Note: Descriptions are shown in the official language in which they were submitted.
';` 2~3337l.~
HO15:CHST ~RTï}SNG~SSi3L~SC}~F~ 0~: 93~F300 Dr. ~/b~
Descrip~Gion
2, 4, 5-l'rihalocinsla~onitrile~ and proc~s ~or their
prepa~ation
5 The pre~eslt is:lvention relate~ to halogonated ci~a:mo-
nitril~3 and to proc~t3eE~ for the~ prep;ar~tion.
The abovemerlkloned compou~d~ are of importance in indu~
'cry a~ termediate~ in the ps0para1:ion of ac:ti~re ingre-
dien o or pharD:Iaceuticals, herbicids~ and ~ungi~id~O
10 The com}?ousld~ who~e preparatiOD. iB noYel can be prepar~d
by the con~rentioD.al route, via the c:inna~nia ~Yt~r~ or the
cinnamalcl~3hyda~, only with graat di~ ulty, ~ince th~a
actual starting ~ tanc2s slec~ ary fox thi~ ~oute are
'c~ae corre~pondi~g 1 rihalobe~zald~}lyd~s (c~ thi~
15 r2spect Hou~e~-Weyl, ~srol~ne 135, p. 362, 1348).
A ~rariant ~ynthe~is, ther~fore~ the arylation o
acrylonitril~. Thi~ rsaation, which ib catalyzod by
palladium compound~, has bsen lcnown in pr~noiple ~i~ce
the work by R. P~. H~ck; comprehe~ xe~ws o~ thi~
20 work can be found in l7Palladiu;n Reage~t~ in Ors~ani~
Synthe~s~", Acad~ic Pre~R N.Y~ (1985~ a~d in Organic
Reaction~ 27, 345-390 (1982). T~e ole~ ompo~erlt~
emlployed are pref e~ably aarylic oster~ and ole~ins,
wherea~ the reactio~ with a~rylonitrile i8 only attempted
25 in a few example~. ~or instance, R. F. ~Iec3~ et al. is~ J.
Or~. Ch~n. 43, 2g45 ~1978) de~ribe exp~rimen~c~ to
~y~the~ize p-aminocin~amo~itril~ from bromoaniline or
iodoaniline~ o:nly the l~ttex gi-~ing a yleld o~ 53~6 w~ile
the :t~romo compo~nd gaYe no target pxodu~t. The prepara-
3û tion of p-Ponnyl~innamoni'crile i~ de~cribed in ~. Organo-
met. C~hem. 258 ~- 9133~, 101 wher~, how~er, it i~ al~o
indi::at~d that th~ react~ity of aryl bromide~ containing
no stab~ti'csuen'cs capable o~ conjugation i~ limlted.
. ~ ."," ," ~...., "..,,~, . ;,.,~,.,., "s~ ~,, ,,,, ~,.,~ .,.~ ..,..~ " ""1,
2~33~7l~
-- 2
Becau~e s:~f the general importanc!2 and the wide range of
applicatio~ of thi~ cla~ of a~l~b~;ta~ca~3, it i~ a worth-
while ob~ ~ct to pro~r~ de s:lo~el compound~3 rom thi~ group
o ~ub~tax~cs~, ln orde~r rlot only to Elupplemen th~
5 ~p~ctrum of th~i~ po~ible u~ but al~o to enrlch and
exterld i'c by ~a ine ad~u~arlt o~ the mat~rial prop~r-
tie~. In addition, these n~-rel com~po~snd~ op~n up further
route~ to th~ pxepar~tio:n o ollow-on productsg who~3
i%lportanc . h . ~ already b~e:~ meD.tion~d ~bove .
10 Thi~ ob~eat i8 achieved by 2,4,5-trihalocir~monitrilee
o~ the for~ula I
N
R 1 ~:
wherein
Rl iB hydroge~ tra~ ght-chai.~ or brancha~l Cl-Cl2 :~
alkyl, f luoro, chloro or phenyl, the phenyl radiaal
being u~ t~ tuted or ~ tttuted, if de~ired, with
Cl-C~ alkyl or Cl-C2 alkoxy~ and ~.
