Aluminum Chloride-Catalïzed Reactions of Phenols With

ALUMINUM CHLORIDE-CATALÏZED REACTIONS OF PHENOLS

WITH HEXACHLOROPROPENE

DISSERTATION

Presented in Partial Fulfillment of the Requirements

for the Degree Doctor of Philosophy in the

Graduate School of The Ohio State

University

SIDNEY SCHIFF, B.S., M.S.

The Olio State University

1958

Approved by

Adviser Department of Chemistry ACKNaJLEDGMENT

I vish to express sincere appreciation to Professor Melvin

S. Nevman for his enthusiastic interest, his helpitil advice and his constructive criticism throughout the course of this investi gation.

I would also like to thank my wife for her constant encour agement, confidence and sacrifices.

IX TABLE OF CONTENTS

INTRODUCTION 1

BACKGROUND 4

DISCUSSION OF RESULTS 38

I, Previous Work by Pinkus 38

II. Determination of Structure of I 4-0

III. Study of Reaction Conditions for Preparing 4& 3,4-Dichlorocoumarins

IV. Reaction of Hexachloropropene with Other Phenols 48

V. Mechanism of Goumarin Formation 55

VI. Reaction of 3,4-Dichlorocoumarin with Bases 64

EXPERIMENTAL

I. Generalizations 69

II. Structure Determination of 3,4-Picbloro- 71 6-methylcoumarin

III. Reaction of Other Phenols with Hexachloropropene 75

IV. Reactions of 3,4-Dichlorocoumarins with Bases 85

SUMMARI 90

FIGURES 92

AUTOBIOGRAPHY 96

iii INTRODUCTION

The present work originated from a study^ made on the reaction

1 , A. G. Pinkus, Ph. D. dissertation. The Ohio State University, 1952; hereafter referred to as "Pinkus dissertation. " of phenols and polyhalogenated compounds in the presence of aluminum chloride as a catalyst. This reaction, called the Zincke-Suhl reac- o tion, yields A-methyl-A-trichloromethyl-2 ,5-oyclohexadienone.

2. T. Zincke and R. Suhl, Ber., Al^S (1906).

Mfu CXfl 3 [O]

OH C In his study, Pinkus attempted to react phenols with other com pounds, such as benzotrichloride and 1 ,1 ,1-trichloroethane, containing the trichloromethyl (001^-) group. One of the compounds available at this time was hexachloropropene. From the reaction of p-cresol with hexachloropropene,3 there was obtained a goodly amount of light gray,

3 . A. G. Pinkus, private communication. amorphous material. From this could be isolated sharp-melting color less crystals. The results of several qualitative tests led Pinkus 1 to consider either 2 ,3-dichloro-6-methylchromone (1 ) or 2-dichloromethylene-6-methylco'ujnarin-3-one (2 ) as the most probable structure

for the compound.

The present study was initially concerned with definitely es

tablishing the structure of the unknown compound. The structure

was deduced to be 3,4-dichloro-6-mothylcoumarin (I) and an unam- Ul

I biguous synthesis of 3 ,4-dichlorocoumarin verified the coumarin

structure.

After elucidating the structure of the product, a study was

made to determine the optimum conditions for running the reaction.

£-Chlorophenol was used as the substrate in this study because the

purification of the product was easier tlian when p-cresol was used.

Simultaneously, a study was made to extend the reaction to other substituted phenols because 3,4-dihalocoumarins have never been reported in the literature.

The reaction of 3,4--âichloro-6-methylcoumarin vjith organic bases was investigated. The 4-chlorine was found to be the more reactive, but the 3-chlorine will react with difficulty. BACKGROUND

I. ALUMimJM GHLORIDE-CATAIÏZED REACTIONS OF PHENOIS WITH TRICHLORO

METHYL C0I4P0UNDS

A, Reaction of Carbon Tetrachloride and Phenols

The initial discovery that trichloromethyl compounds will react with phenols was made when bromination of 3,5-dichloro-p-cresol was attempted in carbon tetrachloride in the presence of aluminum.^ The

1 . T. Zincke and R. Suhl, Ber., 22» 4 M 8 (1906).

carbonate of 2,6-dibromo-3,5-dichloro-p-cresol (A) was obtained in

stead of the anticipated 2,6-dibromo-3,5-dichloro-p-cresol (B). ce.

ct ov\

o M

o-c— 0

WTien B was treated with aluminum clfLoride in carbon tetrachloride, A was

obtained. VJlien p-cresol was brominated in carbon tetrachloride id.th

aluminum chloride present, a mixture of a 26 per cent yield of the

tetrabrorao-p-cresol (C) and a 50 per cent yield of the carbonate ester

(D) was obtained. When C was subjected to the same reaction conditions. Brv P rv o-co— o Q Brv the intermediate E was isolated.

B v

-CUL 13 iv E 3 The results of the Zincke-Suhl reaction which are most important in their relationship to the present work were obtained when £-cresol was treated with carbon tetrachloride and aluminum chloride. A AO per

cent yield of a cyclic ketone, which was shown to be A-^ethyl-A-tri-

chloromethyl-2,5-cyclohexadienone (F), was obtained. In a later study

of the Zinke-Suhl reaction, the yield of this reaction was increased

to 60 per cent.^

1. M. S, Nevman and A. G. Pinkus, J. Org. Chem., !£, 978 (1954).

On the basis of products isolated in their study, Zincke and Suhl

proposed the existence of the trichloromethyl ether of p-cresol as an M&/ CC2-5

I I OH O intermediate in the reaction.^ Two other Intermediates, (G) and (H),

1 . T. Zincke and R. Suhl, Ber,, 22; 4148 (1906).

Ob oH

II H were later proposed,^

2, K, kvMers and W. Julicher, ibid.. $5, 2167 (1922),

On the basis of the latest work,^ the following reaction mechanism

3, M. S. Newman and A. G, Pinlois, J. Org. Chem., 12,, 978 (1954). was formulated. Aluminum chloride and p-cresol first form the dichloro-

aluminum-p-cresolate salt, of which the p-cresolate ion can be written in the three resonance structures pictured. The trichloromethyl

M ® r\ J K ketone is obtained by reaction^ through K.

1. For the sake of simplicity, the monomeric structure will be used for aluminum chloride, although it probably exists as a dimer.

f ; b - 5 ^ + a.aî-cfl-3 O A c e ^

Reaction through J was postulated as the cause of the large amount

of polymer that formed during the reaction. An attempt was made to force the reaction to occur more completely in the angular position by using 2,6-dibromo-p-cresol in the r e a c t i o n . ^ However, only a 9 per cent

2. M. S. Newman and A. G. Pinlcus, J. Org. Chem., 1^, 978 (1954). yield of the desired ketone was obtained, along with two other products which were not investigated. No dark polymer was obtained, however.

The analogous reaction with 2 ,6-dichloro-2-cresol yielded 36 per cent

of 2,6-dicliloro-4-methyl-4-trichloromethyl-2,5-cyclohexadienone, along 8 with a large amount of unreacted cresol. Again, no dark polymeric material was obtained, nor were there any by-products found as in the case of 2 ,6-dibromo-p-cresol.

B. Reaction of benzotrichlorides and phenols

The reaction of phenol with other trichloromethyl compounds was studied. VJhen benzotrichloride was used,^ and the reaction mixture

1. M. S. Newman and A. G. Pinlcus, J. Org. Chem., 985 (1954). was hydrolyzed with water, the expected Zincke-Suhl product (L) was

not obtained. Instead, the dioxocin (M) was isolated in 29 per cent

yield. %drolysis of the reaction mixture with calcium carbonate and ice instead of with water or acid resulted in 2-hydroxy-5-methylbenzophenone in 76 per cent yield. No dioxocin was obtained. The same results were obtained by using absolute methanol instead of water. In addition, a small amount of 2 ,b-dibenzoyl-^-cresol was isolated and identified. The alxnnlnum chloride-catalyzed reaction of phenol and benzo trichloride produced only ^hydroxybenzophenone in 90 per cent yield.

When 2-chlorobenzotrichloride was reacted with p-cresol,^ a

1 . M, S. Newman and A. G. Pinkus, J. Org. Chem., 2^, 996 (1954).

19 per cent yield of 2-methylxanthone (N) was obtained in addition O

OK ÜL Q Q N to a 17 per cent yield of the dioxocin and a 35 per cent yield of

2 '-chloro-2-hydroxy-5-methylbenzophenone. The xanthone was absent

when the reaction was run in benzene.

The dioxocin, the hydroxybenzophenone and the xanthone were all

obtained when the reaction was run with 2 ,4-dichlorobenzotrichloride.

The yields were, respectively, 32 per cent, 22 per cent, and 11

per cent.

When 3,4-dichlorobenzotrichloride was used, no xanthone was

possible, since cyclization to a xanthone requires a chlorine in the

2 ’ position. In addition to isolating a dioxocin in 9 per cent yield

and a hydroxybenzophenone in 57 per cent yield, a 2 ,6-dibenzoyl-£-

cresol was obtained in 14 per cent yield. 10

The formation of the xanthones and o-hydroxybenzophenones in dicates that reaction can occur through J,

C. Miscellaneous Reactions of Trichloromethyl Compounds and

Phenols

In the study made by Nevman and Pinkus,^ g-cresol and 1,1,1-

1 , M. S. Newman and A. G. Pinlcus, J. Org. Chem,, 3^, 978 (1954).

trichloroethane were reacted in carbon disulfide. A 1.6 per cent

yield of the expected Zincke-Suhl product was isolated from the dark

polymer which formed on hydrolysis.

Mii,

+ C d j - C H 3 >

II O

In another study,^ trichloroacetonitrile and phenol were reacted

2. J. Houben and W. Fischer, J. prakt. chem., 123. 262 (1929).

with aluminum chloride in chlorobenzene to afford trichloromethyl 2“

hydroxyphenyl ketone (O). No yield was given.

OH 0 11

In a different study, the cyanohydrin of chloral was reacted

1. A. Chwala and H. Wassmuth, Monatsch., 81, 84.3 (1950). with phenol in the presence of aluminum chloride to afford j^-hydroxyphenyl trichloromethylacetic acid (P) in 60 per cent yield. The same product was obtained in 42 per cent yield by starting with anisole.

'"O C0.,CH(0H)C,N M a CH-COOM

cce.^ P 12

II. SYNTHESIS OF COHMARINS-*

1 . This section is not intended to be a complete review of synthetic methods for preparing coumarins. Rather, it is meant to provide a short resume of some of the methods used, with particular refer ence to the scope and limitations of the reactions discussed. Two excellent reviews on the topic are: (1) S. M. Sethna and N. M. Shah, Chem. Rev., ]6 , 1 (194-5)j (2) R. G. ELderfield, "Heterocyclic Compounds," Vol. II, John Wiley and Sons, Inc., N. Y., 1951, pp. 173-216.

A, From Phenols

1. Pechmann condensation. The Pechmann condensation has been found to have greater application for the synthesis of coumarins than any other method. This method involves the reaction of phenols vriLth

Ç-keto esters in the presence of a catalyst, usually sulfuric acid.^

2. H. Pechmann and C. Duisberg, Ber., 2119 (1883).

The course of the reaction is influenced by (1) the nature of the

t CU^CoCH^COoeb

phenol, (2 ) the nature of the ^-keto ester and (3) the condensing

agent.

Phenols with electron-donating groups, such as hydroxyl, methoxyl,

amino, alkylamino, dialkylamino and alkyl, in the meta position con

dense readily. 4--Ethylresorcinol^ reacts with acetoacetic ester to

3 . R. D. Desai and M. Ekhlas, Proc. Indian Acad. Sci., 567 (1938). 13 yield 80-85 per cent of Q. m-Cresol reacts readily with ethyl aceto-

acetate while phenol, o-cresol and p-cresol react with difficulty,^

1. K. Pries and W. KLostermann, Ber., 22.t ^71 (1906).

Similarly, it was found^ that m-diethylaminophenol condensed more

2. H. Pechmann and M. Schaol, ibid.. 32. 3681 (1899). readily than the isomeric o- and p- isomers. Anhydrous zinc chloride was used as the condensing agent.

Halogenated phenols are much less effective. m-Chlorophenol yields

6 per cent of the expected coumarin while only 3 per cent is obtained with p-chlorophenol . 3 o-Chlorophenol gives no coumarin. In the poly-

3 . A. Clayton, J. Chem. Soc., 2016 (1908). hydroxy benzene series, resorcinol, 5-methylresorcinol, pyrogallol, and phloroglucinol all react very readily, whereas hydroquinone and

catechol resemble phenol.^ o^-Naphthol^ resembles phloroglucinol in

4. H. Pechmann and E. Graeger, Ber., 378 (1901).

5. D. Chakravarti, J. Indian Chem. Soc., 8 , 4.07 (1931). u reactivity, vhereas -naphthol^ resembles phenol.

1 , D. Chakravarti, Proc. Indian Acad. Sci., 389 (1932).

2 Electron-attracting substituents in phenol prevent condensation.

2, A. Clayton, J. Chem. Soc., 2016 (1908). t'Jhen these groups are introduced into reactive polyhydroxybenzenes, they may depress or prevent condensation. This effect is greater in the A-position than in the 2-position. 2-Acetylresorcinol forms cou marins whereas A-acetylresorcinol does not.^

3, R. D. Desai and M. Ekhlas, Proc. Indian Acad. Sci., 567 (1938).

