxygen cleavage (vide sup-a), it certainly wouId not occur in This then provides at least one reason to preference to proton-oxygen cleavage. explain why hydroxyl participation is not and cannot be significantly evidenced in the product formed from the acid catalyzed methanolysis of I (n = 2). (However, the unknown product formed in 3*9 % yield in the SIOW uncatalyzed methanolysis could be the ortho ester X). The work of Winstein et al. l3 has demonstrated that methyl-oxygen cleavage of oxonium intermediates may occur by either or both of two processes: (1) nucleophilic attack by the anion or (2) nucleophilic attack by solvent.18 Since formation of dimethyl ether was indeed observable in the present work (ca., I % maximum concentration in the reaction mixture), there remains the possibility that methyl-oxygen cleavage (i.e., VIII --f IX) occurs via nucleophilic attack by methanol. The dimethyl ether thus formed might then react with the hydrogen bromide to give methyl bromide as the preponderant cleavage product. l* However, by means of a control run in which a 4-5 y0 solution of dimethyl ether in methanol was submitted to the conditions of the solvolysis it was established that no detectable ether cleavage occurs. It thus appears that methyl-oxygen cleavage (VIII -+ IX) takes place through attack by bromide ion. The smal1 amount of methyl ether formed in the reaction must then derive from the reaction of methyl bromide with methanol. In another control experiment it was found that a typical mixture of these two substances at 60” produces approximately a 1% concentration of dimethyl ether, even in the absence of added acid. I5 In this discussion it is assumed that trans-interaction is sterically prevented. Although systems containing two five-membered rings fused tram to each other are known in the carbocyclic series, they are thermodynamically decidedly unstable relative to their c&fused isomecs.1el17 I6 R. P. Linstead and E. M. Meade, J. Chem. Sm. 935 (I934); A. H. Cook and R. P. Linstead, Ibid. 946 (1934). l7 R. Granger, P. Nau and J. Nau, Bull. Sm. Chim. Fr. [5j 27, 1350 (1960). l8 Unpublished work by E. L. Allred has shown that ethanolysis of 5-methoxy-l-pentyl brosylate leads to production of 41% tetrahydropyran but no formation of methyl brosylate. - This case of methyloxygen cleavage occurs exclusively uia nucleophilic attack by ethanol. I* R. L. Burwell, Jr., and M. E. Fuller, J. Am. Chem. DC. 79,2332 (1957), found that, at high concenrrakms and even at room temperature. hydrogen bromide cleaves ethers more readily than it does the corresponding alcohols. We are indebted to a referee for calling OUTattention to this work and in suggesting the alternate mode of methyl-oxygen cleavage that, c&sequently, must be considered. 2

H. E.

ZAUGG

and R. J. MICHAELS

EXPERIMENTAL Methandysis

of 3-@-&romoethyl)-3-phenyl-2-benzofurarwne (I, n = 2)

