Use of Malonic Acid Derivative Compounds for Retarding Plant Growth

Brief Summary of the Invention Technical Field

This invention relates to the use of malonic acid derivative compounds for retarding plant growth. This invention further relates to novel malonic add derivative compounds and processes for the preparation thereof.

Background of the Invention

Certain malonic acid derivative compounds have been known for some time in the art. See, for example, U.S. Patent 2,504,896 and U.S. Patent 3,254,108. Some malonic acid derivative compounds have been described in the art as capable of providing certain plant growth regulating responses such as prevention of fruit drop, rooting of cuttings and formation of parthenogenetic fruit.

U.S. Patent 3,072,473 describes N-arylmalonamic acids and their esters and salts, N, N'-diarylmalonamldes, N-alkyl-N-arylmalonamic acids and their esters and salts, and N, N'-dialkyl-N, N'-diarylmalonamides which may be useful as plant growth reguiants and herbicides. Japanese Patent 84 39,803 (1984) describes malonic acid anilide derivative compounds which may be useful as plant growth regulators. The plant growth regulating properties of substituted malonyl monoanilides are described by Shindo, N. and Kato, H., Meiji Daigaku Noogaku-bu Kenkyu Hokoku, Vol. 63, pp. 41-58 (1984).

However, certain malonic acid derivative compounds and the use of malonic acid derivative compounds for retarding plant growth as described herein have not been disclosed in the art.

Accordingly, it 1s an object of this invention to provide a method for the use of malonic acid derivative compounds to retard plant growth. It is another object of this invention to provide novel malonic acid derivative compounds and processes for the preparation thereof. These and other objects will readily become apparent to those skilled in the art in light of the teachings herein set forth.

Disclosure of the Invention

This invention relates to a method for retarding plant growth which comprises applying to the plant an effective amount, sufficient to retard plant growth, of a compound having the formula:

< 3 Y4

\ /

R- _ Y- - C C C - Y;

11 II Yc Y< wherei n R. , R , Y_ , Y_ , Y_ , Y . , Y, and I 2 1 2 3 4 5

Y, are as defined hereinafter. 6

This invention also relates to novel malonic acid derivative compounds and to processes for the prepartion of said compounds.

Detailed Description As indicated above, this invention relates to a method of retarding plant growth by use of

certain malonic acid derivative compounds. More particularly, this invention involves a method for retarding plant growth which comprises applying to the plant an effective amount, sufficient to retard plant growth, of a compound having the formula:

Y3 Y4

\ /

R ₁ _ γ ₁ - C C C - Y ₂ - R ₂ 1

II II

Y5 Yδ wherein:

R_ and R„ are independently a substituted or unsubstituted, carbocyclic or heterocyclic ring system selected from a monocyclic aromatic or nonaromatic ring system, a bicyclic aromatic or nonaromatic ring system, a polycyclic aromatic or nonaromatic ring system, and a bridged ring system which may be saturated or unsaturated in which the permissible substituents (Z) are the same or different and are one or more hydrogen, halogen, alkylcarbonyl, alkylcarbonylalkyl, formyl , alkoxycarbonylalkyl , alkoxycarbonylalkylthio, polyhaloalkenylthio, thlocyano, propargylthio, hydroxyimino, alkoxylmino, trlalkylsilyloxy, aryldlalkylsilyloxy, triarylsHyloxy, formamidlno, alkylsulfa ido, dlalkylsulfa ido, alkoxysulfonyl , polyhaloalkoxysulfonyl, hydroxy, amino, azido, azo, amlnocarbonyl, alkylaminocarbonyl , hydrazino, dialkylaminocarbonyl , aminothiocarbonyl , alkyla inothiocarbonyl , dlalkylaminothiocarbonyl , nitro, cyano, hydroxycarbonyl and derivative salts, formamido, alkyl, alkoxy, polyhaloalkyl , polyhaloalkoxy, alkoxycarbonyl, substituted amino in which the permissible substituents are the same or different and are one or two propargyl, alkoxyalkyl,

alkylthioalkyl, alkyl, alkenyl, haloalkenyl or polyhaloalkenyl; alkylthio, polyhaloalkylthio, alkylsulfinyl, polyhaloalkylsulfinyl , alkylsulfonyl, polyhaloalkylsulfonyl , alkylsulfonylamino, alkylcarbonylamino, polyhaloalkylsulfonylamino, polyhaloalkylcarbonylamino, trialkylsilyl, aryldialkylsilyl, triarylsilyl , sulfonic acid and derivative salts, phosphonic acid and derivative salts, alkoxycarbonyla ino, alkylaminocarbonyloxy, dialkyla inocarbonyloxy, alkenyl, polyhaloalkenyl, alkenyloxy, alkynyl, alkynyloxy, polyhaloalkenyloxy, polyhaloalkynyl , polyhaloalkynyloxy, polyfluoroalkanol , cyanoalkylamino, semicarbazonomethyl, alkoxycarbonylhydrazonomethyl, alkoxylminomethyl , unsubstituted or substituted aryloxyiminomethyl, hydrazonomethyl , unsubstituted or substituted arylhydrazonomethyl, a hydroxy group condensed with a mono-, di- or polysaccharide, haloalkyl, haloalkenyl, haloalkyπyl, alkoxyalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylthioalkyl, arylthioalkyl , arylsulfinyl, arylsulfonyl, haloalkylsulfinyl , haloalkylsulfonyl, haloalkenyloxy, haloalkynyloxy, haloalkynylthio, haloalkenylsulfonyl, polyhaloalkenylsulfonyl , isocyano, aryloxysulfonyl, propargyloxy, aroyl, haloacyl, polyhaloacyl, aryloxycarbonyl , aminosulfonyl, alkyla lnosulfonyl, dialkylaminosulfonyl , arylaminosulfonyl , carboxyalkoxy, carboxyalkylthio, alkoxycarbonylalkoxy, acyloxy, haloacyloxy, polyhaloacyloxy, aroyloxy, alkylsulfonyloxy, alkenylsulfonyloxy, arylsulfonyloxy, haloalkylsulfonyloxy, polyhaloalkylsulfonyloxy,

aroylamlno, haloacylamino, alkoxycarbonyloxy, arylsulfonylamino, aminocarbonyloxy, cyanato, isocyanato, isothiocyano, cycloalkylamino, trialkylammonium, arylamino, aryl(alkyl)amino, aralkyla ino, alkoxyalkylphosphinyl , alkoxyalkylphosphinothioyl , alkylhydroxyphosphinyl, dialkoxyphosphino, hydroxyamino, alkoxyamino, aryloxyamino, aryloxyimino, oxo, thiono, diazo, alkylidene, alkylimino, hydrazono, semicarbazono.dialkylsulfoniurn, dialkylsulfuranylidene, dialkyloxosulfuranylidene,

-Λ, = Λ, -A = R_ , = Λ-R_,

_ _ R ₃ , _ p _ YgR ₄ , _Y _1Q _ p YgR ₄

' Y9R5 Y9R5 or

R and R are Independently hydrogen or derivative salts, or a substituted heteroatom or substituted carbon atom, or a substituted or unsubstituted, branched or straight chain containing two or more carbon atoms or heteroatoms in any combination 1n which the permissible substituents are Z as hereinbefore defined; Y- and Y are independently a substituted or unsubstituted heteroatom 1n which the permissible substituents are Z as hereinbefore defined;

Y- and Y. are Independently hydrogen, or a substituted or unsubstituted heteroatom or

substituted carbon atom, or a substituted or unsubstituted, branched or straight chain containing two or more carbon atoms or heteroatoms in any combination, or halogen, alkylcarbonyl , formyl, alkylcarbonylalkyl , alkoxycarbonylalkyl , alkoxycarbonylalkyIthio, polyhaloalkenylthio, thiocyano, propargylthio, trialkylsilyloxy, aryldialkylsilyloxy, triarylsilyloxy, formamidino, alkylsulfamido, dialkylsulfa ido, alkoxysulfonyl, polyhaloalkoxysulfonyl, hydroxy, amino, hydrazino, azo, aminocarbonyl, alkylaminocarbonyl , azido, dialkylaminocarbonyl , aminothiocarbonyl, alkyla inothiocarbonyl , dialkylaminothiocarbonyl , nitro, cyano, hydroxycarbonyl and derivative salts, formamido, alkyl, alkoxy, polyhaloalkyl , polyhaloalkoxy, alkoxycarbonyl, substituted amino in which the permissible substituents are the same or different and are one or two propargyl, alkoxyalkyl, alkylthioalkyl, alkyl, alkenyl, haloalkenyl or polyhaloalkenyl; alkylthio, polyhaloalkylthio, alkylsulfinyl, polyhaloalkylsulfinyl , alkylsulfonyl, polyhaloalkylsulfonyl , alkylsulfonylamino, alkylcarbonylamino, polyhaloalkylsulfonyl mino, polyhaloalkylcarbonylamlno, trialkylsilyl, aryldialkylsilyl, triarylsilyl, sulfonic acid and derivative salts, phosphonic acid and derivative salts, alkoxycarbonylamino, alkylaminocarbonyloxy, dialkylamlnocarbonyloxy, alkenyl, polyhaloalkenyl, alkenyloxy, alkynyl, alkynyloxy, polyhaloalkenyloxy, polyhaloalkynyl , polyhaloalkynyloxy, polyfluoroalkanol , cyanoalkylamino, semicarbazonomethyl , alkoxycarbonylhydrazonomethyl , alkoxyiminomethyl, unsubstituted or substituted

aryloxyimlnomethyl, hydrazonomethyl, unsubstituted or substituted arylhydrazonomethyl, a hydroxy group condensed with a mono-, di- or polysaccharide, haloalkyl, haloalkenyl, haloalkynyl, alkoxyalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylthioalkyl, arylthioalkyl , arylsulfinyl , arylsulfonyl , haloalkylsulfinyl , haloalkylsulfonyl , haloalkenyloxy, haloalkynyloxy, haloalkynylthio, haloalkenylsulfonyl , polyhaloalkenylsulfonyl , isocyano, aryloxysulfonyl , propargyloxy, aroyl, haloacyl, polyhaloacyl , aryloxycarbonyl, aminosulfonyl , alkylaminosulfonyl , dialkylamlnosulfonyl, arylaminosulfonyl , carboxyalkoxy, carboxyalkylthio, alkoxycarbonylalkoxy, acyloxy, haloacyloxy, polyhaloacyloxy, aroyloxy, alkylsulfonyloxy, alkenylsulfonyloxy, arylsulfonyloxy, haloalkylsulfonyloxy, polyhaloalkylsulfonyloxy, aroylamino, haloacylamino, alkoxycarbonyloxy, arylsulfonylamino, aminocarbonyloxy, cyanato, isocyanato, Isothiocyano, cycloalkylamino, trialkylammonium, arylamino, aryl(alkyl)amino, aralkylamino, alkoxyalkylphosphinyl , alkoxyalkylphosphinothioyl , alkylhydroxyphosphinyl , dialkoxyphosphino, hydroxyamino, alkoxyamlno, aryloxya ino,

-X, -X = R ₃ ,

-X - R ₃ , - P - Y ₈ R ₄ , -Y _1Q - ^Y ₈ R ₄

Y9R5 ^Y 9 ^R 5

or

in which the permissible substituents are Z as hereinbefore defined; or

Y„ and Y. taken together are oxo, 3 4 thiono, diazo, = X or = X - R , or substituted or unsubstituted alkylidene, alkyllmino, hydrazono, dialkylsulfuranylidene, dialkyloxosulfuranylidene semicarbazono, hydroxyimino, alkoxyimino or aryloxyimino in which the permissible substituents are Z as hereinbefore defined; Y and Y may be linked together to form a substituted or unsubstituted, carbocyclic or heterocyclic ring system selected from a monocyclic aromatic or nonaromatic ring system, a bicyclic aromatic or nonaromatic ring system, a polycyclic aromatic or nonaromatic ring system, and a bridged ring system which may be saturated or unsaturated in which the permissible substituents are Z as hereinbefore defined; and

Y _c and Y _c are independently oxygen or 3 0 sulfur; wherein:

X is a covalent single bond or double bond, a substituted or unsubstituted heteroatom or substituted carbon atom, or a substituted or unsubstituted, branched or straight chain containing two or more carbon atoms or heteroatoms in any

combination in which the permissible substituents are Z as hereinbefore defined;

R- is a substituted or unsubstituted, carbocyclic or heterocyclic* ring system selected from a monocyclic aromatic or nonaromatic ring system, a bicycϋc aromatic or nonaromatic ring system, a polycyclic aromatic or nonaromatic ring system, and a bridged ring system which may be saturated or unsaturated in which the permissible substituents are Z as hereinbefore defined; or

R„ is a substituted heteroatom or substituted carbon atom, or a substituted or unsubstituted, branched or straight chain containing two or more carbon atoms or heteroatoms in any combination in which the permissible substituents . are Z as hereinbefore defined;

The alkyl-containlng moieties in formula 1 may contain from about 1 to about 100 carbon atoms or greater, preferably from about 1 to about 30 carbon atoms, and more preferably from about 1 to about 20 carbon atoms. The polysaccharide moiety may contain up to about 50 carbon atoms. It is appreciated that all compounds encompassed within formula 1 are compounds having no unfilled bonding positions. In regard-to the malonic acid derivative compounds used in this Invention, it is preferred that R and R are independently other than hydrogen, alkyl or aryl when both Y and Y are -NH-.

As used herein, hydrogen or derivative salts refer to hydrogen or any appropriate derivative salt substituents which may be substituted therefor. Illustrative derivative salt substituents include, for example, ammonium, al ylammonium, polyalkylammonium, hydroxyal ylammonium, poly(hydroxyal yl)ammonium, alkali metals, alkaline earth metals and the like including mixtures thereof.

Monocyclic ring systems encompassed by R- , R- and R„ in formula 1 may be represented by generalized formula 2. as follows:

wherein B represents a saturated or unsaturated carbon atom and A represents a ring-forming chain of atoms which together with B forms a cyclic system containing from 0 to 3 double bonds or from 0 to 2 triple bonds. A may contain entirely from 2 to 12 carbon atoms, may contain a combination of from 1 to 11 carbon atoms and from 1 to 4 heteroatoms which may be selected independently from

N, 0, S, P or other heteroatoms, or may contain 4 ring-forming heteroatoms alone.

Monocyclic ring systems encompassed by Y and Y. linked together in formula 1 may include 4 ~ any monocyclic ring system of R , R and R

I C appropriately positioned in formula 1.

Ring-forming heteroatoms may in some cases bear oxygen atoms as in aromatic N-oxides and ring

systems containing the sulfinyl, sulfonyl, selenoxlde and phosphine oxide moieties.

Selected carbon atoms contained in cycles formed by B and A containing at least 3 ring-forming atoms may bear carbonyl, thiocarbonyl , substituted or unsubstituted i ino groups or substituted or unsubstituted ethylidene groups.

The group designated as Z represents one or more substituents selected independently from among the group of substituents defined for Z herein.

Bicyclic ring systems encompassed by R, , R and R in formula 1 may be represented by generalized formulae 3. and 4 as follows:

wherein B and 8 may be independently a saturated or unsaturated carbon atom or a saturated nitrogen atom, A„ and A„ independently represent the ring-forming chains of atoms described below and Z represents one or more substituents selected independently from among the group of substituents defined for Z herein. Combinations of A and A

may contain in combination with B or B from 0 to 5 double bonds. A and A , independent of

B and B , may contain entirely from 1 to 11

2 3 carbon atoms, may contain a combination of 1 to 3 heteroatoms which may be selected independently from among N, 0, S, P or other heteroatoms together with from 1 to 10 carbon atoms or may contain from 1-3 ring-forming heteroatoms alone.

Ring-forming heteroatoms may in some cases bear oxygen atoms, as in aromatic N-oxides and ring systems containing the sulfinyl, sulfdnyl, selenoxide and phosphine oxide groups. Selected carbon atoms contained in A and A may bear carbonyl, thiocarbonyl, substituted or unsubstituted imino groups or substituted or unsubstituted ethylidene groups.

Bicyclic ring systems encompassed by Y ^* and Y linked together in formula 1 may include any bicyclic ring system of R_ , R„ and R„

1 2 3 appropriately positioned in formula 1.

