United States Patent r191 ·
`Pfiffner
`
`(11]
`
`(45]
`
`4,202,894
`May 13, 1980
`
`(54] PIPERIDINES MORPHOLINES, ETC., AND
`FUNGICIDAL COMPOSITIONS THEREOF
`
`Attorney, Agent, or Firm-Jon S. Saxe; George M.
`Gould; Peter R. Shearer
`
`(75]
`
`Inventor: Albert Pfiffner; Bulach, Switzerland
`
`(73] Assignee: Hoffmann-La Roche Inc., Nutley,
`N.J.
`
`(21] Appl. No.: 852,768
`
`Nov. 18, 1977
`(22] Filed:
`(30]
`Foreign Application Priority Data
`Nov. 22, 1976 [AT] Austria ............................ A 8660/76
`
`(51]
`
`Int. Cl.2 ..................... C07D 295/02; AOIN 9/22;
`C07D 211/14
`(52] U.S. 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
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`9/1940 Leffier .................................. 544/178
`2,213,469
`7/1953 Archer et al .................... 260/293.65
`2,647,122
`2,662,886 12/1953 Ruddy et al .................... 260/293.72
`4,104,383
`8/1978 Krausz ................................. 544/178
`
`FOREIGN PATENT DOCUMENTS
`1164152 9/1964 Fed. Rep. of Germany .
`1173722 1/1965 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 .
`
`(57]
`ABSTRACT
`Heterocyclic compounds characterized by the formula
`
`R
`
`wherein R, Rt, R1, RJ, }4, Rs, R6, X and z are as herein(cid:173)
`after set forth,
`prepared, inter alia, by reacting a compound character(cid:173)
`ized by the formula
`
`R
`
`CH-Y
`I
`RJ
`
`Rt
`
`with an amine characterized by the formula
`
`II
`
`III
`
`OTHER PUBLICATIONS
`Cannata et al., "Tetrahedron", vol. 27, pp. 5247-5254,
`(1971).
`Primary Examiner-Alan L. Rotman
`Assistant Examiner-Robert T. Bond
`
`wherein R, Ri, R1, RJ, }4, Rs, R6, X and Y are as here(cid:173)
`inafter set forth,
`are described. The end products are useful as fungicidal
`agents.
`
`140 Claims, No Drawings
`
`1
`
`CFAD Exhibit 1026
`
`

`
`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
`
`2
`also groups which are mono- or di(lower alkyl)-sub(cid:173)
`stituted in the lower alkyl moiety. Exemplary of aryl(~
`lower alkyl) groups are benzyl, phenylethyl, (lower
`alkyl)-benzyl, for example, methylbenzyl and dimethyl-
`5 benzyl, naphthylmethyl, 2-phenyl-propan-2-yl, 1 -phe(cid:173)
`nyl-I-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(cid:173)
`halic acids, for example, hydrochloric acid and hydro(cid:173)
`bromic acid, phosphoric acid, nitric acid, monofunc(cid:173)
`tional and bifunctional carboxylic acids and hydrox-
`15 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, 1,5-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 bas[c can be prepared by
`(a) reacting a halide of the formula
`
`R~·· R4
`.
`...
`I \_Y....
`
`. ,•'
`
`·:
`
`"·
`
`'
`
`R2
`
`,
`
`;-t-yRs
`
`N
`
`X
`
`R1
`
`RJW
`
`R6
`
`(O)z
`
`I 10
`
`wherein R, R1, R2, R3, R.4, Rs, R6, X and z are as herein(cid:173)
`after described.
`In another aspect, the invention relates to fungicidal 20
`compositions and methods.
`In yet another aspect, the invention relates to com(cid:173)
`pounds useful as intermediates.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`The present invention comprises heterocyclic com(cid:173)
`pounds of the formula
`
`25
`
`R'Oy"'.
`
`:
`
`Rz
`
`••
`
`,.· CH-Y
`.
`I
`R1
`RJ
`
`II
`
`I 30
`
`35
`
`wherein R, Ri. R2, R3 and the dotted bonds are as
`previously described, and Y is chlorine, bromine or
`iodine, with an amine of the formula
`
`III
`
`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 40
`to 12 carbon atoms, phenyl or aryl-(lower alkyl) of 7 to
`12 carbon atoms; Ri. R2 and R3, independently, are
`hydrogen or alkyl of 1 to 8 carbon atoms; R.4, Rs and R6,
`independently, are hydrogen or alkyl of 1 to 8 carbon
`atoms, and two of R.4, Rs and R6 can each be bonded to 45
`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 R.4, Rs and R6 is alkyl 50
`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(cid:173)
`genated, and acid addition salts of those compounds of
`formula I which are basic.
