CA1086744A - Benzo 1,3 dioxin derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Processes for the manufacture of benzo [1,3] dioxin derivatives of the formula:-- wherein X and Y are each a 2,2,2-trichloroethylidene radical or a dichlorovinylidene radical; and R1 - R4 are variously selected from hydrogen, chlorine amino, nitro, acetamido, ammonium sulphonato, carbamoyl, carboxy, chloroformyl, cyano,ethoxy carbonyl, phenylsulphamoyl, sulphamoyl, sulpho or 2,2,2-trichloro-1-hydroxy-ethylcarbamoyl.

The benzo [1,3] dioxin derivatives are of use in animal husbandry to improve animal rate of growth or feed efficiency.

Description

7~

This invention relates to methods, compositions and chemical compounds for use in the husbandry of ruminant animals to improve the rate of growth or feed efficiency, or both.
In ruminant animals, a significant proportion of the gross energy intake in the form of food is lost as methane, formed during fermentakion of the food in the rumen, . .
and a further signi~icant proportion o~ ~he gross energy intake is lost as heat of fermentation. For example, in lambs, methane can account ~or about 10% of the gross energy .
intake, and heat o~ fermentation accounts for about a further 6% of the gross energy intake. By suppressin~
methane production in the rumen, thereby also consequentially reducing the energy loss as heat of fermentation, the energy ingested as food is more efficiently utilised, for .
example by increa`sing the production of volatile fatty acids, resulting in better rates of growth in the animals, : and improved feed efficiency.
Thus, according to the invention~ there is provided a method for use in the husbandry of ruminant .
animals which comprises orally administering to such animals~ for examplesheep or cattle, a benzo~l33~dioxin derivative of the formula:-~2 ~ 1 I ¦
~:
: R :

- 2 - . .

~``-.

q44 wherein either X is a 2,2,2-trichloroethylidene,2,2-dichloro-vinylidene, or 2,2-dichloro-2-(C1 3alkoxy)ethylidene radical and Y is a 2,2-dichlorovinylidene or 2,2-dichloroethylidene radical, or X and Y are each a 2,2,2-trichloroethylidene radical; and Rl9 R2, R3 and R4, which may be the same or di~erent, are each a hydro~en or halogen atomj an amino, carbamoyl, carboxy~ chloroformyl, cyano, formyl, ~ormyloxymethyl, hydrazinocarbonyl, hydroxy, nitro, sulphamoyl, sulpho or .
ammonium sulphonato radical; an alkanoyl, mono- or di- .
alkanoylamino, alkanoylhydrazonomethyl, alkanoyloxy, alkoxy, .
alkoxycarbonyl, alkoxyhydroxymethyl, alkyl, mono or di- .
alkylsulphamoyl, mono- or di-alkylcarbamoyl, hydrazonoalkylg hydroxyalkyl or hydroxyalkylcarbamoyl radical, wherein each .
alkanoyl, alkoxy and alkyl pa~ is of up to 4 carbon atoms and i9 optionally substituted by one or more halogen atoms, .. ...
especially chlorine atoms; a benzoyl,benzyloxy, benzylideneamino, phenylhydrazinomethyl, mono- or di-phenylsulphamoyl or phenylthioureido radical~ in each of which the phenyl ring is optionally substituted by one to three halogen atoms, especially chlorine atoms, or Cl_4 alkoxy or nitro radicals; or a tetrazol-5-yl radical, or, when Rl is a carboxy radical and R2 is a l-hydroxyalkyl radical, a r-lactone thereof; and for those compounds containing a carboxy or sulpho group, base addition salts thereof~ for example alkali metal and ammonium salts, and ~or those compounds containing a basic amino group, acid addition salts thereof, for example hydrochloride, sulphate or nitrate salts~
A particular value for X when it is a 2,2-dichloro-2-.

- 3 ~

79~ ' ~Cl_3 alkoxy)ethylidene radical is, ~or example, a 2,2-dichloro-2-ethoxyethylidene radical. .
A suitable value for R1J R2~ R3 or R4 when i~ is a ' hal~gen atom is~ for example, a chlorine, bromine, iodine or ~luorine'atom, particularly a chlorine or bromine atom~ .
an~ especially a chlorine atom. .
A sultable value for R2 when it is an alkanoyl, .
mono- or di-alkanoylamino, alkanoylhydrazonomethyl, alkanoyloxy, .
a~koxy, alkoxycarbonyl, alkyl, mono- or di-alkylsulphamoyl~ -mono- or di-alkylcarbamoyl, hydrazonoalkyl~ alkoxyhydroxyalkyl, hydroxyalkyl or hydroxyalkylcarbamoyl radical as defined aboveg is, for example'an acetyl, propionyl, butyryl, acet'amido, propionamido, butyramido~ diacetylamino, 2-acetyl-hydrazonomethyl, 2-propionylhydrazonomethyl, 2-bu~yrylhydrazono-S methyl, acet'oxy, propionyloxy, butyryloxy, methoxy, ethoxy, propoxy, butoxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, methyl, ethyl propyl~ butyl, methylsulphamoyl, dimethylsulphamoyl, ethyl~ulphamoyl, diethylsulphamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, ' propylcarbamoyl, dipropylcarbamoyl, hydraæonomethyl, l-hydrazono-ethyl, l-hydr4xy-l-methoxymethyl, l-ethoxy-l-hydroxymethyl, .
hydroxymethyl, l-hydroxyethyl, 2,2,~-trichloro-1-hydroxyethyl~
l-hydroxypropyl or 2,2,2-trichloro-1-hydroxyethylcarbamoyl 25radicalO . ' ' : , . .' . ~'4~~ . :
. .
.-10~674~ 1 A suitable value for R2 when it is a ben70yl, benzoyloxy, benzylideneaminog phenylhydrazonomethyl, mono-or di-phenylsulphamoyl~ or phenylthioureido radical substituted by one to three halogen atoms or Cl 4 alkoxy or nitro radicals as defined above, is, ~or example a 3-chlorobenzoyl~ 3,5-dinitrobenzyloxy, 4-chlorobenzylideneamino, 3,4,5-trimethoxybenzylideneamino, 4-nitrobenzylideneamino, 2,4-di~itrophenylhydrazonomethyl, 4-chlorophenylsulphamoyl or 3-methoxyphenylthioureido radical.
A suitable 'value for R3 is an alkanoyloxy radical a~ defined above, for example an acetoxy, propionyloxy or butyryloxy radical.
A suitable value for R4 is an alkanoyloxy, alkoxycarbonyl or dialkanoylamino radical as de~ined abovej for example an 15' acet`oxy, propionyloxy, butyryloxy, ethoxycarbonyl~ 2,2,2-trichloroethoxycarbonyl or diacetylamino radical A particu~r valu~ for Rl is, for example,a hydrogen, chlorine or bromine atom, or a carboxy radical.
A particular value for R2 is, for example, a hydrogen or chlorine atom, or an amino, carbamoyl, carboxy3 chloroformyl, cyano, formyl~ ~ormyloxymethyl, hydrazinocarbonyl, hydroxyg nitro, sulphamoyl, sulpho9 ammonium sulphonato, acetyl, propionyl, acet'amido, diacetylamino, propionylhydrazonomethyl, acetoxy, methoxy~ methoxycarbonyl, ethoxycarbonyl, n-butoxy-*arbonyl, methyl, die~hyl~ul~hamoylj diethylcarbamoyl, ~ 5 ~

I' .

674~

l-hydrazonoethyl, l-hydroxy-l-methoxyvmethyl, hydroxymethyl, 2,2,2-trichloro-1-hydroxyethyl, 2,2,2-trichloroethoxycarbonyl, 2~2,2-trichloro-1-hydroxyethylcarbamoyl, tetrazol-5-yl, benzoyloxy, benzylideneamino, phenylhydrazonomethyl, phenylthioureido, 4-chlorobenzylideneamino, 3,4,5-trimethoxybenzylideneamino or 4-nitrobenzylideneamino radical.
A particular value for R3 is a hydrogen or bromine atom~ or a hydroxy or acetoxy radical~
A particular value'for R4 is a hydrogen or chlorine atom, or an acet'oxy, amino, carbamoyl~ carboxy~ 2,2,2-trichloroethoxycarbonyl, diacetylamino, ethoxycarbonyl, hydroxy or nitro radical.
A preferred group of benzo[l,3~dioxin derivatives ' ~or use'in the met'hod of the invention comprises compounds of the formula I wherein X and Y are each a 2,2,2-trichloro-ethylidene radical, Rl, R3 and R4 are each a hydrogen atom9 and R2 is a hydrogen atom or an amino, carboxy, chloroformyl, ~ormyloxymethyl, sulphamoyl or Cl_4 hydroxyalkyl radical.
A ~urther pre~erred group of benzo~1,3]dioxin der'ivatives ~or use'in the method of the invention comprises compounds of the'~ormula I wherein X is a 2,2,2-trichloro-ethylidene radical, Y is a 2,2-dichlorovinylidene radical, Rl, R3 and R4'are'each a hydrogen atom, and R2 is an amino, di~Cl 4alkyl)carbamoyl~ carboxy~ nitro or tetrazol-5-yl radical.
Particular pre~erred' benzo[l,3~dioxin derivatives for use in the method of the invention are 2,4-bis(trichloromethy~
benzo~l,3~dioxin,'6-amino 294-bis(trichloromethyl)ben20tl~3~-.., q, ~:.