Other studies have shown that the qualitative order of electron-

attracting groups in regard to their deactivating effect is:

-ON -CHO -SO3H -COGH3 -NC^ -COOH -COOCH3

In addition to acetoacetic ester, various substituted aceto

acetic esters have been investigated. With reactive phenols, -methyl-,

ethyl-, propyl-, butyl-, allyl-, phenyl-, benzyl-, and p-methoxyphenyl-

acetoacetic esters will react fairly readily to form coumarins. With

the less reactive phenols, such as phenol, p-cresol, -naphthol, etc.,

the yield of coumarin, which is poor with the unsubstituted aceto

acetic ester, is further diminished as the bulk of the -allcyl sub

stituent increases.

Ethyl -chloroacetoacetate reacts with phenols to yield 15

3-chlorocoumarins.

1. B. B. Dey, J. Chem. Soc., 1606 (1915)J R. Robertson and W. F. Sandrock, ibid., 180 (1932); P. K. Grover, T. R. Seshadrl and S. Varadarjan, J. Sci. Ind. Research (India), llB. 50 (1952).

M ^ œ cÜ^cotHCOOàt

2-Carbethoxycyclohexanones and 2-carbethoxycyclopentanones^ are

2. N. A. Chowdry and R. D. Desai, Proc. Indian Acad. Sci., Bk, 12, (1928); R. D. Desai, i ^ . , 345 (1947). comparable to ethyl«X-methylacetoacetate in their behavior. Nega tively substituted alkyl acetoacetic esters, such as ethyl aceto- 3 succinate, are as reactive as, or even more reactive than, the

3. N. M. Shah and R. C. Shah, J. Indian Chem. Soc., 1^, 481 (1942).

corresponding unsubstituted o^alkylacetoacetic ester. With ethyl o(-cyanoacetoacetate4 or ethyl o^acetylacetoacetate,^ elimination of

4. A. Held, Compt. rend., 116. 720 (1893).

5. H. Pechmann and E. Hanke, Ber., 354 (1901).

the c<-substituted group occurs in the condensation. "^-Alkyl substi tuted acetoacetic esters, such as ethyl butyroacetate, react less 16 readily than the corresponding o<-alkyl acotoacetic ester.

1, N. G. Kotv/ani, S. M. Sethna and G. D. Adwani, Proc. Indian Acad. Sci., I5A, 441 (1942).

Negative groups, such as those in acetonedicarboxylic acid or its ester modify the reaction very little.^

2, V. M. Dixit, A. M. Kandutl and L. M. l'îulay, J. Indian Chem. Soc., 22, 207 (1945).

Coumarins with no substituents in the pyrone ring can be made from malic acid? ^-%droxybenzoic a c i d , 4 for example, yields

3. H. Pechmann, Ber., 17, 929 (I884); Y. Ito, H. Kitagowa, B. Tamaoki and S. Tsurufuji, J. Pharm. Soc. Japan, JO, 730 (1950).

4. D. Papa, E. Schwenk and H. F. Ginsberg, J. Org. Chem., 253 (1951).

11 per cent of 6-carboxycoumarin. Citric acid also condenses vd.th

HOOC C.UOM -h

phenols to give 4-substituted coumarins.^

5. S. C. Laskowski and R. 0. Clinton, J. Am. Chem. Soc., 72 , 3987 0-95O). 17

I ^ + HOCCOOH

By condensing ^-keto esters with phenols in the presence of phosphorus pentoxide,^ chromones, rather than coumarins, are obtained,

1. H. Simonis and co-workers, Ber,, 2014 (1913); 42» &92, 2229 (1914).

This, the Simonis reaction, has been widely studied and the following 0

^ ll HO -4- generalizations can be made:

a. Sulfuric acid as a condensing agent always gives a coumarin,

provided the reaction occurs,

b. Phenols which react readily in the presence of sulfuric

acid invariably give coumarins with phosphorus pentoxide.

c. Phenols which react with difficulty or not at all vriLth sul

furic acid give chromones with phosphorus pentoxide.

d. ^-Keto esters with a small (?(-alkyl substituent favor chromone

formation with phosphorus pentoxide. Negatively substituted

esters give coumarins in good yields, but if the substituent is

of a strongly negative character, it is eliminated. 18

e. Except for phosphorus oxychloride, phosphorus pentoxide is

1. A. Robertson and I. Goodall, J. Chem. Soc., 426 (1936).

the only condensing agent which promotes chromone formation.

Seventy-three per cent sulfuric acid is preferable to concen trated sulfuric acid as a condensing agent when sulfonation may take place easily. Anhydrous zinc chloride is the best reagent to use with aminophenols. It has also been used to condense phenols with cyanoacetic acid or ester.^ The intermediate imine can be hydrolyzed

2. I. Y. Postovskii and M. A. Panyukova, Zhur. Obschei Khim., 2 1 . 1717 (1951)? S. Iguchi, J. Pharm. Soc. Japan, 22, 122 (1952). vrith acid to the 4-hydroxy coumarin.

a s % R'

HO OH KO'

Other condensing agents that have been tried are hydrogen chloride in acetic a c i d 3 or in alcohol,'^ phosphoric acid, sodium ethoxide, boric

3. C. Bulow, Ber., 474 (1905).

4. H. Appel, J. Chem. Soc., 1031 (1935). anhydride, sodiim acetate,^ ferric chloride, stannic chloride and

5. D. Chakravarti, J. Indian Chem. Soc., 12, 536 (1935). 19 titanium chloride.^

1. Z. Horii, J. Hiarm. Soc, Japan, 52.» 201 (1939).

Anhydrous aluminum chloride has recently been used and has been found to give good yields and to promote condensation with compounds, such as phenol and o-cresol, which reacted poorly or failed with other 2 reagents.

2. S. M. Sethna, N. M. Siah and R. C. Shah, Current Sci., 6 , 93 (1937).

2. Miscellaneous condensations. Resacetophenone condenses with ethyl ethoxymethyleneacetoacetate^ in the presence of alcoholic sodium

3. R. Weiss and E. Merksammer, Monatsch., 52, 115 (1928). methoxLde to give R. This method has been extended to the similarly

COOH- [Hi + R substituted malonates.4

4. R. Weiss and A. Kratz, ibid.. 51. 386 (1929).

ïÿrogallol and c<-naphthol react with ethyl phenyl cyanopyruvate^

5. W. Borsche and U. T.annagat, Ann., 569. 81 (1950).

to yield coumarins. 20

eûOütr CAHfCH[cN)COCOO%:

OH OW HO

B. From Salicylaldéhydes

1. Perkin reaction. The first synthesis of coumarin was by

Perkin,^ who heated salicylaldéhyde with acetic anhydride and sodium

1. y. H. Perkin, J. Chem. Soc., 53 (1868); ibid.. 388 (1877). acetate. The intermediate salt of o-hydroxycinnamic acid spontaneously cyclizes upon acidification.

OH CH^COOUo^ ■OH COONlc^

This preparation is limited because the initial o-hydroxyaldehydes are difficult to obtain and the yields are poor. The poor yields may be ascribed to the formation of resins and/or to the formation of o-acetylcoumaric acids (S). The covmiaric acids or their esters may be

c o o w

OCOCH 21 converted to the els isomers, the ccumarinic acids, or directly into 1 o coumarins by ultraviolet light and iodine,"^ by sunlight, hydrogen

1. R. Stoermer, Ber., 637 (1911)j R. Stroemer and H. Ladewig, ibid.. 42, 1795 (1914).

2. B. B. Dey, R. H. Rao and T. R. Seshadri, J. Indian Chem. Soc., 11, 743 (1934). chloride in alcohol, mercuric chloride in water,^ sodium bisulfite^ or

3. T. R. Seshadri and R. H. Rao, Proc. Indian Acad. Sci., 46, 157 (1936).

4 . F. D. Dodge, J. Am. Chem. Soc., 2^, 446 (I9I6 ). sodium sulfite.5 The introduction of iodine^ into the reaction mixture

5. B. B. Dey and K. K. Row, J. Chem. Soc., 554 (1924).

6 . H. Yanagisawa and H. Kondo, J. Pharm. Soc. Japan, A72. 498 (1921). increases the yield of coumarin to 70 per cent.

Other fatty aliphatic acid anhydrides and salts may be substituted for acetic acid derivatives and give 3-substituted coumarins. Succinic anhydride and its sodium salt yields 24 per cent of 3-coumarylacetic acid. The reaction of N-acetylglycine with the diacetate of 5-hydroxy- salicylaldehyde gives a 27 per cent yield of T.*^

7. J. P. Lambooy, J. Am. Chem. Soc., 71, 3758 (1949). 22

moOy^Zs.,/^NHCOCH:! 0 0 ° T 2, Knoevenagel reaction. Good yields of 3-substituted coumarins can be obtained by condensing a salicylaldéhyde with ethyl malonate, ethyl acetoacetate, etc., In the presence of an organic base such as piperidine or pyridine.

The basic catalysts may affect the yield and products formed.

Malonlc acid with little or no added organic bases give 3-carboxy- coumarlns directly.^ lyrldlne as a catalyst causes a mixture of

1. A, A. Khan, P. H. Kurlen and K. C. Pandya, Proc. Indian Acad, Sci., lA, 4A0 (1935). coumarlc acid, sallcylldenemalonlc acid and unidentified products 2 to be formed. With aniline as the basic catalyst, a 53 per cent

2. K. C. Pandya and R. K. Pandya, ibid., ISA. I64 (1943). yield of 3-carboxycoumarln Is obtained.^ With malonlc acid derivatives,

3. H. Ichlbagase and S. Terada, J. Pharm. Soc. Japan, 72, 876 (1952). there Is no possibility for coumarlc acid formation and coumarins can often be obtained In good jdLelds. Diethyl malonate reacts with 3- and 5-substltuted salicylaldéhydes to give 6- and 8-substltuted-3- 23 ceurbethoxycotunarlns in 10-88 per cent yields.^ Other malonic ester

1, R. 0. Clinton and S. G. Laskowski, J. Am. Chem. See., 71, 3^02 (1949). derivatives react with 3-methoxysalicylaldehyde to give the correspond ing 3-substituted coumarins in 33-94 per cent yields.^

2. E. G. Horning and M. G. Horning, J. Am. Ghem. Soc., 968 (1947).

R C H x o o e f c D H C ^ H „ N o O M ^ O M J L

(R = G5H5GO, CH3GO, GN, GOOBb, GOGH^GGGEb)

Other less reactive compounds, such as glycine,^ which gives

3. K. G. Pandya and T. S. Sodhi, J. Univ. of Bombay, 8, 173 (1939).

3-aminocoumarin, benzyl cyanide, 4 which gives 3-phenylcoumarin andUJ-

4 . W. Porsche and F. Streitberger, Ber., 22» 3163 (1904).

cyanoacetophenone,5 which gives 3-benzoylcoumarin, enter into the

5 . S. G. Ghosal, J. Indian Ghem. Soc., 105 (1926).

reaction.

3. Reformatsky reaction. % using the Reformatsky reaction, 3-

methylcoumarin can be prepared in 16 per cent yield from salicylaldéhyde 24 and ethyl o<-bromopropionate.^ o-Methoxybenzaldehydes,^ in the same

1. L. Baldakowski, J. Russ. Rhys. Chem. Soc., J7, 902 (1905).

2. D. Chakravarti and S. A. Momen, J. Indian Chem. Soc., 338 (1943). reaction, give coumaric acids which do not cyclize upon treatment with hydrogen iodide.

C, From o-HydroxvDhenvl Ketones

1. Reformatslcy reaction. The Reformatsky reaction v/ith o-methoxy-

phenyl ketones, gives, upon dehydration and déméthylation, 4-sub-

stituted and 3,4-disubstituted coumarins. Ethyl o-methoxyphenyl o

HI e" I o coo<üo orA-a-

ketone gives a 30 per cent yield of 4-ethylcoumarin.^

3. Cocker, B, E. Cross, J. T. Edwards, D. S. Jenkinson and J. McCormick, J. Chem. Soc., 2355 (1953).

Chakravarti and I«Iajumdar4 concluded from a study they made that

4. D. Chalcravarti and B. Majumdar, J, Indian Chem. Soc., 136 (1938); 16, 389 (1939). 25

(1) when there are allcyl substituents in both the cX- and (^positions of the expected cinnamic acid, the cis acid is formed and can be easily cyclizedj (2) when there is no alkyl substituent in either the or

^position of the expected cinnamic acid, the trans acid which is ob tained resists cyclization.