In the following procedure, scrupulous care was exercised to insure the use of dry reagents and apparatus. A solution of I (n = 2) (25-4 g, O-08 mole) in methanol (125 ml) was refluxed for 22 hr. The methanol was removed by distillation, the residual solid was stirred with 100 ml of warm hexane and collected at the filter. The product (16-7 g, 82%, m.p. 157-160”) was recrystallized once from 95 % ethanol to give pure 2-(o-hydroxyphenyl)-2-phenyI4hydroxybutyric acid y/-lactone III, m.p. 16&161”, identical (mixed m.p. and IR spectrum) with the authentic material.* The hexane extract was concentrated to dryness and the residual material (4.5 g, m.p_ 57-60”) was recrystallized twice from 95 % ethanol to give 2-O g (7.9 “/,) of recovered bromide I, m.p. 74-75’, identified by mixed m.p. The filtrate from the first recrystallization was concentrated to dryness to give an oil (1.0 g) which, judging from its IR spectrum, consisted mainly (65-75 ‘A) of starting bromide I (;lac’ mBx8 5.56 p) mixed with appreciable amounts (2&25 %) of an ester (i.~~~*a5.77 p), most likely II, n = 2” (absorption peaks at 7.24 ,Uand 9.50 ,u were common to both II, n = 2, and the mixture, but were absent in I, n -T-2). Several smaller runs were carried out with somewhat shorter reflux times (16-l 8 hr). Yields of III ranged from 75 % to 88 ‘A. In one run conducted at only 40” (for 1 wk) a 72 ‘A yield of I11 was isolated. Titration of some of these reaction mixtures with standard alkali revealed that only 12 to 12.5 % of the solvolyzed bromine couId be accounted for as hydrogen bromide. Quantitative gas-liquid chromatography demonstrated that the balance went to form methyl bromide. Reaction time was shortened appreciably by the presence of exogenous acid (hydrogen bromide or p-toluenesulfonic acid), In one run catalysed by p-toluenesulfonic acid, a 75 % yield of III was isolated after only 7 hr of reflux. Inhibitian of methanolysis by fi-pinene A solution of I (n = 2) (5.0 g, O-0158 mole) and #?-pinene (7 ml) in dry methanol (50 ml) was refluxed for I6 hr during which it remained neutral. Isolation by the foregoing procedure led to recovery of 93 % of the starting material with no indication of the presence in the residues of any solvolysis product III (IR absorption at 5.74 ,Uand 5.65 pa). Essentially the same results were observed when the quantity of #?-pinene was reduced to 1.93 g (O-0142 mole). Other attempted sofuofyses 3#-Chloroethyl)-3-phenyl-2-benzofuranone (I, n = 2, Br = Cl)* (5 g, O-018 mole) was refluxed for 20 hr in dry methanol (50 ml) containing hydrogen chloride (O-379 N). Isolation in the usual way gave 4.0 g (80 %) of recovered starting material and 0.3 g (6.5 %) of III, m.p. and mixed m-p. 159-161’. Addition of lithium perchlorate (0.05 mole) to the reaction mixture or substitution ofp-toluenesulfonic acid (0.1 M) for the hydrogen chloride in this procedure did not favor the formation of III. 3-Bromomethyl-3-phenyl-2-benzofuranone (I, n = 1)” (5.0 g, 0.0165 mole) was submitted to the foregoing procedure but hydrogen bromide was used as the catalyst. There was obtained a quantitative recovery of starting material of m.p. only 1” less than it was originally. Results with p-toluenesulfonic acid as a catalyst were no better. 3-(y-Bromopropyl)-3-phenyl-2-benzofuranone (I, n = 3) was just as inert to methanolysis as was its bromomethyl homolog. Results were the same whether it was refluxed (16 hr) in methanol alone or in the presence of hydrogen bromide or ptoluenesulfonic acid. It was always recovered quantitatively in virtually pure form. Reactivity of the bromides I (n = 1,2, 31 with siluer salts In Table 2 are summarized the relative reactivities of these bromides, at room temp (cold) and in boiling solvent (hot), towards silver nitrate in ethanol, and towards silver trifluoroacetate and silver perchlorate in both ethanol and benzene. Comparisons were made in test tubes by observing the rapidity of precipitation of silver bromide. In Table 2 reactivities are divided into three arbitrary groups: no reaction (-), relatively slow reaction (+) and relatively rapid reaction (i- +). Reactivities towards silver trifluoracetate and silver perchlorate were also tested in a third solvent, 1,2-dimethoxyethane, with results essentially the same as in benzene.

Neighboring

group reactions-V

899

Casual inspection of Table 2 serves to show that the three bromides I are less reactive towards these silver salts than is n-butyl bromide. Reactions with antimony pentachloride 2-(pNitrophenyl)-1,34oxolenium hexachioroantinwnate (VI) was prepared according to Meerwein’ by treating a cold (dry i-acetone) solution of #?chloroethylp-nitrohnzoate [6*90 g, 0.03 mole, m.p. . 5I -52”, AE:t 5-80 (C=O)J in dichloromethane (15 ml) with a cold solution of antimony pentachloride (9.0 g 3.85 ml, 0.03 mole) in dichloromethane (7 ml). After standing overnight at room temp, the pale yellow precipitate of VI[14.0 g, 88 %, m-p. 138-14O”, i?zgl 5.83 p (C=O)] was collected at the filter, washed with dichloromethane and dried. (Found: C, 20.25 ; H, l-53. CoH,CleNO,Sb requires: C, 20.44; H, I.53 %). It is interesting to note that. the IR carbonyl band of VI is shifted to longer wave lengths by only 0.03 p relative to that of the ester V. When either the b-chloroethyl or @-bromoethylbenzofuranone (I, n = 2, Br = Cl or Br) was treated with antimony pentachloride according to the foregoing procedure no evidence of reaction TABLE

2. RELATIVE

REACTIVITTESOF BROMIDESTOWARDS

SILVER SALTS

Reaction with Compound I(n = 1) cold hoc I(n = 2) cold hot I(n = 3) cold hot n-C,H,Br cold hot

--. 1 7 -- -k ‘+ Tf

AgClO,

Ag(O,CCF,)

AgNO, in C,H,OH

in C,H,OH

in C,H,

-

_-. ._. .*___ .