In regard to structures encompassed within formulae 3. and 4_, it is noted as follows:

(a) When B and B are both nitrogen, the groups A and A. should each contain no

2 3 fewer than three ring atoms;

(b) When B but not B is nitrogen, either of A„ or A„ should contain at least three 2 3 ring atoms and the other at least two _. ring atoms;

(c) When either of groups A or A contains fewer than three ring atoms, the other should contain at least three ring atoms and the bridgehead atoms should be saturated;

(d) When the group A or A contains a

carbon atom bearing a carbonyl, thiocarbonyl, imino or methylidene group, it should together with B and B form a cycle having at least four members;

(e) When a annular double bond is exocyclic to either of the two rings represented in structures 3. and 4., it should be contained in a ring containing at least five members and be exocyclic to a ring containing at least five members; and

(f) When a group A or A 1s joined to the bridgehead atoms B„ and B„ by 2 double

2 3 bonds, the group A or A is understood to contain one double bond and the bridgehead atoms are considered to be unsaturated.

It is recognized that bicyclic ring systems defined for R , R , R and Y and Y

I -. J T" linked together may be spirocyclic ring systems and are not limited to the fused bicyclic structures of formulae 3. and 4. Spirocyclic ring systems may be saturated or unsaturated carbocyclic or heterocyclic and may be independently substituted by one or more substituents Z as defined herein.

Polycyclic ring systems, I.e., greater than 2 rings, encompassed by R-* , R ₂ and R ₃ in formula 1 may be represented by generalized formulae 5., 6_, 1 and 8. as follows:

₂

wherein B,, B_, B _r and B_, may be 4 5 6 7 independently a saturated or unsaturated carbon atom or a saturated nitrogen atom, and A., A _c , A _c

4 D 0 and A independently represent ring forming chains of atoms which may contain together with one or the other (but not both) of their two associated bridgehead atoms, from 0-2 double bonds. The groups Z represent one or more substituents selected independently from among the group of substituents defined for Z herein.

The ring-forming elements of A., A _c ,

4 3

A. and A., independent of 8„, B_, B _Λ and 6 7 4 5 6

B may contain from 1-11 carbon atoms, may contain a combination of from 1-10 carbon atoms and from 1-3 heteroatoms which may be selected independently from among N, 0, S, P or other heteroatoms, or may contain from 1-3 heteroatoms alone. Ring-forming heteroatoms may 1n some cases bear oxygen atoms as in aromatic N-oxides and ring systems containing the sulfinyl, sulfonyl, selenoxide and phosphine oxide

groups. The group A may at times be defined as a bond. Selected carbon atoms contained in A .

4

A , A and A may bear one or more carbonyl,

5 6 7 thiocarbonyl or substituted or unsubstituted imino groups.

On structure 8. the groups B , 8 and o y

B represent independently a saturated or unsaturated carbon atom or a saturated nitrogen atom. The group B.. may represent a saturated or unsaturated carbon atom or a nitrogen or phosphorous atom. The groups A _Q , A. and A.., represent o y iu ring-forming chains of atoms which may contain together with 1 of the groups B , B , B and o Iu

B from 0-2 double bonds.

The ring-forming elements of groups A ,

8

A and A independent of groups B , 8 ,

8 and B may contain from 2-10 carbon atoms, may contain from 1-10 carbon atoms in combination with 1-3 heteroatoms which may be selected independently from among N, 0, S, P or other heteroatoms, or may contain from 2-3 heteroatoms alone. Ring-forming heteroatoms may in some cases bear oxygen atoms as 1n aromatic N-oxides and in ring systems containing the sulfinyl, sulfonyl, selenoxide and phosphine oxide groups. Selected carbon atoms contained in groups A , A and

A may bear one or more carbonyl, thiocarbonyl or substituted or unsubstituted imino groups.

It is recognized that polycyclic ring systems defined for R, , R„, R„ and Y„ and

1 2 3 3

Y linked together may be spirocyclic ring systems and are not limited to the fu_ed polycyclic structures of formulae 5_, 6., 7. and 8.. Spirocyclic

ring systems may be saturated or unsaturated, carbocyclic or heterocyclic and may be independently substituted by one or more substituents Z as defined herein.

Polycyclic ring systems encompassed by Y„ and Y, linked together in formula 1 may include

4 ^~ " any polycyclic ring system of R , R and R appropriately positioned in formula 1.

Bridged bicyclic structures encompassed by R , R and R in formula 1 may be represented by generalized formulae 9, TJ), and H as follows:

u

wherein B and B may be independently a saturated carbon atom optionally substituted by Z or a nitrogen atom, and the groups A , A and A Independently represent ring-forming chains of atoms which may contain, Independently of B and B , from 0-2 double bonds. The groups Z represent one or more substituents selected independently from among the groups of substituents defined for Z herein.

The ring-forming elements of A , A and A , independent of B and B , may

I I t_. I

contain entirely from 1-11 carbon atoms, may contain a combination of from 1-10 carbon atoms and from 1-3 heteroatoms which may be selected independently from among N, 0, S, P or other heteroatoms, or may contain from 1-3 heteroatoms alone with the proviso that when one of the groups A , and A is a single heteroatom, the other two groups should contain two or more ring-forming atoms. A second proviso is that when one or both of the groups B and B is nitrogen, the groups A , A and A should contain at least two saturated ring-forming atoms.

Ring-forming heteroatoms may in some cases bear oxygen atoms as in the sulfinyl, sulfonyl, selenoxide and phosphine oxide moieties. Selected carbon atoms contained in A , A and A may bear one or more carbonyl, thiocarbonyl or • substituted or unsubstituted Imino groups.

Bridged bicyclic structures encompassed by

Y„ and Y, linked together in formula 1 may 3 4 ^— include any bicyclic bridged system of R , R and R appropriately positioned in formula 1.

It is readily apparent that formula 1 encompasses a wide variety of malonic acid derivative compounds. Illustrative malonic acid derivative compounds within the scope of formula 1 which may be used for retarding plant growth are included in Tables 1 through 11 below.

IABU I

Representative Haloπlc Acid Derivative Compounds

O o

II II

R -C-CH^C - ^NH -^jr '

OC ₂ H ₅

OCH

3 OH

OC.H.

ONa

₅

.

OH

OCH

O-n-C.H,

OH

0C_H.

OH OCH.

IABI t 1 (Conl.j-. Representative Haloπlc Acid Derivative Compounds

O O

, II II Ry-C-CH _jj -C - ^NH~ ^

V .

_-F-4-Br-5-Cl OH

2 2--FF--44--BBrr--55--Cl OC.H-

. 2-Cl-4-Br-5-F O-n-C.H _j

₄ ,H ^» „ ₉

lABlt I (Conl.) Representative Halonlc Add Derivative Compounds

^Z ' B ^R, 7

H,

lAUt t 2

Rep'resentat lve Waloπlc Add Deriva tive Compounds

o o z,

R _r C "-CH ₂ -C--NHH -^ _Υ V

__ ___

OCH CH.OH 2-CH -4-Br

2 2 ^J

OCH CH OH 2- F-4-Br

0CH-CH-0H 3,4-Cl -

0CH(CH ₃ )C0 _{2 2} H. 2-CH ₃ -4-8r

0CH(CH ₃ )CO ₂ C ₂ H. 4 Cl

O OCCHH ₂ CH ₂ H(CH ₃ ) ₂ 22..'-'1--8r ₂

SCH. 2.4.5-Cl

3 3

S.C.H 3.5-Br ₂

S- ₃ H ₇ 2.<- . ₂

OCH CO C H 3-F-5-Br

SCH CO C H. 2-CH ₃ -4-Br

^SCH 2 ^C °2 ^C 2 ^H S 2-CH ₃ -4-Br-5-CI

0CH„CH„SCH, 2-F-4-8r

OCH ² CH ^Z S0_C ³ H ₃ .3,.5-.C.l.

0CH ₂ CH ₂ S0 ₂ CH ₃ 3,5-Br ₂

0CH ₂ CCH ₃ 3-Br-5-Cl 0

1ABLE. 2 (Cont.) Representative Halonlc Add Dertvatlve Compounds

o .z

II Rf-C --CCHH ₂ j-' C-NH -nr v.

OCH CCH 2.1-Cl.

0CH(CH )C±N 2-CH -4-Br

0CH(CH )C _d N 4-Br

0-N.CHCH 4 Cl

0-N.C(CH ) 3,4-CI

/ ^CH 3 ^S H ₃

OCH CH KHCO CH 2-CH -4.Br

OCH ₂ CH ₂ 0-C-HHC ₂ H ₅ 4- Cl

0

_^ -*0CH ₃ SCH ₂ P . 3.4 Cl ₂

" ^■" *- ^» QCH3 0

OCH CONH 3,5 (C .^

TABU 2 (Coπt.) Representative Malonic Add Derivative Compounds

R'J-C-CHJ-C-NH ^! =7

«'β ^Z ' ₉

' ° ^C b ^H 5 SCH ₂ CH-P-^_ 3-C1-5-CF-

• ^ OC.H.

0

0

OCH CH SCH CH OH 3-Br-5-C

OCH CH SO CH CH OH 3-F-4-Br OCH C-N 4-1 OCH CH Ci« 2.4-Cl ₂ 0-C(CH ₃ ) ₂ C.N 4 Cl

OCH CH OCH 3-F-5-C1

2 2 3 0CH ₂ 0 ₂ C ₂ H ₅ 3-F-4-C1

OCH ₂ CH ₂ H * 2-F-4.5-Cl ₂

ODUCHj-iCH.SC.Hj 2-F-4-CI-5-Br

OCH C0CH ₃ 2-F-4-Br-5-Cl OCH C»N 2-F-4.5-Br ₂

0-N-C'CH )-CO C H 2,4-Cl -5-F O-CH SO MH 2-Cl-4-8r-5-F

O-CH SO NHCH 2.4-8r ₂ -5-F

0-CH ₂ S0 ₂ N(C ₂ H.) ₂ 2 Br-4 C1-5-F

S-CH CH SCH 2 CH 4 C1-5-F

S-CH ₂ C0 ₂ C ₃ H, 2 CH 4-Br-5-F

TABLE 2 (Cont.) Representative Malonic Add Derivative Compounds

V.

OCH CH OC H 2-F-4-CF 0

OCH CH SCH 2-F-4-1

0CH(CH )C0 C ₂ H- 3-Br-4-Cl

SC H 2-CF 0-4-F

NHCH CH OH 2-CH -4-Br

NHCH CH OH 3-F-4-C1

NHCH CN 3.S-C1

1A0U 3

Representative Malonic Add Derivative Compounds

lABLl 3 (Cont.) Representative H_ Ionic Add Perlv-ttve Compounds

10

CH .CH- H 3.4-8r Oil

2 2

N^C- H 2-CII -4-Br

N.C- H 2.4-Cl OCH

2 3

N^C- ^c ", 3-f-4-Br OCH CONII

3 2 2

0 N- Cl 2, 4, 5-Cl, OCH CH Oil

2 3 2 2

N.C- Br 3-Br-5-F OCH CH SCH 2 2 3

HCONH- H .5-(CF ₃ ) ₂ oc _? ...

HC-C- II 2.5-CL

2 ^SC 6 ^H 5

C H, F 3-Cl-5-Cf_ OCII COCH

2 S 3

CH,Q- CH, 4 Br OCH,

3 1 t 4 Cl

° ^C 2"5

O 2-CI -4 Cl OH

^CH 3 3

HO- HO- 2 CH. 4 Br OC.H.

IALU 3 (Cont.) Representative Malonic Add Derivative Comuounds

HtPr.ttnt4tlvt t* Ionic Add Derivative Compounds

v. 10

1\ l_>

H ₃

!____.._

Representative Malonic Add Derivative Compounds

*'l "'fl 9 ' 10 ^Y *6 ^R '.o *'.!

H H II II II OH 2-C II -4-CI

H H II II II OCH, 2 C ₂ H.-4 C|

H H II II II OH 2 C ₂ H. Br

H H II II II 2-C H -4-Br

^0C 2"S

II II II II OH 4 Cl

^C "3

II II II II ONa 4 Br

^CH 3

H H II II OH 3,4 Cl.

^CH 3

H H .1 II CM, OC ₂ H. 2 CI-4-Br

II H H .1 OH 2 1-4 Br

^£,l 3

II H II II H OH 3 F-4 Cl

H H II II II OC.., 3 F 4-Br

II H II II II 2 CH -4-Br

^NM 2

II H II II II OHII 2 CH -4 Br

H H II II 01. 2 1 4 Cl

^C,, 3

Cl Cl CH, II II OK 2 CH 4 Cl

u z x z x u r x x z u >- x x x o o o α o o o o o o o Q o o **"*• o o o

w w X X U X X

IλUII. 5

Representatl.ye Malonic Add PerI .tl e Compounds

O

Y' ¥' 1' Y' ro * 11 ^Y 'l2 13 14 ' 15 ' 16 ^■ Ή '.2

1

H 1. H II .1 1. OC.H. 2.4 Cl ₂

H H H II II H 0.1 2,4 Cl ₂

H II II 11 II II OC.H. 3.4 Cl_

II H H I. II II OH 3,4 Cl ₂

H II II 1. II II ^ϋC Λ 4 Cl

II II II I. II II υιι 4 Cl

H H II tl II II OCH. 2 f 4 Cl

H 1. II .1 II 1. 0N.1 2 1 4 Br

II II II 1. II 1. ON.) 2 Cl 4 Br

H H II If 1. H OCH, 2 Br-4 Cl

II H II II .1 II OK 4 Br

II H 1. .1 .1 II OH 2 Cf ₃ 4 Br

II 1. 1. II OH 2 CH 4 Br

^CH 3 ^CH 3 II H II II OCH, 4 Cl ^£H 3 ^£,, 3 3

C", II n, 1. I. II IJNJ 4 Br

IABU 5 (Cont.l

Representative Halonic Add Derivative Compounds

CO

CO ^v 'ιι Y' Y ¹ Y'

12 13 14 ^Y, .5 ^V ".6 ^■ '.. ,2

1. II .1 «... 2,4 Br

^CH 3 ^CH 3 ^£H 3 Cl Cl II 1. II H OH 3,4 Cl.,

H H Cl Cl II H OCH, 2 C.H.-4 Br

CH ₃ H H H Cl Cl 0N.< ₄ 4 Cl Cl H II .1 Cl H oc _Λ 3 F 4-CI cl Cl II Cl II 0.1 3.4 Br ₂

^CH 3

Cl H II H II OCH 2 CH -4-CI

^CH 3 3 3

Cl It II UNa 3,4 Cl _?

^CH 3 ^CH 3 ^CH 3 1. H II II It II OH 3 Br 4 Cl

II I. H It II H ONa 2 CH 0 4.5 Cl

H II 1. II I. I. 01. 2 CH.O 3.5 Cl 3 2

H H .1 1. 1. .. OCH 2 Cl 4 Br 3

H 1. H I. I. II OK 2 Cl 0 4 Cl

I ABU 6

Representative Halunlc A id Derivative Compounds

Y' R\

IB 19 20 21 Ir- lS 12

H H H II II 2 CH -4 Hr OCH.CH.QCH, 4»

H H H II H 2 CH, 4 Itr OC.I _? C.I ₂ OH

II II H II II 4 Cl 0CH ₂ CH ₂ SO ₂ CH ₃

H H II .1 II 2-C1-4-BI OCH ₂ COCH ₃

H H H .. II 2 l-4-Br OCII(CH C.-N

H II II II H 2- Cl. -4 Itr OCH ₂ CH ₂ S0 ₂ CH ₂ OH

H H II H 3.4 Br. OCH.CH, OH

^CH 3 2 2

H II 4 Br 0 N-CHCH

^CH 3 ^CH 3 ^CH 3 Cl Cl II II 2.4 Cl. OCH CONII.

^CH 2 2

H H 4 Cl SCH ₃

^C,, 3 ^CH 3 ^CH 3 II II 3 F 4 Cl SCH CO,CH

^CH 3 ^CH 3 ^C "3 7 2 3 Cl Cl II 2 Cf -4-Hr OCH.CH.OH

^C,, 3 ^CH 3 ? 2

H H II II H 2.1 Br. OCH.CII OCH.CH OH

2 2 2 2

H II II II II 3 Br-4 Cl ^S< V_

II II II 1. H 2 Cl 0 4 . OCH CH OH 3 ? 2

II H H II II 2 C ₃ 4 I OCH.COCH.

