AU647401B2 - Novel glyoxylates and herbicidal and plant growth regulant activity of glyoxylates - Google Patents

Description

VEitSION 1 ANNOUNCEMENT OF THE LATER PUBLICATION OFRE VISED VERSIONS~~~ P1 ~OF INTERNA TIONA L SEA RCH REPORTS Vllp 59 c C INTERNATIONAL APPLICATION PUBLISHED UNDER [HE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification (11) International Publication Number: 'NO 91/00009 AO IN 43/00,6, 43/43/0A (43) International Publication Date: 10 January 1991 (10.01.91) C07D 265/30, 295/00, 405/06 (21) International Application Number: PCT/US9O/03672 (74) Agents: MINNICH. Richard, J. et al.; Fay, Sharpe. Beall, Fagan, Minnich McKee, 1100 Superior Avenue, Suite (22) International Filing Date: 27 June 1990 (27.06.90) 700, Cleveland, 011 441 14-2518 (US).

Priority data: (81) Designated States: AT (European patent), AU, BE (Euro- 373,210 29 June 1989 (29.06.89) us pean patent), BR, CA, CH (European patent), DE (Eunctt-ffise 25 June 1990 (25.06.90) us ropean patent)*, DK (European patent), ES (European 6 L"Lpatent), FR (European patent), GB (European patent).

j~ TC 'C t I-U, IT (European patent), JP, LU (European patent), (71) Applicant: FE-R-M-ENTA-SG--CR-PO-RAT1N-LUS44Us]; NL (European patent). SE (European patent), SU.

5966 Heisley Road, Mentor, OH4 44061 (US).

(72) Inventors: BARNES, Keith, D. ;227 Canterbury Court, Published Newtown, PA 18940 HOTZMAN, Frederick, W. Wihz a ievo~u, rcrtiuf o4 1he imerntff laI sct(i It rcporl 144 Independence Drive, Morrisville, PA 19067 (US).

LIMPEL, Lawrence, E. ;22350 Lakemont Avenue, Euc- (88) Date or* publication of' the revised version of' the, lid, OH 44123 MAGEE, Thomas, A. ;7301 Case international search report: I I Jun LI192 (1 t.0o 92) Avenue, Mentor, OH 44060 (US).

G4 -7 (54)Title: NOVEL GLYOXYLATES AND HERBICIDAL AND PLANT GROWTH REGULANT ACTIVITY OF GLYOX

YLATES

(57) Abstract 2H-dibenzold,g1 I,3]dioxocin-6-carboxylic acid and certain derivatives thereof (glyoxylates) exhibit plant growth regulant and herbicidal activity when applied to a plant lot-us.

N 1 11, 1 111492 11 1 NOVEL GLYOXYLATES AND HERBICIDAL AND PLANT GROWTH REGULANT ACTIVITY OF GLYOXYLATES BACKGROUND OF THE INVENTION s The invention relates broadly to 12H-dibenzo[d,g] [l,3]dioxocin-6-carboxylic acid and certain derivatives thereof, generally referred to herein as "glyoxylates", and their use as plant growth regulant and/or herbicidal agents and more particularly to their use, usually in combination with appropriate carriers and surfactants, in influencing the growth and development of crops, ornamentals and turf grasses.

Some of the compounds which find utility in the present invention are known generically, and specifically in the case of the methyl ester, from U.S. Patent 3,553,234.

Therein, a class of compounds described as 12H-dibenzo[d,g][l,3] dioxocin-6carboxylic acids and their esters and having the formula

Y

X

Y

0 X -COOR X

Y

x y wherein X and Y are hydrogen or a halogen and R is hydrogen or lower alkyl are disclosed to have utility as In:\lihxxlnn383:SEF 2 hypolipidemic agents for warm blooded animals. Also mentioned are the pharmaceutically acceptable salts of such acids. An improved class of hypolipidemic agents are disclosed by the same inventors in U.S. Patent No. 3,941,173 wherein carboxamides are also contemplated. However, no utility in the agricultural field is suggested, and on tests of the specific compounds disclosed in U.S. Patent No. 3,553,234 and U.S. Patent No. 2,941,173 no herbicidal activity was found.

The present invention is based upon the discovery that a selected group of such compounds possesses unexpected activity when employed as plant growth regulant and/or herbicidal agents at controlled dosages, while other closely related compounds within the genus of U.S. Patent 3,553,234 displays no significant agrochemical activity.

As used herein, "plant growth regulant" means a glyoxylate compound of the invention or composition containing such a glyoxylate compound which affects the maturation and metabolism of plants. Hence, a "plant growth regulant" has many effects on plant growth. However, not all plant growth regulant active compounds affect plants 1i the same way. For example, they could affect vegetative growth by retarding or stimulating terminal growth, and/or stimulating side branching and could inhibit new grow th such as the development of new sprouts of woody plants, the sprouting of tubers and rhizomes and the development of sucker growth. Such regulants could affect flowering plants by eliminating early flowe;ing, by thinning of blossoms or by increasing the number of flowers. Fruit-bearing trees and bushes could be affected by increases in the number, size and quality the fruit, by producing seedless fruit, by accelerating a In:,:'h1x]00391:SEF WO 91/00009 I'CT/US90/03672 -3senescence and fruit ripening. Both flowering and fruit plants could be affected by accelerating plant dormancy and maintaining bud dormancy. A "plant growth regulant" could cause selective postemergent control of weeds by reducing their vigor and competitiveness, and thus prevent their spread and stop normal seeding.

Some specific applications of plant growth regulants include: preventing lodging of cereals; increasing production of harvestable tea leaves by promoting side branching; inhibiting sprouting of potatoes and onions in storage; suppressing growth of grass, trees, shrubs, and other vegetation in decorative lawn areas, parks, golf courses and along highways and other rights-of-way; accelerating fruit ripening and thus, aiding mechanical harvesting by a single or reduced number of pickings; defoliating cotton to permit mechanical harvest; inhibiting new growth of defoliated cotton and, thus, reducing staining of fiber during mechanical harvesting; increasing the quality of the harvested crop, sugar content of sugar cane, sugarbeets, grapefruit, grapes, and other fruits; aiding mechanical harvesting of nut crops by accelerating ripening, stimulating husk cracking and promoting abscission; protecting crops from drought; WO 91/00009 PCT/US9o/03672 -4protecting fruit crops from frost by stimulating early dormancy and/or preventing premature breaking of dormancy; increasing latex flow of rubber; increasing frost resistance of winter cereals; reducing the flowering or bolting of lettuce, sugar beets and tobacco; controlling tobacco suckering; stimulating increased fruit set of soybeans, peanuts, cotton, tomatoes, melons, and other fruits and enhancing fruit color and quality; stimulating branching of pot plants; e.g.

heather, azalea, chrysanthemum and geranium; growth retardation in pot plants, e.g.

poinsetta, petunia, chrysanthemum and azaleas; stimulating branching of young fruit trees, e.g. apple and pear.

"Plant growth regulant" also means the retardation of terminal vertical) growth of plants.

In grasses and weeds, this regulant activity will retard the grass height and, hence, grass growth. In bushy plants, on the other hand, the resultant retardation of terminal growth by the regulant activity often results in enhancement of lateral growth, an effect desired, e.g. in tomato plants.

SUMMARY OF THE INVENTION re There has now been discovered a method of /-modi-f-yi-n-the natural growth and development of a plant, which method comprises applying to the plant locus an effective, nonlethal, plant regulating amount of a compound i.aving the formula 4 0 A

H

O

H /s

Y

4 wherein: A is COOR, COSR, CONR'R", CSNH 2 or CN R, is H, Na, K, di(C 1

C

4 alkylammonium, diethanolammonium, N(3-aminos propyl)N-oleylammonium, C, Cg alkyl, aryl, heteroaryl, C 2

C

8 alkoxyalkyl, C 2

C

4 hydroxyalkyl, (alkoxycarbonyl)alkyl, aialkylaminoalkyl, cycloalkyl, tetrahydrofurfuryl or dimethydioxolanylmethyl; R' and R" may be the same or different, and each is a member selected from the group consisting of H lower alkyl cycloalkyl. aryl, heteroaryl, heteroalkyl, or alkoxycarbonylalkyl; or NR'R" taken together represent a saturated monocylic heterocyclic group such as pyyrolidino piperidino, morpholino, piperazino or N-(lower alkyl)-piperazino; Z is H, CH 3

CH

3 S, CH 3 S(O) COOR; Y is H C 1

C

4 alkyl or alkoxy CF 3 or X; and is X is F, Cl or Br, provided that where more than one of Y is other than H on either ring they must be in the 3, 4, 8 and/or 9 positions and, where Y is in the 1, 2, 10 or 11 positions on the rings, no more than one of Y is other than H. In other embodiments, no more than one of Y is other than H on either ring.

In:\libxx10033:SEF I -I There has further been found a method of controlling the growth of undesired vegetation, which method comprises applying to the vegetation locus especially by postemergent application, a herbicidally effective amount of a compound having the same formula as above.

There has still further been found a composition of matter useful in the regulation of plant growth and development, which composition comprises a compound having the same formula as above, an inert carrier and a surfactant.

In one embodiment of the method of the present invention, there is method according to Claim 1, wherein NR'R" taken together are pyrolidino, morpholino, piperazino or N-(lower alkyl)-piperazino.

provided a piperidino, In a further embodiment of the foregoing methods and composition of the present invention Y and Z are all H, resulting in a compound having the formula In a still further embodiment of the foregoing methods and composition of the present invention, Z is H, resulting in a compound having the formula In:\lihx lin(3X3:SEF The invention also encompasses certain novel compounds having herbicidal and/or plant growth regulating activity having the formula wherein: A is COOR, COSR, CONR'R", CSNH 2 or CN; R is C 2 Cg alkoxyalkyl, cycloalkyl, C 2

C

4 hydroxyalkyl, (alkoxycarbncyl) alkyl, dialkylaminoalkyl, tetrahydrofurfuryl and dimethylclioxolanylmethyl; In:\lih xx (003 3:SE 8 R' and R" may be the same oi different and each is a member selected from the group consisting of H, lower alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl or alkoxycarbonylalkyl; or NR'R" taken together represent a saturated monocylic heterocyclic group such as pyyrolidino piperidino, morpholino piperazino or N-(lower alkyl)-piperazino; Z is H, CH 3

CH

3 S, CH 3 S(O) or COOR; Y is H, C 1

C

4 alkyl or alkoxy, CF 3 or X; and X is F, C1 or Br; provided that where more than one of Y is other than H on either ring they must be in the 3, 4, 8, and/or 9 positions and, where Y is in the 1, 2, 10 or 11 positions on the rings, no more than one of Y is other than H. In other embodiments no more than one of Y is other than H on either ring.

Another group of novel compounds within the scope of the invention has the formula Yn H0. A

H-

H wherein: r r/ fn:\lih\b.x00383:SEF 9 A is COOR, COSR, CONR'R", CSNH 2 or CN R is H, Na, K, di(CI C 4 )alkylammonium N(3-amiino-propyl)N-oleylammonium,

C

1

C

8 alkyl, aryl, heteroaryl, C 2

C

8 alkoxyalkyl, C 2

C

4 hydroxyalky, (alkoxycarbonyl)alkyl, dialkylaminoalkyl, cycloalkyl, tetrahydrofurfuryl, or s dimethydioxolanylmethyl; R' and R" may be the same or different and each is a member selected from t:he group consisting of H, lower alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or alkoxycarbonylalkyl; or NR'R" taken together represent a saturated monocylic heterocyclic group such as pyyrolidino, piperidino, morpholino, piperazino or N-(lower alkyl)-piperazino; Z is H, CH 3

CH

3 S, CH 3

COOR;

Y and W are C 1

C

4 alkyl or alkoxy or CF 3 m and n are 0-2 and the sum of m plus n is 1-4; with the proviso the compound is not N, N-dibutyl-12H-dibenzo [1,3]-dioxoein-6-carboxamide.

is By way of illustration, and not by way of limitation, the following are moieties suitable for use as A, Z and Y in the compositions of the present invention.

As examples of moieties suitable for use as A mention may be made of a carboxyl group (-COOH), simple csters such as:

COOCH

3

COOCH

2

CH

3

COOCH

2 CHqCH 3

COOCH(CH

3 )2

COOCH

2

CH

2

CH

2

CH

3 COOC(CH3) 3 I n:\libxx0033 :SEF wo 91/00009 WO 9 100009 CT/ US90/03672

COOCH

2

(CH

2 6

CH

3

COOCH

2 CH (CH 2

CH

3

CH

2

CH

2

CH

2

CH

3 C00C 6

H

1 1

COOCAH

substituted esters such as:

COOCH

2

CH

2

OCH

3 COO CH 2

CH

2 0 CH 2

CH

2

CH

2

CH

3

COOCH

2 CH (OH) CH 2 0H 0 0

COOCH

2

CH-CH

2

COOCH

2 0 COOCH (CH 3

COOCH

2

CH

3

COOCH

2

CH

2 N (CH 3 2

COOCH

2

CH

2 N (CH 3 2 HC1 amides such as:

CONH

2

CONHCH

3

COHNC

6

H

CON (CH 3 2 salts such as: COONa

COOK

COOH. (CH 3 2

NH

COOH. (HOCH 2

CH

2 2HH COOH. CH 3

(CH

2 7 CH=CH (CH 2 81HCH 2

CH

2

CH

2

NH

2 and other moieties such as:

CH

2 0H

CH

2

OSO

2

C

6

H

6

-CH

3 4

CH(OH)CN

CH=CHCOOCH

2

CH

3

~W~T

CN

C= S) NH 2 C( =O)SCH 2

CH

3 C= O)NHNJ 2 Z may be:

H

CH

3

CH

3

S

CH

3

S(O)

C(=zO)OCH2CH 3 and Y may be:

H

CH

3 In Iilx x Inf393 -S FF

(CH

3 3

C

F

Cl

HO

C

6

H

5

CH

2 0

CH

3

C(=O)O

NO

2 a nitrogen ring structure such as pyridine derivatives.

These and other aspects of the invention will become clear to one skilled in the art from the specification and claims that follow.

DETAILED DESCRIPTION 1i When used in the present invention, the terms "plant growth regulant" or "plant growth regulating effect" refer to the ability of a glyoxylate compound of the invention or a compo:ition containing such a glyoxylate compound, when applied to a plart locus, to influence the growth and development of useful crops, ornamentals and turf as for example described by illustration hereinbefore. A variety of effects may be obtained depending upon, among other considerations, the plant in question, the glyoxylate selected and the manner, amount and timing of application. Generally the result obtained by application of a glyoxylate is the desirable promotion, inhibition and/or alteration of a plant's physiological or morphological processes, such as accelerating or retarding leaf, shoot and root growth, reduction in stature, increased branching, tillering, terminal inhibition, inhibition of regrowth after pruning thereby ee ,M ln:\hbxx100391:SEF 13 reducing the need for follow-up pruning, increased root growth, delayed budding, increased bud count, yield increases, etc. In particulnr, the glyoxylates of the present invention have been found to be effective growth retardants when applied to turf grasses such as perennial rye, red and tall fescue and Kentucky bluegrass. A further example of a plant growth regulating effect is the ability of a glyoxylate compound, when timely applied (preferably in the second or third growth stage) to act as a straw shortening agent on wheat, an especially useful effect where highi nutrient levels are employed to increase grain yield.

The use of the terms "herbicide" or "herbicidal effect" refers to the application of a glyoxylate compound of the invention to kill or at least substantially inhibit the growth of, an undesired plant. Especially significant examples are the use of one of the glyoxylates to control the growth of weeds, including grassy weeds, in wheat and reduce flowering in bolting weed beets. The glyoxylates have been found to be particularly useful in controlling the growth of the generally hard to control sedges, especially yellow nut sedge, when applied to the soil in 'hich the nut sedge tubers are beginning to germinate.

[n:\lihxxIO0383:SEF \VO 91/0009 1,C]'/US90/03672 -14- Each of the defined glyoxylate compounds has been found to have a herbicidal and/or plant growth regulating effect. In addition to activity and selectivity considerations, a particular ester or salt form of a glyoxylate will often be chosen for its convenience of handling and application, an example being the choice of the n-butyl ester, which has reduced volatility, over the methyl ester form. On the other hand, where volatility is desirable, for application by fumigation (smoke bombs) in a greenhouse to induce branching of ornamentals, compounds such as the nitrile and lower esters methyl, ethyl and propyl) which are more volatile, may be preferred.