`Unless stated to the contrary, the term "lower alkyl" 55
`as used herein denotes a straight-chain or branched(cid:173)
`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, 60
`for example, butyl, isobutyl, tert.-butyl, neopentyl, 1,1-
`dimethylpropyl, l, 1-dimethylpentyl, I, 1-diethylpropyl,
`1, 1-dimethylbutyl, 1-isopropyl-3-methyl-but-1-yl,
`1-
`ethyl-1-methylbutyl, dodecyl, and the like. The term
`"cycloalkylalkyl" includes, in particular, those groups 65
`in which the alkyl moiety is branched. The term "aryl(cid:173)
`(lower alkyl)" includes not only groups which are
`mono- or di(lower alkyl)-substituted in the aryl ring but
`
`wherein R.4, Rs, R6 and X are as previously described,
`or
`(b) catalytically hydrogenating or reducing with for(cid:173)
`mic acid the aliphatic double bond in a compound
`of the formula
`
`R
`
`IV.
`
`R4
`;-t-yRs
`x
`
`N
`
`\_Y....R6
`
`R1
`
`wherein R, R1, R2, R.4, Rs, R6, X and the dotted
`bonds are as previously described, or
`(c) reacting a compound of the formula
`
`v
`
`wherein R, R1, R2, R3 and Y are as previously
`described, with an amine of formula III, or
`
`2
`
`

`
`(d) catalytically hydrogenating a compound of the
`formula
`
`4,202,894
`
`~
`
`rJ-x.-Rs
`
`N
`
`x
`
`VI
`
`5
`
`R1
`
`R3
`
`"-...::f.....R6
`
`4
`wherein R, R1, Ri, RJ, R.4, Rs, R6, X and the dotted
`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, Rt. Ri, RJ, R.4, Rs, R6, X and 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(cid:173)
`tion of formulas Ila, lib and IV. In Formula Schemes A
`and B, the symbols R, Rt. Ri, RJ, R.4, Rs, 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
`
`VII 15
`
`Formula Scheme A
`
`/
`~
`LJ,;yk·'
`t
`
`X
`N
`"-...::f.....R6
`
`R1. R3
`
`(Ia) ~
`
`(Vllb)
`
`l
`
`R1
`
`R2 RWr
`
`•••
`
`:
`
`•• • • • ,...
`
`y
`
`R1 R3
`
`1
`1
`
`3
`
`

`
`5
`
`4,202,894
`
`6
`
`Formula Scheme B
`
`R~. [JR
`,o + 0 'P=C-COOE•
`
`,
`
`.
`
`12
`
`•'
`....
`
`•
`:
`
`R1
`
`(XI)
`
`R~
`
`0CHO
`
`(XII)+
`
`R2
`I
`(E10)2-P-CH-COOE1
`I
`0
`R2
`I
`Zn/Br-CH-COOE1
`
`~o
`R~.·
`
`•
`
`:
`
`R2
`
`• • • •
`
`· •
`
`,
`
`COOE1 (X')
`
`R2
`
`OAc
`
`R~ rCH~
`
`v+R1
`
`OAc
`
`(XV)
`
`{XIV)
`
`l
`R2 ROyL
`
`'
`
`~ OAc
`
`I
`
`RJ
`(XVI)
`
`(IXa)
`
`R1
`
`J
`
`R1
`
`(XIII)
`
`R~ ~2
`~OH
`
`R1
`
`(Vllld)
`
`R-oy·· R~
`
`I
`
`R1
`
`R2
`
`CHO
`
`•
`
`•• ••
`
`:
`
`•
`
`R2
`, CHO~ '
`R1
`
`(IXb)
`
`(IXc)
`
`R1=H
`
`l
`'\:
`l /~· .. ··,
`.,
`RDA
`OH /~OH
`R~ ~2
`
`~ (Vlllb)
`R ~1=H
`3 ~
`
`(Vllla)
`
`I
`
`R2
`
`'
`
`OH
`
`R1
`
`R1
`
`(Vlllc)
`
`4
`
`

`
`7
`
`4,202,894
`
`-continued
`Formula Scheme B
`
`15
`
`30
`
`(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 Ila 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 reflux
`temperature of the reaction mixture. The reaction is 20
`preferably carried out at the boiling point of the reac(cid:173)
`tion mixture.
`When a halide of formula lib 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- 25
`ticularly preferred. The reaction is preferably carried
`out at a temperature in the range of from about so· c. to
`about lS0° C. In a particularly preferred aspect, the
`reaction is carried out using ethylene glycol as the inert
`solvent and at a temperature of 100°-110° C.
