CA1273958A - 2,3-dichlorophenacylamine - Google Patents

Abstract

ABSTRACT
Novel 2,3- dichlorophenacylamine of the formula

Description

73~

This is a divisional application of application Serial No. 490,3~1 filed September 10, 1985.
The parent application relates to a novel process for the preparation of 4-phenylpyrrole derivatives of the forrnula I

n ~ Rl (I) wherein Rl is CN, CHO or COO(Cl-C6)alkyl, R2 is hydrogen, CH2CH2CN
or CH2CH2COO(Cl-C6)alkyl, R is halogen, Cl-C6alkyl or Cl-C6halo-alkyl, and n is 0, 1 or 2.
This application relates to novel 2,3~dichlorophenacyl-amine of the formula ~ C~CH2-NH2 Cl Cl or an acid addition salt thereof.
It should be noted that in this specification the term "invention" includes the subject matter of both the parent and the divisional applications.
Depending on the indicated number of carbon atoms, alkyl by itself or as moiety of another substituent, such as haloalkyl and the like, comprises e.g. the following straight chain or branched groups: methyl, ethyl, propyl, butyl, pentyl, hexyl etc., and the isomers thereof, e.g. isopropyl, isobutyl, tert-butyl, isopentyl etc. Throughout this specification, a substituent pre-fixed by "halo" will be understood as meaning that said substituent ~k ~æ~
~la- 21489-6789D

may be monohalogenated or perhaloyenated. Halogen and halo signify in particular fluorine, chlorine or bromine. Hence halo-alkyl denotes a monohalogenated to perhalogenated alkyl radical, e-g- CHC12, CH2F, CC13, CH2Cl, CHF2, CH2CH2Br, C2C15, CHBr~
CHBrC1 etc., with CF3 being preferred.

`' ~.. Z~8 , 4-Phenylpyrrole derivatlve3 of formula I, whereln n is O, 1 or 27 Rl i9 cyano and R2 i3 hydrogen or acetyl, are ~nown an plant funglcldes from GPrman Offanlegungggchrlft 29 27 4801). A~ wlll be shown below, compounds of formula I, wherein Rl i8 CHO or COO(CI-C6)-alkyl or R2 1~ CH2CH2CN or C~lzCH2COO(CI-C6)alkyl~ can be ~onverted in simple manner lnto thc known fungicldal 4-phenyl-3-cyanopyrroles and thu~ have the charscter of intermediates.

A proce~s for the preparation of 4-phenyl-3-cyanopyrrole derlvatlve~
whlch ~ known from Tatrahedron Lett0ra No. 52, pp. 5337-5340, l~722), is dlsclo~ed ln Ger~an Offenlegungsschrlft 29 27 4801). In thls process, known as the TosMIC process, a cinnamic acld derl-vatlve of formula X

(X) -CH~CH-CN

n ba6e (NaH) t ~ -CN
- CH3--~ ~--SO2~ (XXX) (XX) CH3-~ SO2CHzNC

19 cycll~ed wlth tosyl methyl lsocyanlde (XX) [TosMIC], in the presence of a ~trong base, e.g. sodlum hydrlde, to glva 4-phenyl-3-cyanopyrrole derivatives of formula (XXX). In the above formulae, R is a~ defined for formula I and n i8 O, 1 or 2.

Although numerous pyrrole syntheses are known (q.v. J.M. Patterson, Synthe~ia 1976, pp. 281-304 )), only the TosMIC procaas outllned above has so far led direct to the fungicidally useful 4-phenyl-3-cyanopyrrole derlvatlves. However, reference 2) indlcate~ for the preparstlon of 4-phenyl-3 cyanopyrrole a yield of only 35 Yo, whlch 18 low for lnduDtrial purposes. It has been found that the reagent TosMIC has grave dlsadvantAges for lndu~trial syntheses. For example, at elevated temperatures above 90C (normal drying con-ditlon~), TosMIC has the propensity to decompose exploslvely. On the `~ ~L2~

other hand, resldual moisture consumes some of the bafle employed (danger of hyd~olysls/reduction in yield). Further, TosMIC hns physlologlcal haæards and cause~3 savare lrrltatlon to the eyes and skin.

The flhortcomings referred to above show that useful laboratory methods are unsuitable for the industrial production of 4-phenyl-pyrrole derivatives. A novel, more economic and environmentally more acceptable process f~r the preparation of these compounds in surprlsingly high yield has now been found.