The choice of substituents to be placed on the benzene rings, on the other hand, seems to affect the nature and extent of plant growth regulating effect to be obtained and such substitution is limited with respect to the identity of the substituent, location on the ring or rings and number of substitutions that may be accommodated. Substitution opportunities are particularly limited when placed in the 1, 2, 10 and 11 positions according to the following number system: 3 12 WO 91/00009 CI/ US9O/03672 In such cases, substitution of a methyl group at no more than one position has been found possible without a significant loss of herbicidal activity.

Substituent possibilities at the remaining benzene ring positions 4, 8 and in order to vary the growth regulating and/or herbicidal effect obtained without significant overall loss of activity, are more numerous.

While it is preferred that not more than one position on either ring be substituted, the choice of substituents may be increased as defined above.

Generally the glyoxylates will be applied to the plant locus as the active ingredient in a composition also comprising a carrier and a surfactant, that is, a dispersing, emulsifying or wetting agent, although diluents, extenders and other active ingredients having a differing or complementary utility may be present. The compositions may thus be in the form of finely divided particulate solids, granules, wettable powders, solutions and dispersions.

The inert carrier may be solid clays, natural or synthetic silicates, talcs) or liquid water, alcohols, esters, aromatic hydrocarbons, petroleum fractions). The surface active agents may be anionic, cationic or non-ionic salts of lignosulfonic acids, alkyl-aryl sulfonic acids, acetates of alkylamines and condensates of ethylene oxide with fatty alcohols or acids). In addition, the compositions may contain thickeners, adhesives, stabilizers, preservatives and ether adjuvants known to the art.

The glyoxylates may be applied by conventional techniques spreading, dusting or spraying or via WO 91/00009 PCT/US90/03672 -16fumigation smoke bombs in confined areas such as greenhouses) in a variety of forms solutions, suspensions, wettable powders or granules).

The compositions of the present invention generally will contain from 5 to 95 percent by weight of the active glyoxylate compound and will be applied at a rate of from 0.5 to 4 kilograms per hectare, when used as herbicides. While in a plant growth regulating composition the amount of active ingredient may be comparable, the amount employed will vary greatly depending upon the particular glyoxylate chosen and the effect in question, generally ranging from 0.01 gram to 4 kg per hectare. Conveniently, such applications are obtained by spraying a solution containing from 0.1 to 500 ppm active ingredient to run-off, depending on the plant species to be treated.

Some of the compounds which are the subject of the present invention are derived from the acid form which may be prepared by methods known to the art, for example, according to the teachings of U.S. Patent 3,836,543 incorporated herein by reference.

Modifications and variations of these procedures where benzene ring substituents are other than those described in the '543 patent and where substitution is desired at the 12 position, are shown in the examples below.

Thereafter, they may be converted to the final form generally according to methods also known in the art, for example, conventional esterification when preparing a lower alkyl ester.

In order that those skilled in the art may more readily understand the present invention and certain preferred embodiments by which it may be carried into effect, the following specific examples are afforded. The following examples illustrate novel compounds according to the present invention, or compounds which are suitable for use in the novel methods or compositions of the present invention, or other related compounds. The compounds of examples 1-19, 23-37, 39-44, 46, 47, 62, 63, 65-69, 73-76, 78, 79, 84-86, 94, 95, 110, 112, 116, 118 and 121-123 are novel compounds as claimed herein or are compounds for use in the novel compositions or methods claimed herein.

PREPARATIONS

EXAMPLE 1 12H-Dibenzo[d,g][ .3dioxocin-6-carboxylic acid Into a 12 liter 3-neck flask fitted with an air-driven overhead stirrer and a condenser are placed 2 2'-methylene bisphenol (200.24 gram 1.0 mol) 4 liter of isopropyl alcohol and then potassium carbonate (552.84 gram 4.0 mol), while stirring.

Dichloroacetic acid, (82.5 ml, 1.0 mol) is added over a period of 2 minutes. During the addition of -the dichloroacetic acid some effervescence is observed. The reaction mixture, which is a white, easily stirred, heterogenous mixture, is heated at reflux and stirred vigorously. After 24 hours, the reaction mixture is cooled to room temperature and an additional 82.5 ml (1.0 mol.) of dichloroacetic acid is added. Again some effervescence is observed. The reaction mixture is then heated at reflux for an additional 72 hours. Total reflux time is 96 hours. After 48 hours of total reflux time the reaction mixture thickens and vigorous stirring is maintained.

Once the 96 hour reflux period is complete the condenser is replaced with a distillation head and 200 ml of isopropyl alcohol is distilled off at atmospheric pressure and replaced with 200 ml of H20. This is repeated until the distillation temperature reaches 95-100 0 C. During the distillation procedure, once H 2 0 is S In:\lihux l00383:SEF WO 91/00009 PCT/US90/03672 added, the reaction mixture becomes much more fluid and eventually a reddish brown homogenous solution is obtained. After the distillation temperature reaches 95-100'C, the reaction mixture is cooled to room temperature. Upon cooling, solids form, therefore it is important to maintain vigorous stirring. The reaction mixture is then made strongly acidic by the careful addition of concentrated HC1 (800 ml) over a period of 1-2 hours. Extreme caution must be taken during the addition of the HC1 because of effervescence. The effervescence is particularly vigorous during the latter stage of HC1 addition. Once the HC1 has been added, the reaction is stirred an additional 2 hours at room temperature. The solids are collected by filtration and washed well with H 2 0.

These solids are then placed in a separatory funnel with 2 liters of ethyl acetate and 2 liters of 1N HC1 and shaken vigorously. The organic layer is separated, washed with brine, dried over MgSO 4 and concentrated. The solids obtained are then dried in a vacuum oven to afford 239 grams (93 percent) of crude product as a brown-tan solid, which are then placed in a Soxhlet extraction apparatus and exhaustively extracted with refluxing cyclohexane (2 liters). Periodically the cyclohexane solution is cooled and the precipitated product collected by filtration. The rate of the extraction depends on how vigorously the cyclohexane refluxes and recycles. There is obtained 147 grams of 12H-dibenzo[d,g][l,3]dioxocin-6-carboxylic acid as a white solid: mp 153-157*C; IR (KBr) 5.78, 6.76, 6.93, 8.12, 10.1, 13.1 cm' 1 'H NMR (60 MHz, DMSO-d 6 3.64 and 4.38 (2d, 2, CH 2 5.09 1, CH), 6.9-7.6 8, WO 91/00009 PC/ US9O/03672 Ar-H); greater than 99 percent purity as determined by liquid chromatography.

EXAMPLE 2 n-Butyl 12H-Dibenzo[d.il 1.3ldioxocin-6-carboxylate Into a 500 ml round bottom flask fitted with a stir bar and a Dean-Stark apparatus is placed 111.4 grams of crude (87 percent) 12H-dibenzo[d,g)[1,3]dioxocin-6carboxylic acid in 300 ml of 2:1 n-butanol:toluene. The mixture is stirred at room temperature for 15 minutes to effect the complete dissolution of the acid.

Concentrated sulfuric acid (4.0 ml) is then added and the reaction mixture is heated to reflux. Immediately upon attaining reflux, an aqueous layer begins to separate out in the Dean-Stark apparatus. After 2 hours at reflux, no additional water formation is observed and the reaction is cooled to room temperature with a cold water bath. A total of 10 ml of water is collected, the majority of this water being formed in the initial 30 minutes of reflux. The cooled reddish-yellow reaction solution is diluted with 200 ml of toluene, washed with 300 ml of water, 300 ml of saturated aqueous NaHCO 3 300 ml of brine and then concentrated under reduced pressure on a rota-vap. Toluene (200 ml) is added to the residue and the solution again is concentrated under reduced pressure. This evaporation with toluene facilitates the remo-'al of n-butanol. The residue obtained is taken up into 300 ml of 2:1 toluene:ether and washed with 200 ml of 5 percent NaOH. Brine, 50 ml, is added to break up the emulsion that forms with the 5 percent NaOH wash.

WO 91/00009 PCT/US90/03672 The organic solution is then washed with 200 ml of brine, dried over MgSO 4 and concentrated under reduced pressure to afford a thick light reddish-yellow liquid (130 grams). This liquid is then subjected to vacuum distillation, using a Claisen adapter as the distillation head and an oil bath for heating. Care is taken during the course of the distillation to avoid solidification of the product in the distillation condenser. A forerun (11 grams) is collected having a b.p. 70"C to 170°C at 0.25 mm. Pure n-butyl ester, 84.3 grams (62 percent), is then collected from 171°C to 180°C at 0.25 mm as a thick clear liquid which readily solidifies on cooling to afford a white solid: mp 63-66*C (softening at 60°C); greater than 99 percent purity as determined by L.C. bp 189-195"C/0.4mm; IR (neat) 3.45, 5.75, 6.95, 8.35, 10.4 cm'1; H NRM (60 MHz, CDC13) 0.9-1.9 7,

OCH

2

CH

2 CH2CH 3 3.42 and 4.6 (2d, 2, CH2), 4.35, 2,

OCH

2

CH

2

CH

2

CH

3 5.05 1, CH), 7.0-7.4 8, Ar-H)).

Anal. Calcd. for C 9

H

2 0 0 4 C, 73.06; H, 6.45 Found: C, 73.0; H, 6.7 EXAMPLE 3 Ethyl 12H-Dibenzord,lqfl.31dioxocin-6-carboxylate A solution of 12H-dibenzo[d,g][1,3]dioxocin-6carboxylic acid (31.8 grams, 0.124 mol) and conc. H 2

SO

4 (1.6 ml) in 215 ml of ethanol is heated at reflux, allowing the condensate to pass through 4A molecular WO 91/00009 PCT/US90/03672 -21sieves. After 2 hours, the reaction is cooled to room temperature and 100 ml of methylene chloride is added and then neutralized by the addition of solid Na 2 CO,. The salts are removed by filtration and the filtrate concentrated. The residue is taken up into CH 2 Cl 2 washed with water, 5 percent aq. NaOH and brine, dried over MgSO 4 and concentrated to afford 31.1 grams (88 percent) of product as a white solid: mp 86.5-88.5*C; IR (KBr) 5.63, 6.7, 6.88, 7.2, 8.12, 8.98, 9.25, 10.1 cm" 1 'H NMR (60 MHz, CDC13) 1.4 3, CH 3 3.43 and 4.6 (2d, 2, CH 2 4.42 2, CH 2

CH

3 5.1 1, CH) 7.0-7.4 8, Ar-H).

Anal. Calcd. for C 1 7

H

16 0 4 C, 71.82; H, 5.67 Found: C, 71.7; H, 5.8 EXAMPLE 4 Methyl 12H-Dibenzord,qlfl,31dioxocin-6-carboxvlate Preparation proceeds as described in Example 3, only substituting methanol for ethanol. Obtained is a white solid: mp 107-110*C; IR (KBr) 5.69, 6.77, 8.2, 9.3, 10.05 cm'1; 1H NMR (60 MHz, CDC13) 3.5 and 4.62 (2d, 2, CH 2 3.98 3, CH 3 5.1 1, CH), 7.0-7.5 8, Ar-H).

Anal. Calcd. for C 16

H

14 04: C, 71.10; H, 5.22 Found: C, 71.0; H, 5.1 WO 91/00009 WO 91/1)009 penUS90/03672 -22- EXAMPLE n-Propvl 12H-Dibenzord~cl ri.3ldioxocin-6-carboxylate Preparation proceeds as in Example 3, only substituting a like quantity of n-propanol for the ethanol, to obtain a white solid: mp 82-85*C; IR (KBr) 5.7, 8.35, 9.4, 10.15 cif 1 1 H NMR (60 MHz, CDCl 3 1.05 3, CH 3 1.95 (mn, 2, CH 2

CH

2

CH

3 3.47 and 4.65 (2d, 2, CU 2 4.33 CH 2

CH

2

CH

3 5.1 1, CH) 6.9-7.5 (mn, 8, Ar-H).

Anal. Calcd. for C 1

.H

1 .0 4 C, 72.47; U, 6.08 Found: u, 72.7; H, EXAMPLE 6 iso-Prolpyl 12H-Dibenzord,rlrl,31dioxocin-6-carboxvlate The subject product is prepared as described in Example 3, only substituting iso-propanol for ethanol, yielding a white solid: mp 94-97*C; IR (KBr) 5.73, 6.78, 8.25, 9.05, 9.4, 10.1 cmf'; IH NMR (60 MHz, CDCl 3 1.4 6, CH-(gfi 3 2 3.46 and 4.6 (2d, 2, CU 2 5.03 (s, l,0-CU-0), 5.25 (mn, 1, CH(CH 3 2 6.9-7.5 (mn, 8, Ar-H).

Anal. Calcd. for C 1

,H

18 0 4 C, 72.47; H, 6.08 Found: C, 72.4; H, 5.9 WO 91/00009 PCT/ US90/03672 -23- EXAMPLE 7 t-Butyl 12H-Dibenzo[d,ql[1,31dioxocin-6-carboxylate A solution of 12H-dibenzo[d,g][l,3]dioxocin-6carboxylic acid (3.0 g, 0.0117 mol) in 45 ml of thionyl chloride is heated at reflux. After 4 hours at reflux, the excess thionyl chloride is distilled off at atmospheric pressure and then under vacuum to remove traces of thionyl chloride. The acid chloride obtained is dissolved in 35 ml of toluene and added dropwise over a period of 20 minutes to a solution of t-butyl alcohol ml) containing N,N-dimethylaniline (1.8 ml, 0.01405 mol). After stirring 23 hours at room temperature, the reaction mixture is concentrated under reduced pressure and the residue obtained is taken up into ethyl acetate, washed with water and brine, dried over MgSO 4 and concentrated to yield 3.4 g of a syrupy residue. Dry column chromatography (elution with 1:4 ethyl acetate-hexanes) afforded 1.57 g (43 percent) of product as a white solid: mp 94-97*C; IR (KBr) 5.75, 8.22, 8.7, 9.43, 10.22, 13.21 cm'1; 'H NMR (60 MHz, CDC13) 1.6 9, C(CH 3 3 3.45 and 4.6 (2d, 2, CH2), 4.93 1, CH) 6.95-7.4 8, Ar-H).

Anal. Calcd. for CH 2 00 4 C, 73.06; H, 6.45 Found: C, 73.0; H, 6.3 WO 91/00009 PCT/US90/03672 -24- EXAMPLE 8 n-Octyl 12H-Dibenzord. r l1,31dioxocin-6-carboxylate 12H-Dibenzo[d,g] 3]dioxocin-6-carboxylic acid g, 0.0156 mol) and 45 ml of thionyl chloride are refluxed/distilled as in Example 7. The acid chloride is then dissolved in 50 ml of toluene and added dropwise over a period of 10 minutes to a solution of n-octyl alcohol (20 ml) containing triethylamine (2.0 ml, 0.0187 mol). After stirring 20 hours at room temperature, the insolubles that form are filtered off and the filtrate concentrated under reduced pressure.

The residue obtained is taken up into CHCl 3 washed with then brine, dried over MgSO 4 and concentrated. The residue obtained is purified by dry column chromatography (elution with 1:10 ether-petroleum ether) to afford 4.18 g (73 percent) of product as a clear syrup; IR (neat) 3.42, 5.63, 6.71, 6.87, 8.95, 10.1 cm'1; 'H NMR MHz, CDC1 3 0.9-2.0 15, OCH 2 (CH2)6 (CH 3 3.48 and 4.62 (2d, 2, 4.35 3, OCH 2 (CH) 6 CHS)), 5.07 1, CH), 7.0-7.5 8, Ar-H).

