Note: Descriptions are shown in the official language in which they were submitted.
- 1 ~ 21489-6789~
This is a divisional application of application Serial
No. 490~301 filed September 10, 1985.
The parent application relates to a novel process for
the preparation of 4-phenylpyrrole derivatives of the formula I
n ~ (I)
R2
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 compounds of formula
IV
n R2 (IV)
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.
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 numher 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
v~d~
- la - 21489-6789E
etc., and the isomers thereof, e.g~ isopropyl, isobutyl, tert-
butyl, isopentyl etc. Throughout this specification, a substituent
prefixed by "halo" will be understood as meaning that said
substituent may be monohalogenated or perhalogenated. Halogen
and halo signify in particular fluorine, chlorine or bromine.
Hence haloalkyl denotes a monohalogenated to perhalogenated
alkyl radical, e.g. CHC12, CH2F, CC13, CH2Cl, CHF2, CH2CH2Br,
C2Cl5, CHBr, CHBrCl etc., with CF3 being preferred.
- 2 -
4-Phenylpyrrole derivatlves of formula I, wher0in n ia 0, l or 2,
Rl 19 cyano and Rz 19 hydrogen or acetyl, are known na plant
fungic~des from German Offenlegungsgchrift 29 27 4~01). As wlll be
shown below, compound3 of formula I, wherein Rl i8 CHO or COO(Cl-C6~-
sl~yl or R2 18 CH2CH2CN or C~izCH2COO(Cl-C6)alkyl, can be converted
in ~lmple manner lnto the known funglcldal 4-phenyl-3-cyanopyrroles
and thu~ have the character of lntermedlutes.
A proce3s for the preparatlon of 4-phenyl-3-cyanopyrrole derlvatlv
whlch 18 known from Tetrahedron Letter~ No. 52, pp. 5337-5340,
l9722), i~ discloaed ln German OffenlegungsDchrlft 29 27 4801). In
thls process, known 88 the To~MIC procass, a clnnamic acld derl-
vatlve of formuln X
(X) ~ CH~CH-CN
n ba8e (NaH) ~ CN
- CH3~ SO2H R~ . ~ . (XXX)
(XX) CH3~ SOzCH2NC
is cyclised wlth tosyl methyl isocyanide (XX) ¦ToaMIC], ln the
presence of a strong base, e.g. sodlum hydrlde, to glve 4-phenyl-
3-cyanopyrrole derivatlves of formula (XXX). In the above formulae,
R 18 as definad for formula I and n i8 0~ 1 or 2.
Although numerous pyrrole synthesae are known (q.v. J.M. Patterson,
Synthesi~ 1976, pp. 281-3043)), only the TosMIC process outllned
above has 80 ar led dlrect to the fungicidally useful 4-phenyl-
3-cyanopyrrole derivatives. However, reference 2) indicates for the
preparation of 4-phenyl-3-cyanopyrrole a yiel~ of only 35 %, which
18 low for lndustrial purposes. It has been found that the reagent
TosMIC has grave di~advantages for industrlal syntheses. For
example, at elevated temperatures above 90C (normal drying con-
dltlon~), Tos~IC ha~ the propensity to decompose exploslvely. On the
-- 3 --
other hand, re~ldual moistu~e consumes some oE tha baae employed
~danger of hydrolysi~reductlon ln yield). Further, TosMIC has
physiologloal hazards and causss ~evere irrltatlon to the eye~ and
skin.
The shortcoming~ referred to above show that useful laboratory
methodn are un~3uitsble for the indu~3trlal production of 4-phenyl-
pyrrole derivatives. A novel, more economic and envlronmentally more
acceptabla process for the preparatlon of these compound~ ln
surprl~ingly hlgh yleld has now been found.
The novel process of thiq lnvention for the preparation of the
4-phenylpyrrole derivatlv2s of the formula I a9 deflned at the
outset comprise~ reacting a phenacylamine of formula Il
~ ~-~-CH2-~H (II)
n
in the form of an acid additlon ~alt, wlth a compound of formula III
T-CH~CH-Rl (III)
to giVQ an intermediate of formula IV
~ CH2-~-CN~CH-Rl (IV)
R ~ 2
and cyclising thls aompound of formula IV, in th~ pre8Qnce of a
base, to a compound o~ formula I. In the formulae II, III and IV
above, the substituents Rl, R2 and Rn are as defined for formula I,
T is a group selected from -OZ, -N(R3)(R4), -OCORa, -OSO2Rb, -SRC or
halogen, where Z is Cl-C6alkyl, unsub~tituted or aub~tltuted phenyl,
an alkall metal atom or an alkallne earth metal atom, each of Ra and
Rb independently of the other i~ Cl-C6a1kyl or unsubstituted or
substituted phenyl, Rc i8 Cl-C3alkyl, Cl-C3haloalkyl or unsub-
~tituted or sub~3tituted phenyl; and ~ach of R~ and R4 independently
of the other is Cl-C6alkyl or, together with tha amlne nltrogen
atom, form ~ satursted 5- or 6~membered het0rocycllc rlng whlch
contains, as hetero atom, elther only the amine nitrogen atom or a
further hetero ~to~.