` ~O~I~iq4~ 1 dioxin9 2,4-bis(trichloromethyl)benzo[1,3~dioxin-6-carboxylic acid, 2,4 bis(trichloromethyl)benzo[1,3Jdioxin-6-carbonyl chloride, 6-hydroxymethyl-2,4-bis(trichloromethyl)benzo[1,3~-dioxin, 6-sulphamoyl-2,4-bis(trichloromethyl)benzorlg3~-dioxin, 4-dichloromethylene-6-nitro-2-trichloromethylbenzo~1,3~-dioxin, 5-amino-4-dichloromethylene-2-trichlorome~hylbenzo[1,3~-dioxin, 4-dichloromethylene-6-diethylcarbamoyl-2-trichloro-methylbenzo~l,3~dioxin, 4-dichloromethylene-2-trichlorometh benzo[1,3]dioxin-6-carboxylic acid, 4-dichloromethylene-6-(tetrazol-5-yq)-2-trichloromethylbenzocl~33dioxin~ 4-dichloro-methyl-2-trichloromethylbenzo[1,3~dioxin-6-carboxylic acid and 6-~ormyloxymethyl-2,4-bis(trichloromethy~l)benzo~1,3]dioxin.
In the method of the invention, the benzo[1,3~dioxin derivative is preferably administered orally to the animals as part of their normal food or drink~ that is to say in admixture with an ordinary solid feedstuff or feedblocks, incorporated into a salt lick, or dissolved in the drinking water, or in the form of a slow-release, intra-ruminal pellet. The benzo~l,33dioxin derivative is incorporated into food, feed block, salt Iick or drinking water to such an extent that each animal ingests from O.Olmg./kg. body weight to 30mg./kg. bodyweight per day o~ the benzo~1,3~dioxin deri~ative or from O.Olmg./k~. to lOmg.Ikg. per day of a preferred ben~o~ dioxin derivative.
According to a further ~eature of the invention, ., ~ - 7 ~
.
, ,.
.

36~

there is pro~ided a composition for use in the method of the invention which comprises a benzorl,3~dioxin derivative, as defined above~ ~ogether with a solid or liquid edible, non-toxic diluent or carrier.
Suitable benzo[l,3~dioxin derivatives ~or use in the composition of the invention are those de~ined above, and preferred groups o~ benzo~1,3~dioxin derivatives and particular preferred individual compounds for use in the composition o~ the invention are those mentioned above.
A suitable liquid diluent or carrier is, for .
example,' drinking water. A suitable solid~ edible, non-toxic diluent or carrier may be, ~or example, a conventional nutritionally balanced' ruminant feedstu~f, for example a typical cattle or sheep diet consisting o~ cereal products, such as barley meal, maize meal or wheat feed, nut and seed products, such as decorticated ground nut cake or cotton seed cake, or extracted cotton seed cake, together with minor amounts of, ~or example, feather meal~ seaweed meal, bone meal, .
bone flour, chalk, salt, urea, molasses', vitamins and trace miner'als; or it may be'an inert solid diluent or carrier oP no nutritional value, for example kaolin, talc, calcium carbonate, ruller'e earth, attapulgus clay, ground oyster shells, ground limestonei or starch or lactose.
The composition of the invenkion may take the Porm of ~5 a ~upplemented feedstuff for direct feeding ko animals 9 in which case it will contain from 5 ppm to 3000 ppm of a benzo-~1,3~dioxin derivative,' or from 5 ppm to lOOOppm of a preferred , ' . . .' .

~enzo~1~3~dioxin deriva-tive in aami~ture wlth a conventional ruminant feedstuf~; o~ it may take the form of a concentrate~
premix ~or dilution wi~h a conventional ruminant feedstu~f to proauce a supplemented feeds~uff suitable for direct feeding, and such a premix will contain from 0 3% w/w to 50% w/w of a benzo~ , ydioxin derivative in admixture wit~ either a conventional,nutritionally balanced ruminant feedstuff, an inert solia diluent, for example ground limestone, or starch or lactose.
According to a fur~her feature ~ ~he invention there is provided a process ~or the manufacture of a solid composition of the invention which comprises uniformly mixing a benæo~ , ~ .
dioxin derivative as defined above with a sol;d, edible,non-toxic diluen~ or carrier. . -The benzo ~, ~ dioxin is preferably serially diluted .
with the diluent or carrier in two or more successive s~ages, to ensure even mixing. Certain o~ the benzo ~,~7dioxin , derivatives de~ined above are novel compounds, Thus, according to a urther ~eature of the invention there is provided a novel 2~ benzo~ ~ dioxin derivative of ~he formula I wherein:-~a) X ~nd Y are bo~h 2,2,2-trichloroethylidene radicals, R2 is a ~ydrogen atom, and Rl, R3 and R4, which may be the same or di~feren~, have any of the meanings defined abo~e, provided ~hat not all o Rl, R3 and R4 are hydrogen atoms;
. .
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.,, _g~ .
.
. ' ' ' '.
' . ' ... , . ~ :

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(b) X and Y are both 2,Z,2-trichloroethylidene radioals, Rl, R3 and R4 are hydrogen atoms, and R2 is a bromine, iodine or fluorine atom; a formyl, formyloxymethyl, hydrazinocarbonyl . .
or hydroxy radical, an alkanoyl, alkanoylhydrazonomethyl, alkanoyloxy, alkoxy, alkoxyhydroxymethyl, mono or dialkyl-sulphamoyl, mono- or dialkylcarbamoyl, hydrazonoalkyl or hydroxyalkyl radical, wherein each alkanoyl, alkoxy or alkyl part is of up to 4 carbon atoms, a mono- or dîalka~oylamino .
radical wherein each alkyl part is Or 3 or 4 carbon a~oms,or an alkyl radical of 3 or 4 carbon atoms, any of which radicals is optionally substituted by halogen atoms, especially chlorine atoms; a chloroalkoxycarbonyl radical o~ up to 4 carbon atoms; a hydroxyalkylcarbamoyl radical wherein the alkyl part is of 1 to 4 carbon atoms, optionally substituted by halogen atoms, except 2,2,2-trichloro-1-hydroxyethylcarbamoyl, or a benzoyl~ benzoyloxy, benzylideneimino, phenylhydrazonomethyl~
diphenylsulphamoyl or phenylthioureido radical, in each o~ .
which the phenyl ring is substituted by one to three halogen :
atoms, especially chlorine atoms, or Cl 4 alkoxy or nitro radicals; or a phenylsulphamoyl radical substituted by one to three halogen atoms, especially chlorine atoms, or Cl_4alkoxy, or nitro radicals; ~ -(c) X and Y are both 2~2,2-trichloroethylidene radicals, and Rl, R2, R3 and R4 have any of the meanings defined above provided that not more than two are hydrogen atoms, and excepting compound~ wherein: R2 is a nitro radical, and . . .'.
.~ , . ,.'' I

' ~: `

either R~ ;s a methyl radical or Rl is a methyl or nitro radical; R2 is an amino radical, and either R3 is a bromine atom or R4 is an amino or methyl radical; R2 is an acetamido radical and R3 is a bromine atom; R2 is a benzamido radical and R4 is a methyl radical; R2 is a hydroxy or methoxy radical and ~1 and R3 are chlorine atoms; R2 is a methyl radical and either R3 is a nitro radical or R4 is a nitro or amino radical; or R2 is a chlorine atom and either R4 is a chlorine atom, or an amino9 acetamido or nitro radical, or Rl and R4 are chlorine atoms; or R2 is a 2,2~2-trichloro-i-hydroxyethyl radical and Rl is a carboxy radical, and R1 and R2 together form a y-lactone ring, and R3 and R4 are both acetoxy radicals; and any o~ Rl, R2, R3 and R4 not ' otherwise defined are hydrogen atoms; ' (d) X and Y are both 2,2-dichlorovinylidene radicals, and Rl, R2, R3 and R4 have any of the meanings defined above, excepting those compounds wherein: R2 is an amino radical;
Rl and R3 are chlorine atoms and R2 is a hydroxy or methoxy radical; R2 is a methyl radical and either R3 is a nitro radical or R4 is an am;no radical; and any of Rl, R2, R3 and R4 not otherwise'defined are hydrogen atoms;
(e) X i5 a 2,2,2-trichloroethylidene radical, Y is a 2,2-dichlorovinylidene radical, and Rl, R2~ R3 and R4 have the meanings defined above,` e.xcepting those compounds wherein R2 i5 a nitro radical and ei'ther R3 is a methyl radical or ; R4 is a nitro radical, and any of Rl~ R3 and R4 not otherwise ' ,:

.
. . ~
., .
..
' , .

defined are hydrogen atoms;
(f) X is a 2,2-dichloro-2-(C1 4alkoxy)ethylidene radical, for example a 2,2-dichloro-2-ethoxyethylidene radical, Y is a 2,2-dichlorovinylidene radical and Rl, R2, R3 and R4 have the meanings defined above;
(g) ~ is a 2,2,2-trichloroethylidene radical, Y is a 2,2-dichloroethylidene radical and Rl, R2~ R3 and R4 have the meanings de~ined above.
Suitable values for Rla R2, R3 and R4 are those given above.
Particular values for Rl, R3 and R4 in compounds of type (a), (f) and (g) are those given above.
In compounds of type (b), a particular value for R is, for example, a formyl, formyloxymethyl~ hydroxy, acetyl, propionyl, diacetylamino, propionylhydrazonomethyl, acetoxy, methoxy9 methoxycarbonyl, ethoxycarbonyl, n-butoxycarbonyl, methyl, diethylsulphamoyl, l-hydrazonoethyl, l-hydroxy-l-methoxymethyl, hydroxymethyl, 2,2,2-trichloroethoxycarbonyl, benzoyloxy, phenylhydrazonomethyl, benzylideneamino, 4-chlorobenzylideneaminog 3,4,5-trimethoxybenzylideneamino or

4-nitrobenzylideneamino radical. ~
In compounds o~ type~(c), a particular value for R2 is, for example, a carboxy, methyl or diacetylamino radical and a particular value for R4 is, for example, a carboxy~
carbamoyl, diacetylamino, ethoxycarbonyl, 232,2-trichloroethoxy-carbonyl or nitro radical. Particular compounds of this type are .
.. .
.
:

. .