The novel process of th~s lnvention for the preparatlon of the 4-phenylpyrrole derivatives of the formula I as defined at the outset comprises reacting a phenacylamine of formula II

~ -CH2-~H (II) R~ 2 ln the form of an acid addition salt, wlth a compound of formula III

T-CH~C~-Rl (III) to give an intermediate of formula IV

~ ~-C-CH2- ~ CH~CH-Rl (IV) and cyclislng this compound of formula IV, in the presence of a base, to a co~pound of formula I. In the formulae II, III and IV
sbove, the subfltituents Rl, R2 and Rn are afl defined for formula I, T is a group selected from -OZ, -N(R3)~R4), -OCORa, -oso2Rb~ -SRC or halogen, where Z is Cl-C6alkyl, unsubfltituted or flubstituted phenyl, an alkali metal atom or an alkal~ne earth metal atom, each of R and Rb independently of ~he other is Cl-C6alkyl or unsubstituted or ~ubstituted phenyl, Rc 13 cl-c3alkyl~ cl-c3haloalkyl or unflub-~tltuted or substituted phenyl; and each of R3 and R4 lndependently of the other i8 Cl-C6alkyl or, together wlth the amine nitrogen atom, form ~ saturated 5- or 6-membered h0terocycllc rlng which contalns, a~ het~ro atom, elther only th~ amine nltrogen atom or further hetero atom.

An unsubstituted or substituted phenyl group 1~ ln particular phenyl or phenyl which is sub3tltuted ln the para-position by halogen, preferably chlorine or bromine, and by Cl-C3alkyl, preferably methyl. Alkall metal atom3 or alkallne earth metal atoms may be Ll, Na and ~, preferably Na and K, or Mg, Ca, Sr snd Ba, preferably Mg, CA and Ba. Where the -N(R3)(R4) group denotes a saturated 5- or S-membered heterocycllc ring containing N a~ hetero atom or a further hetero atom, ssid ring may be selected from the following heterocycllc ring sy~tems: pyrrolldine, piperazine, perhydro-thlazine, morpholine, piperazine, oxazolidlne, thiazolldine, imidazolidinel pyrazoline and the llke. A further hetero atom 1 prefersbly N, O or S.

In the procefis of this invention it is not necessary to isolate the intermedinte (IV) first and then to cyclis0 it to co~pounds of formula I. To the contrary, the reaction of (II) wlth (III) may also be carried out direct ln the pre6ence of a base, utillsing a slngle reactlon vessel for both steps, to give the flnal product~. In thi~
procedure, the lntermedlate (IV) is further processed dlrect without ~solstion. On the other hand, it may be convenient to prepare the ~ntermedlate (IV) first in especially pure form, e.g. by repeated recrystAlllsatlon, and then to cycllse lt to a compound of formula I. A preferred embodiment of the process of this invention accord-lngly comprises reactlng the phenacylamlne II ln the form of an acid addltion salt, in the presence of a base, direct with a compound of formula III to glve the final product I.

The second preferred embodlment of the process comprises first reacting the phenacylamine II in thè form of an acld addition salt, ln the absence of a base, to glve the intermediate (IV) and then converting (IV) to (I) by cycllsatlon ln the presence of a base.

The reactant~ (II), (III) and, where appropriate, (IV), are con-venlently employed in equimolar amounts. It is pref~rred to add an equlmolar amount or an excess of baaa.

Typical representatives of the compound~ of formula III, the list of whloh i9 not exhau~3tiva, are tha following compou~ds a) to t), of which compound~ a) to 1) ars particularly advantag~ou~3 and thflrefor~
pref~rred:

a) ~CH3)2N-CH~CH-CN
b) (CzHs)2N-CH~CH-CN
_ --c) ~ ~N-CH#CH-CN
_ --_--d) ! ~N-CH-CH-CN

e) ¢ ~N-CH-CH-CN
f) NaO-CN~CH-CN
g) ~O-CH-CH-CN
h) (CH3)2N-CH~CH-COOCH3 i) (C2Hs)2N-CH~-CH- COOCH3 k) (CH3)zN-CH~CH-CHO
1 ) ( C 2 Hs)z N-CHnCH-CHO
m) Cl-CH~CH-CN
n) Cl-CH~CH-COOCH3 o) CH302SO-CH~CH-CN
p) [C6R4CH3(4)~-CH~CH-CN
q) CH30-CN~CH-CN
r) C2HsO-CH-CH-CN
~) C3H70-CH~CH-CN
t) [C6H4Cl~4)]0-CH~CH-COOCE~3 The proce~s of thl6 invention la conveniently carried out in an inert solvent or mlxture of solvents. Thus one or more inert ~olvents or diluent~ may be employe~. Examples of suitable solventa and diluents are: allphatlc and aromatic hydrocarbona ~uch as benzene, toluene, xylenes, petroleum ether; halog0nated hydrocarbons such as chlorobenzene, methylene chloride, ethyl0ne chlorlde, chloroform, carbon tetrachloride, tetrachloroethylene; ether~ and ethereal compounds such as dialkyl ethers (diethyl ether, diiso-propyl ether, tert-butylmethyl ether etc.), anisole, dioxane, tetrahydrofuran; nitriles such as scetonitrile and propionitrile;
N,N-dinlkylated amide3 such as dimethylformamide; dimethylsulfoxide;
ketonea such as acetone, diethyl ketone, methyl ethyl ketone;
alcohol3, in particular me~hanol, Qthsnol, prGpanols, butanolD and the like; and water snd aqueous two-phase mixtura0 and mlxtures of the above solvent~.

