CA1272728A - Substituted thieno-and furoimidazopyrrolspyridinedione compounds having herbicidal activity - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
There are provided novel (2-imidazolin-2-yl)-thieno and furo compounds, and intermediate compounds for the preparation thereof, and a method for control-ling a wide variety of annual and perennial plant species therewith.

Description

1~:'7~

29,348 (2-IMIDAzoLlIN-2-y-L)T~lIENo- AND _UROL2,3~hl AND
~3,2-hlPYR:[DINES AND INTERME,DIATES FOR_TIIE PREPARATION
_IEREOF~ AND USE OF SAID COMPOUNDS AS llERBICIDAL AGENTS

The present divisional invention relates to novel (2-imidazolin-2-yl)thieno-and Europyridine compounds, and intermediates for the preparation oE said pyridine compounds and a method for controlling undesirable annual and perennial plant species therewith. It is a divisional application divided out oE
parent application no. 455,178 iled on the 1st of June, 1984.
The parent application relates to 6-(2-imidazolin-2-yl)thieno- and furo[2,3-b] and 5-(2-imidazolin-2-yl)thieno- and furo[3,2-b]pyridine compounds and the corresponding 2, 3-dihydrothieno and 2,3-dihydroEuro compounds having the structures (Ia) and (Ib):

Y ~ X ~N ~ ~ W ~ R2 B B

[2,3-b] [3,2-b]
(Ia) (Ib) ~ ~7Z~

wllcrci~ rcprcscllts a s:lngle or a ~loub:lc bond; Rl :is Cl~C4 alkyl;
R2 is Cl-C4 al~yl or C3-C6 cycloalkyl; and whell Rl and R~ aro takcn together with carbon to which they are attaclled they may represent C3-C6 cycloalkyl optionally substituted with methyl; A is COOR~, CiiO, 011, COC~120H, CONIIC1-l2Cll20~l, CON~10}1, or --<
RD

K3 iS hydrogen, Cl-Cl~ alkyl, ~ ich may be interrupted by one or more O or S and is optionally substituted with one of the following groups:
Cl-C3 alkoxy, halogen, hydroxy, C3-~6 cycloalKyl ~ benzyioxy, furyl, p~lenyl, ~urfuryl, halophenyl, lo~eralkylphenyl, loweralkoxyphenyl, nitro-phenyl, carboxyl, loweralkoxycarbonyl, cyano, Cl-C~ alkylthio or tri-loweralkylammonium, C3-C6 alkenyi oplionally substituted with one of the following groups: Cl-C3 alkoxyJ phenyl, halogen or witn two Cl-C3 alkoxy groups or two halogen groups: C3-C6 cycloalkyl optionally sub-stituted with one or two Cl-C~ alkyl groups; C~-~ alkynyl optionally substituted witn phenyl, halogen or C1120~1; or a cation for example a cation of al~ali metals, alkaline earth metals, (Ca, Ba) manganese, copper, iron, ammonium or organic ammonium; RC and RD are H or ~`H3; B
is H, COR4 or SO2R5, provided that when B is COK4 or SO2R5, and A is ZO COOR3, R3 cannot be hydrogen or a salt-~orming cation; R4 is Cl-Cll alkyl~ chloromethyl or phenyl optionally substituted with one chloro, one nitro, one methyl or one methoxy group; R5 is Cl-C~ alkyl or phenyl optionally substituted with one methyl group, chloro or nitro;

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l~ is O or S; X is ~, S, or, wllere -_ is a singlc bond, ~5-0; Y nnd Y', Z and Z' are hydrogen, )lalogcn, Cl-C6 "lkyl, Cl-C~ hydroxylower^
alkyl, Cl-C6 alkoxy, Cl-C6 acyloxy, benzoyloxy optionally substituted Wi~h one or ~wo Cl-C4 alkyl, Cl-C~ alkoxy, halogen; Cl-C4 alkylthio, phenoxy, Cl-C4 haloalkyl, Cl-C4 haloalkoxy, ni.tro, cyanO, Cl-C4 alkyl~
amino, Cl~C4 dialkylamino, Cl~C4 alkylsulfonyl or phenyl optionally substituted with one or two Cl-C4 alkyl, Cl-C4 alkoxy, halogen, or any combination of two of these groups and wherein Y and Z are the same group provided that Y and Z are H, hologen, alkyl or alkoxy, and when Y and Y' or Z and Z' are the same group they are hydrogen or alkyl;
and, when taken together, ~ and Z may form a ring in which YZ are rep-sented by the structure -(CH~)n-, where n is an integer selected from 3 or 4; or IL 1l IQ l7 -C - C - C - C-, where L, M, Q and R7 each represent hydrogen, halogen, nitro, Cl-C4 loweralkyl, Cl-~4 lowcralkoxy, methoxy, phcnyl and phenoxy, with the proviso that only one of L, M, ~ or R7, may rep-resent a substituent other than hydrogen, halogen, Cl-C4 alkyl or Cl-C4 alkoxy; or the pyridine N-oxides thereof, when W is O or S and A
is COOR3; and when Rl and R2 are not the same, the optical isomers thereof, and, except when R3 is cation, the acid addition salts there-of.

~ 7~7~ ~

A preferred group of 6 (2-imidazolin 2-yl)-thieno- and furo[2,3-b]pyridine and 5~ imidazolin

2-yl)thieno- and furo[3,2 b]pyridine compounds have the formula shown as (Ia) and (Ib) above, wherein Rl is methyl; R2 is methyl, ethyl, propyl, isopropyl, or when taken togethPr form a cyclohexyl or methylcyclohexyl ring; W is oxygen or sulfur; B is hydrogen; A is COOR3, where R3 is as described above; Y and Z are hydrogen, Cl-C3 alkyl, Cl-C3 alkoxy, alkylthio, halo, nitro, cyano, trifluoromethyl, monofluoromethyl, difluoro-methyl, monofluoromethoxy, difluoromethoxy, trifluoro-methoxy, methylsulfonyl, methylsulfonamido, methyl-amino, dimethylamino, or isopropylamino and when Y and Z are taken together, YZ is -(CH2)3~ -(CH2)4-~ or -CH=CH-CH=CH-.
The most preferred formula (Ia) and (Ib) (2-imidazolin-2-yl)thieno and furo compounds are those wherein B is H, Y and Z are hydrogen, chloro, methyl or methoxy provided ~hat one of either Y or Z is hydrogen;
W is oxy~en; A is COOR3 where R3 is hydrogen, furfuryl, propynyl, C3-haloalkenyl, Na~ or isopropylammonium and Rl and R2 are as defined for the preferred compounds.
It should also be understood that when B is H the imidazolinyl thieno- and furo[2,3-b] and [3,2-b]-pyri~dines represented by formula (Ia~ and (Ib) above may be ~automeric. While, for convenience, they are depicted by single structures identified as formula (Ia) and ~Ib), they may exist in either of the tauto-meric forms illustrated as follows:

~"l~R2 ~ R~
W HN W ,' H
or or ~;R 2 ~R ~ ~
N W N W ., ,, As such, both tautomeric forms of ~aid imidazolinyl pyridlnes are meant to be included under the formula (Ia) and (Ib) d~finiti.on.
The divisional invention relates to novel substituted thieno- and furoimidazopyrrolopyridinedione co~pound~ of structure (Ila) and (IIb) below and a method for con~rolling undesirable annual and perennial plant species therewith in soybeans and certain cereal crop~:

~ Y X~ '`".
2 5 Z ~ l l N ---= ~ ~ II N ~o ...
X N N --- R 2 1 ~--<~N~R 2 Y' . ~1 7' Rl ~.

~IIa~ (lIb) ;,.

. . .
":, : .
: .

~ ~t7Z~

wherein X, Y, Y', ~, Z', W, Rl and R2 are as described for (Ia) and (Ib) above and wherein X, Y, Z, W, Rl and R2 in the preferred and most pre~erred formula (IIa) and (IIb) compounds are as described for the preferred and most preferred formula (Ia) and formula (Ib) com pounds.
Herbicidal substituted pyridine and quino-line2-imida~olin-2-yl acids~ esters and salts are disclosed in the Canadian Patent 1187498, which issued May 2, 1385. The present inven-tion relates to novel thieno- and furo~2~3~~pyridines and thieno- and furo~3,2-b]pyridines which when substituted in the 6 or 5 position with an imidazo-linone ring and in the 5 or 6 position with a group A
as previously defined, provide potent herbicidal lS agents. The finding that imidazolinyl thieno- and -furopyridines provide potent herbicides is unexpected as there is no prior indication tha~ such [2,3-b] or [3,2-b] ring systems may be employed for any agronomic or herbicidal utility. This new class of herbicidal agents is highly effective when applied as a pre- or postemergence treatment, and individual members of this class exhibit unusual selectivity in soybean and cereal crops such as wheat, barley, rice, rye and oats. Further, it has been found that selectivity in cereals may be enhanced when A is C02H, by the preparation of esters, particularly furfuryl, alkynyl and haloalkenyl esters.
Additionally some members of this class exhibit unexpected plant growth regula~ing effects such as reduced plant height and antilodging activity and increased tillering in cereal crops.

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~:L 1.09-7~87n 29,34 The compounds oE the parent invention may conveniently be prepared from the appropriately sub-stituted thieno- and furol2,3-b~ and l3,~-b]pyridine-dicarboxylic acids and esters oE Eormula (IIIa) and (IIIb):
S

y~ ~r 0 R and ~ ~

(I3Ia~ tIIIb) wherein X, Y and Z are as previously described and R is methyl or ethyl.
Methods suitable for preparing novel ~ormula (Ia) and formula (Ib) unsaturated compounds wherein - -is a double bond from the novel ~ormula (IIIa) and (IIIb) pyridinedicarboxylic acid esters are illustrated in Flow Diagram I below.
Thus formula (IIIa) an~ (IIIb) diesters may be hydrolyzed to the corresponding thieno- and ~uro-2,3-pyridinedicarboxylic acids of ormula ~IVa) and (IVb) by reaction thereof with a strong base such as potassium hydroxide or sodium hydroxide. Acid anhy-drides oE formula (Va) and (Vb) may then be prepared by treatment oF the formula (IVa) and (IVb) pyridine-dicarboxylic acids with, for example, acetic anhydride.

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Reaction of formula (Va) and (Vb) anhydrides with an appropriately substituted aminocarboxamide or amino-thiocarboxamide depicted by formula (VI) yields car bamoyl nicotinic acids of formula (VIIa) and (VIIb).
Treatment of the thus-formed formula (VIIa) and (VIIb) carbamoyl nicotinic acids with about 2 to lO molar equivalents oÇ aqueous or aqueous alcoholic sodium or potassium hydroxide, preferably under a blanket of inert gas such as nitrogen, cooling and acidifying tO
pH 2 to 4 with a strong mineral aoid such as hydro-chloric acid or sulfuric acid gives herbicidally effective 6-(4,4-disubstituted-5-oxo-(or thioxo)-2-imidazolin-2-yl)thieno- and furo[2,3-b]pyridine-5 carboxylic acids, and 5-(4,4-disubstituted-5-oxo-(or thioxo)-2-imidazolin-2-yl)thieno- and furo[3,2-b]-pyridine-6-carboxylic acids encompassed by formulas (Ia) and (Ib).
Formula (Ia) and (Ib) 5 or 6-(2-imidazolin-2-yl)thieno- and furopyridine esters, wherein A is COOR3 and R3 represents a substituent other than hydrogen or a salt-forming cation, and Rl, R2, Xt Y and Z are as described above can be prepared by reacting a novel thieno- or furoimidazopyrrolopyridinedione, represented by formulas (IIa) and (IIb), hereinbelow, in Flow Diagram (II), with an appropriate alcohol and corres-ponding alkali metal alkoxide at a temperature ranging between about 20C and about 50C.
Formula (IIa) and (IIb) novel ~hieno- and furoimidazopyrrolopyridinediones may conveniently be prepared from formula (Ia) and (Ib) acids, where B is H
by treatment with one equivalent of dicyclohexylcarbo-diimide in an inert solvent such as methylene chloride as illustrated in Flow Diagram (II) below.