-

-_

++ T t- + ++ _t.f.

in C,H,OH

-

-

-

-

__

._ T+

-

__

1.. ; ++

in C,H,

._

++ i-f ++

-

.

7. + + ++

was apparent . No heat of reaction was noticeable and no salt precipitated. Removal of the solvent by distillation and treatment of the residue with water, followed by the usual work-up, gave only recovered starting material and no lactone III, the hydrolytic product which would have been obtained6 had any V (X- = SbQ-) been present in the reaction mixture. .

. Gas chromutogruphic measurements of kirdcs The instrument used was a PodbeIniak “Chromacon” (Series 9475) with a thermistor detector cell operated at 8 milliamperes. The column (6’ x l/4” copper tube) was packed with 30-80 mesh Celite (Podbelniak # 9391) carrying di-n-d-1 phthalate and used at a temp of 74” (injection temp, 80”). The carrier gas (helium) had a flow rate of la1 10” ml/min (14 lb/in*). Retention times were measured by the distances of the peak maxima from the injection point, and quantitative estimation of components was accomplished by graphical determination of relative peak areas. Methyl bromide and dimethyl ether were identified in the unknowns by comparisons of retention times with those of known solutions of these substances in methanol. Retention times were, for dimethyl ether, 39 set, for methyl bromide, 85 set and for methanol, 104 sec. No distinct peak for hydrogen bromide was observed. Nicely symmetrical peaks were obtained for the first two less polar substances, but considerable tailing of the methanol peak seriously lowered the reproducibility and consequently the quantitative precision of this procedure. However, it sufficed to demonstrate the presence of an induction period in the methanolysis. To this end, two 0.5 M solutions of I (n = 2) in dry methanol were prepared, one of them also 0.268 N in hydrogen bromide. Both were placed in a bath held at 60” f O-1‘_ At intervals samples were withdrawn by syringe and injected into the chromatographic instrument. The percentages of methyl bromide observed after corresponding elapsed times (in min in parentheses) were, for the solution without hydrogen bromide, 0(174), O-22(324), l-19(527), 1.53(630), 4*81(1440), 5.5q1800) and for the solution with hydrogen bromide, O-86(1W), 1l 23(240), 1*42(330), 2.12(W), 2.79(580), 3*31(760),

900

H. E.

ZAUCG

and R. J. MICHAELS

5*28(1410). In both runs the concentration of dimethyl ether increased to a maximum of approximately 1% (in 1800 min). This by-product undoubtedly arose from the reaction of methyl bromide with methanol. This was demonstrated in a control run whereby a 368% (w/v) solution of methyl bromide in methanol, O-054 N in hydrogen bromide, was thermostatted at 60”. In 2OtM min, the concentration of dimethyl ether reached l-O% and the methyl bromide concentration decreased to 25%. A nearly identical result was observed in the absence of exogenous hydrogen bromide. Although, as was to be expected, methyl bromide was formed in a dil (O*268N) solution of hydrogen bromide in methanol, its rate of formation (as determined by a control run) was considerably slower than that observed in the exogenously catalysed methanolysis of I (n = 2). To determine the extent of methyl ether cleavage under the conditions of the solvolysis, a 4.5 % solution of (CH&O in methanol, 0.115 N in HBr, was kept at 60” and analysed at l-3 hr intervals by gas chromatography. Over a period of 30 hr, the ether concentration remained essentially constant (4.5 & 0.1%) while the methyl bromide concentration increased from zero to a constant value (ca., 1%). Hence, methyl bromide is not formed from methyl ether under these conditions. Infrared measurements

uf kinetics

The instrument used was a Perkin-Elmer Model 137-G equipped with a screen to allow only 60% transmittance of the reference beam. The cell was made of IRTRAN-2 (Connecticut Instrument Corporation) accommodating a solution thickness of O-027 mm. Reaction kinetics were measured by the rate of disappearance of the absorption peak at 5.53 p, present in I (n = 2) but absent in the product 111. To calibrate the method the absorbances (at 5.53 p) of a number of synthetic mixtures of reactant (1) and product (1II) (ranging from 50 to 100 mole % of 1) dissolved in methanol (total molarity = O-167) were determined and plotted against the corresponding mole o/oof I. This gave a straight line of slope 0.92 & O-04. Each absorbance in subsequent determinations was corrected for this slight deviation from unity. All solvolyses were carried out at 60” I~ O-1, at initial reactant concentrations of 0.167 M and the procedure involved in transferring solution from reaction vessel to absorption cell was standardized in order to minimize errors arising from this relatively short time interval during which the reaction temperature was not controlled. Pseudo-firstorder rate constants (k,) were determined by plotting the logarithm of the corrected absorbance against time (min) and calculating the slope of the resulting straight line statistically. Multiplication of the slope by the factor -2.303 gave k, directly. Most runs were carried to 3w ‘A of completion. Results of six runs are summarized in Table 1. Gas chromatugraphic

