United States Patent [191
`Pfiffner
`
`[54] PIPERIDINES MORPHOLINES, ETC, AND
`FUNGICIDAL COMPOSITIONS THEREOF
`[75] Inventor: Albert Pfiffner,‘ Bulach, Switzerland
`[73] Assignee: Hoffmann-La Roche Inc., Nutley,
`NJ.
`[21] Appl. No.: 852,768
`[22] Filed:
`Nov. 18, 1977
`[30]
`Foreign Application Priority Data
`Nov. 22, 1976 [AT] Austria .......................... .. A 8660/76
`
`[51] Int. Cl.2 ................... .. C07D 295/02; AOlN 9/22;
`C07D 211/14
`[52] US. Cl. ............................... .. 424/248.4; 424/258;
`424/267; 544/105; 544/173; 544/178; 546/141;
`546/ 149; 546/ 153; 546/164; 546/ 165; 546/ 150;
`.
`546/ 192; 542/429; 542/469
`[58] Field of Search .................... .. 260/293.65, 293.72;
`544/105, 178, 173; 546/141, 149, 153, 165, 164,
`192, 150; 424/248, 267, 258; 542/429, 469
`References Cited
`U.S. PATENT DOCUMENTS
`2,213,469
`9/1940
`2,647,122‘
`7/1953
`2,662,886 12/1953
`4,104,383
`8/1978
`
`[56]
`
`FOREIGN PATENT DOCUMENTS
`1164152 9/1964 Fed. Rep. of Germany .
`1173722 l/ 1965 Fed. Rep. of Germany .
`1198125 8/1965 Fed. Rep. of Germany .
`1320244 1/ 1963 France .
`92920 10/1972 German Democratic Rep. .
`116739 12/1975 German Democratic Rep. .
`7713685 12/ 1967 Netherlands .
`
`[111
`[45]
`
`4,202,894
`May 13, 1980
`
`Attorney, Agent, or Firm—Jon S. Saxe; George M.
`Gould; Peter R. Shearer
`[57]
`ABSTRACT
`Heterocyclic compounds characterized by the formula
`
`wherein R, R1, R2, R3, R4, R5, R6, X and z are as herein
`after set forth,
`prepared, inter alia, by reacting a compound character
`ized by the formula
`
`R
`
`with an amine characterized by the formula
`
`R4
`
`r-b ,Rs
`
`HN
`
`X
`
`\JKR 6
`
`11
`
`III
`
`OTHER PUBLICATIONS
`Cannata et al., “Tetrahedron”, vol. 27, pp. 5247-6254,
`(1971).
`Primary Examiner-Alan L. Rotman
`Assistant Examiner-Robert T. Bond
`
`wherein R, R1, R2, R3, R4, R5, R6, X and Y are as here
`inafter set forth,
`are described. The end products are useful as fungicidal
`agents.
`
`140 Claims, No Drawings
`
`FlatWing Ex. 1019, p. 1
`
`

`

`1
`
`4,202,894
`
`PIPERIDINES MORPHOLINES, ETC., AND
`FUNGICIDAL COMPOSITIONS THEREOF
`
`BRIEF SUMMARY OF THE INVENTION
`The invention relates to heterocyclic compounds of
`the formula
`'
`'
`
`5
`
`(0):
`
`wherein R, R1, R2, R3, R4, R5, R6, X and z are as herein
`after described.
`In another aspect, the invention relates to fungicidal
`compositions and methods.
`In yet another aspect, the invention relates to com
`pounds useful as intermediates.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`The present invention comprises heterocyclic com
`pounds of the formula
`
`R
`
`(0):
`
`15
`
`25
`
`30
`
`35
`
`wherein R is alkyl of 4 to 12 carbon atoms, cycloalkyl of
`3 to 7 carbon atoms, mono(lower alkyl)-substituted
`cycloalkyl of 4 to 7 carbon atoms, cycloalkylalkyl of 4
`to 12 carbon atoms, phenyl or aryl-(lower alkyl) of 7 to
`12 carbon atoms; R1, R2 and R3, independently, are
`hydrogen or alkyl of l to 8 carbon atoms; R4, R5 and R6,
`independently, are hydrogen or alkyl of l to 8 carbon
`atoms, and two of R4, R5 and R5 can each be bonded to
`the same carbon atom or together can form a fused
`alicyclic or aromatic 6-membered ring; provided that
`when R is tert.-butyl, at least one of R1 and R3 is alkyl
`of 2 to 8 carbon atoms or R2 is hydrogen or alkyl of 2 to
`8 carbon atoms or at least one of R4, R5 and R6 is alkyl
`of 5 to 8 carbon atoms; X is methylene or an oxygen
`atom; z is zero or 1 and the dotted bonds can be hydro
`genated, and acid addition salts of those compounds of
`formula I which are basic.
`Unless stated to the contrary, the term “lower alkyl”
`as used herein denotes a straight-chain or branched
`chain hydrocarbon group of 1 to 4 carbon atoms, such
`as, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and
`tert.-butyl. Alkyl groups of 4 to 12 carbon atoms are
`straight-chain or branched-chain hydrocarbon groups,
`for example, butyl, isobutyl, tert.-butyl, neopentyl, 1,1
`dimethylpropyl, l, l-dimethylpentyl, l,l-diethylpropyl,
`l, l-dimethylbutyl, l-isopropyl-3-methyl-but- l-yl,
`l
`ethyl-l-methylbutyl, dodecyl, and the like. The term
`“cycloalkylalkyl” includes, in particular, those groups
`in which the alkyl moiety is branched. The term “aryl
`(lower alkyl)” includes not only groups which are
`mono~ or di(lower alkyl)-substituted in the aryl ring but
`
`45
`
`55
`
`65
`
`2
`also groups which are mono- or di(lower alkyl)-sub7
`stituted in the lower alkyl moiety. Exemplary of aryl(
`lower alkyl) groups are benzyl, phenylethyl, (lower
`alkyl)-benzyl, for example, methylbenzyl and dimethyl
`benzyl, naphthylmethyl, Z-phenyll-propan-Z-yl, l -phe
`nyl-l-ethyl, or the like.
`‘
`Compounds of formula I which are basic form salts
`with organic and inorganic acids. Preferred salts are
`those formed with physiologically acceptable acids,
`including, in particular, the salts formed with hydro
`halic acids, for example, hydrochloric acid and hydro
`bromic acid, phosphoric acid, nitric acid, monofunc
`tional and bifunctional carboxylic acids and hydrox
`ycarboxylic acids, for example, acetic acid, maleic acid,
`succinic acid, fumaric acid, tartaric acid, citric acid,
`salicylic acid, sorbic acid and lactic acid, and sulfonic
`acids, for example, 1,S-naphthalene-disulfonic acid.
`Salts of this type are prepared in a known manner.
`The compounds of formula I and acid addition salts
`of those compounds which are basic can be prepared by
`(a) reacting a halide of the formula
`
`R
`
`wherein R, R1, R2, R3 and the dotted bonds are as
`previously described, and Y is chlorine, bromine or
`iodine, with an amine of the formula
`'
`"
`
`R4
`
`R5
`
`EN
`
`X
`
`III
`
`wherein R4, R5, R6 and X are as previously described,
`or
`(b) catalytically hydrogenating or reducing with for
`mic acid the aliphatic double bond in a compound
`of the formula
`
`IV.
`
`wherein R, R1, R2, R4, R5, R6, X and the dotted
`bonds are as previously described, or
`(c) reacting a compound of the formula
`
`R
`
`R2
`
`/
`R1
`
`CH-Y
`I
`
`wherein R, R1, R2, R3 and Y are as previously
`described, with an amine of formula III, or
`
`FlatWing Ex. 1019, p. 2
`
`