~c S y~CO~R Z~N~
(IIIb) ( IIIa) ~ 1. Aqueous ethanolic NoOlt l 2. HCl Z~COOH Y~/ ~ ~OOH
OOH
Y~XlN _COOH N
( IVb) ( IVa ) .~ I
lAc20 R
zYr~ O Yz~O

(Vb) (Va) 7~

FLOW DIAGRAM (I) (Continued) (Vo) (Vb) ~1 NH 2~W~NH 2 (VI ) Z~COOH ~1 Y~ ~OOH ~1 Y~ ,~ LCONH~j:~W--NH~ R2 (VIIa) (VIIb) ,~
NaOH

~: 25 ~/~R2 Z~ ~ R2 11 _W ~ WH H

(Ia) (Ib) '7~7'~3 _LO~

z_ ~COOH Rl y__f X ~COOH Rl y~ ~/N~R2 z.~l~ /~L</ =~w2 H H
( Ia) ( Ib) DCC
t ~3R2 N ~2 Rl R
(IIa~ (IIb) R30-Ml+
.

z~CO~R3 Rl y~ ~l~cOOR3 Rl 2 5 y~ ~1~ ~k~N~R 2 Z I ~ /) </N~R 2 X N 1~--W N 111 W
H H
( la) ( Ib) ~7~

where Ml ls an alkali metal, and X, Y, Z, Rl, R2 and R3 are as above defined.
Many formula (IlIa) thieno[2,3-b]pyridinedi-carboxylic acids and (IIIb~ thieno[3,2-b]pyridinedi-carboxylic acids may conveniently be prepared by reacting the appropriately substituted 2 or 3-amino-thiophene of Eormula (VIlIa) or ~VIIIb), where R is hydrogen or chloro, with a Cl-C4 alkyl ester of acetylenedicarboxylic acid of formula (IX) as described by Blecker~ et al. Chem. Ber. 1978, 106S 368. The thus-formed ~-aminothieno-a,~-unsaturated ester of formula (X) is then reacted with an immonium salt de-picted by the formula Cl-CH=N-(R''')2 C~ wherein R''' is Cl-C6 alkyl or Cl-CH= ~(CH2)n' Cl where n' is 4 or 5, in the presence o a low boiling chlorinated hydro-carbon solvent such as methylene chloride or dichloro-ethane at a temperature between about 40C and 90C, for a period of time sufficient to essentially complete the reaction and yield the formula (IIIa) [2,3-b]-thieno- or (IIIb) [3,2-b]thieno 2,3-pyridinedicarbo-; 20 xylic acid as the dialkyl ester as illustrated in Flow Diagram (III) below.
Formula (Illb) furo[3,2-b]pyridinedicarbo-xylic acids may be prepared by reacting 3-amino-2-formylfuran of formula (XI) prepared by the method of S. Gronowitz et al., Acta Chemica Scand B29 224(1975) with ethyl oxalacetate to give formula (IIIb) furo-pyridine compounds directly, as illustrated in Flow Diagram (IV) below while formula (IIIa) furo[2,3-b]-pyridine compounds where Y and Z are H are obtained by bromination of the reaction product (XII) of acetoace tamide with the diethyl ester of ethoxymethyleneoxal-acetic acid followed by treatment with sodium boro-hydride and ~ toluene sulfonic acid in refluxing xylene as illustrated in Flow Diagram (V~ below.

2'~2' -l3-Formula ~IIIb) 2,3-dihydrouro[3,2-b] and ~hieno[3,2-b~pyridines may be prepared by the reaction of diethyletlloxymethylene oxalacetate with a mixture of enamines derived from 3-keto-tetrahydrouran or 3-keto-tetrahydrothiophene, followed by ~reatment with ammonia or ammonium, as illustrated in Flow Diagram (VI).

. ~ , ~l`

o_n ~

Z I I Z~NH2 I I or I I .
Y--~ ' - NH 2 Y--~ ~--R
S S
(VIIIa) (VIIIb) R " O~C--C_C~OOR "

( I X ) ~: 15 ~1 ~ Z I rN~--COOR "
Y--~ S /~N~j;--COOR " or YJ~ ~R HC--COOR "
HC--COOR "

(X~) (Xb) ¦C1 CH=N (R1l1)2 .Cle ¦CI--CH=N3 CH2 ) n ~ Cl ~

Z~OOR " Y~OOR "
COOR " OOR "
S N N

(IIla) (IIIb) FLOW DIAGRAM ( IV) Y~H O

( X I ) C2H502C~j~H2~02C2H5 - y~ ~C02C2~5 Z I ~ N/kO~C2H5 ~ IIIb) '`"' v ~
7~

FLOW DIAGRAM (V) .~

CH3~ CH2~--NH2 + C2H50--~C~C02C2H5 C~H50H/NaOAc H
C~i3--C~C02C2H5 48%H~r/Br2 o~ ~L 2C2HS
H
: (XII) BrCH2 ~ 2C2~5 NaBH4 15 o2C2H5 ~H

~H
20BrCH2-CH ~ 2C2~i5 (C2H5)3N
O ~ ~ 02C2H5 H

~ 02C2H5 p-Toluenesulfonic acid o N 02C2H5 ~ - -~C02C2H5 ~ ~ / ~ O~C2H~

(IIIa~

~. ,. J
.,.,~
7~

(VI ) lHNRlR2 ~;jRlR2 C~NRlR2 ~ C2H50--C--C--CO--C2C2~15 2. NH3 or NH4~X

x ~C02C2H5 ll~ /~LCO2C2H5 N
(IIIb) ~.~

~ 7~

wherein Rl and R2 each represents Cl C6 alkyl or taken together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated heterocyclic ring, optionally containing at most 2 hetero atoms.
Formula (IIIa) furo[2,3-b]pyridine compounds where Z is H and Y is alkyl or optionally substituted phenyl are prepared by reaction o an acetylene com-pound with the iodopyridine diester (VII) [preparation of this compound VII is described in J. Prakt. Chem., 148; 72(1537?3, in the presence of cuprous salts, an amine base, and a palladium (II) catalyst as shown in Flow Diagram (VII).

i~

FLOW DIAGRAM (VI I ) r~o2cH3 Y--C_CH + ol~ ,LCOiCH3 H

( V I I ) CuI
Et3N
( Ph3 P ) 2 PdCl 2 .~ 15 r~ 02CH3 Y~ 02CH3 O N

( IIIa) ~L~7 Substituents represented by Y and Z in formula ~Ia), (Ib), (IIa) and (IIb) compounds of ~he present invention may be prepared either by using the appropriately substituted starting material for the preparat.ion of formula (IIIa) and (IIIb) thieno- and furopyridine-5,6-d;carboxylic acid esters or by elec-trophilic substitution (halogenation, nitration, sul-fonation, etc.) directly upon Formula (IIIa) or (IIIb) diesters or Formula (Ia) or (Ib) final products, where-in at least one of Y or Z is hydrogen. These substituted Formula (IIIa), ~IIIb), (Ia) and (Ib) compounds then may be used as starting materials for additional Y and Z substitution by displacemen~, reduction, oxidation, etc. Representative substitu~ed (IIIa~ and (IIIb) compounds which may be prepared by these procedures are as illustrated below.

ZT~co2R y ~ X ~I~C02R
20Y ~ X ~ N/ k o2R ~ 1 ~ / ~ o2R

~IIIa) (IIIb) X Y

S H Br CH3 S C~3 H CH3 S H Cl CH3 S Cl Cl CH3 S H No2 CH3 S Br Br CH3 ~ f~r,~'~g'rD~

X Y Z R
S CH3 Cl CH3 S H C~13 CH3 S Cl H CH3 S CH3 C~3 CH3 S H N(CH3)2 CH3 O H Br CH3 O H Br C2H5 ; 0 H Cl CH3 : O H Cl C2H5 : 0 CH3 H C2H5 : O C2Hs H CH3 S -(CH2)3- CH3 S -(CH2)4- CH3 S -(CH)4- CH3 .

~r .~

X Y Z R

0 H No2 C2H5 0 Br Br C2~15 0 H C6HsS C2H5 i5 . ~

~3v~ r~

Additionally, novel herbicidal 2,3-dihydro-thieno[2,3-b] and [3,2-bJpyridine compounds may be obtained by starting the sequence in Flow Diagram (III) above with a dihydrothiophenimin hydrochloride. Novel herbicidal 2,3-dihydro furo[2,3-b] and [3,2-b]pyridines may be prepared by catalytic reduction of the formula (Ia) or (Ib) (2-imidazolin-2-yl~ product, or (IIIa) and (XIIb) furo~2,3-b] and ~3,2-b]pyridine~5,6-diesters as for example with hydrogen and palladium on carbon, provided that Y and Z are substituents which are not reduced by such a procedure. Other 2,3-dihydrofuro-[2,3-b]pyridines are prepared by the reduction-re-arrangement of a bromo ketone with sodium borohydride followed by treatment with triethylamine, and p-toluene-sulfonic acid as shown in Flow Diagram (VIII). This then provides novel 2,3-dihydro herbicidal compounds illustrated below.

Y' z_ ~ C02R3 Rl Y- ~X ~ C02R3 R
~ ~ yN ~ R2 z_ ~ ~ /N - ~ R2 Y- X ~ ; !' ~ ~=W
B B
. :
: 25 wherein X, Y, Y', Z, Z', W, B, Rl and R3 are as described for (Ia) and (Ib).

FLOW DIAGRAM (VI I I ) __. __ R fo2C2H5 (CH3)2CH C CH2~N + C~H50 ~0~02C2H5 H
¦ C2 H5OH/Na OAC
(CH3 ) 2CH C~/ ~CO2C2H5 od~ ~C02C~H5 H

l48 /0 HBr/Br2 ;

~r ~
(CH3 ) 2C~Q2C2H5 o=~ J C02C2H5 t . ~

FLOW DIAGRAM (VIII) (Continued) S ~CH3)2C CHf ~02C2H5 O 02c2~l5 HOCH2~( CH3 ) 2~02C2H5 ~ X 2C2 H5 ¦OH

o2c2H5 HOCH2--C(cH3)2 f 2~2H5 CH3~ )\\N 02C2H5 0 02C2H5 ~-Toluenesulfonic acid CH3~CC02C2H5 co2C2Hs The formula (Ia) and formula (Ib) 6-(2~
imidazolin-2 yl)thieno and furo~2,3-b]pyrid;nes and 5~ imidazolin-2-yl)thieno- and furo[3,2-b]pyridines and the formula (IIa) and formula (IIb) imidazopyrrolo-pyridinediones of the present invention are exceedingly effec~ive herbicidal agents useful for the control of an exceptionally wide variety of herbaceous and woody annual and perennial monocotyledonous and dicotyledo-nous plants. Moreover, these compounds are herbici-dally effective for controlling weeds indigenous to both dry land and wet land areas. They are also useful as aquatic herbicides and are unique in their effec-tiveness in controlling the above-said plants when applied ~o the foliage thereof or to soil or water containing seeds or other propagating organs of said plants such as tubers, rhizomes or stolons, at rates of from about 0.016 to 4.0 kg/ha, and preferably at rates from about 0.032 to 2.0 kg/ha.
It is, of course, obvious that rates of application above the 4.0 kg/ha level can also be used to effectively kill undesirable plant species; ~owever, rates of application of toxicant above t~e level neces-sary to kill the undesirable plants should be avoided since application of excessive amounts of toxicant is cos~ly and serves no useful function in the environment.

~;~72'7~'~

Among the plants which may be controlled with the compounds of this invention are: Elatine triandra9 pygmaea, Scirpus hotarui, Cyperus serotinus, Ecli~ta alba, Cyperus _fformis, Rotala indica, Lindernia pyridoria, Echinochloa ~ ~8~ Digitaria ~ , Setaria viridis, Cyperus rotundus, Convol-vulus arvensis, A~ropyron repens, Datura stramonium, Alopercurus myosuroides, Ipomoea spp., Sida spinosa, Ambrosia artemisiifolia9 Eichhornia crassie~s, Xanthium pensylvanicum, Sesbania exaltata, Avena fatua, Abutilon theophrasti, Bromu_ tectorum, Sorghum halepense, Lolium , Panicum dichotomiflorum, Matricaria ~ , Amaran-thus retroflexus, Cirsium arvense and Rumex iaponicus.
It has been found that the formula (Ia) and - 15 (Ib) t2-imidazolin-2-yl)thieno- and furopyridines are generally selective herbicides, particularly effective for controlling undesirable weeds in the presence of leguminous crops such as soybean5, and cereal crops such as wheat, barley, oats and rye. However9 certain of the formula (Ia) and formula (Ib) compounds are less selective than others in this series.
It has also been found that several of the formula (Ia) and formula (Ib) (2-imidazolin-2-yl)-pyridines are effective as antilodging agents in cereal crops when applied at rates of application between about 0.016 to 4.0 kg hectare. At rates of application not exceeding about 0.010 kg per hectare, it has also been found that certain of the formula (Ia~ and formula (Ib) thieno- and furopyridines are effective for in-creasing branching of leguminous crops and tillering of cereal crops.

~ ~';72~

Since the formula (Ia) and formula (Ib) imidazolinylthieno- and furopyridines and derivatives, wherein R3 is a salt-forming cation, are water solublet these compounds can simply be dispersed in water and applied as a dilute aqueous spray to the foliage of plants or to soil containing propagating organs there-of. These salts also lend themselves to formulation as flowable concentrates.
The formula (Ia) and formula (Ib) (2-imidazo-lin-2-yl)thieno- and furopyridines and the formula (IIa) and formula ~IIb) imidazopyrrolopyridinediones can also be formulated as wettable powders, flow con-centrates, emulsifiable concentrates, granular formu-lations and the like.
Wettable powders can be prepared by grinding together about 20% to 45% by weight of a finely divided carrier such as kaolin, bentonite, diatomaceous earth, attapulgite, or the like, 45% to 80% by weight of the active compound, 2% to 5% by weight of a dispersing agent such as sodium lignosulfonate, and 2% to 5% by weight of a nonionic surfactant, such as octylphenoxy polyethoxy ethanol, nonylphenoxy polyethoxy ethanol or the like.
A typical flowable liquid can be prepared by admixing about 40% by weight of the active ingredient with about 2% by weight of a gelling agent such as bentonite, 3% by weight of a dispersing agent such as sodium lignosulfonate, 1% by weight of polyethylene glycol and 54% by weight of water.