Anal. Calcd. for C 23

H

28 0 4 C, 74.97; H, 7.66 Found: C, 74.6; H, 8.2 WO 91/00009 PCT/US90/03672 EXAMPLE 9 n-Butoxyethyl 12H-Dibenzo[d. q1l,3]dioxocin-6-carboxylate Crudel2H-dibenzo[d,g][1,3]dioxocin-6-carbonyl chloride (4.8 g, 17.5 mmol) is dissolved in toluene and treated with a solution of 2-butoxyethanol (2.77 ml, 21 mmol) and 5 ml of triethylamine in toluene at 0 C under argon. The mixture is heated at reflux for 2 hours and then cooled to room temperature. The mixture is poured into 150 ml of water and extracted with 4 x 100 ml of ethyl acetate. The organic solution is washed with percent hydrochloric acid, 5 percent sodium hydroxide and then brine, dried with magnesium sulfate and filtered.

The solvent is removed to leave a yellow liquid which is chromatographed on dry column silica gel, using ethyl ether/hexane as the solvent, to give a yellowish oil (4.3 g, 69 percent). An analytically pure material is obtained by using prep thin layer chromatography. IR (neat) 1770, 1582 cm' 1 'H NMR (CDC13) 0.75-1.3 (m, 3H, CH 3 1.2-2.0 4H, CH 2 3.3-4.0 5H, OCH 2 and benzylic), 4.4-4.9 3H, OCOCH 2 and benzylic), 5.6 (s, 1H, CH), 6.9-7.5 8H, aromatic).

Anal. Calcd. for C 21

H

24 0 5 C, 70.7; H, 6.79 Found: C, 70.4; H, 6.9 WO 91/00009 PCT/US90/03672 -26- EXAMPLE Cyclohexyl 12H-Dibenzord,.q[1,31dioxocin-6-carboxylate Crudel2H-dibenzo[d,g][1,3]dioxocin-6-carbonyl chloride (4 g, 14.5 mmol) is dissolved in 45 ml of toluene and treated with cyclohexanol (1.75 g, 17.5 mmol) and 3 ml of triethylamine at 0°C under argon. The mixture is heated at reflux for 2 hours, cooled, washed with 5 percent sodium hydroxide then brine, dried with magnesium sulfate and filtered. The solvent is removed to leave a brown liquid which is chromatographed on dry column silica gel, using ethyl ether/hexane as solvent, to isolate a yellow solid. This solid is decolorized with charcoal to give a off-white solid (4.32 g, 87.7 percent), mp 120-125°C: IR (KBr) 1755, 1580 cmi. 'H NMR (CDC13) 1.0-2.4 11H, cyclohexyl), 3.37, 3.6, 4.51 and 4.73 2H, CH 2 5.05 1H, OCH) 6.9-7,45 8H, aromatic).

Anal. Calcd. for C 21

H

22 0 4 C, 74.54; H, 6.55 Found: C, 74.3; H, 6.6 EXAMPLE 11 Tetrahydrofurfuryl 12H-Dibenzo[d,g][1,3]dioxocin-6carboxylate To a solution of crude 12H-dibenzo[d,g][l,33 dioxocin-6-carbonyl chloride (4.25 g, 15 mmol) in toluene is slowly added a solution of tetrahydrofurfuryl alcohol WO 91/00009 PCT/US90/03672 -27- (1.8 ml, 18 mmol) and 3 ml of triethylamine in toluene at 0°C under nitrogen. The mixture is heated at reflux for 1 hour, cooled and treated with water and ethyl acetate.

The organic layer is washed with 10 percent sodium hydroxide then brine, dried with magnesium sulfate and filtered. The solvent is removed leaving a yellowish oil which is chromatographed on dry column silica gel using ethyl acetate/hexane as the solvent. The resultant (still yellow) oil is decolorized with charcoal and solidified to yield a white solid (4.12 g, 78 percent) mp 83-85"C: IR (KBr) 1760, 1580, cm' 1 H NMR (CDC13) 1.6-2.4 4H, CH 2 3.35, 3.57, 4.5 and 4.71 2H, CH 2 3.7-4.1 2H, CH 2 4.1-4.5 3H,

OCH

2 CHO), 5.1 1H, CH) 6.95-7.5 8H, aromatic).

Anal. Calcd. for C 20

H

20 0 5 C, 70.58; H, 5.92 Found: C, 70.8; H, 5.9 EXAMPLE 12 Ethyl 12H-Dibenzo[d,fl[l,3]dioxocin-6-thiocarboxylate To a solution of 12H-dibenzo[d,g][l,3]dioxocin -6-carboxylic acid (1 gram, 3.9 mmol) and ethanethiol (0.8 ml, 5.9 mmol) in 10 ml of dry tetrahydrofuran at is added dicyclohexyl carboximide (DCC, 2 grams, 9.8 mmol) under argon. The mixture is stirred at for 2 hours and then kept in the refrigerator overnight.

The mixture is warmed to room temperature and to it is added an aqueous solution of oxalic acid to destroy the excess DCC. The mixture is diluted with ethyl ether and WO 91/00009 PCT/US90/03672 -28filtered. The solid is washed with ethylacetate and the filtrate separated. The organic layer is washed with percent sodium hydroxide and then with water twice and brine once. The organic solution is next dried over magnesium sulfate and filtered. The solvent is removed to give a yellowish viscous oil which was chromatographed on dry column silica gel using ethyl acetate/hexane (1:2) as the solvent to give a yellowish viscous oil (890 mg).

This oil was solidified in petroleum ether to give a white solid, mp 77.5-79°C: IR (KBr) 1690, 1000, 7580 cm'1; 'H NMR (CDC13) 1.2-1.6 3H, CH 3 2.82-3.28 2H, SCH 2 3.37, 3.58, 4.49 and 4.69 2H, CH 2 4.99 1H, CHO), 7.02-7.45 8H, aromatic).

Anal. Calcd. for C 1

,H

16 0 3 S: C, 67.98; H, 5.37 Found: C, 67.8; H, EXAMPLE 12A 12H-Dibenzo[d,ql[1,31dioxocin-6-thiocarboxamide A stirred solution of 12H-dibenzo[d,g][1,3] dioxocin-6-carboxamide (3.88 grams, 0.0152 mol) and Lawesson's reagent (3.69 grams, 0.00912 mol) in 40 ml of toluene is heated at reflux. After 2.5 hours, the reaction is cooled to room temperature and concentrated under reduced pressure to afford a dark gummy residue.

Flash chromatography of this material (elution with

CH

2 C12) affords 1.6 grams of product as a tan solid.

Recrystallization from hexanes results in 1.1 grams of product as an off white solid: mp. 165-169"C; IR (KBr) WO 1/00009 PCT/I S90/03672 -29- 3380, 3140, 1615, 1440, 1220, 975 cm1; 'H NMR (DMSO-d 6 3.65 and 4.41 (2d, 2, 12a and 12b), 5.17 (s, 1, H 6 7.0-7.6 8, Ar-H).

Anal. Calcd. for C 1 5

H

13

NO

2 S: C, 66.4; H, 4.8; N, 5.2 Found: C, 66.5; H, 4.9; N, 5.1 EXAMPLE 13 12H-Dibenzo[d,q [1,31dioxocin-6-nitrile To a stirred solution of 12H-dibenzo[d,g][1,3] dioxocin-6-carboxamide (8.24 grams, 0.0323 mol) and pyridine (5.74 ml, 0.071 mol) in 80 ml of 1,4-dioxane at 0°C, is added trifluoroacetic anhydride (5.0 ml, 0.0355 mol). After stirring for 5 minutes at 0°C, the reaction is warmed to room temperature and stirred for 3 hours.

The volatiles are removed under reduced pressure, the residue taken up into ethyl acetate, washed with IN HC1,

H

2 0, saturated aqueous NaHCO 3 brine, dried over MgSO, and concentrated to afford 6.8 grams of a white solid.

Recrystallization from cyclohexane affords 5.46 grams (71 percent) of product as a white solid; mp 127-130'C; IR (KBr) 6.28, 6.71, 6.85, 7.44, 8.1, 8.45, 8.96, 13.1 cm"1; 'H NMR (60 MHz, CDC13) 3.83 and 4.29 (2d, 2, CH 2 5.84 1, CH), 7.2-7.0 8, Ar-H).

Anal. Calcd. for C 1 5 HNO: C, 75.94; H, 4.07; N, 5.90 Found: C, 75.8; H, 4.0; N, 5.9 WO 91/00009 PCT/US90/03672 EXAMPLE 14 Sodium 12H-Dibenzod,fl[1,31dioxocin-6-carboxvlate A solution of 12H-dibenzo[d,g][1,3]dioxocin-6carboxylic acid (1.3 grams, 0.00507 mol) and NaOH (0.41 grams, 0.0101 mol) in 50 ml of methanol is refluxed for minutes. The reaction mixture is then concentrated under reduced pressure and the residue recrystallized from ethanol-water to afford 0.65 grams (45 percent) of product as a white solid: mp greater than 320*C; IR (KBr) 3.0, 6.2, 7.0, 8.25, 8.35, 10.45, 13.3 cm'1; 'H NMR MHz, DO) 3.3 and 4.4 (2d, 2, CH 2 4.8 1, CH), 6.8-7.4 8, Ar-H).

Anal. Calcd. for C 15 H,,0 4 Na 1/2 H 2 0: C, 62.7; H, 4.2 Found: C, 63.0; H, 3.9 EXAMPLE Potassium 12H-Dibenzo[d,.lfl,31dioxocin-6-carboxylate A mixture of 12H-dibenzo[d,g][l,3]dioxocin-6carboxylic acid (5.0 g, 0.0195 mol) and potassium carbonate (1.95 g, 0.0195 mol) in 100 ml of water is stirred at room temperature for 4 hours then at 45°C for 2 hours. The reaction mixture is then cooled to room temperature, treated with charcoal and concentrated to afford a wet off-white solid. This material is recrystallized from ethanol to give 2.27 g (39.5 percent) of product as a white-gray solid: mp 275-290"C; IR (KBr) WO 91/00009 WO 910009PTL S90/03672 -31- 2730-3600, 1610, 980, 760 cm- 1 I H NMR (C~DC 3 3.5 and 4. 35 (2d, 2, CH- 2 4. 5 1, H 6 6. 8-7. 5 (in, 8, Ar-H) Anal. Calcd. for C 15

H

11

O

4 K-l/2 H 2 0: C, 59.4; H, 3.99 Found: C, 59.2; H, EXAMPLE 16 Diethanolamine Salt of 12H-Dibenzo[d,g] [l,3]dioxocin-6carboxylic Acid To a stirred solution of 12H-dibenzo[d,g] [1.3] dioxocin-6-carboxylic acid (4.0 grams, 0.0156 mol) in ml of tetrahydrofuran is added diethanolainine (1.64 grams, 0.0156 mol). After 2 hours at room temperature, the solids that formed are collected by filtration, washed with ether and dried to afford 5.04 grams (89 percent) of product as a white solid: mp 114-116*C; IR (KBr) 3.0-4.0, 6.25, 6.79, 7.05, 8.1, 10.35 cm- 1 1 H NMR MHz, DMSO-d 6 3.05 (mn, 4, (CH 2

CH

2

OH)

2 3.55 and 4. 37 (2d, 2, CM 2 3.75 (in, 4, (CH 2

CIH

2

OH)

2 4.69 (s, l,CH), 6.4-7.5 (in, 12, Ar-H and 4 exchangeable).

Anal. Calcd. for C,9" 23 0 6 C, 63.15; H, 6.41; N, 3.88 Found: C, 63.2; H, 6.4; N, WO 91/00009 WO 91/00009 C!US90/0367 2 -32- EXAMPLE 17 12H-Dibenzo~d,g] 3]dioxocin-6-carboxylic acid dimethyl amine salt To a solution of 12H-dibenzo g]1, 3 ]dioxocin -6-carboxylic acid (5 g, 19.5 mmol) in ethyl acetate/benzene is added~ excess liquid dimethylamine at 0 0 C under nitrogen. The mixture is stirred overnight at room temperature under nitrogen. The resultant solid is filtered and dried to yield 5.5 g of white solid, mp 164-172*C: IR (KBr) 1640 crtf 1 'H NIIR (CDCl 3 2.51 6H, NCH 3 3.6, 4.25, and 4.4 2H, CR 2 4.55 111, CHCO 2 6.8-7.5 (in, 8H, aromatic).

Anal. Calcd, for C 17

H

19 0 4 1'1: C, 67.76; H, 6.36; N, 4.65 Found: C, 67.7; H, 6.5; N, EXAMPLE 18 4(2,2-Dimethyl-l,3-dioxolanyl)methyl 12H-dibenzo~d,g] 1.,31 dioxocin-6-carboxvlate 12H-Dibenzo[d,g][1,3]dioxocin-6-carbonyI chloride (10 g, 39 mmol) is dissolved in toluene and added to a solution of glycerolketal (5.6 ml, 45 inmol) and 10 ml of triethylamine in toluene at 0-l0*C under argon. The mixture is heated at reflux for 5 hours, cooled to room temperature, poured into 150 ml of water and extracted with 4 x 150 ml of ethyl acetate. The organic solution is washed with 5 percent HCl, 5 percent WO 91/00009 PCT/US90/03672 -33- NaOH and then brine, dried with magnesium sulfate and filtered. The solvent is removed and the residue chromatographed on dry column silica gel using ethyl ether/hexane as the solvent to give a yellowish liquid which is crystallized in petroleum ether. The solid is filtered and washed with petroleum ether to give a white solid, mp 109-11C: IR (KBr) 1780, 1581 cm" 1 1 H NMR (CDC13) 1.4 and 1.47 (2S, 6H, CH 3 3.36, 3.58, 4.49 and 4.7 2H, CH 2 3.7-4.4 3H, CHO and 4.4-4.6 2H, OCH2), 5.1 1H, OCHO), 6.95-7.45 (m, 8H, aromatic).

Anal. Calcd. for C 21

H

22 0 6 C, 68.10; H, 5.99 Found: C, 68.3; H, EXAMPLE 19 Methyl-6-Methyl-12H-Dibenzo[dg][1,3]dioxocin-6carboxylate To a stirred solution of isopropyl cyclohexyl amine (2.92 ml, 0.0178 mol) 15 ml of dry tetrahydrofuran (THF) under N 2 at 0°C is added n-BuLi (11.84 ml of 1.5 M in hexane). After stirring 15 minutes at 0°C, the solution is cooled to -65"C and a solution of methyl 12H-dibenzo[d,g] [1,3]dioxocin-6-carboxylate g, 0.0148 mol) in 10 ml of THF is added dropwise over a period of 5 minutes. The solution is stirred at -65C for an additional 10 minutes and then added via syringe over a period of 2 minutes to a solution of methyl iodide (1.84 ml, 0.0246 mol) in 25 ml of dry WO 91/00009 PCTr/US90/03672 -34dimethyl sulfoxide at room temperature. After stirring for 30 minutes, the reaction mixture is diluted with 300 ml of CH 2 C1 2 washed with H 2 0, IN HC1 and then brine, dried over MgSO 4 and concentrated. The residue obtained is purified by dry column chromatography (elution with 1:4 ethyl acetate-hexanes) to afford 2 g of a yellow syrup. This material was subjected to HPLC purification (Waters 500, 2 columns, 4 cycles, elution with 1:7 ethylacetate- hexanes) to afford 1.1 g (26 percent) of 1.1 product as a clear syrup: IR (neat) 5.65, 6.3, 6.7, 6.85, 7.25 cm 'H NMR (60 MHz, CDC1 3 1.36 3,

CH

3 3.71 and 4.32 (2d, 2, CH 2 3.9 3, OCH 3 6.95-7.4 8, Ar-H).