X, Y a~d Z are ideIltical or differe~t and are fluoro,
chloro or bromo.
P~ c~rtai~ degree o i~pox anc~ 1~ at'cached to the aom~
20 pound~ e~f ~he ~ormula (I) ih which Rl ~ a hydroge~ or
slethyl arld 2~, Y aDd Z are :E~ uoro or c~loro .
Al~o of intere~t are the compouIld~ of the fo~snul~
which X, Y ~d Z ar~ fluoro, in particular wh~n Rl 18
hydrog~n or methyl.
25 In addition, emphalsis ~hould b~ gi-rerl to the compou~ds of
thQ :Eormula I i~ which X and Y are chloro all~ Z 1~ $1uoro
or Y a~d Z are fluoro and X i~ ~hls~ro, in parti~ular wher
Rl i hydros~en or methyl.
:; 2 ~ 3 3 3 14
The~ haloge~Lat@d ci~n~onitrile~ ~a~ be prepared ad~a~-
tageoll~ly by reacting acrylonitrll~ c~r ~ tituted
a~rylo~i'cril~3s of the $ormula ~XI)
~ ~g
in which R1 i6 a;3 alr~ady de~ed with a compousld o the
5 ~ormula III
A
r ~x
in which X, Y and Z ~r~ as deflTl~d aboY~ and A iB iodo,
hrcmo or ~hlo:ro, in the pr-3senc~e o~ a palladium cataly~t,
a ba~e a3~, if de~lrsd, a 301v~ t and/or a ~tabllizing
ligand and/or an a~nonlu~ ~al at tesnperaturef) of
10 û0-200~C.
In ge~ral it i~ po~ible to emE~loy thoes aryl halide~
(III) in which, independently o~ the pattern o~ ti'cu-
tion o~ ~he radical3 ~, Y and Z, A i~ arl lodine atom. If
the radical~ X, Y and Z are~ o~ly luorine or chlorine
15 ato~s~ then aryl :bro3ni~s~ are pref.erably employed. In the
ca~e o~ the preferrod ~ub~titutios~ patt~rn, where
Y = z = fluoro and X ~ chlo~o, . A may ad~a~tag20ul31y
likewi~e be chlors:.
. ..
The rea~cio3l i~ senerally carried out in ~olutiorl. Inert
20 organic IElOï~re~ltY which are 3uitabl~ may b~ alipha'cic or
aromatic hydrocarborls~ chloro or dichlorobon~ne, ~thar~
su~h 8 tetr~h~rdrofuran, dioxa~e, di- tri- or te~tragly~
an E3oïe, ~itriles ~uch as as:etonitrll~ obutyrollitrile
or benzonil;rile~ or alcc~hols ~uch as but~nol or 2-ethyl-
hexanol. ~ow~er, preferen~ i8 ~ n ko u~ng polaraprotic ~olvent~ ~uch as ~ thyl or diethyl ~ul~oxide,
N,N-dialkylamid~ of aliphati~ carboxyli~ acids, or
~ .. ... ;.. :.,.. ,.... .- - .. ~;
~",' ,'.' . '.', ~"' "''''","-''' ';`'~' " ' ' ' "'' '.
- ~ - 2~33~ -
alkylat~d lactam~. Pa:rticularly ~uit3ble Bolverlt~ ara
N,N-dimethylacetamide, N,N-dim~'c~l:Eo~namide a~d
N-m0thylpyrrolidone.