2, Kostanecki-Robinson reaction. The condensation of an o- hydroxyaryl ketone v/ith an acid anhydride and the sodium salt of an acid is an uncertain method for preparing coumarins because the pro duct of the reaction may be the desired coumarin, an acyl derivative of the starting ketone, a chromone (U), a 3-acylated chromone,^ a

1. T. C. Chada, H. S. Mahal and K. Venkataraman, J. Chem. Soc,, U 5 9 (1933).

. U 4-acylmethylcoumarin,^ or a mixture of these. The product obtained in

2. S. M. Sethna and R. H. Shah, J. Indian Chem. Soc., 17, 487 (1940).

the reaction depends upon the v/ay in which water is lost from the

intermediate acyl derivative (V). iJith o-hydroxybenzophenones, only

4-phenylcoumarins are possible.^ If benzoic anhydride and sodium

3. F. W. Carter, A. R. I4artin and A. Robertson, J. Chem. Soc., 1877 (1931). 26

k ' c o k P - O H R ' c o o H Q

R — Ct, H <.~

benzoate are used, 2-phenylchromones^ are obtained. With other com-

1. J. Allan and R. Robinson, J. Chem. Soc., 2192 (1924). binations, the results -will depend upon the relative reactivities of the methylene groups involved.

Studies on o-hydroxyacetophenones (W) show that the yields of

Q. o V/ chromone increase as R changes as follows

2. T. G. Chada, H. S, Mahal and K. Venkataraman, ibid., 1459 (1933).

Thus, when R is phenyl, the chief product is the chromone and when R 27 is hydrogen, the coumarin predominates,^ V/hen the same o-hydroxy-

1. I. M. Heilbron, D. H. Hey, and B, Lythgoe, J. Chem. Soc., 1581 (1934). phenyl ketone is used, the formation of coumarin is increased as the higher acid anhydride and salts are used.^ Phenylacetic acid^ gives

2. A. B. Sen and T. N. Kakaji, J. Indian Chem. Soc., 22, 950 (1952).

3. I. M. Heilbron, D. H. Hey, and B. lythgoe, J. Chem. Soc.. 295 (1 9 3 6 ); V’. Balcer and F. M. Eastwood, ibid., 2897 (1929). mainly coumarins. The yields of 5,6-benzocoumarlns4 are good when

4 . A. B. Sen and T. K. Kakaji, J. Indian Chem. Soc., 2^, 127 (1952). alkyl 2-bydroxy-l-naphthyl ketones are used. c o c h e r . o OH o

3 . Miscellaneous reactions. 4-Hydroxycoumarins are formed in

excellent yields by the condensation of o-hydroxyphenyl ketones with diethyl carbonate.5

5. J. Boyd and A. Robertson, J. Chem. Soc., 174 (1948). 28

^OH Ncu/oo'

^llydroxyacetophenone condenses with ethyl cyanoacetate to afford a 79 per cent yield of 3-cyano-4.-inethylco'umarin.^

1. G. H. Schroeder and K. P. Link, J. Am. Ghem. Soc., 75., 1886 (1953).

OB o

D. From Salicyclic Acid Derivatives

Reactions of o-aceto%ybenzoyl chlorides with the sodinm deriva tives of ethyl acetoacetate, ethyl malonate or ethyl cyanoacetate produce 3-substltuted-4--hydroxycoumarins

2. R. Anschutz, Ann., ^62, 169 (1909); iMd., j68, 23 (1910); I. M. Heilbron and D. VI. Hill, J. Ghem. Soc., 1705 (1927); K. G. Ghosh, J. Indian Chem. Soc., 321 (1947); Y. Ishii, J. Agr. Chem. Soc. Japan, 26, 510 (1952).

o o.- L—OL a

(R = -GN, -GOCH» -GOOEt) 29

o-Acetoxybenzoyl chloride reacts with ethyl phenylacetate in ether in the presence of sodium triphenylmethyl to give a $6 per cent yield of (X), which cyclizes to ^-hydroxy-3-phenyl coumarin in O

(jfca>.coo^ cooêJt Opic

66 per cent yield when treated with sodium carbonate in absolute ethanol.^

1. B. S. midi, J. Qrg. Chem., 16, 4-07 (1951).

4.-Hydroxycoumarins are formed when methyl acylsalicylates 2 undergo Claisen condensation. The yields range from 7-30 per cent.'^

2. A. Muller, R. Syrovatka and E. masak, Monatsch., 81, 174 (1950) j K. 0. Ghosh, J. Indian Chem. Soc., 2^, 323 (194^717 M, A. Stahmann and K. P. link, Brit. Pat. 578,589, 1946.

O (\ , 0 - 0 O

E. Miscellaneous Starting Materials

1. o-Bromobenzoic acids. o-Bromobenzoic acid may be coupled with resorcinol to give 7-hydroxy-3,4-benzocoumarin in 52 per cent yield.^

3. R. Adams, D. C. Pease, J. H. Clark and B. R. Baker, J. Am. Chem. Soc., 62. 2197 (1940) J R. Mams, C. K. Cain and B. R. Balcer, ibid., 62. 2201 (1 9 4 0 ). 30

2. Quinones. Tetramethyl-£-quinone, when treated with ethyl sodio- malonate in benzene, forms a dihydrocoumarin which is usually dehydro

genated to a coumarin during the reaction.^ This reaction is success-

1. L. I. Saith and F. J. Dobrovolmy, J. M. Chem. Soc,, 1^93 (1926).

fui for 2 ,3-dlmethyl-1 ,^-naphthoquinone,^ bromotrimethylquinone,^

ethyltrimethylquinone^ and dibromo-m-xyloquinone.^

2. L. I. anith and I.M. Webster, ibid.. 59. 662 (1937).

3. L. I. Smith and P. F. Wiley, ibid.. 6Û, 887 (1946).

4. li. I. Snith and J. W. C^ie, ibid., 62, 932 (1941).

5. L. I. anithand D. J. Byers, ibid.. 6 3 . 612 (I94I).

3 . From o-('K-chloroallyl'jphenol ethers. A lengthy method for pre

paring coumarins from o-(^-cl:iloroallyl)phenol ethers has been

reported.^ This method involves converting, by either of two methods,

6 . L. Bert, Compt. rend., 214. 230 (1942).

the o-(^-chioroallyl)phenol ether into an ether of o-hydroxycinnam-

aldehyde and then oxidizing it to the cinnamic acid and cyclizing the

acid to the coumarin. 31

o R/

OR, < r

CH^CUft-vCRÔTuOl C,ri=:C.HûHiDR,

j N c ^ O R , '

oÇL 0(x,

CM' Ok=6M(LH^UL

L_w V rf^°^ m i a j jw

tltrC-AtOOt^ j H 8 v

4. From non-armatic compounds. VJhen ethyl isodehydroacetate (Y) is treated with cold sodium methoxide in alcohol, ethyl 3-acetyl-4., 5,7- trimethylcoiHnarin-6,8-dicarboxylate is obtained in 30 per cent yield.^

1. L. A. Jordan and J. F. Thorpe, J. Chem. Soc., 387 (1915). 32

A & t O H & Mo, V ^ " o C O O et

Y / V o u O ^

cocii & 0 0 c e o c H ^

fLoo'e^j

c o o t t 33

III. SYNTHESIS OF 3- AND 4-HAL0G0UI4ARINS

Substituted 3-chioro-^-methylcoumarins have been prepared from phenols and ethyl cs<-chloroacetoacetates by the use of the Pechmann reaction,^ 3-Chloro- and 3-bromo-A-carbethoxycouitiarins have been

1. This dissertation, p. I4 . prepared by the Pechmann reaction of phenol with the corresponding diethyl oxalohaloacetate,^ The yields were 15 per cent,

2. E. H. Huntress and R. T. Olsen, J. Am. Ghem. Soc., 22» 2831 (194-8).

0 0 0 tfc 0 ta

3-Bromocoumarins can be prepared directly from the coumarins by bromination. Goumarin adds bromine and forms a dibromide (Z) which

easily loses hydrogen bromide and forms 3-bromocoumarin.^ The use of

3. W. H. Perkin, Ann., I57, 115 (1871).

N-bromosuccinimide for the preparation of 3-bromocoumarins has been 34 demonstrated.^ If the 3-position is occupied by a methyl or ethyl

1. D, Mblho and C. Mentzer, Compt. rend., 223. 1141 (1946).

group, theo^-carbon atom of this group will be bromiDated by N-

bromosuccinimide.

3-Chlorocoumarin has been prepared by passing chlorine into 2 molten coumarin and by passing chlorine into a carbon tetrachloride

2. W. C. Stoesser and E. H. Sommerfield, U. S. Pat. 2,562,873, 1951.

solution of coumarin followed by dehydrohalogenation of the dichloride

with sodium carbonate, sodium bicarbonate or ammonium h y d r o x i d e . 3

3. J. C. Heath, S. Z. Cardon and H. S. Halbedel, U. S. Pat. 2,466,657, 1949.

Coumarin can also be chlorinated in tetrachloroethane or pentachloro-

ethane, followed by a dehydrohalogenation with p r o p a n o l . 4

4. H. S. Halbedel and J. C. Heath, U. S. Pat. 2,478,824, 1949.

3-Bromo-4-hydroxy coumarin has been prepared in almost quantita- 5 tive yield by the bromination of 4-hydroxycoumarin in absolute ethanol.

5. H. R. Eisenhauer and K. P. Link, J. Am. Ghem. Soc., 76, 1647 (3-954).

The use of chloroform as a solvent decreases the yield to 62 per cent.^

6. C. F. Huebner and K. P. Lihlc, J. Am. Chem. Soc., 99 (1945). 35

Chlorination of 4-hydroxycoumarin in acetic acid yields a mixture of 3-chloro-4-hydrox5’'couinarin and starting material if equimolar quan tities of chlorine and coumarin are used. With an excess of chlorine,

A ’ and B* are obtained in addition to the expected product,^ 3-Chloro-

1. G. Mentzer and P. Meunier, Compt. rend., 225. 1329 (1947).

OH A/

4-hydroxycoumarin can best be made by reflux!ng 3-bromo-4-hydroxycoumarin with concentrated hydrochloric acid.^

2. F. Arndt, L. Loewe, R. Un and E. Ayca, Ber., 8 4 , 319 (1951).

4-Halocoumarins are prepared by treating 4-hydroxycoumarins with phosphorus pentahalides.^ A 4-bromocoumarin has been prepared by the

3. R. Anschutz, Ann., 367. I69 (1909)j R. Anschutz, J. Wagner and P. Junkersdorf, ibid., 367. 253 (1909); C. Mentzer and P. Meunier, Bull. soc. chim., 356 (1943); D. P. Spalding, H. S. Mosher and F. C. Vlhitmore, J. An. Chem. Soc., % , 5338 (1950). cyclization of ^ -bromo-^ ( 3-chloro-2 ,4 -dimethyl-6-methoxyphenyl ) - acrylic acid.^

4 . R. Adams and R. S. Ludington, ibid., 67. 794 (1945). 36

K\iî-

H B n , OOOH 0-c.OH O M t .

In all of the known methods of preparation of coumarins, no method yields 3 ,A-dihalocoumarins and no 3 ,^-dihalocoianarins have ever been reported in the literature. 37

IV. SUBSTITUTIONS OF 4-HALOCOUI'IARlNS

4.-Halocoumarins can be reacted with organic bases to afford

^.-substituted coumarins.

a ^ B

B--H " 4- H C & . •o

3-Carbethoxy-4.-chlorocovimarin reacts with sodium ethoxide, aniline and phenylhydrazine.^ The corresponding 4-bromo compound

1. R. Anschutz, Ann., 367. 219 (1909). reacts with aniline and piperidine. Other organic bases that react with 4--halocoumarins include sodium methoxide, ethylamine and p- toluidine. ^-Ghlorocoumarin, with morpholine, affords a 71 per cent yield of 4- (A-morpholinyl)coumarin.^

2. D. P. Spalding, H. S. Mosher and F. C. VJhitmore, J. Am. Chem. Soc., 72, 5338 (1950).

There are no known reactions of 3-halocoumarins similar to the

displacement reactions of A-halocoumarins. DISCUSSION OF RESULTS

I. PREVIOUS WORK BY PINKUS^

1. A. G. Pinkus, private communication.

The reaction of j)-cresol and hexachloropropene in carbon di sulfide in the presence of aluminum chloride followed by hydrolysis produced a light gray amorphous material from wliich a compound (I),

(^10% % ( ^ ^ 2 ) m.p. 1 6 1 .0-1 6 2 ,2 °, was obtained by vacuum sublimation.

The infrared spectrum showed strong carbonyl absorption and no ab sorption in the hydroxyl region.

Attempts to prepare carbonyl derivatives of I failed. I failed to react vri.th ferric chloride, alcoholic silver nitrate, bromine in carbon tetrachloride and potassium permanganate. I was reported to be insoluble in 10 per cent sodium hydroxide, even on heating, but to react vrf.th alcoholic potassium hydroxide with the precipitation of potassium chloride. No organic product was isolated from this reac tion. Oxidation of I vdth sodium dichromâte in sulfuric acid afforded a white, chlorine-containing compound which was soluble in sodium bicarbonate solution and which was still inert to alcoholic silver nitrate. These results indicated the oxidation of the methyl group from the p-cresol to a carboxyl group.

On the basis of this work, Pinkus considered I to be one of four compounds: 3,A-dicliloro-6-methyl coumarin (I), 3-dichloromethylene-6-methylcoumarane-2-one (II), 2,3-dicliloro-6-methylchromone

38 39

(III), and 2-dichloromethylene-6-methylcoumarane-3-one (IV). Because

I IL

HE of the lack of reactivity i-d.th alkali, Pinlcus suggested that III and

IV were the most probable. 40

II. DETERMENATION OF STRUCTURE OF I

Upon repeating the qualitative tests mentioned in the preceding

section, the same results were obtained in all instances except one.