~ j744 those wherein R2 is a carboxy radical and R4 is a nitro radical, R2 and R4 are bokh diacetylamino radicals, or R2 is a methyl radical and R4 is a carboxy, carbamoyl, ethoxycarbonyl or 2,2,2-trichloroethoxycarbonyl radical.
2 In compounds of type (d), a particular value for R is, for examplè an amino, carbamoyl, carboxy or cyano radical~
In compounds of type ~e)~ a particular value for R2 iS3 for example, an amino, carboxy, cyano, hydrazinocarbonylg diethylcarbamoyl3 su1phamoyl, tet'razol-5-yl radical.
Preferr~d novel benzo[1,3~dioxin derivatives for use in the method or the composition of the invention are 6-hydroxymethyl-2,4-bis(trichloromekhyl)benzo~1,3]dioxin, 6-sulphamoyl-2,4 bis~trichloromethyl)benzo[1~3~dioxin, 4-dichloromethylene-6-diethylcarbamoyl-2-trichloromethylbenzo-[1,3~dioxin~ 4-dichloromethylene-2-trichloramethylbenzo~193~-dioxin-6-carboxylic acid, 4-dichloromethylene-6-(tetrazol-5-yl)-2-trichloromethylbenzo[1,3~dioxin, 6-amino-4-dichloromethylene-2-trichloromethylbenzo~1,3~dioxin3 4-dichloromethyl-2-trichloro-m~ethylbenzo~l,3~dioxin-6-carboxylic acid, and 6-formyloxymethyl-2,~-bis(trichloromethyl)benzo[1,3~dioxin. ' ' The'novel benzo~l,3~dioxin deritives of the invention may be manufactured by methods known in themselves ~or the manu~acture of analogous compounds. Thus, according ' ~5 to a ~urt~er feature of the invention the 'following processes are provided ~or the manufacture'of a novel benzo~1,3]dioxin o~ the'formùla I, wherein Rl, R2, R3, R , X and Y have the meanings derined above in the definition of new compounds, 741~ ' unles's otherwise'specified:~(a) the reaction of a phenol of the'formula:-~ . II . ' R~ ~ . .. -.
~1 with two mOlecular equivalent proportions of chloral hydrate in the presence of a strong acid, for example sulphuric acidg whereafter, when a benzo[1,3]dioxin derivative wherein Y is a 2,2-dichlorovinylidene radical or both X and Y are 2,2-dichlorovinylidene radicals is required, the product so obtained, wherein X and Y are both 2,2~2-trichloroethylidene . .
radicals,is reacted with respectively one or two molecular -eq'uivalents of an alkali metal azide or cyanide,or a base, for example an alkali metal hydroxide such as sodium hydroxide, :
, an alkali metal alkanoate such as sodium aoetate, or an alkali metal alkoxide such as sodium ethoxide, wherea~ter if desired particular substituents Rl, R2, R3 and R4 may be ..
trans~ormed to other substituents as defined above by conventional methods known in the art of organic chemistry. .
.
~xamples of such transformations are the esterification of a carboxylic acid substituent to produce an alkoxycarbonyl ; 20 substituent; the reduction of an alkoxycarbonyl substituent to a hydroxymethyl substituent; the acetylation of an amino substituent; or the diazotisation and subsequent reduction of an amino substituent to give a hydrogen substituent. Many , other examples of conventional transformations of one claimed ., . i ., l~ iS744 substituent to another will be readily apparent to a chemist of normal skill;
tb) for those compounds wherein at least one of Rl, R2, R3 and R4 is an acylamino or acyloxy radical, the reaction o~ a .
corresponding benzo[l,3]dioxin derivative of the formula I~
wherein at least one of Rl, R2, R3 and R4 is an amino or hydroxy radical, with an alkanoyl or aroyl halide, for example acetyl chloride or benzoyl chloride;
(c) for those compounds wherein at least one of Rl, R2, R3 and R4 is a hydrogen atom, the reaction of a corresponding benzo~l93~dioxin derivative of the formula I, wherein at least one of Rl, R2, R and R4 is a diazo radical, with an acid, for example concentrated sulphuric acid, and a reducing agent~
for example ethanol;
(d) for those compounds wherein at least one of Rl, R2, R3 and R4 is a formyl radical, the reduction of a corresponding benzo~1,3]dioxin deriv~tive of the formula I, wherein at least one of Rl, R2~ R3 and R4 is a chloroformyl radical, for example with a complex metal hydride such as tri-t-butoxy ~0 lithium aluminium hydride;
(e) ~or those compounds wherein at leask one of Rl, R2, R3 and R4 is an alkoxyhydroxymethyl radical, the reaction of a corresponding benzo~l,3~dioxin derivative of the formula I,.
whenein at least one of Rl, R2~ R~ and R4 is a formyl radical, with an alkanol o~ 1 to 4 carbon atoms, for example methanol or ethanol, In the presence o~ an acid;
.

- 15- ~
.' .
.

6~

(f) for those compounds wherein at least one o~ Rl, R2~ R3 and R4 is a sulphamoyl radical or a mono- or di-alkylsulphamoyl radical, the reaction of a corresponding benzo[l,~dioxin derivative of the ~ormula I, wherein a~ leas~ one of Rl, R2, R3 and R4 is a chlorosulphonyl radical, with ammonia or a mono- or di-alkylamine wherein each alkyl part is of 1 to 4 carbon atoms;
(g) ~or those compounds where;n at least one of Rl, R2, R3 and R4 is a benzylideneamino radical, the reaction o~ a corresponding benzo[l,~dioxin derivative Or the formula I, wherein at least one of Rl, R2 3 R3 and R4 is an amino radical, with a benzaldehyde, optionally substituted by one to three halogen atoms, or Cl L~ alkoxy or nitro radicals, .
(h) for those compounds wherein ~t leas~ one of Rl~ R2, R3 and R4 is a phenylthioureido radical, the reaction of a corresponding benzo~l,3~dioxin derivakive o~ the ~ormula I, wherein at least ! one of R1, R23 R3 and R4 i9 an amino radical, with a phenylisothiocyanate, optionally substituted by one to three halogen atoms, or Cl_ll alkoxy or nitro radicals; .
(i) for those compounds wherein at least one of Rl, R2~ R3 and R4 is a bromine atom, the reaction of a corresponding.
benzorl,3]dioxin derivative of the formula I, wherein at least one o~ Rl, R2, R3 and R4 is a hydrogen atom, with bromine;
~ or those compounds wherein at least one of R1, R2, R3 .
and R4 is an alkoxycarbonyl radical, or a carbamoyl3 mono- or di-alkylcarbamoyl radical~ the reaction of a corresponding benzo~l53~dioxin derivative of the formula I9 wherein at least ~ne o~ Rl, R2, R3 and Rl is a ch1oroformyl rad~cal, with respectively a Cl ll a].kanol optionally substituted by one or more halogen atoms, or ammonia or a mono~ or di-alkylamine, wherein each alkyl part is of 1 to 4 carbon atoms;
(k) for those compounds wherein at least one OL Rl~ R2, R3 and R4'is a hydroxy radical, the reaction of a corresponding benzo[l,3~dioxin derivative of the formula'~, wherein at least one of Rl, R2, R3 and R4 is a diazo radical, with an acid, ~or example concentrated sulphuric acid~ in an aqueous medium; ' ~1) for those compounds wherein at least one 0~ ~1, R2,~R3 and R4 is a formyloxymethyl rad;cal, the reaction o~ a corresponding benzo~l~3]dioxin derivative of the formula I, wherein at least one of Rl, R2?,R3 and R~ is a hydroxymethyl radical, with aCl_4 alkyl ~ormate, for example methyl ~
formate, in the presence of an acid;
(m) for those compounds wherein at least one of Rl, R~, R3 ' and R4 is a hydrazinocarbonyl radical, the reaction of a corresponding benzo[l,3]dioxin derivative of the formula I, wherein at least one of Rl, R2, R3 and R4 is an alkoxycarbonyl .
radical, with hydrazine hydrate;
(n) for those compounds wherei'n X is a 2,2,2-trichloroethylidene radical and Y is a 2,2-dichlorovinylidene radical, the reaction of a corresponding benzo[l,3~dioxin derivative o~ the ~ormula I, wherein X and Y are each a 2,2,2-trichloroethylidene radical, with an alkali metal azide'or cyanide, for example sodium azide or cyanide,' or an alkali met'al a~kanoate or alkoxide.
~o) ~or those'compounds wherèin X and Y are'each a 2,2-dichlorovinylidene radical, the reaction of a corresponding '.

367'~

benzo[1,3]dioxin derivative of the ~ormula I, wherein X and Y
are each a 2,2,2-trichloroekhylidene radical, with a strong base, ~or example an alkali metal alkoxide such as potassium t-butoxide;
(p) ~or those compounds wherein at least one of Rl, R2, R3 and R4 is a cyano radical, the dehydration of a corresponding benzo~l,3~dioxin derivative of the formula I~ wherein at least one of Rl, R23 R~ and R4 is a carbamoyl radical, for example with thionyl chloride;
(q) for those compounds wherein X is a 2~2,2-trichloroethylidene radical, and Y is a 2,2-dichloroethylidene radical, the reaction of a 2-(2,2-dichloro-1-hydroxyethyl)phenol of the formula:-R2~CH(OII).C}}C12 . ¦

wit~ chloral hydrate in the presence of a strong acidg for example concentrated sulphuric acid,(r) for those compounds wherein X is a 2,2-dichloro-2-(C1 4-alkoxy)ethylidene radical and Y is a 2,2-dichlorovinylidene radical, the reaction of a corresponding benzo[1~3~dioxin derivative of the formula I, wherein X and Y are each a 292,2- .
trichloromethyl radical, with an alkali metal Cl_4-alkoxideg .~or example a sodium Cl ~I-alkoxide; ~ ~
~9 ) for those compounds wherein at least one of Rl, R2, R3 and R4 is an alkanoylhydrazonomethyl, hydrazonoalkyl or ~

phenylhydrazonomethyl radicaI~ the reaction of a corresponding `, . :
.