8i3~1C3 hydroge~ hal~ de i~ gl~re~ o durirlg the xeaction,
5 it i advantageou~ to trap lt l:y adding a ba~e. Suitable
ba~e~ ar~ ter'ciary æ~ e~3, suc:h as triall~yl~ls~e~ haviRg
C2-C6 alkyl radic~ r cyclit: ~econd~ry amine~ 3uch a~3
piperidine, piperaziale or morp~oli~ 3, and th& alkali
metal or alkaline earth met~l ~3al'cs si~ aliphati6 or
10 aromat~c carboxylic acid~ or of carbonlc acid, such a
Rodium ace~atQ, pota~3sium ace'cate or calcium acetat0 ;ar;ld
sodiu~n carbo~ate or pot~ssium carbonate.
The reactio~ i~3 accel~rate~ both homoge~eouElly by so1uble
palladium compound~ ~d by hetaroge~ou~ pall~dium cata-
lyst~
Solubl~ p~lladium compou~ds which are suitable arepalladium acetate, palladium chlor~d~ or palladium
bromide and th~ tetrachloro- a~d tetra~romopalladate~
which are readily acces~ibls ther~rom a~ alkali ~et~l or
ammoniu~ ~alt~. Other ~ighly ~uita~bl0 catalyst precur~or~
are the complex0~ of palladium chlorld~ with acokoni-
trile, benzonitrile or triphanylpho~phi~e, or the com-
plexes of ~ero-valent palladil~m ~uch a~ tetraki~-
(triphenylpho~phi~e)palladium.
I~ order to ~tabilize the active ~ataly~t i~ th~ r~actlo~
BolUtiOn it may bs advantag00u~ to add complaxing agent~.
Compou~ds suitable ~or thi~ purpo~e ar~ ~itrile~,
ni~rogen-co~taining lagan~ ~uch a~ 2,2'-bipyridyl or
o-phenanthroline, or pho3phit~. Pref~r~nce is gl~en to
~mploying pho~phinos and guaternary ammonium ~alt~, whlch
alo~e or i~ co~bination bring ~bout the stabill~atio~ a~d
activatio~ of the pall~d~um ~ataly~t.
Particuli~rly ~uitable mo~od~tat~ monopho~phine~ ar~
triarylphoaphi~, dialkylarylpho~phi~e~,
: - 5 - ~ ~3337
diarylpho~phin~, diaryla.lkylpho~phi~oa a~d
trialkylphv~phi~e~, the al~yl group~ co~ta~i~g 1 to 12
carbon atom~ a~d th~ aryl group~ being phe~yl or ~aphthyl
grQUp~, either of ~hich ~y be eub~ituted ~ith C1 C~
alkyl, Cl-C3 alkoxy or S03Na.
Ex~mple~ are ~riphen~lphoRphi~e, tri-o- and tri-p-tolyl-
pho~phina, ~ri(methoxyphenyl~phosphine, tri(m-sul~o~ato-
phe~yl)pho~phi~ tricyclohexylphoaphine~ trii~opropyl-
pho~phi~e ~nd dii~opropylphenylpho~phi~e. ~mo~g the
monodentat~ pho~ph~nea, tr~phe~ylpho~ph~ne, tri~o-tolyl-
pho~phin2 and tricyclohexylpho~phi~e are amployed wlth
particular pr~ere~ce.
:
It ~ay be ad~antageou~ to ~mploy chelati~g b~spho phi~ea,
alone or a~ a mixture w th the ~onophosph~ , i~ which
ca~e bi~5di~h~ylpho~phino~ethan~ or bie(diphenyl-
pho~phi~o)propane i~ pre~erably ~m~loyed.
The additio~ of ammonium brom~del~ or ~mmo~lum chloride~
has a highly adYantagsous e~ect o~ the progres~ of the
catalyzed reactio~. Owlng to th~ir very ready ~olubllity
and their high ~tability in the re~action m~xture, quater-
nary ammonium ~alt~ are preferred and may be added to the
cataly~t system in qua~tities of from 1 to 100 mol%,
b~ed on the aryl halide to be r2acted. Thoae w~i~h hav~
pro~en particularl~ ~uitabl~ ar~ tetraethyl-,
tetrabutyl-, tetrahe~yl-, ~e~hyltrioctyl-, b~z~
triethyl- a~d be~zyltributylammonium chl~r~da a~d the
corr~sponding bromide~.