An unsubstltuted or ~ubatitut~d phenyl group is ln particular ph0nyl
or phenyl whlch 18 sub~tltuted ln tha para-posltlon by halog0n,
preferably chlorlne or bromlne, and by Cl-C3alkyl, preferably
methyl. Alkall metnl atoms or slkallne earth metal atom~ mny be Ll,
Na and R, preferably ~a and K, or Mg, Ca, sr and Ba, preferably Mg,
Ca and Ba~ Where the -N( R3 3 ( R4 ) group denotes a 3aturated 5- or
6-membered heterocycllc rlng containlng N as hetero atom or a
further hetero atom, sald rlng m~y be selected from the followlng
heterocycllc ring systems: pyrrolidlne, plperazine, perhydro-
thiazine, morpholine, plperazlne, oxazolldlne, thiazolldlna,
imidazolidine, pyrazoline and the llke. A further hetero atom 1
preferably N, 0 or S.
In the process of thls inventlon lt 18 not necessary to isolate the
lntermedlate (IV) first and then to cyclise it to compounds of
formula I. To the contrary, the reactlon of (II) with (III) may also
be carried out direct in tha pre~ence of a b~se, utill~lng a single
reaction ve3sel for both steps, to give the flnal products. In thls
procedure, the lntermediata (IV) 18 further processed direct without
lsolation. On the other hand, it may be convenient to prepare the
intermedlate (IV) fir~t ln especially pure form, e.g. by repeated
secrystallisation, and then to cyclise it to a compound of formula
I. A preferred embodiment of the proces~ of thi~ invention accord-
lngly comprises reacting the phenacylamlne II in the fnrm of an
acid additlon salt, in the presence of a base, direct with a
compound of formuls III to give the final product I.
The second preferred embodiment of the process comprlses fir~t
reacting tha phenacylamine II in the form of an acld addition flalt,
in the absence of 8 base, to give the intermedlate (IV) and then
convertlng (IV) to (I) by cyclisatlon ln the presence of a bsse.
- 5 -
The reactant~ (II), (III) and, where ~ppropriate, (IV), are con-
veniently amployed ln equimolar smounts. It i8 preferred to add an
equimolar amount or fln exc~ss of ba~e.
Typical representativ~s of th~ compounds of formula III, the 11st of
which is not exhaustive, are the follo~7ing compounds a~ to t), of
which compounds a) to 1) are particularly advantsgeo~s and therafore
preferred:
a) (CH3)2N-CH~CH-CN
b) (C2Hs)2N-CHCCH-cN
0_0
c) ~ ~N-CH-CH-CN
_--
d) ! ~N-CH~CH-CN
_--
~) O~ ~-CH-CH-CN
f) NaO-CH-CH-CN
g) RO-CH-CH-CN
h) (CH3)2N-CH~CH-COOCH3
1) (C2Rs)2N-CH~CH-COOCH3
k) (C)i3)2N-CHYCH CHO
1) (C2Hs)2 N-CH~CH-CHO
m) Cl-CHoCH-CN
n) Cl-CH~CH-COOCH3
o) CH302SO-CH~CH-CN
p) [C6H4CH3~4)~-CH~CH-CN
q) CH30-CH~CH-CN
r) C2HsO-CH~CH-CN
8) C3H70-CH~CH-CN
t) [C6H4Cl(4)]0-CH~CH-COOCH3
-- 6 --
The process of thl6 invention i8 conveniently carried out in an
inert solvent or mixture of 301vents. Thu~ one or more lnert
solvents or diluents may be employed. Exsmplea of sultAble solvent0
snd diluents are: aliphatic and aromatic hydrocarbon~ 0uch aB
benzene, toluene, xylenes, petroleum ~ther; halogenated hydroc~rbons
3uch as chlorobenzene, methylene chloride, ethylene chloride,
chloroform, carbon tetrachlorlde, tetrachloroethylene; ethers and
ethereal compounds such as dlalkyl ether~ (diethyl ether, diiso-
propyl ether, tert-butylmethyl ether etc.), anisole, dloxane1
tetrahydrofuran; nitrile~ such ag sceton~trlle and propionltrile;
N,N-dialkylated amides such as dimethylformamide; dimethylsulfoxide;
ketones such as acetone, dlethyl ketone, methyl ethyl ketone;
alcohol~, in particular methanol, ethanol, propanols, butanol~ and
the llke; and water snd aqueous two-phane mlxtures and mixtures of
the above solvents.