4~

benzo~1,3~dioxin derivative of the ~ormula I, wherein atleast one o~ Rl~ R2, R3 and R4 is a formyl or alkanoyl radical, with respectively an alkanoylhydrazine wherein the alkanoyl part is o~ up to 4 carbon atoms, hydrazine, or a phenylhydrazine wherein the phenyl ring is optionally , .
substituted by one to three halogen atoms or ~1 4 alkoxy or nitro radicals; or (t) for those compounds wherein at least one of Rl, R2, R3 and R4 is an alkoxy radical, the reaction of a corresponding benzorl,3~dioxin derivative of the ~ormula I wherein at least one o~ Rl, R2, R3 and R4 is a hydroxy radioal, with a Cl_4-alkyl halide, for example an alkyl iodide. -In process (n), it will be appreciated thatif one or more of Rl~ R2, R3 and R4 is a cyano radical and an excess of alkali metal azide is used, one or more o~ the cyano radicals will be converted into one or more tetrazol-5-yl ;`
.
radicals during the course of the reaction.-~ he starting material of the formula III may beobtained by acid hydrolysis o~ a corresponding benzo~l,3]dioxin o~ the formula I wherein X and Y are each a dichloromethylene . .~
radical, to give a 2-dichloroacetylphenolg which is reduced to give the required ~tarting material III.

The invention is illustrated but not limited by the ~ollowing examples:-" ' .
-19-~

:

~3G74~ ;

~xample 1 A solution o~ ethyl 2,4-bis(trichloromethyl)benzo-[1,3]dioxin-6-carboxylate (2.0 g.) in anhydrous ether (25 ml.) was added at room temperature during 20 minutes to a suspension of lithium aluminium hydride (0.2 g.) in anhydrous ether (25 ml.). The mixture was stirred for 1 hour, then ethyl acetate (5 ml.~ was added, followed by water (10 ml.).
The mixture was filteredj and the ether layer of the filtrate was separated. The aqueous phase was ex~racted with ether (3 x 10 ml.)~ the combined extracks were dried, and the solvent was evaporated. The residue was crystallised from ethanol to give 6-hydroxymethyl-2,4-bis(trichloromethyl)benzo-~1,3]dioxin, m.p. 134-136C.
Example 2 A mixture of 2,4-bis(trichloromethyl)benzo[1~3]-dioxin-6-carbonyl chloride ~5.0 g.~ and 2,2~2-trichloroethanol (25 ml.~ was warmed on a steam bath for 2 hours. The reaction mixture was cooled, and wàter was added to produce a white precipitate which was filtered off and crystallised from a mixture of ether and petroleum ether (b.p. 60-~0C.) to gi~e 2,2,2-trichloroethyl 2~bis(trichloromethyl)benzo[1,3]dioxin~
6-carbo~ylate, m.p. 129-13QC. `
In a similar manner, using the appropriate alcohol in place of 2,2,2-trichloroeth~nol, there were obtained;
methyl 2,4-bis(trichloromethyl)benzo[1,3]dioxin-6-carboxylate, m.p. 149.5-150.5C.; and n-butyl 2~4-bis(trichloromethyl~benzo-' - 20 - !~

i744 [1,3]dioxin-6-carboxylate, m.p. 60-62C.
xample ~
Nitric acid (d = 1.54, 10 ml.) was added to a stirred suspension of 2,4-bis(trichloromethyl)benzo[1,3]-dioxin-6-carboxylic acid (5 gO) in concentrated sulphuric acid (25 ml. )3 and the resulting suspension was stirred at room temperature ~or 2 hrs. The reaction mixture was filtered, and the solid product was crystallised from a mixture of petroleum ether (b.p. 60-80C.) and ether to give 8-nitro-2,4-bis(trichloromethyl)benzo[1~3Jdioxin-6-carboxylic acid, m.p. 211-212C.
Example 4 A mixture of 2~4-bis(trichloromethyl)benzo[1,3]-dioxin-6-carbonyl chloride (2 g.) and diethylamine (25 ml.) was heated under reflux for 2 hrs., cooled, and filtered to remove diethylamine hydrochloride. The filtrate was evaporated to dryness under reduced pressure, and the residue was crystallised from ethanol to give 4-dichloromethylene-N,N-diethyl-2-trichloromethylbenzo[1,3]dioxin-6-carboxamide, m.p. 123-124C.
Example 5 Premixes suitable for dilution with an animal feedstuff may be manufactured by incorporating 10, 25, 509 100 or 250 g. of 2,4-bis(trichloromethyl~benzo[1,3]dioxin-25 6-carboxylic acid in ground limestone so that the final weight of the premix is 500 g. ~
., ~
- 21 - ~
1~

~.

15~6~44 Similar premixes may be manufactured using similar quantities of any o~her benzo[l,~]dioxin derivative as hereinbefore defined.
Example 6 An animal feedstuf~ suitable for direc~ feeding to ruminants may be manufactured by intimately mixing 500 g. of a premix, obtained as described in Example 5~ with 999.5 kg.
of a typical cattle feeding stuff, to obtain a ruminant feedstuff containing 10, 25, 50, 100 or 250 g. of a benzo[l,3]-dioxin derivative per metric ton, according to the concentration of benzo[l,3]dioxin derivative in the premix used.
Suitable cattle feedingstuffs are:

Dairy Cake cwt.
Barley meal 10 Maize meal 1 Decorticated ground nut cake 1 Decorticated cotton seed cake 1 ~xtracted cotton seed cake 1 Wheat feed 3 Feather meal Seaweeq meal Bone meal ; Chalk Molasses 1 Vitamins and trace mineral mix '. :, .-.

~ - 22 -., ' . :
.
.''' . .
. .

67~

Beef Cube Barley meal ll cwt.
Wheat feed 5~ cwt.
Decorticated ground nut cake 4 cwt.
5Extracted ground nut cake 42 lbs.
Bone flour 4 cwt.
Chalk 42 lbs.
Salt 14 lbs Molasses 2 cwt.
10 Urea 4 cwt.
Vitamins and trace mineral mix 14 lbs.
- 20 cwt.
Example 7 The ability of the benzoC1,3]dioxin derivatives to inhibit the production of methane without increasing the production of hydrogen, and to increase the production of useful fatty acids, is demonstrated in vivo as follows:-A sheep fitted with a ruminal fistula is starved overnight, and then is offered its normal diet supplemented with 60 mg./kg. of 2,4-bis(trichloromethyl)benzo[l,3]dioxin-6-carboxylic acid. Samples of rumen fluid (15 to 20 mls.) are then withdrawn through the fistula at hourly intervals.
Each sample is filtered, and l ml. of 1% w/v sucrose solution is added to 9 ml. of the filtrate in a McCartney bottle, which is then closed with a rubber seal. The bottle is then filled with nitrogen through a hypodermic needle pushed through the rubber seal, and the displaced air is vented through a second similar needle. The bottle is incubated at :, .

~9C. for 3 hours~ and the composition of the gas in the bottle above the rumen fluid is sampled, and analysed by gas chromatography.
The following results were obtained:-Time Methane Hydrogen Acetic Acid Butyric (hrs.) % v/~ % v/v ~g./ml. ~g.Jml. ~g./ml.

.2 0.2 1.93 1.74 0.53 2 o.3 o.l 1~89 1.77 o.59 3 0.2 0.3 1.91 1.80 0.60 4 0~2 0.0 2.01 ~.87 o.64 Control 0.9 0.0 1.81 1.13 0.45 Example 8 The ability of the benzo~l,3~dioxin derivativesof the invention to inhibit the production of methane from rumen ~luid may conveniently be demonstrated by an i _ ro a8say, as ~ollows:-Rumen ~luid is obtained ~rom a cow via a rumenfistula3 and strained to remove large particulate matter.
Sterile Macartney bottles are used as fermenters, and are made up to contain 8.9 ml. of strained rumen ~luida l.Oml. of 1% w/v sucrose solution, and 0.1 ml. of a solution oP a compound under test dissolved in dimethylsulphoxide. The bottle is then .
closed with a rubber seal fitted with two hypodermic needles passing through it, one o~ which protrudes just through the seal to provide a gas outlet, while the other protrudes into the solution in the bottle to provide a gas inlet.

I
I
.. .

10~3l;74~L I

The air is then flushed from the bottle by introducing nitrogen through the inlet needle, and allowing the air/
nitrogen mixture to escape ~rom the bottle through the outlet nee'dle. Nitrogen is passed for 30 seconds, then the supply is shut off, and the outlet needle is removed from the rubber seal first, followed by the inlet needle. The contents o~ the'bottle are gently mixeda and the bottle is maintained at 39-40C~ in a water bath for 3 hours. The needle of an a;r-tight syringe is introduced through the rubber cap into the gas space above the liquid, the syringe is filled and emptied several times and a sample of the fermentation gas is withdrawn. The fermentation gas is then analysed by gas chromatography on two columns in succession, first a column packed with a mixture of Porapak Q
and Diatomite in the ratio 3:2, which separates carbon dioxidé from the mixture, and second a column packed with Molecular Sieve 5A, preoonditioned by heating to 250C. for 1~ hours in argon, which separates methane from hydrogen~
nitrogen and oxygen. Methane has the longest retention time, and from the area of the methane peak on the chromatogram, by comparison with chromatograms of standard concentrations of methane~ the concentration of methane in the fermentation gas is determined. A test compound is examined at various concent~tions in the rumen ~luid~ usually 1, 3, 10~ 30 and lOO~g./
ml., and the lowest of these concent~tions which achieves more than 50% .inhibition of methane production is recorded. For the benzo~1,'3~dioxin derivatives' indicated in the following table, the minimum 50% inhibitory concentrations (M.I.C;) were as shown~-- 25~

67~

~\~_CC13 R ~ ~<V

.- _ _ _ _ _ R2 M.I.C . R2 M.I.C.
t~g, /ml; ) . .(ug. ~ml; ) _ H 1 C2H5 . 10 Cl 3 C6H5 NH- S2 3 .
NH2 1 CH 30 . CH ( OH ) 3 CH3CO. NH 10 CH3CO 3 .
(CH3CO)2N 3 (C2H5)2N-S02 10 CN 3 NH2 N: C ( CH3 ) 30 CH~; 30 H . CO 3 COOH 1 H3 ( CH2 ) 2CO . NH . N CH 30 .
NH2CO 3 C13 . CH (OH) . NH. CO 10 Cl . CO . 1 C6H5 . CH: N 10 CH(CH ) O. CO30 4-Cl ~ C6H4 C}l N 10 C2H50.CO 10 3,4,5-~CH30)3.C6H4-CH:N' 10 CH30. CO 10 4-No2 ' C6H4 CH N 30 .
. HO ~ C~ 1 C 6H 5NH . CS . NH 10 N . CO . OCH2 1 C 6H5NH . N: CH 100 ~
CC13CH20. CO 10 HO 10 i N02 3 CH3CO. O 30 NH4~ . S03 100 C6H5C O 30 N~2S2 1 .
' ~ ___ , .