The active ~taly~t i~ preferably formed fr~m the co~po-
ne~t~ in the r~action ~olutio~, or dir~ctly be~oroha~d in
a 3epar~e ~olutlon; ne~ther ~olatio~ ~or a complex
preparation pro~dur~ i~ nece~ary. The ~uastity of
palladi~m employed i8 from 0.01 to 5 mol%, preferably
from 0.2 to 1.0 ~o~%, b~ed o~ the ~ryl hallde~
Heteroge~ous palladium cataly~t~ are metalli~ palladi~m,
. - 6 - 2~333~
palladium black o:c palladium fixed o~ a s~upport ~aterial.
2~y in~rt ~301ids ca~ be ~nploy~d aL~ eupport ~ aterial~.
Examples ~r~ active charcoal, alumi~um oxideR, sillc:on
oxides, magn~ium oxide, alumo~illcate~, pota~Rium
5 caxbonate, barium ~ul~ate and ~alcium carborlake. Particu-
larly ~u1ta~le l3upport materials are actiYe ~harcoal,
aluminu~ oxide, ~ilicon d~oxide and tit~x~ium d~ oxide .
The im~lementatior~ of th~3 proc~ permit~s a ra~ge o~
variant~9 the mo~ imple varian~c bea~g that in which all
10 o ~chc ~c~mponerlts ax~ placed togeth~r i~ ths r~actio~
~lask arld th~ ~ixtur~ !brought to he re~auir~d tempera-
tu:re i~or a ~ufficient ime.
Where the acrylo~itrile deri~ati~e~ are of particular
polymerizability, an ispro~ame~t in ~e eelecti~ity ca~
be achieved by meteri~g i~ the~e derivati~e~ during ~he
r~action. I~ the ca~e of batche~ which are di~tinctly
larger tha~ i~ conventio~al in th~ laboratory, ~.t i~
neceBsary for reaæonR 0~ ~afety to control the reaction
~uch that controlled diesipat~on of the heat of r~action
i~ po~sibla. Thi~ Gan be carrled out, ~or ~xample, by
u~ing a liguid organic baae which i~ matered i~ under the
reaction condition~, ~imultaneou~ly ~ d~ired with the
cataly~t pre~ur~or.
Te~perature~ o~ 80-200C are nece~ary for the reactio~;
aryl bromide~ reaot at 80-160C, pre~erably 120-140C,
while aryl chloside~ reguire tem~erature~ of 120-200C,
prefer~bly 140-180C.
The time~ requised ~or a high co~ver~io~ range ~etween 1
and 16 hour~.
Exa~ple 1
2,4-Dichloro-5-fluoro~innamo~itrlla
24.4 g (0.1 mol) of 1-bromo-2,4-di~hlo~o-5~1uorobenzene,
12.7 g ~0.1 mol) o~ sodium ~arbo~ate ~ground ~ dried) a~d
- 7 - 2~3~37~
10.6 g (0~2 mol) of acrylonitr~l~ ar~ pla~ed i~ a rç3a~-
tion f la~k togeth~r wi 'ch 4 0 ~1 o di:methylaceta:mid~ . A
~olution o~ 0 . 22~ g (1. O mm~ pall~dium ~aet~te arld
1t)o5 53~ ~0~05 mol) of tetraethyl~mnoaiu~n bromid~ in 30 ml
5 o~ dime'chylac:etamida i~ propared ~e~paratelyO Thie ~olu-
tiorl iB the~ add~d to the su~pen~io~ of ~he othor compo-
nen~, wit~ thorough ~tirrl~g, a~d thc mixtur~ i~ h~ated
to 135C. Quantitatl~ on~rer0iox~ ~ ach~ evad ov~r tlle
~OU~ 3 h.