The following solvents for example are ~uitable for tha orgsnic
water-immlscible pha~e: aliphatic and aromatic hydrocerbons such as
pentane, xylenes etc.; halo~enated hydrocarbons ~uch as dichloro-
methane, chloroform, carbon tetrachloride, ethylene dlchloride,
1,2-dichloroethane, tetrachloroethylene and the like, or aliphatic
ethsrs such a3 diethyl ather, dlisopropyl ether, tert-butylmethyl
ether and the liks. The addltlon of a phaae transfer catalyst may be
advanta~eous. Examples of ~ultable phase transfer catalysts are:
tetraalkylammonium halides, hydrogen aulfate3 or hydroxides, e.g.
tetrabutylammonium chloride, tetrabutylammonlum bromlde, tetrabutyl-
ammonium iodide, triethylbenzylammonium chloride or triethylbenzyl-
ammonium bromlde, tetrapropylammonium chloride, tetrapropylammonium
bromlde or tetrapropylammonlum iodlde etc. Suitable phase transfer
catslyst~ are also phosphonlum salts. The ammonium salt of for-
mula II ltself acts as pha~e transfer catalyst.
Partlcularly sultable solvents are nltrile~ and lower alkanols,
preferably acetonltrile and ethanol, a~ well a~ mlxture~ of
alkanol/water (ethanol/water).
-- 7
In all partial 3teps and in the single ve~sel reaction, the reaction
temperatures arQ generally in the range from 0 to ~120C, pre-
ferably from +30 to ~80C.
Owing ~o the reduced ~hermal 0tablllty of the ~tartlng phenacyl-
amine, the compound of formula II i3 employed ln the form of lt~
more atable ammonium salt, which can be obtalned by conventional
additlon of an organic or inorganic acld to ths fre0 amln0.
Examples of s~lt-formlng acld~ are lnorganlc aclds, e.g. hydrohallc
aclds such as hydrofluoric acld, hydrochloric acid, hydrobromic acid
or hydriodic acid, as well ~8 sulfuric acld, phosphoric acid,
pho3phoroua acid, nitric acid and the like; and organic acids ~uch
as acetic acld, trlfluoroacetic acid, trlchloroacetic acid, pro-
pionic acid, glycollic acid, lactic acld, succinlc acid, benzoic
scld, cinnsmic acid, oxalic acid, formic acid, benzenesulfonic acid,
p-toluenesulfonic acid, methanesulfonlc acid, salicycllc acid,
2-phenoxyoenzoic acid or 2-acetoxybenzoic acid and the liko.
Preferred salt-forming acid~3 are strong aclds such as the hydrohallc
acid~, phosphoric acid, nitric acid9 and the ~ulfonic acids such as
p-toluenesulfonic acid. Hydrochlorlc acid 1~ especlally praferred.
The reactlon of (II) with (III) direct to give (I), or of (IV) to
give (I), is conducted ln the presence of a base. Example~ of
auitable ba~es are lnorganic ba~es such as the oxides, hydrides,
hydroxides, carbonates, carboxyllc acid aalts and alcoholates of
alkaline earth metals, preferably of alkali metals, in particular of
sodium and potassium [e.g. NsH, NAOH, ROH, Na2CO3, RzC03, CaC03,
CH3COONa, C2HsCOOK~ CzHsONa~ CH30Na ~nd the llke], prefer~bly the
alkali metal alcoholates such as sodium ethylate or sodium
methylate. Suitable organic bases are e.g. tri~thylamlne,
piperidine, pyridine, 4-dimethylaminopyridine and the like.
- $~73g~7 J
- 8 -
In the processes of thls inventlon, lnte~medlate~ nnd fln~l product3
may be isolated from the reactioll medlum and, if deslred, purifled
by one of the commonly employed mothodn, for exampl~ by extractlon,
crystalllsHtion, chromato~r~phy, distlllation and the like. However,
the preparation of the compoundD of formula I cnn be carried out
generally ln good yleld and in excellent purity utlli~lng a single
ves3el for both reaction steps without inolation of lntermediatea.
Preferred embodiments of the process of thi~ inventlon are e.g.
those which comprisa:
a) the use of ~tartlng material~ of formula II, ~here~n R 1~
halogen, preferably fluorine, chlorine or bromine, most pre-
ferably chlorlne, n 19 1 or preferably 2, wlth th0 proviso that,
lf n i9 2, the ortho- and meta-positlons are partlcularly
prsferred, Ri ls CN and Rz i9 hydrogen;
b) the U9C of reagents of formula III, wherein T 18 a group selected
from -N(CH3)2, -N(C2Hs)2,
-N\ j , -N~ \O , -OK or -ONa,
and Rl is CN, COOCH3 or CHO, preferably CN;
c) the us~ of lntermedlates of formula IV, wherein Rl, R2 and R are
as defined in a) and b) above;
d) the use of acld addltion salts of formula II, whlch contaln, aD
acid component, a hydrohaiic acid, preferably hydrochloric acld,
a Rulfonic acid, pref~rably benzene~ulfonic or p toluene~ulfonic
acid, or sulfuric acid;
e) carrying out the reactlon of (II) with (III) such that the
lntermediate IV is further proces~ed direct without isolation;
f) carrylng out the proce~s in the temperature ranga from ~30 to
~80C.