.Alt. I i

Representative Halonic Add Derivative Compounds

Y* I' . R'

21 22 23 24 25 26 .4 13

II H II H 2 4 Hr OCH Cl. OCH

^U, 3 2 7 3 CO H H .1 II 2 4 ^* "_ Br OCH.CH SO CH.CH OH

2 2 7 2 2 H H II H 2. 4 Bi OCH.CH OCH CH.OH

/ 2 7 7 7 H H II II 3. ,4 Cl 1. SCH Cϋ.C H

2 7 2 5 CH. CH. II I. 7 . 4 Ul 0 N-CHCH.

C.

CH ₃ Cl.j 7 4 Cl o N _* C;

SC.I3

Cl Cl I. H II II 2 4 Br OCH CONH

^U 3

H H Cl Cl II H 4 cl OCH C-N

II H I. II Cl Cl 4 «r SCH ₂ P(OC ₂ H ₅ ) ₂

0

CH, Cl II II 3 . 4 Cl OCH CH NHCO C H

2 2 2 2 5

H Cl Cl 2.1 Cl^ OCH COCH

^CH 3 2 3 H H II i. 2 LI 1 Cl 0 OCH CH CONK

3 3 2 2 2

H H II II 2 L .. 4 1 OCH CH OH

7 5 2 2

H H I. I. 7 Ur 4 Cl SC.LCH.OCH.

2 2 3

u w u u u u

Representative Malonic Add Derivative Compounds (Cont.)

I O

Y'

28 21 14 15

OC_H. 2.4 Cl_

-CH ₂ CH.CH ₂ CH_- S

NH ₂ 2 Br-4 CN

-CM_CH.CH.CH_- 0

OC.H. 4 C....0

-CH ₂ CH _? CH ₂ CH ₂ - 0

-CH_CH_CH_CH _? - s 0.1 3.5 Cl ₂

NIICII CII.OCI., 4 Cl

-CH ₂ CH ₂ CH ₂ CH ₂ - 0 3,4 Br _?

-CH_CH_- 0 ^SC 6 ^M 5 CII.OII 3 Br-5 Cl

-CH_CH_CH_- 0 SCH

-Cll CH.CH - 0 SCH, 2 Cl -4-βr 2 7 2 (CI,) ₂

-CH ₂ CH _? - s OC. 3.5.

IABU 9

Representative Halunlc A id Oerlvatlve Compounds

~ ^"

1AUU 10

R?P ^r J?l- ⁿ J_t**"L !*Λ loιιlc_ Ac Id Derivative Compounds

R'.

33 34 Y'_

32 16 lϊ

CO

H H NH 4 Hr CO

OC.H. 2 CH -

H H NH OC.H. 2-1-4 Br

H H NH OC.H. 2 F 4-CI

H H NH OC.H. 3.5 Cl ₂

H H NH 01. 3.4 B ₂

H H Nil OC, 2,4,5 Cl

CH H NH OC 1. 2 CH 4 IT 3 2 5 3

H NH OCH, 3.5 Br.

^CH 3

CH II NH SCH CH OCH 4 Cl 3 7 2 3

H N(CH,) OCH.CH. OH 3 1 4 Br

^CH 3

CH .1 0 «... 3.4 Cl 3

.1 S OCH 2.4 Cl.

^CH 3

H Nil 01. 2 Cl 4 hi

^CH 3 3

H NH OC.H. 2 C O 4.'ι

NH OC.H. 4 Cl

^CH 3 ^CH 3

:

TAult 10 (Cont.l

Repres ι*J_a t e Malonic Add Derivative Coooounds

33 34 32 16 17

1AB..I II

Representative Halonic Add Derivative Compounds

Y' Y' R" R' -t-

36 31 35 IB U ro

Nil _ _Λ JO

Cl

, N

NH 0.n-C,H. Q ^cι

Cl

- 43a-

- 44 -

It is appreciated that the particular compounds listed in Tables 1 through 11 hereinabove are illustrative of malonic acid derivative compounds which can be used for retarding plant growth according to this invention. This invention is not to be construed as being limited only to the use of these compounds; but rather, this invention includes the use of those malonic acid derivative compounds encompassed within formula 1 hereinabove.

The novel malonic acid derivative compounds of this invention can be depicted by the following formulae:

wherein:

Z. is independently substituted or unsubstituted halogen, haloalkyl, polyhaloalkyl, polyhaloalkoxy, alkyl, alkoxy, alkylthio, alkylsulfonyl, alkylsulfinyl, aryl, aryloxy, arylthio, arylsulfonyl , nitro, cyano, dialkoxyphosphinyl, acyl, aroyl, alkoxycarbonyl, alkoxycarbonylalkyl, acyla ino, sulfonylamino, alkylsulfonylamino, acyloxy, alkenyl or -CH=CHCH=CH-; n is a value of from 0 to 5;

Y is 0, S or NR wherein R is hydrogen or alkyl;

Y is 0, S, NH or N (alkyl); and R is ammonium, alkylammonium,

0 polyalkylammon um, hydroxyalkylammonium,

- 45 -

poly(hydroxyalkyl)ammonium, an alkali metal or alkaline earth metal or substituted or unsubstituted hydroxyalkyl, alkoxyalkyl, alkoxycarbonylalkyl, alkylaminoalkyl, dialkylaminoalkyl, aryl, εrcaptoalkyl , alkylthioalkyl, arylthioalkyl , aryloxyalkyl, alkylsulfonylalkyl, alkylsulfinylalkyl, acylalkyl, aroylalkyl, dialkoxyphosphinyl lkyl, diaryloxyphosphinylalkyl, hydroxyalkylthioalkyl, hydroxyalkylsulfonylalkyl, alkoxyalkylthioalkyl, alkoxyalkylsulfonylalkyl, poly(oxyalkylene)alkyl, cyanoalkyl, nitroalkyl, alkylideneamino, carbamoylalkyl , alkylcarbamoylalkyl , dialkylcarba oylalkyl , aminoalkyl, acylaminoalkyl , acyloxyalkyl , alkoxycarbonylaminoalkyl, cyanoaminoalkyl , carbamoyloxyalkyl, alkylcarbamoyloxyalkyl, dialkylcarbamoyloxyalkyl , alkoxycarbonyloxyalkyl , alkoxycarbonylthioalkyl, aminosulfonylalkyl, alkylaminosulfonylalkyl or dialkylaminosulfonylalkyl;

wherein:

Z is independently substituted or unsubstituted halogen, haloalkyl, polyhaloalkyl , polyhaloalkoxy, alkyl, alkoxy, alkylthio, alkylsulfonyl, alkylsulfinyl, aryl, aryloxy, arylthio, arylsulfonyl, nitro, cyano, dialkoxyphosphinyl, acyl, aroyl, alkoxycarbonyl, alkoxycarbonylalkyl, acyla ino, sulfonylamino, alkylsulfonylamino, acyloxy, alkenyl or -CH=CHCH=CH-;

46

n is a value of from 0 to 5;

Y is 0, S or NR wherein R is hydrogen or alkyl;

Y is 0, S, NH or N (alkyl);

Y. _c and Y are independently hydrogen, 15 16 alkyl, halogen, alkoxy, alkylthio, alkenyl, alkynyl, hydroxy, cyano, nitro, formyl, amino, alkylcarbonyl, dialkoxyalkyl, alkylcarbonyla ino, formyla ino, hydroxyalkyl, haloalkyl or polyhaloalkyl provided that when Y. 15. is alkyl then Z„ is not halogen or polyhaloalkyl at the para- position, and further provided that at least one of Y.l_ and Y.l. is other than hydrogen;

Y._ and Y_, may be linked together to 15 lb form a substituted or unsubstituted heterocyclic ring system selected from a monocyclic aromatic or nonaromatic ring system, a bicyclic aromatic or nonaromatic ring system, a polycyclic aromatic or nonaromatic ring system and a bridged ring system which may be saturated or unsaturated; and

R8 is hydrogen or Rb;,

wherei n :

1 is Independently substituted or unsubstituted halogen, haloalkyl, polyhaloalkyl, polyhaloalkoxy, alkyl, alkoxy, alkylthio, alkylsulfonyl, alkylsulfinyl, aryl, aryloxy, arylthio, arylsulfonyl, nitro, cyano,

- 47 - ^•

dialkoxyphosphinyl, acyl, aroyl, alkoxycarbonyl, alkoxycarbonylalkyl, acylamino, sulfonylamino, alkylsulfonylamino, acyloxy, alkenyl or -CH=CHCH=CH-; n is a value of from 0 to 5;

Y ₁₇ is 0, S or NR... wherein R.. is hydrogen or alkyl ;

Y _]8 is 0 or S;

Y and Y are independently hydrogen, alkyl, alkoxy, alkylthio, halogen, haloalkyl or polyhaloalkyl; or

Y and Y _ may be linked together to form a substituted or unsubstituted, carbocyclic or heterocyclic ring system selected from a monocyclic aromatic or nonaromatic ring system, a bicyclic aromatic or nonaromatic ring system, a polycyclic aromatic or nonaromatic ring system and a bridged ring system which may be saturated or unsaturated; and

R. _n is hydrogen or R.; IU b and

Y ₃ Y ₄ l

Rl - Yi - C C C - Y ₂ - R ₂ (iv)

H .1

^* *5 ^' *6

wherein:

R and R are independently a substituted or unsubstituted, carbocyclic or heterocyclic ring system selected from a monocyclic aromatic or nonaromatic ring system, a bicyclic aromatic or nonaromatic ring system, a polycyclic aromatic or nonaromatic ring system, and a bridged ring system which may be saturated or unsaturated; or

- 48 -

R and R are independently hydrogen or derivative salts, or a substituted heteroatom or substituted carbon atom, or a substituted or unsubstituted, branched or straight chain containing two or more carbon atoms or heteroatoms in any combination;

Y and Y are independently a substituted or unsubstituted heteroatom;

Y_ and Y, are linked together to form a 3 4 substituted or unsubstituted, carbocyclic or heterocyclic ring system selected from a monocyclic aromatic or nonaromatic ring system, a bicyclic aromatic or nonaromatic ring system, a polycyclic aromatic or nonaromatic ring system, and a bridged ring system which may be saturated or unsaturated; and

Y- and Y. are independently oxygen or 5 6 sulfur; in which the permissible substituents for formulae

(i) through (iv) above are Z as hereinbefore defined,

Novel malonic acid derivative compounds within the scope of formula (iv) above can be depicted by the following formulae:

wherei n :

1. is independently substituted or unsubstituted halogen, haloalkyl, polyhaloalkyl,

- 49 -

polyhaloalkoxy, alkyl, alkoxy, alkylthio, alkylsulfonyl, alkylsulfinyl, aryl, aryloxy, arylthio, arylsulfonyl, nitro, cyano, dialkoxyphosphinyl, acyl, aroyl, alkoxycarbonyl, alkoxycarbonylalkyl, acyla ino, sulfonylamino, alkylsulfonylamino, acyloxy, alkenyl or -CH=CHCH=CH-; n is a value of from 0 to 5;

Y is 0, S or NR wherein R is hydrogen or alkyl;

Y is 0, S, NH or N (alkyl); ^γ -2*4,» ^γ -2,_5 ^{and γ} -2,_6 ^are independently hydrogen, alkyl or halogen; and

.. . i s hydrogen or R _c ; 1 b or

wherein :

Z- is independently substituted or unsubstituted halogen, haloalkyl, polyhaloalkyl, polyhaloalkoxy, alkyl, alkoxy, alkylthio, alkylsulfonyl, alkylsulfinyl, aryl, aryloxy, arylthio, arylsulfonyl, nitro, cyano, dialkoxyphosphinyl, acyl, aroyl, alkoxycarbonyl, alkoxycarbonylalkyl, acylamino, sulfonylamino, alkylsulfonylamino, acyloxy, alkenyl or -CH=CHCH=CH-; n is a value of from 0 to 5;

Y,,., is 0, S or NR._ wherein R._ is cl 15 15 hydrogen or alkyl;

- 50 -

Y__ is 0 S, NH or N (alkyl);

28

^Y 2- _Λ 9. ^γ -3,0-. ^γ 3--1> ^γ 3--2» _^ 33 and Y3-4, are independently hydrogen, alkyl or halogen; and

R.. is hydrogen or 14 V

wherein:

Z. is independently substituted or

0 unsubstituted halogen, haloalkyl, polyhaloalkyl, polyhaloalkoxy, alkyl, alkoxy, alkylthio, alkylsulfonyl, alkylsulfinyl, aryl, aryloxy, arylthio, arylsulfonyl, nitro, cyano, dialkoxyphosphinyl, acyl, aroyl, alkoxycarbonyl, alkoxycarbonylalkyl, acylamino, sulfonylamino, alkylsulfonylamino, acyloxy, alkenyl or -CH=CHCH=CH-; n 1s a value of from 0 to 5;

Y_- is 0, S or NR._ wherein R._ is 0 I / 17 hydrogen or alkyl ;

R-, is hydrogen or R.;

1o b in which the permissible substituents for formulae (v) through (vii) are as described for Z above for formulae (1) through (iv).

The malonic acid derivative compounds encompassed within formula 1 and the intermediate compounds used in the preparation thereof can be prepared by conventional methods known in the art and many may be available from various suppliers. The novel malonic acid derivative compounds of

- 51 -

formulae (1) through (vii) above which can be used in ^' the method of this invention can be prepared by reacting appropriate starting ingredients in accordance with conventional procedures described in the art as illustrated below.

The novel malonic acid derivative compounds of formula (1) can be prepared by the following general reaction scheme:

o o

. II II (∑ l Jn

* 6 — ^γ 12— ^C — CH ~C — Cl ^Hγ n-cy

Scheme I

wherein Z.. , n, Y _ιn , Y_. and R _c are as 1 I I I d b defined hereinabove. Reactions of this general type for preparing malonic acid derivative compounds of formula (i) including process conditions are described for example by Richter, G.H., Textbook of Organic Chemistry, Third Edition, John Wiley and Sons, New York, p. 486. In the Schotten-Baumann procedure described therein, cold aqueous sodium hydroxide is illustrated as the acid acceptor.

- 52

The novel malonic acid derivative compounds of formula (ii) can be prepared by the following general reaction scheme:

Ac Acd o ^Y,δ \ ' ^" /-V' ^Z" -"

"e"pt-"r ^■ → R,_γ _v - c-C-C-Y, ₃ -< >

Scheme II

wherein Z_, n, Y^, Y_. _t Y._, Y_ ₆ and R _g are as defined hereinabove. Reactions of this general type for preparing malonic acid derivative compounds of formula (11) Including process conditions are described for example by Richter,

G.H., supra, according to the known Schotten-Baumann procedure.

The novel malonic acid derivative compounds of formula (iii) can be prepared by the following general reaction scheme:

53 -

Scheme III

wherei n Zg . n . Y. _ , Y. g , Y^ , Y.. and

R are as defined hereinabove. Reactions of this general type for preparing malonic acid derivative compounds of formula (iii) including process conditions are described for example by Richter,

G.H., supra, according to the known Schotten-Baumann procedure.

The novel malonic acid derivative compounds of formula (iv) can be prepared by the following general reaction scheme:

54 -

^Y 3 ^Y 4

^■ Y« — c — c— c — Cl HY ₂ — R ₂

Acid

\ / ^{4 Acceptor} _► R ^' —Y — C — C — C — Y ₂ — R ₂

-HCl ¹ II » 5 ^* 6

Scheme IV

wherei n R. , R_ , Y. , Y. , Yg, Y^ Y. and

Y. are as defined hereinabove. Reactions of this 6 general type for preparing malonic acid derivative compounds of formula (iv) Including process conditions are described for example by Richter, G.H., supra, according to the known Schotten-Baumann procedure.

The novel malonic acid derivative compounds of formula (v) can be prepared by the following general reaction scheme: ^'

- 55

Scheme V

wherein 1^, n, Y.. , Y._, Y..., _ _4> Y._,

Y and R are as defined hereinabove. 26 1

Reactions of this general type for preparing malonic acid derivative compounds of formula (v) including process conditions are described for example by Richter, G.H., supra, according to the known Schotten-Baumann procedure.