`

`v;
`
`5
`
`4,202,894
`4
`3
`(d) catalytically hydrogenating a compound of the
`wherein R, R1, R2, R3, R4, R5, R6, X and the dotted
`formula
`bonds are as previously described, with hydrogen
`peroxide or a peracid, or
`(f) converting a compound of formula I which is basic
`into a salt with an acid in a known manner.
`The Roman numerals mentioned in the following text
`relate to the structural formulas given earlier and/or to
`the structural formulas given in the following Formula
`Schemes and/or to the structural formulas given in the
`10 description in connection with the preparation of the
`wherein R, R1, R2, R3, R4, R5, R6,Xand the dotted,
`starting materials. Some of the formulas given in the
`bond are as previously described, or
`text are elaborated in Formula Schemes A and B. Thus,
`(e) treating a compound of the formula
`for example, formula I hereinbefore includes all of the
`>
`formulas given in Formula Scheme A with the excep
`VII 15 tion of formulas Ila, IIb and IV. In Formula Schemes A
`and B, the symbols R, R1, R2, R3, R4, R5, R6, X and Y
`and the dotted bonds are as previously described. In
`Formula Scheme B, Et is ethyl and Ac is acetyl.
`
`R
`
`R
`
`R
`
`R2
`
`R2
`
`Formula Scheme A
`R4
`
`R5 R
`
`R2
`
`R1 R3
`
`R1
`
`Lil“
`
`R1 R3
`
`_> (lb)
`
`0
`
`o (Ie)
`
`FlatWing Ex. 1019, p. 3
`
`

`

`4,202,894
`
`Formula Scheme B
`
`Ra
`.
`+ OC P=C—COOEt
`
`3
`
`R
`
`Aa”
`+R,
`
`(XV)
`
`(XIV)
`
`R2
`|
`
`(E10)—CH~COOE|
`oO
`,
`Ry
`Zn/Br—CH—COOE
`
`R,
`
`®
`
`(xD
`
`20
`R1
`
`CHO
`
`(XH) +
`
`FASCOOF;(x)On
`
`avy.
`
`Ri
`
`OAc
`
`(XII)
`
`R.
`
`(VIIId)
`
`R2
`
`a”
`Ri
`
`OH
`
`(Xa)
`
`OHOt
` Nr
`Lo
`
`(VHla)
`
`(VIllc)
`
`(VIIIb)
`
`x
`
`R2
`
`R2
`
`CHO
`
`Ri
`
`Ry
`
`Ri
`
`OH
`
`Ri
`
`FlatWing Ex. 1019, p. 4
`
`FlatWing Ex. 1019, p. 4
`
`