The follow~ng solvents for example are suitable for the organi.c water-immiscible phase: aliphatic and aromatic hydrocarbon~ such as pentane, xylenes etc.; kdlogenated hydrocarbons such as dichloro~
methane, chloroform, carbon tetrachloride, ethylene dlchloride, 1,2-dichloroethane, tetrachloroethylene and the like, or aliphatic ethers 3uch as diethyl ether, dilsopropyl ether, tert-butylmethyl ether and the like. The addition of a phase transfer catalyst may be Advantageous. Examples of suitable phase transfer catalysts are:
tetraalkylammonium halides, hydrogen sulfate~ or hydroxides, e.g.
tetrabutylammonlum chloride, tetrabutylammonium bromide, tetrabutyl-ammonium lodide, triethylbenzylammonium chloride or triethylbenzyl-ammonlum bromide, tetrapropylammonlum chloride, tetrapropylammonium bromlde or tetrapropylammonium iodlde etc. Suitable phase transfer cataly~ts are also phosphonlum salts. The ammonium salt of for-mula II itself acts as phase trsnafer catalyst.

Particularly suitable 601vents are nitriles and lower alkanols~
preferably acetonitrile and ethanol, as well as mixtures of alkanol/water (ethanol/water).

In all partlal steps and in the single ve~sel reactlon, the reaction temperaturas are generally in the range from 0 to ~120~7C, pre-ferably from +30 to ~80C.

Owing to the reduced thermal stabillty of the ntartlng phenacyl-amine, the compound of formula II i9 employed ln the form of its more ~3table ammonlum salt, which can be obtained by conventlonal additlon of an organic or inorganic acid to the free amine.

ExAmples of salt-forming aclds sre inorganic eclds, e.g. hydrohalic acid~ such a~ hydrofluori¢ acid, hydrochloric acld, hydrobromic acid or hydriodic acid, as well as sulfuric acid, phosphoric acid, phosphorous acld, nitric acid and the llke; and organic acids such - as acetic acld, trlfluoroacetic acid, trichloroacetic acid, pro-pionlc acld, glycollic acid, lactlc acid, succinlc acid, ben~.oic acid, cinnamlc scid, oxallc acid, formic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, salicyclic acid,

2-phenoxybenzoic acid or 2-acetoxyben~olc acid and the like.

Preferred salt-form~ng acids are ~trong acidn 3uch as the hytrohalic acids, pho~phoric acld, nitric acld; and the zulfonic acids such as p-toluenesulfonic acid. Hydrochlorlc acid i~ especially preferred.

The reaction of (II) with (III) direct to give (I), or of (IV) to glve (I), i9 conducted in the presence of a base. Examples of suitable bases are lnorganic bases such as the oxldes, hydrides, hydroxides, carbonates, carboxylic acid ~3alts and alcoholates of alkaline earth metals, preferably of alkall metals, in partlcular of ~30dium and potasslum [e.g. NaH, NaOH, KOH, Na2CO3, KzCO3~ CaC03, CH3COONa, CZHscooK7 CzHsoNa~ CH30Na and the like], preferably the alkall metal alcoholates such as sodium ethylate or sodium methylate. Suitable organlc ba~e~3 are e.g. triethylamine, plperidine, pyridine, 4-dimethylaminopyridlne and the like.

In the proces~ea of thl~ invention, intermediatQs ~nd final product~
may be isolated from the resction medium and, if deslred, purlfied by one of the commonly employet m~thods, for example by 0xtractlon, crystallisation, chromatography, diDtillation and the like. How0ver, the preparation of the compounda of formula I can be carried out generally in good yield and in excellent purity utili~ing a ~ingle ve~sQl for both reflction step~ wlthout i~olation of lntermediate~.

Preferred embodiments of the procesa of this invention are e.g.
tho~e which compri~e:

9) the use of starting material~ of formula II, wherein R 18 halogen, preferably fluorine, chlorlne or bromlne, most pre-ferably chlorlne, n i8 1 or prefersbly 2, with the proviso that, if n i9 2, the ortho- and meta-positions are particularly preferred, Rl is CN and R2 i9 hydrogen;

b) the u~e of reagent~ of formula III, wherein T 1~ a group ~elected from -N(CH3)2, -N(C2Hs)2, 0 , -OK or -ONa, and R~ i9 CN, COOCH3 or CHO, preferably CN;

c) the u~e of intermediate~ of formula IV, ~herein Rl, Rz and Rn ara as deflned in a) and b) above;

d) the use of acid addltlon sslt~ of formula II, whlch contain, a~
scid component, a hydrohalic scid, prefersbly hydrochloric scld, a ~ulfonlc acid, preferably benzenesulfonic or p-tolueneaulfonlc acid, or ~ulfurlc acid;

e) csrrying out the reaction of (II) with (III) such that the lntermediate IV i8 further proce~sed direct without isolation;

_ 9 _ f) carrying out the process in the temperature range from ~30 to ~80C.