Anal. Calcd. for C 17

H

16 0 4 C, 71.82; H, 5.67 Found: C, 71.8; H, 5.7 EXAMPLE (cis and trans) Methyl-12-Methyl-12H-Dibenzo[d,g][1,3] dioxocin-6-carboxylate A mixture of 2,2'ethylidenebisphenol (10.0 grams, 0.0467 mol), dichloroacetic acid (3.85 ml, 0.0467 mol) and potassium carbonate (25.8 grams, 0.187 mol) in 200 ml of isopropyl alcohol is heated at reflux for 24 hours with vigorous stirring, after which an additional 3.85 ml of dichloroacetic acid is added and the mixture refluxed with stirring for 70 hours. The isopropyl alcohol is removed by distillation at atmospheric pressure and replaced gradually with H 2 0. The reaction WO 91/00009 WI'/C, US90/03672 mixture is cooled, acidified by addition of concentrated HC1 and extracted into chloroform. The chloroform extract is washed with brine, treated with charcoal, dried over MgSO 4 and concentrated to afford a quantitative yield of crude acid. This material is then converted to the methyl ester by refluxing in a methanol solution (100 ml) in the presence of conc. H 2

SO

4 (0.6 ml) for 2 hours. The solution is cooled, 50 ml of CH 2 C1 2 is added and the mixture neutralized by the addition of solid Na 2

CO

3 The inorganic salts are removed by filtration and the filtrate concentrated and taken up into CH 2 Cl 2 washed with brine, dried over MgSO4 and concentrated to afford 11.5 grams of a dark semi-solid.

Dry column chromatography (elution with 1:4 EtOAc-hexane) yields 5.0 grams (38 percent) of product as a white solid consisting of a 1:1 mixture of cis and trans isomers: mp 95-120'C; IR (thin film) 5.62, 6.7, 6.9, 8.2, 9.25, 10.05, 13.05 cm'1; 'H NMR (60 MHz, CDC13) 1.66 and 1.89 (2d, 2, CH 3 3.88 and 3.95 (2s, 3, OCH 3 3.95 and 5.1 (2q, 2, CH), 5.0 and 5.36 (2s, 1, CH), 7.0-7.5 8, Ar-H).

Anal. Calcd. for C 17

H

16 0 4 C, 71.82; H, 5.67 Found: C, 71.6; H, 5.7 EXAMPLE 21 Ethyl 12,12-Dimethyl-12H-dibenzo[d,g][1,3]dioxocin-6carboxylate A mixture of 2,2'-isopropylidene bisphenol (3.65 g, 0.01594 mol), potassium hydroxide (2.68 g of WO 91/00009 PCTI US9/03672 -36percent, 0.0478 mol) and dichloroacetic acid (1.31 ml, 0.01594 mol) in 65 ml of isopropyl alcohol is heated at reflux. After 20 hours at reflux, an additional 1.79 g of 85 percent KOH and 1.31 ml of dichloroacetic acid are added and the reaction mixture is heated at reflux for 2 days. The reaction mixture is then diluted with 200 ml of H 2 0, acidified by the addition of concentrated HC1 ml) and extracted into ethyl acetate. The ethyl acetate solution is washed with brine, dried over MgS04 and concentrated. The residue is washed with petroleum ether to afford 3.7 g of crude product as a red-brown syrup. This material is then purified by an esterification-saponification-esterification procedure (esterification agent methanol, H 2 SO4). Dry column chromatography yields 0.97 g of crude product, which is saponified (NaOH, MeOH-H 2 and purified by dry column chromatography to afford 0.60 g of a white solid.

Esterification of this material (EtOH, H2SO 4 and purification by preparative thin layer chromatography (elution with 1:4 ethyl acetate-hexanes) yields 0.25 g of product as a clear syrup: IR (neat) 3.34, 5.65, 6.95, 8.2, 13.2 cm' 1 1 H NMR (CDC1,) 1.28 3, CH 2

CH

3 1.75 and 1.9 (2s, 6, (CH 3 2 4.24 2, CH2CH 3 1, CH), 6.9-7.6 8, Ar-H); m/e 312.

Anal. Calcd. for C 19 20 0 4 C, 73.06; H, 6.45 Foind: C, 72.4; H, 5.7 WO 91/00009 PCY/ US90/03672 -37- EXAMPLE 22 12H-Dibenzo[d,g][l,3]dioxocin-12-hydroxy-6-carboxylic acid Lactone To a stirred solution of 12H-dibenzo[d,g][l,3] dioxocin-12-keto-6-carboxylic acid (10.0 g, 0.0370 mol) and sodium hydroxide (1.63 g, 0.0407 mol) in 200 ml of 5:3 ethanol-water is added sodium borohydride (1.40 g, 0.0370 mol) and the reaction is heated to 55*C. After 16 hours at 55*C, the reaction is cooled to room temperature and poured cautiously onto 1 HC1 (500 ml), then extracted with ethyl acetate. The ethyl acetate solution is washed with brine, dried over MgSO 4 and concentrated to affoid a quantitative yield of a mixture of alcohols and lactone. This mixture and p-toluenesulfonic acid (0.05 g) in 250 ml of benzene is heated at reflux. After 2 hours, the reaction is cooled to room temperature, diluted with ethyl acetate and filtered to remove insoluble polymeric material. The filtrate is washed with saturated ar,'ieous NaHC0 3 then brine, dried over MgS04 and concentrated to afford 6.1 g (64 percent) of a i B white solid (approximately 95 percent pure).

Analytically pure material is obtained by dry column chromatography (elution with 1:2 EtOAc-hexanes), followed by recrystallization from benzene-hexanes: mp 147-149"C; IR (KBr) 5.73, 6.74, 7.76, 8.41, 9.74, 13.36 cm" 1 'H NMR MHZ, CDC1 3 5.97 1, CHCO 2 6.39 1, Ar 2 CH-0), 6.8-7.4 8, Ar-H).

Anal. Calcd. for C 15

H

10 0 4 C, 70.86; H, 3.96 Found: C, 71.2; H, WO 91/00009 WO 91/0009 P ll S0/03672 -38- EXAMPLE 23 Ethyl 1-Methyl 12H-dibenzo[d,g][l,3]dioxocin-6carboxylate A mixture of 6-methyl-2,2'-methylene bisphenol (3.1 g, 0.0145 mole), potassium hydroxide (2.87 g of percent, 0.0434 mol) and dichloroacetic acid (1.2 ml, 0.0145 mol) in 55 ml of isopropyl alcohol is heated at reflux. After 22 hours at reflux, an additional 1.91 g of 85 percent KOH and 1.2 ml of dichloroacetic acid are added and the reaction mixture is refluxed for 4 hours.

The reaction mixture is then cooled, diluted with 150 ml of H 2 0, acidified by the addition of concentrated HCl and extracted into ethyl acetate. The ethyl acetate solution is washed with brine, dried over MgSO 4 and concentrated to afford the crude acid as a gummy yellow-tan solid. A solution of the crude acid and concentrated H 2

SO

4 (0.2 ml) in 25 ml of ethanol is heated at reflux.

After 2 hours, the solution is cooled to room temperature, diluted with CH 2 C12 (15 ml) and neutralized by the addition of solid Na 2

CO

3 The inorganics are removed by filtration and the filtrate is concentrated under reduced pressure. The residue obtained is taken up into ethyl acetate, washed with H20, then brine, dried over MgSO 4 and concentrated to afford 3.9 g of an amber syrup. Dry column chromatography (elution with 1:4 ethyl acetate-hexanes) followed by recrystallization from WO 91/00009 PC'/ IUS90/03672 -39cyclohexane yields 1.0 g of product as a white solid: mp 78-83*C; IR (KBr) 1759, 1205, 1065, 980 cm'1; 'H NMR (CDCl 3 1.41 3, CH 2 2.52 3, CH 3 3.69 and 4.45 (2d, 2, (AR) 2

-CH

2 4.4 2, CH2CH 3 5.05 1, CH), 6.85-7.5 7, Ar-H); mass spectrum, m/e 298.

EXAMPLE 24 Methyl 2-Methyl-12H-dibenzo[d,g][l,3]dioxocin-6carboxylate Into a 3-neck round bottom flask fitted with a mechanical stiirer and a condenser, is placed 4-methyl bis (l-hydroxy-2-phenyl)-methane (10.2 g, 48 mmol) and potassium carbonate (26.33 g, 190 mmol) in 200 ml of isopropanol. Dichloroacetic acid (3.93 ml, 48 mmol) is then added and the mixture is heated at reflux for 1 day.

More dichloroacetic acid (3.93 ml, 48 mmol) is added and reflux is resumed for 3 more days. 400 ml of water is then added and the mixture is acidified with hydrochloric acid. After stirring the mixture for 2 hours at room temperature and extracting with 200 ml of ethyl acetate twice, the combined organic layer is next washed with 200 ml of 1M HCl and 150 ml of brine, dried with magnesium sulfate and filtered. The solvent is removed, yielding about 17 g of brown oil. This oil is used directly for esterification. It is dissolved in 150 ml of methanol and 0.3 ml of concentrated sulfuric acid is added. The mixture is heated to reflux for 2 hours and then cooled to room temperature. Sodium carbonate is added and the mixture is stirred for hour. Following filtration of WO 91/00009 PCITL/S90/03672 the mixture, the solvent is removed and the crude solids dissolved in methylene chloride, washed with 100 ml of percent sodium hydroxide and 150 ml of brine, dried with MgSO 4 and filtered. The solvent is then removed to yield about 7 g of brown solid, which is chromatographed on dry column silica gel using ethyl ether/hexane as the solvent to give about 5.5 g of white solid. This solid was re-crystallized in ethyl ether/hexane to give 4.51 g of white solid. mp 106-108.5*C. IR (KBr): 1761, 1748 cm" 1 ?H NMR (CDC1 3 2.27 3H, CH 3 3.3, 4.46 and 4.67 2H, CH), 3.92 3H, OCH 3 5.02 (s, 1H, CHO), 6.85-7.5 7H aromatic H).

Anal. Calcd. for C 17

H

16

H

4 C, 71.82, H, 5.67 Found: C, 71.5; H, 5.7 EXAMPLE 3-Methyl-12-H-dibenzord,g rl,31dioxocin-6-carboxvlic acid To a suspension of sodium hydride (5.7 g of a percent dispersion in oil, washed with petroleum ether; 0.1193 mol) and 18-crown-6 (0.45 g) in 65 ml of 1,4-dioxane is added slowly, dropwise, a solution of dichloroacetic acid (4.0 ml, 0.049 mol) in 65 ml of 1,4-dioxane over a period of 15 minutes, followed by the dropwise addition of 5-methyl-2,2'methylenebisphenol (6.36 g, 0.0297 mol) in 85 ml of 1,4-dioxane over a period of 45 minutes. The reaction mix is then heated at about 90"C for 18 hours and then at reflux for 4 hours.

Next, it is cooled to room temperature, poured onto WO 91/00009 PCT/US90/03672 -41- 600 ml of H 2 0, acidified by the addition of concentrated HC1 and extracted with ethyl acetate (2 x 500 ml). The ethyl acetate extract, is washed with brine, dried over MgSO, and concentrated to afford 9.9 g of crude product as a semi-solid. Purification via extraction with cyclohexane in a Soxhlet apparatus yields 5.0 g (62.3 percent) of product as a white solid: mp 149-152'C; IR (KBr) 1730, 1245, 1220, 1015 cm' 1 'H NMR (DMSO-d 6 2.2 3, CH 3 3.54 and 4.3 (2d, 2, h 12 a H 1 2 5.01 (s, 1, H 6 6.8-7.5 7, Ar-H).

Anal. Calcd. for C 1

H

1 4 0 4 C, 70.7; H, 5.3 Found: C, 71.1; H, 5.22 EXAMPLE 26 Methyl 4-methyl-12H-dibenzo[d,g][1,3]dioxocin-6carboxylate A mixture of crude 6-methyl 2,2'-methylene bisphenol (7.0 g, 0.0327 mol), potassium hydroxide g, 0.098 mol) and dichloroacetic acid (2.7 ml, 0.0327 mol) in 130 ml of isopropyl alcohol is heated at reflux for 23 hours, following which an additional 5.5 g of potassium hydroxide (0.098 mol) and then 2.7 ml of dichloroacetic acid (0.0327 mol) are added and the reaction mixture is again heated at reflux for an additional 3 hours. The mixture is then cooled to room temperature, diluted with 400 ml of water, acidified by the addition of concentrated HC1 (15 ml), extracted with ethyl acetate (200 ml) and the resultant organic solution WO 91/00009 PCT/US90/03672 -42is washed with brine, dried over MgSO 4 and concentrated.

The residue is then co-evaporated with toluene to afford g of crude acid as a tan solid. A L Lution of the crude acid and concentrated HSO0 4 (0.6 ml) in 100 ml of methanol is heated at reflux for 2 hours, after which the reaction mixture is cooled to room temperature, diluted with 25 ml of CH 2 Cl and neutralized by the addition of solid Na 2

CO

3 The inorganic salts are removed by filtration and the filtrate concentrated under reduced pressure. The residue is taken up into a mixture of EtOAc-ether, washed with water, 5 percent aqueous NaOH, then brine, dried over MgSO 4 and concentrated to afford g of a yellow syrup. Dry column chromatography (elution with 1:4 EtOAc-hexanes) afforded 4.1 g (44 percent) of product as a white solid; greater than percent purity. Recrystallization from cyclohexane afforded 2.1 g (23 percent) of pure product: mp 107-109?; IR (KBr) 5.74, 6.97, 8.3, 9.5, 10.2, 13.5 cm 1 1 H NMR (90 MHz, CDC1 3 2.23 3, CH 3 3.41 1, H-CH), 3.95 3, OCH 3 4.62 1, H 5.04 1, OCHO), 6.9-7.4 7, Ar-H).

Anal. Calcd. for C 17

H

16 0 4 C, 71.82; H, 5.67 Found: C, 71.8; H, 5.6 EXAMPLE 27 2-Methoxyethyl 12H-Dibenzo[d,g][1,3]dioxocin-6carboxylate 12H-Dibenzo[d,g][1,3]dioxocin-6-carbonyl chloride (5.33 g, 19.5 mmol) is dissolved in toluene and WO 91/00009 W 9CT/ US90/03672 -43added to a solution of 2-methoxyethanol (2.2 ml, 27.6 mmol) and 7 ml of triethylamine in toluene at 0°-10°C under argon. The mixture is heated at reflux for 3 hours, cooled to room temperature, poured into 150 ml of water and extracted with 4 x 100 ml of ethyl acetate.

The resultant organic solution is washed with 5 percent hydrochloric acid, 5 percent sodium hydroxide and brine, dried with magnesium sulfate and filtered. The solvent is removed to give a brownish solid which is chromatographed on dry column silica gel, using ethyl ether/hexane as the solvent, to give a yellowish oil. This oil is solidified, the solid is filtered and washed with ethyl ether/hexane to yield a white solid: mp 74-76*C: IR (KBr) 1779, 1581 cm'1; 1 H NMR (CDC13) 3.42 3H, CH 3 3.3-4.0 3H, CH and

OCH

2 4.35-4.8 3H, CH and OCH 2 5.1 1H, OCHO), 6.9-7.45 8H, aromatic).

Anal. Calcd. for C 18

H

1 8 0 5 C, 68.78; H, 5.77 Found: C, 69.1; H, 5.9 EXAMPLE 28 2-Ethvlhexyll2H-Dibenzord,.q[1,31dioxocin-6-carboxylate To a stirred solution of 12H-dibenzo[d,g] dioxocin-6-carbonyl chloride (4 g, 0.015 mol) in 45 ml of toluene is added a solution of 2-ethylhexanol (2.28 g, 0.017 mol) and 4 ml of triethylamine in toluene at 0 C under argon. The mixture is heated at reflux for 2 hours, cooled, washed with 5 percent NaOH and then brine, dried with magnesium sulfate and filtered. The solvent WO 91/00009 PCT/ US90/03672 -44is removed to give a brown liquid which is chromatographed on dry column silica gel using ethyl ether/hexane as the solvent to yield a yellowish oil IR (neat) 1770, 1580 cm' 1 'H NMR (CDC1 3 0.5-2.0 15H, CH 2 and CH 3 3.33, 3.53, 4.48, and 4.68 2H, CH 2 4.15-4.35 2H, OCH 2 5.2 1H, CH), 6.9-7.4 8H, aromatic).