.
.

1~)i967~4 'EXample 9 .
The'procedure described in Example 8 was repeated, using the ben'zo~1,3~dioxin derivatives indicated in the following table, a~d the'resul~s obtained were as shown:-R ~ ~ CCl ~ 3 R ~ ~

Rl H CC13 _ _ Rl R3 R4 M.I.C. .
. (~g./ml;) .
H No2 H NO2 10 Br NH2 Br H 3 H CH3 H NH2 10 :

Cl Cl H Cl 100 H COOH H NO2 ¦'3 H (CH3CO)2N H (CH3CO)2N 3 . H CH3 ' H C2H50~CO 10 }I CH3 H CC13CH20.CO 30 .
~, EXà~l'e'10 The procedure described in Example ~ was repeated, .
using the benzo~l,3~dioxin derivatives indicated in the - 10 ~ollowing table,' and the results obtained were as shown:-.

;7~ ' /~CC13 R2~o _ _ R M.I.C. R M.I.C.
( ~g. /ml; ) ( ~Ig. /ml; ) , . - .

NH2NH. CO 3 5-tetrazolyl 1 2 5 2 1 l NH2 1 Exam~le ll The procedure described in Example 8 was repeated3 u~ing the benzo~l~3]dioxin derivatives indicated in the following table~ and the results obtained were as shown:-~CC12 ' ., R7J~

R M.I.C. R M.I.C.
(~g. /ml; ) (llg. /ml; ) , . . _ _ ._ NH2. CO 100 iCOOH lôO , __~. . _ ., Example 12 The procedure described in Example 8 was repeated, using the following benzo[l,3]dioxin derivatives, to 8ive .
; the results indicated--~ - 28 -~',' ' . .

.

7~
, 4-dichloromethylene-2-(1,1-dichloro-2-oxabutyl)benzoC1,3]dioxin-6-carboxylic acid, M.I.C. = lOO~g./ml.
4-dichloromethyl-2-methylben~o[1~3~dioxin-6-carboxylic acid, M.I.C. - l~gO/ml.
7~8-dihydroxy-5-(1-hydroxyethyl)-2~4-bis(trichloromethyl)benZO-[1,3]dioxin-6-carboxylic acid y-lactone, M.I.C. = lO~g./ml.
7,8-diacetoxy-5~ hydroxyethyl)-2,4-bis(trichloromethyl)benzo-[1,3~dioxin-6-carboxylic acid y-lactoneJ M.I.C. = lO~g./ml~
EXampIe'13 A mixture of 6-amino-2,4-bis(trichloromethyl)benzo-~1,3~dioxin (l.Og;), acety~chloride (lml;) and acetic anhydride (25ml;) was warmed on a steam bath for 5 hours. The reaction mixture was cooled and evaporated to dryness under reduced pressure~' Trituration of the oily residue with aqueous ethanol gave a solid product, which was crys~allised from ethanol to give 6-diacetylamino-2,4-bis~trichloromethyl)-benzoC1,3]dioxin, m.p. 147-148C.
Example 14 Solid sodium nitrite (1.34g;) was added in portions to a boiling suspension of 8-amino-6-methyl-2,4-bis(trichloro-methyl)benzo~l,3~dioxin (4.7g;) in a mixture'of absolute ethanol (20ml;), toluene (5ml;) and concentrated sulphuric acid (1.34ml;). The mixture was heated under reflux for 3 hours, cooled to ambient temperature and evaporated to dryness ~5 under reducèd pressure. The oily residue was triturated with petroleum ether (b.p. 60-80C;) and filtered, and the solid was crystallised from aqae'ous ethanol to give 6-methyl~
2,4-bis(trichloromethyl)benzo~1,3]dioxin m.p. 134-135C.
. ` .

~ .' .~ .
~. .

~ ~ 67 ~ ~ , Example 15 Chloral hydrate (~6.4g;) was added in portions to a stirred solution of p-hydroxypropiophenone (15g.) in concentrated sulphuric acid (lOOml;). A~ter the addition was completed, the mixture was stirred at room temperature for 3 hours and then kept for 5 days. The reaction mixture was poured onto ice, and the resulting solid product was filtered o~f~dissolved in diethyl ether (200ml;) and filtered to remove any metachloral and unreacted starting material. The filtra~e was dried, and evaporated ~o dryness under reduced pressure. Trituration of the residue with petroleum ether (b~p. 60-80C;) gave a solid product, which was crystallised ~rom aqueous ethanol to give 6-propionyl-2~4-bis(trichloromethyl)benzo~l~3~dioxin, mOp. 96-97C.
In a similiar manner using p-hydroxyacetophenone in place o~ ~-hydroxypropiophenone, there was obtained 6-acetyl-2,4-bis(trichloromethyl)benzo[1,3~dioxin3 mOp. 104-105C., and using 2-hydroxy-4-methylbenzoic acid there was obtained 6-methyl-2~4-bis(trichloromethyl)benzo~1,3~dioxin-8-carboxylic-acid, m.p. 290-291C.
Exam~le 16 Chloral hydrate (36.4g,) was added to a stirred solution o~ ~-hydroxybenzaldehyde (1202g;) in concentrated ~ùlphuric acid (lOOml;) and then kept at ~mbient temperature ~or 3 weeks. The reaction mixture was poured onto ice~ and the ' ~ 30 - I
I
.

i74L~ ~

solid product was filtered off, washed thoroughly with water (3 x lOOml;), and dried; The solid product was extracted with boiling methanol, from which, on cooling~
a crude product crystallised. The crude product was suspended in die~hyl ether, filtered through silica to remove unchanged startlng material9 and the filtrate was concentrated to dryness under reduced pressure. Crystallisation of the residue from methanol gave 6~ hydroxy-1-methoxymethyl)-2,4-bis~trichloromethyl)benzo~l,33dioxin, m.p. 123-125C.
EXample 17 Diethylamine (o.8g;) was added dropwise to a stirred suspension of 2,4-bis(trichloromethyijbenzo~1,3]dioxin-6-sulphonyl chloride (4.7g;) in absolute ethanol (20ml;), the mix~ure was maintained ~n~r gentle reflux for 2 hours, and the resulting solution was allowed to cool slowly to give a crystalline product, which was recrystallised from aqueous methanol to give 6-diethylsulphamoyl-2,4-bis(trichloromethyl)-benzo~l~3]dioxin, m.p. 125-126C.
Example 18 ~
A solution of tri-t-butoxy lithium aluminium hydride (prepared from lithium aluminium hydride (1.75g;) and dry t-butanol (13ml;) by the method described in Journal of t~e American Chemical Society, 1958, 80, 5377) in dry bis(2-methoxyethyl)ether (lOOml;) was added dropwise during 1 hour to a stirred solution of 2,4-bis~trichloromethyl)benzoC1,3]dioxin-6-carbonyl chloride (20g.) .
. .
.

~, ` .

.. .
.

in dry bis(2-methoxyethyl)ether (lOOml;) at -78C. The internal temperature was maintained at 50C. by the addition rate, and after the addition was complete, the reaction mixture was allowed to warm to ambient temperature and then t was poured onto crushed ice. The resulting precipitate was removed by filtration, and extracted with boiling glacial acet'ic acid. The extract was diluted with water, 2,~-bis-(trichloromethyl)benzo~1,3~dioxin-6-carboxaldehyde, mLp.
128-129C. crystallised out.
Example 13 ' A mixture of 2,4-bis(trichloromethyl)benzo[l,~]dioxin-6-carboxaldehyde (l.Og;) and phenylhydrazine (0.27g;) in chloro-form (35ml;) was heated under gentle reflux for 1 hour. The resulting solution was cooled and evaporated to dryness 15 under reduced pressure, and the residue was crystallised from ethanol to give 6~phenylhydrazonomethyl-2,4-bis(trichloro-methyl)benzo~ ]dioxin, m.p. 203-204~C.
In similar manner, using propionyl~hydrazine in place of phenyl~hydrazine there was obtained 2,4-bis(trichloromethyl)-20 benzo~l,3~dioxin-6-carboxaldehyde-n-propionylhydrazone, m.p. 191-192~C.
; 'Exampl'e'20 A mixture'of 6-amino-2,4-bis(trichloromethyl)benzo-~1,3~dioxin (2.0~;) and benzaldehyde (0.6g;) in absolute .
25 ethanol (25ml;) was heated' under re~lux for 5 hours. On cool;n~ the reaction mixture, 6-benzylideneamino-2,4-bis-(trichloromethyl)benzorl,3]dioxin,~m.p. 152-15~C. crystallised out.

:

: ' ~
~, ~ ,~ ` ' ' J
7~ ~

In a similar manner, using the appropriate aldehyde in place of benzaldehyde, there were obtained 6-(4-chlorobenzyl-idineamino) 2,4-bisttrichloromethyl)benzo[1,3]dioxin, m.p.
171-172C., 6-(LI-nitrobenzylideneamino)-2,ll-bis(trichloro-methyl)benzo[l,~dioxin; and m.p. 169-171C; 6-(3,4,5-trimethoxybenzylideneamino)-2g4-bis(trichloromethyl)benzo[1,3]-dioxin, m.p. 122-124~C.
ExampIe 21 A mixture of 6-amino-2,4-bis(trichloromethyl)benzo~-~1,3~dioxin (1.93g;) and phenylisothiocyanate (0.7g.) in chloroform (25ml;) was heated under reflux for 6 hours. The reaction solution was evaporated to dryness, and the residue was crystallised from benzene to give 6-phenylthioureido-2,4-bis(trichloromethyl)benzo~1,3]dioxin, m.p. 112-113C.
Ex~mple 22 A solution of bromine (1.59ml.) in glacial acetic acid (lOml;) was added in portions to a stirred suspension of 6-am$no-2,4-bis(trichloromethyl)benzoC1,3~dioxin (3.86g;) in glacial acetic acid (lOml;). The reaction mixture was then heated slowly to boiling~-and was heated under reflux for 15 minutes. After coolingg the crystalline product which separated was removed by filtration, washed with acetic acid~
and crystallised from ethanol t20ml;) to give 6-amino-5,7-dibromo-2,4-bis(trichloromethyl)benzo~ ]dioxin, m.p. 158-159C.
Examp`le 23 A mixture o~ 6~8-diamino-2,4-bis(trichloromethy ~ enzo-- 33 ~
.