~ 7~ 6l109-7237D

A typical ~mulslfiable concentrate can be preparc~ by dissolvin~ abou~ 5~ to 25~ by welcJht o~ ~he activ~ ln~Jre~lel-t ln about G5~ to 90% hy weight of N-metllylpyrrolidone, lsophorone, butyl cellosolve, methylacetate or the like and dispersiny therei about 5~ to 10% by weight of a nonionic surfactant such as an alkylphenoxy polyetlloxy alcohol. This concen~rate is dispersed in water for application as a liquid spray.
When the compounds of the inven~ion are to be used as herbicides where soil treatments are involved, the compounds may be prepared and applied as granular products. Preparation of the granular product can be achieved by dissolving the active compound in a solvent such as methylene chloride, N-methylpyrrolidone or the llke and spraying ~he thus prepared solution on a granular carrier such as corncob grlts, sand, attapulgite, kaolin or the like.
The granular product thus prepared generally comprises about 3~ to 20% by weight of the active ingredient and about 97 ~o 80~ by weight of the granular carrier.
In order to facilltate a further understanding of the invention of the parent and divisional applica~ion, the following examples are presented primarily for the purpose of illustrating certain more specific detalls thereof. The invention is not to be deemed 11mited thereby excapt as defined in the claims. Unless otherwise noted, all parts are by weight.

I hl. ' Preparation oE dimethyl thieno~ pyridine-5,6-dicarbox~late NHCO 2 P r i L~ ~L NH 2 DMAD

SPOC13/DMF ~ S ~C02CH3 ~ ~ IrC02CH31~ co2CH3 ~ ~ L-C02CH3 N
H

A mixture of isopropyl-3-thiophenecarbamate (177 g; 0.975 mol) in methanol (1.2 1) and water (2.8 1) containing sodium hydroxide (200 g) is heated at reflux for our hours. Methanol is removed under reduced ~ pressure and the cooled reaction extracted with ether ; (S 1), and these extracts are washed with water, aqueous sodium chloride and dried. Evaporation under reduced pressure afEords 3-aminothiophene as an oil in 57%
crude yield.

3-Aminothiophene is redissolved in methanol (500 mL) cooled in an ice bath and dimethylacetylene-~icarboxylate (80 g; 0.50 mol) is added dropwise. The mixture is stirred at room temperature for 15 hours and 30 minutes, the me~hanol removed under reduced pressure and 1,2-dichloroethane is added. This solvent is also evaporated off to give dimethyl 3-thienylaminobutene-dioate as an oil.

~, .. -, ...... . ..

A Vilsmeier reagent is prepared by adding dropwise, with stirring phosphorus oxychloride (86 g, 0.56 mol) to a cooled (5C) solution of DMF (41 g, 0.56 mol) in 1,2-dichloroethane (200 mL). This reagent is stirred at room temperature for one hour and 40 minutes, diluted with 1,2-dichloroethane (100 mL), cooled to 5C and then the above dimethyl ester dis-solved in 1,2-dichloroethane (400 mL) is added to the Vilsmeier reagent at 5C dropwise over a 25 minute period. The reaction temperature is raised to room temperature for 15 minutes, then to reflux for a further two hours and 25 minutes. The cooled reaction mixture is chromatographed directly on a silica gel column a~fording 3~.7 g (15%) oE dimethyl thieno[3,2-b ]pyridine-5,6-dicarboxylate mp 124-125.5C after crystallization from hexane-ethylacetate. A second crop 10.3 g with mp 121-124C is obtained giving an overall yield from isopropyl 3-thiophenecarbamate of 19%.
Utilizing the above procedure and substituting the appropriate substituted aminothiophene for isopropyl 3-aminothiophenecarbamate yields the compounds illus-trated below.

y,~ s ~COOR
Z I ~ ~ N/ ~ OOR

Y Z R mpC
-H H CH3 12~-127 Cl H CH3 149-151 ^w ~

Preparation of dime~yl thienoL3,2-bl pyridine-5,6-dicarb_xylate 1. H2S4 ~ S~CO2CH3 NHCOCH3 3 POC13/DMF Ll~ /~02CH3 To concentrated sulfuric acid (170 mL), stirred at room temperature is added in portions 3-acetylamino-2-formylthiophene (17~5 g, 0.103 ~ol). The mixture is heated at 50C for 30 minutes, cooled and poured into an ice-water mixture. After neutralizing with an excess of sodium acetate, the mixture is ether (1 x 2 mL) extracted. The organic layer was dried over anhydrous Na2S04 and stripped to a dark red gum con-sisting of 3-amino-2-formylthiophene. Dimethylacetyl-enedicarboxylate (DMAD) (13 mL) in acetic acid (5 mL), piperidine (5 mL), methylene chloride (100 mL) and toluene (100 mL) is added to the 3-amino-2-formylthio-phene and the mixture stirred overnight. Methylene chloride is removed by distillation and then the mixture heated at reflux for 24 hours. After cooling an addi-tional 13 mL of DMAD is added and the reaction heated to reflux again for seven and one-half hours. After standing for 60 hours at room temperature, the solvents are removed and the dimethyl thieno[3,2-b]pyridine-5,6-dicarboxylate product is obtained by chromatography, after eluting with hexane-ethyl acetate, mp 124 125C.

~ r Pre~aration of dimethyl 3-chloro[3,2-kL~ ne-5,6-dicarboxylate and dimethyl 2,3-dichlorothieno[3,2-~]-pyrid_ne-5,6-dicarboxylate / ~ C02CH3 C12 Cl S ~ 02CH3 ~ 02CH3 Cl ~ N/ ~ 02C~I3Cl ~ / ~ ~2CH3 A solution of dimethyl thienol3,2-b]pyridine-5,6-dicarboxylate (15 g 0.0525 mol) in acetic acid (680 mL) and sodium acetate (86 g, 0.093 mol) is main-tained at 58C while chlorine is slowly introduced during five hours and 45 minutes. After reaction is complete, the mixture is flushed with nitrogen, ethyl acetate ~200 mL) is added and solid sodium chloride filtered off and washed with ethyl acetate. The mother liquors and washes are combined and the solvents removed under reduced pressure. The residue is dissolved in methylene chloride and the solution washed with water, back extracted with methylene chloride and the combined methylene chloride layers washed with aqueous sodium bicarbonate, dried and stripped to give 18 g of solid.
Chromatography on silica gel with 15% ethyl acetate-hexane, then 20% ethyl acetate-hexane gives the 2,3-dichloro compound, mp 173-178C, 1.3 g, followed by the 3-chlorothieno compound mp 166-173C after crystalliza-tion from ethyl acetate-hexane.

~7~

~paration of dimethyl 3-bromothieno~3,2-b]pyridine-5,6-dicarboxylate S ~ 02CH3 Br~ ~ S ~ 02CH3 02cH3 Br I ~ f~ ~02CH3 N

A solution of bromine t20 g, 0.125 mol) in acetic acid (50 ml) ;s added dropwise over three hours to a solution of dimethyl thieno[3,2-b]pyridine~5,6-di-carboxylate, (26.3 g, 0.104 mol), containing sodium acetate (17.2 g, 0.2 mol) in acetic acid (300 mL) at 85C. Additional sodium acetate (18 g) and bromine (20 g) in acetic acid (50 mL) is added over an hour and the mixture stirred at 85C overnight. Bromine (10 g) is added in one portion then left at 85C for four hours. The mixture is cooled and treated with aqueous sodium bisulfite, diluted with ethyl acetate and con-centrated. The reaction product is partitioned between water and methylene chloride and the organic layer washed with aqueous sodium chloride and the solvent removed. The residue is washed with ether to give 25 g of crude product, mp 165-168C. Recrystallization from methanol gave needles of dimethyl 3-bromothieno[3,2-b]-pyridine-5,6-dicarboxylate, mp 168-16gC.

3~

Preparation of ~hicno[3,2-~]pyridine-5,6-di~ y~
acid _ .

02CH3 N OH~ 5\ ~ ~ 02H
O~CH3 H20 02H
N N

10Dimethyl thieno[3,2-b]pyridine-5,6-dicarboxy-late (3~75 g, 0.0149 mol) is added to a solution of sodium hydroxide (1.8 g, 0.045 mol) in water (~0 mL) and the mixture is warmed at 60C for 20 hours. The reaction mixture is diluted with water, cooled in an 15ice bath, and acidified by the addition of concentrated hydrochloric acid. A precipitate of thieno[3,2-b]-pyridine-5,6-dicarboxylic acid is filtered off and dried overnight to give 3.1 g (93%) mp >380C.
Utilizing the above procedure and substi-tuting the appropriate substituted thieno[3,2-b]-pyridine-5,6-dicarboxylic acid diester yields the compounds illustrated below.
.

; 25 y ~ a2H

N

.1~

~'7~';i'~8 ~36-Y Z mpC
H H >380 H Cl None taken H Br >380 H
H F
H CN

H NO~ -H N(CH3) 2 H SO2N (CH3) 2 C~,Hs H
- (CH2) 3-- (CH2) 4~
- (CH) 4~
Cl Cl H C6Hs : H C2H5 H SC6Hs H CHO
H CH2Cl ~72 ~ ~

EXAMPL~ 6 aration of 3-chlorothieno~3,2-~]pyridine 5,6-dicarboxylic acid anhydride cl~J_ COOH Cl ~

iO 3-Chlorothieno[3,2-b]pyridine-5,6-dicarboxylic acid (1.45 g) is heated at 85 to 90C for 30 minutes then 90 to 102C for 30 ~inutes in acetic anhydride ~7 mL). The reaction is cooled, the solids filtered off and washed with ether to give 1.2 g of 3-chloro-thieno[3,2-b]pyridine~5,6-dicarboxylic acid anhydride.
The proton magnetic resonance spectrum is consistant with the structure.
Utilizing the above procedure and substitu-ting the appropriate pyridine-5,6-dicarboxylic acid for ~ 3-chlorothieno[3,2-b]pyridine-5,6-dicarboxylic acid yields the compounds illustrated below.

z ~ O
N

1;~7~

- 3 ~ -Y Z ~pC
___ H Cl Sol id no mp obta ined H Br >380 Cl H
Cl Cl H N (CH3) 2 H F
. H
CH3 C~3 H CN

H S02N(CH3) 2 - ( CH2) 3 -- (CH2) 4- _ - (CH) 4 -H C6Hs C6Hs H
:~ H OC6Hs 30 . CF3 H

H C2Hs H CH2Cl .. ..

t~ 7,~

Preparation of 5-[(1 carbamoyl-~ lpro~ 3-chlorothieno ~

o + NH2~j:--CONH2 N o CH(CH3)2 ~ OOH fH3 Cl N
CH(CH3)2 2-Amino-2t3-dimethylbutyramide tO.71 g) all in one portion is added to a stirred solution of 3-chloro-~hieno[3,2-b]pyridine-5,6-dicarboxylic acid anhydride, (1.2 g) in THF (1~0 mL). After s~anding for five minutes, the ice bath is removed and the reaction stirred at room temperature for 28 hours. THF (5 mL) is added and the mixture hea~ed at reflux for two hours and then set aside overnight. The cooled mixture is filtered and the collected solid washed with ether to give 1.4 g of the desired 5-[(l-carbamoyl-1,2-dimethylpropyl~carbamoyl]-3-chlorothieno[3,2-b]pyridine-6-carboxylic acid.
Utilizing the above procedure and substituting the appropriate pyridine-5,6-dicarboxylic acid anhydride for 3-chlorothieno[3,2-b]pyridine-5,6 dicarboxylic acid anhydride and the appropriate aminoamide yields the compounds illustrated below.

~'~ 7~2 y ~ S ~ O~H ~1 Z I 1~ CONH ~ f~CONH2 _ Z Rl R2 mpC
H H CH3 i-C3~17 H Cl CH3 i_C3H7 not pure Cl H CH3 i_C3H7 Cl Cl CH3 i_C3H7 H Br C~13 i_C3H7 H CH3 CH3 i-C3H7 : H No2 CH3 i-C3H7 H N(CH3)2 CH3 i-C3H7 H SCH3 CH3 i_C3H7 : H OCH3 CH3 i_C3H7 CH3 H CH3 i-C3H7 H H CH3 C2~5 H OCHF2 CH3 i-C3H7 CH3 CH3 CH3 i_C3H7 H CN CH3 i_C3H7 H F CH3 i_C3H7 H I CH3 i_C3H7 H S02N(CH3)2 CH3 i_C3H7 C6H5 H CH3 i-C3H7 -(CH2)3- CH3 1-C3H7 -(CH2)4- CH3 1-C3H7 -~CH34- CH3 i-C3H7 ~2'~ 2 y Z Rl R2 I~.pc_ C2H5 H CH3 i-C3~17 : H 0C6H5 CH3 1_C3H7 H CH2Cl CH3 1_C3H7 CF3 H CH3 i_C3H7 H C2H5 CH3 1_C3H7 H CH0 CH3 1_C3~17 H CF3 CH3 1_C3H7 H SC6H5 CH3 i_C3H7 .
`:

~;.
.

:

-~2-lin-2-yl)thieno[3,2 ~]pyridine-6-carboxylic acid 5 S 2H S~
~C Ac~O ~ ~l O
--~ ~J CO2H N O
fH3 10NH2--f~CONH2 ~ S ~02H fH3 CH ( CH3 ) 2 1 ~ /~CONH--Cl -CONH2 CH ( CH 3 ) 2 ¦ 1. NaOH
12. H+

~CH~ ) 2 Thieno[3,2-b]pyridine-5,6-dicarboxylic acid (2.5 g, 0.011 mol) is heated slowly to 85C for one hour with acetic anhydride (25 mL), then cooled, fil-tered and washed with diethyl ether to give the anhy-dride as a solid, mp 266-267C. A mixture of the an-hydride and 2-amino-2,3-dimethylbutyramide (2.6 g, 0.02 mol) in THF (70 mL) is stirred at room temperature for 15 hours.
, !