`

`4,202,894
`
`-continued
`Formula Scheme B
`
`R4
`
`R
`
`R
`
`R
`
`m R2
`
`/ Y
`
`N
`\
`
`ri-yks
`
`X
`
`R2
`
`R1
`
`R3
`
`R1
`
`R6
`
`(Ilb)
`
`15
`
`20
`
`25
`
`40
`
`(IV)
`‘
`(Ila)
`According to process embodiment (a), a halide of
`formula II is reacted with an amine of formula III in an .
`inert solvent, preferably an ether, such as, diethyl ether,
`tetrahydrofuran or dioxane, in the presence of a base,
`for example, triethylamine or an excess of the amine of
`formula III.
`When a halide of formula 11a is used as the starting
`material, diethyl ether is preferably used as the inert
`solvent. A particularly suitable reaction temperature
`lies in the range of from about 0° C. to about the re?ux
`temperature of the reaction mixture. The reaction is
`preferably carried out at the boiling point of the reac
`tion mixture.
`When a halide of formula 11b is reacted with an amine
`of formula III, a high boiling alcohol is preferably used
`as the inert solvent. Ethylene glycol or glycerol is par
`ticularly preferred. The reaction is preferably carried
`out at a temperature in the range of from about 50° C. to
`about 150° C. In a particularly preferred aspect, the
`reaction is carried out using ethylene glycol as the inert
`solvent and at a temperature of 100°-l 10° C.
`According to process embodiment (b), a compound
`of formula IV is catalytically hydrogenated or is re
`duced with formic acid. Particularly suitable catalysts
`are noble metal catalysts, for example, platinum, palla
`dium (optionally precipitated onto charcoal) and Raney
`nickel. Palladium-on-charcoal is the preferred catalyst.
`Suitable inert solvents for the catalytic hydrogenation
`are hydrocarbons, such as, benzene, toluene or xylene,
`and alcohols, such as, methanol or ethanol. Toluene is
`the preferred inert solvent. The catalytic hydrogenation
`is advantageously carried out at a temperature in the
`range of from about 0° C. to about 50° C., preferably at
`room temperature. The reduction of a compound of
`formula Iv with formic acid is preferably carried out in
`the absence of a solvent. Formic acid is added dropwise
`45
`to a compound of formula IV at a temperature in the
`range of from about 0° C. to about 100° C., preferably at
`50° to 70° C., if necessary while cooling.
`According to process embodiment (c), a compound
`of formula V is reacted with an amine of formula III
`under the conditions described earlier in connection
`with process embodiment (a).
`According to process embodiment (d), a compound
`of formula VI is catalytically hydrogenated. Platinum
`or palladium is preferably used as the catalyst, with
`water or alcohol being used as the solvent. In order to
`avoid a possible hydrogenolysis, at least one equivalent
`of acid, preferably hydrochloric acid, is added to the
`catalytic hydrogenation mixture. When a perhy
`drogenation is desired, the catalytic hydrogenation is
`carried out utilizing platinum in glacial acetic acid with
`the addition of perchloric acid. The aromatic ring is
`completely hydrogenated under these conditions.
`According to process embodiment (e), a compound
`of formula VII is treated with hydrogen peroxide or a
`peracid. When a compound of formula Ia, VIIa or VIIb
`(see Formula Scheme A) is used as the starting material,
`the treatment is carried out with hydrogen peroxide. In
`
`this case, an alcohol, such as, methanol, ethanol or iso
`propanol, is used as the solvent, with isopropanol being
`preferred. The treatment with hydrogen peroxide is
`preferably carried out at a temperature in the range of
`from about 0° C. to about 50° C., especially at 40° C.
`When a compound of formula Ia or VIIb is used as the
`starting material, the treatment is preferably carried out
`with a peracid, such as peracetic acid, perbenzoic acid,
`m-chloroperbenzoic acid, peradipic acid, etc., or with
`hydrogen peroxide in a corresponding acid or acid
`anhydride. A halogenated hydrocarbon, such as, meth
`ylene chloride, chloroform or ethylene chloride, is pref
`erably used as the solvent when a peracid is used. Suit
`able treatment temperatures are the same as those men
`tioned earlier in connection with the treatment with
`hydrogen peroxide.
`A preferred class of compounds of formula I com
`prises those wherein R is l,l-dimethylpropyl. Also pre
`ferred are those compounds of formula I wherein R is
`phenyl.
`Preferred compounds of formula I are:
`l-[3-(p-Tert.amyl-phenyl)-2-methyl-propy1]-piperi
`dine,
`l-[3-(p-tert.amyl-phenyl)-2-methyl-propyl]-3-methyl
`piperidine,
`l-[3-(p-tert.amyl-phenyl)-2-methyl-propyl]-3,5
`dimethyl-piperidine,
`4-[3-(p-tert.amyl-phenyl)-2-methyl-propyl]-2,6
`dimethyl-morpholine,
`l-[3-(4-tert.amyl-cyclohexyl)-2-methyl-propyl]
`piperidine,
`l-[3-(4-tert.amyl-cyclohexyl)-2-methyl-propyl]-3
`methyl-piperidine,
`l-[3-(4-tert.amyl-cyclohexyl)-2-methyl-propyl]-3,5
`dimethyl-piperidine,
`4-[3-(4-tert.amyl-cyclohexyl)-2-methyl-propyl]-2,6
`dimethyl-morpholine,
`4-[3-(4-tert.amyl-cyclohexyl)-2-methyl-2-propenyl]
`2,6-dimethyl-morpholine,
`l-[3-(4-tert.amyl-cyclohexyl)-2~methyl-2-propenyl]
`piperidine,
`l-[3-(4-tert.amyl-cyclohexyl)-2-methyl-2-propenyl]
`3-methyl-piperidine,
`l-[3-(4-tert.amyl-cyclohexyl)-2-methyl-2-propenyl]
`3,5-dimethyl-piperidine,
`l-[3-(p-tert.amyl-phenyl)-2,3-dimethyl-2-propenyl1
`piperidine,
`l-[3-(p-tert.amyl-phenyl)-2,3-dimethyl-2-propenyl]-3
`methyl-piperidine,
`l-[3-(p-tert.amyl-phenyl)-2,3-dimethyl-2-propenyl]
`3,5-dimethyl-piperidine,
`4-[3-(p-tert.amyl-phenyl)-2,3-dimethyl-2-propenyl]
`2,6-dimethyl-morpholine,
`1-[3-(p-tert.amyl-phenyl)-2,3-dimethyl-propyl1
`piperidine,
`l-[3-(p-tert.amyl-phenyl)-2,3-dimethyl-propyl1-3
`methyl-piperidine,
`
`50
`
`65
`
`FlatWing Ex. 1019, p. 5
`
`