The novel malonic acid derivative compounds of formula (vi) can be prepared by the following general reaction scheme:

- 56

^r 32. , ^γ 31

Scheme VI

wherei n Z_ , n , Y... Y... Y. _g , Y _3Q , Y ₃₁ ,

Y--» Y _ΛΛ . Y-. and R, , are as defined 32 33 34 14 hereinabove. Reactions of this general type for preparing malonic acid derivative compounds of formula (vi) including process conditions are described for example by Richter, G.H., supra, according to the known Schotten-Baumann procedure.

The novel malonic acid derivative compounds of formula (vii) can be prepared by the following general reaction scheme:

57

Scheme VII

wherein Z., n, Y._, Y„ _c and R _1c are as b ob l defined hereinabove. Reactions of this general typ-: for preparing malonic acid derivative compounds of formula (vii) including process conditions are described for example by Richter, G.H., supra, according to the known Schotten-Baumann procedure.

In addition to the above, other illustrative procedures which can be employed in preparing malonic acid derivative compounds encompassed within formula 1 and intermediate compounds used in the preparation thereof are described, for example, in the following: Breslow, O.S. et al., Jour. Amer. Chem. Soc. 66., 1286-1288 (1944); Svendsen, A. and Boll, P.M., Jour. Org. Chem. 40, 1927-1932 (1975); Sen, A.K. and Sengupta, P., J. Ind. Chem. Soc. 46, (9), 857-859 (1969); Thiers, R. and Van Dormael, A., Bull. Soc. Chim.

58

Belg. 61, 245-252 (1952); Brown, R.F.C., Austral. Jour, of Chem. 8, 121-124 (1955); U.S. Patent 3,951,996; United Kingdom Patent 1,374,900; Chiriac, C.I., Revue Romaine de Chimie 25_, (3), 403-405 (1980); Weiner, N., Org. Syn. Coll., Vol. II, 279-282 (1950), Sixth Printing, John Wiley & Sons, New York; Block, Jr., Paul, Org. Syn. Coll. Vol. V, 381-383 (1973), John Wiley and Sons, New York; Reliquet, F. et al., Phos. and Sulfur 24, 279-289 (1985); Palmer, C.S. and McWherter, P.W., Org. Syn. Coll. Vol. I, 245-246 (1951), Second Edition, John WHey and Sons, New York; Straudinger, H. and Becker, H., Berichte 50, 1016-1024 (1917); Purrington, S.T. and Jones, W.A., J. Org. Chem. 4_8, 761-762 (1983); Kitazume, T. et al., Chem. Letters (1984) 1811-1814; Wolff, I.A. et al., Synthesis (1984), 732-734; Zambito, A.J. and Howe, E.E.., Org. Syn. Coll. Vol. V, 373-375 (1973), John Wiley and Sons, New York; and Hartung, W.H. et al., Org. Syn. Coll. Vol. V, 376-378, John Wiley and Sons, New York.

Still other illustrative procedures which can be employed in preparing malonic acid derivative compounds encompassed within formula 1 and intermediate compounds used in the preparation thereof are described, for example, in the following: Rathke, M.W. and Cowan, P.J., J. Org. Chem. _, 50, 2622-2624 (1985); Fones, W.S., Org. Syn. Coll. Vol. IV, 293 (1963), John Wiley and Sons, New York; Go pper, R. and Topfl, W., Chem. Ber. 95., 2861-2870 (1962); Gompper, R. and Kunz, R., Chem. Ber. 99, 2900-2904 (1966); Ono, N. et al., J. Org. Chem. 50,

- 59 -

2807-2809 (1985); U.S. Patent 4,154,952; Blankenship, C. and Paquette, L.A., Synth. Comm. ]_4, (11), 983-987 (1984); Baldwin, J.E. et al., Tet. Lett. 26, (4), 481-484 (1985); Kawabata, N. et al., Bull. Chem. Soc. Jpn. 55, (8), 2687-2688 (1982); Bodanszky, H. and du Vignaud, V., J. Am. Chem. Soc. 81, 5688-5691 (1959); Neelakantan, S. et al., Tetrahedron 21, 3531-3536 (1965); U.S. Patent 4,020,099; Japan Patent Application 148,726 (1979); Fuson, R.C., Advanced Organic Chemistry, p. 202 (1950), John Wiley and Sons, New York; Duty, R.C., Anal. Chem. 49, (6), 743-746 (1977); Korner, G., Contradi, AH1 acad. Lincei 22., T, 823-836 (CA. 8, 73 (1914)); Schimelpfenig, C.W., J. Chem. Soc. Perk. Trans. I, 1977 (10), 1129-1131; Kim, Y.S. et al., Taehan Hwahak Hoechi 18, (4), 278-288 (1974); German Patent 2,449,285; U.S. Patent 3,962,336; and U.S. Patent 3,992,189.

Copending U.S. Patent Application Serial No. (D-15299), filed on an even date herewith, describes the use of malonic acid derivative compounds of formula 1 for increasing crop yield. Copending U.S. Patent Application Serial No. (D-15298), filed on an even date herewith, describes synergistic plant growth regulator compositions containing (1) an ethylene response or an ethylene-type response inducing agent and (ii) a malonic acid derivative compound of formula 1. Both of these applications are incorporated herein by reference.

The malonic aci derivative compounds of formula 1 have been found to significantly retard

- 60 -

plant growth in comparison with untreated plants at similar conditions. In addition, the malonic acid derivative compounds used in this invention are substantially non-phytotoxic to growing plants.

As used herein, an effective amount of a malonic acid derivative compound for retarding plant growth refers to a growth retarding effective amount of the compound sufficient to retard plant growth. The effective amount of compound can vary over a wide range depending on the particular compound employed, the particular plant to be treated, environmental and climatic conditions, and the like. The amount of compound used preferably does not cause substantial phytotoxicity, e.g., foliar burn, chlorosis or necrosis, to the plant. In general, the compound can preferably, be applied to plants at a concentration of from about 0.01 to 15 pounds of compound per acre as more fully described below.

The malonic acid derivative compounds contemplated by formula 1 can be employed according to a variety of conventional methods known to those skilled in the art. Compositions containing the compounds as the active ingredient will usually comprise a carrier and/or diluent, either liquid or solid.

Suitable liquid diluents or carriers include water, petroleum distillates, or other liquid carriers with or without surface active agents. Liquid concentrates can be prepared by dissolving one of these compounds with a nonphytotoxic solvent such as acetone, xylene,

- 61 -

nitrobenzene, cyclohexanone or dimethyl formamide and dispersing the active ingredients in water with the aid of suitable surface active emulsifying and dispersing agents.

The choice of dispersing and emulsifying agents and the amount employed are dictated by the nature of the composition and the ability of the agent to facilitate the dispersion of the active ingredient. Generally, it is desirable to use as little of the agent as is possible, consistent with the desired dispersion of the active ingredient in the spray so that rain does not re-emuls1fy the active Ingredient after it is applied to the plant and wash 1t off the plant. Nonionic, anionic, or cationic dispersing and emulsifying agents may be employed, for example, the condensation products of alkylene oxides with phenol and organic acids, alkyl aryl sulfonates, complex ether alcohols, quaternary ammonium compounds, and the like.

In the preparation of wettable powder or dust compositions, the active ingredient is dispersed in and on an appropriately divided solid carrier such as clay, talc, bentonite, diatomaceous earth, fuller's earth, and the like. In the formulation of the wettable powders, the aforementioned dispersing agents as well as Hgnosulfonates can be included.

The required amount of the active ingredient contemplated herein can be applied per acre treated in from 1 to 200 gallons or more of liquid carrier and/or diluent or 1n from about 5 to 500 pounds of inert solid carrier and/or diluent.

- 62

The concentration in the liquid concentrate will usually vary from about 5 to 95 percent by weight and in the solid formulations from about 0.5 to about 90 percent by weight. Satisfactory sprays or dusts for gerveral use contain from about 0.001 to about 100 pounds of active ingredient per acre, preferably from about 0.01 to about 15 pounds of active ingredient per acre, and more preferably from about 0.1 to about 5 pounds of active ingredient per acre.

Formulations useful in the conduct of this invention can also contain other optional ingredients such as stabilizers or other biologically active compounds, insofar as they do not impair or reduce the activity of the active ingredient and do not harm the plant being treated. Other biologically active compounds include, for example, one or more insecticidal, herbicidal, funglcidal, nematicldal, -miticidal , plant growth regulators or other known compounds. Such combinations can be used for the known or other purpose of each ingredient and may provide a synergistic effect.

The malonic acid derivative compounds of formula 1 are preferably applied to plants under substantially average or normal growing conditions. The malonic acid derivative compounds used in this invention may be applied during the plant vegetative growth phase or the plant reproductive growth phase to obtain plant growth retardation.

Such compounds are useful in agriculture, horticulture and related fields and can be applied

63 -

in general to both gymnosperms and angiosperms, in particular, to vegetation such as woody plants and turfgrasses to retard plant growth. The compounds are useful, for example, in controlling the height of vegetation in right-of-way areas and for growth retardation following pruning of trees and shrubs and the like with no adverse ecological effect.

As used herein, plants refer 1n general to any agronomic or horticultural plants, woody plants, ornamentals and turfgrasses. Illustrative of woody plants which can be treated by the malonic acid derivative compounds of formula 1 according to the method of this invention Include, for example, red maple, sycamore, red oak, American elm, linden, ginkgo, oaks, ashes, maples, apple trees, Chinese elm, crabapples, Russian olive, silver maple, sugar maple, water oak, poplars, conifers and the like. Illustrative of other plants which can be treated by the compounds of formula 1 according to the method of this invention include, for example, corn, cotton, sweet potatoes, white potatoes, alfalfa, wheat, rye, rice, barley, oats, sorghum, dry beans, soybeans, sugar beets, sunflowers, tobacco, tomatoes, canola, deciduous fruit, citrus fruit, tea, coffee, olives, pineapple, cocoa, banana, sugar cane, oil palm, herbaceous bedding plants, woody shrubs, turfgrasses, ornamental plants, evergreens, trees, flowers, and the like.

The malonic acid derivative compounds contemplated herein are effective in retarding plant growth. Such compounds have a high margin of safety in that when used in sufficient amount to provide a

- 64 -

growth redardation effect, they do not burn or injure the plant, and they resist weathering which Includes wash-off caused by rain, decomposition by ultraviolet light, oxidation, or hydrolysis in the presence of moisture or, at least, such decomposition, oxidation, and hydrolysis as would materially decrease the desirable plant growth retardant characteristic of the active ingredient or impart undesirable characteristics, for instance, phytotoxicity, to the active ingredients. Mixtures of the active compounds can be employed 1f desired as well as combinations of the active compounds with other biologically active compounds or ingredients as indicated above.

This invention is illustrated by the following examples.

- 65 - .

Example I Preparation of ethyl 3-f(4-fluorophenvDaminol- 3-oxopropaπoate Into a nitrogen-purged, air-stirred reaction flask was charged 4.44 grams (0.04 mole) of 4-fluoroanil1ne, 4.05 grams (0.04 mole) of triethyla ine and 200 mi11iliters of tetrahydrofuran solvent. A 6.02 gram (0.04 mole) portion of ethyl malonyl chloride was then added rapidly by a dropping funnel to the mixture with good stirring at room temperature followed by a few miHiliters of tetrahydrofuran as a rinse. The temperature of the stirred mixture rose to 42°C and a white precipitate of triethylamine hydrochloride separated therefrom. The mixture was then stirred ^" at ambient temperature for about 2 hours and the triethylamine hydro¬ chloride filtered off, washed with solvent and dried to give 5.2 grams (0.04 mole). The filtrate was freed of solvent on a rotary evaporator and the resulting purple solid dissolved in methylene chloride, which solution was washed in succession with 2N HCl (3 x 75 mmiHters), and water (2 x 75 milimters), and then dried over magnesium sulfate and solvent vacuum stripped to give a crude solid product. Recrystallizatlon from ethyl acetate- cyclohexane followed by flash column chromatography gave 3.47 grams (0.015 mole) of ethyl 3-[(4-fluoro- phenyl)amino]-3-oxopropanoate having a melting point of 68°C-71°C. Elemental analysis of the product indicated the following:

- 66

Analysis: C-,-,"^^

Calculated: C, 58.66; H, 5.37; N, 6.22

Found: C, 58.61; H, 5.35; N, 6.36

This compound is referred to hereinafter as Compound

1.

Example II In a manner similar to that employed in Example I, other compounds were prepared. The structures and analytical data for Compounds 2 through 76 are set forth in Table A below.

- 67

lABU A (Cont.l Representative Halonic Add Derivative Compounds

o - o

II II

^* .1< -C-CH»-C- *θf

Substlϊuenti __________L___L___1__ Heltlπg <

Compound ^•* 'l ⁱ "ι V'ι Calculate? found P int cr.

No. H H ^• C CO

17 C.H. 4-CH ₃ NH HHR (C0C1-): 1.17-1.39 (t.3H). 2.33 (j, 3H), BO-83

3.45 (_.2H),- 4.07-4.42 (q,2H). 6.99-7.57 (m,4H).

8.9-9.3 (br ti, H) ppm. lβ C.H- 2.6-(CH ₃ ) ₂ NH NMR (CDCI ₃ ):J- 1.15 1.46 (t.3H), 2.23 (J.6H), 97-100

2.50 (J.2H). 4.07-' 1.50 (q.2H), 7.10 (I.3H).

TABLE A (Con Representative Halonic Acid Oerlvatlve Compound-,

O O

RJO-C-CHJ-C-Y,-^ )

Substituents Elemental Analysis HeIting

Coapound Calculated found Point No. C H N c H N ^♦ C rr,

__

28 3.5-(Cf_)_ NH 45.49 3.23 4.08 45.96 3.23 4.02 72-75 1

^C 2«5 29 C.H. 2-CH ₃ 0-5-CI NH 53.04 5.19 5.16 53.65 5.31 5.14 86-87 30 4-1 NH 39.66 3.63 4.20 39.30 3.6B 4. OB 108- 110

^C 2 ^M 5 31 C.H. 4-C.H.0- NH 62.13 6.82 5.57 62.45 7.03 5.77 100-101 32 4-n-C.H.- NH 68.41 B.04 5. ?2 68.91 8.29 5.86 011

^C 2 ^H 5 33 4-n-C.H ₎₃ 0- NH 66.42 8.20 4.56 67. IB B.35 4.58 66-68

^C 2 ^H 5 34. 4-n-C^H.O- NH 64.49 7.58 5.01 65.09 7.75 4.77 82-83

^C 2 ^H 5 35 C.H. 2.4.5-Cl ₃ NH 42.54 3.25 4.51 42.40 3.09 4.39 104- 105 36 2.1- ^β r ₂ NH 36.19 3.04 3.84 36.29 2.93 3.77 83-85

^C 2 ^H 5 3? 2-Cl-4-Br NH 41 .21 3.46 4.37 41 .29 3.42 4.35 78-80

^C 2 ^H 5 38 2-Br-4-Cl NH 41 .21 3.46 4.37 41 .59 3.61 4.55 81 -83

^C 2 ^H S 39 4-C.H.CO- NH 69.44 5.51 4.50 69.75 5.51 4.48 87-88.5

^C 2 ^H 5 D 3 40 C.H. 3.4-Br. NH 36.19 3.04 3.84 36.27 3.33 3.68 64-67 41 C.M. 2-r-4-Br NH 43.44 3.65 4.61 43.49 3.88 3.95 78.5-80

•42 ^• 2-CH 0-4-C1 NH 53.04 5.19 5.16 53.38 5.23 5.10 71 -73

I ^C 2 ^H 5

1ABLE A (Cont.) Representative Halonic Add Derivative Compounds

o O II ^" II ,o-c- CH, -c- «θf

Substituents Elemental Analysis He1ting

Compound *'l *Y *- f'l Caliculated found Point .