Accordingly, a particularly preferred embodiment of the proces~ of the invention comprises reacting 2r3-dichlorophenacylamlne in the form of an scid additlon salt, prefarably in the form of tho hydrochlorida, with a compound of formula III, wheraln R~ i~ CN and T i8 a group ~electod from -N(CH3)2, ._ . , _ . , _, ~ o -OK or ~ONn prefsrably -N(CHI)2~ ¢ ~- or -N~ ~0 to give 3-(2,3-dlchlorophenacylemino)acrylonltrlle, and cycllslng this intermediate, elther as substance or preferably ln sltu, ln the presence of a base, preferably of a lower alkanolate, sodium hydroxlde, potassium hydroxido, ~odlum scetate, potassium acetate or 8 trl-lower alkylamine, to glve 4-(2,3-dlchlorophenyl)-3-cyano-pyrrole.

Most of the startlng materlals of formula II are known or can be prepared in similar manner to the known repre~entatives. However, 2,3-dlchlorophenacylamine and the acid addition salts thereof are novel. In vlew of its structure, thls compound is de3tlned for use a~ intermediate for the preparatlon of fungicidally active 4-(2,3-dlchlorophenyl)-3-cyanopyrrole and therefore constltutas an ob~ect of thls lnventlon. It~ prepsration will be described expllcitly below.

Compounds of formula II, whereln R2 is CHzCHzCN or CH2cH2coo(cl-c6) alkyl, can be prepared e.g. as follows from the starting phenacyl-amines (II) (R2 ~ H): The acld additlon salt (e.g. the HCl salt)of an N-~ubstitutod phenacylamine of formula II is roacted, in tho - lo -presence of an equlmolar amount of acrylonltrile or of a Cl-C6alkyl ester of acrylic acid, preferably in the preDence of one of ths bases specified abov0 and under the conditions for the rea~tion of (II), with (III) to give (I).

Within the scope of the present invention, typlcal representatlves of compounds of formula I are for exampl~ the compounds li0ted in Table 1.

Table l: Compound~ of formula II

~ ~_CR_cH2-NH-R2 (II) R #-Compoond _Rn R2 1.2 3-Cl H
1.3 2,4-C12 H
1.4 4-Cl H
l.5 4-F
1.6 3-CH3 H
1.7 3-~ H
l.8 3~Br H
l.9 3-CF3 H
l.lO 2-Cl H
l.ll 2,3-C12 H
l.l2 2,5-C12 H
l.l3 2-Br H
l.14 2,6-C12 ~l 1.15 H CH2CH2CN
1.16 3-Cl CH2CH~CN
l.l7 2-Cl CdzCH~CN

Table 1 (continustion) Compound Rn R2 . ~_. _ 1.18 2,3-Clz CHzCH2CN
l.l9 3-F CH2CH2CN
1.20 3-Cl CH2CH2COOCH3 1.21 2,3-ClzCH2CH2COOCH3 1.22 2-Cl C~i2CI~2C00CII3 1.23 2,3-C12CH2CH2C00C2Hs 1.24 2,3-ClzCH2CH2COOC3H7 1 . 2 5 2 -Br 'CH 2CH2COOCH~

The compounds of ormula III are in general commercially available and thus known substancea or compounds which can be prepassd ln similar manner to their known representatives.

The preparstion of the intermediates of formula IV 1~ an obJect of the pr2sent lnvention and ha~ been described in detail above. These intermediates IV can be converted by simple basic cyclisation into the useful fungicides of formula I, have themselves fungicidal activity, and Rccordingly constitute an es~ential ob~ect of the present invention.

Within the scope of this lnventlon, typical representatives of intermediates of formula IV are:

Table 2: Compounds of the formula ~ CH2-~-CH~CH Rl (IV) Compound Rn R~ ~1 . .~, 2.1 H H CN
2.2 3-Cl _ . CN

7~

Tabl~ 2: (continuation) _ _ Compound Rn Rz Rl 2.3 2,4-Cl H CN
2.4 4-Cl H CN
2.5 4-F H CN
2.6 3-CH3 ll CN
2.7 3-F H CN
2.8 3-Br H CN
2.9 3-CF3 , H CN
2.l0 2-Cl H CN
2.11 2,3-C12 H CN
2.12 2,5-Clz H CN
2.13 2-Br H CN
2.14 2,6-Clz H CN
2.15 2,3-C12 B COOCH3 2.16 H H CHO
2.17 3-Cl H COOCH3 2.18 3,4-C12 B COOCH3 2.19 2-Cl H COOCH3 2.20 2,3-Clz H COOC3H7 2.21 2,3-C12 CH2CH2COOCH3 CN
2.22 2,3-C12 CH~CHzCN CN
2.23 H CH2CH2CN CN
2.24 3-Cl CHzCH2CN CN
2.25 2-Cl CH2CH2CN CN
2.26 2,3-C12 CH2CH2COOC2Hs CN
2.27 3-F CHzCH2CN CN
2.28 3-Cl CH2CH2COOCH3 CN
2.29 2-Cl CH2CH2COOCH3 CN
2.30 2,3~C12 CH2CHzCOOC3H7 CN