`

`4,202,894
`9
`l-[3-(p-tert.amyl-phenyl)-2,3-dimethyl-propyl]-3,5
`dimethyl-piperidine,
`4-[3-(p-tert.amyl-phenyl)-2,3-dimethyl-propyl]-2,6
`dimethyl-morpholine,
`l-[3-[p-(l,1-diethyl-propyl)-phenyl]-2-methyl
`propyl]-3-methyl-piperidine,
`l-[3-[p-( 1 , l -dimethyl-pentyl)-phenyl]-2-methyl
`propyl]-3-methyl-piperidine,
`l-[3-[p-(l , 1-dimethyl-pentyl)-phenyl]-2-methyl
`propyl]-piperidine,
`4-[3-(4-biphenylyl)-2-methyl-propyl]-2,6-dimethyl- '
`morpholine,
`l-[3-[p-(a,a-dimethyl-benzyl)-phenyl]~2-methy1
`propyl]-piperidine,
`1-[3-[p-(a,a-dimethyl-benzyl)-phenyl]-2-methyl
`propyl]-3-methyl-piperidine,
`l-[3-[p-(a,a-dimethyl-benzyl)-phenyl]—2-methyl
`propyl]-3,S-dimethyl-piperidine,
`4-[3-[p-(a,a-dimethyl-benzyl)-phenyl]-2-methyl
`propyl]-2,6-dimethyl-morpholine,
`l-[3-[p-(ma-dimethyl-benzyl)-phenyl]-2,3-dimethyl
`2-propenyl]-3,S-dimethyl-piperidine,
`l-[3-[p-(a,a-dimethyl-benzyl)-phenyl]-2,3-dimethyl~
`propyl]-3,5-dimethyl-piperidine,
`1-[3-[4-(l-cyclohexyl-1-methyl-ethyl)-cyclohexyl]-2
`methyl-propyH-piperidine,
`4-[3-[4-(1-cyclohexyl-1-methyl-ethyl)-cyclohexyl]-2
`methyl-propyl]-2,6-dimethyl-morpholine,
`1-[3-[p-(1-cyclohexyl-l-methyl)-phenyl]-2-methyl
`propyl]~piperidine, ,
`1-[3-[p-(1—cyc1ohexyl-l-methyl)-phenyl]~2-methyl
`propyl]-3,5-dimethyl~piperidine and
`4-[3-[p—(1-cyclohexyl-l-methyl)-phenyl]-2-methyl
`propyl]-2,6-dimethyl-morpholine.
`Some of the starting materials of formulas II, IV, V,
`VI and VII are novel.
`The compounds of formulas VI and VII are prepared
`40
`by alkylating an amine of formula III with a halide of
`formula II or V. The alkylation is carried out in the
`same manner as described earlier in connection with
`process embodiment (a).
`The halides can be prepared in a known manner from
`a corresponding alcohol of the formula
`
`15
`
`20
`
`25
`
`35
`
`45
`
`R
`
`VIII
`
`50
`
`VIIId
`
`55
`
`OH
`
`R1
`
`wherein R, R1, R2 and R3 and the dotted bonds are as
`previously described,
`by treatment with a phosphorus halide, such as, phos
`phorus tribromide, phosphorus trichloride, phosphorus
`pentabromide or phosphorus pentachloride, with or
`without the addition of a tertiary base.
`An alcohol of formula VIII or VIIId is obtained in a
`known manner from a compound of the formula
`
`65
`
`10
`
`IX
`
`COOCzI-Is
`
`wherein R, R1, R2, R3 and the dotted bonds are as previ
`ously described,
`by reduction with a suitably complex hydride. Suitable
`complex hydrides for the reduction of a compound of
`formula IX are, for example, 'borohydrides, such as,
`sodium borohydride, or alanates, such as, lithium alumi
`num hydride. Lithium aluminum hydride is suitable for
`the reduction of a compound of formula X.
`The compounds of formulas IX and X are obtained
`from an aldehyde or ketone of the formula
`
`R
`
`/O
`R1
`
`wherein R, R1 and the dotted bonds are as previously
`described,
`by means of a Wittig reaction, Homer reaction or
`Reformatzky reaction (see Formula Scheme B).
`Synthesis (1974), page 122 et seq. is referred to as
`exemplifying the Wittig reaction and the Horner reac
`tion. The relevant secondary literature is also cited in
`this literature reference. Examples of the Reformatzky
`reaction are described in Bull. Soc. Chim. France
`(1961), page 2145 et seq. A detailed bibliography for the
`Reformatzky reaction is also given in this literature
`reference.
`In order to prepare a compound of formula IXa,
`wherein R2 and R3, individually, are alkyl, or R2 is alkyl
`and R3 is hydrogen, the aldehyde of formula XII is
`reacted with a ketone or aldehyde of formula XVI
`under the conditions of a Claisen-Schmidt condensation
`in a known manner. The relevant literature is given in
`“Narnenreaktionen der organischen Chemie”, Dr. Al
`fred Huthig Verlag GmbH, Heidelberg 1961, page 94.
`A compound of formula IXc is prepared from a com
`pound of formula XIII by saponi?cation in a known
`manner. The saponi?cation is carried out, for example,
`as described in Bull. Soc. Chim. France (1961), page
`1194 et seq. A compound of formula XIII is prepared
`from the compound of formula XV and a compound of
`formula XIV by a Friedel-Crafts reaction, also in a
`known manner. The Friedel-Crafts reaction can be
`carried out, for example, in an analogous manner to the
`examples which are given in the aforementioned litera
`ture reference.
`A compound of formula VIIlld is oxidized to a com
`pound of formula IXb in a known manner. For example,
`the methods described in J. Org. Chem., 39, 3304 (1974)
`can be utilized.
`
`FlatWing Ex. 1019, p. 6
`
`