Accordlngly, a particularly preferred embodlment of the proceas of
the invention comprises reactlng 2,3-dichlorophenacylamine in the
form of qn acid addition salt, preferably ln the fGrm of th0
hydrochloride, with a compound of formula III, wherein Rl i8 CN and
T is R group selectad from -N(CH3)2,
~ `o . -OK or -ONa
prefersbly -N(CH3)2, ~ ~ ~ ~0
~, , _ ,
to glYe 3-(2,3-dichlorophenacylamino)~crylonitrlle, and cycllsinK
this intermediate, either as substance or preferably in ~itu, in the
presence of a base, preferably of a lower alkanolate, sodium
hydroxlde, pota~sium hydro~ide, sodium acetate, potassium acetate or
a tri-lowar alkylamine, to give 4-(2,3-dlchlorophenyl)-3-cyano-
pyrrole.
Most of the starting materials of formula II are known or can be
prepared in similar manner to the known representatives. However,
2,3-dichlorophenacylamine and the Acid addltion salta thereof are
novel. In view of its structura, thi~ compound is destined for use
a8 intermediate for the preparation of fungicidally active 4-(2,3-
dichlorophenyl)-3-cyanopyrrole and therefore constitutes an ob~ect
of this invantion. Its preparatlon will be described cxplicitly
below.
Compounds of formula II, wherein Rz 18 CHzCH2CN or CHzCH2COO(Cl-C6)-
alkyl, can be prepared e.g. as follow3 from the starting phenacyl-
amines (II) (R2 ~ H): The acid addition salt (e.g. the HCl ~alt)of
an N-substituted phenacylamine of formula II 18 reacted, ln the
-
-- 10 --
presence of ~n equlmolar amount of acrylonltrilo or of 8 C~-C~alkyl
ester of acryllc acld, preferably ln the pr0Dence oE one of the
ba~es apeclfied above nnd under tha condltlong for the r~ctlon of
(II), wlth (III) to give (I).
Ulthin the scope of the present lnvention, typicnl repre~entntlves
of compounds of formula I nre for ex~mple the compo~ndD li~ted ln
Table 1.
Table 1: Compounds of formul~ II
~ RC_CH2_NH_R2 (II)
R ~
, .. .. _ .
Compound R
1.1 H ~ H
1.2 3-Cl H
1.3 2,4-Clz H
1.4 4-Cl H
1.5 4-F H
1.6 3-CH3 H
1.7 3-~ H
1.8 3-Br H
1.9 3-CF3 H
1.10 2-Cl H
1.11 2,3-C12 H
1.12 2,5-Clz H
1.13 2-Br H
1.14 2,6-C12 H
1.15 H CHzCHzCN
1.16 3-Cl CH2CHzCN
1.17 2-Cl - . CHzCH2CN
Table 1 (continuation)
. _ . _
Compound Rn R2
. . __ ___ . __
1.18 2,3-C12 C~lzCH2CN
1.19 3-F CHzCH2CN
1.20 3-Cl CH2CH2COOCH3
1.21 2,3-C12 CH2CHzCOOCH3
1.22 2-C1 CH2CHzCOOCH3
1.23 2,3-C12 CH2CH2COOC2Hs
1.24 2,3-C12 CH2CHzCOOC3H7
1.25 2-Br ~ CHzCH2COOCH3
. . ___ . .
The compound~ of formula III are in general commercially available
and thu~ known substances or compounds whlch can be prepared in
similar manner to their known representatives.
The preparation of the intermQdiates of formula IV ia an ob~ect of
the prasent invention snd haA been deacrlbed in detail above. These
intermediates IV can be converted by aimple baslc cyclisation into
the u~eful fungicides of formula I, have themselves fungicidal
activity, snd accordingly constitute an esaential ob~ect of the
present invention.
,
Within the BCope of this invention, typical representatives of
lnter~ediates of formula IV are:
Table 2: Compounds of the formula
~ cR-cH2-~-cH~cH-R (IV)
. . . . ~
Compound R Rz R
~ n , ________________
2.1 H R CN
2.2 3-Cl _ _ CN
- 12 -
Table 2: (continuatlon)
Compound _ __ Rz . .
n __ . . ~ .