~7~ 7 After heating at reElux for two hours, the mixture is cooled and diluted with THF (50 mL). Solid 5-[(1-car-bamoyl-1,2-dimethylpropyl)carbamoyl]thieno[3,2-b]-pyridine-6-carboxylic acid is filtered off, washed with ether and dried. The above solid is mixed with an aqueous 60 mL) solution of sodium hydrox;de (6 g 0.05 mol) and heated at 85C for two hours and 30 minutes, then set aside at room temperature overnight. Af~er cooling in an ice bath, the mixture is acidified to pH 3 with concentrated hydrochloric acid. A solid (3 g) is filtered off and dried. Crystallization from ethyl acetate affords (5-(5-isopropyl-5-methyl-4-oxo 2-imidazo-lin-2-yl)thieno~3,2-b]pyridine-6-carboxylic acid, mp 242-244C in 46% yield.
Utilizing the above procedure and substituting the appropriate pyridine-5,6-dicarboxylic acid for thieno[3,2-b]pyridine-5,6-dicarboxylic acid yields the compounds illustrated below.

Y~02H H3 /J~/~CH ( CH 3 ) 2 1' o H

y z mpC

H Cl 238-239 H Br 226-227 Cl H 247-248 3L2~'7~3 Y Z mpC
Cl Cl C~13 H N(CH3) 2 }~ CH
H So2N(cH3) 2 - (CH2) 3-(CH2)4- _ - (CH2) 4-H C6Hs H OC6Hs H C2Hs : H
H F
H CHO
H CH2Cl ' H CF3 _reparation of diethyl furo[3,2~ ridine-5,6-dicarbo-xylate ~ ~10 ~`~ 02C2Hs N~12 co2C2H5 3-Amino-2 formylfuran, prepared from 3-azido-2-formylfuran (8.9 g 0.065 mol) is dissolved in ethanol and to this solution diethyl oxalacetate (12.23 g, 0.065 mol) and ten drops of piperidine are added. In addition pulverized 3A molecular sieve is added and the reaction stirred at 65-60C for three hours, then additional diethyl oxalacetate (2.2 g) is added. The reaction is essentially complete ater 12 hours at 55 60C. On cooling the reaction is filtered, and the filtrate concentrated and then dissolved in ethyl ace-tate, water washed, then brine washed, dried over an hydrous magnesium sulfate and stripped to dryness. The residue is dissolved in 3:1 hexane:ethyl acetate and passed through a flash chromatographic column in two stages. First it is filtered by vacuum through a four to Eive inch pad of silica from which ~he last three fractions containing the required product are collected and combined. These combined fractions are then passed through a six inch column eluting under pressure with ethyl acetate:hexane 3:1 and 2.1. Diethyl furo[3,2~b]-pyridine-5,6-dicarboxylate 4.15 g (24%) is obtained after crystallization from hexane-ether, of mp 60-64C, and with a mass spectrum m/e of 264.

~'7~

Utilizing the above procedure and substituting the appropriate furan for 3-am:ino-2-formylfuran ylelds the compounds illustrated below.

Y- ~ ~ CO~R
z L ~ ",L C02R
N

y z R mpC
_ H Cl C2Hs CH3 c~3 C2H5 , ~:

~7~
-~7-Preparation_of iUIO 3 Z hlpYridi -5~6_dicarboxylic acid ~ 2C2H5 , ~ ~ C2 Furo[3,2-b]pyridine-5,6-dicarboxylic acid, diethyl ester (1.1 g, 0.0042 mol) is dissolved in 95%
ethanol (20 mL) containing 10% aqueous sodium hydroxide (20 mL) and set aside at 0C for two days. The mixture is cooled, acidified and the solvent removed under reduced pressure. Wa~er 5 mL is added and the hydrated product diacid obtained as a brown solid by filtration, ; 3.31 g (99%), mp 183C (dec). Anal calcd. as CgHsNOs.2 1/2 H2O C, 42.86; H,3.99; N,5.55 found:
C,42.63; H, 2.63; N,5.46.
. Utilizing the above procedure and substituting the appropriate furo[3,2-b]pyridine-5,6-dicarboxylic ester yields the compounds illustrated below.
Y Z R mpC
H H H 183 (dec) H Cl C2Hs : H CH3 C2Hs H C2~5 C2Hs CH3 CH3 C2~5 _r~e~ration of furo[3,2-b]pyridine-5,6--dicarboxylic acid anhydride ~ ~ o H ~ 0 FuroE3,2-b]pyridine-5,6-dicarboxylic acid (3.3 g, 0.0159 mol) in acetic anhydride (100 mL) is heated to 70-30C for six hours. The reaction mixture is cooled, Eiltered and the solid is washed with ether to give 3.01 (100%) of crude furo[3,2-b]pyridine-5,6-dicarboxylic acid anhydride.
Utilizing the above procedure and substituting the appropriate furo[3,2-b]pyridine-5,6-dicarboxylic acid yields ~he compounds illustrated below.
Y Z
H H
H Cl ; H CH3 H ~2H5 Preparation of 5-[(1-carbamoyl--1,2-dimethylpropyl)-carbamoyl]furo[3,2-b~pyridine-6-carboxylic acid and 5-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)furo-[3,2-b]pyrldine-6-carboxylic _c d ~ fH (CH3 )2 L~ ,1 / H2N--f~CONH2 N ~ CH3 ~ o ~ C02H fH3 CH ( CH3 ) 2 1. NaOH
2 . Ac id 2 5~ O ~COOH ~;H ( CH3 )2 ~ //L</N~H3 H

~7~2 Furo[3,2-b]pyridine-5,6-dicarboxylic acid anhydride (3.01 g, 0.015 mol) is suspended in THF
(lQ0 mL) to which 2-amino-2,3-dime~hylbutyramide (2.3 g, 0.018 mol) is added. After stirring for 20 hours, the solution is stripped to an oily solid which dissolves in a water/dilute sodium hydroxide solut;on. The alkaline solution is extracted with methylene chloride, and then acidified and reextracted with methylene chloride but on stirring only minute traces of material is isolated. The water layer is concentrated to an oily solid which is dissolved in ethanol, filtered and concentrated to a purple gum which is predominantly the crude product, 5-[(1-carbamoyl-1,2-dimethylpropyl)-carbamoyl]furo[3,2-b]pyridine-6-carboxylic acid and is used without further purification to prepare the final 2-imidazolin-2-yl product by dissolving it in 10%
sodium hydroxide solution (40 mL) and warming at 80C
for three hours. On cooling the reaction is acidified and a small am~unt of solid precipitated out and was filtered off. Concentration of mother liquors gives a second crop, which is collected and combined with the first crop. Purification is e~fected by taking half of the material and separating on silica gel preparative glass plates as bands. The slower running band using methylene chloride:ethyl acetate:chl~roform: methanol l:l:l:l as eluant, affords the desired 2-imidazolin-2-yl product9 mp 214-223C(dec), Esters may then be pre-pared by the procedures described in Example 20.

Utili~ing the above procedure and substituting the appropria~e furo[3,2-b~pyridine-5,6-dicarboxylic anhydride yields the compounds illustrated below.

~H ( CH3 ) 2 N O

y z mpC
_ _ H ~ 214-223 (dec) H Cl ~ CH3 H
: H CH3 : CH3 CH3 ' , ~'7~

__.
Prepara~ion of dime~hyl th _ o[2,3-b]pyridine-5L6-dicar-e -_ rC02CH3 DMF~,[~02CH3 ~ 5 1 N ~LCO2CH3 POC1302CH3 I
H

A Vilsmeier reagent is prepared by adding dropwise, with stirring, phosphorus oxychloride (40.29 g, 0.26 mol) to a cooled (10C) solution of DMF
(19.0 g, 0.26 mol) in 1,2-dichloroethane (40 mL) in an N2 atmosphere. This reagent is stirred at room tempera-: ture for one hour and 45 minutes. Dimethyl-2-thienyl-aminobutenedioate (63.4 g, 0.26 mol) dissolved in 1,2-dichloroethane (300 mL) is added dropwise to ~he Vilsmeier reagent at 7-10C. The reaction temperature is raised to room temperature for 15 minutes, then to reflux for 12 hours. The cooled reaction mixture is ` concentrated and the residue chromatographed on a silica gel column with ethyl acetate-hexane, affording dimethylthienol2,3-b3pyridine-5,6-dicarboxylate (29 g, 2S 45%) as a solid.

~0 ~,V~'~2'7 -~3-Utili~ing the above procedure and substituting the appropriate dimethyl-2-thienylaminobutenedioate yields the compounds illustrated below.

~ ~ 02CH3 S N O~CH3 y z mpC

6~l5 H
~F3 H
-(CH2)4- 118-121.5 ,~
. 20 '7~ 8 Preparation of dim_t~y~ othieno[2,3-bley_~ __e_ 5,6-dicarboxylate , ~ C02C~I3 Br2 Br- r ~ ~ 02CH3 C02CH3 NaOAc 02CH3 Bromine (0.33, 0.00206 mol) in acetic acid (8 mL) is added to a stirred solution of dimethyl-thieno[2,3-b]pyridine-5,6-dicarboxylate (0.5 g, 0.00187 mol) in acetic acid containing sodium acetate (0.31 g, 0.00377 mol) at 40C. The reaction mixture is heated at 75C for 18 hours. Evaluation of the mixture by tlc (sil;ca gel~ indicated incomplete reaction.
Additional bromine (0.33 g) in acetic acid and sodium acetate (0.31 g) is added and heating at 75C continued for six hours. The reaction mixture is diluted with water and extracted into ethyl acetate. The separated organic layer is dried over anhydrous MgS04, filtered, and the filtrate concentrated to an oil which solidifies ~; on standing. Crystallization of the crude product from ethyl acetate-hexanes yields the dimethyl 3-bromothieno-[2,3-b~pyridine-5,6-dicarboxylate as white needles mp 86-~7.5C.
This compound may be readily converted to a variety of substituted-thieno[2,3-b]pyridine compounds as illustrated below, while electrophilic substi~ution sueh as nitration or halogenation yields additional compounds listed below.

; 7 Z ~02CH3 S N O~CH3 Y Z mpC
H H
H Cl 104-110 H Br 86-87. 5 H
H F
H CN

H N(CH3) 2 H CHO
H CH2Cl H CH3 oil Cl Cl ~1 84-~9 H S02N(CH3) 2 -(CH2)4- 118.5 - 121.5 - (CH) 4- _ - ( CH2 ) 3 -H . OC6Hs T~ r~

Preparation oE thieno[2,3-~]pyridine-5,6-dica acid -r ~ _ 02CH3 KOH . ~ 2~J

A solution containing dimethyl th;eno~2,3-b]-pyridine-5,6-dicarboxylate (27.75 g, 0.11 mol) and potassium hydroxide (30.98 g, 0.55 mol) in methanol (200 mL) under a N2 atmosphere is heated at reflux for two hours. The reaction mixture is cooled and suffi-cient water added to dissolve any solids present before evaporating the mix~ure to dryness. The resulting solid is dissolved in a minimum volume of water, cooled in an ice bath and acidified with concentrated H2S04 to pH~l. Thieno[2,3-b~pyridine-5,6-dicarboxylic acid is filtered off and dried overnight to give 23.36 g mp 272-275~.
Utilizing the above procedure and substituting the appropriate substituted dialkylthienol2,3-b]-pyridine-5,6-dicarboxylate yields the compounds illus-~rated below.

~;~;p~,t~
- 57 - 61109~7287D
z ~ ~J c02H
Y -- S - ~-~CO2H

Y Z ~?C

H Cl > 300 H Br > 315 H
H F
H C~ -H N(CH3)2 H CH2Cl H CH3 180-183 (dec) Cl H
Cl Cl . C6H5 H
H S02N ( CH3 ) 2 -(CH2)3-- ( C~H2 ~ 4- 280-290 -(CH)4-'7 EXAMPLE: 16 Preparation of thieno[2,3-~]pyridlne-5,6-dicarboxylic anhydride rsf~o2H Ac20 ~\~0 Acetic anhydride (37.4 g, 0.366 mol) is added to a stirred suspension of thieno[2,3-b]pyridine-5,6-dicarboxylic acid (21.52 g, 0.096 mol) in dimethoxy-ethane (175 mL) in an inert N2 atmosphere. Upon addi-tion of pyridine (16.78 g, 0.21 mol) at room tempera-ture an exotherm to 45C is observed and a homogeneous solution results. The reaction mixture is then stirred at room temperature and the resulting solid Eiltered off, washed with ether and air dried to give 14.8 g (75%) of thieno~2,3-b]pyridine-5,6-dicarboxylic acid anhydride.
Utilizing the above procedure and substituting the appropriate substituted thieno[2,3-b]pyridine-5,6-dicarboxylic acid yields the compounds illustrated below.