' .
.

74~4 '.

[1,3~dioxin tlg.), acetic anhydride ~25ml;) and acetyl chloride (2ml;) was hea'ted on the steam bath for 10 hours. After cooling, the reaction mixture was evaporated to dryness under reduced pressure, and the residue was triturated with aqueous ethanol. The solid product thus obtained was crystalllsed from ethanol to give 6,8-bis(diacetylamino)-2~4-bis(trichloromethyl)benzo~l,3]dioxin, m.p. 182-183C.

Example ?4 A mixture of 6-methyl-2,4-bis(trichloromethyl)benzo-[193~dioxin-8-carbonyl chloride (2.0g;) and ethanol (20ml.) was warmed in the steam bath for 2 hours. The reaction mixture was cooled to produce a white crystalline precipitate, which was filtered off and crystallised from ethanol to give ethyl 6-methyl-2,4-bis(trichloromethyl)benzo[1,3]dioxin-6-carboxylate, m.p. 128-129C. ' In a similar manner~ using 2,2,2-trichloroethanol in place of ethanol~ there was obtained 2,2,2-trichlo~oethyl 6-methyl-2,4-bisttrichloromethyl)benzo[1,~3dioxin-6-carboxylate m.p. 134-135C.
Example''25 A mixture of 6-methyl-2,4-bis(trichloromethyl)benzo-Cl,3~dioxin-8-carbonyl chloride ( 2.0g:) concentrated ammonia (lOml;) and ethanol ~lOml;) was heated under reflux for 2 hours.
~ complete solution was not obtained, but the reaction mixture was cooled and filtered, and the solid product was washed with et'hanol and dried, to give 6-methyl-2,4-bis(trichloromethyl)-b~n~.o~l,3]dioxln-8-carboxa~ide m p. 281-283C

.' .

;7~4 Examp l'e''26 A mixture of 2,4-bis(trichloromethyl)benzo[1,3]dioxin-6-diazonium chloride (5g;) concentrated sulphuric acid (125ml.) and water (125 ml.) was stirred and heated at 160C. for '5 20 minutes. ~he reaction mixture was cooled to ambient temperature ~nd the product was filtered off~ washed with water, and crystallised from cyclohexane, to give 6-hydroxy-2,4-bis(trichloromethyl)benzorl,3]dioxin, m.p. 167-169C.
The diazonium chloride used as starting material in the above process may be prepared as follows:-A solution of sodium nitrite (1.96g.) in water (30ml;) was added to a stirred' suspension of'6-amino-2,4-bis(trichloro-methyl)benzo~1,3]dioxin'(10g;) in a mixture of hydrochloric acid (40ml;) and water (180ml;), cooled to 0-5C. The ~uspension was stirred for 1 hour at 0-5C., the mixture was filtered, and the solid product was washed with water, dr;ed ' and crystallised from water to give'2,4-bis(trichloromethyl)-benzorl,3]dioxin-6-d~azonium chloride, m.p. 140-142C.
''Exanip'le'27 A mixture of 6-hydroxy-2,4-bis(trichloromethyl)benzo-rl,3~dioxin (l.Og.) and acetic anhydride (lOml;) was warmed on the steam bath for 15 minutes, and then cooled to ambient ' temper`ature.' Water (40ml;) was added, and the mixture stirred for 1 hour. The product was removed by filtration, washed with water, dried and crystallised from ethanol to give .' , ~ . .

~ 35~

&,7~4 6-acetoxy-2~4-bis(krichloromethyl)benzo[l~3~d:io~lrl~ m.p. 142-14llC.
''Example''28 A mixture of 6-hydroxy-2,4-bis(trichloromethyl)benzo-[1,3~dioxin (l.Og;), benzoyl chloride (0.35ml.) and toluene (20ml.) was warmed on the steam bath for 1 hour. The resulting solution was cooled to ambient temperature and evaporated to dryness under reduced pressure to give an oily residue. The residue was triturated with ethanol (~ml.) to give a white solid, which was crystallised from ethanol to give 6-benzoyloxy-2,4-bis(trichloromethylbenzorl,3~dioxin, m.p. 167-169C.
Exampl'e_29 A solution of 2,4-bis(trichloromethyl)benzo~1,3]dioxin-6-carboxaldehyde (l.Og;) in diethylether (lOml;) was added to a mixture of aluminium chloride (1.17g;) and lithium alumini~ ~Ydride { 0.95g;) in diethyl ether (15ml;). A vigorous reaction was observed dùring this addition, the mixture was stirred for 1~ hours, and then a solution of methyl formate (5ml;) in diethyl ether (20ml.) was added at 0C. The reaction mixture was allowed to reach ambient temperature, and 20X sulphuric acid (25ml;) was added. The organic layer was separated, dried, and concentrated under reduced pressure to give an oily product which readily solidi~ied on trituration with petroleum ether (b.p. 60-80~C;j to give 6-formyloxymet~yl-2,4-bis-~trichloromethyl)benzo[1,3~dioxin, m.p. 75-77C.
' EXamp'l'e'30 A mixture o~ 7,8-dihydroxy-6-(2,2,2-trichloro-1-hydroxyethyl)-2,4-bis(trichloromethyl)benæorl,3]dioxin-~-~67~ 3 carboxylic acid y-lactone (l.Og;), concentrated sulphur;c acid (0.5ml.) and acetic anhydride (25ml.) was warmed on a steam ba~h for 5 hours. The reaction mixture was cooled, and evaporated to dryness under reduced pressure, and the residue was triturated with petroleum ether (b.p. 60-80C;) to give a solid product. The solid product was crystallised ~rom ethanol to give 7,8-diacetoxy-6-(2,2~2-trichloro-1-hydroxyethyl)-2,4-bis(trichloromethyl)benzo~1,3]dioxin-5-carboxylic acid y-lactone, m.p. 209-210C.
EXampl'e 31 ' ~ A mixture of ethyl 294-bis(trichloromethyl)benzo-C1,3~dioxin-6-carboxylate (6.4g;), 100% hydrazine hydrate (3ml,) and ethanol (30ml;) was warmed on the steam bath ~or 30 hours.
The reaction mixture was cooled, and thenevaporated to dryness~
under reduced pressure. The oily residue was triturated ~lth petroleum ether (bcp. 60-80C;) and the solid product thus obtained was crystallised from ethanol, to give 4-dichloro-methylene-2-trichloromethylbenzo[1,3~dioxin-6-carbohydrazide, ; m.p. 182-183C.
Example'32 A mixture of 2,4 bis(trichloromethyl)benzo[l,3]dioxin-6-carboxylic acid (2~08g;), ammonium chloride ~0.33g;) and Rodium azide (0.36g.) in anhydrous dimethylsulphoxide (lOml~) was warmed on the steam bath for 16 hours. The reaction ~5 m;xture was caoled, poured onto ice and kept for 16 hours. The white product was filtered' of~, washed with water and dried~
and crystallised ~rom aqueous ethanol to give 4-dichloro-- 37 ~

. , . ' :

mekhylene~2-trichloromethylbenzo[1,3)dioxin-6-carboxylic acid, m.p. 222-223C.
In a similar manner, using the appropriate 2,4-bis(trichloromethyl)benzo[l,3]dloxin~there were obtained 6-cyano-4-dichloromethylene-2-trichloromethylbenzo [13 3]dioxin, m.p. 131~133C.; and 6-amino-4-dichloromethylene-2-trichloro-methylbenzoC1,3]dioxin, m~p. 125-126C.
Exam Ie 3~
P -. ,:
A mixture of 6-cyano-2,4-bis(trichloromethyl)benzo-[1,33dioxin (1~98g.), ammonium chloride (0.33g:) and sodium azide in anhydrous dimethylformamide was warmed on the steam bath for 16 hours. The reaction mixture was cooled, poured onto ice and kept for 16 hours. The amorphous white product was filtered off, triturated with acetic acid, and crystallised from chloro~orm to give 4-dichloromethylene-6-(tetrazol-5-yl)-2-trichloromethylbenzo[1,3~dioxin, m.p. 222C~
EXampIe 34 A mixture of 2,4-bis(trichloromethyl)benzo[1,3]dioxin-6-carboxamide (3.14g;) and potassium t-butoxide (2.5g.) in 50% aqueous dimethylsulphoxide (50ml;) was heated a~ 80-90G.for 2 hours. The solid productwas filtered off, dried and crystallised from ethanol ~o give 2,4-bis~dichloromethylene)benzo~1,3~dioxin-6-carboxamide, m.p. 217-218C.
In a similar mannerS using 2,4-bisttrichloromethyl)-benzoC193~dioxin-6-carboxylic acid~ there was obtained 2,4-bis~dichloromethylene)benzo~l,3]dioxin-6-carb~oxylic acid m.p.
199-200C. ~
.

- :' ~, ' .