`According to process embodiment (b ), a compound
`of formula IV is catalytically hydrogenated or is re(cid:173)
`duced with formic acid. Particularly suitable catalysts
`are noble metal catalysts, for example, platinum, palla(cid:173)
`dium (optionally precipitated onto charcoal) and Raney 35
`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 40
`is advantageously carried out at a temperature in the
`range of from about 0° C. to about S0° 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
`so· 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 50
`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 55
`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(cid:173)
`drogenation is desired, the catalytic hydrogenation is 60
`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 65
`peracid. When a compound of formula Ia, Vila or Vllb
`(see Formula Scheme A) is used as the starting material,
`the treatment is carried out with hydrogen peroxide. In
`
`(lib)
`
`this case, an alcohol, such as, methanol, ethanol or iso(cid:173)
`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 o· c. to about so· c., especially at 40• c.
`When a compound of formula Ia or Vllb 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(cid:173)
`ylene chloride, chloroform or ethylene chloride, is pref(cid:173)
`erably used as the solvent when a peracid is used. Suit(cid:173)
`able treatment temperatures are the same as those men(cid:173)
`tioned earlier in connection with the treatment with
`hydrogen peroxide.
`A preferred class of compounds of formula I com(cid:173)
`prises those wherein R is 1,1-dimethylpropyl. Also pre(cid:173)
`ferred are those compounds of formula I wherein R is
`phenyl.
`Preferred compounds of formula I are:
`1-[3-(p-Tert.amyl-phenyl)-2-methyl-propyl]-piperi(cid:173)
`dine,
`1-[3-(p-tert.amyl-phenyl)-2-methyl-propyl]-3-methyl(cid:173)
`piperidine,
`1-[3-(p-tert.amyl-phenyl)-2-methyl-propyl]-3,S(cid:173)
`dimethyl-piperidine,
`4-[3-(p-tert.amyl-phenyl)-2-methyl-propyl]-2,6-
`dimethyl-morpholine,
`1-[3-( 4-tert.amyl-cyclohexyl)-2-methyl-propyl](cid:173)
`piperidine,
`1-[3-( 4-tert.amyl-cyclohexyl)-2-methyl-propyl]-3-
`methyl-piperidine,
`1-[3-( 4-tert.amyl-cyclohexyl)-2-methyl-propyl]-3,S(cid:173)
`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,
`1-[3-( 4-tert.amyl-cyclohexyl)-2-methyl-2-propenyl](cid:173)
`piperidine,
`1-[3-( 4-tert.amyl-cyclohexyl)-2-methyl-2-propenyl]-
`3-methyl-piperidine,
`1-[3-( 4-tert.amyl-cyclohexyl)-2-methyl-2-propenyl]-
`3,S-dimethyl-piperidine,
`1-[3-(p-tert.amyl-phenyl)-2,3-dimethyl-2-propenyl](cid:173)
`piperidine,
`1-[3-(p-tert.amyl-phenyl)-2,3-dimethyl-2-propenyl]-3-
`methyl-piperidine,
`1-[3-(p-tert.amyl-phenyl)-2,3-dimethyl-2-propenyl]-
`3,S-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-propyl](cid:173)
`piperidine,
`1-[3-(p-tert.amyl-phenyl)-2,3-dimethyl-propyl]-3-
`methyl-piperidine,
`
`5
`
`

`
`,.·
`
`:
`.
`
`Rz
`
`.·
`··
`R1
`
`c=o
`I
`R3
`
`IX
`
`x
`
`RYTI Vyo
`
`Rt
`
`4,202,894
`
`s
`
`10
`
`15
`
`25
`
`30
`
`VIII
`
`VIIId
`
`R~·
`
`,•
`
`:
`
`Ri
`
`••••
`
`••••
`
`OH
`
`or
`
`R1
`
`R3
`
`• •
`
`:
`
`Ri
`
`R~·
`• ~ OH
`
`• • ••
`
`Ri
`
`10 R00
`..
`·.
`or R00
`
`:
`
`.
`
`,.·
`
`.