727~B
~ 59 - 61 l09 -7287D
z~
Y S N~

Z mp C

H Br 228.5-231 H Cl 230-300 ( slow dec ) H
H F
H CN

N(CH3)2 ~ H N2 i H CHO
H CH2Cl Cl H
Cl Cl H S2~ (CH3) 2 -(cH2)3-- (CH2) 4- 220-222 -(C~1)4 H C2Hs ''! ,~
~`'`.1 ~'7~'7 Preparation of 6-[(1-carbamoyl-1,2-dime~hylpropyl)-carbamoyl]thieno~2,3-b]p~__dine-5-carboxylic_ cid ~ 5 R
~ ~H3 "l +H2N~f--CONH2 S N ~I~ CH(CH3)2 ~ ~ C02H fH3 /~ CONH--f ~ ONH2 S N
CHlCH3)2 2-Amino-2,3-dimethylbutyramide (9.84 g, 0.076 mol) is added to a stirred suspension of thieno-[2,3-b]pyridine-5,6-dicarboxylic acid anhydride (14.8 g, 0.072 mol) in THF under an inert atmosphere of N2 at room temperature. The dark solution is stirred at room temperature overnight and the resulting solid filtered off, washed with THF and air dried to give 17.35 g (72%) of 6~ carbamoyl-1,2-dimethylpropyl)carbamoyl]-thieno[2,3-b]pyridine-5-carboxylic acid.
Utilizing the above procedure and substituting the appropriate substituted thieno[2,3-b]pyridine-5,6-dicarboxylic acid ar.hydride yields the compounds illus-trated below.

z~CO~H fH3 Y CONH~f~CONH~
S N CH(CH3)2 y Z mD C_ H Br 176-178 H Cl 156-158 H H
H
H F
H CN

H N(CH3) 2 H CHO
H CH2Cl Cl H
Cl Cl C6H5 ~ _ H SO2N(CH3) 2 -(CH2)3-- (CH2) 4- sol id - ( CH) 4 -H OC6Hs ?~

1~7~7 Preparation of 6-(5-isopropyl-5-methyl-4-oxo-2-imidazo-lin-2-yl)~hieno[2,~-b~pyrldine-5-carboxylic acid S ~
l~ \ ~ C02H fH3 CH(CH3)2 ~ C02H H3 ~ S ~ / ~ /N ~ H(CH3)2 H

6-[(l~Carbamoyl-1,2-dimethylpropyl)carbamoyl]-: thieno~2,3-b~pyridine-5-carboxylic acid (17.35 g, : 20 0.052 mol) i5 added to water (225 mL) containing sodium hydroxide (10.35 g, 0.26 mol). The resulting basic : solution is heated at 80C for two hours and 45 minutes, cooled in an ice-water bath ancl acidified with 6N H2S04.
The product 6-(5-isopropyl-S-methyl-4-oxo-2-imidazolin-2-yl)thieno[2,3-b]pyridine-S-carboxylic acid is filtered off, washed with water and air dried yielding 1.54 g, 70.3%, mp 221-223C.

'7~8 -Pre~ara _ n of_5_______zo[1',2':1,2~pyrrolo[3,4-b]-thienol3,2-elpyridine-3~2~)_,5-dione, 2-iso~ro~ 2-methyl ~1~
N CH(C~3)2 IDCC

~ H(C~3~2 Dicyclohexylcarbodiimide (1.07 g, 0.005 mol) in methylene chloride (20 mL) is added dropwise to a stirred methylene chloride (30 mL) suspension o~ 6-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)thieno-[2,3-b]-5-carboxylic acid (1.5 g, 0.0047 mol) under an N2 atmosphere. After stirring the reaction mixture for 16 hours, it was clarified by filtration, concentrated to dryness and the resulting ma~erial purified by column chromatography on silica gel eluting with acetonitrile/
methylene chloride (1/2). The solid product was crystal-lized from toluene to give the pure 3,5-dione as white crystals mp 214.5-216.5C.

5-methyl 4-oxo-2-imidazolin-2-yl)thieno[2,3-glpyridine-5-carboxylate l- ~ N 0 HOH2CC--CH

S N N=CH(CH3)2 ~ CH2C-CH

N ~ H(CH3)2 Sodium hydride (2.4 g, 60%, 0.126 mol) is added to the 3,5-dione tO.9 g, 0.003 mol) in propargyl alcohol (25 mL) at 10C under an inert N2 atmosphere.
The reaction mixture is stirred at room temperature for 60 hours and then neutralized with a saturated ammonium chloride solution. The resultin~ mixture is concentrated on a rotary evaporator, diluted with water and extracted with ethyl ace~ate. The organic layer is separated, dried over anhydrous MgS04 and concentrated to dryness.
Purification of the product by column chroma-tography on silica gel with methylene chloride/acetoni-trile (85/15) yields 2-propynyl 6-(5-isopropyl-5-methyl-

4-oxo-2-imidazolin-2-yl)pyridine 5-carboxylate7 which after crystallization from toluene has a mp 188-189.5C.

~A
~72'7Z~

Utilizing the procedures of Examples 18, 19 and 20 and substituting the appropriate thieno [3,2-b]-pyridine or thieno [2,3-b]pyridine compounds, yields the compounds illustrated below~

Z ~ 02R3 ÇH(CH3)2 Y ~ S ~ N~

Y Z R~ mpC

H H H 220-223.5 (dec) H H -CH2C-CH 188-189.5 H H ~ 140-142 -. --CH2~ o J
:~ ICH3 29 H H CH2~=CH2 108-110 CH3 H H 225.5-227.5 H Br H 274-276 H Cl H 266-267 H NO2 -CH3 201-202.5C
H N02 H 260 (dec) Cl H H
Cl Cl H

H N(CH3)2 H

Z~

Y Z

H CN H
H S02N(CH3) 2 H

- (CH2) 3- H
- (CH2) 4 H
- (CH2) 4- H
H oC6H 5 H

H I H
H F H
~: H CH0 H
~ H CH2Cl H
-~ 20 H CF3 H
: H SC5H6 H

7'~

: y ~ S ~ C02R3 H(CH3)2 Z I I / k yN ~ H3 y z R3 mpC

H Cl H 238-239 H Br H 226-227 H H ~ 156-157 ~H2~ J
Cl H H 266-267 Cl I H

; 15 H F H
CH3 H ~ _ Cl Cl H
: H NO2 :~ H N(CH3)2 H

; H OCH3 H

H CHO H

H CN H
H SO2N(CH3)2H
C6Hs H H

iJ ~ 8 -6~ -Y Z R3 mpC
- (CH2) 3~ H
-(CH2)4- H
- (CH2) 4~ H
H C6~5 H

~2H5 H ~ _ H CH2Cl H
H SC6Hs H

:, ~' .

Prepara~ion of methyl 6-~4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-3-nitrothieno[2,3-b]pyridine-5-carboxy-1_ ~CO2CH3 ~H ( CH3 ) 2 ~5 ~ N/) </N~ 3 ¦HNO3 H

02N~CO2CH3 H ( CH3 ) 2 /~</~cH3 Methyl 6 (4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)thieno[2,3-b]pyridine-5-carboxylate (3.94 g, 0.0119 mol) is dissolved in 200 mL concen-trated H2S04 at room temperature. While cooling to 3C
in an ice bath, 1.5 mL (0.024 mol) concentrated HN03 is added, then the mixture is allowed to warm to room temperature. AEter three hours, the reaction mixture is poured onto ice, neutralized with solid NaHC03 to pH 6 and is extracted with methylene chloride. The extract is filtered, then dried over sodium sulfate, refiltered and concentrated to a yellow solid weighing 4.33 g (97%~, which upon crystallization from methanol water has mp 201-202.5G.

:

~70-reparation of 6-(4-isopropyl-4-methyl-5-oxo-2-imi azo-lin 2-yl)-3-nitrothienoL2~3-~]pyridine-5-carboxylic acid o2N I ~CO2CH3 ~H(C~3)2 S N ~H3 MeOH

02NT~C02H H(CH3 ) 2 <~ N=j~CH 3 S N N --O
H

The ester (1.0 g, .00266 mol) from Example 21 is stirred in lO0 mL methanol and lO mL 10% sodium ;~ hydroxide solution for 24 hours. Water (25 mL) is added and the methanol removed in vacuo. Acidification of the aqueous layer ~ives a brown precipitate which upon filtration and crystallization from methanol-water has mp 260C.

1~ 7~7 EXAMPL~ 23 Preparation oE diethyl 5-acetyl-1,6-dihydro-6-oxo-2,3-f~ (j)C2115 t;OOC2H5 5CH3--C--CH2~ NH2 ~ O~C~ C=O

jSodium acet~te CH3 Rf ~2C2~15 o 02C2H5 1' H

Sodium acetaee ~30 g, 0.37 mol~ is added to a stirred mixture of diethyl(ethoxymethylene)oxal-acetate (87 g, 0.36 mol) and acetoacetamide (36 g, 0.36 mol~ in absolute ethanol ~300 mL). After stirring the reaction mixture for 30 minutes, the ethanol is distilled off under reduced pressure9 the residue acidified to pH 2 with dilu~e aqueous hydrochloric acid and the resulting solid filtered off. Crystallization from an ethanol-water mixture affords diethyl 5-acetyl-1,6-dihydro-6-oxo-2,3-pyridinedicarboxylate as crystals mp 101-110C.

'~1~ ~, L~7;~7~1 3 -72~

__ yl acetonitrile (~H3)2CHC02CH3 + CH3CN

1. NaH
2. HCl ( CH3 ) 2CHCCH 2CN

NaH (61.55 g of 60% dispersion, 1.54 mol) is added to 650 mL anhydrous TH~ under N2. The suspension is heated to reflux. Methyl isobutyrate (lO0 g, 98 mol) and acetonitrile (63.16 g, 1.54 mol) are mixed in 140 mLs anhydrous THF and added dropwise over one hour to the refluxing suspension. The resulting solution is refluxed for 16 hours. Enough water is added to the reaction mixture to dissolve the salt that is formed. The THF
is removed in vacu_, and the basic aqueous solution is extracted with ether, then acidified to pH 4 with con-centrated HCl. The solution is extracted with ether.
The extracts are wasned with brine and dried over anhy-drous MgS04, filtered and the solvent is removed in vacuo, giving 97~25 g, (89.4%) of the title product ___ an orange oil.

1~7;~7~8 Preparation of diethyl-5 (2-methylpropionyl)-1,6-di-hvdro-6-oxo-2,3-pvridinedicarboxylate `: R =~C2H5 COOC2H5 (CH3)2CHCCH2CN ~ O ~ C=O
CH--OC2 Hs l~laOAc lo R
( CH 3 ) CH/ \ ~CO 2C2 H5 o ~C02c2H5 N
H

Isobutyl acetonitrile (50 g, 0.45) 24 and diethyl(ethoxymethylene)oxalacetate (110 g, 0.45 mol) are dissolved in absolute ethanol and then is added sodium acetate (36.9 g, 0.45 mol) and one drop of piperidine. After 12 hours, he mixture is concen-trated, acidified with dilute hydrochloric acid then extracted with methylene chloride. The extracts are concentrated and recrystallized to give the title product as a white solid 21.7 g (19.5%) mp 116-118C.

~'7~'7 74~
EXAMPL.E 26 Preearati_n of diethyl 5-(bromoacetyl)-1,6-dihydro-6~oxo-2,3 ~yridinedicarboxylate CH3-C // ~ 02C2H5 Br2BrCH2--C~ o2c2Hs 0 02C2H5 HBr 0 02C2H5 ' H H
Bromine (8.0 g, 0.050 mol) in 48% HBr is added dropwise to a stirred solution of diethyl-5-acetyl-1,6-dihydro-6-oxo-2,3-pyridinedicarboxylate (14.05 g, 0.05 mol) in 48% HBr (200 mL). Upon com-pletion of this bromine addition the reaction mixture is poured onto ice (200 g) and the mixture is stirred until the ice has melted. The crude product is col-lected by filtration and crystallized twice from an ethyl acetate-hexane mixture (1/2) affording diethyl

5-(bromoacetyl)~1,6-dihydro-6-oxo-2,3-pyridinedicarbo-xylate with mp 141-142C.
Utilizing the the above procedure using diethyl 2-methylpropionyl-2-pyridone-dicarboxylate yields diethyl 5-(2-bromo-2-methylpropionyl)-1,6-dihydro-6-oxo~2,3-pyridinedicarboxylate, mp 124-126C.

w75 _reparation of d;e~hyl 5-(2-bromo-l_hydroxyet:hyl)-1,6-dihydro-6~oxo-2,3-py~_dinedicarboxylate and diethy~
2,3-di~ydro-3-hydroxy~furo[2,3-b]pyridine-5,6-dicarbo-BrCH2-C ~ 02C2Hs N~BH4 0 ~ ~ 02C2H5 i-C3H70H
H
~H
BrCH2-CH ~ 2C2H~ (C2H5)3N
o=l~ o2C2H5 1' H

OH~C02C2H5 20~ 0 1~N ~ o2C2H5 Sodium borohydride ~2.54 g, 0.066 mol) is added in portions over a 30 minute period to a stirred suspension of diethyl 5-(bromoacetyl)-1,6-dihydro-6-oxo-2,3-pyridinedicarboxylate (57.2 g, 0.159 mol) at 10-20C. Upon completion of the sodium borohydride addition, the reaction mixture is stirred while attain-ing room temperature. Ice (100 g) is added and the mixture stirred until the ice has melted. The mixture is then concentrated in vacuo and the residue crystal-lized twice from an ethyl acetate-hexane mixture to give pure diethyl 5-(2-bromo-1-hydroxyethyl)-1,6-dihydro-6-oxo-2,3-pyridinedicarboxylate mp 134-138C.

`~
';7~

Stirring this compound with triethylamine (1.0 mL/g of solid) in methylene chloride for one hour, followed by washing the organic solution with dilute hydrochloric acid, water9 brine and drying over anhydrous MgS04 yields the crude furo[2,3-b]pyridine as an oil upon removing the solvent in vacuo. Crystallization Erom a cyclohexane-toluene mixture affords pure diethyl 2,3-dihydro-3-hydroxy-furo[2,3-b]pyridine-5,6 dicarboxylate ~p 73-77C.