74~ ~

EXam~le 35 2,4-Bis(dichloromethylene)benzo~1,3]dioxin-6-carboxamide ~3.0g.) was added in portions to a stirred mixture of thionyl chloride (15m~;) in dimethylformamide t60ml;) at 50C. A precipitate rapidly formed which, a~ter cooling the reaction mixture to ambient temperature, was filtered off, dried, and crystallised from ethanol to give 6-cyano-2,4-bis-(dichloromethylene)benzo[1,3~dioxin, m.p. 167-168C.
Example 36 A mixture of 2,2-dichloro~ 2-hydroxy-5-carboxvphenyl)-ethanol ~1.25g; )J chloral hydrate (l.Og.) and concentrated sulphuric acid (12.5ml;) was stirred at room temperature for 3 days, The reaction mixture was poured onto ice, and the product was ~iltered off, was~ed with water, dried and .
crystallised from aqueous acetic acid to give 4-dichlorometh~l;
2-trichloromethylbenzo~1,3~dioxin-6-carboxylic acid, m,p.
209C. ~
The 2,2-dichloro-1-(2 hydroxy-5-carboxyphenyl)etbanol used as starting material in the above process may be prepared as follows:-A mixture `of 2,4-bis(dichloromethylene)benzo[1l3~dioxin-6-carboxamide (lOg;),acetic acid (150ml;) and hydrochloric acid (150ml.) was heated under reflux for 3 hours. The solution wa~ cooled, and evaporated to dryness under reduced pressure and the res`idue was crystallised from acidified water to give 4-carboxy a,~-dichloro-2-hydroxy-acetophenone, m.p. 161-162C.
.

_ 3g ~
.

~ ..

. ~ .

i7~

4-Carboxy-a,~-dichloro-2-hydroxyacetophenone (2.49g.) was added in portions to an ice-cooled solu~ion of sodium borohydride (o.56g;) in ethanol (lOml.). The'reaction was stirred for 1 hour, and evaporated to drvness to give a yellow oily solid, which on treatment with 2N hydrochloric acid gave a white solid, which readily crystallised from water to give'2,2-dichloro-1-(2-hydroxy-5-carboxyphenyl)ethanol, m.p.
214-215C.
'Example 37 A mixture of 2,4-bis(trichloromethyl)benzo[1,3]dioxin-6-sulphonamide (2.0g.), sodium cyanide (l.Og.), ethanol (25ml;) and water (lOml.) was stirred and heated at 55-60Co for 24 hours. The reaotion mixture was cooled and acidified with concentrated hydrochloric acid. The solid product was filtered off and crystallised from aqueous methanol to give 4-diohloromethylene-2-trichloromethylbenzo[l~3~dioxin-6- ..
! sulphonomide, m.p. 151-152C.
Exam~Ie'38 ; A mixture of 6-acetyl-2,4-bis(trichloromethylbenzo[1,3]-dioxin (2.0g;) and 100% hydraz;ne hydrate (0.25g;) in absolute ethanol (25ml;3 was heated under re~lux for 16 hours, and cooled to give 6-acetyl-2,4-bis(trichloromethyl)benzo[1,3]dioxin hydrazone~ m.p. 159C.
`~
.
A solution of sodium hydroxide (0.52g;) in ethanol (50ml;) was added dropwise to a stirred' solution of 6-hydroxy-29~-bis(trichloromethyl)benzo~1,3~dioxin (5g.) in ethanol (lOOmlO) and the resulting solution was stirred for 15 minutes. Methyl .~
., .
."
.

7~L4 iodide (1.7ml:) was then added, the reaction mixture was warmed on a steam bath for 1 hour, and evaporated to dryness under reduced pressure, and the oily residue was triturated with diethyl ether and filtered to remove sodium iodide.
The filtrate was chromatographed on silica (Kieselgel 60, 200g;) and the product was crystallised from ethanol to give 6-methoxy-2,4-bis(trichloromethyl)benzo[1,3]dioxin, m.p.
105-107C.
ExampIe 40 A mixture of 2,4-bis(trichloromethyl)benzo[1,3~dioxin (20g; 3~ potassium hydroxide (48go ) and ethanol (200ml;) was warmed on the steam bath ~or 30 minutes during which a white solid ~ormed. Water (200ml;) was added, giving a red solution which was concentrated to 200ml.total volume to give a solid sodium salt which was removed by filtration and treated with 2N hydrochloric acid to liberate the free acid. The white solid proced was extracted with diethyl ether, and the organic extract was dried and concentrated under reduced pressure.
The residue was crystallised from cyclohexane to give 2-(1,1-dichloro-1-ethoxymethyl~4-dichloromethylenebenzoC1,3~-dioxin 6-carboxylio acid, m.p. 121-lZ2C.
.

-41- 1~ ~

Claims (24)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the manufacture of a benzo [1,3] dioxin derivative of the formula:- I
wherein:-(i) X and Y are both 2,2,2-trichloroethylidene radicals, R2 is a hydrogen atom, and R1, R3 and R4, which may be the same or different, are each a substituent Q, which is a hydrogen or halogen atom; an amino, carbomoyl, carboxy, chloroformyl, cyano, formyl, formyloxymethyl, hydrazinocarbonyl, hydroxy, nitro, sulphamoyl, sulpho or ammonium sulphonato radical, an alkanoyl, mono- or di-alkanoylamino, alkanoyl-hydrazonomethyl, alkanoyloxy, alkoxy, alkoxycarbonyl, alkoxy-hydroxymethyl, alkyl, mono- or di-alkylsulphamoyl, mono- or di-alkylcarbamoyl, hydrazonoalkyl, hydroxy-alkyl or hydroxyalkylcarbamoyl radical wherein each alkanoyl, alkoxy and alkyl part is of up to 4 carbon atoms and is optionally substituted by one or more halogen atoms; a benzoyl,benzoyloxy, benzylideneamino, phenyl-hydrazonomethyl, mono- or diphenylsulphamoyl or phenylthioureido radical, in each of which the phenyl ring is optionally substituted by one to three halogen atoms or C1-4 alkoxy or nitro radicals; or a tetrazolyl radical; or, when R1 is a carboxy radical and R2 is a 1-hydroxyalkyl radical, optionally substituted as defined above, a .gamma.-lactone thereof; or, for those compounds containing a carboxy or sulpho group, base addition salts thereof, or, for those compounds containing a basic amino group, acid addition salts thereof, provided that not all of R1, R3 and R4 are hydrogen atoms;
(ii) X and Y are both 2,2,2-trichloroethylidene radicals, R1, R3 and R4 are hydrogen atoms, and R2 is a bromine, iodine or fluorine atom; a formyl, formyloxy-methyl, hydrazinocarbonyl or hydroxy radical; an alkanoyl, alkanoylhydrazonomethyl, alkanoyloxy, alkoxy, alkoxyhydroxymethyl, mono- or dialkylsulphamoyl mono-or dialkylcarbamoyl, hydrazonoalkyl or hydroxyalkyl radical, wherein each alkanoyl, alkoxy or alkyl part is of up to 4 carbon atoms, a mono- or di-alkanoylamino radical wherein each alkyl part is of 3 to 4 carbon atoms, or an alkyl radical of 3 or 4 carbon atoms, any of which radicals is optionally substituted by halogen atoms, a chloroalkoxycarbonyl radical of up to 4 carbon atoms; a hydroxyalkylcarbamoyl radical wherein the alkyl part is of 1 to 4 carbon atoms, optionally substituted by halogen atoms, except 2,2,2-trichloro-1-hydroxyethylcarbamoyl, or a benzoyl, benzoyloxy, benzylideneamino, phenylhydrazonomethyl, diphenylsulphamoyl or phenylthioureido radical, in each of which the phenyl ring is substituted by one to three halogen atoms, or C1-4 alkoxy or nitro radicals; or a phenylsulphamoyl radical substituted by one to three halogen atoms, or C1-4 alkoxy or nitro radicals;
(iii) X and Y are both 2,2,2-trichloroethylidene radicals, and R1, R2, R3 and R4 have any of the meanings defined above for a substituent Q, provided that not more than two are hydrogen atoms, and excepting compounds wherein:
R2 is a nitro radical, and either R3 is a methyl radical or R4 is a methyl or nitro radical;
R2 is an amino radical, and either R3 is a bromine atom or R4 is an amino or methyl radical; R2 is an acetamido radical and R3 is a bromine atom; R2 is a benzamido radical and R4 is a methyl radical; R2 is a hydroxy or methoxy radical and R1 and R3 are chlorine atoms; R2 is a methyl radical and either R3 is a nitro radical or R4 is a nitro or amino radical; or R2 is a chlorine atom and either R4 is a chlorine atom, or an amino, acetamido or nitro radical, or R1 and R4 are chlorine atoms; or R2 is a 2,2,2-trichloro-1-hydroxyethyl radical and R1 is a carboxy radical, and R1 and R2 together from a .gamma.-lactone ring, and R3 and R4 are both hydroxy radicals; and any of R1, R2, R3 and R4 not otherwise defined are hydrogen atoms;
(iv) X and Y are both 2,2-dichlorovinylidene radicals, and R1, R2, R3 and R4 have any of the meanings defined above for a substituent Q, excepting those compounds wherein:
R2 is an amino radical; R1 and R3 are chlorine atoms and R2 is a hydroxy or methoxy radical; or R2 is a methyl radical and either R3 is a nitro radical or R4 is an amino radical; and any of R1, R2, R3 and R4 not otherwise defined are hydrogen atoms;
(v) X is a 2,2,2-trichloroethylidene radical, Y is a 2,2-dichlorovinylidene radical and R1, R2, R3 and R4 have the meanings defined above for a substituent Q, excepting those compounds wherein R2 is a nitro radical and either R3 is a methyl radical or R4 is a nitro radical, and any of R1, R3 and R4 not otherwise defined are hydrogen atoms;
(vi) X is a 2,2-dichloro-2-(C1-4alkoxy)ethylidene radical, Y is a 2,2-dichlorovinylidene radical and R1, R2, R3 and R4 have the meanings defined above for a substituent Q;
(vii) is a 2,2,2-trichloroethylidene radical, Y is a 2,2-dichloroethylidene radical and R1, R2, R3 and R4 have the meanings defined above for a substituent Q, which comprises:-(a) the reaction of a phenol of the formula:- II

With two molecular equivalent proportions of chloral hydrate in the presence of a strong acid:
(b) for those compounds wherein at least one of R1, R2, R3 and R4 is a hydrogen atom, the reaction of a benzo[1,3]dioxin derivative of the formula I, wherein at least one of R1, R2, R3 and R4 is a diazonio radical, with an acid and a reducing agent, in a substantially non-aqueous medium;
(c) for those compounds wherein at least one of R1, R2, R3 and R4 is a hydroxy radical, the reaction of a salt of a benzo[1,3]dioxin derivative of the formula I wherein at least one of R1, R2, R3 and R4 is a diazonio radical, with an acid in an aqueous medium;
(d) for those compounds wherein X is a 2,2,2-trichloro-ethylidene radical and Y is a 2,2-dichloroethylidene radical, the reaction of a 2-(2,2-dichloro-1-hydroxy-ethyl)phenol of the formula:- III
with chloral hydrate in the presence of a strong acid;
whereafter, when a benzo[1,3]dioxin derivative wherein Y is a 2,2-dichlorovinylidene radical, or both X and Y are 2,2-dichloro-vinylidene radicals, is required, the product so obtained, wherein X and Y are both 2,2,2-trichloroethylidene radicals, is reacted with respectively one or two molecular equivalents of an alkali metal cyanide or a base, whereafter, if desired, particular substituents R1, R2, R3 and R4 may be transformed to other such substituents, as defined above.