10 Th~ rea~tion t301utio~ :LB :EirEt :~il ered and the~ poured
int~ 500 ml o~ cold wat~3r. The targ~3t product ~3eparatos
out a~ a ligh brow:cl ~olid, wi~ h i~ collec~ed on a
f il~ce:r ancl dried . T~ crud~ product i~ re~ryRtalliz~d
f rom cyclohexane .
The prima3:y ~roduct comprise~ 36% ci~ i~om~r and 64%
tran~ ~eomerO t:rysti~lllzatlo~ yields
~ractio~ 12.7 g (56% oi~ theory3;
af ter concen'crating the ~olven'c
fraction 2: 9 . O g (41% o$ kheory) crysta:l lizes .
In ~raction 1 the traIts isomer h2l8 concentrated to 94%~
The 3na~s spectrum ron~ or both i~OmerB tha nominal
molar maR3 (ba~ed on th~ 35Cl i~otrope) o ~i = 215.
E ~qR ~pec t:ca:
H ~C N
F~H Ib
el Gl
Ha = 5 78~5 95 PP~ Jab = 17 E~z
~Ib o 7 . 63/7 .79 ppm
i '. ' ''''',~ ' . .'~ ' . ~ J'~ ,~ `. `1 ,' '
- 8 - 2~3337~
NC H~
~a = 5O60/5~73 ppm J~ - 12.5 ~z
Hb - 7.85/7.96 ppm
Example 2 ~ ~
2,4-Dichloro-5-1uorocl~namonitrile ~ ~:
,
The co~pound oan ~l~o ba prepared u~ing a phosphi~e-
~tabilized cataly~t ~y~tem.
12.2 g (0.05 mol) o~ 1-bromo-2,4-dichloro-5-~luoro-
benzene, 5.0 g (0.06 mol) o~ ~odium acetate and 5.~ g
(0.1 mol) of a~rylonltr~le are pl~ed in a re~tio~ la~k
together w~th 15 ml o~ DMAc.
' :
~10 mg (0.5 mmol) of palladium are di~ol~ed in 10 ml of
di~ethylacetamide, and 264 mg ~1.0 mmol) of triphe~yl-
phosphine a~d 200 mg (0.5 ~mol) of bis(diphe~yl-
pho~phino)ethane ~DIP~OS) are added. After bri~ ~tirring
at room temperature the Pd(IX)-pho~phine co~plex i~
ormed.
Thi~ ~olution is added ~o the mix ure of tho ~tarti~g
~ubetan~e~, a~d the entir~ batch i~ h~ated to 140C.
After 8 h a con~eraion of 95% ha~ been aahievedD To wo~
20 up ~he rea~tion mixture it 1~ diluted with methyl t~butyl
ether, the psoduat ~ extract~d br shaki~y with w~ter,
and the orga~ic pha~e i~ co~centrat~d. The ~rude product
which ~Q~ain~ i~ recry~tallized fro~ cyclohex~no. A yl~ld
of 10.0 g (76% o~ theo~y) wa~ a~hi~Yed.
25 A de~o~rated ~r the GC and }~ pe~tra, the produc~
i~ ide~'cical wi'ch th~ sub~tance ~ro3D. Exam~;31e 1 with
regard to the dl0tributio~ o~ Ci8 a~d trans i~omer~ ar~d
;~
the purity. 213 3 3 7 ~ ~
Example 3
2,4,5-Trifluorocin~amonitrile
10.6 g (O.OS mol) of 2,4,X-~ri~luorobro~obsnzene/ 5.0 g
~0.06 ~ol) of ~odiu~ a~etate and 5.4 g (0.01 ~ol3 of
acrylon~rll~ are pla~d i~ a reaction ~las~ together
with 20 ml of dime~hylac0tamide.