Anal. Calcd. for C 23

H

2 O0 4 C, 74.97; H, 7.66 Found: C, 75.1, H, 7.9 EXAMPLE 29 Ethyl 3-t-Butyl-12H-dibenzo[d,g][l,3]dioxocin-6carboxylate A mixture of 4-t-butyl-2,2' -methylene bisphenol (3.67 g, 0.0143 mol), potassium hydroxide (2.84 g of percent, 0.0429 mol) and dichloroacetic acid (1.18 ml, 0.0143 mol) in 55 ml of isopropyl alcohol is heated at reflux. After 17 hours at reflux, an additional 1.90 g of 85 percent KOH and 1.18 ml of dichloroacetic acid is added and reflux is continued for 4 hours. Thereafter, the reaction mixture is cooled to room temperature, diluted with 150 ml of H 2 0, acidified by the addition of concentrated HCl and extracted into ethyl acetate. The ethyl acetate solution is washed with brine, dried over MgSO 4 and concentrated to afford crude acid as a yellow-brown syrup. A solution of the crude acid and p-toluene sulfonic acid (0.07 g) in 25 ml of 10:1 CHCl 3 -ethanol is heated at reflux for 1.5 hours with azetropic removal of water. The solution is then cooled WO 91/00009 PCI!l US9/03672 to room temperature, diluted with 50 ml of CHC1 3 washed with H 2 0, 5 percent aqueous NaOH and then brine, dried over MgS04, and concentrated to afford 3.93 g of a yellow-brown syrup. Dry column chromatography (elution with 1:4 EtOAc-hexanes) yields 2.4 g (49 percent) of product as a cloudy syrup: IR (neat) 2975, 1770, 1755, 1485, 1410, 1260, 76 cm'1; 1H NMR (CDC13) 1.24 9, C(CH)3), 1.43 3, CH 2

CH

3 3.A3 and 4.51 (2d, 2

AR

2

CH

2 4.39 2, CH 2

CH

3 5.05 1 CH), 7.0-7.4 (m, 7, Ar-H); mass spectrum, m/e 340, CH 3 323,

CH

3 CH20H) 294, C 4

H

9 283, CO 2 Et) 267.

EXAMPLE Ethyl3-Trifluoromethyl-12H-dibenzo(d,g][1,3]dioxocin-6carboxvlate To a suspension of sodium hydride (2.55 g of a percent dispersion in oil, washed with petroleum ether, 0.0531 mol) and 18-crown-6 (0.2 g) in 30 ml of 1,4-dioxane is slowly added dropwise, a solution of dichloroacetic acid (1.81 Ml, 0.0219 mol) in 30 ml of 1,4-dioxane over a period of 15 minutes, followed by the dropwise addition of 5-trifuoromethyl-2 2'-methylene bisphenol (3.56 g, 0.0133 mol) in 40 ml of 1,4-dioxane over a period of 45 minutes. The reaction is then heated at reflux for 20 hours, cooled to room temperature, poured into 300 ml of H 2 0, acidified by the addition of concentrated HC1, and extracted with ethyl acetate (2 x 200 ml). The ethyl acetate extract is washed with brine, dried over MgSO 4 and concentrated to afford an WO 91/00009 PCI'/US90/03672 -46oily residue which is further washed with petroleum ether to give 4.6 g of an orange-yellow semi-solid. A solution of this material and p-toluene sulfonic acid (0.07 g) in ml of 10:1 CHCl 3 -ethanol is heated at reflux for 1 hour with azetropic removal of water. The solution is then cooled to room temperature, diluted with 50 ml of CHC1 3 washed with H 2 0, 5 percent aqueous NaOH, and then brine, dried over MgS04, and concentrated to afford 3.75 g of a dark residue. Flash chromatography of this material (elution with 1:6 ethyl acetate-hexanes) affords 1.91 g (41 percent) of product as a white solid: mp 78-81"C; IR (KBr) 1765, 1325, 1115, 990 cm' 1 1H NMR (CDC13) 1.41 3, CHCH 3 3.52 and 4.51 (2 d, 2,

H

12 a, H 12 4.41 2, CH 2

CH

3 5.09 1, H 6 7.0-7.5 7, Ar-H).

Anal. Calcd. for C 1 8 Hs 1

F

3 0 4 C, 61.37; H, 4.29 Found: C, 61.4; H, 4.2 EXAMPLE 31 Methyl 4,8-Dimethyl 12H-dibenzo[d,g][l,3]dioxocin-6carboxylate A mixture of 2,2'-methylene bis-6-methyl phenol g, 0.0175 mol), dichloroacetic acid (1.45 ml, 0.0175 mol) and potassium carbonate (9.7 g, 0.070 mol) in 100 ml of isopropyl alcohol is heated at reflux for 24 hours with vigorous stirring after which an additional 1.45 ml of dichloroacetic acid is added and the mixture refluxed with stirring for 70 hours. The isopropyl alcohol is removed by distillation at atmospheric WO 91/00009 PCT/US90/03672 -47pressure and replaced gradually with H 2 0. The mixture is cooled to 0°C and the solids collected by filtration.

Water (75 m) is added to the solids and the mixture made strongly acidic with concentrated HC1. The mixture is extracted into CH 2 C12, washed with brine, dried over MgSO 4 and concentrated to afford 3.0 g (73 percent) of the carboxylic acid. Esterification (methanol, H 2 S0 4 reflux) followed by dry column chromatography (elution with 1:4 ethyl acetate- hexanes), affords 1.9 g percent) of product as a white solid: mp 134-135"C; IR (KBr) 5.65, 6.72, 8.2, 13.1 cm'1; 'H NMR (60 MHz, CDC13) 2.21 6, 2 CH 3 3.38 and 4.62 (2d, 2, CH 2 3, CH 3 4.99 1, CH), 6.9-7.3 6, Ar-H).

Anal. Calcd. for C 18

H,

1 0 4 .1/4 H 2 0: C, 71.4; H, 6.16 Found: C, 71.2; H, 6.1 EXAMPLE 32 Methyl 4,8-Dichloro 12H-dibenzo[d,g][1,3]dioxocin-6carboxylate A mixture of 2,2'-methylene bis-6-chlorophenol (10.0 g, 0.0372 mol), dichloroacetic acid (3.07 ml, 0.0372 mol) and potassium carbonate (20.6 g, 0.149 mol) in 150 ml of isopropyl alcohol is heated at reflux for 24 hours with vigorous stirring after which an additional 3.07 ml of dichloroacetic acid is added and the mixture refluxed with stirring for 67 hours. The isopropyl alcohol is removed by distillation at atmospheric pressure and replaced with water, gradually. The reaction mixture is cooled, acidified by addition of WO 91/00009 PCT/US90/03672 -48concentrated HCl and extracted with CHC 3 e. The chloroform extract is washed with brine, treated with charcoal, dried over MgSO 4 and concentrated to afford 12.39 of crude carboxylic acid. Esterification (methanol, H 2

SO

4 reflux) followed by dry column chromatography (elution with 1:4 ethyl acetate-hexanes) affords 5.29 g of product as a white solid: mp 114-116*C; IR (KBr) 5.65, 6.95, 8.29, 9.47, 10.3 cm1 'H NMR (60 MHz, CDC13) 3.47 and 4.67 (2d, 2, CH 2 3.99 3, CH 3 5.04 1, CH), 6.9-7.3 m, Ar-H).

Anal. Calcd. for C 16 H1 2 C10 4 C, 56.66; H, 3.57 Found: C, 56.7; H, EXAMPLE 33 3,9-Dimethyl-12H-dibenzo[d,g][l,3]dioxocin-6-carboxylic acid A mixture of 2,2'-methylenebis(5-methylphenol) (8.3 g, 0.0364 mol), dichloroacetic acid (3.0 ml, 0.0364 mol) and potassium carbonate (20.1 g, 0.145 mol) in 220 ml of isopropyl alcohol is heated at reflux for 24 hours with vigorous stirring after which an additional ml (0.0364 mol) of dichloroacetic acid is added and the mixture is refluxed for an additional 72 hours. The isopropyl alcohol is distilled off and replaced with water. The reaction mixture is then cooled to room temperature and acidified by the addition of concentrated HCl (35 ml). The solids that form are collected by filtration, taken up into ethyl acetate and the ethyl acetate solution is washed with IN HC1, then brine, dried WO 91/00009 PCT/US90/03672 -49over MgSO 4 and concentrated to afford a quantitative yield of crude product as a tan solid. Extraction of the crude product with hot cyclohexane in a Soxhlet extraction apparatus results in 4.55 g (44 percent) of product as a white solid from the cooled cyclohexane solution. Recrystallization from benzene-hexanes yields an analytically pure material: mp 172-174°C; IR (KBr) 3.4, 5.8, 8.0, 8.9 cm'1; 1 H NMR (60 MHz, DMSO-d 6 2.21 6, 2 CH 3 3.52 1, H-C-H) 4.23 1, H-C-H), 6.8-7.4 m, Ar-H).

Anal. Calcd. for C 17

H

10 0 4 C, 71.82; H, 5.67 Found: C, 72.1; H, 5.7 EXAMPLE 34 Methyl 3,9-Dimethoxy-12H-dibenzo[d,g][l,3]dioxocin-6carboxylate To a solution of potassium hydroxide (1.29 g, 23 mmol) in 100 ml of isopropanol is added l,l'-methylene bis(4-methoxy-2-phenol) (1.8 g, 6.9 mmol) and then, 0.6 ml of dichloroacetic acid (7.2 mmol). The mixture is heated at reflux overnight. The mixture is then cooled to room temperature and potassium hydroxide (1.29 g, 23 mmol) and dichloroacetic acid (0.6 ml, 7.2 mmol) are added. The mixture is again refluxed overnight. The solvent is removed on a rotavap and water is added. The mixture is then acidified with concentrated hydrochloric acid and extracted with ethyl acetate three times. The organic layer is washed with brine, dried with magnesium WO 91/00009 PCT/ US9/03672 sulfate and filtered. The solvent is removed, leaving a yellow oil. This oil is dissolved in 30 ml of methanol and 1 ml of boron trifluoride etherate is added. The mixture is next stirred at room temperature for 4 hours, poured into saturated aqueous sodium chloride (50 ml) and extracted with ethyl acetate three times. The resulting organic solution is washed with 5 percent sodium hydroxide (50 ml) and brine, dried with magnesium sulfate and filtered. The solvent is removed to leave a yellow oil which is chromatographed on a dry column silica gel using ethyl acetate/hexane as the solvent to give a white solid (1.16 mp 102-106"C: IR (KBr) 1750, 1620, 1505 cm 'H NMR (CDC1 3 3.25, 3.4, 4.31 and 4.45 2H, CH 2 367 6H, OCH 3 3.92 3H, OCH 3 5.06 2H, OCH), 6.5-7.25 6H, aromatic).

Anal. Calcd. for C 18

H

18 0 6 C, 65.45; H, 5.49 Found: C, 65.7; H, EXAMPLE Methyl 4-t-Butyl-12H-dibenzo[d,g][l,3]dioxocin-6carboxylate To a suspension of sodium hydride (1.65 g of a percent dispersion in oil, washed with petroleum ether, 0.0343 mol) and 18-crown-6 (0.13 g) in 16 ml of 1,4-dioxane is added slowly, dropwise, a solution of dichloroacetic acid (1.17 ml, 0.0142 mol) in 18 ml of 1,4-dioxane over a period of 15 minutes followed by the dropwise addition of 6-t-butyl-2,2'-methylene bisphenol WO 91/00009 PCI'/US90/03672 -51- (2.2g, 0.00858 mol) in 21 ml of 1,4-dioxane over a period of 25 minutes. The reaction mixture is then heated at reflux. After 24 hours at reflux, tne reaction mixture is cooled to room temperature, poured into 150 ml of H 2 0, acidified by the addition of concentrated HC1 (10 ml) and extracted with ethyl acetate (2 x 103 ml). The extract is washed with brine, dried over MgSO 4 and concentrated to afford crude carboxylic acid as a yellow-brown syrupy residue. This material is taken up into ether (15 ml) and treated with excess ethereal diazomethane (about 0.6 g in 30 ml of ether). After standing overnight at room temperature, the reaction mixture is evaporated and the residue purified by dry column chromatography (elution with 1:4 EtOAC-hexanes) to afford 0.66 g of slightly impure product. Preparative TLC (elution with 1:10 ether: petroleum ether) yields 0.44 g (16 percent) of pure product as an off white solid: mp 113-117*C; IR (KBr) 2950, 1760, 1205, 970 cm'1; 'H NMR (CDC13) 1.3 9, (CH 3 3 3.42 and 4.6 (2d, 2, CH 2 3.94 3,

COOCH

3 5.05 1, CH), 6.97-7.4 7, Ar-H).

Anal. Calcd. for C 20

H

22 0 4 C, 73.6; H, 6.79 Found: C, 73.5; H, EXAMPLE 36 4-Methyl-12H-dibenzo[d,g][1,3]dioxocin-6-carboxylic acid, diethanolamine salt A solution of 4-methy 1 12H-dibenzo[d,g] [1,3] dioxocin-6-carboxylic acid (0.64 g, 0.00237 mol) and WO 91/00009 I)CT/ US90/03672 -52diethanolamine (0.25 g, 0.00237 mol) in 6.4 ml of THF is stirred at room temperature. After 18 hours, the clear solution is concentrated under reduced pressure and the residue stirred for 1 hour with 15 ml of ether. The ether is then decanted away, leaving a clear syrup which is dried under vacuum to afford 0.88 g (99 percent) of a white hygroscopic crystalline foam: IR (thin film) 6.15, 8.12, 10.32; 'H NMR (CDC13) 2.21 3, CH 3 3.1-3.5 5, 2 CH 2 and (Ar) 2 3.8-4.2 4, 2

CH

2 4.45 1, (Ar) 2 4.8 1, CH), 6.8-7.4 (m, 7, Ar-H).

EXAMPLE 37 N-Phenyl-12H-dibenzord,qlrl,31dioxocin-6-carboxamide To a stirred solution of crude 12Hdibenzo[d,g] [1,3]dioxocin-6-carboxylicacid chloride (4.3 g, 0.016 mol) and triethylamine (3.3 ml, 0.24 mol) in ml of toluene was added dropwise a solution of aniline (1.6 ml, 0.017 mol) in 10 ml of toluene over a period of minutes. After being stirred 4.5 h at RT, the reaction was filtered to remove the insolubles that formed, the filtrate was concentrated under reduced pressure. The residue obtained was purified by dry column chromatography (elution with 1:2 ethyl acetat-hexanes) to afford 3.2 g of product. Recrystallization from ethyl acetate-hexanes gave 1.8 g of product as a white solid: mp 164-165:C; IR (KBr) 6.0, 6.79, 6.97, 8.28, 10.35, 13.27m; 'H NMR (60 MHz, CDC13) 3.45 and 4.55 (2d, 2, CH 2 5.07 1, CH), 7.0-8.8 8, Ar-H), 8.6 (b, 1, NH).

WO 91/00009 PCT/US90/03672 -53- Anal. Calcd. for C 21 I1: 7 0 3 N: C, 76.1; H, 5.2; N, 4.2.

C, 76.0; H, 5.3; N, 4.3 EXAMPLE 38 l-Aza-12H-Dibenzord,q l,31dioxocin-6-carboxylic acid To a suspension of sodium hydride (4.93 g of a dispersion in oil which was washed with petroleum ether, 0.1 mol) and 18-crown-6 (0.39 g) in 55 ml of 1,4dioxane was added dropwise a solution of dichloroacetic acid (3.5 ml, 0.04 mol) in 55 ml of 1,4-dioxane of a period of 15 min. followed by the dropwise addition of 3hydrosy-2-(2'-hydroxybenzyl)pyridine (5.17 g, 0.026 mol) in 75 ml of 1,4-dioxane of a period of 40 minutes. The reaction was then heated at reflux. After 24 h at reflux the reaction was cooled to room temperature, poured onto 500 ml of H 2 0, cautiously neutralized by the addition of 1H HC1 and extracted with ethyl acetate (3 x 500 ml).

The ehtyl acetate extract was washed with brine, dried over MqSO 4 and concentrated to afford the crude carboxylic acid as a yellow-brown solid.