`
`'•,
`
`Ri
`
`••••
`R1
`
`COOC2Hs
`
`wherein R, R1, R2, RJ 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
`20 formula IX are, for example, borohydrides, such as,
`sodium borohydride, or alanates, such as, lithium alumi(cid:173)
`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
`
`9
`1-[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,
`1-[3-[p-(l, 1-diethyl-propyl)-phenyl]-2-methyl(cid:173)
`propyl]-3-methyl-piperidine,
`1-[3-[p-(1, 1-dimethyl-pentyl)-phenyl]-2-methyl(cid:173)
`propyl]-3-methyl-piperidine,
`1-[3-[p-(l, 1-dimethyl-pentyl)-phenyl]-2-methyl(cid:173)
`propyl]-piperidine,
`4-[3-( 4-biphenyl yl)-2-methyl-propyl]-2,6-dimethyl(cid:173)
`morpholine,
`1-[3-[p-( a,a-dimethyl-benzyl)-phenyl]-2-methyl(cid:173)
`propyl]-piperidine,
`1-[3-[p-( a,a-dimethyl-benzyl)-phenyl]-2-methyl(cid:173)
`propyl]-3-methyl-piperidine,
`1-[3-[p-(a,a-dimethyl-benzyl)-phenyl]-2-methyl(cid:173)
`propyl]-3,5-dimethyl-piperidine,
`4-[3-[p-(a,a-dimethyl-benzyl)-phenyl]-2-methyl(cid:173)
`propyl]-2,6-dimethyl-morpholine,
`1-[3-[p-( a,a-dimethyl-benzyl)-phenyl]-2,3-dimethyl-
`2-propenyl]-3,5-dimethyl-piperidine,
`1-[3-[p-(a,a-dimethyl-benzyl)-phenyl]-2,3-dimethyl-
`propyl]-3,5-dimethyl-piperidine,
`1-[3-[ 4-( 1-cyclohexyl-1-methyl-ethyl)-cyclohexyl]-2-
`methyl-propyl]-piperidine,
`4-[3-[4-(l-cyclohexyl-1-methyl-ethyl)-cyclohexyl]-2-
`methyl-propyl]-2,6-dimethyl-morpholine,
`1-[3-[p-( 1-cyclohexyl-1-methyl)-phenyl]-2-methyl(cid:173)
`propyl]-piperidine,
`wherein R, R1 and the dotted bonds are as previously
`1-[3-[p-(l-cyclohexyl-1-methyl)-phenyl]-2-methyl-
`described,
`propyl]-3,5-dimethyl-piperidine and
`35 by means of a Wittig reaction, Homer reaction or
`4-[3-[p-(l-cyclohexyl-1-methyl)-phenyl]-2-methyl-
`Reformatzky reaction (see Formula Scheme B).
`propyl]-2,6-dimethyl-morpholine.
`Synthesis (1974), page 122 et seq. is referred to as
`Some of the starting materials of formulas II, IV, V,
`exemplifying the Wittig reaction and the Homer reac-
`VI and VII are novel.
`The compounds of formulas VI and VII are prepared 40 tion. The relevant secondary literature is also cited in
`by alkylating an amine of formula III with a halide of
`this literature reference. Examples of the Reformatzky
`formula II or V. The alkylation is carried out in the
`reaction are described in Bull. Soc. Chim. France
`same manner as described earlier in connection with
`(1961), page 2145 et seq. A detailed bibliography for the
`Reformatzky reaction is also given in this literature
`process embodiment (a).
`The halides can be prepared in a known manner from 45 reference.
`In order to prepare a compound of formula IXa,
`a corresponding alcohol of the formula
`wherein R2 and RJ, individually,, are alkyl, or R2 is alkyl
`and RJ is hydrogen, the aldehyde of formula XII is
`reacted with a ketone or aldehyde of formula XVl
`so under the conditions of a Claisen-Schmidt condensation
`in a known manner. The relevant literature is given in
`"Namenreaktionen der organischen Chemie", Dr. Al(cid:173)
`fred Huthig Verlag GmbH, Hddelberg 1961, page 94.
`A compound of formula IXc is prepared from a com-
`55 pound of formula XIII by saponification in a known
`manner. The saponification 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
`60 formula XIV by a Friedel-Crafts reaction, also in a
`.
`known manner. The Friedel-Crafts reaction can be
`wheretn R, R1, R2 and RJ and the dotted bonds are as
`previously desc~bed,
`carried out, for example, in an analogous manner to the
`.
`by treatment with a phosphorus halide, such as, phos-
`examples which are given in the aforementioned litera-
`ture reference.
`phorus tribromide, phosphorus trichloride, phosphorus
`pentabromide or phosphorus pentachloride, with or 65 A compound of formula VIHd is oxidized to a com-
`pound of formula IXb in a known manner. For example,
`without the addition of a tertiary base.
`An alcohol of formula VIII or Vllld is obtained in a
`the methods described in J. Org .. Chem., 39, 3304 (1974)
`known manner from a compound of the formula
`can be utilized.