A cataly~ ~olutio~ prepared from 22 mg (Ool ~mol~ o~
pallad~um acetats, 524 mg (0.2 mmol) o~ triphenyl-
pho phine and 400 mg (0.1 mmol) o bi~diphanyl
pho~phino~ethane (= DIP~OS) i~ 30 ~1 of di~ethylacetamide
i~ prepared ~epar t~ly.
A~ter ~he catalyst compo~e~t~ have d~olved a~d the
yellow palladium complex has ~ormed, this ~olution i~
added to the abov~ bakch and th~ batch ~ h~ated to 140C
with thorough stirring.
A conver~io~ of 86% i~ achieved over a pariod of 7 h. The
sole product i0 the desired 2~4,5-trifluorocinnamo-
nitrile, which i~ obtained a~ a~ approximately 40:60
mixtur~ of the ci~ and tranB ieomerB ~
The product i~ isolated ~rom th~ reac lon ~olution by
first diluti~g it with dichloro~thanQ a~d the~ carryi~g
out ext~aatio~ with wat~r. The ~olutio~ i~ C~2Cl2 is
co~centrated ~d finally the concentx~te is distilled.
The boili~g poi~t o th~ target product is 65C at
9 1 mbar m p. ~ 94-g7C.
. .
The ma~s ~pectrum co~firm~ ~or both isomer~ th~ molar
ma~ o~ ~ - 183. ThR ~ ~MR Bpectru~ co~firms the stru~
tur~. ~ v
. '~ ''' '
.
1 0
H~ CN
3337~ -
~Hb
~a - 5.R6/6.94 ppm ~ ~ 17 ~%
~b - 7030/7.49 ~pm
~1~1 b
F~a = 5 . 54/5 . 66 pp~n ;r,~", ~ 12 . 5 ~z
Hb = 6.95/7.09 p~m
Example 4
2,4-Dichloro-5-fluoro(a-~thyl)~Lnnamonitrlle
24.4 g (0.1 mol) of 1-bromo-2,4-d~.~hloro-5-fluorobenzene,
10 12.7 ~ (0.12 mol) o~ eodium c~rbonat~ a~d 13.4 g
(9.2 ~ol) of ~et~acrylonitrile are pl~ced i~ a raa~tion
fla~k tog2ther with 40 ml o~ dimethylacetamide. A ~olu-
tion of 0.224 g ~1.0 mmol) o~ palla~iu~ acetate 2~d
1005 g (0.05 ~ol) o~ etra~thylammonium bro~ide ln 30 ml
of dimethylac~ta~ide i~ prepared ~aparately. Thia e~lu-
tion i8 added to th~ suop~ion of ths other ~ompone~t~
wi~h thorou~h ~tirring, and the r~action m~xtur~ i~ th~n
~sated t~ 135C. Qua~t~tat~v~ convar~io~ i~ found by GC
after 2 h.
The reac~io~ mixture i~ worked up by diluting it with
met~yl t-butyl ether, extractin~ the produ~t by ~ha~ing
with w~ter, a~d di~tllli~ the organia pha~e. Af~r
re~oval o the soIvent by di~t~ tion there rsmai~e a
213~37~
crude product which ia di~tilled i~ ~racuo; b~p.l _ 105C.
The iEiolaked ~UbB anca compxi~e~ three ieomer~ whic:h,
ba~ed on the ma~ pectn~m, all ha~e a mol~cular maes : .
M = 229 (ba~ed o~ the 35Cl i~o ope). The ~I N~ pectrum
S CO~f1rmB t~e followin~ ~stru~turo~:
I o~ner A, 68%:
a ~ C N
~ ~Hb
el~cl
Ha z 2 . 20 ppm (doublet)
Hb = 7.70/7878 ppm
.' '
10 I~omer 13, 29%
NC~fCII~
~H b
Cl ~1
~a = 2 . 04 pp~n (doublat)
~Ib = 7.14/7,26 ppm
IE;Omer C, 2%
~eH2o
~H~
3 Hb
~ 1~ \ I
Ha = 5.74/6-~ PP~
Hb = 3 . 64 ppm ~;