Recrystallization from methanol gave 1.5 g of pure product as an off white solid; mp 224-227:C IR (KBr) 1748, 1440, 1225, 975 cm'1; 'H NMR (DMSO-d 6 )D=d3.8 and 4.55 (2d, 2, H,2a and Ht2b), 5.2 1, H 6 7.0-7.5 (m, 6, H 3

H

4 Hg, Hg, H 10

H

11 8.2 H 2 Anal. Calcd. for C 14

H,

1 N0 4

H

2 0: C, 63.15, H, 4.5; H, 5.3 C, 63.0; H, 4.2; H, 54- EXAMPLES 39 THROUGH 97 AND 110 THROUGH 124 Additional examples of compounds that fall within the scope of the present invention are described in Table A. These were prepared by procedures analogous to those given in the preceding examples.

Compounds 110-124 are more specifically identified as follows:

H

0 o 110. N-Butyl-12H-dibenzo dioxocin-6-carboxamide 111. N-Benzyl-12-H-dibenzo dioxocin-6-carboxamide

I

OC/

dAO 112. N-Cyclohexyl-12H-dibenzo dioxocin-6-carboxamide KXW/154983.DOC 54a 113. N-(2,N,N-dimethylaminoethyl)-1 2H-dibenzo dioxociri-6carboxamide 0 -0 0 -o 114. N--Pheny-12-methyl-12H-dibenzo dioxocin-6carboxamide

H

0Ow

C

115. N-8utyl-1 2-methyi-i 2H-dibenzo (1,31 dioxociri-6car Iboxamide.

KXW/ 154983 .DOC 54b H 0-C XOCH 3 0 116. 4'-Methoxy-1 2H-dibenzo [1 ,31-dioxocin-6-carboxanilide 0 0-K 117. Potassium 1 2-methyl-i 2H-dibenzo dioxocin-6carboxylate

S

113. N-(2'm thyiethyl)-1 2H-dibenzo [d,g 13 ~xcn--abxmd KXW/ 154983.DOC 54c

H

0 N-(CH92 3

N(CH

3 2 o -0 119. N-(3-N,N-dimethylaminopropyl)-1 2H-dibenzo [11,31-dioxocin- 6-carboxamide 120. N-(3-Butoxyprupyl)-1 2H-dibenzo [1 ,31-dioxocin-6carboxamide

H

0 121. a'-Chloro-12H-dibenzo dioxocin-6-carboxanilide KXN/ 154983 .DOC 54d H C, 2

H

C

1 22. 6'-diethyl-1 2H-dibenzo El1,3] dioxocin-6-carboxanilide 0 123. 4-(1 2H-dibenzo dioxocin-6-carboxyl)-morphaline.

0 c /N 2 0 11 1 24. 1 2-methyl-i 2H-dibenzo [1,31 dioxocin-6-carboxamicie Compounds 110, 1 11, 11 2, 11 5, and 11 3 illustrate com'nounds where A is N R' R" and R' is a lower alkyl or cycloalkyl moiety while R' is H.

Compounds 113, 119, and 1 20 illustrate compounds where A is N R' R" and R' is a heteroalkyl moiety while R" is H. Compounds 114, 11 6, 1 21, and 122 illustrate compounds when A is N R' R" and R' is aryl. Compound 1 23 illustrates a compound where A is N R' R" and N R' R" taken together are morpholine.

KXW/154983.DOC Is TABLE A Exaapte A Z 'I w B m~elting Calculated Founid Number Point .c %C 2 H 39 -C0OH.H NCH H H H H oil

-COOCH

3 H 2-CH 3 10-CIH 3 H 161-3 70.4 6.2 70.7 6.1 41 -CONH 2 H H H H 102-4 70.6 5.1 70.7 4.9 42 -CGNHC 6 H H H H H 164-5 .76.1 5%.2 76.0 5.3 43 -CONHCH, H H H H 105-7 71.4 5.6 71.0 5.9 44 -CON(CH 3 H H H H 160-4 72.1 6.1 171.9 6.2 -CONHNH2 H H H H 178-80 66.7 5.2 66.7 5.4 46 -COOHQ H COCH 2

CH.

1 H H H oil I 47 -COCH H 1-CH, 11-CH 3 H 180-2 71.8 5.7 71.3 5.7 48 -COOCH 3 H H H cis-CH 3 59-63 49 -COOCH.

1 H H H trans-CHI_ 59-63 -COOH H H H =0 134-8 1 51 -COOCIII H H H CH-A- 144-160 52 -COOCH 3 H H H C 0- 118-121 t 53 -CH=CHCOOCH 2

CH

3 H H H H- 83-4- I 54 -C0OCH-I H H H I (CH 3 ),Cfl 155-65 173.1 6.4 72.7 j 6.2 Exanple A 2 U 8melt i rg Calculated Found Muiter Point 'C C Xii XC X11 -CONH, H H H 1o i5-8 56 -CN H H h =0 181-3 71.7 3.6 71.8 57 -COUCHI H H H HO- 195-200 58 -COOCH 1 H 2-HO- H H 195-202 59 -CONK,~ H H HO- 66.4 4.8 66.4 5.1 -CONH, H H H CH 1 COO- 195-7 65.2 4.8 165.1 4.9 61 -COOCHI H H H CH 1

CH

2 125-31 72.5 6.1 72.1 6.2 62 -COOCH, H 2-Cl H H 151-4 61.2 4.5 61.5 63 -COOCH, H 2-CH 1 O 10-CH,0 H 138-40 65.5 5.5 65.5 5.8 64 -COOCHI H 2-NO 2 H H 186-90 61.0 4.2 61.2 4.3 -CODCH5 H H H H 133-6 75.9 4.9 76.0 4.7 66 -COOCH2CH3 H H H 63-74 65.4 5.5 65.3 4 67 -CODCHCHOHCH70H H H H H 99-100 65.5 5.5 65.4 5.6 68 -COOCH2CH 3 1 H 9- (,H 3 )Ic H 103-8 69 -COOCH,CH,N(CH,) 2 H H H H 61-4 69.7 16.5 69.6 -CH(OH)CN H_ H H H 147-9 71.9 4.9 71.7 4.8 71 -COUCHI H H H -CH20 oil 72 -COU)CHI H H H (CH,)2CHOJ 181-5 67.4 5.7 67.3 5.7 73 -COOH H 3-CH3 H H 149-52 71.1 5.2 70.7 5.3 74 -COOCH 2 CH H H H H- 62.7 6.1 62.1 6.2 IJCCH,)( -COUH.HN H 2-Ct 10-Cl H 134-6

(CH

2

CH

2 I 76E -COUCH 2 CH3 -S(D)CH3 H H H -1 92-6 62.4 15.2 62.2 15.3 r.4

I-

0 0

U

U)

0 0 0 0 Exanpi c A Z y w B Met t ing CaLcutated Fourd Nunber Point c c I %H c Xif 77 -COaCH 3 H HH =CH 2 78 -CO)OCH(CH 3 Hf H H Hf 72-3 67.4 5.7 66.9 5.8 CCOCH ,C H, 79 -C0ONHCH 2 H H H Hf 97-9 66.9 5.6 66.3 5.7 COOCH 2CHI -COOCH; H H -H CHCH,0- 110-6 73 .4 5.4 73.3 81 -COOCH 3 H H H 144-60 82 -CH,0:H H H H H 170-1 74.4 5.8 74.3 5.7 83 -CH 2 0SO 2

C

6 4CH 3 H H H H 134-6 67.7 5.1 66.6 -5.1 84 _COOCHX H 4-CL 8-CL H 114-6 56.7 3.6 56.7 -COOH H 2-CH, 10CH 3 H 86 -COOCH 3 H H H H oil 70.3 4.7 70.4 87 -COOH H 2F br H 211-3 61.5 3.5 61.4 4.3 88 -COOCHI H H H =0 133-5 67.6 4.3 68.0 4.3 89 -COOCHI H H H CHIO Syrup -CN H HH CH-,COO- 145-8 91_OClH 2-CHC00- H H 129-33 92 -COOCHA Hf H H CF, 89-110 60.4 3.9 60.5 3.7 93 -COOK H H H CH 94 -COOJ.IIN- if 4-CL 8-Ct If (CH ,CH H 2 CH 2

-CDOCH

3 H -CHI 11-CH 3 H 96 -COOCH 2 CH I H 2-CL 10-CLCH 97 -LuWH H1 Z-CH.,-CHl0 H 110-6 73.41 5.4 73.3 rl-- r Example Number Melting Point

C

Calculated Found 4 110 CONMCIICI11 C1EC II II H 115-6 73.3 6.8 73.2 6.8 111- COICII2Cs II H Ii HI 128-9 76.5 5.5 76.3 5.7 112 CONIIC/HH If If If If 166-8 74.8 6.9 74.4 7.1 113 COICCI2,N (CI1) 2 If H 1I 112-3 69.9 6.8 69.7 6.8 114 COMIIC6Ir If II H H 154-7 76.5 5.3 75.9 5.8 115 CONIICH 1 CIIC 2 C11 1 If Ii I Wax 73.8 7.1 72.9 7.2 116 CONMICAi, (OCII,) -4 If if If 11 163-4 73.1 5.3 73.3 5.3 117 COOK -0.4 1 O II If 11 CH I 310 dec 60.9 4.4 60.6 4.4 118 COHH11CII (CHI) 1 H H 146-8 72.7 6.4 73.0 6.2 119 Com] (CII)) -t (CiI,2 H II H1 H1 09-91 70.6 7.1 70.1 7.1 120 COI(CH,) 10 (C12) IC'ff I If If If oil 71.7 7.1 69.6 7.4 121 COfIfIIC 1 U-4 H H1 11 11 150-1 69.0 4.4 60.7 4.4 122 2 -26 11 It II It 184-5 77.5 6.5 77.1 6.7 123 CON O I 1 II 1I 194-6 70.1 5.9 69.8 124 II II II if} WO 91/00009 PCT/US90/03672 -58- EXAMPLE 98 Pre and Post Emergent Herbicidal Activity The herbicide screening test is designed to identify compounds that exhibit pre-emergence (Pre) and/or post-emergence (Post) herbicidal activity.

Plantings of the indicated test species are seeded in separate fiber pans X 10" X 3" deep) containing pasteurized soil. The Post pans are seeded two weeks prior to treatment. The Pre pans are seeded one day prior to application of the test compounds. One Pre and one Post pan is employed for each compound, unless otherwise indicated. Prior to application of the test formulation, the Pre nans are mist watered to stabilize the soil surface. The standarl laboratory formulation at the 8 kg/ha treatment rate is prepared by weighing 73.6 mg of the test compound into a 125 ml flask to which is then added 40 ml of acetone followed by 40 ml of 0.1% Ortho X-77 surfactant. If the test compound appears insoluble in the formulation, it is treated for 1-2 minutes with an ultrasonic probe. If still insoluble, the particle size is reduced by grinding to a size sufficient to allow it to pass through the spray nozzle.

Following preparation of the test formulations, each is then sprayed equally and completely on the Pre and Post pans employing a handheld spray gun with an air atomizing nozzle. Acetone is employed to rinse the spray gun between application of each formulation. The treated pans ar then moved to a growth room, or greenhouse, where they are maintained and appropriately watered for 13 days following treatment. At this time, the pans are WO 91/00009 PCT/US90/03672 -59then evaluated to determine the percent kill/inhibition/ suppression relative to an untreated control. The rating numbers range from 0, indicating no injury, to 100, indicating complete kill or control. Compounds that show 80% control Post and 50% control Pre against any 3 species are considered for further testing. Results are shown in the following Table.

TABLE 1 TEST DOSE PIG- VEL. MUS- RED FOX B.Y.

COMPOUND BATCH TYPE KG/HA WEED LEAF TARD MIL. TAIL GRSS JOHN HEMP MORN WILD SON SESB GLRY OATS Exp. 1 1 Pre 8 4 2 1 Post 8 4 2 1 40 60 100 50 100 30 100 95 100 25 90 10 80 0 70 50 50 100 0 20 100 50 0 20 10 100 10 0 2 Pre 4 4 2 2 1 1 70 100 70 100 50 100 Post 4 4 2 2 1 1 50 100 100 100 100 100 50 60 90 90 50 100 50 60 80 60 20 80 30 100 70 100 20 60 100 10 60 :Ps~%lj~Bss~-- TABLE 1 TEST DOSE PIG- VEL. MUS- COMPOUND BATCH TYPE KG/HA WEED LEAF TARD RED FOX B.Y. JOHN HEMP MORN WILD MIL. TAIL GRSS SON SESB GLRY OATS Exp. 2 1 Pre 8 4 2 1 Post 8 4 2 1 2 Pre 4 2 1 50 30 90 10 10 50 0 0 50 0 0 50 100 100 100 70 100 100 40 90 80 30 60 40 90 50 100 90 10 100 90 0 90 0 0 0 100 100 60 50 20 Post 4 2 1 80 100 20 50 50 30 100 Exp. 3 1 Pre 8 4 4 2 2 1 1 40 100 10 100 90 100 0 0 10 0 Post 8 4 4 2 2 1 1 95 100 100 60 100 90 100 100 100 60 50 90 100 100 100 50 40 90 50 90 80 100 100 100 100 100 TABLE 1 TEST DOSE COMPOUND BATCH TYPE KG/HA PIG- VEL. MUS- RED FOX WEED LEAF TARD MIL. TAIL B.Y. JOHN HEMP MORN WILD GRSS SON SESB GLRY OATS Exp. 4 1 Pre 8 4 2 1 100 95 90 90 95 100 45 100 15 95 0 90 100 Post 8 4 2 1 100 100 80 90 90 75 80 80 50 40 80 95 100 65 55 20 2 Pre 8 4 2 1 Post 8 4 2 1 1 Pre 8 4 2 1 100 85 75 75 40 100 30 100 10 10 70 100 100 95 100 100 90 90 90 90 Exp. 5 Post 8 4 2 1 70 90 90 90 90 100 100 100 100 30 40 100 20 100 30 100 30 100 0 TABLE 1 TEST DOSE PIG- VEL. MUS- RED FOX B.Y. JOHN COMPOUND BATCH TYPE KG/HA WEED LEAF TARD MIL. TAIL GRSS SON HEMP MORN WILD SESB GLRY OATS Exp. 6 1 Pre 8 4 2 1 Post 8 4 2 1 1 Pre 8 4 2 1 70 100 80 100 100 70 100 20 0 Exp. 7 Post 8 4 2 1 40 100 100 90 100 40 Exp. 8 1 Pre 8 4 2 1 1 Post 8 4 2 1 1 Pre 4 2 1 1 Post 4 10 0 100 0 0 80 99 85 100 80 30 Exp. 9 100 90 70 70 10 20 20 10 60 70 TABLE 1 TEST DOSE TYPE KG/HA COMPOUND BATCH Exp. 10 1 PIG- VEL. MUS- RED FOX B.Y. JOHN HEMP MORN WILD WEED LEAF TARD MIL. TAIL GRSS SON SESB GLRY OATS 20 0 40 0 0 0 20 30 0 20 '.0 Pre 4 Exp. 11 1 Post 4 2 1 Pre 4 2 1 1 Post 4 2 1 1 Pre 8 4 2 1 40 100 50 0 40 100 0 80 100 100 50 0 80 0 0 40 40 100 0 0 Exp. 12 Post 8 4 2 1 20 100 100 30 100 80 20 100 70 40 40 40 40 40 100 30 100 10 Exp. 12A 1 Pre 4 1 Post 4 90 90 100 1 60 2 90 20 10 60 40 100 0 0 TABLE 1 TEST DOSE PIG- VEL. MUS- COMPOUND BATCH TYPE KG/HA WEED LEAF TARD RED FOX B.Y. JOHN HEMP MORN WILD MIL. TAIL GRSS SON SESB GLRY OATS Exp. 13 1 Pre 8 4 2 1 90 100 70 50 Post 8 4 2 1 80 100 60 100 20 0 100 100 70 90 60 80 40 80 30 95 70 100 50 100 0 100 30 40 100 40 30 Exp. 14 1 Pre 8 4 2 1 Post 8 4 2 1 10 0 0 0 0 35 100 0 70 0 30 0 30 Exp. Exp. 16 1 Pre 8 4 2 1 Post 8 4 2 1 1 Pre 4 1 Post 4 100 100 Exp. 17 80 0 70 0 0 0 20 20 0 0 40 50 100 0 20 0 30 100 20 TABLE 1 TEST DOSE PIG- VEL. MUS- RED FOX B.Y. JOHN HEMP MORN WILD COMPOUND BATCH TYPE KG/HA WEED LEAF TARD MIL. TAIL GRSS SON SESB GLRY OATS Exp. 18 1 Pre 4 2 1 Post 4 2 1 95 90 75 100 60 90 40 20 100 20 Exp. 19 1 Pre 8 1 Post 8 1 Pre 8 4 2 1 90 0 90 0 0 0 0 0 0 0 Exp. 20 100 100 100 90 90 100 100 70 70 100 80 100 50 100 20 100 0 90 70 100 60 100 20 100 10 70 0 10 0 20 100 0 0 80 C Post 8 4 2 1 Exp. 21 1 Pre 4 2 1 1 Post 4 2 1 90 70 90 40 60 20 80 100 60 100 60 40 30 40 20 50 100 0 80 100 0 0 TABLE 1 TEST DOSE PIG- COMPOUND BATCH TYPE KG/HA WEED VEL. MUS- RED LEAF TARD MIL.