'7'~

_ Preparation of diethyl 2,3-dihydro-3-methoxyfuro[273-.bl-~g~'~

Hl~
~C02C2~15 co2C2Hs O N

NaH
THF

.~
~C~3 ~C02Et C02Et Sodium hydride, 60% dispersion in mineral oil (2005 g, 0.0512 mol) and iodomethane (7.9 mL, 0.128 mol) are added to a solution of the hydroxy diester of Example 27 (12.00 g, 0.0427 mol) in tetrahydrofuran t400 mL) under N2. After stirring overnight at room temperature, the reaction is heated to 50C under a stream o N2 to remove excess iodomethane. The reaction is then cooled, filtered, stripped and chromatographed over silica gel. Eluting with hexane/ethyl acetate (4:1) gives the product as a yellow oil in 57.3% yield.
Calcd. for C14Hl7N06; C, 56.94; 4,5.80, N, 4.74. Found:
C, 56.93; H, 5.59; N, 4.83.

t7~7~3 -7~-r ~ ~dlne=~LL ~_ arbo _ _ .
xylate H0 ~ ~ 02C2H5 P toluene sulf~nic acid O~C2Hs~ xylene Q N

CC) 2C 2 H 5 A xylene solution of the hydroxy-furo com-pound obtained in Example 23, (3.7 ~) containing ~
toluene sulfonic acid (0.01 g) is heated at reflux for two hours. The solution is cooled and the xylene solu-tion decanted off. The residue is extracted with ether - and the extracts combined with the xylene. Distillation - of the solvents gives a yellow solid which is crystal-lized from a cyclohexane-~oluene mixture to give pure diethyl furo[293-b]pyridine-5,6-dicarboxylate mp 66-77C.

- 79 - 61l09-7287D

EXAMPL,E_30 Prepa ation o-f dimethyl_?. _e~yl-furo ~ ~3-5,6-dicarboxylate I _ ~ CO2CH3 - 0=~ , C02CH3 H

CuI DMSO
Pd(P~3)2C12 (C2H5)3N

~' /~--C02CH3 CH3 ~ 0 / ~ N/ ~ C02CH3 Propyne (3.0 mLs, 0.045 mol) is condensed in a graduated cylinder in a dry ice/acetone bath and added to a stirred sus-pension of dimethyl 1,6-dihydro-5-iodo-6-oxo-2,3-pyridinedi-carboxylate ~13.48 g, 0.04 mol), cuprous iodide (0.38 g, 0.002 mol) and bis(triphenylphosphine)palladium II) chlor~de (2.81 g, 0.004 mol) in 150 mLs DMS0 and 50 mLs triethylamine at 10C.
After addition of the propyne the reaction mixture is stirred at room temperature ~or 60 hours. Water is added and the mixture is extracted with ethyl acetate. The ethyl acetate solution is washed with water and dried over anhydrous MgS04~ then concent-rated ln vacuo to give a mixture of materials. The crude product is isolated by flash column chromatography using 9:1 methylene chloride, ethyl acetate. The fractions containing the title pro-duct are concentrated in vacuo and the residue is recrystallized from cyclohexane to give the pure compound mp 115-118C.

~,.
. ~ .

1~7~7;~B

-~o -Utilizing the above procedure and substituting the appropriate substituted acetylene yields the com-pounds illustrated below.

~ C02CH3 R ~ ~ /~ C02CH3 R ~

Phenyl 152-153 :~ 20 EXAMPL,E 31 Pre~_rat;on of diethyl 2,3-d~ydro-3~3-dimethylfur [2,3-~]pyridine-5,6-dicarbo~ylate 5(CH3)2f----c ~ 2C2~5 Br o ~ ~ C02C2H~ 3 ~2toluene H sulfonic acid CH3 ~02C2H5 HO-~02C2H5 15(major) (minor) The 5-(2-bromo-2-methylpropy ketone diester of Example 26 (20 g, 0.052 mol) is dissolved in 200 mL
absolute ethanol and 3.0 g sodium borohydride (0.078 mol) is added at 0C, the temperature is then allowed to rise gradually to 15C. After the mixture is stirred for one additional hour, the ethanol is removed in vacuo.
The solidified mass is treated with water and extracted with methylene chloride. The organic extract is then washed wi~h water and a saturated sodium chloride solution, dried and concentrated. The residue, weighing 12 g is redissolved in xylene and 1.0 g p-toluenesulfonic acid is added. The solution is refluxed for 12 hours then cooled. The xylene solution is decanted and the residue washed with several portions of ether. The combined organic solutions are concentrated then chromatographed with 9:1 methylene chloride/ethyl acetate to obtain 3.2 g of the oily diester ~21~/o); mass spectrum M ~ l/e = 294.

From a later chromatographic Eraction is obtained 1.4 g of 2,2-dimethyl-3-hydroxyfuro[2,3-b]-pyridine-5,6~dicarboxylate (11.5%).

~7 EXAMPLF, 32 Pr~ tion of diethyl 3-bromofuro[2,3-_]pyridine-5,6-dicarboxylate ~ ~ 1. Br r~ 5 O N 2C2~15 2. DBU o N O~C2H5 The diester of Example 29 (6.0 g, 0.0228 mol) is dissolved in 200 mL methylene chloride containing 4.6 g sodium acetate, and bromine is added (7.3 g, 0.0556 mol) at reflux. Following the addition, the mixture was stirred for 15 minutes at reflux, then eooled, washed with aqueous sodium bisulfite, dried with sodium sulÇate and filtered. The filtrate was stripped to 8.8 g o~ the crude dibromo compound which was redissolved in methylene c hloride and treated with 3.16 g DBU (0.021 mol) at room temperature for 30 minutes. The mixture was then concentrated in vacuo, and chromatographed over silica gel with hexane-ethylacetate to give 7~1 g (90%) of the diethyl 3-bromo-furo[2,3-b]pyridine-5,6-dicarboxylate mono bromo diester mp 49.5-52C.

5 7 6-dicarboxylate Br O N

NclOAc ¦
Br2 Br Br~(~cC02C2H5 B r~ C02C2 H5 H N

¦DBU

Br I ~ \`rC02C2Hs Br~~ J~ /; C02C2Hs O N

-~5-Sodium acetate (2.40 g, 0.0292 mol) and bromine (7.5 mL, 0.146 mol) are added to a solution of die~hyl 3-bromofuro[2,3-b]pyridine-5,6-dicarboxylate (5.00 g, 0.0146 mol) in methylene chloride (150 mL).
The mixture is stirred at room temperature for four days then washed with aqueous sodium bisulfate to remove unreacted bromine. The aqueous solutian is then back extracted with methylene chloride. The organic solu~ion is combined, dried over sodium sulfate and filtered. To the filtrate is added 1,8-diazabicyclo-[5.4.0]undec-7-ene(4.4 mL, 0.032 mol), and the mixture is st-rred at room temperature for one hour. The solu-tion is then concentrated in vacuo. The residue is chromatographed over silica gel eluting with 20% ethyl acetate in hexane, yielding the crude 2,3-dibromofuro-12,3-b]pyridine as a white solid in 95% yields recrystal-lization from a methylene chloride-hexane mixture affords diethyl 2,3-dibromofurol2,3-b]pyridine-5,6-dicarboxylate mp 96-98C in 75.9% recrystallized yield.

2~

, .... . . ~

2'~7 _reparation of diethyl 3-trifluoromethyl~
pyridine-5,6-dicarbox~late 5~1 ~ C02Et LC02Et CF3CO2Nc O N

10N-methylpyrrolidone ¦CUI

CF3 r ~ CO~Et C02Et To a solution of sodium trifluoroacetate ; (0.0234 mol) in N-methylpyrrolidone (50 mL) is added 3-bromofuropyridine of Example 32 (2.02, 0.00585 mol) and cuprous iodide (2.2 g, 0.0119 mol). The mixture is heated to 160C for three hours under N2, cooled to room temperature, treated with EtOAc (100 mL) and hexene (100 mL), and filtered. The filtrate is washed with H20 (4x~00 mL), dried over Na2S04 and stripped ~o an oil which is chromaEographed over silica gel with hexane-ETOAc (7:3) elution. The product is collected as a pale yellow solid; mp 50-55C.

..

~L~ 7~ d3~

EXAMPL,E 3 5 Preparation of turo[2,3-~]~ ridine-5,6-dicarboxylic acid _ r~ 02c2~15 K011 ~ 02~1 Potassium hydroxide (5.60 g, 85%, 0.087 mol) in water (5 mL) is added ~o a stirred suspension of diethyl furo[2,3-b]pyridine-5,6-dicarboxylate (9.3 g, 0.035 mol) in absolute ethanol (100 mL). The reaction mixture is heated at 60C for one hour, then cooled and anhydrous acetone added. The precipitate is ~iltered off, dried, suspended in dry acetone and treated with hydrogen chloride to adjust to a pH of 2. Crystal-lization of the isolated solids from an ethyl ace~ate-acetone mixture affords furo[2,3-b]pyridine-5,6-dicar-boxylic acid mp 189-192C.

Pre~aration_of furo[2,3-b3~yridine-5,6-dicarboxylic anhydride C02H ~cetic_anhydride /,LCO2H

D N ~

Furo[2,3-b]pyridine-5,6-dicarboxylic acid (6.7 g, 0.032 mol) is heated at 60C for 30 minutes in acetic anhydride (150 mL~. The reaction mixture is cooled to room temperature and concentrated ln vacuo and the residue triturated with cyclohexane-ether(5:1), filtered off and dried to give 5.35 g furo[2,3-b]-pyridine-5,6-dicarboxylic acid anhydride.

7~47V~;~

~5~lLa~r~ f ~ carbamoy~ 2-dimethylpropyl)-carbamoyl]=furo[2,3-b]pyridine-5-carboxylic acid R
~: ~ fH3 ~ ~ J " ~ NH2--cl~ONH2 O N ~ CH(CH3)2 02H fH3 ONH--Ç--CONH2 O N CH(cH3)2 2-Amino-2,3-dimethylbutyramide (2.1 g, 0.016 mol~ is added to a stirred suspension of furo-~: [213-b~pyridine-5,6-dicarboxylic acid anhydride (3.0 ~, 0.016 mol) in tetrahydrofuran (7.5 mL) and the mixture allowed to stir at room temperature for 16 hours. The reaction mixture is then stirred at 60C for one hour, cooled to room temperature, et~er added, and the solid filtered off and dried to give 5 g of 6-[(1-carbamoyl-1,2-dimethylpropyl)carbamoyl]furo[2,3-b]pyridine-5-carboxylic acid mp 192-196C (dec).

7~1~

-so -Preparation of 6-(4-iso~ropyl-4-methyl~S-oxo-2-imidazo-lin-2-yl)furo~2,3-b]pyridine-5-carboxylic acid ~co2H fH3 H20 o ~ N/~CONH--CI~ONH2 Nc10H
CH ( CH3 ) 2 ~02H H3 ~ o~ /,L</N~H(CH3)2 H
A solution containing 6-[(1-carbamoyl-1,2-dimethylpropyl)carbamoyl]furo[2,3-b~pyridine-5-carbo-xylic acid (3.8 g, 0.012 mol) ;n aqueous sodium hydroxide 2.4 g, 0.06 mol) in water (40 mL) is stirred at 65C for three hours. The reaction mixture is t~en heated at 75C for one hour, a:Llowed to cool, poured into ice, acidified to pH 2-3 and the resulting solid filtered off and dried. Crystallization from an acetone-methanol mixture affords pure 6-t4-isopropyl-4-methyl-5-oxo-2-imidazolin~2-yl)furo[2,3-blpyridine-5-carboxylic acid mp 237-244C.

Preparation of 6-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-3-nit ofuro[2,3-b~pyridine-5-carboxylic acid COOH

\O ~ N J ~ N ~ CI-I(CH3)2 N --- O

Sulfolane N02 ~
COOH
O~N~ E(CH3)2 I . O
H
~ itryl hexafluorophosphate (0.75 g, 0.00391 mol) is added to a suspension of 6-(4-isopropyl-4-methyl-5-oxo-2-imidazo-lin-2-yl)-furo[2,3-b] pyridine-5-carboxylic acid (1.07 g, 0.00355 mol) in sulfolane (63 mL) under nitrogen. The temperature of the reaction is maintained between 64C and 8$C for three days during which time the solids dissolve. The mixture is cooled to 30C and chromatographed over silica gel. Elution with 1:1 hexane to ethyl acetate removes the sulfolane. Elution with 1% to 10 methanol in methylene chloride followed by recrystalli2ation from acetone-hexane yields 6-(4-isopropyl-4-methyl-5-oxo-2-imida~olin-2-yl)-3-nitro-furoC2,3-b]pyridine-5-carboxylic acid, mp 220-237C

~L~ B

Pre aration of 2 iso ro 1-2-methyl-5H-furo[2,3-b]-. . P _ . P PY
im dazo[2',1'.5,1]pyrrolo[3,4-~]pyridine-3(2H),5-dione ~C02H

O N ~N --o N= ~CH ( CH 3 ) 2 Ac20 DME
Pyr dine G ~ ~ ~ H(CH3)2 To a suspension of 6-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-furo[2,3-b]-pyridine-5-car-boxylic acid (11.7 g, 0.039 mol) in lO0 mL dimethoxy-ethane (DME) is added 7.3 mL acetic anhydride and 3.9 mL pyridine. After stirring 24 hours at room temperature, the solids are filtered and washed wi~h ether and the mother liquor is concentrated by adding xylene to aid removal of pyridine. The residue is triturated with ether to obtain solids which are combined with the first crop to give 11.1 g (100%) of product. Recrystallization from 2:1 ethyl acetate-hexane gives an analytical sample mp 193-205C.