`
`6
`
`

`
`4,202,894
`
`30
`
`35
`
`ll.11
`A compound of formula IXb or IXc can be converted
`into a compound of formula VIHb or VIiie in a known
`manner by means of a Grignard reaction. When R3, in a
`compound of formula IXa, is hydrogen, a compound of
`formula VIIlb, wherein R3 is other than hydrogen, is 5
`also obtained by means of a Grignard reaction. With
`respect to the Grignard reaction, the monograph
`"Grignard Reactions of Nonmetallic Substrates", Ver(cid:173)
`lag Prentice-Hall Inc., New York, 1954, is referred to.
`A compound of formula IXa, IXb, VIiia or VIIIb is 10
`converted into a compound of formula IXc or VIiie in .
`a known manner by dissolution in an alcohol, preferably
`methanol or ethanol, optionally with the addition of
`water and water-soluble inorganic bases, for example,
`sodium carbonate, potassium carbonate or calcium hy- 15
`droxide, and hydrogenation at room temperature in the
`presence of palladium/charcoal.
`· A compound of formula IV (see Formula Scheme B)
`is prepared from an aldehyde of formula IXc by reac(cid:173)
`tion with an amine of formula III. For this purpose, an 20
`excess of the amine of formula III is added to the alde(cid:173)
`hyde and the mixture is heated under reflux in benzene
`or toluene, the water which forms distilled azeotropti(cid:173)
`cally (see "Advances in Organic Chemistry", Vol. 4,
`pp. 9 et seq., Verlag Interscience Publishers, New York, 25
`London, 1963).
`Preferred starting materials of formula IXb arid IXc
`hereinbefore are:
`p-Tert.amyl-a,,8-dimethyl-cinnamaldehyde,
`p-( a,a-dimethyl-benzyl)-a,,8-dimethyl-cinnamalde-
`hyde,
`3-(p-isobutyl-phenyl)-2-methyl-propionaldehyde,
`3-(p-neopentyl-phenyl)-2-methyl-propionaldehyde,
`3-(p-tert.-amyl-phenyl)-2-methyl-propionaldehyde,
`3-[p-(l, 1-dimethyl-pentyl)-phenyl]-2-methyl-pro-
`pionaldehyde,
`3-[p-(l, 1-diethyl-propyl)-phenyl]-2-methyl-pro-
`pionaldehyde,
`3-(p-tert.butyl-phenyl)-2-ethyl-propionaldehyde,
`3-(p-tert.butyl-phenyl)-2-isopropyl-propionaldehyde,
`3-(p-cyclohexyl-phenyl)-2-methyl-propionaldehyde,
`3-(p-biphenylyl)-2-methyl-propionaldehyde,
`3-(p-tert.butyl-phenyl)-2-octyl-propionaldehyde,
`3-[p-(l-propyl-1-methyl-pentyl)-phenyl]-2-methyl-
`propionaldehyde,
`3-[p-(l-ethyl-1-methyl-butyl)-phenyl]-2-methyl-pro(cid:173)
`pionaldehyde,
`3-[p-(l,2-dimethyl-propyl)-phenyl]-2-methyl-pro(cid:173)
`pionaldehyde,
`3-[p-(1-isopropyl-3-methyl-butyl)-phenyl]-2-methyl(cid:173)
`propionaldehyde,
`3-[p-(a,a-dimethyl-benzyl)-phenyl]-2-methyl-pro(cid:173)
`pionaldehyde,
`3-[ 4-cyclohexyl-1-methyl-ethyl)-cyclohexyl]-2-meth(cid:173)
`yl-propionaldehyde and
`3-[p-( 1-cyclohexyl-1-methyl)-phenyl]-2-methyl-pro(cid:173)
`pionaldehyde.
`Preferred starting materials of formula Ila hereinbe-
`fore are:
`3-(p-Tert.amyl-phenyl)-1-methyl-allyl bromide,
`3-(p-tert.amyl-phenyl)-2-methyl-allyl bromide,
`3-(p-tert.amyl-phenyl)-3-methyl-allyl bromide,
`3-(p-tert.amyl-phenyl)-1,2-dimethyl-allyl bromide,
`3-(p-tert.amyl-phenyl)-1,3-dimethyl-allyl bromide,
`3-(p-tert.amyl-phenyl)-2,3-dimethyl-allyl bromide,
`3-(p-tert.amyl-phenyl)-1,2,3-trimethyl-allyl bromide,
`3-(4-tert.amyl-cyclohexyl)-2-methyl-allyl
`bromide,
`and
`
`3-[p-(a,a-dimethyl-benzyl)-phenyl]-2,3-dimethyl(cid:173)
`allyl bromide.