2.3 2,4-Cl H CN
2.4 4-Cl H CN
2.5 4-F N CN
2.6 3-CH3 H CN
2.7 3-P H CN
2.8 3-Br H CN
2.9 3-CF3 , H CN
2.10 2-Cl H CN
2.11 2,3-Clz H CN
2.12 2,5-C12 H CN
2.13 2-Br H CN
2.14 2,6 C12 H CN
2.15 2,3-Clz H COOCH3
2.16 H H CHO
2.17 3-Cl H COOCH3
2.18 3,4-Clz H COOCH3
2.19 2-Cl H COOCH3
2.20 2,3-C12 H COOC3H7
2.21 2,3-C12 CHzCH2COOCH3CN
2.22 2,3-Clz CH2CH2CN CN
2.23 H CH2CH2CN CN .
2.24 3-Cl CHzCH2CN CN
2.25 2~Cl CHzCH2CN CN
2.26 2,3-C12 CH2CH2COOC2Hs CN
2.27 3-F CH2CH2CN CN
2.28 3-Cl CH2CH2COOCH3CN
2.29 2-Cl CH2CH2COOCH3CN
2.30 2,3-c12 CH2CH2CO0C3H7 CN
2.31 2-Br CH2CH2COOCH3CN
2.32 2,3-C12 CH2CH2CN CHO
- l3 -
As mentloned st the out~et, ~ome of th~ compound~ of formula I have
the character of lntermediate~. The~e compound~ are tha ~epre3en-
tatives of formula I herelnafter referred to a~ subgroup Ia, wherein
Rn is as defined for formulz I; And in tho~e compounds in which Rl
i3 C~O or COO(CI-C6)alkyl, R2 1~ at the ~ame tlme hydrogen, CH2CH2CN
or CH2CH2COO(Cl-C6)alkyl, or in those co~npounds in which Rl i~ CN,
R2 i9 at the 8ame time CH2CH2CN or CH2CH2COO(Cl-C6)alkyl. The~e
novel pyrrole derivatives, which also have fungicidal propertie~,
can be converted in simple manner into the funglcidal 4-phanyl~3-
cyAnopyrroles known from German Offenlegungssohrift 29 27 480, a8
CHO and COO(CI-C6)alkyl can be converted into CN, and CH2CH2CN and
CH2CH2COO(CI-C6)alkyl a3 substituents at the pyrrole nltrogen atom
sre easily removable groupa. On account of these advantageous
properties, the compounds of ~ubgroup Ia constltute a further ob~ect
of th~ present invention.
Typical Qxamples of compounds of subgroup Ia are llsted below.
Table 3: Compounds of formula Ia
ll ll Rl (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-CF3 CHO H
3.9 2,3-C12 CHO ~
- 14 -
Table 3 (contlnuatlon)
Compound n ~ _ _ RZ
3.10 2~6-Clz CHO H
3.12 3-Cl COOCH3 H
3.13 2-Cl COOCH3 H
3.14 4-~ COOCH3 H
3.15 2,3-Clz COOCH3 H
3.16 3-Cl CN CHzCHzCN
3.17 2-Cl CN CHZcH25N
3.18 3-CH3 CN CHzCHzCN
3.19 2,3-C12 CN CHzCH2CN
3.20 4-F CN CHzCH2COOCH3
3.21 2-Cl CN CHzCH2COOCH3
3.22 2,3-C12 CN CH2CHzCOOCH3
3.23 2,3-C12 CHO CHZcH2coocH3
3.24 2,3-C12 COOCN3 CH2CH2CN
The convQrsion of CH0 lnto CN can be effected in a manner known per
8e, for example as follow~: An nldehyde of formula I (Rl - CH0) 1~
converted at 0 to 100C, in an inert aolvent (e.g. an alcohol, an
ether, pyridlne, triethylamine and the like) into the corresponding
oxime (syn/anti mlxture), which 19 converted into the n~trile by
trestment with a dehydratlng agent (a.g. acetic anhydride, cysnurlc
chlorlde/pyridine, (PNCl2)3, dicyclohexyldicarbodllmide/CuCl2/trleth-
ylamine, P20s, tosyl chloride/pyrldine, TiCl4/pyridine and the
like).
If it i~ desired to convert the ester group COO~CI-C6)alkyl into the
CN group, a ~tart i9 begt made from the free scid, which i~ prapared
in a manner known per se by ester hydroly~i~ with an aqueou~ mineral
acid (e.g. HCl/HzO), in the pre~ence of a ~olubill~er (e.g. slcohol,
dioxane, tetrahydrofuran and the like), most conveniently under
reflux tempersture. The free ~cid i~ then converted into the acid
amite elther direct with smmonia at elevatad tamperature or via the
'-` ~P739S7
_ 15 _ 2l48g-6789
acld cll10ride ~-C001~ + thionyl chloride ~ -COCl) with ammonla at
room temperature, and the acld amlde i~ converted to tha nltrile
with ona of the prevlou~ly mentloned dehydratlng ngent~ ln the
temperature range from 80 to 220C.