~ 7 Preparation of methyl 6-(4-isopropyl-4~methy~5-oxo-2-imidazolin-2-yl)-furo[2,3-b]pyridine-5-carboxylate ~CH(CH3):Z

¦ MeOH
l NaOMe ~ -CO~CH3 0 N ~ \ ~ CH(CH3)~

The compound prepared in Example 40 (10.5 g, 0.037 mol) is suspended in 150 mL absolute methanol and 4.0 g sodium methoxide is added. After stirring for 72 hours at room temperature the mixture is poured onto ice containing acetic acid to maintain the pH at 3-4.
A white solid forms and is filtered yielding 9.8 g (84%) of the title compound with mp 134-137G.

~w~

_9~,_ Preparation of methyl 3-chloro-6-(4~ o~_____ethyl-5-oxo-2-imidazolin-2-yl)-furo[2_3-~]pyridine-5-carboxylate ~1 Cl2 l~N2H
N ~0 2. DBU O N =
N- I CH(CH3)2 N ¦- CH(C~13)2 The methyl ester described in Example 40 is dissolved (1.4 g, 4.4 mmol) in 20 mL acetic acid and sodium acetate (1.0 g, 12.2 mmol) is added. Gaseous chlorine is passed into the stirred solution for two hours during which time the temperature reaches 40C.
After cooling and pouring onto 50 g ice, the mixture is extracted with ethyl acetate, washed with distilled water then with saturated sodium carbonate solution.
The organic layer is then concentrated to a foam, re-dissolved in 20 mL methylene chloride and treated with 10 mL diazabicyclo-[5.4.0]undec-5-ene (DBU). After ten minutes, the mixture is treated with 20 nlL cold dilute hydrochloric acid. The methylene chloride layer is removed, dried over anhydrous magnesium sulfate. The solution is then passed through a one-quarter inch pad of silica gel and concentrated in vacuo. Recrystalliza-tion from hexane-ethyl acetate gives 0.85 g (57%) of the 3-chloro compound mp 150-156C.

.2~'7;~

Preparation of 3-chloro-6-(4-isopropyl-4~ y~
oxo 2-imidazolin-2-~,1)-furol2,3-b~ pyridine-5-carbox~'lic acid 2cH3 C02H
1. NaOH I I ~ H
O N ~ \ ~ 2. Mel O N ~ N---lt-0 N t CH(CH3)2 N ¦-CH(CH3)2 CH3 C~3 The ester from Example 42 ~0.55 g, 1.157 mmol) is dissolved in 10 mL 95% ethanol and 0.28 g 50% sodium hydroxide solution is added. After one hour the mix-: 20 ture is treated with 10% hydrochloric acid to pH 2, and the product separates as a solid, which is filtered, dried and recrystallized from acetone to give 0.35 g (67.3%) mp 239-240C.

. .

Preparation of (+)-6-(4-isopropyl-4-methy~-S-oxo-2-imidazolin 2-~1?-furo[2,3-~]~yridine-5-carboxylic acid ~ C02H ~H3 CH(CH3)2 O N N___L=o H
(~)-iso~er Furo~2,3-b]pyridine-5,6-Dicarboxylic anhydride (2.50 g, 0.013 mol~ is suspended in 40 mLs anhydrous THF and (+)-2-amino-2,3-dimethylbutyramide (1.72 g, 0.013 mol) is added. The mixture is stirred under N2 a~ room temperature for 16 hours. The solution is poured into 150 mLs anhydrous ether, and the resulting solid is collected in 88.6% crude yield. The unpuri-fied adduct is converted to the indicated product in the manner described in Example 38 for the racemic mixture. The (~)-isomer is recrystallized from absolute ethanol, and is isolated in 27.0% yield ~rom the adduct.,mp 244-245C E~ = 44 5 ~-~ 7 Pre.para_ion_of sodium 6-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)furo[_2,3-b]pyridine-5-carboxylate Il ~02H
O N ~ - o N - ~ H(CH3)2 ¦NaOH
MeOH

r ~ 2- Na~
O N ~ ~ = O
H(CH3)2 NaOH ~0.13 g, .0033 mol) is dissolved in 50 mLs anhydrous methanol under N2. The Eree car-boxylic acid (1.00 g, .0033 mol) is added, dissolving to give a yellow solution. The solvent is removed in vacuo to give a yellow oil. The oil is dissolved in anhydrous ethanol and the solvent removed in vacuo to give a solid. The solid is dissolved in anhydrous ethanol and reprecipitated with anhydrous ether9 giving 0.60 g (56.1%) of the title sodium salt as a yellow solid, mp 240->2S0C.

'7 -98~

Preparation of 6-(4-isopropy1-4 methyl-5-oxo-2-imidazo-lin-2-yl)furo~2,3-b]pyridine-5-carboxy~ate ~compound with isopropylamine (1:1) . COOH
N ~H3 ~ NH2CH(CH3~2 O N ~/ ~CH(CH3) 2 ~ ,1 o H
CH30H Acetone ~COO H3NCH ( CH3 ) 2 O N'~ CH(CH3)2 N O
H

Isopropylamine (0.25 mL, 0.00266 mol) is added to a suspension of the carboxylic acid (0.80 g, 0.00266 mL) and methanol (SO mL). The reaction is stirred at room temperature for one-half hour, during which time all the solids dissolve. The solvent is removed in vacuo, and the residue is slurried in ether and filtered, yielding the isopropyl amine salt in 78.1% yield, mp 100-220C with slow decomposition.

' 35 .r Preparation oE imldazolin-2-yl thieno- and ~uro-~ridines Utilizing the procedures oE the preceeding examples and substituting the appropriate thieno or furol3,2-b~pyridine or thieno or furo~2,3-b]pyridine compounds, yields the compounds illustrated below.

Z T~C02R3 H ( CH3 ) 2 Y~ X ~J~ N /~L</~

X Y Z R3 mpC

S H H H 220-223.5 (dec) S H H -CH2C_CH 188-189.5 S H H ~ 14G-142 -C~2-~ O ~
~H3 S H H -CH2~=CH2 108-110 S CH3 H H 225.5-227.5 S H Br H 274-276 S H Cl H 266-267 S H No2 CH3 201-202.5 S H NO2 H 260 (dec~
S Cl Cl H
S H N(CH3)2 H
S H SC6Hs H

7~3 - 1 o o -X Y Z R3 mpC
_~ _ _ ____ 0 H Cl H 239-240 0 H Br H 239-245 : 0 C2H5 H H 170-172 O C6Hs H H 244 245 S Cl H H 268 (dec) S - t CH2) 4 ~ H 234 - 237 O H SC~Hs H

0 H H - CH2 - - ~ J 137-141 O

: S Cl H ~NH3-CH(CH3) 2 Anal:
ok f or S and Cl .
S H S02N(CH3) 2 H
S C6H~ H H
S -(CH2)3- H
S -(CH)4- H

, S C2H5 H H
.. H C2H5 H
S H I H
S H F H
S H CHO H

O H N0~ H 220-237 (dec) X Y Z R3 rnpC
O H N(CH3) 2 O Cl H H -0 Cl Cl H

O H CN .H
0 H S02N~CH3)2 H
O -(CH2)4- H
O -(CH2)~ - H
- (CH) 4- H
O H C6Hs H
0 H OC6Hs H

o H C2H5 H
O H I H
O H F H

O H CH2Cl H

127:~7~1 y ~ ~ 02R3 H(CH3)2 Z ~ / ~ ~ ~ CH3 H

X Y Z R3 ~IpC

S H Cl H 238~239 S H Br H 226-227 S H H ~ 156-157 ~H2l~ J
o S Cl H H 266-267 O H Cl H

: O CH3 H H
o C2H5 H H

CH3 ~H3 H
S H CN H

S H No2 H
S H N(CH3)2 : S H OCH3 H

S Cl Cl H

',~

X Y Z R3 mpC
__ S H S02N(CH3) 2 H
S C6H5 H ' H
S H C6Hs H
S -(CH2)3- H
S - (CH2)4- H
S - (CH) 4 w H
S H OC~Hs H

S H I H
S H F H
S H CHO H
S H CH2Cl H

S H SC6Hs H
~.
, ~0 V~2'~

Preparation of 6--(4-isopropyl-4-methyl-5-thioxo-2-lmida-zolin-2-yl)-furo[2,3-b]pyridine-5-carboxylic acid H

5,6-Dicarboxylic anhydride-furo[2,3-b]pyridine (1.35 g, 0.0071 mol) is suspended in 25 mLs anhydrous THF and 2-amino-2,3-dimethylthiobutyramide (1.04 g, 0.0071 mol) is added. The mixture is stirred under N2 at room temperature for three hours. The suspended solid is collected and the filtrate is stripped to a solid. The combined yield is 2.30 g ~96~2D/o)~ Both solids arc added together to KOH (1.91 g, 0.034 mol) in 20 mLs water. The solution is warmed to 60C for four hours, then stirred at room temperature for 16 hours.
The slightly cloudy solution is filtered to give a clear filtrate, which is acidified to pH 4 with 10%
HCl. The resulting yellow solid is collected and re-fluxed in 100 mLs xylene for 16 hours. The indicated product crystallized from the xylene solution in 28.0%
yield, mp 231-232C dec.
In the same manner as described above for the furo[2,3-b]pyridine compound, 6-(4-isopropyl-4-methyl-5-thioxo-2-imidazolin-2-yl)-thieno[2,3-b]pyridine-5-carbo-xylic acid is prepared in 37% yield having a mp 242C.

Preparation of 2,3-dihydro-6-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)furo[2,3 b]~yridine-5-carboxylic acid ~ ~ H(CH3)2 H2 ~ 02H H3 ~o 1\N~ CH(CH3)2 A solution of 6-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)furo[2,3-D3pyridine-5-carboxylic acid (1.7 g 0.056 mol) and 1.0 g (0.0972 mol) potassium carbonate in 200 mL 9:1 ethanol:water is added to 100 mg 5% palladium on carbon catalyst in a 500 mL pressure bottle. The bottle is ~itted to a Parr hydrogenation apparatus, pressurized to 30 psi, with hydrogen, then shaken at room ~emperature for 10 hours. The catalyst is removed by filtration through a sintered ~lass fun-nel, and the filtrate concentrated in vacuo to 10 mL.
Acidification of the residue to pH 2 gives a white precipitate which is removed by filtration, washed with water and air dried to give 1.0 g (63%) of 2,3-dihydro-

6-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)furo-[2,3-b]pyridine-5-carboxylic acid as an off-white solid, mp 189-192C.

By the above procedure, a solution of 5-(4-isopropyl~4-methyl-5-oxo-2-imidazolin-2-yl)furo[3,2-b]-pyridine (400 mg) may be converted to 2,3-dihydro-5-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)furo[3,2-b]-pyridine-6-carboxylic acid, mp 205-206C.

EXAMPLE .50 Preparation of 4-mer~5s~ EL~

CH3CSH + BrCH2CH2CH2CN
R

CH3~C--S~ H2CH2CH2CN

Thiolacetic acid (49 mL, 0.69 mol) is added to potassium carbonate (93.4 g, 0.68 mol) dissolved in water (150 mL~. Ethanol (260 mI.) is added and then 4-bromobutyronitrile is added at 15 to 28C and the reaction mixture stirred at room temperature for 16 hours. The resulting inorganic solids are filtered oEf and the filtrate extracted with toluene. The organic layer is separated, dried over anhydrous Na2S04 and concentrated to give the desired 4-mercaptoacetyl butyronitrile as a yellow oil~

,7 Preparation of dihydrothiophenimine hydrochloride CH3--C--S--CH2--CH2CH~CN HCl r~
~ S ,~NH HCl Hydrogen chloride is introduced to a cooled solution of the nitrile in methanol (220 mL) for one hour and the mixture then stirred at room temperature for 16 hours. The resulting product is filtered off, washed with ether and dried to give 55.38 g of dihydro-thiophenimine hydrochloride, mp 189-195C.

~DV ,~, P paration of dimeth~ [(tetrahydro-2-th enylidene)-amino]fumarate (and maleate)acid 1~ fO2CH3 ~ ~ NH HCl ~ C f fj,"~:O2CH3 ,C--C02CH3 Dimethylacetylenedicarboxylate (0.45 mL, 15 0.037 mol) is added to a stirred solution of dihydro-thiophenimine hydrochloride (0.5 g, 0.0036 mol) in methanol (60 mL) containing sodium acetate (0.3 g, O.OQ36 mol) under an inert N2 atmosphere at -15C.
After stirring for 16 hours at room temperature, the 20 solvent is removed on a rotary evaporator and the resulting mixture separated by column chromatography on ~ silica gel eluting with a methylene chloride-aceto-: nitrile mixture (19:1) yielding 0.68 g (78% yield) of the desired mixed isomeric acid esters as a yellow oil.

t' Y ~

- 1 1 0 -' Preparation o dimethyl 2L3-dih~drothieno[2,3-b]-pyridine-5,6-dicarboxylate ~02CH3 oxal yl chlorLde _ 1I DMF
S ~ N ~CO 2CH3 ~ co2CH3 A Vilsmeier reagent is prepared by adding oxalyl chloride (0.25 mL, 0.0028 mol) to a stirred solution of DMF (0.22 mL, 0.0028 mol) in 1,2-dichloro-ethane (50 mL) at room temperature in an inert N2 at-mosphere. A 1,2-dichloroethane (50 mL) solution of dimethyl {(tetrahydro-2-thienylidine)amino]fumarate (and maleate) (0.0028 mol) is added to the Vilsmeier reagent and the reaction mixture heated at reflux for four hours. The reaction mixture is quenched with water, made basic with sodium bicarbonate and the organic layer separated and dried over anhydrous Na2SO4.
The solvent is removed in vacuo and the residue purified by column chromatography on silica gel, eluting with a methylene chloride-acetonitrile mixture (19:1). Crystallization from toluene-hexane affords dimethyl 2,3-dihydrothieno[2,3-b]pyridine-5,6-dicarboxylate as a white solid with mp 102-103.5C.