When I was swirled in warm 10 per cent sodium hydroxide, solution was

effected and a red color developed. Acidification of this solution

produced a solid different from starting material. This solid could

not be re-converted to I. Therefore, the possibility of a lactone

structure such as I or II was considered.

Catalytic and chemical reductions of I were unsuccessful. A

compound (V), C^gH^C^Clg, was obtained upon oxidation of I with sodium

dichromate in sulfuric acid. This confirms Pinkus' suggestion that a

methyl group had been oxidized to a carboxyl group.

At that stage of the work, it was thought that if phenol would

react vd.th hexachloropropene to form 3 ,A-dichiorocoumarin (VI), it migib

later prove more fruitful to compare known compounds with products C d •Cl

ÏÏL derived from VI rather than with products derived from I. Accordingly,

phenol was reacted with hexachloropropene to yield VI, CgH^C^Clg,

m.p. 106.7-107.5°. On the basis of their infrared spectra and chemical

reactivity, I and VI were deemed to be homologs.

When VI was reacted \d.th two equivalents of sodium methoxide in 41 absolute methanol, a compound (VII), (X, H-,^0^,, m.p. 75.4-76.8°, was obtained. This suggested that the chlorines in VI had been replaced by methoxy groups.

CgH^C^Cl2 ^NaOCHg^ (OGH^)^^ 2 Nad

A literature search revealed that both 3,4-dimethoxycoumarin, m.p. 80°, and 2,3-dimethoxychromone, m.p. 85°, were known.^ The

1. F. Arndt, L. Loewe, R. Un and E. Ayca, Ber., 319 (1951). proximity of these melting points to that of VII suggested the need for comparison. A mixed melting point of VII with 3,4-dimethoxycou- 2 marin showed no depression. The infrared spectra of the two samples

2. Gratitude is expressed to Dr. Arndt, from whose laboratory in Istanbul, Turkey, was obtained a sample of 3,4-dimethoxyconmarin and to Dr. Loewe, who forwarded the sample at the request of Dr. Arndt, who was out of the country at the time. No sample of 2 ,3-dimethoxychromone was available. were identical.

Since VII was known to be 3 ,4-dimetho;xycoumarin and was prepared from VI by sodium methoxide treatment, it seemed likely that VI was

3,4-âichlorocoumarin. However, it was still possible that VI was

2,3-dichlorochromone and had been converted to a coumarin during the reaction with sodium methoxide. The coumarin and chromone ring systems

are interconvertible under some conditions.^ 2,3-Dimethoxychromone reacts with sulfuric acid to form 3 ,4 -dibydroxycoumarin and 3-chloro- 42

4-hydroxycoumarin, while with diazomethane, it yields not only the expected 3-chloro-4.-methoxycoumarin but also 3-chloro-2 -methoxy- chromone. For this reason, additional proof of the structure of VI was sought. This proof was provided by an independent synthesis of

3 ,4-dichJLorocoumarin.

OCOCH 3

COCH _Q_ 3 ~OH

1)6 a ) H c s ,

P C a

o-Hydroxyacetophenone, obtained by the Fries rearrangement of 43 phenyl acetate,^ condensed with diethyl carbonate and sodiim^ to yield

4-hydroxycoumarin. 4-Bydroxycoumarin was brominated^ and the resulting

1. E. Miller and W. H. lîartung, Or g. Syn., Vol. II, 543 (1943).

2. J. Boyd and A. Robertson, J. Chem. Soc., 174 (1948).

3. C. F. Huebner and K. P. Linlc, J. Am. Chem. Soc., 6%, 99 (1945).

3-bromo-4-hydroxycoumarin ims converted to 3-chloro-A-hydroxycoumarin by refluxing with concentrated hydrochloric acid.^ By treating

4. F. Arndt, L. Loewe, R. Un, and E. Ayca, Ber., 8 ^ 319 (1951).

3-chloro-4-hydroxycoumarin %d.th phosphorus, oxychloride and dry pyridine, an 87 per cent yield of yellow product, m.p. 100-104-°

(uncor.)> was isolated. By means of chromatography, a 60 per cent yield of 3,4-dichlorocoumarin was obtained which was shown, by mixed melting point and infrared spectra, to be identical with VI.

As a final check on the structure, the infrared spectra of 3,4- dichlorocoumarin, coumarin,^ 3-bromo-4-hydroxycoumarin, 3-chloro-4.-

5. Merck and Co., Rahway, New Jersey. hydroxycoumarin and 3,4-dimethoxycoumarin were compared and shown to be similar to each other and different from that of 6-methylchromone.^

6. Prepared from 2-hydroxy-5-methyl-acetophenone and ethyl formate by method of R. Mozingo, Org. Syn., Vol. 21, 42 (1941 ); the acetophenone was prepared from p-tolyl acetate by method of K. Fries and A. Finck, Ber., 4I, 4271 (1908). UK

Carbonyl absorption in the infrared is reported^ at 5.70-5.90 microns

1. E. Knoblock and F. Prochazka, Chemicke Listy , % 1285 (1953). for coumarins and at 6.00-6.10 microns for chromones. All of the coumarins listed above have carbonyl absorption in the range of

5 .76-5.89 microns, whereas 6-raethylchromone absorbs at 6.02 microns.

The coumarins also have a very small absorption peak or shoulder at a

Table 1

Carbonyl Absorption in Infrared

Compound Max., microns

3,4-dichlorocoumarin 5.76

3-chloro-^-hydro%ycoumarin 5.87

3-bromo-4-hydroxycoumarin 5.89

3,4“dimethoxycoumarin 5.85 coumarin 5.78

6-methylchromone 6.02 wave length just below that of the carbonyl peak. The location of the carborçrl absorption peak and the presence of the characteristic shoulder on this absorption band was used in later work to verify the formation of coumarins, rather than chromones, in Ik*iedel-Crafts reactions involving other phenols. 45

Thus, 3,4-dichloroooumarln was synthesized and was shown, by means of a mixed melting point and a comparison of spectra, to be identical with VI. Since I and VI are homologs, I is 3,4-dichloro-

6-methylcoumarin. 4-6

III. STUDY OF REACTION CONDITIONS FOR PM5PARING 3 ^^.DICHLOROCOUl-IARINS

The early yields of 3 ,4-dichlorocotimarin and 3,A-dichloro-6- methylcoumarin were loif. The best yield of the former compound was

28 per cent while, until very recently,^ the best yield of the latter

1, A 72 per cent yield of 3,4--diohlorocoumarin has been obtained by very careful sublimation. This experiment is described in the Experimental section. compound was 52 per cent. It was believed that the yield of coumarin might be increased by varying the reaction conditions. Unfortunately, phenol was chosen as the compound to study. It was soon discovered that almost any change in the reaction conditions or in the workup either lowered the yield or resulted in intractable tars. In order to extend the reaction to other phenols, g-chlorophenol had been reacted with hexachloropropene. The product, 3,4-,6-trichlorocoumarin, could be purified without resorting to sublimation. This pointed out the possibility of using p,-chlorophenol as the substrate while study ing the effect of varying the reaction conditions.

Carbon disulfide was used as solvent throughout because of its high volatility and consequent ease of removal by aspiration. Dry benzene was used as a solvent once, but only tar resulted. Since the reaction seemed to involve first the formation of a salt formed from the phenol and aluminum chloride, it was thought best not to alter the order of addition. Thus, the only variation of conditions was the ratio of reactants and time the reaction was allowed to proceed before hydrolyzing. All reactions were run at room temperature. The 4.6a results of this study are summarized in Table 2.

The use of equimolar quantities of p-clilorophenol, hexachloro propene, and a 10 per cent excess of catalyst, afforded yields of

52 per cent, 57 per cent and 65 per cent as the reaction time was increased from 20 to 25 to 30 minutes. Allowing the same quantities to react for 2 hours increased the yield to 74 per cent. l.hen a

50 per cent excess of he:cachloropropene was used, with a 20 minute reaction time, the yield was 74 per cent. Unreacted hexachloropro pene was detected.

I'-hen equimolar amounts of the phenol and hexachloropropene were reacted with 2.2 equivalents of aluminum chloride for only 15 minutes,

77 per cent of trichlorocoumarin was obtained, whereas after 2 hours, a 90 per cent yield was obtained. A final reaction, using equimolar amounts of p-chlorophenol and hexachloropropene and a 60 per cent excess of aluminum chloride, afforded an 86 per cent yield of tri chlorocoumarin after reacting 50 minutes.

The best yield was obtained when 2,2 equivalents of aluminum chloride was used and the reaction was run for 2 hours. However, the slight gain in yield over that obtained when only a 60 per cent excess of catalyst was used does not v/arrant the use of the addi tional aluminum chloride. But it does appear as though somewhat more than an equivalent amount of catalyst is required. Also, it seems best to let the reaction run as long as gas is being liberated in order to ensure the maximum yield of coumarin. 47

Table 2

Yields of 3,4>6-Trichlorocoumarin Obtained Under Various Conditions^

£-chlorophenol C3CI6 A1 C13 time^ % yield (moles ) (moles) (moles) (minj

0.103 0.103 0.113 20 52

0.10 0.10 0.11 25 57

0.10 0.10 0.11 30 65

0.10 0.10 0.11 120 74

0.10 0.15 0.11 20 74

0.10 0.10 0.22 15 77

0.10 0.10 0.22 120 90

0.030 0.030 0.048 5q 3 86

1. The procedure giving the best yield is reproduced in the Experi mental section.

2. Time is measured as of the beginning of the dropwise addition of hexachloropropene, which usually required ten minute^ to the beginning of aspiration of carbon disulfide.

3. Reaction allowed to stir only as long as gas evolved. 48

IV. REACTION OF HEXACHLOROPROPENE T-JITH OTHER PHENOLS

A study was made to determine the scope of this Friedel-Crafts reaction of phenols and hexachloropropene. Table 3 summarizes the results of this reaction with phenols which yield coumarins or trichloroacrylic esters of phenols. The latter products will be dis cussed later in more detail.

In several of the runs with p-chlorophenol, p-chlorophenyl trichloroacrylate (VIII) was isolated as a side product. The struc-

ture of VIII was shown by analysis and by comparing it with the 2,4-- dichlorophenÿL trichloroacrylate (IX) obtained when 2,4-dichlorophenol

IK was reacted with hexachloropropene. The best yield of p-chlorophenyl• trichloroacrylate was % per cent.

VJhen 2,4-dichlorophenol was reacted, a 4-6 per cent yield of

3,4,6,8-tetrachlorocoumarin was obtained. In addition, the reaction yielded 18 per cent of IX, CgH^OgGlg, m.p. 94.8-95.3°. Saponification of IX with aqueous sodium hydroxide afforded a 52 per cent yield of 49

Table 3

Yields of Coumarins and Trichloroacrylatea

Phenol Goumarin % coumarin % trichloro- acylate

Phenol 3,4-dichloro^ 28

E-cresol 3,4-dichloro-6-methyl^ 72

2rinethoxyphenol 3,4-dichloro-6-methoxy^ 4.1

£-chlorophenol 3,4,6-trichloro 90 2.4 m~chlorophenol 3,4,7-trichloro^ 18 o-chlorophenol 3,4,8-trichloro^ 1.6

2 ,4-dichlorophenol 3,4,6,8-tetrachloro 46 18

3,4-dichlorophenol 3,4,6,7-tetrachloro 69

2,4,5-trichlorophenol 26

3-methyl-4“Chlorophenol 3,4,6-trichloro-7-methyl 85

^-bromophenol 6-bromo-3,4-dichloro 44

1. % sublimation; before sublimation, product left an ash on ignition.

2, By extraction from large amount of tar. 50 trichloroacrylic acid. The infrared spectmm indicated that IX was 2,4.-dichlorophenyl trichloroacrylate. This structure was con firmed by comparison of IX with an authentic sample prepared by acylation of 2 ,^-dichlorophenol with trichloroacrylyl chloride.

IJhen 3,4.-dichlorophenol was used, a 69 per cent yield of X,

C9H3 O2CI5, was obtained. Since the starting phenol was unsymmetrical and both positions ortho to the hydroxyl group were unoccupied, it was possible that the product was either 3,4-, 6,7-tetrachlorocoumarin WL ^ QSL Cl ^ ^

• e oO' ‘O X Xo. (X) or 3,4,5,6-tetrachlorocoumarin (Xa). A similar isomer problem was

encountered when hexachloropropene was reacted with 4-cbloro-3-^ethyl- phenol and with m-chlorophenol. 1-3.th 4-Ghloro-3-methylphenol, both

7-methyl-3,4,6-trichlorocoumarin (XI) and $-methyl-3,4,6-trichloro-

coumarin (XIa) are possible and with m-chlorophenol, the product might ÜL M-a- Cl

M&- 'O o I Xf be either 3,4,7-trichlorocoumarin (XII) or 3,4,5-trichlorocoumarin

(Xlla). 51

e t e t QSL a

a X The structures assigned to the coumarins obtained from these three phenols were indicated by the fact that sulfonation of 3,4-- didhlorophenol,^ 4--chloro-3-methylphenol,^ and i^chlorophenol^ yields,

1. W. F. Beech, J, Chem., Soc., 23.2 (194-8).

2. R. F. von Walther and K. Demmelmeyer, J. prakt, Chem., g2, 107 (1915).

3. H. H. Hodgson and A. Kershaw, J. Chem. Soc., 141-9 (1930). respectively, 4-»5-dichloro-2-hydroxybenzenesulfonic acid, 5-chloro-2- hydroxy-4-raethylbenzenesulfonic acid and 4--chloro-2-hydroxybenzene-

sulfonic acid. Since it was assumed that the reaction of hexachloro propene with these phenols would occur at the same position, the

coumarin obtained from 4-chloro-3-methylphenol is assumed to be XI and the product obtained from m-chlorophenol is assumed to be XII.