`

`5
`
`25
`
`30
`
`35
`
`4,202,894
`fill
`112
`3-[p-(a,a-dimethyl-benzyl)-phenyl]-2,3-dimethyl-r
`A compound of formula IXb or IXc can be converted
`allyl bromide.
`into a compound of formula VIIIb or VIIIc in a known
`Preferred starting materials of formula IIb hereinbe
`manner by means of a Grignard reaction. When R3, in a
`compound of formula IXa, is hydrogen, a compound of
`fore are:
`3-(p-tert.amyl-phenyl)-l-methyl-propyl bromide,
`formula VIIIb, wherein R3 is other than hydrogen, is
`3-(p-tert.amyl-phenyl)-2-methyl-propyl bromide,
`also obtained by means of a Grignard reaction. With
`3-(p-tert.amyl-phenyl)-3-methyl-propyl bromide,
`respect to the Grignard reaction, the monograph
`3-(p-tert.amyl-phenyl)-1,2-dimethyl-propyl bromide,
`“Grignard Reactions of Nonmetallic Substrates”, Ver
`3-(p-tert.amyl-phenyl)- l,3-dimethyl-propyl bromide,
`lag Prentice-Hall Inc., New York, 1954, is referred to.
`3-(p-tert.amyl-phenyl)-2,3-dimethyl-propyl bromide,
`A compound of formula IXa, IXb, VIIIa or VIIIb is
`3-(p-tert.amyl-phenyl)-1,2,3-trimethyl-propyl
`bro
`converted into a compound of formula IXc or VIIIc in .
`mide,
`a known manner by dissolution in an alcohol, preferably
`methanol or ethanol, optionally with the addition of
`3-(p-tert.amyl-phenyl)-2-methyl-propyl bromide and
`3-[p-(a,a-dimethyl-benzyl)-phenyl]-2,3-dimethyl
`water and water-soluble inorganic bases, for example,
`propyl bromide.
`sodium carbonate, potassium carbonate or calcium hy
`droxide, and hydrogenation at room temperature in the
`Preferred starting materials of formula IV hereinbe
`presence of palladium/charcoal.
`fore are:
`l-[3-(p-Tert.-amyl-phenyl)-2-methyl-l-propenyl]
`‘ A compound of formula IV (see Formula Scheme B)
`piperidine,
`is prepared from an aldehyde of formula IXc by reac
`1-[3-(p-tert.amyl-phenyl)-2-methyl-l-propenyl]-3
`tion with an amine of formula III. For this purpose, an
`methyl-piperidine,
`excess of the amine of formula III is added to the alde
`l-[3-(p-tert.amyl-phenyl)-2-methyl-1-pr0penyl]-3,5
`hyde and the mixture is heated under re?ux in benzene
`dimethyl-piperidine,
`or toluene, the water which forms distilled azeotropti
`4-[3-(p-tert.amyl-phenyl)-2-methyl-l-propenyl]-2,6
`cally (see “Advances in Organic Chemistry”, Vol. 4,
`dimethyl-morpholine,
`pp. 9 et seq, Verlag Interscience Publishers, New York,
`London, 1963).
`l-[3-[p-( l , 1-diethyl-propyl)-phenyl]-2-methyl- l
`propenyl]-3-methyl-piperidine,
`Preferred starting materials of formula IXb an'd IXc
`hereinbefore are:
`l-[3-[p-( l , 1-dimethyl-propyl)-phenyl]-2-methyl-l
`p-Tert.amyl-(LB-dimethyl-cinnamaldehyde,
`propenyl]-3-methyl-piperidine,
`p-(a,a-dimethyl-benzyl)-a,B-dimethyl-cinnamalde
`l-[3-[p-(l , 1-dimethyl-propyl)-phenyl] ~2-methyl- l
`hyde,
`propenyl]piperidine,
`3-(p-isobutyl-phenyl)-Z-methyl-propionaldehyde,
`4-[3-(4-biphenyl)-2-methyl-l-propenyl]-2,6-dimethyl~
`3-(p-neopentyl-phenyl)-2-methyl-propionaldehyde,
`morpholine,
`3-(p-tert.-amyl-phenyl)-2-methyl-propionaldehyde,
`l-[3-[p-(a,a-dimethyl-benzyl)-phenyl]-2-methyl-l
`propenyl]-piperidine,