No. C H N C H N ^• c

O

43 C.H. 2-CH ₃ 0-4.5-Cl ₂ Nil 47.08 4.28 4.58 47.31 4.64 4.59 95-98 . 44 2-CH ₃ -3.4-CI ₂ NH 49.67 4.52 4.83 49.86 4.62 4.69 90-93

^C 2 ^H 5 45 2-r-4-CI NH 50.88 4.2 ^* 7 5.39 50.90 4.56 5.21 66-69 ^C 2 ^H 5

46 C.H. 3-Br-5-C1 NH 41.21 3.46 4.37 41.26 3.67 4.14 78-80

4) n-C ₄ H. 2-CH -4-Br NH 51.23 5.53 4.27 51.59 5.41 4.17 91-93

48 2-C0 ₂ H-4-Br NH HHR (DHSO

^C 2 ^H 5 d.): Jl .16-1.43 (t. 311). , 3.48 151-154

(s. 21.) . 4 .06-4.7 {«. 1H). 7.5 -8.7 ( , 3H) ppm.

49 C.N. 2-CH ₃ -3.5-Cl ₂ NH 49.6) 4.52 - 49.22 4.43 - 116-120

50 2-CH ₃ -4.5-Cl ₂ NH 49.67 4.52 4.83 49.68 4.40 4.45 134-135.5

^C 2 ^H 5

SI 2-C ₂ H.-4-Cl NH 57.89 5.98 5.19 58.26 6.06 5.24 98-99

^C 2 ^H 5

52 2-CH -3-C1 NH 56.37 5.52 5.48 56.49 5.49 5.47 103-105

^C 2 ^H 5

53 C.H. ^• 3-NO -4-CI NH 46.OB 3.87 9.77 46.52 4.00 9.43 81-83

54 C H 2-CH NH 65.14 6.83 6.33 63.60 6.51 6.12 68-71 2 5 3 55 ^" 2-CH ₃ 0 NH 60.75 6.3) 5.90 60 82 6.28 5.84 62-64

^C 2 ^H 5

56 2.5-(CH ₃ ) ₂ -3.4- NH 51.33 4.97 4.61 51.65 4.92 4.33 119-120

^C 2 ^M 5 ^C, 2

TABLE A (Cont Representative Halonic Add Derivative Compounds

O O

. II II

R,0-C-CH _z -C → _' -σ ^1' '

Substituents Elemeπital Analysis Melting

Compound R-, *-'l " ^■ ι Calculated found Point .

No. C H N C II H ^• c

57 2-CH 0-3.5-Cl NH 47.08 4.28 4.56 47.10 4.22 4.61 90-92 |

^C 2 ^H 5

58 2-CH ₃ -4-Br-5-C1 NH 43.0) 3.92 4.19 41.85 4.31 3.72 132-135

^C 2 ^H 5

59 C ₂ H. 4-(4-ClC.H,0) NH 61.18 4.83 4.20 61.2) 4.94 4.14 86-8)

Cl

60 -o- CH ₂ - NH 58.55 5.16 3.41 SB.91 5.23 3.29 Oi l

^C 2 ^H 5 cι - -cH

CH.

61 c _Λ -_ccα NH 71.3) 6.56 3.96 70.97 6.66 3.72 98-100

- 73 -

Example III Preparation of ethyl l-(2-methyl-4,5-dichloro- pheny1amiπocarbonyl)eyelopropanecarboxylate Into a nitrogen-purged round bottom flask was charged 5.53 grams (0.03 mole) of 2-methyl- 4,5-dichloroaniline, 3.18 grams (0.03 mole) of triethylamine and 190 milliliters of tetrahydrofuran solvent. With vigorous stirring, a 5.55 gram (0.03 mole) portion of ethyl 1-chlorocarbonylcyclopropane- carboxylate prepared in Example XVIII was added in one portion, after which the mixture was stirred at ambient temperature for a six-hour period. A precipitate of triethylamine hydrochloride was then filtered off and the filtrate vacuum stripped to give a light yellow solid. The solid was taken up in ether and the solution water-washed, dried over magnesium sulfate, and solvent evaporated to give a yellow powder. Recrystallization from ethyl acetate-hexane gave 4.51 grams (0.01 mole) of ethyl l-(2-methyl-4,5-dich1orophenylaminocarbonyl)cyclo- propanecarboxylate having a melting point of 105°C-107°C. Elemental analysis of the product Indicated the following:

Analysis: C..H Cl NO. 14 15 2 3

Calculated: C, 53.18; H, 4.78; N, 4.43 Found: C, 53.41; H, 4.76; N, 4.44

This compound is referred to hereinafter as Compound

77.

Example IV In a manner similar to that employed in Example III, other compounds were prepared. The structures and analytical data for Compounds 78 through 96 are set forth in Table B below.

- 74 -

I

IΛBIE B (Cont.l

Representative Halonic AcId Derivative Compounds

H ₂ C CH_

\ / r ^L l

R-O- C-NH <f ^~ II V.:.: O

I

Substituents Elemental Analysis Melting

Con-pound "'2 t'z Calculated Found Point

• Ho. c tl H C 1. H 'C

92 2-f-4-Br 47.29 3.97 4.24 46.87 4.07 4.02 102-103

^C 2 ^H 5

93 H 66.83 6.47 6.00 66.54 6.48 5.80 85-89

^C 2 ^H 5

94 c. ^H _ 3.5-Cl 51.67 4.34 4.64 51.52 4.52 4.36 64-67

2 5

95 4-C;N 65.10 5.46 10.05 65.02 5.51 10.67 129-132

^C 2 ^H 5

96 C ₂ H ₅ .2-CH ₃ -4-Br 51.55 4.94 4,29 51.72 4.74 4.31 B9-91

- 76 -

Example V

Preparation of 3-r(4-bromo-2-methy1phenyl)- aminol-3-oxopropanoic acid

A 6.0 gram (0.02 mole) portion of ethyl 3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanoate prepared in Example I (Compound No. 75) was dissolved in approximately 80 milliliters of ethanol and 1.2 grams (0.03 mole) of sodium hydroxide pellets were added to the resulting mixture. The mixture was stirred for four hours and then allowed to stand overnight. The mixture was then evaporated to dryness and water added to give a yellow cloudy solution. This solution was extracted with methylene chloride and then acidified with 10% hydrochloric acid causing a white precipitate to form. The white precipitate was worked up to give 1.8 grams (0.01 mole) of 3-[(4-bromo-2-methylphenyl)- am1no3-3-oxopropano1c acid as a white solid having a melting point of 163°C-165°C. Elemental analysis of the product indicated the following:

Analysis: C.gH.-BrNO-

Calculated: C, 44.14; H, 3.70; N, 5.15

Found: C, 43.90; H, 3.68; N, 5.11 This compound Is referred to hereinafter as Compound 97.

Example VI In a manner similar to that employed in Example V, other compounds were prepared. Compound 108 was obtained from Research Services, P.O. Box 11212, Santa Ana, California 92711.

- 77 -

Compound 109 was obtained from Dr. A.K. Mittal, 32/17 E. Patel Nagar, New Delhi 110 008, India. The structures and analytical data for Compounds 98 through 109 are set forth in Table C below.

1ABIE C

Represen'atlve Halonic Add Derivative Compounds

Substlti _ents Elemental Anallysis Heltlng

Compound it's - ^~ - ^* 3 Calculated found Point 1 No. C H N C H N •c •—l

CD

98 H 4 Cl 50.60 3.77 6.56 50.6) 3.80 6.37 140-141 .

99 H 2-CH ₃ -4-Br-5-Cl 39.10 2.96 4.5) 39.36 3.14 4.44 181-182

100 H 3.5-Br. 32.OB 2.09 - 4.16 32.34 2.33 4.04 164-165.5

101 H 2-f-4-Br 39.15 2.5b 5.07 39.24 2.42 4.94 161-162

102 H 2.4.5-C1 ₃ 38.26 2.14 4.96 38.51 2.12 4.84 174-174.5

103 H 2-Br-4-CH ₃ HNR(C0C1- /OHSO-d,): / 2.2)(s, 3H), 3.4(s.2H), 154-157

6.95 -a .01 (M.4H). 9.5-9.7 (br s. H)ppm.

104 H 2-BI--4-C1 36.95 2.41 4.79 37.18 2.77 4.71 159-161

105 H 2-Cl-4-Br 36.95 2.41 4.79 37.10 2.60 4.76 165.5-167

106 H 2.4-Br. 32.08 2.09 4.16 32.27 2.23 4.13 157-159

107 H 3.4 Br ₂ 32.00 2.09 4.16 31.96 2.22 4.08 14. 4

108 H 2.4-Cl NHR(C0CI_/DHSO-d ): J 2.49-2.64 (brS.H). 3.52 ($,2H),

7.11-8.24 (m.3H), 9.86-10.05 (br s,H)ppm.

109 3-C1-4-CH, NHR(CDC1./OHSO-d.): J 2.30 (s.3H). 2.45-2.63 (br S. H), 3.34 (S.2H),

7.05-7.86 (m. 3H). 10.04-10.23 (br s.H)ppα.

- 79 -

Example VII

Preparation of l-(2-methyl-4.5-dichloro- phenylaminocarbonyDcyclopropanecarboxylic acid

A solution containing 0.34 gram (0.006 mole) of potassium hydroxide and 0.109 gram (0.006 mole) of water in 80 milliliters of ethanol was prepared in a 250 miliniter round bottom flask. With cooling to a temperature of 0°C in an 1ce/NaCl bath and stirring, a solution of ethyl l-(2-methyl-4,5-dichlorophenylaminocarbonyl)cyclo- propanecarboxylate prepared in Example III in a small volume of ethanol was added and the mixture allowed to stir with warming to room temperature over a 72 hour period. The mixture was vacuum evaporated to give a white solid residue which was dissolved in water and extracted twice with ether. The ether extracts were discarded. The water solution was acidified to a pH of 2 with 25% HCl solution causing separation of a solid which was taken up Into ether, and the acidified aqueous phase was extracted four times. The combined ether extracts were dried over magnesium sulfate and vacuum evaporated to give a white solid. This white solid was water-washed and dried in a vacuum oven to give 1.85 grams (0.006 mole) of l-(2-methyl-4,5- d1chlorophenylaminocarbonyl)cyclopropanecarboxyl1c acid having a melting point of 248°C-251°C. Elemental analysis of the product indicated the following:

Analysis: C^H.-Cl-NO,.

Calculated: C, 50.02; H, 3.85; N, 4.86

Found: C, 50.51; H, 4.31; N, 4.83

- 80 -

T i csr.j.υu ^' .d H referfed to hereinafter as Compound 110.

Example VIII ^' . . ".nner similar to that employed in Example , . ^{' '} . , c.isr compounds were prepared. The structures _r._ analytical data for Compounds 111 through 128 are set forth in Table D below.

TABLE D Representative Ha lonic Add Deri vative Compounds

sv.stit.r t Elemental Ana lysis Mel ting

Compd . Ca l culated Found Point 1 No . c H U C H r.

Ill 2-CK.-4-Br 48.34 4.06 . 4.70 48.20 ( .06 4.b6 204.5-206

1 112 2.4,5-Cl ₃ 42.82 2.61 ^• 4.54 43.11 3.14 4.42 250 113 2.5-C1- 4B.20 3.31 . 5.11 48.33 3.26 4.96 223.5-226 114 2.4-C1. 48.20 3.31 ^" 5.11 45.26 3.40 5.03 189-190 115 2-F-4-C1 51.27 3.52 5.4< 51 .18 3.70 5.22 202-204 116 4-C1 55.12 4.21 5.84 54.69 4.35 5.59 217-219 117 4-Br 46.50 3.55 4.93 46.36 3.45 4.86 220-222 118 3,4-Br ₂ 36.39 2.50 3.86 37.13 2.70 3.83 224-226.5 119 3.5-Br. 36.39 2.50 3.86 36.99 2.60 3.82 211-212 120 2.4-Br ₂ 36.39 2.50 3.86 36.61 2.95 4.04 222-225 121 2-C1-4-8. 41.47 2.85 4.40 39.74 3.90 3.95 166-16B(dec. ) 122 2-Br-4-Cl 41.47 2.85 4.40 41.67 3.28 3.91 210-211 123 ^• 3-Cl-4-Br 41 .47 2.85 4.40 41 .70 3.23 4.11 211-214 124 2-CH -4-Br-5-Cl 43.33 3.33 4.21 45.47 4.08 3.9) 231-234 125 2-F-4-Br 43.73 3.00 4.64 43.97 3.05 4.30 203.5-207 126 4-cr ₃ 52.75 3.69 5.13 52.73 3.90 5.04 195-196.5 127 3.5-Cl, NHR (CDC1_: ): 1.52 (s ,4H) , 7.02-7.74 (m,4H) . 10.08 198-202

(ϊ . H) pm -

128 3 , 4-Cl, 48.20 3.31 5.11 4B.79 3.80 5.26 220-222.5

- 82 -

Example IX Preparation of ethyl l-(4-bromo-2-methylphenyl- aminocarbonyDcvclobutanecarboxylate Into a nitrogen-purged reaction flask was charged 2.74 grams (0.01 mole) of 4-bromo-2-methyl- aniUne and 1.49 grams (0.01 mole) of triethylamine dissolved in 200 milliliters of tetrahydrofuran. With vigorous stirring, 2.80 grams (0.01 mole) of ethyl 1-chlorocarbonylcyclobutanecarbox lathe prepared in Example XIX were added and the resulting mixture stirred at ambient temperature for 6 hours. A precipitate of triethylamine hydrochloride was removed by filtration. The filtrate was vacuum stripped and the residue taken up in methylene chloride. This solution was washed successively with 2N HCl (2 x 75 milliliters) and water, and then dried over magnesium sulfate. Rotary evaporation gave a crude product which was flash chromatographed on silica using 7:3 hexane-ethyl acetate to give 3.68 grams (0.01 mole) of ethyl l-(4-bromo-2-methyl- phenylaminocarbonyl)cyclobutanecarboxylate as a white solid. A small sample which was recrystallized from hexane had a melting point of 61 ⁰ C-64°C. Elemental analysis of the product indicated the following:

Analysis: C- ₅ H ₁₈ BrN0- Calculated: C, 52.92; H, 5.33; N, 4.12 Found: C, 52.99; H, 5.44; N, 4.05 This compound is referred to hereinafter as Compound 129.

83 -

Exampl e X

In a manner similar to that employed in Example IX, other compounds were prepared. The structures and analytical data for Compounds 130 through 134 are set forth in Table E below.

TABLE E

Representat ive Ha lonic Add Derivat ive Con-pounds

Substltuents ^' Elemental Analysis Melting'

Compd. *'. 2'5 - ^* Calculated Found Point .

No. C H N C H N ^• c

- ιb

130 C-H. 3.5-Cl. 53.18 4.78 4.43 52.84 4.87 4.23 76.5-80 1

131 2.4,5-Cl ₃ 47.95 4.02 4.00 41.25 3.70 3.94 47-49

^C 2 ^H 5 132 2.4-Cl. 53.18 4.78 4.43 52.84* 4.67 5.11 011 ^C 2 ^H 5

133 C ₂ H ₅ 3,4-Cl. 53.18 4.78 4.43 53.14 4.71 5.92 011 134< ^a > C-H- 4-C1 59.68 5.73 59.89 5.70 85.5-87

^-"Prepared by the mixed anhydride procedure of Example XXXIII.

85 -

Example XI

Preparation of l-(3.5-dichlorophenyl- aminocarbonvDcyclobutanecarboxylic acid

A 2.0 gram (0.006 mole) portion of ethyT l-(3,5-d1chlorophenylaminocarbonyl)cyclobutanecarboxy- late prepared in Example X (Compound 130) was hydrolyzed in the presence of water (0.114 gram, 0.006 mole) and ethanolic potassium hydroxide (0.355 gram, 0.006 mole). The potassium salt of the acid was then acidified with 25% HCl solution and worked up 1n a manner similar to that described 1n Example VII to give 0.92 gram (0.003 mole) of l-(3,5-di- chlorophenylam1nocarbonyl)cyclobutanecarboxylic acid as a beige-colored solid having a melting point of 159°C-160°C. Elemental analysis of the product indicated the following:

Analysis: C.^-Cl-. ^" --^

Calculated: C, 50.02; H, 3.85; N, 4,86

Found: C, 50.20; H, 3.83; N, 4.84 This compound 1s referred to hereinafter as Compound 135.