1'Jhen m-chlorophenol was used, sublimation was required to isolate

any product from the gray-brown material which was obtained upon hydrolysis of the reaction mixture. This gray-brown material left

an ash on ignition and could not be recrystallized.

The reaction of o-chlorophenol and hexachloropropene also

produced a product which left a large amount of residue on ignition. 52

However, only a 1.6 per cent yield of 2,4.,8-trichlorocoumarin was obtained by sublimation,

2 -Bromophenol was run to determine if any halogen exchange would occur during the aluminum chloride-catalyzed reaction. Although the analysis of the 6-bromo-3,4.-dichlorocoumarin, obtained in 44 per cent yield, was 0,8 per cent low in bromine, the carbon, hydrogen and chlor ine analyses were good, indicating that there had been no appreciable halogen interchange.

IJhen 2 -methox5’phenol was reacted with hexachloropropene, a dark polymeric material was obtained. A 4.1 per cent yield of 3,4-dichloro-

6-methoxycoumarin was obtained from this dark material by means of extraction. No visible Friedel-Crafts reaction occurred at room temperature and it was necessary to heat the reaction mixture to 60° for 45 minutes for even a slight amount of typical Friedel-Crafts coloration to develop.

Attempts to obtain coumarins from the reaction of hexachloro propene with other phenols failed. The results of these reactions with other phenols are summarized in Table 4* Some of the phenols gave no visible reaction with aluminum chloride and unreacted phenol was recovered. Hie remainder of the phenols reacted to form tars or colored materials which left an ash on ignition. Tliese colored sub stances, which were probably metallic complexes of organic substances, resisted all efforts to extract organic material from them. 53

Table 4

Reaction of C^Cl^ with Phenols 1-Jhich Didn’t Give Coumarins

Phenol Results g-nitrophenol no reaction with AICI^J phenol recovered

4-chloro-2-nitrophenol no reaction with AlCl^j phenol recovered resorolnol no reaction with AlCl^; phenol recovered

(i-naphthol no reaction with AlCl^; phenol recovered

£-phenylphenol no reaction with AICI^J phenol recovered p-phenylphenol^ blue solid; left ash on ignition; no organic material o<-naphthol black solid; left ash on ignition; no organic material l-chloro-2-naphthol reaction occurs; 1 % yield of ^-naphthol isolated p-t-butylphenol tar; 44^ of 3,4-dichlorocoumarin obtained by sublimation m-methoxyphenol tar

1,4-dichloro-2-naphthol tar

1. Ghlorobenzene solvent. 54

A study of Tables 3 and 4 shows that the best yields of 3,4- dichlorocoumarins are obtained from para-substituted phenols, especial ly 2-chloro-and p-methyl phenols. A nitro group on the molecule deactivates the phenol, Wethoxy phenols cause tar formation. p-Phenylphenol and naphthols, if they react at all, also yield tars. 55

MECHANISM OF COHMARIH FOK-IATION

From the study of the aluminum chloride-catalyzed reaction of phenols with hexachloropropene, mechanisms may be suggested to ex plain the facts.

As the reaction is run in the laboratory, a solution of the phenol in carbon disulfide is added to a slui’ry of aluminum chloride in carbon disulfide, with the resulting evolution of approximately one mole of hydrogen chloride. This gas evolution obviously signi fies the formation of the dichloroaluminum-phenolate salt (XIII).

[cKLCt^ X

The phenolate ion can be written in the following resonance

structures and has been shown to react as though all these forms were

present. Reaction through XIV is indicated by the fact that bromin-

ation of 3,$-dlchloro-p-cresol and carbon tetrachloride id.th aluminum

chloride present yields the carbonate of 2,6-dibromo-3,5-dichloro-p-

cresol (XVIIAlso, tetrabromo-p;-cresol^ yielded the trichloromethyl

1. T, Zincke and R. Suhl, Ber., 32.» 414-8 (1906). 56

ether when reacted with carbon tetrachloride and aluminum chloride.

M t M.L.

B IV y B n / c a ^

OH O G O L ^

Evidence for reaction at the ortho position was shoifn in the aluminum chloride-catalyzed reaction of g-cresol with benzotrichloride.^

1. M. S. Newman and A. G. Pinkus, J. Org. Chem,, 985 (1954).

2-Hydro3qr-5-methylbenzophenone was one of the products isolated from the reaction. VJhen o-cblorobenzotrichloride was used, the xanthone

Hit-

Q '^^COCfcHs-.(J. OH

(XIX) was obtained, probably from cyclization of XVIII.

2. Ibid., p. 996. 57

ûl

S 2 I Evidence for reaction of the phenolate ion in the para position is provided by the fact that the Zincke-Suhl reaction of p-cresol with carbon tetrachloride yields 4--methyl-4— trichloromethyl-2,5- cyclohexadienone

1. T. Zincke and R. Suhl, Ber., 22.» 4-14-8 (1906): M. S. Newman and A. G. Pinkus, J. Org. Chem., l^, 978 (195A).

Since the phenolate ion XIII exhibits reactivity at four positions, all forms of this resonating anion must be considered for subsequent

reaction of XIII. It is therefore possible that the dichloroaluminum-

phenolate salt, upon reacting with hexachloropropene, can yield either

the pentachloroallyl phenyl ether XX or the o- or pentachloroallyl-

phenol (XXI and XXII, respectively).

XXII, of course, cannot cyclize to a coumarin. The frequent

formation of tars from those phenols which have a free para position

may be due to the presence of the phenolic group, the allylic double

bond or the benzylic chlorines on the side chain of XXII. 58

ca.îCce-caj.. COL f d m C.CSJk. 'O oi.ca^

m z %

H £?■ ^ C L

ccs.^ C% OW: + a&c&: x z XXT

h^Œ^f,a=ca^ CCP_a,COLzC%

^ (UL& a ë +QÊffi; OH

E2 XX When a para-substltuted phénol is used, the reaction of hexachloropropene at the para position of the phenol would produce XXIII. R._CaaCCSl=CC!L3,

: m 59

XXIII is similar to the 4--methyl-4.-trichlcromethyl-2,5-chclohexadienone obtained from the Zincke-Suhl reaction^ of g-cresol and carbon tetra-

1. T. Zincke and R. Suhl, Ber., 22» 4148 (1906).

asia-.

chloride. Since no product of structure XXIII was isolated, it can be assumed that when a para-substituted phenol is reacted 'vn.th hexa chloropropene, reaction at the ortho position or at the oxygen is preferred to reaction at the para position.

The only para-substituted phenols which produced tars or complexes were p-phenylphenol, l-chloro-2-naphthol, and l,4 -dichloro-2-naphthol, all of which can transfer the negative charge through the para posi tion to the other ring. In these cases, reaction with hexachloro propene would still produce a product susceptible to polymerization and comolex formation.

O a

) 60

Thus it appears that phenols with no para substitution prefer

to react with hexachloropropene at the para position and afford tars and some type of colored complex which leave a residue on ignition.

However, para-substituted phenols react to yield primarily coumarins.

The dichlorocoumarins appear to be formed via XXI, which may arise

in two vra.ys. Reaction of hexachloropropene with the phenolate ion

in the ortho position yields XXI directly, whereas reaction of the phen

olate ion on the oxygen yields an allyl phenyl éther (XX) which may

undergo a Glaisen rearrangement to XXI.

XX In the alkylation of the phenoxide ion with allyl chloride,

both 0- and C(ortho)-allcylation occurs.^ However, rearrangement of

1. L. Claisen, F. Kromers, F. Roth and E. Tietze, Ann., XX2. 210 (1925).

the 0-allyl product to the C-allyl product requires high temperature.^

2. R. Adams, W. E. Bachmann, L, F. Fieser, J. R. Johnson, H. R. Snyder, Org. Reactions, Vol. II, John Wiley and Sons, N. Y., 1944, P. 2.

Ko study has yet been made to determine the temperature require

ments for the rearrangement of polyhaloallyl phenyl ethers or to

determine the effect a catalyst, such as aluminum chloride, might

have on the temperature of rearrangement. 61

The isolation of the polychlorinated phenyl acrylates, such as

2-chlorophenyl trichloroacrylate, in several of the Friedel-Crafts reactions, shows that reaction of the phenolate ion at the oxygen does occur to jdeld XX, which, on hydrolysis, produces trichloroacrylates. Trie fact that 2,4.-dichlorophenyl trichloroacrylate can be cyclized, with aluminum chloride in carbon disulfide, to 3 ,4 ,6 ,8-

tetrachlorocoumarin in 5 per cent yield indicates that the coumarins

OiOfi

'OLOCC&JiClP.

may be formed from XX. Since the acrylate is never present in the

reaction mixture, it is possible that XX readily forms a coumarin,

wliile the acrylate, the hydrolysis product of XX, reacts very slowly.

Mother explanation for the presence of the acrylate in the

reaction mixture is that competitive reactions are occurring.

Reaction of phenol at the ortho position leads to 3,4-dichloro coumarin

by cyclization of XXI, while reaction at the oxj’'gen yields an inter

mediate which affords the ether XX and on hydrolysis yields the ester.

As the starting phenol varies from the p-chloro- to the 2,4-dichloro-

to the 2 ,4 ,5-trichlorophenol, the competition shifts from mostly

coumarin formation to mostly acrj’'late formation.

Cyclization of XXI to a coumarin may occur in the following manner.

Reaction of XXI with aluminum chloride produces another dichloro-

aluminumphenolate salt (XXffH) which cyclizes to the tetrachloro- 62

m z

“S,»,

XX2 benzopyran XXVI3I, Hydrolysis of the dichloromethylene group of XXVIII yields a dichlorocoumarin.

Thus, the follov/ing mechanism may be suggested.

1. The initial reaction between the phenol and aluminum chloride

proceeds to form a dicliloroaluminum-phenolate salt.

2. 3, /^-Dichlorocoumarins are formed from ^-substituted phenols

by way of o-pentachloroallylphenol. This can occur by either

of two sequences: (a) the reaction of hexacliloropropene at

the ortho position of the phenolate ion forms o-pentachloro

allylphenol, wliich undergoes an aluminum chloride-catalyzed

cyclization to the 3 ,4-dichlorocoumarin; (b) the reaction of

hexachloropropene at the oxygen of the phenolate ion forms

pentachloroallyl phenyl ether which undergoes a Glaisen re

arrangement to the o-pentachloroallylphenol which in turn

cyclizes to the 3 ,4-dichlorocoumarin. 63

3 . Hienyl trichloroacrylates are formed by the hydrolysis of

pentachloroallyl phenyl ethers.

4-. % e n the para position of the phenol is unsubstituted, further

reaction of the dichloroaluminur^henolate salt with hexa

chloropropene seems to jjredominate at the para position.

Reaction throu^v this position produces a product which cannot

cyclize to a coumarin and hence seems to form tars or complexes

which leave an ash on ignition. 64

VI. REACTION OF 3,4-DICHLOROCOlIl-îAHINS TOTH BASES

A. Reaction with Organic Bases

3,4-Dichloroconmarin and 3,4-dichloro-6-methylcoimiarin are susceptible to nucleophilic substitution reactions. One or both of the chlorine atoms may be replaced.

VJhen equimolar amounts of 3,4-di chi oro coumarin and an organic base are reacted, a single pure product is obtained, indicating that the two chlorines have different reactivities. The active chl.orine was found to be the one in the 4 -position by comparing an authentic sample of 3-cltLoro-4-methoxycoumarin^ with the product obtained by

1. F. Arndt, L. Loewe, R. Un and E. Ayca, Ber., 8 4 , 3I9 (1951). reacting equimolar quantities of 3 ,A-dlchlorocoumarin and sodium methoxide. The infrared spectra of the two were identical and the melt ing point of a mixture of the two samples was not depressed. It was assumed that the chlorine in the 4-position is the reactive one with other basic reagents also.

Table 5 summarizes the substitution reactions of 3,4-dichloro-

coumarin and 3 ,4-dlchloro-6-methylcoumarin.

CSL 65

Table 5

Substitution Reactions of 3,4-W.chlorocouniarins

CSL CL Base

0 0 :

lIaCS>fe 90$ 80$

2NaCre 70$ 56$

C^^H^CH^SNa 87$ 72$ piperidine 82$

NaOC^H^ 30$

1. Reaction with sodium methoxide. Sodium methoxide reacted rapidly with both 3 ,4--d.icblorocoumarin and 3 ,4-'Hchloro-6-methylcoumarin, Methoxide ion was the only organic base that would replace both chlorine atoms. The yields of mono-substituted product were greater than those of the di-substituted coumarins.