`Preferred starting materials of formula Ilb hereinbe(cid:173)
`fore are:
`3-(p-tert.amyl-phenyl)-1-methyl-propyl bromide,
`3-(p-tert.amyl-phenyl)-2-methyl-propyl bromide,
`3-(p-tert.amyl-phenyl)-3-methyl-propyl bromide,
`3-(p-tert.amyl-phenyl)-1,2-dimethyl-propyl bromide,
`3-(p-tert.amyl-phenyl)-1,3-dimethyl-propyl bromide,
`3-(p-tert.amyl-phenyl)-2,3-dimethyl-propyl bromide,
`3-(p-tert.amyl-phenyl)-1,2,3-trimethyl-propyl
`bro-
`mide,
`3-(p-tert.amyl-phenyl)-2-methyl-propyl bromide and
`3-[p-(a,a-dimethyl-benzyl)-phenyl]-2,3-dimethyl(cid:173)
`propyl bromide.
`Preferred starting materials of formula IV hereinbe(cid:173)
`fore are:
`1-[3-(p-Tert.-amyl-phenyl)-2-methyl-1-propenyl](cid:173)
`piperidine,
`1-[3-(p-tert.amyl-phenyl)-2-methyl-1-propenyl]-3-
`methyl-piperidine,
`1-[3-(p-tert.amyl-phenyl)-2-methyl-1-propenyl]-3,5-
`dimethyl-piperidine,
`4-[3-(p-tert.amyl-phenyl)-2-methyl-1-propenyl]-2,6-
`dimethyl-morpholine,
`1-[3-[p-( 1, 1-diethyl-propyl)-phenyl]-2-methyl-1-
`propenyl]-3-methyl-piperidine,
`1-[3-[p-(l, 1-dimethyl-propyl)-phenyl]-2-methyl-1-
`propenyl]-3-methyl-piperidine,
`1-[3-[p-(1,l-dimethyl-propyl)-phenyl]-2-methyl-l-
`propenyl]piperidine,
`4-[3-( 4-biphenyl)-2-methyl-1-propenyl]-2,6-dimethyl(cid:173)
`morpholine,
`1-[3-[p-( a,a-dimethyl-benzyl)-phenyl]-2-methyl-1-
`propenyl]-piperidine,
`1-[3-[p-( a,a-dimethyl-benzyl)-phenyl]-2-methyl-1-
`propenyl]-3-methyl-piperidine,
`1-[3-[p-( a,a-dimethyl-benzyl)-phenyl]-2-methyl-1-
`propenyl]-3,5-dimethyl-piperidine,
`4-[3-[p-(a,a-dimethyl-benzyl)-phenyl]-2-methyl-1-
`propenyl]-2,6-dimethyl-morpholine,
`1-[3-[p-(l-cyclohexyl-1-methyl)-phenyl]-2-methyl-1-
`propenyl]-piperidine,
`1-[3-[p-(1-cyclohexyl-1-methyl)-phenyl]-2-methyl-1-
`propenyl]-3,5-dimethyl-piperidine and
`4-[3-[p-(1-cyclohexyl-1-methyl)-phenyl]-2-methyl-1-
`propenyl]-2,6-dimethyl-morpholine.
`It is not necessary to isolate the compounds of for(cid:173)
`mula IV. Such compounds can be converted directly
`50 into compounds of formula VIIb, without working up,
`either by adding formic acid or by hydrogenation.
`The compounds of formula I possess fungicidal activ(cid:173)
`ity and can, accordingly, be used for combatting fungi
`in agriculture and in horticulture. The compounds are
`55 particularly suitable for combatting powdery mildew
`fungi such as, for example, Erysiphe graminis (powdery
`mildew of cereals), Erysiphe cichoracearum (powdery
`mildew of cucumbers), Podosphaera /eucotricha (pow(cid:173)
`dery mildew of apples), Sphaerotheca pannosa (powdery
`60 mildew of roses) and Oidium tuckeri (powdery mildew
`of vines), rust diseases, for example, those of the genera
`Puccinia, Uromyces and Hemileia, especially Puccinia
`graminis (stem rust of cereals), Puccinia coronata (crown
`rust of oats), Puccinia sorghi (corn rust), Puccinia striifor-
`65 mis (stripe rust of wheat), Puccinia recondita (leaf rust of
`cereals), Uromycesfabae and appe11diculatus (bean rusts),
`as well as Hemileia vastatrix (coffee rust) and Phrag(cid:173)
`midium mucronatum (leaf rust of roses).