2. A process as claimed in claim 1 for the manufacture of a compound of the formula I wherein at least one of R1, R2, R3 and R4 is an alkanoyloxy or a mono- or di-alkanoylamino radical wherein each alkyl part is of 1 to 4 carbon atoms or a benzoyloxy radical, which comprises the reaction of an initially-formed product of the formula I, wherein at least one of R1, R2, R3 and R4 is an amino or hydroxy radical, with an alkanoyl halide of 1 to 4 carbon atoms or a benzoyl halide, which may optionally be substituted as defined in claim 1.

3. A process as claimed in claim 1 for the manufacture of a compound of the formula I wherein at least one of R1, R2, R3 and R4 is a formyl radical, which comprises the reduction of an initially-formed product of the formula I wherein at least one of R1, R2, R3 and R4 is a chloroformyl radical.

4. A process as claimed in claim 1 for the manufacture of a compound of the formula I wherein at least one of R1, R2, R3 and R1 is an alkoxyhydroxymethyl radical wherein the alkoxy part is of 1 to 4 carbon atoms, which comprises the reaction of an initially-formed compound of the formula I, wherein at least one of R1, R2, R3 and R4 is a formyl radical, with an alkanol of 1 to 4 carbon atoms, optionally substituted as defined in claim 1, in the presence of an acid.

5. A process as claimed in claim 1 for the manufacture of a compound of the formula I wherein at least one of R1, R2, R3 and R4 is a sulphamoyl radical, or a mono- or di-alkyl-sulphamoyl radical in which each alkyl part is of 1 to 4 carbon atoms, which comprises the reaction of an initially-formed compound of the formula I, wherein at least one of R1, R2, R3 and R4 is a chlorosulphonyl radical, with ammonia or a mono- or di-alkylamine wherein each alkyl part is of 1 to 4 carbon atoms, optionally substituted as defined in claim 1.

6. A process as claimed in claim 1 for the manufacture of a compound of the formula I wherein at least one of R1, R2, R3 and R4 is a benzylideneamino radical, which comprises the reaction of an initially-formed compound of the formula I, wherein at least one of R1, R2, R3 and R4 is an amino radical, with a benzaldehyde optionally substituted as defined in claim 1.

7. A process as claimed in claim 1 for the manufacture of a compound of the formula I wherein at least one of R1, R2, R3 and R4 is a phenylthioureido radical, which comprises the reaction of an initially-formed compound of the formula I, wherein at least one of R1, R2, R3 and R4 is an amino radical, with a phenylisothiocyanate, optionally substituted as defined in claim 1.

8. A process as claimed in claim 1 for the manufacture of a compound of the formula I wherein at least one of R1, R2, R3 and R4 is a bromine atom, which comprises the reaction of an initially-formed compound of the formula I, wherein at least one of R1, R2, R3 and R4 is a hydrogen atom, with bromine.

9. A process as claimed in claim 1 for the manufacture of a compound of the formula I, wherein at least one of R1, R2, R3 and R4 is a carbamoyl radical, or an alkoxycarbonyl or mono- or di-alkylcarbamoyl radical wherein each alkyl or alkxoy part is of 1 to 4 carbon atoms, which comprises the reaction of an initially-formed compound of the formula I, wherein at least one of R1, R2, R3 and R4 is a chloroformyl radical, with respectively ammonia, a C1-4 alkanol, or a mono- and di-(C1-4-alkyl)amine optionally substituted as defined in claim 1.

10. A process as claimed in claim 1 for the manufacture of a compound of the formula I, wherein at least one of R1, R2, R3 and R4 is a formyloxymethyl radical, which comprises the reaction of an initially-formed compound of the formula I, wherein at least one of R1, R2, R3 and R4 is a hyrdroxymethyl radical, with a C1-4 alkyl formate, in the presence of an acid.

11. A process as claimed in claim 1 for the manufacture of a compound of the formula I, wherein at least one of R1, R2, R3 and R4 is a hydrazinocarbonyl radical, which comprises the reaction of an initially-formed compound of the formula I, wherein at least one of R1, R2, R3 and R4 is an alkoxycarbonyl radical, wherein the alkoxy part is of 1 to 4 carbon atoms, with hydrazine hydrate.

12. A process as claimed in claim 1 for the manufacture of a compound of the formula I, wherein X is a 2,2,2-trichloro-ethylidene radical and Y is a 2,2-dichlorovinylidene radical, which comprises the reaction of an initially-formed compound of the formula I, wherein X and Y are each a 2,2,2-trichloro-ethylidene radical, with an alkali metal azide.

13. A process as claimed in claim 1 for the manufacture of a compound of the formula I, wherein at least one of R1, R2, R3 and R4 is 2 cyano radical, which comprises the dehydration of an initially-formed compound of the formula I wherein at least one of R1, R2, R3 and R4 is a carbamoyl radical.

14. A process as claimed in claim 1 for the manufacture of a compound of the formula I, wherein X is a 2,2-dichloro-2-(C1-4 alkoxy)ethylidene radical and Y is a 2,2-dichlorovinylidene radical, which comprises the reaction of an initially-formed compound of the formula X, whrein X and Y are each a 2,2,2-tri-chloroethylidene radical, with three or more equivalent proportions of an alkali metal C1-4 alkoxide,

15. A process as claimed in claim 1 for the manufacture of a compound of the formula I, wherein at least one of R1, R2, R3 and R4 is an alkanoylhydrazonomethyl radical, wherein the alkanoyl part is of 1 to 4 carbon atoms, or a phenylhydrazono-methyl radical, which comprises the reaction of an initially-formed compound of the formula I, wherein at least one of R1, R2, R3 and R4 is a formyl radical, with respectively an alkanoylhydrazine wherein the alkanoyl part is of 1 to 4 carbon atoms, or a phenylhydrazine, optionally substituted as defined in claim 1.

16. A process as claimed in claim 1 for the manufacture of a compound of the formula I, wherein at least one of R1, R2, R3 and R4 is a 1-hydrazonoalkyl radical, wherein the alkyl part is of 1 to 4 carbon atoms, which comprises the reaction of an initially-formed compound of the formula I, wherein at least one of R1, R2, R3 and R4 is a formyl radical or an alkanoyl radical of 1 to 4 carbon atoms optionally substituted as defined in claim 1, with hydrazine.

17. A process as claimed in claim 1 for the manufacture of a compound of the formula I, wherein at least one of R1, R2, R3 and R4 is an alkoxy radical of 1 to 4 carbon atoms, which comprises the reaction of an initially-formed compound of the formula I, wherein at least one of R1, R2, R3 and R4 is a hydroxy radical, with a C1-4 alkyl halide, optionally substituted as defined in claim 1.

18. A process as claimed in claim 1 for the manufacture of a compound of the formula I wherein at least one of R1, R2, R3 and R4 is a hydroxymethyl radical, which comprises the reaction of an initially-formed compound of the formula I, wherein at least one of R1, R2, R3 and R4 is an alkoxycarbonyl radical of 2 to 5 carbon atoms with a reducing agent.

19. A process as claimed in claim 1 for the manufacture of a compound of the formula I wherein at least one of R1, R2, R3 and R4 is an alkoxycarbonyl radical of 2 to 5 carbon atoms optionally substituted by one or more halogen atoms, which comprises the reaction of an initially-formed compound of the formula I wherein at least one of R1, R2, R3 and R4 is a chloroformyl radical with an alkanol of 1 to 4 carbon atoms, optionally substituted by one or more halogen atoms.

20. A process as claimed in claim 1 for the manufacture of a compound of the formula I wherein at least one of R1, R2, R3 and R4 is a nitro radical, which comprises the nitration of an initially-formed compound of the formula I wherein at least one of R1, R2, R3 and R4 is a hydrogen atom.

21. A process as claimed in claim 1 for the manufacture of 4-dichloromethylene-2-trichloromethylbenzo[1,3]dioxin-6-carboxylic acid which comprises the reaction of p-hydroxybenzoic acid with two molecular proportions of chloral in the presence of a strong acid, whereafter the product so obtained is reacted with approximately one molecular equivalent of an alkali metal cyanide or a base.

22. 4-Dichloromethylene-2-trichloromethylbenzo[1,3]dioxin-6-carboxylic acid whenever manufactured by the process claimed in claim 21 or by an obvious chemical equivalent thereof.

23. A process as claimed in claim 1 for the manufacture of 4-dichloromethylene-6-(tetrazol-5-yl)2-trichloromethylbenzo-[1,3]dioxin which comprises the reaction of p-hydroxybenzonitrile with two molecular proportions of chloral in the presence of a strong acid, whereafter the product so obtained is reacted with an alkali metal azide.

24. 4-Dichloromethylene-6-(tetrazol-5-yl)-2-trichloro-methylbenzo[1,3]dioxin whenever manufactured by the process claimed in claim 23 or by an obvious chemical equivalent thereof.