2. Reaction with sodium benzylmercautan. Sodium benzylmercaptan reacted very rapidly with the 3,4-di chlorocoumarins. Sodium chloride precipitated almost immediately after refluxing began. An attempt to replace both chlorines vriLth benzylmercaptan resulted in the formation of a foul-smelling oil which was not worked up.

3. Reaction with piperidine. Piperidina reacts rapidly with 66

3,4--dichlorocoumarin. A one mole excess of piperidine is necessary to absorb the hydrogen chloride liberated.

Reaction with sodium phenoxide. Molten phenol was the only solvent from which 3-chloro-A-phenoxycovunarin could be isolated.

The use of methanol resulted in the substitution of methoxide.

Impure materials were obtained when dimethylformamide and dioxane were used as solvents.

5. Reaction of piperidine with 3-chloro-A-methoxy-6-methylcoumarin. 3-Chloro-A-hydroxy-6-methylcouraarin (XXIV) was obtained

hs. ^

m z when 3-chloro-A-methoxy-6-methylcoumarin was reacted with piperidine in absolute ethanol.^ The structure of XXIV was shown by analysis and by comparison of its infrared.spectinm with that of the known

1. Since the conversion of the methoxy group to a hydroxy requires water, the ethanol must not have been "absolute," as the label indicated.

3-chloio-A-hydroxycoumarin. Reaction of 3-chloro-A-methoxy-6-methylcoumarin with piperidine which had been dried over barium oxide gave a a product which had a high decomposition temperature and which con tained chlorine but no nitrogen. This product was not studied further.

6 . Mechanism of chlorine substitution. Although the chlorines in 3 ,4-dichlorocoumarin are vinylic, the reactivity of the A-chlorine 67 atom is not surprising. Since the 4-ohlorine is vinylic it probably does not react by direct displacement but by a Michael addition to form XXV which may then lose a chloride ion to yield the replacement

B e>- ■O XXV product XXVI,

Since the 3-carbon can only react by direct displacement, it

is expected to possess the usual vinylic unreactivity.

B. Reaction of 3.A-Dichlorocoumarin with Sodium Hydroxide

3,4-Dichlorocoumarin, in warm aqueous 10 per cent sodium hydroxide,

slowly dissolves with the formation of a red color. Acidification

yields a yellow product (0.78 g. from 1.00 g. of 3 ,4-dichlorocoumarin)

which is not 3 ,4-dlchlorocoumarin and which cannot be converted to the

coumarin. Although attempts to purify this material wore unsuccess

ful, an analysis was obtained. The fact that the chlorine content had

been reduced from 33 per cent in 3 ,4-dichlorocoumarin to 17 per cent

in the impure product indicated that one of the chlorines had been lost

during reaction. The possibility of a coumarin-coumarilic acid re

arrangement^ was considered and the infrared spectrum of the product

1. S. S. Lele and S. Sethna, J. Sci. Ind. Research (India), 14B. 101 (1955); Qcg. Syn., Coll. Vol. Ill, 209 (1955); G. Pappalardo and F. Duro, Boll sci, fac. chim. ind. Bologna, 10, 168 (1952). 68

COOH-

showed carbonyl, hydroxyl and double bond absorption. An attempt to prepare the ester of the coumarilic acid by reaction with diazomethane resulted in the formation of an intractable gum. Additional work is necessary before a structure can be assigned. EXPERBIEHTAL

I. GENERALIZATIONS

1. All melting points are corrected unless stated otherwise.

2. Analyses are by Galbraith laboratories, Knoxville, Tennessee,

except for those marked with an asterisk (*), which were run by

IJ. H. Deebel, Department of Chemistry, The Ohio State University,

Columbus, Ohio.

3. The phrase "usual resin flask setup" refers to a two-liter

resin flask equipped \d.th a mechanical stirrer, a separatory

funnel and a condenser which in turn was connected to a gas-

washing bottle containing a solution of sodium hydroxide to trap

the hydrogen chloride evolved. Stirring was continued throughout

the reaction,

A. The phrase "hydrolyzed with sulfuric acid and ice" refers to

the procedure whereby 75 ml. of concentrated sulfuric acid was

added to the Eriedel-Crafts mixture and when effervescence was

completed, the dark mixture was poured onto 300 grams of ice.

5. The phrase "dried in the usual manner" indicates that the

organic solution was washed with a saturated sodium chloride solu

tion and filtered through anhydrous magnesium sulfate.

6 , The Skellysolves (petroloum ether) used for crystallizations

were: Skellysolve F, b.p. 35-55°; B, b.p. 65-69°; 0, 90-97°.

69 70

7. Infrared (I.E.) data is noted by indicating the functional group and the wavelength, in microns, of maximum absorption.

A letter, w, m, or s in parentheses, follows the wavelength to indicate the intensity of the band, weak, medivmi or strong. n

II. STRUCTURE DETERMINATIOH OF ^r^.-DICHLORO-6-I-lETHYLCOUMAElN

A, 3.A-Dlchloro-6-methylcoinnarln

The usual resin flask setup was used, A solution of 9.9 g.

(0.092 moles) of distilled p-cresol in 25 ml. of carbon disulfide was added to a slurry of 20.0 g. (0 .I5 moles) of aluminum chloride^

1. Powdered aluminum chloride, obtained from Ohio-Apex Division of Food ^îachinery and Chemical Corp., Nitro, VJ. Va., was used for all Friedel-Crafts reactions.

in 20 ml. of carbon disulfide. After 10 minutes, g. (0.16 moles)

of hexachloropropene^ was added dropwise. The mixture turned dark

2, Hexachloropropene was obtained from Halogen Cliemicals, Inc., Columbia, S. Car., and was distilled, b.p. 75-780/7-8 mm., n/5 1.5473.

and was stirred 30 minutes. The carbon disulfide was removed iu vacuo

and the mixture was hydrolyzed by adding about 100 g. of ice and water.

The resulting khaki-colored product was collected, washed vdth water

and air-dried. Chromatography over alumina resulted in the decom

position. of the coumarin. The colored material was vacuum sublimed

in small portions (about 1 g.) at 180°. The yellmf sublimate, upon

recrystallization from ethanol,yielded 15.1 g. (72^) of yellow needles.

Sublimation at 140° afforded a smaller yield of colorless 3,4-dichloro-

6-methylcoumarin, m.p. 161.0-162.2°, I. R., 0=0, 5.89 (s)j C=C,

6.29 (m).

Anal. ; Calcd. for CiQ^ClgO^: C, 52.4; H, 2.6

Found; C, 52.6; H, 2.9 72

Attempts to reduce 3,A-dichloro-6-methylooumarln failed.

Catalytic hydrogenations using platinum oxide and potassium acetate in absolute ethanol, and rhodium on alumina catalyst and potassium

acetate in absolute methanol and platinum oxide and potassium acetate in glacial acetic acid all resulted in the recovery of unreacted

coumarin. Chemical reductions using sodium in liquid ammonia, zinc

in absolute ethanol and lithium aluminum hydride likewise resulted

in the recovery of unreacted starting material.

Refluxing, for 2 hours, a mixture of 3,4-dichloro-6-methylcoumarin,

hydroxylamine hydrochloride, pyridine and absolute ethanol gave an

impure product which contained nitrogen but no chlorine. No further

purification of this product was attained. A refluxing mixture of

3,A-dlchloro-6-methylcoumarin and excess aniline yielded, after

1 3/A hours, a nitrogen-containing, chlorine-free product which could

not be obtained pure enough for an analysis.

B. 3.A-Dichloro-6-carboxycoumarin.

A solution of 0.25 g. (0.0011 moles) of 3,A-dichloro-6-methyl-

coumarin in 8 ml. of concentrated sulfuric acid was added dropvri.se

to a solution of 1.1 g. of sodium dichromate in 7 ml. of water. The

mixture heated up and a white precipitate formed. VJhen addition was

complete, the green mixture was poured onto ice and the product was

collected and washed with water. The product v/as soluble in 10 per

cent sodium hydroxide and in 10 per cent sodium bicarbonate. Re-

crystallization from acetone-water yielded 0.145 g. (51^) of colorless

powder, m.p. 301-305° (d) (uncor.), I. R. : 0=0, 5.72 (s), 5.92 (s)j G=e, 6.20 (s).

Anal.: Calcd. for C, 46.4; H, 1.6; Cl, 27.4

Found: C, 46.7; H, 1.6; Cl, 27.1

C. 3.4-Dichlorocoumarin

1. From phenol and hexachloropropene. A 250 ml., 3-necked flask was equipped with a stirrer, a separatory funnel and a condenser attached to a gas absorption trap containing a potassium hydroxide solution. A solution of 7.84 g. (O.O83 moles) of distilled phenol^

1. Merck and Co., Inc., Rahway, N. J. in 15 ml. of carbon disulfide was added dropwise to a slurry of 13.3 g.

(0.099 moles) of aluminum chloride in 15 ml. of carbon disulfide. The mixture was stirred 10 minutes after addition ^vas complete and then

17.7 g. (0.083 moles) of hexachloropropene was added dropvd.se over a 10 minute period. The reaction mixture turned brovm and then very dark as stirring was continued for an additional 10 minutes.

Tlie carbon disulfide was removed in vacuo and the black residue v;as hydrolyzed with dilute hydrochloric acid. A gray precipitate v;as collected, washed with water and air-dried. The gray residue was vacuum-sublimed in small portions. The v;hite sublimate was not recrystallized further but can be recrystallized from ethanol to yield colorless needles. The yield of 3,4-dichlorocoumarin, m.p. 106.7-

107.5°, was 5.07 g. (28%). I. R., C-0, 5.76 (s); G=C, 6.27 (m).

Anal.: Calcd. for C^H^^ClgC^: C, 50.3; H, 1.9; Cl, 33.0

Found: C, 50.5; H, 1.9; Cl, 32.0 n

2, From 3-chloro-A-hydro3cyco\gnarln. A mixture of 1.00 g.

(0.0051 moles) of 3-chloro-A-hydroxycoumarin,^ 8 ml. of phosphorus

1. Prepared by method of F. Arndt, L. Loewe, R. Un and E. Ayca, Ber., 8A. 319 (1951) from 3-bromo-^-hydroxycoumarln, which was obtained by brominating A-hydroxycoumarin by the method of H. R. Eisenhauer and K. P. Link, J. Am. Chem. Soc., 76, 16a? (1954). 4-Hydroxy- coumarin was prepared by the method of J. Boyd and A. Robertson, J. Chem. Soc., 174 (1948) from ethyl carbonate (U. S. Industrial Chemicals, Inc.) and o-hydroxyacetophenone. oxychloride,^ and 2 ml. of sodium hydroxide-dried pyridine was re-

2. Baker Chem. Co. fluxed for 1 hour. The resulting purple solution was poured into 35 ml.

of water. The aqueous slurry was extracted twice with ether and the

ethereal solution was dried in the usual manner and evaporated to

dryness.

The yellow residue was chromatographed three times through a

six-inch column of a 2:1 silicic .acid-Celite mixture. The solvent was a 1:2:200 solution of ether-benzene-Skellysolve B. A total yield of 0.66 g. (60^) of 3,4-dichlorocoumarin, m.p. 105-107° (uncor.) was obtained. A mixture of this product with a sample obtained from

the Friedel-Crafts reaction melted at 105.5-107.0° (uncor.). The

infrared spectra of the two samples were identical. 75

III. REACTION OF OTHER HiEHQLS IJITH HEXACHLOROPROPENE

A. 3.A .6-Trichlorocoumarin and p-chlorophenyl trichloroacrylate

The usual resin flask setup was used. To a slurry of 2 9 . g.

(0.22 moles) of aluminum chloride in 50 ml. of carbon disulfide was added a solution of 12.8 g, (O.IO moles) of £-chlorophenol^ in 60 ml.

1. Eastman Kodak white label. of carbon disulfide. After the mixture was stirred for 10 minutes,

24.8 g. (0,10 moles) of hexachloropropene was added and the reaction mixture was stirred an additional 2 hours. The carbon disulfide was removed in vacuo and the residue was hydrolyzed with sulfuric acid and ice. The product was collected and recrystallized from ethanol to yield 22.3 g. (90^) of yellow needles, m.p. 133-134° (uncor.).

Repeated recrystallizations of a small portion produced an analytical sample of colorless needles, m.p. 133.1-134.6°; I. R., C=0, 5.77 (s)j

C-C, 6.31 (m).

Anal. ; Calcd. for CgH^Gl^C^: C, 43.3; H, 1.2; Cl, 42.6

Found: C, 43.1; H, 1.4; Cl, 42.6

43.2 1.5 42.4

In some of the preparations of 3,4,6-trichlorocoumarin, the final crop of crystals was washed with carbon tetrachloride. The mother liquor, upon evaporation, and recrystallization from ethanol, yielded

0.7 g. (2.4%) of g-chlorophenyl trichloroacrylate, colorless needles, m.p. 66.9-67.3°, I. R., C%0, 5.73 (s); G=C, 6.46 (m). Anal.; Calcd. for GgH^Cl^C^; G, 37.8; H, 1.4; Cl, 49.6

Found: G, 37.8; H, 1.4; Gl, 49.7

37.8 1.4 49.5

B. 3.A .7-TrIchlor0cotunarln

The usual resin flask setup was used. To a slurry of 8.0 g.