If it 1~ de6ired to form the free pyrrole by removal of the CH2C1lzCN
or C~l2CII2COO(C1~C6)alkyl radlcnl, thio ~ay ba done e.~. by treatment
with n base in the temperature range from -20 to ~180C, ln n
suitable lnert ~olvent. Exemplary oE 0uitable reactlon condltlonD
are:
n) sodium hydride in dlmethylformamida at 0C
b) ammonia/water/dloxane at 180C
c) potas~lum hydroxide/water/alcohol at 100C.
Preparstory Example3
Example Pl: Preparatlon of
C~ ~Cl base '~ -CN
~CH1~2N-CII~CH-CN
4-~2.3-Dichlorphen~ 3-c~anopYrrole
8) Preparntlon o$ the precuroor:
N-acetYl-2,3-dichlorophenacylamine
150 g of 2,3-dichlorobenzoyl cyanide are hydrogcnat~d with ~lement-
al hydrogen under normal pressure at 70~C in 1.5 ~ of glacl~l acetlc
acld and 84.15 g of acetic anhydride over 5 g of PtO2. After
absorptlon of 112 % of the calculated amount of hydrogen ~tim0
tnken: c. 5 hours), the hydrog~nntlon is diocontlnued, thn renction
mlxture i9 flltered snd the filtrate is concentrated by evaporatlon.
The resldual yellow oll i8 crystalllned by addltlon of hexsne/
dlethyl ether. The cry~tall~ne product l~ i~olated by flltration and
- ~z~
- 16 -
drled. M.p. 107-109~C. IR (aolid/KBr) ln cm 1 3300 (NH); 1735 (C0);
1650 (C0). IH-NMR (CDClJ) in ppm: 2.08 (~,3H); 4.55 (d,2H); 6.2-6.6
(broad 9, lH); 7.25 (m,3H).
b) Preparatlon of the precursor:
2,3-dichlorophenacylamine hydrochloride
50.0 g of the N-acetyl-2,3-dichlorophenacylamlna obtalned in a) are
heated for 2 hours under reflux in 500 ml of hydrochloric scld. The
31ightly turbid reactlon solution 1~ concentrated by eYaporatlon and
the resldue ~8 digested wlth ethyl acetate. The crystalline 2,3-di-
chlorophenacylamine hydrochloride 1~ i~olated by filtratlon and
driad. Meltlng point: 217-218C. IR (solidtXBr) in cm 1 1695 (C0).
(Another cry3tsl modification showa two carbonyl resonance bands at
1690 and 1705 cm 1), lH-NMR (DMS0, d6) in ppm: 4.54 (8, 2H); 7.6 (t,
IH); 7.9 (m, 2H); 8.6 (~, 3H, replaceable wlth DzO).
c) Preparatlon of the flnal product
4-(2,3-dichlorophenyl)-3-cyanopyrrole
20.0 g of 2,3-dichlorophenacylamlne hydrochlorlde and 10.0 g of
3-dimethylaminoacrylonitrile are heated for 1 hour under reflux in
300 ml of ethanol. Then an ethanolic ~olution of sodium ethylAte,
prepared from 2.1 g of sodlum and 30 ml of ethanol, i3 rapldly added
dropwise and the reactlon mixture is stirred for another 10 minutes
under reflux. The reaction mlxture i8 cooled to room temperature and
then poured into ice/hydrochloric scid and the resultant mixture is
stirred for 1 1/2 hour~. The precipitate is iaolated by flltratlon,
wa~hed with water and dried, affosding 15.4 g (78 X0 of thaory) of
title compound with a melting polnt of 152-154C.
\
- 17
Examples P2 to P4: Preparation of
P2: ~ CH~CH-CN C~ ~Cl Cl
. _ ~ ~ - -CH2-Nfl2 ~ HCl C~
P3 ! ~ -CH~CH-CN ba~e ~~ il-CN
P4: 0~ ~ -CH~CH-CN
_o :
4-(2,3-Dichlorophenyl)-3-cynnop~rrole
Following the procedure de~crlbad in Example P1c), but replacing
3-dlmethylaminoacrylonitrile by
N-piperidlnylacryloni~rile,
N-pyrrolldinylacrylonitrile, or
N-morpholinylacrylonitrile,
and increasing the reaction time from 1 hour to 3 to 4 hours, pure
4-( 2,3-dichlorophenyl)-3-cyanopyrrole 1~ obtained in all thr0e
Examples in yiqlds ranging fsom 76 to 85 % of theory. Melting point:
150-154C.