Example XII In a manner similar to that employed 1n Example XI, other compounds were prepared. The structures and analytical data for Compounds 136 through 139 are set forth 1n Table F below.

TABLE f

Representative Halonic Add Derivative Compounds

Substituent Elemen tal Analysis Heltlng

Co p . 2'6 Cal culateo found Point No. C ^" H N C H N ^• c

136 2.4.S-C1 ₃ 44.68 ^" 3.12 4.34 44.88 3.14 4.23 146-147

137 2.4-Cl ₂ 50.02 3.85 -- 50.22 4.30 — 129-132

138 3.4-C1 ₂ 50.02 3.85 — 50.22 4.10 — 151-153

139 4-C1 56.81 4.77 56.99 4.94 — 159-161

- 87 -

Example XIII Preparation of ethyl l-(4-bromo-2-methylphenyl- aminocarbonyDcyclopentanecarboxylate Ethyl 1-chlorocarbonylcyclopentane- carboxylate (3.10 grams, 0.02 mole) prepared in Example XX, 4-bromo-2-methylan1line (2.82 grams, 0.02 mole) and triethylamine (1.53 grams, 0.02 mole) were reacted in tetrahydrofuran (200 milliliters) under conditions similar to those described in Example I to give 2.40 grams (0.007 mole) of ethyl l-(4-bromo-2-methyl henylaminocarbonyl)eyelo- pentanecarboxylate which, after recrystallization from hexane, had a melting point of 64°C-67°C. Elemental analysis of the product indicated the following:

Analysis: C--H ₂₀ _.rNO- Calculated: C, 54.25; H, 5.69; N, 3.95 Found: C, 54.05; H, 5.55; N, 3.81 This compound is referred to hereinafter as Compound 140.

Example XIV Preparation of ethyl 2-(4-bromo-2- ^• methy1phenylaminocarbonyl)butanoate Ethyl 2-(chlorocarbonyl)butanoate (5.8 grams, 0.03 mole), 4-bromo-2-methylan1l1ne (5.0 grams, 0.03 mole) and triethylamine (3.27 grams, 0.03 mole) were reacted under conditions similar to that described for Example I to give 7.4 grams (0.02 mole) of ethyl 2-(4-bromϋ-2-methylphenylam1no- carbonyl)butanoate as a white solid having a melting

88

point of 98°C-100°C. Elemental analysis of the product indicated the following:

Analysis: C-„H. _n BrN0- 1 18 3

Calculated: C, 51.23; H, 5.53; N, 4.27 Found: C, 51.40; H, 5.63; N, 4.25

This compound 1s referred to hereinafter as Compound

141.

Example XV In a manner similar to that employed in Example XIV, other compounds were prepared. The structures and analytical data for Compounds 142 through 152 are set forth in Table G below.

lable G

Representative Halonic Acid Derivative Compounds

Heltlng rlemental Analysis

Substituent} found Point

C II N ^• c

Compound . »'- __C H H 1 No. 17 57.39 4.78 3.95 115-1 H.-4-8r 57.46 4.82 3.72

142 ^C 6 ^H 5 ^C 2-C

-Λ2"5

C ₂ H- 2,3-(CH-CIICI.-C.I)- 75.66 5.74 4.20 75.60 6.02 4.11 115-111 143 3.68 3.62 0(1

^C 6 ^H 5 39.72 3.85 3.56 40.13 144 Br CH. C-H ₅ 2-CH.-4-Br 3.92 4.19 43.24 4.29 3.99 Oil

CH C.H. 4-C1 43.07

145 Br 3 "2"5 39.58 3.74 Oil

CH, C'H; 3.4-C1- 39.05 3.28 Oil

146 Br 39.56 3.54 3.BB

CH. C ₂ H- 2.4-C1. 39.05 3.2B 3.80

147 Br 3.53 3.B6 Oil

CM C ₂ H ₅ 3.5-Cl. 39.05 3.28 3.80 39.80

148 Br 17 Oil _c „ 2-CH ₃ -4-Br 51.23 5.53 4.27 51.49 5.55 4.

149 CH. 53. B9 6.36 3.52 on cl ₂ H- 2-C..-4-Br 53.94 6.23 3.93

150 C.H. 49.59 5.18 4.41 117-118

H C.H 2-CH ₃ -4-Br 49.70 5.13 4.46 17 4.5 8.74 Oil

151 3

^C »3 _{CH t} H 4-CK 448B..0022 44..0 _U 3 _J 8-..6 ^« 2 48. -

152 Br

- 90 -

Exampl e XVI

Preparati on of 3-[ ^* ( 4-bromo-2-methyl phenyl ) - ami nol-2-bromo-2-methyl -3-oxopropano1 c acid

A 1 .25 gram ( 0.003 mol e) porti on of ethyl

3-[ ( 4-bromo-2-methylphenyl ) ami no ]-2-bromo-2-methyl -3- oxopropanoate prepared in Example XV (Compound 144) was hydrolyzed with water (0.06 gram, 0.003 mole) and ethanolic potassium hydroxide (0.21 gram, 0.003 mole). The potassium salt of the add was then acidified with concentrated HCl and worked up 1n a manner similar to that described in Example VII to give 1.04 grams (0.003 mole) of 3-[(4-brαmo-

2-methylphenyl)amino]-2-bromo-2-methyl-3-oxopropanoic acid as a white solid having a melting point of

133°C-136°C. NMR analysis of the product indicated the following:

NMR (CDCl.-DMSQ d,): -> 2.05 (s, 3H) , ά o

2.20 (s, 3H), 2.4-2.6 (br s, H) , 7.2-7.53 (m, 3H), 9.6-9.8 (br s, H) ppm.

This compound 1s referred to hereinafter as Compound

153.

Example XVII Preparation of N-butyl 3-r(4-bromo-2- methylphenyl)am1nol-3-oxopropanamide A mixture of 4.90 grams (0.02 mole) of ethyl 3-[(4-bromo-2-methylphenyl)amino]-3- oxopropanoate prepared in Example I (Compound No. 75), 358 grams (4.9 moles) of n-butylam1ne , 150 mminters of ethanol and 5 drops of water was stirred at room temperature for about 16 hours. After this period, rotary evaporation gave a crude

- 91 -

product as a white solid. The white solid was recrystallized from ethyl acetate-hexane to give

3.08 grams (0.009 mole) of N-butyl

3-[(4-bromo-2-methylphenyl)amino]-3- oxopropanamide having a melting point of 123°C-125°C. Elemental analysis of the product indicated the following:

Analysis: C-.H__BrN.0- 14 19 2 2

Calculated: C, 51.38; H, 5.85; N, 8.56 Found: C, 51.42; H, 5.91; N, 8.69

This compound is referred to hereinafter as Compound

154.

Example XVIII Preparation of ethyl 1-chlorocarbonyl- cvclopropanecarboxylate Into a stirred solution containing 15.1 grams (0.27 mole) of potassium hydroxide in 240 milliliters of ethanol and 4.83 grams (0.27 mole) of water was added dropwise, with cooling at a temperature of Q°C, 50.0 grams (0.27 mole) of diethyl 1 ,1-cyclopropanedicarboxylate. The mixture was stirred for about 16 hours at room temperature. Solvent was removed under reduced pressure to give a white residue which was dissolved in water and extracted with ether. The water solution was acidified to a pH of 2 with 25% aqueous hydrochloric add and the organic add was extracted from the aqueous suspension with ethyl ether (4 x 400 ramniters). The ether extract was dried over magnesium sulfate and vacuum stripped to give the monocarboxylic add as a clear liquid. The clear liquid was dissolved In 300 mmmters of methylene

- 92

chloride after which 74 grams (0.62 mole) of thionyl chloride were added, and the resulting mixture was then heated under reflux for approximately 16 hours. Volatiles were removed, under reduced pressure to give 45.7 grams (0.25 mole) of ethyl 1-chlorocarbonylcyclopropanecarboxylate. NMR analysis of the product Indicated the following:

NMR (CDC1-): c_ 1.22-1.50 (t, 3H) , 1.75

(s, 4H), 4.1-4.52 (q, 2H) ppm. This compound is referred to hereinafter as Compound 155.

Example XIX Preparation of ethyl 1-chlorocarbonylcyclo- butanecarboxylate Dlethyl 1 ,1-cyclobutanedicarboxylate (20.0 grams, 0.10 mole) was saponified with 6.59 grams (0.10 mole) of potassium hydroxide in a mixture of 200 mmmters of ethanol and 1.80 grams (0.10 mole) of water and worked up to give the monocarboxylic add which was reacted with thionyl chloride (8.86 grams, 0.07 mole) 1n methylene chloride solution as' described 1n Example XVIII. Removal of the solvent gave 7.48 grams (0.04 mole) of ethyl 1-c-hlorocarbonylcyclobutanecarboxylathe. NMR analysis of the product indicated the following: NMR (CDC1-): __ 1.10-1.44 (t, 3H) , 1.7-2.85 (m, 6H) , 4.05-4.5 (q, 2H) ppm. This compound 1s referred to hereinafter as Compound 156.

- 93

Example XX Preparation of ethyl 1-chlorocarbonyl- cvclopentanecarboxylate In a manner similar to the procedure described in Example XVIII, with the exception that refluxlng with thionyl chloride in methylene chloride was conducted for only a 2 hour period, a 10 gram (0.05 mole) portion of dlethyl 1,1-cyclo- pentanedicarboxylate was converted into 5.67 grams (0.03 mole) of ethyl 1-chlorocarbonylcyclopentane- carboxylate. NMR analysis of the product indicated the following:

NMR (CDCl.):^ 1.10-1.49 (t, 3H) , 1.56-2.48 (m, 8H) , 4.0-4.5 (q, 2H) ppm. This compound is referred to hereinafter as Compound 157.

Example XXI Preparation of ethyl 2-bromo-2-chloro- carbonylpropanoate In a manner similar to the procedure described in Example XVIII, except that refluxlng with thionyl chloride 1n methylene chloride solution was conducted only for a 6 hour period followed by standing at room temperature for about 16 hours, a 25.0 gram (0.10 mole) portion of dlethyl 2-bromo-2-methylmalonate was converted Into 12.94 grams (0.05 mole) of ethyl 2-bromo-2-chloro- carbonylpropanoate. This compound was employed 1n the preparation of Compound Nos. 144-148 and 152 1n Example XV. NMR analysis of the product indicated the following:

- 94

NMR ( CDC1 - ) : 1 .10-1 .47 (t, 3H) , 2.05-2.17 ( s pai r, 3H) , 4.05-4.55 ( q pai r , 2H) ppm.

Thi s compound 1 s referred to hereinafter as Compound

1 58.

Example XXII

Preparation of ethyl 3-r(4-ch1orophenyl)aminol-3- oxopropanoate

4-Ch-loroan1line (25.4 grams, 0.20 mole) and dlethyl malonate (48 grams, ^' 0.30 mole) were reacted in a manner similar to the procedure described by A.K. Sen and P. Sengupta, Oour. Indian Chem. Soc. 46. (9), 857-859 (1969). The reaction afforded a greenish colored solid which was recrystallized from toluene-hexane (1:1) and then from Isopropyl ether to give 9.0 grams (0.04 mole) of ethyl 3-[(4-chloro- phenyl)am1no]-3-oxopropanoate as white crystals having a melting point of 82°C-83°C. Elemental analysis of the product indicated the following:

Analysis: C.-H--C1N0.

Calculated: C, 54.67; H, 5.01; N, 5.80

Found: C, 54.90; H, 4.94; N, 6.07 This compound 1s referred to hereinafter as Compound 159.

Example XXIII

Preparation of ethyl 3-r(4-methylth1azol-2-yl) am1nol-3-oxopropanoate

In a manner similar to the procedure described 1n Example I, 2-amino-4-methylth1azole was reacted with ethyl malonyl chloride employing

95

triethylamine as the acid acceptor 1n tetrahydrofuran solution. The ethyl 2-[(4-methylth1azol-2-yl)amino]-3-oxopropanoate product (7.5 grams, 0.03 mole) was obtained as an off-white solid having a melting point of 133°C-141°C. Elemental analysis of the product indicated the following:

Analysis: C-H.-N.O-S Calculated: C, 47.36; H, 5.30; N, 12.27 Found: C, 47.50; H, 4.62; N, 11.77 ^τ r: ^J _ compound is referred to hereinafter as Compound ISO.

Example XXIV In a manner similar to that employed 1n Ξxa.-.ple XXIII, other compounds were prepared. _o-pound 173 was obtained from Clarkson College of Technology, Potsdam, New York. The structures and analytical data for compounds 161 through 173 are set forth In Table H below.

- 96

= _.-_

<ι c|

J5

TABLE H (Cont.l Representative Halonic Add Derivative Compounds

o o

II II H _j C ₂ 0-C-CH ₂ -C-NH-R,

Elemental Analysis Heltlng

Compound « ^• » Calculated found Point «o Ho. H -C -4

1(5 50.94 5.70 ^" 13.20 50.63 5.15 13.32 127-129

CH, o

CHj

166 " Dt L 47.36 5.30 12.27 47.41 5.46 11 .76 90-92

167 xτJ. 32.78 3.09 9.56 32.76 2.34 9.62 163-165

Br

168

169

lABtl H (Cont.l Representative Halonic Derivative Compounds

O II

H _j C ₂ θ-C -CH-f-C- NH-R,

Elemental Analysis Heltlng t

Compound t'i Calculated found Point Ho. c H H C H H ^• c <_> oo

170 49.50 4.57 11.54 49.34 4.64 11.69 99-100

Ul 46.61 4.70 16.31 49.88 4.83 16.24 132-136

112 52.85 5.16 6.16 53.01 5.81 6.11 Oil

173

- 99 --

Example XXV Preparation of ethyl 2-chlorocarbonyl-3- methyl-2-butenoate Dlethyl 1sopropyl1denemalonate (30 grams, 0.15 mole) was saponified with 10.0 grams (0.15 mole) of potassium hydroxide in 200 mllimters of ethanol solution and worked up to give the monocarboxyHc acid which was then reacted with thionyl chloride (10 milliliters, 0.1 mole) 1n methylene chloride solution in a manner similar to the procedure described in Example XVIII. Removal of solvent gave 9.6 grams (0.05 mole) of ethyl 2-chlorocarbonyl-3- methyl-2-butenoate. NMR analysis of the residue product in CDC1- solution indicated complete conversion of the carboxylic acid to the acid chloride as evidenced by absence of a downfleld carboxylic acid proton. This compound 1s referred to hereinafter as Compound 174.

Example XXVI Preparation of ethyl 2-r(4-bromo-2-methylphenyl)- am1nocarbonvn-3-methyl-2-butenoate In a manner similar to the procedure described 1n Example I, ethyl 2-chlorocarbonyl- 3-methyl-2-butenoate (9.6 grams, 0.05 mole) prepared 1n Example XXV, 4-bromo-2-methylan1l1ne (5.3 grams, 0.03 mole) and triethylamine (4.0 miπmters, 0.03 mole) were reacted to give 2.9 grams (0.009 mole) of ethyl 2-[(4-bromo- 2-methylphenyl)-aminocarbonyl]-3- methyl-2-butenoate as a white solid having a melting point of n6 ⁰ C-119°C. NMR analysis of the product Indicated the following:

100

NMR(COCl-): 1.17-1.43 (t,3H), 2.10-2.19 (d,6H), 2.28 (S,3H), 4.08-4.50 (q,2H), 7.21-8.20 (m,4H) ppm. This compound 1s referred to hereinafter as Compound

175.

Example XXVII Preparation of 3.4-d1chloro-2.5-d1methylan1line A solution of 5.0 grams (0.03 mole) of 3, -dichloro-2,5-d1methyl-l-nitrobenzene in 70 -rM11liters of ethanol was hydrogenated at room temperature at 50 psi in the presence of 0.25 gram of ^" ;C% palladium on activated carbon as ^' a catalyst. Working up the reaction mixture gave 1.21 grams (0.006 mole) of 3,4-dichloro-2,5-dimethylanπine as a yellow solid having a melting point of 72°C-76°C. .---- analysis of the product indicated the following: NMR(CDC1 ₃ ): £ 2.24 (s,3H), 2.32 (s,3H), 3.60 (br s,2H), 6.50 (s,H) ppm. This compound is referred to hereinafter as Compound 176.