`
`40
`
`45
`
`7
`
`

`
`°6
`
`51
`
`4,202,894
`
`13
`14
`the leaf surface infected by Erysiphe graminis was deter-
`Furthermore, the compounds of formula I are also
`mined in % relative to the leaf surface of the infected
`active against the following phytopathogenic fungi:
`Ustilago avenae (loose smut of oats), Venturia inae-
`untreated control. The results are summarized in Table
`qua/is (apple scab), Cercospora arachidicola (peanut early
`I hereinafter.
`leaf spot), Ophiobolus graminis (cereal take-all), Septoria S (b) Puccinia coronata
`nodorum (cereal leaf spot) or Marssonina rosae (rose
`30-40 oat seedlings of the FILAEMINGSKRONE
`blackspot). The compounds of formula I possess pro-
`variety (distributed on 2 pots of 7 cm diameter:), each
`nounced subsidiary activity against various species of
`seedling being in the one-leaf stage, were thoroughly
`sprayed from all sides with an aqueous dispersion of the
`the following genera: Rhizoctonia, Tilletia and Helmin-
`thosporium, and also, in part, against Peronospora, 10 test substance (processed in the usual manner as a spray-
`Coniophora, Lenzites, Corticium, Thielaviopsis and
`able powder) and were then grown in a climatically
`controlled chamber at 17° C. and 70-80% relative atmo-
`Fusarium.
`Furthermore, compounds of formula I are also active
`spheric humidity with a light period of 16 hours. After
`against phythopathogenic bacteria, for example, Xan-
`2 days, the test plants were infected by spraying with
`thomonas vesicatoria, Xanthomonas oryzae and other IS uredospores (300,000 spores/ml) of Puccinia coronata
`Xanthomonades as well as against various species of
`suspended in distilled water. The plants were then incu-
`Erwinia, such as, Erwinia tracheiphila.
`bated in the dark for 24 hours at 20° C. and an atmo-
`The compounds of formula I are also active as insecti-
`spheric humidity above 90%, and were subsequently
`moved into a greenhouse at a temperature of 22° -26° C.
`cides and acaricides, and, to some extent, insect growth-
`regulating effects and anti-feedant effects are also 20 and a relative atmospheric humidity of 70% with a light
`found. Thus, for example, l-{3-[(l-isopropyl-3-methyl-
`period of 18 hours. On the 9th dlay after infection, the
`leaf surface infected by Puccinia coronata was deter-
`butyl)-phenyl]-2-methyl-propyl}-3,4-dirnethyl-piperi-
`dine showed a 100% activity in the larvicide test with
`mined in % relative to the infected untreated control.
`Adoxophyes orana at a dosage of 10-6 g/cm2 and a 50%
`The results are summarized in Table I hereinafter.
`activity at a dosage of 10- 7 g/cm2.
`2S (c) Venturia inaequalis
`3 small apple plants (distributed in 3 pots of 5 cm
`As will be evident from the following biological tests,
`the compounds of formula I are active under green-
`diameter) raised from seeds of tlb.e GOLDEN DECI-
`CIOUS variety, the plants being in the 4- to 5-leaf stage,
`house conditions even at a concentration of as little as 5
`mg. to 500 mg. of ~ctive ingredi~nt, that is, a compound
`were thoroughly sprayed on all sides with an aqueous
`of formula I, per liter of spray liquor. In the open, con- 30 dispersion on the test substance (processed in the usual
`centrations of 100 g to 2,500 g. of active ingredie?~ per
`manner as a sprayable powder). The treated plants were
`hectare and p~r treatment are advantageously .utilized.
`then grown for 2 days at 17° C. and 70-80% relative
`For example, m ord~r. to combat powdery mildew of
`atmospheric humidity with a light period of 14 hours.
`cer~als successfully, 1t 1s advantageous to use a concen-
`Thereafter, the plants were infected by spraying with a
`trat10? o~ 200 g: to 1,000 g., preferably 200 ~· t~ 600 g., 3S suspension of conidia of Venturia inaequalis in distilled
`of actlv~ mgred1ent per .h7ctare and per application. For
`water (200,000 conidia/ml). After the infection, the
`co~battmg cereal rust, 1t 1s advantag~ous to use concen-
`plants were incubated in the dark for 48 hours at
`16°-18° c. and a relative atmospheric humidity of
`trat10ns of 500 g. to 2,500 g. and particularly preferably,
`in the c~e o~ the ~ost active members, 500 g. t? 2,~ above 90%, and were then moved to a shaded green-
`g., of active mgred1ent per hectare and pe~ applicat1?n. 40 house at a temperature of 22° -26° C. and a relative
`Som~ of t~~ compounds of formula I display a high
`atmospheric humidity of above 80%. On the 13th day
`systemic act1v1ty. Untreated parts of t~e P!ant~ can also
`after the infection, the leaf surface infected by Venturia
`be pro~ected ~ a result of secon.dary d1stnbut1on of the
`inaequalis was determined relative to that of the in-
`active mgred1ent (gas phase action).