2.31 2-Br CH2CH2COOCH3 CN
2.32 2,3-Clz CH2CH2CN CHO
. _ _~ . _ As mentloned at the outset, some of the compound~ of ~ormula I hnvo the character of lntermediates. These compound~ are the represen-tatives of formuln I hereinafter referred to as ~ubgroup Ia, wheraln R i9 as defined for formula I; and in thoDe compounds in which R1 i8 CilO or COO(C1-C6)alkyl, R2 i8 at the nama tima hydrogen, CH2CH2CN
or CHzCH2COO(Cl-C6)alkyl, or in thos0 compounds ln which Rl is CN, R2 i9 at the same time CH2CH2CN or CH2CH2COO(C1-C6)alkyl. These novel pyrrole derivatives, which al~o hsve fungicldal propertie~, can be converted in simple manner into the fungicidal 4-phsnyl-3-cyanopyrrole3 known from German Offenlegungsschrift 29 27 480, as CHO and COO(C~-C6)alkyl can be converted into CN, and CH2CH2CN and CH2CH2COO(C1-C6)alkyl as 3ubstltuents at the pyrrole nitrogen atom are easily removable groups. On account of these advantageous propertles, the compounds of subgroup Ia constitute a further ob~ect of the present invention.

Typical example3 of compounds of subgroup Ia are listed belo~.

Table 3: Compound~ of formula Ia ~ ~ / ll ll R1 (Ia) Compound Rn Rl R2 . _ _ . _ _

3.1 H CHO H
3.2 3-Cl CHO H
3.3 2,4-C12 CHO H
3.4 4-Cl CHO H
3.5 4-F CHO H
3.6 3-CH3 CHO H
3.7 3-F CHO H
3.8 3-C~3 CHO H
3.9 2,3-C12 CHO ~

Table 3 (contlnuation) Compound Rn Rl __ _ ~ _ 3.10 2,6-C12 CHO H
3.12 3-Cl COOCH3 3.13 2-Cl COOCH3 H
3.14 4-F COOCH3 H
3.15 2~3-Clz COOCH3 H
3.16 3-Cl CN CH2CH2CN
3.17 2-Cl CN CHzCH2CN
3.18 3-CH3 CN CHzCH2CN
3.19 2,3-C12 CN CH2CH2CN
3.20 4-F CN CH2CH2COOCH3 3.21 2-Cl CN CH2CH2COOCH3 3.22 2,3-C12 CN CH2CH2COOCH3 3.23 2,3-C12 CHO CH2CH2COOCH3 3.24 2,3-C12 COOCH3 CHzCH2CN

The converslon of CHO into CN can be effected in a manner known per ae, for example as follows: An ~ldehyde of formula I (Rl ~ CHO) i9 convert2d at 0 to lO0C, in an lnert solvent (e.g. an alcohol, an ether, pyridine, tricthylamine and the like) lnto the corre~ponding oxime (syntantl mlxture), which 18 converted lnto the nitrlle by treat~ent with a dehydr~tlng agent (e.g. acetlc anhydrlde, cyanurlc chloridelpyrldlne, (PNCl2) 3, dicyclohexyldicarbodilmide/CuCl2/trieth-yla~lne, P20s, tosyl chloride/pyridine, TiCl4/pyrldine snd the like).

If it i9 desired to convert the ester group COO(CI-C6)alkyl into the CN group, a 3tart i9 best made from the free acld, which i3 prepared ln a manner known per se by ester hydrolysiA wlth an Aqueous mlneral acid (e.g. HCllH20), in the presence of a solubiliser (e.g. slcohol, dioxane, tetrahydrofuran and the llke), most convenlently under reflux temperature. The free acld 19 then converted into the scid amide either direct with ammoniQ at elevsted temperature or via the _ 15 _ 21489-6789 acld chloride (-Coo~ ~ thionyl chlorlde ~ -COCl) w~th smmonia at room temperature, and the acid amlde i~ converted to the nltrlle with one of the prevlously mentioned dehydrating agent~ in tho temperatUrQ range from 80 to 220~C.

If lt 18 de61red to form the free pyrrolo by removal of the C~2C~2CN
or CH2CH2COO(Cl-C6)alkyl radlcnl, this may be dons e.g. by treatment with a base in the temperature range from -20 to ~180~C, ln a suitable inart solvent. Exemplnry of ~ultsble reactlon conditlons are:
a) sodium hydride ln dlmethylformamide at 0C
b) ammonis~water/dioxane at 180C
c) potassium hydroxlde/water/alcohol at 100C.