Example XXVIII Preparation of 4.5-d1chloro-2-methoχyannine

Part A: Preparation of 2.2-d1methyl-N-(4-chloro- 2-methoχyphenyl)propanam1de Into .a stirred solution containing 10.0 grams (0.06 mole) of 4-chloro-2-methoxyan1line and 6.42 grams (0.06 mole) of triethylamine 1n 200 ' mnnnters of tetrahydrofuran was added 7.65 grams (0.06 mole) of trlmethylacetyl chloride 1n a small

101 -

amount of tetrahydrofuran solvent. The resulting mixture was stirred for two hours at room temperature. Triethylamine hydrochloride precipitated and was filtered off and the filtrate vacuum stripped to give a dark liquid which was taken up in methylene chloride. This solution was washed with 2N HCl (2 x 100 mmmters), then with water (1 x 100 milliliters), dried over magnesium sulfate and solvent evaporated to give a crude product which was crystallized from hexane to give 6.82 grams (0.03 mole) of 2,2-d1methyl-N-(4-chlαro- 2-methoxyphenyl)propanam1de as a first and second crop. NMR analysis of the product indicated the following:

NMR (CDC1 ₃ ): £ 1.32 (S, 9H), 3.91 (s, 3H), 6.83-7.08 (m, 2H), 8.28-8.52 (d, 2H) ppm.

Part B: Preparation of 2.2-dimethyl-N- (4.5-dichloro-2-methoχyphenyl)propanam1de Into a stirred solution containing 6.82 grams (0.03 mole) of 2,2-d1methyl-N-(4-chloro-2- methoxyphenyl)propanam1de prepared 1n Part A in 150 milliliters of chloroform was added 3.81 grams (0.03 mole) of sulfuryl chloride over a 40 minute period. The resulting reaction mixture was heated under reflux for a 3 day period, each day cooling the mixture and adding an additional 3.81 grams (0.03 mole) of sulfuryl chloride before continuing the reflux. At the end of 3 days, thin layer chromatographic analysis of the mixture Indicated the reaction to be complete. Volatiles were removed

- 102 -

from the reaction mixture and 3.70 grams (0.01 mole) of 2,2-d1methyl-N-(4,5-dichloro-2-methαxyphenyl)- propanamide recovered as a light yellow-orange solid by flash column chromatography eluting with dlchloromethane. NMR analysis of this product indicate the following:

NMR (CDC1-): j 1.34 (s, 9H) , 3.92 (s, 3H) , 6.94 (s, H), 8.08 (br s H), 8.67 (s, H) ppm.

Part C: Preparation of 4.5-dichloro-2- methoxyanillne

The 2,2-d1methyl-N-(4,5-dichloro-2-methoxy- ρhenyl)propanamide (3.70 grams, 0.01 mole) prepared 1n Part B was dissolved in ethanol: 12N HCl (1:1), the mixture heated under reflux overnight and then freed of volatiles under rotary evaporation. Partition between 2N HCl and dlchloromethane gave an acid-soluble fraction which.was worked up to give 1.1 grams (0.01 mole) of pure 4,5-d1chloro-2- methoxyanlUne as determined by thin layer chromatographic analysis. The dlchloromethane fraction from above was freed of solvent giving starting material which was again refluxed overnight with ethanol: 12N HCl and worked up to give an additional 1.2 grams (0.01 mole) of pure 4,5-dichloro-2-methoxyannine as determined by thin layer chromatographic analysis. NMR analysis of the product Indicated the following:

NMR (CDC! ) $ 3.88 (s, 5H) , 6.73-6.90

(d, 2H) ppm. This compound is referred to hereinafter as Compound 177.

- 103 -

Example XXIX

Preparation of l-(4-bromo-2-methylpheny1am1no- carbonyDcvclobutanecarboxylic add

A 3.0 gram (0.009 mole) portion of ethyl l-(4-bromo-2-methylphenylaminocarbonyl)cyclobutane- carboxylate prepared 1 ^' n Example IX (Compound 129) was hydrolyzed 1n a manner similar to that described in Example XI to give 2.19 grams (0.007 mole) of 1-( -bromo-2-methy1phenylaminocarbonyl)cyclobutane- carboxyHc acid, Compound 181, having a melting point of 154°C-155°C.

Example XXX

^• Preparation of ethyl (chlorocarbonyl)methoχyacetate

Part A. Preparation of dlethyl methoxymalonate

A mixture of 50.4 grams (0.3 mole) of dimethyl methoxymalonate, para-toluenesulfonic acid (2.76 grams) and 300 mmiHters of ethanol was heated under reflux for a period of about 24 hours. Volatile materials were then removed under reduced pressure, employing a water bath at about 25°C. A second 300 ramiHter-portion of ethanol was added and the mixture then refluxed for about 5 hours after which 1t was stirred at room temperature for an approximate 64-hour period. Removal of ethanol from the mixture under reduced pressure gave 61.0 grams (0.3 mole) of dlethyl methoxymalonate, employed 1n the subsequent steps without purification.

- 104 -

Part B. Preparation of mono-ethyl methoxymalonate

A mixture of 30.0 grams (0.2 mole) of dlethyl methoxymalonate (Part A, above), 8.85 grams (0.2 mole) of potassium hydroxide, 2.84 grams (0.2 mole) of water and 300 mπimters of ethanol was stirred at room temperature for about 72 hours and volatiles then removed under reduced pressure. The residue was dissolved 1n water and the pH of the solution adjusted to 10 by addition of potassium hydroxide. The solution was saturated with potassium chloride and extracted with methylene chloride (3x100 mnnnters) to remove unsaponlfled diester. Acidification to pH=l and continuous extraction with methylene chloride afforded 9.45 grams (0.06 mole) of mono-ethyl methoxymalonate as a liquid.

Part C. Preparation of ethyl (chlorocarbonyl) methoxyacetate

A mixture of 5.88 grams (0.04 mole) of mono-ethyl methoxymalonate from Part B, above, 8.63 grams (0.07 mole) of thionyl chloride and 150 mnnnters of methylene chloride was stirred for about 17 hours and then evaporated free of volatile materials. As NMR examination Indicated the reaction to be Incomplete, the above thionyl chloride treatment 1n methylene chloride was repeated for a period of about 65 hours. A third treatment with 8.63 grams of thionyl chloride in 150

-105-

miimiters of methylene chloride was finally given, refluxlng for a period of approximately 7 hours. Removal of volatiles under reduced pressure gave 6.0 grams (0.03 mole) of ethyl (chlorocarbonyl) methoxyacetate, Compound 211. NMR analysis of the product Indicated the following:

Η NMR (CDCl.) 1.16-1.53(t, 3H, CH.), 3.58(s, 3H, CH-0), 4.13-4.56 (q, 2H, CH.) 4.62 (s, H, CH) ppm.

Exampl e XXXI

Preparation of ethyl 3-r ( 3 , 5-d1 chlorophenvnam1no l-

-2-methoχy-3-oxopropanoate

3,5-D1chloroan1line (2.69 grams, 0.02 mole) and ethyl (chlorocarbonylJmethoxyacetate (3.0 grams, 0.02 mole), prepared 1n Example LIII (Compound 211), were reacted 1n the presence of triethylamine (1.68 grams, 0.02 mole) in 200 mnnnters of methylene chloride in a manner similar to that described 1n Example I to give 1.34 grams (0.004 mole) of ethyl 3-[(3,5-d1chlorophenyl)amino]-2-methoxy-3-oxopropano- ate, Compound 213, having a melting point of 89.5°C-92.5°C.

Example XXXII Preparation of mono-methyl methoxymalonate

Dimethyl methoxymalonate (50.0 grams, 0.3 mole) was saponified with potassium hydroxide (17.3 grams, 0.3 mole) 1n a mixture of 500 mlimiters of methanol and 5.55 grams (0.3 mole) of water

^■ 106-

accordlng to the general procedure of Example VII but employing a reaction period of approximately 16 hours. The reaction mixture was evaporated free of solvents and the residue dissolved in water and extracted twice with ether to remove any unreacted diester. The aqueous layer was then saturated with potassium chloride, acidified with 2H HCl and extracted twice with ethyl ether. As this procedure enabled recovery of only a minor amount of product the aqueous phase was then subjected to three 16-hour periods of continuous liquid-liquid extraction with methylene chloride, adjusting the pH from 4 to 1 at the beginning of the second extraction period. Workup of the combined extracts gave 29.24 grams (0.2 mole) of mono-methyl methoxymalonate, Compound 214. NMR analysis of the product indicated the following:

^■ H NMR (CDC1-) £ 3.54(S, 3H, alpha CH-0), 3.86(s, 3H, ester CH-0) , 4.51 (s, H, CH), 9.36(s, H, C0 ₂ H) ppm.

Example XXXIII

Preparation of methyl 3-f(4-bromo-2-fluoro- phenv am1nol-2-methoxy-3-oxopropanoate

To a stirred mixture of 2.78 grams (0.02 mole) of mono-methyl methoxymalonate prepared 1n Example LVI (Compound 214) and 3.56 grams (0.02 mole) of 4-bromo-2-fluoroan1l1ne 1n approximately 100 mnnnters of dry tetrahydrofuran was fed

-107-

dropwise a solution of 3.87 grams (0.02 mole) of 1 ,3-d1cyclohexylcarbod11mide 1n about 30 milliliters of dry tetrahydrofuran, while cooling the reaction mixture 1n an 1ce-water bath. The reaction mixture was allowed to warm slowly to room temperature and stirring continued for an approximate 65-hour period. The precipitated 1 ,3-dicyclohexylurea by-product (3.15 grams) was removed by filtration and the filtrate vacuum evaporated and the residue dissolved in methylene chloride. The latter solution was extracted with dilute HCl and then water, then dried (MgSO ) and solvent vacuum evaporated to give a colorless liquid. Flash column chromatography of the latter on silica, eluting with hexane-ethyl acetate (7:3) gave, after workup, a liquid which crystallized on standing. RecrystalUzation from hexane containing a small amount of ethyl acetate gave 2.3 grams (0.01 mole) of methyl 3-[(4-bromo-2-fluorophenyl)am1no]- -2-methoxy-3-oxopropanaote, Compound 215, having a melting point of 51°C-53°C.

Example XXXIV

In a manner similar to that employed in Example XXXIII, other compounds were prepared. The structures and andlytlcal data for Compounds 216 through 219 are set forth in Table I below.

TABLE I

Representative Halonic Add Derivative Compounds

-t 1 rt-

CD

-1 CO

Elemental Analysis Melting 0* cr

Compound . Substituent Calculated Found Point

<τ>

No. __« •c

216 3.4-Cl ₂ 45.23 3.45 4.BO 45.21 3.91 4.20 78-81

217 -CF3 49.49 4.15 4.81 49.88 4.29 4.91 101-103

218 4-Br 43.73 4.00 43.73 4.04 55-59

219 3.4,5-Cl ₃ 40.46 3.09 40.44 3.22 117-121

-109-

Example XXXV

Preparation of t-butyl 3-r(3.5-d1chlorophenyl)am1nol

-2-methoxy-3-oxopropanoate

Part A Preparation of t-butyl methyl methoxymalonate

To a stirred solution of 9.26 grams (0.06 mole) of methyl (chlorocarbonyl)methoxyacetate 1n 25 mnnnters of carbon tetrachlorlde was added a mixture of 4.94 grams (0.07 mole) of anhydrous t-butyl alcohol, 4.50 mlinnters (0.06 mole) of pyrldine and 25 mlimiters of carbon tetrachlorlde over an approximate 20-m1nute period, with cooling to 0°C-5°C by an 1ce bath. On completing the addition, the cooling bath was removed and the mixture allowed to stir for a 4-hour period at ambient temperature after which pyrldine hydrochlorlde was removed from the mixture by filtration. The filtrate was diluted with 100 mlimiters of methylene chloride and partitioned with 100 mnnnters of saturated aqueous sodium bicarbonate following which the organic phase was extracted with cold 10% hydrochloric add (3 x 100 mnnnters), then with cold water (3 x 100 mlimiters) after which it was dried (MgSO^) and solvents then flash evaporated. The residue was vacuum distilled to give 7.57 grams (0.04 mole) of t-butyl methyl methoxymalonate having a boiling point of 93.5°C-95°C at 4.0 mm Hg.

-110-

Part B Preparation of mono-t-butyl methoxymalonate

t-Butyl methyl methoxymalonate (7.57 grams, 0.04 mole), prepared in Part A, was saponified with potassium hydroxide (2.45 g, 0.04 mole) 1n a mixture of 25 mlimiters of methanol and 668 mlcroliters (0.04 mole) of water according to the general procedure of Example VII but employing a reaction period of 20 hours. Workup according to the general method of Example VII gave 5.42 grams (0.03 mole) of mono-t-butyl methoxymalonate. NMR analysis of the product indicated the following:

Η NMR (CDC1.) _3 1.45(s, 9H, t-butyl), 3.58(S, 3H, CH-0), 4.45(s, H, CH) , 10.51(s, H, CO-H) ppm.

Part C Preparation of t-butyl 3-r(3.5-dichloro- phenv1)aminol-2-methoχy-3-oxopropanoate

Mono-t-butyl methoxymalonate (5.42 grams, 0.03 mole), prepared 1n Part B, 3,5-d1chloroan1l1ne ^" (4.62 grams, 0.03 mole) and 1 ,3-dicyclαhexyl- carbod11m1de (5.88 grams, 0.03 mole) were reacted 1n a manner similar to that described in Example LVII to give 2.92 grams (0.009 mole) of t-butyl 3-[(3,5-d1chlorophenyl)amino]-2-methoxy-3-oxopro- panoate having a melting point of 129.5°C-131.5°C.

- Ill -

Example XXXVI

Preparation of methyl 3-r(3.5-dichlorophenyl)aminol-

-2-methoxy-3-thioxopropanoate

A mixture of 3.50 grams (0.01 mole) of methyl 3-[(3,5-d1chlorophenyl)amino]-2-methαxy- 3-oxopropanoate (Compound 233, Example LXX), 2.42 grams (0.006 mole) of 2,4-bis(4-methoxyphenyl)-l ,3- dith1a-2,4-d1phosphetane-2,4-disulf1de and 35 mlimiters of anhydrous 1 ,1-dimethoxyethane was stirred at room temperature for a period of about 20 hours after which stirring was continued with testing at 55°C for a 168-hour interval. Solvent was removed from the reaction mixture under reduced pressure and the residue worked up by flash column chromatography to give 2.31 grams (0.007 mole) of methyl 3-[(3,5-dichloro-phenyl)am1no]-2-methoxy- 3-th1oxopropanoate, Compound 238, having a melting point of 144°C-147°C.

Example XXXVII Preparation of 2-cvclopropenyl-l-carboethoxy-l-rN-

(2-methy1-4-bromophenyl)lcarboxam1de

Part A. Preparation of dlethyl b1s(2.3-tr1methyl- silvncyclopropene-l .l-d1carboχylate A 50 mmmter round-bottom flask was equipped with a magnetic stirring bar and a reflux condenser with N„ Inlet. The flask was charged with 183.0 grams (1.07 mole) of bis(tr1methyls1lyl) ^' acetylene and 0.40 gram (0.0015 mole) of cupric ace- tylacetonate. Using an oil bath the temperature of

- 112 -

the stirred mixture was raised to 145°C. Using a syringe pump 39.3 grams (0.21 mole) of dlethyl diazomalonate were added over 36 hours. Heating at 1450C was continued for an additional 12 hours after all of the diazomalonate had been added. The excess b1s(tr1methylsilyl)acetylene was removed by vacuum distillation. The residue product was purified by flash chromatography eluting with 80:20 hexane-ethyl acetate to give 17.0 grams (0.05 mole) of dlethyl b1s(2,3-tr1methylsilyl)cyclopropene- 1 ,1-dicarboxylate as a yellow liquid. NMR analysis of the product Indicated the following:

Η NMR (CDCl-): ^ 0.23(s,18H), 1.20 (t, 6H),4.17(q, 4H) ppm.