FOX B.Y. JOHN HEMP MORN WILD TAIL GRSS SON SESB GLRY OATS Exp. 22 1 Pre 8 4 2 1 Post 8 1 Pre 4 0 30 60 10 30 20 20 10 30 0 0 0 30 0 0 0 0 0 0 0 Exp. 23 Post 4 50 20 100 0 0 0 0 80 0 0 Exp. 24 1 Pre 8 4 2 1 1 Post 8 4 2 1 30 100 30 60 0 60 0 0 0 0, 0 3 0 0 Exp. 25 1 Post 2 90 1 80 60 100 90 80 Exp. 26 1 Pre 8 4 2 1 1 Post 8 4 2 1 70 80 100 100 100 70 100 70 100 100 100 TABLE 1 TEST DOSE PIG- VEL. MUS- RED COMPOUND BATCH TYPE KG/HA WEED LEAF TARD MIL.

FOX B.Y.

TAIL GRSS JOHN HEMP MORN WILD SON SESB GLRY OATS Exp. 27 Exp. 28 Exp. 29 1 Pre 4 2 1 1 Post 4 2 1 1 Pre 4 1 Post 4 1 Pre 4 1 Post 4 Pre 4 1 Post 4 2 1 1 Pre 8 4 2 1 1 Post 8 100 20 0 100 70 0 100 80 70 30 0 40 0 0 0 30 50 20 0 30 50 95 0 40 40 40 100 40 50 100 0 0 0 50 0 0 0 0 0 20 0 0 0 20 90 0 0 0 0 40 40 0 40 20 70 0 0 0 0 0 0 0 Exp. 30 100 100 Exp. 31 50 60 90 0 0 0 0 70 10 TABLE 1 TEST DOSE PIG- VEL. MUS- RED FOX B.Y. JOHN HEMP MORN WILD COMPOUND BATCH TYPE KG/HA WEED LEAF TARD MIL. TAIL GRSS SON SESB GLRY OATS Exp. 32 1 Pre 8 1 Post 8 4 2 1 1 Pre 8 4 2 1 80 0 80 0 0 0 0 0 0 0 80 100 80 70 100 10 30 0 Exp. 33 40 90 70 100 50 100 50 100 100 100 20 70 20 60 70 20 100 100 70 100 80 80 70 70 100 100 100 0 0 100 100 Post 8 4 2 1 Exp. 34 Exp. 35 1 Pre 4 1 Post 4 2 1 1 Pre 4 1 Post 4 1 Pre 4 2 1 1 Post 4 0 0 20 0 0 0 0 40 0 0 0 0 0 0 0 0 70 80 0 0 0 0 60 20 0 0 10 0 0 0 0 0 10 0 Exp. 36 0 30 100 10 20 40 90 0 0 0 20 90 40 WO 91/00009 PCF/US90/03672 -69- The following examples and tables illustrate some of the plant growth regulation activities of the glyoxylate compositions of the present invention.

EXAMPLE 99 Effect on Turf Growth The acid form of the glyoxylate prepared in Example 1 was evaluated as a turf growth retardant on four grass species at varying rates as indicated in Table 2.

Turf species were planted in 8 by 8 cm fiber pots using steam pasteurized soil, and allowed to grow until well established, roots extended to the bottom of the fiber pot. The turf was clipped periodically to keep the thatch at a manageable level and fertilizer was applied on a regular basis. Prior to application of the compound to the turf, the grass was cut to one cm. The compound was formulated in 15 X 125 mm disposable test tubes and foliar applications were made in a hood using a DeVilbliss Model EGA-502 hand held sprayer.

Height measurements were taken two weeks after application of the compound, with the results set forth in Table 2.

WO 91/00009 PCT/US90/03672 TABLE 2 HEIGHT* (cm)

RATE

kg/ha FESTUCA POA FESTUCA LOLIUM ARUNDINACEA PRATENSIS RUBRA PERENE 0.1 5 5.5 4 4 3 3.5 3 2.5 3.5 3 2 1.5 3 2 1 1 2 Check 6 7 4 Average of two replications Despite some phytotoxicity observed with this method of application, good retardant effect, especially on Kentucky Bluegrass, was demonstrated.

EXAMPLE 100 Effect of Application Method on Turf Retardancy Using the turf species set forth and grown as in Example 99, the effect of the method of application of the compounds of Examples 16 and 2 is evaluated, with results set forth in Table 3. Weight measurements are taken by cutting each turf pot, after two weeks, to a uniform height, combining the clippings from all species and oven drying prior to weighing.

WO 91/00009 PCT/US90/03672 -71- TABLE 3 RATE DRY WEIGHT* (kg/ha) COMPOUND kg/ha FOLIAR SOIL DRENCH GRANULAR Example 16 0.25 1.78 2.26 1.58 0.50 1.11 2.25 1.08 0.75 1.06 1.10 0.55 0.65 0.52 AV. 1.05 1.55 1.07 Example 2 0.25 1.10 1.51 2.44 0.50 1.45 0.83 2.48 1.12 0.72 2.10 1.20 0.32 2.33 AV. 1.21 0.84 2.26 Check 2.49 2.49 2.49 Average of two replications Granular application is found to result in the lowest degree of phytotoxicity to the grass species.

EXAMPLE 101 Growth Regulation of Wheat Wheat testing is done in 13 cm round plastic pots. The wheat is planted in a mixture of 75 percent soil and 25 percent sand which has been steam pasteurized to control indigenous weed seed and pathogens. Seeds are planted and then covered with approximately 1 cm soil/sand mix and placed on finer matting in the WO 91/00009 (PCri US9/03672 -72greenhouse. The pots are both mist watered and bottom watered until seedlings emerged. After emergence, only bottom watering is done. At the times of treatment, the growth stage is recorded, and pots are removed to a spray hood for treatment. The compound to be applied is placed in a 15 by 125 mm test tube and dissolved in 12 ml of acetone and water. The compound is sprayed onto the foliage using a hand held Devilbiss spray gun (Model EGA-502). This sprayer emits an extremely fine spray particle and results in maximum coverage of the foliage.

Operating air pressure is 840 gm/cm 2 Applications are made at four different rates at each of six growth stages. The growth stages are as follows: I. one leaf II. three to four leaf, some initial tillering III. three to four leaf, distinct tillers with two to three leaves IV. five to six leaf, with four to five tillers V. flag leaf present, inflorescence within culm VI. boot stage, inflorescence emerging from culm Results (being an average of all indicated readings) for the compounds of Examples 1 and 16 are set forth in Tables 4 and 5, respectively.

WO 91/00009 'PCT/US90/03672 -73- TABLE 4 EFFECT ON GRAIN WEIGHT, HEIGHT, INTERNODE LENGTH AND BREAKING STRENGTH GRAIN PLANT LENGTH LENGTH BREAKING TREATMENT WEIGHT HEIGHT cm cm STRENGTH kg/ha gm cm INTERNODE A INTERNODE B gm 0 0.62 28.3 24.8 8.6 61.0 2 0.61 31.7 19.9 7.1 66.7 4 0.53 31.5 20.0 7.0 53.9 Weight necessary to break a 10 cm segment of Internode A.

TABLE EFFECT ON NUMBER OF TILLERS PRODUCING GRAIN, GRAIN WEIGHT, STRAW WEIGHT AND PLANT HEIGHT GRAIN STRAW PLANT RATE TILLER WEIGHT WEIGHT HEIGHT kg/ha COUNT gm gm cm 0 16.2 12.1 13.4 23.3 1/2 18.1 12.6 14.7 23.7 1 19,0 12.8 15.2 22.5 2 19.7 13.7 15.8 22.9 4 19.2 13.1 15.0 22.9 EXAMPLE 102 Effect on Wheat Tillering Single soft red winter wheat (Triticum aestivum) seedlings growing in soil in 4 inch R plastic WO 91/00009 PCT/ US90/03672 -74pots are treated with broadcast spray applications of the compound of Example 15. At the time of treatment, the plants are starting to tiller. Most seedlings have one tiller, while a few have two or no tillers. Treatments are replicated six times (except 5 times at 3 gm/ha). At various times during the course of the study, various parameters are determined: number of flag leaves, number of seed heads and yield measurements. These and other determinations are reported in Table 6. No commercial standard is included, because none is known. The yield increases are attributed to increased tillering (flag leaf counts) and therefore more seed heads per plant.

The high dosage (1,000 gm/ha tends to delay tillering.

TABLE 6 !l l, Total Grain Dosage Number Flag Number Seed ga Seed Ut.

gmaha Leaves/Plant Heads/Plant of control) ag/Seed 3 6.4 1.5 10.4 3.5 10.2 t 4.1 27.1 (136) 30.4 6.0 1.3 8.3 3.1 8.2 2.2 20.7 (104) 29.2 9.0 2.4 11.7 2.7 11.8 t 3.7 28.9 (145) 28.2 100 7.5 1.5 13.7 2.1 14.0 1.7 33.5 (168) 27.7 300 6.0 1.4 13.3 3.3 13.5 4.4 33.9 (170) 28.5 1000 3.7 t 3.1 15.3 2.6 14.7 3.3 35.0 (176) 27.9 Control 5.8 2.5 8.0 3.8 7.3 3.4 19.9 (100) 27.0

DAT

1 57 96 145 (harvest) 162 162 1 DAT Days After Treatment NOTE: Grain was pooled for each treatment and weighed 17 days after harvest (162 DAT).

The 3 gm/ha treatment was adjusted to 6 replicates.

WO 91/00009 PCI'/US90/03672 EXAMPLE 103 Effect on Weed Beets In some areas where sugar beets (Beta vulcaris) are grown, many fields become infested with weed beets which do not form usable roots. These weed beets can also bolt any time during the season thus insuring continuing infestations. No herbicide is selective enough to control weed beets in sugar beets. A possible weed beet management approach would be to prevent seed production by early treatment of flower stalks with wipe-on or recirculating sprayer applications. To this end, three greenhouse studies are attempted and reported in Table 7. Test plants are grown in 5" R plastic pots.

Treatments are applied as directed sprays onto developing flower stalks. Percent reduction is based on fresh weight of surviving floral growth. The compound from Example 1 is prepared as an acetone/water/ surfactant lab formulation. ROUNDUPTM (Monsanto) and A-RESTTM (Eli Lilly) are commercial herbicide and plant growth regulant formulations, respectively.

WO 91/00009 PCI'/US90/03672 -76- TABLE 7 Percent Reduction of Floral Parts Dosage Compound mg/Plant Test A Test B Test C Example 1 0.1 16 100 100 0.3 35 100 100 0.9 100 100 100 Roundup T M 2.0 (56)2 39 11 98 18.0 100 100 A-RestM 0.33 21 69 92

DAT

1 28 63 32 1 DAT Days After Treatment 2 Denotes percent increase EXAMPLE 104 Effect on Maple Seedlings Actively growing seedlings of Acer palmatum (Japanese cutleaf maple) are sprayed to runoff with aqueous dilutions of the compound of Example 15 and ATRINALTM (a commercial formulation by MAAG of dikegulac). Pinched as well as untreated controls are included. All treatments (4 replicates each, recorded 78 days after treatment) are listed in Table 8.

I I WO 91/00009 PCT/US90/03672 -77- Glyoxylate dosages bracket the range from no effect to an excessive effect at the dosages tested.

TABLE 8 Compound Concentration Mean Number (ppm) Terminals/Plant Example 15 5 1.0 0.0 5.8 2.2 9.5 150 9.8 2.4 500 greater than 14 Artrinal 1500 11.5 3000 9.0 0.8 Control 0.0 Pinched Control 1.3 1.51 1 Two of the four seedlings went dormant after pinching.

EXAMPLE 105 Effect on Azaleas Rooted single-stem cuttings of azaleas (Rhododendron sp., cv 'Elsi Lee') are transplanted to artificial potting medium in 4 inch round plastic pots.

These cuttings are pinched as they were moved. After growth resumes, these plants are sprayed to run-off using a hand held spray unit. Treatments employ the K salt of Example 15 and dikegulac, a commercial plant growth regulator which is used to induce branching and to WO 91/00009 PCVT/US90/03672 -78prevent regrowth after pruning. Treatments, based on five replicates of each are listed in Table 9.

Flower bud counts are recorded 122 days after treatment. Glyoxylate treatments induced increases in flower bud numbers.

TABLE 9 Concentration Mean Number Compound (ppm) Flower Buds/Plants Example 15 10 3.2 1.9 8.4 3.1 15.8 4.3 23.2 5.8 160 Partial defoliation, Stunted Dikegulac 1500 5.2 3000 5.4 2.7 6000 5.2 3.7 Control 3.0 0.7 Pinched Control* 7.2 2.4 All plants are pinched when potted. The "pinched control" is pinched a second time, when the other plants are sprayed.

I I WO 91/00009 PICTIUS90/03672 -79- EXAMPLE 106 Effect on Branching of Beans In order to determine their effect on branching patterns in plants, compounds were evaluated on Charlevoix climbing beans. Under normal conditions, these plants exhibit strong apical dominance with little or no branching. Plants were grown individually in 4" diameter pots in the greenhouse, and were treated when the 1st trifoliate leaf was expanded (plants approximately 10" tall). Two independent studies were conducted. In the first, compounds were applied at ppm, while in the second the application rate was increased to 100 ppm. In both studies, compounds were sprayed on plants to runoff using a hand-held sprayer.

Compounds were dissolved in a solvent system of 67% water and 33% acetone with 0.067% Tween 20 added as a surfactant. For some compounds not soluble in this system, 100% acetone with Tween 20 was used. For each compound, three replicate plants wei treated and evaluated. Plants were grown in the greenhouse for an additional 3 weeks before the compounds' activity was evaluated. Results are summarized in Table wo 91/00009 WO 91/0009r/US90/03672 TABLr, EFFECT OF COMPOUNDS (DESIGNATED BY EXAMPLE NUMBER) ON BRANCHING IN CLIMBING BEAN, THREE WEEKS AFTER TREATMENT Rating Code: 0 =Mo effect t=Slight effect on bud break 2 =Moderate effect on bud break and branching 3 =Strong enhancement of bud break and branching Example RateneExmlRaeKn LOO25 LO 2 3 3 3.0281_32.

3 2 3 2.5 29 0 1 2 3 2.5 30 0 1 6 2 3 2.5 31 0 1 7 1 2 1.5 32 1 8 1 3 2.0 33 2 1 9 3 1 2.0 34 1 1 3 3 3.0 35 2 0 11 3 3 3.0 36 1 3 12 1- 3 2.0 38 2 1 12A 3 3 3.0 39 2 3 13 1 3 2.0 40 1 2 14 2 3 2.5 41 3 3 3 3 3.0 42 3 3 1 16 1 3 2.0 43 2 1 17 3 3 3.0 442 1 18 3 3 3.0 45 2 1 19 0 1 0.5 46 1 1 0 1 1 0.5 47 2 1 21 1 2 1.5 48 2 1 22 2 1 1.5 49 2 3 24 1 1 1.0 50 2 1 1 26 1 1 3 1 2.0 52 2 I I WO 91/00009 PCT/US9/03672 -81- Example Rate Nean Example Rate Neon SRating 9 Rating LOO 25 100 53 2 1 1.5 75 2 1 54 1 1 1.0 76 1 1 1 1 1.0 77 2 1 56 1 1 1.0 78 3 3 57 1 1 1.0 79 3 3 58 2 0 1.0 81 2 1 59 2 0 1.0 82 2 1 1 1 1.0 83 0 1 61 1 1 1.0 83 0 1 62 1 1 1.0 85 1 0 63 1 3 2.0 86 0 1 64 1 3 2.0 87 0 1 3 3 3.0 88 0 1 66 1 3 2.0 89 0 1 67 1 3 2.0 90 0 1 68 2 1 1.5 91 1 0 69 3 1 2.0 92 0 1 2 2 2.0 93 3 3 71 1 2 1.5 94 0 1 72 1 1 1.0 95 0 1 73 3 1 2.0 96 0 1 74 2 3 2.5 97 1 3 All of the compounds ellicited some degree of increased bud break and/or branching in climbing beans.