Preparatory ~.xsmple~

Example Pl: Preparation Gf C~ ~Cl C~ ~Cl ~ _CIl2-Nll2 ~ IlCl ~ ~ l_CN

(C~13) 2N-C~-CH-CN

4-(2,3-DichlorphenYl)-3-cyanopyrrola a) Preparatlon of the precur80r:
N-acetyl-2,3-dichlorophenacYlamin0 l50 g of 2,3-dichlorobenzoyl cyanlde are hydrogenated wlth element-al hydrogen under normal prQs~ure at 70C in 1.5 ~ of glacl~l acetic acid and 84.15 g of acetic anhydrlde over 5 g of PtO2. After absorption of 112 % of tha cnlculnted amount of hydrogen (tlme taken: c. 5 hours), the hydrogenatlon 18 dl0contlnued, the rosctlon mixture 19 flltered and the flltrate 18 concentrated by evaporation.
The re~idual yellow oll is cry~talllsed by addltion of hexane/
diethyl ether. The cry8tall~ne product 18 lsolnted by filtrntion nnd dried. M.p. 107-109C. IR (~olld/KBr) in cm 1: 3300 (Nl~); 1735 (C0);
1650 (C0). IH-NMR (CDCl3) in ppm: 2.08 (~,3H); 4.55 (d,2H); 6.2-6.6 (broad ~,lH); 7.25 (m,3H).

b) Preparation of the precursor:
2,3-dichlorophenacYlamlne hYdrochloride 50.0 g of the N-acetyl-2,3-dichlorophenacylamine obtained ln a) are heated for 2 hours under reflux ln 500 ml of hydrochlorlc acid. The slightly turbld reaction solution i9 concentrated by evaporatlon and the residue i9 digested with athyl acetate. The ~rystalline 2l3-di-chlorophenacylamine hydrochloride 18 lsolated by flltratlon nnd drled. Heltlng point: 217~-218C. IR (solld/KBr) ln cm 1 1695 (C0).
(Another cryst~l modlflcation 3hows two carbonyl resonance band3 at 1690 and 1705 cm ~ H-NMR (DMS0, d6) ln ppm: 4.54 (8, 2H); 7.6 (t, lH); 7.9 (m, 2H); 8.6 (9, 3H, replaceable with D20).

c) Preparatlon of the flnal product 4-(2,3-dichlorophenvl)-3-cyanopYrrole 20.0 g of 2,3-dlchlorophenacylamine hydrochlorlde and 10.0 g of 3-dimethylaminoacrylonltrile are heated for 1 hour under reflux in 300 ml of ethanol~ Then an ethanolic solutlon of sodium ethylste, prepared from 2.1 g of sodlum and 30 ml of ethanol~ i~ rapidly added dropwise and the reactlon mlxture 19 ~tirred for another 10 mlnutes under reflux. The reaction mixture is cooled to room temperature and then poured into lce/hydrochloric acid and the re~ultant mlxture is ~tirred for 1 112 hours. The precipitate is isolated by filtratlon, washed with water and dried, affording 15.4 g (78 % of theory) of title compound with a melting point of 152-154C.

-` ~73~

Examples P2 to P4: Preparation of P2: ~ ~ -CH~CH CN C~ /Cl C Cl . _ . ~ - -CH2-NH2 ~ HCl P3~ CH~CH-CN baBe ~ -CN
.__.
Pb: 0\ ~ -CH~CH-CN
_ .

4-~2~3-Dichlorophenyl)-3-cYanopYrrole Following the procedure described in Example Plc), but replacing 3-dimethylaminoacrylonitrile by N-plperidlnylacrylonitrlle, N-pyrrolidinylacrylonitrile, or N-morpholinylacrylonltrile, and incrssslng the reaction tlme from 1 hour to 3 to 4 hours, pure 4-(2,3-dichlorophenyl)-3-cyanopyrrole is obtained in all three Examples in ylelds ranglng from 76 to 85 % of theory. Melting point:
150-154C.

Example P5: Preparation of -CANH-CH~CH-CN base ,~

4-~2~3-dichloroPhenvl)-3-cyanop~rrole a) Preparation of the lntermediate:
3-(2~3-dlchlorophenacylamino)acrylonitrlle 20.0 g of 2,3-dlchlorophenacylamlne hydrochloride and 10.0 g o~
3-dimethylaminoacrylonltrile are heated for 1 hour under reflux in 300 ml of ethanol. After cooling it to room tempersture, the reaction ~olution i8 poured into a mlxture of ice/dilute hydrochlor-ic acld. After e~traction wlth ethyl acetate, the comblned extract~
are drled over sodium sulfata, filtered7 and the filtrate i8 concentrsted. ~he oily residue 18 purified by column chromatography (8ilica gel: elutlon with a 4:1 mixture of toluene/ethyl acetate).
M.p. 125-127C. IR (solid/KBr) ln cm 1 3380 ~NH), 2200 (C~), 1715 (C0) 1625 (C~C). IH-NMR (DMSOd6) in ppm: 4.09 ~d, J ~ 15 Hz, lH); 4.45 (d, J ~ 7 H~, 2H); ~.2 (q, lH); 7.4 (broad ~,lH);
7.45-7.85 (m, 3H). Mass spectrum: molecular peak at 254.