analysis of the uncaralysed methanolysis

A solution of I (n =‘2) (5.0 g, 0*0158 mole) and p-pinene (7 ml) in dry methanol (50 ml) was refluxed for 2 weeks. The neutral mixture was worked up in the usual way to give 3.4 g (68 %) of recovered I (n = 2), m.p. 67-69”, and l-2 g of a thick yellow oil. Dilute solutions of this oil in chloroform were then submitted to analysis in two different columns in a Barber-Coleman Model 10 gas chromatograph equipped with a strontium-90 argon ionization detector (at 600 volts potential). Both columns (8 ft) were equilibrated at 170” (injection chamber, 225”) with a gas flow rate of 75 mllmin (20 lb/in* argon pressure). ln each column the carrier consisted of 60-80 mesh siliconized chromosorb W. The only difference consisted in the liquid phase. In one column it cornprized 4 y. SE-30 (General Electric methyl silicone) and in the other, 3 ‘A F-50 (General Electric Versilube oil). Four peaks were obtained in both chromatographs and by using synthetic mixtures of known substances in both columns, and comparing retention times and peak areas with the unknown mixture, three of the four components were identified and the relative amounts of all four were quantitatively estimated. Results are summarized in Table 3. The IR spectrum of the yellow oil (1.2 g) checked with the gas chromatographic results. A strong peak at 5.53 p (mainly starting material, plus IV) was accompanied by weak absorption at 5.77 ~1 characteristic of II (n = 2). The relative intensities of the two peaks indicated that the ester II (n = 2) comprised between 2% and 5% of the mixture. Synthetic mixtures of the bromide I (n = 2) and the lactone III could not be resolved in either of the above named chromatographic columns. However, success was achieved using a column containing O-25“/, Dow-Corning XF-1-5 as the liquid phase with a gas flow rate of 85 ml/min. Using this system and comparing the chromatogram of the crude mixture (1.2 g) with those of synthetic mixtures it was estimated that the lactone III was formed in the uncatalysed reaction only to an extent corresponding to an 0.26 “/, yield (0.88 ‘A in the crude mixture).

Neighboring 3-(8-Methoxyethyl)-3-phenyl-2-benzufuranone

group reactions-V

901

(IV)

A solution in dimethylformamide (60 ml) of the sodium derivative prepared in the usual wayfrom 3-phenyl-2-benzofuranone (10.5 g, 0.05 mole) and sodium hydride (0.055 mole) was heated on the steam bath for 2 hr with 7.7 g (0.055 mole) of @methoxyethyl bromide. Solvent was removed by TABLE

3.

RESULTSOF

CHROMATOGRAPHIC

ANALYSISOFTHE

SE-30 Column Compound

____.

-

Time (min) *

__. _-_ Unknown II(n -2) IV I (n = 2)

-. 8.5 9.9 11-I 17.0

_.~

~._ %-t

UNCATALYZED

F-50 Column

Yield --_ .

*.----

Time (min)*

._~_

14-o 2.7 2.5 80.8

METHANOLYSIS

10.9 12.9 14.8 246

%t 13-5 3.2 2.9 80-4

.-

%$

___. . --3-9 0 0.8 0.9 87-5”

* Retention time. t Based on relative peak areas. $ Based on 5-Og (0*0158 mole) of starting material I (n = 2), and the average of the relative amounts in the mixture (1.2 g) as measured by the two columns. 0 Based on a molecular weight of 268. * Including the 3.4 g of solid I (n = 2) recovered. distillation under red press and the residue was taken up in a mixture of ether and water and separated. The ether layer was washed with water and dried over anhydrous magnesium sulfate. Filtration, removal of the ether by distillation and vacuum distillation of the residue gave 9.7 g (72 %) of alkylated product, b.p. 177-182” (2.5 mm), On standing it solidified. Recrystallization from hexane gave 5 g (Found: C, 76.10; H, 6.01; 0, 17.89. C,,H,,O, of pure IV, m.p. 56-58”, ;I~*:‘D 5-55 p (C-0). requires: C, 76.15; H, 6.1 I ; 0, 17.96%). Acknowle&ements-We are indebted to Miss Joan Zimmer, Mr. Preston He&en and Dr. Ilmar Merits for help with the gas chromatographic analyses, to Mr. Fred Scheske for the infrared determinations and to Mr. Paul Sanders for the statistical calculations. Several helpful suggestions concerning the discussion of mechanism were provided by Dr. P. H. Jones.