For most compounds, activity tended to be greater at 100 ppm than at 25 ppm. In summary, these compounds are effective as branching enhancement agents in beans.

WO 91/00009 PCT/ US90/03672 -82- EXAMPLE 107 Effect on Size Maintenance of Privet Hedge Ten compounds were evaluated to determine their efficacy in size maintenance of privet hedge. Potted privet plants were overwintered in a protective cool greenhouse and transferred to a warm greenhouse in early March. Bud break and leaf development were allowed to continue for 1 month until plant height was approximately cm. Because privet hedge plants are commonly trimmed to a desired shape, one-half of the plants were trimmed prior to chemical application. Plants were sprayed to runoff using a hand-held sprayer. Compounds were applied at a concentration of 20 ppm in a solvent system of water, and 50% acetone containing 0.1% Triton X-100 as a surfactant. For each treatment, 2 replicate trimmed plants and 2 replicate non-trimmed plants were treated.

Plant height of each plant was recorded on the day of treatment and compared to the plant height at 29 days after treatment. Table 11 shows the net increase in plant height after treatment.

I -1.

WO 91/00009 PCT/US90/03672 -83- TABLE 11 EFFECT OF COMPOUNDS ON HEIGHT CHANGE OF GOLDEN PRIVET 29 DAYS AFTER TREATMENT Net change in plant height Example (cm) Trimmed* Non-Trimmed** Plants Plants Non-Sprayed Control 8.0 Sprayed Control 7.0 1 0.0 2 -2.5 3 1.5 9 -1.0 -0.5 0.0 41 -1.0 42 0.0 -1.0 0.0 78 0.5 0.0 79 -0.5 0.0 *Average plant height at time of treatment was 30 cm.

**Average plant height at time of treatment was 40 cm.

Trimmed and non-trimmed plants responded similarly to application of the compounds. Control plants (both non-sprayed and those sprayed with the solvent) grew from 7 to 8.5 cm. In contrast, plant height remained essentially the same in all plants treated with the compounds. Thus, these compounds were quite effective in maintaining plant size both in trimmed and non-trimmed privet hedge plants.

WO 91/00009 PCT/US90/03672 -84- EXAMPLE 108 Effect on Terminal Elongation of Green Ash Ten compounds were applied to green ash seedlings to determine if they could control elongation of terminal buds. Potted green ash seedlings were overwintered in a cool greenhouse and transferred to a warm greenhouse in early March. Within 1 month terminal buds were released and began to grow. Plants were then sprayed to runoff using a hand-held sprayer. Compounds were applied at two concentrations, 20 ppm and 100 ppm, in a solvent system of 50% water, 50% acetone containing 0.1% Triton X-100 as a surfactant. For each treatment, 4 replicate plants were treated. Plant height of each plant was recorded on the day of treatment and compared to the plant height at 28 days after treatment.

Table 12 shows the net increase in plant height after treatment.

WO 91/00009 PCT/US90/03672 TABLE 12 EFFECT OF COMPOUNDS ON HEIGHT CHANGE OF GREEN ASH SEEDLINGS 28 DAYS AFTER TREATMENT Net change in plant height* Example (cm) ppm 100 ppm Non-Sprayed 18.3 Control Pinched Non-Sprayed 11.0 Control Non-Pinched Sprayed Control 15.0 Pinched Sparyed Control 8.5 Non-Pinched 1 0.0 -0.3 2 -0.3 0.8 3 1.5 -0.3 9 0.0 0.8 0.0 17 0.0 -0,1 41 1.3 0.8 42 1.3 0.3 0.5 79 0.3 *Average plant height at time of treatment was 34 cm.

Non-sprayed control plants in which the terminal bud was pinched grew 18.3 cm while non-sprayed non-pinched plants grew 11 cm. Similarly, pinched control plants sprayed with the solvent increased in

I

WO 91/00009 PCT/US90/03672 -86height 15 cm and non-pinched, non-sprayed plants grew cm. In contrast, all compounds tested essentially eliminated terminal bud elongation, regardless of concentration of the applied solution. Thus, these compounds appear to have excellent utility when used to reduce vertical growth of this tree species.

EXAMPLE 109 Effect on Turfqrass Growth Twenty-three compounds were tested for their utility as turfgrass retardants. Bluegrass, cv Baron and perennial ryegrass, cv Pennfine were planted in 3" sqaure pots in late February. Grass was allowed to grow for 6 weeks before treatment. Grass was cut and fertilized on a regular basis to provide a thick turf. Just prior to chemical treatment, the bluegrass and ryegrass were trimmed to heights of 20 mm and 15 mm, respectively.

Four replicate pots of each species were treated at two rates, 0.5 kg/ha and 2.0 kg/ha. Compounds were sprayed in 50% acetone, b0% water containing Triton X-100 at 0.1% as a surfactant. Some compounds were sprayed in 100% acetone containing Triton X-100. Plant heights 2 weeks after treatment were recorded and are summarized in Table 13.

wo 91/00009 WO 9100009PCIT/US90/03672 -87- TABLE 13 EFFECT OF COMPOUNDS ON PLANT HEIGHT OF BLUEGRASS AND RYEGRASS 14 DAYS AFTER TREATMENT Plant Height (cu) B luegrass* RMrass Exaple 0.5 2.0 0.5 kg/ha kg/ha kg/ha kg/ha Non-Sprayed Control 137.5 126.3 Sprayed Control 132.5 130.0 Embtark 30.3 30.3 50.5 49.8 Limit (2.5 qt/acre) 43.5 53.0..

1 44.3 40.8 31.8 26.3 2 49.8 40.5 27.5 26.8 3 39.8 3.4.0 33.8 33.3 44.0 32.0 30.3 29.0 8 51.3 31.8 27.0 30.8 9 41.3 34.3 30.3 27.8 43.0 34.5 32.3 13.4.3 11 41.0 38.5 34.8 29.8 33.8 34.8 25.8 26.8 16 47.0 44.0 29.0 29.3 17 39.0 31.8 28.3 2f.8 18 42.8 4.8 28.3 21.3 27 42.8 31.0 30.5 24.3 36 95.0 81.8 40.5 42.0 39 67.5 "4.3 34.8 32.8 41 48.8 39.8 43.8 3.

42 117.5 106.3 101.3 8.

47.8 45.8 1 33.3 132.8 66 68.3 51.5 58.8 38.8 74 35.0 33.3 35.3 32.0 WO 91/00009 PC'/US90/03672 -88- Plant Height (cm) Bluegrass* Ryegrass** Ex tple 0.5 2.0 0.5 kg/ha kg/ha kg/ha kg/ha 78 33.8 33.0 36.0 33.8 79 45.8 52.5 40.0 45.8 93 34.0 33.0 41.3 31.0 *Average plant height at time of treatment was 20 mm.

**Average plant height at time of treatment was 15 mm.

Both bluegrass and ryegrass controls grew to a total height of approximately 130 mm (net growth of 115 mm) during the two week preiod after treatment. The commercial standards, Limit and Embark, reduced total plant height to approximately 30 to 50 mm, depending upon rate and species. Similar plant height reductions were observed in many of the compounds tested. Several compounds, however, showed little or no activity. In addition, responses also varied between the two species, with ryegrass growth appearing to be more susceptible to chemical retardation, particularly at low rates. In summary, turf retardant activity of this class of chemistry appears to be at least comparable to the currently available commercial standards.

Claims (9)

1. A compound having the formula wherein: A is COOR, COSR, CONR'R", CSNH 2 or CN; R is C 2 -Cg alkoxyalkyl, cycloalkyl, C 2 -C 4 hydroxyalkyl, (alkoxycarbonyl)alkyl, dialkylaminoalkyl, tetrahydrofurfuryl and dimethyldioxolanylmethyl; R' and R" may be the samp or different, and each is a member selected from the group consisting of H, lower alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or alkoxycarbonylalkyl; or NR'R" taken together represent a saturated monocyclic heterocyclic group; Z is H, CH 3 CH 3 S, CH 3 S(O) or COOR; each Y is independently H, C 1 -C 4 alkyl or alkoxy, CF 3 or X; and X is F, Cl or Br; is provided that where more than one of Y is other than H on either ring they must be in the 3, 4, 8 and/or 9 positions and, where Y is in the 1, 2, 10 or 11 positions on the rings, no more than one of Y is other than H.

2. A compound having the formula Wm wherein: A is COOR COSR, CONR'R", CSNH 2 or CN; R is H, Na, K, di(Ci-C 4 )alkylammonium, N(3-amino-propyl)N-oleylammonium, C 1 -C 8 alkyl, aryl, heteroaryl, C 2 -C 8 alkoxyalkyl, C 2 -C 4 hydroxalkyl, (alkoxycarbonyl)alkyl, dialkylaminoalkyl, cycloalkyl, tetrahydrofurfuryl or dimethydioxolanylmethyl; IG:kWPUSER\LIBZIOO1 27:TCW:SEF R' and R" may be the same or different, and cach is a member se!ecled from the group consisting of lower alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or alkoxycarbonylalkyl; or NR'R" taken together represent a saturated monocyclic heterocyclic group; Z is H, CH 3 CH4 3 S, CH 3 COOR; each Y and W are independently C 1 -C 4 alkyl or alkoxy or C17 3 m and n are 0-2 and the sum of mn plus n is 1-4; with the proviso the compound is not N, N-dibutyl- 12H-dibenzo [d [1 ,3]-dioxocin-6-carboxamide.

3. A compound according to Claim 1 or 2, wherein NR'R" taken together are lo pyrollidino, piperidino, morpholino, piperazino or N-(lower alkyl)-piperazino.

4. 12H-dibenzo [d [1,31 dioxocin-6-thiocarboxamide.

I Potassium 12H-dibenzo [d dioxocin-6-carboxyl ate.

6. Phenyl 12H-dibenzo dioxocin-6-carboxylate.

7. N-ethoxycarbonyl methyl- 12H-dibenzo [d [1 dioxocin-6-ca:. -)xamide.

8. N-(2-N,N-dimethylaminoetlhyl)-12H-dibenzo dioxocin-6-carbox- amide.

9. Derivatives of 12-dibenzo dioxocin-6-carboxylic acid, substantially as hereinbefore described with reference to any one of Examples 9, 11, 12A, 131 18, 23 to 27, 29 to 31, 33-35, 37, 40 to 44, 47, 63, 67 to 69, 73, 74, 78, 79, 85, 95, 110, 112, 116, 118 and 119-123. Dated 14 January, 1994 ISI( Biotech Corporation Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON IN:\LIBXXIOO393:SEF90o2 90 of 2 RfEV S VERSION INTERNATIONAL SEARCH REPORT International Application No PCT /US9O /03672 t. CLASSIFICATION OF SUBJECT MATTER (it several classification symools aooiy. indicate ail)I According to international Patent Classification lIPC) or to botn National Classification ano IPC AO1N 43100;43148;43140;43/36;43/24;CO7D 265/30;295/00 C07D40506 i1/6,8,92 ,94,95 ,75,78;549/349,L.67 ;544/158,162,176,378;546/197;54E 11 FIELDS I Minimum Documentation Searcheo Classification Svyatem C 'lassification Symoola us 71/76,88,92,94,95 75,78; 549/349,267; 544/158,162,176,378; 546/197; 548/526 Documentation Searched other than Minimumn Documentatiinn to the Extent that aucn Documents are included in the Fields Searchedo Ill. DOCUMENTS CONSIDERED TO BE RELEVANT I Category Citation of Document, I with inoication. where appropriate. of the relevant passages It Relevant to Claim No. I XY US, A, 3,553,234 (JOHNSON ET AL) 05 January 1971 8-15/8-15 see entire document X U US, A, 3,836,543 (GRISAR) 17 Septemrier 1974 8-15/8-15 see entire document Y US, A, 3,931,173 (PARKER ET AL) 06 January 1976 see column line 65 to column 2 line A, E I US, A, 4,938,790 (SMITnH ET AL) 03 July 1990 1-15 see column 1 line 27 to column~ 2 line *Special categories of cited documents: 1 T" later document puolished slter the international filing oate document defining the general state of the art nhich isno or priority dateand hot in conflict with the aoplication out considered to be of particular relevance cited to underatand the princiole or theory unoierlying the invention earlimf document but published on or altar the international X" document of parlicular relevance: the claimed invention riling date cannot be ccnasioerea novel or cannot be consiored to "L document which may throw doubts on oriority claim(s) or involve an inventive step whi ch is cited to establish the ouolication date of another 'Yr" document at particular relevance: the claimed invention citation or other special reason (as soecifled) cannot be considered to involve an inventive step when the document referring to an oral disclosure, use, exhibition or o.)cumeht as combined with one or more other such docu- other means manis, such combination baing obvious to a person siiilled "P document published orior to the international iling date but in the art. later than the priority date claimed 6* document member of the same patent family IV. CERTIFICATION Date of the Actual Comoletion of the International Search 2 Date of Mailing of this International Search Report 1 21 AUGUST 1990 9 NOV 1990 international Searching Authority I Signature of Authoried Offie IISA/US AMELIA A. T3QA DI Si01 Form PCT/iSA/210 (second sheet) Way 1986) 5-63 International Application No. PCT/US9/03672 FURTHER INFORMATION CONTINUED FROM THE SECOND SHEET OBSERVATIONS WHERE CERTAIN CLAIMS WERE FOUND UNSEARCHABLE I This international search report has not been established in respect of certain claims under Article 17(2) for the following reasons: Claim numbers because they relate to subject matter i not required to be searched by this Authority, namely: Claim numbers because they relate to parts of the international application that do not comply with the prescribed require- ments to such an extent that no meaningful international search can be carried out 1. specifically: 3. Claim number because thsy re dsepedent claims not drafted in accordance with the second and third sentences of PCT Rule 6.4(a). OBSERVATIONS WHERE UNITY OF INVENTION IS LACKING 2 This International Searching Authority found multiple inventions In this international application as follows: I. Plant Growth Regulant method (PGR) claims 1, 8, 14, 15 no additional heterocycles 71/76; 549/349, 267 See attachment I 1.S3 As all required additional search fees were timely paid by the applicant, this international sea;..h report covers all searchable claims of the international application. 2. As only some of the required additional search fees were timel, paid by the applicant, this international report covers only those claims of the international application for which fees were paid, specifically claims: 3. No required additional search fees were timely paid by the applicant. Consequently, this international search report is restricted to the invention First mentioned in the claims; it is covered by claim numbers: As all searchable claims could be searched without effort lustifying an additional lee, the International Searching Authority aid not invite oayment of any additional fee. Remark on Protest E] The additional search fees were accompanied by applicant's protest. No protest accompanied the payment of additional search fees. Form PCT/ISA210 (supplemental Ihet (2 (Rev. 4-9 See nouesn a ncoayrg r PCT/US90/03672 Attachment I II. PGR method claims 1,8,14,15 No additional heterocycles but additional uses 71/78,75 III. PGR mehtod claims 1,8,14,15 with pyrrolindino 71/95; 548/526 IV. PGR method claims 1,8,14,15 with piperdino 71/94; 546/197 V. PGR method claims 1,8,14,15 with morpholino 71/88; 544/158,162,176 VI. PGR method claims 1,8,14,15 with piperzino/N(alKgl) piperazino 71/92; 544/378 VII. Herbicidal method claim 2 71/88 Claims 3-13* are generic and are examinable with any of Groups II to VI.