b) Preparation of the final product 4-2,3-dlchlorophenyl)-3-cyanopyrrole To 4.2 g of the 3-(2,3-dichlorophenacylamlno)acrylonltrile obtained in a) i8 added 0.5 g of ~odlum ethylate ln 50 ml of ethanol. The reaction mixtu~e l~ heated to reflux temperature, cooled to room temperature, poured into a mixture of dllute hydrochloric scid and ic~, and stlrred for c. 1 hour. The precipitate i~ laolated by filtration, washed with water and dried, affording the title compound ln quantitatlve yleld. Melt~ng point: 149-150C.

Example P6: (Formulae, see Ex. P5) a) Preparation of the intermediate 3-(2.3-dichlorophenacYlamino)acrYlonitrile 2 g of 2,3-dichlorophenacylamine hydrochloride, 1 g of 3-hydroxyacrylo-nltrile, sodium ~alt, and 20 ml of ethanol are heated for 2 hour3 under reflux. The reactlon mixture is concentrated by evaporation and the oily re31due i8 purifled by column chromatography (~lllca gel; elution with a 4:1 mixture of toluene/ethyl acetate), affording 3-(2,3-dlchlosophenacylamino)acrylonitrile in the cis/trans ratio of

5:1. Malting point: 122-125C.

b) Preparation of the final product 4-(2,3-dichlorophenyl)-3-cyanopyrrole 4.2 g of the 3-(2,3-dlchlorophenacylamino)acrylonitrile obtalned in a) are reacted in 50 ml of ethanol with 0.5 g of sodium ethylate as described in Example P5 b), affording the title compound ln quan-titative yield. Melting point: 150-152C.

~ 19 -Example P7: Preparation of c~ /Cl C~ /Cl ~'-il tl-COOCH3 ~ S~
.~, "~. ... .~.

4-(2~3-dichloroPhenyl)-3-cYanopyrrole a) PreParation of 3-carbomethoxy-4-(2,3-dichlorophenYl)pyrrole 10.7 g of 2,3-dlchlorophenacylsmine hydrochlorlds and 6 g of methyl 3-dlmethylaminoacrylate are heated for 2 hours under reflux ln 120 ml of ethanol. Then a solution of 4 g of sodium ethylate in 40 ml of ethanol iB added dropwlse and the reactlon mixture iB
heated for another hour under reflux. The reaction mixture i8 then concentrated by evaporation and the oily reaidue i8 purified by column chromatography (8illc8 gel; elutlon with a 3:1 mlxture of toluene/ethyl acetate. Melting polnt: 205-206C.

b) Preparation of the precursor 4-(2,3-dichlorophenyl)pyl~role-3-carboxylic acid 3.2 g of the 3-carbomethoxy-4-(2,3-dichlorophenyl)pyrrole obtained in a) and 40 ml of a 1:1 mixture of methanol and 5N HCl are stlrred for hours ae 70C. After it has coled to room te~perature, the resction mixture iB poured on~o ice snd extrscted with ethyl acetate. The ester phase iB in turn extracted with 10 % sodium hydroxlde solution. The aqueous extract is washed twice with ethyl acetate, acidified with hydrochlorlc acid and extracted wlth ethyl acetate. The orgsnic phase i8 washed with water, dried ovor magnes-lum sulfate and filtered. The filtrate i5 concentrated by evapornt-lon and the resultant 4-(2,3-dichlorphenyl)pyrrole-3-carboxyllc acld melt0 at 180-182C.

- ~LZ;.739~3 c) Preparation of the final product:
4-( ? ~ 3-dlchlorophenyl)~3-cvanopyrrole 2.1 g of the free 4-(2,3-dichlorophenyl)pyrrole-3-carboxyllc acid obtsined 1n b) are dlssolved in 30 ml of ethanol. The solution 19 made alkaline ~ith concentrated ammonia and then evaporatad to dryness. The residue 1D dissolved in 50 ml of ethanol. NH3 ga~ i3 added (20 atm) to this solution at room temperatur0 in an autoclave and the reaction mixture is kept for 15 hours nt 220C. The reaction mixture, which has cooled to room temperature, is poured lnto ice/HCl, the pracipitate 18 i~olated by flltratlon and drled at 60~C. The re~ultant powder 18 heated with 17 g of polyphosphoric ncld in an open vessel at 180C, the hot mixture i9 dropped onto lce, made alkaline with NaOH and extracted with ethyl acetate. The comblned extracts are concentrated by 0vaporation and the reslduQ i8 purlfled by column chromatography (sllica gel; elutlon wlth a 4:1 mixture of toluenelethyl acetate), affordlng 4-(2,3-dlchlorophenyl)-3-cyanopyrrole of m.p. 148-150C.