(0.060 moles) of aluminum chloride in 15 ml. of carbon disulfide was added a solution of 3.84 g. (0.030 moles) of m-chlorophenol^ in 25 ml.

1. Eastman Kodak white label; distilled, b.p. 71-74°/3 mm. of carbon disulfide. ETien the gas evolution had ceased, 7.50 g.

(0.030 moles) of hexachloropropene was added. Gas was evolved and the mixture turned black, khen reaction had ceased, as indicated by the gas evolution, the carbon disulfide was removed in vacuo and the residue was hydrolyzed with sulfuric acid and ice. A brovm-gray precipitate was collected and dried. This material weighed 8.5 g. and was sublimed in small portions. The sublimate was recrystallized from ethanol to yield 1.39 g. (18$) of colorless needles, m.p. 129.1-

129.7°, I. R., G=0, 5.75 (s); G=G, 6.30 (s).

Anal.: Galcd. for GgH^Gl^Og: G, 43.3; H, 1.2; Cl, 42.7

Found: G, 43.3; H, 1.5; Gl, 42.5

G. 3.4.8-Trichlorocoumarin

The usual resin flask setup was used. To a slurry of 8.0 g.

(0.060 moles) of aluminum chloride in 20 ml. of carbon disulfide vjas added a solution of 3.84 g. (0.030 moles) of o-chlorophenolP- in 25 ml.

2. Eastman Kodak yellow label; purified by method of W. J. Wohlleben, Ber., 42, 4369 (1909); b.p. 171-172°. 77 of carbon disnlfide. V!hen the gas evolution had ceased, 7.50 g.

(0.030 moles) of hexachloropropene was added. When the renewed

evolution of gas had ceased, the carbon disulfide was removed in vacuo and the residue was hydrolyzed with sulfuric acid and ice. A

grey-brown product was collected and dried. This product was insol uble in alcohol and left a residue on ignition. The material was

sublimed in small portions and the sublimate was recrystallized

from ethanol to yield 0.12 g. (1.6%) of colorless prisms, m.p.

179.0-180.0°, I. R., 0=0, 5.79 (s); 0=0, 6.34 (m).

Anal.: Oalcd. for GgH^Ol^C^: 0, 43.3; H, 1,2; 01, 42.7

Found; 0, 43.3; H, 1.2; 01, 42.4

43.5 1.1 42.5

D, 6-Bromo-3.4-dichlorocoumarin

The usual resin flask setup was used. To a slurry of 14.7 g.

(0.11 moles) of aluminum chloride in 25 ml. of carbon disulfide was

added a solution of 7.5 g. (0.050 moles) of p-bromophenol^ in 25 ml.

1. VI. Korner, Ann., 200 (1866).

of carbon disulfide. VIhen the gas evolution had ceased, 12.4 g.

(0.050 moles) of hexachloropropene was added. V,hen the gas evolution

had again ceased, the carbon disulfide was removed ^ vacuo and the

residue was hydrolyzed with sulfuric acid and ice. A tan product was

collected and recrystallized first from ethanol and then from Skelly-

solve C to yield 13.0 g. (44^) of yellow-orange needles. Careful re-

crystallization from ethanol of a small portion of this product 78 afforded an analytical sample of light yellow needles, m.p. 147.5-

143.3°, I. R., C=0, 5.74 (s); C=G, 6.28 (m).

Anal.; Calcd. for Cg%Cl;,BrC^: C, 36.8 ; H, 1.0; Cl, 24.1, Br, 27.2

Found : C, 36.6; H, 1.2; Cl, 24.0; Br, 26.4

E. 3.4.6.7-Tetrachlorocoumarin

The usual resin flask setup was used. A slurry of 4.80 g.

(0,030 moles) of 3,4-dichlorophenol^ in 45 ml. of carbon disulfide

1. Prepared by the method of H. Hodgson, Eng. Pat. 200,714, from 3,4-di clilor oaniline. was added to a sluriy of 8.0 g. (O.O6O moles) of aluminum chloride in 20 ml. of carbon disulfide. After 5 minutes, 7.50 g. (O.O30 moles) of hexachloropropene was added. The mixture turned black and was stirred for 1 3/4 hours. The carbon disulfide was removed in vacuo and the residue was hydrolyzed with sulfuric acid and ice. A gray product was collected, dried and recrystallized from Skellysolve C to yield 5.80 g. (69%) of white powder, m.p. 152.0-152.9°, I. R.,

0=0, 5.75 (s); C=C, 6.25 (s).

Anal.: Calcd. for C^HgCl^Og: C, 38.1; H, 0.7; Cl, 49.9

Found: C, 38.0; H, 0.8; Cl, 49.2

F. 3.A.6.8-Tetrachlorocoumarin and 2.A-dichloronhenvl trichloro

acrylate

1. From 2.A-di chloronhenol and hexachloropropene. The usual

resin flask setup was used. A solution of 45.7 g. (0.28 moles) 79

of 2,^-dicbloropbenol^ in 1^0 ml. of carbon disulfide was added slowly

1, Paragon Testing laboratories. Orange, N. J., m.p. >4,0.5-42.5° (uncor.) to a slurry of 40.0 g. (0.30 moles) of aluminum chloride in 100 ml.

of carbon disulfide. Addition required 15 minutes and the mixture was stirred an additional 15 minutes, followed by the dropwise addi

tion of 69.4 g. (0.28 moles) of hexachloropropene over a 10 minute

period. The mixture was stirred for l-y hours as the color changed

from green to brown to vei-y deep red. The carbon disulfide was

removed ^ vacuo and the residue was hydrolyzed with sulfuric acid

and ice.

ïiie product was collected and recrystallized twice from ethanol

to yield 33.4 g. of 3,4,6,8-tetrachlorocoumarin. The mother liquor

from the first recrystallization was diluted with an equal volume of

water and the resulting precipitate was collected and dried. The dry

solid was washed with Skellysolve F and filtered. The residue, upon

recrystallization from ethanol, gave a second crop of 3,4,6,8-tetra-

chlorocoumarin, colorless plates, m.p. 161.6-163.3°, I. R., 0=0,

5.74 (s); 0=0, 6.29 (m). The total jdeld was 36.4 g. (46%^.

Anal.; Oalcd. for OgEgCl^Og: 0, 38.1; H, 0.7; 01, 49.9

Found: 0, 38.0; H, 1.2; Cl, 50.4

38.0 1.1 50.1

The Skellysolve F wash solution was evaporated to dryness. The

residue was recrystallized from ethanol to yield 16.5 g. (18^) of 80

2,4.-dichlorophenyl trichloroacrylate, colorless needles, m.p. 94.8-

95.3°, I. R., 0=0, 5.64 (s); 0=0, 6.24 (m).

Anal.! Calcd. for CgH^Cl^Og: C, 33.7; H, 0.9; 01, 55.3

Found: C, 33.4; H, 1.3; 01, 55.6

2. 3.4.6.8-Tetrachlorocoumarin from 2.4-dichloronhenyl tri chloroacrylate . A 250 ml., 3-neck flask was equipped with a magnetic stirrer, a separatory funnel and a condenser topped with a calcium ciiloride tube. To a sluriy of I .46 g. (O.Oll moles) of aluminum chloride in 10 ml. of carbon disulfide was added a solution of I .60 g. (0.005 moles) of 2,4-dichlorophenyl trichloroacrylate in 20 ml. of carbon disulfide. The mixture slowly turned dark as it was stirred.

After 30 minutes, a solution of 3 ml. of concentrated hydrochloric acid in 20 ml. of water was added.

Tlie resulting colorless mixture was extracted twice with ether.

The ethereal solution was washed with water, dried in the usual manner and evaporated to dryness. The residue was recrystallized from ethanol to yield a mixture of colorless plates and colorless needles. The mixture was washed with Skellysolve F and filtered. The filtrate, upon evaporation, afforded 1.30 g. (Sljlj) of unreacted 2,4-dichloro

phenyl trichloroacrylate, m.p. 94-96° (uncor.). No depression of melting point was observed when the product was mixed with a sample

from the Friedel-Crafts reaction; mixed m.p. 94.5-96.0° (uncor.).

The residue from the Skellysolve F washing was 70 mg. (5^) of

3,4,6,8-tetrachlorocoumarin, m.p. 161-165° (uncor.). No depression

of melting point was observed when the product was mixed with a sample 81 from the BViedel-Crafts reaction; mixed m.p. 162-165° (uncor.).

The infrared spectra of the two samples were identical.

3. 2.^.-Dichlorophenyl trichloroacrylate from 2.A-dichlorophenol

and trichloroacrylyl chloride. A mixture of 5.76 g. (0.033 moles) of

trichloroacrylic acid^, 10 ml. (16.5 g., O.IA moles) of distilled

1. A. Roedig and E.Degerier, Ber., 86, A^>9 (1953).

thioiqrl chloride and 65 ml. of benzene were refluxed for 22 hours.

The mixture was concentrated to 25 ml. by distillation, 50 ml. of

benzene was added and the distillation was continued till the volume

was again 25 ml.

A 250 ml., 3-neck flask was equipped with a condenser, a mag

netic stirrer and a separatory funnel. The flask was charged with

5.38 g. (0.033 moles) of 2,1-dichlorophenol, 6 ml. (5.9 g., 0.11

moles) of pyridine (dried over sodium hydroxide) and 25 ml. of benzene.

The bensenic solution of trichloroacrylyl chloride was added dropid.se

to the cooled, stirred phenol solution. A precipitate formed as the

reaction proceeded. The addition required 30 minutes followed by

stirring for an additional 30 minutes.

A solution of 10 ml. of concentrated hydrochloric acid in 75 ml.

of water was added. The aqueous layer was washed with two 20 ml.

portions of ether. The combined organic layers were dried in the usual

manner and evaporated to dryness. The residue, on recrystallization

from ethanol, afforded 4.32 g. (41^) of silky colorless needles, m.p. 82

95.0-96.5° (uncor.) . No depression of melting point was observed when a sample was mixed with a sample of 2,4-dichlorophenyl trichloro acrylate obtained from the Friedel-Crafts reaction; mixed m.p. 94-96°

(uncor.)

4. Saponification of 2.4-dichlorophenvl trichloroacrylate. A mixtui-e of 1.00 g. (0.0031 moles) of 2,4-dichlorophenyl trichloro acrylate, 4.0 g. (O.IO moles) of sodium hydroxide and 50 ml. of water were refluxed for 50 minutes. The red solution was extracted with ether. The aqueous layer was acidified and then brought to pH 8 by the dropwise addition of lO^b potassium bicarbonate solution. The

solution was extracted with ether and then acidified and extracted

once again with ether. This last ethereal extract was dried in the

usual manner and evaporated to dryness. Becrystalllzation of the

residue from Skellysolve B afforded 0.29 g. (52/fe) of trichloroacrylic

acid, m.p. 71.5-74*0° (uncor.). No depression of melting point was

observed when a sample was mixed with trichloroacrylic acid prepared

by the hydrolysis of hexachloropropene;^ mixed m.p. 72.0-74.5°

1. A. Roedig. and E. Degener, Ber., 86, 469 (1953).

(uncor.).

G. 3.4.6-Trichloro-7-methylcoumarin.

The usual resin flask setup was used. To a slurry of 8.0 g.

(0.060 moles) of aluminum chloride in 20 ml. of carbon disulfide was g added a solution of 4.28 g. (O.O30 moles) of 4-chloro-3-methylphenol

2. Eastman Kodak white label, m.p. 65.0-65.5° (uncor.) 83 in 25 ml. of carbon disulfide. After 10 minutes 7.50 g. (0.030 moles) of hexachloropropene was added, lihen the slow liberation of gas was over, the carbon disulfide was removed ^ vacuo and the residue hy drolyzed with sulfuric acid and ice. ïhe product was collected, dried, and recrystallized from ethanol to yield 6.68 g. (85JG) of colorless needles, m.p. 178.2-178.8°, I. R., 0=0, 5.77 (s), 0=0, 6.32 (s).

Anal. ; Oalcd. for C^QtyCl^O^: 0, 45.6; H, 1.9; 01, 40.4

Found; 0, 45.7; H, 1.9; Cl, 40.3

45.6 1.8 40.6

H. 3.4-Dichloro-6-methoxycovimarin.

Tlie usual resin flask setup was used. A slurry of 12.4 g. (O.lO moles) of 2 -methoxyphenol^ in 25 ml. carbon disulfide was added to a

1. Eastman Kodak white label, m.p. 52-54° (uncor.). slurry of 14.7 g. (O.ll moles) of aluminum chloride in 35 ml. of carbon disulfide. Solution occurred as stirring was continued for

15 minutes, after which time 24,8 g. (0,10 moles) of hexachloropropene was added. No visible reaction occurred. After stirring for 8 hours, the carbon disulfide was removed in vacuo. The residue was hydrolyzed with sulfuric acid and ice. The brown mixture was extracted with three 50 ml. portions of 1:1 ether-benzene. The brown, tarry residue was discarded. The organic extracts were dried in the usual manner and evaporated to dryness. The residue was recrystallized from ethanol- water to yield 1.0 g. (4%) of colorless needles, m.p. 157.1-158.3°, 84

I. R., 0=0, 5.80 (s); 0=0, 6.24 (m).

Anal.; Calcd. for Cj^q H^CI^O^: 0, 49.0; H, 2.5; Cl, 28.9

Pound: C, 4 8 .8 ; H, 2.5; 01, 28.8

49.0 2.6 28.9

I. 2.4.5-Trichloronhenyl trichloroacrylate

The usual resin flask setup was used. To a slurry of 29.4 g.