`3-[p-( l , l -dimethyl-pentyl)-phenyl]-2-methyl-pro
`pionaldehyde,
`l-[3-[p-(a,a-dimethyl-benzyl)-phenyl]-2-methyl-l
`propenyl]~3-methyl-piperidine,
`3-[p-( l , 1-diethyl-propyl)-phenyl]-2-methyl-pro
`pionaldehycle,
`l-[3-[p-(a,a-dimethyl-benzyl)-phenyl]-2-methyl-l
`3-(p-tert.butyl-phenyl)-2-ethyl-propionaldehyde,
`propenyl]-3,5-dimethyl~piperidine,
`3-(p-tert.butyl-phenyl)-2-isopropyl-propionaldehyde,
`4-[3-[p-(a,a-dimethyl-benzyl)-phenyl]-2-methyl-l
`3-(p-cyclohexyl-phenyl)-2-methyl-propionaldehyde,
`propenyl]-2,6-dimethyl-morpholine,
`3-(p-biphenylyl)-2-methyl-propionaldehyde,
`l-[3-[p-(l-cyclohexyl-l-methyl)-phenyl]-2-methyl-l
`3-(p-tert.butyl-phenyl)~2-octyl-propionaldehyde,
`propenyl]-piperidine,
`3-[p-(l-propyl-l-methyl-pentyl)-phenyl]-2-methyl
`l-[3-[p-(l-cyclohexyl-1-methyl)-phenyl]-2-methyl-l
`propionaldehyde,
`propenyl]-3,5-dimethyl-piperidine and
`3-[p-( l-ethyl-1-methyl-butyl)-phenyl]-2-methyl-pro
`4-[3-[p-(1-cyclohexyl-1-methyl)-phenyl]-2-methyl-1
`pionaldehyde,
`propenyl]-2,6-dimethyl-morpholine.
`3-[p-(1,2-dimethyl-propyl)-phenyl]-2-methyl-pro
`It is not necessary to isolate the compounds of for
`pionaldehyde,
`mula lV. Such compounds can be converted directly
`3-[p-(l-isopropyl-3-methyl-butyl)-phenyl]-2-methyl
`into compounds of formula VIIb, without working up,
`propionaldehyde,
`either by adding formic acid or by hydrogenation.
`S-[p-(a,a-dimethyl-benzyl)-phenyl]-2-methyl-pro
`The compounds of formula I possess fungicidal activ
`pionaldehyde,
`ity and can, accordingly, be used for combatting fungi
`3-[4-cyclohexyl- l-methyl-ethyl)-cyclohexyl] -2-meth
`in agriculture and in horticulture. The compounds are
`yl-propionaldehyde and
`particularly suitable for combatting powdery mildew
`3-[p-(l-cyclohexyl-l-methyl)-phenyl]-2-methyl-pro
`fungi such as, for example, Erysiphe graminis (powdery
`pionaldehyde.
`mildew of cereals), Erysiphe cichoracearum (powdery
`Preferred starting materials of formula IIa hereinbe
`mildew of cucumbers), Podosphaera Ieucotricha (pow
`dery mildew of apples), Sphaerotheca pannosa (powdery
`fore are:
`3-(p-Tert.amyl-phenyl)- l-methyl-allyl bromide,
`mildew of roses) and Oidium tuckeri (powdery mildew
`3-(p-tert.amyl-phenyl)-Z-methyl-allyl bromide,
`of vines), rust diseases, for example, those of the genera
`3-(p-tert.amyl-phenyl)-3-methyl-allyl bromide,
`Puccinia, Uromyces ‘and Hemileia, especially Puccinia
`3-(p-tert.amyl-phenyl)-l,2-dimetl1yl-allyl bromide,
`graminis (stem rust of cereals), Puccinia coronata (crown
`3-(p—tert.amyl-phenyl)-1,3-dimethyl-allyl bromide,
`rust of oats), Puccinia sorghi (corn rust), Puccinia strizfor
`3-(p-tert.amyl-phenyl)-2,3-dimethyl-allyl bromide,
`mis (stripe rust of wheat), Puccinia recondita (leaf rust of
`3-(p-tert.amyl-phenyl)-1,2,3-trimethyl-allyl bromide,
`cereals), Uromycesfabae and appendiculatus (bean rusts),
`3-(4-tert.amyl-cyclohexyl)-Z-methyl-allyl
`bromide,
`as well as Hemileia vastatrix (coffee rust) and Phrag
`and
`midium mucronatum (leaf rust of roses).
`
`60
`
`40
`
`45
`
`50
`
`55
`
`65
`
`FlatWing Ex. 1019, p. 7
`
`