Part B. Preparation of dlethyl cyclopropene-U- dicarboxylate

A 500 mmmter round-bottom flask was equipped with a magnetic stlrrer and N~ inlet. The flask was charged with 21.0 grams (0.07 mole) of dlethyl bis (2,3-tr1methylsilyl)cyclopropene- ,1- dicarboxylate, 125 milliters of acetonitrlle, 12.2 grams (0.21 mole) of anhydrous KF, and 6.50 grams (0.02 mole) of dicyclohexano-18-crown-6 ether. The mixture was stirred 6 hours at room temperature. The mixture was filtered and the filtrate concentrated under reduced pressure to a deep red oil. This oil was taken up in 100 mnnnters of methanol and stirred 24 hours at room temperature. The methanol was removed under vacuum and the residue purified by flash column chromatography to give 6.25 grams (0.02 mole) of dlethyl cyclo-

-113-

propene-1 ,1-dicarboxylate as a yellow oil. NMR analysis of the product indicated the following: ^• H NMR (CDC1 ₃ ) : <_. 1.25 (t, 6H), 4.23 (q, 4H) ; 7.08 (S, 2H).

Part C. Preparation of mono-ethyl cvclopropene-1.1- dlcarboxylate

A 250 mπmiter round-bottom flask was equipped with a magnetic stirring bar and an addition funnel with N. Inlet. The flask was charged with 6.15 grams (0.03 mole) of diethyl- cyclopropene-1 ,1-dicarboxylate and 50 mlimiters of ethanol. The stirred mixture was cooled in an 1ce bath and a solution of 1.33 grams (0.03 mole) of NaOH 1n 5.0 mil11liters of water was added dropwise. The mixture was allowed to come to room temperature and stirred for 3 days. The reaction mixture was concentrated to 1/4 of the original volume under reduced pressure, diluted with ice water, and extracted twice with ether. The basic aqueous phase was acidified with 1ce cold 10% HCl, and extracted three times with ethyl acetate. The ethyl acetate was dried (MgSO.) and the solvent removed under reduced pressure to leave an orange colored solid. This was recrystallized from hexane- ethyl acetate to give 3.65 grams (0.02 mole) of mono- ethyl cyclopropene-l,l-d1carboxylate as a light yellow solid having a melting point of 76.00C-77.50C. NMR analysis of the product Indicated the following:

•H NMR (CDC1-): _51.20 (t, 3H) , 4.25 (q, 2H), 6.80 (s, 2H), 11.5 (br s, 1H) ppm.

-114-

Part D. Preparation of 1-carboethoxy-l-ethoχy- carbonyloxycarbony1-2-cvclopropene A 250 mπmiter round-bottom flask was equipped with a magnetic stirrer and an addition funnel with inlet. The flask was charged with 1.30 grams (0.008 mole) of mono-ethyl cyclopropene- 1,1-dicarboxylate, 50 mlimiters of dry THF, 2.3 grams (0.02 mole) of potassium carbonate (anhydrous), and 450 milligrams of dicyclohexano-18- crown-6 ether. The stirred reaction mixture was cooled to 00C, and 0.90 gram (0.008 mole) of ethyl chloroformate in 10 mlimiters of THF was added dropwise. The mixture was stirred for 2 1/2 hours at 00C. At this time an aliquot from the reaction mixture showed a very strong anhydride carbonyl stretch at 1820 cm ^" in the infrared Indicating the formation of the mixed anhydride 1-carbo- ethoxy-1-ethoxycarbonyloxycarbonyl-2-cyclo- propene. The balance of the reaction mixture containing the mixed anhydride was carried on to Part E.

Part E. Preparation of 2-cyclopropenyl-l-carbo- ethoxy-1-TN-(2-methyl-4-bromophenv1)1 carboxamjde

A solution of 1.40 grams (0.0075 mole) of 2-methyl-4-bromoan1line 1n 10 mlimiters of tetrahydrofuran was added dropwise to the reaction mixture from part D at OOC. The mixture was allowed to come to room temperature and stirred for 2 hours. The reaction mixture was filtered and the

115 -

filtrate concentrated under reduced pressure to give an orange colored solid. This solid was washed with ether and recrystallized from hexane-ethyl acetate to give 1.5 grams (0.004 mole) of 2-cyclopropenyl-l- carboethoxy-l-[N-(2-methyl-4-bromophenyl) ]carboxamide, Compound 256, as a white crystalline solid having a melting point of 1510C-1530C.

116

Example XXXVIII Effect of Representative Malonic Acid Derivative Compounds on Plant Growth

Retardation-Snapbeans and Wheat Solutions of the test compounds identified in Table I below were prepared by dissolving 68.8 milligrams of the particular compound in 5.5 mlimiters of acetone and then adding water to a final volume of 11.0 mlimiters. If clouding of the solution occurred as the water was added, the use of water was discontinued and acetone was added to a final volume of 1.0 milliliters. The resulting stock solutions contained 6255 parts per million by weight of the particular compound. The test concentration 1n parts of the test compound per million parts by weight of final solution employed in the growth retardation tests in Table _ were obtained by appropriate dilutions of the stock suspension with acetone and water (50/50 volume/volume) .

Seeds of snapbeans, wheat, velvetleaf, cucumber, sunflower, flax, buckwheat, tomato, perennial rye, marigold, soybean, barnyard grass, wild oats and pea were planted 1n a sandy loam soil 1n a flat having the following dimensions: 3.5 Inches 1n width x 7.9 Inches 1n length x 1.0 Inches 1n height. Twelve to fourteen days after planting at the time the first trifoliolate leaf of snapbean 1s at least 3.0 centimeters long, each concentration of the test compounds Identified 1n Table _ was applied to one flat as a foliar spray by use of an aspirated spray apparatus set at 10 psig air

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pressure (all flats sprayed at a rate of 4 pounds per acre). As a control, a water-acetone solution containing no test compound was also sprayed on a flat. When dry, all of the flats of plants were placed in a greenhouse at a temperature of 80°F +, 5°F and humidity of 50 percent + 5 percent. Visual indications of growth retardation activity were observed and recorded 10 to 14 days after treatment.

Visual observations of growth retardation were recorded employing a ^' system of numerical ratings. Numerical ratings from "0" to "10" were used to designate the degree of growth retardation activity observed in comparison with the untreated control. A "0" rating indicates no visible response, a "5" rating Indicates 50 percent more growth retardation 1n comparison with the control, and a "10" rating Indicates 100 percent more growth retardation 1n comparison with the control. Stated in a similar way, a "5" rating indicates that the increment in plant growth 1s only half that of the control or that the plant has increased 1n growth at half the rate of the control. This rating system Indicates any retardation of plant height as compared to the untreated control. The results are reported 1n Table 3.

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TABLE J Effect of Representative Malonic Acid Derivative Compounds on Plant Growth Retardation - Snapbeans

Compound Growth Retardation No. Rating

Control 0

1 2

2 4 5 7

10 2

11 7

13 2

14 2

15 4 18 1

20 2

21 6

22 9

25 6

26 4

28 6

29 2

30 2

33 2

34 6

35 8

36 2

37 5

38 5 40 3 43 2

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TABLE J (Cont.l Effect of Representative Malonic Acid Derivative Compounds on Plant Growth Retardation - Snapbeans

Compound Growth Retardation No. Rating

44 2

45 2

46 9

47 2

49 3

50 3

51 3

57 6

58 4 63 2

66 5

67 2

69 2

70 5

71 2

74 2

75 6

78 2

79 5

80 2

81 2

82 3

83 2

84 4

85 2

86 2

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TABLE J (Cont.) Effect of Representative Malonic Acid Derivative Compounds on Plant Growth Retardation - Snapbeans

Compound Growth Retardation No . Rating

87 2

88 3

90 2

92 4

94 2

95 3

98 3

99 4

100 3

101 2

102 7

104 2

105 3

107 3

108 2 no 4 in 9

112 3

114 4

115 3

116 7

117 2

118 2

120 2

121 4

122 4

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TABLE J (Cont.) Effect of Representative Malonic Acid Derivative Compounds on Plant Growth Retardation - Snapbeans

Compound Growth Retardation No. Rating

123 3

1 25 5

1 26 4

1 28 2

129 5 135 3

140 3

141 1

144 6

145 4

146 3

147 4

148 5

149 3

150 1

1 51 3

153 3

154 2 159 4 168 1 173 2 175 4

V.f

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TABLE J (Cont.) Effect of Representative Malonic Acid Derivative Compounds on Plant Growth Retardation - Snapbeans

Compound Growth Retardation

No. Rating

212 2

213 8 216 3

218 3

219 2

222 2

223 2

224 4 226 2 228 2

232 2

233 6

234 10

235 8

236 8

237 2

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TABLE J

Effect of Representative Malonic Acid Derivative Compounds on Plant Growth Retardation - Wheat

Compound Growth Retardation No. Rating

Control 0

22 1

46 2

69 3

82 2

84 2

88 2

92 3

107 2

110 2

111 3

114 4

115 5

11 6 2

117 2

1 21 2

122 2

123 2

125 2

126 2 129 2

144 3

145 3

146 2

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TABLE 3 (Cont.)

Effect of Representative Malonic Acid Derivative Compounds on Plant Growth Retardation - Wheat

Compound Growth Retardation

No. Rating

212 1

213 1 ^> 216 3

218 2

219 5 224 2

233 5

234 5

235 5

236 5

237 4

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The results 1n Table 3 demonstrate that treatment of plants with certain malonic acid derivative compounds provides significant growth retardation in comparison with untreated control plants.

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Example XXXIX

Effect of Representative Malonic Acid

Derivative Compounds on Plant

Growth Retardation-Wheat

Solutions of the test compounds identified in Table J below were prepared by dissolving the compounds 1n acetone/water (50:50 volume/volume) containing 0.05 percent volume/volume of Triton X-100 surfactant commercially available from Rho and Haas Company, Philadelphia, Pennsylvania. As detailed below, these solutions of test compounds were applied to wheat at a concentration of 0.5 pounds of active ingredient per acre or 1.0 pounds of active ingredient per acre.

Wheat seeds were planted in a sandy loam soil in a flat having the following dimensions: 3.5 inches 1n width x 7.9 inches in length x 1.0 Inches in height. Eight days after emergence at the 2-3 leaf growth stage of wheat, each concentration of the test compounds identified in Table 0 was applied to one flat as a foliar spray by use of an aspirated spray apparatus set at 10 psig air pressure (all flats sprayed at a volume of 120 gallons per acre). As a control, a water-acetone solution containing no test compound was also sprayed on a flat. When dry, all of the flats of wheat were placed 1n a greenhouse at a temperature of 80°F + 5°F and humidity of 50 percent ± 5 percent. Visual Indications of growth retardation activity were observed and recorded 14 days after treatment.

Visual observations of growth retardation were recorded employing a system of percentage

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ratings. These percentage ratings from 0 to 100 were used to designate the degree of growth retardation activity observed in comparison with the untreated control. A 0 percent rating indicates no visible response, a 50 percent rating indicates that the Increment in wheat growth 1s only half that of the control or that wheat has increased in growth at half the rate of the control and a 100 percent rating indicates a maximum response. This rating system indicates any retardation of wheat height as compared to the untreated control. The results are reported in Table K.

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TABLE K

Effect of Representative Malonic Acid Derivative Compounds on Plant Growth Retardation - Wheat

Compound Rate Percent Growth

No. (Pounds/Acre) Retardation

Control — 0

Compound 96 0.5 30

1.0 40

Compound 111 0.5 60

1.0 70

Compound 114 0.5 20

1.0 30

Compound 82 0.5 10

1.0 10

Compound 115 0.5 30

1.0 40

Compound 116 0.5 40

1.0 70

Compound 117 0.5 50

1.0 60

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The results in Table K demonstrate that treatment of wheat with certain malonic acid derivative compounds provides significant growth retardation in comparison with untreated control wheat.

130 -

Example XL

Effect of Representative Malonic Acid

Derivative Compounds on Plant Growth Retardation-Red Maple and Sycamore

Solutions of the test compounds identified in Table K below were prepared by dissolving the compounds in acetone/water (50:50 volume/volume) containing 0.1 percent volume/volume of Triton X-100 surfactant commercially available from Rhom and Haas Company, Philadelphia, Pennsylvania. As detailed below, these solutions of test compounds were applied to red maple and sycamore at a concentration of 1.0, 2.0 or 4.0 pounds of active ingredient per acre.

Bare-root seedlings of red maple (Acer rubrum) and sycamore (Platanus occidentalls) were obtained commercially and grown in one gallon plastic containers containing a sandy loam soil. The seedlings were maintained in a greenhouse at a temperature of 80°F + 5°F and humidity of 50 £ 5 percent. After a period of one month, the developing trees were disbudded to one main dominant shoot 4-6 inches in length. At this time, each concentration of the test compounds identified in Table K was applied to separate trees as a foliar spray by use of an aspirated spray apparatus set at 10 psig air pressure (all trees sprayed at a volume of 120 gallons per acre). As a control, a water-acetone solution containing no test compound was also sprayed on certain trees. When dry, all of the trees were returned to the greenhouse for a period of one month. Measured indications of growth

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retardation activity were observed and recorded at this time (one month after treatment).

The percent retardation of shoot elongation in Table L was determined by actual measurement of the shoot of each tree which was compared to the untreated control. The average shoot length of the untreated control trees was 48 centimeters for red maple and 53 centimeters for sycamore. The results in Table L represent the average of 3 repetitions.

TABLE L

Effect of Representative Malon 1c Acid Derivative

Compounds on Plant Growth Retardation - Red Maple and Sycamore

Percent Retardation of Shoot Elongation

Compound Rate Red No. (Pounds per Acre) Maple Sycamore

Control 0 0

Compound 96 1.0 34 15 2.0 40 16 4.0 43 20

Compound 111 1.0 76 77 2.0 97 84 4.0 97 88

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The results in Table L demonstrate that treatment of red maple and sycamore with certain malonic acid derivative compounds provides significant growth retardation in comparison with untreated control red maple and sycamore.

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Example XLI

Effect of Representative Malonic Add

Derivative Compounds on Plant Growth Retardation-Red Maple and Sycamore

Solutions of the test compounds identified in Table M below were prepared by dissolving the compounds in acetone/water (50:50 volume/volume) containing 0.1 percent volume/volume of Triton X-100 surfactant commercially available from Rhom and Haas Company, Philadelphia, Pennsylvania. As detailed below, these solutions of test compounds were applied to red maple and sycamore at a concentration of 1.0 or 2.0 pounds of active Ingredient per acre.

Bare-root seedlings of red maple (Acer rubrum) and sycamore (Platanus ocddentalis) were obtained commercially and grown 1n one gallon plastic containers containing a sandy loam soil. The seedlings were maintained 1n a greenhouse at a temperature of 80 ^β F 5°F and humidity of 50 £ 5 percent. After a period of 3 months, the developing trees were pruned to a 50 percent reduction 1n height. At 24 days after pruning, each concentration of the test compounds Identified in Table M was applied to separate trees as a foliar spray by use of an aspirated spray apparatus set at 10 psig air pressure (all trees sprayed at a volume of 120 gallons per acre). As a control, a water-acetone solution containing no test compound was also sprayed on certain trees. When dry, all of the trees were returned to the greenhouse for a period of 45 days. Visual indications of growth

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retardation activity were observed and recorded at this time (45 days after treatment).

The percent retardation of regrowth in Table M was determined by visual observation of the regrowth of each tree 1n comparison with the untreated control. A 0 percent rating Indicates no visible response, a 50 percent rating indicates that the increment 1n tree growth 1s only half that of the control or that the tree has increased 1n growth at half the rate of the control, and a 100 percent rating indicates a maximum response. This rating system Indicates any retardation of regrowth as compared with the untreated control. The results 1n Table M represent the average of 3 repetitions.

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TABLE M

Effect of- Representative Malonic Acid Derivative Compounds on Plant Growth Retardation - Red Maple and Sycamore

Percent Retardation of Regrowth

Compound Rate Red No. (Pounds per Acre) Maple Sycamore

Control 0

Compound 96 1.0 47 8

2.0 42 9

Compound 111 1.0 85 43

2.0 91 46

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The results in Table M demonstrate that treatment of red maple and sycamore with certain malonic acid derivative compounds provides significant retardation of regrowth in comparison with untreated control red maple and sycamore.