Example P8: Preparatlon of ~ i-CHO --~ -CH~NOH --~ l-CN
\~ ~

4~~ ? . 3-dlchlorophenyl)-3-cYanopyrrole a) Preparation of 3-formyl-4-(2,3-dichlorophenyl)pyrrole 5-4 8 Of 3-dlmethylaminoacrolein, 3.2 g of 2,3-dlchlorophenacylamine hydrochlorlde and 60 ml of ethanol are heated for 1 1/2 hours under reflux. Then A solutlon of sodium ethylate ln ethanol (prepared from 1 g of sodlum and 15 ml of ethanol) 18 added dropwl~ and the reaction mlxture ls heated under reflux for another 30 mlnutes.
After lt has cooled to room temperature, the reaction mixture is poured onto lce/water ant neutrallsed wlth hydrochlorlc acid. The '' ~LZ~7~
- 21 ~

preclpitate is wa~hed with water, drled ln vacuo, and the dry resldue 1~ purified by column chromatography (Dlllc~ gel; elution with a 4:1 mixture of toluene/ethyl acetate). M.p. 152-154C.
IR (solid/KBr) in cm 1 1655 (CO). 1H-NMR (CDCL3) ln ppm: 7.0 (broad 9, lH); 7.3 (m, 2~); 9.66 (9, lH); 11,9 (9, IH, H replaceable with D20). Ma~s peak at 204. This sub~tance is nov01, ha~ fungicidal activlty, and falls within the ambit of the invention.

b) Preparation of hydroxYlminomethYl-4-(2.3-dichloroPhenYl)pyrrole 5.0 g of the 3-formyl-4-(2,3-dichlorophenyl)pyrrole obtained ln a), 1.7 g of hydroxylamine hydrochloride and 2.4 g of sodium acetate are stirred for 3 hours at 80C in 80 ml of ethanol. After it ha3 cooled to room temperature, the reaction mixture i8 poured onto ice and stirred for 30 minutes. The precipitate i8 i~olated by filtration, washed with water and dried, affordlng 5.02 g of 3-hydroxyimino-methyl-4-~2,3-dichlorophenyl)pyrrole as syn/anti mixture of m.p.
158-160C. Thl~ substance i8 alBo novel, ha9 fungicidal activity ~nd falls withln the amblt of the lnvent~on.

c) Preparation of the final product 4-(2,3-dichlorophenyl)-3-cyanopyrrole 3.2 g of the 3-hydroxylminomethyl-4-(2,3-dlchlorophenyl)pyrrole obtained in b) are kept for 5 hours at c. 100C in 50 ml of acetic anhydride, then cooled to room temperature, poured into ice/NaOH, and the resultAnt mixture i8 ~tirred for 2 hourfl~ The precipitate is di~solved in ethyl acetate, ~ashed with water, and the ester pha~e i9 dried over magnesium sulfate. The resldue is purified by column chromatography (silica gel; elution with a 4:1 mixture of toluene/
ethyl acetate). Melting polnt: lb9~-151C.

The compound~ of formula I li~ted in Table 4 are also prepared by methods corresponding to tho~e descrlbed above.

~ R1 (I) n ~2 Table 4 . _ _ Compound Rn R1 R2 I m-p- 1C]
_ 4.1 H CN H 120-123 4.2 3-Cl CN H 138-140 4.3 2,4-Clz CN H 150-152 4.4 4-Cl CN H 153-155 4.5 4-F CN H 137-139 4.6 3-CH3 CN H 109-111 4.~ 3-F CN H 138-139 4.8 3-Br CN H 132-134 4.9 3-CF3 CN H 87-89 4.10 2-Cl CN H 136-138 4.11 2,3-C12 CN H 152-154 4.12 2,5-C12 CN H 137-142 4.13 2-Br CN H 135-138 4.14 2,3-C12COOCH3 N 205-206 4.15 2,3-Clz CHO H 152-154 4.16 3-Cl COOCB3 H 187-189 4.17 3,4-Cl 2COOCH3 H 183-186 4.18 2-Cl COOCH3 H 198-200 4.19 2,3-c12COOC3H7-i H 153-156 4.20 2,3-C12COOC2Hs H 149-151 4.21 2,3-C12 CN CH2CH2CN
4.22 2,3-cl2 CN CHzCH2COOCH3 The d~cribed process, including all partl~l ~teps, con~t1tute~ ~n ob~ect of this invention.

Claims

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

1. 2,3-Dichlorophenacylamine of the formula or an acid addition salt thereof.