`

`13
`Furthermore, the compounds of formula I are also
`active against the following phytopathogenic fungi:
`Ustilago avenue (loose smut of oats), Venturia inae
`qualis (apple scab), Cercospora arachidicola (peanut early
`leaf spot), Ophiobolus graminis (cereal take-all), Septoria
`nodorum (cereal leaf spot) or Marssonina rosae (rose
`blackspot). The compounds of formula I possess pro
`nounced subsidiary activity against various species of
`the following genera: Rhizoctonia, Tilletia and Helmin
`thosporium, and also, in part, against Peronospora,
`Coniophora, Lenzites, Corticium, Thielaviopsis and
`Fusarium.
`Furthermore, compounds of formula I are also active
`against phythopathogenic bacteria, for example, Xan
`thomonas vesicatoria, Xanthomonas oryzae and other
`Xanthomonades as well as against various species of
`Erwinia, such as, Erwinia tracheiphila.
`' The compounds of formula I are also active as insecti
`cides and acaricides, and, to some extent, insect growth
`regulating effects and anti-feedant effects are also
`found. Thus, for example, 1-{3-[(l-isopropyl-3-methyl
`butyl)-phenyl]-2-methyl-propyl}~3,4-dimethyl-piperi
`dine showed a 100% activity in the larvicide test with
`Adoxophyes orana at a dosage of 10'6 g/cm2 and a 50%
`activity at a dosage of 10*7 g/cm2.
`25
`As will be evident from the following biological tests,
`the compounds of formula I are active under green
`house conditions even at a concentration of as little as 5
`mg. to 500 mg. of active ingredient, that is, a compound
`of formula I, per liter of spray liquor. In the open, con
`centrations of 100 g to 2,500 g. of active ingredient per
`hectare and per treatment are advantageously utilized.
`For example, in order to combat powdery mildew of
`cereals successfully, it is advantageous to use a concen~
`tration of 200 g. to 1,000 g., preferably 200 g. to 600 g.,
`of active ingredient per hectare and per application. For
`combatting cereal rust, it is advantageous to use concen
`trations of 500 g. to 2,500 g. and particularly preferably,
`in the case of the most active members, 500 g. to 2,000
`g., of active ingredient per hectare and per application.
`Some of the compounds of formula I display a high
`systemic activity. Untreated parts of the plants can also
`be protected as a result of secondary distribution of the
`active ingredient (gas phase action).
`For practical purposes, the compounds of formula I
`can be said to be substantially non-toxic to vertebrates.
`The toxicity of the compounds of formula I is on aver
`age above 1,000 mg. per kg. of body weight in the acute
`toxicity test on mice. Individual members show LD50
`values, determined on mice, in the range of from about
`400 to about 1,000 mg. per kg. of body weight, while
`other members show LD50 values which are in the
`range of from about 1,000 to about 10,000 mg. per kg. of
`body weight in the acute toxicity test on mice.
`The biological tests described hereinafter illustrate
`the activity of the compounds of formula I, the results
`are summarized in the Tables which follow.
`(a) Eryszphe graminis
`30-40 barley seedlings of the HERTA variety (dis
`tributed on 2 pots of 7 cm diameter), the seedlings being
`in each case in the one-leaf stage, were thoroughly
`sprayed from all sides with an aqueous dispersion of the
`test substance (processed in the usual manner as a spray
`able powder) and were then grown in a greenhouse at
`22°-26° C. and 80% relative atmospheric humidity with
`a light period of 16 hours. The infection was effected 2
`days after the treatment by dusting the test plants with
`conidia of Erysiphe graminis. 7 days after the infection,
`
`14
`the leaf surface infected by Erysiphe graminis was deter
`mined in % relative to the leaf surface of the infected
`untreated control. The results are summarized in Table
`I hereinafter.
`(b) Puccinia coronata
`30-40 oat seedlings of the FILAEMINGSKRONB
`variety (distributed on 2 pots of 7 cm diameter), each
`seedling being in the one-leaf stage, were thoroughly
`sprayed from all sides with an aqueous dispersion of the
`test substance (processed in the usual manner as a spray
`able powder) and were then grown in a climatically
`controlled chamber at 17° C. and ‘70—80% relative atmo
`spheric humidity with alight period of 16 hours. After
`2 days, the test plants were infected by spraying with
`uredospores (300,000 spores/ml) of Puccinia coronata
`suspended in distilled water. The plants were then incu
`bated in the dark for 24 hours at 20° C. and an atmo
`spheric humidity above 90%, and were subsequently
`moved into a greenhouse at a temperature of 22°-26° C.
`and a relative atmospheric humidity of 70% with a light
`period of 18 hours. On the 9th day after infection, the
`leaf surface infected by Puccinia caronata was deter
`mined in % relative to the infected untreated control.
`The results are summarized in Table I hereinafter.
`(c) Venturia inaequalis
`3 small apple plants (distributed in 3 pots of 5 cm
`diameter) raised from seeds of the GOLDEN DECI
`CIOUS variety, the plants being in the 4- to 5-leaf stage,
`were thoroughly sprayed on all sides with an aqueous
`dispersion on the test substance (processed in the usual
`manner as a sprayable powder). The treated plants were
`then grown for 2 days at 17° C. and 70—80% relative
`atmospheric humidity with a light period of 14 hours.
`Thereafter, the plants were infected by spraying with a
`suspension of conidia of Venturia inaequalis in distilled
`water (200,000 conidia/ml). After the infection, the
`plants were incubated in the dark for 48 hours at
`l6°-l8° C. and a relative atmospheric humidity of
`above 90%, and were then moved to a shaded green
`house at a temperature of 22°—26° C. and a relative
`atmospheric humidity of above 80%. On the 13th day
`after the infection, the leaf surface infected by Venturia
`inaequalis was determined relative to that of the in
`fected untreated control. The results are summarized in
`Table II hereinafter.
`
`Table I
`Concentration
`(in mg/l of spray
`liquor)
`500
`160
`50 '
`16
`5
`500
`160
`50
`16
`5
`500
`160
`50
`16
`5
`500
`160
`50
`l6
`5
`500
`160
`
`Activity (in %!
`Erysiphe
`Puccinia '
`graminis
`comma
`100
`100
`97
`85
`5S
`100
`100
`100
`95
`75
`100
`100
`100
`90
`85
`100
`l00
`100
`.‘ 95
`60
`I00
`100
`
`100
`50
`10
`0
`100
`100
`90
`10
`O
`100
`98
`87
`20
`10
`100
`100
`93
`40
`0
`100
`35
`
`Test substance
`l-[3-[p-(l,l-
`Diethyl-propyD-
`phenyl]-2-methyl- >
`propyl]-
`piperidine
`l-[3l'[p-(l,l-
`Diethyl-propyly
`phenyl]-2-methyl-
`propyl]-3-methyl-
`piperidine
`l-[3-(p'TerLamyl-
`phenyl)-2-methyl-
`propyll-piperidine
`
`l-[3-(p-'Tert.amyl-
`phenyl)~2-methyl-
`propyl]-3-methyl-
`piperidine
`
`l-[3-[p-(l,l-
`Dimethyl-pentyl)—
`
`4,202, 8 94
`
`15
`
`20
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`>
`
`FlatWing Ex. 1019, p. 8
`
`