"~

EXAMPLE_54 Prepara~ion oE 2,3-dihydro-6-(5-isopropyl-5-methyl-4-oxo-2~imidazolin-2-yl)thieno[2,3-b]pyridine-S-carboxylic acid, l-oxide ~C02H

S N ~ N ~Fo N TCH(CH3)2 CH2Cl 2 m~CPBA

~\ C02H CH3 .~ S N /~ CH ( CH3 ) ~=0 m-Chloroperbenzoic acid (2.0 g, 0.0094 mol) is added to a solution of the dihydro thieno pyridine in methylene chloride (400 mL) and methanol (40 mL) at 0C under a nitrogen atmosphere. After stirring for 16 hours while attaining 18C, water 100 mL is added, followed by the addition of 1~0 mL of a saturated NaHC03 solution. The aqueous layer is separated off and washed with methylene chloride. Acidification with concentrated HCl, precipitates m-chlorobenzoic acid ; 30 which is removed by filtration prior to adjusting the pH of the aqueous layer to pH 1. Extraction of this acidified layer with methylene chloride and removal of the solvent yields the title product as a white solid, mp 216-218C dec.

~ff~ ~

Preearation of diethyl d~hydrothieno[3,2-b]pyridine-S=L
--O

Piperidine ¦

`~ N~ ~ =~ N~

~ I ) _ ( I I ) ~C2 H5 HC~
~ f_CO2C2H5 ,c~

. I

~02C2H5 o2C2H5 * ~ ~7 ~o a solution o te~rahydrothiophene-3-one tMaybridge Chem. Co; 20.0 g, 0.196 mol) in benzene (100 mL), stirred at room temperature, is added piperi-dine (16.7 g, 0.196 mol) and ~-toluenesulfonic acid monohydrate (0.20 g, 0.001 mol). The mixture is heated at reflux under a Dean-Stark trap for four hours, cooled and stripped to a dark brown oil consisting of a 1:1 mixture of 2,3- and 2,5-dihydrothiophene enamines (I
and II; Recl. Trav. Chim., 92, 865(1973).
To the above enamine mixture is added ethanol (lOQ mL) and diethyl ethoxymethylene oxalacetic carbo xylate (72.1 g, 0.294 mol) and the mixture is stirred for 45 minutes. Ammonium acetate (45.3 g, 0.588 mol) is added in one portion and the mixture is heated at reflux for 45 minutes. After cooling, the solvents are stripped and the yellow oily diethyl dihydrothieno[3,2-b]-pyridine-5,6-dicarboxylate product is obtained by chromatography after eluting with hexane-ethyl acetate.
The mass spectrum shows the parent peak tm+l/e) at 282.

~d~ 7~ 72 Preparation of diethyl 5,7-dihydrothieno[3,4-~]pyridine-2,3-dicarboxylate and diethyl-2,3-dihydrofuro[3,2-bJ -pyridine-5,6-dicarboxyl~te 0~
O
Piperidine¦

=L N~' ~ ~LN~>

f_CO2C2H5 " ~
co2C2H5 = 2C2H5 - ,,, ~ ,. . -, .

~L~7Z'7 To a solution of tetrahydrofuran-3-one (J.
Pharm. Sci, 59 1678(1970); 46.55 g, 0.540 mol) in benzene (250 mL), stirred at room temperature, is added piperidine (45.98 g, 0.540 mol) and ~-toluenesulfonic acid monohydrate (0.46 g, 0.002 mol). The mixture is heated at reElux under a Dean-Stark trap for four hours, cooled and stripped to a dark brown oil con-sisting of a 1:1 mixture of 2,3- and 2,5-dihydrothio-phene enamines. Then ethanol (500 mL) and diethyl ethoxymethylene oxalacetic carboxylate (178.79 g, 1.35 mol) is added and stirring continued for 45 minutes. Ammo-nium acetate (124.87 g (1.62 mol) is added and the mixture is heated at reflux for 45 minutes. After cooling, the solvents are removed and the yellow oily diethyl dihydrofuro[3,2-b]pyridine-5,6-carboxylate is purified by chromatography on silica gel, eluting with hexane-ethyl acetate. The mass spectrum shows the parent peak (m+l/e) at 266.

:, . '' ''~

`:t!h.............................................. .. _~
'.~1 -11.6-.
Preparation oE 2,3~dihydro-5 and 6-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl) furo and thieno-[2,3-b]
and [372-b]pyridines Utilizing the procedures of Examples 8, 10, 12, 15, 18, 27, 35, 36, 37, 38, 49, 53, 54, 5S an 56 yields the dihydro compou~ds illustra~ed below.

z~C02R3 H(cH3)2 X N ~
Y' X Y Y' Z Z' R3 mpC

S=0 H H H H H 216-218 O H H H H H 189-lg2 : 20 0 H H CH3 CH3 ~ 193-198 Y' y ~ X ~ C2R3 CH(CH3)2 1, N ~ t ~
H

; X Y Y' Z Z' R3 mpC

` 'NW
~ 7 Postemergence herbicidal evaluation of test compounds The postemergence herbicidal activiey of the compounds of the present invention is demonstrated by the following tests, wherein a variety of monocotyledo nous and dicotyledonous plants are treated with test compounds dispersed in aqueous acetone mixtures. In the tests, seedling plants are grown in jiffy flats for about two weeks. The test compounds are dispersed in 50/50 acetone/water mixtures containing 0.5% TWEEN~ 20, a polyoxyethylene sorbitan monolaurate surfactant of Atlas Chemical Industries, in sufficient quantities to provide the equivale~t of about 0.16 kg to 10 kg per hectare of active compound when applied to the plants through a spray nozzle operating at 40 psig for a pre-determined time. After spraying, the plants are placedon greenhouse benches and are cared for in the usual manner, commensurate with conventional greenhouse prac~
tices. From four to five weeks after treatment, the seedling plants, are examined and rated according to 20 the rating system provided below. The data obtained are recorded in Table I below.
% DiEference in Growth Rating Systemfrom the Check*
_ 0 - No Effect 0 2~ 1 Possible effect 1-10 2 - Slight effect 11-25 3 - Moderate effect 26-40 5 - Definite injury 41-60 6 - Herbicidal effect 61-75 t 30 7 - Good herbicidal effect76-90 8 - Approaching complete kill91-99 9 Complete kill 100 4 - Abnormal growth, that is, a definite physiological malformation but with an over-all effect less than a 5 on the rating scale.

~2'~2 ~Z8 In most cases the data are for a single testl but in several instances, they are average values obtained from more than one test.
Plant Speeies Used Barnyardgrass (Echinochloa crusgalli) Green foxtail (Setaria viridis) Purple Nutsedge (Cyperus rotundus L.) Wild Oats (Avena fatua) Quack~rass (Agropyron repens) Field Bindweed (Convolvulus arvensis L.) Cocklebur (Xanthium pensylvanicum) Morningglory (Ipomoea purpurea) Ragweed (Ambrosia artemisiifolia) Velvetleaf (Abutilon th_~phrasti) Barley (Hordeum vul~are) Corn (Zea mays) Rice (Oryza sativa) Soybean (Glycine max) Sunflower (Helianthus annus) Wheat (Triticum aestivum) - l:L9 - 61109--72~37D

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F.XAMPLE 59 Preemer ence herbicidal evaluation of test compounds _ g . _ _.__ _ _ The preemergence herbicidal activity of the compounds of the present invention is exemplified by the following tests in which the seeds of a variety of monocotyledonous and dicotyledonous plants are separa-tely mixed with potting soil and planted on top of approximately one inch of soil in separate pint cups.
After planting, the cups are sprayed with the selected aqueous acetone solution containing test compound in sufficient quantity to provide the equivalent of about 0.016 to 10 kg per hectare of test compound per cup.
The treated cups are then placed on greenhouse benches, watered and cared for in accordance with conventional greenhouse procedures. From four to five weeks after treatment, the tests are terminated and each cup is examined and rated according to the rating system set forth above. The herbicidal proficiency of the active ingredients of the present invention is evident from the test results which are recorded in Table II below.
Where more than one test is involved for a given com-pound, the data are averaged.

7~ ~

- 124 - 611.09~7287D

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-1~8-P t_~rowth re~ulant evaluation of the compounds The plant growth regulant activity of the compounds of the present invention is demonstrated by the following test, wherein barley (H_rdeum ~ ) is treated with a test compound dissolved in aqueous ace-tone. In the test., the compound dissolved acetone/
water mixtures S0/50 containing 0.25% by volume of Colloidal Multi-film X-77~surfactant (alkylarylpolyoxy ethyleneglycols, free fatty acids and isopropanol) of Colloidal Products Corporation (Petaluma, California) in sufficient quantities to provide the equivalent of about 0.00625 kg to 0.10 kg per hectare of active com-pound when applied to the plants when the first node is detectable (Zadok~30). After spraying, the plants are lS placed on greenhouse benches and are cared for in the usual manner, commensurate with conventional greenhouse practices. From 11 to 12 weeks after treatment the plants are measured and harvested. The heads are removed and dried for 48 hours at 85 to 90C and weights recorded~ The data obtained are recorded in Table III
below ~a27~

TABLE III
Plant growth regulant activity test Total %
Rate Head Increase Compound ~ Replicate Dry wtlg Head wt Untreated control - 1 56.7 - 2 55.9 - 3 60.6 Average 57.7 Furfuryl 6-(4-iso- 0.10 1 64.6 pro w1-4-methyl-5- 2 68.2 oxu-2-imidazolin- 3 66.1 2-yl)-thieno[2,3-bj- Average 66.3 14.9 pyridine;-5-carboxylate 0.05 1 66.6 2 74.1 3 77.7 Average 72.8 26.1 : 0.025 1 5~.9 2 70.6 :: 3 68.7 Average 64.0 10.9 0.0125 1 64.~
2 72.6 ~5 3 75~5 Average 71.0 23.0 0.00625 1 58.6 2 67.5 3 68.4 Average 64.9 12.5

Claims (7)

29,348 THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A compound having the structure:

(c) (d) wherein ? represents a single or a double bond; R1 is C1-C4 alkyl; R2 is C1-C4 alkyl or C3-C6 cycloalkyl; and when R1 and R2 are taken together with the carbon to which they are attached they may represent C3-C6 cycloalkyl optionally substituted with methyl;
X is O, S, or, where ? is a single bond, >S=O; Y and Y' Z and Z' are hydrogen, halogen, C1-C6 alkyl, C1-C4 hydroxyloweralkyl, C1-C6 alkoxy, C1-C6 acryloxy, benzoyloxy optionally substituted with one or two C1-C4 alkyl, C1-C4 alkoxy, halogen; C1-C4 alkylthio, phenoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, nitro, cyano, C1-C4 alkylamino, C1-C4 dialkylamino, C1-C4 alkylsulfonyl or phenyl optionally substituted with one or two C1-C4 alkyl, C1-C4 alkoxy, 29,348 halogen, or any combination of two of these groups and whereLn Y
and Z are the same group provided that Y and Z are H, halogen, alkyl or alkoxy, and when Y and Y' or Z and Z' are the same group they are hydrogen or alkyl; and, when taken together, Y and Z may form a ring in which YZ are represented by the structure -(CH2)n-, where n is an integer selected from 3 or 4; or ,where L, M, Q and R7 each represent hydrogen, halogen, nitro, C1-C4 loweralkyl, C1-C4 loweralkoxy, methoxy, phenyl and phenoxy, with the proviso that only one of L, M, Q or R7, may represent a substituent other than hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy; and when R1 and R2 are not the same, the optical isomers thereof, or an acid addition salt thereof.

2. A compound according to claim 1 wherein Y is hydrogen or methyl and Z is hydrogen, bromine or chlorine.

3. 5H-Imidazo[1',2':1,2]pyrrolo[3,4-b]-thieno[3,2-e]pyridine-3(2H), 5-dione, 2-isopropyl-2-methyl.

4. 2-Isopropyl-2-methyl-5H-furo[2,3-b]-imidazo [2',1':5,1]pyrrolo[3,4-e]pyridine-3(2H); 5-dione.

5. A method for the control of monocotyledonous and dicotyledonous annual, perennial and aquatic plant species comprising: applying to the foliage of said plants or to soil or water containing seeds or other propagating organs thereof, a herbicidally effective amount of a compound according to claim 1.

29,348

6. A method for regulating the growth of plants and increasing the yield of graminaceous and leguminous crops, comprising applying to the foliage of said plants and plant growth regulating effective amount of a compound according to claim 1.

7. A process for preparing a compound according to claim 1 which process comprises cyclizing a compound of the formula:

wherein R1, R2, X, Y, Y', Z and Z' are as defined in claim 1, and, if required forming an acid addition salt thereof.