Exsmple P5: Preparatlon of
,~ N-CH~CH-CN ba~e
`` `X'
4-(2,3-dlchlorophenyl) 3-cyanop~rrole
a~ Preparation of the intermediate:
3-(2,3-dlchlorophenacYlamlno)acr,y-lonitril-e
20.0 g of 2,3-dichlorophenacylamlne hydrochloride and 10.0 g of
3-dlmethylaminoacrylonitrile are heated for 1 hour under reflux in
300 ml of ethanol. After coollng lt to room temperature, the
reaction ~olutlon 1~ poured into ~ mlxture of ice/dilute hydrochlor-
- 18 -
ic acid. After extractlon with ethyl ~cetate, the combined extract~
are dried over sodium sulfate, flltered, and the filtrste i8
concentr~ted. The oily re3id~e 18 purified by column chromatography
(~llica gel: elution with a 4:1 mixture of toluene/ethyl ncetate).
M.p. 125-127~C. IR (solid/K~r) ln cm 1 3380 (NH), 2200 (CN),
1715 (C0) 1625 (CYC). ~-NMR (DMSOd6) in ppm: 4.09 (d, J ~ 15 Hz,
IH); 4.46 (d, J ~ 7 Hz, 2H); 7.2 (q, lH); 7.4 (broad ~,lH);
7.45-7.85 (m, 3H). Ma3s spectrum: molecular peak at 254.
b) Preparation of the final product
4-2~3-dichlorophenyl~-3-cy_nopyrrole
To 4.2 g of the 3-(2,3-dichlorophenacylamlno)acrylonitrlle obtalned
ln a) i8 added 0.5 g of sodlum ethylate in 50 ml of ethanol. The
reaction mixture is heated to reflux temperature, cooled to room
temperature, poured into a mixture of dilute hydrochlorlc acid and
ice, and atirred for c. 1 hour. The precipitate 19 isolated by
flltration, wa~hed with wat0r and dr~ed, affording the tltle
compound in quantltative yisld. Melt~ng point: 149-150C.
Example P6: (Formulae, see Ex. P5~
a) Preparatlon of the lntermedlata
3-(2,3-dichlorophenacylamino~acrylonitrils
2 g of 2,3-dichlorophenacylamine hydrochloride, 1 g of 3-hydroxyacrylo-
nitrile, 30dium salt, and 20 ml of ethanol are heated for 2 ho~rs
under reflux. The react~on mixture i~ concentrated by evaporation
nnd the oily residue iB purifled by column chromatography (sllica
gel; elution with 8 4:1 mixture of toluene/ethyl acetate), affording
3-(2,3-dlchlorophenacylamino)acrylonitrlle in the cis/trsn~ ratio of
5:1. Meltlng point: 122-125C.
b) Preparation of the flnal product
4-(2,3-dichlorophenYl)-3-cyanopyrrole
4.2 g of the 3-t2,3-dichlorophenacylamino)acrylonitrile obtained ln
a) are reacted in 50 ml of ethanol with 0.5 g of sodium ethylate as
descrlbed in Example P5 b), affording the titla compound in quan-
titatlve yield. Melting point: 150-152C.
- l9 -
Example P7: Preparatlon of
COOCU~ --~ -COOII ~ l-CN
4-( 2, 3-idichloroPhenyl~-3-cyanopyrrole
a) Pseparation of 3-carbomethoxy-4-(2,3-d~chlnrorhenyl)~r~ole
10.7 g of 2,3-di~hlorophenacylamln0 hydrochloride 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 is added dropwlse and the reaction mixture is
heated for another hour under reflux. The reaction mixture i6 then
concentrated by evaporation and the oily resitue i8 purified by
colu~n chromatography (silica ~el; elution with a 3:1 mixture of
toluene/ethyl acetate. Melting point: 205-206C.
b) Preparation of the precur~or
4-(2,3-dichlorophenyl3pYrrole-3-carboxylic acid
3.2 g of the 3-carbomethoxy-4-(2,3-dichlorophenyl)pyrrola obtained
in a) and 40 ml of a 1:1 mlxture of methanol and SN HCl are stirred
for hours at 70C. After lt has coled to room temperature, the
reaction mlxture 19 poured onto ice and extracted with ethyl
acetate. The ester phase is ln turn extracted with 10 % sodium
hydroxlde solutlon. The aqueous extract i8 washed twice with ethyl
acetate, acldlfied with hydrochloric acid and extracted wlth ethyl
acetate. The organic pha~e 18 wsshed with water, drled over magnes-
lum sulfate and filtered. The filtrate i~ concentrated by evaporat-
lon and the resultant 4-(2,3-dichlorphenyl)pyrrole-3-carboxyllc acid
~elts at 180-182C.