`

`4,202,894
`
`16
`Table II-continued
`! Venturia inaegualis!
`\,
`Concentration
`(in mg/] of spray
`liquor)
`160
`5O
`I6
`5
`500
`160
`50
`16
`5
`500
`160
`50
`16
`5
`500
`160
`so
`I6
`5
`
`5
`
`Test substance
`pentyl)-phenyl]-2-methyl-
`propyl]-piperidine
`
`1o 4-[3-(p-Tert.amyl-phenyl)-
`2-methyl-propyl]-2,6-
`dimethyl-morpholine
`
`'
`
`4-[3-[p-(a,ot-Dimethyl-
`15 benzyl)-phenyl]-2-methyl-
`propyl]-2,6~dimethyl-
`morpholine
`
`'
`
`4-[3-[p-(1-Ethyl-l-
`methyl-butyl)-phenyl]-2-
`20 methyl-propyl]-2,6-
`dimethyl-morpholinc
`
`Activity (in %)
`95
`90
`30
`10
`100
`100
`90
`50
`10
`100
`l00
`100
`90
`70
`100
`100
`95
`50
`30
`
`‘
`
`15
`Table I-continued
`Concentration
`(in mg/l of spray
`liquor)
`so
`16
`5
`500
`160
`50
`16
`5
`500
`160
`50
`16
`5
`500
`160
`50
`‘6
`5
`500
`160
`50
`i6
`5
`
`'
`
`5o
`16
`5
`
`5Q
`16
`50(5)
`160
`.50
`16
`5
`500
`160
`50
`1‘;
`500
`160
`50
`1?
`500
`160
`i2
`5
`500
`160
`i2
`5
`
`Test substance
`phenyllaqnethyk
`propyl]-
`piperidine
`l-[3—[p-(l,1-
`Dimethyl-pentyD-
`phenyll‘z‘methyl'
`propyll-3'melhyl-
`piperdine
`4~[3-(p-Tert.amyl-
`phenyl]-2-rnethyl-
`propyl]—2,6-
`dimethyl-
`morpholine
`l-[3-(4~Tert.amyl-
`cyclohexyl)-2-
`methyl-propyl1-
`Pipe?dlnc
`
`l-[3-(4-Tert.amyl-
`cyclohexyl)-2~
`methyl-2-
`propenyl]-
`Pipel'idine
`
`butyl)_phenyn,z_
`methyl—propyl]-
`Pllw?dme h l
`i?jtil’i?jgwil'):
`pheny|]_2_methy|_
`propyl]:
`glpfndl'ieE h l
`lingtlil'éljbuttyil'):
`phgnyll-Z-methy]-
`p_ropy1]-2,6-
`giznetlll‘g'lli'ne
`H?gmphenyb
`yl)-2-methyl-
`prom/114,6
`?lone‘rll‘gi'ne
`1_[3r_p[p_(a,a_
`Dimethyl—benzyl)~
`phenyll-l-methyl-
`;{gggg’ne
`1.[3_[P_(a,a_
`Dimethyl-benzyl)-
`Phe"y1l1'§'m=*:>'l1‘
`ggggigi'néme' y '
`4.[3-[p.(a,u_
`Dimethyl-benzyly
`grgglq'g'g‘gimyl'
`methylm’mphmine
`
`Activity tin %}
`Erysiphe
`Puccinia
`graminis
`coronta
`95
`10
`35
`0
`75
`0
`100
`100
`93
`35
`75
`100
`95
`93
`85
`65
`100
`95
`35
`30
`65
`100
`95
`85
`65
`6°
`183
`80
`7s
`55
`100
`90
`40
`5
`98
`35
`20
`0
`100
`100