`fected untreated control. The results are summarized in
`For practical purposes, the compounds of formula I 4S Table 11 hereinafter.
`can be said to be substantially non-toxic to vertebrates.
`Table I
`The toxicity of the compounds of formula I is on aver-
`age above 1,000 mg. per kg. of body weight in the acute
`Activity (in%)
`Concentration
`toxicity test on mice. Individual members show LD50
`(in mg/I of spray
`Erysiphe
`Puccinia
`values, determined on mice, in the range of from about SO
`.;.T;;;es;,;.t .;,;su;,;.bs.;,;ta.;,;n;,;.ce.;.._ _____ 1iq.:..u_o..:.r) __ .....;;K;..'a_m_in_is __ c_o_ro_n_1a_
`400 to about 1,000 mg. per kg. of body weight, while
`1-[3-[p-(l,l-
`500
`100
`100
`other members show LD50 values which are in the
`Diethyl-propyl)-
`160
`phenylJ-2-methyl-
`97
`range of from about 1,000 to about 10,000 mg. per kg. of
`propyl]-
`85
`body weight in the acute toxicity test on mice.
`piperid.ine
`55
`The biological tests described hereinafter illustrate SS 1-[3:'[p-(1,1-
`100
`100
`the activity of the compounds of formula I, the results
`Diethyl-propyl)-
`100
`are summarized in the Tables which follow.
`phenyl]-2-methyl-
`propylJ-3-methyl-
`(a) Erusinhe graminis
`95
`..,, ,.
`piperidine
`75
`30-40 barley seedlings of the HERTA variety (dis-
`1-[3-(p-Tert.amyl-
`100
`tributed on 2 pots of7 cm diameter), the seedlings being 60 phenyl)-2-methyl-
`100
`100
`in each case in the one-leaf stage, were thoroughly
`propyl]-piperidine
`90
`sprayed from all sides with an aqueous dispersion of the
`85
`test substance (processed in the usual manner as a spray-
`1-[3-(p"Tert.amyl-
`100
`phenyl)-2-methyl-
`able powder) and were then grown in a greenhouse at
`100
`100
`22° -26° C. and 80% relative atmospheric humidity with 6S propyl]-3-methyl-
`. 95
`a light period of 16 hours. The infection was effected 2
`piperidine
`60
`days after the treatment by dusting the test plants with
`l-[3-[p-(1,1-
`100
`conidia of Erysiphe graminis. 7 days after the infection,
`Dimethyl-pentyl)-
`100
`
`100
`50
`10
`0
`100
`100
`90
`10
`0
`100
`98
`87
`20
`10
`100
`100
`93
`40
`0
`100
`35
`
`5
`500
`160
`50
`16
`5
`500
`160
`~~
`5
`500
`160
`50
`1~
`500
`160
`
`8
`
`

`
`4,202,894
`
`15
`Table I-continued
`Concentration
`(in mg/I of spray
`liquor)
`
`50
`16
`5
`500
`160
`50
`16
`5
`500
`160
`50
`16
`5
`500
`160
`50
`16
`5
`500
`160
`50
`16
`5
`500
`160
`50
`16
`5
`500
`160
`50
`16
`5
`500
`160
`.50
`16
`5
`
`500
`160
`50
`16
`5
`500
`160
`50
`16
`5
`500
`160
`50
`16
`5
`500
`160
`50
`16
`5
`
`Test substance
`
`phenyl]-2-methyl-
`propyl]-
`piperidine
`1-[3-[p-(l,I-
`Dimethyl-pentyl)-
`phenyl]-2-methyl-
`propyl]-3-methyl-
`piperdine
`4-[3-(p-Tert.amyl-
`phenyl]-2-methyl-
`propyl]-2,6-
`dimethyl-
`morpholine
`1-[3-(4-Tert.amyl-
`cyclohexyl)-2-
`methyl-propyl]-
`piperidine
`
`1-[3-(4-Tert.amyl-
`cyclohexyl)-2-
`methyl-2-
`propenyl]-
`piperidine
`1-[3-[p-( 1-Iso-
`propyl-3-methyl-
`butyl)-phenyl]-2-
`methyl-propyl]-
`pip