~ 20 -
c) Preparation of the flnal product:
4-(2,3-dlchlorophenyl)-3-cyanopyrrole
2.1 g of the free 4-(2,3-dlchlorophenyl)pyrrole-3-carboxyllc acld
obtained in b) are disqolved in 30 ml o ethanol. Tho solution 19
made alkaline with concentrated ammonia and then evaporated to
dryness. The residue 1B dissolved in 50 ml of ethsnol~ NH3 ga~ i~
added (20 atm) to this solution at room temperature in an autoclave
and the reactlon mixture is kept for 15 hours at 220~C. The reaction
mixture, which hfls cooled to room temperature, i8 poured lnto
ice/HCl, the precipitate is i301ated by flltratlon and dried at
60C. The resultant powder iB heated with 17 g of polyphosphorlc
acid in an open vessel at 180C, the hot mlxture i8 dropped onto
ice, made alkaline wlth NaOH and extracted ~ith ethyl acetate. The
combined extracts are concentrated by evaporatlon and the re~idue i8
purified by column chromatography (sllica gel; elution with a 4:1
mlxture of toluene/ethyl acetste), affording 4-(2,3-dlchloroph0nyl)-
3-cyanopyrrole of m.p. 148-150C.
Example P8: Preparation of
~ -CHO ~ -CH~NOH ~ Cl
Y
4-(2,3-dichlorophenyl)-3-cyanopvrrole
a) Preparation of 3-formyl-4-(2~3-dichlorophenYl)pyrrole
5.4 g of 3-dimethylaminoacrolain, 3.2 g of 2,3-dlchlorophenacylamine
hydrochloride and 60 ml of ethanol are heated for 1 1/2 hours undsr
reflux. Then a solution of sodium ethylate in ethanol ~prapared from
1 g of sodium and 15 ml of ethanol) is added dropwise and the
reaction mixture is heated under raflux for another 30 mlnutes.
After lt has cooled to room temparature, the reaction mixture is
poured onto lce/water and neutralisad with hydrochloric acid. The
3~ "
- 21 -
preclpltate is wsshed wlth water, dried ln vacuo, and the dry
residue i9 purlfled by column chromatography (8ilica gel; elutlon
with a 4:1 mlxture of toluene/ethyl acetate). M.p. 1S2-154~C.
IR (solid/KBr) in cm 1 1655 (CO). IH-NMR (CDCL3) ln ppm: 7.0 (broad
9, IH); 7.3 (m, 2H); 9.66 (8, lH); 11,9 (8, lH, H replaceable with
D20). Maos peak at 204. This ~ubstance i3 nov~l, has funglcidsl
sctivlty, and falls wlthin the amblt of the invention.
b) Preparatlon of hydroxYlminomethYl-4-(2~3-dichloroPhenyl~pYrrole
5.0 g of the 3-formyl-4-(2,3-dichlorophenyl)pyrrole obtained in a),
1.7 g of hydroxylamine hydrochlorlde and 2.4 g of sodlum acetate are
stirred for 3 hours at 80C in 80 ml of ethanol. After lt has cooled
to room temperature, the reaction mlxture is poured onto ice and
stirred for 30 minutes. The preclpitate i~ isolQted by filtration,
wAshed with water and drled, affording 5.02 g of 3-hydroxylmlno-
methyl-4-(2,3-dichlorophenyl)pyrrole as syn/antl mlxture of m.p.
158-160C. Thls substance i8 also novel, has fungicidal activlty
and falls within the ambit oP the invention.
c) Preparation of the final product
4-(2.3-dichlorophenyl)-3-cyanoPYrrole
3.2 g of the 3-hydroxylminomethyl-4-(2,3-dichlorophenyl)pyrrole
obtalned in b) are kept for 5 houro at c. 100C in 50 ml of acetlc
anhydride, then cooled to room temperature, poured into ice/NaOH,
and the resultant mixture is stirred for 2 hours. The precipltate 18
dissolved in ethyl acetate, washQd with water, and the ester phase
18 dried over magnesium sulfate. The residue is purified by column
chromatography (silica gel; elution with a 4:1 mixture of toluene/
ethyl acetate). Melting point: 149-151C.
The compounds of formula I llsted in Table 4 are alao prephred by
method~ corresponding to thooe described above.
~2~
- 22 -
R
Table 4
. ... _ ..... . . .
Compound Rn R1 R2 I m.p. ¦~c~
........ _ ,._ ~_ _
4.1 H CN H 120-123
4.2 3-Cl CN H 138 140
4.3 2,4-C12 CN H 150-152
4.4 4-Cl CN H 153-155
4.5 4-F CN H 137-139
4.S 3-CH3 CN H 109-111
4.7 3-F CN H 138-139
4.8 3-~r 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-C12 COOCH3 H 205-206
4.15 2,3-Clz CHO H 152-154
4.16 3-Cl COOCH3 H 187-189
4.17 3,4-C12 COOCH3 H 183-186
4.18 2-C1 COOCH3 H 198-200
4.19 2,3-Clz COOC3H7-i H 153-156
4.20 2,3 Cl~ COOC2Hs H 149-151
4.21 2,3-C12 CN CH2CH2CN
4.22 2,3-Clz CN CHzCH2COOCH3
The de~3crib~d proces~, lnoludlng ~11 p~rtlal ~eeps, con~titutes ~n
ob~ect of this invention.