(0.22 moles) of aluminum chloride in 50 ml. of carbon disulfide was added a solution of 19.7 g. (O.lO moles) of 2,4,5-trichlorophenol^

1, Eastman Kodak yellow label; recrystallized from Skellysolve B, m.p. 62-63è‘° (uncor.). in 35 ml. of carbon disulfide. After 10 minutes, 24.9 g. (O.IO moles) of hexachloropropene was added and the mixture was stirred for IS hours.

The carbon disulfide was removed Iji vacuo and the oily residue was hydrolyzed by the addition of 100 g. of ice. A dark brown product was collected and recrystallized thrice from ethanol to yield 9.2 g.

(26%) of sillcy, colorless needles, m.p. 105.7-106.4° (uncor.), I. H.,

0=0, 5.73 (s); 0=0, 6.43 (s).

Anal. : Calcd. for C9H2 CI5O2 ; 0, 30.4; H, 0.6; 01, 59.9

Found: 0, 30.3; H, 0.6; 01, 59.2 85

IV. REACTIONS OF l.A-DICHLOROCOUMARINS VJITH BASES

A. Reactions of 3.A-dichlorocoumarin vith bases

1. 3-Chloro-A-methoxycouniarin. A sodium methoxide solution vas made by reacting 0,19 g. (0.0083 moles) of metallic sodium with 20 ml. of absolute methanol. To this solution was added 1.90 g. (0.0083 moles) of 3,4-dichlorocoumarin and the resulting orange-brown mixture was refluxed for 30 minutes. The cooled solution was poured onto 25 g. of ice. A precipitate was collected, washed with water, dried and recrystallized from Skellysolve B to yield 1.55 g. {90%) of cream- colored needles, m.p. 87.9-88.6°, I. R., C%0, 5.84 (s)j C-=Cj 6.23 (s).

Anal. ; Galcd. for C^qHi^GIO^: C, 57.0; H, 3.4, Gl, 16.8

Found: C, 57.0; H, 3.4; Gl, 16.8

2. 3.4-Dimethoxycoumarin. In a 50 ml. flask, 0.28 g. (0.012 moles) of metallic sodium was reacted with 25 ml. of absolute methanol. l-Jhen all the sodium had reacted, 1.31 g. (0.0061 moles) of 3,4-dichloro coumarin was added and the mixture was refluxed for 3 hours. The re action mixture was poured onto 25 g. of ice. A white precipitate was collected, washed with water, dried and recrystallised from Skellysolve

B to yield 0.88 g. (70%J of colorless needles, m.p. 75.4-76.8°, I. R.,

0=0, 5.85 (s); G=G, 6.22 (s).

Anal.: Galcd. for G^iH^gO^; G, 64.1; H, 4.9

Found : G, 63.6; H, 4.9

3. 3-Ghloro-4-pineridinocoumax-in. A mixture of I .40 g. (O.OI65 86 moles) of piperidine,^ 1.76 g. (0.0082 moles) of 3,4--dichlorocoimarin

1. Eastman Kodak yellow label, distilled, b.p. 103-105°. and 20 ml. of absolute ethanol was refluxed for 2 hours. The mixture was evaporated to dryness and the powdered residue was washed with water and re-dried. Recrystallization of the residue from Skelly solve B yielded 1.78 g. (82%) of yellow needles, m.p. 123.6-125.0°,

I. R., 0=0, 5.87 (s); 0=0, 6.25 (s).

Anal. ; Galcd. for 0]pHiy^ClNC^ ; G, 63.8; H, 5.A; Gl, 13.A; N, 5.3

Found: G, 63.7; H, 5.6; Gl, 13.6; N, 5.3

A. A-Benzylthio-3-chlorocoumarin. In a 50 ml. flask, 0.15 g.

(0.0065 moles) of metallic sodium was reacted with 25 ml. of absolute ethanol. To this sodium ethoxide solution was added 0.80 g. (O.OO65 moles) of bcnzylmercaptan and l.AO g. (O.OO65 moles) of 3,A-dichlorocoumarin. The resulting yellow mixture was refluxed for 1 hour and then evaporated to dryness. The yellow residue was washed with water and recrystallized from ethanol, to yield 1.72 g. (87^) of colorless crystals, m.p. 96.9-97.6°, I. R., 0=0, 5.78 (s); 0=0, 6.22 (m).

Anal. : Galcd. for G^^BnClSC^ : Gl, 11.7; S, 10.6

Found: 01, 11.8; S, 10.7

5. 3-Ghloro-A-phenoxycoumarin. To A.30 g, (O.OA6 moles) of molten phenol was added 0.070 g. (O.OO3O moles) of metallic sodium. The mixture was warmed to 70° and when all the sodium had reacted, O .65 g.

(0.0030 moles) of 3,A-dichlorocoumarin was added and the mixturer.was 87 heated in an oil bath at 115-120° for 1 hour. The brown mixture was washed into a micro steam distillation apparatus and the volatile organic materials were steam-distilled till the distillate gave only a very faint ferric ciiloride coloration. The residue was poured into

15 ml. of water and cooled.

The resulting tan solid was recrystallized from ethanol-water to yield 0.25 g. (31?^) of white plates, m.p. 88.8-90.4°, I. R., 0=0,

5.79 (s); C=C, 6.24 (s).

Anal.; Calcd. for C^^HgClO^: C, 66.Ij K, 3.3; 01, 13.0

Found: 0, 65.7; H, 3.2; 01, 13.1

65.8 3.4 12.9

B. Reactions of 3.4-dichloro-6-methylcouiaarin idLth bases

1. 3-Chloro-4^methoxy-6-methvlcoumarin. A sodium methoxide solution was made by reacting 0.20 g. (0.0087 moles) of metallic sodium with 25 ml. of absolute methanol. To this solution was added

2.00 g. (0.0037 moles) of 3,4-dichloro-6-methylcoumarin and the mix ture was refluxed for 3 hours, after which time it %ms poured onto

50 g. of ice. The white product was collected, washed \d.th water, dried, and recrystallized from methanol-water to yield 1.56 g. (80^) of colorless needles, m.p, 107.8-108.5°, I. R., 0=0, 5.80 (s); 0=0,

6,20 (m).

Anal.! Calcd. for O^^H^OIO^: 0, 58.8; H, 4.0; 01, 15.8

Foundl 0, 53.9; H, 4.3; 01, 15.7 88

2. 3. A-Dimet.hoxy-6-methylcoumarln. A sodimn methoxide solution was made by reacting O.AO g. (0.017A moles) of metallic sodium with 25 ml. of absolute methanol. To this solution was added 2.0 g.

(0.0087 moles) of 3,4-dichloro-6-methylcoumarin. The resulting yellow solution was refluxed for 3 hours, poured onto 25 g. of ice and stirred till precipitation occurred. The product was collected, washed with water, dried and recrystallized from ethanol-water to yield 1,07 g.

(56%) of cream-colored needles, m.p. 63.9-64.8°, I. R., 0=0, 5.92 (s);

0=0, 6.30 (s).

Anal. ; Calcd. for 0^2%2^4* 6$.4; H, 5.5

Found : 0, 65.4j H, 5.7

3. 4-Benzylthio-3-chloro-6-methylcoumarin. In a 50 ml. flask,

0.14 g. (0.0061 moles) of metallic sodi'.jm was added to a solution of

0.75 g. (0.0061 moles) of benzylmercaptan in 25 ml. of absolute ethanol.

Vlhen all the sodium had reacted, 1.39 g. (O.OO6I moles) of 3,4-dichloro-

6-methylcoumarin was added and the mixture was refluxed for 40 minutes.

The yellow solution was filtered and the filtrate was evaporated to

dryness. Recrystallization of the residue from ethanol-water afforded

1.39 g. (72^) of yellow needles, m.p. 122.6-123.8°, I. R., 0=0, 5.78

(s); 0=0, 6.30 (m).

Anal.; Galcd. for O17H13OISO2 : 0, 64.4 ; E, 4 .I; 01, 11.2; S, 10.1

Found; 0, 64.6; H, 4.1; 01, 11.1; S, 10.3

0. 3-0hloro-4-hydrox:/’-6-methylcoumarin. A mixture of O .85 g.

(0.0038 moles) of 3-chloro-4-methoxy-6-methylcoumarin, O .65 g. 89

(0.0076 moles) of piperidine and 25 ml. of ethanol was refluxed for 138 hours. The mixture was poured onto ice and acidified. A white product was collected, washed with water and dried. Recrystal lization of this product from ethanol afforded 0.73 g. (91^) of colorless needles, m.p. 2A8.5-2A9.5° (uncor.), I. R., C-=0, 5.88

(s); C=C, 6.17 (s); G-OH, 3.17 (m).

Anal.; Calcd. for CiQByClO^: C, 57.0; H, 3.4; Cl, 16.8

Found: C, 57.1; H, 3.5; Gl, 16.9

57.0 3.6 16.6 SUl»mBY

1. Phenol reacts with hexachloropropene in carbon disulfide in the

presence of aluminum chloride to form 3,4-dichlorocoumarin in

28 per cent yield,

2. 3,4-Dichlorocoumarin was synthesized by an unambiguous method.

3. The following phenols react with hexachloropropene to yield the

corresponding 3,4-diclilorocoumarins: p-cresol (72%); p-chlorophenol

(90%); m-chlorophenol (18%); o-chlorophenol (1.6%); 2,4-dichloro-

phenol (46%); 3,4-dichlorophenol (69%)j 3-methyl-4-chlorophenol

(85%); p-bronophenol (4A%); p-mothoxyphenol (4,1%).

4 . 2,4-Dichlorophenol, in the same reaction, forms 2,4-dichlorophenyl

trichloroacrylate in 18% yield. 2,4,5-Trichlorophenol and p-chloro-

phenol also form pheiyl trichloroacrylates in 26% and 2.4% yields,

respectively.

5. 2,4-Dichlorophenyl trichloroacrylate can be converted to 3,4,6,8-

tetrachlorocoumarin in 5% yield.

6. Tlie reaction of p-chlorophenol and hexachloropropene was studied

to obtain conditions affording a maximum yield of 90%.

7. Unreacted phenol, tars or some type of organometallic complex are

obtained from the reaction of hexachloropropene vdth the following

phenols: p-nitrophenol, 4-chloro-2-nitrophenol, resorcinol,

c^-naphthol, Ç-naplithol, p-phenylphenol, p-t-butylphenol, 1-chloro-

2-naphthol, l,4-dichloro-2-naphthol and m-methoxyphenol.

8. A mechanism for the reaction of hexachloropropene with phenols is

proposed.

90 91

9. 3, ,^-Dichloro coumarin is shown to undergo preferential nucleo-

philic displacement in the ^-position with sodium methoxide, sodium

benzylmercaptan, piperidine and sodium phenoxide.

10. Only sodium methoxide displaces the chlorine in the 3-position. 100

60 OH

40 KBr 20 Figure

0-100

80 o0> oc 60 E CO c o 40 KBr

O-IOC

60 OH

40 KBr 20 Figure 3

Wove length in microns 100

20 KBr Figure 4 0-100 u0) 80 oc E 60

40 o>c "oa„ 20 — CHCI3 solvent a! 0.025 mm. cell Fig ire 5 0-100

CH3 , 40

j Nujol mull 20 Figure 6

Wove lengfti in microns FIGURES 4,5.6 100

40 CH; 20 KBr Figure 7 0-100

80 c o

E 60

2 40

20 a! KBr Figure 8 0-100

20 CHCI3 solvent 0 . 2 mm. cell I Figure 9

Wave length in microns FIGURES 7. 8 .9 100

KBr 20 Figure 10

0-100

80 c p VÜ U l E 60 oc 40 CHCI3 solvent 0 . 2 mm. cell Figure II Q_ 20

0-100

40 KBr 20 Figure 12

Wove length in microns FIGURES 10, II, 12 AUTOBIOGRAPHY

I, Sidney Scliiff, was born in Chicago, Illinois, on June 9,

1929. I received my secondary school education in the public schools

of Chicago, Illinois. % undergraduate training was obtained at the

Illinois Institute of Technology in Chicago, from which school I

received the degree Bachelor of Science in 1951. I entered the

Graduate School of The Ohio State University in September, 1951.

1‘Jhile completing the requirements for the degi’ee Doctor of Philosophy

and the degree Master of Science, which was obtained in 1951, I was

a teaching assistant for general and organic chemistry from 1951 to

1958.